An international randomised placebo-controlled trial of a four-component combination pill ("polypill") in people with raised cardiovascular risk

PILL Collaborative Group, Anthony Rodgers, Anushka Patel, Otavio Berwanger, Michiel Bots, Richard Grimm, Diederick E Grobbee, Rod Jackson, Bruce Neal, Jim Neaton, Neil Poulter, Natasha Rafter, P Krishnam Raju, Srinath Reddy, Simon Thom, Stephen Vander Hoorn, Ruth Webster, Anthony Rodgers, Anushka Patel, Otavio Berwanger, Michiel Bots, Richard Grimm, Diederick E Grobbee, Rod Jackson, Bruce Neal, Jim Neaton, Neil Poulter, Natasha Rafter, P Krishnam Raju, Srinath Reddy, Simon Thom, Stephen Vander Hoorn, Ruth Webster, Angela Wadham, Vanessa Selak, Natasha Rafter, Steve Vander Hoorn, Joy Jiang, Rina Prasad, John Faatui, Tamsin Scott, Amanda Milne, Barry Gray, Colleen Ng, Johan Strydom, Anushka Patel, Bindu Patel, Paula Zeman, Oscar-Hazel Donaldson, Joseph Canalese, Patrick Groenstein, Kumara Mendis, David Sullivan, Kerry Kearns, Nicole Li, Toni Monico, Evelyn Nangle, Chloe Runeckles, Otavio Berwanger, Ligia Nasi Laranjeira, Anna Maria Buchler, Andrea Di Vanna, Alexandre Biasi, Helio Penna Guimaraes, Nora Falconi, Cyntia Da Silva, Elaine Bastos De Menezes, Anushka Patel, Bindu Patel, M Abdul Salam, Ashok Kumar Dash, Kalyana Chakravarthy, Gundala Anil Krishna, Panchangam Sampath Kumar, Ravi Jayam, Mohammed Abdul Azeem Imran, Vemulakonda Sushma, Hari Obulesu, Syed Fayaz, Kasparam Mahesh, Anthony Rodgers, Angela Wadham, Fiona McLean, James Smith, Christine Forster, Malcolm Lowe, Harley Aish, John Cameron, Denise Miller, Diederick E Grobbee, Michiel Bots, Lizeth Vendrig, Gonnie Vierstra, Ischa Vissers, Jacobien Vermande, Karin Groot, Deborah Font-Julia, Hans Zuidema, Marcel VanDyk, Ron Peters, Sara Rafi, Suthesh Sivapalaratnam, Janneke van den Brink, Liselotte Kok, Lydeke Zwart, Trees Groenveld, Hanneke Basart, Simon Thom, Neil Poulter, Thiagarajah Sasikaran, Filomena Paciello, Judith Mackay, Hannah Lanzon-Miller, Jill Bunker, Candida Coghlan, Rachel Chapman, Rebecca Webb, Wendy Callister, Richard Grimm, Rachel Moor, Margaret Dimond, Mobin Malik, Alexa Camarena-Michel, Raghu Cidambi, Asit Datta, Haranath Robby, Arvind Ananthakrishnan, Prakash Shenthar Mahalinga, Neetta Mohit, Rajesh Dubey, Rekha Sinha, PILL Collaborative Group, Anthony Rodgers, Anushka Patel, Otavio Berwanger, Michiel Bots, Richard Grimm, Diederick E Grobbee, Rod Jackson, Bruce Neal, Jim Neaton, Neil Poulter, Natasha Rafter, P Krishnam Raju, Srinath Reddy, Simon Thom, Stephen Vander Hoorn, Ruth Webster, Anthony Rodgers, Anushka Patel, Otavio Berwanger, Michiel Bots, Richard Grimm, Diederick E Grobbee, Rod Jackson, Bruce Neal, Jim Neaton, Neil Poulter, Natasha Rafter, P Krishnam Raju, Srinath Reddy, Simon Thom, Stephen Vander Hoorn, Ruth Webster, Angela Wadham, Vanessa Selak, Natasha Rafter, Steve Vander Hoorn, Joy Jiang, Rina Prasad, John Faatui, Tamsin Scott, Amanda Milne, Barry Gray, Colleen Ng, Johan Strydom, Anushka Patel, Bindu Patel, Paula Zeman, Oscar-Hazel Donaldson, Joseph Canalese, Patrick Groenstein, Kumara Mendis, David Sullivan, Kerry Kearns, Nicole Li, Toni Monico, Evelyn Nangle, Chloe Runeckles, Otavio Berwanger, Ligia Nasi Laranjeira, Anna Maria Buchler, Andrea Di Vanna, Alexandre Biasi, Helio Penna Guimaraes, Nora Falconi, Cyntia Da Silva, Elaine Bastos De Menezes, Anushka Patel, Bindu Patel, M Abdul Salam, Ashok Kumar Dash, Kalyana Chakravarthy, Gundala Anil Krishna, Panchangam Sampath Kumar, Ravi Jayam, Mohammed Abdul Azeem Imran, Vemulakonda Sushma, Hari Obulesu, Syed Fayaz, Kasparam Mahesh, Anthony Rodgers, Angela Wadham, Fiona McLean, James Smith, Christine Forster, Malcolm Lowe, Harley Aish, John Cameron, Denise Miller, Diederick E Grobbee, Michiel Bots, Lizeth Vendrig, Gonnie Vierstra, Ischa Vissers, Jacobien Vermande, Karin Groot, Deborah Font-Julia, Hans Zuidema, Marcel VanDyk, Ron Peters, Sara Rafi, Suthesh Sivapalaratnam, Janneke van den Brink, Liselotte Kok, Lydeke Zwart, Trees Groenveld, Hanneke Basart, Simon Thom, Neil Poulter, Thiagarajah Sasikaran, Filomena Paciello, Judith Mackay, Hannah Lanzon-Miller, Jill Bunker, Candida Coghlan, Rachel Chapman, Rebecca Webb, Wendy Callister, Richard Grimm, Rachel Moor, Margaret Dimond, Mobin Malik, Alexa Camarena-Michel, Raghu Cidambi, Asit Datta, Haranath Robby, Arvind Ananthakrishnan, Prakash Shenthar Mahalinga, Neetta Mohit, Rajesh Dubey, Rekha Sinha

