TIPS 2: Full-Dose Polypill Boosts Efficacy, With No Increased Side Effects

Shelley Wood

April 20, 2012

April 19, 2012 (Dubai, United Arab Emirates) — A full-dose polypill strategy, combining aspirin, three antihypertensives, and a statin, not surprisingly produced greater drops in blood pressure and LDL cholesterol than those seen in the original half-dose combination pill, but with no significant differences in adverse effects, results of the TIPS 2 trial show.

Presenting the results here at the World Congress of Cardiology (WCC) 2012, Dr Alben Sigamani (St John's Research Institute, Bangalore, India) explained that part of the original rationale for creating a combination pill with doses half of those proven in prior studies was to reduce the risk of adverse effects.

"The important findings in TIPS 2 were that the [full] dose was more effective and did not increase the adverse events: it was as well tolerated as the [half] dose," Sigamani told heartwire .

As previously reported, the first TIPS trial evaluated the Polycap (Cadila Pharmaceuticals), which combined aspirin, atenolol, ramipril, a thiazide, and simvastatin (with the three BP-lowering drugs and statin given as half-doses) in a high-risk primary-prevention cohort.

For TIPS 2, Sigamani and colleagues shifted to a secondary-prevention population of 518 patients (preexisting vascular disease or type 2 diabetes), randomizing them to either two polypills (to emulate a full-dose capsule) or a single polypill.

After three months, the double-dose strategy reduced systolic BP by an additional 2.82 mm Hg and diastolic BP by an added 1.73 mm Hg, compared with the half-dose formula. Heart rate was no different between groups, but LDL was 0.19 mmol/L lower in the double-dose group. Importantly, no differences in side effects were seen between groups, and drug discontinuation rates were the same.

Polypill Promises

Leaders for a number of polypill initiatives worldwide discussed the progress, potential, and pitfalls in this area during a separate WCC 2012 session.

Dr Dorairaj Prabhakaran (Public Health Foundation of India, New Delhi), primary investigator for the ongoing UMPIRE trial, pointed out that the original proposition for the polypill envisioned a sweeping role for the pill in primary prevention--something that could be given by a nonphysician to everyone over the age of 55, with no need for screening or monitoring.

The concept, he said, was "theoretically brilliant" but "overestimated benefits" in primary prevention and was perhaps a bit "radical" in its approach. It also sent the "wrong message to patients" that a "magic bullet" could help reduce risk, without the need for improvements in lifestyle and diet.

By contrast, he said, a polypill in secondary prevention "is a no-brainer," with the potential for far greater cost efficacy than in primary prevention. The 2000-patient UMPIRE trial, testing the "Red Heart" polypill (Dr Reddy's) against usual care, is looking at medication adherence as well as reductions in blood pressure and cholesterol out to two years. Results are expected by the end of the year, Prabhakaran said today.

Also speaking in today's session, Dr Salim Yusuf (McMaster University, Hamilton, ON), a coinvestigator on the TIPS trial series, agreed with Prabhakaran that any polypill approach would need to be part of a more comprehensive diet and lifestyle program. A number of other trials are ongoing, he noted, looking either at a combo/polypill specifically (TIPS 3 and HOPE 3) or a polypill "strategy" (looking at distribution and care by a nonphysician), being investigated in HOPE 4.

Yusuf also said that he had already had two meetings with the US FDA and predicted that the polypill will be available in the US within six months to a year and that Canada, Southeast Asia, and South America area have approval "procedures under way."

Several key questions remain to be answered. Chief among them is whether a single-pill strategy not only will prove effective but will also actually increase compliance. Dr Valentin Fuster (Mount Sinai Medical Center, New York, NY), principal investigator for the FREEDOM trial, announced today that the trial had concluded and would be presented as a late-breaker at the AHA 2012 meeting in Los Angeles this fall. But offering a snippet of data for the audience, Fuster warned that even in this trial, with regular monitoring and rigorous patient reminders, only 20% of patients reached target risk-factor levels.

That news echoes results of a trial on everyone's tongues here today--PURE--which showed that even in wealthy nations and in countries with drug coverage plans, compliance with medications is astonishingly low, falling to rock-bottom levels in low- and middle-income nations.

"Maybe this is a problem that the polypill can solve, but we have to first prove that one pill is better than three for adherence and also that the cost of the pills is affordable," Fuster said. The FOCUS 2 study, now enrolling, is looking at both of these issues, he noted.

The Elephant in the Room

Drs Wilhelm Rutishauser (moderator), Salim Yusuf, Dorairaj Prabhakaran, and David Wood debate the merits of the polypill.

Indeed, costs both of developing a polypill and of taking it were recurring themes in today's session. Prabhakaran called the topic "the elephant in the room," since the success of a polypill strategy in underdeveloped countries requires that the drug be cheap, yet companies are leery of developing a pill that won't bring them return on their investment.

Fuster claimed to have approached 10 drug companies before finding one in Spain that would help him develop the combination used in FREEDOM; Salim's group has gone with a company in India, but they also faced rejections.

A TIPS coinvestigator in the audience, Dr Denis Xavier (St John's Research Institute, Bangalore, India), went to the microphone to point out that even assuming a drug can be commercialized and approved at an affordable price, it will face the additional problem of physician uptake.

"We as physicians could be impediments, one of the reasons being that there is not Big Pharma backing for this so they won't be influencing prescribing," Xavier said.

Yusuf agreed but suggested that a polypill is the kind of strategy that will need to be pitched directly to governments and large insurance companies trying to cut costs.

Dr David Wood (Imperial College London, UK) agreed, pointing out that organizations like NICE in the UK have increasing sway when it comes to drug usage and approval. "Don't underestimate the power of government in this process," Wood said.