medical digest oct - dec 2011

Medicaldigest

Oct.Nov.Dec. 2011

MICA (P) 031/04/2010

contents1 STOP DENGUE

4 CLOPIDOGREL-PROTON PUMP INHIBITOR DRUG INTERACTION AND ITS CLINICAL RELEVANCE

10 DIFFERENT HEALTH CARE, PART 1

20 RADIOLOGY QUIZ

23 ECG QUIZ

From The Editor

Dr Leong Khai PangEDITOR

Medical Digest

I love lists, especially if they are about doctors and medicine. They contain adviceand instruction and sometimes amusement. Of course they are not gospel truthsand they often reveal the writers’ foibles and idiosyncrasies. For example, thislist is known as Loeb’s laws of Medicine (published in Matz R in NY State J Med1977; 77:99-101 and quoted by Zollo AJ in Medical Secrets, Hanley & Belfus,Inc, Philadelphia PS, 1991):1. If what youíre doing is working, keep doing it;2. If what youíre doing is not working, stop doing it;3. If you donít know what to do, donít do anything;4. Above all, never let a surgeon get your patient.

This 80-year-old list that is rather bitter and worldly (Brown WW. California andWestern Medicine 1926; 24:662):1. Thou shalt have no favorites in newspaper correspondents in order to see thy

name in print;2. Thou shalt not bow down to graft, nor to the image of gold;3. Thou shalt hold thy tongue when sued for malpractice, remembering silence

is golden and that thy adversary is after thy gold and will get it if thou art notdiscreet;

4. Remember the Sabbath day and keep it holy; six days shalt thou labor andon the seventh also, if thou hast an opportunity to do good or the prospectof a good fee;

5. Honor the fathers of thy profession, that thy days may be long upon the landand thy usefulness lengthened, through the example and achievements of thyfathers;

6. Thou shalt not sanction adultery nor produce an abort ion;7. Thou shalt not steal thy brother's patients nor forgive him when he steals

thine;8. Thou shalt not kill thy brother's opportunity for earning a living, nor murder

his chance of usefulness. He, probably, is thy superior;9. Thou shalt not bear false witness against thy neighbor, nor speak evil of his

good name. His reputation may be better than thine;10.Thou shalt not covet the specialist's fee, nor dispute over a division. Let him

have all the money; he may think he earned it. You must be content with glory.

Commandment number 7 of 21 from this list is worth a look (Zavehura P. WorldJ Surg 2005; 29:1200): “Give your patients all the time they need to talk to youand listen to what they say. If they don’t need surgery just yet, tell them so, evenwhen your schedule is empty. The word in the community will be that you don’toperate when unnecessary and they will come back to you for everything in thefuture.”

My favourite list was written circa 1640:1. Do not harbour sinister designs;2. Diligently pursue the Art;3. Cultivate a wide range of interests in the arts;4. Be knowledgeable in a variety of occupations;5. Be discreet regarding one’s commercial dealings;6. Nurture the ability to perceive the truth in all matters;7. Perceive that which cannot be seen by the eye;8. Do not be negligent, even in trifling matters;9. Do not engage in useless activity.Actually, it was not written by a doctor. Musahi (this translation comes fromBantam Books 1982) wrote them to teach us how we can the best in our profession.

But I think only two principles are sufficient, which has been underpinningeverything we publish in Medical Digest:1. In all things, think for yourself, after taking all facts and opinions into

consideration; and2. Do what is appropriate for the patient.

Thank you for supporting our magazine all these years. The editorial board wishesall Readers the very best in 2012.

Oct.Nov.Dec. 2011

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accurate at the time of publication,

Tan Tock Seng Hospital shall not be

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EDITORDr Leong Khai Pang

MEMBERSDr Jackie Tan

Dr Jaideepraj Rao

Dr Lee Cheng Chuan

Dr Khian Chong Yaw

Dr David Foo

Dr Gregory Kaw

Dr Nikol le Tan

Dr Ernest Kwek

Ms Lim Wan Peng

EDITORIALASSIST ANT

Ms Michelle Lee

DESIGNERMs Zaonah Yusof

Review

STOP Dengue

Dengue is the most rapidly spreadingmosquito-borne viral disease in theworld. In the last 50 years, incidencehas increased 30-fold with geographicexpansion to new countries. Anestimated 50 million dengue viralinfections occur annually andapproximately 2.5 billion people live indengue endemic countries accordingto the World Health Organisation(WHO).1 It is of no surprise that dengueremains one of the main themes at thisASTMH meeting. STOP Dengue, oneof the five high-profile local translational

clinical research programs, made asignificant impact at the meeting bypresenting high quality work. Theclinicians together with collaboratorspresented 5 posters and 2 oralpresentations. These include 2 postersselected for young investigatorcompetition and one poster for specialmention at poster-walk sessions bythe world experts.

The work presented at the meetingrange from accurate early diagnosisof dengue, early identification of those

likely to progress to severe disease,factors predicting fatal outcome, alandmark phase 2 dengue vaccine trial,estimating the burden of dengueinfections and comparing costeffect iveness i f vaccine wereintroduced to Singapore.

Dengue viral infection has been welldescribed to have a wide-spectrum ofclinical manifestations. The earlydisease is non-specific illness and itis challenging for clinicians todistinguish dengue from other febrile

1:M E D I C A L D I G E S T

This is a summary of the work we presented at the America Society of Tropical Medicine and Hygiene (ASTMH)Meeting at Philadelphia in December 2011.

This year marks the 60th annual meeting of the ASTMH. North America is well developed so that basic public hygieneis probably no longer an issue, but this may not be the case across the Americas and in many other part of the world.Conferences promoting global health through prevention and control of infectious diseases that disproportionatelyafflict the less-developed countries continue to stay relevance. This remains the focus of this meeting after 60 years.

illnesses. The Prospective AdultDengue Study (PADS) started recruitingparticipants with febrile illnesses atthe Communicable Disease Centre inJanuary 2010. This provided an idealplatform to develop and validate earlydiagnostic tools. Currently, the twocommonly used confirmatory tests inthe laboratory to diagnose dengue arethe polymerase chain reaction (PCR)and non-structural protein NS1 tests.Both tests have an average turnaroundtime of a day. We found that in the142laboratory-confirmed dengue patients,NS1 was comparable to PCR duringearly stage of illness and out-performed PCR at later stage of illnessfrom day 4 onwards.2 The next stageof our research is to study the differentNS1 rapid test kits aiming for a point-of-care-test that clinicians can rely onin the clinic to diagnose dengue in lessthan half an hour.

When we can diagnose dengue early,how do we best manage it? There isa wide range of disease manifestationsand most patients have mild tomoderate illness that can be safely

managed in the outpatient setting.However, a small proportion developsfatal illness. Early accurate predictionof severe illness is an area of intenseresearch. Which patients should beadmitted to hospital and how theyshould be managed remain importantclinical questions.

Using the same prospective cohort,PADS at Communicable DiseaseCentre, we validated two diagnosticmodels that were developed based onthe 2004 retrospective dengue cohort.The two models are the probabilityequation translated into a denguehemorrhagic fever (DHF) calculatorthat is available in the Cluster SharedPatient Record System (CPRS) and,the user-friendly clinician decisiontree.3,4 These two models weredesigned to identify risk factorsassociated with progression to severedisease fulfilling the criteria of denguehemorrhagic fever.5 Using theprospective PADS cohort, thesensitivity and specificity of denguehemorrhagic calculator and decisiontree for admission were 86% and 48%,

and 100% and 32%, respectively.6

This means that DHF calculator andthe decision tree identified 86% and100% of the dengue cases thatprogressed to DHF. These patientsshould ideally be hospitalized for closermonitoring and treatment. Highsensitivity was chosen over specificityin support of safer practice. Ironically,the definition of severe illness is stilldebated as there are two sets of WHOguidelines. Clearly, more work needsto be done.

The most severe form of dengueinfection results in mortality. Wereported 28 fatal cases from 5 majorpublic hospitals over 5 years from 2004to 2008.7 A case-control study wasconducted to identify predictors offatal outcome at the time of hospitaladmission. Cases and control werematched for age and duration of illness.

Using the definition of DHF in the 1997WHO dengue guidelines, only one thirdof the fatal cases were identified. Incontrast, with the severe denguedefinition in the WHO 2009 guidelines,

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all fatal cases could be identified.However, the warn ing s ignsrecommended in the 2009 WHOguidelines did not discriminate fatalcases and controls. Multivariateanalysis using clinical and laboratoryvariables showed that only white bloodcells and urea had weakly significantassociation with fatal outcome(adjusted odds ratio of 1.48 (95% CI1.004-2.2) and 1.64 (95% CI 1.1-2.45)respectively).8 To this day, the reasonswhy adults succumb to dengue remainelusive. Sadly, permission for academicautopsies to answer this question ishard to obtain in the Asian context.

To date, there is no anti-viral agenteffective against dengue. The work todevelop a dengue vaccine has beengoing on for more than three decades.This shows how difficult the challengehas been. Last year, one of the mostadvanced dengue vaccines wasstudied in a phase-3 clinical trial inThailand. Prior to that, this live-attenuated chimera vaccine combiningall 4 dengue serotypes (CYD-TDV)developed by Sanofi Pasteur wastested in Singapore. The phase-2

double-blind randomized 5-year study,involving participants aged 2 to 45years, was designed to assess safetyand immunogenicity. The volunteersreceived three injections at 0, 6 and12 months and are currently on post-vaccination follow-up to assessimmunogenicity over five years.Through this multi-centre study, it wasshown that the dengue vaccine has asimilar safety profile to control vaccines(influenza and hepatitis A vaccines). Asubstantial antibody increase close to80% and above against all 4 serotypeswas observed after the completion ofthe three CYD dengue injections.9

Another study assessing denguedisease burden and cost of diseaseprevention suggested that the denguevaccine if cost at reasonable amountcan achieve cost-effectiveness incontrolling dengue in Singapore.10

CONCLUSIONDengue continues to be a major publichealth problem in Singapore and thispart of the world. We are finding waysto detect the disease early, to predictthose who will develop life-threateningillness and to immunize those at risk.

The robust dengue research activitiesat Communicable Disease Centre willcontinue to produce results that canbe translated to clinical practice. It isalso a testament that Tan Tock SengHospital is well-placed to conductimpactful clinical research.

Associate Professor Leo Yee-Sin is theHead and senior consultant of theDepartment of Infectious Diseases, TanTock Seng Hospital.

References1. Dengue guidelines for diagnosis, treatment, prevention and control. The World Health Organization WHO 2009.2. Gan V, Dimatatac F, Thein TL, Leo YS and Lye DC. Rapid diagnosis of dengue in a hospital-based cohort. Am Society Trop Med Hyg 2011.

