Polycap

2009-06-01T22:45:00.000-07:00

" If your lifestyle doesn’t permit you even a short nap,
If instead of six packs, your tummy looks like a sac,
If you enjoy smoking cigarettes without any gap,
If your friend love to smoke lying in your lap,
Then my dear friend, it’s time to wear a thinking cap,
In short, it’s time to start now with Polycap "

CBS HEALTHWATCH

2009-05-17T21:48:00.000-07:00

CBS Healthwatch on Polycap with Dr. Suzanne steinbaum, Cardiologist, Lenox Hill Hospital

INDIA TODAY, MAY 4, 2009

2009-04-28T01:12:00.000-07:00

THE LANCET - Editorial

2009-04-24T21:45:00.000-07:00

Can the polypill save the world from heart disease?
The concept is simple. Several diff erent drugs are available (generically and thus inexpensively) to treat many of the cardiac risk factors. So, combining them in one pill could reduce heart disease by 80%. This approach has obvious appeal, and vast implications for global health, because heart disease is the leading cause of death worldwide. The Indian Polycap Study (TIPS), reported in The Lancet today,1 moves us one step closer to realising this dream.

TIPS is a large phase II randomised trial that assessed the effects of nine different pills containing either single agents or combinations of two, three, four, or five (the polypill) drugs, to measure their eff ect on risk factors such as blood pressure and cholesterol concentrations, as well as the feasibility and tolerability of administering a single pill to a relatively unselected group of patients. The study was not a large outcomes trial to show that the polypill reduced mortality. The of patients studied is one that has been increasing rapidly in numbers in the past decade with the increase in obesity across the world—middle-aged (45–80 years) men and women without previous cardiac disease, but with at least one cardiovascular risk factor: high blood pressure, obesity (measured by the hip to waist ratio), high cholesterol, diabetes, or smoking). Patients were recruited from 50 centres in India, a fi tting reminder of the globalisation of both the burden of heart disease and of clinical trials aimed at reducing such burden.

The results from TIPS show that each of the components of the polypill did what was intended: the statin reduced cholesterol, the three antihypertensives reduced blood pressure—and the more of them, the greater the reduction—and aspirin reduced the clotting ability of the blood. They found one unexpected issue with the Polycap: the degree of cholesterol lowering was slightly less with the Polycap than in patients who got simvastatin alone. This effect seems to be related to the rate of conversion of simvastatin in the Polycap. This finding highlights the importance of a phase II study such as TIPS to identify any such issues with the polypill, before testing in a large outcomes trial. Also, in view of the safety and tolerability in large trials of simvastatin 40 mg,2 the next generation polypill might shift to that higher dose (or to a moderate dose of a more potent statin which should become available generically in a few years).

A key and very promising fi nding from TIPS was the tolerability of the Polycap. Although the rates of discontinuation were higher than one might have anticipated in a 12-week study (about 15%), much of it was apparently due to social reasons and patients refusing treatment. There was, however, not a significantly higher rate overall of discontinuation with the Polycap compared with the other combinations. Some regimens seemed to be a little better tolerated, and those with triple antihypertensives had a slightly higher rate of hypotension (as would be expected). On the other hand, some components of the polypill might help counteract side-eff ects of others (eg, potassium concentrations for the angiotensin-converting-enzyme inhibitor and the diuretic). Fortunately the absolute rate of drug-specific discontinuations was low, which means that the overall feasibility and tolerability of the polypill approach does seem to work. Interestingly, if we recall that the patients had to have only one risk factor to participate in the trial (eg, hypertension, diabetes, smoking), all patients had all risk factors treated. So a smoker without a history of high blood pressure or high cholesterol was nonetheless treated for both, and was able to tolerate the treatment. This approach illustrates the feasibility of the principle that one can treat patients with multiple classes of drugs for cardiovascular risk factors, even if the patients do not have some of these risk factors.

