Statins over prescribed

Publicity about Recent Studies on the Cholesterol-lowering Statin Drugs: Misinterpretations

There has been an extraordinary amount of news attention focused on recent studies concerning statins and heart disease, presented at the American College of Cardiology meetings in March and, in one case, published in the April 8, 2004 New England Journal of Medicine.

Without disparaging the importance of the studies themselves, we believe that spin-doctors and a scientifically uncritical news media have interpreted and stretched the findings in ways that go far beyond the actual data from the studies. A few examples will illustrate this:

Misinterpretation #1

Statins will prevent heart disease even in people who have not yet had a heart attack, stroke, angina or other kinds of cardiovascular disease if they have elevated cholesterol levels.

These recent studies are so-called secondary prevention studies. That is, the drugs were given to people who, in the case of one study, had been hospitalized with an “acute coronary syndrome,” meaning either a heart attack or high risk unstable angina.

{WEAK EVIDENCE FOR STATINS FOR THOSE WITH ONLY HIGH CHLOSTERAL}:

Although there are some earlier studies involving people without previous evidence of cardiovascular disease (angina, heart attacks, bypass surgery, angioplasty or strokes), the evidence for treatment of these people, especially with cholesterol-lowering drugs, is weaker and is known as primary prevention. This is especially so for those people who do not have more than one of the risk factors listed below:

These risk factors include hypertension, diabetes, smoking, obesity, or a close family history of premature heart attacks or strokes. Other predisposing risk factors include a sedentary life style and a high-fat diet. It is likely that millions of people being given cholesterol-lowering drugs such as statins for primary prevention do not have more than one of these risk factors and are only being treated because of their total cholesterol or LDL cholesterol levels.

Thus, it is extremely important to look at the global risk of cardiovascular disease rather than focusing on just the blood pressure or just the cholesterol level. For primary prevention, it is usually most prudent to attempt to improve your cardiovascular risk through sensible programs of diet and exercise.

A case example of primary prevention involving someone who will, unfortunately, more times than not be recommended to start statins follows:

Ben is a 55-year-old man with a total cholesterol of 240 and an HDL of 50. However, his blood pressure is a normal 120/90 and he is neither a diabetic nor does he smoke. Ben turns out to have a 5-year risk of having a cardiovascular event (heart attack, stroke, etc) of only 5.1%, about one-half of the 5-year risk of over 10% that might merit drug treatment. It would be a good idea for Ben — or most people, for that matter—-to adopt the non-drug approaches to lowering his cholesterol discussed above, but since his global risk is as low as it is, drug treatment is not indicated even if his total cholesterol and HDL cholesterol stay the same.

In summary, these new studies did not even examine the role of statins in primary prevention. There are many people who have had heart attacks and strokes with elevated cholesterol levels who are not being aggressively enough encouraged and helped to lower their subsequent risk with diet, exercise or statins, the very kinds of secondary prevention the studies did address.

Misinterpretation #2

The study showed that atorvastatin (LIPITOR) prevents heart attacks.

The study published in the New England Journal of Medicine was designed primarily to see if the subsequent occurrence of a combination of adverse cardiovascular events was different in those taking a high or “intense” dose of atorvastatin (LIPITOR) versus those using the “standard” dose of pravastatin (PRAVACHOL). The combination included death from any cause, a heart attack, unstable angina (chest pain) requiring hospitalization, bypass surgery or angioplasty, or a stroke.

It is correct that the study showed that those taking atorvastatin were significantly (16%) less likely than those taking pravastatin to have any of the above events — and this is an important finding. However, there was not a significant reduction in heart attacks alone, death alone, or in the combination of death and heart attacks. The most significant reduction in the Lipitor group was in the subsequent occurrence of unstable angina requiring hospitalization.

Misinterpretation #3

The studies prove that atorvastatin (LIPITOR) is superior to pravastatin (PRAVACHOL).

As mentioned above, the purpose of the study was to see how intensive statin therapy (80 milligrams daily of atorvastatin) compared to standard therapy (40 milligrams of pravastatin) in people who had already had a cardiovascular event. There is reason to believe that the most important variable may be the intensity of the treatment rather than characteristics of the individual drugs.