Abstract #1324.3. Lee VJ, Lye DC, Sun Y, Fernandez G, Ong A and Leo YS. Predictive value of simple clinical laboratory variables for dengue hemorrhagic fever

in adults. J Clin Virol 2008;42:34-9.4. Lee VJ, Lye DC, Sun Y and Leo YS. Decision tree algorithm in deciding hospitalization for adult patients with dengue hemorrhagic fever in

Singapore. Trop Med and International Health.2009;14(9):1154-9.5. Dengue haemorrhagic fever: diagnosis, reatment, prevention and control. 2nd Edition. Geneva: World Health Organization 1997.6. Gan V, Go CJ, Thein TL, Leo YS and Lye DC. Validation of dengue severity predictive algorithms derived from primary care and hospitalized cases

in a secondary care cohort. Am Society Trop Med Hyg 2011. Abstract #1323.7. Leo YS, Thein TL, Fisher D, Low JG, Oh HM, Narayanan R, et al. Confirmed adult dengue deaths in Singapore: 5-year multi-centre retrospective

study. BMV Infect Dis 2011;11:123.8. Thein TL, Gan V, Lee VJ, Fisher D, Lye DC and Leo YS. Risk factors for fatality among confirmed adult dengue inpatients in Singapore: a matched

case-control study. Am Society Trop Med Hyg 2011. Abstract #826.9. Leo YS, Wilder-Smith A, Shek L, Chong CY, Leong HN, Oh HLM, et al. Immunogenicity and large scale safety of the CYD live, attenuated tetravalent

dengue vaccine in 2-45 year-olds in Singapore. Am Society Trop Med Hyg 2011. Abstract #834.10. Carrasco LR, Lee LK, Lee VJ, Thein TL, Ooi EE, Cook AR, et al. Economic impact of dengue illness and the cost-effectiveness of future vaccination

programs in Singapore. Am Society Trop Med Hyg 2011. Abstract #1443.

M E D I C A L D I G E S T

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Phamaceutical Update

Clopidogrel-Proton Pump InhibitorDrug Interaction and itsClinical RelevanceAcute coronary syndromes (ACS), including unstable angina and myocardial infarctions (MI), are life-threateningmanifestations of coronary artery disease. The cause of ACS is the formation of a thrombus at the site of atheroscleroticplaque rupture or fissure. After an ACS, patients tend to be in a hypercoagulable state which may persist for morethan 6 months. This will in turn increase the risk of secondary ischemic events, including ischemic stroke, recurrentMI or vascular death.1

In the CAPRIE trial, clopidogrel has been proven to be an effective alternative to aspirin for the prevention of ischemicevents in patients with symptomatic atherosclerosis.2 Post-hoc analyses have also amplified the benefits of clopidogrelover aspirin in high-risk subgroups, including those with diabetes mellitus (DM), previous ischemic stroke or previousMI.3

Randomized clinical studies, such asCURE and CREDO, have establishedthat synergism between clopidogreland aspirin is a more effectiveapproach than monotherapy ininhibiting platelet aggregation inpatients with ACS or in thoseundergoing percutaneous coronaryintervention (PCI).4,5 Current treatmentguidelines recommend intensive dual

antiplatelet therapy (DAPT) to be givenfor more than a month with bare metalstents (BMS) and more than a yearwith drug-eluting stents (DES) toprevent stent thrombosis.6

Prolonged use of DAPT is associatedwith increased risk of gastrointestinal(GI) bleeding.7 Proton-pump inhibitors(PPIs) have been widely recommended

as concomitant therapy with DAPT forthe attenuation of GI bleeding by recentconsensus guidelines.8 Becauseclopidogrel and PPIs share a commonmetabolic pathway involving thecytochrome P450 (CYP450), PPIs arehypothesized to reduce the activationof clopidogrel, impair its antiplateleteffect and result in adverse clinicaloutcomes. As a result, the potential

+CYP1A2CYP2B6

Intestinal Absorption

Hepatic Metabolism

CYP3A4/5CYP2B6 +CYP2C9

Figure 1. Porential mechanisms of drug-drug interaction between clopidogrel and omeprazole, adapted from reference 14.


5

drug-drug interaction betweenclopidogrel and PPIs has attractedsignif icant attention from theCardiology community and is a topicof intense debate presently. This articlesummarizes current evidence of theeffect of this interaction on clinicaloutcomes and discusses therecommendations.

C L O P I D O G R E L A N D I T SMETABOLISMClopidogrel bisulfate, an adenosined iphospha te (ADP ) - recep to rantagonist, is a second-generationthienopyridine. It is a prodrug requiringactivation by the hepatic CYP450enzymes.

When clopidogrel is consumed, 85%of it is hydrolyzed by intestinalesterases to the inactive carboxylicacid derivative. Only 15% of theremaining drug is absorbed andundergoes oxidative biotransformationto its active metabolite via a 2-stepprocess, mainly involving CYP2C19isozyme. The first step is carried outby CYP2C19, CYP1A2 and CYP2B6to form an intermediate compound,2-oxo-clopidogrel, whereas the secondstep involving CYP2C19, CYP3A4/5,CYP2C9 and CYP2B6 is responsiblefor converting the intermediate to theactive thiol metabolite (figure 1).9

The active metabolite forms a disulfidebridge with two extracellular cysteineresidues located on the ADP P2Y12platelet receptor, resulting in irreversibleblockade of ADP binding and henceinhibition of platelet activation andaggregation.10

PPIs AND THEIR METABOLISMPPIs are the most effective acidsuppressants available for treatmentof gastrointestinal disorders. They havebeen shown to reduce incidence ofgastrointestinal hemorrhage whenadded to antiplatelet therapy. Somepatients are also prescribed PPIs forconditions unrelated to DAPT, such aspeptic ulcer disease or gastrointestinalreflux, and hence may already be onchronic PPI therapy. Omeprazole isthe most commonly prescribed PPIbecause of its low cost and easyaccessibility. Other PPIs include

l a n s o p r a z o l e , r a b e p r a z o l e ,pantoprazole and esomeprazole.

PPIs reduce basal and stimulated acidsecretion in a dose-dependent mannervia inhibition of H+/K+ adenosinetriphosphatase (ATPase or proton-pump) that is located in the highlyacidic luminal domain of the gastricparietal cells. Most PPIs have veryshort circulating half-lives (1-2 hours),but their action is prolonged due toirreversible inhibition of H+/K+ ATPase,which requires least 3-4 days forrecovery.11

Like clopidogrel, PPIs also rely greatlyon CYP2C19 for metabolism but theirp h a r m a c o k i n e t i c a n dpharmacodynamic profi les aredifferent. Omeprazole is a potentinhibitor of CYP2C19. It is convertedto hydroxyomeprazole and omeprazolesulfate by CYP2C19 and CYP3A4respectively. Although lansoprazoleinhibits CYP2C19 to a similar extentas omeprazole, in vivo studies haveshown that drug metabolism ofCYP2C19 subst ra te are notsignificantly affected by lansoprazole.12

Esomeprazole, the S-enantiomer ofomeprazole, is metabolized to agreater extent through CYP3A4 andless through CYP2C19, whereaspantoprazole has much lower affinitiesfor these enzymes and potently inhibitsanother isozyme, CYP2C9.13 Amongall, rabeprazole has the lowestpropensity for drug interactionsbecause it is metabolized primarily vianon-enzymatic pathways.11

POSSIBLE MECHANISMS OFCLOPIDOGREL-OMEPRAZOLEINTERACTIONThe first possible mechanism of theclopidogrel-omeprazole interaction isthe competition for intestinal P-glycoprotein transporter. Absorptionof both drugs may be affected bysingle nucleotide polymorphism of theABCB1 gene coding for P-glycoprotein(figure 1). Furthermore, bioavailabilityof clopidogrel, whose dissolution isgreater in acidic environment, couldbe reduced by an increase of pH dueto the action of omeprazole. The latterinteraction is class-specific and is thusnot different between individual PPIs.14

The major site of interaction betweenclopidogrel and omeprazole appearsto involve CYP2C19, which is the majormetabolic enzyme for both drugs(figure 1). Omeprazole has been shownto competitively inhibit CYP2C19-mediated metabolism of clopidogrel.Gilard et al were the first to drawattention to relevant drug-druginteractions between clopidogrel andPPIs in an observational study.15 Later,in 2008, they published a randomizedstudy, the OCLA trial, showingdetrimental effects of omeprazole onclopidogrel action in patients receivingDAPT after PCI via VASP assay.16

However, the study duration was only7 days, which was too short to beused as a fair representation of actualclinical practice (DAPT for 1 month forBMS and 1 year for DES) .Nevertheless, these studies provideduseful preliminary information onpossible lowering of clopidogrelefficacy by omeprazole in early daysafter PCI, which may lead tounfavourable outcomes such as majoradverse cardiac events (MACE) andstent thrombosis.

EVIDENCE FOR NEGATIVE IMPACTO F C L O P I D O G R E L - P P IINTERACTION ON CLINICALOUTCOMESSeveral large retrospective trials foundstatistically significant increases inadverse cardiovascular outcomes withclopidogrel-PPI co-therapy. Results ofthe Clopidogrel Medco OutcomesStudy were finalized and published in2010. In this cohort study, in whichmore than 16,000 post-PCI patientswere given one-year clopidogreltherapy; those receiving PPIsconcurrently had higher rates of MACE(25% versus 17.9% with no PPI).MACE included hospitalization forstroke, ACS, revascularizationprocedures and death.17

In the population-based cohort studyof 734 patients conducted by Juurlinket al, there was an association betweenreadmission due to recurrent MI(occurring within 90 days after indexacute MI) and concurrent use ofclopidogrel and PPIs. Furthermore,among the older patients, an estimatedreadmission rate of 7.4% due to re-


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infarction occurred as a result ofconcomitant therapy.18

Ho et al demonstrated, in a multi-centre cohort study involving 8205patients with ACS, that concomitantPPI treatment was linked to higher riskof death or re-hospitalization forrecurrent ACS and revascularizationprocedures, but not all-cause mortality.It is prudent to note that there weresignificantly more patients with co-morbidities such as COPD, DM, priorMI, heart failure, cancer, hepatic andrenal diseases in the PPI group,implying that these patients wereinherently sicker at baseline.19

EVIDENCE AGAINST NEGATIVEIMPACT OF CLOPIDOGREL-PPIINTERACTION ON CLINICALOUTCOMESIn an European observationalretrospective study of more than 1300ACS patients who received DES, nosignificant difference was observedbetween PPI and non-PPI users interms of in-hospital MACE and majoror minor bleed as well as 1-year MACE,death, stent thrombosis and major orminor b leed.2 0 Resu l ts f romretrospective analyses of PRINCIPLE-TIMI 44 and TRITON-TIMI 38 trials alsosuggested a lack of associationbetween PPI co-administration and anincreased risk of the compositeendpoint of vascular death, stroke orMI, or a decreased risk of bleeding.21

A non-significant increase in risk ofhospitalization and death in 3 largecohorts of ACS patients aged at least65 years was shown in anotherretrospective study by Rassen et al,when co-therapy was prescribed.22

COGENT is the only randomizedprospective clinical trial designed toaddress safety and efficacy ofclopidogrel-omeprazole co-therapy in3267 patients with ACS or PCI.Unfortunately, the study wasprematurely terminated due to sponsorbankruptcy. In this study, each armwas randomized to receive either acombination pill containing omeprazole20 mg and clopidogrel 75 mg (CGT-2168) or clopidogrel 75 mg alone. Whileresearchers found no significantdifference in MACE incidence between

PPI and non-PPI users, there was asignificant reduction in GI bleeding riskwith PPI use.23 Although the resultsseem promising, there were multiplelimitations to the study, includinginadequate statistical power and earlytermination. The use of the CGT-2168pill with possibly different releasekinetics from normal clopidogrel mayhave limited the generalizability of theresults.

