Volume 2 No 2 Cardiology Newsletter

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June 2011

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CoAprovel® 150/12,5 & CoAprovel® 300/12,5. Each tablet contains 150 mg or 300 mg of irbesartan and 12,5 mg of hydrochlorothiazide. Reg. Nos. 33/7.1.3/0324; 33/7.1.3/0325. sanofi-aventis south africa (pty) ltd. Reg. No. 1996/010381/07. 2 Bond Street, Grand Central Ext. 1, Midrand.Telephone (011) 256 3700. Facsimile: (011) 256-3707. www.sanofi-aventis.com ZA.IRB.09.09.01 oBP = Blood Pressure

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Page 3 Volume 2 No 2 June 2011

Editorial board Dr A.J. Dalby (Editor)CardiologistMyocardial Ischaemia and InfarctionMilpark HospitalJohannesburg

Prof B. RaynerNephrologistNephrology and HypertensionGroote Schuur Hospital &University of Cape Town

Prof B. JacobsonHaemotologistThrombosis and Haemostasis University of Witwatersrand

Dr R. JardineCardiologistArrythmiasGlynwood Hospital

Dr A. ThorntonCardiologistElectrophysiologySunninghill HospitalJohannesburg

Dr J. HarrisbergPaediatric CardiologistSunninghill HospitalJohannesburg

Prof. K. Sliwa-HanhleCardiovascular ResearchHatter Cardiovascular Research Institute and Institute of Infectious Disease and Molecular Medicine, University of Cape TownHeart Failure/Translational Research

Dr L. SteingoCardiologistInterventional CardiologyMorningside Clinic

Editorial

The views expressed by the authors in this newsletter do not necessarily reflect those

of the sponsor and editorial board.

This newsletter is proudly sponsored by

If you have any suggestions or topics you would like to see published or have articles and/or case studies for publishing, please email us at: ajd@hot.co.za or lakeann@mweb.co.za.

ype 2 diabetes has emerged as a worldwide epidemic. In almost every country, huge numbers of people are

affected, with increases being observed particularly in developing nations. It is expected that soon, the diabetic population of China will equal the entire population of the USA. Many States in the USA have over 15% of their population affected by diabetes. Most of these diabetics will die from cardiovascular disease. With the overwhelming case load, traditional diabetic clinics can no longer cope.

Thus it is appropriate that all family practitioners, physicians and cardiologists closely acquaint themselves with how they will manage diabetics. As treatment generally begins with an oral agent, a clear knowledge of the appropriate choice of drug is important. Amongst the oldest of the available agents are some within the sulphonylurea group. In this edition Dirk Blom of the Lipid Clinic

Dr Anthony J. DalbyCardiologist

Milpark Hospital, Johannesburg

at Groote Schuur Hospital gives us an excellent review of their safety.

The business of managing your practiceIt is my experience that, as medical practitioners, we immerse ourselves in clinical practice to the extent that, though we are always “busy”, the effort put into practice does not translate into an adequate income partly because

of poor management skills.

Furthermore, given what income does derive from practice, investment planning is often pushed

aside because we are too “busy”. Too frequently the profit from our practice is swallowed up creating a lifestyle that will be difficult if not impossible to maintain unless we keep on working. Retirement becomes something other people do. Inflation becomes a terrifying threat. Considering the span of my professional career, I recall what was once said in a TV advertisement: in 1970 R 1 000 bought a motor car, in 1980 it bought a motorcycle, in 1990 it bought a bicycle and in 2000 a pair of

Cover image: www.fragileart.com

it is appropriate that all family practitioners, physicians and cardiologists closely acquaint themselves with how they will manage diabetics

Production Editor: Ann Lake Publications - Ann Lake, Helen GonçalvesDesign: Jane GouveiaSponsors: sanofi aventisEnquiries: Ann Lake Publications, PO Box 265, Gallo Manor, 2052Fax: 086 671 9397Email: lakeann@mweb.co.zaWebsite: www.annlakepublications.co.za

Volume 2 No 2 June 2011 Page 4

running shoes. In this light, consider retiring at 65 and living on into your mid-80’s!

Grant Pettitt has contributed an article on the subject of practice management and investment which is valuable to “read, understand and inwardly digest” as my headmaster would have said. Escaping from “busy-ness” into a more business-like approach to practice cannot only be more profitable but also allow one to avoid the fear of retirement.

This edition also carries the regular “Vital Signs” and “10 points” features.

B-type natriuretic peptide (BNP) 1. is expressed mostly in the atria of normal hearts. Its production is upregulated in states of high wall stress (e.g. heart failure and renal failure), promoting diuresis, natriuresis, vasodilation, and antagonism of the renin-angiotensin-aldosterone system (RAAS). PreproBNP is cleaved to form 2. proBNP. This is then cleaved into BNP (biologically active) and N-terminal (NT)-proBNP (biologically inactive). Patients with heart failure often have high concentrations of relatively inactive glycosylated proBNP which cannot be converted to active BNP - the so-called ‘natriuretic peptide paradox.’ BNP is cleared via endopeptidases, 3. clearance receptors, and by the kidneys. NT-proBNP is cleared passively by high blood flow organs (i.e., liver and kidney). Renal dysfunction leads to elevation of

both peptides. In general, NT-proBNP levels are higher due to a longer half-life. Natriuretic peptides are neither heart 4. failure nor heart disease specific. Because natriuretic peptide may vary 5. 30-50% in the same patient, only large changes (>30%) can be deemed clinically important. It follows that frequent blood sampling during acute management is not recommended. Natriuretic peptide levels may not be 6. elevated despite acute hemodynamic compromise and pulmonary congestion in those with preserved ejection fraction, constrictive pericarditis, and acute mitral regurgitation. Both BNP and NT-proBNP have 7. reduced sensitivity in severe obesity. In the setting of normal renal function 8. and body mass index, a BNP <100 ng/L and NT-proBNP <300 ng/L makes the diagnosis of heart failure less likely. Similarly, a BNP level >500

10 Points to remember about Natriuretic Peptides in Heart Failure

ng/L makes a heart failure diagnosis more likely in the correct clinical setting. Natriuretic peptide measurements 9. on admission can provide risk stratification and predict short- and long-term mortality. A BNP that reduces >30% from admission at the time of discharge is associated with improved survival. Natriuretic peptide measurements 10. can be prognostic in the setting of several conditions not related to cardiac failure, such as acute pulmonary embolism, acute coronary syndrome, and acute lung injury.

Abstracted by Cowger JA for Cardiosource Weekly Journal Scan from Thygesen K, Mair J, Mueller C, et al. Recommendations for the Use of Natriuretic Peptides in Acute Cardiac Care: A Position Statement From the Study Group on Biomarkers in Cardiology of the ESC Working Group on Acute Cardiac Care. Eur Heart J, 2011.

Some guidelines for BNP interpretationA variety of biomarkers are used to assess the likelihood of certain conditions. However almost all of them are non-specific (i.e. not absolutely diagnostic) and need to be interpreted in the light of the clinical setting and the metabolic mileau of the patient. Troponins and natriuretic peptides are good examples of this. The 10 points feature provides a summary of the use and interpretation of brain natriuretic peptide (BNP) which I found very helpful.

Amongst the Vital Signs items you will find current information on the safety of intensely lowering LDL cholesterol, the interaction between clopidogrel and proton pump inhibitors, the magnitude of grown-up congenital heart disease (GUCH), the safety of angiotensin receptor blockers, and new data on the outcomes after left main stenting.

