Thursday, 30 November 2006

Polypill with Statins + 5, Brilliance or Ridiculous? - July 2003

  • 05 July 2003
  • From New Scientist Print Edition.

IT IS, depending on who you talk to, either the most important idea in medicine for over half a century or a crazy, dangerous fantasy.

"No other preventive measure would have a greater impact on public health in the western world," say Nicholas Wald and Malcolm Law of the Wolfson Institute of Preventive Medicine in London, who proposed the "polypill" in last week's British Medical Journal. "I thought it was a joke," says Steve Nissen, a cardiologist at Ohio State University. "It is stupid and ridiculous."

The idea is to combine five cheap off-patent drugs and the vitamin folic acid in a single pill offered to everybody over the age of 55. The polypill, claims Wald, would slash the risk of heart attacks by 88 per cent and strokes by 80 per cent (see "How the polypill would work"), extending people's lives without these diseases by up to 11 years. If his calculations are right, in the US alone, it could save nearly 800,000 lives a year. Given to everyone in developed countries, where heart disease is the biggest killer, it would save many millions.

Wald and his colleagues, who are patenting the idea, now hope to find a backer to finance the polypill's development. They want to carry out small trials involving a few hundred volunteers to identify the specific drugs to include in the polypill, and then larger trials involving thousands of volunteers and various different combinations of placebo and drugs to prove it really does deliver the benefits they claim.

"The necessary trials should be started immediately," BMJ editor Richard Smith told a press conference last week. But such trials will be very expensive, and big pharma companies may not be keen to back a cheap pill that could slash demand for their more expensive patented drugs. Nor will getting approval from regulators be easy.

The polypill idea is radical for several reasons. Giving drugs to healthy people to prevent disease, rather than just to those at high risk, has been proposed before, but has never been tried on a large scale. In 2001, for instance, after a massive 7-year trial showed that a statin called simvastatin (a potential polypill ingredient) reduces the chances of a heart attack or stroke by a third, without serious side effects, the researchers suggested it should be prescribed far more widely (New Scientist, 24 November 2001, p 7).

Wald points out that most people who suffer a heart attack or stroke are not known to be at risk - so if you want to make a big difference, you have got to give the polypill to everyone over 55. Efforts to prevent heart disease by changing lifestyle factors such as smoking, diet and exercise make much less difference, he says, and anyway the polypill should be seen as an addition to these efforts, not a replacement.

Critics say the polypill could have serious side effects: aspirin can cause internal bleeding, while blood pressure drugs can cause dizziness and fainting. But Wald claims the benefits will far outweigh the risks: a third of people taking it would live longer as a result, he calculates, whereas only 8 to 15 per cent would suffer any side effects.

While aspirin can cause bleeding and strokes, he admits, it prevents more strokes than it causes. And the strategy of combining three blood pressure drugs at half the usual dose will minimise any side effects. Even people with average blood pressure will benefit, Wald says. "All the evidence suggests the lower, the better."

Another contentious issue is combining so many drugs in one pill and giving the same pill to everyone. "People are different," says Nissen. "It is just not safe." Nissen sat on the US FDA advisory panel that assessed Pravigard, the first combination pill containing a statin and aspirin, which was approved last week for people suffering from heart disease. But the application was initially rejected, until Bristol-Myers Squib came back with more combinations of different doses - six in all. If the same principle were applied to the polypill, there would be over a hundred different combinations. Wald accepts the polypill may have to be adjusted to suit some individuals. But to keep costs down "you start with one-size-fits-all, then you start tailoring", he says.

There are also more mundane problems. Pravigard still comes as two pills, because of problems with the stability of a combined pill. Putting six drugs in one tablet will be even more of a challenge.

But convincing critics like Nissen may prove even harder. "Getting the idea accepted will require a shift in attitudes," says Wald. "I recognise the obstacles. But I don't think they are insurmountable."

From issue 2402 of New Scientist magazine, 05 July 2003, page 4
How the polypill would work

The four main risk factors for cardiovascular disease are high levels of low-density lipoprotein (LDL) cholesterol and homocysteine in the blood, high blood pressure, and the tendency of blood to clot or platelet aggregation. (The link with homocysteine remains controversial.) The idea of the polypill is to combine six different drugs that lower these risks in a single pill.

