High-Intensity Statins Guideline Expectations and Clinical Application

There have been major advances in the understanding and management of atherosclerotic cardiovascular disease (ASCVD). Central to these was the discovery of the role of cholesterol-containing lipoprotein particles in the atherosclerotic process and the development of lipid-lowering agents, particularly statins. Despite substantial and consistent evidence to support a causal link between statin use and prevention of ASCVD events, there is still debate regarding the appropriate administration of statins, particularly with regard to primary prevention.

Reference: JAMA. 2017;317(24):2543-2544.

Effect of Evolocumab on Progression of Coronary Disease in Statin-Treated Patients: The GLAGOV Randomized Clinical Trial

Importance  Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated.

Objective  To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients.

Design, Setting, and Participants  The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography.

Interventions  Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins.

Main Outcomes and Measures  The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated.

Results  Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, −56.5 mg/dL [95% CI, −59.7 to −53.4]; P < .001). The primary efficacy parameter, PAV, increased 0.05% with placebo and decreased 0.95% with evolocumab (difference, −1.0% [95% CI, −1.8% to −0.64%]; P < .001). The secondary efficacy parameter, normalized TAV, decreased 0.9 mm3 with placebo and 5.8 mm3 with evolocumab (difference, −4.9 mm3 [95% CI, −7.3 to −2.5]; P < .001). Evolocumab induced plaque regression in a greater percentage of patients than placebo (64.3% vs 47.3%; difference, 17.0% [95% CI, 10.4% to 23.6%]; P < .001 for PAV and 61.5% vs 48.9%; difference, 12.5% [95% CI, 5.9% to 19.2%]; P < .001 for TAV).

Conclusions and Relevance  Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes.

Trial Registration  clinicaltrials.gov Identifier: NCT01813422

Discontinuation and restarting in patients on statin treatment: prospective open cohort study using a primary care database

Objectives To estimate rates of discontinuation and restarting of statins, and to identify patient characteristics associated with either discontinuation or restarting.

Design Prospective open cohort study.

Setting 664 general practices contributing to the Clinical Practice Research Datalink in the United Kingdom. Data extracted in October 2014.

Participants Incident statin users aged 25-84 years identified between January 2002 and September 2013. Patients with statin prescriptions divided into two groups: primary prevention and secondary prevention (those already diagnosed with cardiovascular disease). Patients with statin prescriptions in the 12 months before study entry were excluded.

Main outcome measures Discontinuation of statin treatment (first 90 day gap after the estimated end date of a statin prescription), and restarting statin treatment for those who discontinued (defined as any subsequent prescription between discontinuation and study end).

Results Of 431 023 patients prescribed statins as primary prevention with a median follow-up time of 137 weeks, 47% (n=204 622) discontinued treatment and 72% (n=147 305) of those who discontinued restarted. Of 139 314 patients prescribed statins as secondary prevention with median follow-up time of 182 weeks, 41% (n=57 791) discontinued treatment and 75% (43 211) of those who discontinued restarted. Younger patients (aged ≤50 years), older patients (≥75 years), women, and patients with chronic liver disease were more likely to discontinue statins and less likely to restart. However, patients in ethnic minority groups, current smokers, and patients with type 1 diabetes were more likely to discontinue treatment but then were more likely to restart, whereas patients with hypertension and type 2 diabetes were less likely to discontinue treatment and more likely to restart if they did discontinue. These results were mainly consistent in the primary prevention and secondary prevention groups.

Conclusions Although a large proportion of statin users discontinue, many of them restart. For many patient groups previously considered as “stoppers,” the problem of statin treatment “stopping” could be part of the wider issue of poor adherence. Identification of patient groups associated with completely stopping or stop-starting behaviour has positive implications for patients and doctors as well as suggesting areas for future research.

BMJ 2016;353:i3305

Impact of statin related media coverage on use of statins: interrupted time series analysis with UK primary care data

Objective To quantify how a period of intense media coverage of controversy over the risk:benefit balance of statins affected their use.

Design Interrupted time series analysis of prospectively collected electronic data from primary care.

Setting Clinical Practice Research Datalink (CPRD) in the United Kingdom.

Participants Patients newly eligible for or currently taking statins for primary and secondary cardiovascular disease prevention in each month in January 2011-March 2015.

Main outcome measures Adjusted odds ratios for starting/stopping taking statins after the media coverage (October 2013-March 2014).

Results There was no evidence that the period of high media coverage was associated with changes in statin initiation among patients with a high recorded risk score for cardiovascular disease (primary prevention) or a recent cardiovascular event (secondary prevention) (odds ratio 0.99 (95% confidence interval 0.87 to 1.13; P=0.92) and 1.04 (0.92 to 1.18; P=0.54), respectively), though there was a decrease in the overall proportion of patients with a recorded risk score. Patients already taking statins were more likely to stop taking them for both primary and secondary prevention after the high media coverage period (1.11 (1.05 to 1.18; P<0.001) and 1.12 (1.04 to 1.21; P=0.003), respectively). Stratified analyses showed that older patients and those with a longer continuous prescription were more likely to stop taking statins after the media coverage. In post hoc analyses, the increased rates of cessation were no longer observed after six months.

Conclusions A period of intense public discussion over the risks:benefit balance of statins, covered widely in the media, was followed by a transient rise in the proportion of people who stopped taking statins. This research highlights the potential for widely covered health stories in the lay media to impact on healthcare related behaviour.

BMJ 2016;353:i3283