cvja volume 21, issue 6

AFRICA

NOVEMBER / DECEMBER 2010VOL 21 NO 6

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CardioVascular Journal of Africa (official journal for PASCAR)www.cvja.co.za

Cardiovascular Journal of A

frica . Vol 21, No 6, N

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• Stents for the treatment of diffuse coronary lesions

• Serum CRP levels in children

• New anti-coagulant therapies

• Mitral valve prolapse and conduction disturbances

• Post-infarction ventricular septal defect

• Pulmonary arterial hypertension

• ARBs and risk of cancer

• Dabigatran etexilate for stroke prevention in atrial fibrillation

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EditorsEditor-in-Chief (South Africa)PROF AJ BRINK

Assistant EditorPROF JAMES KER (JUN)

Regional Editor (Cameroon)PROF JC MBANyA

Regional Editor (Kenya)DR F BUKAChI

Regional Editor (South Africa)PROF R DELPORT

Editorial BoardPROF PA BRINKExperimental & Laboratory CardiologyPROF R DELPORTChemical PathologyPROF MR ESSOPhaemodynamics, heart Failure & Valvular heart DiseaseDR OB FAMILONIClinical CardiologyDR V GRIGOROVInvasive Cardiology & heart FailurePROF J KER (SEN)hypertension, Cardiomyopathy, Cardiovascular PhysiologyDR J LAWRENSONPaediatric heart Disease

PROF A LOChNERBiochemistry/Laboratory SciencePROF BM MAyOSIChronic Rheumatic heart DiseaseDR MT MPECardiomyopathyPROF DP NAIDOOEchocardiographyPROF B RAyNERhypertension/SocietyPROF MM SAThEKGENuclear Medicine/SocietyPROF yK SEEDATDiabetes & hypertensionPROF h DU T ThERONInvasive Cardiology

intErnational advisory BoardPROF DAVID CELEMAJERAustralia (Clinical Cardiology)PROF KEITh COPELIN FERDINANDUSA (General Cardiology)DR SAMUEL KINGUECameroon (General Cardiology)DR GEORGE A MENSAhUSA (General Cardiology)PROF WILLIAM NELSONUSA (Electrocardiology)DR ULRICh VON OPPELWales (Cardiovascular Surgery)PROF PETER SChWARTZItaly (Dysrhythmias)PROF ERNST VON SChWARZUSA (Interventional Cardiology)

PuBlishing ConsultantMike Gibbs

AFRICA

ISSN 1995-1892 (print)ISSN 1680-0745 (online)

Cardiovascular Journal of Africa www.cvja.co.za

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Editorial309 associations of serum C-reactive protein with physical activity, fitness and fatness in

south african adolescentshS Kruger

CardiovasCular toPiCs311 outcomes of stenting with overlapping drug-eluting stents versus overlapping

drug-eluting and bare-metal stents for the treatment of diffuse coronary lesions SE Kassaian • M Salarifar • M Raissi Dehkordi • M Alidoosti • E Nematipour • hR Poorhosseini • AM hajizeinali • D Kazemisaleh • A Sharafi • M Mahmoodian • N Paydari • AV Farahani

316 significant differences between serum CrP levels in children in different categories of physical activity: the Play studyB harmse • hS Kruger

sPECial rEPort 323 new anti-coagulant therapies set to revitalise

clinical haemotology practice annual meeting of the southern african

society of thrombosis and haemostasisJ Aalbers • P Wagenaar • E Klug

CasE rEPorts327 Mitral valve prolapse and conduction

disturbances: the forgotten associationA D’Aloia • E Vizzardi • E Antonioli • E Chiari • A Curnis • L Dei Cas

329 Post-infarction ventricular septal defect: triggered by valsalva manoeuvre?M Baskurt • N Turhan • A Hatemi • M Cani̇koglu • B Karadag • S Kucukog

It's theshell that

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Safety-CoatedR

81mgThe ORIGINAL low dose aspirinfor optimum cardio-protectionHp

Each tablet contains Aspirin 81mg. Reg.No.: 29/2.7/0767Pharmafrica (Pty) Ltd, 33 Hulbert Road, New Centre, Johannesburg 2001Under licence from Goldshield Pharmaceuticals Ltd. U.K.

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assistant Editor sPECial assignMEntsJULIA AALBERSTel: 021 976 4378Fax: 086 610 3395e-mail: [email protected]

ProduCtion EditorShAUNA GERMIShUIZENTel: 021 785 7178Fax: 086 628 1197e-mail: [email protected]

Editorial assistant & CirCulationELSABÉ BURMEISTERTel: 021 976 8129e-mail: [email protected]

ProduCtion Co-ordinatorWENDy WEGENERTel: (021) 976-4378e-mail: [email protected]

gautEng ContriButorPETER WAGENAARCell 082 413 9954e-mail : [email protected]

Editorial BoardThe Cardiovascular Journal of Africa, incorporating the Cardiovascular Journal of South Africa, is published six times a year, the deemed publication date being the seventh day of the second designated month, i.e. 7 February, 7 April, 7 June, 7 August and 7 October.

COPyRIGhT: Clinics Cardive Publishing, Pty, Ltd.

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PRINTER: Durbanville Commercial Printers

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Electronic submission by means of an e-mail attachment may be considered under exceptional circumstances.Postal address: PO Box 1013, Durbanville, 7551

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The views and opinions expressed in the articles and reviews published are those of the authors and do not necessarily reflect those of the editors of the Journal or its sponsors. In all clinical instances, medical practitioners are referred to the product insert documentation as approved by the relevant control authorities.

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334 Contemporary insights into the pathogenesis, diagnosis and therapy of pulmonary arterial hypertensionMR Essop

oPinions in hyPErtEnsion ManagEMEnt338 arBs and risk of cancer: international and south african expert comment

C Lombard • A Nosworthy • J Aalbers

drug trEnds341 Fda committee unanimously recommends approval of dabigatran etexilate for stroke

prevention in atrial fibrillationJ Aalbers • A Bryer • E Klug

rivaroxaban equals warfarin treatment in atrial fibrillation patients at high risk of strokeJ Aalbers

development of new anticoagulant highly honoured: Bayer’s Xarelto® recognised with 2010 international Prix galien award

Myocardial salvage after myocardial infarction depends on early therapyJ Aalbers

your liFE and your hEart348 vitamin d is a prognostic marker in heart failure

J Aalbers

It's theshell that

makes

safer.

R

Safety-CoatedR

81mgThe ORIGINAL low dose aspirinfor optimum cardio-protectionHp

Each tablet contains Aspirin 81mg. Reg.No.: 29/2.7/0767Pharmafrica (Pty) Ltd, 33 Hulbert Road, New Centre, Johannesburg 2001Under licence from Goldshield Pharmaceuticals Ltd. U.K.

L.ZA.GM.10.2010.0070 P-6023www. .co.za :

It's theshell that

makes

safer.

R

Hp

Each tablet contains Aspirin 81mg. Reg.No.: 29/2.7/0767 Pharmafrica (Pty) Ltd, 33 Hulbert Road, New Centre, Johannesburg 2001 Under licence from Goldshield Pharmaceuticals Ltd. U.K.

Safety-CoatedR

81mgThe ORIGINAL low dose aspirinfor optimum cardio-protection

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 6, November/December 2010AFRICA 309

Editorial

associations of serum C-reactive protein with physical activity, fitness and fatness in south african adolescents

Globally the prevalence of overweight is increasing signifi-cantly, not only in economically developed regions, but also in developing countries. In South Africa, the prevalence of combined overweight and obesity among high-school children increased from 21.2% in 20021 to 25% in 2008,2 with 35% of high-school girls being overweight or obese.2

The metabolic syndrome (MS) is a cluster of biological markers that together predict the development of cardiovascular disease and type 2 diabetes. These markers are hypertension, insulin resistance, central adiposity, hypertriglyceridaemia and decreased high-density lipoprotein cholesterol (HDL-C). The MS is now increasingly emerging among children and adoles-cents.3 Low-grade systemic inflammation is proposed as a significant component of the MS.4

C-reactive protein (CRP) is secreted by the liver and adipose tissue in response to infections and inflammatory conditions.5 Levels of CRP decrease during the early convalescent phase and are usually low in healthy subjects. In the absence of infection, low-grade inflammation characterised by serum CRP levels of between 1 and 10 mg/l are associated with an increased risk of the development of cardiovascular disease.6 Serum CRP concen-trations in this range can be detected using high-sensitivity methods and are generally referred to as high-sensitivity CRP (hsCRP).6

Although the MS has been described in paediatric populations from many different countries, limited evidence on the MS and risk for cardiovascular disease among South African children is available.7-9 Studies on blood lipid levels of South African chil-dren without familial hyperlipidaemia are scarce, but published data indicate very little evidence of hypertriglyceridaemia and decreased HDL-C among black South African children.8 However, South African studies indicate a positive association between overweight in children and increased blood pressure,9 plasminogen activator inhibitor-1 activity, plasma fibrinogen and the thrombin–anti-thrombin complex,10 as well as higher fasting plasma insulin possibly increasing the risk for future cardiovascular disease.7,9

Increased adiposity has been associated with higher serum CRP concentrations in US children aged three to 16 years from the National Health and Nutrition Examination survey (NHANES) 1999–2004.11 In a review of research linking obesity and low-grade inflammation in children, a significant posi-tive correlation between body mass index (BMI) and CRP was confirmed.12 Ruiz et al.13 found a significant positive association between body fat, derived from five skin folds, and serum CRP in Swedish children, aged nine to 10 years.

Other variables describing body composition were investi-gated with regard to their power to predict low-grade inflam-mation in Caucasian adolescents. Although waist circumference

and waist:height ratio showed a significant, positive predictive power to detect elevated serum CRP, BMI was the best predictor of elevated serum CRP levels in these adolescents.14 Abdominal obesity in children was also associated with higher serum CRP concentrations in Norwegian children, nine and 15 years old. In the same study, serum CRP was positively associated with blood pressure, blood glucose, insulin and triglyceride concentrations.15 In a study of asymptomatic European adolescents, serum hsCRP was also associated with risk for cardiovascular disease. No lifestyle factors showed an association with cardiovascular risk in this study.16 These results confirm the value of elevated serum hsCRP as an early marker for cardiovascular disease in older children and adolescents.15,16

Ridker17 reviewed large-scale prospective studies that showed hsCRP is an independent predictor of future cardiovascular events, as well as of hypertension and type 2 diabetes mellitus. Studies in animal models suggest, however, that hsCRP may not promote atherosclerosis directly, but only serve as a marker of vascular inflammation.18 Recently Ridker reviewed the evidence from retrospective as well as primary-prevention trials and found that hsCRP was the strongest predictor of risk of vascu-lar events.19 A meta-analysis of 54 prospective cohort studies identified and confirmed CRP as an independent risk marker for cardiovascular disease.20

A cross-sectional study in Swedish children nine to 10 years old showed a significant negative association between cardio-vascular fitness, measured by ergometer bike test, and CRP. No association between physical activity measured by accelerome-try and CRP could be found, although physical activity was posi-tively associated with cardiovascular fitness. After controlling for body fat, serum CRP was no longer negatively associated with cardiovascular fitness. The influence of fatness on serum CRP in these children was greater than the influence of fitness.

The results suggest that the beneficial effects of physical activity on low-grade inflammation may be mediated through the association with cardiovascular fitness, but that excessive fatness may decrease the beneficial effects of physical activity in children.13 Interventions resulting in about a 5% weight loss in obese children resulted in a decrease in serum CRP concentra-tions.12 Apparently, overweight and obesity in children have a stronger association with serum CRP than physical activity, but physical activity may help to prevent excessive body fat accu-mulation in children and may even result in moderate fat loss in obese children.

Most studies of body composition, physical activity and low-grade inflammation in children have been done in Caucasian populations. Longitudinal studies in larger cohorts of different age groups and ethnic backgrounds are needed. Further research is also necessary to assess the changes and effects of other

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 6, November/December 2010310 AFRICA

inflammatory mediators, such as tumour necrosis factor alpha (TNF-α), interleukin 6 (IL-6) or IL-8.12

In this edition of the Cardiovascular Journal of Africa, the results of a study in black South African adolescents indicate a trend of higher serum hsCRP levels in boys with a higher percentage of body fat.21 Waist circumference in girls was significantly positively associated with serum hsCRP. In the boys, there was an inverse correlation between percentage body fat and fitness, and between fitness and serum hsCRP, indicating a beneficial effect of physical activity and fitness to decrease their risk for cardiovascular disease. In the girls, a significant difference was found between serum hsCRP levels in the differ-ent physical activity categories, with lower serum hsCRP values in girls in the higher physical activity group.

The results indicate that South African children in low-income areas with a low prevalence of obesity are not necessarily protected from an increased risk of cardiovascular disease. Low physical activity has been described among children in such communities.1,2 Obesity should be prevented in South African children and adolescents by encouraging increased physical activity.

h SALOME KRUGER, [email protected] of Excellence for Nutrition, North-West University, Potchefstroom, South Africa

References1. Medical Research Council (MRC). Umthente uhlaba usamila: the 1st

South African National Youth Risk Behaviour Survey. Cape Town: South African Medical Research Council, 2002. http://www.mrc.ac.za/health-promotion/healthpromotion.htm

2. Reddy SP, James S, Sewpaul R, Koopman F, Funani NI, Sifunda S, et al. Umthente Uhlaba Usamila – The South African Youth Risk Behaviour Survey 2008. Cape Town: South African Medical Research Council; 2010. http://www.mrc.ac.za/healthpromotion/healthpromotion.htm

3. Nelson RA, Bremer AA. Insulin resistance and metabolic syndrome in the pediatric population. Metab Syndr Relat Disord 2010; 8(1): 1–14.

4. Nemet D, Wang P, Matsuzawa Y, Tanaka S, Engelman L, Cooper DM. Adipocytokines, body composition, and fitness in children. Pediatr Res 2003; 53(1): 148–152.

5. Pepys MB, Hirshfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111(12): 1805–1812.

6. Kushner I, Rzewnicki D, Samols D. What does minor elevation of

C-reactive protein signify? Am J Med 2006; 199: 166.e17–166.e28. 7. Zeelie A, Moss SJ, Kruger HS. The relationship between body composi-

tion and selected metabolic syndrome markers in black adolescents in South Africa: PLAY study. Nutr Int J Appl Basic Nutr Sci 2010; 26: 1059–1064.

8. Steyn K, de Wet T, Richter L, Cameron N, Levitt NS, Morrell C. Cardiovascular disease risk factors in 5-year-old urban South African children – the Birth to Ten Study. S Afr Med J 2000; 90(7): 719–726.

9. Monyeki KD, Kemper HC, Makgae PJ. Relationship between fat patterns, physical fitness and blood pressure of rural South African chil-dren: Ellisras Longitudinal Growth and Health Study. J Hum Hypertens 2008; 22(5): 311–319.

10. Nienaber C, Pieters M, Kruger HS, Stonehouse (Oosthuizen) W, Vorster HH. Overfatness, stunting and physical inactivity are determinants of PAI-1act, fibrinogen and TAT in African adolescents. Blood Coagul Fibrinol 2008; 19: 361–368.

11. Dowd JB, Zajacova A, Aiello AE. Predictors of inflammation in U.S. children aged 3–16 years. Am J Prev Med 2010; 39(4): 314–320.

12. Tam CS, Clement K, Baur LA, Tordjman J. Obesity and low-grade inflammation: a pediatric perspective. Obes Rev 2010; 11(2): 118–126.

13. Ruiz JR, Ortega FB, Warnberg J, Sjöström M. Associations of low-grade inflammation with physical activity, fitness and fatness in prepu-bertal children; the European Youth Heart Study. Int J Obes 2007; 31(10): 1545–1551.

14. Jung C, Fischer N, Fritzenwanger M, Figulla HR. Anthropometric indices as predictors of the metabolic syndrome and its components in adolescents. Pediatr Int 2010; 52(3): 401–409.

15. Steene-Johannessen J, Kolle E, Reseland JE, Anderssen SA, Andersen LB. Waist circumference is related to low-grade inflammation in youth. Int J Pediatr Obes 2010; 5(4): 313–319.

16. Wijnstok NJ, Twisk JW, Young IS, Woodside JV, Mcfarlane C, McEnery J, et al. Inflammation markers are associated with cardio-vascular diseases risk in adolescents: the Young Hearts project 2000. J Adolesc Hlth 2010; 47(4): 346–351.

17. Ridker PM. C-reactive protein and the prediction of cardiovascular events among those at intermediate risk: moving an inflammatory hypothesis toward consensus. J Am Coll Cardiol 2007; 49: 2129–2138.

18. Genest J. C-reactive protein: risk factor, biomarker or therapeutic target? Can J Cardiol 2010; 26(Suppl A): 41A–44A.

19. Ridker PM. Establishing a clinical basis for hsCRP in the prevention and treatment of cardiovascular disease. Clin Chem 2010; 56: 1186–1187.

20. The Emerging Risk Factors Collaboration. C-reactive protein concentra-tion and risk of coronary heart disease, stroke, and mortality: an indi-vidual participant meta-analysis. Lancet 2010; 375: 132–140.

21. Harmse B, Kruger HS. Significant differences between serum CRP of children in different physical activity categories: The PLAY study. Cardiovasc J Afr 2010; 21(6): 316–322.


Cardiovascular topics

outcomes of stenting with overlapping drug-eluting stents versus overlapping drug-eluting and bare-metal stents for the treatment of diffuse coronary lesions SE KASSAIAN, M SALARIFAR, M RAISSI DEhKORDI, M ALIDOOSTI, E NEMATIPOUR, hR POORhOSSEINI, AM hAJIZEINALI, D KAZEMISALEh, A ShARAFI, M MAhMOODIAN, N PAyDARI, AV FARAhANI

summaryIntroduction: We investigated the outcomes of stenting with overlapping drug-eluting stents (DES) versus overlapping stenting with a combination of drug-eluting and bare metal stents (BMS) in very long coronary lesions (≥ 25 mm).Methods and Results: Fifty-two patients treated with either overlapping DES-DES (n = 22) or DES-BMS (n = 30) were selected from a registry of 588 patients with very long coro-nary lesions. Patients with acute myocardial infarction (MI) within the preceding 48 hours were excluded. The DES-DES combination was more frequently used for longer lesions compared with the DES-BMS group (47.95 ± 9.25 vs 39.98 ± 9.15 mm, p = 0.003). Left anterior descending artery lesions were also more frequently treated with the DES-DES combination (95.5 vs 66.7%, p = 0.02). In four patients in the DES-BMS group, overlapping stents were used for the cover-age of dissections. Peri-procedural non-Q-wave MI occurred in one patient in the DES-BMS group. On follow up, only one case of non-fatal MI occurred in a patient with overlapping DES-DES.Conclusion: Overlapping a BMS in the proximal part of a long DES instead of exclusive deployment of two or more overlapped DES seems to be a safe and feasible therapeutic strategy in our practice.

Keywords: angioplasty, stents, restenosis, overlapping stents, drug-eluting stents

Submitted 11/2/09, accepted 10/3/10

Cardiovasc J Afr 2010; 21: 311–315 www.cvja.co.za

DOI: CVJ-21.006

Percutaneous intervention in long coronary lesions was previous-ly associated with poorer short- and long-term results than that in discrete lesions.1 Owing to their associated low angiographic and procedural success rates and their higher dissection and threat-ened or acute vessel closure rates, these lesions were considered a contraindication to balloon angioplasty.2 Nevertheless, promis-ing results were obtained when using drug-eluting stents (DES), making these lesions inviting targets for percutaneous coronary intervention (PCI).3-5

In the bare-metal stent (BMS) era, there were conflicting data regarding the efficacy of overlapping stents for the treatment of long lesions.1,6-8 However, in the contemporary DES era, multiple stent implantations in long lesions have been widely used.4,5,9 Nevertheless, concerns remain about potential local toxicity with delayed endothelial coverage that could contribute to an excess in very late stent thrombosis, most likely at adjacent DES strut overlaps,10 and also greater in-stent late lumen loss and angio-graphic restenosis.11

In our practice, combinations of drug-eluting and bare-metal stents have sometimes been used for covering very long lesions. One of the reasons was the unavailability of appropriate sizes of DES for overlapping coverage of these types of lesions, especial-ly during the first two years of DES usage. Another reason was the high cost of DES in our country, which many people could not afford. However, the use of an additional stent was occasion-ally unplanned in cases such as dissections. To our knowledge, few clinical studies have to date systematically investigated the outcomes of a combination of overlapping DES and BMS.

In this study at our centre, we report on cases of multiple overlapping stenting in two groups of patients with implantation of DES and a combination of DES and BMS in coronary lesions of ≥ 25 mm in length.

MethodsDES were first used at our centre in March 2003 in selected, planned procedures. Then, on the basis of contemporary stud-ies, their use increased so that by March 2004, DES were used as often as BMS. Since then, the use of DES at our institute has steadily increased, accounting for about 60% of the procedures in the last year.

Between April 2003 and March 2005, a total of 588 consecu-tive patients with lesions ≥ 25 mm underwent PCI at the catheter laboratory of our hospital, which performs 2 000 PCI proce-dures per year using six expert operators. After the exclusion

department of interventional Cardiology, tehran heart Center, tehran university of Medical sciences, tehran, iran SE KASSAIAN, MD, [email protected] SALARIFAR, MDM RAISSI DEhKORDI, MD M ALIDOOSTI, MDE NEMATIPOUR, MDhR POORhOSSEINI, MDAM hAJIZEINALI, MDD KAZEMISALEh, MDA ShARAFI, MDM MAhMOODIAN, MD N PAyDARI, MDAV FARAhANI, MD


of patients with acute MI within the preceding 48 hours of the procedure, a total of 52 patients were diagnosed for multiple overlapping stent implantation in their coronary arteries, using at least two overlapping stents, including one or more DES.

All angioplasty procedures were done with a 6 or 7 French guiding catheter and a femoral approach. If judged possible by the operator, direct stenting was attempted; however, in most cases pre-dilatation with an undersized balloon was used before DES implantation. High-pressure (> 12 atm) inflation was used in the majority of cases (n = 40, 76.9%). Stent overlaps were always post-dilatated at higher pressure with a non-compliant balloon or with the balloon of a proximally implanted stent. In total, 114 stents were used for the coverage of 52 lesions.

Seventy-eight drug-eluting stents were used: 63 sirolimus-eluting stents (Cypher, Johnson & Johnson Cordis Corp) and 15 paclitaxel-eluting stents (Boston Scientific Corp, Natick, MA). The bare-metal stents used were diverse: one S670, one S660 and two S7 (Medtronic AVE, Minneapolis, MN), seven Biodivysio (Biocompatibles, Galway, Ireland), seven BX-Sonic (Cordis/Johnson & Johnson, Warren, MI), six Driver (Medtronic Vascular, Santa Rosa, California), six Express 2 (Boston Scientific, Natick, MA), three Vision, and three Zeta (Guidant, Santa Clara, CA).

