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CardioPulse ArticlesFocused Update of the ESC Guidelines on device therapy in heart failureESC recommendations for individual certification and institutional cardiovascular magnetic resonance accreditation, in EuropeThe final, Climbing the academic ladder in cardiology: USAThere are two different career tracks for academic medicine in the USACompany success: GenzymeGenzyme's research in cardiovascular disease, putting rare conditions on centre stageTowards individualized preventive therapy

DOI: http://dx.doi.org/10.1093/eurheartj/ehq358 2559-2566 First published online: 1 November 2010

Focused Update of the ESC Guidelines on device therapy in heart failure

Two subspecialties refreshed two sets of Guidelines and modified the way evidence is used to make guideline recommendations

The 2010 Focused Update of the European Society of Cardiology (ESC) Guidelines on device therapy in heart failure not only bring together two subspecialties to refresh two sets of Guidelines, they also modify the way evidence is used to make Guideline recommendations.

Two sets of Guidelines are updated: the 2008 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure and the 2007 ESC Guidelines for cardiac resynchronization therapy (CRT).

The new recommendations concern five groups: CRT in NYHA class III/IV, NYHA class I/II, atrial fibrillation and pacing indications, as well as left ventricular assist devices.

The primary need for the focused update stems from the emergence of new data. Two important new trials had been published that identified a new target population, patients with mild heart failure, that were not in the 2008 heart failure Guidelines. The next ESC Guidelines will be in 2012 and two years was a long wait, particularly since USA guidelines are updated quickly.

A second factor necessitating the update was recognition that there were a large number of patients receiving devices who had mild symptoms, or atrial fibrillation, or an indication for permanent pacing. Previous Guidelines had not given formal indications, recommendations and levels of evidence for these patients.

There were no specific recommendations in these populations because the evidence was not considered strong enough. Much of the evidence, especially in atrial fibrillation, is based on many good but small studies and some strong meta-analyses that have now been published.

‘Our understanding of how you have to prepare a patient with atrial fibrillation for CRT has matured’, says Prof. Kenneth Dickstein, Professor of Medicine at the University of Bergen in Stavanger, Norway, and joint chairman of the focused update task force with Prof. Panos Vardas. ‘The update will bring clarity to an area that was previously rather cloudy for a lot of clinicians’.

Another reason for the focused update was a strong new trial on left ventricular assist devices as destination therapy in patients ineligible for transplantation, which alone may not have necessitated an update but is an important device for a limited population.

The proposal for a focused update on two sets of Guidelines came from the ESC Committee for Practice Guidelines (CPG). It was agreed that CRT therapy could not be adequately addressed by heart failure management experts or by electrophysiology (EP) experts alone.

It was a collaborative effort between the European Heart Rhythm Association (EHRA) and the Heart Failure Association (HFA), which reflects the multidisciplinary nature of collaboration required for selection, implantation, and management, of patients with devices in clinical practice. Dickstein is a past president of the HFA and Vardas is president of the EHRA, and both the task force and review committee had equal representation from the two associations. It's the first time the two associations have worked together to produce a single document.

But even more innovative was the task force's approach to the evidence. ‘We did something relatively revolutionary’, says Dickstein. When he chaired the heart failure Guidelines in 2008 he worked closely with Prof. Philip Poole-Wilson. ‘We felt that the time had come to admit that in guidelines the actual cohort that participated in the trial is frequently different than the population described in the protocol’.

It would have been too radical to have applied this approach selectively in the main 2008 heart failure Guideline. However, the 2010 focused update offered the opportunity to adopt the approach in the limited area of devices for a trial with convincing data.

The MADIT-CRT study, probably the most powerful piece of evidence in the update, included NYHA I and II patients. But the study population had just 15% NYHA I patients and the remaining 85% were NYHA II. The results for the small group of NYHA I patients did not show a statistically significant benefit.

