One Pill to Cure Them All: Single-Drug Polypharmacy in Cardiovascular Disease

September 28, 2012

September 28, 2012 (Hamilton, Ontario)— Dr Richard Smith (UnitedHealth, London, UK), a longtime editor of BMJ, doesn't know his own blood pressure or LDL levels, but he believes he's keeping cardiovascular disease at bay by taking a polypill every day. Smith, who was enrolled in one of the early polypill trials, says he's done this since he was 56 years old.

Dr Richard Smith

Source: St George's,

University of London,


"If I had to go to the doctor every three months to get my blood pressure measured and my lipids measured and have to go back to have my drugs titrated, I couldn't be bothered with all that," he said. "Because I get [my polypills] through the post, and I just take it every night, it's extremely simple." 

Low-dose combination tablets go by many names--the term "polypill" was trademarked by an enterprising US pharmacist. Cardiovascular researchers working in this area have settled on "polypharmacy" or single-tablet multidrug combination therapy, but like its name, the ideal makeup for a polypill is still largely undecided. Proponents of the polypharmaceutical approach, where a single tablet contains a statin, ACE inhibitor, beta blocker, diuretic, and aspirin, say it might one day form the cornerstone of primary- and secondary-prevention treatment for cardiovascular disease.

Smith was just one high-profile name attending the Global Summit on Combination Polypharmacy for Cardiovascular Disease, organized by Dr Salim Yusuf (McMaster University, Hamilton, ON). Calling cardiovascular disease the biggest epidemic the world has ever known, "bigger than HIV," affecting nearly one in three individuals, Yusuf believes the magnitude of the problem and the ensuing worldwide shortage of cardiologists and specialists to treat cardiovascular morbidities cry out for new treatment paradigms.

Dr Salim Yusuf

"This is not about a pill," Yusuf told heartwire . "This is about a strategy to reduce cardiovascular disease by 50% globally in a cost-effective manner."

The two-day summit took place this week at the McMaster University Population Health Research Institute and included some of cardiology's biggest names grappling with the medical, scientific, legal, regulatory, economic, and social issues of trying to get polypharmacy treatments on the market for patients with existing cardiovascular disease, as well as for those at high risk for cardiovascular disease.

The Wald and Law BMJ Paper

The polypill concept gained notoriety in a 2003 paper by Sir Nicholas Wald and Dr Malcolm Law (University of London, UK) in BMJ that provocatively claimed a combination polypill with a statin, three blood-pressure-lowering medications at half doses, an ACE inhibitor, aspirin, and folic acid could reduce the risk of ischemic heart disease by 88% and stroke by 80%. The British doctors raised the possibility of one day using the drug to treat all patients with cardiovascular disease as well as those 55 years of age and older, without measuring any risk factors.

This is about a strategy to reduce cardiovascular disease by 50% globally in a cost-effective manner.

"There is merit in the idea of treating all patients 55 years of age and older with a polypill, but right now there is too much resistance," Yusuf told heartwire . "That is a bridge that we might cross five years from now, but it will be debated. If you start to think of prevention and treatment paradigms, think about LDL cholesterol. The targets have been coming down and treatment has become more aggressive. And the targets have been getting closer and closer for the whole population. Right now, the low-hanging fruit is in secondary prevention for the implementation of the polypill, high-risk primary prevention for research, and the whole population for the future."

Dr Sidney Smith

Dr Sidney Smith (University of North Carolina, Chapel Hill), the president of the World Heart Federation, told heartwire that one of the greatest challenges is simply getting patients to change their lifestyle, including stopping smoking, increasing physical activity, and eating healthier foods. The challenge after that monumental task is get these same individuals to adhere to those changes.

"I personally do not think that taking medication should be a substitute for changing lifestyle," said Smith. "Now, in many areas, the cost of medication, when it is needed, is high and in many instances patients need to take more than one pill. I think the broadest initial application for a multidrug pill, the so-called polypill, will be in populations that are at high risk or have known disease and in countries that are low income or middle income and developing. Large populations of patients, such as in China and India, where the economies are developing and the healthcare systems are not set up to practice individualized medicine as we see in the US, might be best suited to the delivery of multidrug therapy by other healthcare workers."

Dr Srinath Reddy (Public Health Foundation, India) agreed there is concern the use of the polypill would overshadow the needed changes to lifestyle and diet. He said the use of the polypill raises the specter of two competing visions of society. In the first, social and personal changes are used to bring about intergenerational benefits, such as tobacco-cessation programs, so that each successive generation has a lower risk of cardiovascular disease than the one preceding it. The other vision would be a more medicalized society, one in which ailments and disease are treated with drug therapies. While such a strategy has the potential to reduce the risk of cardiovascular disease and stroke, it provides no health benefits to the following generations.

Dr Srinath Reddy

Experts All Gathered in One Room

Throughout the meeting, the major discussions surrounding polypharmacy centered on who should be treated, what doses and formulations should be included in the polypill, how would the drug get approved by various regulatory agencies, who should administer medical treatment, and how the drugs would be distributed in low- to middle-income countries that lacked sufficient healthcare infrastructure. Aside from these massive hurdles, the experts agreed that adherence to medical treatment, whether the drug was in a single pill or treatment requiring multiple tablets, remains the elephant in the room.

I personally do not think that taking medication should be a substitute for changing lifestyle.

Dr Valentin Fuster (Mount Sinai School of Medicine, New York) noted that adherence to medical therapy declines 40% in the first six months after starting treatment. Fuster cited data from the Prospective Urban Rural Epidemiology(PURE) study showing large treatment gaps between affluent and underdeveloped countries with regard to proven secondary-prevention therapies. In addition, data from other trials, including the soon-to-presented FREEDOM trial of patients with diabetes mellitus, shows that just one in five patients had their cardiovascular risk factors controlled at follow-up. Similar rates of risk-factor control were observed in COURAGE and BARI 2D.