Baseline, clinical, angiographic and procedural characteristics and in-hospital outcomes were obtained by research physicians and entered into a computerised database by computer opera-tors. Finally, clinical outcomes, including major adverse cardiac events (MACE) were obtained by research physicians in clinics at one, six and 12 months post surgery, and once a year thereaf-ter, or by formal telephone interviews, and these were recorded in datasheets, which were later entered into our computerised database.

All patients gave individual written informed consent for participation in this study and for the PCI procedure. The Ethics Committee in our centre approved this study, according to the Declaration of Helsinki as revised in 2000.

Coronary proceduresPatients received 300 mg of clopidogrel and 325 mg of aspi-rin before and 7 500–10 000 IU of heparin at the start of the procedure. The femoral sheath was removed after normalisation (< 40 s) of the partial thromboplastin time. Clopidogrel was followed at a dose of 75 mg/day for at least three months in 2003, and at least six months since 2004, and aspirin was given indefinitely to all patients. Beta-blockers, angiotensin converting enzyme inhibitors and statin drugs were administered as appro-priate in the absence of a specific contraindication. Abciximab was not used in any cases. Angiographic findings such as vessel dimensions, pre- and post-procedural stenoses, lesion length, and thrombolysis in myocardial infarction (TIMI) flow grade were determined by visual estimation.

DefinitionsAngina symptoms were defined according to the classifica-tion of the Canadian Cardiovascular Society.12 Lesion types were noted according to the American College of Cardiology/American Heart Association (ACC/AHA) lesion characteristics classification.13 Q-wave MI was defined as the presence of new Q waves in post-procedure electrocardiogram, with a two-fold

increase in MB fraction of creatinine kinase. Non-Q-wave MI was defined as a two-fold increase in MB fraction of creatinine kinase without the development of new Q waves.

Angiographic success was defined as residual stenosis < 20% plus normal TIMI flow grade 3. Procedural success was defined as angiographic success without major complications (death, MI, emergency bypass surgery or PCI) during hospitalisation. MACE was defined as the presence of cardiac death, non-fatal MI, or target-vessel revascularisation (TVR) during the follow-up period. TVR was defined as ischaemia-driven repeat percuta-neous intervention or bypass surgery of the target vessel. Target lesion revascularisation (TLR) was defined as ischaemia-driven repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel.

Statistical analysisNumerical variables were presented as mean ± SD, while catego-rised variables were shown as numbers (%). Continuous vari-ables were compared using the Student’s t-test or non-parametric Mann-Whitney U-test whenever the data did not appear to have normal distributions, and categorical variables were compared using the Chi-square or Fischer’s exact test. The analyses were conducted with SPSS software version 13 for Windows (Statistical Package for the Social Sciences, Inc, Chicago, IL). All p-values were two-tailed, with statistical significance taken as p < 0.05.

resultsBaseline and immediate resultsDuring the study period, 22 patients were treated with two homogenous overlapping DES (in 17 cases, two overlapping Cypher stents; and in five, two overlapping Taxus stents were used). Thirty patients were treated with at least one DES combined with at least one BMS in an overlapping manner (in 25 cases, Cypher stents and in five cases, Taxus stents were used, combined with a variety of bare-metal stents, as stated in the methods section). In 23 cases, only one BMS was used. In four cases, two BMS, and in three cases, three bare-metal stents were used for the coverage of residual lesions. All the overlapping stents were placed for very long lesions (mean lesion length in the total population: 43.36 ± 9.93 mm).

The patients’ clinical characteristics are listed in Tables 1 and 2. As shown, the patients in these two groups were similar in baseline demographic characteristics. Lesions were estimated to be on average longer and the mean inflation pressure per lesion was higher in the DES-DES group, compared with the DES-BMS group (47.95 ± 9.25 vs 39.98 ± 9.15 mm, p = 0.003, and 16.29 ± 2.26 vs 14.52 ± 2.22 atm, p = 0.01, respectively). Moreover, a higher percentage of procedures were performed on the left anterior descending artery in the DES-DES group (Tables 2, 3).

During hospitalisation, angiographic failure occurred in one patient in each group. In the DES-BMS group, non-Q-wave MI occurred in one patient (Table 4). He was treated with two overlapping Cypher stents (2.75 × 33 mm) and one Express 2 (3.5 × 8 mm). Six months later, he underwent repeat coronary angiography, which showed patent stents.

All dissections were treated with a combination of drug-


eluting and bare-metal stents (Table 4). In two cases, four stents; and in one case, three stents were used; in one patient, two stents were used for the coverage of lesions. In all cases, the first implanted stent was a DES. In the case with three stents, the second stent was also a DES. All the other stents were BMS. In our total population, the mean length and diameter of DES vs BMS was 27.96 ± 6.53 vs 16.53 ± 7.59 mm (p < 0.0001) and 2.58 ± 0.32 vs 3.01 ± 0.43 mm (p = 0.025), respectively. In the DES-BMS group, the mean length and diameter of DES vs BMS was 31.21 ± 3.67 vs 16.53 ± 7.59 mm (p < 0.001) and 2.84 ± 0.35 vs 3.01 ± 0.43 mm (p = 0.071), respectively.

Late outcomesThe mean follow-up duration was 13.5 ± 4.6 months. Of the 52 patients, 50 were followed up with clinic visits: all 22 patients treated with overlapping DES and 28 of the 30 patients treated with a combination of DES and BMS. At 30 days’ and six months’ follow up, MACE did not occur in any patient.

MI did however occur in a patient treated with two overlap-ping Cypher stents (3 × 33 and 3 × 18 mm). He was an ex-smok-er and the diseased location was distal LAD. He continued to

receive clopidogrel for seven months. After 13 months, he was admitted due to post MI angina. Re-angiography showed mini-mal CAD and development of coronary aneurysm in the coro-nary segment that had received overlapping stents. The patient underwent implantation of an intra-cardiac defibrillator (ICD) due to ventricular fibrillation and ejection fraction of 15%.

With univariate analysis, the composite endpoint of TVR, MI and cardiac death (MACE) was not related to any variable listed in Table 4.

discussionIn the present report, we describe the clinical outcomes of a small, consecutive series of patients treated with overlapping DES or overlapping DES and BMS. The data presented here demonstrate that overlapping stents may be used for the treat-ment of long coronary lesions, with both a high acute success rate and a good mid-term clinical outcome.

TABLE 1. SELECTED BASELINE CLINICAL CHARACTERISTICS IN PATIENTS TREATED WITH OVERLAPPING DRUG-ELUTING STENTS

VERSUS COMBINED BARE-METAL AND DRUG-ELUTING STENTS

DES-DES (n = 22)n (%)

DES-BMS (n = 30)n (%) p-value

Female gender 4 (18.2) 8 (26.7) 0.53

Positive family history 7 (31.8) 15 (50) 0.19

Age (years) 56.13 ± 10.75 54.80 ± 14.63 0.71

Smoking 14 (63.6) 14 (46.7) 0.22

Diabetes mellitus 2 (9.1) 9 (30) 0.09

Hyperlipidaemia 13 (59.1) 19 (63.3) 0.76

Hypertension 5 (22.7) 11 (36.7) 0.28

MI history 8 (36.4) 12 (40) 0.79

Prior PCI 1 (4.5) 0 0.42

Prior CABG 0 3 (10) 0.25

*Mean ± SD. MI: myocardial infarction; PCI: percutaneous coronary interven-tion; CABG: coronary artery bypass grafting.

TABLE 2. LESION CHARACTERISTICS IN PATIENTS TREATED WITH OVERLAPPING DRUG-ELUTING STENTS VERSUS COMBINED BARE-METAL AND DRUG-ELUTING STENTS

DES-DES (n = 22) n (%)

DES-BMS (n = 30) n

(%) p-value

Type B2/C lesions 24 (100) 30 (100) –

Multi-vessel disease 7 (31.8) 12 (40) 0.56

Pre-procedural stenosis* (%) 90.95 ± 9.08 92.07 ± 6.50 0.61

Lesion length* 47.95 ± 9.25 39.98 ± 9.15 0.003

Ostial lesion 1 (4.5) 0 0.42

Lest anterior descending artery 21 (95.5) 20 (66.7) 0.02

Right coronary artery 1 (4.5) 8 (26.7) 0.06

Left circumflex artery 0 2 (6.7) 0.50

Calcified 2 (9.1) 4 (13.3) > 0.999

Eccentric 3 (13.6) 7 (23.3) 0.49

Angulated segments 1 (4.5) 6 (20) 0.22

Thrombus 0 1 (3.3) > 0.999

Total occlusion 5 (22.7) 3 (10) 0.26

*Mean ± SD.

TABLE 3. PROCEDURAL CHARACTERISTICS IN PATIENTS TREATED WITH OVERLAPPING DRUG-ELUTING STENTS VERSUS

COMBINED BARE-METAL AND DRUG-ELUTING STENTS

DES-DES (n = 22)(Cypher-Cypher: 17)

(Taxus-Taxus: 5)n (%)

DES-BMS (n = 30)(Cypher-BMS: 25)

(Taxus-BMS: 5)n (%) p-value

Stent length (mm)*# 50.91 ± 8.35 55.79 ± 16.37 0.17

Mean stent length per lesion* (mm)

25.68 ± 4.34 23.81 ± 3.96 0.11

Mean stent diameter per lesion* (mm)

2.86 ± 0.25 2.94 ± 0.35 0.34

Mean stent inflation pres-sure per lesion* (atm)

16.29 ± 2.26 14.52 ± 2.22 0.01

Number of stents per lesion

2 22 (100) 23 (76.7)

3 0 4 (13.3)

4 0 3 (10)

*Mean ± SD, #the reported stented length is based on the cumulative length of the adjacent stents.

TABLE 4. IN-HOSPITAL AND LATE CLINICAL OUTCOMES IN PATIENTS TREATED WITH OVERLAPPING DRUG-ELUTING STENTS

VERSUS COMBINED BARE-METAL AND DRUG-ELUTING STENTS

DES-DES (n = 22) n (%)

DES-BMS (n = 30) n (%) p-value

In-hospital outcomes

Peri-procedural non-Q-wave MI 0 1 (3.3) > 0.999

Angiographic success 21 (95.5) 29 (96.7) > 0.999

Procedural success 21 (95.5) 28 (93.3) > 0.999

Dissection 0 4 (13.3) 0.13

Abrupt closure 0 0 –

Long-term outcomesn = 22 (100%)

n = 28 (93.3%)

Mean follow-up duration (months) 13.9 ± 4.2 13.3 ± 4.8 0.65

MACE 1 (4.5) 0 0.44

Cardiac death 0 0 -

Non-fatal MI 1 (4.5) 0 0.44

TVR 0 0 -

TLR 0 0 -

CABG 0 0 -

*Mean ± SD. MI: myocardial infarction; MACE: major adverse cardiac events; TVR: target vessel revascularisation; TLR: target lesion revascularisation; CABG: coronary artery bypass grafting.


Long coronary lesions comprise up to 20% of current inter-ventional practice and are considered difficult both technically and in terms of achieving successful clinical outcomes.1,14 To date, both single long stents and multiple contiguous stents have been used for the successful treatment of coronary artery lesions.5,15-17

Stent length was previously an independent predictor of restenosis; however, the use of DES has greatly attenuated this relationship. As a result, long DES tend to be selected for complete lesion coverage, but if this approach is not possible or a residual segment of the lesion is left uncovered, additional stenting is considered, with some overlap to eliminate the risk of a residual stent gap.18,19 Some reports have shown an increased rate of peri-procedural myonecrosis in overlapping stents, which may be a limitation of this approach.9,20 A pooled analysis of five clinical trials showed that BMS overlap was associated with an increased incidence of MI and total MACE that was not apparent for DES overlap.11

On the other hand, Finn et al. reported that, in a histological analysis in an animal study, overlapping DES further delayed the arterial healing and promoted inflammation compared to over-lapping BMS.21 Therefore they concluded that patients receiving overlapping DES needed more frequent follow up than patients with non-overlapping stents. It is noteworthy that many studies show comparable results after PCI with homogeneous and heter-ogeneous drug-eluting stents,22,23 and a low rate of repeat revas-cularisation irrespective of stent type, with no safety concerns at medium-term follow up.24,25

In 2006, Burzotta et al. distributed their report on a consecu-tive series of 40 patients in Italy, treated with overlapping stents. These stents were used to cover minor dissections and plaque shifts, treat other contiguous lesions in the same vessel, or obtain full lesion coverage. In a subgroup of patients, an appropriate (length and size) similar type of DES was not available, so the additional stent necessary to complete the procedure was a BMS or another type of DES. In their study, 24 patients were treated with overlapping homogeneous DES, eight with overlapping heterogeneous DES, and eight with overlapping DES-BMS. In their experience, three out of the 24 patients (12.5%) in the over-lapping homogeneous DES group developed MACE: two, target lesion revascularisations and one, coronary bypass surgery. No MACE occurred in the overlapping heterogeneous DES group. In the overlapping DES-BMS group, the rate of MACE was 50% (three target-vessel revascularisations and one death after cardiogenic shock in a patient who developed ST-elevation MI 110 days after PCI).22

As stated in the results section, we used homogeneous drug-eluting stents in all 22 patients treated with overlapping DES, which matches the Burzotta study. However, we used a combina-tion of DES and BMS in a much higher number of patients than in their registry (30 vs eight), and no MACE was experienced. In our study, MACE only included MI after 13.2 months in a patient treated with two overlapping Cyphers, yielding a MACE rate of 4.5%, compared to 0% in patients treated with DES-BMS. We must point out that we used the definition of a CKMB rise two-fold above baseline, although the new definition of MI is based on troponin level.26

Angiographic restenosis was detected in two of the six patients who had undergone follow-up angiography. Since we only performed follow-up angiography when considered

clinically appropriate (in 11.5% of cases), the true angiographic restenosis rate in our cohort could not be established with certainty, compared to Burzotta et al., who performed follow-up angiography in more than 80% of cases. In their experience, MACE was detected only in those patients who had undergone follow-up angiography and patients without follow-up angiogra-phy did not show MACE at nine months.

In the Burzotta study, total stent length was shorter in patients treated with DES-BMS than DES-DES [39 ± 16 mm in the DES-BMS vs 50 ± 10 mm in the overlapping Cypher and 42 ± 7 mm the overlapping Taxus group (p = 0.09)].22 Their results also showed more intimal hyperplasia at the site of stent overlap in DES-BMS overlaps than when homogeneous or heterogene-ous DES were used. The higher late lumen loss translated into a higher in-segment binary restenosis rate in lesion segments covered with DES-BMS, therefore decreasing the possible benefits associated with DES implantation.

In the setting of long dissections, multiple short stent place-ments have proven to be equivalent to the use of long stents.27 In our practice, in four patients, all dissections were successfully treated with overlapping DES-BMS (Table 4). In addition, as stated in the results section, the additional bare-metal stents used for coverage of residual lesions, both in the case of dissections or for long lesions, were smaller and had larger diameters. Since the number of endpoints was small in our study, we may not reach a definite conclusion, but we hypothesise that the smaller lengths and larger diameters of the bare-metal stents used for coverage of residual lesions may have reduced the risk of MACE in the group treated with overlapping DES-BMS.

On the other hand, we found that lesions were estimated to be significantly shorter in the DES-BMS group, suggesting another potential factor for the reduced risk of MACE. However, total stent lengths were not significantly different between the two groups. This may be explained by the fact that all the patients treated with more than two stents were in the DES-BMS group, and additional bare-metal stents were used for the coverage of residual lesions.

Our results showed that bare-metal stents with relatively short lengths and large diameters can be overlapped in the proximal portion of a long drug-eluting stent for the coverage of residual lesions when the DES length would not suffice for the coverage of the total lesion, or in the case of proximal edge dissection. In our practice, this procedure was both feasible and safe, with no increased rate of late stent thrombosis, as opposed to the use of two or more drug-eluting stents, which have been frequently known to be associated with stent thrombosis, especially at the site of overlapping stent struts.

Limitations of this study include the fact that it was a retro-spective analysis of consecutive and non-randomised patients, different stent types were used, and stent deployment techniques varied between the operators. Also, these data reflect the current clinical practice at our institution. Routine follow-up angiogra-phy was therefore not performed, which blurred the true rate of acquired restenosis within the study population.

ConclusionIn clinical practice, there are patients in whom the interventional cardiologist is required to overlap two or more stents in order to cover residual lesions or dissecting flaps of a long atherosclerotic


plaque. In our patients, there were no differences in mid-term clinical outcomes whether there was more than one overlapped drug-eluting stent, or a bare-metal stent had been deployed and overlapped in the proximal portion of a long drug-eluting stent.

Regarding the risk of late thrombosis when using two or more overlapped drug-eluting stents, our experience showed that this therapeutic strategy is both safe and feasible for the coverage of either dissections or residual lesions. Considering the small sample size of our study, a prospective, randomised clinical trial is recommended in future to determine the advantage of one technique over the other.

References1. Kastrati A, Elezi S, Dirschinger J, Hadamitzky M, Neumann F, Schomig

A. Influence of lesion length on restenosis after coronary stent place-ment. Am J Cardiol 1999; 83: 1617–1622.

2. Ryan TJ, Bauman WB, Kennedy JW, Kereiakes DJ, King SB (3rd) McCallister BD, et al. Guidelines for percutaneous transluminal coro-nary angioplasty. A report of the American Heart Association/American College of Cardiology Task Force on Assessment of Diagnostic and Therapeutic Cardiovascular Procedures (committee on percutaneous transluminal coronary angioplasty). Circulation 1993; 88: 2987–3007.

3. Stone GW, Ellis SG, Cox DA, Hermiller J, O’Shaughnessy C, Mann JT, et al. TAXUS-IV investigators. A polymer-based, paclitaxel-eluting stent in patients with coronary artery disease. N Engl J Med 2004; 350: 221–231.

4. Degertekin M, Arampatzis CA, Lemos PA, Saia F, Hoye A, Daemen J, et al. Very long sirolimus-eluting stent implantation for de novo coronary lesions. Am J Cardiol 2004; 93: 826–829.

5. Tsagalou E, Chieffo A, Iakovou I, Ge L, Sangiorgi GM, Corvaja N, et al. Multiple overlapping drug-eluting stents to treat diffuse disease of the left anterior descending coronary artery. J Am Coll Cardiol 2005; 45: 1570–1573.

6. Bauters C, Hubert E, Prat A, Bougrimi K, Van Belle E, McFadden EP, et al. Predictors of restenosis after coronary stent implantation. J Am Coll Cardiol 1998; 31: 1291–1298.

7. Hoffmann R, Herrmann G, Silber S, Braun P, Werner GS, Hennen B, et al. Randomized comparison of success and adverse event rates and cost effectiveness of one long versus two short stents for treatment of long coronary narrowings. Am J Cardiol 2002; 90: 460–464.

8. Pan M, de Lezo JS, Medina A, Romero M, Gonzalez S, Segura J, et al. Influence of stent treatment strategies in the long-term outcome of patients with long diffuse coronary lesions. Catheter Cardiovasc Interv 2003; 58: 293–300.

9. Lee CW, Park KH, Kim YH, Hong MK, Kim JJ, Park SW, et al. Clinical and angiographic outcomes after placement of multiple overlapping drug- eluting stents in diffuse coronary lesions. Am J Cardiol 2006; 98: 918–922.

10. Wilson GJ, Polovick JE, Huibregtse BA, Poff BC. Overlapping paclitaxel eluting stents: Long-term effects in a porcine coronary artery model. Cardiovasc Res 2007; 76: 361–372.

11. Kereiakes DJ, Wang H, Popma JJ, Kuntz RE, Donohoe DJ, Schofer J, et al. Periprocedural and late consequences of overlapping Cypher sirolimus-eluting stents: pooled analysis of five clinical trials. J Am Coll Cardiol 2006; 48: 21–31.

12. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproduc-ibility and validity of systems for assessing cardiovascular functional class: advantages of a new specific activity scale. Circulation 1981; 64: 1227–1234.

13. Smith SC Jr, Dove JT, Jacobs AK, Kennedy JW, Kereiakes D, Kern MJ, et al; American College of Cardiology/American Heart Association task force on practice guidelines (Committee to revise the 1993 guidelines for percutaneous transluminal coronary angioplasty); Society for Cardiac Angiography and Interventions. ACC/AHA guidelines for percutaneous coronary intervention (revision of the 1993 PTCA guidelines) – execu-tive summary: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committeeto revise the 1993 guidelines for percutaneous transluminal coronary angioplasty) endorsed by the Society for Cardiac Angiography and Interventions. Circulation 2001; 103: 3019–3041.

14. Kim YH, Park SW, Lee CW, Hong MK, Gwon HC, Jang Y, et al. Comparison of sirolimus-eluting stent, paclitaxel-eluting stent, and bare metal stent in the treatment of long coronary lesions. Catheter Cardiovasc Interv 2006; 67: 181–187.

15. Rozenman Y, Mereuta A, Mosseri M, Lotan C, Nassar H, Hasin Y, et al. Initial experience with long coronary stents: the changing practice of coronary angioplasty. Am Heart J 1997; 134: 355–361.

16. Chauhan A, Vu E, Ricci DR, Buller CE, Moscovich MD, Monkman S, et al. Early and intermediate term clinical outcome after multiple coronary stenting. Heart 1998; 79: 29–33.

17. Mushahwar SS, Pyatt JR, Lowe R, Morrison WL, Perry RA, Ramsdale DR. Clinical outcomes of long coronary stents: a single-center experi-ence. Int J Cardiovasc Intervent 2001; 4: 29–33.

18. Degertekin M, Regar E, Tanabe K, Smits PC, van der Giessen WJ, Carlier SG, et al. Sirolimus-eluting stent for treatment of complex in-stent restenosis: the first clinical experience. J Am Coll Cardiol 2003; 41: 184–189.

19. Tanabe K, Serruys PW, Grube E, Smits PC, Selbach G, van der Giessen WJ, et al. In-stent restenosis treated with stent-based delivery of pacli-taxel incorporated in a slow-release polymer formulation. Circulation 2003; 107: 559–564.

20. Chu WW, Kuchulakanti PK, Torguson R, Wang B, Clavijo LC, Sudd ath WO, et al. Impact of overlapping drug-eluting stents in patients under-going percutaneous coronary intervention. Catheter Cardiovasc Interv 2006; 67: 595–599.