Abstract

Background: There has been widespread interest in the potential of combination cardiovascular medications containing aspirin and agents to lower blood pressure and cholesterol ('polypills') to reduce cardiovascular disease. However, no reliable placebo-controlled data are available on both efficacy and tolerability.

Methods: We conducted a randomised, double-blind placebo-controlled trial of a polypill (containing aspirin 75 mg, lisinopril 10 mg, hydrochlorothiazide 12.5 mg and simvastatin 20 mg) in 378 individuals without an indication for any component of the polypill, but who had an estimated 5-year cardiovascular disease risk over 7.5%. The primary outcomes were systolic blood pressure (SBP), LDL-cholesterol and tolerability (proportion discontinued randomised therapy) at 12 weeks follow-up.

Findings: At baseline, mean BP was 134/81 mmHg and mean LDL-cholesterol was 3.7 mmol/L. Over 12 weeks, polypill treatment reduced SBP by 9.9 (95% CI: 7.7 to 12.1) mmHg and LDL-cholesterol by 0.8 (95% CI 0.6 to 0.9) mmol/L. The discontinuation rates in the polypill group compared to placebo were 23% vs 18% (RR 1.33, 95% CI 0.89 to 2.00, p = 0.2). There was an excess of side effects known to the component medicines (58% vs 42%, p = 0.001), which was mostly apparent within a few weeks, and usually did not warrant cessation of trial treatment.

Conclusions: This polypill achieved sizeable reductions in SBP and LDL-cholesterol but caused side effects in about 1 in 6 people. The halving in predicted cardiovascular risk is moderately lower than previous estimates and the side effect rate is moderately higher. Nonetheless, substantial net benefits would be expected among patients at high risk.

