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Medical digest

MICA (P) 031/04/2010

Oct.Nov.Dec. 2011


F rom Th e Editor

Oct.Nov.Dec. 2011

Dr Leong Khai Pang

I love lists, especially if they are about doctors and medicine. They contain advice and instruction and sometimes amusement. Of course they are not gospel truths and they often reveal the writers foibles and idiosyncrasies. For example, this list is known as Loebs laws of Medicine (published in Matz R in NY State J Med 1977; 77:99-101 and quoted by Zollo AJ in Medical Secrets, Hanley & Belfus, Inc, Philadelphia PS, 1991): 1. If what youre doing is working, keep doing it; 2. If what youre doing is not working, stop doing it; 3. If you dont know what to do, dont 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 and Western 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 not discreet; 4. Remember the Sabbath day and keep it holy; six days shalt thou labor and on the seventh also, if thou hast an opportunity to do good or the prospect of a good fee; 5. Honor the fathers of thy profession, that thy days may be long upon the land and thy usefulness lengthened, through the example and achievements of thy fathers; 6. Thou shalt not sanction adultery nor produce an abortion; 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. World J Surg 2005; 29:1200): Give your patients all the time they need to talk to you and listen to what they say. If they dont need surgery just yet, tell them so, even when your schedule is empty. The word in the community will be that you dont operate when unnecessary and they will come back to you for everything in the future. 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 ones 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 from Bantam 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 underpinning everything we publish in Medical Digest: 1. In all things, think for yourself, after taking all facts and opinions into consideration; and 2. Do what is appropriate for the patient. Thank you for supporting our magazine all these years. The editorial board wishes all Readers the very best in 2012.

Dr Jackie Tan Dr Jaideepraj Rao Dr Lee Cheng Chuan Dr Khian Chong Yaw Dr David Foo Dr Gregory Kaw Dr Nikolle Tan Dr Ernest Kwek Ms Lim Wan Peng


Ms Michelle Lee

Ms Zaonah Yusof

We value your feedback. Please email your questions, comments or suggestions to: Please also contact us for notification of change of postal address or for requests of additional copies.

While every endeavour is made to ensure that information herein is accurate at the time of publication, Tan Tock Seng Hospital shall not be held liable for any inaccuracies. The opinions expressed in this publication do not necessarily reflect those of Tan Tock Seng Hospital. The contents of this publication may not be reproduced without written

permission from the publisher.

Dr Leong Khai Pang EDITOR Medical Digest





STOP Dengue
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 hygiene is 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 disproportionately afflict the less-developed countries continue to stay relevance. This remains the focus of this meeting after 60 years.

Dengue is the most rapidly spreading mosquito-borne viral disease in the world. In the last 50 years, incidence has increased 30-fold with geographic expansion to new countries. An estimated 50 million dengue viral infections occur annually and approximately 2.5 billion people live in dengue endemic countries according to the World Health Organisation (WHO).1 It is of no surprise that dengue remains one of the main themes at this ASTMH meeting. STOP Dengue, one of the five high-profile local translational

clinical research programs, made a significant impact at the meeting by presenting high quality work. The clinicians together with collaborators presented 5 posters and 2 oral presentations. These include 2 posters selected for young investigator competition and one poster for special mention at poster-walk sessions by the world experts. The work presented at the meeting range from accurate early diagnosis of dengue, early identification of those

likely to progress to severe disease, factors predicting fatal outcome, a landmark phase 2 dengue vaccine trial, estimating the burden of dengue infections and comparing cost effectiveness if vaccine were introduced to Singapore. Dengue viral infection has been well described to have a wide-spectrum of clinical manifestations. The early disease is non-specific illness and it is challenging for clinicians to distinguish dengue from other febrile




illnesses. The Prospective Adult Dengue Study (PADS) started recruiting participants with febrile illnesses at the Communicable Disease Centre in January 2010. This provided an ideal platform to develop and validate early diagnostic tools. Currently, the two commonly used confirmatory tests in the laboratory to diagnose dengue are the polymerase chain reaction (PCR) and non-structural protein NS1 tests. Both tests have an average turnaround time of a day. We found that in the142 laboratory-confirmed dengue patients, NS1 was comparable to PCR during early stage of illness and outperformed PCR at later stage of illness from day 4 onwards.2 The next stage of our research is to study the different NS1 rapid test kits aiming for a pointof-care-test that clinicians can rely on in the clinic to diagnose dengue in less than half an hour. When we can diagnose dengue early, how do we best manage it? There is a wide range of disease manifestations and most patients have mild to moderate illness that can be safely

managed in the outpatient setting. However, a small proportion develops fatal illness. Early accurate prediction of severe illness is an area of intense research. Which patients should be admitted to hospital and how they should be managed remain important clinical questions. Using the same prospective cohort, PADS at Communicable Disease Centre, we validated two diagnostic models that were developed based on the 2004 retrospective dengue cohort. The two models are the probability equation translated into a dengue hemorrhagic fever (DHF) calculator that is available in the Cluster Shared Patient Record System (CPRS) and, the user-friendly clinician decision tree. 3,4 These two models were designed to identify risk factors associated with progression to severe disease fulfilling the criteria of dengue hemorrhagic fever. 5 Using the prospective PADS cohort, the sensitivity and specificity of dengue hemorrhagic calculator and decision tree for admission were 86% and 48%,

and 100% and 32%, respectively.6 This means that DHF calculator and the decision tree identified 86% and 100% of the dengue cases that progressed to DHF. These patients should ideally be hospitalized for closer monitoring and treatment. High sensitivity was chosen over specificity in support of safer practice. Ironically, the definition of severe illness is still debated as there are two sets of WHO guidelines. Clearly, more work needs to be done. The most severe form of dengue infection results in mortality. We reported 28 fatal cases from 5 major public hospitals over 5 years from 2004 to 2008.7 A case-control study was conducted to identify predictors of fatal outcome at the time of hospital admission. Cases and control were matched for age and duration of illness. Using the definition of DHF in the 1997 WHO dengue guidelines, only one third of the fatal cases were identified. In contrast, with the severe dengue definition in the WHO 2009 guidelines,




all fatal cases could be identified. H o w e v e r, t h e w a r n i n g s i g n s recommended in the 2009 WHO guidelines did not discriminate fatal cases and controls. Multivariate analysis using clinical and laboratory variables showed that only white blood cells and urea had weakly significant association with fatal outcome (adjusted odds ratio of 1.48 (95% CI 1.004-2.2) and 1.64 (95% CI 1.1-2.45) respectively).8 To this day, the reasons why adults succumb to dengue remain elusive. Sadly, permission for academic autopsies to answer this question is hard to obtain in the Asian context. To date, there is no anti-viral agent effective against dengue. The work to develop a dengue vaccine has been going on for more than three decades. This shows how difficult the challenge has been. Last year, one of the most advanced dengue vaccines was studied in a phase-3 clinical trial in Thailand. Prior to that, this liveattenuated chimera vaccine combining all 4 dengue serotypes (CYD-TDV) developed by Sanofi Pasteur was tested in Singapore. The phase-2

double-blind randomized 5-year study, involving participants aged 2 to 45 years, was designed to assess safety and immunogenicity. The volunteers received three injections at 0, 6 and 12 months and are currently on postvaccination follow-up to assess immunogenicity over five years. Through this multi-centre study, it was shown that the dengue vaccine has a similar safety profile to control vaccines (influenza and hepatitis A vaccines). A substantial antibody increase close to 80% and above against all 4 serotypes was observed after the completion of the three CYD dengue injections. 9 Another study assessing dengue disease burden and cost of disease prevention suggested that the dengue vaccine if cost at reasonable amount can achieve cost-effectiveness in controlling dengue in Singapore. 10 CONCLUSION Dengue continues to be a major public health problem in Singapore and this part of the world. We are finding ways to detect the disease early, to predict those who will develop life-threatening illness and to immunize those at risk.

The robust dengue research activities at Communicable Disease Centre will continue to produce results that can be translated to clinical practice. It is also a testament that Tan Tock Seng Hospital is well-placed to conduct impactful clinical research.

Associate Professor Leo Yee-Sin is the Head and senior consultant of the Department of Infectious Diseases, Tan Tock Seng Hospital.

References 1. 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.