Dr Valentin Fuster

"We have a problem," said Fuster. "We can talk about any intervention we want, from stents to surgery to anything at all, but 80% of people are not reaching the risk-factor profile they are supposed to reach." The abysmal control of risk factors is occurring in clinical trials, Fuster pointed out, including the FREEDOM trial, where investigators were reminded every week to make sure patients were taking statins, aspirin, and other medications.

The underlying assumption of polypharmacy for cardiovascular disease is that a single drug with multiple compounds would improve risk-factor control because patients would be more likely to adhere to one medication. That, however, has not yet been proven in clinical trials. As Smith pointed out, adherence is a complex issue involving access, cost, and patient motivation, among other things. In the MI FREEE trial, for example, eliminating the copay for evidence-based cardiovascular medicines resulted in an adherence rate of less than 50%, a figure that was significantly higher than patients who had to make copayments, but low nonetheless.

Dr Susan Shurin

Source: NHLBI

Dr Susan Shurin (National Heart, Lung, and Blood Institute, Bethesda, MD), who spoke on the North American perspective of incorporating combination polypharmacy into a national strategy, believes that the development of a polypill belongs in the hands of the pharmaceutical companies and not the US government, but if such a multidrug strategy is to be approved or sanctioned, researchers would have to show the treatment had a "high impact" in that access and adherence were better and the single-combination tablet solved a problem the other generically available medicines could not.

Some of the Concerns About the Polypill

Despite acknowledging the gap between ideal and real-world risk factor control across all types of cardiovascular disease and the fact that 15% of the world's population consumes 90% of the medicine, a discrepancy that afflicts poor and middle-income countries most, many of the summit's speakers said there are concerns about the limitations of single-drug polypharmacy. In fact, resistance to the polypill often comes from physicians who are concerned about side effects, the inability to titrate the individual drugs, and the risks if a patient misses multiple days of treatment or if they decide to take "drug holidays."

While titrating the doses of drugs, especially blood-pressure drugs, can further reduce individual risk factors, the net result would be a minimal reduction in overall clinical events, argued the researchers, and simply not worth the trade-off of increased side effects. Dr Anthony Rodgers (George Institute, Sydney, Australia) called such fiddling with doses "rapidly diminishing marginal returns in the pursuit of perfection."

If you use complicated risk-scoring systems or just age, you end up treating almost the same people.

At the extreme end of the polypill debate--prescribing the medicine to patients 55 years of age and older regardless of risk factors--many physicians would be reluctant to ignore cardiovascular risk scoring systems in favor of a one-size-fits-all approach to healthcare.

Former BMJeditor Smith, however, argues that age alone can be used to treat a vast majority of patients. "If you go around and use complicated risk-scoring systems, like Framingham, or use just age, in men and women, you end up treating almost the same people," said Smith. "There are some differences, but there aren't that many." And the simplicity of the concept, he pointed out, ultimately reduces costs. 

To heartwire , Smith said he believes, as do other physicians, that there is currently enough available evidence to approve a polypill today for secondary prevention given that each individual component of the drug has been shown to reduce cardiovascular risk factors and clinical events. In secondary prevention, the collective wisdom is that treatment with a polypill would reduce clinical events by 50% to 60%. In primary prevention, however, the panelists, speakers, and audience members all agreed that more research needs to be done. The state of evidence right now is that there is sufficient rationale for starting new trials, but many expect outcome studies will be needed for a primary-prevention polypill to see the regulatory light of day.

The Next Stages

During the summit, Dr Norman Stockbridge (Food and Drug Administration, Bethesda, MD) noted that the agency has not previously approved anything like the polypill. While there are at least 44 two-drug combinations for hypertension, there is no precedent for a three-, four-, or five-drug combination tablet. He added that the polypill concept also changes the practice of medicine, whereby physicians maximize the effectiveness of one drug before moving on to another. Dr Peter Mol (Medicines Evaluation Board, Utrecht, the Netherlands) said that regulatory agencies in Europe would likely want confirmatory clinical trials, and these studies vary depending on how the drug is to be used (first- vs second-line therapy).

Currently, there are a host of ongoing clinical trials, including the 600-patient FREEDOM study in patients with diabetes and the 4000-patient FOCUS study. One study, Use of a Multidrug Pill in Reducing Cardiovascular Events (UMPIRE), scheduled to be presented at the American Heart Association meetingin November, is part of a collaborative effort called Single Pill to Avert Cardiovascular Events (SPACE) being run by the George Institute in Sydney, Australia. Other trials in the SPACE collaboration include the Kanyini Guidelines Adherence with the Polypill (GAP) study, which is completed but unpublished, and the Improving Adherence Using Combination Therapy(IMPACT) trial, which is ongoing in New Zealand.

The HOPE-3 study is also testing polypharmacy in patients at moderate risk for cardiovascular disease (based on age and one other risk factor) and will include cardiovascular death, nonfatal MI, and stroke as the primary outcome. TIPS-3 is ongoing, and TIPS-4 is scheduled to launch in three months.

Another possibility of gaining regulatory approval is to bypass the agencies altogether and appeal to the World Health Organization to get a multidrug combination tablet on the "Essential Medicines" list. Before that, however, there is a need to develop a consensus statement about the unmet healthcare need, the safety and efficacy of the polypill in the intended population, including the minimum data required for secondary-prevention patients, and its relative cost-effectiveness compared with other agents.