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.