A New Wonder Drug For Heart Disease?

Why an affordable and effective four-in-one pill has not reached the U.S.

Published on October 22, 2012by Arti Virkud

In 2000, Sir Nicholas Wald, director of the Wolfson Institute at Queen Mary, invented what could become the most revolutionary drug in preventive medicine.

The polypill.

A four-in-one cocktail pill that combines blood pressure and cholesterol medication, the polypill is designed to be taken daily to prevent the leading cause of death in the world, cardiovascular disease. The polypill contains three blood-pressure lowering medications and one statin, a LDL-cholesterol lowering drug. Each component of the polypill is a generic compound that is currently prescribed for the treatment of cardiovascular disease. Its main purpose is to improve medication adherence by reducing the number of pills.

It has taken twelve years for researchers to scientifically support the value of this idea. But only in other countries. The potentially preventative reach of the Polypill has yet to take hold in the United States.

This past July, a British study found that the polypill can cut the risk of a heart attack by 72 percent and a stroke by 64 percent. Led by Wald’s son, Dr. David Wald from Queen Mary, University of London, the study identified a 12 percent reduction in mean systolic blood pressure, an 11 percent reduction in diastolic blood pressure, and a 39 percent reduction in LDL cholesterol.

The 6-month study was a randomized, double-blind, placebo-controlled crossover trial. This rigorous experimental design was selected to improve the precision and validity of the results and to increase statistical power to detect a difference between the polypill and placebo. The trial, which consisted of two 12-week phases, randomized assignment of placebo or active polypill as the first phase, and neither the physicians nor the patients were allowed to know the sequence of the assignments. In the second phase, patients “crossed over” to take the alternate compound. So, patients taking the polypill in phase one were switched to placebo in phase two and vice versa. The 12-week time period for each phase allowed the active medication both to take effect and to “wash out” for those assigned initially to the polypill—meaning that the risk factors targeted by the polypill could return to their pre-medication levels.

The trial enrolled 84 participants aged 50 and older, making it the first polypill trial to target at-risk populations by age alone. Previous studies have targeted sample populations with established histories of cardiovascular risk or established cardiovascular disease. The study used a polypill cocktail of amlodipine (calcium-channel blocker for blood pressure), losartan (angiotensin II receptor antagonist for blood pressure), hydrocholorthiazide (a diuretic for blood pressure), and simvastatin (a statin to lower cholesterol), created by Cipla, an Indian pharmaceutical manufacturer.

This most recent study has not been the only experimentation with the polypill, nor is there a single formulation. Dr. Wald conducted one of the first meta-analyses to determine the ideal contents of the pill in 2003. This formulation contained a statin, three blood pressure medications, folic acid and aspirin. Aspirin and folic acid were eliminated in the final formulation, however. Folic acid was excluded because of its lack of proven efficacy in clinical trials. Aspirin, while recently indicated as a having a protective effect against cancer, has been shown to increase risk of bleeding in people without existing cardiovascular disease. Since this study targeted populations at risk because of age and not history of cardiovascular disease, this risk was deemed “unacceptable in relation to the expected benefit.”

Dr. Wald’s study has been praised for its thoroughness in study design. From using a crossover clinical trial design to closely monitoring adherence by counting the remaining pills in “blister-packs,” — packaging containing the polypills — great efforts were taken to ensure that patients adhered to their drug regimen.

And the results are promising.

“If people took the polypill from age 50, an estimated 28 percent would benefit by avoiding or delaying a heart attack or stroke during their lifetime,” said Dr. Wald.

Passport for prevention?

So far, four clinical trials are underway with participants from South America, Europe, Asia, and Australia, and two trials are pending in China and South Africa. All clinical trials use similar versions of the polypill. Only two Indian pharmaceutical companies, Dr. Reddy’s Laboratories and Cipla, have manufactured a polypill for the purposes of clinical trials. Dr. Reddy’s Laboratories calls their pill the “Red Heart Pill,” for which they have two formulations. Both versions are virtually identical except one contains hydrochlorothiazide, a diuretic to lower blood pressure, and is intended for those with a history of stroke or cerebrovascular disease.

