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CardioPulse ArticlesA look at the polypill story 10 years laterPioneers of cardiologyProf. Shahbudin H. Rahimtoola MB, FRCP, MACC, MACP, FESC, DSc (Hon) has been described as a cardiologist of the world and the father of research and clinical practice in myocardial hibernationCardioPulse Survey Series: JapanThe strengths and limitations of the Japanese healthcare systemACE inhibitor reduces radiation injury to myocardium

DOI: http://dx.doi.org/10.1093/eurheartj/eht215 2019-2024 First published online: 14 July 2013

A look at the polypill story 10 years later

Interest in the polypill continues with an on going study in the UK

It is almost exactly a decade since two eminent epidemiologists, Nicholas Wald and Malcolm Law, first took to the BMJ to publish their model for a ‘polypill’, combining six medications in a low-dose formulation to be taken by the over fifty-fives to prevent cardiovascular events. Those preliminary calculations predicted a potential drop in heart attacks and strokes by as much as 80%.

The idea immediately caught the imagination of newspaper editors and there was much media hype around this magic pill which would put an end to early deaths from cardiovascular disease. It would be fair to say not everyone was signed over to the idea from the start with concerns raised among the public and within cardiology circles over the medicalization of a vast section of ‘healthy’ adults and potential dangers of handing over drugs to people who some argued did not need treatment.

Ten years later, we have not yet seen this wholesale shift to population rather than individual-based treatment, although with a dramatic surge in the use of statins as a preventive measure, it is perhaps a more accepted approach than it once was.

What we have seen is some important proof-of-concept studies. This includes a randomized double-blind placebo-controlled cross-over trial published last year by the original architects of the polypill concept which showed a drop in systolic BP of 11%, diastolic BP of 12%, and LDL cholesterol of 39% among individuals with no prior history of heart disease. This Polypill, manufactured for the UK-based study group by an Indian pharmaceutical company, contained amlodipine 2.5 mg, losartan 25 mg, and hydrochlorothiazide 12.5 mg—all at half standard doses—and simvastatin 40 mg.

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Study lead author Dr David Wald, based at the Wolfson Institute of Preventive Medicine, said this study—and there have been a few others over the years including the Polycap Trial in India—was an important addition to the evidence because of its design. Dr Wald, the son of Prof. Nicholas Wald who first proposed the idea of the polypill, said it is important to distinguish between trials that have used and are using a randomized parallel-group design compared with the randomized cross-over design they chose.

‘The difference is important, because parallel group trials underestimate the efficacy of the polypill in lowering blood pressure and cholesterol because people who stopped taking the treatment still had to be included in the intention-to-treat analysis to avoid selection bias’, he explains. ‘About one quarter of patients did not adhere to their treatment in the published parallel group trials’, he adds. ‘In the event, only two people in our trial did not complete their treatment, and the design ensured we obtained a true estimate of efficacy, which was, almost exactly that which had been predicted almost 10 years earlier, and substantially greater than estimates from the previously published parallel group trials’.

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Polypill. Photo credit The Wolfson Institute of Preventive & Medicine

So where now for the polypill? There are several available in different formulations, for primary and secondary prevention and that includes the Polypill developed by Wald and colleagues, which is designed to be taken by those with no previous signs of heart disease. It does differ from that originally proposed in that it does not include aspirin or folic acid. In August last year, the statin component was also reduced from 40 to 20 mg in response to a Medicines and Health products Regulatory Agency recommendation.

‘Aspirin is the only polypill component that runs a reasonable chance of causing significant harm without warning. We took the view, that in primary prevention, once you had already achieved the substantial benefits of the cholesterol and blood pressure reduction, the risks of aspirin might outweigh any further benefit – although the recently described cancer preventive effect may alter this assessment’, explains Wald. ‘We excluded folic acid, not because there is any evidence of harm, but because there is uncertainty over its benefits based on the results of clinical trials’.

The team also took the decision to avoid using an ACE-inhibitor due to side effects. ‘We use an angiotensin receptor blocker (losartan) instead, which has the same blood pressure lowering effect as an ACE-inhibitor and rarely causes a cough’.

Currently medical checks are required by a doctor, pharmacist or nurse, before the Polypill can be dispensed but Wald still envisages a time in the future where it will be available OTC. Some argue, until this happens its usefulness on a population level will be limited, especially in lower-income countries lacking in healthcare infrastructure.

Wald explains that even getting to this stage, where the evidence for the effectiveness of the Polypill is starting to build has been more difficult than it should have been for several reasons. He lists the barriers they have hit: ‘Finding a pharmaceutical manufacturer, regulatory issues, cost, insufficient understanding of the evidential basis and the need to make the polypill accessible to healthy adults’.