Phamaceutical Update

Clopidogrel-Proton Pump Inhibitor Drug Interaction and its

Clinical Relevance
Acute coronary syndromes (ACS), including unstable angina and myocardial infarctions (MI), are life-threatening manifestations of coronary artery disease. The cause of ACS is the formation of a thrombus at the site of atherosclerotic plaque rupture or fissure. After an ACS, patients tend to be in a hypercoagulable state which may persist for more than 6 months. This will in turn increase the risk of secondary ischemic events, including ischemic stroke, recurrent MI or vascular death.1 In the CAPRIE trial, clopidogrel has been proven to be an effective alternative to aspirin for the prevention of ischemic events in patients with symptomatic atherosclerosis.2 Post-hoc analyses have also amplified the benefits of clopidogrel over aspirin in high-risk subgroups, including those with diabetes mellitus (DM), previous ischemic stroke or previous MI.3 Randomized clinical studies, such as CURE and CREDO, have established that synergism between clopidogrel and aspirin is a more effective approach than monotherapy in inhibiting platelet aggregation in patients with ACS or in those undergoing percutaneous coronary intervention (PCI).4,5 Current treatment guidelines recommend intensive dual antiplatelet therapy (DAPT) to be given for more than a month with bare metal stents (BMS) and more than a year with drug-eluting stents (DES) to prevent stent thrombosis.6 Prolonged use of DAPT is associated with increased risk of gastrointestinal (GI) bleeding.7 Proton-pump inhibitors (PPIs) have been widely recommended as concomitant therapy with DAPT for the attenuation of GI bleeding by recent consensus guidelines. 8 Because clopidogrel and PPIs share a common metabolic pathway involving the cytochrome P450 (CYP450), PPIs are hypothesized to reduce the activation of clopidogrel, impair its antiplatelet effect and result in adverse clinical outcomes. As a result, the potential

Intestinal Absorption

Hepatic Metabolism

+ CYP1A2 CYP2B6 CYP3A4/5 CYP2B6 + CYP2C9

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



drug-drug interaction between clopidogrel and PPIs has attracted significant attention from the Cardiology community and is a topic of intense debate presently. This article summarizes current evidence of the effect of this interaction on clinical outcomes and discusses the recommendations. CLOPIDOGREL AND ITS METABOLISM Clopidogrel bisulfate, an adenosine diphosphate (ADP)-receptor antagonist, is a second-generation thienopyridine. It is a prodrug requiring activation by the hepatic CYP450 enzymes. When clopidogrel is consumed, 85% of it is hydrolyzed by intestinal esterases to the inactive carboxylic acid derivative. Only 15% of the remaining drug is absorbed and undergoes oxidative biotransformation to its active metabolite via a 2-step process, mainly involving CYP2C19 isozyme. The first step is carried out by CYP2C19, CYP1A2 and CYP2B6 to form an intermediate compound, 2-oxo-clopidogrel, whereas the second step involving CYP2C19, CYP3A4/5, CYP2C9 and CYP2B6 is responsible for converting the intermediate to the active thiol metabolite (figure 1). 9 The active metabolite forms a disulfide bridge with two extracellular cysteine residues located on the ADP P2Y12 platelet receptor, resulting in irreversible blockade of ADP binding and hence inhibition of platelet activation and aggregation.10 PPIs AND THEIR METABOLISM PPIs are the most effective acid suppressants available for treatment of gastrointestinal disorders. They have been shown to reduce incidence of gastrointestinal hemorrhage when added to antiplatelet therapy. Some patients are also prescribed PPIs for conditions unrelated to DAPT, such as peptic ulcer disease or gastrointestinal reflux, and hence may already be on chronic PPI therapy. Omeprazole is the most commonly prescribed PPI because of its low cost and easy accessibility. Other PPIs include

lansoprazole, rabeprazole, pantoprazole and esomeprazole. PPIs reduce basal and stimulated acid secretion in a dose-dependent manner via inhibition of H+/K+ adenosine triphosphatase (ATPase or protonpump) that is located in the highly acidic luminal domain of the gastric parietal cells. Most PPIs have very short circulating half-lives (1-2 hours), but their action is prolonged due to irreversible inhibition of H+/K+ ATPase, which requires least 3-4 days for recovery.11 Like clopidogrel, PPIs also rely greatly on CYP2C19 for metabolism but their pharmacokinetic and pharmacodynamic profiles are different. Omeprazole is a potent inhibitor of CYP2C19. It is converted to hydroxyomeprazole and omeprazole sulfate by CYP2C19 and CYP3A4 respectively. Although lansoprazole inhibits CYP2C19 to a similar extent as omeprazole, in vivo studies have shown that drug metabolism of C Y P 2 C 1 9 s u b s t r a t e a re n o t significantly affected by lansoprazole.12 Esomeprazole, the S-enantiomer of omeprazole, is metabolized to a greater extent through CYP3A4 and less through CYP2C19, whereas pantoprazole has much lower affinities for these enzymes and potently inhibits another isozyme, CYP2C9.13 Among all, rabeprazole has the lowest propensity for drug interactions because it is metabolized primarily via non-enzymatic pathways.11 POSSIBLE MECHANISMS OF CLOPIDOGREL-OMEPRAZOLE INTERACTION The first possible mechanism of the clopidogrel-omeprazole interaction is the competition for intestinal Pglycoprotein transporter. Absorption of both drugs may be affected by single nucleotide polymorphism of the ABCB1 gene coding for P-glycoprotein (figure 1). Furthermore, bioavailability of clopidogrel, whose dissolution is greater in acidic environment, could be reduced by an increase of pH due to the action of omeprazole. The latter interaction is class-specific and is thus not different between individual PPIs.14

The major site of interaction between clopidogrel and omeprazole appears to involve CYP2C19, which is the major metabolic enzyme for both drugs (figure 1). Omeprazole has been shown to competitively inhibit CYP2C19mediated metabolism of clopidogrel. Gilard et al were the first to draw attention to relevant drug-drug interactions between clopidogrel and PPIs in an observational study.15 Later, in 2008, they published a randomized study, the OCLA trial, showing detrimental effects of omeprazole on clopidogrel action in patients receiving DAPT after PCI via VASP assay. 16 However, the study duration was only 7 days, which was too short to be used as a fair representation of actual clinical practice (DAPT for 1 month for BMS and 1 year for DES). Nevertheless, these studies provided useful preliminary information on possible lowering of clopidogrel efficacy by omeprazole in early days after PCI, which may lead to unfavourable outcomes such as major adverse cardiac events (MACE) and stent thrombosis. EVIDENCE FOR NEGATIVE IMPACT OF CLOPIDOGREL-PPI INTERACTION ON CLINICAL OUTCOMES Several large retrospective trials found statistically significant increases in adverse cardiovascular outcomes with clopidogrel-PPI co-therapy. Results of the Clopidogrel Medco Outcomes Study were finalized and published in 2010. In this cohort study, in which more than 16,000 post-PCI patients were given one-year clopidogrel therapy; those receiving PPIs concurrently had higher rates of MACE (25% versus 17.9% with no PPI). MACE included hospitalization for stroke, ACS, revascularization procedures and death.17 In the population-based cohort study of 734 patients conducted by Juurlink et al, there was an association between readmission due to recurrent MI (occurring within 90 days after index acute MI) and concurrent use of clopidogrel and PPIs. Furthermore, among the older patients, an estimated readmission rate of 7.4% due to re-




infarction occurred as a result of concomitant therapy.18 Ho et al demonstrated, in a multicentre cohort study involving 8205 patients with ACS, that concomitant PPI treatment was linked to higher risk of death or re-hospitalization for recurrent ACS and revascularization procedures, but not all-cause mortality. It is prudent to note that there were significantly more patients with comorbidities such as COPD, DM, prior MI, heart failure, cancer, hepatic and renal diseases in the PPI group, implying that these patients were inherently sicker at baseline.19 EVIDENCE AGAINST NEGATIVE IMPACT OF CLOPIDOGREL-PPI INTERACTION ON CLINICAL OUTCOMES In an European observational retrospective study of more than 1300 ACS patients who received DES, no significant difference was observed between PPI and non-PPI users in terms of in-hospital MACE and major or minor bleed as well as 1-year MACE, death, stent thrombosis and major or m i n o r b l e e d . 2 0 R e s u l t s f ro m retrospective analyses of PRINCIPLETIMI 44 and TRITON-TIMI 38 trials also suggested a lack of association between PPI co-administration and an increased risk of the composite endpoint of vascular death, stroke or MI, or a decreased risk of bleeding.21 A non-significant increase in risk of hospitalization and death in 3 large cohorts of ACS patients aged at least 65 years was shown in another retrospective study by Rassen et al, when co-therapy was prescribed.22 COGENT is the only randomized prospective clinical trial designed to address safety and efficacy of clopidogrel-omeprazole co-therapy in 3267 patients with ACS or PCI. Unfortunately, the study was prematurely terminated due to sponsor bankruptcy. In this study, each arm was randomized to receive either a combination pill containing omeprazole 20 mg and clopidogrel 75 mg (CGT2168) or clopidogrel 75 mg alone. While researchers found no significant difference in MACE incidence between

