IMPORTANCE:

Current guidelines for atherosclerotic cardiovascular disease focus on high-intensity statins and targeting or using a threshold low-density lipoprotein cholesterol (LDL-C) level of less than 70 mg/dL for the highest-risk patients. Whether further reduction of LDL-C beyond these boundaries would be beneficial is unknown.

OBJECTIVE:

To compare outcomes of evolocumab vs placebo in patients with stable atherosclerotic cardiovascular disease and a baseline LDL-C of less than 70 mg/dL and in those receiving background treatment with a maximal-potency statin.

DESIGN, SETTING, AND PARTICIPANTS:

This secondary ad hoc analysis of the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial compared randomized treatments in 2 subgroups of patients with stable atherosclerotic cardiovascular disease currently receiving statin. Patients were classified by a baseline LDL-C of less than 70 or at least 70 mg/dL and by statin intensity (maximal: atorvastatin calcium, 80 mg/d, or rosuvastatin, 40 mg/d; submaximal: all other dosages). Patients with baseline LDL of less than 70 mg/dL either had a final screening LDL-C of at least 70 mg/dL or a final screening non-high-density lipoprotein cholesterol level of at least 100 mg/dL. Data were retrieved from 2013 to 2016 and analyzed in 2017 based on intention to treat.

MAIN OUTCOMES AND MEASURES:

The primary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The secondary efficacy endpoint was the composite of cardiovascular death, myocardial infarction, or stroke. Safety outcomes included adverse events and events of interest identified in the FOURIER trial. Interaction testing was used to assess the consistency of results in patients who did vs did not satisfy the above criteria.

RESULTS:

A total of 27 564 patients (75.4% men and 24.6% women; mean [SD] age, 62.5 [9.0] years) were included in the analysis. Of 2034 patients (7.4%) who had a baseline LDL-C of less than 70 mg/dL, evolocumab reduced the risk for the primary endpoint (hazard ratio [HR], 0.80; 95% CI, 0.60-1.07) to a similar degree as in the 25 529 patients who had baseline LDL-C of at least 70 mg/dL (HR 0.86; 95% CI, 0.79-0.92; P = .65 for interaction; 1 patient was missing baseline LDL-C data). Of 7533 patients (27.3%) receiving maximal-potency statins, evolocumab significantly reduced the primary endpoint (HR, 0.86; 95% CI, 0.75-0.98) to a similar degree as in the 20 031 patients not receiving a maximal-potency statin (HR, 0.85; 95% CI, 0.78-0.93; P = .88 for interaction). The key secondary endpoint was reduced to a similar degree in both analyses. No major safety concerns were identified.

CONCLUSIONS AND RELEVANCE:

Evolocumab was equally effective in reducing cardiovascular events in patients with stable atherosclerotic cardiovascular disease regardless of whether the baseline LDL-C was less than 70 or at least 70 mg/dL and whether the background statin was of maximal or submaximal potency.

BACKGROUND:

The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events.

METHODS:

FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia.

RESULTS:

Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.0098) and without PAD (HR 0.86; 95% CI, 0.80-0.93; P=0.0003; Pinteraction=0.40). For the key secondary end point, the HRs were 0.73 (0.59-0.91; P=0.0040) for those with PAD and 0.81 (0.73-0.90; P<0.0001) for those without PAD (Pinteraction=0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38-0.88; P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL.

CONCLUSIONS:

Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events.

CLINICAL TRIAL REGISTRATION:

URL:

https://www.clinicaltrials.gov. Unique identifier: NCT01764633.

Statins effectively lower low-density lipoprotein cholesterol (LDL-C), reducing cardiovascular morbidity and mortality. Most patients tolerate statins well, but approximately 10% to 20% experience side effects (primarily muscle-related) contributing to diminished compliance or discontinuation of statin therapy and subsequent increase in cardiovascular risk. Statin-intolerant patients require more effective therapies for lowering LDL-C. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a compelling target for LDL-C-lowering therapy. Evolocumab (AMG 145) is a fully human monoclonal antibody that binds PCSK9, inhibiting its interaction with the LDL receptor to preserve LDL-receptor recycling and reduce LDL-C. Phase 2 studies have demonstrated the safety, tolerability, and preliminary efficacy of subcutaneous evolocumab in diverse populations, including statin-intolerant patients. This article describes the rationale and design of the Goal Achievement After Utilizing an anti-PCSK9 Antibody in Statin-Intolerant Subjects 2 (GAUSS-2) trial, a randomized, double-blind, ezetimibe-controlled, multicenter phase 3 study to evaluate the effects of 12 weeks of evolocumab 140 mg every 2 weeks or 420 mg every month in statin-intolerant patients with hypercholesterolemia. Eligible subjects were unable to tolerate effective doses of ≥2 statins because of myalgia, myopathy, myositis, or rhabdomyolysis that resolved with statin discontinuation. The primary objective of the study is to assess the effects of evolocumab on percentage change from baseline in LDL-C. Secondary objectives include evaluation of safety and tolerability, comparison of the effects of evolocumab vs ezetimibe on absolute change from baseline in LDL-C, and percentage changes from baseline in other lipids. Recruitment of approximately 300 subjects was completed in August 2013.