21. Finn AV, Kolodgie FD, Harnek J, Guerrero LJ, Acampado E, Tefera K, et al. Differential response of delayed healing and persistent inflammation at sites of overlapping sirolimus- or paclitaxel-eluting stents. Circulation 2005; 112: 270–278.

22. Burzotta F, Siviglia M, Altamura L, Trani C, Leone AM, Romagnoli E, et al. Outcome of overlapping heterogenous drug-eluting stents and of overlapping drug eluting and bare metal stents. Am J Cardiol 2007; 99: 364–368.

23. Kang WC, Oh KJ, Han SH, Ahn TH, Chung WJ, Shin MS, et al. Angiographic and intravascular ultrasound study of the effects of over-lapping sirolimus- and paclitaxel-eluting stents: Comparison with same drug-eluting overlapping stents. Int J Cardiol 123: 12–17.

24. Aoki J, Ong AT, Rodriguez Granillo GA, McFadden EP, van Mieghem CA, et al. ‘Full metal jacket’ (stented length ≥ 64 mm) using drug-eluting stents for de novo coronary artery lesions. Am Heart J 2005; 150: 994–999.

25. Chu WW, Kuchulakanti PK, Torguson R, Wang B, Clavijo LC, Suddath WO, et al. Comparison of clinical outcomes of overlapping sirolimus- versus paclitaxel-eluting stents in patients undergoing percutaneous coronary intervention. Am J Cardiol 2006; 98: 1563–1566.

26. Thygesen K, Alpert JS, White HD; Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Eur Heart J 2007; 28: 2525–2538.

27. De Scheerder IK, Wang K, Kostopoulos K, Dens J, Desmet W, Piessens JH. Treatment of long dissections by use of a single long or multiple short stents: clinical and angiographic follow-up. Am Heart J 1998; 136: 345–351.

CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 6, November/December 2010

Cardiovascular topics

316 AFRICA

significant differences between serum CrP levels in children in different categories of physical activity: the Play studyB hARMSE, hS KRUGER

summary Low-grade systemic inflammation is emerging as a compo-nent of the metabolic syndrome. The purpose of this study was to assess the association between serum C-reactive protein (CRP), physical activity and body composition in 193 black children aged 13 to 18 years from a South African township. Demographic information and anthropometric measurements were taken, and fasting blood samples were analysed for high-sensitivity serum CRP. Body fat was meas-ured by air displacement plethysmography.

There was a trend towards higher serum CRP in the boys with a higher percentage body fat. After multiple regression analyses, waist circumference in the girls was significantly associated with serum CRP. In the boys, there was an inverse correlation between percentage body fat and fitness, and between fitness and serum CRP. Significant differences were found between serum CRP in the different physical activity categories, with lower serum CRP in the girls in the higher physical activity group. Obesity should be prevented in South African children by encouraging physical activity.

Keywords: C-reactive protein, inflammation, physical activity, adolescent, metabolic syndrome, body composition



Obesity is currently the most common and costly nutritional problem in developed countries,1 with 10% of the world’s school-aged children estimated to be overweight.2 The preva-lence of overweight is rising significantly in most parts of the world, especially in economically developed regions. This rapid increase implicates environmental rather than genetic factors,2 although one cannot exclude the interaction between genes and the environment.3

The metabolic syndrome (MS), a cluster of five biological markers that together predict the development of cardiovascu-lar disease and type 2 diabetes, is now increasingly emerging among children and adolescents.4 These markers are hyperten-

sion, insulin resistance, central adiposity, hypertriglyceridaemia and decreased high-density lipoprotein cholesterol. Low-grade systemic inflammation is increasingly being observed as a significant component of the MS.5 Various cytokines and chemi-cal messengers, which induce their effects individually or in interaction with each other, constitute the main regulators of the inflammatory process.5

Young people in lower-income families are particularly vulnerable to obesity because of poor diet and limited opportuni-ties for physical activity. In developing countries, obesity among the youth is most prevalent in wealthier sections of the popula-tion, but it is also rising among the urban poor in these countries, possibly due to their exposure to westernised diets, coinciding with a history of under-nutrition.2 Lobstein et al.2 emphasised that children from socio-economically deprived environments in most western societies have a greater risk of obesity than chil-dren from more affluent groups.

Adolescence is an important period during development, and significant somatic growth and maturation are evident during this time. The pubertal growth spurt is associated with significant changes in body composition, where girls tend to accumulate more fat than boys.4 Adolescence is one of the most vulnerable periods for the development of overweight and obesity.2 Although the mechanism is unclear, it is possible that fat distribution patterns established during adolescence play a role.2 The maximum body mass index attained at post-pubescence is strongly associated with the degree of fatness in adulthood.3

South Africa is a developing country with both under- and over-nutrition. The prevalence of obesity is high among black women, whereas it is low in children.6 Stunting is a very common nutritional disorder in South Africa and local research has shown that there may be a link between stunting and the development of overweight or obesity.7 According to Monyeki et al.,8 obesity is not only common in South African women, but also in female adolescents. In 2002 the first South African National Youth Risk Behaviour survey stated that the prevalence of overweight among secondary school learners was 17% and obesity 4%.9 These data also showed that the co-existence of stunting and being over-weight is a public health problem among adolescents in South Africa.9

Obesity during childhood seems to increase the risk of subse-quent morbidity, whether obesity persists into adulthood or not, with obese children being at an increased risk of metabolic and cardiovascular disorders later in life.10 Recent South African studies indicate that measures of overweight were positively

school of Physiology, nutrition and Consumer science, north-west university, Potchefstroom, south africa BERNA hARMSE, MSch SALOME KRUGER, PhD, [email protected]


associated with increased blood pressure,11 plasminogen activator inhibitor-1 activity, plasma fibrinogen and the thrombin–anti-thrombin complex,12 as well as higher fasting plasma insulin and leptin levels and insulin resistance. These possibly increase the risk for cardiovascular disease.13 No South African studies on body composition and low-grade inflammation in children or adolescents could be found in the literature.

C-reactive protein (CRP), synthesised in the hepatocytes, is an acute-phase reactant that responds non-specifically to infec-tions, immuno-inflammatory diseases and malignancies.14 CRP is also a surrogate marker for interleukin (IL)-6 activity and is proven to predict the development of type 2 diabetes and mortal-ity.15 Levels of CRP are usually low or undetected in healthy subjects, but they increase up to 100 times during acute illness or inflammation.16 In the absence of infection, elevations of CRP levels, generally below 10 mg/l, are associated with an increased risk of the development of atherosclerotic cardiovascular disease.

In recent years CRP values, as measured by a high-sensitivity assay (hs-CRP), have been recognised as a useful and sensitive predictor of the future risk of myocardial infarction and stroke.17 Pepys and Hirschfield14 noted that CRP values cannot be used diagnostically, but should be interpreted with full knowledge of all other clinical and pathological results. Upon interpretation of CRP values, low-risk inflammation is defined as a level less than 1 mg/l, average risk is 1.0–3.0 mg/l, and high-risk values are 3–10 mg/l.18

There is a link between basal inflammation, MS and obesity. The release of IL-6 from the visceral adipose tissue may induce low-grade systemic inflammation in subjects with increased body fat, resulting in clinically raised CRP levels in obese adults.14,18 However, the limited number of studies on children causes uncertainty about the clinical significance of inflamma-tion in overweight children.4,5,16,17,19

Body fatness and central body fat distribution are related to an adverse risk profile in the youth.17 A higher degree of cardio-respiratory fitness has been shown to relate to a healthier meta-bolic profile in children. Isasi et al.19 showed in a study in the USA that CRP levels did not differ between boys and girls and fitness level was inversely correlated to CRP in the boys. There are, however, few data about the association between obesity, physical activity and serum CRP concentrations in black South African children.

Early assessment of the inflammatory status of South African children could be useful to decrease CVD risks, particularly in individuals at intermediate risk, such as overweight or physi-cally inactive children. The purpose of this study was to assess the association between serum C-reactive protein and physical activity, as well as body composition in 193 black high-school children aged 13 to 18 years from a township in South Africa.

MethodsThis study was performed as part of the PLAY study (PhysicaL Activity in the Young) on the effects of physical activity in chil-dren. For the purposes of this study, baseline data were used for cross-sectional analysis.

The PLAY study was approved by the Ethics Committee of the North West University (Potchefstroom campus). All grade 9 children (13–18 years old) from two secondary schools, situ-ated in a low-income area in Potchefstroom in the North West

Province of South Africa, were provided with a permission form to be signed by their parents before inclusion in the study. Permission was also obtained from the school principals and consent from the children. In total 193 boys and girls were avail-able for inclusion.

The children were picked up at the schools and brought to the University metabolic unit on the study days. They started at the blood station, where fasting blood samples were taken. Thereafter body composition (height, weight, waist circumfer-ence, skin folds, and body volume and density) was measured. The children then received food and proceeded to the question-naire stations (demographic, Tanner and PDPAR).

Data regarding age, gender, home language, socio-economic status, housing, accessibility to water and electricity, smoking status and general health of the children, as well as educational level and occupation of the parents/caregivers were obtained by individual interviews, performed by fieldworkers in each subject’s language of preference.

Body composition and anthropometryThe subjects were measured and weighed in their under-wear by trained postgraduate biokinetics students according to standard ISAK (International Society for the Advancement of Kinanthropometry) methods.20 The height (cm) of the subjects was taken with a vertical stadiometer to the nearest 0.1 cm. Body weight was measured to the nearest 0.1 kg on an electronic scale (Precision Health scale, A & D Co, Saitama, Japan). The scale was calibrated with a 10-kg standardised weight.

Anthropometrical nutritional status was defined by Centers for Disease Control (CDC) z-scores21 and international body mass index (BMI)-for-age cut-off points.22 A flexible steel meas-uring tape (Lufkin, Cooper Tools, Apex, NC, USA) was used for measuring waist and hip circumferences to the nearest 0.1 cm and waist:hip ratio (WHR) was calculated by dividing waist circumference by hip circumference. Skin folds were measured using a John Bull® (British Indicators, London, UK) skin-fold calliper to the nearest 0.1 mm of the triceps, sub-scapula, medial calf, abdominal and supra-spinal skin folds. Landmarks were drawn first where-after post-graduate biokinetics students with a level 2 anthropometic qualification did the measurements.

The children’s body composition (percentage muscle and fat) was measured by air-displacement plethysmography (BOD-POD, Life Measurement Inc, Concord, CA), which was calibrated at the start of each day’s measurements with a cylinder of standardised volume. The BOD-POD system uses the principle of whole-body densitometry to obtain the amount of fat and lean body mass in the body. For accuracy of measurement, the subjects wore tight-fitting clothing and a swimming cap, removed all jewellery and emptied the bladder before testing. Minimal movement of the subjects within the BOP-POD was ensured. The subjects were shown how to use the thoracic gas volume tubes and a measure-ment was taken to compensate for lung volume.

Body volume (litre) was measured with the BOD-POD, using the ratio between pressure and volume, as explained by Boyle’s law. The ratio is used to calculate the unknown volume by meas-uring the pressure directly. The pressure in both chambers reacts immediately and the difference in pressure represents the relative volume of air in each chamber.

Body density (Db) was calculated by dividing the body’s


mass by the volume, using the Siri equation.23 From Db, the fat percentage, fat mass, lean body mass and lung volume could be obtained. Two measurements were taken and the aggregate was used.

Trained professionals in private rooms used the Tanner stag-ing scale questionnaire to estimate the physical maturity of the boys and girls.24

Blood samples and biochemistryRegistered nurse practitioners obtained fasting blood samples from the subjects. The vena cephalica was used to draw 20 ml venous blood for the preparation of EDTA plasma and serum. Blood was centrifuged for 15 minutes at 4ºC and 2 000 × g for serum and plasma preparations, divided into Eppendorff tubes and frozen at –84ºC until the analyses were done.

High sensitivity C-reactive protein (hs-CRP) was measured by immuno-nephelometry (Cardiophase hsCRP, Dade Behring, 2004) at an accredited laboratory (Ampath Laboratories, Pretoria). Control serum with a concentration of 13.5 mg/l was used as an external standard. The mean concentration of the controls was 13.53 mg/l, with a range of 13.0–14.3 mg/l and a coefficient of variation of 8.6%.

Physical activity and fitnessTrained field workers used the Previous day physical activity recall questionnaire (PDPAR) to obtain information regarding subjects’ physical activity of the previous day (24 hours) and a 24-hour day the previous weekend.25

Cardiovascular fitness was determined by means of the bleep test. Participants had to run a 20-m distance, timed by a metro-nome. The running pace increased with each level (levels 1 to 6). When a participant could no longer complete the distance within the allocated time, the test was terminated and the correspond-ing level of fitness was recorded. The levels were converted to indirect maximum rate of oxygen consumption (VO2 max) values using a conversion calculator.26

Statistical analysisThe Statistica computer data analysis software system from Statsoft, Inc (2004), version 7 was used to analyse data. CRP data were not normally distributed and were transformed loga-rithmically. Descriptive statistics were used to describe the char-acteristics of the subjects. The Mann-Whitney U-test, as well as Kruskall-Wallis tests were performed to assess differences between serum CRP levels of the children in the different catego-ries of habitual physical activity, as well as to compare serum CRP levels of children with normal or low percentage body fat with those with high body fat percentages. Spearman correlation was performed to assess the correlation between body composi-tion variables, serum CRP (log transformed), reported physical activity and fitness of the children.

resultsThe sample comprised black children living in a poor socio-economic setting. The type of housing was generally of galva-nized zinc or brick with partial water and electricity supplies. Subjects in the two schools were in a similar growth phase and

socio-economic status, with comparable eating habits and physi-cal activity levels. Only 5.7% of the children admitted to smok-ing, and one was a girl. The median age of starting to smoke was 15 years (interquartile range 13–17) and they smoked a median of six cigarettes per day (interquartile range 2–10).

The serum CRP concentrations of the children ranged between < 0.2 and 39.8 mg/l. Three girls and three boys with high serum CRP concentrations, above 10 mg/l, were excluded from further analysis because this could have been due to acute inflammation.16,17 Most of the children had serum CRP concen-trations within the normal range (< 3 mg/l), and only a few had raised levels. The children’s serum CRP concentrations were then compared with regard to habitual physical activity level and body fat percentage. Because the data were not normally distributed, median and interquartile ranges were also calculated.

The descriptive statistics of girls and boys per category of habitual physical activity are shown in Table 1. For the purpose of this study, ‘inactive’ was defined as children with a score of 1, moderately active was a score of 2, and ‘most active’ was a score of 3, according to the coding for the PDPAR, as proposed by Weston et al.25

There were significant differences between serum CRP concentrations for the three physical activity categories of girls and boys. The Kruskall-Wallis value for the difference in log CRP in the girls was H = 7.33 (p = 0.025) and for the boys H = 7.5 (p = 0.02). The difference in CRP between activity groups showed lower median serum CRP with higher physical activity in the girls, as seen in Table 1. In the boys there was no clear trend, with the highest median serum CRP in those with a moderate physical activity level (Table 1).

With correlation analyses, in the girls there was a significant positive correlation between the reported physical activity level and their bleep test results (number of laps completed). The bleep test result also correlated negatively with all body composition variables indicating obesity (BMI, waist circumference, skin folds, body fat percentage).

In the boys, a significant negative correlation was found between the bleep test result and body fat percentage, as well as skin fold thickness, but no correlation between bleep test result and reported physical activity was found (Table 2). There was,

TABLE 1. DESCRIPTIVE STATISTICS OF CHILDREN PER CATEGORY OF HABITUAL PHYSICAL ACTIVITY

(MEAN ± SD/MEDIAN, INTERQUARTILE RANGE#)

Variable n* Inactive nModerately

active n Most active

Girls

BMI (kg/m2) 59 20.43 ± 2.94 35 19.96 ± 3.60 10 20.22 ± 3.02

Bleep test score 58 3.27 ± 0.90 37 3.64 ± 1.31 9 4.47 ± 0.93

CRP (mg/l)# 58 0.33 (0.15–0.94) 38 0.46 (0.26–1.75) 10 0.22 (0.21–0.26)

WC (cm) 60 64.54 ± 5.90 38 63.82 ± 6.42 10 63.35 ± 4.13

TSF (mm) 60 16.60 ± 5.91 38 14.50 ± 4.47 10 14.12 ± 5.13

Boys

BMI (kg/m2) 18 19.35 ± 2.58 34 18.56 ± 2.43 23 19.51 ± 2.92

Bleep test score 18 6.43 ± 2.49 33 6.2 ± 1.75 23 7.00 ± 1.91

CRP (mg/l)# 17 0.19 (0.15–0.38) 32 0.59 (0.28–1.06) 21 0.31 (0.16–0.95)

WC (cm) 18 66.42 ± 4.95 33 64.81 ± 5.90 22 66.41 ± 5.60

TSF (mm) 18 9.12 ± 4.09 33 8.41 ± 4.11 22 9.36 ± 4.94

BMI: body mass index; CRP: C-reactive protein; WC: waist circumference; TSF: triceps skin fold. *Number of subjects differs due to missing data.


however, a significant negative correlation between serum CRP and the number of laps completed by the boys, as well as calcu-lated VO2 max, indicating an inverse association between fitness and serum CRP. In the girls, the association was in the same direction, but not statistically significant.

Comparison of girls with a body fat percentage above 25% (over-fat) with lean girls showed the lean group had a median serum CRP of 0.30 mg/l (interquartile range 0.15–0.9) and the over-fat group a median of 0.34 mg/l (interquartile range 0.2–1.0) (Table 3). There was therefore no significant difference in serum CRP levels between the two groups.

Comparison of the data for serum CRP in the boys showed a similar result, where the boys with higher body fat percentages (> 20%) had a median serum CRP value of 0.5 mg/l (interquar-tile range 0.2–1.9) and the lean boys a median of 0.32 mg/l (interquartile range 0.15–0.8). The Mann-Whitney U-test for the difference in CRP levels in boys was z = 1.39 (p = 0.16), indicating no significant difference, but a trend towards higher serum CRP concentrations in the boys with higher percentages of body fat.

Multiple regression analyses were performed with age, ciga-rette smoking, body fat percentage, waist circumference and physical activity level as predictor variables and serum CRP (log transformed) as dependent variable. Children with a serum CRP level > 10 mg/l were excluded from these analyses. For the boys, no variable was significantly associated with serum CRP. In the girls’ group, age and waist circumference were statistically significantly associated with serum CRP, although the adjusted R2 was small (adjusted R2 = 0.08, p = 0.007).

discussionThe purpose of this study was to assess the association between serum CRP levels, physical activity and body composition in black adolescents in two township schools. The most active girls had the lowest serum CRP values, similar to the findings of Isasi et al.,19 with a significant difference between the CRP values of active girls versus girls with low habitual physical activity. The girls probably reported their physical activity more accu-rately than the boys because their physical activity correlated significantly with their bleep test scores, which measures actual fitness.27

The results for the boys, however, are difficult to explain because the boys in the inactive group had lower serum CRP

values than those in the most active group. A possible reason may be that most boys were relatively fit and active and that other factors were more important determinants of their serum CRP concentrations. Alternatively, the boys may not have report-ed their physical activity as accurately as the girls, or some of the boys may recently have become inactive. Another reason may have been the absence of organised physical activity in the town-ship, but that the boys participated in active play on an irregular basis and could keep fit in this way.

The boys’ group on the whole, however, (inactive plus active) showed trends as expected regarding physical activity and CRP levels. The fitness level of the boys, measured by number of laps completed in the bleep test, correlated negatively with body fat percentage and abdominal skin fold, as well as with serum CRP levels. If fitness is taken as a measure of habitual physical activity, this was an indication of an inverse association between physical activity and serum CRP levels in the boys.

As was expected, physical activity was higher in the boys than the girls.28 Studies have shown a negative correlation between physical activity and body fatness.1,2 It has been suggested that decreased physical activity or increasing inactivity is probably the main factor accounting for the reduction in total energy expenditure, leading to a positive energy balance and increased prevalence of obesity.1,2 Egger and Swinburn29 concluded that even incidental activity can increase energy expenditure, and intensity of activity also plays a role. Such incidental activity

TABLE 2. PEARSON PARTIAL CORRELATIONS FOR BOYS AND GIRLS ADJUSTED FOR AGE AND SMOKING

Parameters Boys n p Girls n p

BMI and log CRP 0.01 72* NS 0.21 112 0.04

Waist circumference and log CRP –0.03 69 NS 0.22 112 0.03

Triceps skin fold and log CRP 0.10 69 NS 0.15 112 NS

Sub-scapular skin fold and log CRP 0.16 69 NS 0.20 112 0.05

Supra-spinal skin fold and log CRP 0.12 69 NS 0.28 112 0.004

Abdominal skin fold and log CRP 0.13 66 NS 0.21 112 0.03

Body fat percentage and log CRP 0.16 53 NS 0.14 106 NS

Bleep test laps completed and log CRP –0.30 71 0.012 –0.15 109 NS

Bleep test laps completed and PDPAR score

0.06 112 NS 0.22 131 0.01

Bleep test laps completed and body fat percentage

–0.26 81 0.02 –0.33 128 < 0.0001

*Number of subjects differs due to missing data.

TABLE 3. DESCRIPTIVE STATISTICS FOR GIRLS WITH HIGH BODY FAT PERCENTAGE VERSUS GIRLS WITH

NORMAL BODY FAT PERCENTAGE

Body fat % > 25% (n = 35)

Body fat % > 25% (n = 101)

VariableMean/number

Standard deviation/%

Mean/number


Age (years) 15.43 1.24 15.55 1.41

Weight (kg)# 43.98 5.88 51.80 8.52

Height (cm) 155.6 0.04 155.0 6.67

BMI (kg/m2)# 18.12 2.11 21.53 3.09

Waist circumference (cm) 60.55 4.24 66.28 5.78

WHR 0.75 0.04 0.76 0.05

Triceps skin fold (mm)# 10.99 3.87 18.11 5.93

Sub-scapular skin fold (mm)# 9.00 2.95 13.99 5.51

Abdominal skin fold (mm)# 12.82 4.15 22.09 7.11

Fat %# 20.60 4.64 32.06 4.74

Muscle mass (kg) 33.57 5.16 34.66 5.28

Tanner stage 1* (14 years) 2 5.7% 0 0

Tanner stage 2* (14.4 ± 0.6, 13–15 years)

5 14.3% 5 4.9%


10 28.6% 46 45.5%


16 45.7% 43 42.6%


2 5.7% 7 6.9%

Median Interquartile

range MedianInterquartile

range

Serum CRP (mg/l) 0.30 0.15–0.91 0.34 0.20–1.23

Differentiated on account of fat percentage, girls with fat percentages > 25% were classified over-fat, according to Lohman.28

*Tanner stage based on breast/genital development stage (1 = no development, 5 = mature)21 with age, mean ± SD (range), #significant differences between groups. BMI: body mass index; CRP: serum C-reactive protein concentration; WC: waist circumference; TSF: triceps skin fold.


may have played a role in the relatively low number of boys with a body fat percentage above 20% in the study sample.