PPI and non-PPI users, there was a significant reduction in GI bleeding risk with PPI use.23 Although the results seem promising, there were multiple limitations to the study, including inadequate statistical power and early termination. The use of the CGT-2168 pill with possibly different release kinetics from normal clopidogrel may have limited the generalizability of the results. META-ANALYSES ASSESSING CLOPIDOGREL-PPI INTERACTION Recent meta-analyses and systematic reviews by Kwok et al and Siller-Matula et al revealed inconsistencies in the reported clinical relevance of the clopidogrel-PPI interaction. This may be due to substantial heterogeneity in study types and methods of analysis. Overall, the results suggest that combination therapy may be associated with significantly increased risk of both MACE and MI, but not mortality.24,25 Although results from the supporting

studies were mostly statistically significant, important limitations were also noted. The first limitation is that most studies were retrospective and observational in nature. This implies possible confounders may not be fully accounted for. In many circumstances, data on baseline cardiovascular risk factors, such as smoking status, blood pressure and lipid levels, were lacking. Second, patients receiving PPIs were generally older with more co-morbid illnesses. They had higher cardiovascular risk at baseline (including post-PCI patients), which made them intrinsically more susceptible to recurrent cardiovascular events. Furthermore, these patients may be receiving PPIs because of possibly higher GI bleeding risk. As a result, selection bias could be a likely explanation for poorer cardiovascular outcomes observed in some of the studies. Third, many studies may not have considered essential confounders such




Genetic Polymorphisms - CYP450 (CYP2C19 *2,*3,*4,*5) - P2Y12 receptor

Cellular Rapid platelet turnover Reduced CYP activity Increased platelet exposure to ADP Up-regulation of purinergic and non-purinergic signaling pathways Poor drug absorption Drug-drug interactions

Clinical Non-compliance Elevated body mass index (obesity) Diabetes Hypercholesterolemia Smoking

(table 1). Other important factors that have been cited as potential mechanisms for variable platelet reactivity are drug-drug interactions and genetic polymorphisms.33 Because the CYP2C19 isozyme contributes substantially to clopidogrel metabolism, genetic polymorphisms in the gene coding this enzyme isoform are pivotal. Patients who are carriers of the CYP2C19*2 allele are found to have impaired clopidogrel metabolism and are termed as poor metabolizers.10 This variant had been associated with higher platelet aggregation and residual platelet reactivity in ACS and post-PCI patients, which may in turn increase the risk for secondary cardiovascular events.34 Indeed, carriers of this allelic variant had significantly lower levels of active clopidogrel metabolite, diminished platelet inhibition, >50% higher risk of MACE and a 3-fold increased risk of stent thrombosis.35 R E C O M M E N D AT I O N S TO H E A LT H C A R E P R O V I D E R S Current standpoints from the FDA, EMEA and Expert Consensus Guidelines Following the emergence of the first retrospective cohort study showing an association of clopidogrel-PPI interaction with increased risk of cardiovascular events in 2009, the two most important regulatory authorities, US Food and Drug Administration (FDA) and European Medicines Agency (EMEA), have published statements to discourage concurrent prescribing of clopidogrel and PPIs.36 In 2010, as more pharmacogenomics data surfaced, FDA highlighted that reduced effectiveness of clopidogrel is likely more related to patients who are poor metabolizers of the drug. Although there were no recommendations to indicate that genomic testing in individuals is mandatory before starting clopidogrel, FDA alerted that such tests are available in the market.37 FDA also revised its statement to emphasize t h a t t h e re c o m m e n d a t i o n f o r concurrent prescribing is only against omeprazole and not all other PPIs. The ACCF/ACG/AHA 2010 Expert

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

as non-compliance to clopidogrel treatment, which can contribute to poor platelet response. They were also unable to account for ethnic variations and CYP2C19 genetic polymorphisms, which may have implications on platelet reactivity. Therefore, further prospective randomized studies are required in order to fully elucidate the potential clinical impact of clopidogrelPPI co-therapy on clinical outcomes. IS THIS A CLASS EFFECT? In view of varying degrees of CYP2C19 inhibition by different PPIs, mechanistic studies have suggested that the clopidogrel-PPI drug interaction may not be a class effect. Indeed, the lack of negative effects from concomitant treatment of pantoprazole or esomeprazole with clopidogrel has been seen in two observational studies by Siller-Matula et al and Sibbing et al, although both PPIs are relatively potent CYP2C19 inhibitors in vitro.26,27 A pharmacodynamic study provided reassurance that pantoprazole does not attenuate the efficacy of clopidogrel at standard doses when simultaneously administered.28 Similar results have been shown in another randomized crossover trial carried out in post-MI patients.29 A recent crossover study showed that in healthy volunteers, omeprazole cotreatment with clopidogrel resulted in consistent reduction of active thiol metabolite levels, leading to an increase in platelet activity. However, this effect was significantly less marked when pantoprazole was used instead.30 Rabeprazole, which primarily undergoes metabolism by non-CYP pathways, was analyzed in several observational studies and was not

found to be associated with increased adverse outcomes. Similar outcomes have been noticed for lansoprazole, although lansoprazole exhibits potent in vitro inhibition of CYP2C19.21,22 In general, most studies to date still indicate that omeprazole is the main interacting PPI associated with unfavourable clinical outcomes in ACS patients on clopidogrel co-treatment. Therefore, it may be reasonable to consider combining other PPIs than omeprazole with clopidogrel, given their lower interaction potential. THE CONCEPT OF CLOPIDOGREL RESISTANCE Any factor that can contribute to clopidogrel resistance may intensify the degree of interaction between clopidogrel and PPIs. Clopidogrel resistance or non-responsiveness is a term used to describe poor response to clopidogrel and may be defined as the failure of clopidogrel to cause complete blockade of the P2Y12 platelet receptor. Identification of such resistance requires deployment of various laboratory techniques that allow detection of the P2Y12 receptor activity prior to and after administration of clopidogrel.31 FACTORS AFFECTING C L O P I D O G RE L RE S I S T A N C E As a result of lack of standardized laboratory methods for platelet function testing and the use of diverse assays in different studies, the prevalence of clopidogrel non-responsiveness has varied from 4% to 30%.32 Resistance could occur in many ways, including reduced drug bioavailability from patient non-compliance or reduced prodrug intestinal absorption and variations in P2Y12 receptor density




Consensus Guidelines recommend that the individuals overall risks and benefits from clopidogrel therapy with regard to possible cardiovascular or GI complications should be assessed and the need for a PPI should be carefully judged.38 While a PPI is indicated for patients with prior history of GI bleed or multiple risk factors for GI bleed (e.g. warfarin therapy, advanced age, steroid use, NSAID use or H. pylori infection), gastroprophylaxis is not required in lower risk patients. Alternative strategies to counteract clopidogrel-omeprazole interaction Given that all PPIs are equally effective for gastric acid suppression at appropriate doses and that the pharmacodynamic interaction with clopidogrel is CYP450-mediated, prescribing less CYP2C19-inhibiting PPIs such as rabeprazole or pantoprazole may be considered. Histamine-2 antagonists such as famotidine or ranitidine are also possible options for prevention of GI events in low-risk patients. Another option is to separate the administration of clopidogrel and omeprazole. Based on the fact that the elimination half-lives (~8 hours for clopidogrel, 1-2 hours for omeprazole) and plasma circulating times of both drugs are short, this strategy may be sensible approach to minimise competitive inhibition at the target site of CYP2C19. Spacing the drugs 8 to 12 hours apart theoretically prevents such competitive inhibition, although the evidence suggests otherwise.39 A third approach is to escalate the maintenance dose of clopidogrel to overcome response variability, since platelet inhibition is dose-dependent. However, Cuisset et al demonstrated that clopidogrel 600 mg loading dose followed by 150 mg daily for 30 days did not overcome interaction with omeprazole 20 mg daily.40 Currently, the role of dose escalation has not been established and is not supported by FDA. The greater risk of GI bleeding should be borne in mind. Newer P2Y12 inhibitors such as prasugrel, ticagrelor and cangrelor have been developed and serve as promising

alternatives to overcome clopidogrel resistance. Compared to clopidogrel, these drugs are activated more efficiently and rely less on the hepatic CYP450 system for drug metabolism, hence there is lower potential for drugdrug interaction with PPIs. Finally, the use of genetic testing and ex vivo platelet function testing to individualize therapy and guide management may become an option in future. Presently, many studies investigating these tests are underway and they are gradually incorporated into consensus guidelines. Optimizing other factors contributing to poor clopidogrel response Ensuring patient compliance is of utmost importance, as premature discontinuation of clopidogrel is related to higher mortality and increased risk of stent thrombosis in post-PCI patients.41 As polypharmacy is likely to be common in patients with coronary artery disease, interventions aimed at reducing drug interactions should be routinely performed. Aggressive control of risk factors such as hyperlipidemia, diabetes, hypertension, renal impairment, proteinuria and obesity also play a major role in enhancing response to clopidogrel therapy because they enhance platelet reactivity and expose patients to accelerated thrombopoiesis and greater risk of atherothrombotic events.10 CONCLUSION The interaction between clopidogrel and PPIs is still a debatable topic of interest. Though many studies have demonstrated the association of adverse cardiovascular outcomes with taking both drugs concomitantly, they a re l a rg e l y re t ro s p e c t i v e a n d observational in nature. The only prospective study thus far found no significant difference in MACE incidence between PPI and non-PPI users. Until prospective, randomized, double-blinded, multicenter trials with statistical power have been conducted, the causality between clopidogrel-PPI co-therapy and adverse outcomes remains inconclusive.