META-ANALYSES ASSESSINGCLOPIDOGREL-PPI INTERACTIONRecent meta-analyses and systematicreviews by Kwok et al and Siller-Matulaet al revealed inconsistencies in thereported clinical relevance of theclopidogrel-PPI interaction. This maybe due to substantial heterogeneity instudy types and methods of analysis.Overall, the results suggest thatcombinat ion therapy may beassociated with significantly increasedrisk of both MACE and MI, but notmortality.24,25

Although results from the supporting

studies were mostly statisticallysignificant, important limitations werealso noted. The first limitation is thatmost studies were retrospective andobservational in nature. This impliespossible confounders may not be fullyaccounted for. In many circumstances,data on baseline cardiovascular riskfactors, such as smoking status, bloodpressure and lipid levels, were lacking.

Second, patients receiving PPIs weregenerally older with more co-morbidi l l nesses . They had h ighe rcardiovascular risk at baseline(including post-PCI patients), whichmade them intr insical ly moresusceptible to recurrent cardiovascularevents. Furthermore, these patientsmay be receiving PPIs because ofpossibly higher GI bleeding risk. As aresult, selection bias could be a likelyexplanation for poorer cardiovascularoutcomes observed in some of thestudies.

Third, many studies may not haveconsidered essential confounders such


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as non-compliance to clopidogreltreatment, which can contribute topoor platelet response. They were alsounable to account for ethnic variationsand CYP2C19 genetic polymorphisms,which may have implications onplatelet reactivity. Therefore, furtherprospective randomized studies arerequired in order to fully elucidate thepotential clinical impact of clopidogrel-PPI co-therapy on clinical outcomes.

IS THIS A CLASS EFFECT?In view of varying degrees of CYP2C19inhibition by different PPIs, mechanisticstudies have suggested that theclopidogrel-PPI drug interaction maynot be a class effect. Indeed, the lackof negative effects from concomitanttreatment of pantoprazole oresomeprazole with clopidogrel hasbeen seen in two observational studiesby Siller-Matula et al and Sibbing etal, although both PPIs are relativelypotent CYP2C19 inhibitors in vitro.26,27

A pharmacodynamic study providedreassurance that pantoprazole doesnot attenuate the efficacy of clopidogrela t s t a n d a r d d o s e s w h e nsimultaneously administered.28 Similarresults have been shown in anotherrandomized crossover trial carried outin post-MI patients.29

A recent crossover study showed thatin healthy volunteers, omeprazole co-treatment with clopidogrel resulted inconsistent reduction of active thiolmetabolite levels, leading to anincrease in platelet activity. However,this effect was significantly less markedwhen pantoprazole was used instead.30

Rabeprazole, which pr imar i lyundergoes metabolism by non-CYPpathways, was analyzed in severalobservational studies and was not

found to be associated with increasedadverse outcomes. Similar outcomeshave been noticed for lansoprazole,although lansoprazole exhibits potentin vitro inhibition of CYP2C19.21,22

In general, most studies to date stillindicate that omeprazole is the maininteracting PPI associated withunfavourable clinical outcomes in ACSpatients on clopidogrel co-treatment.Therefore, it may be reasonable toconsider combining other PPIs thanomeprazole with clopidogrel, giventheir lower interaction potential.THE CONCEPT OF CLOPIDOGRELRESISTANCEAny factor that can contribute toclopidogrel resistance may intensifythe degree of interaction betweenclopidogrel and PPIs. Clopidogrelresistance or non-responsiveness is aterm used to describe poor responseto clopidogrel and may be defined asthe failure of clopidogrel to causecomplete blockade of the P2Y12platelet receptor. Identification of suchresistance requires deployment ofvarious laboratory techniques thatallow detection of the P2Y12 receptoractivity prior to and after administrationof clopidogrel.31

F A C T O R S A F F E C T I N GCLOPIDOGREL RESISTANCEAs a result of lack of standardizedlaboratory methods for platelet functiontesting and the use of diverse assaysin different studies, the prevalence ofclopidogrel non-responsiveness hasvaried from 4% to 30%.32 Resistancecould occur in many ways, includingreduced drug bioavailability frompatient non-compliance or reducedprodrug intestinal absorption andvariations in P2Y12 receptor density

(table 1). Other important factors thathave been cited as potentialmechanisms for variable plateletreactivity are drug-drug interactionsand genetic polymorphisms.33

Because the CYP2C19 isozymecontributes substantially to clopidogrelmetabolism, genetic polymorphismsin the gene coding this enzyme isoformare pivotal. Patients who are carriersof the CYP2C19*2 allele are found tohave impaired clopidogrel metabolismand are termed as poor metabolizers.10

This variant had been associated withhigher platelet aggregation and residualplatelet reactivity in ACS and post-PCIpatients, which may in turn increasethe risk for secondary cardiovascularevents.34 Indeed, carriers of this allelicvariant had significantly lower levelsof active clopidogrel metabolite,diminished platelet inhibition, >50%higher risk of MACE and a 3-foldincreased risk of stent thrombosis.35

R E C O M M E N D AT I O N S T OH E A LT H C A R E P R O V I D E R SCurrent standpoints from the FDA,EMEA and Expert ConsensusGuidelinesFollowing the emergence of the firstretrospective cohort study showing anassociation of clopidogrel-PPIinteraction with increased risk ofcardiovascular events in 2009, the twomost important regulatory authorities,US Food and Drug Administration(FDA) and European Medicines Agency(EMEA), have published statements todiscourage concurrent prescribing ofclopidogrel and PPIs.36

In 2010, as more pharmacogenomicsdata surfaced, FDA highlighted thatreduced effectiveness of clopidogrelis likely more related to patients whoare poor metabolizers of the drug.A l t h o u g h t h e r e w e r e n orecommendations to indicate thatgenomic testing in individuals ismandatory before starting clopidogrel,FDA alerted that such tests areavailable in the market.37 FDA alsorevised its statement to emphasizethat the recommendat ion forconcurrent prescribing is only againstomeprazole and not all other PPIs.The ACCF/ACG/AHA 2010 Expert

Table 1. Genetic, cellular and clinical factors affecting clopidogrel responsiveness

Genetic Cellular ClinicalPolymorphisms Rapid platelet turnover Non-compliance- CYP450 Reduced CYP activity Elevated body mass

(CYP2C19 – Increased platelet index (obesity)*2,*3,*4,*5) exposure to ADP Diabetes

- P2Y12 receptor Up-regulation of purinergic Hypercholesterolemiaand non-purinergic Smokingsignaling pathwaysPoor drug absorptionDrug-drug interactions


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Consensus Guidelines recommend thatthe individual’s overall risks and benefitsfrom clopidogrel therapy with regardto possible cardiovascular or GIcomplications should be assessed andthe need for a PPI should be carefullyjudged.38 While a PPI is indicated forpatients with prior history of GI bleedor multiple risk factors for GI bleed (e.g.warfarin therapy, advanced age, steroiduse, NSAID use or H. pylori infection),gastroprophylaxis is not required inlower risk patients.

Alternative strategies to counteractclopidogrel-omeprazole interactionGiven that all PPIs are equally effectivefor gastric acid suppression atappropriate doses and that thepharmacodynamic interaction withclopidogrel is CYP450-mediated,prescribing less CYP2C19-inhibitingPPIs such as rabeprazole orpantoprazole may be considered.Histamine-2 antagonists such asfamotidine or ranitidine are alsopossible options for prevention of GIevents in low-risk patients.

Another option is to separate theadministration of clopidogrel andomeprazole. Based on the fact that theelimination half-lives (~8 hours forclopidogrel, 1-2 hours for omeprazole)and plasma circulating times of bothdrugs are short, this strategy may besensible approach to minimisecompetitive inhibition at the target siteof CYP2C19. Spacing the drugs 8 to12 hours apart theoretically preventssuch competitive inhibition, althoughthe evidence suggests otherwise.39

A third approach is to escalate themaintenance dose of clopidogrel toovercome response variability, sinceplatelet inhibition is dose-dependent.However, Cuisset et al demonstratedthat clopidogrel 600 mg loading dosefollowed by 150 mg daily for 30 daysdid not overcome interaction withomeprazole 20 mg daily.40 Currently,the role of dose escalation has notbeen established and is not supportedby FDA. The greater risk of GI bleedingshould be borne in mind.Newer P2Y12 inhibitors such asprasugrel, ticagrelor and cangrelor havebeen developed and serve as promising

alternatives to overcome clopidogrelresistance. Compared to clopidogrel,these drugs are activated moreefficiently and rely less on the hepaticCYP450 system for drug metabolism,hence there is lower potential for drug-drug interaction with PPIs.

Finally, the use of genetic testing andex vivo platelet function testing toindividualize therapy and guidemanagement may become an optionin future. Presently, many studiesinvestigating these tests are underwayand they are gradually incorporatedinto consensus guidelines.

Optimizing other factors contributingto poor clopidogrel responseEnsuring patient compliance is ofutmost importance, as prematurediscontinuation of clopidogrel is relatedto higher mortality and increased riskof stent thrombosis in post-PCIpatients.41 As polypharmacy is likelyto be common in patients with coronaryartery disease, interventions aimed atreducing drug interactions should beroutinely performed.

Aggressive control of risk factors suchas hyper l ip idemia , d iabetes ,hypertension, renal impairment,proteinuria and obesity also play amajor role in enhancing response toclopidogrel therapy because theyenhance platelet reactivity and exposepatients to accelerated thrombopoiesisand greater risk of atherothromboticevents.10

CONCLUSIONThe interaction between clopidogreland PPIs is still a debatable topic ofinterest. Though many studies havedemonstrated the association ofadverse cardiovascular outcomes withtaking both drugs concomitantly, theyare largely retrospect ive andobservational in nature. The onlyprospective study thus far found nosignificant difference in MACEincidence between PPI and non-PPIusers. Until prospective, randomized,double-blinded, multicenter trials withstatistical power have been conducted,the causality between clopidogrel-PPIco-therapy and adverse outcomesremains inconclusive.

Considering the benefits of PPIs in theprevention of GI bleeding, they shouldstill be prescribed concurrently withclopidogrel in high-risk patients onDAPT. However, it is prudent for theclinician to weigh the risks and benefitson cardiovascular and GI complicationsbefore starting a PPI with clopidogrel.

Most retrospective studies have foundthat omeprazole has significantinteractions with clopidogrel, implyingthat the interaction may not be a classeffect. H2-antagonists or lessinteracting PPIs such as pantoprazoleor rabeprazole can be considered asalternatives. Bearing in mind thatomeprazole is still the cheapest PPIavailable and affordability does affectpatient compliance, it may still beconsidered in patients with high GIrisks requiring a PPI.

Since carriers of the CYP2C19*2 variantgene appear to be more affected bythe clopidogrel-omeprazole interactionand have worse clinical consequences,in future, clinicians may considerperforming ex vivo platelet function orgenomic tests to tailor drug regimensto patients who need antiplatelettherapy.

Ms Mindy Tay is a pharmacist in theDepartment of Pharmacy, Tan Tock SengHospital.