This study aimed to investigate the impact of intensive cholesterol-lowering therapy (including evolocumab), drug treatment for high-risk plaques (Vulnerable plaques) with a high probability of developing acute coronary syndrome. The purpose of this study is to determine the effect of the change in the Lipid core burden index and compare the rate of cardiac events over 12 months following cholesterol therapy.

Background and Aims: Lerodalcibep (LIB), a small recombinant fusion protein of a PCSK9‐binding domain (adnectin) and albumin, demonstrated highly effective PCSK9 and LDL‐C suppression in Phase 2 studies. This global Phase 3 trial included India and Turkey, evaluated safety and efficacy of LIB 300 mg SC QM compared to evolocumab (EVO) 420 mg SC QM in genetically confirmed HoFH patients with novel variants on stable lipid lowering therapy not receiving LDL‐apheresis. Methods: Eligible patients (age ≥10 years) were randomized to either LIB or EVO for 24 weeks (Period A) followed by an 8 week ‘washout’ and crossed over to the alternate therapy for the next 24 weeks (Period B). Results: Of 82 HoFH patients screened, 65 entered Period A and 56 completed both Periods (mean age 29; range 10‐58 years; 45% male; mean baseline LDL‐C 401 mg/dL); Mean (SD) reduction in LDL‐C was ‐9.6% (24.3) on LIB and ‐11.7% (27.4) on EVO. LDL‐C reductions were highly variable but were similar with LIB and EVO in individual subjects (r=0.79; p<0.001) ‐ figure. Mean free PCSK9 levels were decreased by 81% at trough on LIB. Both drugs were well tolerated, with no treatment related safety concerns or deaths. [Formula presented] Conclusions: LIBerate‐HoFH is the largest randomized and diverse global trial conducted in genetically confirmed HoFH patients. Despite robust PCSK9 suppression, the LDL‐C response was highly variable but similar with both drugs. PCSK9 inhibitors remain standard of care in HoFH with good residual LDLR activity and worth assessing for those with novel variants but unknown LDLR activity.

BACKGROUND:

Efficacy and safety of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, alirocumab (ALI) and evolocumab (EVO) have previously been evaluated through controlled clinical trials with selective patient groups. Post-commercially, in patients with heterozygous familial hypercholesterolemia (HeFH) and/or cardiovascular disease (CVD) with suboptimal LDL cholesterol (LDLC) lowering on maximal tolerated cholesterol lowering therapy, we assessed efficacy and safety of ALI and EVO.

METHODS:

Post-commercially, we started 25 patients on ALI 75 mg, 15 on ALI 150 mg, and 32 on EVO 140 mg bi-weekly added to entry LDLC lowering regimen, with follow-up for a median 24 weeks. History, physical exam, demographics, and adverse event data were collected. Changes in LDLC and AHA and NIH calculated 10-year CVD risks were assessed on ALI and EVO.

RESULTS:

Of 72 patients, 25 had HeFH only, 25 CVD only, 22 had both, median age was 65 years, 63% females, 38% males, 86% Caucasian, 11% African-Americans, 17% diabetics, 63% on anti-hypertensives, and 7% smokers. At entry, 30 (42%) were on a statin and 42 (58%) could not tolerate any statins. At 24-weeks, median LDLC decreased on ALI 75 mg from 117 to 62 mg/dL (-54%), on ALI 150 mg from 175 to 57 mg/dL (-63%), and on EVO 140 mg from 165 to 69 mg/dL (-63%), p <0.0001 for all. Absolute and percent LDLC reduction did not differ (p >.05) between ALI 150 and EVO 140 mg, but were less on ALI 75 mg vs ALI 150 mg and EVO 140 mg (p <.05). Percent reductions in 10-year CVD risks by AHA and NIH calculators, respectively were ALI 75 mg -22 and -44%, ALI 150 mg -31 and -50%, and EVO 140 mg -29 and -56%, p ≤.002 for all. The three most common adverse events included flu-like myositis 10%, respiratory tract symptoms 8%, and injection site reaction 6%.