Similarly, patients with a QRS ≥130 ms were eligible to participate. The Steering Committee prospectively chose a cut off ≥150 ms which defined a group that was expected to respond particularly favourably. The results showed that almost the entire benefit was in this population.

Rather than adopt the usual approach of taking the protocol literally and providing an indication for all patients (NYHA I and II and >130 ms) the task force decided to look at which patients had actually benefited from the intervention.

The Guideline indication was restricted to NYHA II patients with a QRS >150 ms, the population with a high likelihood of a favourable response. The recommendation was class I level of evidence A.

Dickstein says: ‘We agreed that rather than give a weak recommendation to a larger population we would narrow it down to the population we think had a high likelihood of response and give that a strong recommendation’.

He adds: ‘We did not want to violate statistical principles and only looked at pre-specified criteria. We didn't cherry pick’.

It will create some differences between Europe and the USA, since the latter rarely deviates from the conventional method of making recommendations that concern the entire cohort included in the study.

The focused update sends a challenge out to trialists that if they want an indication for a general group, they have to make sure that all the categories of patients are adequately represented in the trial. ‘That is something that has troubled me for years in guideline development’, says Dickstein.

The backlash Dickstein expected has not occurred and the vast majority of practising clinicians have indicated their approval of this approach which looks at the actual cohort included and identifies the patients who did well, so that doctors can target those expected to have the best results. This is especially important with regard to a substantial intervention like device implantation.

Dickstein predicts that the focused update will increase the use of devices in broader indications. Clinicians have learned from their own anecdotal experience that patients with mild heart failure, atrial fibrillation, or an indication for a pacemaker benefit from devices but until now there was no formal recommendation.

Dickstein says: ‘The CPG felt that these new indications necessitated a focused update prior to the development of the next Heart Failure Guidelines in 2012’.

J. Taylor, MPhil

ESC recommendations for individual certification and institutional cardiovascular magnetic resonance accreditation, in Europe

Increased regulation brings credibility but over-regulation can lead to reduced use of the technique

The use of cardiovascular magnetic resonance (CMR) in cardiology is increasing in Europe, particularly when compared with the USA. But, while the technique is part of the cardiology core curriculum of the European Society of Cardiology (ESC), there is no current European document that sets out requirements for basic training and subspeciality training in CMR.

The ESC's Working Group on CMR decided that it was important to outline the European training requirements in a position statement. The statement sets out recommendations in two areas: training of individuals who want to perform and report CMR studies in Europe; and accreditation of centres performing CMR studies and wanting to offer CMR training.

The recommendations were prepared in close discussion with the ESC Board and the ESC committee for accreditation.

Indications for cardiovascular magnetic resonance

Today, the primary indications for CMR include congenital heart disease and adult congenital heart disease, ischaemic heart disease (for detection of myocardial scar and ischaemia, and cardiac function), and cardiomyopathies (for verifying the type of cardiomyopathy, such as dilated cardiomyopathy, hypertrophic cardiomyopathy, or arrhythmogenic cardiomyopathy).

There is also a large set of other indications which include cardiac tumours, pericardial disease, myocarditis, coronary artery anomalies, and valvular disease.

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Sven Plein

As for the future, ‘dramatic changes’ are occurring in CMR, says Dr Sven Plein, MD, PhD, Wellcome Trust Clinical Fellow at the University of Leeds and lead author of the working group's statement.

Although CMR is an established application in congenital heart disease and adult congenital heart disease, its use is increasing as patients live longer. Cardiomyopathy is currently seeing a dramatic rise in the indications for CMR, but the biggest growth area is likely to be in ischaemic heart disease. In the next 5 years, it is expected that in some countries up to 20% of ischaemia studies may use CMR, up from less than 5% at the moment.

A typical CMR study in the public sector takes around 1 h and costs €400–800.