Trial registration: Australian New Zealand Clinical Trials Registry ACTRN12607000099426.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. CONSORT flow chart.
Figure 1. CONSORT flow chart.
This figure shows the flow of patients through the trial according to the criteria recommended in the CONSORT Guidelines.
Figure 2. Baseline frequency distributions of age,…
Figure 2. Baseline frequency distributions of age, LDL-cholesterol, SBP and 5-year cardiovascular risk.
This figure shows the frequency distribution of participants according to their baseline levels of age, LDL-cholesterol, SBP and 5-year cardiovascular risk.
Figure 3. Blood pressure and LDL-cholesterol changes.
Figure 3. Blood pressure and LDL-cholesterol changes.
This figure shows the changes in blood pressure and LDL-cholesterol over the 12 week trial period, according to active (dark line) or placebo (grey line).

References

    1. World Health Organization. World Health Organization - Wellcome Trust meeting report 1 - 3 August 2001, Geneva; 2002. Secondary prevention of non-communicable disease in low and middle income countries through community-based and health service interventions.
    1. World Health Organization. The World Health Report 2002. In: Reducing risks,promoting healthy life WHO, editor. Geneva: WHO; 2002.
    1. Yusuf S. Two decades of progress in preventing vascular disease. Lancet. 2002;360:2–3.
    1. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. British Medical Journal. 2003;326:1427–1431.
    1. Law MR, Wald NJ, Rudnicka AR. Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. British Medical Journal. 2003;326:1423–1430.
    1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. British Medical Journal. 2003;326
    1. Wald NJ, Law MR. Formulation For The Prevention Of Cardiovascular Disease. WO. 2001.
    1. Fourth joint task force of the European Joint Society of Cardiology and Other Societies on cardiovascular disease prevention in clinical practice. European guidelines on cardiovascular disease prevention in clinical practice: executive summary. European Heart Journal. 2007;28:2375–2414.
    1. British Cardiac SocietyBritish Hypertension SocietyDiabetes UKHeart UKPrimary Care Cardiovascular Society. JSB2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart. 2005;91:1–52.
    1. The National Vascular Disease Prevention Alliance (Diabetes Australia KHA National Heart Foundation of Australia, and National Stroke Foundation of Australia) Consensus statement for the prevention of vascular disease. Australian Family Physician. 2004;33
    1. New Zealand Guidelines Group. The assessment and management of cardiovascular risk. New Zealand Guidelines Group; 2003. Evidence-based best practice guideline.
    1. European Agency for the Evaluation of Medicinal Products (EMA) Guideline on the Evaluation of Medicinal Products for Cardiovascular Disease Prevention. 2008.
    1. Anderson K, Wilson P, Odell P, Kannel W. An updated coronary risk profile. A statement for health professionals. Circulation. 1991;83:356–362.
    1. Jackson R, Barham P, Bills J, Birch T, McLennan L, et al. Management of raised blood pressure in New Zealand: a discussion document. British Medical Journal. 1993;307:107–110.
    1. Riddell T, Wells S, Jackson R, Lee AW, Crengle S, et al. Performance of Framingham cardiovascular risk scores by ethnic groups in New Zealand: PREDICT CVD-10. New Zealand Medical Journal. 2010;123:50–61.
    1. Therapeutics Letter; 2007. Using Framingham for primary prevention cardiovascular risk assessment. 63/ MAR - APR.
    1. Law MR, Morris JK, Wald NJ. Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. British Medical Journal. 2009;338
    1. Blood Pressure Lowering Treatment Trialists C. Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. British Medical Journal. 2008;336:1121–1123.
    1. Cholesterol Treatment Trialists' (CTT) Collaboration. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins. Lancet. 2005;366:1267–1278.
    1. Antithrombotic Trialists Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. The Lancet. 2009;373:1849–1860.
    1. Law M, Wald N. Risk factor thresholds: their existence under scrutiny. British Medical Journal. 2002;324:1570–1576.