What are the challenges? First, we need a large phase III trial with longer follow-up to assess the true feasibility of this strategy. How can the use of a polypill be implemented in a broad population? What is the full safety profi le (there were 3–8% of patients who had increases in creatinine and potassium and in liver function tests; what adjustments need to be made to those
patients?). Do they stop the polypill if one component causes a side-effect? How does the doctor decide which component caused the side-effect? Second, we would also like to have a large outcomes trial, to document a reduction in death, myocardial infarction, and stroke with the polypill approach compared with current practice. Third, there is the issue of dose, which is a fascinating difference from current practice. The Polycap had just one dose (generally a moderate dose) of each agent. Currently for combination pills, regulatory authorities require that the pill be available in every dose combination of each drug, so the combination pill would not limit treatment. However, this approach would obviously not be feasible with a pill with five or
six components and each having two to four doses (which would lead to more than a hundred strengths of the polypill). Thus what is designed to be a simple pill would turn into a complicated prescribing morass. It might be feasible to consider having two or three broad strengths with some different doses of some components (eg, the antihypertensives) or there could be versions with only some components of the polypill that would, for example, have fewer antihypertensive
drugs. That approach might help when treating a patient with only single risk factors (eg, a smoker without high blood pressure). Should such a patient be put on three antihypertensives, and thus have the risk of angio-oedema, glucose intolerance, or bradycardia? A final challenge: would the availability of a single magic bullet for the prevention of heart disease lead people to abandon exercise and appropriate diet? Would this make two of the major root causes of heart disease worse? Hopefully not, but the medical profession would need to help ensure that this would not happen.

Where would this polypill fi t into current medical practice? The major appeal is its simplicity and (presumed) low cost, which could improve compliance.3 Such appeal could have broad applicability in areas of the world with less access to medical treatment, where just one or two interactions with medical professionals could be the start of treatment that could lead to long term cardiovascular prevention. But the polypill could also fit well into more modern medical systems, in which large proportions of patients with risk factors are untreated.4 If all these patients knew they could simply take their polypill, they might be more receptive to it—and as such vastly broaden the number of patients who might benefi t from drugs that had been proven in multiple trials to reduce cardiovascular disease and mortality. Although TIPS does not provide all the answers, the study does take a fi rst and crucial step forward and raises hope that, in conjunction with other global efforts to improve diet and exercise, the polypill could one day substantially reduce the burden of cardiovascular disease in the world.

Christopher P Cannon
Cardiovascular Division, Brigham and Women’s Hospital, Boston,
MA, USA; and Harvard Medical School, TIMI Study Offi ce,
Boston, MA 02115, USA
cpcannon@partners.org
I am a senior investigator on the TIMI Study Group. I receive research support from Accumetrics, AstraZeneca, Bristol-Myers Squibb/Sanofi Partnership, GlaxoSmithKline, Merck, and Merck/Schering Plough Partnership. I serve as a clinical adviser and hold equity in Automedics Medical Systems.
1 The Indian Polycap Study (TIPS). Eff ects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial. Lancet 2009; published online March 30. DOI:10.1016/S0140-6736(09)60611-5.
2 Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20 536 high-risk individuals: a randomised placebo controlled trial. Lancet 2002; 360: 7–22.
3 Lee JK, Grace KA, Taylor AJ. Eff ect of a pharmacy care program on medication adherence and persistence, blood pressure, and low-density lipoprotein cholesterol: a randomized controlled trial. JAMA 2006; 296: 2563–71.
4 Kotseva K, Wood D, De Backer G, De Bacquer D, Pyorala K, Keil U, for the EUROASPIRE Study Group. Cardiovascular prevention guidelines in daily practice: a comparison of EUROASPIRE I, II, and III surveys in eight European countries. Lancet 2009; 373: 929–40.