Individual certification

When preparing the recommendations for individual certification, the working group looked at international recommendations from the Society for Cardiovascular Magnetic Resonance (SCMR) and at guidelines from the European Association of Echocardiography (EAE). The aim was to create a statement that was distinct in some aspects but fitted-in with current recommendations. The SCMR and EAE were both asked to review the statement.

The working group's standards for individual certification differ from the SCMR's in one main respect. In Europe, individuals at levels 2 and 3 of training (level 1 is the most basic) will be required to take an exam. The SCMR will accept European CMR accreditation but if SCMR-accredited individuals wish to obtain European accreditation, they will have to pass the European exam.

The use of an exam in individual certification has been modelled around the EAE guidance for imaging training in echocardiography. In addition, the CMR working group has run its own exam for a number of years and it felt that this should become part of the training requirements. It is proposed that in the future, the exam and accreditation process are overseen by an external, unbiased authority.

Institutional accreditation

Institutional accreditation is a hot potato and something most associations and societies have steered clear of. The issue is normally handled on a national basis and there are no guidelines at the European or international level.

The document of the CMR working group is a first attempt at setting criteria for institutional accreditation. In order to make sure that institutions are up to the task of training people to an adequate level, the requirements include a case load of at least 400 CMR studies per year, a wide and representative case mix, a structured training programme, safety measures, and quality control.

Plein says: ‘With an expanding imaging technology we felt it was important to give trainees a feeling for how many cases, what sort of cases, and in which environment they needed to be trained, in order to become competent in that particular imaging technology’.

He adds: ‘[It] should bring credibility to those institutions if they want to train people in CMR’.

Accreditation will be voluntary, but Plein believes that as institutions become accredited trainees will want to be trained at one of these centres. That will in turn drive institutions towards taking part in the process.

Quality control will be an integral part of institutional accreditation. One proposed route for quality control will be through the working group's EuroCMR registry, which to date holds around 20 000 CMR studies from around Europe in a central database.

Institutions will input clinical information and scan results for every case into the registry, and in a percentage of cases, the registry will ask for the original imaging data so that a quality review can take place.

A cardiology or radiology issue?

The debate over whether CMR is part of radiology or cardiology continues to be a hot topic and the arrangements vary by country and sometimes within a country. In the UK, for example, it is more common for CMR laboratories to be run by cardiologists than radiologists.

Germany has 16 states which all have slightly different regulations. Many institutions have shared access to a scanner. Formal responsibility for the safety of the scanner often lies with the radiology department but cardiologists use the scanner for cardiovascular examinations.

In some countries, CMR is by definition radiology and cardiologists cannot independently run a service.

Regulation: a view from Professor Jeroen Bax, MD, PhD, Professor of Cardiology, Leiden University Medical Centre, The Netherlands.

The current position paper on recommendations of CMR is an excellent piece of work, trying to further define the use of CMR in clinical practice. It outlines the boundaries of the use (and non-use) of CMR carefully and provides suggestions for different levels of expertise, hands-on training, and self-study. Although ‘regulation’ is needed in any field of medicine, one has to be careful with ‘over-regulating’. Particularly, when prescribing the numbers of procedures and hours of self-study needed to be able to perform procedures. Indeed, much experience and continued practicing is needed for the best results. But, the real world is always different from the ideal world, and if the numbers for procedures and study hours become too high, it may result in the opposite effect, namely that various centres, where CMR is not the only thing that is practised, may no longer perform the procedures based on the proposed regulations. In the real world, most centres are not highly specialized academic centres, but mainly perform clinical cardiology, in which CMR is a relatively small (but highly needed) part. Keeping in mind the large differences among levels of care in different countries throughout the world, it is best to try to improve the global level of care; to avoid that CMR cannot be performed in some countries with little experience.