The CRP values of some of the children were above normal concentrations. On interpretation of CRP values, low risk is defined as a level less than 1 mg/l, average risk is 1.0–3.0 mg/l and high risk is values of 3–10 mg/l.18 In this study, when subjects with markedly increased CRP levels (> 10 mg/l) were excluded, a significant association was observed between physical activity and CRP levels in the girls and between fitness and CRP levels in the boys. The relevance of such findings in adolescents is useful because CRP level is proven to predict the development of type 2 diabetes and mortality.5,30 Future risk can therefore be assessed in adolescents.

Smoking is a well-known predictor of high serum CRP levels.19 Only 5.7% of the children admitted to smoking and among those who smoked, only one was a girl. Adjustment for smoking in the correlation analyses did not, however, make any difference to previously non-significant correlations. In this low-income setting, children could probably not afford to smoke regularly.

A larger number of girls in comparison with boys were clas-sified as over-fat. Only 15 out of a total of 85 boys had a fat percentage higher than the cut-off of 20%. Out of 134 girls, only 35 had a fat percentage equal to or below 25%, with 101 girls having fat percentages above this norm.31 According to Monyeki et al.,8 obesity is not only common in South African

women, but also in female adolescents. Adolescence is one of the most vulnerable periods for the development of overweight and obesity.2,3

The girls in our study live in a low socio-economic environ-ment, and it is possible that low physical activity and conse-quently a low fitness level played a role in the development of their high body fat percentages. Almost 50% of the girls were in Tanner stages 4 and 5 and 74% of the girls had a body fat percentage above 25%, compared to 71% of the boys in Tanner stages 4 and 5, but only 18% of them had a body fat percentage above 20%.

With regard to skin folds, the greatest difference between the group of boys with a body fat percentage above 20% and the group with a normal body fat percentage was for the abdominal skin fold. This indicates that fat accumulation in this group of boys was mainly in the abdominal area.

Tables 3 and 4 show the differences in body composition and fat distribution between the boys and girls. The girls had greater skin fold thicknesses than the boys, but smaller WHR, indicat-ing more abdominal fat distribution in the boys, compared to more peripheral fat distribution in the girls. This difference in body composition between the boys and girls is probably the main reason for the gender differences found in the associations between body composition and serum CRP levels. It is well-known that adolescent girls generally have a larger proportion of body mass as fat, and are more likely to deposit fat subcutane-ously and on their hips, whereas adolescent boys are more likely to have more muscle mass and they deposit fat in the abdominal region, as shown in Tables 4 and 5. Oestrogen levels appear to underlie many of these gender differences.32

The release of IL-6 from the visceral adipose tissue may induce low-grade systemic inflammation in subjects with increased body fat. This may explain the association between BMI and CRP levels.16,19 Although in this study there was no statistically significant difference between the serum CRP levels of children with a normal body fat percentage versus those with a high body fat percentage, serum CRP values correlated posi-

TABLE 4. DESCRIPTIVE STATISTICS FOR BOYS WITH HIGH BODY FAT PERCENTAGE VERSUS BOYS WITH

NORMAL BODY FAT PERCENTAGE

Body fat % > 20% (n = 70)

Body fat % > 20% (n = 15)

VariableMean/number


Mean/number


Age (years) 15.88 1.56 15.65 1.44

Weight (kg)# 47.96 8.55 53.80 14.46

Height (cm) 161.31 8.66 159.51 10.30

BMI (kg/m2)# 18.32 2.28 20.87 3.69

Waist circumference (cm) 65.11 4.94 69.60 7.12

WHR 0.84 0.06 0.83 0.04

Triceps skin fold (mm)# 7.74 2.60 14.14 6.28

Sub-scapular skin fold (mm)# 7.18 1.82 12.20 8.18

Abdominal skin fold (mm)# 9.50 4.33 21.32 11.01

Fat %# 16.16 4.21 29.62 4.23

Muscle mass (kg) 40.45 7.49 37.99 10.50

Tanner stage 1* (–) 0 0 0 0


6 8.6% 1 6.7%


14 20% 4 26.6%


44 62.8% 9 60%


6 8.6% 1 6.7%

MedianInterquartile

range MedianInterquartile

range

CRP (mg/l) 0.39 0.15–0.90 0.59 0.20–1.65

Differentiated on account of fat percentage, boys with fat percentages > 20% were classified over- fat, according to Lohman.28

*Tanner stage based on genital development stage (1 = no development, 5 = mature)21 with age, mean ± SD (range), #significant differences between groups.BMI: body mass index; CRP: serum C-reactive protein concentration; WC: waist circumference; TSF: triceps skin fold.

TABLE 5. DIFFERENCES BETWEEN ANTHROPOMETRIC VARIABLES AND CORRELATION BETWEEN PERCENTAGE

BODY FAT AND ANTHROPOMETRIC VARIABLES IN BOYS AND GIRLS WITH A HIGH BODY FAT PERCENTAGE VERSUS BOYS AND

GIRLS WITH A NORMAL BODY FAT PERCENTAGE

Correlation coefficient (level of significance) for the correlation between percentage body fat and skin-fold thickness

Boys Girls

Variable

Body fat % > 20% (n = 70)

Body fat % > 20%

(n = 15)

Body fat % > 20% (n = 35)

Body fat % > 20%

(n = 101)

Triceps skin fold (mm) 0.16 (NS)

0.63 (p = 0.001)

0.33 (NS)

0.63 (p = 0.001)

Sub-scapular (mm) –0.03 (NS)

0.67 (p < 0.0001)

0.25 (NS)

0.67 (p < 0.0001)

Abdominal (mm) 0.28 (p = 0.04)

0.68 (p < 0.0001)

0.37 (p = 0.05)

0.68 (p < 0.0001)

Percentage difference between groups of boys and girls

Boys with body fat % > 20% compared with boys with body fat %

> 20%

Girls with body fat % > 25% compared with girls with body fat %

> 25%

Body weight (kg) 12.13% 17.78%

Waist circumference (mm) 6.9% 9.5%

Percentage body fat 83.3% 55.6%


tively with BMI, waist circumference and truncal skin folds in the girls. Among the boys, no significant positive correlation was found, but there was a trend towards an association in the same direction. Using multiple regressions with both physical activity and body composition variables, waist circumference was posi-tively associated with serum CRP levels in the girls.

Also in line with previous reports, there was a trend towards an inverse correlation between fitness and percentage body fat in the boys in this study.1,28 Obesity and central body fat distribution are related to an adverse risk profile in the youth, and reports suggest that physical activity exerts a positive effect on risk factors for chronic disease. A higher degree of cardio-respiratory fitness has also been shown to relate to a healthier metabolic profile in children.10

Rapid urbanisation and westernisation are becoming the norm in South Africa and this may be causal to the notion that overweight in childhood could become a public health issue.8,9 Lobstein et al.2 and Simon et al.33 emphasised that children from socio-economically deprived environments in most westernised societies, such as the subjects of low socio-economic status in this study, have a greater risk of obesity than those from more affluent groups.

Findings in this study have broad implications, especially with regard to the link between body composition, cardiovascu-lar risk and the metabolic syndrome. Many obese children, and especially adolescents, tend to become obese or overweight as adults and it has been suggested that 33% of adult obesity starts in childhood.1,3 Obesity during childhood seems to increase the risk of subsequent morbidity, whether or not obesity persists into adulthood,1,34 with obese children being at an increased risk of metabolic and cardiovascular disorders later in life.3,5

Limitations of this study include the fact that the age range of children recruited from one high school class varied between 13 and 22 years. Learners older than 18 years were excluded from the analysis and the remaining children were therefore not all at the same stage of physical development, with resulting effects on their body composition. Not all recruited children gave consent for taking blood samples, so the sample size was relatively small when the groups of children were compared.

ConclusionThis study showed a statistically significant association between serum CRP levels and physical activity in the girls, and an inverse correlation between serum CRP levels and fitness in the boys. Waist circumference was a significant predictor of serum CRP levels in the girls. These associations indicate a link between body fat, physical activity and inflammation. Obesity should be discouraged in South African children by encouraging physical activity.

This work is based on research supported by the National Research Foundation (NRF) of South Africa. Any opinions, findings and conclusions or recommendations expressed in this article are those of the authors and the NRF does not accept any liability in regard thereto. The North-West University of Potchefstroom, South Africa, also provided financial support. The authors thank the children from the two township schools in Ikageng, South Africa, who participated in this study. We also acknowledge the contribution of the PLAY research team, particularly Prof Anita Pienaar for supervision of physical activity and fitness testing and Dollien Naudé for body composition measurements.

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8. Monyeki, KD, Van Lenthe FJ, Steyn NP. Obesity: does it occur in African children in a rural community in South Africa? Int J Epidemiol 1999; 28: 287–292.

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11. Monyeki KD, Kemper HC, Makgae PJ. Relationship between fat patterns, physical fitness and blood pressure of rural South African chil-dren: Ellisras Longitudinal Growth and Health Study. J Hum Hypertens 2008; 22(5): 311–9.

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13. Kruger HS, Pienaar AE, Naude D, Moss SJ. Improved insulin sensitiv-ity after a physical activity intervention in overfat township children. Abstract: 10th International Congress on Obesity, Sydney, Australia, 3–8 September 2006.

14. Pepys MB, Hirshfield GM. C-reactive protein: a critical update. J Clin Invest 2003; 111(12): 1805–1812.

15. Ballantyne CM, Nambi V. Markers of inflammation and their clinical significance. Atherosclerosis 2005; 6(Suppl): 21–29.

16. Wu D-M, Chu N-F, Shen M-H, Chang J-B. Plasma C-reactive protein levels and their relationship to anthropometric and lipid characteristics among children. J Clin Epidemiol 2003; 56: 94–100.

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Don't miss the CVJA Workshop on Scientific Writing at PASCAR 2011 on Thursday, 26 May 2011


Special Report

New anti-coagulant therapies set to revitalise clinical haemotology practiceAnnual meeting of the Southern African Society of Thrombosis and HaemostasisJ AALBERS, P WAGENAAR, ERIC KLUG


Clinical and laboratory-based haematologists are likely to experience more requests for advice and support from their colleagues in cardiology, orthopaedics and neurology as the impact of newly registered anti-coagulant therapies unfolds. This is because the new anti-thrombotic and anti-platelet agents will need to be understood on the basis of their individual attributes and not as inter-changeable drugs within their respective class. Also, usage of the new factor Xa inhibitors such as rivaroxaban, and direct thrombin inhibitors such as dabigatran, while not requiring monitoring for routine clinical practice, have differ-ent effects on standard coagulation tests which may require expert interpretation prior to surgery or percutaneous coronary interventions (PCI), or to assess compliance with medication or suspected over-dosing.

A practical approach to new anti-platelet agentsDr Eric Klug, Sunninghill Hospital, Johannesburg‘There is an association between bleeding events and long-term mortality; the occurrence of a major bleeding event is associated with a continued higher risk of death at one year’, Dr Eric Klug noted. The key risk factors associated with bleeding risk include impaired renal function, older age, female gender, preceding anaemia and heart failure.1 ‘This list of course also overlaps critically with the increased risk of ischaemic events’, Dr Klug pointed out.

The choice of antiplatelet agents has expanded from aspirin with its well-accepted role in primary and secondary prevention of cardiovascular and cerebrovascular events to include new agents such as clopidogrel, prasugrel and ticagrelor.

‘Concern has been expressed about prior aspirin use and outcomes in acute coronary syndromes (ACS). This was recently evaluated in data from 60 000 patients with ACS who partici-pated in myocardial infarction clinical trials.2 The increased mortality found in patients taking aspirin prior to presentation

with an ACS was related to the inherent higher risk of these patients rather than to any adverse effects of the aspirin’, Dr Klug advised. With regard to preventing post-stent thrombosis, dual anti-platelet therapy (DAPT) is the gold standard; aspirin is used together with a thienopyridine such as clopidogrel, prasugrel or ticagrelor.

‘These agents are very effective, but the problem with regard to cardiovascular events after the stenting procedure is related to withdrawal of dual anti-platelet therapy. In the largest study of drug-eluting stent-associated thrombosis,3 a higher incidence of stent thrombosis occurred following the discontinuation of both aspirin and clopidogrel (or other thienopyridine) within a short period, relating to the drug discontinuation’, Dr Klug said.

‘It is clear that we should always try to maintain aspirin therapy at least at 81 mg/day during and post stenting, and also where possible delay non-cardiac surgery for at least three months after the PCI. In the latter case, a risk remains, but the delay of surgery is beneficial’, Dr Klug added. He noted that a tapered withdrawal of the selected anti-platelet therapy to avoid the so-called rebound phenomenon is not required and the clopi-dogrel can be stopped abruptly.4

The anti-platelet action of clopidogrel is lessened in patients with homozygous genetic variations of the CYP2C 19 gene, which can be significant in high-risk patients. ‘This is also true for prasugrel as both are pro-drugs, requiring conversion via the cytochrome P450 enzyme. However, as cardiologists, we cannot wait for genetic studies; nor has it been shown that doing routine genetic testing improves clinical outcomes. It is for this reason that the FDA has taken the decision to warn clinicians about this possibility, but not mandate genetic testing’, Dr Klug said.

Evidence for the additional value of prasugrel compared to clopidogrel in achieving a greater reduction of stent thrombosis, cardiovascular death, myocardial infarction and stroke in patients with ACS undergoing PCI comes chiefly from the TRITON TIMI 38 trial.5 ‘The benefits of prasugrel over clopidogrel unfortunately occurred with an increased risk of major bleed-ing, including fatal bleeding’, Dr Klug pointed out. ‘Subsequent clinical use has helped define a group of patients who should not be given the more potent thienopyridine (prasugrel) as being those older than 75 years, or with a history of stroke/transient ischaemic attack (TIA), or with a low body weight, less than 60 kg.’ Prasugrel can however be used for NSTEMI patients and for STEMI patients treated with PCI.

Dr Klug presented insights on the newer oral anti-platelet agents such as ticagrelor, which is more effective than clopido-grel without the penalty of increased bleeding rates. Dyspnoea

J AALBERS, Special Assignment EditorP WAGENAAR, Johannesburg correspondentE KLUG, Sunninghill Hospital, Johannesburg

‘For all patients with stents undergoing surgery or other revascularisation procedures, do not stop the low-dose aspirin of 81 mg. If you have to, withdraw the thienopyridine and reintroduce as soon as possible’ – Dr Eric Klug


is however common, but seems to be self-limiting and results in less than 1% of patients discontinuing the drug. New reversible P2y(12) receptor inhibitors such as elinogrel and cangrelor are currently in clinical development trials.

‘Clearly, the “one size fits all” and “one mechanism fits all” usage of anti-platelet agents reflects limitations of current evidence and of our lack of understanding. This will change in the near future’, Dr Klug concluded.

Anti-coagulation in atrial fibrillationProf Lord Kakkar, London, UK‘Anti-coagulation to prevent thrombo-embolic stroke is vital, as about one-sixth of all strokes are due to pre-existing atrial fibrillation’, Prof Kakkar stressed at the outset of his presenta-tion. While his talk concentrated on the role of anti-coagulation to prevent thrombo-embolic stroke, Prof Kakkar noted that co-morbid conditions that heighten the potential risk of stroke in atrial fibrillation patients, such as hypertension, heart failure, arterial disease and diabetes, also require treatment with the increasingly effective therapies that are now available.

Warfarin became the standard of care from the early studies of vitamin K antagonists, which compared warfarin use to placebo and showed a 70% reduction in the frequency and morbidity of strokes. ‘Warfarin is also better than aspirin in preventing thrombo-embolic stroke; while full-dose warfarin, reaching INR targets of between 2 and 4, is better than low-dose warfarin’, Prof Kakkar noted. ‘Despite warfarin’s known benefits, if we look at the atrial fibrillation (AF) studies in some 11 000 patients in the USA from either clinical trials or registries, only 50 to 60% of patients are treated with this agent. So large numbers of patients who could derive benefit are not receiving medication to reduce their stroke risk.’

With regard to novel anti-coagulant drugs, a number are under development, and target different factors in the coagula-tion cascade, such as activated factor X or activated factor II (thrombin). As there are limited data from prospective phase III randomised clinical trials of these new agents, Kakkar concen-trated on available results of rivaroxaban and the evidence for dabigatran, an orally active direct inhibitor of thrombin.

The ROCKET study of rivaroxaban in atrial fibrillation has been presented at the American Heart Association meeting. It is a large study of 14 000 patients randomised to receive either warfarin to a target INR of 2.5 mg or rivaroxaban 20 mg once daily or 15 mg/day for patients with moderate renal impairment. It showed non-inferiority of rivaroxaban to warfarin in AF.

Apixaban, a second orally active Xa inhibitor is being stud-ied in the ARISTOTLE study in AF, with dosages of 5 mg bid apixaban versus warfarin. The results of the AVERROES study on patients with atrial fibrillation who are unsuitable for a vitamin K antagonist was announced at the European Society of Cardiology in September 2010. Apixaban was shown to be significantly better than aspirin in reducing the frequency of stroke or systemic embolic events in this study. ‘This is certainly interesting data as there was no significant increase in major bleeding complications with apixaban versus aspirin’, Prof

Kakkar pointed out. Recently an ACS trial with apixiban added to aspirin has been stopped early because of increased bleeding in the combination arm compared to aspirin alone.

Results of the RE-LY study of two doses of dabigatran (110 or 150 mg bid) compared to warfarin dosages aimed at an INR of 2.5 in at-risk atrial fibrillation patients have been published. ‘These results are quite striking, with the lower dose of dabi-gatran being equal to warfarin (1.53 event rate vs 1.69) in reduc-ing the rate of stroke and systemic embolic events. The 150-mg dabigatran dose BD not only achieved non-inferiority, but was superior to warfarin in reducing events. Both doses of dabigatran were associated with a lower incidence of haemorrhagic stroke than seen with warfarin. This is certainly the most striking of the positive results for dabigatran, as this is a most feared bleeding event’, Dr Kakkar stressed.

Importantly, dabigatran performed well throughout the two-and-a-half years of follow up across all INR ranges of warfarin treatment and regardless of whether patients were exposed previ-ously to vitamin K antagonists or were vitamin K naïve.

Rivaroxaban – the latest Einstein resultsProf Harry Buller, Amsterdam, NetherlandsThe results of several Einstein studies provide the clinician with some valuable insights into the utility of rivaroxaban as a treatment option for long-term anticoagulation. Prof Buller reviewed these findings and their implications at the Southern African Society of Thrombosis and Haemostasis conference on 31 October 2010.

In the initial treatment of venous thrombo-embolism (VTE), there are a number of treatment options, of which low-molecular-weight heparin is the most frequently used. However, vitamin K antagonists have been the only choice for extended treatment, i.e. three to six months or longer. The question of how long to continue treatment is now being reconsidered and there is a strong move in the USA and Canada towards continuing treat-ment indefinitely. ‘Our understanding of anticoagulation at the molecular level also means that the number of anticoagulants available to us has increased dramatically in recent years – and there are many more still in development’, said Prof Buller. He cautioned against viewing the new drugs by class, underscoring that each needed to be viewed individually.

Three Einstein studies recently evaluated rivaroxaban rela-tive to enoxaparin followed by a vitamin K antagonist, with a view to showing non-inferiority. The Einstein DVT (deep-vein thrombosis) and PE (pulmonary embolism) studies were 30-day observational studies that evaluated rivaroxaban (15 mg twice daily or 20 mg once daily). The Einstein Extension study looked at patients with combined DVT and PE.

The Einstein DVT study’s main efficacy measure was the prevention of recurrences, while safety was assessed in terms of major and clinically relevant non-major bleeding. The findings in respect of first symptomatic recurrence of VTE were 2.1% for rivaroxaban and 3% for enoxaparin plus warfarin. For recurrent DVT, they were 0.8% for rivaroxaban and 1.6% for enoxapa-rin plus warfarin. ‘There was therefore strong evidence that rivaroxaban – a single drug given in a fixed dose – is at least as good as the comparator’, continued Prof Buller. ‘When primary efficacy outcomes were evaluated by subgroup, there was also a tendency in favour of rivaroxaban, with variables such as gender,

‘Evidence-based medicine provides the structure; in the care of the individual patient clinical insight and judgement are always paramount’ – Dr Eric Klug


body weight and creatinine clearance making no difference to the drug’s efficacy.’

When it came to safety, the results were similar, suggesting that rivaroxaban is as safe as it is effective. Once again, the subgroup analysis showed no outliers. Findings in respect of key secondary outcomes were as follows: net clinical benefit – 2.9% for rivaroxaban vs 4.2% for enoxaparin plus warfarin; total mortality – 2.2 vs 2.9%; cardiovascular events – 0.7 vs 0.8% and liver complications – 0.1 vs 0.2%, respectively.

Summarising, Prof Buller concluded that the findings suggest that rivaroxaban offers a single-drug approach for both acute and long-term anticoagulation. It is non-inferior to enoxaparin plus warfarin in respect of efficacy and safety, works consistently across subgroups, and has no associated liver toxicity.

The Einstein Extension study evaluated rivaroxaban against placebo. Patients were treated for an average of 249 days. Symptomatic recurrent VTE occurred in 7.1% of patients on placebo vs 1.3% on rivaroxaban. The figures were 5.2% and 0.8%, respectively, for recurrent DVT. The principal safety outcome – recurrence of major bleeding – was of course, 0% for placebo but only 0.7% for rivaroxaban.

Clinically relevant non-major bleeding did occur, however, in 5.4% of those treated with rivaroxaban, versus 1.2% of those on placebo. This was a statistically significant finding. Prof Buller underscored, therefore, that it is important to bear in mind that rivaroxaban’s long-term efficacy advantage does come at a cost.

‘Rivaroxaban brings about an 82% relative risk reduction in the recurrence of VTE, he concluded, and it’s a simpler treatment option. What is important is the need to consider very carefully whether continued anticoagulation is indeed indicated.’

Clinical trials and bleeding – making sense of the resultsProf Sylvia Haas, Technical University, Munich, GermanyProf Haas spotlighted the many confounders that play a role in the widely varying rates of major bleeding seen in hip and knee arthroplasty trials. Among the factors that need to be considered are: definition of what constitutes major bleeding; timing of assessment of bleeding, whether pre or post surgery; timing of administration of anticoagulants including the comparator agent (enoxaparin), whether pre or early/late post surgery; dose and duration of anticoagulation; and the collection of bleeding data and adjudication of events. ‘And then there’s also the play of chance’, she added.