But what has not wavered is the belief that this approach will make a real difference to the burden of cardiovascular disease. ‘The Polypill could prevent about two-thirds of heart attacks and strokes. Not everyone will want to take the Polypill, but even if only half of all people over the age of 50 took a daily Polypill it would avoid many thousands of cardiovascular deaths in the UK and many millions worldwide, as well as avoiding much of the disability that follows non-fatal heart attacks and strokes in the population’, says Wald.

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Pioneers of cardiology
Prof. Shahbudin H. Rahimtoola MB, FRCP, MACC, MACP, FESC, DSc (Hon) has been described as a cardiologist of the world and the father of research and clinical practice in myocardial hibernation

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The Distinguished Professor at the University of Southern California started his journey as a reluctant medical student at the University of Karachi, Pakistan in the 1950s. After finding his métier in cardiology and ‘the joy and pleasure of making detailed diagnoses as a bedside physician’, he worked in various locations around the UK. He received his FRCP from Edinburgh in 1963.

He left Europe for the USA in 1963 as co-director at the cardiac catheterization laboratory of the Mayo Clinic in Rochester, Minnesota. The ‘expert, scholarly and innovative milieu’ he found at the Mayo numbered such luminaries as John Kirklin, Dwight McGoon, Howard Burchell, Patrick Ongley, Earl Wood, John Shepherd, Jeremy Swan, and Jack Titus who contributed to the cutting edge feeling of the cardiology community there.

During his first year at The Mayo, Rahimtoola read a book which would change his direction. The Pursuit of Excellence by John W. Gardner of the Carnegie Foundation, with its potent message that excellence requires perseverance and commitment, inspired and sustained Rahimtoola's future work and the potential of combining his physician role with that of an academic researcher took shape in his mind.1

When Rahimtoola took up a professorship at the University of Oregon in 1972, he used his observations as ‘an astute and insightful physician’ to develop research themes. During his time as Principal Investigator of a National Institute of Health (NIH) funded Program Project Grant studying the effects of coronary artery bypass surgery, he worked with the renowned cardiovascular surgeon Albert Starr, and began to develop a ground breaking concept which contradicted current teaching.

He says: ‘I had observed that in one of my patients, increasing the blood flow to areas of the myocardium that appeared to be dead had returned these areas to a near-normal state. I was on sabbatical analysing some results and couldn't get over that this was happening to areas of the heart which one would normally have assumed were dead. This fired up the whole hibernating myocardium thing’.

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Hibernating myocardium. (Composite image from an original left ventriculogram before and after PTCA, from a patient who had hibernating myocardium.)

Despite Rahimtoola's ‘eureka moment’, his simple assertion that ‘if the heart recovers, it's not dead’, was met with scepticism by the scientific community. When he introduced the notion at an NIH symposium in 1980, not only was it rejected, but it was also roundly rebuffed by some of the leading investigators who suggested he did not really know what he was talking about. An article in Circulation in 1981 was similarly dismissed.2

However, true to his principles of perseverance in the pursuit of excellence and showing a characteristic disregard of scientific dogma, he revisited the topic at an NIH symposium in 1985. This time he was ready for his detractors and had coined a memorable phrase for his concept. The ‘hibernating myocardium’, as opposed to previous more lengthy descriptions went down well and provoked a major rethink. Eugene Braunwald, cardiologist at the Brigham and Women's Hospital, then went back to Harvard, revisited his data and wrote an editorial saying he realized that Rahimtoola was correct.3

Following the acceptance of hibernating myocardium, Rahimtoola was keen to validate his findings and worked with basic scientist and cardiologist Gerd Heusch from the University of Essen in Germany who was able to reproduce the concept in animals. Jeroen Bax from the University of Leiden in the Netherlands and Roberto Ferrari in Ferrara, Italy, were two European colleagues who helped build up evidence in favour of the discovery. In the USA, cardiologists George A. Beller at the University of Virginia, Charlottesville and Robert Bonow at Northwestern University, Chicago and Heinrich Schelbert, University of California, Los Angeles were early converts to the idea.

Ten years after Rahimtoola first formulated the concept, myocardial revascularization of dysfunctional segments of the left ventricle would become part of routine clinical practice and would have a profound effect on patient outcomes. Similarly, his research and findings into reversible left ventricular dysfunction and the management of patients with valvular heart disease have informed and been translated into standard clinical practice.

His pursuit and attainment of excellence has been widely and warmly recognized by the clinical and academic community. He is one of a small number of cardiologists from outside Europe to receive the Gold Medal of the European Society of Cardiology (ESC)—awarded at the Annual Congress in 2009—where the discovery of hibernating myocardium was hailed a ‘transformative moment in cardiovascular medicine’. In 2013, he received the prestigious Lifetime Achievement Award of the American College of Cardiology for his ‘enormous and sustained contributions to clinical cardiology over the last 4 decades’.

