Long-term WOSCOPS data published: Durable prevention 10 years after treatment

October 11, 2007

Glasgow, Scotland - Long-term follow-up of the West of Scotland Coronary Prevention Study (WOSCOPS) has now been published, and the results show that men prescribed statin therapy for five years during the clinical-trial period had fewer cardiovascular events a decade later, despite a large majority of the study cohort having stopped taking their cholesterol-lowering medication[1].

Over the posttrial period, when treatment was in the control of the patients and their physicians, there remained a statistically significant reduction in death from coronary heart disease or nonfatal MI among those treated with statin therapy compared with those treated with placebo, report investigators.

"In the original report of our study, we described a significant reduction in the risk of coronary events with the use of pravastatin," write lead author Dr Ian Ford (University of Glasgow, Scotland) and the WOSCOPS investigators in the October 11, 2007 issue of the New England Journal of Medicine. "We now report that during an extended follow-up period of approximately 10 years after the end of the trial, there was evidence of an ongoing reduction in the risk of major coronary events among study participants treated with pravastatin during the trial."

The results, say investigators, are presumably due to the stabilization of existing plaque and a slowing of the progression of coronary artery disease.

In an editorial accompanying the published study, Dr Michael Domanski (National Heart, Lung, and Blood Institute, Bethesda, MD) writes that there should no longer be any doubt that the reduction of LDL-cholesterol levels has a role in the prevention and treatment of disease[2].

"The central remaining question is, What is the greatest therapeutic benefit that can be gained, particularly for primary prevention of the emergence of clinical coronary disease?" he writes. "This question has two parts: How early should treatment be started? And how low should the target LDL-cholesterol level be set?"

Statins in primary prevention

The landmark WOSCOPS study, first published in the New England Journal of Medicine in 1995, was a randomized, double-blind, placebo-controlled clinical trial of pravastatin (Pravachol, Bristol-Myers Squibb) in 6595 middle-aged men without a history of MI. Investigators, testing a concept that was novel at the time, hypothesized that statin therapy could be used in the primary prevention of coronary artery disease, whereas at the time statins were used only in patients with existing disease.

Subjects, aged 45 to 64 years with a mean baseline LDL cholesterol level of 192 mg/dL, were randomly assigned to pravastatin 40 mg or placebo. Treatment with the statin reduced LDL cholesterol 26% compared with no lowering in the placebo arm. After approximately five years, the combined outcome of death from definite coronary heart disease or nonfatal MI was 5.5% among those treated with pravastatin compared with 7.9% among placebo-treated patients.

 
One possible result is that sufficient lowering will reduce the incidence of coronary disease to the point that it becomes a relatively uncommon diagnosis.
 

The posttrial study was a comparison of clinical outcomes of interest for the two original study groups—pravastatin and placebo—regardless of the actual subsequent use of lipid-lowering therapy during the posttrial period. Fewer than 40% of patients in both treatment arms remained on statin therapy after the completion of the trial, mainly because doctors still thought the drugs should be used only among those with existing disease. The posttrial period allowed investigators to determine whether the use of statins in primary prevention had any lasting effect.

In the period approximately 10 years after the completion of the study, the risk of death from coronary heart disease or nonfatal MI was 10.3% in the placebo group and 8.6% in the pravastatin-treatment arm. When extended over the entire follow-up period, approximately 15 years, the combined coronary heart disease death and nonfatal MI rate was 15.5% in the placebo arm and 11.8% in the pravastatin group.

Coronary heart disease, stroke, and mortality outcomes

Event Posttrial period: Placebo Posttrial period: Pravastatin p Total follow-up period: Placebo Total follow-up period: Pravastatin p
CHD-related death or nonfatal MI 10.3 8.6 0.02 15.5 11.8 <0.001
CHD-related death or hospitalization 19.0 15.6 <0.001 25.8 20.5 <0.001
Fatal or nonfatal stroke 5.6 5.1 0.22 6.8 5.9 0.06
Death from all causes 17.1 16.1 0.15 20.5 18.7 0.03
Cardiovascular death 7.2 6.4 0.11 9.0 7.6 0.01
CHD death 4.7 4.1 0.12 6.3 5.1 0.02
Posttrial follow-up: approximately 10 years; total trial follow-up: approximately 15 years

In addition, similar reductions were observed in the combined rate of death from heart disease and hospitalization for coronary events in both periods, and the rate of death from cardiovascular causes or any cause was reduced over the entire follow-up period.

The investigators say the results should be compared with those observed in the long-term follow-up of the Scandinavian Simvastatin Survival Study (4S) and the LIPID trial, both secondary-prevention studies. Whereas the 4S study found no ongoing benefit with respect to a reduction in the rate of death from any causes or from cardiovascular disease, the LIPID study investigators did observe an extended benefit two years after trial completion with respect to a reduction in deaths from coronary disease and any cause.

Because of these disparate findings, taken together with the WOSCOPS extension data, investigators say the extended benefit of a period of treatment with a statin likely depends on the severity of coronary disease at baseline. As a result, these long-term findings should not be extrapolated to patients with established coronary heart disease, write the authors.

Of note, the WOSCOPS investigators observed no evidence of an overall risk of death from noncardiovascular causes or cancer or in the incidence of cancer.

Role of LDL in preventing and treating coronary disease

In his editorial, Domanski notes that the early initiation of therapy appears to have "durably mitigated the atherosclerotic process." As to the optimal target for LDL-cholesterol levels, despite the progressive reduction in cardiovascular event rates with declining LDL-cholesterol levels, there are no studies that provide information about events below an LDL-cholesterol level of 90 mg/dL, and none of these trials address the issue in adults in their early to middle years, writes Domanski.

"Is there an LDL-cholesterol level below which incident coronary heart disease is essentially eliminated, or does the relationship approach asymptote at some nonzero risk level?" he asks. "The geometry of the relationship of clinical coronary events and LDL cholesterol, in patients without prior coronary events, has not been studied at LDL-cholesterol levels anywhere close to those achievable with modern therapy. . . . One possible result is that sufficient lowering will reduce the incidence of coronary disease to the point that it becomes a relatively uncommon diagnosis."

Bristol-Myers Squibb sponsored the original WOSCOPS trial and Bristol-Myers Squibb and Sankyo funded the first five years of follow-up.

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