In addition, we have witnessed a strong trend of ‘super-specialization’ in cardiology over the past years, with the development of ‘imaging cardiologists’, who were specialized in only one imaging modality. The current trend is to develop ‘multimodality imaging cardiologists’, to avoid working in ‘silos’. I would like to take that one step further and emphasize that even ‘imaging cardiologists’ may become too disconnected from daily clinical cardiology. In most centres, cardiologists may have a field of specialization (e.g. multimodality imaging), but should also remain involved in clinical cardiology to maintain clinical integration. Keeping that in mind, the general cardiologist needs to perform many hours of self-study in different fields, so raising the bar for CMR self-study too high will also result in reduced performance of CMR.

Finally, one needs to be careful with the legal status of these ‘position papers’, which can easily result in legal problems, also resulting in less performance of CMR.

I have discussed the potential threats of over-regulation in relation to CMR, but this issue applies to all position papers concerning regulatory issues in any field of cardiology.

In other words: if requirements are too high, adoption of the valuable recommendations will be limited in daily practise.

The ideal solution, says Plein, is to have some form of collaboration between radiology and cardiology. As a working group of the ESC, the new statement is specific to cardiology training, but the intention has always been that a next step would be to enter into discussions with the European Society of Radiology (ESR) and other imaging bodies about the possibility of a joint document in the future.

The aim of the working group is not to take a position on whether CMR should be performed by any particular medical speciality, but to ensure that an individual wishing to perform a CMR study is trained to an appropriate level, whatever their medical background.

He admits that the recommendations may seem exclusive of other groups and that some may question why they were not written jointly with radiologists, nuclear cardiologists, and nuclear radiologists. But, it was important for the working group to come up with its own contribution to the discussion in the first instance.

The ultimate goal is to have a joint European recommendation for training in cardiac imaging that is multimodality. ‘There's no point in having the CMR curriculum and training guidelines and [the same for] echo, nuclear and CT,’ says Plein. The ESC's Working Group on CMR has put its cards on the table and is open for discussion.

J. Taylor, MPhil

The final, Climbing the academic ladder in cardiology: USA
There are two different career tracks for academic medicine in the USA

The standard academic track emphasizes basic research, including epidemiology, and involves advancement from assistant and associate professor to full professor. Tenure is generally available at associate professor level. Movement between levels hinges upon publications and grant funding, with associate professors having about 40 publications in peer-reviewed journals and full professors having more than 80.

The more clinically oriented track places a greater importance on clinical responsibilities and clinical teaching. Research involves clinical trials and analysis of databases and registries. Depending on the institution, it may or may not lead to tenure and a full professorship.

The decision of which track to follow should be made by the time doctors start their subspeciality Fellowship so they can be directed towards the appropriate mentor and research area, says Prof. Bernard J. Gersh, DPhil, FRCP, FACC, Professor of Medicine and a consultant in the Division of Cardiovascular Diseases at the Mayo Clinic in Rochester, MN, USA.

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B.J. Gersh

He adds that too much has been made of academic tenure, which generally guarantees a minimal basic salary from the university and makes it more difficult to get fired.

Prof. Robert D. Simari, MD, FAHA, FACC, Professor of Medicine at the Mayo Clinic and Vice Chair of the Cardiovascular Division for Research, agrees. ‘It's highly sought after; it's overrated, and doesn't have a lot of meaning at the end of the day’.

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R.D. Simari

At the Mayo, to qualify for associate and full professorships, candidates must provider clear evidence of national and, for full professor, international recognition. Evidence could include invited visiting professorships at prestigious institutions, invited lectures at the annual scientific sessions of the European Society of Cardiology/American College of Cardiology/American Heart Association (AHA), being on editorial boards, and being on a grant review committee for the National Heart, Lung, and Blood Institute (NHLBI) of the National Institutes of Health (NIH).

In the USA, the number of professorships is not limited, although professorship posts that carry funds with them are.

The two tracks in academic medicine and academic cardiology have their roots in the 1960s and 1970s when the traditional concept was that to be successful in academic medicine, you did basic research funded by NIH R01 grants, established a lab, and become chief.