Considering the benefits of PPIs in the prevention of GI bleeding, they should still be prescribed concurrently with clopidogrel in high-risk patients on DAPT. However, it is prudent for the clinician to weigh the risks and benefits on cardiovascular and GI complications before starting a PPI with clopidogrel. Most retrospective studies have found that omeprazole has significant interactions with clopidogrel, implying that the interaction may not be a class effect. H2-antagonists or less interacting PPIs such as pantoprazole or rabeprazole can be considered as alternatives. Bearing in mind that omeprazole is still the cheapest PPI available and affordability does affect patient compliance, it may still be considered in patients with high GI risks requiring a PPI. Since carriers of the CYP2C19*2 variant gene appear to be more affected by the clopidogrel-omeprazole interaction and have worse clinical consequences, in future, clinicians may consider performing ex vivo platelet function or genomic tests to tailor drug regimens to patients who need antiplatelet therapy.

Ms Mindy Tay is a pharmacist in the Department of Pharmacy, Tan Tock Seng Hospital.




References 1. 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: 528-32 4. 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;108:16827. 5. Steinhubl SR, Berger PB, Mann JT III, et al., for the CREDO Investigators. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002; 288:241120. 6. King SB, Smith SC, Hirshfeld JW, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention. 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 Inhibitors and Thienopyridines: A Focused Update of the ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use : A Report of the American College of Cardiology Foundation Task Force on Expert Consensus Documents. 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: 769784. 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; 32:821-27 14. 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: 25089. 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; 51:25660. 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; 30:78796. 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; 180:7138 19. 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; 301:93744. 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. ODonoghue 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: 98997. 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: 190917 24. 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 23 25. Siller-Matula JM, Jilma B, Schr'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;8:262441 26. 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.e15 27. Sibbing D, Morath T, Stegherr J, et al. Impact of proton pump inhibitors on the antiplatelet effects of clopidogrel. Thromb Haemost 2009; 101: 7149 28. 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;56:917 29. 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 pharmacokinetics of clopidogrel in healthy subjects: randomized, placebo-controlled, crossover comparison studies. Clin Pharmacol Ther 2011; 89:6574. 31. De Miguel A, Ibanez B, Badimn JJ. Clinical implications of clopidogrel resistance. Thromb Haemost 2008; 100:196203. 32. Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol 2005; 45:115764. 33. Sweeny JM, Gorog DA, Fuster V. Antiplatelet drug resistance part 1: Mechanisms and clinical measurements. Nat Rev Cardiol 2009; 6:273282 34. 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: 23127. 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; 357:200115 36. European Medicine Agency. Public statement of interaction between clopidogrel and proton pump inhibitors. 17 March 2010. Http:// 37. 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. 38. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the ACCF/ACG/AHA 2008 Expert Consensus Document on reducing the gastrointestinal risks of antiplatelet therapy and NSAID use. Circulation 2010; 122: 261933. 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; 54:114953 41. Jeremias, A, Sylvia, B, Bridges, J, et al. Stent thrombosis after successful sirolimus-eluting stent implantation. Circulation 2004; 109:1930-2.





Different Health Care, Part 1

This is the Dilbert comic strip of 21 July 1995 in words: Dilbert, his mother and his girlfriend Liz were chatting. His mother said that things have been different since they lost Dilberts Dad. Liz asked, When did he die? Dilbert explained that he was not dead, merely missing in the mall since Christmas 92. Liz was surprised: why didnt they go and look for him? Dilberts mother said, I said its different, not worse. This is the first of two articles in which we present exciting ideas that have changed or are going to change health care delivery at the macro and the micro levels (health care and healthcare are both acceptable and the White House uses the former) . We shall talk about national issues and large health systems in this article, and innovations within hospitals in the next. They will be underpinned by reviews o f re c e n t l y p u b l i s h e d b o o k s . We ask these questions and wonder what the answers might be: Is there a better way to organize our hospitals? On what basis should we re-organise? What makes up a national health care system? What are the responsibilities of the payer, the Types of work Who should deliver service insurance and the health care providers? What is the best way to pay for health care? Purely by government? Purely private? A mixture of the two? Improving health care delivery at the macro level and optimizing the quality of the hospital and careproviders are two sides of the same coin. Like many of our readers, I am a medical practitioner who has spent more than half his life and all his w o r k i n g l i f e t re a t i n g p e o p l e s illnesses; therefore, the angle is necessarily from bottom up. I am not a hospital administrator or a policy-maker, so my analysis of the issues may seem blunt or na'efve to professionals, and may even be wrong. Anyway, my aim is to raise Value-adding processes Anyone who has been trained and certified competent to perform the procedure Ability to perform procedure competently without complications. Fortunately, checklists of uniformly agreed, evidence-based steps can be developed. awareness and initiate discussion. HOW HOSPITALS ARE ORGANIZED In The Straits Times of 6 April 2008, Warren Fernandez reported that many zi char stalls have been forced to close because they could not find workers.1 I think that labour shortage is not the only reason these stalls fail. Zi char stalls are inherently not efficient. They offer 100 items in their menus and have to stock all the ingredients all the time. The cooks need to know how to cook all of them but there is no guarantee that two of them will do it in the same way. They have to assemble the ingredients from various places every time a new order is received. In contrast, fast food joints have short menus and standardized ways of preparing food (this was the genius of Ray Kroc). The cooks never Facilitated network Facilitators

Solution shop Experts and experienced practitioners Ability to extract information from various sources and diagnose. Unfortunately, intuition is sometimes needed and this cannot be put into a protocol. Fee for service New case clinics, emergency departments.

What is required of provider

Share the knowledge of members around so that collective experience benefits everyone

Ideal form of payment Examples

Fee for output Endoscopy, surgeries for known conditions, angioplasty.

Fee for membership Treatment of chronic diseases such as diabetes mellitus, hypertension, asthma, and rheumatoid arthritis.

Table 1. Three types of work in health care




have to walk very far and every cooking step is timed, from frying potato chips to grilling beef patties. Many assert that the health care institution should be better organized for efficiency. Many doctors are against re-organisation, arguing that our work is too complex to be reduced to simple checklists or algorithms, and insisting on absolute autonomy in the way we treat our patients. We think that our hospitals are more like zi char stalls than fast food restaurants. But if we think about it for a moment, we realize that sometimes our work resembles zi char and sometimes fast food. The Innovators Prescription (reviewed later) tells us that medical work may be divided into three categories, based on ystein Fjeldstads idea.2 Solution shops handle medical problems usually of a diagnostic nature (table 1). Patients bring their problems that do not admit of simple solution. The practitioners are highly skilled and because there is no algorithm or rule to solve every problem, they sometimes rely on intuition. Valueadding processes (VAPs) take in incomplete or broken things and transform them into more complete outputs of higher value. Facilitated networks are enterprises in which people exchange things with each other. The authors suggest that facilitated networks may handle chronic diseases but I think that, at best, this is a model for self-help groups. Thus, this forms the rational basis for right siting. Things that can be competently and consistently performed by people of a certain level must not be carried out by more highly paid or over-qualified people. The Innovators Prescription points that we have always organized our hospital, its processes and even its training like a giant solution shop. This i s w ro n g b e c a u s e VA P s a n d management of chronic illness are not solution-shop activities. For example, in sequence, we have the house officer, the medical officer and the registrar interview the patient for the medical

history because we think that a doctor of lower grade may misdiagnose some obscure ailment. This is grounded in solution-shop thinking and is quite inefficient. Why dont we use the most experienced to make the diagnosis and initiate treatment, and let the less experienced carry it through? Of course, there must be a method to ensure that the first diagnosis is indeed correct in the course of the hospital stay, and the junior doctors are trained in the exquisite skill of diagnosismaking. Therefore, the diagnosing or triaging personnel is very important to ensure that the appropriate patient is sent to the right VAP program. Physicians often marvel how surgeons spend less time than they do in taking a meticulous history and examining the patient from head to toe, and yet rarely run into trouble. This is because most of their patients only require VAP treatment, such as appendectomy for appendicitis, Whipples procedure for pancreatic cancer and craniotomy for brain tumour. Physicians can be sure that surgeons flag out medically complicated patients for comanagement.