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References1. Dipiro TP, et al. Pharmacotherapy: A Pathophysiologic Approach. Sixth Edition. New York. McGraw Hill. 2005.2. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet

1996; 348: 1329-39.3. Ringleb PA, Bhatt DL, Hirsch AT, et al. Benefit of clopidogrel over aspirin is amplified in patients with a history of ischemic events. Stroke 2004;

35: 528-324. Peters RJ, Mehta SR, Fox KA, et al., for the CURE Trial Investigators. Effects of aspirin dose when used alone or in combination with clopidogrel

in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.Circulation 2003;108:1682–7.

5. Steinhubl SR, Berger PB, Mann JT III, et al., for the CREDO Investigators. Early and sustained dual oral antiplatelet therapy following percutaneouscoronary intervention: a randomized controlled trial. JAMA 2002; 288:2411–20.

6. King SB, Smith SC, Hirshfeld JW, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronaryintervention. Circulation 2008; 117:261 – 95.

7. Bhatt DL, Fox KA, Hacke W, et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med.2006; 354:1706 –17.

8. Abraham NS, Hlatky MA, Elliott M, et al. ACCF/ACG/AHA 2010 Expert Consensus Document on the Concomitant Use of Proton Pump Inhibitorsand Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risksof Antiplatelet Therapy and NSAID Use : A Report of the American College of Cardiology Foundation Task Force on Expert ConsensusDocuments. Circulation 2010; 122:2619-2633

9. Plosker GL, Lyseng-Williamson KA. Clopidogrel, a review of its use in the prevention of thrombosis. Drugs 2007; 64:613-46.10. Giusti B, Gori AM, Marucucci R, Abbate R. Relation of CYP2C19 loss-of-function polymorphism to the occurrence of stent thrombosis. Expert

Opin Drug Metab Toxicol 2010; 6:393-40.11. Blume H, Donath F, Warnke A, Schug BS. Pharmacokinetic drug interaction profiles of proton pump inhibitors. Drug Safety 2006; 29: 769-

784.12. Desta Z, Zhao XJ, Shin JG, Flockhart DA. Clinical significance of the cytochrome P450 2C19 genetic polymorphism. Clin Pharmacokinet 2002;

41:913-58.13. Li XQ, Andersson TB, Ahlstrom M, Weidolf L. Comparison of inhibitory effects of the proton pump-inhibiting drugs: Omeprazole, Esomeprazole,

Lansoprazole, Pantoprazole and Rabeprazole on human cytochrome P450 activities. DMD 2004; 32:821-2714. Tantry US, Kereiakes DJ, Gurbel PA. Clopidogrel and Proton Pump Inhibitors. J Am Coll Cardiol Intv 2011; 4:365-80.15. Gilard M, Arnaud B, Le Gal G, Abgrall JF, Boschat J. Influence of omeprazole on the antiplatelet action of clopidogrel associated to aspirin. J

Thromb Haemost 2006; 4: 2508–9.16. Gilard M, Arnaud B, Cornily JC, et al. Influence of omeprazole on the antiplatelet action of clopidogrel associated with aspirin: the randomized,

double-blind OCLA (Omeprazole CLopidogrel Aspirin) study. J Am Coll Cardiol 2008; 51:256–60.17. Kreutz,RP, Stanek EJ, Aubert R, et al. Impact of Proton Pump Inhibitors on the Effectiveness of Clopidogrel After Coronary Stent Placement:

The Clopidogrel Medco Outcomes Study. Pharmacotherapy 2010; 30:787–96.18. Juurlink DN, Gomes T, Ko DT, et al. A population-based study of the drug interaction between proton pump inhibitors and clopidogrel. CMAJ

2009; 180:713–819. Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors

following acute coronary syndrome. JAMA 2009; 301:937–44.20. Rossini R, Capodanno D, Musumeci G, et al. Safety of clopidogrel and proton pump inhibitors in patients undergoing drug-eluting stent

implantation. Coronary Artery Disease 2011; 22:199-205.21. O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugel with or without

a proton-pump inhibitor: an analysis of two randomised trials. Lancet 2009; 374: 989–97.22. Rassen JA, Choudhry NK, Avorn J, Schneeweiss S. Cardiovascular outcomes and mortality in patients using clopidogrel with proton pump

inhibitors after percutaneous coronary intervention or acute coronary syndrome. Circulation 2009; 120:2322-2329.23. Bhatt DL, Cryer BL, Contant CF, et al. COGENT Investigators. Clopidogrel with or without omeprazole in coronary artery disease. N Engl J

Med 2010; 363: 1909–1724. Kwok CS, Loke YK. Meta-analysis: effects of proton pump inhibitors on cardiovascular events and mortality in patients receiving clopidogrel.

Aliment Pharmacol Ther 2010; 31:810 –2325. Siller-Matula JM, Jilma B, Schrö'f6r K, Christ G, Huber K. Effect of proton pump inhibitors on clinical outcome in patients treated with clopidogrel:

a systematic review and meta-analysis. J Thromb Haemost 2010;8:2624–4126. Siller-Matula JM, Spiel AO, Lang IM, et al. Effects of pantoprazole and esomeprazole on platelet inhibition by clopidogrel.Am Heart J 2009;

157:148.e1–527. Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101:

714–928. Neubauer H, Engelhardt A, Kruger JC, et al. Pantoprazole does not influence the antiplatelet effect of clopiodgrel: a whole blood aggregometry

study after coronary stenting. J Cardiovasc Pharmacol 2010;56:91–729. Fontes-Carvalho R, Albuquerque A, Araujo C, Pimentel-Nunes P, Ribeiro VG. Omeprazole, but not pantoprazole, reduced the antiplatelet effect

of clopidogrel : A randomized clincal crossover trial in patients after myocardial infarction evaluating the clopidogrel-PPIs drug interaction.Eur J Gastroenterol Hepatol 2011; 23:396-404

30. Angiolillo DJ, Gibson CM, Cheng S, et al. Differential effects of omeprazole and pantoprazole on the pharmacodynamics and pharmacokineticsof clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther 2011; 89:65–74.

31. De Miguel A, Ibanez B, Badimón JJ. Clinical implications of clopidogrel resistance. Thromb Haemost 2008; 100:196–203.32. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 2005; 45:1157–64.33. Sweeny JM, Gorog DA, Fuster V. Antiplatelet drug ‘resistance’ part 1: Mechanisms and clinical measurements. Nat Rev Cardiol 2009; 6:273–28234. Buonamici P, Marcucci R, Migliorini A, et al. Impact of platelet reactivity after clopidogrel administration on drug-eluting stent thrombosis. J

Am Coll Cardiol 2007; 49: 2312–7.35. Wiviott SD, Braunwald E, McCabe CH, et al. TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in patients with acute coronary

syndromes. N Engl J Med 2007; 357:2001–1536. European Medicine Agency. Public statement of interaction between clopidogrel and proton pump inhibitors. 17 March 2010.

Http://www.emea.europa.eu/docs/en_GB/document_library/Public_statement/2010/03/WC500076346.pdf37. U.S. Food and Drug Administration. FDA Drug Safety Communication: Reduced effectiveness of Plavix (clopidogrel) in patients who are poor

metabolizers of the drug. 12 March 2010.http://www.fda.gov/drugs/drugsafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm

38. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused updateof the ACCF/ACG/AHA 2008 Expert Consensus Document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use.Circulation 2010; 122: 2619–33.

39. Ferrerio JL, Ueno M, Capodanno D, et al. Pharmacodynamic effects of concomitant versus staggered clopidogrel and omperazole intake:results of a prospective randomized crossover study. Circ Cardiovasc Interv 2010; 3:436-41

40. Cuisset T, Frere C, Quilici J, et al. Comparison of omeprazole and pantoprazole influence on a high 150-mg clopidogrel maintenance dose:the PACA (Proton Pump Inhibitors and Clopidogrel Association) prospective randomized study. J Am Coll Cardiol 2009; 54:1149–53

41. Jeremias, A, Sylvia, B, Bridges, J, et al. Stent thrombosis after successful sirolimus-eluting stent implantation. Circulation 2004; 109:1930-2.


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Perspective

Different Health Care, Part 1This is the Dilbert comic strip of 21 July 1995 in words: Dilbert, his mother and his girlfriend Liz were chatting. Hismother said that things have been different since they lost Dilbert’s Dad. Liz asked, “When did he die?” Dilbert explainedthat he was not dead, merely missing in the mall since Christmas ‘92. Liz was surprised: why didn’t they go and lookfor him? Dilbert’s mother said, “I said it’s different, not worse.

This is the first of two articles in whichwe present exciting ideas that havechanged or are going to change healthcare delivery at the macro and themicro levels (‘health care’ and‘healthcare’ are both acceptable andthe White House uses the former) . Weshall talk about national issues andlarge health systems in this article, andinnovations within hospitals in the next.They will be underpinned by reviewsof recent ly publ ished books.

We ask these questions and wonderwhat the answers might be:• Is there a better way to organize our

hospitals? On what basis should were-organise?

• What makes up a national healthcare system? What are theresponsibilities of the payer, the

insurance and the health careproviders?

• What is the best way to pay forhealth care? Purely by government?Purely private? A mixture of the two?

Improving health care delivery at themacro level and optimizing thequality of the hospital and care-providers are two sides of the samecoin. Like many of our readers, I ama medical practitioner who has spentmore than half his life and all hisworking l i fe t reat ing people’sillnesses; therefore, the angle isnecessarily from bottom up. I amnot a hospital administrator or apolicy-maker, so my analysis of theissues may seem blunt or naï'efveto professionals, and may even bewrong. Anyway, my aim is to raise

awareness and initiate discussion.HOW HOSPITALS ARE ORGANIZEDIn The Straits Times of 6 April 2008,Warren Fernandez reported that manyzi char stalls have been forced to closebecause they could not find workers.1

I think that labour shortage is not theonly reason these stalls fail. Zi charstalls are inherently not efficient. Theyoffer 100 items in their menus andhave to stock all the ingredients all thetime. The cooks need to know how tocook all of them but there is noguarantee that two of them will do itin the same way. They have toassemble the ingredients from variousplaces every time a new order isreceived. In contrast, fast food jointshave short menus and standardizedways of preparing food (this was thegenius of Ray Kroc). The cooks never

Value-adding processesAnyone who has been trainedand certified competent toperform the procedure

Ability to perform procedurecompetently withoutcomplications. Fortunately,checklists of uniformly agreed,evidence-based steps can bedeveloped.

Fee for output

Endoscopy, surgeries for knownconditions, angioplasty.

Types of workWho should deliverservice

What is required ofprovider

Ideal form of payment

Examples

Solution shopExperts andexperiencedpractitioners

Ability to extractinformation fromvarious sources anddiagnose.Unfortunately,intuition is sometimesneeded and thiscannot be put into aprotocol.

Fee for service

New case clinics,emergencydepartments.

Facilitated networkFacilitators

Share the knowledge ofmembers around so thatcollective experience benefitseveryone

Fee for membership

Treatment of chronic diseasessuch as diabetes mellitus,hypertension, asthma, andrheumatoid arthritis.

Table 1. Three types of work in health care


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have to walk very far and every cookingstep is timed, from frying potato chipsto grilling beef patties.