If you failed at basic research, you became a so-called clinical researcher, which meant that you took care of patients and every once in a while did a published report on your clinical experience and clinical observations.

But Prof. Christopher B. Granger, FACC, FAHA, FESC, Director of the Cardiac Care Unit at Duke University Medical Center in Durham, NC, USA, says: ‘Over the past 20 years, in some institutions I think more than others, has emerged a rigorous clinical research academic discipline’.

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C.B. Granger

But is clinical research still viewed as second best? ‘Overall in the United States in academic medicine basic research is still considered to be a higher valued academic pursuit, but in some medical centers there is more parity’, he says.

He advises junior doctors who want to be academic cardiologists that they are equally likely to be successful if they pursue basic or clinical research and they should follow their passion.

But the risk with clinical research in cardiology in the USA is that there is a greater chance that doctors will leave academic medicine and go into private practice.

The two main professional societies for cardiologists in the USA are the American College of Cardiology and the AHA. Both are important for academic cardiology and being involved is valued by tenure and promotions groups.

The AHA financially supports Fellows and early career faculty, whereas the NHLBI provides grants for early career development.

The burden of teaching in academia varies enormously and cardiologists can to some extent determine their own destiny, says Gersh. ‘If you're very, very heavily involved in highly productive research no one's going to expect you to give that up for teaching duties’.

For Europeans who want to pursue an academic or clinical career in the USA, Simari advises making the move after medical school and getting internal medicine training and subspeciality training in the USA. That makes it easier to become Board Certified in the USA.

Doctors who come over just for subspeciality training may have to redo part of their training in the USA.

Academic medicine in the USA differs in many ways from Europe. The USA is very accepting of Europeans who want to come over at all levels of their training for research experience.

Americans themselves are more mobile, a characteristic of the society in general, and often academic promotion and success brings the ability to move around.

In the USA, advancement is based on merit. ‘Who you know has very little to do with it,’ says Gersh. ‘I think it's a very transparent process and there are certain criteria to be met’.

The US system is also less hierarchical. Cardiologists in the USA are much less attached to a significant individual within an institution. Although in Europe, the chief can be very dominant and a cardiologist works for him until he leaves, in the USA, most people would say that they work for the institution rather than for a specific individual.

A plus side in Europe is that PhDs do not carry the burden of class work that they do in the USA. Simari says: ‘That limits our numbers of people who get that dedicated research training in the lab for a PhD’.

One of the biggest challenges in academic cardiology in the USA, says Granger, is to convince young talented people that a career in academic cardiology is worth the trade-off of control and financial reward in private practice.

Efforts are underway to enable people in academic medicine to have a bigger impact. To date, academic medical centres have not been so good at taking discoveries from basic labs into clinical studies. The NIH is now funding academic medical centres to help those transitions occur more effectively.

The traditional view that basic research was of the highest value means that ‘the clinical research IQ of the average graduating medical student in the United States is quite low’, says Granger. Medical schools need to place more emphasis on the principles of evidence-based medicine and of interpreting clinical research findings and applying them in practice.

And more support needs to be given during the transition between Fellowship training and becoming a young faculty member. All too often new faculty members are left on their own, delve into clinical work, and neglect their research, then after 2–3 years go into private practice. They need a mentor, protected time for research, and funding.

The K award grants from the NIH have been specifically designed for young faculty and require 75% of their effort to be reserved for research by law.

J. Taylor, MPhil

CardioPulse announces a new series: the personal experiences of émigré cardiologists

CardioPulse is starting a new series about the personal experiences of cardiologists who have moved to practice in another country/culture. Their views and feelings on confronting another language, another healthcare system, different lifestyle habits, how their families cope, and adjust to the new environment.