There are therefore uncertainties and imponderabilities when comparing bleeding rates across trials. When one looks at the phase III trials of hip and knee replacements, one sees varying definitions between trials and hence variance in the bleeding rates from trial to trial. The bleeding rates in RE-NOVATE 1 and 2 (which evaluated dabigatran versus enoxaparin in total hip replacement) differed because the comparator bleeding results with enoxaparin at the same dose in each trial was different. The adjudication of venograms may be different between trials as well, and are only standardised within a particular trial; therefore across-trial comparisons are often not helpful or accurate.

She underscored that it was therefore important to only compare what can be directly compared. A study by Huisman et al. (submitted for publication) pooled the dabigatran trials, excluding RENOVATE 2, and proved non-inferiority of dabi-

gatran’s efficacy relative to that of enoxaparin, in respect of the primary endpoints of symptomatic VTE and all-cause mortal-ity. Similarly, in a pooled study of the RECORD trials, without RECORD 2, that evaluated rivaroxiban relative to enoxaparin with the same endpoints, it showed the clear-cut superiority of rivaroxaban.

‘One RECORD trial on its own met the primary endpoint criteria of superiority, but with the added value of the other two trials, there was a highly significant result in favour of rivar-oxaban’, Prof Haas said. She warned that meta-analyses don’t necessarily provide proof but are primarily hypothesis generat-ing, as those undertaking them usually don’t have access to the source data.

Prof Haas and her team did, however, have access to the source data when they undertook a pooled analysis of RECORD 1–4 (submitted for publication). ‘The authors have been able to include almost all (98%) patient data’, she said. ‘The efficacy results were highly statistically significant for rivaroxaban versus enoxaparin. While the combined results initially disfavoured rivaroxaban, when it came to major bleeding, the differences disappeared when we looked at only the period when all patients were on active study medication. There was also no statistical difference in bleeding rates using this approach, regardless of whether we applied the ISTH or EMEA definitions of major bleeding’, she added.

Concluding, she gave the following take-home messages:• Objective assessment of bleeding in patients undergoing

surgery is a challenge, as there are just too many factors influ-encing the rates of major bleeding.

• Meta-analyses are helpful for hypothesis generation, but much less so for providing confirmed results.

• The increasing number of meta-analyses does not help solve the problem.

• Well-designed non-interventional studies could be more important to assess bleeding rates in the real world.

Monitoring of direct coagulation inhibitors – the way forward?Prof Sylvia Haas, Technical University, Munich, Germany Addressing what users of these new agents need to know in the clinical setting, Prof Haas pointed out that indirect factor Xa inhibitors such as fondaparinux interact with free factor Xa and do not alter prothrombin time (PT) measurements and interpreta-tion thereof. However, the direct factor Xa inhibitors rivaroxaban and apixaban directly interact with the factor Xa molecule and the prothrombinase complex, thereby influencing prothrombin time and related measurements. ‘They interfere with INR reli-ability and if you do this test and get INR values of between 2 and 4, you could think that the patient is fully anti-coagulated, but this is not necessarily so’, she pointed out.

For rivaroxaban, PT is the most sensitive anti-coagulation test as there is a concentration-dependent prolongation, but interpre-tation depends on the specific reagents being used. Applying a standard calibration curve to the PT test results allows for corre-lation with the plasma concentrations of rivaroxaban.6

Dabigatran, the direct thrombin inhibitor weakly influences PT and strongly affects the partial thromboplastin time (PTT), while only weakly affecting the INR measurement and interpre-tation. ‘A new test, hemoclot, which is a diluted thrombin test,


offers promise in assessing dabigatran anti-coagulation, but is not yet available on the market.

‘The discussion is, however, ongoing with regard to the most useful tests and we are encouraging manufacturers to develop appropriate safety tests for their therapies’, Prof Haas stressed. Currently the chromagenic assays will give the most accurate reflection of rivaroxaban or dabigatran levels and anti-coagulant status’, Prof Haas pointed out.7 At a pragmatic level, a pocket card with the t-max and t-half-life of these agents can be useful to assess the coagulation state if the time and dose of last medi-cation is known.

D-dimers – how do we use this test clinically?Prof Harry Buller, Amsterdam, NetherlandsIt is essential to assess the clinical probability of either deep- vein thrombosis or pulmonary embolism in an individual patient before initiating and interpreting a D-dimer test, Prof Buller advised. ‘The D-dimer is a valuable test to identify fibrin-derived products. Although the ELISA version is highly sensitive, clinical urgency does not often allow time for this test. Instead, latex-based tests are used; they are sensitive and rapid, but have a lower specificity.’

In an evaluation of published trials that determined the preva-lence of DVT using clinical prediction rules for the diagnosis of DVT, Wells and colleagues8 determined the likelihood ratios of DVT in low, moderate and high clinical probability-assessed groups. ‘Patients with a low clinical probability of DVT, using the Wells predictive rule, and a subsequent negative D-dimer test can be excluded from ultrasound evaluation’, Prof Buller noted. ‘Patients in the moderate-risk category with a raised D-dimer value should undergo compression ultrasound for confirmation of DVT. In high-risk VTE patients, one should rather ignore the need to do the D-dimer test and go directly to compression ultrasound’, Prof Buller advised.

A useful diagnostic management protocol to determine the probability of pulmonary embolism has been developed and prospectively tested by the so-called Christopher study group.9 Prof Buller commented; ‘this option is attractive in that 30% of patients with clinically suspected pulmonary embolism can be excluded by using the clinical probability score in combination with a normal D-dimer test result. In all other patients, computed tomography (CT) scans effectively rule out pulmonary embo-lism without using other imaging tests. In fact, there was only a 1.3% incidence of VTE in the subsequent three months in patients with a negative CT scan.’

In conclusion, Prof Buller referred to new data indicating that the cut-off values for D-dimer tests may well be higher in the elderly, and a prospective study is currently underway to determine normal values in this patient population. With regard to using D-dimer tests to determine optional length of anti-coagulation therapy, Prof Buller noted that the normal D-dimer test has little value in this situation, as the sensitivity is very low

(43%). ‘We would harm the majority of patients if we used this parameter and stopped anti-coagulation therapy too early’, he added. In cancer patients, D-dimer tests can be predictive and prognostic to some extent, but this is still at a research stage.

Thrombolytics in stroke patientsDr Jody Pearl, Sunninghill Hospital, JohannesburgFacing a lack of therapeutic innovation in the treatment of stroke, Dr Pearl referred to the successful stroke intervention protocol set up at the Vergelegen Medi-Clinic, Somerset West. This unit provides a 24-hour intervention service similar to the acute stroke units in London, which have successfully intervened to significantly drop the mortality from stroke. The concept is that ‘time is brain’ and the patient needs to get to the appropriate centre quickly, where neurologists and interventional radi-ologists or cardiologists are on call and available to provide a 24-hour support service. Fibrinolytic therapy and/or percutane-ous thrombosis aspiration devices are the current options avail-able, depending on the patient characteristics. This approach should be adopted more widely in South Africa.

Minimally invasive surgery for carotid disease – where are we?Prof Talib Abdul Carrim, University of Kwazulu-Natal, DurbanWhile the debate continues as to whether carotid artery stenting (CAS) or carotid endarterectomy (CAE) is the preferred strategy for carotid disease, two issues remain: (1) what are the indica-tions in 2010 for each procedure; and (2) is treating asympto-matic patients with significant stenoses – CAS – unethical as the procedure itself may be associated with a 6.9% increased risk. Prof Carrim indicated that some clarity was emerging as to which procedure best suits which patient and when one should submit a patient.

After the CREST study,10 which showed no difference in over-all short- and long-term outcomes of these two techniques, new analyses are beginning to identify appropriate patient selection. In CREST, it was shown that outcomes with CAS were better than CEA for patients less than 70 years of age. In two recent meta-analyses,11,12 CEA was shown to be better than CAS; but both reviews acknowledge that the treatment strategy chosen should best meet the individual patient’s risk.

‘At this juncture we can conclude that CAS is not indicated in the elderly, in those with disease situated in difficult-to-reach sites of the carotid artery, and those with echolucent plaques that are more liable to rupture.

continued on p. 337…

Summary of CAS and CEA characteristics

CAS •increased peri-operative stroke incidence

•higher restenosis rates

•poor outcomes in those older than 70 years

•higher death rates in the elderly and in high-risk sites (difficult to reach and echolucent plague)

•longer term outcome equal to CEA

CEA •remains the gold standard

•periprocedural MI and cranial nerve injury higher than in CAS

•better for patients with unstable plaque

Monitoring of direct coagulation inhibitors

•There is no need for routine monitoring, as a standard dose of the new anti-coagulants is used.

•New anti-coagulant agents affect conventional clotting tests.

•Do not routinely measure PTT/PT when using these agents.

•Use the specific tests, as advocated by the manufacturers, for suspected over- or under-dosing.


Mitral valve prolapse and conduction disturbances: the forgotten associationA D’ALOIA, E VIZZARDI, E ANTONIOLI, E ChIARI, A CURNIS, L DEI CAS

summaryVarious cardiac arrhythmias and conduction defects have been described in patients with mitral valve prolapse. We describe a case of a young woman affected by a mitral valve prolapse, involving the posterior mitral leaflet, with mild mitral regurgitation and an episode of syncope due to asys-tolia. It is hoped that this short communication will once again focus attention on the as yet unexplained association between mitral valve prolapse and various cardiac conduc-tion disorders.



Various cardiac arrhythmias and conduction defects have been described in patients with mitral valve prolapse (MVP).1-4 These include: sino-atrial and atrio-ventricular (AV) node dysfunction,

prolongation of the QT interval, cases of refractory ventricular tachycardia and fibrillation, and dysautonomia.5-9 In sympto-matic patients with mitral valve prolapse, infranodal conduction abnormalities as well as dual AV nodal pathways have been documented in electrophysiological studies.10

This is a case report of a 23-year-old woman who presented to our Department of Cardiology with an episode of syncope. Clinical examination revealed a grade II systolic murmur and the electrocardiogram showed a first-degree atrio-ventricular block (Fig. 1). Echocardiography demonstrated mitral valve prolapse involving the posterior leaflet, with mild mitral regurgitation (Figs 2, 3).

Further diagnostic tests, including a chest X-ray, thyroid function tests and coronary angiography were all within normal limits. Telemetric electrocardiography revealed multiple episodes of asystole, the longest of which lasted for four seconds (Fig. 4). Following this, a permanent cardiac pacemaker was inserted.

Tachyarrhythmias have been shown to represent the most frequent and potentially dangerous clinical manifestation of MVP and there is an association between mitral valve prolapse and sudden cardiac death.11-13

Atrio-ventricular conduction disturbances occur in mitral valve prolapse but the true mechanism(s) of arrhythmia is still unclear. In some patients with mitral valve prolapse, electro-

Case report

department of Cardiology, university of Brescia, italyANTONIO D’ALOIA, MDENRICO VIZZARDI, MD, [email protected] ANTONIOLI, MDERMANNA ChIARI, MDANTONIO CURNIS, MDLIVIO DEI CAS, MD

Fig. 1. ECg showing first-degree atrio-ventricular block.


physiological studies have demonstrated prolonged atrio-hisian intervals and/or abnormal responses to atrial pacing. In addition, a significant proportion of these patients had abnormalities of both sinus and atrio-ventricular node function, as well as distal His-Purkinje conduction abnormalities.

Atrio-ventricular block of all three degrees are well docu-mented in mitral valve prolapse,2,14,15 and in some patients, it has been shown that atropine administration led to normalisa-tion of atrio-ventricular conduction. This has led to speculation that in patients with mitral valve prolapse, an increased vagal tone is responsible for many of the conduction abnormalities.15 However, non-vagal causes are also possible and include the following: atrio-ventricular node developmental anomalies (as part of the floppy mitral valve) and/or compression of the atrio-ventricular nodal artery by the prolapsing leaflet, as the artery courses along the border of the mitral annulus.16

The prevalence of AV conduction disturbances among patients with mitral valve prolapse is probably higher than expected. It is hoped that this short communication will focus attention on the

as yet unexplained association between mitral valve prolapse and various cardiac conduction disorders.

References1. Swartz MG, Teicholz LE, Domosso E. Mitral valve prolapse: a review of

associated arrhythmias. Am J Cardiol 1977; 62: 377–389.2. Greenspon AJ, Schaal SF. AV node dysfunction in the mitral valve

prolapse syndrome. PACE 1980; 3: 600–604.3. Schaal SF, Fontana ME, Wooley CF. Mitral valve prolapse syndrome

– spectrum of conduction defects and arrhythmias. Circulation 1974; 97(suppl III): 49–50.

4. De Maria AN, Amsterdam EA, Vismara LA, Neumann A, Mason DT. Arrhythmias in the mitral valve prolapse syndrome. Ann Intern Med 1976; 84: 656–660.

5. Coghlan HC, Phares P, Cowley M, Copley D, James TN. Dysautonomia in the mitral valve prolapse. Am J Med 1979; 67: 236–-244.

6. De Silva RA, Shubrook SJ. Mitral valve prolapse with atrioventricular and sinoatrial node abnormalities of long duration. Am Heart J 1977; 93: 772–775.

7. Pocock WA, Barlow JB. Etiology and electrocardiographic features of the billowing posterior mitral leaflet syndrome. Am J Med 1971; 51:

Fig. 2. Echocardiography showing mitral valve prolapse involving the posterior leaflet, with mild mitral regurgita-tion.

Fig. 3. Echocardiography showing mitral valve prolapse involving the posterior leaflet, with mild mitral regurgita-tion.

Fig. 4. telemetric ECg showing multiple episodes of asystole.


731–739.8. Bekheit SG, Ali AA, Deglin SM, Jain AC. Analysis of QT interval in

patients with idiopathic mitral valve prolapse. Chest 1982; 81; 620–625.9. Ritchie JL, Hammermeister KE, Kennedy JW. Refractory ventricular

tachicardia and fibrillation in a patient with the prolapsing mitral leaflet syndrome: successful control with overdrive pacing. Am J Cardiol 1976; 37: 314–316.

10. Ware JA, Magro S, Luck J, Mann DE, Nielsen AP, Rosen KM, Wyndham CR. Conduction system abnormalities in symptomatic mitral valve prolapse: an electrophysiologic analysis of 60 patients. Am J Cardiol 1984; 53: 1075–1078.

11. Hancock EW, Cohn K. The syndrome associated with midsystolic click and later systolic murmur. Am J Med 1996; 41: 183–188.

12. Shappel SD, Marshall CE, Brown RE, Bruce TA. Sudden death and the familial occurrence of midsystolic click, late systolic murmur syndrome. Circulation 1973; 48: 1128–1134.

13. Jeresaty RM. The syndrome associated with midsystolic click and/or late systolic murmur syndrome. Chest 1971; 59: 643–645.

14. Levy S, Blanc A, Clementy J, Dallocchio M, Bricaud H. Mitral valve prolapse: do rhythm disorders have an electrophysiologic substratum? Arch Mal Coeur Vaiss 1982; 75(6): 671–676.

15. Chandraratna PAN, Ribas-Meneclier C, Littman BB and Samet P. Conduction disturbances in patients with mitral valve prolapse. J Electrocardiol 1977; 10: 233–239.

16. McAlpine WA. Coronary arteries and arrhythmias. In: Heart and Coronary Arteries. Berlin Berlin: Springer Verlag, 1975.

Post-infarction ventricular septal defect: triggered by valsalva manoeuvre?M BASKURT, N TURHAN, A HATEMİ, M CANİKOGLU, B KARADAG, S KUCUKOGLU

summaryPost-infarction ventricular septal defect (VSD) is a fatal mechanical complication of myocardial infarction. Although the incidence has decreased to less than 1% after the exten-sive use of reperfusion strategies, post-infarction VSD still carries a high mortality risk. Management is controversial, whether to wait for surgery after a stabilisation period or to perform emergency surgery when diagnosed. We report on a case of post-infarction VSD that was detected with severe haemodynamic instability, beginning immediately after the patient’s Valsalva manoeuvre on the sixth day of a non-reper-fused inferior myocardial infarction. In the early period, the post-infarction VSD was repaired via a trans-aneurysmal approach.

Keywords: ventricular septal defect, post myocardial infarction complications



CVJ-21.009

The incidence of post-infarction ventricular septal defect (VSD) was 1–3% in the pre-thrombolytic era, but it has declined to near-ly 0.2% in the era of thrombolysis.1 The average time interval for a post-infarction VSD to occur is at five to six days if thrombo-lytic therapy is not used, and one day with thrombolytic adminis-tration.2 In-hospital mortality is still more than 90% with medical therapy and between 19 and 60% with a surgical approach.3 VSD complicating an inferior myocardial infarction (MI) has a poorer prognosis than a VSD complicating an anterior MI.4

We report on a case of post-infarction VSD in a patient who did not receive thrombolytic therapy because of late presentation. On the sixth day of the inferior MI, after a period of Valsalva manoeuvre, she developed sudden haemodynamic deterioration and symptoms and signs of acute heart failure. After the diagno-sis of post-infarction VSD, we performed emergency surgery and repaired the defect by teflon strip with pladgeted prolene sutures via a trans-aneurysmal approach.

Case reportA 62-year-old female patient was admitted to our hospital with typical enduring chest pain that had started two days earlier. Her

department of Cardiology, institute of Cardiology, istanbul university, haseki, istanbulMURAT BASKURT, MD, [email protected]İHAN TURHAN, MDSERDAR KUCUKOGLU, MD

department of Cardiovascular surgery, institute of Cardiology, istanbul university, haseki, istanbul ALİCAN HATEMİ, MDMUSTAFA CANİKOGLU, MD

department of Cardiology, Cerrahpasa school of Medicine, istanbul university, Cerrahpasa, istanbulBİLGEHAN KARADAG, MD

Case report


past medical history was normal and she was a non-smoker. Her physical examination was normal. Surface electrocardiogram showed 2-mm ST elevation in leads D2, D3 and aVF with patho-logical Q waves and negative T waves, suggesting a sub-acute phase of inferior MI. Her biochemical markers of MI were higher than the upper limits of normal.

She was admitted to the coronary care unit with a diagnosis of sub-acute inferior MI and started on isosorbite mononitrate 60 mg/day (p.o.), metoprolol succinate 100 mg/day (p.o.), acetyl-salicylic acid 300 mg/day (p.o.), clopidogrel 75 mg/day (p.o.) and enoxaparine 1 mg/kg, bid, (s.c.). Transthoracic echocardi-ography was performed in the first hour after admission to the coronary care unit on day one and showed akinesia in the basal septum and mid-basal inferior wall, with a calculated ejection fraction of 45%.

The patient was transferred to a room after an uncomplicated course of 36 hours. On the second day, at 08:00 her medical exam-ination was normal. One hour later, after using the toilet and after several attempts at Valsalva manoeuvres, she felt sudden chest pain, dyspnoea and nausea. Her heart rate was 110/minute, blood pressure was 80/60 mmHg, and a new systolic murmur was recorded at the left sternal border with thrill and bilateral rales at the basal level of both lungs. Her surface electrocardiogram was unchanged. She was immediately transferred to the coronary care unit. This was the fourth day after admission to hospital.

A second transthoracic echocardiography was performed and revealed a left ventricular infero-basal aneurysm, infero-mid and infero-septal akinesia and a ventricular septal defect in the basal mid-interventricular septum, creating a peak 80-mmHg gradient and mild pericardial effusion (Fig. 1a–d). Intravenous saline was

Fig. 2. a. right ventricle inferior wall showing aneurysmal dilatation. B. ventricular septal defect visualised by the surgeon’s finger from the aneurysmotomy through the left ventriculotomy. C. ventricular septal defect fixed by teflon felt sutures from the left ventriculotomy to the aneurysmotomy (right ventricle wall).

a B C

Fig. 1. the echocardiography and coronary angiogram of the patient. a. in this sub-costal view, the ventricular septal defect is clearly seen in the mid-portion of the interventricular septum (arrow). B. in the same view as a, the defect was measured as 0.8 cm at the largest diameter (arrow). C. in the same view as a, colour doppler reveals turbulent flow from the left to the right ventricle (arrow). d. in the same view as a, on continuous wave doppler there was a peak 80-mmhg gradient across the defect. E. the coronary angiogram of the patient demonstrates a totally occluded dominant right coronary artery (this view was taken from left anterior oblique 30° and cranial 0°). F. in this view, the discrete 60% narrowing of the left anterior descending artery is seen (cranial 30°, left anterior oblique 0°). lv: left ventricle; la: left atrium; rv: right ventricle; ra: right atrium; vsd: ventricular septal defect.

a B C

d E F


started and after stabilising her haemodynamic status, a coronary angiogram was performed the following day. It showed total occlusion in the mid segment of a dominant right coronary artery and a discrete 60% narrowing in the mid-portion of the left ante-rior descending artery (Fig. 1e, f). She had recurrent hypotension and dyspnoea after catheterisation, and an intra-aortic balloon pump (IABP) was inserted. Early surgical repair was planned.

The patient underwent an operation two days after success-ful IABP insertion in the coronary care unit. The operation was performed with aorto-bicaval cannulation under extra-corporeal circulation (ECC). The heart was arrested by anterograde and retrograde blood cardioplegia. Exploration of the ventricular septum showed an inferior aneurysm in the right ventricular side approach (Fig. 2). Inspection showed no other aneurysm forma-tion, necrosis or ischaemic region.

The ventricular septal defect that was near the apex of the septum was closed with the trans-aneurysmal approach. It was infixed to the left ventricular free wall to be repaired by teflon strip with pladgeted prolene sutures. The aneurysmotomy was closed in a buttress of strips of teflon felt and sutured with pladgeted prolene sutures (Fig. 2). After a right coronary artery bypass with a saphenous vein graft, anostomosis of the left internal mammary artery to the left anterior descending artery was performed.