Published Online March 30, 2009 DOI:10.1016/S0140- 6736(09)60652-8 See Online/Articles
DOI:10.1016/S0140-6736(09)60611-5

EXPRESS PHARMA, April 16-30, 2009

2009-04-24T02:10:00.000-07:00

For Happy Heart

2009-04-16T23:16:00.000-07:00

Everytime you smoke a cigarette you give poison to your heart. Be serious if you are falling under any of these catagories-

1. Cigarette smoking

2. Being overweight by 30 percent

3. Hypertension -- high blood pressure

4. High cholesterol levels (specifically, high LDL cholesterol and low HDL cholesterol and high triglycerides)

5. Stressful lifestyle

6. Sedentary lifestyle [ Walk, Run & Play outdoor sports & see the change !!]

10 Health Tips for you !!

2009-04-16T22:39:00.000-07:00

1. Drink plenty of water.

2. Eat breakfast like a king, lunch like a prince and dinner like a beggar.

3. Eat more foods that grow on trees and plants and eat less food that is manufactured in plants.

4. Live with the 3 E's -- Energy, Enthusiasm, and Empathy.

5. Make time to practice meditation, yoga, and prayer.

6. Play more games.

7. Read more books than you did in earlier.

8. Sit in silence for at least 10 minutes each day.

9. Sleep for 6 hours at least.

10. Take a 10-30 minutes walk every day. And while you walk, smile.

Doctor's Take on Polycap

2009-04-15T23:13:00.000-07:00

"The thought that people might be able to take a single pill to reduce multiple cardiovascular risk factors has generated a lot of excitement, it would certainly revolutionize heart disease prevention as we know it," says McMaster cardiologist Dr. Salim Yusuf, a lead author.

"Number one, it will reduce the cost of the pills. And it will improve compliance. We know that more people are apt to take one pill compared to five or six pills," Dr. Ruth McPherson, the director of the Lipid Clinic and Lipid Research Laboratory at the University of Ottawa Heart Institute.

"President Obama is trying to offer the greatest care to the greatest number. This very much fits in with that." "Widely applied, this could have profound implications," said Dr. Robert Harrington, an American College of Cardiology spokesman and chief of Duke University's heart research institute.

The polypill also has big psychological advantages, said Dr. James Stein of the University of Wisconsin-Madison.

"That was a big surprise. I would have expected five times the number of people to have side effects," because of the possibility the drugs would interact and magnify any problems, said Dr. Christopher Cannon, a cardiologist at Harvard-affiliated Brigham and Women's Hospital in Boston who had no role in the study.

A spokeswoman for the British Heart Foundation said: "The results suggest that the polypill has the potential to reduce the incidence of cardiovascular disease.”

Joanne Murphy of The Stroke Association said: "By combining these medications in one pill, it will make it easier for people to take their medication. However, it is important that more research and investigation is done into this pill to ensure its safety."

ABC News on Polycap

2009-04-15T20:33:00.000-07:00

Newspapers are singing Polycap song !!

2009-04-10T21:20:00.000-07:00

Polycap

2009-04-09T23:19:00.000-07:00

Dr. Arun Maseeh, VP Medical Services is showing Polycap !!

Q&A The Polypill (Source:BBC News)

2009-04-09T00:00:00.000-07:00

Q&A: The Polypill
Experts are hailing a pill that combines five drugs into one tablet as the magic bullet to heart-related problems.

What is the Polypill?
The polypill contains five drugs that experts believe can halve the risk of strokes and heart attacks in middle-aged people.
It contains aspirin to thin the blood, a statin drug to lower cholesterol levels and three blood pressure-lowering medications - an ACE inhibitor, a beta-blocker and a diuretic.
It also includes folic acid to reduce the level of homocysteine in the blood which is another risk factor for heart disease.
Combining all of the drugs into one easy to take tablet should improve compliance.

What is the big idea?
Doctors want to use the polypill against the worldwide epidemic of cardiovascular disease.
Currently, doctors treat high risk patients but many who would benefit from treatment do not receive it.
The polypill idea is for mass prescription to everyone over a certain age - 50 for men and 60 for women - not just those with pre-existing cardiovascular disease.
By doing this, tens of millions of lives could be saved worldwide, experts believe.
Yet a decade since its first inception, a marketable product is still at least five years away.

Why is it taking so long?
The polypill does not promise big profits for pharmaceutical companies.
Although the tablet would be taken on a daily basis by millions of people, the five constituent medicines are cheap and are already available separately. These are non-patented drugs.