I trust you enjoy reading Heart Matters and as always look forward to your comments and suggestions.

Tony Dalby

Page 5 Volume 2 No 2 June 2011

Dr Dirk J. Blom MBChB (UCT), FCP (SA), M. Med (UCT), PhD (UCT)Lipid Laboratory, Department of Medicine, University of Cape Town

The Cardiovascular Safety of Sulphonylureas

he prevalence of type 2 diabetes mellitus is rapidly increasing worldwide, with the largest increases predicted to occur in middle and lower income

countries. The epidemic of diabetes may well overwhelm the already overburdened healthcare systems in poorer countries. Managing type 2 diabetes mellitus is costly as multiple medications are usually required to treat the elevated glucose and associated co-morbidities such as hypertension and dyslipidaemia. Frequent contact with the healthcare system and regular laboratory monitoring are necessary and contribute substantially to the cost of care. Poor glycaemic, blood pressure and lipid control leads to a high prevalence of macrovascular and microvascular complications further increasing the cost of care.

Cardiovascular disease is the commonest cause of death in patients with type 2 diabetes.1 Cardiovascular event rates are two- to threefold higher in type 2 diabetics with a high case fatality rate and worse outcome after coronary revascularisation when compared to non-diabetic controls.2 The pathogenesis of atherosclerosis in type 2 diabetes is complex and multifactorial.3 The role of strict glycaemic control in reducing cardiovascular events has been controversial.4-7 However, there is no doubt that glycaemic control is an important component of overall diabetes management. Many studies have shown that good glycaemic control reduces microvascular complications. However there is no conclusive evidence that improving glycaemic control in patients with long-standing diabetes reduces cardiovascular risk8 although epidemiological evidence consistently identifies elevated HbA1C as a CV risk factor9;10 and long-term follow-up of diabetes trials suggests that good glycaemic control early in the disease may be rewarded with lower cardiovascular event rates many years down the line.11;12

Traditionally, the medical profession has viewed type 2 diabetes as a primarily metabolic disorder characterised by hyperglycaemia. Considering that most patients with type 2 diabetes die of cardiovascular disease it may be appropriate to shift focus and view type 2 diabetes as a high cardiovascular risk state accompanied by hyperglycaemia. This shifts the therapeutic focus from

purely controlling hyperglycaemia to asking whether hypoglycaemic therapy also reduces cardiovascular risk or at least does not increase it further. This question is particularly topical considering the recent controversy regarding the cardiovascular safety of glitazones and the removal of rosiglitazone from the market.4 This article reviews the data on the cardiovascular safety of another class of agents, the sulfonylureas, which are prescribed extensively in diabetes.

Sulphonylureas Metformin is the standard first-line oral hypoglycaemic recommended in most guidelines. Guidelines recommend metformin because it generally does not lead to weight gain, rarely causes hypoglycaemia as monotherapy, is safe when prescribed appropriately, may have cardioprotective effects, may protect against some cancers and is inexpensive and readily available.13 However, many patients do not achieve adequate glycaemic control on metformin alone and will require a second agent. Guidelines do not recommend one class of agent over another

as second line therapy and physicians are free to add either a sulfonylurea, basal insulin or a glitazone (with caution). In practice, sulfonylureas are the most popular choice as they are effective, easy to use and also relatively inexpensive. Because they are taken orally, they are also more acceptable than insulin to most patients. However, since the publication of the University Group Diabetes Programme (UGDP) in 1970 where it was found that cardiovascular mortality was higher in patients treated with tolbutamide compared to those on insulin or placebo, there have been ongoing concerns regarding the cardiovascular safety of sulfonylureas.14

Mechanism of action of sulfonylureasSulfonylureas are insulin secretagogues. They act by binding to and closing ATP-dependant potassium (K+) channels in pancreatic beta-cells (SUR1/Kir 6.2). Closure of these channels leads to beta-cell depolarisation, calcium influx and subsequent insulin release. This effect on ATP-dependant K+ channels has lead to concerns regarding the cardiovascular safety of sulfonylureas as similar, but not identical, channels are also found in the myocardium (SUR2A) and in vessels (SUR2B).15 In the myocardium sulfonylureas may inhibit ischaemic preconditioning by binding to these channels and inhibiting their opening during periods of ischaemia. The cell is then unable to hyperpolarise and protect itself against recurrent ischemia by impeding calcium influx. This effect on ischemic preconditioning is not seen with all sulfonylureas and has not been reported with the newer, more pancreas-specific sulfonylureas, viz. gliclazide, glipizide and glimepiride.15-18

Cardiovascular outcomes with sulfonylureasCardiovascular outcome studies with sulfonylureas have conflicting results. Some studies have suggested cardiovascular harm from sulfonylureas; many report neutral effects and some studies suggest benefit.19

These studies were done at different times with different sulfonylureas, in different populations (e.g. patients with or without known cardiovascular disease) and with very different concomitant medications for other cardiovascular risk factors such as hypertension and dyslipidaemia. Also,

Since the publication of the University Group Diabetes Programme (UGDP) in 1970, where it was found that cardiovascular mortality was higher in patients treated with tolbutamide compared to those on insulin or placebo, there have been ongoing concerns regarding the cardiovascular safety of sulfonylureas.14

Volume 2 No 2 June 2011 Page 6

many studies were not designed with cardiovascular outcomes as the primary endpoint. Much data derives from retrospective analyses and cohort studies and is therefore potentially subject to confounding bias. Non-randomised studies in which cardiovascular events are not the primary outcome must therefore always be interpreted with caution. For instance many studies have shown higher cardiovascular mortality in patients treated with insulin.20 This does not mean that insulin has cardiovascular toxicity but is explained by the fact that insulin prescription usually correlates with longer durations of diabetes and is therefore a risk marker rather than a risk factor.

The UGDP study that raised initial concerns about the cardiovascular safety of sulfonylureas treated patients with tolbutamide a first generation sulfonylurea that is no longer used today. The UGDP was also subsequently heavily criticised for study design flaws. In the United Kingdom Prospective Diabetes Study (UKPDS) newly diagnosed diabetics free of overt cardiovascular disease were treated with chlorpropamide, glibenclamide or glipizide with a marginally significant reduction in cardiovascular outcomes in the sulfonylurea group compared to the dietary therapy group.21 Long-term follow-up of patients from the UKPDS showed that therapy with sulfonylureas compared to dietary management was associated with improved outcomes.11 The patients that were randomised to sulfonylureas were therefore not harmed by taking the sulfonylurea but ultimately benefited. Glibenclamide differs from other modern sulfonylureasOf the sulfonylureas still in common use the cardiovascular safety of glibenclamide is of special concern as it has been shown to negatively affect ischemic preconditioning in vitro.22 In a French registry study of diabetic patients admitted to hospital following acute myocardial infarction in-patient mortality was much higher (7.5%) in patients taking glibenclamide than in those taking gliclazide or glimepiride (2.7%).20 This was clearly not a randomised trial and allocation bias, incomplete data collection and other confounders may have affected the results. The results, however, remained essentially unchanged following multiple statistical adjustments and data was collected prospectively rather than

retrospectively abstracted from medical records. In an Italian observational study the odds ratio for mortality in patients treated with the combination of glibenclamide and metformin was about twice that seen in patients treated with metformin in combination with either gliclazide, glimepiride or repaglinide.23 A Danish study also found an increased risk of myocardial infarction in patients prescribed glibenclamide rather than glimepiride or gliclazide.24 Glibenclamide also causes more hypoglycaemia than either gliclazide or glimepiride.25 However glibenclamide does not lower glycated haemoglobin (HbAIC) more than other sulfonylureas. A strong case can therefore be made for no longer prescribing glibenclamide considering its propensity to cause hypoglycaemia and its doubtful cardiovascular safety. 26

