ACC 2009: First Polypill Data Show Promise; Larger Trials Next Step

March 30, 2009

March 30, 2009 (Orlando, Florida) — A phase 2 trial described as being the critical first step on the journey to discover whether a polypill could work effectively has shown just that [1]. The pill (Polycap), consisting of three antihypertensive drugs, a statin, and aspirin--developed by the Indian firm Cadila Pharmaceuticals--could cut cardiovascular risk by half in healthy, average people, say the researchers.

Dr Salim Yusuf (McMaster University, Hamilton, ON) reported the findings of The Indian Polycap Study (TIPS) at a late-breaking clinical trials session here at the American College of Cardiology (ACC) 2009 Scientific Sessions today, and they were simultaneously published in the Lancet.

Importantly, those who took the polypill in the study had no more adverse effects than eight other groups enrolled who were taking one of the components of the polypill alone or, in some cases, a combination of two or three of the components. And there appeared to be no drug-drug interactions. But the degree of cholesterol lowering was slightly less with the polypill than in patients who got simvastatin alone, and the reduction in BP was lower than projected from the antihypertensives included. "Our findings emphasize that the effects of the polypill cannot be assumed to equal the combined effects of its individual components," the researchers caution. Nevertheless, the findings are key, they say. Dr Denis Xavier (St John's Medical College, Bangalore, India), a coinvestigator of the TIPS trial, told heartwire : "We are encouraged by the results--this trial has demonstrated that the Polycap is well tolerated and does modify physiological parameters as expected at three months and can potentially be given to a large proportion of individuals with cardiovascular risk factors. But what we do not yet know is whether it would reduce mortality and other major cardiovascular events. So prior to its widespread use, we must test it in a large primary-prevention clinical trial with cardiovascular events as outcomes. This has prompted us to firm up plans for the next trial."

Yusuf told heartwire that the Polycap will be available in India "within a matter of weeks" and that its use in secondary prevention is feasible because large morbidity and mortality trials have already been conducted with the individual components. But he agrees that a large trial is needed before such a pill can be given to apparently healthy people. "The polypill is a wonderful concept, but there are lots of steps before we put it into practice."

In an accompanying comment in the Lancet [2], Dr Christopher P Cannon (Brigham and Women's Hospital, Boston, MA) says the concept of a polypill has "obvious appeal and vast implications for global health," with the possibility of reducing heart disease by 80%. The TIPS trial "moves us one step closer to realizing this dream," says Cannon.

Following the presentation at ACC, there was a lively debate surrounding the lower-than-expected reductions in LDL cholesterol and blood pressure; compliance, which was not as high as would have been expected; and the ideal target population for such a pill. Dr Steven Nissen (Cleveland Clinic, OH) asked what this would be for, "the developed or the developing world?" Yusuf replied: "It's for the sensible!"

Moderator of the press conference, Dr Hani Sabbah (Henry Ford Health System, Detroit, MI), was fairly critical of the study. "I think Yusuf way overrated his conclusion based on the data they have, which is not quite ready to go as a primary intervention. He wants to treat the world, or at least everybody over the age of 50, with a polypill. I share his enthusiasm, but I'm not quite ready to jump on the bandwagon of treating nations," he told heartwire . But Dr Timothy Gardner (Christiana Care Health Services, Wilmington, DE) said he was reassured somewhat by the data: "Some of the concerns about a polypill in the general population were not seen."

BP Lowering Good and Aspirin Effectiveness Maintained in Polypill

TIPS, a double-blind study, enrolled 2053 patients aged 45 to 80 years without cardiovascular disease but with one risk factor--type 2 diabetes, high blood pressure, smoker within past five years, increased waist-to-hip ratio, or abnormal lipids--at 50 centers in India. They were randomly assigned to one of nine groups for 12 weeks: 412 received Polycap, with hydrochlorothiazide 12.5 mg, atenolol 50 mg, ramipril 5 mg, simvastatin 20 mg and aspirin 100 mg. The remainder were assigned to eight other groups, with around 200 patients in each, including the same doses of aspirin alone, simvastatin alone, hydrochlorothiazide alone, three combinations of two BP-lowering drugs, three BP-lowering drugs alone, and an arm with three BP-lowering drugs plus aspirin. All participants were also counseled on appropriate lifestyle modification.

The polypill lowered blood pressure similarly to the added effects of each of its three BP-lowering components, with an average reduction of 7 mm Hg systolic, with no interference of aspirin with the BP-lowering effects. Heart rate (an indicator of beta blockade) and urinary 11-dehydrothromboxane B2--a measure of aspirin effectiveness--were also lowered to a similar degree with the polypill as with the individual components.

Following the presentation, both Dr Sidney C Smith (University of North Carolina, Chapel Hill) and Nissen questioned what they said was a poor showing of the polypill in terms of antihypertensive-lowering effects. Yusuf reminded them the pill contained only half doses of antihypertensives, and "these data are telling us you can lower BP reasonably safely in this population. With full doses, how well will they be tolerated, and how much more of a benefit will we get? We have to follow this up with further trials to look at clinical outcomes." Smith agreed: "The true test is not what happens to BP, but whether it affects your rate of events. If you give it to this population, what are the outcomes going to be?"