Ideally, the study should have explored both the different drugs and different doses — standard or intense — of each.

Cholesterol-lowering Drugs For People 70 or Older

Aside from these recent papers, there is still some misinformation about the evidence for treating — in the form of primary prevention — elevated cholesterol levels in people over 70 years of age.

It is clear that the relationship between moderately elevated cholesterol levels and increased risk of heart disease is not as clear as people get older. As geriatricians Fran Kaiser and John Morely have written: “Given the uncertainty of the effects of cholesterol manipulation in older individuals, what should be the approach of the prudent geriatrician to hypercholesterolemia [elevated blood cholesterol levels]? In persons over 70 years of age, lifelong dietary habits are often difficult to change and overzealous dietary manipulation may lead to failure to eat and subsequent malnutrition. Thus in this group minor dietary manipulations such as the addition of some oatmeal [or other sources of oat bran or soluble fiber] and beans and modest increases in the amount of fish eaten, may represent a rational approach. Recommending a modest increase in exercise would also seem appropriate. Beyond this, it would seem best to remember that the geriatrician’s dictum is to use no drug for which there is not a clear indication.”

The use of cholesterol-lowering drugs in people 70 or older should be limited to patients with very high cholesterol levels (greater than 300 milligrams) and those who manifest cardiovascular disease (previous history of heart attack or angina, stroke). More recent reviews of this topic have reached similar conclusions: In one review, it was concluded that “unanswered questions include cholesterol treatment for primary prevention in the elderly, gender effect, and benefit of treatment in persons older than 70.” There are even questions as to whether elderly people who are hypertensive should have their cholesterol lowered by drugs. One review concluded that “Further trials are required before routinely suggesting that it is advantageous to lower cholesterol in an elderly hypertensive who does not have pre-existing evidence of coronary heart disease.”

What You Can Do

If your doctor recommends a cholesterol-lowering drug, especially for primary prevention, ask on what basis this is being done. This is especially true if you either are over age 70 or have no more than one risk factor.

http://www.aspirin-foundation.com/uses/cardio/thrombosis.html

Aspirin and Coronary Thrombosis

Once the anti-aggregant effect of aspirin on platelets had been described in the mid 1960s, calls for trials of aspirin in myocardial infarction were made by John O’Brien in the UK (19) and by Harvey Weiss and others in the USA.21

In fact, these calls had been anticipated. Laurence Craven, a family practitioner in Glendale, California, published a series of three papers on aspirin in the early 1950’s (22-24). Each of these focused on some aspect of bleeding.

In the first, Craven pointed out that women take aspirin rather often for their pains and aches, while men tend to scorn such an ‘effeminate’ remedy and he went on to wonder if this difference might explain the sex difference in the incidence of heart attacks. (22) In his second paper,

Craven described bleeding in tonsillectomy patients given Aspergum, a mint flavoured gum impregnated with aspirin. (23) His third paper reports uncritically a remarkable benefit of aspirin on heart attacks and strokes (see panel). Craven’s ideas were however so unacceptable at that time, and his experimental work so flawed that he had difficulty reporting his findings and had to submit his papers to a rather obscure journal. (24)

Craven died of an MI a few years later.
The calls of O’Brien and Weiss were however heard in the MRC Epidemiology Unit in Cardiff, and in 1969 a double-blind placebo-controlled randomised trial of low-dose aspirin was commenced. (25) Men who had been recently discharged from local hospitals following an MI were invited to cooperate. Those who agreed were randomised to receive either 300 mg aspirin in a gelatine capsule or a placebo capsule.

Two points about the published report on this first trial are worth noting (see panel below). First, the journal published it under the headline: ‘For debate’. This was totally appropriate. Clinical practice should never be based on the results of a single trial, however convincing these are.

