The Need to Test the Theories Behind the Polypill: Rationale Behind the Indian Polycap Study
Denis Xavier; Prem Pais; Alben Sigamani; Janice Pogue; Rizwan Afzal; Salim Yusuf; on behalf of The Indian Polycap Study (TIPS) Investigators
Nat Clin Pract Cardiovasc Med. 2009;6(2):96-97. ©2009 Nature Publishing Group
Posted 02/12/2009
Antihypertensive, lipid-lowering and antiplatelet drugs are proven to reduce cardiovascular disease (CVD) events when used in primary and secondary prevention.[1-5] Their use is suboptimal, however, owing to factors both at the level of individual patients (cost, multiple dosing and real or perceived adverse effects), and at the health-care-provider level (inadequate time and motivation to emphasize long term adherence). In 2002, Yusuf proposed that use of a four-drug combination consisting of aspirin, a beta-blocker, a statin and an angiotensin-converting-enzyme (ACE) inhibitor for secondary prevention would result in a 75% reduction in patients' cumulative risk of CVD events.[6] In an extensive analysis published in 2003, Wald and Law proposed a six-drug combination 'Polypill' that could potentially reduce ischemic heart disease events by 88% and stroke by 80%.[7] The combination contained three antihypertensive drugs at half doses (a thiazide, beta-blocker and ACE inhibitor), aspirin, a statin and folic acid. The authors recommended that this pill be taken by all individuals who had a CVD event and by anyone >55 years, without reference to their cardiovascular risk or monitoring treatment to attain specific targets.
These theoretical projections of benefit are based on extrapolations from studies that involved patients with hypertension or hyperlipidemia, and also on an unvalidated assumption that the magnitude of antihypertensive effect of this combination therapy would be large. No data are available on the extent to which this therapy would reduce blood pressure and lipid levels in individuals for whom these parameters were within the normal range. Furthermore, these assumptions do not take into account long-term adherence to the treatment, or its tolerability. We have, therefore, set out to test Wald and Law's hypothesis comprehensively in a multicenter, randomized, controlled, double-blind trial -- The Indian Polycap Study (TIPS).
Despite compelling observational epidemiological data that showed a graded correlation between homocysteine levels and CVD risk,[8] randomized, controlled trials that evaluated the effect of using folic acid to lower homocysteine levels showed no improvement in treated patients' clinical outcomes.[9] We decided, therefore, not to include folic acid in our version of the Polypill. Similarly to Wald and Law, we have chosen to include half doses of three generic antihypertensives. The beta-blocker atenolol was chosen because it is suitable for once daily use, the diuretic hydrochlorothiazide was incorporated because it is cheap and effective at half dose, and the ACE inhibitor ramipril was included because good evidence exists that it improves patient's clinical outcomes. For the statin, we chose simvastatin at half dose because the target population of patients does not have raised LDL levels; consequently the TIPS investigators did not approve use of a full statin dose in this low-risk population. Simvastatin is cheap, as its patent protection has expired in most parts of the world, and its efficacy and safety has been demonstrated previously.[10] Aspirin was a natural choice for the antiplatelet component owing to its low price, widespread acceptance and ample evidence for benefit. We called our version of the Polypill the 'Polycap' (Quintapill®, Cadila Pharmaceuticals India Ltd., India), because the drugs are contained in a capsule.
The primary objective of TIPS is to determine whether the effects of the Polycap are noninferior to those of its equivalent components. Specifically, we aim to test whether the Polycap reduces blood pressure to the same extent as a combination that contains the same three antihypertensive drugs alone, reduces LDL levels to the same extent as simvastatin alone, and reduces platelet function (as measured by urine thromboxane excretion) similarly to aspirin alone. We also aim to test if the Polycap will be associated with a similar rate of adverse effects to those of its component drugs. The secondary objective of TIPS is to evaluate whether the Polycap is superior to formulations that contain fewer than three antihypertensive drugs. We therefore aim to determine if the Polycap is superior to a single antihypertensive drug (thiazide), or to two antihypertensive drugs (thiazide plus ramipril, thiazide plus atenolol, and ramipril plus atenolol). The formulations used in TIPS are shown in Box 1 ; the eight comparators and the Polycap are contained in capsules that are indistinguishable from each other.
As a first step, we chose to test the Polycap in a primary prevention setting to optimise applicability and ease of trial conduct. We envisage that disagreements over drug choices and dosages are more likely to occur in a secondary prevention setting than in a primary one, and expect that the results of this trial will suggest strategies for secondary prevention. We have specified a minimum age that is 10 years lower than that recommended by Wald and Law, as CVD manifests about a decade earlier in the Indian population.[11] The upper age limit of 80 years was specified to improve adherence to trial procedures and drug regimens without affecting the generalizability of the study's results. Further, we decided to include individuals with at least one cardiovascular risk factor to increase acceptability of the study medication among the participants, and because we believe that the Polycap is most likely to be used in such individuals. Participants enrolled in TIPS, therefore, are between 45 and 80 years of age and have at least one CVD risk factor, such as stable type 2 diabetes mellitus, hypertension, tobacco smoking within the last 5 years, a raised waist-to-hip ratio (>0.85 for women and >0.9 for men) or moderately elevated LDL cholesterol (>120 mg/dl). We excluded the following individuals: those who are on any study medication(s) that cannot be stopped, hypertensive (>160/100 mmHg) and hypotensive (<110/70>175 mg/dl), and individuals with abnormal renal function, known renal artery stenosis, or any other condition that has an indication or contraindication to any of the drugs used in the Polycap.
The outcome measures of TIPS are differences in relevant physiological parameters (i.e. change in diastolic blood pressure, serum LDL levels, heart rate and platelet function) between patients in the Polycap and key comparator groups, at the end of a 3-month follow-up period. A 3-month evaluation period was chosen because all the drugs should exert optimal changes in this period of time. This study design will provide an evaluation of short-term adherence to treatment as well as tolerability. Results of the follow-up of 2,050 subjects from 57 centers are expected to be available in April 2009.
TIPS is currently the largest trial to comprehensively test the Polypill hypothesis in a primary prevention setting. We believe that use of a robust study design will lead to several clear answers on the efficacy and safety of the full Polycap and various comparators that we designed and formulated. The results will enable the design of long-term trials to evaluate the influence of these formulations on clinical outcomes in primary and secondary prevention.
The Polycap and the Comparator Groups Used in the Indian Polycap Study
Polycap: atenolol, thiazide, ramipril, simvastatin and aspirin
Comparator A: aspirin
Comparator B: simvastatin
Comparator C: thiazide
Comparator D: thiazide and ramipril
Comparator E: thiazide and atenolol
Comparator F: ramipril and atenolol
Comparator G: thiazide, ramipril and atenolol
Comparator H: thiazide, ramipril, atenolol and aspirin
References
1. Antithrombotic Trialists Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324: 71-86.
2. Baigent C et al. (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366: 1267-1278.
3. Law MR et al. (2003) Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 326: 1423.
4. Law MR et al. (2003) Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 326: 1427.
5. Turnbull F (2003) Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 362: 1527-1535.
6. Yusuf S (2002) Two decades of progress in preventing vascular disease. Lancet 360: 2-3.
7. Wald NJ and Law MR (2003) A strategy to reduce cardiovascular disease by more than 80%. BMJ 28: 1419.
8. Eikelboom JW et al. (1999) Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 131: 363-375.
9. Lonn E et al. (2006) Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354: 1567-1577.
10. Collins R et al. (2003) MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361: 2005-2016.
10. Xavier D et al. (2008) Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data. Lancet 371: 1435-1442.
Funding Information
The Indian Polycap Study is sponsored by Cadila Pharmaceuticals India Ltd. The study is registered with www.clinicaltrials.org (NCT00443794) and the Clinical Trials Register of India (CTRI/2008/091/000015, dated: 10-03-2008).
Denis Xavier; Prem Pais; Alben Sigamani; Janice Pogue; Rizwan Afzal; Salim Yusuf; on behalf of The Indian Polycap Study (TIPS) Investigators
Nat Clin Pract Cardiovasc Med. 2009;6(2):96-97. ©2009 Nature Publishing Group
Posted 02/12/2009
Antihypertensive, lipid-lowering and antiplatelet drugs are proven to reduce cardiovascular disease (CVD) events when used in primary and secondary prevention.[1-5] Their use is suboptimal, however, owing to factors both at the level of individual patients (cost, multiple dosing and real or perceived adverse effects), and at the health-care-provider level (inadequate time and motivation to emphasize long term adherence). In 2002, Yusuf proposed that use of a four-drug combination consisting of aspirin, a beta-blocker, a statin and an angiotensin-converting-enzyme (ACE) inhibitor for secondary prevention would result in a 75% reduction in patients' cumulative risk of CVD events.[6] In an extensive analysis published in 2003, Wald and Law proposed a six-drug combination 'Polypill' that could potentially reduce ischemic heart disease events by 88% and stroke by 80%.[7] The combination contained three antihypertensive drugs at half doses (a thiazide, beta-blocker and ACE inhibitor), aspirin, a statin and folic acid. The authors recommended that this pill be taken by all individuals who had a CVD event and by anyone >55 years, without reference to their cardiovascular risk or monitoring treatment to attain specific targets.
These theoretical projections of benefit are based on extrapolations from studies that involved patients with hypertension or hyperlipidemia, and also on an unvalidated assumption that the magnitude of antihypertensive effect of this combination therapy would be large. No data are available on the extent to which this therapy would reduce blood pressure and lipid levels in individuals for whom these parameters were within the normal range. Furthermore, these assumptions do not take into account long-term adherence to the treatment, or its tolerability. We have, therefore, set out to test Wald and Law's hypothesis comprehensively in a multicenter, randomized, controlled, double-blind trial -- The Indian Polycap Study (TIPS).
Despite compelling observational epidemiological data that showed a graded correlation between homocysteine levels and CVD risk,[8] randomized, controlled trials that evaluated the effect of using folic acid to lower homocysteine levels showed no improvement in treated patients' clinical outcomes.[9] We decided, therefore, not to include folic acid in our version of the Polypill. Similarly to Wald and Law, we have chosen to include half doses of three generic antihypertensives. The beta-blocker atenolol was chosen because it is suitable for once daily use, the diuretic hydrochlorothiazide was incorporated because it is cheap and effective at half dose, and the ACE inhibitor ramipril was included because good evidence exists that it improves patient's clinical outcomes. For the statin, we chose simvastatin at half dose because the target population of patients does not have raised LDL levels; consequently the TIPS investigators did not approve use of a full statin dose in this low-risk population. Simvastatin is cheap, as its patent protection has expired in most parts of the world, and its efficacy and safety has been demonstrated previously.[10] Aspirin was a natural choice for the antiplatelet component owing to its low price, widespread acceptance and ample evidence for benefit. We called our version of the Polypill the 'Polycap' (Quintapill®, Cadila Pharmaceuticals India Ltd., India), because the drugs are contained in a capsule.
The primary objective of TIPS is to determine whether the effects of the Polycap are noninferior to those of its equivalent components. Specifically, we aim to test whether the Polycap reduces blood pressure to the same extent as a combination that contains the same three antihypertensive drugs alone, reduces LDL levels to the same extent as simvastatin alone, and reduces platelet function (as measured by urine thromboxane excretion) similarly to aspirin alone. We also aim to test if the Polycap will be associated with a similar rate of adverse effects to those of its component drugs. The secondary objective of TIPS is to evaluate whether the Polycap is superior to formulations that contain fewer than three antihypertensive drugs. We therefore aim to determine if the Polycap is superior to a single antihypertensive drug (thiazide), or to two antihypertensive drugs (thiazide plus ramipril, thiazide plus atenolol, and ramipril plus atenolol). The formulations used in TIPS are shown in Box 1 ; the eight comparators and the Polycap are contained in capsules that are indistinguishable from each other.
As a first step, we chose to test the Polycap in a primary prevention setting to optimise applicability and ease of trial conduct. We envisage that disagreements over drug choices and dosages are more likely to occur in a secondary prevention setting than in a primary one, and expect that the results of this trial will suggest strategies for secondary prevention. We have specified a minimum age that is 10 years lower than that recommended by Wald and Law, as CVD manifests about a decade earlier in the Indian population.[11] The upper age limit of 80 years was specified to improve adherence to trial procedures and drug regimens without affecting the generalizability of the study's results. Further, we decided to include individuals with at least one cardiovascular risk factor to increase acceptability of the study medication among the participants, and because we believe that the Polycap is most likely to be used in such individuals. Participants enrolled in TIPS, therefore, are between 45 and 80 years of age and have at least one CVD risk factor, such as stable type 2 diabetes mellitus, hypertension, tobacco smoking within the last 5 years, a raised waist-to-hip ratio (>0.85 for women and >0.9 for men) or moderately elevated LDL cholesterol (>120 mg/dl). We excluded the following individuals: those who are on any study medication(s) that cannot be stopped, hypertensive (>160/100 mmHg) and hypotensive (<110/70>175 mg/dl), and individuals with abnormal renal function, known renal artery stenosis, or any other condition that has an indication or contraindication to any of the drugs used in the Polycap.
The outcome measures of TIPS are differences in relevant physiological parameters (i.e. change in diastolic blood pressure, serum LDL levels, heart rate and platelet function) between patients in the Polycap and key comparator groups, at the end of a 3-month follow-up period. A 3-month evaluation period was chosen because all the drugs should exert optimal changes in this period of time. This study design will provide an evaluation of short-term adherence to treatment as well as tolerability. Results of the follow-up of 2,050 subjects from 57 centers are expected to be available in April 2009.
TIPS is currently the largest trial to comprehensively test the Polypill hypothesis in a primary prevention setting. We believe that use of a robust study design will lead to several clear answers on the efficacy and safety of the full Polycap and various comparators that we designed and formulated. The results will enable the design of long-term trials to evaluate the influence of these formulations on clinical outcomes in primary and secondary prevention.
The Polycap and the Comparator Groups Used in the Indian Polycap Study
Polycap: atenolol, thiazide, ramipril, simvastatin and aspirin
Comparator A: aspirin
Comparator B: simvastatin
Comparator C: thiazide
Comparator D: thiazide and ramipril
Comparator E: thiazide and atenolol
Comparator F: ramipril and atenolol
Comparator G: thiazide, ramipril and atenolol
Comparator H: thiazide, ramipril, atenolol and aspirin
References
1. Antithrombotic Trialists Collaboration (2002) Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 324: 71-86.
2. Baigent C et al. (2005) Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet 366: 1267-1278.
3. Law MR et al. (2003) Quantifying effect of statins on low density lipoprotein cholesterol, ischaemic heart disease, and stroke: systematic review and meta-analysis. BMJ 326: 1423.
4. Law MR et al. (2003) Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 326: 1427.
5. Turnbull F (2003) Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 362: 1527-1535.
6. Yusuf S (2002) Two decades of progress in preventing vascular disease. Lancet 360: 2-3.
7. Wald NJ and Law MR (2003) A strategy to reduce cardiovascular disease by more than 80%. BMJ 28: 1419.
8. Eikelboom JW et al. (1999) Homocyst(e)ine and cardiovascular disease: a critical review of the epidemiologic evidence. Ann Intern Med 131: 363-375.
9. Lonn E et al. (2006) Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med 354: 1567-1577.
10. Collins R et al. (2003) MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 361: 2005-2016.
10. Xavier D et al. (2008) Treatment and outcomes of acute coronary syndromes in India (CREATE): a prospective analysis of registry data. Lancet 371: 1435-1442.
Funding Information
The Indian Polycap Study is sponsored by Cadila Pharmaceuticals India Ltd. The study is registered with www.clinicaltrials.org (NCT00443794) and the Clinical Trials Register of India (CTRI/2008/091/000015, dated: 10-03-2008).
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