The reduced risk of a heart attack or stroke due to treating each risk factor individually can be calculated from the results of clinical trials. The polypill's proponents believe these trials also show that the benefits of treating each risk factor are independent of each other. In other words, if you lower cholesterol and blood pressure, the reduction in risk is greater than if you just lower one or the other.

To work out the overall effectiveness of the polypill, they multiplied the relative risks. To understand what this means, imagine 100 people at risk of heart attacks are given a statin that reduces the risk by 60 per cent over five years. Only 40 out of the 100 will then suffer heart attacks in the next 5 years. If all 100 are also given a blood-pressure drug that lowers the risk of heart attacks by 50 per cent, only the 40 still vulnerable to heart attacks stand to benefit - but only half of them (20) will suffer heart attacks. Together the two drugs will have reduced the risk by 80 per cent (60 + 20).

A key point, say the polypill's proponents, is that if someone does not benefit from one component, they could still be helped by another. If the statin does not save them, the blood pressure drugs might.

Wonder Pill - slash heart attack or strokes - June 2003

A wonder pill that could slash the rate of deaths from heart attack or stroke by over 80 per cent is being proposed by UK researchers.

The "Polypill" would contain a cocktail of six existing drugs and should be given to everybody over the age of 55, the researchers argue. It could potentially save 200,000 lives every year in the UK alone, they say.

"There's probably no other preventative measure which would have greater impact on public health in the Western world," says Nicholas Wald, research leader and an expert in preventative medicine at the Wolfson Institute of Preventive Medicine, London.

"In people who start taking it at 55, about a third would expect to benefit," he says. "Each of these individuals would gain about 12 years extra life - that is enormous." In some cases the increase in longevity might be as much as 20 years, says the proposal.

"This is extremely important," says Richard Smith, editor of the British Medical Journal, which released three papers by Wald's group on Thursday. "Heart attack and stroke kill half of the British population." Smith suggested that the BMJ issue in which the proposals appear might be the most important for 50 years.

Key risk factors

The proposal is underpinned by a massive analysis of earlier trials of drugs that can lower different aspects of the risk of cardiovascular disease. Over 750 trials involving 400,000 people were assessed. However, the "Polypill" has yet to be tested in any clinical trials.

The pill would combine different drugs to try to lower the four key risk factors for heart disease: cholesterol, high blood pressure, high homocysteine blood levels and blood platelet function.

A statin would reduce high levels of the "bad" LDL cholesterol, slashing the risk of heart disease, while three blood pressure lowering drugs would reduce stroke risk, says Wald.

Folic acid in the pill would cut high homocysteine levels, which can encourage the build up of fatty plaques in arteries. And finally aspirin would be added to regulate the function of blood platelets. Overall, the wonder pill would cut the risk of heart disease by 88 per cent and stroke by 80 per cent, the scientists estimate.

The pill could also be produced cheaply, says Wald, as the patents on many of the components have expired or will do soon.

Little to lose

Eventually the drug could be given to everyone over 55, without requiring a medical examination, says Wald. He believes that age is a more powerful predictor of cardiovascular disease than the risk factors usually considered. "In Western society, the risk factors are high in us all, so everyone is at risk," he says. "There is much to gain and little to lose by the widespread use of these drugs."

Rory Collins, a British Heart Foundation professor of medicine and epidemiology at Oxford University told New Scientist he supports the Polypill concept, noting the idea has been mooted before.

"I think, in principle, it would produce substantial reductions in risk," says Collins, leader of the UK Heart Protection Study. "The idea is a perfectly sensible one in that the effect of these treatments do appear to be largely independent of one another."

Wald and colleagues are planning a small trial examining combinations of blood pressure lowering drugs for use in the Polypill. But he says clinical trials of the pill itself may be "tricky" as pharmaceutical companies are unlikely to be keen on funding the development costs of a pill containing off-patent drugs.