What has the latest study shown?
It is a proof of concept study that shows the constituent drugs can be safety combined and work in the way intended, lowering blood pressure and cholesterol levels.
Reassuringly, few patients had side effects and the pill was well tolerated.
More work is now underway to see if the pill cuts deaths and disease by as much as experts hope.

What do critics say?
Critics are concerned that people will see the polypill as an excuse not to address lifestyle issues, such as poor diet and lack of exercise, linked with cardiovascular disease.
And one size fits all may not work.
Each of the constituent drugs has side effects. By combining them you do not get rid of those risks.
By and large, the benefits far outweigh any risks, but Professor Peter Weissman of the British Heart Foundation said: "If money was no issue I would want to know exactly what my cardiovascular risk is and I would want my doctor to treat each of those risk factors optimally rather than the fire and forget approach that the polypill will produce."

http://news.bbc.co.uk/1/hi/health/7973588.stm

abcnews

2009-04-08T23:53:00.000-07:00

Once-a-Day Heart Combo Pill Shows Promise in Study
Once-a-day combo pill of 5 heart medicines shows promise as cheap prevention, doctors say
By MARILYNN MARCHIONE AP Medical WriterORLANDO, Fla. March 30, 2009 (AP)
It's been a dream for a decade: a single daily pill combining aspirin, cholesterol medicine and blood pressure drugs — everything people need to prevent heart attacks and strokes in a cheap, generic form. Skeptics said five medicines rolled into a single pill would mean five times more side effects. Some people would get drugs they don't need, while others would get too little. One-size-fits-all would turn out to fit very few, they warned. Now the first big test of the "polypill" has proved them wrong.
The experimental combo pill was as effective as nearly all of its components taken alone, with no greater side effects, a major study found. Taking it could cut a person's risk of heart disease and stroke roughly in half, the study concludes.
The approach needs far more testing — as well as approval from the Food and Drug Administration, something that could take years — but it could make heart disease prevention much more common and more effective, doctors say.
"Widely applied, this could have profound implications," said Dr. Robert Harrington, an American College of Cardiology spokesman and chief of Duke University's heart research institute. "President Obama is trying to offer the greatest care to the greatest number. This very much fits in with that."
The polypill also has big psychological advantages, said Dr. James Stein of the University of Wisconsin-Madison.
"If you take any medicines, you know that every pill you see in your hand makes you feel five years older. Patients really object to pill burden" and respond by skipping doses, he said.
No price for the polypill has been disclosed, but its generic components cost only a total of $17 a month now and doctors expect the combo would sell for far less.
The study was led by Dr. Salim Yusuf of McMaster University in Hamilton, Ontario, and Dr. Prem Pais of St. John's Medical College in Bangalore, India. The findings were presented Monday at the cardiology college's conference in Florida and published online by the British medical journal Lancet.
The study tested the Polycap, an experimental combo formulated by Cadila Pharmaceuticals of Ahmedabad, India. It contains low doses of three blood pressure medicines (atenolol, ramipril and the "water pill" thiazide), plus the generic version of the cholesterol-lowering statin drug Zocor, and a baby aspirin (100 milligrams).
Doctors have talked about such a possibility for years. As the patents on many heart medicines expired and the drugs became available as cheap generics, a few companies started trying to develop all-in-one pills.
Formulating a single pill of five drugs that work in five different ways is a complex task — more complex than simply mixing the medicines. Pills have coatings and other ingredients that control the rate at which the medicine is released into the bloodstream. The polypill must be designed so that the five drugs work as intended.
The Polycap is the furthest along, and this is the largest study of one so far.
The study involved about 2,000 people at 50 centers across India, average age 54, with at least one risk factor for heart disease — high blood pressure, high cholesterol, obesity, diabetes or smoking.
Four hundred were given the polypill. The rest were placed in eight groups of 200 and given individual components of the pill or various combinations. Treatment lasted 12 weeks.
Compared to groups given no blood pressure medicines, those who got the polypill lowered their systolic blood pressure (the top number) by more than 7 units and their diastolic (the bottom number) by about 6 — comparable to levels for people who were given the three drugs without aspirin and the cholesterol drug.
These drops were modest, probably because doses were low and most participants had only moderately high blood pressure to start with, Yusuf said.
LDL, or bad cholesterol, dropped 23 percent on the polypill versus 28 percent in those taking the statin drug separately. Triglycerides dropped 10 percent on the combo pill versus 20 percent with individual statin use. Neither pill affected levels of HDL, or good cholesterol.
Anti-clotting effects seemed the same with the polypill as with aspirin alone.
Side effect rates were the same for the polypill as for the five medicines individually.
"That was a big surprise. I would have expected five times the number of people to have side effects," because of the possibility the drugs would interact and magnify any problems, said Dr. Christopher Cannon, a cardiologist at Harvard-affiliated Brigham and Women's Hospital in Boston who had no role in the study.
Collectively, the results show the polypill could cut the risk of heart disease by 62 percent and the risk of stroke by 48 percent, based on what previous studies show from lowering risk factors by these amounts, the study concludes.
Polycap's maker sponsored the study, and Yusuf has been a paid speaker for several makers of heart drugs.
A bigger study is now needed to see whether the polypill actually does cut heart attacks and strokes, he wrote in a commentary in the medical journal.
"It's a first step. I would caution against jumping to the conclusion this is the magic solution to our prevention problems," said Dr. Raymond Gibbons of the Mayo Clinic, a former American Heart Association president.
Studies show that healthy diets and exercise give better protection than pills, and too many people already think "that because they're on a statin, they can go to McDonald's," Gibbons said.
A big issue is who should get the polypill. The study tested it in people with risk factors that would already qualify them for treatment.
"Should high-risk people who do not yet have heart disease take it? My guess is, that's where the field will go to rapidly," Yusuf said.
Conversely, people with established heart disease may need more medicines than the modest amounts in this all-in-one pill.
"It won't be for everybody," Cannon said. Some people would be overtreated by getting medicines for conditions they don't yet have, such as high cholesterol. Others may be undertreated by too-low doses in the combo pill. Several polypills of different strengths may be needed, he said.
"We have to be cautious about assuming that one size fits all," Stein said. "Treating risk factors is a lot like cooking — the ingredients count."
A polypill also would need FDA approval, even though all of its components have long been sold separately. And establishing the proper doses could become a regulatory nightmare, Cannon warned.
http://abcnews.go.com/Health/WireStory?id=7208507&page=1