Sulfonylureas in combination with metforminMetformin and sulfonylureas are very commonly prescribed in combination but there is surprisingly little data regarding the safety of this combination. In the UKPDS patients treated with combination therapy had higher mortality rates than those treated with sulfonylurea monotherapy.21

In a recent meta-analysis, the combination of metformin with a sulfonylurea was associated with a higher relative risk for the composite endpoint of cardiovascular disease hospitalisation and mortality (RR

1.43; 95% confidence interval 1.10 to 1.85). Cardiovascular or all-cause mortality analysed individually were not statistically different. 27 This meta-analysis could not conclusively adjudicate the cardiovascular safety of combination therapy as it was plagued by very wide confidence intervals, marked heterogeneity between the various studies, differences in the reference group and residual confounding with patients on combination therapy often having a longer duration of disease and possibly more aggressive disease that progressed more rapidly. The study also did not differentiate between the various sulfonylureas.

Patients with pre-existing ischemic heart diseaseThe optimal treatment of hyperglycaemia in patients with pre-existing ischemic heart disease (IHD) has not been determined conclusively. Glibenclamide as monotherapy or in combination with metformin should be avoided.28 In the BARI-2D study patients with pre-existing IHD were randomised to either treatment using an insulin provision strategy (insulin or sulfonylurea) or an insulin sensitisation strategy (metformin or glitazone). Cardiac outcomes did not differ significantly between the two glucose control strategies although insulin sensitisation was associated with less weight gain, less hypoglycaemia and higher high density lipoprotein cholesterol.29 Some patients in the insulin sensitisation group required addition of insulin or sulfonylureas to achieve glycaemic control. The combination of metformin with sulfonylureas was not specifically tested. Insulin sensitisation may therefore be a better initial strategy in diabetics with CAD based on data from intermediary outcomes. However, it is important not to lose focus on the debate about how to control glycaemia in those with diabetes and IHD and forget about the benefits of blood pressure control, lipid-lowering, smoking cessation and appropriate revascularisation strategy. Getting each of these modalities right is likely to produce greater benefits for the individual than choosing the “correct” hypoglycaemic therapy.

ConclusionSulfonylureas were introduced into medical practice more than forty years ago and licensed based on their demonstrated ability to lower blood glucose. Cardiovascular outcome data

Metformin and sulfonylureas are very commonly prescribed in combination but there is surprisingly little data regarding the safety of this combination.

Page 7 Volume 2 No 2 June 2011

were not required and specific studies addressing this issue were not requested by licensing authorities. We are therefore left with a mixed bag of data, with the majority of evidence suggesting that while there is no certain evidence that sulfonylureas are cardioprotective there is also no convincing evidence of cardiovascular harm particularly if the older sulfonylureas including glibenclamide are avoided. Sulfonylureas do cause weight gain and hypoglycaemia and these known disadvantages must be weighed against their ease of use and low cost when deciding on therapy for the individual patient.

Newer oral hypoglycaemic agents such as the glitazones and DPP-IV inhibitors act via mechanisms different to sulfonylureas and may theoretically be associated with improved cardiovascular outcomes apart from causing less hypoglycaemia and weight neutrality for DPP-IV inhibitors. That the transition from theoretical attraction to proven clinical efficiency is difficult is illustrated by rosiglitazone which ultimately had to be withdrawn from the market because of ongoing concerns regarding its cardiovascular safety. DPP-IV inhibitors are likely the last class of hypoglycaemic agents to be licensed without cardiovascular outcome data since the FDA now requires more stringent assessment following the rosiglitazone debacle. What we ultimately need are large outcome studies comparing modern sulfonylureas with metformin and newer hypoglycaemic agents both as monotherapy and in combinations.26 It remains to be seen whether the pharmaceutical industry or other funding agencies rise to this challenge.

ReferencesStamler J, Vaccaro O, Neaton JD, Wentworth 1. D. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993; 16(2):434-444.Stone PH, Muller JE, Hartwell T, York BJ, Rutherford 2. JD, Parker CB et al. The effect of diabetes mellitus on prognosis and serial left ventricular function after acute myocardial infarction: contribution of both coronary disease and diastolic left ventricular dysfunction to the adverse prognosis. The MILIS Study Group. J Am Coll Cardiol 1989; 14(1):49-57.Bianchi C, Penno G, Malloggi L, Barontini R, Corfini 3. M, Giovannitti MG et al. Non-traditional markers of atherosclerosis potentiate the risk of coronary heart disease in patients with type 2 diabetes and metabolic syndrome. Nutr Metab Cardiovasc Dis 2008; 18(1):31-38.Stafylas PC, Sarafidis PA, Lasaridis AN. The 4. controversial effects of thiazolidinediones on

cardiovascular morbidity and mortality. Int J Cardiol 2009; 131(3):298-304.Sherifali D, Punthakee Z. To lower or not to lower? 5. Making sense of the latest research on intensive glycaemic control and cardiovascular outcomes. Evid Based Med 2009; 14(2):34-37.Ray KK, Seshasai SR, Wijesuriya S, Sivakumaran 6. R, Nethercott S, Preiss D et al. Effect of intensive control of glucose on cardiovascular outcomes and death in patients with diabetes mellitus: a meta-analysis of randomised controlled trials. Lancet 2009; 373(9677):1765-1772.Hill D, Fisher M. The effect of intensive glycaemic 7. control on cardiovascular outcomes. Diabetes Obes Metab 2010; 12(8):641-647.Schernthaner G. Diabetes and Cardiovascular 8. Disease: Is intensive glucose control beneficial or deadly? Lessons from ACCORD, ADVANCE, VADT, UKPDS, PROactive, and NICE-SUGAR. Wien Med Wochenschr 2010; 160(1-2):8-19.Coutinho M, Gerstein HC, Wang Y, Yusuf S. The 9. relationship between glucose and incident cardiovascular events. A metaregression analysis of published data from 20 studies of 95,783 individuals followed for 12.4 years. Diabetes Care 1999; 22(2):233-240.Khaw KT, Wareham N, Luben R, Bingham S, Oakes 10. S, Welch A et al. Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of european prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ 2001; 322(7277):15-18.Holman RR, Paul SK, Bethel MA, Matthews DR, 11. Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008; 359(15):1577-1589.Nathan DM, Cleary PA, Backlund JY, Genuth SM, 12. Lachin JM, Orchard TJ et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med 2005; 353(25):2643-2653.Nathan DM, Buse JB, Davidson MB, Ferrannini E, 13. Holman RR, Sherwin R et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of

therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 2009; 32(1):193-203.Meinert CL, Knatterud GL, Prout TE, Klimt CR. A 14. study of the effects of hypoglycemic agents on vascular complications in patients with adult-onset diabetes. II. Mortality results. Diabetes 1970; 19:Suppl-830.Lee TM, Chou TF. Impairment of myocardial 15. protection in type 2 diabetic patients. J Clin Endocrinol Metab 2003; 88(2):531-537.Flynn DM, Smith AH, Treadway JL, Levy CB, Soeller 16. WC, Boettner WA et al. The sulfonylurea glipizide does not inhibit ischemic preconditioning in anesthetised rabbits. Cardiovasc Drugs Ther 2005; 19(5):337-346.Maddock HL, Siedlecka SM, Yellon DM. Myocardial 17. protection from either ischaemic preconditioning or nicorandil is not blocked by gliclazide. Cardiovasc Drugs Ther 2004; 18(2):113-119.Mocanu MM, Maddock HL, Baxter GF, Lawrence 18. CL, Standen NB, Yellon DM. Glimepiride, a novel sulfonylurea, does not abolish myocardial protection afforded by either ischemic preconditioning or diazoxide. Circulation 2001; 103(25):3111-3116.Bianchi C, Miccoli R, Daniele G, Penno G, Del Prato 19. S. Is there evidence that oral hypoglycemic agents reduce cardiovascular morbidity/mortality? Yes. Diabetes Care 2009; 32 Suppl 2:S342-S348.Zeller M, Danchin N, Simon D, Vahanian A, Lorgis 20. L, Cottin Y et al. Impact of type of preadmission sulfonylureas on mortality and cardiovascular outcomes in diabetic patients with acute myocardial infarction. J Clin Endocrinol Metab 2010; 95(11):4993-5002.Intensive blood-glucose control with 21. sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998; 352(9131):837-853.Riddle MC. Editorial: sulfonylureas differ in 22. effects on ischemic preconditioning--is it time to retire glyburide? J Clin Endocrinol Metab 2003; 88(2):528-530.Monami M, Luzzi C, Lamanna C, Chiasserini 23. V, Addante F, Desideri CM et al. Three-year mortality in diabetic patients treated with different combinations of insulin secretagogues and metformin. Diabetes Metab Res Rev 2006; 22(6):477-482.Johnsen SP, Monster TB, Olsen ML, Thisted H, 24. McLaughlin JK, Sorensen HT et al. Risk and short-term prognosis of myocardial infarction among users of antidiabetic drugs. Am J Ther 2006; 13(2):134-140.van Staa T, Abenhaim L, Monette J. Rates of 25. hypoglycemia in users of sulfonylureas. J Clin Epidemiol 1997; 50(6):735-741.Riddle MC. More reasons to say goodbye to 26. glyburide. J Clin Endocrinol Metab 2010; 95(11):4867-4870.Rao AD, Kuhadiya N, Reynolds K, Fonseca VA. Is 27. the combination of sulfonylureas and metformin associated with an increased risk of cardiovascular disease or all-cause mortality?: a meta-analysis of observational studies. Diabetes Care 2008; 31(8):1672-1678.Fisman EZ, Tenenbaum A, Motro M, Adler Y. Oral 28. antidiabetic therapy in patients with heart disease. A cardiologic standpoint. Herz 2004; 29(3):290-298.Frye RL, August P, Brooks MM, Hardison RM, 29. Kelsey SF, MacGregor JM et al. A randomised trial of therapies for type 2 diabetes and coronary artery disease. N Engl J Med 2009; 360(24):2503-2515.

Newer oral hypoglycaemic agents such as the glitazones and DPP-IV inhibitors act via mechanisms different to sulfonylureas and may theoretically be associated with improved cardiovascular outcomes

Volume 2 No 2 June 2011 Page 8

Grant Pettitt, B. Comm CA (SA)Chief Financial Officer , sanofi-aventis south africa (pty) ltd 1996/010381/07,

a member of the SANOFI Group

Sound practice management

ust as you care for your health, having regular check-ups, so too should you care for your finances. Producing income consumes your valuable time every day and is crucial for your day-to-day and long term

welfare. However it is also an area that far too many people find mystifying. This article seeks to demystify the subject and assist you in assessing and managing your financial position with more confidence. Because you wouldn’t begrudge the hour you squeeze into your schedule for exercise, why begrudge the time spent reviewing your financial health?

Financial Reports

Your accountant or auditor produces financial accounts for a certain specified period. These reports will most likely consist of two key documents – an income statement or profit and loss account and a balance sheet. Possibly the first thoughts that come to mind when reading them are where to start and how to interpret what are they telling you.

Most people will go straight to the income statement. This reflects a natural interest in seeing how much profit has been made. This approach may be of little value; a lot of businesses make great profits but don’t succeed because they can’t make cash. So start with your balance sheet. You need to ask:

Has cash been generated? 1. Cash can be in a variety of forms – loans, overdrafts, loans from you the owner and cash investments. Whatever the structure of your business financing, ask whether you are increasing your holding in cash each month or reducing your borrowings. If yes, you are in a strong position; if no; drastic action is needed.

Items where cash generation can be improved are:

Debtorsa. Debtors – those who owe you money – are normally the greatest problem. Two pointers to watch are

the amount outstanding andi. Days’ Sales Outstanding or DSO. ii. DSO measures how many days of income is owed to your practice. If both the outstanding amount and DSO are increasing you need action urgently as it indicates that patients are taking longer and longer to pay. If the value is increasing but the DSO is going down – give your debtors clerk a bonus as this means your income is growing and the cash is coming into the business quicker.

Stockb. As with debtors, watch the two pointers on a monthly basis:

the amount of stock on hand and i. another ratio called stock ii. turnover which measures how many times you sell or use your stock in a year. The million Rand question is always how much stock and there is no one answer to this. It will really depend on your practice and your suppliers – how reliable are they? How

quickly can they deliver? And remember that special price for a big order may not be that special as there are a lot of hidden costs in inventory such as the cost to finance stock, the cost of storage and available space, the cost of shrinkage and the cost of wastage. Also don’t buy every day except for certain particular items as this also has the hidden costs of administration, handling and interruptions in someone’s daily work activities.

Creditors c. A simple answer is pay late as that will generate cash. This is entirely true but an alternative view is negotiate hard with suppliers on the price and on the payment terms. However, once agreed, be sure to honour the terms. Many a practice will go through a bad time at some time or another when it really cannot pay and that’s when you need help from your suppliers. A good customer will almost always get support from the supplier who knows that you are reliable and will keep to your commitments.

The next question is whether a 2. profit has been made or not. The income statement will reflect the position and indicate whether it is better or worse than previously.

Drivers that improve profit are:Increase sales or income a. But, you will probably ask, how do I do this? I cannot increase my fees and I’m already working 16 hours a day. The answer lies in the way you work, how you perform procedures, how you set up procedures, whether your nurse or an assistant can do some of the work you do yourself. Quality of care must not change but how you provide quality can. A lot is currently written about an Indian cardiology hospital formed by a Dr Shetty which has just announced the building of a facility in the Cayman Islands to attract the American patients. His procedures cost a small

Because you wouldn’t begrudge the hour you squeeze into your schedule for exercise, why begrudge the time spent reviewing your financial health?

Page 9 Volume 2 No 2 June 2011

percentage of what US facilities charge and studies report that his outcomes are comparable to those in US facilities. A number of factors make him successful including reviewing how his facility works and organises its procedures. It may be well worthwhile considering a similar approach to one’s practice.Containing the cost of running the b. practice Examine:

expenses and i. the ratio of expenses to income. ii. This ratio is important as it shows whether or not your business is running efficiently. A ratio that increases is bad news and mandates cutting down on any unnecessary costs.