There was no difficulty weaning the patient from the ECC with 2:1 IABP assistance in sinus rhythm. The postoperative course was uncomplicated. Early transthoracic echocardiography revealed no shunt. The patient was weaned from the IABP on the first postoperative day and inotropic drugs were reduced on the third postoperative day with stable haemodynamic parameters.

discussionPost-infarction VSD was first shown by Latham in an autopsy in 1845, and clinical diagnostic criteria were first introduced by Sager in 1934.5 Reported studies defined risk factors for devel-oping post-infarction VSD to be advanced age, female gender, hypertension, non-smoker, higher Killip score at admission, no known coronary heart disease and first MI.6,7

Post-infarction VSD is usually located in the anterior or apical portion of the ventricular septum (about 60% of cases) as a result of an anterior MI. Twenty to 40% of patients have a defect in the posterior portion of the ventricular septum as a result of an inferior MI.2 However, unexpected locations for ruptures also appear in the literature.1 VSD is usually associated with complete obstruction of a coronary artery.6

Symptoms are mostly chest pain, dyspnoea, and symptoms due to low output and cardiogenic shock.2 Almost all patients have a new harsh, loud, pansystolic murmur located at the left sternal border, spreading to the apex. A thrill usually accompa-nies this. Doppler echocardiography has 100% sensitivity and specificity for diagnosis.1 Transoesophageal echocardiography and right heart catheterisation are further techniques when transthoracic echocardiography is inconclusive but with a high clinical suspicion.1

In patients who do not receive thrombolytic therapy, coagu-lation necrosis begins within three to five days of infarction. Neutrophils penetrate into the necrotic zone. By triggering apop-tosis, released lytic enzymes cause the necrotic myocardium to rupture.1 With the rupture of the septum, a shunt from the left to the right ventricle occurs, which increases volume load of the

right ventricle and also pulmonary blood flow, left atrial and left ventricular volumes. The magnitude of VSD, pulmonary–systemic vascular resistance, Qp/Qs ratio and left–right ventricu-lar functions determine the amount of shunt.1 If left ventricular systolic functions deteriorate, forward flow would decrease and compensatory vasoconstriction would raise systemic vascular resistance, leading to increased shunt flow.

Although the exact mechanism of rupture was not known, we presume that on the sixth day post MI, after our patient performed several forceful Valsalva manoeuvres, the thinned, necrotic septum was affected by the sudden volume and pres-sure changes created by the Valsalva manoeuvres. This may have caused the septum to rupture.

It has been shown that an approximately 20-mmHg fall in the systemic blood pressure occurs during early phase 2, which is followed by an abrupt rise in phase 4 of the Valsalva manoeuvre (about 43 mmHg) in a patient who is sitting and performing it.8 An overshoot of arteriolar vasoconstriction during late phase 2 and a 42% transient increase of the cardiac output above resting state are believed to be the reason for the blood pressure rise during phase 4.9 ACC/AHA practice guidelines recommend daily stool softeners in the hospital management of ST-elevation MI and our opinion is that this recommendation should be closely followed.10

Previously reported studies have shown that mortality is higher with: early VSD with surgery in the first 24 hours, inferior MI, the need for inotropic agents, cardiogenic shock, low mean pulmonary arterial pressure (PAP) and pulmonary capillary wedge pressure (PCWP), low cardiac index (CI < 1.75 ml/min/m2), serious right ventricular dysfunction and low systolic blood pressure.4,11 If the right ventricle can handle the volume overload, the mean PAP and PCWP increases, as well as the survival rate.11

The first repair by Cooley et al. in 1957, a case of acquired ventricular septal defect, was accomplished using an approach through the right ventricle with incision of the right ventricular outflow tract.12 This approach, which was adapted from surgical techniques for closure of congenital ventricular septal defects, proved to be disadvantageous for many reasons. Subsequently, Heimbecker et al. introduced and others adopted a left-sided approach (left ventriculotomy) with incision through the area of infarction. Such an approach frequently incorporates infarc-tectomy and aneurysmectomy, together with repair of the septal rupture.12

Our choice was to attach the apical-septal VSD to the left ventricular free wall and repair with teflon strips and pladgeted prolene sutures. The aneurysmotomy was closed and buttressed with strips of teflon felt and sutured with pladgeted prolene sutures after RCA bypass with a saphenous vein. The left internal mammary artery to the left anterior descending anastomosis was performed at the last stage.

It was recently reported that a small or medium-sized post-infarction VSD could be treated successfully with a ventricular septal occluder. This intervention may be permanent or it may stabilise the patient and allow myocardial fibrosis, thus facilitat-ing delayed subsequent surgical correction.13

ConclusionPost-infarction VSD is a serious mechanical complication of MI. Close monitoring of the non-reperfused patients is mandatory and a forceful Valsalva manoeuvre may facilitate the rupture of


the myocardium, causing post-infarction VSD. Repair of post-infarction VSD can be accomplished with a trans-aneurysmal approach. The potential advantage of this technique is that an incision in the intact left ventricular myocardium is avoided.

References1. Anderson DR, Adams S, Bhat A, Pepper JR. Post-infarction ventricular

septal defect: The importance of site of infarction and cardiogenic shock on outcome. Eur J Cardiothorac Surg 1989; 3: 554–557.

2. Mishra A, Sanghi P, Batra R. Post-infarction ventricular septal defect – a case report. Kardiologia Polska 2008; 66: 551–554.

3. Radford MJ, Johnson RA, Daggett WM Jr, Fallon JT, Buckley MJ, Gold HK, Leinbach RC. Ventricular septal rupture: a review of clinical and physiologic features and an analysis of survival. Circulation 1981; 64: 545–553.

4. Crenshaw BS, Granger CB, Birnbaum Y, Pieper KS, Morris DC, Kleiman NS, et al. Risk factors, angiographic patterns, and outcomes in patients with ventricular septal defect complicating acute myocardial infarction. GUSTO-I (Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries) trial investigators. Circulation 2000; 101: 27–32.

5. Jeppsson A, Liden H, Johnsson P, Hartford M, Rådegran K. Surgical repair of post infarction ventricular septal defects: A national experience. Eur J Cardiothorac Surg 2005; 27: 216–221.

6. Birnbaum Y, Fishbein MC, Blanche C, Siegel RJ. Ventricular septal rupture after acute myocardial infarction. New Eng J Med 2002; 347:

1426–1432.7. Moore CA, Nygaard TW, Kaiser DL, Cooper AA, Gibson RS.

Postinfarction ventricular septal rupture: The importance of location of infarction and right ventricular function in determining survival. Circulation 1986; 74: 45–55.

8. Singer W, OpferGgehrking TL, Mcphee BR, Hilz MJ, Low PA. Influence of posture on the Valsalva manouevre. Clinical Sci 2001; 100: 433–440.

9. Brooker JZ, Alderman EL, Harrison DC. Alterations in left ventricular volumes induced by Valsalva manouevre. Br Heart J 1974; 36: 713–718.

10. Antman EM, Anbe DT, Armstrong PW, Bates ER, Green LA, Hand M, et al. American College of Cardiology; American Heart Association Task Force on Practice Guidelines; Canadian Cardiovascular Society. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines for the Management of Patients with Acute Myocardial Infarction). Circulation 2004; 110: e82–292.

11. Murday A. Optimal management of acute ventricular septal rupture. Heart 2003; 89: 1462–1466.

12. Agnihotri AK, Madsen JC, Daggett WM (jun). Surgical treatment of complications of acute myocardial infarction: postinfarction ventricular septal defect and free wall rupture. In: Cohn LH, Edmunds LH (jun), eds. Cardiac Surgery in the Adult. New York: McGraw-Hill, 2003: 681–714.

13. Maltais S, Ibrahim R, Basmadjian AJ, Carrier M, Bouchard D, Cartier R, et al. Postinfarction ventricular septal defects: towards a new treatment algorithm? Ann Thorac Surg 2009; 87: 687–692.

IntroducIng rEVAtIo® A wEll EstAblIshEd PdE-5 InhIbItor rEgIstErEd for usE In PulmonAry ArtErIAl hyPErtEnsIon (PAh)REVATIO® helping your patients to do more...• Significantly improves exercise capacity (p<0.001) (1)

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...without holding them back• Convenient oral dosing: 20 mg tds with or without meals• Adverse events are generally transient and mild to moderate (1,3)

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References: 1. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, et al. Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2005;353(20):2148-2157. 2. Pepke-Zaba J, Gilbert C, Collings L, Brown MCJ. Sildenafil Improves Health-Related Quality of Life in Patients With Pulmonary Arterial Hypertension. Chest 2008;133:183-189. 3. Croom KF, Curran MP. Sildenafil. A Review of its Use in Pulmonary Arterial Hypertension. Drugs 2008;68(3):338-397.

S4 REVATIO® Film-coated tablets (Reg. No. A40/7.1.5/0131). COMPOSITION: Each tablet contains 20 mg of sildenafil, as the citrate. PHARMACOLOGICAL CLASSIFICATION: A 7.1.5 Vasodilators – peripheral. INDICATIONS: Treatment of pulmonary arterial hypertension. REVATIO has been shown to improve exercise ability and to reduce mean pulmonary arterial pressure. CONTRA-INDICATIONS: Known hypersensitivity to any component of the tablet. Patients concurrently using nitric oxide donors or organic nitrates in any form. Concomitant use with ritonavir, erythromycin, saquinavir, ketoconazole and itraconazole. Severe hepatic or renal function. Pregnancy and Lactation. WARNINGS: No controlled clinical data in MI, stroke, or life-threatening arrhythmia within the last 6 months; resting hypotension (BP <90/50) or hypertension (BP >170/110); cardiac failure or CAD causing unstable angina and retinitis pigmentosa. Physicians should carefully consider whether patients with underlying CVD could be affected adversely by transient decreases in supine BP, especially in combination with sexual activity. Serious events, including MI, sudden cardiac death, ventricular dysrhythmia, cerebrovascular haemorrhage, transient ischaemic attack, and hypertension have been reported. Most patients had pre-existing CV risk factors. Use with caution in patients with anatomical deformation of the penis, or conditions which may predispose to priapism. Patients taking alpha-blocker therapy may lead to symptomatic hypotension. Administer with caution to patients with bleeding disorders or active peptic ulceration. Decreased vision or loss of vision, has been reported. Exercise caution before driving, operating hazardous machinery or performing hazardous tasks. DOSAGE AND DIRECTIONS FOR USE: 20 mg three times a day approximately 6 to 8 hours apart with or without food. Dose adjustments may be required when co-administered with bosentan or other CYP3A4 inducers. SIDE-EFFECTS AND SPECIAL PRECAUTIONS: Most commonly reported side-effects included headache, flushing, dyspepsia, back pain, diarrhoea and limb pain. Other common side-effects include cellulitis, influenza, sinusitis, anaemia, fluid retention, insomnia, anxiety, migraine, tremor, paraesthesia, burning sensation, hypoaesthesia, visual acuity reduced, retinal haemorrhage, visual disturbance, photophobia, diploplia, chromatopsia, cyanopsia, abnormal sensation in eye, eye irritation, vertigo, bronchitis, epistaxis, rhinitis, cough, gastritis, gastroenteritis, gastro-oesophageal reflux disease, haemorrhoids, abdominal distension, alopecia, erythema, myalgia, gynaecomastia, pyrexia and weight increase. A sudden unilateral or bilateral decrease or loss of hearing (sensorinearal deafness) with or without associated vestibular symptoms has been reported. LICENCE HOLDER: Pfizer Laboratories (Pty) Ltd. Reg. No.: 1954/000781/07. P.O. Box 783720, Sandton 2146. Tel. No.: 0860 PFIZER (734937). PI Ref: 13/07/09. Please refer to the detailed package insert for full prescribing information. 01/01/REV/10/JA


review article

Contemporary insights into the pathogenesis, diagnosis and therapy of pulmonary arterial hypertensionMOhAMMED R ESSOP

summaryCurrent data challenge the concept that pulmonary arterial hypertension (PAH) is purely a disorder of impaired vasomo-tor tone. Instead, we recognise today that the phenotype of PAH represents the complex and disordered regulation of expression of key signalling molecules and abnormal molecu-lar trafficking. Discovery of mutations of the ubiquitous receptors of the transforming growth factor beta (TGF-b) superfamily in many patients with PAH has been instrumen-tal in unravelling the pathobiology of this otherwise fatal disorder. Much still needs to be learnt before we are able to substantially alter the natural history of PAH. Until such time, therapies that fundamentally attempt to restore vaso-motor tone continue to be developed and tested.

Current clinical research in the therapeutic arena is focused on defining the best permutation of the three major groups of drugs – prostacyclin analogues, phosphodiesterase type-five inhibitors and the endothelin receptor antagonists. However, if we are to make any significant impact on the otherwise dismal outcome of PAH, we have to recognise that even more important than the challenge of new therapies, is the challenge in diagnosing the condition early in the course of its relentless progression to right heart failure and even-tual death.

Keywords: pulmonary hypertension, mechanisms, therapy



DOI: CVJ-21.074

Since the first recorded description of pulmonary arterial hyper-tension by Romberg in 1891,1 a series of landmark observations have culminated in a deeper understanding of the pathobiology, diagnosis and therapy of the disease as we know it today. This review, compiled by a search strategy of PubMed, using the terms pulmonary arterial hypertension with specification for articles published in English, seeks to provide contemporary and concise answers to the specific questions posed and concentrates specifically on category 1 (see later) pulmonary hypertension (PH) under the rubric of pulmonary arterial hypertension (PAH). For a more general overview, the reader is referred to several

excellent recently published documents on guidelines, classifica-tion and therapy of PH.2-5

An increased awareness of PH in South Africa is particu-larly important for several reasons, all of which have served as an impetus for the formation of the Pulmonary Hypertension Interest Group. Firstly, there is reason to believe that PH in general is a prevalent condition in this country. Apart from the frequent contribution of valvular heart disease, cardiomyopathy and congenital heart disease, missed at the time of birth and during infancy, to the overall burden of PH, preliminary data from elsewhere suggest that retroviral infection may now be the leading cause. The incidence of PAH in cohorts of patients with HIV is estimated at about 0.5%.4 Even with a conservative preva-lence of five million people infected with HIV in South Africa, this would translate to some 25 000 patients with PAH. This complication is rarely diagnosed, unfortunately carries with it a poor prognosis independent of the CD4 count or viral load, and does not appear to be responsive to highly active anti-retroviral therapy. Secondly, as in many countries elsewhere, an advocacy group is sorely required here to promote all aspects of the diag-nosis and therapy of PAH and importantly, to lobby funders not to shirk their responsibility toward the management of this small but desperate group of patients.

what are the pathological hallmarks of Pah?PAH is a disease of the pre-capillary pulmonary arterial bed, including the medium-sized pulmonary arteries and pulmonary arterioles characterised by vascular obliteration. Current knowl-edge implicates unchecked proliferation of smooth muscle cells and dysregulated control of endothelial cells with apoptosis and dysfunction in some areas and profuse proliferation in others.

Plexiform arteriopathy (Fig. 1) is the pathological hallmark of advanced PAH and represents a chaotic assembly of proliferating endothelial cells, smooth muscle cells, fibroblasts and possibly circulating and bone marrow-derived endothelial progenitor cells. Proximal to these lesions, the pulmonary arterioles are dilated, have a paucity of endothelial lining, and show prolif-erative smooth muscle cells, fibroblasts and adventitia. Whereas distal loss of vasculature was previously thought to be second-ary to more proximal obstruction, compelling recent evidence suggests that this may be an active process linked to increased apoptosis of endothelial cells and pericytes.5

While pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis share some features in common with other causes of PAH, they are pathologically distinct and have been included in a separate category termed 1′ by the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) guidelines.3

division of Cardiology, Baragwanath hospital and univers-ity of the witwatersrand, Johannesburg, south africa, and Chairman, Pulmonary hypertension interest groupMOhAMMED R ESSOP, MBBCh, MRCP, FCP, FRCP, FACC, [email protected]


is there a unifying pathogenetic mechanism for Pah?The complexity of receptor activation, signalling molecules and downstream pathways with cross-talk at different levels between these makes it unfortunately difficult to pinpoint a precise mech-anism for PAH (Fig. 2). Nevertheless, the discovery of a loss-of-function mutation in bone morphogenetic receptor II (BMPR2), a member of the TGF-b superfamily, in 20 to 30% of patients with idiopathic PAH (IPAH) and 60% of patients with familial PAH immediately paved the way for elucidating the pathobiology of the disease.6,7

TGF-b receptors together with their ligands (proteins that bind to the receptor) control diverse processes involved in vascu-lar remodelling, including among others, cell proliferation and apoptosis, cellular differentiation, and collagen and extracellular matrix turnover. These are all processes that are fundamentally involved in PAH but the precise link between the genotype and the expression of the pulmonary hypertensive phenotype remain elusive.

According to the current hypothesis, a loss-of-function mutation in the BMPR2 receptor results in an imbalance in the equilibrium between the opposing effects of TGF-b and BMP signalling, which in the smooth muscle cell (SMC) favours a pro-proliferative and anti-apoptotic response but in the case of the endothelial cell (EC), has an anti-proliferative and pro-apoptotic effect (Fig. 3). Although the reason for the contrasting effect of BMP signalling on the SMC and EC remain unknown, the model

provides compelling evidence for the pathobiological underpin-nings of PAH. Furthermore, emergence of apoptosis-resistant clones of ECs may account for unregulated proliferation and the formation of plexogenic lesions.8

how is Ph best defined, classified and investigated?Although PAH is optimally defined on pathology, this is rarely possible except post-mortem. From a haemodynamic perspec-tive, pulmonary vascular resistance is the best measure of the resistance of the pulmonary circulation to flow but this in general requires invasive cardiac catheterisation, which is inappropriate as a screening test. Therefore an estimate of pulmonary artery pressure forms the starting point for diagnosis of PH.

The time-honoured clinical methods, including a left paraster-nal heave, palpable P2, pulmonary ejection click and narrow A2-P2 split are important, as are the ECG showing P-pulmonale, right-axis deviation and a tall R in V1 and chest X-ray with characteristic dilatation of the proximal pulmonary arteries and attenuation of distal third of the vasculature. However, echo-Doppler is an easily available, inexpensive and non-invasive way of obtaining a comprehensive assessment of pulmonary haemodynamics and is recommended as the initial investigation of choice in most guidelines.2,3

Fig. 1. typical plexiform lesion showing marked intimal hyperplasia due to disordered enthothelial cell prolifera-tion and obliteration of the lumen.

intima

lumen

Media

Fig. 2. Pathobiological mechanisms in pulmonary arterial hypertension.

apoptosis Proteolysis

Platelet activity and thrombosis

Endothelial cell differentiation and migration

inflammation Chemotaxis

Collagen and extracellular

matrix deposition

smooth muscle cell

differentiation and proliferation

Expression of vasodilator and vasoconstrictor peptides, and growth factors

Et-1, endothelin 1; 5-ht, serotonin; Kv, potassium channel; Pgi2, prostacyclin; tXa2, thromboxane a2; viP, vasoactive intestinal peptide

5-htviPKv

EMPstgF-b

MMPsElastase

vEgFPdgFEgF

FgFEt-1no

Pg12

tXa2

left heart pathology and

shunts

auto-immune disease; hiv; polycythaemia; sickle cell disease,

cirrhosis; hypoventilation

lung abnormality;

thrombo-emoblic disease

Echo suggestive

of pulmonary hypertension

Blood screen indicating auto-antibodies; hiv,

haemoglobin, liver functions, arterial blood gas (aBg)

Chest X-ray; v/Q scan; Ct;

pulmonary angiogram;

lung function

Cardiac catheterisationvascular testing

Pulmonary angiography

Fig. 4. recommended sequence of investigations in patients with pulmonary hypertension.

Fig. 3. unifying mechanism for smooth muscle cell prolif-eration, endothelial loss and proliferation in patients with loss-of-function mutation in BMPr2.

sMC

sMC proliferation

EC loss/dysfunction

EC hyperplasiaEC = endothelial cell; sMC = smooth muscle cell

Mutant BMPr2

tg-b

apoptosis resistant cell

sMC Pro-proliferative anti-apoptotic

anti-proliferative pro-apoptotic

Proliferative anti-apoptotic EC


Apart from measuring pulmonary artery systolic and dias-tolic pressure from the tricuspid and pulmonary regurgitant jets, respectively, echocardiography allows exclusion of left heart pathology and congenital shunts as possible aetiologies. Additionally, right ventricular size and function, which have important prognostic value, may be derived using a variety of indices. The echocardiographic definition of PH is a pulmonary artery systolic pressure greater than 40 mmHg.

Once suspected, a series of investigations should be under-taken (Fig. 4) in order to define the cause of PH. The sequence of testing indicated in the algorithm serves merely as a guideline – investigations should be guided by the most cost-effective approach and based on sound clinical judgment.

The classification of PH has undergone a series of modifi-cations since the original description endorsed by the WHO in 1973, with the latest proposal published from a symposium held in Dana Point, California.4 The classification essentially seeks to create categories of PH that share pathological and clinical features and have similar therapeutic options and is summarised in Table 1.

Is cardiac catheterisation indicated in every patient with suspected PAH?Despite advances in non-invasive imaging, including echocardi-ography, CT and MRI, invasive left and right heart catheterisa-tion is imperative to confirm pulmonary hypertension, rule out passive (category 2) aetiologies and intra-cardiac shunts, assess for acute vaso-reactivity and for prognostication purposes. Pulmonary angiography is not routinely necessary but may be useful to exclude thrombo-embolic disease, vasculitis and peripheral pulmonary artery stenosis.

The haemodynamic definition of PAH is a mean pulmonary artery pressure greater than 25 mmHg at rest or 30 mmHg with exercise, with a pulmonary capillary wedge pressure or left ventricular end-diastolic pressure less than 15 mmHg and a pulmonary vascular resistance greater than 3 ru. When there are marked respiratory variations in wedge pressure, values should be measured at end-expiration.

Oxygen and inhaled nitric oxide (10–30 ppm) are the most useful agents for acute vaso-reactivity testing in the catheterisa-tion laboratory. Inhaled nitric oxide has the advantage that it acts selectively on the pulmonary circulation, since it is rapidly inactivated by haemoglobin on entry into the blood stream and it does not cause ventilation–perfusion mismatch because it is only distributed to lung segments that are normally ventilated.

Only 5 to 10% of patients subjected to vaso-reactivity testing are classified as responders, variously defined as an absolute reduction in mean pressure greater than 10 mmHg to a mean value less than 40 mmHg, or a greater-than 20% reduction in mean pressure and pulmonary vascular resistance.9

what is optimal medical therapy for Pah?General measures for patients with PAH include limitation of physical effort, vaccination against influenza and home oxygen for hypoxic individuals. Although not supported by rigorous evidence, prophylactic warfarin anticoagulation, diuretics for those with systemic venous congestion and digitalis for right ventricular dysfunction may be appropriate. Women of child-bearing age should be strongly discouraged from falling preg-nant since maternal mortality is in excess of 50%, and should utilise appropriate techniques for contraception.

Patients identified as acute responders on vaso-reactivity testing benefit from high-dose dihydropyridine calcium antago-nists but should be monitored closely since about one-half may relapse in the long term. Empirical use of calcium antagonists without vaso-reactivity testing, a practice that is not infrequent, should be strongly discouraged.