Journal reference: British Medical Journal (vol 326, p 1419, 1423, 1427)

Tuesday, 21 November 2006

Aspirin may help to prevent Cancer

From Google Health I read in Yahoo HealthDay that:-

"Along with its other benefits, an aspirin a day may help keep head and neck cancers away, a new long-term study suggests. It wasn't so much the amount of aspirin that was taken but the length of time that people were on the drug that mattered. Taking aspirin for under 10 years did not have a significant effect but taking it 10 years or more was associated with a 30 percent reduction in cancer" said study co-author Mary E. Reid, an assistant professor of oncology at Roswell Park Cancer Institute, in Buffalo, N.Y.

But it's still too early to recommend routine use of aspirin as a cancer-preventive measure, said Dr. Michael Thun, vice president for epidemiology and prevalence research at the American Cancer Institute.

Aspirin's cancer-fighting effect appears to be linked to the molecular mechanism by which NSAIDs fight pain. The medications inhibit an enzyme called cox-2, whose activity is known to increase in pre-malignant lesions. Inhibiting the enzyme may also help slow the proliferation of cells.

Anyone who wants to take aspirin as a cancer preventive should first consult their physician, Reid cautioned. "You should always talk to a physician before taking anything chronically," she said.

Taking aspirin each day does have its risks, Thun said. "At this point, aspirin is still not recommended for prevention of any cancer because of the risks of bleeding, particularly gastrointestinal," he said. "What is still missing is proof that the benefits of taking aspirin outweigh the risks."

More info on Aspirin & Cancer: National Cancer Institute

Wednesday, 8 November 2006

Mark Porter discusses heart attacks

From this discussion:
  • i will carry aspirin with me to take in the event of a (suspected) heart attack
  • consider the evidence for taking half an aspirin a day
  • consider the evidence (again) for taking statins - which reduce risk of heart attack or stroke by a THIRD EVEN IF cholesterol levels are average

pdf file transcript (page same as link in title). CASE NOTES 5. - Heart Attacks

British Heart Foundation Professor of Medicine and Epidemilogy at Oxford. TOM MARSHALL visiting fellow at Harvard Medical School



I want to go back to aspirin. Tom, there has been some coverage in the press suggesting that we should all be carrying an aspirin around with us, just in case we get chest pain, what do you think of that?

I think it's important, I carry aspirin for that reason, just in case someone falls over when I'm on the train or something. Aspirin alone is as effective as one of the clot buster drugs, alone at saving lives, solving heart attacks, it's very important. Given in combination with one of these clot buster drugs it's even more powerful. And as an emergency first aid measure for suspected heart attack it's a pretty good thing.

What about low dose aspirin - a daily half or quarter of an aspirin?

Yes I think the current guidance on this is that if you've got a cardiac diagnosis you should have been prescribed low dose aspiring almost ad infinitum but if you haven't had a diagnosis then it's probably best to discuss with your GP or practice nurse before starting to take that treatment because even low dose aspirin isn't totally without risk.

Statins & Cholesterol levels

Statins - a family of cholesterol lowering drugs that can protect against heart disease. At the moment they are only prescribed on the NHS to people at the highest risk, but there is now good evidence that far more us could benefit them - and there are moves to make them available over-the-counter in the near future. The global prescription market for statins is already worth billions of pounds a year - could the over-the-counter market soon follow suit? Dr I started by asking Tom how the statins work?

Because it's possible isn't it to have a higher than ideal cholesterol level, even if you don't eat a particularly poor diet.

There's a lot of variation between individuals, so that what we find is that different individuals have different cholesterol levels. We know that whatever your cholesterol level is if you eat a diet that's more high in saturated fat your cholesterol will be higher and if you eat a diet that's less high in saturated fats - bit more polyunsaturates - you'd have a lower cholesterol. So there's variation between individuals but there's also variation caused by what people eat. Approximately what they do is whatever your chances are of getting heart disease they knock about a third off that. So if you take a statin it will reduce your risk of heart disease by about a third and probably similar for stroke.

Pretty significant given that heart disease and stroke of course are the biggest killers of Americans and British people. But it actually doesn't make an awful lot of difference what your cholesterol level is to start with does it.

Well that's the curious thing about it because originally we thought that what we were treating was high cholesterol levels and if you brought them down to a more normal sort of level that was really what the advantage was coming from. But what we're finding more and more, for example from the heart protection study, it was a very large study in the UK a couple of years back, is that it doesn't really make a lot of difference what your cholesterol level is, it still reduces your risk. So if you're at high risk, even if your cholesterol level's pretty well average you're better off having a lower cholesterol level. And so the general rule about cholesterol is lower the better.