Evaluating gross profit c. The important item is your gross profit as a percentage of sales or income. This is an indicator of how your practice is doing and not an absolute. Practitioners often focus on the percentage profit they make and not on the amount of profit. Remember your bank manager wants repayment in Rand!

A report not very often used is the cash flow statement. This shows essentially where your money is coming from and where it is going to. It’s usually one of the most complicated of all the financial reports. However there is no need to have this report strictly in IFRS or GAAP formats. Have your accountant or auditor give you one that makes sense to you. Of all financial reports, the cash flow statement allows you to draw the most important conclusions. A budget is a necessity which allows you to see how you are tracking against your plans. How much detail you want is up to the practice owner.

So next month ask your accountant or auditor for two new reports:

a simplified cash flow statement 1. anda report of ratio’s or Key 2. Performance Indicators (KPI’s) but

no more than five ratio’s that are important to you.

Compare this month vs. last month vs. the same month last year and vs. the budget if you have one. It is also recommended that you colour them green (better than last month) or red (worse than last month) as within 10 seconds you will be able to see what needs urgent attention and what does not.

Investment

With the constraints imposed by current laws and regulations, specific investment advice is inappropriate. However, these are some tried and trusted principles:

Financial and investment advisors 1. are specialists in their field. Choose an advisor with whom you are comfortable and who communicates well. If you are a natural risk taker, don’t use an advisor that is conservative and prefers low risk investments, and vice versa. If you are someone that expects answers in five minutes, don’t use someone who is slow to respond or too busy to react quickly. Once you

have found your advisor, work on building a long-term relationship. Over time, both parties will develop the good understanding and communication that is important in any relationship.Look at the type of product you wish 2. to invest in and understand how it will work. If you have problems in understanding an investment product, stay away.Unbelievable returns are a warning 3. sign, even if the specialist in the rooms next door has been getting these unbelievable returns for some time now. A lot of schemes take a while before they collapse.Understand how your investment 4. advisor is getting paid for what he/she is advising you. Ask him/her to detail what they receive. It’s your money and you have the right to know.What sort of communication will 5. you get on the results of your investment? Some investment administrators give detailed daily updates via the internet, while others provide a short written report at the end of each year which tells you nothing. You need good information on how your investment is progressing.Maintain a balanced portfolio. 6. Never have all your eggs in one basket.When investing the old adage 7. of “time in the market is more important that timing the market” is 100% true. We all like to say, “I bought at rock bottom price and I sold at top price,” but the chance of getting this right every time is extremely small.

I trust that these thoughts will prove helpful. Do not forget, even if you are at the pinnacle of the medical profession, finance and investment is someone else’s profession, so do not hesitate to seek advice from the experts.

Do not forget, even if you are at the pinnacle of the medical profession, finance and investment are someone else’s profession, so do not hesitate to seek advice from the experts.

Volume 2 No 2 June 2011 Page 10

The ARBs Trialists Collaboration.J Hypertens 2011; 29: 623-35.

Objective:Candesartan, irbesartan, telmisartan, valsartan and losartan were assessed for incident cancers in 15 large parallel long-term multicenter double-blind clinical trials of these agents involving 138 769 participants.

Overview:ARBs reduce blood pressure and

cardiovascular and renal disease in high risk individuals, but there is conflicting data on risk of cancer. Angiotensin II stimulates neovascularisation, a requirement for tumour growth, and therefore both ACE inhibitors and ARBs may reduce risk of cancer especially in animal models. A recent meta-analysis by Sipahi et al caused considerable concern amongst physicians and patients alike when they reported that ARBs, particularly telmisartan, may be associated with increased risk of cancer, although no pathophysiological mechanism could explain the findings. In fact, the increased cancer risk was seen only in patients who received ARBs and ACE inhibitors in combination, raising concerns about the validity of these findings.

New Evidence:The ARB trialists conducted a new meta-analysis of all 15 randomised controlled long-term clinical trials on 5 ARBs, each of which enrolled at least 500 patients and had an average follow-up of at least 12 months because cancer risk would take that much time to become evident. Overall data was available on 134 914 patients of the 138 769 enrolled into these studies. Overall the cancer risk was 6.16% in the ARB treatment vs. 6.31% assigned to non-ARB treatment (OR 1, 95% CI 0.95-1.04, p=0.86). There was no increased risk associated with any individual ARB, combination therapy with ACE inhibitor or in comparison to ACE inhibitors. There was also no increased risk of lung, breast or prostate cancer.

Comment:This study should reassure both physicians and patients alike that ARBs or combination of ARBs and ACE inhibitors are not associated with cancer. Importantly this study included a further 75 000 patients not included in the Sipahi meta-analysis, and all the data was tabulated directly from the investigators thus avoiding publication or reporting bias. In addition the reported increased risk of lung cancer by Sipahi was based on only 5 ARB trials. In conclusion ARBs are not associated with increased cancer risk whereas their cardiovascular, cerebrovascular and renal benefits are well established.

Reviewed by Professor Brian Rayner

Commentary on Current Journal Articles

ARBs and cancers: a meta-analysis of 15 trials.

Jong-Young L, Duk-Woo P, Young-Hak K et al.J Am Coll Cardiol, 2011; 57:1349-1358

Study Question: What is the incidence and what are the predictors and long-term outcomes of patients with in-stent restenosis (ISR) after percutaneous coronary intervention (PCI) with drug-eluting stents (DES) for unprotected left main coronary artery (LMCA) disease?

Background: There is little information about the clinical course and management of patients experiencing restenosis after DES treatment for unprotected LMCA disease.

Methods: Between February 2003 and November 2007, 509 consecutive patients with unprotected LMCA disease underwent DES implantation, with 402 (80.1%) undergoing routine surveillance or clinically driven angiographic follow-up. A major adverse cardiac event was defined as the composite of death, myocardial infarction (MI), or target-lesion revascularisation.

Results: The overall incidence of angiographic in-stent restenosis in LMCA lesions was 17.6% (71 of 402 patients), 57 with focal-type and 14 with diffuse-type ISR. Forty patients (56.3%) underwent repeat PCI, 10 (14.1%) underwent bypass surgery, and 21 (29.6%) were treated medically. During long-term follow-up (a median of 31.7 months), there were no deaths, 1 (2.2%) MI, and 6 (9.5%) repeated target-lesion revascularisation cases. The incidence of major adverse cardiac events was 14.4% in the medical group, 13.6% in the repeat PCI group, and 10.0% in the bypass surgery group (p = 0.91). Multivariate analysis showed that the occurrence of DES-ISR did not affect the risk of death or MI.

Conclusions: The incidence of ISR was 17.6% after DES stenting for LMCA patients with unprotected LMCA disease. Female sex, initial restenotic lesions, distal bifurcation lesions, and the use of complex procedures were identified as major predictors of LMCA-ISR.

Comments: The long-term clinical prognosis of patients with DES-ISR associated with LMCA stenting might be benign, given that the treatment of these patients was guided by the treating physician’s clinical judgment.

