Richard Smith: Treating cardiovascular disease as well as we treat TB and HIV

richard_smith_2014Globally, about 70% of people diagnosed with tuberculosis and about 40% of those with HIV are treated, but less than 20% of those who have had heart attacks or strokes receive the treatments known to reduce further events substantially, said Anthony Rodgers at the Global Cardiovascular Clinical Trials Forum in Washington earlier this month.

Even in high income countries, less than 40% of cardiovascular patients receive recommended drugs long term. There is, said Rodgers, “enormous undertreatment.”

Then, said José Castellano, a cardiologist from Madrid and New York, less than half of those prescribed the necessary drugs are fully adherent. In the United States, three quarters of patients with all conditions do not take their drugs as prescribed, and the result is 125 000 deaths and annual costs of $300 billion—13% of health expenditure. The causes are myriad but include cost, complexity of treatment, and poor communication. The average time spent by a physician in the US on communicating with a patient about new drugs is 49 seconds, said Castellano. Adherence is a particular problem in patients with heart disease as they must take their drugs for the rest of their lives, may well have no symptoms, and are likely to be elderly.

The polypill (which surely requires no further explanation in The BMJ) can help with both undertreatment and adherence, and they are now beginning to appear around the world.

Polypills include drugs that are off patent and can be made very cheaply, making them more accessible to poor people. They can probably as well be administered by non-physician health workers, and a trial is underway to test the effectiveness of that form of distribution. In most low and middle income countries physicians are scarce, particularly in rural areas.

Four trials of the polypill against usual treatment have now shown that it can improve adherence by about 50% (from 30% to 60%). The biggest improvement is seen in those who are the most undertreated, meaning that the polypill may be a way to improve equity. There is now evidence that those who take the polypill don’t change lifestyle measures, addressing the fear that people might take the polypill instead of adopting healthy lifestyles.

Polypill enthusiasts (of whom I’m one) are divided into those who believe the polypill should be used mainly (or initially) in secondary prevention (in those who have had heart attacks or strokes), and those who think the big gains will come in using it for primary prevention. The most extreme strategy, advocated first in The BMJ, is to offer the polypill to everybody over the age of 50 or 55 (I note in passing that that this paper has now been cited 1365 times). Some call this the “vaccination strategy,” although as Nick Wald, one of the originators of the strategy points out, it’s “reversible vaccination.”

In many ways the division is simply tactical. Drug regulators seem willing to consider a polypill for secondary prevention based simply on studies showing it works the same as the component drugs, whereas for primary prevention, they want trials with major cardiovascular events or deaths as an endpoint. Such trials are underway, but some see them as almost unethical, as could the informed patient or the prescriber really be in equipoise over whether a placebo or a combination of antihypertensives and a statin will be superior.

A counter tactical argument is that secondary prevention often belongs to cardiologists, who tend to prefer titrating individual drugs, and primary prevention to primary care doctors, who are more sympathetic to polypills.

Some “secondary care enthusiasts” are sceptical about the benefits of the polypill in primary prevention, but, as Wald asked one of them at a public meeting, “Can you think of anything that prevents a second event that doesn’t prevent a first event?” The answer has to be no and using the polypill only for secondary prevention would, as Wald has said, be like requiring people to wear seat belts only once they’d had a car crash. In their turn, some “primary care enthusiasts” think that once you have had an event you should have your drugs titrated against your blood pressure and lipids, and might need much higher doses of the drugs than is in polypills.

There continue to be two big challenges for the polypill: getting it through regulators and finding a business model. The European Medicines Agency has not yet approved a polypill and the impression given at the meeting was that it would be a hard road to follow. In contrast, the Food and Drug Administration in the US seems to be moving towards a licence for substitution treatment in secondary prevention (those already on the same drugs), plus some sort of pragmatic grounds for patients not receiving all treatment—such as those without long-term follow-up—on the grounds that a patient “would be better off with some drugs than nothing.” One company, CardioPharma, does seem to have approached the FDA with a polypill.

Getting the polypill through regulators is part of the business problem in that it’s an expensive process, and because the generic companies who manufacture polypills have little experience of getting new drugs through regulators. The other business problem is achieving high uptake: again the generic companies don’t usually have to do any marketing. Several companies that initially manufactured polypills have now given up.

Despite these difficulties, one Spanish company, Ferrer, has a polypill Trinomia, which contains aspirin, ramipril, and simvastatin, and which is licensed in 22 countries, most of them in Latin America but seven in Europe (Spain, Sweden, Belgium, Greece, Poland, Ireland, and the Czech Republic). The company’s challenge now is to get the polypill widely used, and one question is how to price it.

Enthusiasts like me imagine the polypill being very cheap, perhaps a dollar a month, and eventually this might be possible—with a high volume, low margin business model. But for now and for Europe, a higher price may be needed to meet the costs of regulation and marketing. A modelling study from Britain, which assumes improved adherence of 10% over 10 years in patients who have had heart attacks or strokes and consequently a 6.7% reduction in major cardiac events, would mean a cost per QALY of £2200 if the pill was priced at 50% above that of the component drugs or £9700 if it was priced at 150%. Either way it should be safely inside the limits of the National Institute for Health and Care Excellence.

One way to solve the business problem might be for payers of healthcare to commit to a large scale purchase of the polypill once it is licensed. Companies would then be willing to invest more, having greater confidence of an acceptable return. This “market pull” mechanism has been used with vaccines, but no payer is presently willing to make such a commitment.

A friend of mine bet British Rail in 1960 that man would land on the moon before the gas lighting at Kidbrooke Station was replaced with electric lighting. He won his bet. My bet with myself is that the polypill, which I’ve been enthusing about since 2003, will be widely available before I die, but it may be touch and go. But then the polypill I take may keep me going until it’s available for everybody.

Richard Smith was the editor of The BMJ until 2004. He is now chair of the board of trustees of icddr,b [formerly International Centre for Diarrhoeal Disease Research, Bangladesh], and chair of the board of Patients Know Best. He is also a trustee of C3 Collaborating for Health.

Competing interest: RS was editor of The BMJ when it published the original polypill papers. He’s been taking the polypill (originally in its component parts) for primary prevention (without knowing his blood pressure or serum lipids) for about seven years and was in a cross over trial of the polypill. He works for UnitedHealth Group, which helped fund this meeting and previous meetings on the polypill. Neither he nor UnitedHealth Group have a direct financial interest in the polypill. (Almost everybody has an indirect financial interest in that the polypill could make treatment more affordable, accessible, and effective.)