    1. Law MR, Wald NJ, Morris JK. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy. British Medical Journal. 2003;7
    1. Yusuf S, Pais P, Afzal R, Xavier D, et al. The Indian Polycap Study. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet. 2009;373:1341–1351.
    1. Asia Pacific Cohort Studies C. Joint effects of systolic blood pressure and serum cholesterol on cardiovascular disease in the Asia Pacific region. Circulation. 2005;112:3384–3390.
    1. Prospective Studies C, Lewington S, Whitlock G, Clarke R, Sherliker P, et al. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007;370:1829–1839.
    1. Glasziou PP, Irwig LM. An evidence based approach to individualising treatment. British Medical Journal. 1995;311:1356–1359.
    1. Jackson R, Lawes CMM, Bennett DA, Milne RJ, Rodgers A. Treatment with drugs to lower blood pressure and blood cholesterol based on an individual's absolute cardiovascular risk. The Lancet. 2005;365:434–441.
    1. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Journal of the American Medical Association. 2003;289:2560–2572. The JNC 7 Report.
    1. Law MR, Watt HC, Wald NJ. The underlying risk of death after myocardial infarction in the absence of treatment. Arch Intern Med. 2002;162:2405–2410.
    1. Steg PG, Goldberg RJ, Gore JM, Fox KAA, Eagle KA, et al. Baseline characteristics, management practices, and in-hospital outcomes of patients hospitalized with acute coronary syndromes in the Global Registry of Acute Coronary Events (GRACE). American Journal of Cardiology. 2002;90:358–363.
    1. Boissel JP, Gueyffier F, Boutitie F, Pocock S, Fagard R. Apparent effect on blood pressure is only partly responsible for the risk reduction due to antihypertensive treatments
    1. Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. The Lancet Volume. 2001;358:1305–1315. [Erratum appears in Lancet 2002 Jan 26;359(9303):360]
    1. Malekzadeh F, Marshall T, Pourshams A, Gharravi M, Aslani A, et al. A pilot double-blind randomised placebocontrolled trial of the effects of fixed-dose combination therapy (‘polypill’) on cardiovascular risk factors. International Journal of Clinical Practise. 2010;64:1220–1227.
    1. Soliman E, Mendis S, Dissanayake W, Somasundaram N, Gunaratne P, et al. A Polypill for primary prevention of cardiovascular disease: A feasibility study of the World Health Organization. Trials. 2011;12:3.
    1. Jackson R, Lawes C, Bennett D, Milne R, Rodgers A. Treatment with drugs to lower blood pressure and blood cholesterol based on an individual's absolute cardiovascular risk. Lancet. 2005;365:434–441.
    1. Thompson AM, Hu T, Eshelbrenner CL, Reynolds K, He J, et al. Antihypertensive treatment and secondary prevention of cardiovascular disease events among persons without hypertension: a meta-analysis. JAMA. 2011;305:913–922.
    1. De Backer G, Ambrosioni E, Borch-Johnsen K, Brotons C, Cifkova R, et al. European guidelines on cardiovascular disease prevention in clinical practice: Third Joint Task Force of European and other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of eight societies and by invited experts). European Journal of Cardiovascular Prevention & Rehabilitation. 2003;10:S1–S78.
    1. Wells S, Broad J, Jackson R, Wells S, Broad J, et al. Estimated prevalence of cardiovascular disease and distribution of cardiovascular risk in New Zealanders: data for healthcare planners, funders, and providers. New Zealand Medical Journal. 2006;119:U1935.
    1. Kotseva K, Wood D, De Backer G, De Bacquer D, Pyörälä K, et al. Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries. The Lancet. 2009;373:929–940.
    1. Webster RJ, Heeley EL, Peiris DP, Bayram C, Cass A, et al. Gaps in cardiovascular disease risk management in Australian general practice. Medical Journal of Australia. 2009;191:324–329.
    1. Kumar A, Fonarow GC, Eagle KA, Hirsch AT, Califf RM, et al. Regional and practice variation in adherence to guideline recommendations for secondary and primary prevention among outpatients with atherothrombosis or risk factors in the United States: a report from the REACH Registry. Critical Pathways in Cardiology: A Journal of Evidence-Based Medicine. 2009;8:104–111.
