cholesterol-lowering

Cholesterol Lowering in Intermediate-Risk Persons without Cardiovascular Disease

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BACKGROUND

Previous trials have shown that the use of statins to lower cholesterol reduces the risk of cardiovascular events among persons without cardiovascular disease. Those trials have involved persons with elevated lipid levels or inflammatory markers and involved mainly white persons. It is unclear whether the benefits of statins can be extended to an intermediate-risk, ethnically diverse population without cardiovascular disease.

METHODS

In one comparison from a 2-by-2 factorial trial, we randomly assigned 12,705 participants in 21 countries who did not have cardiovascular disease and were at intermediate risk to receive rosuvastatin at a dose of 10 mg per day or placebo. The first coprimary outcome was the composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke, and the second coprimary outcome additionally included revascularization, heart failure, and resuscitated cardiac arrest. The median follow-up was 5.6 years.

RESULTS

The overall mean low-density lipoprotein cholesterol level was 26.5% lower in the rosuvastatin group than in the placebo group. The first coprimary outcome occurred in 235 participants (3.7%) in the rosuvastatin group and in 304 participants (4.8%) in the placebo group (hazard ratio, 0.76; 95% confidence interval [CI], 0.64 to 0.91; P=0.002). The results for the second coprimary outcome were consistent with the results for the first (occurring in 277 participants [4.4%] in the rosuvastatin group and in 363 participants [5.7%] in the placebo group; hazard ratio, 0.75; 95% CI, 0.64 to 0.88; P<0.001). The results were also consistent in subgroups defined according to cardiovascular risk at baseline, lipid level, C-reactive protein level, blood pressure, and race or ethnic group. In the rosuvastatin group, there was no excess of diabetes or cancers, but there was an excess of cataract surgery (in 3.8% of the participants, vs. 3.1% in the placebo group; P=0.02) and muscle symptoms (in 5.8% of the participants, vs. 4.7% in the placebo group; P=0.005).

CONCLUSIONS

Treatment with rosuvastatin at a dose of 10 mg per day resulted in a significantly lower risk of cardiovascular events than placebo in an intermediate-risk, ethnically diverse population without cardiovascular disease.

Source: NEJM

PCSK9 inhibition better than standard therapy for cholesterol-lowering

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PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibition is showing significant promise in reducing cardiovascular (CV) events with effective cholesterol-lowering, based on impressive results from the OSLER-1 and -2 (Open-Label Study of Long-Term Evaluation Against LDL-C) trials.

OSLER-1 and -2 showed that the investigational PCSK9-inhibitor evolocumab (Repatha, Amgen) along with standard therapy, reduced LDL-cholesterol (LDL-C) by 61 percent vs standard therapy alone; from a median 120 mg/dL to 48 mg/dL after a median 11.1 month follow-up (p<0.001). [N Engl J Med 2015, e-pub 15 March, doi:10.1056/NEJMoa1500858]

In a prespecified exploratory analysis, evolocumab also reduced the incidence of CV events, defined as death, MI, unstable angina, coronary revascularization, stroke, transient ischemic attack, or heart failure, at 1 year (0.95 percent) vs standard therapy alone (2.18 percent) (p=0.003). This 53 percent reduction with evolocumab was consistent across each major CV event.

“The reduction in LDL-C was profound and that may be why we saw a marked reduction in CV events so quickly,” said Dr. Marc Sabatine of the Brigham and Women’s Hospital in Boston, MA, USA, a TIMI (Thrombolysis in Myocardial Infarction) Study Group investigator and lead author of OSLER-1 and -2.

“It suggests that if we can drive a patient’s LDL-C down a large amount to a very low level, we may start to see a benefit sooner than would be expected with a more modest intervention.”

These results follow similar results with the PCSK9-inhibitor alirocumab (Praluent, Sanofi/Regeneron), presented earlier at the 2015 European Society of Cardiology Congress, which showed a 61 percent reduction in LDL-C vs a 1 percent increase with placebo (p<0.0001). [N Engl J Med 2015, e-pub 15 March, doi:10.1056/NEJMoa501031]

“We now have many studies in a variety of different populations where we’ve seen the ability of these drugs to significantly reduce LDL-C,” said Sabatine. “And all the data we have point to the fact that the reduction in clinical events is tied to the reduction in LDL-C.”

In the open-label OSLER trials, 4,465 patients who had participated in 1 of 12 previous parent trials of evolocumab were randomized to receive intravenous evolocumab 140 mg every 2 weeks or 420 mg monthly plus standard therapy or standard therapy alone.

Adverse events occurred similarly between the two arms, however, evolocumab was associated with slightly more neurocognitive events.

An ongoing trial to study the effect of evolocumab on CV outcomes is expected to answer key questions regarding its clinical potential. The study, involving 27,500 patients, is not expected to see results until 2017.