Sunday, May 20, 2007

Should women be offered cholesterol lowering drugs to prevent cardiovascular disease

Docs debate cholesterol lowering for women in BMJ

May 15, 2007

Head to head

Should women be offered cholesterol lowering drugs to prevent cardiovascular disease?

Scott M Grundy, professor : Yes

Malcolm Kendrick, general practitioner: No

Dallas, TX and Macclesfield, UK - British general practitioner Dr Malcolm Kendrick takes on the eminent Dr Scott Grundy (University of Texas Southwestern Medical Center, Dallas) in a head-to-head debate in the May 12, 2007 issue of BMJ about whether women should be offered cholesterol-lowering treatment for the primary prevention of cardiovascular disease [1,2].

Kendrick—the author of a book recently published in the UK entitled The Great Cholesterol Con—says this discussion "is effectively about the use of statins," since no other cholesterol-lowering drug has been shown to improve survival. He maintains that statins fail to provide any overall health benefit in women and represent a massive financial drain on health resources. In addition, they cause substantial adverse effects, a problem that is underrecognized, he says.

Grundy, who supports the use of cholesterol-lowering drugs in women at moderate risk, told heartwire that his article was deliberately not statin-specific: "Statins are but one drug among others. Just because Dr Kendrick tried to frame the question in terms of statins, I made it very clear to BMJ that I would only discuss cholesterol-lowering therapy. What about the other drugs for lowering LDL—where do they fit in? And where does diet fit in? "
Lack of data should not mean lack of treatment

Grundy—a consultant to most of the major statin manufacturers—says: "The essential issue here is whether women as well as men should be considered for cholesterol-lowering drugs when their 10-year risk is 10% to 20%—that is, moderately high."

He accepts that there is insufficient evidence of the benefit of cholesterol-lowering drugs in primary-prevention trials in women and that some people use this as a reason not to give such therapy to women at risk of cardiovascular disease.

But he argues—and says most investigators believe—that primary and secondary prevention "is an artificial distinction that should give way to a strategy based on absolute risk for future cardiovascular events, regardless of whether previous events have occurred."

Clinical trials that have included both men and women at moderately high risk have shown overall risk reduction from cholesterol-lowering therapy. But post hoc analyses limited to women failed to show significant risk reduction because of a lack of statistical power. "Not enough women were included to provide a definitive result. . . . Some investigators take this result to mean lack of efficacy. But without adequate power, the results are simply not informative," Grundy maintains.

Until a large-scale trial of cholesterol lowering is performed in women at moderately high risk of CVD, there are two options, he says. One is to exclude such women from therapy; the alternative is to consider treatment based on a combination of clinical-trial evidence and epidemiological data.

He notes that dietary therapy is also important, but that there is even less clinical-trial evidence for the benefits of this intervention than for drug treatment in this specific group of women.

"Since a substantial proportion of women ultimately develop cardiovascular disease and die from it, withholding treatment in moderately high-risk women that has proved protective in men and in women at high risk seems to be stretching the restrictions of evidence-based medicine beyond reason," he concludes.

Should women receive statins at all?

GP Kendrick reduces the discussion to one on statins alone. He not only disagrees with Grundy regarding the treatment of women at moderate risk, he also questions whether women should be receiving statins at all.

"None of the large trials of secondary prevention with statins has shown a reduction in overall mortality in women. Perhaps more critically, the primary-prevention trials have shown neither an overall mortality benefit nor even a reduction in cardiovascular end points in women," he maintains.

Kendrick told heartwire that Grundy's main point "appears to be that, although there is no evidence of benefit in giving women statins (no overall mortality benefit at all, in any study, ever) that we shouldn't be too bothered about this."

Kendrick also questions Grundy's notion that the difference between primary and secondary prevention is an artificial distinction: "He states that the concept of primary prevention is arbitrary and should not really be used. Well, the major clinical trials on statins—the ones that everyone uses to quote benefit—did exactly this. Should we now go back and strike all primary-prevention trials/data from the record? In which case, you wouldn't have much data to go on and we would end up not prescribing statins at all."

Kendrick says he does prescribe statins in his practice, on the basis that in secondary prevention, in men, they have been shown to have cardiovascular and overall benefit. However, he does not prescribe statins to women, "but if other doctors in the practice do so, I do not take them off, as that is not my clinical decision to make. I try to convince as many people as I can that statins are not of value in women and only of value in secondary prevention in men."

And don't forget adverse events and costs

Kendrick also says that studies show doctors often dismiss adverse events associated with statins and that the side effects are not as benign as they have been made out to be. For example, the US FDA adverse-event reporting system shows that between November 1997 and May 2004, simvastatin was reported as a direct cause of 49 350 adverse events and 416 deaths, he notes.

"If a patient complains of side effects that I believe are related to their statin, I will not hesitate to lower the dose or take them off to see if the side effects go," he added to heartwire.
And statins represent the single greatest drug expenditure in the UK National Health Service, Kendrick notes. In 2006, the cost in England was £625 million ($1.2 billion), and this is expected to reach £1 billion in 2007. This money could be diverted to treatments of proven value, he argues.

"Spending millions on a treatment that has no proven benefit and may cause serious harm goes against the rationale of evidence-based prescribing," Kendrick concludes.
Costs trivial, decision should be made in terms of safety, efficacy.

Grundy told heartwire that the cost of statins is now "trivial" since generic versions became available. "At Wal-Mart in the US, you can get statins for 13 cents per tablet (per day). I am sure that the UK health system can get them for less. Therefore, Dr Kendrick cannot use the cost argument any longer but must argue on the basis of lack of efficacy and/or lack of safety."

Grundy continues: "The FDA's postmarketing reports are not a good way to assess safety, and the vast majority of people who take statins and other approved cholesterol-lowering drugs do not have side effects. But of course, drugs should not be taken without any expectation of benefit (efficacy).

"I personally do not believe that there is a distinction between primary and secondary prevention, but it is the absolute risk of patients that determines whether they are candidates for cholesterol-lowering drugs," he concludes.


Kendrick M. Should women be offered cholesterol-lowering drugs to prevent cardiovascular disease? No. BMJ 2007; 334: 983.

Grundy SM. Should women be offered cholesterol-lowering drugs to prevent cardiovascular disease? Yes. BMJ 2007; 334: 982.

Related links

Lancet Comment questions benefit of statins in primary prevention [HeartWire > Cardiometabolic risk; Jan 25, 2007]

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