Should you wish to contribute, please contact Dr Andros Tofield at docandros@bluewin.ch

Company success: Genzyme
Genzyme's research in cardiovascular disease, putting rare conditions on centre stage

Emma Wilkinson, MA, talks to Gilbert Wagener, MD, PhD, vice president of clinical research at Genzyme, about the overlooked diseases historically ignored by big pharma

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G. Wagener

An oft-repeated criticism in medical research is that pharmaceutical companies are only interested in the big money spinners—the drugs for common diseases where investment is likely to reap rewards in terms of global reach and sales.

But over the past two decades, one biotechnology company has shown that this is not the only model for success. That concentrating on the rare, overlooked conditions can be a fruitful strategy. Set up in 1981 as a small start up, Genzyme now employs more than 11000 staff worldwide and in 2009 reported revenues of $4.5 billion with its main goal to focus on and deliver medicines and treatments for patients who have no other viable therapeutic options.

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Genzyme office

One of its main areas of expertise to date, and the area which kick-started its success, has been in a group of inherited metabolic diseases known collectively as lysosomal storage disorders. It has developed four enzyme replacement products, including treatments for Type 1 Gaucher's disease and Fabry disease. Success stories also include the fields of oncology and organ transplant. In addition, the company has become one of the largest international providers of diagnostic tests.

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Inside Genzyme headquarters

Yet more recently, Genzyme has published some key trials on treatments for rare and previously overlooked cholesterol disorders. Dr Gilbert Wagener, vice president of clinical research, based in the Genzyme's European headquarters in Amsterdam, is particularly keen to talk over the successes of mipomersen, a treatment which was discovered and initially developed by ISIS Pharmaceuticals. In 2008, Genzyme and Isis completed a licensing agreement that provides Genzyme with exclusive worldwide rights to the treatment. A recent Lancet paper showed that the drug—an antisense inhibitor of apolipoprotein B synthesis—produced a 25% average drop in LDL cholesterol in a group of patients with homozygous familial hypercholesterolaemia, compared with a 3% drop in the placebo group. These patients were already being treated with the maximum possible dose of a statin.

‘This fits very much into our thinking, it is very clear that we would never compete with a drug like a statin or a fibrate, but this is an injectable drug, to be given weekly, which is designed for patients who are otherwise sub-optimally treated and have been overlooked’, says Wagener.

Another product developed by Genzyme, Cholestagel, which inhibits cholesterol absorption, needs six tablets a day and likewise studies have been aimed at those with primary hypercholesterolaemia who are not being managed successfully on standard treatments. ‘Due to its non systemic way of action, there are practically no side effects’, says Wagener. ‘But this kind of treatment can only work with highly motivated patients because it's such a burden to take the number of tablets required. The journal Clinical Therapeutics recently published a study which shows a 15–16% reduction in LDL-C’.

Patients with homozygous familial hypercholesterolaemia have very high LDL cholesterol levels—in the range of >13mmol/L—unsurprisingly, they suffer very early cardiovascular disease and rarely live beyond 30 if untreated. It is an incredibly rare condition with some estimates putting its prevalence at one in one million.

‘We have a very clear commitment to look into therapeutic areas where there is a clear unmet medical need and where there is no alternative treatment. It's about a desire to serve populations that are neglected by big pharmaceutical companies—where the population is seen as too small for it to be worth developing a drug’, says Wagener. ‘The interesting thing is, these companies are now reconsidering this principle and there now seems to be interest in these smaller markets. In addition, personalised medicine is a trend which we see more and more focus on, and is a promising approach for the future. Genzyme started as a small company with just a couple of people so it shows it is possible to work in these areas of unmet clinical need’, he adds.

One area where the company invested a fair amount of resources before abandoning the project was myoblast stem cell therapy in heart failure. Ultimately, the proof of concept failed and although there is a debate to be had about why that might have been and if further trials could have turned the story around, Genzyme decided to pull out. Wagener admits that the major strides made in biotechnology in the past two decades have been inspiring but when it comes to stem cell therapy, scientists have probably been guilty of trying to go too fast. ‘Regarding stem cell therapy, we probably didn't do our homework; we don't really understand how it works. The original idea is to replace defective tissues with something that grows de novo, but we haven't really understood that mechanism’.