So potentially nearly everyone could benefit from taking a statin?

Well that's an interesting question. In principle, it would be very hard to prove that you were really benefiting people who very rarely get heart disease anyway but in principle that's probably correct, that virtually everybody can reduce their risk of heart disease, their chances of getting heart disease by about a third by taking a statin. But the key question is a third of what? Because if I've got a very high chance of getting heart disease then reducing my chances by a third seems like a pretty good idea but if I'm the sort of person who is very unlikely to get heart disease it means an awful lot of people like me are going to take the tablet and very few of us are actually going to really prevent anything.

Well at the moment statin use is effectively rationed by the NHS to those who need it most - put simply, at around, I suppose, a £1 per day a person, the NHS couldn't afford to supply these drugs to everyone who, the latest evidence shows, may benefit from them. Rory, it's going to a difficult problem to solve.

Well you call it a problem, I call it a solution. The fact is that the statins and cholesterol lowering therapy are much more effective than we had realised - they're more effective for a much wider range of individuals at high risk, they're effective for people at high risk not just of heart attacks or strokes, they're protective for people throughout the cholesterol levels that we see in Western populations. So we can produce benefits for a very much wider range of people who are otherwise going to have a heart attack, stroke and die - or be disabled by those conditions. So I see it as solution. And you say it's an expensive treatment but you know so too is being hospitalised with a heart attack, so too is being disabled with a stroke. And in fact when we do analyses of the benefits in terms of cost terms - leaving aside the human benefits - actually these treatments turn out to be cost effective for a much wider range of individuals than have previously been thought to be the case. And of course now that sinvastatin is no longer protected by patent and is available as a generic drug, as the cost of the drug falls the cost effectiveness of the treatment increases and it will become cost effective, cost saving, for a very much wider range of patients.

So what are the downsides Tom?

Statins do have side effects. There are some that are considered relatively minor and seem to be reversible when you stop them like sometimes people have suffered a little bit of hair loss and things like that. But the most important kind of side effect is a type of muscle damage which can be sort of mild, in the sense that people get some muscle pain and some blood tests show that there's some evidence of muscle damage and they can stop the treatment or in its more severe form can actually be quite a serious problem where there's breakdown of the muscles and this is referred to as rhabdomyolysis.

Are there doubts about the current statins that we're using, because this is quite an unusual side effect isn't it?

It's a very - yeah it's a very unusual thing and when it happens in its full blown form it's pretty serious - people can die from it. In its very serious form it's quite infrequent - it's in the region of 1 in 10,000 or even less frequent than that, so it's really quite infrequent.

Rory, what impact do you think deregulation of statins is going to have?

I think number one, the fact it's going over-the-counter emphasises our very good evidence about the safety of this treatment. I think the other thing is that it will bring to the attention, not just of the people that the over-the-counter is targeted at, but also the higher risk patients, the possibility that there are ways of lowering their risk and it may, I hope, encourage them to go and talk to their family doctors to get on to prescribed statin for people with vasc disease or diabetes or hypertension.

PORTER Tom, Katherine - do either of you take a statin?

I don't but I measure my cholesterol and I know that I don't need to.

What about you Tom?

I did, my cholesterol was a little bit high, as was my blood pressure, but the statins didn't agree with me so I've now bought a bicycle and try and cycle more and eat less but I don't take a statin.

Take One Aspirin a day to prevent heart attack or stroke?

Evidence about daily use of Aspirin to prevent heart attacks or stroke. But how does it work?

Low dose Aspirin is an antiplatelet agent (clot buster).

Aspirin has a risk of internal bleeding (Am J Medicine): -
Conclusions of this report was

Low-dose aspirin increases the risk of major bleeding by ~70%, but the absolute increase is modest: 769 patients (95% CI, 500-1250) need to be treated with aspirin to cause one additional major bleeding episode annually.

For Many Women, Daily Aspirin Can Protect the Heart

11.05.06, 12:00 AM ET SUNDAY, Nov. 5 (HealthDay News) -- The message is clear, but not enough women heed it: Taking an aspirin a day can help prevent heart attacks and stroke in some women, and even prevent further problems if you already have cardiovascular disease.

