Long-term Follow-up of Statin Prevention Study: Instead of lifetime risk, a look at lifetime benefit

ACCEL | The West of Scotland Coronary Prevention Study (WOSCOPS) was the first major primary prevention trial of statin therapy, composed of 6,595 men with hypercholesterolemia (total cholesterol of 272 ± 23 mg/dL, considered “moderate” hypercholesterolemia in 1989) and no history of myocardial infarction (MI). Participants were randomized to pravastatin (40 mg) or placebo for five years. The combined outcome of death from definite coronary heart disease (CHD) or definite nonfatal MI was reduced from 7.9 percent to 5.5 percent (p < 0.001) in the treatment group.1 Extended follow-up data were obtained.2 Five years after the trial ended, 38.7 percent of the original statin group and 35.2 percent of the original placebo group were being treated with a statin. During extended follow-up, there remained a significant difference in the risk of CHD-related death or nonfatal MI, favoring the original statin group: 10.3 percent in the placebo group and 8.6 percent in the pravastatin group (p = 0.02); for the entire follow-up period, the rate was 15.5 percent versus 11.8 percent in the pravastatin group (p < 0.001). There were no excess deaths from noncardiovascular causes or excess fatal or incident cancers.

Upon reporting the original WOSCOPS results, investigators strongly recommended to the primary care physicians of all participants that they consider long-term statin therapy for all of the study patients. However, 20 years ago, there was no strong push for primary prevention; consequently, only 31 percent of the patients in each arm ended up on statin therapy post-study.

Even Longer-Term Follow-Up

There are now 20 years’ worth of data and the only difference between the two arms of the trial is the extra five years of active therapy in the original pravastatin arm. Across the entire period of follow-up, assignment to pravastatin remained associated with a 27 percent risk reduction in CHD mortality (p < 0.001) and a 13 percent risk reduction in all-cause mortality (p < 0.001). After 20 years, there was no significant difference in noncardiovascular deaths (p = 0.12), even when analyzing five specific types of cancer. (Early on, there was some concern that statin therapy was associated with increased risk of cancer.)

Investigators looked at key cardiovascular disease (CVD) outcomes. Hospitalization rates for percutaneous coronary intervention (PCI) or coronary artery bypass graft (CABG) surgery were significantly lower in the original pravastatin group (p = 0.0032) as was hospitalization for heart failure (HF) (p = 0. 0.0068), but there was no such difference in hospitalization for stroke (p = 0.19).

The 20-year follow-up period for WOSCOPS covers the age range (mean age 55 to 75 years) when premature CVD occurs so lifetime benefit can be estimated. Because the National Health Service of Scotland has a comprehensive national database of hospital discharges and deaths, the WOSCOPS investigators were able to link to the database to capture all utilization of medical services.

A few years ago, investigators published the impact on healthcare resource utilization, costs, and quality of life across 15 years following the original statin use in WOSCOPS. Five years of treatment with pravastatin significantly reduced CV hospital admissions, incremental costs of events, and net costs taking into account the cost of the drug and associated monitoring.3

For the 20-year analysis, the same beneficial economic effects continued for those men randomized to pravastatin compared to placebo (TABLE).

Information Graphic

Lifetime Benefit

Chris J. Packard, MBBS, argues that this is a good picture of lifetime benefit as opposed to lifetime risk. “These are real events happening to real people,” he said, “not predictions.” The biggest surprise, according to Packard is the 31 percent reduction in risk of hospitalization for heart failure. Given that the study participants had the youngest mean age (55 years) of any major statin trial and they had only hypercholesterolemia with no history of MI, incidence of HF was very low at the original five year follow-up; now, after 20 years, there is a trend favoring the group randomized to pravastatin.

Typically, WOSCOPS participants experienced a 20 percent drop in LDL-C during five years of pravastatin from a baseline of 190 mg/dL. The number needed to be treated (NNT) for five years to prevent one cardiovascular hospital admission over a 20-year period was six. Moreover, for every 10 patients on statin therapy for five years, an average of 19 hospital days were avoided over the course of 20 years.

What about men with lower baseline levels of LDL-C? For patients with a baseline LDL-C of 120 mg/dL, for every 10 patients treated for 5 years, the NNT was 10, and 12 hospital days were saved over a 20-year period.

However, there was no interaction with age and treatment. Based on other studies, Dr. Packard surmises that the coronary disease prevention benefits of statins are expressed within the first 12 months of therapy initiation. Consequently, once this year passes, any unstable plaque is reduced to a stable one and individuals then form a new trajectory going forward that delays CHD and CV events.

Thus, in an asymptomatic phase of CHD, there still may be fatty streaks or unstable lesions and statin therapy postpones coronary events leading to a gain in event-free years. In WOSCOPS, patients treated with pravastatin for five years during the trial gained an average of 5 extra years free of nonfatal MI or cardiovascular death at 20 years of follow-up.

Take-aways

  • The 20-year follow-up to the first major primary prevention trial of statin therapy demonstrates continued benefit in terms of persistent risk reduction of CVD outcomes after five years of statin therapy compared to placebo.
  • Non-cardiovascular events and cancers show equal incidence rates in active- and placebo-treated arms.

References

  1. Shepherd J, Cobbe SM, Ford I, Isles CG, et al. N Engl J Med. 1995;333:1301-07.
  2. Ford I, Murray H, Packard CJ, Shepherd J, et al.. N Engl J Med. 2007;357:1477-86.
  3. McConnachie A, Walker A, Robertson M, et al. Eur Heart J. 2014;35:290-8.

Clinical Topics: Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Statins

Keywords: CardioSource WorldNews, Cholesterol, Coronary Artery Disease, Hypercholesterolemia, Myocardial Infarction, Pravastatin, Primary Prevention, Scotland


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