Current therapy specifically targeted at PAH comprises the prostanoids, endothelin antagonists and phosphodiesterase type-5 inhibitors. The prostanoids may be administered intravenously (epoprostenol, trepostinil and iloprost), subcutaneously (treposti-nil), by inhalation (iloprost) or orally (beraprost). Endothelin antagonists may cause non-specific blockade of both the type A and B receptor (bosentan) or selective inhibition of the type A receptor (sitexantan and ambrisentan). The phosphodiester-ase type-5 inhibitors (sildenafil, revatio and tadalafil) increase nitric oxide availability by inhibiting the breakdown of the second messenger, cyclic guanosine monophosphate. For a more detailed account of these drugs the reader is referred to a recent review,10 but unfortunately, apart from the phosphodiesterase

TABLE 1. UPDATED CLINICAL CLASSIFICATION OF PULMONARY HYPERTENSION (DANA POINT, 2008)

1 Pulmonary arterial hypertension (PAH)

1.1 Idiopathic

1.2 Heritable

1.3 Drugs and toxin induced

1.4 Associated with (APAH)

1.41 Connective tissue disease

1.42 HIV infection

1.43 Portal hypertension

1.44 Congenital heart disease

1.45 Schistosomiasis

1.46 Chronic haemolytic anaemia

1′ Pulmonary veno-occlusive disease and/or pulmonary capillary haemagiomatosis

2 Pulmonary hypertension due to left heart disease

2.1 Systolic dysfunction

2.2 Diastolic dysfunction

2.3 Valvular disease

3 Pulmonary hypertension secondary to lung disease and/or hypoxia

3.1 Chronic obstructive pulmonary disease

3.2 Interstitial lung disease

3.3 Lung diseases with mixed restrictive and obstructive patterns

3.4 Sleep-disordered breathing

3.5 Alveolar hypoventilation disorders

3.6 Chronic high-altitude exposure

3.7 Developmental abnormalities

4. Chronic thrombo-embolic pulmonary hypertension

5. Pulmonary hypertension with unclear and/or multifactorial mecha-nisms

5.1 Haematological disorders: myeloproliferative disorders, sple-nectomy

5.2 Systemic disorders: sarcoidosis, neurofibromatosis, vasculitis

5.3 Metabolic disorders: glycogen storage disease, Gauchers, thyroid disorders

5.4 Others: tumour obstruction, fibrosing mediastinitis, chronic renal failure on dialysis


type-5 inhibitors, none of these therapies are available in this country.

Based on published evidence, all class 4 patients should receive intravenous epoprostenol, since this is the only therapy that has demonstrated a survival benefit in patients with PAH.10 The choice of therapy in class 2 to 3 patients and the optimum combination of drugs are as yet unclear. Also unknown is whether therapy should be initiated in asymptomatic patients with confirmed PAH. Apart from epoprostenol in class 4 patients, importantly, no therapy has shown significant survival benefit and the nature and magnitude of an appropriate surrogate endpoint are still debatable.

Patients refractory to medical therapy and with advanced symptoms may be considered for balloon atrial septostomy or lung transplantation. The rationale of creating a right-to-left shunt percutaneously is based on the fact that patients with Eisenmengers syndrome have a much better survival than other groups of PAH, perhaps because of the possibility of unload-ing the right ventricle and increasing systemic blood flow, even though this may be at the expense of desaturated blood.

does the future hold any promise for new therapies for Pah?The still-dismal outcome of patients with PAH has stimulated intense and exciting avenues of research into new therapies that would hopefully reverse the pulmonary hypertensive phenotype. As we delve deeper into the pathobiology of PAH, we increas-ingly realise the complexity of pathways involved in vascular remodelling. While many new approaches have shown promise at the bench side and in the monocrotaline-induced rat model of PAH, these remain to be tested in the clinical arena.

Inhibition of TGF-b receptors with antibodies or losartan, statins which increase BMPR2 gene promoter function, inhibi-tion of tyrosine kinase, which is an important mediator of cellular proliferation and migration, with drugs such as imatinib, and alter-ation of intracellular signalling via the SMAD pathway are but a few examples of potential therapeutic targets. Since right ventric-ular function may be an even more robust predictor of outcomes than the actual level of pulmonary pressure, more detailed study

of right ventricular remodelling and the molecular determinants of hypertrophy and failure of this chamber are also crucial.

ConclusionIn the not-too-distant future, we may be able to provide our patients with PAH with a cure. Until such time, however, it behoves us as clinicians to always consider the possibility of PAH, institute a diligent workup to make a precise diagnosis and assessment of severity and reversibility, and do all we can to make available potential therapies to this desperate group of patients.

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6. Lane KB, Machado RD, Pauciulo MW, et al. Heterozygous germ line mutations in BMPR2, encoding a TGF-beta receptor, cause familial primary pulmonary hypertension. Nat Genet 2000; 26: 81–84.

7. Deng Z, Morse JH, Slager SL, et al. Familial primary pulmonary hyper-tension (gene PPH1) is caused by mutations in the bone morphogenetic protein receptor-II gene. Am J Hum Genet 2000; 67: 737–744.

8. Sakoa S, Taraseviciene-Stewart L, Lee JD, et al. Initial apoptosis is followed by increased proliferation of apoptosis –resistant endothelial cells. FASEB J 2005; 19: 1178–1180.

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12. Meier P, Knapp G, Tamhane U, Chaturvedi S, Gurm HS. Short-term and intermediate-term conparison of endarterectomy versus stent-ing for carotid artery stenosis: systematic review and meta-analysis of randomised controlled clincal trials. Br Med J 2010; 340: c467. doi:10.1136/bmj.c467


opinions in hypertension ManagementarBs and risk of cancer: international and south african expert comment

The suggestion from a recent meta-anal-ysis that angiotensin receptor blockers (ARBs) are associated with an increase in new cancer occurrence but not cancer deaths,1 has resulted in the initia-tion of a safety review of this class of drugs by both the FDA (Federal Drug Administration) and the EMA (European Medicines Authority) in accordance with good regulatory practice. This was also advocated by Dr Steve Nissen in his edito-rial comment.2 In the interim, a review of the published meta-analysis plus input from Boehringer-Ingelheim is pertinent to clinical practice.

Meta-analysis of randomised control trials1

This meta-analysis pooled the published randomised, controlled trials of ARBs and found that ARB use may be associ-ated with a modest increased risk of new cancers – predominantly lung cancer. Patients who were randomly assigned to receive ARBs had an increased risk of new cancer occurrence compared with

patients in the control groups (7.2 vs 6.0%, risk ratio 1.08, 95% CI, 1.01–1.15). When analysis was limited to those trials (LIFE, ONTARGET and TRANSCEND) where cancer was a pre-specified endpoint, the risk ratio was 1.11 (95% CI, 1.04–1.18, p = 0.001). The authors concluded that the findings of the meta-analysis warrant further investigation.

The meta-analysis reviewed 60 trials and included published and available FDA data from nine different trials (Table 1) to assess overall cancer risk and risk of specific solid-organ cancers associated with ARBs plus ACE inhibitor therapy, compared with ACE inhibitors alone. Cancer was a pre-specified endpoint of special interest in three of the five trials that included new cancer data for analysis of cancer occurrence (LIFE, ONTARGET and TRANSCEND).

In the ONTARGET and TRANSCEND trials, information on the occurrence of malignancies was also collected prospec-tively in more detail than usual for trials of cardiovascular outcomes, thereby plac-ing the spotlight on telmisartan which

was the study drug in 30 014 (85.7%) of the ARB-treated patients included in the meta-analysis. The association of ARBs with the occurrence of solid-organ cancers, new lung, prostate and breast cancer from the meta-analysis is summa-rised in Table 2.

Comment from Boehringer IngelheimBoehringer-Ingelheim commented that peer-reviewed meta-analyses of aggregate published data such as that of Sipahi et al.1 have their appropriate place in scien-tific research. However, these publica-tions have well-recognised limitations, including the following:• the analyses did not include the indi-

vidual patient data for any of the trials• the trials were not designed to explore

cancer outcomes• the adjudication of cancer diagnoses

was not uniform among included stud-ies

• the analyses did not consider the laten-cy for the malignancies

TABLE 1. RANDOMISED CONTROLLED TRIALS OF ANGIOTENSIN RECEPTOR BLOCKERS THAT REPORTED CANCER DATA

Condition studied

Mean or median

duration, years

Number of

patients Study drug Control

History of cancer at baseline (%)

Study drug Control

Trials with data on new cancer, new specific solid-organ cancers, and cancer death

LIFE (2002) Hypertension 4.8 9 193 Losartan up to 100 mg (n = 4605) Atenolol up to 100 mg (n = 4588)

NA NA

ONTARGET (2008)

Cardiovascular disease* or diabetes with end-organ damage

4.7 25 620 Telmisartan 80 mg (n = 8542) or Telmisar-tan 80 mg + ramipril 5 mg (n = 8502)

Ramipril 5 mg (n = 8576)

6.3 6.3

TRANSCEND (2008)

ACE inhibitor-intolerant patients with cardiovascular disease* or diabetes, with end-organ damage

4.7 5 926 Telmisartan 80 mg (n = 2954) Placebo (n = 2972) 4.9 4.9

PROFESS (2008) Recent (< 90 days) ischaemic stroke

2.5 20 332 Telmisartan 80 mg (n = 10146) Placebo (n = 10186) NA NA

Trials with data on new specific solid-organ cancers and cancer death

CHARM-Overall programme (2003)

Heart failure 3.1 7 599 Candesartan up to 32 mg (n = 3803) Placebo (n = 3796) 7.1 6.4

Trials with new-cancer data only

TROPHY (2006) Pre-hypertension 3.6 787 Candesatran 16 mg (n = 391) Placebo (n = 381) NA NA

Trials with cancer death data only

VAL-HEFT (2001)

Heart failure 1.9 5 010 Valsartan up to 120 mg twice daily (n = 2511)

Placebo (n = 2 499) NA NA

OPTIMAAL (2002)

Acute myocardial infarction 2.7 5 477 Losartan up to 50 mg daily (n = 2 744) Captopril up to 50 mg three times daily

NA NA

VALIANT (2003) Acute myocardial infarction 2.1 14 626 Valsartan up to 80 mg twice daily (n = 4 885) or Valsartan up to 40 mg twice daily + captopril up to 25 mg three times daily (n = 4 862)

Captopril up to 25 mg three times daily (n = 4 879)

NA NA

ACE = angiotensin converting enzyme. NA = not available. *Includes coronary, peripheral, or cerebrovascular disease


TABLE 2. SOLID-ORGAN CANCERS REPORTED IN RANDOMISED CONTROLLED TRIALS OF ANGIOTENSIN RECEPTOR BLOCKERS

Lung cancer ARB (%) Control (%) RR (95% CI) % p-value

All available trials

LIFE 29/4605 (0.6) 12/4588 (0.3) 2.41 (1.23–4.71) 0.01

CHARM-Overall 31/3803 (0.8) 25/3796 (0.7) 1.24 (0.73–2.09) 0.43

TRANSCEND 35/2954 (1.2) 27/2972 (0.9) 1.30 (0.79–2.15) 0.30

ONTARGET 229/17044 (1.3) 101/8576 (1.2) 1.14 (0.90–1.44) 0.27

PROFESS 37/10016 (0.4) 30/10048 (0.3) 1.24 (0.77–2.00) 0.39

Meta-analysis 361/38422 (0.9) 195/29980 (0.7) 1.25 (1.05–1.49) 6.6 0.01

With background ACE-inhibitor treatment

CHARM-Added 12/1276 (0.9) 7/1272 (0.6) 1.71 (0.68–4.33) 0.26

ONTARGET (telmisartan + ramipril vs ramipril)

129/8502 (1.5) 101/8576 (1.2) 1.29 (0.99–1.67) 0.055

Meta-analysis 141/9778 (1.4) 108/9848 (1.1) 1.32 (1.03–1.69) 0 0.031

Without background ACE-inhibitor treatment

LIFE 29/4605 (0.6) 12/4588 (0.3) 2.41 (1.23–4.71) 0.01

TRANSCEND 35/2954 (1.2) 27/2972 (0.9) 1.30 (0.79–2.15) 0.30

ONTARGET (telmisartan vs ramipril) 100/8542 (1.2) 101/8576 (1.2) 0.99 (0.76–1.31) 0.97

CHARM-Alternative 10/1013 (1.0) 3/1015 (0.3) 3.34 (0.93–12.10) 0.066

Meta-analysis 174/17114 (1.0) 143/17151 (0.8) 1.50 (0.93–2.41) 65 0.097

Prostate cancer*


LIFE 58/2118 (2.7) 42/2112 (2.0) 1.38 (0.93–2.04) 0.11

CHARM-Overall 32/2617 (1.2) 27/2582 (1.0) 1.17 (0.70–1.95) 0.55

TRANSCEND 35/1674 (1.2) 27/1705 (1.6) 1.32 (0.80–2.17) 0.27

ONTARGET 275/12544 (2.2) 128/6245 (2.0) 1.07 (0.87–1.32) 0.53

PROFESS 36/6455 (0.6) 32/6418 (0.5) 1.12 (0.70–1.80) 0.64

Meta-analysis 436/25408 (1.7) 256/19062 (1.3) 1.15 (0.99–1.34) 0 0.076

With background ACE-inhibitor treatment

CHARM-Added 7/1006 (0.7) 9.1000 (0.9) 0.77 (0.29–2.07) 0.61


141/6252 (2.3) 128/6245 (2.0) 1.10 (0.87–1.39) 0.43

Meta-analysis 148/7258 (2.0) 137/7245 (1.9) 1.08 (0.86–1.36) 0 0.52

Without background ACE-inhibitor treatment

LIFE 58/2118 (2.7) 42/2112 (2.0) 1.38 (0.93–2.04) 0.11

TRANSCEND 35/1674 (2.1) 27/1705 (1.6) 1.32 (0.80–2.17) 0.27

ONTARGET (telmisartan vs ramipril) 134/6292 (2.1) 128/6245 (2.0) 1.04 (0.82–1.32) 0.75


Meta-analysis 235/10775 (2.2) 200/10753 (1.9) 1.17 (0.97–1.41) 0.10

Breast cancer†


LIFE 37/2487 (1.5) 36/2476 (1.5) 1.02 (0.65–1.61) 0.92

CHARM-Overall 17/1186 (1.4) 17/1214 (1.4) 1.02 (0.52–2.00) 0.95

TRANSCEND 20/1280 (1.6) 17/1267 (1.3) 1.16 (0.61–2.21) 0.64

ONTARGET 60/4500 (1.3) 34/2331 (1.5) 0.91 (0.60–1.39) 0.67

PROFESS 20/3561 (0.6) 15/3630 (0.4) 1.36 (0.70–2.65) 0.37

Meta-analysis 154/13014 (1.2) 119/10918 (1.1) 1.04 (0.82–1.32) 0 0.74

With background ACE inhibitor treatment


33/2250 (1.5) 34/2331 (1.5) 1.00 (0.61–1.66) > 0.99

Without background ACE inhibitor treatment

LIFE 37/2487 (1.5) 36/2476 (1.5) 1.02 (0.65–1.61) 0.93

TRANSCEND 20/1280 (1.6) 17/1267 (1.3) 1.16 (0.61–2.21) 0.64

ONTARGET (telmisartan vs ramipril) 27/2250 (1.2) 34/2331 (1.5) 0.83(0.50–1.36) 0.45


Meta-analysis 89/6339 (1.2) 91/6398 (1.4) 0.99 (0.74–1.32) 0 0.93

ARB = angiotensin receptors blocker. RR = risk ratio. ACE = angiotensin converting enzyme. *Analysis limited to men. †Analysis limited to women, all breast cancers were assumed to have occurred in women. Breast cancer data were not available for the CHARM-Added trial.

• the analyses did not take into account the effect of gender, age, smoking or other known risk factors for malignan-cies.

Boehringer-Ingelheim had conducted a comprehensive internal safety data analy-sis including malignancy data, which has formed part of the submission package to regulatory bodies since 2008. This analy-sis includes patient level time-to-event data, which are presented as malignancies per 100 patient years, and no statistically significant difference was observed.

The Cardiovascular Journal of Africa obtained comment from Dr Carl Lombard, director of the Biostatistics Unit at the South African Medical Research Council (MRC) and Dr Adam Nosworthy, senior specialist physician and medical oncologist, University of the Witwatersrand, Charlotte Maxeke Johannesburg Academic Hospital, and clinical adviser to the South African Oncology Consortium. They reviewed the published and Boehringer-Ingelheim data for the Journal, and their comments follow.

Comment from Dr Carl Lombard on Boehringer-Ingelheim analysisSystematic reviews, which evaluate different trials around the same question often lead to a formal pooled analysis of the relevant information through a meta-analysis. This is often a crude analysis since only the summarised data from trials are available from the publications.

The methodology of meta-analysis is well established and is a useful tool to pick up small signals of benefit or risk across trials with varying levels and direction of effect sizes. Sipahi et al.1 utilised the meta-analysis methodology to look at the risk of solid-organ cancers in randomised, controlled trials of angio-tensin receptor blockers. The conclusions reached from this analysis are balanced and qualified and clearly outline the limi-tations and need for further analysis.

Three of the trials involved in this analysis used the Boehringer-Ingelheim ARB, telmisarton. Boehringer-Ingelheim has provided additional information involving patient-level information on the incidence and progression of cancers in the study participants of these trials (Fig. 1, Table 3).


TABLE 3. NUMBER OF PATIENTS WITH MALIGNANCIES BY ORGAN PER 100 PATIENT YEARS BY STUDY

ONTARGET TRANSCEND

TR T R ∆T-R T P ∆T-P

Randomised (n) 8502 8542 8576 2954 2972

Patients with neoplasms1 2.14 1.96 1.88 0.08 1.72 1.48 0.25

Gastrointestinal 0.33 0.28 0.28 0 0.28 0.28 –0.01

Skin 0.39 0.34 0.37 –0.03 0.23 0.21 0.02

Prostate 0.36 0.33 0.31 0.01 0.25 0.2 0.05

Lung 0.32 0.23 0.25 –0.01 0.25 0.17 0.07

Genito-urinary 0.1 0.14 0.12 0.03 0.15 0.13 0.02

Blood 0.12 0.09 0.08 0.01 0.09 0.09 0

Breast 0.09 0.07 0.09 –0.02 0.14 0.13 0.01

Gynaecological 0.09 0.09 0.07 0.02 0.07 0.02 0.04

Head and neck 0.06 0.08 0.05 0.03 0.04 0.04 0

Metastases 0.05 0.05 0.03 0.02 0.02 0.01 0.01

Liver 0.05 0.06 0.05 0 0.04 0.03 0.01

Pancreas 0.05 0.05 0.05 0.01 0.06 0.05 0.01

CNS 0.03 0.03 0.04 –0.01 0.02 0.03 –0.01

Benign 0.01 0.01 0.01 0.01 0.01 0.01 0

NOS 0.03 0.03 0.02 0.01 0.03 0.01 0.01

Melanoma 0.04 0.04 0.04 0.01 0.01 0.03 –0.02

Endocrine 0.01 0.01 0.01 –0.01 0.01 0 0.01

Bone 0.01 0.01 0.01 0 0.01 0.01 0

Sarcoma 0.01 0.01 0 0 0.01 0.01 0.01

Abdominal 0.01 0.01 0 0 0 0.01 –0.01

Neuroendocrine 0 0 0 0 0 0 0

∆ represents the difference between treatment arms: + occurred more frequently and – less frequently in telmisartan group; T = telmisartan, R = ramipril, P = placebo.

The information provided across the three trials is differential and limited, which does not allow an appropriate pooled analysis across them. For the TRANSCEND and ONTARGET trials for example, the patient years of follow up is absent, whereas it is provided for the PRoFESS trial. The report reviews the results of the three trials separately.

(telmisartan vs placebo), ONTARGET (telmisartan + ramipril, telmisartan vs ramipril)], the incidence rate ratio was 1.07; 95% CI: 0.99–1.14.

2. With background ACE inhibitor treat-ment [ONTARGET (telmisartan + ramipril vs ramipril)], the incidence rate ratio was 1.14; 95% CI: 1.03–1.16.

3. Without background ACE inhibitor treatment [PRoFESS (telmisartan vs placebo), TRANSCEND (telmisartan vs placebo), ONTARGET (telmisartan vs ramipril)], the incidence rate ratio was 1.03; 95% CI: 0.96–1.12.

These analyses still have some limitations in that they utilise only patient follow up and do not adjust for latency and other confounders. However, the comparisons are between large groups of patients that have been properly randomised, and with the same intensity of follow up and malig-nancy ascertainment.

From analysis 3 in which monotherapy telmisartan was compared to either place-bo or ramipril, there is no evidence of risk for overall malignancy with regard to this product. With regard to the telmisar-tan/ramipril combination arm, there is evidence of risk with regard to the inci-dence of overall malignancies.

The conclusion made by Boehringer-Ingelheim in their safety report is there-fore objective: ‘There was a modest imbalance in malignancies seen in some of the recently completed cardiovascu-lar outcome studies with telmisartan. This imbalance was primarily in the telmisartan/ramipril combination arm in ONTARGET, as opposed to monotherapy arms of telmisartan vs rampipril.’

However, the call for further analysis by Sipahi et al.1 still stands, since the safety report of Boehringer-Ingelheim does not utilise the full potential of the available individual-level data for pooled analyses.

Comment from Dr Adam NosworthyThe findings published by Sipahi et al.1 in the 14 June issue of the Lancet raise the concern of most doctors involved in clini-cal trials. (1) Do the treatments intended to offer benefit result in long-term harm to patients? (2) The latest trend of regula-tory bodies to grant fast-track approval to new medications needs to be carefully reviewed.

In an attempt to offer patients the latest

Making approximate estimates for the patient years in TRANSCEND and ONTARGET from the information provided, and performing pooled analyses for overall malignancies, similar to that done by Sipahi et al.,1 the following was found:1. In all three trials [PRoFESS (telmisar-

tan vs placebo), TRANSCEND

Fig. 1. Fatal and non-fatal malignancies: ontargEt and transCEnd

12

8

4

0t/r

8502t

8542r

8576t

2954P

2972

Patie

nts

% 9.7 8.98.0

6.9

1.14 (1.03–1.26)*

1.17 (0.97–1.41)

this analysis clearly proves that there is no significant increase of telmisartan vs ramipril or placebo in ontargEt and transCEnd. there is however a

significant increase in the combination arm (telmisartan + ramipril) vs ramipril.

ontargEt transCEnd

total n randomised

8.6

824 762 735 236 204

1.09 (0.99–1.21) 1.05 (0.94–1.16)

* significant hr (95% Ci).t = telmisartan, r = ramipril, P = placebo


benefits, are we doing more harm than good in the long run? Having said that, the inferences made from the Sipahi et al.1 study that the risk of cancer is increased in patients taking ARBs is concerning to say the least.