However, most of our hospitals and clinics are not organized in the most efficient and correctly sited way. Tradition and inertia tend to keep things going the way they are. In USA, it is said that barriers to integrated care at hospital and at macro levels are not technical but political.3 Nonetheless, efficiency must be tempered with moderation. Dr Edmond wrote a piece about the scenario in modern hospitals seen through the eyes of a doctor trained in the last century, like many of us. 4 The residents time was so stretched (in the name of efficiency) that anything that was not deemed to contribute to management or disposal was eliminated. He lamented that humanity and joy had been sucked out of the practice of medicine. PA YING FOR HEAL TH CARE Providing health care is not the same as selling a product or operating a restaurant.5 While we can do without a lifestyle product or restaurant food, we cannot do without treatment when we are sick. In many societies, access to health care is considered a right. A well known exception is USA, in which




Model Payer Insurer Provider Some characteristics

Bismarck Private Private Private The money to fund this system comes from contributions of the employer and employee, not government. There is a great variety in the way insurance and providers are regulated. USA, Germany, Japan, France, Belgium, Singapore public health system.

Beveridge Government Government Government The government looks after the health of her people from conception to coffin. Patients do not get to see a bill. Taxation is used to pay for health care.

National Health Insurance Government Government Private May have long waiting time to see specialist and to receive elective treatment. Government insurance has clout to negotiate for low prices with providers.

Out-of-pocket Private Nil Private In countries with no nationally organized health care, this is the only available model. No accessible care to those unable to pay.


Britain, Italy, Spain, most Scandinavian countries, USA VA Health System,

Canada, Taiwan, South Cambodia, India, Egypt, Singapore private health Korea care.

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

universal health care is not a given. There are two additional problems associated with health care cost. First, how much it costs to treat a medical problem is not predictable at the disease outset. For example, headache can be due to tension or brain tumour. Second, there is a disparity in the knowledge of the patients and the provider. The doctor diagnoses the disease and proposes the treatment and the patient is rarely in a position to judge if the recommendation is correct. In The Healing of America, which we later review, Professor Uwe Reinhardt of Princeton University was quoted as saying, Every nations health care system reflects that nations basic moral values. Once a nation decides that it has a moral obligation to provide health care for everybody, then it can build a system to meet that obligation. To be fair, by 2013, President Obamas Health Care Reform will extend insurance to more than 30 million people, by expanding Medicaid and helping lower- and middle-income Americans buy private insurance. What should hospital CEOs to say if asked to choose between job growth and spending cuts? Economist David

Dranove offers this: Yes, health care spending is high and we need to eliminate waste. But on average you get more for your health care dollar than on anything else you can buy. There is no greater gift than the gift of health, and our hospital teams help people live longer, healthier lives. As we move forward, we will continue to eliminate inefficiencies but we must also be responsive to the needs of an aging population. We will continue to promote wellness and prevention, but we must also be prepared to take advantage of medical breakthroughs that will allow us to better cope with cancer, heart disease, and the many other afflictions that we must all eventually face. The question should not be whether we are spending too much or too little on health care, but whether we are spending our money wisely. If we are and I believe we are making major strides in that direction then we will have the appropriate labor force to meet our communitys needs. An efficient health care system that grows in response to community needs that is my vision, and it is one that generates jobs without wasting dollars.6 What Dranove said is not controversial; health care savings should come from reducing waste a n d i n c re a s i n g e ff i c i e n c y b y

e x p l o i t i n g t e c h n o l o g y, n o t eliminating essential services. National health care models The three main components of any national health care system are the payer, the insurer and the provider. The various models of national health care systems differ in the way these three interact. I have taken the names of the system from Reids book and I shall leave you to read the book to find out why he named them so. In fact, more than one model may be found in an individual, but one tends to predominate. Singapore has a mixed financing system, with multiple tiers of funding.7 First, all Singaporeans can access subsidized health care, where up to 80% of the bill is paid with public fund. There is the compulsory saving Medisave. Contribution to ones Medisave is split between the employee and the employer. Medisave is a medical saving scheme, not an insurance because the funds are not pooled.8 MediShield, a basic medical insurance, provides supplementary payment for people above 65 years. Finally, MediFund supports those who cannot pay their medical bills. Our system actually does cover everybody.




Based on Reids classification, ours is a combination of the Bismarck system (Medisave and MediShield), National Health Insurance (Medifund) and Outof-Pocket (private practitioners). All the systems (except Out-of-Pocket) have the potential to perform very well if they are well managed. In the US, it has even been shown repeatedly that the Veterans Health Administration (in which the payer, insurance and provider are all government-controlled) consistently does better than private providers using commonly accepted performance indicators.9 Insurance Besides the payer and provider, insurance is necessary because the cost of health care is unpredictable for an individual with a medical complaint. The WHO World Health Report 2000 stated Insurance systems entail integration of resources from individual contributors or sources both to pool and to share risks across the population. Achieving greater fairness in financing is only achievable through risk pooling that is, those who are healthy subsidize those who are sick, and those who are rich subsidize those who are poor.10 The state of Vermont, like the rest of USA, is worried about the number of uninsured people and the rising cost of health care. It commissioned Professor William Hsiao and his team of the Department of Health Policy and Management, Harvard School of Public Health, to find a solution.11 Professor Hsiao surmised that to cover the uninsured, he would have to use the savings derived from reforming the system. He also had to maintain the premium coverage the currently insured Vermonters already enjoy. He could not reduce income of the physicians, hospitals and other providers. His solution was a singlepayer, one insurance fund that covers everyone with a standard benefit package, paying uniform rates to all providers through a single payment mechanism and claims-processing system. He calculated that the system will immediately save 8% from simplification and consolidation of

administrative fees and 5% from reduction in fraud and abuse. His team proposes payment by capitation than fee-for-service. Eventually, the state will save 25% in health care expenditures over 10 years. For another example of a superb health care system designed by Professor Hsiao, please read the summary of The Healing of America. The responsibilities of each component The amount of money that a country spends on health care (often expressed as percentage of GDP) ultimately depends what the citizens want; there is no best figure. It is all too clear that more money does not mean better health care. For example, a famous paper informed us that patients in the USA received just above 50% of the treatment recommended for their conditions.12 If too little is spent on health, long waiting times and overburdened clinics and hospitals will result. There may not be resources for research, innovation, or education in the health care system. Health care providers may have to put in heroic efforts to meet service demands. If too much is spent, it will lead to waste and inefficiency and deprive other national initiatives of funds. Health care providers and organisations tend to be better paid in these countries. Therefore striking a balance is important. For comparison, in 2008, Australia 8.5% spent of her GDP on health, 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, the SARS epidemic of 2003 led to 20% fall in health utilization (the extent to which a given group uses a particular service in a specified period) for chronic diseases.14 The authors examined the mortality rate in ten conditions (infectious diseases, cancer, nervous system diseases, diabetes mellitus, cerebrovascular disease, heart and vascular disease, respiratory diseases, digestive diseases, genitourinary system diseases and accidents) over this period. There was significant rise in mortality from diabetes mellitus and

cerebrovascular diseases. They concluded that governments, especially in developing countries, should carefully evaluate potential negative consequences of reduced h e a l t h c a re u t i l i z a t i o n w h e n experiencing major epidemics that lead to reduced health care utilization, and also when they plan to reduce health care insurance coverage or implement a large spectrum of cost-containment practices. How much should be paid by an insurance system and how much by the patient? I quote the WHO again: It is only when direct payments falls to 15-20% of total health expenditures that the incidence of financial catastrophe and impoverishment falls to negligible levels.15 The insurance should be efficient and should not generate excessive profit. The premiums should be affordable and every person should be able to afford. Ideally, no one should be denied insurance because of pre-existing illness. The coverage should not be watered down when the insured person falls sick. All these problems are addressed in President Obamas Health Care Reform, if it is passed. His speech to a joint session of the 111th United States Congress on September 9, 2009 is an excellent presentation of the proposals ( resident-Obama-Address-toCongress-on-Health-InsuranceReform). The health care providers have the responsibility to integrate and innovate to eliminate inefficiency and waste. The right work must be done by the right people. If best practice exists, it must be consistently applied in the appropriate patients. My admiration for Singapores health care system grew as I was writing this article. The highly influential World Health Report 2000 issued by WHO ranked the Singapore health system as 6th in the world, an extremely coveted position to be.8 Our system covers everyone including those who cannot pay, is not too expensive,




poorly implemented is worse than useless; it becomes a millstone around everyones neck. IT in the hospital IT in hospitals is known to increase adherence to guideline-based care, enhance surveillance and monitoring, and decrease medication errors, possibly resulting in fewer complications, lower mortality and lower costs.19,20 In a study conducted in an intensive care unit, orders made through the computer compared to a paper-based system led to fewer prescription errors because of the automatic checks for allergies, drug interactions and dosages.21 In the same study, it was found that the number of errors rose with the number of drugs p re s c r i b e d , b u t n o t w i t h t h e computerized orders. As for any technology, the implementation must be carried well with due respect for doctors and other end-users requirements.22 possesses reasonable quality, and yet costs less than 4% of the GDP. Of course it can be improved in many places, but all the major cogs are in place. This conclusion was drawn by Dr Gro Harlem Brundtland, Director-General of WHO, published in the introduction to the Report: Ultimate responsibility for the performance of a countrys health system lies with government. T h e c a re f u l a n d re s p o n s i b l e management of the well-being of the population stewardship is the very essence of good government. The health of people is always a national priority: government responsibility for it is continuous and permanent. THE ROLE OF TECHNOLOGY In The Healing of America, the author laid the major portion of the blame for the huge cost of health care in US on the insurance companies. A recent article suggests otherwise. 16 Dr Emanuel states that it is not malpractice costs, insurance companies profits (though it was a hefty US$11.7 billion in 2010), drug costs or million dollar babies (patients who consume massive amount of health care) that keep the costs up. Approximately10% of the population consumes about 64% of the cost. These are patients with chronic disease who suffer from complications that could have been prevented. And one way to minimize complications from chronic diseases is to manage the patients well through the providers adherence to best practice and appropriate monitoring, both of which can be facilitated by technology. I think that technology will make Medicine more efficient (bringing professionals with different expertise together to treat a specific patient seamlessly either virtually or physically), more precise (imaging and other diagnostic modalities making diagnoses more certain) and better guided (electronic physician orders and interactive patient-appropriate recommendations aiding doctors in t h e i r d a i l y w o r k ) . I n t ro d u c i n g innovations (whether IT or processes) into health care is not a straightforward matter. Successful implementation requires continuous, not sporadic, effort, preparation of the system to accept the change and securing buyin by the end-users. 18 Technology Universal medical record system There are many benefits if all health care providers can access and review a patients medical records: The history of past medical problems will be more accurate than the patients recalled account; There will be less need to repeat investigations; All the treatment that the patient is receiving will be known, reducing the risk of duplication and drug interaction. One great advantage that the French system has over almost every other country in the world except Germany and Taiwan is the Carte Vitale. This smart card, introduced in 1998, is carried by everyone who is eligible, about 59 million people. It contains the persons medical history, billing, tests, organ donation status, blood group and name of the doctor-in-charge. Clinics have done away with filing cabinets to hold medical records. In addition, after the doctor has entered his record for the current visit, the bill is sent to the French Social Security or Assurance Maladie electronically, reducing the need for secretaries and administrators.




Granted, using electronic records has its share of problems, especially patient confidentiality.24 Singapore too will soon launch a US$144 million National Electronic Health Record system.25 The NEHR will contain patient demographics, diagnosis, medications, tests, procedures and discharge summaries. It has been suggested that electronic health records may provide savings in the management of chronic diseases.16 The physician will be able to check on her patients health status more efficiently. She will be able to use decision supports to increase adherence to treatment pathways. She will be able to use this information for better interaction between patients, caregivers, and clinic staff and care coordinators. Precision medicine Precision medicine has recently been described as coupling established clinicalpathological indexes with

state-of-the-art molecular profiling to create diagnostic, prognostic, and therapeutic strategies precisely tailored to each patients requirements. 17 A key point in Innovators Prescription is that, as much as possible, the practice of medicine should be shifted away from the realm of intuition to that of routine and certainty. Indeed, with improved diagnostic testing and personalized therapeutic strategy, the face of medicine will once again change in our lifetime. It is very telling that Roche Holdings, the Swiss pharmaceutical and diagnostic test giant, is making a $5.7 billion takeover for Illumina, a leading maker of genetic sequencing equipment.26 CONCLUSION The health care system every country has depends on its history and the will of its people. Fortunately, most countries accept that health care is a human right and have provided for those who are unable to pay. The payer,

the insurance and the provider each have their roles and responsibilities. If they all carry out their roles appropriately, the health care system will be strong and will serve the needs of the people. If technology is properly used in an integrated health system, it is hard to believe that it will not bring much good.

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

Micheal Rachlis. Prescription for Excellence. How Innovation is saving Canadas Health Care System. HarperCollins Canada, Limited, 2005. 418 pages. The entire book may be legally and freely downloaded from AUTHOR Rachlis, M.D., is a specialist in community medicine and a health policy analyst. needs to be pumped in, nor do private insurance companies need to enter the market. He presented this position: 1) Public finance still makes sense. It provides for services to be delivered according to peoples needs, reduces administrative overhead, and dramatically reduces costs to business; 2) Money isnt the main issue. Medicare does need adequate, predictable, sustainable funding, but the main issue is the poor organization and management of services; 3) Innovation in service delivery can provide better quality care without breaking the bank. As an illustration, he described how Saskatchewan successfully dealt with the influenza outbreak of 1999/2000. First, one case of influenza-like illness was enough to trigger the response (as opposed to two cases or one laboratoryconfirmed case in other states). Second, patients in nursing home receive a pre-calculated dose of amantadine within an hour of the discovery of an index case in their institution. Third, with pre-planning, fewer than 5% of patients in acute hospitals were waiting for long-term or home care, so that there is capacity to absorb surges in demand. Fourth, the hospitals were organized such that there was always one that could take emergency cases should one ER be closed. There was a central command that could reduce the number of elective cases as necessary to prevent a crisis. Chapter 2 is a detailed defence of Medicare, Canadas much-vaunted

BOOK SUMMARY In the introductory chapter 1, the author wrote It is said that every system is perfectly designed to achieve its outcomes. In January 2000, the Toronto health system was perfectly designed to achieve gridlock, and it did. Rachlis is a supporter of Medicare, Canadas single-payer system in which everyone is covered. He does not think that more money




publicly funded universal health insurance system. Rachlis recounts Medicares checkered past in the hands of the many political parties since its launch in 1947. In chapter 3, the author described the problems with the Canadian health care system that are blamed on but ultimately not due to Medicare. One is that medicine is fractured into more and more subspecialties. today in urban areas, general inter nists find themselves mainly managing elderly patients with multi-system pathology. Chapter 4 deals with end-of-life care. He quoted Elizabeth Latimer who wrote that we could learn from people in the Middle Ages, who practiced ars moriendi, the art of dying. People died at home; as death drew near, they got their affairs in order by forgiving longstanding conflicts, wrapping up legal and financial affairs and saying final words to loved ones. The next chapter discusses the management of chronic illnesses, citing the work of Group Health. It has a road map for diabetes with four elements: an electronic diabetes registry implemented in 1995; regular educational talks by a team of diabetologist and a nurse; development of evidence-based clinical guidelines and a patient selfhelp book. The late Dr Hui Lee of the groups Health Promotion Initiative initiated a system that provided feedback to individual doctors so they knew their own compliance with clinical guidelines compared with anonymised physicians. Chapter 6 discusses home care. Home care allows patients who fall sick to remain at home and hospitalized patients to be discharged earlier. Victoria also initiated a program called Quick Response Team that can be rapidly mobilized to care for patients with fairly complex problems. The author quoted a Vancouver study which showed that administering intravenous antibiotics to a patient at home saved $7,000 per episode compared with hospital treatment. Rachlis also describes other programs that provide comprehensive

outpatient care to poorer folks and even homeless people. An innovative idea at Seaton House, Canadas largest mens hostel, is that the staff do not insist on alcohol abstinence when homeless people come in. They provide alcohol in a controlled fashion because they found that, otherwise, these people would get drunk and injured and have themselves admitted to hospital, necessitating CT scans and other tests. Chapter 7 is about improving long-term institutional care, in particular, by tackling the three plagues of loneliness, helplessness and boredom. Chapter 8 begins with preventing diseases associated with drug abuse, and later moved on to social medicine. Rachlis told an unfamiliar story about a familiar character, Rudolf Virchow. Apparently, he was already a famous doctor when he was 26. He was asked by the Berlin council to investigate an outbreak of typhus in Poland. He discovered that the abject living c o n d i t i o n t h e re w a s d u e t o mismanagement by the government. Of course, the council was miffed to receive his report, calling it a political tract. He then made his now famous statement: Medicine is a social science and politics is nothing but medicine writ large. Chapter 10 explores why Canada seemingly does not have enough doctors. One reason is how doctors are paid: '85 fee for service pays doctors much more to cut and prod than to listen and think. Doctors were attracted to work that paid well, leaving disciplines like family practice, palliative medicine, paediatrics and psychiatry, among others, relatively understaffed. His proposed solutions are team work (where doctors work with nurses, and generalists with specialists), more realistic remuneration and salaried payment for doctors. He cites examples of effective teams. In the Somerset West Community Health Centre in Ottawa where doctors and nurse practitioners work together, 93% of the walk-in cases did not require a doctors consultation. Chapter 10 tackles the high costs of

