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May 28, 2009 — Blood-pressure-lowering drugs should be offered to everyone, regardless of their blood pressure level, as a safeguard against coronary heart disease and stroke, researchers who conducted a meta-analysis of 147 randomized trials (comprising 958,000 people) conclude in the May 19 issue of BMJ .
"Guidelines on the use of blood-pressure-lowering drugs can be simplified so that drugs are offered to people with all levels of blood pressure," write Drs Malcolm R Law and Nicholas Wald (Wolfson Institute of Preventive Medicine, Barts and the London School of Medicine, Queen Mary University of London, UK). "Our results indicate the importance of lowering blood pressure in everyone over a certain age, rather than measuring it in everyone and treating it in some."
"Whatever your blood pressure, you benefit from lowering it further," Law told heartwire . "Everyone benefits from taking blood-pressure-lowering drugs. There is no one who does not benefit because their blood pressure is so-called normal."
Six years ago, Law and Wald advocated the use of a polypill--containing a statin, three blood-pressure-lowering drugs (each at half the standard dose), folic acid, and aspirin--which they maintained could prevent heart attacks and stroke if taken by everyone 55 years and older and by everyone with existing cardiovascular disease .
In the current meta-analysis, which included people aged 60 to 69, they singled out blood-pressure-lowering drugs to determine the quantitative efficacy of different classes of antihypertensive agents in preventing coronary heart disease (CHD) and stroke. They also sought to determine who should receive treatment.
All Antihypertensives Prevent CHD and Stroke
Overall, the results of the meta-analysis showed that in people aged 60 to 69 with a diastolic blood pressure before treatment of 90 mm Hg or a systolic blood pressure of 150 mm Hg, three drugs at half standard dose in combination (as in the polypill) reduced the risk of CHD by approximately 46% and of stroke by 62%. However, when used individually, a single antihypertensive agent at standard dose had about half this effect.
The five main classes of blood-pressure-lowering drugs--thiazides, beta blockers, angiotensin-converting-enzyme inhibitors, angiotensin-receptor blockers, and calcium-channel blockers--were similarly effective in preventing CHD events and strokes, with the exception of calcium-channel blockers, which had a greater preventive effect on stroke than the other four agents (relative risk, 0.92; 95% confidence interval, 0.85 to 0.98).
People with and without cardiovascular disease derived equal benefit, with similar percentage reductions in CHD events and stroke, and regardless of what their blood pressure was before treatment. Even patients with blood pressures considered to be low--110 mm Hg systolic and 70 mm Hg diastolic--showed fewer CHD events and a reduced incidence of stroke when taking an antihypertensive.
Law and Wald also report that calcium-channel blockers reduced the incidence of heart failure by 19%, and that the other antihypertensive agents reduced heart failure by 24%.
In an accompanying editorial , Dr Richard McManus (University of Birmingham, UK) and Dr Jonathan Mant (University of Cambridge, UK) write that the findings of Law and Wald will contribute to debate on the management of hypertension in several areas. "Taken at face value, these findings provide tacit support for the use of a 'polypill' to lower the risk of cardiovascular disease in people likely to be at high risk (such as all people over the age of 55) without first checking their blood pressure."
In a comment to heartwire , McManus added that he believes that the findings reinforce the view that treatment to lower blood pressure should be offered on the basis of risk, regardless of blood pressure.
Throwing the Baby Out With the Bath Water
On the other side of the Atlantic, hypertension experts were not so sanguine in their opinion of Law and Wald's conclusions.
Commenting on this study for heartwire , Dr James Elliott (Rush Medical College, Chicago, IL) said he took issue with the authors' suggestion that the measuring of blood pressure was unnecessary.
"Professors Wald and Law made the revolutionary comment some years ago that we should abandon blood pressure and simply treat everyone at high CVD risk with their magic polypill, which they claimed reduced heart disease and stroke by 90%.This meta-analysis is an unusual compilation of data that supports that hypothesis."
Abandoning blood pressure measuring is like throwing the baby out with the bath water, Elliott said.
Elliott also took issue with the meta-analysis, which he called "old-fashioned."
"I think Wald and Law have become the ultimate lumpers. They have included the 37 studies where beta blockers were used against placebo in people with heart attacks, and they have lumped those in with all the other kinds of therapies that we use to lower blood pressure and prevent other events. Nobody, as far as I can remember, has ever included that set of 37 trials in with the other antihypertensive trials because it represents such a different population. They have done the old-fashioned, simple meta-analysis. But there are better ways to understand the data."
A Meta-Analysis Is Like a Sausage
Adding his opinion, Dr Franz Messerli (St Luke's-Roosevelt Hospital Center, New York City) said that by including 147 trials in their meta-analysis, the authors had to make numerous assumptions, "some possibly valid, others clearly not."
Because the "blood pressure fall was not reported in patients with a history of coronary heart disease, they estimated this fall from a meta-analysis of blood pressure trials. This is clearly inappropriate since the fall in blood pressure depends on the pretreatment level, and patients with coronary heart disease who often are hypotensive (particularly post MI) will not respond the same way as do patients with hypertension," he told heartwire.