Reviewed by Dr Len Steingo

CPD AccreditationDoctors can acquire CPD points with this newsletter by visiting www.saheart.org.za (Cardiologists), www.mycpd.co.za (GPs), www.mycpd.co.za (Physicians) and completing an online form of ±15 questions. Accreditation is available only for a limited time on the site. Should you have any queries regarding the accreditation, please contact E2 Solutions at: 011 888 9620 or 011 340 9100 or gertrude@e2.co.za

Incidence, Predictors, Treatment, and Long-Term Prognosis of Patients With Restenosis After Drug-Eluting Stent Implantation for Unprotected Left Main Coronary Artery Disease

Page 11 Volume 2 No 2 June 2011

Hsia J, MacFayden JG, Monyak J et al.

J Am Coll Cardiol, 2011; 57, 1666-75 Study question: Were there benefits and / or additional side-effects in patients who achieved very low LDL cholesterol levels (<1.3 mmol) during the JUPITER trial?

Background: The JUPITER trial evaluated the effect of

rosuvastatin 20 mg daily vs. placebo in asymptomatic patients with no history of cardiovascular disease or diabetes who had an an LDL cholesterol <3.4 mmol and an high sensitivity CRP of >2 mg/L. The main trial showed a benefit of treatment in this apparently low risk group. There was a 44% reduction in the composite of death, myocardial infarction, stroke and unstable angina, regardless of the baseline LDL cholesterol.

Methods:Subjects whose on-treatment lipid profile was evaluated during the trial were included. This group was divided according to whether they received placebo (8 150 subjects) or attained an on-treatment LDL cholesterol >1.3 mmol (4 000 subjects) or <1.3 mmol (4 154 subjects).

Results:The primary endpoint of death, myocardial infarction and stroke was

Cardiovascular Event Reduction and Adverse Events Among Subjects Attaining Low-Density Lipoprotein Cholesterol <50 mg/dl With Rosuvastatin

Tantry US, Kereiakes DJ and Gurbel PA.

J Am Coll Cardiol Intv, 2011; 4, 365-80 Purpose: Dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is used to prevent recurrent ischaemic events after acute coronary syndromes and after stent implantation. DAPT is associated with an increased bleeding risk which is predominantly gastrointestinal in origin. In this setting, proton pump inhibitors

(PPI’s) have been recommended to prevent gastrointestinal bleeding (GIB). This state-of-the-art paper examines in detail the interactions between PPI’s and DAPT.

Important points: Prolonged aspirin therapy is associated with gastrointestinal ulceration and bleeding. Aspirin inhibits prostaglandins that increase mucosal blood flow, proliferation of gastric epithelial cells and stimulate mucous and bicarbonate secretion. Aspirin also inhibits production of thromboxane A2 that promotes platelet aggregation and growth factor release at sites of vascular injury. Collectively, these inhibitory effects of aspirin increase susceptibility to both ulceration and bleeding.

Unlike aspirin, clopidogrel does not cause gastric mucosal injury but may exacerbate bleeding and retard healing.

DAPT carries an increased risk of GIB especially in the elderly and in high bleeding risk patients and provides the rationale for concomitant PPI therapy.

Clopidogrel absorption is aided by p-glycoprotein transporter and is metabolised to its active form by a series of cytochrome P450 (CYP) isoenzymes. Polymorphisms of CYP, especially CYP2C19*2, as well as

Clopidogrel and Proton Pump Inhibitors. Influence of Pharmacological Interactions on Clinical Outcomes and Mechanistic Explanations.

lower in those whose LDL was <1.3 mmol during the trial. Compared to placebo, the risk of the primary endpoint was reduced by 65% vs. 24% for those who did not attain these low values.

The rates of adverse events were similar whether low or very low LDL cholesterol values were achieved during the trial. There was no increment in the frequency of myalgia, muscle weakness or myopathy between the two treated groups. Psychiatric conditions, fatigue, peripheral neuropathy, haemorrhagic stroke, cancer, elevation in AST, proteinuria and renal failure did not differ significantly between the groups, nor from the placebo group. Small non-significant increments in the frequency of diabetes and haematuria were observed in the group with LDL cholesterol <1.3 mmol.

Comment: While this study is a sub-group analysis of a trial and thus “hypothesis generating”, it includes a large group of subjects and illustrates the effectiveness and safety of treating with potent statin therapy to achieve very low levels of LDL cholesterol. The JUPITER trial aimed at primary prevention in subjects who according to existing guidelines would not have qualified for lipid-lowering therapy; whose LDL cholesterol was <3.4 mmol and CRP >2 mg/L. Though the results are not strictly applicable to patients with established atherosclerotic vascular disease or diabetes who require very stringent control of their LDL cholesterol, it provides supportive evidence of the greater benefit and, in particular, the safety of doing so.

Reviewed Dr Tony Dalby

drug interactions affect clopidogrel metabolism and may reduce its antiplatelet efficacy.

Omeprazole absorption also is influenced by p-glycoprotein transporter and is hydroxylated by CYP2C19. All PPI’s with the exception of rabeprazole are metabolized to lesser or greater extent by CYP2C19 and CYP3A4 and competitively inhibit the these isoenzymes.Thus, PPI’s (and omeprazole in particular) may partially inhibit clopidogrel absorption and conversion to its active metabolite.

Multiple studies have demonstrated that PPI’s (in particular omeprazole) reduce the antiplatelet effect of clopidogrel and have suggested that co-administration may increase the incidence of recurrent ischaemic events. However the findings have been inconsistent. The authors of a recent randomised study concluded that there is no clinically relevant interaction between clopidogrel and PPI treatment.

If a clinically meaningful interaction between clopidogrel and PPI is suspected, possible alternative strategies are: 1. the use of rabeprazole or pantoprazole, 2. an increase in the maintenance dose of clopidogrel, 3. splitting the timing of clopidogrel and PPI administration as both have short plasma half-lives, 4. the use of prasugrel in place of clopidogrel, 5. the use of ticagrelor, a non-thienopyridine P2Y12 inhibitor, and 6. the use of an H2-receptor antagonist or antacid.

Comment: Cardiac patients require DAPT to prevent potentially fatal recurrent events. The cost of DAPT is an increased bleeding risk. Bleeding in this situation confers a worse prognosis for death and recurrent ischaemia. As the most frequent site of bleeding is in the gastrointestinal tract, the co-administration of a PPI to prevent bleeding seems logical. However, even if definitive evidence is lacking, it is wise to select the PPI expected to have the least influence upon clopidogrel’s antiplatelet effect.

Reviewed Dr Tony Dalby

Volume 2 No 2 June 2011 Page 12

Nielsen JC, Thomsen PEB, Højberg S et al.

Eur Heart J 2011; 32: 686-96.

Study QuestionWhich is the preferred permanent pacemaker in patients with sick sinus syndrome: single-lead atrial pacing (AAI-R) or dual-chamber pacing (DDD-R)?

BackgroundIt is well-established that, when compared

to AAI-R or DDD-R, single-lead ventricular pacing (VVI-R) is not acceptable for patients with sick sinus syndrome. Increases in mortality, atrial fibrillation and the pacemaker syndrome have been observed with VVI-R. On the other hand, AAI-R is associated with the development of atrioventricular block in around 1% of patients annually, and DDD-R may induce ventricular dyssynchrony as a result of unnecessary right ventricular apical pacing. No previous trial has compared AAI-R to DDD-R pacing for sick sinus syndrome.

MethodsThe DANPACE trial was an industry-funded, randomised unblinded comparison of AAI-R versus DDD-R pacing in 1 415 patients with sick sinus syndrome with follow-up for a mean of 5.4 years.