Many assert that the health careinstitution should be better organizedfor efficiency. Many doctors are againstre-organisation, arguing that our workis too complex to be reduced to simplechecklists or algorithms, and insistingon absolute autonomy in the way wetreat our patients. We think that ourhospitals are more like zi char stallsthan fast food restaurants. But if wethink about it for a moment, we realizethat sometimes our work resembleszi char and sometimes fast food.

The Innovator’s Prescription (reviewedlater) tells us that medical work maybe divided into three categories, basedon Øystein Fjeldstad’s idea.2 Solutionshops handle medical problemsusually of a diagnostic nature (table1). Patients bring their problems thatdo not admit of simple solution. Thepractitioners are highly skilled andbecause there is no algorithm or ruleto solve every problem, theysometimes rely on intuition. Value-adding processes (VAPs) take inincomplete or broken things andtransform them into more completeoutputs of higher value. Facilitatednetworks are enterprises in whichpeople exchange things with eachother. The authors suggest thatfacilitated networks may handlechronic diseases but I think that, atbest, this is a model for self-helpgroups.

Thus, this forms the rational basis forright siting. Things that can becompetently and consistent lyperformed by people of a certain levelmust not be carried out by more highlypaid or over-qualified people.

The Innovator’s Prescription pointsthat we have always organized ourhospital, its processes and even itstraining like a giant solution shop. Thisis wrong because VAPs andmanagement of chronic illness are notsolution-shop activities. For example,in sequence, we have the house officer,the medical officer and the registrarinterview the patient for the medical

history because we think that a doctorof lower grade may misdiagnose someobscure ailment. This is grounded insolution-shop thinking and is quiteinefficient. Why don’t we use the mostexperienced to make the diagnosisand initiate treatment, and let the lessexperienced carry it through? Ofcourse, there must be a method toensure that the first diagnosis is indeedcorrect in the course of the hospitalstay, and the junior doctors are trainedin the exquisite skill of diagnosis-making. Therefore, the diagnosing ortriaging personnel is very important toensure that the appropriate patient issent to the right VAP program.

Physicians often marvel how surgeonsspend less time than they do in takinga meticulous history and examiningthe patient from head to toe, and yetrarely run into trouble. This is becausemost of their patients only require VAPtreatment, such as appendectomy forappendicitis, Whipple’s procedure forpancreatic cancer and craniotomy forbrain tumour. Physicians can be surethat surgeons flag out medicallycompl icated pat ients for co-management.

However, most of our hospitals andclinics are not organized in the mostefficient and correctly sited way.Tradition and inertia tend to keep thingsgoing the way they are. In USA, it issaid that barriers to integrated care athospital and at macro levels are nottechnical but political.3

Nonetheless, efficiency must betempered with moderation. Dr Edmondwrote a piece about the scenario inmodern hospitals seen through theeyes of a doctor trained in the lastcentury, like many of us.4 Theresidents’ time was so stretched (inthe name of efficiency) that anythingthat was not deemed to contribute tomanagement or disposal waseliminated. He lamented that humanityand joy had been ‘sucked’ out of thepractice of medicine.

PA YING FOR HEAL TH CAREProviding health care is not the sameas selling a product or operating arestaurant.5 While we can do withouta lifestyle product or restaurant food,we cannot do without treatment whenwe are sick. In many societies, accessto health care is considered a right. Awell known exception is USA, in which


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universal health care is not a given.There are two additional problemsassociated with health care cost. First,how much it costs to treat a medicalproblem is not predictable at thedisease outset. For example, headachecan be due to tension or brain tumour.Second, there is a disparity in theknowledge of the patients and theprovider. The doctor diagnoses thedisease and proposes the treatmentand the patient is rarely in a positionto judge if the recommendation iscorrect.

In The Healing of America, which welater review, Professor Uwe Reinhardtof Princeton University was quoted assaying, “Every nation’s health caresystem reflects that nation’s basicmoral values. Once a nation decidesthat it has a moral obligation to providehealth care for everybody, then it canbuild a system to meet that obligation.”To be fair, by 2013, President Obama’sHealth Care Reform will extendinsurance to more than 30 millionpeople, by expanding Medicaid andhelping lower- and middle-incomeAmericans buy private insurance.

What should hospital CEOs to say ifasked to choose between job growthand spending cuts? Economist David

Dranove offers this: “Yes, health carespending is high and we need toeliminate waste. But on average youget more for your health care dollarthan on anything else you can buy.There is no greater gift than the gift ofhealth, and our hospital teams helppeople live longer, healthier lives. Aswe move forward, we will continue toeliminate inefficiencies but we mustalso be responsive to the needs of anaging population. We will continue topromote wellness and prevention, butwe must also be prepared to takeadvantage of medical breakthroughsthat will allow us to better cope withcancer, heart disease, and the manyother afflictions that we must alleventually face. The question shouldnot be whether we are spending toomuch or too little on health care, butwhether we are spending our moneywisely. If we are – and I believe we aremaking major strides in that direction– then we will have the appropriatelabor force to meet our community’sneeds. An efficient health care systemthat grows in response to communityneeds – that is my vision, and it is onethat generates jobs without wastingdollars.”6 What Dranove said is notcontroversial; health care savingsshould come from reducing wasteand increas ing e ff ic iency by

e x p l o i t i n g t e c h n o l o g y, n o tel iminat ing essent ia l services.

National health care modelsThe three main components of anynational health care system are thepayer, the insurer and the provider. Thevarious models of national health caresystems differ in the way these threeinteract. I have taken the names of thesystem from Reid’s book and I shallleave you to read the book to find outwhy he named them so. In fact, morethan one model may be found in anindiv idual , but one tends topredominate.

Singapore has a mixed financingsystem, with multiple tiers of funding.7

First, all Singaporeans can accesssubsidized health care, where up to80% of the bill is paid with public fund.There is the compulsory savingMedisave. Contribution to one’sMedisave is split between theemployee and the employer. Medisaveis a medical saving scheme, not aninsurance because the funds are notpooled.8 MediShield, a basic medicalinsurance, provides supplementarypayment for people above 65 years.Finally, MediFund supports those whocannot pay their medical bills. Oursystem actually does cover everybody.

Model

Payer

Insurer

Provider

Somecharacteristics

Examples

‘Bismarck’

Private

Private

Private

The money to fund thissystem comes fromcontributions of theemployer and employee,not government. Thereis a great variety in theway insurance andproviders are regulated.

USA, Germany, Japan,France, Belgium,Singapore public healthsystem.

‘Beveridge’

Government

Government

Government

The government looksafter the health of herpeople from conceptionto coffin. Patients do notget to see a bill. Taxationis used to pay for healthcare.

Britain, Italy, Spain,most Scandinaviancountries, USA VAHealth System,

National HealthInsuranceGovernment

Government

Private

May have long waitingtime to see specialistand to receive electivetreatment. Governmentinsurance has clout tonegotiate for low priceswith providers.

Canada, Taiwan, SouthKorea

Out-of-pocket

Private

Nil

Private

In countries with nonationally organizedhealth care, this is theonly available model.No accessible care tothose unable to pay.

Cambodia, India, Egypt,Singapore private healthcare.

Table 2. Models of health care provision, adapted from The Healing of America by Reid.


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Based on Reid’s classification, ours isa combination of the ‘Bismarck’ system(Medisave and MediShield), NationalHealth Insurance (Medifund) and Out-of-Pocket (private practitioners).

All the systems (except Out-of-Pocket)have the potential to perform very wellif they are well managed. In the US, ithas even been shown repeatedly thatthe Veterans Health Administration (inwhich the payer, insurance andprovider are all government-controlled)consistently does better than privateproviders using commonly acceptedperformance indicators.9

InsuranceBesides the payer and provider,insurance is necessary because thecost of health care is unpredictable foran individual with a medical complaint.The WHO World Health Report 2000stated ‘Insurance systems entailintegration of resources from individualcontributors or sources both to pooland to share risks across thepopulation. Achieving greater fairnessin financing is only achievable throughrisk pooling – that is, those who arehealthy subsidize those who are sick,and those who are rich subsidize thosewho are poor.’10

The state of Vermont, like the rest ofUSA, is worried about the number ofuninsured people and the rising costof health care. It commissionedProfessor William Hsiao and his teamof the Department of Health Policy andManagement, Harvard School of PublicHealth, to find a solution.11 ProfessorHsiao surmised that to cover theuninsured, he would have to use thesavings derived from reforming thesystem. He also had to maintain thepremium coverage the currentlyinsured Vermonters already enjoy. Hecould not reduce income of thephysicians, hospitals and otherproviders. His solution was a single-payer, ‘one insurance fund that coverseveryone with a standard benefitpackage, paying uniform rates to allproviders through a single paymentmechanism and claims-processingsystem’. He calculated that the systemwill immediately save 8% fromsimplification and consolidation of

administrative fees and 5% fromreduction in fraud and abuse. His teamproposes payment by capitation thanfee-for-service. Eventually, the statewil l save 25% in health careexpenditures over 10 years. Foranother example of a superb healthcare system designed by ProfessorHsiao, please read the summary ofThe Healing of America.

The responsibil it ies of eachcomponentThe amount of money that a countryspends on health care (often expressedas percentage of GDP) ultimatelydepends what the citizens want; thereis no best figure. It is all too clear thatmore money does not mean betterhealth care. For example, a famouspaper informed us that patients in theUSA received just above 50% of thetreatment recommended for theirconditions.12 If too little is spent onhealth, long waiting times and over-burdened clinics and hospitals willresult. There may not be resources forresearch, innovation, or education inthe health care system. Health careproviders may have to put in heroicefforts to meet service demands. If toomuch is spent, it will lead to waste andinefficiency and deprive other nationalinitiatives of funds. Health careproviders and organisations tend tobe better paid in these countries.Therefore striking a balance isimportant. For comparison, in 2008,Australia 8.5% spent of her GDP onhealth, France 11.2%, Indonesia 2.3%,Japan 8.3%, Malaysia 4.3%,Philippines 3.7%, Singapore 3.3%,USA 15.2%, and UK 8.7%.13

In a natural experiment in Taiwan, theSARS epidemic of 2003 led to 20%fall in health utilization (the extent towhich a given group uses a particularservice in a specified period) for chronicdiseases.14 The authors examined themortality rate in ten conditions(infectious diseases, cancer, nervoussystem diseases, diabetes mellitus,cerebrovascular disease, heart andvascular disease, respiratory diseases,digestive diseases, genitourinarysystem diseases and accidents) overthis period. There was significant risein mortality from diabetes mellitus and

cerebrovascular diseases. Theyconcluded that ‘… governments,especially in developing countries,should carefully evaluate potentialnegative consequences of reducedheal th care ut i l i zat ion whenexperiencing major epidemics that leadto reduced health care utilization, andalso when they plan to reduce healthcare insurance coverage or implementa large spectrum of cost-containmentpractices.’