It is little surprise that beta blockers now, all of a sudden, look better than in any other review ever done, Messerli added. "Numerous meta-analyses have clearly demonstrated that beta blockers do not reduce the risk of coronary heart disease in hypertension, despite the fact that they lower blood pressure. Thus, despite its appearance of being bigger and better, this study is yet another example of my dictum: A meta-analysis is like a sausage, only God and the butcher know what goes in it and neither would ever eat any."
Law and Wald disclosed that they hold patents (granted and pending) on the formulation of a combined pill to simultaneously reduce four cardiovascular risk factors, including blood pressure. McManus disclosed that he has a financial relationship with Sanofi-Aventis, Pfizer, A.Menarini Pharma, and Merck Sharp & Dohme. Elliott and Messerli have disclosed no relevant financial conflicts of interest.
The world's first polypill, a multiple-product pill for heart ailments, has been developed by Dr. Reddy's. Next step: clinical trials
Gina S. Krishnan
HERE WE COME: D. Reddy's API lab in Hyderabad
It could be the blockbuster that Dr. Reddy's has been waiting for. Then again, it may turn out to be a big, fat dud. The Hyderabad-based company is racing to become the first pharma company in the world to introduce the controversial polypill, a superdrug combining several active drugs for the treatment of cardiovascular disease (CVD).
Why CVD? Well, because it is actually a bigger killer than more feared ailments like cancer or HIV/AIDS. Estimates suggest that CVD accounts for 29.3 per cent of deaths globally every year compared to 12.5 per cent for cancer and 4.9 per cent for HIV/AIDS. Predictably, treatment of CVD is big business. According to the World Health Report 2004, healthcare expenses related to CVD (including surgery, hospital stay, medication, etc.) accounted for more than $350 billion in the US in 2003, which was 40 per cent of its total healthcare industry.
But why a polypill? Take Surekha Khanna, a 66-year-old housewife in Delhi, for instance. In 2002, Khanna suffered a mild heart attack. She suffers from hypertension, high cholesterol and diabetes, and none of them are coming under control. Reason: too many pills, nine tablets every day, to be precise. "I hate it. Taking nine pills daily makes me feel ill," she fumes. So, here's what she does: skip the fattest pill, and take any pill whenever she feels like it.
Now, this problem (of compliance as well as cost) could be solved if people like Khanna could take one pill instead of several. This simple logic caught the imagination of the global medical community, and the idea of the polypill was born in the early 2000s. But it has been mired in controversy since. Despite that, Dr. Reddy's went ahead and developed a modified version of the polypill, which is slated to go in for clinical trials in early April.
We'll go into the details of Dr. Reddy's effort a little later. First, a small backgrounder on the polypill.
Polypill: The Genesis
The polypill was first mooted at a meeting of the Wellcome Trust and World Health Organization at Cambridge in 2001.
But the real thing came later.
In the 28 June 2003 edition of the British Medical Journal (BMJ), Nick J. Wald and Malcolm R. Law, professors at London's Wolfson Institute of Preventive Medicine, suggested that a polypill — comprising a statin (lipid lowering agent), aspirin (blood thinner), folic acid (to prevent the build-up of plaque in blood vessels)and three anti-hypertensives (to reduce blood pressure), all in half doses — could reduce ischaemic heart disease (IHD) by 88 per cent and stroke by 80 per cent.
They said that the pill could be safely administered to everyone aged 55 and older, and everyone with existing heart disease. With widespread use, it "would have a greater impact on the prevention of disease in the Western world than any other single intervention".
The Heart of The Matter
Such a tall claim naturally generated intense interest, both positive and negative. Richard Smith, the (then) editor of BMJ, remarked that it was perhaps more than 50 years since the journal had published something as important. And Anthony Rodgers, director, Clinical Trials Research Unit, University of Auckland, who was involved in trials of polypill components in the 1990s (see inter- view on page 96), wrote a highly supportive editorial in the same issue of BMJ.
But not everyone loved the idea. Sceptics pointed out that the study was based on a meta-analysis — a statistical run in a computer program — of 750 trials on over 400,000 patients, and till actual clinical trials were conducted on humans, safety would remain an issue.
Then, it was said that dosages of the component drugs (statin, aspirin, etc.) need to be tailored to a patient's condition and cannot be fixed for everyone. The suggestion that everyone aged 55 or above could be given the polypill (essentially as a prophylactic or preventive measure) came in for flak. There were fears that the polypill could lead to prescription abuse. Others felt that in an age where medicine seeks to work on people based on individual gene profiles, the polypill is a step backward. Finally, it was feared that the polypill would encourage people to skip other important steps like excercise and dieting.
Despite the opposition, the polypill has found pockets of support. In January 2005, a group of experts of the US Centers for Disease Control and Prevention in Atlanta supported the polypill and suggested that placebo-controlled clinical trials be held. However, trials have not yet begun.
The India Connection
While the debate on the polypill still rages, there was no doubt that a single pill to treat CVD, if it actually worked, would be immensely useful for the developing world. That's because the cost of the combo, which used off-patent drugs, would likely be cheaper than that of the individual drugs combined.