But he thinks in terms of the industry standard approach to drug development, the technique of screening thousands of molecules to find the next big blockbuster treatment will prove unsuccessful. ‘This is not the best approach, so many things happen because of chance findings. And a lot of that work is done in academic institutions so we need a lot of collaboration’.

Looking to the future, two recent developments in cardiovascular medicine that have grabbed Wagener's attention are the development of the polypill and the concept of a vaccine against angiotensin—which he describes as a ‘very sophisticated area of research’.

But he says improving patient care will not just be about new and better treatments, or even better tailored treatments, but overcoming the disconnect between what happens in trials and what happens in the real world. ‘We know that if you randomise a patient they do better even if they are in the placebo group and we need to better understand that discrepancy and overcome the gap between the randomised controlled trial and clinical practice’.

Emma Wilkinson, freelance medical journalist

Towards individualized preventive therapy

New and novel concepts for identifying patients to treat in order to prevent coronary artery disease, are presented by Simoons, Sijbrands, and Nieman, from The Netherlands

Medical treatment is generally provided to manage and reduce symptoms or signs of cardiovascular disease, or to cure the underlying disease when possible, but also to improve outcome in patients with cardiovascular disease and even in subjects at risk of developing such disease in future years. It is appreciated that prescribed drugs may not be effective in all patients, as a result of variability among patients in absorption, metabolism, or pharmacological drug effects. When a drug is prescribed for signs or symptoms of a disease such as hypertension or angina, verification of the intended drug effect is straightforward. Accordingly, drug dosages may be changed and ineffective drugs may be replaced. However, for preventive treatment, the situation is more complex. The selection of persons who are likely to benefit from such preventive treatment is an issue open to debate, and the effectiveness of the treatment cannot be judged at the individual level. For example, statins are effective in reducing the risk of recurrent events (death, myocardial infarction, or stroke) in patients with coronary artery disease (CAD), particularly after myocardial infarction, and in high-risk subjects.1 Indeed, mortality is reduced with statins in patients with CAD, but no significant reduction of mortality is achieved by statins in subjects without known CAD.1,2 The number of asymptomatic individuals needed to treat with a statin to avoid one event shows a large variance strongly associated with the a priori risk. Similarly, ∼50 patients with CAD need to be treated for 4.2 years with an angiotensin-converting enzyme (ACE)-inhibitor, or 210 patients for 1 year, to avoid a myocardial infarction or one cardiovascular death.3 Indeed, large groups of patients need to be treated for a prolonged period and at considerable cost to prevent first or recurrent manifestations of CAD, while it remains unknown who will really benefit from this preventive treatment. Recent developments in diagnosis of CAD and pharmacogenetics offer opportunities to significantly improve the effectiveness of prescribed therapy to prevent, or defer, the development of CAD.

Treatment of subclinical coronary artery disease instead of prevention: a new paradigm

Subjects at risk to develop CAD can be identified using traditional risk factors such as a ‘positive’ family history, diabetes mellitus, smoking, hypertension, and elevated serum LDL cholesterol.4 Such risk assessment identifies groups of subjects at increased cardiovascular risk; however, it does not allow the identification of specific individuals who will develop symptomatic CAD. Indeed, some individuals reach an elderly age, despite having familial hypercholesterolaemia.5 Modern computer tomography (CT) offers a unique opportunity to directly detect or exclude both obstructive and non-obstructive coronary atherosclerosis in individual subjects.6 Indeed, the coronary calcium score by CT is the strongest identifier of risk for CAD events in subjects without known CAD, with an incremental predictive value over the classical risk factors.7,8 In addition, the PREDICT study also showed that for diabetic patients, the adverse event rate is very low in the case of a low or negative calcium score.9 Contrast-enhanced CT allows imaging of non-calcified plaque as well, which appears to have an independent predictive value for the development of adverse cardiovascular events.10