ResultsThe primary end-point of all-cause mortality did not differ between AAI-R and DDD-R pacing. The secondary end-points of permanent atrial fibrillation, stroke, peripheral embolism and heart failure also did not differ between AAI-R and DDD-R. Two secondary end-points that occurred more frequently with AAI-R-pacing were paroxysmal atrial fibrillation in 201 (28.4%) vs. 163 (23.0%) (HR=1.27 [1.03-1.56]; p = 0.024) and re-operation in 156 (22.1%) versus 84 (11.9%) (HR = 1.99 [1.53-2.59], p = <0.001). The difference in re-operations arose from the need for mode change; 66 (9.3%) in AAI-R versus 4 (0.6%) in DDD-R.

ConclusionsThe implantation of a ventricular lead (which resulted in 65% ventricular pacing) did not adversely affect survival. The implantation of a ventricular lead avoided re-operations to upgrade from AAI-R to DDD-R pacing because of the development of 2nd or 3rd AV block. The surprise finding of increased paroxysmal atrial fibrillation after AAI-R pacing is thought to be due to prolonged AV conduction resulting in reduced ventricular preload and mitral regurgitaton.

CommentsThe increase in paroxysmal atrial fibrillation is interesting, but the need for re-operation for upgrade to DDD-R was exaggerated by this study which allowed inclusion of patients with a prolonged PR interval (up to 0.22 seconds until age of 70 and up to 0.26 seconds in those over 70 years). The increased cost and complexity of implant and follow-up of a DDD-R versus an AAI-R system were not taken into account. In my view this study affirms the value of AAI-R pacing for sick sinus syndrome so long as there is no AV conduction abnormality.

Reviewed by Dr Ronald M Jardine

A comparison of single-lead atrial pacing with dual-chamber pacing in sick sinus syndrome

Vaclavik J, Sediak R, Plachy M et al.

Hypertension 2011; 57: 1069-1075

ObjectiveThis study was designed to assess the effect on BP of adding 25 mg spironolactone to their other antihypertensive agents in patients with resistant hypertension.

OverviewResistant hypertension is defined as a BP

persistently >140/90 mmHg in a compliant patient taking at least 3-4 antihypertensive drugs, one of which is a diuretic in adequate doses (e.g. hydrochlorothiazide 25 mg daily). It occurs in about 10-15% of treated hypertensives. The most common initial drug classes used are RAAS inhibitors, thiazide or thiazide-like diuretics, and/or β-blockers, but there is currently limited data on which drug should be used to improve blood pressure (BP) control in patients with resistant hypertension.

New EvidencePatients with office systolic BP >140 mm Hg or diastolic BP >90 mm Hg despite treatment with at least 3 antihypertensive drugs, including a diuretic, were enrolled in this double-blind, placebo-controlled, multicenter trial. One hundred seventeen patients were randomly assigned to receive either spironolactone (n=59) or a placebo (n=58) as an add-on to their antihypertensive medication. Analyses were done with 111 patients (55 in the spironolactone and 56 in the placebo groups). At 8 weeks, the primary end point, a difference in mean fall of BP on daytime ambulatory BP monitoring (ABPM), between the groups was –5.4 mm Hg (95%CI –10.0; –0.8) for systolic BP (P=0.024) and –1.0 mm Hg (95% CI –4.0; 2.0) for diastolic BP (P=0.358). The APBM nighttime systolic, 24-hour ABPM systolic, and office systolic BP values were significantly decreased by spironolactone (difference of –8.6, –9.8, and –6.5 mm Hg; P=0.011, 0.004, and 0.011), whereas the fall in the respective diastolic BP values was not significant (–3.0, –1.0, and –2.5 mm Hg; P=0.079, 0.405, and 0.079). A plasma renin activity (PRA) ≤1.34ng/ml and high aldosterone- renin ratio (ARR) > 7 best predicted the response to spironolactone.

CommentThis study provides further evidence for the utility of using low-dose spironolactone for patients with resistant hypertension. Doses above 50 mg should be avoided. The use of the PRA and ARR also adds weight to a targeted approach to using spironolactone to avoid the troublesome side-effects seen in some patients (gynaecomastia, erectile dysfunction, breast tenderness, and hyperkalaemia). Those patients with a suppressed PRA and high ARR had the best response whereas patients with high PRA and low ARR were least likely to respond. In South Africa renin and aldosterone are measured in different units. The recommended level for the direct renin assay is <4 mU/ml and an ARR >63 to predict response to spironolactone. Additionally it should be noted that all measurements were taken on therapy so there is no need to discontinue medication prior measuring aldosterone and renin.

Reviewed by Prof Brian Rayner

Addition of Spironolactone in Patients with Resistant Arterial Hypertension (ASPIRANT). A Randomised, Double-Blind, Placebo-Controlled Trial.

Page 13 Volume 2 No 2 June 2011

Gilboa SM, Salemi JL, Nembhard WN et al.Circulation. 2010; 122:2254-2263.

Study question: Does the trend of decreasing mortality resulting from congenital heart disease (CHD) among infants and young children, extend to older children and adults?

Background: Among infants and young children, congenital heart disease (CHD) is responsible for 30-50% of deaths caused by birth defects, Previous reports suggest

that mortality resulting from congenital heart disease (CHD) has been decreasing in this group but there is little population-based information on CHD mortality trends and patterns among older children and adults in whom the prevalence of CHD is increasing as a result of improved survival at younger ages.

Documentation of survival into middle age or beyond is typically available only from clinical or surgical series. Survival analyses based on birth defects surveillance system records linked to data from death certificates have been useful in understanding infant and child mortality but generally have not examined mortality into adulthood nor trends in CHD-related mortality over time. Such information is needed as a baseline for planning and evaluating the interventions needed to decrease losses to specialty care follow-up among children and adults with CHD and for on-going monitoring of CHD mortality among adults.

The aims of the present study were to examine recent temporal trends in mortality resulting from CHD from 1999 to 2006, to explore differences in CHD mortality by race-ethnicity and to determine whether CHD mortality has declined to the same extent among all race-ethnicities.

Methods and results: For these analyses, the US MCOD (multiple cause of death) data files from 1999 to 2006 were used to identify the underlying and contributing causes of CHD mortality. CHD was highest among non-Hispanic (NH) blacks compared with other race-ethnicities. Mortality caused by CHD was also higher among male than female individuals. Unspecified CHD (34.1%) and other specified CHD (18.8%) contributed the most to overall CHD mortality,

although among specific diagnoses, hypoplastic left heart syndrome was the greatest contributor.

Mortality resulting from CHD declined 24.1% overall and 3.6% annually during the period of 1999 to 2006. CHD mortality was highest among infants and lowest among children 5-17 years of age. Infant mortality caused by CHD decreased by 17.3% overall and 2.8% annually during the study period. Among children 1-4 years of age, mortality caused by CHD decreased 21.0% overall and 2.8% annually. There was a 34% increase in mortality among adults 18-34 years of age compared with children 5-17 years of age. Mortality resulting from CHD was unchanged among adults 18-64 years of age, with a marked increase among individuals over 65 years of age.

Overall, mortality among children 1-17 years of age accounted for 12.4% of all mortality caused by CHD and for 23.9% of mortality resulting from CHD among children who survived the first year of life. Thus, mortality among adults 18 years of age or older accounted for 76.1% of mortality resulting from CHD among individuals who survived infancy.