THE LANCET

2009-04-08T02:33:00.001-07:00

Effects of a polypill (Polycap) on risk factors in middle-aged individuals without cardiovascular disease (TIPS): a phase II, double-blind, randomised trial
Original TextThe Indian Polycap Study (TIPS)‡
Summary
Background
The combination of three blood-pressure-lowering drugs at low doses, with a statin, aspirin, and folic acid (the polypill), could reduce cardiovascular events by more than 80% in healthy individuals. We examined the effect of the Polycap on blood pressure, lipids, heart rate, and urinary thromboxane B2, and assessed its tolerability.
Methods
In a double-blind trial in 50 centres in India, 2053 individuals without cardiovascular disease, aged 45—80 years, and with one risk factor were randomly assigned, by a central secure website, to the Polycap (n=412) consisting of low doses of thiazide (12·5 mg), atenolol (50 mg), ramipril (5 mg), simvastatin (20 mg), and aspirin (100 mg) per day, or to eight other groups, each with about 200 individuals, of aspirin alone, simvastatin alone, hydrochlorthiazide 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 LDL for the effect of lipids, blood pressure for antihypertensive drugs, heart rate for the effects of atenolol, urinary 11-dehydrothromboxane B2 for the antiplatelet effects of aspirin, and rates of discontinuation of drugs for safety. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00443794.
Findings
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. Reductions in blood pressure increased with the number of drugs 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 three drugs). 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).>

Interpretation

This Polycap formulation could be conveniently used to reduce multiple risk factors and cardiovascular risk.

Funding

Cadila Pharmaceuticals, Ahmedabad, India.

Nature

2009-04-07T23:35:00.000-07:00

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).