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

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 (NCT00443794) and the Clinical Trials Register of India (CTRI/2008/091/000015, dated: 10-03-2008).

1 comment:

  1. October 18, 2007悉怛多缽怛囉阿門




    *** <
      讀書使人充實,討論使人機智,筆記使人準確。因此不常作筆記者須記憶特強,不常討論者須天生聰穎,不常讀書者須欺世有術,始能無知而顯有知。讀史使人明智,讀詩使人靈秀,數學使人周密,科學使人深刻,倫理學使人莊重,邏輯修辭之學使人善辯:凡有所學,皆成性格。人之才智但有滯礙,無不可讀適當之書使之順暢,一如身體百病,皆可借相宜之運動除之。滾球利睾腎,射箭利胸肺,慢步利腸胃,騎術利頭腦,諸如此類。如智力不集中,可令讀數學,蓋演題須全神貫注,稍有分散即須重演;如不能辨異,可令讀經院哲學,蓋是輩皆吹毛求疵之人;如不善求同,不善以一物闡證另一物,可令讀律師之案卷。如此頭腦中凡有缺陷,皆有特藥可醫。 >

    Of Study

      STUDIES serve for delight, for ornament, and for ability. Their chief use for delight, is in privateness and retiring; for ornament, is in discourse; and for ability, is in the judgment, and disposition of business. For expert men can exe-cute, and perhaps judge of particulars, one by one; but the general counsels, and the plots and marshalling of affairs, come best, from those that are learned. To spend too much time in studies is sloth; to use them too much for ornament, is affectation; to make judgment wholly by their rules, is the humor of a scholar. They perfect nature, and are perfected by experience: for natural abilities are like natural plants, that need proyning, by study; and studies themselves, do give forth directions too much at large, except they be bounded in by experience. Crafty men contemn studies, simple men admire them, and wise men use them; for they teach not their own use; but that is a wisdom without them, and above them, won by observation. Read not to contradict and confute; nor to believe and take for granted; nor to find talk and discourse; but to weigh and consider. Some books are to be tasted, others to be swallowed, and some few to be chewed and digested; that is, some books are to be read only in parts; others to be read, but not curiously; and some few to be read wholly, and with diligence and attention. Some books also may be read by deputy, and extracts made of them bothers; but that would be only in the less important arguments, and the meaner sort of books, else distilled books are like common distilled waters, flashy things.

      Reading make a full man; conference a ready man; and writing an exact man. And therefore, if a man write little, he had need have a great memory; if he confer little, he had need have a present wit: and if he read little, he had need have much cunning, to seem to know, that he doth not. Histories make men wise; poets witty; the mathematics subtitle; natural philosophy deep; moral grave; logic and rhetoric able to contend. Abeunt studia in mores. Nay, there is no stand or impediment in the wit, but may be wrought out by fit studies; like as diseases of the body, may have appropriate exercises. Bowling is good for the stone and reins; shooting for the lungs and breast; gentle walking for the stomach; riding for the head; and the like. So if a man\'s wit be wandering, let him study the mathematics; for in demonstrations, if his wit be called away never so little, he must begin again. If his wit be not apt to distinguish or find differences, let him study the Schoolmen; for they are cymini sectors. If he be not apt to beat over matters, and to call up one thing to prove and illustrate another, let him study the lawyers\' cases. So every defect of the mind, may have a special receipt.
    參考資料 < cite > < /cite >

    我不想 說 誇大不實ㄉ話
    不妄語 綺語 兩舌 要平等恭敬

    仍戒殺放生 吃素吃蔬食 斷惡修善 [喝酒就會是下地獄ㄉ因]


    悉怛多缽怛囉 不結婚 不讓人貪愛 可以環球367天

    要 和睦相處 '平等對待

    莫殺生 防輕生 要自愛 須放生


    UFO:帶我投胎到 有佛法和功名ㄉ星球去

    把 好ㄉ文明 也攜帶過去!hWtdGeaEER3NLCUj6UChUlk-/article?mid=568!hWtdGeaEER3NLCUj6UChUlk-/article?mid=568
    香巴拉 香格里拉






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    * qubqub32 於 June 4, 2008 03:31 PM 回應 | 來源: | | 刪除 | 設為隱藏


    香格里拉 香巴拉 在雪山

    法輪功不屬於佛教 此功是 來滲透佛教亂佛教ㄉ
    # 版主 於 June 7, 200
    (不要墮落到 三途:貪水災餓鬼道、 瞋火災地獄道、 癡風災畜牲道 )
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    讀書人怎樣論讀書呢? 我們不妨從西方名人對書所作的各種比喻中細心體
    會一下, 也許能幫助我們讀書有嶄新的認識。


    首先, 我們思想一下到底甚麼叫 "讀書" , 讀書的目的是為了甚麼?

    亞里斯多德說: 人類需要三方面的知識-----理論﹑實用及鑒別的能力。

    赫塞說: 學問就是分辦事物異同的能力。

    魯巴金說: 讀書是在別人思想的幫助下, 建立起自己的思想。

    培根說: 讀書不是為了雄辯和駁斥, 也不是為了輕信和盲從, 而是為了思

    愛因斯坦說: 讀書是要找出可以使自己昇華的東西。

    羅曼. 羅蘭說: 從來沒有戈讀書, 只有人在書中省察自己﹑發現自己和檢


    讀書, 既耗時又費神, 何樂之有?

    笛卡兒說: 讀一切的好書, 就是和許多高尚的人談話。

    伊薩克. 巴羅說: 一個愛書的人, 他必不缺少忠實的朋友﹑良好的導師﹑

    羅素說: 知識是使人類快樂的主要因素。

    蘇格拉底說: 讀書是輕易把別人辛苦得來的經驗吸收進來。

    培根說: 史鑒使人明智, 詩歌使人巧慧, 數學使人精細, 博物使人深沉,
    倫理使人莊重, 邏輯與修辭使人善辯。


    那麼, 應該怎樣讀書才能獲益呢?

    史邁爾說: 學間之事, 功夫要精密, 解悟要透徹。蓋學問之益不在讀書之
    多, 而在運用之熟。

    伏爾泰說: 讀書多而不加思考, 就自以為知道得很多; 思考愈多時, 就發

    狄斯雷利說: 多觀察, 多經驗, 多研究, 是學習中的三大棟樑。

    貝靳斯說: 吊兒郎當的學習者並不勝於學習吊兒郎當的人。

    最後, 還是佚名者說得最直接了當: 書, 對懶惰皂人是一堆廢紙, 對虛浮
    的人是裝璜擺設, 只有對勤學的人才是無價寶貝。


    作者: 王
    * zycxxcz1234 於 October 18, 2007 08:20 AM 回應 | 檢舉

    December 30, 2007
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