Replication is essential and if a drug or a preventive measure truly works then it will show in different patient groups, in different situations and in trials run by different trialists. Secondly, the results of the trial were evaluated only in terms of a reduction in total deaths. The inclusion of non-fatal events gives opportunity for bias due to a possible differential reporting of symptoms. Cardiovascular disease makes a substantial contribution to all-cause deaths, and if a measure does reduce it, an effect on total mortality should be seen.

For debate
A Randomised Controlled Trial of Acetyl Salicylic Acid in the Secondary Prevention of Mortality from Myocardial Infarction.

P.C.Elwood, A.L.Cochrane, M.L.Burr, P.M.Sweetnam, G.Williams, E Welsby, S.J.Hughes, R.Renton
British Medical Journal 1974,1, 436-440

Summary
The results of a randomised controlled trial of a single daily dose of acteyl salicylic acid (aspirin) in the prevention of re-infarction in 1,239 men who had had a recent myocardial infarct were statistically inconclusive. Nevertheless, they showed a reduction in total mortality of 12% at six months and 12% at twelve months after admission to the trial. Further trials are urgently needed to establish whether or not the effect is real.

Naturally, clinicians at that time were somewhat more than sceptical of the whole situation, and there was no detectable change in clinical practice. However research groups around the world took note, a number of trials were set up and by 1980 six trials had been reported. (25-30)

An early overview (Seoul conference on aspirin 1980)
TRIAL No of patients Reduction by aspirin

Cardiff 1 (1974)25 1239 26% n.s.
CDP (1976) 26 1529 30% n.s.
Cardiff 2(1979)27 1725 30% n.s.
German (1979)28 626 18% n.s.
AMIS (1980)29 4524 10% n.s.
PARIS (1980)30 1216 18% n.s.

These trials involved 10,859 patients, and the weighted overall effect was:

23% reduction by aspirin (P < 0.0001)

Each of these early trials suggested a beneficial effect of aspirin, but the results of none achieved an acceptable level of statistical significance. Overall, however, there is clearly convincing evidence of benefit.

The reporting of overviews of the results from all relevant published trials relating to a particular clinical intervention is becoming increasingly common throughout clinical practice and the first such overview, or meta-analysis, based on these six trials was presented by Richard Peto and his colleagues of Oxford to the inaugural meeting of the Society for Clinical Trials in Philadelphia in 1980.(31)

This overview was one strand in the thinking that led eventually to the setting up of the Cochrane Collaboration, the worldwide initiative that aims to conduct overviews within every area of clinical activity. (32)

Since that first report, the Oxford group have produced several monumental overviews of aspirin and cardiovascular disease: in 1988 (33) ,1994 (34). and 1997 (35).

The following is based on the overview published in 1994, which combines results from 145 RCTs, with a total of 102,459 patients and 10,943 outcome events. A remarkably consistent reduction in vascular events is demonstrated (22 to 32%).

An overview of RCT's of aspirin and cardiovascular disease

(BMJ 1994;308:81-106)

Patient group No. of trials Reduction in MI stroke or vasc. death.
Prior MI 11 25%
Acute MI 9 29%
Prior stroke/TIA 18 22%
Other high risk 104 32%

All trials 25%

Patient group No. of trials Reduction in MI stroke or vasc. death.
Non-fatal MI 122 34%
Non-fatal stroke 124 25%
Vascular death 144 17%
All-cause death 144 16%

Also considering the following factors
male/female; under/over 65yrs; hypertensive / normotensive; diabetic / non-diabetic gave no evidence of any significant differences in benefit.

An overview of studies with such a large number of clinical outcomes enables the drawing of conclusions from sub-group analyses with a fair degree of confidence. The benefit of aspirin is similar in all groups of patients whatever the prior indication for prophylaxis. Furthermore, there is no evidence of differences in the proportionate reduction by aspirin in different patient groups: males and females, older and younger subjects, diabetic and non-diabetic, hypertensive and normotensive subjects etc.

Together with this overview a Press Release by the group in Oxford was widely reported by the media. (36) This gave the estimate that around 100,000 premature deaths from cardiovascular disease could be prevented world-wide by the appropriate use of low-dose aspirin together with at least this number of non-fatal heart attacks and strokes.