How much should be paid by aninsurance system and how much bythe patient? I quote the WHO again:‘It is only when direct payments fallsto 15-20% of total health expendituresthat the incidence of financialcatastrophe and impoverishment fallsto negligible levels.’15

The insurance should be efficient andshould not generate excessive profit.The premiums should be affordableand every person should be able toafford. Ideally, no one should be deniedinsurance because of pre-existingillness. The coverage should not be‘watered down’ when the insuredperson falls sick. All these problemsare addressed in President Obama’sHealth Care Reform, if it is passed.His speech to a joint session of the111th United States Congress onSeptember 9, 2009 is an excellentpresentation of the proposals(http://www.whitehouse.gov/video/Pre s i d e n t - O b a m a - A d d re s s - t o -Congress-on-Health-Insurance-Reform).

The health care providers have theresponsibility to integrate and innovateto eliminate inefficiency and waste.The right work must be done by theright people. If best practice exists, itmust be consistently applied in theappropriate patients.

My admiration for Singapore’s healthcare system grew as I was writing thisarticle. The highly influential WorldHealth Report 2000 issued by WHOranked the Singapore health systemas 6th in the world, an extremelycoveted position to be.8 Our systemcovers everyone including those whocannot pay, is not too expensive,


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possesses reasonable quality, and yetcosts less than 4% of the GDP. Ofcourse it can be improved in manyplaces, but all the major cogs are inplace.

This conclusion was drawn by Dr GroHarlem Brundtland, Director-Generalof WHO, published in the introductionto the Report: ‘Ultimate responsibilityfor the performance of a country’shealth system lies with government.The care fu l and respons ib lemanagement of the well-being of thepopulation – stewardship – is the veryessence of good government. Thehealth of people is always a nationalpriority: government responsibility forit is continuous and permanent’.

THE ROLE OF TECHNOLOGYIn The Healing of America, the authorlaid the major portion of the blame forthe huge cost of health care in US onthe insurance companies. A recentarticle suggests otherwise.16 DrEmanuel states that it is not malpracticecosts, insurance companies’ profits(though it was a hefty US$11.7 billionin 2010), drug costs or ‘million dollarbabies’ (patients who consume massiveamount of health care) that keep the

costs up. Approximately10% of thepopulation consumes about 64% ofthe cost. These are patients withchronic disease who suffer fromcomplications that could have beenprevented. And one way to minimizecomplications from chronic diseasesis to manage the patients well throughthe providers’ adherence to bestpractice and appropriate monitoring,both of which can be facilitated bytechnology.

I think that technology will makeMedicine more efficient (bringingprofessionals with different expertisetogether to treat a specific patientseamlessly either virtually or physically),more precise (imaging and otherdiagnost ic modal i t ies makingdiagnoses more certain) and betterguided (electronic physician orders andinteract ive pat ient-appropriaterecommendations aiding doctors intheir dai ly work) . Introducinginnovations (whether IT or processes)into health care is not a straightforwardmatter. Successful implementationrequires continuous, not sporadic,effort, preparation of the system toaccept the change and securing buy-in by the end-users.18 Technology

poorly implemented is worse thanuseless; it becomes a millstone aroundeveryone’s neck.

IT in the hospitalIT in hospitals is known to increaseadherence to guideline-based care,enhance surveillance and monitoring,and decrease medication errors,poss ib l y resu l t i ng i n f ewe rcomplications, lower mortality andlower costs.19,20 In a study conductedin an intensive care unit, orders madethrough the computer compared to apaper-based system led to fewerprescription errors because of theautomatic checks for allergies, druginteractions and dosages.21 In the samestudy, it was found that the number oferrors rose with the number of drugsprescr ibed, but not with thecomputerized orders. As for anytechnology, the implementation mustbe carried well with due respect fordoctors’ and other end-users’requirements.22

Universal medical record systemThere are many benefits if all healthcare providers can access and reviewa patient’s medical records:• The history of past medical problems

will be more accurate than thepatient’s recalled account;

• There will be less need to repeatinvestigations;

• All the treatment that the patient isreceiving will be known, reducing therisk of duplication and druginteraction.

One great advantage that the Frenchsystem has over almost every othercountry in the world except Germanyand Taiwan is the Carte Vitale. Thissmart card, introduced in 1998, iscarried by everyone who is eligible,about 59 million people. It contains theperson’s medical history, billing, tests,organ donation status, blood groupand name of the doctor-in-charge.Clinics have done away with filingcabinets to hold medical records. Inaddition, after the doctor has enteredhis record for the current visit, the billis sent to the French Social Security orAssurance Maladie electronically,reducing the need for secretaries andadministrators.


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BOOK SUMMARY In the introductory chapter 1, theauthor wrote ‘It is said that everysystem is perfectly designed toachieve its outcomes. In January2000, the Toronto health system wasperfectly designed to achieve gridlock,and it did.’ Rachlis is a supporter ofMedicare, Canada’s single-payersystem in which everyone is covered.He does not think that more money

needs to be pumped in, nor do privateinsurance companies need to enterthe market. He presented this position:1) Public finance still makes sense. Itprovides for services to be deliveredaccording to people’s needs, reducesadministrat ive overhead, anddramatically reduces costs tobusiness; 2) Money isn’t the mainissue. Medicare does need adequate,predictable, sustainable funding, butthe main issue is the poor organizationand management of services; 3)Innovation in service delivery canprovide better quality care withoutbreaking the bank. As an illustration,he described how Saskatchewansuccessfully dealt with the influenzaoutbreak of 1999/2000. First, one caseof influenza-like illness was enoughto trigger the response (as opposed

to two cases or one laboratory-confirmed case in other states).Second, patients in nursing homereceive a pre-calculated dose ofamantadine within an hour of thediscovery of an index case in theirinstitution. Third, with pre-planning,fewer than 5% of patients in acutehospitals were waiting for long-termor home care, so that there is capacityto absorb surges in demand. Fourth,the hospitals were organized suchthat there was always one that couldtake emergency cases should one ERbe closed. There was a centralcommand that could reduce thenumber of elective cases as necessaryto prevent a crisis.

Chapter 2 is a detailed defence ofMedicare, Canada’s much-vaunted

Micheal Rachlis. Prescription for Excellence. How Innovation is savingCanada’s Health Care System. HarperCollins Canada, Limited, 2005. 418pages. The entire book may be legally and freely downloaded fromhttp://www.michaelrachlis.com/publications.php.

AUTHORRachlis, M.D., is a specialist in community medicine and a health policyanalyst.

Granted, using electronic records hasits share of problems, especially patientconfidentiality.24 Singapore too willsoon launch a US$144 million NationalElectronic Health Record system.25

The NEHR will contain patientdemographics, diagnosis, medications,tests, procedures and dischargesummaries.

It has been suggested that electronichealth records may provide savings inthe management of chronic diseases.16

The physician will be able to check onher patients’ health status moreefficiently. She will be able to usedecision supports to increaseadherence to treatment pathways. Shewill be able to use this information forbetter interaction between patients,caregivers, and clinic staff and carecoordinators.

Precision medicinePrecision medicine has recently beendescribed as ‘coupling establishedclinical–pathological indexes with

state-of-the-art molecular profiling tocreate diagnostic, prognostic, andtherapeutic strategies precisely tailoredto each patient’s requirements’.17

A key point in Innovator’s Prescriptionis that, as much as possible, thepractice of medicine should be shiftedaway from the realm of intuition to thatof routine and certainty. Indeed, withimproved diagnostic testing andpersonalized therapeutic strategy, theface of medicine will once againchange in our lifetime. It is very tellingthat Roche Holdings, the Swisspharmaceutical and diagnostic testgiant, is making a $5.7 billion takeoverfor Illumina, a leading maker of geneticsequencing equipment.26

CONCLUSIONThe health care system every countryhas depends on its history and the willof its people. Fortunately, mostcountries accept that health care is ahuman right and have provided forthose who are unable to pay. The payer,

the insurance and the provider eachhave their roles and responsibilities. Ifthey al l carry out their rolesappropriately, the health care systemwill be strong and will serve the needsof the people. If technology is properlyused in an integrated health system,it is hard to believe that it will not bringmuch good.

Dr Leong Khai Pang is a seniorconsultant in the Department ofRheumatology, Allergy and Immunology.He is also the editor of Medical Digest.


16:

publicly funded universal healthinsurance system. Rachlis recountsMedicare’s checkered past in thehands of the many political partiessince its launch in 1947. In chapter3, the author described the problemswith the Canadian health care systemthat are blamed on but ultimately notdue to Medicare. One is that medicineis fractured into more and moresubspecialties. ‘… today in urbanareas, general internists f indthemselves mainly managing elderlypatients with multi-system pathology’.Chapter 4 deals with end-of-life care.He quoted Elizabeth Latimer whowrote that we could learn from peoplein the Middle Ages, who practicedars moriendi, the art of dying. Peopledied at home; as death drew near,they got their affairs in order byforgiving longstanding conflicts,wrapping up legal and financial affairsand saying final words to loved ones.The next chapter discusses themanagement of chronic illnesses,citing the work of Group Health. Ithas a ‘road map’ for diabetes withfour elements: an electronic diabetesregistry implemented in 1995; regulareducational talks by a team ofd iabeto log is t and a nurse ;development of evidence-basedclinical guidelines and a patient self-help book. The late Dr Hui Lee of thegroup’s Health Promotion Initiativeinitiated a system that providedfeedback to individual doctors sothey knew their own compliance withclinical guidelines compared withanonymised physicians. Chapter 6discusses home care. Home careallows patients who fall sick to remainat home and hospitalized patients tobe discharged earlier. Victoria alsoinitiated a program called QuickResponse Team that can be rapidlymobilized to care for patients withfairly complex problems. The authorquoted a Vancouver study whichshowed tha t admin i s te r i ngintravenous antibiotics to a patient athome saved $7,000 per episodecompared with hospital treatment.Rachlis also describes otherprograms that provide comprehensive

outpatient care to poorer folks andeven homeless people. An innovativeidea at Seaton House, Canada’slargest men’s hostel, is that the staffdo not insist on alcohol abstinencewhen homeless people come in. Theyprovide alcohol in a controlled fashionbecause they found that, otherwise,these people would get drunk andinjured and have themselves admittedto hospital, necessitating CT scansand other tests. Chapter 7 is aboutimproving long-term institutional care,in particular, by tackling the three‘plagues’ of loneliness, helplessnessand boredom. Chapter 8 begins withpreventing diseases associated withdrug abuse, and later moved on tosocial medicine. Rachlis told anunfamiliar story about a familiarcharacter, Rudolf Virchow. Apparently,he was already a famous doctor whenhe was 26. He was asked by theBerlin council to investigate anoutbreak of typhus in Poland. Hediscovered that the abject livingcondit ion there was due tomismanagement by the government.Of course, the council was miffed toreceive his report, calling it a politicaltract. He then made his now famousstatement: ‘Medicine is a socialscience and politics is nothing butmedicine writ large.’ Chapter 10explores why Canada seemingly doesnot have enough doctors. One reasonis how doctors are paid: ‘…'85 feefor service pays doctors much moreto cut and prod than to listen andthink’. Doctors were attracted to workthat paid well, leaving disciplines likefamily practice, palliative medicine,paediatrics and psychiatry, amongothers, relatively understaffed. Hisproposed solutions are team work(where doctors work with nurses, andgeneralists with specialists), morerealistic remuneration and salariedpayment for doctors. He citesexamples of effective teams. In theSomerset West Community HealthCentre in Ottawa where doctors andnurse practitioners work together,93% of the walk-in cases did notrequire a doctor’s consultation.Chapter 10 tackles the high costs of

drugs. He thinks that this is due tothe activities of the pharmaceuticalcompan ies , the inadequateknowledge of the prescribing doctorsand lack of communication with thepharmacists. Chapter 11 concernsthe waiting time for patients typicalof the Canadian-type of nationalmedical system. Rachlis contendsthat it is not inadequate resourcesbut poor coord ina t ion andmanagement (such as multiple queuelines without central control) that leadto long waits. He suggests methodssuch as advanced access, facilitatedreferral, case manager interventionand re-designing the system aroundthe patient. Chapter 12 is an argumentwhy the private sector (insurance andproviders) is not the cure for Canada’shealth problems.