    1. World Health Organisation. Evidence for action. Geneva: WHO; 2003. Adherence to long-term therapies.
    1. Beaglehole R, Ebrahim S, Reddy S, Voûte J, Leeder S. Prevention of chronic diseases: a call to action. The Lancent. 370:2152–2157.
    1. Mendis S, Abegunde D, S Y, Ebrahim S, Shaper G, et al. WHO study on Prevention of REcurrences of Myocardial Infarction and StrokE (WHO-PREMISE). Bulletin of the World Health Organization. 2005;83:820–828.
    1. Sharma KK, Gupta R, Agrawal A, Roy S, Kasliwal A, et al. Low use of statins and other coronary secondary prevention therapies in primary and secondary care in India. Vasc Health Risk Manag. 2009;5:1007–1014.
    1. Selak V, Rafter N, Parag V, Tomlin A, Hoorn SV, et al. Cardiovascular treatment gaps: Closing, but slowly. New Zealand Medical Journal. 2009;122:41–49.
    1. Murray CJL, Lauer JA, Hutubessy RCW, Niessen L, Tomijima N, et al. Effectiveness and costs of interventions to lower systolic blood pressure and cholesterol: a global and regional analysis on reduction of cardiovascular-disease risk. Lancet. 2003;361:717–725.
    1. Gaziano TA, Opie LH, Weinstein MC. Cardiovascular disease prevention with a multidrug regimen in the developing world: a cost-effectiveness analysis. Lancet. 2006;368:679–686.
    1. Goldberg RJ, Currie K, White K, Brieger D, Steg PG, et al. Six-month outcomes in a multinational registry of patients hospitalized with an acute coronary syndrome (The Global Registry of Acute Coronary Events [GRACE]). The American journal of cardiology. 2004;93:288–293.
    1. Lim S, Gaziano TA, Gakidou E, Srinath Reddy K, Farzadfar F, et al. Prevention of cardiovascular disease in high-risk individuals in low-income and middle-income countries: health effects and costs. Lancet. 2007;370:2054–2062.
    1. Longstreth GF. Epidemiology of hospitalization for acute upper gastrointestinal hemorrhage: a population-based study. American Journal of Gastroenterology. 1995;90:206–210.
    1. Lewis JD, Bilker WB, Brensinger C, Farrar JT, Strom BL. Hospitalization and mortality rates from peptic ulcer disease and GI bleeding in the 1990s: relationship to sales of nonsteroidal anti-inflammatory drugs and acid suppression medications. Am J Gastroenterol. 2002;97:2540–2549.
    1. Fox KAA, Steg PG, Eagle KA, Goodman SG, Anderson FA, et al. Decline in rates of death and heart failure in acute coronary syndromes, 1999-2006. JAMA. 2007;297:1892–1900.
    1. Law M, Morris JK, Jordan R, Wald N, Law M, et al. Headaches and the treatment of blood pressure: results from a meta-analysis of 94 randomized placebo-controlled trials with 24,000 participants. Circulation. 2005;112:2301–2306.
    1. Law M, Wald N, Morris J. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy. [Review] [188 refs]
    1. de Galan BE, Perkovic V, Ninomiya T, Pillai A, Patel A, et al. Lowering blood pressure reduces renal events in type 2 diabetes. Journal of the American Society of Nephrology. 2009;20:883–892.
    1. Antiplatelet Trialists'Collaboration. Collaborative overview of randomised trials of antiplatelet therapy–III: Reduction in venous thrombosis and pulmonary embolism by antiplatelet prophylaxis among surgical and medical patients. British Medical Journal. 1994;308:235–246.
    1. Andraws R, Brown DL, Andraws R, Brown DL. Effect of inhibition of the renin-angiotensin system on development of type 2 diabetes mellitus (meta-analysis of randomized trials). American Journal of Cardiology. 2007;99:1006–1012.
    1. Law M, Wald N, Morris J. Lowering blood pressure to prevent myocardial infarction and stroke: a new preventive strategy. Health Technology Assessment (Winchester, England) 2003;7:1–94.
    1. Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. The Lancet. 2010;375:735–742.
    1. Law MR, Rudnicka AR. Statin Safety: A Systematic Review. The American Journal of Cardiology. 2006;97:S52–S60.
    1. Rothwell PM, Fowkes FGR, Belch JFF, Ogawa H, Warlow CP, et al. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. The Lancet. 2011;377:31–41.

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir