Q & A

    1. For whom should I prescribe Polycap?

    Primary prevention of cardiovascular events and stroke in persons with one or more of these risk factors  like hypertension, dyslipidemia, diabetes, central obesity, smoker, family History of IHD.

    2. What is the rationale for Polycap prescription?

    Fixed-dose combinations of two or more drugs are available for the therapy of a number of diseases, including cardiovascular diseases. These combinations are convenient to take and lead to better compliance. Polycap is a fixed-dose combination of atenolol, ramipril, hydrochlorothiazide, simvastatin and aspirin.

    3. What is the rationale for the Polycap and Polycap 4?

    The POLYCAPTM is fixed-dose combination of three blood-pressure-lowering drugs, atenolol 50 mg, ramipril 5 mg, hydrochlorothiazide 12.5 mg, along with a lipid lowering drug, simvastatin 20mg, and an anti-platelet agent, aspirin 100mg.

     

    It was previously hypothesized that a ‘Polypill’1 consisting of lower doses of 3 blood pressure (BP) lowering agents, with a statin and aspirin will be able to reduce cardiovascular (CV) events when given to individuals over the age of 50, irrespective of risk factor levels 1-3. Aspirin4, beta-blockers5, angiotensin converting enzyme inhibitors6 (ACE-I) and statins7 have been shown to reduce cardiovascular disease (CVD).  

    Based on the above hypothesis a fixed-dose combination, i.e. POLYCAP, was formulated consisting of atenolol 50 mg, ramipril 5 mg, hydrochlorothiazide 12.5 mg, with simvastatin 20mg and aspirin 100mg.
    The effect of POLYCAP on blood pressure, lipids, heart rate, and urinary thromboxane B2 levels and its tolerability was assessed in a randomized, double-blind, active-comparator controlled clinical trial conducted in 56 centres in India, The Indian POLYCAP Study (TIPS)9. 2053 individuals without cardiovascular disease, aged 45–80 years, and with one risk factor were selected and randomly assigned, by a central secure website, to the POLYCAP (n=412), or to eight other groups, each with about 200 individuals, of aspirin alone, simvastatin alone, hydrochlorothiazide alone, three combinations of the two blood-pressure-lowering drugs, three blood-pressure-lowering drugs alone, or three blood-pressure-lowering drugs plus aspirin. The primary outcomes were changes in LDL for the effect of lipids, blood pressure for antihypertensive drugs, heart rate for the effects of atenolol, urinary 11-dehydrothromboxane B2 for the anti-platelet effects of aspirin, and rates of discontinuation of drugs for safety.

    Compared with groups not receiving blood-pressure-lowering drugs, the POLYCAP reduced systolic blood pressure by 7·4 mm Hg (95% CI 6·1–8·1) and diastolic blood pressure by 5·6 mm Hg (4·7–6·4), which was similar when three blood-pressure-lowering drugs were used, with or without aspirin. POLYCAP reduced LDL cholesterol by 0·70 mmol/L (95% CI 0·62–0·78), which was less than that with simvastatin alone (0·83 mmol/L, 0·72–0·93; p=0·04); both reductions were greater than for groups without simvastatin (p<0·0001). The reductions in heart rate with POLYCAP and other groups using atenolol were similar (7·0 beats per min), and both were significantly greater than that in groups without atenolol (p<0·0001). The reductions in 11-dehydrothromboxane B2 were similar with the POLYCAPTM (283·1 ng/mmol creatinine, 95% CI 229·1–337·0) and aspirin alone (348·8 ng/mmol creatinine, 277·6–419·9). Tolerability of the POLYCAP was similar to that of other treatments, with no evidence of increasing intolerability with increasing number of active components in one pill.
    In conclusion, regular use of POLYCAP can reduce the risk of coronary heart disease by 62% and of stroke by 48%.

    Majority of adverse events observed in the trial were mild to moderate. Commonly observed adverse events irrespective of causal relationship with POLYCAP included dyspepsia and related disorders (10%), cough (15%), vertigo/dizziness (13%), musculoskeletal complaints (8%), fatigue/weakness (10%).

    Other adverse events seen with POLYCAP were abdominal discomfort/pain, allergic reactions, headache, chest pain, diarrhea, URTI, fever and related symptoms, nausea and vomiting and anxiety disorder. The rates of discontinuing medications were similar across study arms. Elevated creatinine (an increase by >50%) was seen in 7.8%, elevated K+ (>5.5 mmol/l) was seen in 3.9%, or elevated liver enzymes (doubling of SGPT) was seen in 2.9% and were not significantly different between study arms.

    Results from this large trial thus support the earlier proposed hypothesis that a combination of all these drugs will decrease the risk of cardiovascular disease.

    POLYCAPTM is indicated for decreasing the cardiovascular risk in people with or without the presence of cardiovascular disease.

     

    References

    1. Wald NJ, Law MR. A strategy to reduce cardiovascular disease by more than 80%. BMJ. 2003; 326(7404):1419.
    2. 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. BMJ. 2003; 326(7404):1423.
    3. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials.

      BMJ. 2003; 326(7404):1427.

    4. Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002; 324(7329):71-86.
    5. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985 Mar-Apr;27(5):335-71.
    6. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000 Jan 20;342(3):145-53.
    7. Baigent C, Keech A, Kearney PM, Blackwell L, Buck G, Pollicino C, Kirby A, Sourjina T, Peto R, Collins R, Simes R; Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90,056 participants in 14 randomised trials of statins. Lancet. 2005 Oct 8;366(9493):1267-78.
    8. Lonn E, Yusuf S, Arnold MJ, Sheridan P, Pogue J, Micks M, McQueen MJ, Probstfield J, Fodor G, Held C, Genest J Jr; Heart Outcomes Prevention Evaluation (HOPE) 2 Investigators. Homocysteine lowering with folic acid and B vitamins in vascular disease. N Engl J Med. 2006; 354(15):1567-77.
    9. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease: The Indian Polycap Study (TIPS). Lancet. 2009 Mar 30. [Epub ahead of print] PMID: 19339045

    POLYCAP 4

    POLYCAP 4 contains three blood pressure lowering drugs, i.e. atenolol 50mg, ramipril 5mg, hydrochlorothiazide 12.5mg and one lipid-lowering drug, simvastatin 20mg. This product reduces blood pressure and lipid levels, two of the major risk factors for cardiovascular disease.
     
    Rationale:
    Fixed-dose combinations of two or more drugs are available for the therapy of a number of diseases, including cardiovascular diseases. These combinations are convenient to take and lead to better compliance. POLYCAP 4 is a fixed-dose combination of atenolol, ramipril, hydrochlorothiazide and simvastatin.

    Atenolol, ramipril and hydrochlorothiazide are widely used anti-hypertensive drugs. Atenolol lowers blood pressure by major action on the heart; ramipril lowers the blood pressure by major action on the blood vessels; and hydrochlorothiazide is a diuretic which reduces blood pressure by its action on the kidneys. Thus these drugs decrease blood pressure by three different mechanisms and are often co-prescribed. ACE inhibitors alone normalize blood pressure in approximately 50% of patients with mild to moderate hypertension. Ninety percent of patients with mild to moderate hypertension will be controlled by the combination of an ACE inhibitor and either a  adrenergic receptor blocker, or a diuretic.1 Diuretics in particular augment the antihypertensive response to ACE inhibitors by rendering the patient's blood pressure renin-dependent. Also combination products of atenolol and ramipril with diuretics like chlorthalidone and hydrochlorothiazide are already available in the market.

    Efficacy and safety of the atenolol-ramipril-hydrochlorothiazide combination was studied in 204 subjects in The Indian Polycap Study (TIPS).2 The blood pressure reduction observed with this combination was similar to that with Polycap (mean reduction 6.9/5.0 mm Hg with atenolol-ramipril-hydrochlorothiazide combination vs 7.4/5.6 mm Hg with Polycap). Further the reduction in blood pressure seen with three anti-hypertensive drugs was greater than with 2 drug combinations, which reduced the blood pressure by 4.7 mm Hg (95% confidence interval 3.5-5.9) systolic and 3.6 mmHg (95% confidence interval 2.8-4.4) and with thiazide alone, which lowered the BP by 2.2 mm Hg (95% confidence interval 0.6-3.8) systolic and 1.3 mmHg (95% confidence interval 0.2-2.3).  This combination was well tolerated with rate of adverse events not different from other arms of the trial.

    Simvastatin belongs to the family of hypolipidemic drugs, statins, and is used for lowering the levels of LDL cholesterol in patient with dyslipidemia. In the simvastatin arm (n=193) of the TIPS trial2, a significant reduction in LDL cholesterol (0.83 mmol/L [95% CI 0.72-0.93, 27.7%]) and total cholesterol (0.83 mmol/L [95% CI 0.75-0.92, p<0.0001]) was observed compared to the non-simvastatin arms. Decrease in LDL levels by 0.80 mmol/L as observed in the TIPS study has been postulated to decrease the risk of coronary heart disease by 27% and of stroke by 8%.

    Since elevated blood pressure and dyslipidemia are independent risk factors for cardiovascular diseases, lowering of blood pressure and LDL levels with POLYCAP 4 will be helpful in reducing such risk.

    POLYCAP 4 is indicated for decreasing the cardiovascular risk in people with or without the presence of cardiovascular disease and who have intolerance to aspirin or who are using aspirin for some other indication.

    References

    1. Zusman, R.M. Angiotensin-converting enzyme inhibitors: More different than alike? Focus on cardiac performance. Am. J. Cardiol 1993;72:25H-36H.
    2. Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease: The Indian Polycap Study (TIPS). Lancet. 2009 Mar 30. [Epub ahead of print] PMID: 19339045.
    3. What are the reasons for selection of these particular drugs in the Polycap?
    4. Atenolol
      Atenolol as it is off patent. Metoprolol needs twice daily dosing and not suitable for inclusion in the polycap. Metoprolol Sustained Release is still under patent
      Hydrochlorothiazide
      This is one of the most proven, off patent, widely accepted diuretic.
      Ramipril
      This ACE Inhibitor has the best evidence among its class which is also off patent.
      Simvastatin
      This is one of the better accepted and off patent statin.
      Aspirin
      As it is cost effective, widely accepted antiplatelet drug which is also off patent drug.

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