REVIEWThis is an excellent exposition of theproblems facing the Canadian healthsystem in the late 1990’s and theinnovative methods developed tomanage them. Dr Rachlis is a hard-hitting author who does not mincehis words. In the late 1990’s, Canadawas facing the same problems thatwe have: hospitals persistentlyoperating near capacity, frequentlydiversion of ambulances away frombusy hospitals, lack of subacute bedsto absorb patients from acute wards,vulnerability to devastating surges inmedical demand because of seasonalillness like influenza. There has beena massive human and financialinvestment to develop a responsiveand integrated health system outsideof the hospitals in some Canadianstates.

Rachlis did not limit himself todescribing the Canadian healthinsurance system. He delved intoquality, hospital care and institutioncare. The book, though publishedonly in 2005, is slightly dated giventhe pace of progress of health servicedelivery, especially in chapter 5regarding the management chronicdiseases. Nevertheless, this is a goodread especially as it is free-of-charge.


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Clayton M. Christensen, Jerome H. Grossman, Jason Hwang. TheInnovator’s Prescription. A Disruptive Solution for Health care. McGraw-Hill 2009. 440 pages. The introduction may be downloaded for free fromhttp://api.ning.com/files/65s2xmIDt7-EL92IiIoht*SxmMFyH4kFJ7t9izEwFbhZlnaUHpTjSxOpOuQyCRHnj37qmVAVb-ir0no2HlFPKeja-pAvbnq9/Introduction.pdf

AUTHORSChristensen is the Robert and Jane Cizik Professor of BusinessAdministration at the Harvard Business School. He has been analyzingproblems in medicine using business principles since 1998. JeromeGrossman, M.D., was a health care policy expert, CEO of a medical centerand founded four companies. Hwang is an internist as well as the SeniorStrategist in a consulting firm.

BOOK SUMMARYThe great insight, spelt out in theintroduction, is that all businesses,including medicine, consist of threemodels: solution shops, value-adding process (VAP) businesses,and facil itated networks. Wediscussed this previously in thearticle. In chapter 2, the authorsargue that technology can enter therealm of medicine because it hasbecome more of a precision exercisethan an intuitive art especially in butnot limited to the field of infectiousdiseases. Chapter 3 concernsdisrupting the hospital businessmodel, expanding on the threemodels of work. In chapter 4, theauthors suggest that diagnostictechnology at point of care, onlinedecision tools and telemedicine willchange the way medicine ispracticed. Chapter 5 deals with thetreatment of chronic illnesses. Theysuggest that we categorize the typesof chronic illnesses instead ofregarding them as the same. First,they tell us to consider themanagement as intuitive (forconditions such as lupus, obesity,allergies, infertility) and as rule-based(conditions such as type 2 diabetes,HIV infection, gastro-oesophagealreflux and heart failure); the reasonfor doing so is that intuitivec o n d i t i o n s r e q u i r e t e a mmanagement, while rule-basedconditions can be treated by onedoctor. A business model could be

setting up a coherent solution shopto treat patients with complexproblems, such as in Cleveland Clinicin which a patient may see a teamof specialists and completes all theinvestigations in a single day.Subsequently, the authors dividediseases into those with immediateconsequences for nonadherenceand those without, and those withimmediate and those with deferredconsequences. The authors bringup the idea of facilitated networksagain, citing Alcoholic Anonymous,dLife, and patient support groups.They also suggest changing themotivation of health care providersfrom pay-for-service to capitation,quoting the examples of Healthways,Inc. and OptumHealth. They lookafter patients with chronic diseasesand collect fixed fees, so it is in theirinterest to keep patients healthythrough nurse practitioners and closemonitoring. The other model that theauthors like is the integrated fixed-fee providers like Kaiser Permanenteand Geisinger Health System. Theyare combined insurance-and-provider systems and that collectfixed insurance premiums and theymaximize profits when their insuredstay healthy.

Chapter 6 on integration is verygood. Chapter 7 is insightful; itexplains that there are two types ofinsurance – one for catastrophicillness (which most except the veryrich will need) and one for smallmedical bills (which may not be soimportant but drives cost). In chapter

8 the authors discuss their ideas ofthe future of the pharmaceuticalindustry. This is a relative weakchapter probably from the lack ofthe authors’ personal experience.The next chapter on instruments anddevices has two main points. Theultimate level of development ofinstruments is such that they maybe used by the patient in their ownhome without supervision or specialtraining. Devices lead to the‘commercialization’ of medical skills,in that procedures that could onlybe performed by super-specialistsmay now be carried out by less well-trained people with consistentlygood results. Examples are jointreplacement and LASIK.

Chapter 10 is brilliant, applying theprinciples of Toyota manufacturingto medical education in a surprisingway. I will mention another point thatwas made: given that the traditionalschools do not produce health careprofessionals who fit into hospitalsystems, individual hospitals andorganizations will start training theirown staff. This has already happenedin Singapore; Parkway College hasbeen t ra in ing nurses s inceSeptember 2008.27

REVIEWIf you rate a book by the number of‘aha!’ moments, this will top yourlist. This is an inspired book in whichbusiness principles are applied toimprove the whole spectrum ofhealth care. A mantra of the authorsis that old ways of doing business


BOOK SUMMARYChapter 1 starts with the author’squest to avoid shoulder arthroplastyas he sought treatment in variouscities around the world for pain in apreviously operated shoulder. He wasalso trying to answer the questionwhy the health care system in USAwas so poor and the expenditure wasso high. He tabulated the percentageof GDP that selected countries spendon health care in 2005: USA 15.3%(highest in the world), Switzerland11.6%, France 11.1%, UK 8.3%,Japan 8.0%, Taiwan 6.2% (in 2007).As we know, Singapore spends about4% of the GDP on health.7 In chapter2, he describes the four main nationalhealth care models which wediscussed in table 2. In chapter 3,entitled ‘The Paradox’, he lists theproblems with health care in USA.First, not every citizen is covered,especially those who cannot afford

insurance but are not poor enoughto qualify for Medicaid. For those whoare uninsured or underinsured, amajor illness can devastate a familyfinancially. Reid tells us that 700,000people a year in US go bankruptbecause of this. Second, the healthcare may not be top quality givenpoor performance in internationalindices such as the informality rate(6.8 per 1,000 versus 2.5 per 1,000in Sweden), survival from majorillness, healthy life expectancy at sixtyand avoidable mortality. Third, healthcare costs more in USA. True,doctors, nurses, hospital workers anddrug company staff are paid more inUS than in other countries. However,US doctors pay much more inmedical school fees, malpracticeinsurance and are likely to be suedmore than once in their career. Themain driver of cost, according to Reid,is the inefficient private insurancesystem. The for-profit companies onlypay out 80% of the premiums theytake in for health care. When formerCa l i fo r n ia gove r nor A r no ldSchwarzenegger tried to raise this to85%, his bill was blocked by insurers.The administrative cost of health care

is therefore very high, while it is only3% in Canada and 5% in Britain. Thehundreds of insurance plans withdifferent rules and coverage also addto the administrative cost. Insurancecompanies also have the right tochoose their customer, to denypayment for a variety of reasons andto cancel coverage (‘rescission’ inlegalese).

In chapter 4, the start of the meat ofthe book, the author goes to France,which topped the list in WHO’s TheWorld Health Report 2000 “HealthSystems: Improving Performance”.29

He was very impressed by the CarteVitale which we have discussed. Inchapter 5, he described the systemin Germany. In this system, the payersare pr ivate (employers andemployees) and the providers areprivate; the premium costs the samefrom every company. The insurersare non-profit and workers do notlose coverage when they lose theirjobs; unemployment benefits kick into pay. There are adequate providersso waiting times are not long. Thissystem, though, is expensive, costing11% of the German GDP, though

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(or running health care systems) canbe ‘disrupted’ by innovation.

The authors set themselves theambitious goal of reviewing everythingin medical practice and suggestingdisruptive improvements to all ofthem. We have pointed out thechapters that are successful andthose that are less well thoughtthrough; many of them are untested.Typically, the authors describe current

shortcomings of the current situation.They then offer their disruptivesolution (with no explanation whyalternative solutions may not work)and then move on to the next topic,without considering how or whethertheir idea can be implemented.

Even if we do not agree with theauthors, their insights never fail toopen our eyes. The solutions offeredhave not been attempted on a large

scale. Some reviewers commentedthat the authors did not take thepolitical reality into account, whichmay render their suggestionsimpractical in the real world. AsKarunesh Tuli noted, ‘The Innovator'sPrescription will delight supportersof consumer-directed health care, willalarm physician associations andproponents of nationalized healthcare, and will enlighten all’.28

Reid TR. The Healing of America. Penguin Press, New York, 2009. 277pages.

AUTHORReid is a former correspondent of The Washington Post who has workedand consulted doctors and healers around the world. His speech about hisbook at the Commonwealth Club is available at http://fora.tv/2009/09/14/TR_Reid_The_Healing_of_America. You can read an excerpt athttp://abcnews.go.com/ GMA/Books/story?id=8383452#.TuwX6Hoyz_d.


considerably lower than the USA’s.Chapter 6 deals with Japan’s healthsystem, which largely consists ofprivate nonprofit insurance plans andprivate hospitals. Prices are kept lowbecause the government negotiateswith the providers on behalf of theinsurance companies. The Japanesesystem is similar to the Germansystem, but costs only 8% of theGDP. Chapter 7 is entitled ‘The UK:Universal Coverage, No Bills’.Chapter 8 concerns the Canadiansystem. Chapter 9 deals with out-of-pocket systems. Taiwan’s new healthcare system, probably the best-designed in the world, was the focusof chapter 10. The government askedProfessor William Hsiao, health careeconomist at the Harvard School ofPublic Health, to lead a team todesign a system in the late 1980’s.He studied the existing system,determined the will of the people andthe government and organized athree-conference in Taipei to discussthe best and worst aspects of thehealth care systems of six advanced

nations (Japan, USA, Canada,Germany, Britain and France). Hewisely required Taiwanese cabinetministers to chair the sessions sothat they sat through the sessionsand were educated. Eventually, thenew system was a compendium ofthe best parts of the most effectivemodels. Providers were private andthe payer a single national insurancesystem. This is similar to theCanadian system except that theinsurance is not paid for by taxationbut contributions from employersand employees. Each of the 23 millionTaiwanese also carries a smart card,the 32 K IC, containing medical andbilling records like the French CarteVitale. The Bureau of National HealthInsurance has the power to set pricesfor services and drugs. The systemcovers everyone and pays for a verywide set of medical treatment. Whenthe system went operational on 1March 1995, 11 million previouslyuninsured Taiwanese suddenlygained access to medical service.Only 6% of the GDP is spent on

health. Reid was very impressed withthis remarkable new Taiwanesesystem. Chapters 11 to 13 concludethe book and pose a challenge tothe decision makers to improve theUS system.

