A polypill containing a statin, aspirin, and three blood pressure-lowering drugs could massively reduce future incidence of heart attack and stroke in currently healthy people. The findings of the TIPS* study are discussed in
an Article published Online First and in an upcoming edition of The Lancet. Publication of the Article coincides with the announcement of the findings at the American College of Cardiology (ACC) meeting in Florida, USA. Dr Salim Yusuf, Population Health Research Institute, McMaster University, Hamilton, ON, Canada, and  Dr Prem Pais, St John's Medical College, Bangalore, India, and colleagues selected a formulation containing low doses of the blood-pressure-lowering drugs (BPLDs) hydrocholorothiazide (12*5 mg), atenolol (a β-blocker) (50 mg), and ramipril (5 mg); the statin simvastatin (20 mg), and finally aspirin (100 mg) per day,  for the polypill (branded Polycap**). They wanted to address several questions in this study. First, can one pill (or capsule) be formulated that can deliver an effect similar to all its separate components added together? Second, what degree of reduction in blood pressure and LDL (bad) cholesterol can be achieved in people with normal levels of risk factors? Third, will a polypill with five components be tolerated? Fourth, do unexpected interactions arise when these drugs are given in a single pill? Fifth, does aspirin reduce the blood-pressure-lowering effects of the three BPLDs?

In this randomised trial, in 50 centres in India, 2053 people aged 45-80 years - without cardiovascular disease but with one risk factor*** for it - were assigned to Polycap (412 people), or to eight other groups, each with about 200 individuals, of aspirin alone, simavastatin alone, hydrochlorothiazide alone, the three possible combinations of two out of three BPLDs, the three BPLDs alone, or the three BPLDs plus aspirin. All participants were also counselled on appropriate lifestyle modification.

The researchers found that compared with groups not receiving BPLDs, the Polycap  reduced systolic blood pressure by 7.4 mm Hg and diastolic blood pressure by 5.6 mm Hg, which was similar when three BPLDs were used, with or without aspirin. Reductions in blood pressure increased with the number of BPLDs used (2.2/1.3 mm Hg with one drug, 4.7/3.6 mm Hg with two drugs, and 6.3/4.5 mm Hg  with all three). Polycap reduced LDL cholesterol by 0.70 mmol/L, which was slightly less than that with simavastatin alone (0.83mmol/L). The reductions in heart rate with Polycap and other groups using atenolol were similar (7.0 beats/min) and both were substantially greater than in groups without atenolol. The reductions in urinary 11-dehydrothromboxane B2**** were similar in the Polycap (322 ng/mmol) compared with the three BPLDs plus aspirin (389 ng/mmol), and in aspirin alone (388 ng/mmoL) compared with groups without aspirin. Tolerability of the Polycap was similar to the other groups, with no evidence of increasing intolerability with increasing number of active components in one pill.

The authors say: "Our study has shown that the Polycap is non-inferior to its individual components in lowering blood pressure and heart rate (an indicator of β blockade). It lowers LDL cholesterol and urinary 11-dehydrothromboxane B2 substantially, but to a degree that is slightly less than that with simvastatin or aspirin alone.

They add: "The reductions in blood pressure that we recorded in this non-hypertensive population with the Polycap could theoretically lead to about a 24% risk reduction in cardiovascular heart disease and 33% risk
reduction in strokes in individuals with average blood pressure levels...On the basis of the more modest lowering of LDL cholesterol that we noted, a 27% relative risk reduction in cardiovascular heart disease and an 8% risk reduction in stroke can be projected." The authors believe that the combined effects of all the components in the Polycap could potentially halve cardiovascular events, in average, middle-aged individuals.

The authors say that adherence to multiple drugs even in patients after a heart attack is suboptimal, and believe the polypill could substantially improve adherence and therefore the benefits. They conclude: "By including nine groups and a large number of patients, we have been able to assess the effects of various combinations of drugs on a range of outcomes and on safety and tolerability... the formulation of the Polycap used in this study can be conveniently used to reduce multiple risk factors and cardiovascular risk."

In an accompanying Comment, Dr Christopher P Cannon, Cardiovascular Division, Brigham and Women's Hospital, Boston, and Harvard Medical School, Boston, says that a large phase III is now required to fully evaluate the feasibility of the polypill. He also the discusses the problem of getting the doses of each drug right, and the possibility of polypills of different strengths.

Dr Cannon underlines his hopes that use of a polypill would not lead people to abandon appropriate exercise and diet, which would make the root causes of cardiovascular disease worse. He adds that due to simplicity and presumably cheap cost, a polypill would fit well into the health systems of less developed countries, as well as into more modern medical systems, in
which large proportions of patients with risk factors are untreated. He concludes: "The study... raises hope that, in conjunction with other global efforts on improving diet and exercise, the polypill could one day substantially reduce the burden of cardiovascular disease in the world."

Dr Salim Yusuf, Population Health Research Institute, McMaster University, Hamilton, ON, Canada

T: +1 905-527-7327 E: yusufs@mcmaster.ca

Dr Christopher P Cannon, Cardiovascular Division, Brigham and Women's Hospital, Boston, and Harvard Medical School, Boston, USA

T: +1 781-367-2159 E: cpcannon@partners.org

Notes to editors: *TIPS= The Indian Polycap Study ** The Polycap is manufactured by Cadila Pharma, Ahmedabad, India.

***Risk factors: type 2 diabetes; blood pressure >140 mm Hg systolic or > 90mm Hg diastolic, but <160/100mm Hg; smoker within the past five years; increased waist to hip ratio (>0.85 for women and >0.90 for men); or abnormal blood fats (LDL/bad cholesterol >3.1 mmol/L or HDL/good cholesterol <1.04 mmol/L).
****aspirin use blocks the production of 11-dehyrdothromboxane B2, which is important in clot formation in the blood. Thus reduced levels of 11-dehydrothromboxane B2 in urine indicate less clotting in the blood.

Full article available from The Lancet, Volume 373, Issue 9672, Pages 1341 - 1351, 18 April 2009.

 

Published on: 29/4/2009

 

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