drugs. He thinks that this is due to the activities of the pharmaceutical companies, the inadequate knowledge of the prescribing doctors and lack of communication with the pharmacists. Chapter 11 concerns the waiting time for patients typical of the Canadian-type of national medical system. Rachlis contends that it is not inadequate resources but poor coordination and management (such as multiple queue lines without central control) that lead to long waits. He suggests methods such as advanced access, facilitated referral, case manager intervention and re-designing the system around the patient. Chapter 12 is an argument why the private sector (insurance and providers) is not the cure for Canadas health problems. REVIEW This is an excellent exposition of the problems facing the Canadian health system in the late 1990s and the innovative methods developed to manage them. Dr Rachlis is a hardhitting author who does not mince his words. In the late 1990s, Canada was facing the same problems that we have: hospitals persistently operating near capacity, frequently diversion of ambulances away from busy hospitals, lack of subacute beds to absorb patients from acute wards, vulnerability to devastating surges in medical demand because of seasonal illness like influenza. There has been a massive human and financial investment to develop a responsive and integrated health system outside of the hospitals in some Canadian states. Rachlis did not limit himself to describing the Canadian health insurance system. He delved into quality, hospital care and institution care. The book, though published only in 2005, is slightly dated given the pace of progress of health service delivery, especially in chapter 5 regarding the management chronic diseases. Nevertheless, this is a good read especially as it is free-of-charge.




Clayton M. Christensen, Jerome H. Grossman, Jason Hwang. The Innovators Prescription. A Disruptive Solution for Health care. McGrawHill 2009. 440 pages. The introduction may be downloaded for free from*SxmMFyH4kFJ7t9iz EwFbhZlnaUHpTjSxOpOuQyCRHnj37qmVAVb-ir0no2HlFPKejapAvbnq9/Introduction.pdf AUTHORS Christensen is the Robert and Jane Cizik Professor of Business Administration at the Harvard Business School. He has been analyzing problems in medicine using business principles since 1998. Jerome Grossman, M.D., was a health care policy expert, CEO of a medical center and founded four companies. Hwang is an internist as well as the Senior Strategist in a consulting firm. setting up a coherent solution shop to treat patients with complex problems, such as in Cleveland Clinic in which a patient may see a team of specialists and completes all the investigations in a single day. Subsequently, the authors divide diseases into those with immediate consequences for nonadherence and those without, and those with immediate and those with deferred consequences. The authors bring up the idea of facilitated networks again, citing Alcoholic Anonymous, dLife, and patient support groups. They also suggest changing the motivation of health care providers from pay-for-service to capitation, quoting the examples of Healthways, Inc. and OptumHealth. They look after patients with chronic diseases and collect fixed fees, so it is in their interest to keep patients healthy through nurse practitioners and close monitoring. The other model that the authors like is the integrated fixedfee providers like Kaiser Permanente and Geisinger Health System. They are combined insurance-andprovider systems and that collect fixed insurance premiums and they maximize profits when their insured stay healthy. Chapter 6 on integration is very good. Chapter 7 is insightful; it explains that there are two types of insurance one for catastrophic illness (which most except the very rich will need) and one for small medical bills (which may not be so important but drives cost). In chapter 8 the authors discuss their ideas of the future of the pharmaceutical industry. This is a relative weak chapter probably from the lack of the authors personal experience. The next chapter on instruments and devices has two main points. The ultimate level of development of instruments is such that they may be used by the patient in their own home without supervision or special training. Devices lead to the commercialization of medical skills, in that procedures that could only be performed by super-specialists may now be carried out by less welltrained people with consistently good results. Examples are joint replacement and LASIK. Chapter 10 is brilliant, applying the principles of Toyota manufacturing to medical education in a surprising way. I will mention another point that was made: given that the traditional schools do not produce health care professionals who fit into hospital systems, individual hospitals and organizations will start training their own staff. This has already happened in Singapore; Parkway College has been training nurses since September 2008.27 REVIEW If you rate a book by the number of aha! moments, this will top your list. This is an inspired book in which business principles are applied to improve the whole spectrum of health care. A mantra of the authors is that old ways of doing business

BOOK SUMMARY The great insight, spelt out in the introduction, is that all businesses, including medicine, consist of three models: solution shops, valueadding process (VAP) businesses, and facilitated networks. We discussed this previously in the article. In chapter 2, the authors argue that technology can enter the realm of medicine because it has become more of a precision exercise than an intuitive art especially in but not limited to the field of infectious diseases. Chapter 3 concerns disrupting the hospital business model, expanding on the three models of work. In chapter 4, the authors suggest that diagnostic technology at point of care, online decision tools and telemedicine will change the way medicine is practiced. Chapter 5 deals with the treatment of chronic illnesses. They suggest that we categorize the types of chronic illnesses instead of regarding them as the same. First, they tell us to consider the management as intuitive (for conditions such as lupus, obesity, allergies, infertility) and as rule-based (conditions such as type 2 diabetes, HIV infection, gastro-oesophageal reflux and heart failure); the reason for doing so is that intuitive conditions require team management, while rule-based conditions can be treated by one doctor. A business model could be




(or running health care systems) can be disrupted by innovation. The authors set themselves the ambitious goal of reviewing everything in medical practice and suggesting disruptive improvements to all of them. We have pointed out the chapters that are successful and those that are less well thought through; many of them are untested. Typically, the authors describe current

shortcomings of the current situation. They then offer their disruptive solution (with no explanation why alternative solutions may not work) and then move on to the next topic, without considering how or whether their idea can be implemented. Even if we do not agree with the authors, their insights never fail to open our eyes. The solutions offered have not been attempted on a large

scale. Some reviewers commented that the authors did not take the political reality into account, which may render their suggestions impractical in the real world. As Karunesh Tuli noted, The Innovator's Prescription will delight supporters of consumer-directed health care, will alarm physician associations and proponents of nationalized health care, and will enlighten all.28

Reid TR. The Healing of America. Penguin Press, New York, 2009. 277 pages. AUTHOR Reid is a former correspondent of The Washington Post who has worked and consulted doctors and healers around the world. His speech about his book at the Commonwealth Club is available at Reid_The_Healing_of_America. You can read an excerpt at GMA/Books/story?id=8383452#.TuwX6Hoyz_d.

BOOK SUMMARY Chapter 1 starts with the authors quest to avoid shoulder arthroplasty as he sought treatment in various cities around the world for pain in a previously operated shoulder. He was also trying to answer the question why the health care system in USA was so poor and the expenditure was so high. He tabulated the percentage of GDP that selected countries spend on health care in 2005: USA 15.3% (highest in the world), Switzerland 11.6%, France 11.1%, UK 8.3%, Japan 8.0%, Taiwan 6.2% (in 2007). As we know, Singapore spends about 4% of the GDP on health.7 In chapter 2, he describes the four main national health care models which we discussed in table 2. In chapter 3, entitled The Paradox, he lists the problems with health care in USA. First, not every citizen is covered, especially those who cannot afford

insurance but are not poor enough to qualify for Medicaid. For those who are uninsured or underinsured, a major illness can devastate a family financially. Reid tells us that 700,000 people a year in US go bankrupt because of this. Second, the health care may not be top quality given poor performance in international indices such as the informality rate (6.8 per 1,000 versus 2.5 per 1,000 in Sweden), survival from major illness, healthy life expectancy at sixty and avoidable mortality. Third, health care costs more in USA. True, doctors, nurses, hospital workers and drug company staff are paid more in US than in other countries. However, US doctors pay much more in medical school fees, malpractice insurance and are likely to be sued more than once in their career. The main driver of cost, according to Reid, is the inefficient private insurance system. The for-profit companies only pay out 80% of the premiums they take in for health care. When former California governor Arnold Schwarzenegger tried to raise this to 85%, his bill was blocked by insurers. The administrative cost of health care