Cholesterol Lowering Inferior With Polypill, But Tolerability Is Good

The Polycap was well tolerated, with a similar rate of discontinuation in that group compared with the other eight, something Cannon calls "a key and very promising finding."

But Yusuf admitted that compliance was poor in the study overall, with 18% of patients dropping out within the 12 weeks. However, the reasons for this were likely due to lack of staff in the study centers and the fact that six of the centers hadn't ever performed a trial before. It's also possible that generally healthy people stopped taking the pill because they couldn't conceive any benefit, he said.

This holds tremendous promise but it's a first step, and we've got miles to go before we sleep.

Smith stressed that compliance was a key factor to look at in future trials. "What we need to know now is, will people adhere to a polypill better than they would adhere to five pills? Will they take it? It may just be that they aren't going to take pills at all. We need to know that putting them together in one pill improves compliance. We have to show that. This holds tremendous promise, but it's a first step and we've got miles to go before we sleep," he commented to heartwire.

For reasons that the researchers say remain unknown, the polypill did not lower LDL cholesterol to the same extent as simvastatin alone; studies by the sponsor indicate that the drug concentration of simvastatin with the Polycap was 20% lower than with simvastatin alone, they note.

It's very important that if people take a polypill, this is not a substitute for continuing to smoke and be fat and eat the wrong things.

Cannon says this finding "highlights the importance of a phase 2 study such as TIPS to identify any such issues with the polypill" and suggests that perhaps a dose of 40 mg of simvastatin or a moderate dose of a more potent statin, which should become available generically in a few years, may be more appropriate for future larger trials.

Xavier told heartwire that, based on the results, "We are planning to alter some of the components, especially in specific conditions such as hypertension and diabetes. We also propose to have different combinations for primary and secondary prevention; in the former, without aspirin, and in the latter, with aspirin."

Safety Must Be Proven; Lifestyle Must Not Be Neglected

"Even the current polypill will lead to important things," Yusuf told heartwire . But, he said, "Our next step is to test various different formulations, to see if we can improve on the results, to see whether this is still safe and affordable and whether people be willing to use it. My guess is that they will--there are people swallowing pills of ginseng and all kinds of rhinoceros horns and other things."

However, he cautioned: "It's very important that if people take a polypill, this is not a substitute for continuing to smoke and be fat and eat the wrong things, so the polypill has to be on top of good lifestyle behavior."

Sabbah said much more data on safety are needed. "We know that for these patients, for the duration that they were followed (12 weeks), there were no safety issues. But I don't know if safety issues would begin to rear their ugly heads in a year, two years, or three years. You need a much longer follow-up to assess the safety of the polypill. This would have no legs to stand on in the US through the FDA without a larger trial, powered to be able to look at safety issues as well as efficacy. Drugs do not grow on trees. They are chemicals, and if there is no need for that chemical, if you cannot establish a cause for that chemical, patients should not be swallowing those pills. More studies are needed."


Yusuf told heartwire : "The company and I will be meeting with the FDA to share our data with them. I don't know how soon the meeting will be held, certainly it will be in the next few months, and we will try to understand from them what is needed. Maybe what we've already got is good enough. We have very good stability data, which I haven't shown, and we have very good pharmacokinetic data--we've really done a proper development here. We've tested nine formulations, and, usually these things are meant to be four weeks, and this is 12 weeks, so we've done a lot of things that are right, so we just have to wait and see.

"But I think the regulators will be cautious, because when you have something new, they take a while to work things out. The answer is I don't know," he added.

Projected 50% Reduction in Stroke, 60% Reduction in MI

The TIPS investigators have projected the benefits of the polypill on the reduction of cardiovascular disease and stroke, which they note are "significantly less" than the risk reductions predicted by Drs Nicholas J Wald and Malcolm R Law (Wolfson Institute of Preventive Medicine, London, UK), the British doctors who first conceived the idea of a polypill in 2003.

Nevertheless, the calculations overall indicate an estimated 62% reduction in coronary heart disease and 48% reduction in stroke, although Yusuf was keep to stress that these really are "just projections".

Estimated Reduction in CHD/Stroke of a Polypill in Those With Average Risk-Factor Levels

Risk factor Treatment Reduction in risk factor % relative risk reduction in CHD % relative risk reduction in stroke
LDL-C (mmol/L) Simvastatin 20 mg) 0.80 mmol/L 27 8.1
Diastolic BP (mm Hg) 3 drugs, half dose 5.7 mm Hg 24 33
Platelet function ASA 100 mg Similar 32 16
Combined     62 48

Asked by heartwire how much the Polycap is likely to cost, Xavier said: "I am unable to comment on pricing at this point. It is the company's call here, and to the best of my knowledge they have not yet priced it. What I do know for sure is that it will be priced in such a way that the majority of the lower-middle class in India would be able to afford it long term, and the same will apply to other developing countries, too. In developed countries, it will be priced higher."

Yusuf has received fees for lecturing and research grants from Cadila as well as six other pharmaceutical companies that produce CVD drugs. Xavier and some of the other authors have received research funding for this trial from Cadila. Cannon has received research support from Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi, GlaxoSmithKline, Merck, and Merck/Schering-Plough. He serves as a clinical adviser and holds equity in Automedics Medical Systems. He is a senior investigator on the TIMI study group.