New Polypill Data Predict a Halving of CV Events

First placebo-controlled polypill study

May 26, 2011

May 26, 2011 (Sydney, Australia) - The first randomized, placebo-controlled study of a polypill has suggested that use of such a product in primary prevention could bring about a halving of heart disease and stroke events, the authors say [1].

While the authors conclude that a polypill such as this is a potentially highly cost-effective strategy that could alone achieve most of World Health Organization's goals for reducing noncommunicable disease, others see it as a step backward, saying it represents a "dumbing down" of medical practice.

The current study, published online May 25, 2011 in PLoS One, involved 378 individuals without an indication for any component of the polypill but who had an estimated five-year cardiovascular disease risk over 7.5%, determined by the Framingham risk function using data on age, gender, blood pressure, total cholesterol, HDL cholesterol, diabetes status, and cigarette smoking status. They were randomized to the polypill containing aspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg, and simvastatin 20 mg or to placebo. Results showed that the polypill was associated with a 9.9-mm-Hg drop in systolic blood pressure and a 0.8-mmol/L reduction in LDL cholesterol over a 12-week treatment period.

Adverse effects occurred in 58% of the polypill group vs 42% of the placebo patients, with 23% of the polypill group discontinuing therapy vs 18% of the placebo group.

The authors estimate that if individuals stayed on therapy long term, these effects would translate into an approximate 60% reduction in heart disease and ischemic stroke risk, little overall effect on hemorrhagic stroke risk (the beneficial effects of blood-pressure lowering balancing out the adverse effects of aspirin), and a 50% increase in the risk of extracranial bleeding.

One event prevented for every 18 patients treated over five years

They say that a patient group at similar risk to the average in this trial would experience a halving in risk of any major event (stroke, CHD, or major bleed). Over five years of treatment, about one in 18 would benefit in terms of avoiding a major event, with the large majority of the net benefit due to the systolic blood pressure and LDL reduction. Increased benefits would be expected in previously untreated individuals with a history of coronary artery disease.

Lead author Prof Anthony Rodgers (George Institute for Global Health, Sydney, Australia) said: "We know from other trials that long term there would also be a 25% to 50% lower death rate from colon cancer, plus reductions in other major cancers, heart failure, and renal failure. These benefits would take several years to kick in, but of course one of the hopes with a polypill is it helps people take medicines long term."

The current study, known as the Program to Improve Life and Longevity (PILL) pilot, was conducted by a group known as the PILL Collaborative Group, part of a larger collaboration known as the Single Pill to Avert Cardiovascular Events (SPACE). These programs are being coordinated by the George Institute, with the polypill provided by Dr Reddy's of India. Patients for the current study were recruited from seven countries--Australia, Brazil, India, the Netherlands, New Zealand, the UK, and the US.

Prof Simon Thom (Imperial College London, UK), who led the UK arm of the trial, commented to heartwire that although the projected benefits of the polypill from this study were somewhat less than had been predicted when the idea was first mooted and the incidence of side effects were greater, he believes the results are still encouraging.

Moving from theory to real life

"The mathematical predictions for the polypill when it was first devised back in 2003 were rather fantastical--an 80% reduction in cardiovascular disease was never likely to be real. We are now moving from the theoretical to what would happen in real life. Our results suggest that use of this agent could translate into about a 50% to 60% reduction in heart disease. That is pretty striking," Thom said.

He was also not overly perturbed about the side effects seen in the study. "They are what would be expected. Although one in six patients had a side effect with the polypill, this led to discontinuation in only about one in 20."

Thom pointed out that the vast majority of these side effects were attributable to the GI effects of aspirin, and because of its side-effect profile, the place for aspirin in the polypill for use in primary prevention is being debated. Thom explained that because of its narrow risk/benefit ratio in primary prevention of cardiovascular disease, there have been strong arguments against including aspirin in the polypill, but recent data showing it has a protective role against several cancers has swung opinion back in favor of aspirin. "Aspirin is back with a vengeance because of the cancer data, which I believe will expand the degree of acceptance of its GI side effects," he said. He added that the side-effect data from this study shouldn't change the argument about including aspirin either way.

Not a blanket treatment for all

Thom said the new data did, however, argue against use of the polypill as a blanket treatment for everyone above a certain age, which was originally proposed. "The side effects we have seen mean this will not be a fire-and-forget strategy for all middle-aged people. There will have to be some sort of screening involved to identify those at higher risk." He added that the need for such screening is bound to be a barrier to the adoption of the polypill for primary prevention in the developing world, where it will not be possible to test lipid levels in everyone.