With an affordable pill that has the potential to prevent cardiovascular disease across the globe, there should be great fanfare. Not everyone is on board with the new polypill, however.

Natasha Stewart, senior cardiac nurse at the British Heart Foundation, urges everyone to show caution in interpreting the currently available research on polypills. “However interesting this potential new pill is, medicines are not a substitute for living a healthy lifestyle,” said Ms. Stewart to BBC. Others are insisting that the polypill needs larger clinical trials to be conducted before considering mass-production of the drug.

One scientist in the Netherlands even recommended a “polymeal” as a more natural alternative to achieve the same preventive effects, although polypill supporters have scoffed at this recommendation.

Take one and call me in the morning… if you’re not in the U.S.

With up to 200,000 individuals in the U.K. dying of cardiovascular disease, it is no wonder U.K. researchers have called the public availability of the polypill “a matter of urgency.” However, the public availability of the polypill does not seem to be so urgent in the U.S.

But why?

New cases of cardiovascular disease and stroke in the U.S. every year (785,000 and 610,000 individuals, respectively) far exceed our British counterparts’ rates. One study has projected that a polypill used by U.S. adults above 55 years could prevent 3.2 million coronary heart disease events and 1.7 million strokes over 10 years. Given the disturbingly high burden of cardiovascular disease, it is puzzling why there has been little mention of the polypill in the U.S.

For one, physicians could be reluctant to prescribe the polypill. Many physicians may prefer medications other than amlodipine and simvastatin to lower blood pressure and controlling cholesterol. The four generic medications in the polypill could pose unappealing restrictions on physician autonomy. Additionally, the medications are administered simultaneously, whereas many physicians spread out various medications during the day or week in order to avoid excessive dips in blood pressure. While Dr. Wald’s trial results cannot be used to estimate prevalence of side effects in the general population, few problems with the polypill were reported and only three percent of the study population had to stop treatment.

Furthermore, while Nicholas Wald is waiting on the approval of his patent in the U.S., generic manufacturers seem to have minimal interest in the drug. One theory is that the private industry sees the profit margin as too small to warrant the significant expenditure on research and development. So what are the real costs of introducing the polypill to the American drug market?

There are various estimates on the cost for the patient of a polypill, which range from one dollar a month to approximately 16 cents a day. The actual calculations behind these numbers can’t be found, probably because the drug industry is pretty elusive regarding the costs of research and development (R&D). R&D spending for a drug can range from $4 to $11.8 billion. Pfizer’s Lipitor, a drug similar to the simvastatin in the polypill, earned $13.3 billion in 2011, and ranks as the world’s top-selling medicine. However, the earning potential of the polypill is harder to compare to that of Lipitor.

Let’s take the 2003 cost of Medicare spending on in-hospital costs for cardiovascular disease and stroke of roughly $15.9 billion (approximately $12,321 per discharge for acute myocardial infarction (MI), $11,783 per discharge for coronary atherosclerosis, $5,127 per discharge for other ischemic heart disease, and $6,363 per discharge for stroke). Based on the projections of previously cited studies, the introduction of the polypill could mean a total of approximately $7.3 billion reduction from the $15.9 billion spent by Medicare in one year. It would take less than two years for the pharmaceutical industry’s expenditures to be outweighed by Medicare savings.

It is possible that the low potential sales return on the polypill have caused it to be snubbed by big pharmaceutical companies, who would probably rather prioritize their blockbuster drugs. Or perhaps these pharmaceutical companies have determined that the side effects and clinician resistance to the polypill will present too much of a barrier to the success of this new step in preventive medicine. Regardless, it is hard to argue with the need for the U.S. to begin to seriously explore the remarkable benefits of the polypill. It may be a bitter pill for big drug manufacturers to swallow, but the potential gains for population health might just be enough sugar to make the medicine go down.

Edited by Dana March