But it's not a one-size-fits-all prescription. Whether you should -- or shouldn't -- take a daily aspirin depends on a number of factors, including your age and your risk factors for heart disease and stroke, such as high cholesterol levels or diabetes.

One thing's clear: Fewer than half of American women who could definitely benefit -- those who already have cardiovascular disease -- actually take a daily pill, according to recent research. Doctors say the finding underscores the need for women to talk with their health-care provider about what's best for them.

"Aspirin works for women who already have cardiovascular disease, for those with multiple risk factors [for suffering a heart attack or stroke] and for healthy women over the age of 65," said Dr. Nieca Goldberg, chief of women's cardiac care at Lenox Hill Hospital in New York City, and author of The Women's Healthy Heart Program.

Goldberg was summarizing the findings of several recent studies and the latest guidelines issued by the American Heart Association. According to those guidelines, there's good reason to prescribe a daily aspirin for high-risk women. But the decision about aspirin for women at intermediate and lower risk is more difficult, the heart association said.

Doctors should take a more conservative approach with low- and intermediate-risk women, the AHA suggests, and should bear in mind that aspirin therapy has the potential for gastrointestinal bleeding and other side effects. Those side effects may outweigh the benefits in women at low and moderate risk.

Women between the ages of 45 and 65 who haven't had heart disease but do have risk factors -- including diabetes, high blood pressure and high cholesterol -- might benefit from aspirin therapy to prevent cardiovascular disease. But, they should discuss the matter with their doctor to determine their degree of risk, Goldberg said.

Once even healthy women reach the age of Medicare eligibility, it's probably wise to take a daily aspirin, doctors say. "At age 65 and over, for healthy women, it looks like aspirin prevents cardiovascular events," said Dr. Raluca Arimie, a cardiologist at the Santa Monica-UCLA Medical Center, in California.

But for healthy women between the ages of 45 and 65, doctors "haven't found any benefit to the heart, but they found a slight benefit for stroke prevention," said Arimie, who's also an assistant professor of medicine at the University of California, Los Angeles David Geffen School of Medicine.

Goldberg and Arimie agreed that it's crucial to know and understand your individual risk for heart disease and to make any decision on aspirin therapy in concert with your physician.

"Every woman should have a conversation with their own doctor," Arimie said. And, she added, don't necessarily expect to get the same advice doctors might give a man of the same age, or a woman of the same age with a different health status.

It's also important to know that doses in aspirin therapy can vary, Arimie said, with an 81 milligram tablet the typical starting dose for healthy people. "Sometimes it goes to 325 milligrams in those who have already had a heart attack," she said.

"I don't think everybody should be on aspirin," Arimie added. "But it should be decided case by case. If a healthy woman [under age 65] wants to take it to reduce stroke risk, she must be aware of the [GI] bleeding risk."

More information

To learn more about aspirin and heart health, visit the American Heart Association.

Wednesday, 1 November 2006

About Crabsallover

About Crabsallover 
54 yr male 5'7". 1987 
Body Mass Index 21.7 (139 pounds). Never been obese; overweight since 1989. In early
2008 BMI 29.9 (191 pd). StartedHacker's Diet 13/9/08 BMI 27.6
(176.4 pd). At 27/8/10 BMI 25.7 (164 pd).

About HealthNormal BMI 18.5 to 24.9 (118-159 pd
Weight Loss Target
log HD daily, 1pd/wk to
BMI 21.9, 139.9 pd in 2011
650 cals /day deficit:-

Basal Metabolic Rate
1850 cal/dayFood Calories Deficit500 cal/dayDiet1350 cal/day
Exercise Calories Deficit150 cal/day (30min walk) or 1 hour jog twice a week
Total Deficit

Waist Target: 86cm (33"), WHR: 0.9
Maintain Weight for Life
HD daily, BMI 21.9, 140 +/-5 pd. Reduce to ~BMI 19 on Calorie Restricted diet - The Longevity Diet, to be decided.
Maintain Exercise for Life
vigorous 1hr/wk, 486 cal/hr,
eg Run 5mph, 8 cal/kg/hr,
972 cal @ 134 pd

Nutrition plate: 5 a day, x1.5g/week Omega 3 from oily fish