Secondary prevention will be first indication

Thom says that for this reason, the polypill will be introduced first as a treatment for the secondary prevention of heart disease, in patients who have already had a cardiovascular event, in whom the issues are much more straightforward. "These patients have already been identified, and they should all be taking many medications, but most of them aren't because of compliance issues. Most patients in developed countries leave the hospital with a bag full of preventive medicines, but after a year, only half are taking them. A polypill would make compliance much easier. This alone should have a positive effect. And in the developing world, few patients get any of these medications. But if a polypill were made available at a rock-bottom price, this would change."

The SPACE collaboration has a series of trials ongoing in the secondary-prevention population, which are comparing the polypill with usual care (multiple single tablets). These trials are taking pace both in the developing world and Western countries and are testing two different polypills. Both contain aspirin, a statin, and an ACE inhibitor but differ in that the one directed at stroke patients also includes a thiazide, whereas the one directed at MI patients contains a beta blocker.

Others now focusing on primary prevention

While the SPACE collaboration appears to be focusing primarily on the secondary-prevention population, another group, led by Dr Salim Yusuf (McMaster University, Hamilton, ON), is planning a large-scale trial in primary prevention to start later this year.

In a review article on the concept of the polypill published last year in Circulation [2], Yusuf's team report that the TIPS-3 trial will evaluate a polypill, not containing aspirin, vs placebo over five years in 5000 individuals without CVD and with an estimated risk of major cardiovascular disease of 1%/year in India and China. The TIPS-3 trial is the large-scale trial that follows on from two smaller pilot trials--TIPS-1 and -2.

Commenting on the current PILL pilot study for heartwire , Yusuf said: "The results are complementary and almost identical to TIPS-1, and so we believe the two trials reinforce each other. I think it will strengthen the assumptions that we have used to design the full-scale study." He added that they have just finished TIPS-2, which has been submitted to a journal, and hope to present it at one of the major forthcoming meetings this year.

The future: Many different polypills?

Thom believes there will eventually be many types of polypill, with some directed at primary prevention and others at secondary prevention, and there will also be ones directed at patients with diabetes, etc. It would also be sensible to have pills with and without aspirin. "You could start with the aspirin and you would know quite soon if you could tolerate it or not." In addition, in the future, the ACE inhibitor may also be replaced by a generic angiotensin-receptor blocker to avoid the side effect of cough. And simvastatin may be replaced by the more potent atorvastatin, once it comes off patent.

Thom says the polypill will succeed only if patients and healthcare systems will adopt it with enthusiasm, and it may be more easily accepted in countries with a nationalized health system such as the UK than in the US, where the complexity of the market may make it more difficult. He adds that while GPs and patients may favor the idea, opposition is likely to come from specialists who write the guidelines. "They tend to have a favorite statin/antihypertensive drug and they like to tweak this and that to tailor the treatment for each individual patient."

The critic's view

Confirming the specialist's view, Dr Steve Nissen (Cleveland Clinic, OH) told heartwire : "I do not support the concept of a polypill. This article further reinforces my concerns. Medical practice requires that we apply the right therapies for the right patients in the optimal dosages. The polypill dumbs this all down to a single combination for everyone, exposing some patients to therapies they don't need, while undertreating others. Every one of these medications has benefits and risks, including aspirin. If you give aspirin to a patient with a gastric ulcer, you may produce a catastrophe. If a patient experiences an adverse effect on the polypill, physicians may not know which agent produced the side effect, and the patient may simply stop treatment. One size fits all is not good medicine, even in the developing world."

Nissen also objects to the idea of simply projecting long-term benefits from blood pressure and cholesterol changes. "Estimating the benefits of polypill therapy as performed in this manuscript is scientifically unacceptable. If we adopted such analyses, we would simply stop performing high-quality outcomes trials and just 'calculate' benefits."

The trial was funded by the Wellcome Trust, the Health Research Council of New Zealand, the National Heart Foundation of New Zealand, the National Health and Medical Research Council of Australia, the Brazilian Ministry of Health, and the British Heart Foundation. The polypill and matching placebo were provided free of charge by Dr Reddy's Laboratories. The authors have declared that no competing interests exist.


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