is therefore very high, while it is only 3% in Canada and 5% in Britain. The hundreds of insurance plans with different rules and coverage also add to the administrative cost. Insurance companies also have the right to choose their customer, to deny payment for a variety of reasons and to cancel coverage (rescission in legalese). In chapter 4, the start of the meat of the book, the author goes to France, which topped the list in WHOs The World Health Report 2000 Health Systems: Improving Performance.29 He was very impressed by the Carte Vitale which we have discussed. In chapter 5, he described the system in Germany. In this system, the payers a re p r i v a t e ( e m p l o y e r s a n d employees) and the providers are private; the premium costs the same from every company. The insurers are non-profit and workers do not lose coverage when they lose their jobs; unemployment benefits kick in to pay. There are adequate providers so waiting times are not long. This system, though, is expensive, costing 11% of the German GDP, though




considerably lower than the USAs. Chapter 6 deals with Japans health system, which largely consists of private nonprofit insurance plans and private hospitals. Prices are kept low because the government negotiates with the providers on behalf of the insurance companies. The Japanese system is similar to the German system, but costs only 8% of the GDP. Chapter 7 is entitled The UK: Universal Coverage, No Bills. Chapter 8 concerns the Canadian system. Chapter 9 deals with out-ofpocket systems. Taiwans new health care system, probably the bestdesigned in the world, was the focus of chapter 10. The government asked Professor William Hsiao, health care economist at the Harvard School of Public Health, to lead a team to design a system in the late 1980s. He studied the existing system, determined the will of the people and the government and organized a three-conference in Taipei to discuss the best and worst aspects of the health care systems of six advanced

nations (Japan, USA, Canada, Germany, Britain and France). He wisely required Taiwanese cabinet ministers to chair the sessions so that they sat through the sessions and were educated. Eventually, the new system was a compendium of the best parts of the most effective models. Providers were private and the payer a single national insurance system. This is similar to the Canadian system except that the insurance is not paid for by taxation but contributions from employers and employees. Each of the 23 million Taiwanese also carries a smart card, the 32 K IC, containing medical and billing records like the French Carte Vitale. The Bureau of National Health Insurance has the power to set prices for services and drugs. The system covers everyone and pays for a very wide set of medical treatment. When the system went operational on 1 March 1995, 11 million previously uninsured Taiwanese suddenly gained access to medical service. Only 6% of the GDP is spent on

health. Reid was very impressed with this remarkable new Taiwanese system. Chapters 11 to 13 conclude the book and pose a challenge to the decision makers to improve the US system. REVIEW The strength of this very readable and sometimes brilliant book is its analysis of the various health care models the author encountered, always compared to the American system. Even a quick read will help the reader distinguish the various health systems. Reid shows that a countrys history often determines the health care system it possesses. The author is disturbed that the US system leaves many uninsured and goes as far as to say that the lack of universal coverage the central moral flaw of the US health care. The Taiwanese system is held up to be an excellent model for the US to emulate. Unfortunately, the Singapore system was not investigated at depth.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27. 28. 29. Fernandez W. End of zi char? Straits Times 6 April 2008. Available from Stabell CB, Fjeldstad . Configuring value for competitive advantage: on chains, shops and network. Strat Mgmt J 1998; 19:414-9. Berwick DM, Nolan TW, Whittington J. The triple aim: care, health, and cost. Health Aff (Millwood) 2008; 27:759-69. Edmond MB. Taylorized medicine. Ann Intern Med 2010; 153:845-6. Tan ST, Leong FL, Chan BAL, Tan CM, Tan DH. Economics in Public Polices: The Singapore Story. Marshall Cavendish Education, 2009. Available from Available from Hsiao WC. Medical savings accounts: lessons from Singapore. Health Aff (Millwood). 1995; 14:260-6. 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. WHO. The World Health Report 2000. Health Systems: Improving Performance. Available from Hsiao WC. State-based single-payer health care - a solution for the United States? N Engl J Med 2011; 364:1188-90. 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. WHO. World Health Statistics 2011. Available form 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] WHO. The World Health Report 2010: Health Systems Financing: The Path to Universal Coverage. Available from Emanuel EJ. Where are the health care cost savings? JAMA 2012; 307:39-40. Mir nezami R, Nicholson J, Darzi A. Preparing for precision medicine. N Engl J Med 2012 Jan 18. [Epub ahead of print] Campillo-Artero C. When health technologies do not reach their effectiveness potential: a health service research perspective. Health Policy 2012; 104:92-8. 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. 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. 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. Shabot MM. Ten commandments for implementing clinical information systems. Proc (Bayl Univ Med Cent) 2004; 17:265-9. Available from etre-rembourse/la-carte-vitale/la-nouvelle-carte-vitale.php. Khalik S. Protect my medical record better, please. Straits Times 13 January 2012. Available from Available from De La Merced MJ, Pollack A. Roche Makes $5.7 Billion Bid for Illumina. New York Times 24 January 2012. Available from Ho AL. Parkway school to offer nursing diploma. Straits Times 6 March 2008. Available from Tuli K. Book review. N Engl J Med 2009; 360:2038-2039. Available from




A 49-year-old Chinese male presented with a 3-week history of right hip pain, which was worse on internal rotation. There was no history of trauma. He had a history of retroviral illness, hypocortisolism secondary to long-term use of exogenous steroids and psoriasis. On examination, there was tenderness on internal rotation of the right hip which retained full range of 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 patients history? (c) What are some of the possible aetiologies of this condition?




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

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

Question 3
Follow 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.




Answer 1a
Well-defined lucent areas in the right femoral head are present, compatible with subchondral cysts (figure 4). No significant degenerative changes (osteophytes, reduced joint space and subchondral sclerosis) are seen.

Answer 1b
Avascular necrosis of the right femoral head.

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

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

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

Avascular necrosis (AVN) of the hip is most commonly due to trauma, predominantly a neck of femur fracture or dislocation of the hip joint. Use of exogenous steroids, as in this case, can cause AVN. Other causes include vasculitis, alcohol excess and sickle cell disease. However, in some cases, there are no predisposing factors and AVN is idiopathic. AVN of the hip usually occurs in the anterosuperior head of the femur. In this case, the initial radiograph showed subchondral cysts in the femoral head on the initial radiograph with no other significant findings. There are 4 causes of subchondral cysts: (a) degenerative joint disease, (b) rheumatoid arthritis, (c) calcium pyrophosphate dihydrate crystal deposition disease (pseudogout) and (d) AVN. However, conditions (a) to (c) will also have associated radiograph findings in addition to the subchondral cysts, such as osteophytes or chondrocalcinosis to suggest them. Therefore, AVN should be considered if there are subchondral cysts in an otherwise normal joint. Plain radiograph findings may be delayed and evident only months after the patient first presents. Patchy sclerosis of the femoral head is the earliest finding as there is resorption of vascularized bone resulting in areas appearing to be of increased density. Following this, a subchondral lucent line in the weight-bearing area of the femoral head may be seen in some cases (crescent sign). In later stages, plain radiographs will show collapse of the articular surface and flattening of the femoral head. Sclerosis is due to compression of bone and new bone formation. MR imaging is the most sensitive and specific modality for evaluation of probable AVN, even when plain radiographs and radionuclide scans are normal. CT can be used to stage known disease. On MR imaging, AVN of the hip shows a focal area of low or mixed signal on T1WIs. This area has a serpiginous low-signal border. Figure 2 shows these characteristic features. Other bones in which AVN occur commonly are the carpal lunate, tarsal navicular and the tibial tubercle.

Dr Lorna Fan is a resident in the Department of Diagnostic Radiology, Tan Tock Seng Hospital




ECG Quiz
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 of breath. His ECG and CXR are shown below. Is this acute ST-elevation AMI?

No, this is not acute ST-elevation AMI. The ECG shows deep Q waves and persistent ST elevation from V2 to V4. There are no reciprocal ST depressions in the inferior leads of II, III and aVF. The CXR shows gross cardiomegaly with features of acute pulmonary edema. The ECG diagnosis of this ST elevation is left ventricular apical aneurysm which is confirmed with a transthoracic echocardiogram. The cardiac enzymes were never elevated. The clinical diagnosis is acute pulmonary edema with left ventricular apical aneurysm of which coronary artery disease is the likely aetiology.
Dr David Foo is a consultant and Head of the Department of Cardiology, Tan Tock Seng Hospital.




Diary Dates
Public Forums and Continuing Medical Education (CME) Programmes @ TTSH

AHINet Workshop: Functional Movement The Missing Link Allied Health Dept 18 - 19 Feb 2012 9am - 5pm Conference Room 3, TTSH Email: SPA members: $550 Non SPA members: $660 SPA members: $550 Non SPA members: $660 $500 -

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10-11 March 2012 Conference Room 1, 9am - 5pm TTSH 23 - 24 March 9am - 5pm Conference Room 1 and 1, TTSH

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Advanced Hand & Wrist Arthroplasty Workshop & Hand Arthroplasty Workshop

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28 March 2012 1.15pm - 2pm

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