In his editorial in the 28 June 2003 issue of BMJ, Rodgers wrote: "The most important challenge is ensuring such interventions reach the many people at high risk in developing countries who currently receive little or no preventive care. Compared with developed countries many times more lives could be saved, mostly among middle aged people, if combination medications were made affordable and accessible."
India comes into the picture in two ways. One, that India is on the threshold of a virtual CVD epidemic, according to a study conducted last year by the National Commission on Macroeconomics and Health (see 'The Heart Of The Matter'). The study also revealed that Indians are three to four times more at risk to CVD than Caucasians, six times more than Chinese and 20 times more than Japanese.
'The Polypill Needs Top Quality Clinical Trial Evidence'
And two, making the polypill required combining several active drugs into one, a kind of reverse engineering that Indian pharma companies, with their experience in generics, have become adept at. K. Srinath Reddy, head of cardiology at AIIMS, and a prolific researcher of CVD prevention methods, took advantage of that. Reddy, who has emerged as an evangelist of sorts for the polypill, approached Dr. Reddy's in early 2003. "They had the scientific capability to develop the polypill," he says.
Dr. Reddy's, for its part, took up the challenge and Rs 25 crore was set aside for project Little Red Heart Pill (LRHP). A team of international advisers led by Rodgers and including people like professors Stephen MacMahon and Anushka Patel, and associate professor Bruce Neal of the George Institute of International Health, University of Sydney; professors Richard Grimm and Jim Neaton of the University of Minnesota; Krishnam Raju of CARE Hospital; and Srinath Reddy worked with Dr. Reddy's research team and studied various combinations of molecules, dosage forms and therapeutic categories.
After going through multiple iterations, the project team settled on the following combination: two hypertensives, a blood thinner and a lipid lowering agent. Folic acid was eliminated due to lack of sufficient data.
Bioavailability studies were done on healthy volunteers specified by the Drug Controller General of India to understand the plasma concentration of the polypill. And comparative bioequivalence studies were done to ensure that the bioavailability of the polypill was equal to those of the component pills. Says M.S. Mohan, vice-president (research & development), Dr. Reddy's: "It was technically and scientifically the most challenging project for us."
Dr. Reddy's Strategy
Dr. Reddy's looks at the polypill as a product for the world market. To make that happen, the company claims it is following stringent global quality requirements of different regulatory bodies. Says Satish Reddy, managing director and COO: "The magnitude of the problem was such that the only way it could be looked at was globally." To begin with, it is looking at India, Russia, Brazil, Australia and New Zealand.
That will give Dr. Reddy's something it needs in its desire to be a research-led pharma company: experience in launching an NCE (new chemical entity or original molecule) in different markets, although the polypill itself will not be an NCE. The marketing team was brought into the picture early last year. Says Sandeep Sahney, executive vice-president: "We are very excited. It is the first time that an Indian company is looking at a product in the global context."
Each market is being studied to forecast requirement and sales (Dr. Reddy's has offices in 35 countries and its products are marketed in 110). "We have been collaborating with business heads in each country," says Sahney. The business heads are assessing market potential as well as regulatory timelines, which are different for each country.
Within India, 35,000-40,000 doctors (specialists and general physicians) will be targeted for detailing on the polypill.
Pricing is another important factor. The idea is to make the product at the lowest possible cost. Says Raghu Cidambi, head (IPR and strategic planning), Dr. Reddy's, and mentor of the polypill project: "We are looking for the cheapest manufacturer of the API in the world." However, multiple pricing or higher pricing for the developed market to cross-subsidise the cost for developing market have not been considered, according to G.V. Prasad, executive vice-chairman and CEO, Dr. Reddy's.
Meanwhile, Dr. Reddy's polypill follows a completely new approach that has deviated from the original combination prepared by Wade and Law. That's not to say that it won't work, but there are attendant risks that have not been tested yet.
Besides, questions dogging the polypill still remain. Doctors are not happy about the fact they will not be able to regulate the dose per patient.
Counters Satish Reddy: "Doctors would ideally like to titrate the dose with every patient, but aren't compliance and cost equally significant issues?" Srinath Reddy says that it will be a cost-effective solution, particularly for the poor, who cannot remain on expensive multi-pill medication for long.
Dr. Reddy's contention is that at this point, one can only theorise about possible risks. The clinical trials, scheduled for April, should provide some answers. Says J.S. Bakshi, corporate medical director: "In India, clinical trials in phase III will be held in 10 institutes. They would be held at referral hospitals with a mix of rural and urban population."
The financial implications of a successful polypill launch for Dr. Reddy's are not known yet. "There is no formula that can be applied to cover our investment," says Satish Reddy.
Pharma analysts, though, are gung-ho about the prospects of the polypill. Gushes an analyst: "Given time, there is no way that it would not be a blockbuster, at whatever price."
Blockbuster or no, time will tell.
A SCREAMING CONFLICT OF INTEREST HERE! DS
Chapter 6, "HIGH BLOOD PRESSURE", co-authored by Dr. Malcolm R. Law.