The most important tenant of clinical trials is to determine which statistical endpoints need to be defined prior to commencing any study, and any post-hoc analysis needs to be treated with the contempt that it deserves. To group a number of studies involving the ARBs (meta-analysis) and to extrapolate that there is an increased incidence of cancer in certain groups of patients is bad medi-cine and the outcomes of this report should not influence the use of these agents in patients.

The analysis is contradictory – there is an increase in lung cancer, which is claimed to be statistically significant in

the group of patients receiving ARBs, yet the incidence of other cancers is decreased or the same. The group of patients that would typically be enrolled in these studies is firstly, a group of patients that are high risk for lung cancer, as they no doubt include a skewed bias in favour of smokers. All these factors would need to be included in the statisti-cal design of the study prior to drawing these conclusions.

At this stage, I can find no reason to be concerned about the use of ARBs in patients. Far more reliable prospective, randomised data need to be presented prior to considering withdrawing this class of drug from the market.

It is rather ironic that there is a concern regarding a slight increase in cancer inci-dence in patients using ARBs in a retro-spective analysis of numerous studies, yet a medication that is used widely and is

known to have far greater impact on the development of breast cancer in women is prescribed in far greater numbers on a daily basis by doctors around the world – oestrogen replacement therapy – without as much as a mention in widely read medical journals!

C Lombard, Biostatistics Unit, Medical Research Council; Dr Adam Nosworthy, oncologist, Donald Gordon Oncology Centre; J Aalbers, Special Assignments Editor

4. Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang J. Angiotensin-receptor block-ade and risk of cancer: meta-analysis of randomised controlled trials. Published online June 14, 2010 DOI:10.1016/51470-2045(10)70106-6.

5. Nissen SE. Comment: Angiotensin-receptor blockers and cancer: urgent regulatory review needed. Published online. June 14 2010;DOI:10.1016/51470-2045(10)70142X.

Fda committee unanimously recommends approval of dabigatran etexilate for stroke prevention in atrial fibrillation

The US Food and Drug Administration (FDA) Cardiovascular and Renal Drugs Advisory Committee recently voted 9 to 0 in favour of recommending dabigatran etexilate for stroke prevention in patients with atrial fibrillation (AF).

For decades, vitamin K antagonists such as warfarin have been the most efficacious therapeutic option for stroke prevention in AF. Current recommen-dations for patients with non-valvular atrial fibrillation treated with warfarin recommend maintaining an international normalised ratio (INR) in the range of 2.0–3.0 through frequent blood monitor-ing and dose adjustments, which can be challenging for physicians and patients.

In RE-LY®, dabigatran etexilate demonstrated efficacy without the need

for ongoing INR monitoring or dose adjustments. Furthermore, there were no food restrictions on those taking dabi-gatran in RE-LY®. A total of 6.3 million people in the USA, Japan, Germany, Italy, France, UK and Spain were living with AF in 2007 and this is expected to increase to 7.5 million by 2017, primarily due to the ageing population.1

‘We are pleased with the committee’s recommendation, which marks an impor-tant step in advancing care for patients with atrial fibrillation’, said Prof Klaus Dugi, Corporate Senior Vice President Medicine, Boehringer Ingelheim. ‘We believe dabigatran etexilate will offer patients and doctors the first new treat-ment option for stroke prevention in atrial fibrillation in more than 50 years. We

look forward to working with the FDA as it finalises its review of dabigatran.’

Pradaxa (75 and 110 mg) is currently only registered in South Africa for the prevention of venous thromboembolic events in patients who have undergone hip- and knee-replacement surgery. For full prescribing information refer to the package insert approved by the Medicines Regulatory Authority.

For more information visit www.boehringer-ingelheim.com, or contact Sue Thomas, Medical Information Manager on tel: +27 0(11) 348-2514 or e-mail: [email protected]

J Aalbers, A Bryer, E Klug

1. Benyoucef S, Hughes M, Mehta N. Atrial fibrillation. Decision Resources, December 2008.

drug trends in Cardiology


rivaroxaban equals warfarin treatment in atrial fibrillation patients at high risk of strokeRivaroxaban has met its primary objective in the ROCKET trial of non-inferiority to warfarin in the treatment of atrial fibrilla-tion (AF) patients at high risk of stroke. In fact the study included a majority of patients who had already experienced either a stroke or transient ischaemic event, therefore needing warfarin for secondary prevention.

For the primary-efficacy endpoint, rivaroxaban was superior to warfarin, delivering a 21% relative risk reduction in stroke and non-central nervous system (CNS) systemic embolism in the pre-specified on-treatment population (1.70 vs 2.15%, p = 0.015).

Could these results of rivaroxaban in the ROCKET trial have been fore-seen by Prof John Camm, University of London, in his commentary a year ago on the RELY study?1 He pointed out then, ‘much more information will be needed before regulators can decide on the approvability of the drug [in this case, he was referring to dabigatran] for the management of patients with atrial

fibrillation with thrombo-embolic risk (CHADS score greater than 2%)’.

We now know that the FDA has approved the higher dose of dabigatran (150 mg twice daily) to prevent stroke in patients with atrial fibrillation, and a 75-mg dose for patients with severe renal impairment (15–30 ml/mm). The FDA made no additional stipulations for dabigatran usage in AF except to say, ‘for stroke prevention’; while the Canadian approval says, ‘for AF patients in Canada in whom anti-coagulation is appropriate’.

The randomised, double-blind ROCKET study could make an argument for the usage of rivaroxaban in patients with AF and a high CHADS score. In ROCKET, the majority of patients were in the 3–5% CHADS score risk assess-ment, with a mean of 3.48% (Table 1). The CHADS score in the RELY study was 2.1%. The primary efficacy outcome for the ROCKET study is shown in Fig. 1 and Table 2.

The event rate for stroke and non-CNS embolism was 1.7 per 100 patient years for rivaroxaban and 2.15 for warfarin, based on the on-treatment population. The intention-to-treat (ITT) event rates were higher; 2.12 with rivaroxaban and 2.42 for warfarin.

In ROCKET, the time in therapeutic INR range was 57.8%. There were similar rates of bleeding and adverse events in the rivaroxaban and warfarin arms, but less intra-cranial haemorrhage and fatal bleeding with rivaroxa-ban. Prof Kenneth W Maheffey of Duke University concluded that

rivaroxaban has now been shown to be a proven alternative to warfarin for stroke prevention in moderate- or high-risk patients with non-valvular AF.

South Africa participated in the ROCKET study and entered 247 patients into the study.

The discussant of this study at the American Heart Association, Dr Elaine M Hylek, Boston, USA pointed out that ROCKET had recruited the oldest and highest-risk AF patient cohort, with 55% having had a stroke and therefore requiring warfarin for secondary preven-tion, 91% with hypertension, 62% with chronic heart failure (which would have contributed to INR variability), and 39% with diabetes. ‘These were patients at the highest risk for intra-cranial haemorrhage due to age, high blood pressure and prior stroke’, she pointed out.

In this high-risk population, less than 50% achieved the time-in-therapeutic-range (TTR) threshold of > 58–60% need-ed to realise the benefits of warfarin. She pointed out that per-protocol or ‘on-treat-ment analysis’ is important to confirm non-inferiority of a primary intention-to-treat analysis. Then, after non-inferiority is evident, superiority may be assessed, preferably defined at the outset and with an intention-to-treat analysis.2 Dr Hylek’s conclusions are summarised:• Based on both the ITT and per proto-

col (PP) analysis, rivaroxaban is non-

days from randomisation

Fig. 1. Primary efficacy outcome: stroke and non-Cns embolism.

no. at risk:rivaroxaban 6958 6211 5786 5468 4406 3407 2472 1496 634warfarin 7004 6327 5911 5542 4461 3478 2539 1538 655Event rates are per 100 patient-yearsBased on Protocol Compliant treatment Population

hr (95% Ci): 0.79 (0.66–0.96)p-value non-inferiority: < 0.001

rivaroxaban

warfarin

rivaroxaban warfarin

Event rate 1.71 2.16

6

5

4

3

2

1

00 120 240 360 480 600 720 840 960

Cum

ulat

ive

even

t rat

e (%

)

TABLE 2. PRIMARY EFFICACY OUTCOME: STROKE AND NON-CNS EMBOLISM

0 1 2rivaroxaban

betterwarfarin

better

on treatmentn = 14 143

ittn = 14 171

Rivaroxaban event rate

Warfarin event rate

HR (95% CI) p-value

1.70 2.15 0.79(0.65–0.95)

0.015

2.12 2.42 0.88(0.74–1.03)

0.117

Event rates are per 100 patient yearsBased on safety on treatment or intention-to-treat through site-notifi-cation populations

TABLE 1. BASELINE DEMOGRAPHICS

Rivaroxaban (n = 7 081)

Warfarin (n = 7 090)

CHADS2 score (mean)2 (%)3 (%)4 (%)5 (%)6 (%)

3.48134329132

3.46134428122

Prior VKA use (%) 62 63

Congestive heart failure 63 62

Hypertension (%) 90 91

Diabetes mellitus (%) 40 39

Prior stroke/TIA/ embolism (%)

55 55

Prior myocardial infarction (%)

17 18

Based on intention-to-treat population


inferior to warfarin (albeit with TTR = 57%) for the prevention of stroke in AF patients.

• The difference between the ITT and per protocol analysis may be account-ed for by poor adherence. This raises concerns about the relevance of the PP analysis to real-world practice, particu-larly for a drug with a half-life of 5–13 hours vs 20–60 hours for warfarin.

• The ITT result showing no significant superiority is more likely to reflect the actual difference in effectiveness between these treatments.

• Importantly, there were fewer intra-cranial bleeds on rivaroxaban and fewer deaths from bleeding. However, there were more haemorrhages requir-ing transfusions, and drops in haem-atocrit, rendering the overall safety profile less clear.

Additional comments from an interview with Dr Jonathan Halperin, Mount Sinai School of Medicine, New York, USA, who attended the hot line sessionIt is very hard to draw comparisons between the two trials, ROCKET-AF and

RELY, as ROCKET enrolment specifi-cally stipulated the inclusion of high-risk patients – hence the difference in mean CHADS2 risk scores between ROCKET (∼ 3.5) and RELY (2.1). In addition, methodological differences confound comparison: ROCKET was a double-blind study while RELY was an open study with blinded endpoint assessment (probe design).

There was great anticipation about this study, particularly as a press release from Europe indicated that the study had reached its primary objective to demon-strate the non-inferiority of rivaroxaban compared to warfarin. The lead organisa-tion, the Duke Clinical Trials Institute, has done a remarkable job in analysing and organising these data just a few weeks after closure of the trial database. This means, however, that the results presented at this congress are top-line findings, and we certainly anticipate and perhaps even hunger for more detail.

One of the surprising findings of the trial is that warfarin did not perform as well in this double-blind trial (achiev-ing a TTR below 60%) as in the North American SPORTIF-V trial of another anticoagulant, later abandoned due to

liver toxicity, in which warfarin’s TTR was 68%. The reasons for the poorer warfarin control in ROCKET-AF could include the high-risk patient profile or the inclusion of geographically diverse centres, some of which may have more experience with vitamin K antagonists other than warfarin.

The good news is the development of another effective anticoagulant, one that inhibits activated factor X, demonstrating non-inferior efficacy compared to warfa-rin, with lower rates of intra-cerebral haemorrhage. Concern remains about whether the results may have been differ-ent if the quality of warfarin control had been better, and about higher bleeding rates outside the central nervous system with rivaroxaban, leading to comparable rates of major bleeding with both treat-ments overall.

J Aalbers, Special Assignment Editor

1. Camm AJ. The RE-LY study: Randomised Evalution of Long-term anticoagulant ther-apY. Eur Heart J: doi 10.1093/euroheartj/ehp34.

2. Consolidated standards of reporting trials. J Am Med Assoc 2006.

development of new anticoagulant highly honoured: Bayer’s Xarelto® recognised with 2010 international Prix galien award

The highly distinguished Awards Committee of the Galien Foundation has honoured Bayer’s Xarelto® (rivaroxaban) with the Prix Galien International 2010 in the category Best Pharmaceutical Agent. Xarelto® had previously already been recognised with national Prix Galien awards in Belgium, France and Switzerland.

The Prix Galien award recognises outstanding achievements in improv-ing health through the development of innovative therapies, and is regarded as the equivalent of the Nobel Prize in biopharmaceutical research. The Awards Committee of the Prix Galien International 2010, including many Nobel Prize laure-ates, was chaired by Gerald Weissmann, MD, professor of Rheumatology and director of Biotechnology Study Centre,

New York University School of Medicine. The award ceremony was hosted at the American Museum of Natural History in New York, USA.

‘We are very excited about the award and honoured by the recognition of this globally renowned committee. Being awarded the International Prix Galien for Best Pharmaceutical Agent underscores the drive for innovation that character-ises the focus of our company, and our continuing ambition to improve the qual-ity of life of patients’, commented Dr Marijn Dekkers, chairman of the Board of Management of Bayer AG. ‘Xarelto® has consistently demonstrated superior efficacy compared to current standard therapy for the prevention of venous thromboembolism in patients undergoing total hip- or knee-replacement surgery

and has become the market leader among the new oral anticoagulants.’

About rivaroxabanRivaroxaban is a novel oral anticoagu-lant that was invented in Bayer Schering Pharma’s Wuppertal laboratories in Germany, and is being jointly devel-oped by Bayer HealthCare and Johnson & Johnson Pharmaceutical Research & Development, LLC. In clinical studies, rivaroxaban has consistently shown supe-rior efficacy to enoxaparin in preventing venous thromboembolism (VTE) in adult patients following elective hip- or knee- replacement surgery. It has a rapid onset of action with a predictable dose response and high bioavailability, no requirement for coagulation monitoring, and a limited


Myocardial salvage after myocardial infarction depends on early therapyIn a thought-provoking session on triple anti-platelet therapy in acute coronary syndromes, Prof Marco Valgimigli, Ferrara, Italy, argued that the effect of clopidogrel is negligible if given too late to ST-segment elevation myocardial infarction (STEMI) patients. ‘Clopidogrel is not fully absorbed during STEMI. This impaired bio-availability of both the active and inactive metabolite,1 combined with late administration of clopidogrel, results in minimal anti-platelet inhibition. In fact, there is limited clinical evidence supporting the upstream use of clopidog-rel’, he said.

Referring to the BRAVE 3 study of abciximab which, when added to aspi-rin and clopidogrel in STEMI patients, showed a negligible effect in further reducing infarct size and mortality. Prof Valgimigli ascribed this also to late delivery of the study drug. This negative outcome was interpreted by the BRAVE 3 study investigators that abciximab should not be given to STEMI patients in the catheterisation laboratory.

‘In my view this is not the correct interpretation’, said Prof Valgimigli. ‘The problem was that the study drug was given after four hours to more than 50% of patients, and time from symptom onset to PCI was more than five hours in over 50% of the patients. If you consider the relationship between time-to-treatment reperfusion and the extent of myocardial salvage,2 this is not linear. While early reperfusion within at least four hours results in a large reduction in mortality following significant myocardial salvage, later intervention results in a much reduced mortality reduction. Therefore

the overall lack of benefit from abcixi-mab in BRAVE 3 is due to treatment and reperfusion delay.’

Using Medical Research Institute (MRI) studies3 of STEMI patients strati-fied by delay of treatment, Prof Valgimigli pointed out that the area of potential myocardial salvage is largest if time to reperfusion is short and within one to two hours post infarct. Therefore GIIb/IIIa agents are of very significant value if given early.

The evidence for early administra-tion of anti-platelet agents has been well shown in the ON-TIME-2 trial2 of very early upstream bolus tirofiban treatment. At the time of arrival at the PCI centre, patients treated with tirofiban on top of aspirin and clopidogrel had significantly lower residual ST-segment deviation than those receiving only aspirin and clopidog-rel. The one-year survival rate of those patients receiving tirofiban within 75 minutes after diagnosis and primary PCI was 60% lower than those receiving dual anti-platelet therapy.

Is this time-delay concept the same for other anti-platelet agents such as clopi-dogrel? ‘The answer is yes.4 If clopi-dogrel is given within six hours there is a significant benefit on death, re-MI or stroke in patients undergoing primary PCI, which disappears if clopidogrel is given more than 12 hours after diagnosis’, Prof Valgimigli said.

Is there benefit from using GIIb/IIIa in non-STEMI patients? ‘In a recent meta-analysis of 14 RCTs, including 3 424 patients,5 of tirofiban on top of clopidog-rel, and aspirin versus clopidogrel plus aspirin, tirofiban reduced death/MI in the

30 days post-intervention, with an NNT of 16 to save one life or prevent one MI.’ If one looks at the background therapy and asks if clopidogrel is improving the effect of tirofiban, the answer is appar-ently negative.5

‘Overall, the explanation for the added value of GIIb/IIIa might lie within the multiple other pathways of platelet activa-tion which still function in the presence of aspirin and clopidogrel – the platelet aggregation inhibitor action of the GIIb/IIIas is therefore a necessary and useful action’, Prof Valgimigli concluded.

J Aalbers, Special Assignments Editor

1. Heestermans AA, van Werkum JW, Taubert D. Impaired bioavailability of clopidogrel in patients with a ST-segment elevation myocardial infarction. Thrombosis Res 2008; 122(6): 776–781.

2. Gersh BJ, Stone GW, White HD, Holmes DR Jr. Pharmacological facilitation of primary percutaneous coronary intervention for acute myocardial infarction: is the slope of the curve the shape of the future? J Am Med Assoc 2005; 293(8): 979–986.

3. Ripa RS, Nilsson JC, Wang Y, et al. Short- and long-term changes in MI function morphology, edema and infarct mass after ST-segment elevation myocardial infarction evaluated by serial magnetic resonance imag-ing. Am Heart J 2007; 154(5): 929–936.

4. Chen ZM, et al. Oral presentation, ACC 2005.

5. Valgimigli M, Biondi-Zoccai G, Tebaldi M, van’t Hof AW, Campo G, Hamm C, et al. Tirofiban as adjunctive therapy for acute coronary syndromes and percutaneous coro-nary intervention: a meta-analysis of rand-omized trials. Eur Heart J 2010; 31(1): 35–49. E-pub 2009 Sep 14.

potential for food and drug interactions. Rivaroxaban is marketed under the

brand name Xarelto® for VTE preven-tion in adult patients following elective hip- or knee-replacement surgery, and it is the only new oral anticoagulant that has consistently demonstrated superior efficacy over enoxaparin for this indica-tion. Xarelto® is approved in more than 100 countries worldwide and has been successfully launched in more than 75

countries by Bayer Schering Pharma, achieving the market leader position among the new oral anticoagulants.

The extensive clinical trial programme supporting rivaroxaban makes it the most studied oral, direct factor Xa inhibitor in the world today. More than 65 000 patients are involved in the rivaroxaban clinical development programme, which is evalu-ating the product in the prevention and treatment of a broad range of acute and

chronic blood-clotting disorders, includ-ing stroke prevention in patients with atrial fibrillation, secondary prevention of acute coronary syndrome, and VTE preven-tion in hospitalised medically ill patients.

To learn more about thrombosis, please visit www.thrombosisadviser.com.For more information contact Anel Berning at Bayer on tel: +27 (11) 921 5021 or e-mail: [email protected]


your life and your heart

vitamin d is a prognostic marker in heart failureA Dutch study of vitamin D levels in patients with heart failure, presented at the 2010 European Society of Cardiology (ESC) congress in Stockholm, provoked considerable interest among cardiolo-gists as it suggests that they advise their patients to maintain appropriate vitamin D levels.1

Liu and co-workers at the University Medical Centre, Groningen, Netherlands showed that:• a low vitamin D concentration is asso-

ciated with a poor prognosis in heart failure

• the correlation found between vita-min D, plasma renin activity and C-reactive protein suggests that an activated renin–angiotensin system and an altered cytokine profile may play an important role in the asso-ciation between vitamin D and heart failure.

In this study, 548 patients hospitalised due to heart failure were studied, and the correlation was examined between

25-hydroxy vitamin D (nmol/l) levels, plasma renin activity (PRA), the presence of inflammatory cytokines, and the inci-dence of death or heart failure re-hospi-talisations during the 18-month follow up.

The mean age was 71 years and mean left ventricular ejection fraction was 33 ± 14%. Patients were grouped into tertiles according to vitamin D levels (T1: < 29.6; T2: 29.6–43.9; T3: > 43.9 nmol/l). Vitamin D levels were higher in males (p < 0.001) and younger patients (p = 0.002), and those with lower galectin-3 (p < 0.001) and NT-proBNP levels (p < 0.001).

Multivariate linear regression analy-sis showed that plasma renin activity (p = 0.003) and C-reactive protein (CRP) levels (p = 0.002) are independent predic-tors of vitamin D levels. During follow up, 165 patients died and 142 were re-hospitalised. Kaplan-Meier analysis showed that lower vitamin D concentra-tion was associated with an increased risk for all-cause mortality (log rank test, p = 0.014) and increased risk for the

combined endpoint (mortality and heart failure re-hospitalisation; log rank test, p = 0.045).

Importantly, after adjustment in a multivariable Cox regression analysis, high vitamin D concentration remained independently associated with a decreased risk for all-cause mortality (HR: 0.66; 95% CI: 0.44–0.99; p = 0.044) and the combined endpoint (HR: 0.69; 95% CI: 0.51–0.95; p = 0.022).

The results of this study provide compelling evidence that a high vitamin D status is associated with improved survival in heart failure patients. ‘It seems that physicians should advise their heart failure patients to maintain their vitamin D levels by taking supplements, eating oily fish or eggs or ensuring exposure to sunlight’, Ms Liu conluded.

J Aalbers, Special Assignments Editor

1. Liu LCY, et al. Prognostic value of vitamin D in heart failure. P 5675, ESC 2010 Congress. Eur Heart J 2010; 31: 1054.

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CardioVascular Journal of Africa (official journal for PASCAR)www.cvja.co.za

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• Stents for the treatment of diffuse coronary lesions

• Serum CRP levels in children

• New anti-coagulant therapies

• Mitral valve prolapse and conduction disturbances

• Post-infarction ventricular septal defect

• Pulmonary arterial hypertension

• ARBs and risk of cancer

• Dabigatran etexilate for stroke prevention in atrial fibrillation

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