Despite these achievements, he values his role as an educator and has trained between 200 and 250 cardiologists and a large number of internists. He says: ‘It's only possible for me to treat X number of patients in my lifetime, but if I train 250 cardiologists and they go and see X number of patients, then that becomes 250 Xs. What I try to emphasize to my trainees is the importance of the pursuit of excellence and the need to devote time and energy to excelling, not only in academic research and study, but also very importantly, excelling in the way you take care of people’.

With an eye on the future, he believes investigation into putting the heart into a state of hibernation to prevent it from dying is an area that could yield dramatic benefits for clinical practice.

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CardioPulse Survey Series: Japan
The strengths and limitations of the Japanese healthcare system

Results of a brief healthcare survey by Dr Ryozo Nagai, President Japanese Circulation Society

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Ryozo Nagai

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Nations around the world struggle to deliver the promises of modern medicine to their populations. No one knows the ‘right’ answer yet many challenges are remarkably similar across countries. For instance, we live in an era of extraordinary possibility and technological complexity in clinical medicine. This has led to better results for our patients, but also escalating costs and strain on our shared resources.

Although healthcare reform has received greatest attention in the USA, it is no stranger to Europe. Despite sharing fairly consistent goals, Europe's healthcare systems remain varied and distinct. Each country's approach differs as much as their history, culture, and geography. In the UK, global budgets and public providers are distinguishing characteristics. By comparison, the German healthcare system is decentralized with a mixture of public and private funding sources. Each of these reflects widely divergent choices that impact on fundamental issues for their population, such as access to care and out-of-pocket costs.

We believe lessons can be learned from this ‘natural laboratory’ of Europe, particularly in cardiovascular medicine where there has been simultaneous growth in evidence-based medicine and high-end services. Accordingly, we asked cardiovascular leaders from several European and non-European countries to briefly describe the greatest strengths and limitations of their healthcare system, as well as its most important challenges for the next decade.

We think you will find the answers enlightening and agree such collective experiences have much to teach the world. We also are confident that you will enjoy reading this series as much as we enjoyed working on it.

Brahmajee Nallamothu MD, MPH and Thomas Lüscher MD, FRCP

  1. What is the greatest strength of Japan's health system in tackling cardiovascular disease (e.g. prevention, acute treatment, long-term treatment)?

    • – Japan's healthcare system is particularly characterized by universal health insurance coverage. Anyone can visit any medical institution and the medical costs are low.

    • – There is an extensive network of emergency hospitals and emergency medical services throughout Japan although under populated areas are not as well covered. Routine health check-ups are implemented almost as a national obligation, followed by public health nurses’ instructions. Most of the elderly patients with chronic diseases stay in hospital for extended periods.

  2. What is its biggest weakness?

    • – Good access to medical services in Japan requires a concentrated distribution of hospitals. The number of doctors and nurses per bed in Japan are small only half to one-third of those in Europe. This places a heavy burden on young doctors at central hospitals. On the other hand, doctors are concentrated in urban areas, making it difficult to maintain the medical service in rural areas. Furthermore, medical costs are on a sharp rise with the ageing population and controlling costs are becoming increasingly more difficult.

  3. What is being done to measure and improve quality in cardiovascular disease?

    • – Because medical institutions can freely list their clinical departments, cardiac surgery, and coronary interventions are available in many cities. The quality of the medical services varies greatly. To address the quality issues, the academic societies have been trying to establish certification systems for specialists and special hospitals, which however, are not compulsory. Currently, the government is establishing a system that requires each hospital to report its functions. Once the reporting system is legally enforced, hospitals are expected to be more specialized with an improved cooperative network.

    • – Some hospitals have already disclosed their clinical indicators for medical services of cardiovascular diseases. The media frequently take up the records of accomplishment of cardiac surgeries and catheter interventions at individual hospitals.

  4. What is being done to control costs?

    • – Costs for pharmaceuticals and medical techniques are strictly controlled by governmental committees. However, because payment is made as indicated by physicians, the content of medical services is not reviewed as long as reasonable diagnoses are made. The annual medical cost for the elderly aged 75 years or older has exceeded 13 trillion yen recently, due to the increasing population of the elderly and maintaining this is difficult.

    • – To control costs, the government is currently planning to make a database of medical costs and efficacy, of the medical services.

  5. How does Japan address cardiovascular preventive services?

    • – The government is making an effort to prevent life-style-related diseases. It is particularly active in promoting the health check-up campaign for metabolic syndrome in citizens aged 75 years or younger. Following the health check-up, instructions about blood pressure and lipid control are given. Such health check-up practices are aimed to not only detect disease at an early stage, but also, to prevent complications of the disease. The preventive activities have spread more and more and penetrated throughout Japanese citizens.

