Evolocumab Significantly Reduces Risk of CV Events in Patients with PAD (Session LBS.02)
Of the 27,564 patients enrolled in the evolocumab cardiovascular outcomes study, 3,642 of them had symptomatic PAD. Compared to those without PAD, these patients were older and had more CV risk factors including hypertension, smoking and diabetes. At 2.5 years, evolocumab reduced the low-density lipoprotein cholesterol (LDL-C) levels in patients with PAD from a median of 93 to 31 mg/dL (p<0.001). In patients with PAD, evolocumab significantly reduced the composite primary endpoint, which included hospitalization for unstable angina, coronary revascularization,
heart attack, stroke or CV death, by 21 percent (2.5-year Kaplan-Meier rate 13.3 percent versus
16.8 percent, HR 0.79, 95 percent CI 0.66-0.94, p=0.0098) and the secondary composite endpoint of heart attack, stroke or CV death by 27 percent (9.5 percent versus 13.0 percent, HR 0.73, 95 percent CI 0.59-0.91, p=0.0040).
Evolocumab Demonstrated Significant Clinical Benefit Across a Range of High-Risk Patient Populations (Session LBS.02)
In a separate analysis, researchers evaluated the efficacy of evolocumab in different MI subgroups. Patients with a history of MI (N=22,351) were characterized according to the time since their most recent MI event, number of previous MIs and presence of multivessel coronary artery disease (CAD). Treatment with evolocumab resulted in a 24 percent relative risk reduction (RRR) (HR 0.76; 95 percent CI 0.64-0.89; p<0.001) in patients within two years of their most recent MI compared to 13 percent (HR 0.87; 95 percent CI 0.76-0.99; p=0.04) for those whose most recent MI occurred more than two years prior to enrollment. In those with multiple prior MIs, the RRR was 21 percent (HR 0.79; 95 percent CI 0.67-0.94; p=0.006) compared to 16 percent (HR 0.84; 95 percent CI 0.74-0.96; p=0.008) for those with only one previous MI, and patients with a history of multivessel CAD had a RRR of 30 percent (HR 0.70; 95 percent CI 0.58-0.84; p<0.001) compared to 11 percent RRR (HR 0.89; 95 percent CI 0.79-1.00; p=0.055) in patients without multivessel CAD.
Another analysis (Abstract #183) evaluating the totality of the primary endpoint events (both first and recurrent) during the course of the study revealed that treatment with evolocumab improved clinical outcomes with significant reductions in total primary endpoint events driven by decreases in MI, stroke and coronary revascularization. Evolocumab reduced composite primary endpoint events by 18 percent (incidence-rate ratio 0.82, 95 percent CI 0.75-0.90, p<0.001).
The FOURIER trial recently showed that evolocumab reduced major CV events compared to placebo in high-risk cardiovascular patients, including reducing MIs by 27 percent. Another new analysis (Abstract #184) revealed a robust benefit across the size and severity of MIs. Evolocumab was also effective in reducing the risk for MI regardless of size (significant reductions observed regardless of fold elevations in troponin levels) and severity (ST-elevation myocardial infarction/STEMI or non-STEMI). The evolocumab benefit was highly significant and consistent regardless of MI size and reduced the risk of STEMI heart attack by 36 percent (HR 0.64; 95 percent CI 0.49-0.84; p<0.001).
Participants in the evolocumab cardiovascular outcomes study were prospectively stratified according to their Thrombolysis in Myocardial Infarction (TIMI) Risk Score for Secondary Prevention to identify those with the greatest potential for clinical benefit following treatment with Evolocumab. Consistent with previous results, higher risk was associated with greater absolute risk reductions. (Abstract #3025)
Primary Analysis of the evolocumab Cardiovascular Outcomes Study (FOURIER)
The primary analysis included 27,564 patients with established cardiovascular disease. The study was statistically powered around the hard major adverse cardiovascular event (MACE) composite endpoint of first heart attack, stroke or cardiovascular death (key secondary composite endpoint) and found that adding evolocumab to optimized statin therapy resulted in a statistically significant 20 percent (p<0.001) reduction in these events. The study also found a statistically significant 15 percent reduction (p<0.001) in the risk of the extended MACE composite (primary) endpoint, which included hospitalization for unstable angina, coronary revascularisation, heart attack, stroke or cardiovascular death.
Evolocumab Cardiovascular Outcomes (FOURIER) Study Design
FOURIER (Further Cardiovascular OUtcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a multinational Phase 3 randomized, double-blind, placebo-controlled trial, is designed to evaluate whether treatment with evolocumab in combination with statin therapy compared to placebo plus statin therapy reduces cardiovascular events.
Eligible patients with high cholesterol (LDL-C ≥70 mg/dL [1.8mmol/l] or non-high-density lipoprotein cholesterol [non-HDL-C] ≥100 mg/dL [2.6mmol/l]) and clinically evident atherosclerotic cardiovascular disease at more than 1,300 study locations around the world were randomized to receive evolocumab subcutaneous 140 mg every two weeks or 420 mg monthly plus effective statin dose; or placebo subcutaneous every two weeks or monthly plus effective statin dose. Optimized statin therapy was defined as at least atorvastatin 20 mg or equivalent daily with a recommendation for at least atorvastatin 40 mg or equivalent daily where approved. The study was event driven and continued until at least 1,630 patients experienced a key secondary endpoint.
Evolocumab is a human monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9). Evolocumab binds to PCSK9 and inhibits circulating PCSK9 from binding to the low-density lipoprotein (LDL) receptor (LDLR), preventing PCSK9-mediated LDLR degradation and permitting LDLR to recycle back to the liver cell surface. By inhibiting the binding of PCSK9 to LDLR, evolocumab increases the number of LDLRs available to clear LDL from the blood, thereby lowering LDL-C levels.1
Repatha® (evolocumab) is approved in more than 50 countries, including the U.S., Japan, Canada and in all 28 countries that are members of the European Union. Applications in other countries are pending.
Please refer to the UK Summary of Product Characteristics for more information, at: http://www.medicines.org.uk/emc/medicine/30627 (UK) or http://www.medicines.ie/medicine/16437/SPC/Repatha+SureClick/ (Ireland)
EU Therapeutic indications1
Hypercholesterolaemia and mixed dyslipidaemia
Repatha is indicated in adults with primary hypercholesterolaemia (heterozygous familial and non-familial) or mixed dyslipidaemia, as an adjunct to diet:
- In combination with a statin or statin with other lipid lowering therapies in patients unable to reach LDL-C goals with the maximum tolerated dose of a statin or,
- Alone or in combination with other lipid-lowering therapies in patients who are statin- intolerant, or for whom a statin is contraindicated.
Homozygous familial hypercholesterolaemia
Repatha is indicated in adults and adolescents aged 12 years and over with homozygous familial hypercholesterolaemia in combination with other lipid-lowering therapies.
The effect of Repatha on cardiovascular morbidity and mortality has not yet been determined.
Summary of the safety profile
The most commonly reported adverse drug reactions during primary hypercholesterolaemia and mixed dyslipidaemia pivotal trials, at the recommended doses, were nasopharyngitis (4.8%), upper respiratory tract infection (3.2%), back pain (3.1%), arthralgia (2.2%), influenza (2.3%), and nausea (2.1%). The safety profile in the homozygous familial hypercholesterolaemia population was consistent with that demonstrated in the primary hypercholesterolaemia and mixed dyslipidaemia population.