Therefore, we propose that CT may be used to identify or exclude the presence of CAD in ‘high risk’ individuals such as patients with diabetes or familial hypercholesterolaemia. Presumed high-risk individuals lacking evidence of CAD on CT may then be spared intensive preventive therapy, which is unlikely to of benefit. Medical therapy should then be reserved for subjects with CT evidence of subclinical CAD to prevent progression of the disease and the development of subsequent coronary events. This is a paradigm shift. Currently ‘preventive therapy’ can be either aimed at prevention of events in patients with a known diagnosis of CAD (secondary prevention) or prevention of development of CAD in subjects at risk, but yet without recognized disease (primary prevention). According to the new paradigm, CT will be used to exclude or to diagnose CAD, and to treat the latter patients accordingly. Such an approach could increase the effectiveness and cost-effectiveness of preventive therapy. We are currently conducting a series of studies, supported by the Netherlands Heart Foundation, to verify whether this paradigm holds true in clinical practice.

Pharmacogenetic selection of optimal preventive therapy in individual patients

The clinical effect of pharmacological therapy varies among patients, due to differences in compliance, absorption, drug metabolism, and excretion, as well as variations in the target organ receptors. Recently, genetic variations have been described that are responsible for some of these differences in drug response. Clopidogrel, for example, is a pro-drug, which is metabolized by several CYP enzymes in the liver, of which CYP-450 is the most important, before it becomes an active inhibitor of platelet aggregation. Genetic variants of CYP-450 identify about 25% of the patients who do not adequately metabolize clopidogrel and in whom this drug is clinically ineffective.11,12,13 In a recent issue of the European Heart Journal (Eur Heart J 2010;31:1854–1864), we presented a study suggesting that the ACE-inhibitor perindopril is particularly effective in preventing cardiovascular death or myocardial infarction in about 75% of the patients with CAD, while it is ineffective, and may have untoward effects, in the other 25% of patients identified by genetic variants of the bradykinin and angiotensin receptors.14 These results were obtained in a planned substudy of the EUROPA study,15 but require confirmation in other large studies, particularly since the mechanism of the reported observations is not yet understood. Unfortunately, we have so far been unable to identify an appropriate confirmation cohort of sufficient size, although preliminary confirmation of the findings in EUROPA was achieved in Caucasian patients from the PROGRESS study.14,16

Current ESC and other guidelines recommend preventive therapy with statins in subjects at increased risk to develop CAD, such as diabetics, in addition to smoking cessation and other lifestyle modifications. Furthermore, aspirin, clopidogrel, or other P2Y12 inhibitors during the first year after an acute coronary syndrome or anticoagulants, in combination with a statin, with an ACE-inhibitor and with a β-blocker after myocardial infarction4 are recommended in all patients with CAD. We propose that in the near future, preventive medical therapy in subjects at risk for the development of CAD (primary prevention) will shift to treatment of recognized subclinical CAD using imaging technology. The distinction between primary and secondary prevention will thus disappear. Furthermore, we suggest that in individual patients, the choice of preventive drug therapy may be based on pharmacogenetic classifications. The combined application of these novel approaches should reduce the use of drugs for preventive therapies and improve cost-effectiveness, while reducing the side effects of drugs in the population.

Maarten L. Simoons, Eric J. Sijbrands, Koen Nieman, Thoraxcenter, Erasmus MC, Rotterdam

CardioPulse contact: Andros Tofield MD FRCS FACEP, Managing Editor CardioPulse, EHJ. Email: docandros{at}bluewin.ch

The People's Corner Box is about cardiologists: promotions, new positions, prizes won, awards given, retirements and obituaries. Please submit news of yourself or of a colleague (maximum 400 words) to Dr Andros Tofield at docandros{at}bluewin.ch


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