Conclusions: Children of all ages and adults in all age groups have experienced a significant decline in CHD mortality. Overall, infant and child mortality resulting from CHD was higher among NH blacks than among NH whites, and this difference persisted over time.

Comments: Despite the analytic potential of MCOD (multiple cause of death) analyses using death certificate data have limitations and these results should be interpreted with caution.

As CHD mortality continues to decline, and patients with CHD live longer, it is becoming increasingly important to plan for their ongoing care well into adulthood.

In addition to the management of the cardiac sequelae of CHD (e.g. hypertension, cardiac arrhythmias, and endocarditis), the effective care of these adults requires attention to the diagnosis and management of non-cardiac organ dysfunction such as renal impairment and abnormal glucose metabolism as well as counselling on issues such as contraception and pregnancy, potential genetic transmission of CHD, dental care, diet, optimal weight, exercise and physical activity.

Reviewed by Dr Jeff Harrisberg

Mortality Resulting From Congenital Heart Disease among Children and Adults in the United States, 1999 to 2006.

Event/Congress Date Venue Contact5th Congress of Asian Society of

Cardiovascular Imaging (ASCI 2011)

17-19 June 2011

Hong Kong Convention and Exhibition Center,Hong Kong, China

Email: hkcc@hkcchk.com Website: http://www.asci2011.org

EUROPACE 2011 (EHRA 2011) 26 - 29 June 2011

Centro de Conventiones Norte, Madrid

www.escardio.org/CONGRESSES/EHRA-EUROPACE-2011/Pages/welcome.aspx

ESC 2011 - European Society of Cardiology Congress 2011

27-31 August 2011

Paris Nord VillepinteParc d’Expositions Paris, France www.escardio.org/congresses/esc-2011/Pages/welcome.aspx

SA Heart 2011 23 -26 October 2011

East London International Convention Centre

ELICC East London, South Africa

www.saheart.co.zaE-mail Sonja du Plessis: sonja@londocor.co.za

Londocor Tel: +27 11 768 4355, Fax: +27 11 768 1174

Cardiology Congress Calendar 2011

The Paediatric Cardiac Society of South Africa is a voluntary professional association of paediatric cardiologists and cardiac surgeons with an interest in children with heart disease. The objectives of the Society are to improve the quality of care for children with congenital and acquired heart disease by promoting research and supporting education and training of heart specialists. The PCSSA is also the primary advocacy group for children with heart disease in South Africa.

HeFSSA’s mission is to ultimately improve the quality of care Heart Failure patients receive and to promote research and collaboration in all aspects of cardiovascular disease leading to heart failure with a special focus on conditions relevant to the population of Africa.

Contact InformationExecutive Officer - George Nel, Tel 083 458 5954, Fax 086 603 9885

e-mail: info@hefssa.org, www.hefssa.org

The mission of the Cardiac Arrhythmia Society of Southern Africa,an organisation of physicians, scientists and allied professionalsthroughout the subcontinent dedicated to the study and management of cardiac arrhythmia, is to improve the care of patients by promoting research, education and training and providing leadership towards optimal healthcare policies and standards.

Lipid and Atherosclerosis Society of South Africa

Aims of the SocietyLipids and lipoprotein metabolism and atherosclerosis and to facilitate contact between those interested in these areas of study and related subjects

Membership is open to any registered medical or paramedical practitio-ner providing that his/her specialist practice is confined to the speciality of Cardiothoracic Surgery or his/her practice is such as to give him/her a special interest in the subject of Cardiothoracic Surgery.

The Society of Cardiothoracic Surgeons of South Africa

SASCI is an organisation of physicians, scientists and allied professionals with an interest in the study and practice of percutaneous intervention to treat cardiovascular disease.

Contact InformationExecutive Officer - George Nel, Tel 083 458 5954, Fax 086 603 9885, e-mail: sasci@sasci.co.za, www.sasci.co.za

The South African Heart Association was formally constituted in September 1999, from the amalgamation of the Southern African Cardiac Society and the South African

Society of Cardiac Practitioners, becoming the sole organisation representing the professional interests of all cardiologists and cardio-thoracic surgeons in the country.

The South African Society for Cardiovascular Research (SASCAR) was created in 2009 as an interest group of the South African Heart Association (www.saheart.org).

We promote training and research in the cardiovascular field through various symposia, travel grants, an interactive website, workshops with other European Societies in the cardiovascular field, etc.

Contact information:Tel: +27 21 931-8210Fax: +27 21 931-8210Email: erika@saheart.orgWebsite: www.saheart.org

Executive Officer - Franciska du Toitfranciska@cassa.co.zaTel 082 806 1599Fax 086 661 4021www.cassa.co.za

Contact InformationTel: +27 (0)21 797 6112Fax: +27 (0)86 512 5629E-mail: info@pcssa.co.za, www.pcssa.co.za Contact Details

Prof. F.J. Raal, LASSA Secretary Department of Medicine, Johannesburg Hospital, Parktown, 2193 www.lassa.org.za/Tel: Prof. A.D. Marais (Chairperson): +27 (0)21 406 6125 or Prof. F.J. Raal: +27 (0)11 488 3538 email: frederick.raal@wits.ac.za

Contact InformationDr. E. Zigiriadis, Email: zigigabriel@hotmail.com, www.sctssa.org

Cardiac Imaging Society of South Africa (CISSA)

The Heart & Stroke Foundation South AfricaEstablished in 1980 with a vision to create a future where South Africans adopt healthy lifestyles and reduce the number of people who suffer or die from heart, stroke and blood vessel disease. Visit www.heartfoundation.co.za for free health information or call 021 447 4222. All press queries, contact murishca@heartfoundation.co.za

The Southern African Hypertension Society, affiliated to the World Hypertension League, was founded in 1977 by a handful of health professionals, a number of whom are still active in the Society today. It is a professional society open to all who work in the health sector and have an interest in hypertension, the related risk factors and target organ damage.

Contact information: Prof. G. Norton, Email: gavin.norton@wits.ac.za

Special Interest Groups

Other Societies

CISSA is a society dedicated to advancing education and setting standards in all aspects of cardiovascular imaging including echocardiography, magnetic resonance imaging, radionuclide imaging and computed tomography. Membership is open to any medical practitioner or allied healthcare worker registered with the South Africa Heart Association.

Contact: Professor M. R. Essop (essopmr@medicine.wits.ac.za)

STROKE SUPPORT GROUPSupport group for new stroke patients. For more info, visit:www.strokesupport.co.za

Glimepiride

Glimepiride

BALANCE IS EVERYTHING.

Deficiency

Resistance

SCHEDULING STATUS: PROPRIETARY NAME AND DOSAGE FORM: Amaryl®1 mg, per tablet: glimepiride 1 mg, Reg. No.: 30/21.2/0060. Amaryl® 2 mg, per tablet: glimepiride 2 mg, Reg. No.: 30/21.2/0061. Amaryl® 4 mg, per tablet: glimepiride 4 mg, Reg. No.: 30/21.2/0063. NAME AND ADDRESS OF APPLICANT: sanofi-aventis south africa (pty) ltd., Reg no.: 1996/10381/07, 2 Bond Street, Grand Central Ext. 1, Midrand, 1685. Tel: (011) 256 3700. Fax: (011) 256 3707. www.sanofi-aventis.com ZA.GLI.11.05.01

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