  6. How are cardiologists in Japan incorporating innovative drugs and devices (e.g. TAVI) into their practice?

    • – Because there are so many hospitals in Japan, it is difficult to include a large number of subjects into a clinical study. In addition, due to the limited number of reviewers engaged in pharmaceutical affairs including regulatory approval works, the introduction of drugs and medical devices developed in Europe and the USA has tended to be delayed. However, the situation is rapidly improving. Doctors and researchers at university hospitals are encouraged to actively work on commercialization projects and the conditions for funding research and infrastructure are being improved.

  7. What is the greatest challenge facing Japan over the next decade?

    • – The declining birth rate and ageing of its population is the most prominent of any country in the world. Japan is required to address the increasing needs for medical services and nursing care and at the same time to reduce the cost as much as possible. In particularly, the medical service system in Japan is neither based on market principles as found in the USA nor on socialist systems, as found in Northern Europe. Therefore to improve the efficiency of medical costs, data-based discussions may be necessary. How such discussions will be achieved is a great challenge.

Andros Tofield

ACE inhibitor reduces radiation injury to myocardium

Captopril can limit radiation damage to heart and lungs for cancer patients

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Dr Sonja Van der Veen, MSc and colleagues at the University Medical Centre, Groningen, The Netherlands, have just reported a protective effect for radiation-induced myocardial and pulmonary fibrosis by administering captopril in a rat study.

Common cancers such as breast, oesophagus, lung, and Hodgkin's lymphoma are frequently treated with radiotherapy, but the radiation dose that can be safely given is limited by the sensitivity of the healthy lung tissue which is also irradiated. Strategies for lung protection from radiotherapy injury, apart from limiting the dose given and, therefore, the efficacy of the treatment, are few.

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The research was presented at the Second Forum of the European Society for Radiotherapy and Oncology (ESTRO) in Geneva, Switzerland, on 21 April 2013 by Dr Sonja Van der Veen. She had set out with colleagues to see whether the use of an ACE inhibitor could protect against early radiation-induced lung toxicity (RILT). Previous studies had shown that damage to blood vessels can play an important role in the development of RILT,1 so the researchers irradiated the lungs, heart, or heart and lungs of rats and administered the ACE inhibiter captopril immediately after treatment. The rats' lung functions were then measured at two-weekly intervals.

‘Captopril improved the rats’ heart and lung functions, but we were surprised to find that this only occurred when the heart was included in the irradiation field’, said Dr Van der Veen. ‘This was not due to protection of the pulmonary blood vessels, which were equally damaged with or without captopril. So we investigated further and found that the captopril treatment improved the heart's function and decreased the level of fibrosis in the heart soon after irradiation. These new findings show that ACE inhibition decreases RILT by reducing direct acute heart damage’.

Irradiating the heart leads to fibrosis which stiffens the heart and reduces the left ventricle relaxation in diastole. Blood flow into the left atrium is reduced and this can cause pulmonary damage. However, after treatment with captopril, the researchers observed an improvement in ventricular relaxation in the irradiated hearts.

Much progress has been made in radiation treatment over recent years, but in breast cancer, for example, most women still receive high doses to the heart, and this is known to increase the risk of heart disease. A recent study2 has shown that for each Gray (Gy) (One Gray is the absorption of one joule of energy, in the form of ionizing radiation, per kilogram of matter.) of radiation, there is a 7.4% increase in the occurrence of a subsequent major coronary event.

‘Given that most women will receive a dose of between 1 and 5 Gray, and that the dangers are even greater for women with existing cardiac risk factors or coronary disease, this is still a big problem,’ said Dr Van der Veen.

Rats were chosen for the study because, unlike mice, they are big enough for researchers to be able to irradiate different parts of the lungs and heart. The researchers believe that the way in which ACE inhibition works in both animals and humans is similar.

Dr Van der Veen and her colleagues are now collaborating with a research group from the Mayo Clinic, Rochester, MN (USA), in order to design a randomized clinical trial where patients who are treated with radiation to the thoracic area including the heart will be treated with either an ACE inhibitor or a placebo after irradiation. She stated ‘we are confident that our clinical trial will see the same protective effect in humans as that which we have seen in rats. Now we will begin to study the late effects of ACE inhibitors on RILT to see whether it affords similar protection. We believe that our results suggest a promising strategy for shielding patients from radiation damage and improving their quality of life, while at the same time allowing them to receive a high enough dose of radiation to ensure effective treatment of their cancer’.

Andros Tofield


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