REVIEWThe strength of this very readableand sometimes brilliant book is itsanalysis of the various health caremodels the author encountered,always compared to the Americansystem. Even a quick read will helpthe reader distinguish the varioushealth systems. Reid shows that acountry’s history often determinesthe health care system it possesses.The author is disturbed that the USsystem leaves many uninsured andgoes as far as to say that the lack ofuniversal coverage the central moralflaw of the US health care. TheTaiwanese system is held up to bean excellent model for the US toemulate. Unfortunately, the Singaporesystem was not investigated at depth.

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References1. Fernandez W. End of zi char? Straits Times 6 April 2008. Available from http://www.asiaone.com/News/The%2BStraits%2BTimes/Story/A1Story20080406-

58243.html.2. Stabell CB, Fjeldstad Ø. Configuring value for competitive advantage: on chains, shops and network. Strat Mgmt J 1998; 19:414-9.3. Berwick DM, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Aff (Millwood) 2008; 27:759-69.4. Edmond MB. Taylorized medicine. Ann Intern Med 2010; 153:845-6.5. Tan ST, Leong FL, Chan BAL, Tan CM, Tan DH. Economics in Public Polices: The Singapore Story. Marshall Cavendish Education, 2009.6. Available from http://dranove.wordpress.com/.7. Available from http://www.moh.gov.sg/content/moh_web/home/costs_and_financing.html.8. Hsiao WC. Medical savings accounts: lessons from Singapore. Health Aff (Millwood). 1995; 14:260-6.9. Ryoo JJ, Malin JL. Reconsidering the Veterans Health Administration: a model and a moment for publicly funded health care delivery. Ann Intern Med. 2011;

154:772-3.10. WHO. The World Health Report 2000. Health Systems: Improving Performance. Available from http://www.who.int/whr/2000/en/.11. Hsiao WC. State-based single-payer health care - a solut ion for the United States? N Engl J Med 2011; 364:1188-90.12. McGlynn EA, Asch SM, Adams J, Keesey J, Hicks J, DeCristofaro A, Kerr EA. The quality of health care delivered to adults in the United States. N Engl J

Med 2003; 348:2635-45.13. WHO. World Health Statistics 2011. Available form http://www.who.int/whosis/whostat/2011/en/index.html14. Wang SY, Chen LK, Hsu SH, Wang SC. Health care utilization and health outcomes: a population study of Taiwan. Health Policy Plan. 2012 Jan 17. [Epub

ahead of print]15. WHO. The World Health Report 2010: Health Systems Financing: The Path to Universal Coverage. Available from http://www.who.int/whr/2010/en/index.html.16. Emanuel EJ. Where are the health care cost savings? JAMA 2012; 307:39-40.17. Mirnezami R, Nicholson J, Darzi A. Preparing for precision medicine. N Engl J Med 2012 Jan 18. [Epub ahead of print]18. Campillo-Artero C. When health technologies do not reach their effectiveness potential: a health service research perspective. Health Policy 2012; 104:92-8.19. Chaudhry B, Wang J, Wu S, Maglione M, Mojica W, Roth E, Morton SC, Shekelle PG. Systematic review: impact of health information technology on quality,

efficiency, and costs of medical care. Ann Intern Med 2006; 144:742-52.20. Amarasingham R, Plantinga L, Diener-West M, Gaskin DJ, Powe NR. Clinical information technologies and inpatient outcomes: a multiple hospital study. Arch

Intern Med 2009; 169:108-14.21. Colpaert K, Claus B, Somers A, Vandewoude K, Robays H, Decruyenaere J. Impact of computerized physician order entry on medication prescription errors

in the intensive care unit: a controlled cross-sectional trial. Crit Care. 2006 Feb;10(1):R21.22. Shabot MM. Ten commandments for implementing clinical information systems. Proc (Bayl Univ Med Cent) 2004; 17:265-9.23. Available from http://www.ameli.fr/assures/soins-et-remboursements/comment- etre-rembourse/la-carte-vitale/la-nouvelle-carte-vitale.php.24. Khalik S. Protect my medical record better, please. Straits Times 13 January 2012. Available from http://www.asianewsnet.net/home/news.php?id=26327&sec=325. Available from http://www.futuregov.asia/articles/2011/may/03/first-phase-singapore-national-ehr-goes-live/.26. De La Merced MJ, Pollack A. Roche Makes $5.7 Bil l ion Bid for I l lumina. New York Times 24 January 2012. Available from

http://dealbook.nytimes.com/2012/01/24/roche-offers-to-buy-illumina-for-5-7-billion/.27. Ho AL. Parkway school to offer nursing diploma. Straits Times 6 March 2008. Available from http://www.asiaone.com/News/Education/Story/A1Story20080306-

52988.html.28. Tuli K. Book review. N Engl J Med 2009; 360:2038-2039.29. Available from http://www.who.int/whr/2000/en/whr00_en.pdf.


RADIOLOGY QuizQuestionA 49-year-old Chinese male presented with a 3-week history of right hip pain, which was worse on internal rotation. Therewas no history of trauma. He had a history of retroviral illness, hypocortisolism secondary to long-term use of exogenoussteroids and psoriasis. On examination, there was tenderness on internal rotation of the right hip which retained full rangeof movement. Radiographs of the pelvis and hips were performed (figures 1a, b and c).

Figure 1a. Plain AP radiograph of the pelvis.

Figure 1b. Lateral radiographs of the right and left hips.

Question 1(a) What do the radiographs in show?(b) What diagnosis should you consider in view of the patient’s history?(c) What are some of the possible aetiologies of this condition?


21:

Figure 2. Selected coronal T1 weighted images (T1WI) of the hips.

Question 3Follow up radiographs of the pelvis and right hip are shown in Figure 3. What do the radiographs show?

Figure 3b. Plain AP and lateral radiographs of the right hip 8 months later.

Question 2MR imaging of the hips were ordered for further evaluation (figure 2). What are the MR scan findings?


Discussion

Avascular necrosis (AVN) of the hip ismost commonly due to trauma,predominantly a neck of femur fractureor dislocation of the hip joint. Use ofexogenous steroids, as in this case,can cause AVN. Other causes includevasculitis, alcohol excess and sicklecell disease. However, in some cases,there are no predisposing factors andAVN is idiopathic. AVN of the hip usuallyoccurs in the anterosuperior head ofthe femur.

In this case, the initial radiographshowed subchondral cysts in thefemoral head on the initial radiographwith no other significant findings. Thereare 4 causes of subchondral cysts: (a)degenerative joint disease, (b)rheumatoid arthritis, (c) calciumpyrophosphate dihydrate crystaldeposition disease (pseudogout) and(d) AVN. However, conditions (a) to (c)will also have associated radiographfindings in addition to the subchondralcysts, such as osteophytes orchondrocalcinosis to suggest them.

Therefore, AVN should be consideredif there are subchondral cysts in anotherwise normal joint.

Plain radiograph findings may bedelayed and evident only months afterthe patient first presents. Patchysclerosis of the femoral head is theearliest finding as there is resorptionof vascularized bone resulting in areasappearing to be of increased density.Following this, a subchondral lucentline in the weight-bearing area of thefemoral head may be seen in somecases (‘crescent sign’).

In later stages, plain radiographs willshow collapse of the articular surfaceand flattening of the femoral head.Sclerosis is due to compression ofbone and new bone formation.MR imaging is the most sensitive andspecific modality for evaluation ofprobable AVN, even when plainradiographs and radionuclide scansare normal. CT can be used to stageknown disease. On MR imaging, AVN

of the hip shows a focal area of low ormixed signal on T1WIs. This area hasa serpiginous low-signal border. Figure2 shows these characteristic features.

Other bones in which AVN occurcommonly are the carpal lunate, tarsalnavicular and the tibial tubercle.

AnswerAnswer 1aWell-defined lucent areas in the right femoral head are present, compatible with subchondral cysts (figure 4). No significantdegenerative changes (osteophytes, reduced joint space and subchondral sclerosis) are seen.

Answer 1bAvascular necrosis of the right femoral head.

Answer 1cTrauma, steroid use (as in this case), vasculitis, idiopathic and others (see discussion later).

Answer 2The coronal T1WI images show focal serpiginous areas of low signal in the right femoral head, which is likely due toavascular necrosis.

Answer 3Avascular necrosis of the right femoral head has progressed. There is articular surface collapse with flattening of thefemoral head and dense sclerosis of the bone.

Dr Lorna Fan is a resident in theDepartment of Diagnostic Radiology, TanTock Seng Hospital


23:

ECG Quiz

No, this is not acute ST-elevation AMI. The ECG shows deep Q waves andpersistent ST elevation from V2 to V4. There are no reciprocal ST depressionsin the inferior leads of II, III and aVF. The CXR shows gross cardiomegaly withfeatures of acute pulmonary edema.

The ECG diagnosis of this ST elevation is left ventricular apical aneurysm whichis confirmed with a transthoracic echocardiogram. The cardiac enzymes werenever elevated.

The clinical diagnosis is acute pulmonary edema with left ventricular apicalaneurysm of which coronary artery disease is the likely aetiology.

Dr David Foo is a consultant andHead of the Department of Cardiology,Tan Tock Seng Hospital.

This year, I will present a series of cases illustrating the differential causes of ST elevations in ECGs.


A 64-year-old male with a history of hypertension, diabetes and smoking presents with acute-on-chronic shortness ofbreath. His ECG and CXR are shown below. Is this acute ST-elevation AMI?

Question

Answer

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8 March 20121.15pm - 2pm

Choa Chu KangPolyclinic

To register, please call6357 7601


GP Forum: Approach ToCommon Eye Conditions

Department ofOphthalmology

10 March 20121.30pm - 4.30pm

Conference Room @TTSH Eye Centre(Atrium)

To register, please call6357 7687 / 6357 7735

2 CME points will beawarded

Free

GP Talk: The Role of Surgeryin the Treatment of Diabetesand the MetabolicSyndrome


2 March 20121.15pm - 2pm

Jurong Polyclinic To register, please call6357 7601


1st Basic Ilizarov Course Department ofOrthopaedic Surgery

10-11 March 20129am - 5pm


To register, please email:[email protected] OR call 6357 3241

500CME points will beawarded

Advanced Hand & WristArthroplasty Workshop &Hand ArthroplastyWorkshop


23 - 24 March9am - 5pm

Conference Room 1and 1, TTSH

To register please downloadthe registration form fromwww.ttsh.com.sg

SGD$ 800.00 (Day 1only): Advanced Hand& Wrist ArthroplastyWorkshopSGD$ 500.00 (Day 2only): HandArthroplasty WorkshopSGD$ 1100.00 (Bothdays): Advanced Hand& Wrist ArthroplastyWorkshop & HandArthroplasty Workshop

CME points will beawarded

GP Talk: Management ofNeck Lumps in Primary CareSetting


28 March 20121.15pm - 2pm

Yishun Polyclinic To register, please call6357 7601

1 CME point will beawarded

Free