CONCLUSION:

In patients with HeFH and/or CVD, LDLC was lowered by 63% on EVO and ALI 150 mg, and 54% on ALI 75 mg. Adverse events were minimal and tolerable. ALI and EVO represent paradigm shifts in LDLC lowering. Long term, post-commercial safety and efficacy remain to be determined.

BACKGROUND:

Evolocumab (AMG 145), a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) in phase 2 studies of 12 weeks' duration. The longer-term efficacy and safety of PCSK9 inhibition remain undefined.

METHODS AND RESULTS:

Of 1359 randomized and dosed patients in the 4 evolocumab phase 2 parent studies, 1104 (81%) elected to enroll into the Open-Label Study of Long-term Evaluation Against LDL-C (OSLER) study. Regardless of their treatment assignment in the parent study, patients were randomized 2:1 to receive either open-label subcutaneous evolocumab 420 mg every 4 weeks with standard of care (SOC) (evolocumab+SOC, n=736) or SOC alone (n=368). Ninety-two percent of patients in the evolocumab+SOC group and 89% of patients in the SOC group completed 52 weeks of follow-up. Patients who first received evolocumab in OSLER experienced a mean 52.3% [SE, 1.8%] reduction in LDL-C at week 52 (P<0.0001). Patients who received 1 of 6 dosing regimens of evolocumab in the parent studies and received evolocumab+SOC in OSLER had persistent LDL-C reductions (mean reduction, 50.4% [SE, 0.8%] at the end of the parent study versus 52.1% [SE, 1.0%] at 52 weeks; P=0.31). In patients who discontinued evolocumab on entry into OSLER, LDL-C levels returned to near baseline levels. Adverse events and serious adverse events occurred in 81.4% and 7.1% of the evolocumab+SOC group patients and 73.1% and 6.3% of the SOC group patients, respectively.

CONCLUSION:

Evolocumab dosed every 4 weeks demonstrated continued efficacy and encouraging safety and tolerability over 1 year of treatment in the largest and longest evaluation of a PCSK9 inhibitor in hypercholesterolemic patients to date.

CLINICAL TRIAL REGISTRATION URL:

http://clinicaltrials.gov. Unique identifier: NCT01439880.

Este artículo no tiene resumen

Some observational studies raised concern that statins may cause memory impairment, leading to a US Food and Drug Administration warning. Similar questions were raised regarding proprotein convertase subtilisin/kexin-type 9 inhibitors (PCSK9i) and neurocognitive function. No prospectively designed study has evaluated the relationship between long-term PCSK9i use and cognition changes. Patients with prior cardiovascular disease treated with maximally tolerated statin enrolled in FOURIER (the randomized, double-blind, placebo-controlled cardiovascular outcome study of the PCSK9i evolocumab) could participate in this prospective assessment of cognitive function (EBBINGHAUS). Key additional exclusion criteria for EBBINGHAUS were dementia, cognitive impairment, or other significant mental or neurological disorder. Cognitive testing was performed using the Cambridge Neuropsychological Test Automated Battery, a tablet-based tool assessing executive function, working memory, memory function, and psychomotor speed at baseline, weeks 24 and 48, every 48 weeks thereafter, and study end. The primary endpoint was spatial working memory strategy index of executive function (SWMSI). The primary hypothesis was that evolocumab would be noninferior to placebo in the mean change from baseline over time in SWMSI. Fifteen hundred cognitively normal patients completing the assessments provided approximately 97% power to demonstrate that the upper 95% confidence interval for the treatment difference in mean change from baseline in SWMSI over time is <20% of the SD of the mean change in the placebo group. An exploratory analysis will compare neurocognitive function in patients with post-baseline low-density lipoprotein cholesterol <25 mg/dL. EBBINGHAUS will evaluate whether the addition of evolocumab to statin therapy affects cognitive function over time in patients with stable cardiovascular disease.

AIMS:

Two anti-proprotein convertase subtilisin/kexin type 9 (PCSK9) monoclonal antibodies, alirocumab and evolocumab, have been approved for the treatment of hypercholesterolaemia in certain patients. We reviewed data from phase 3 studies to evaluate the efficacy and safety of these antibodies.

METHODS:

We systematically reviewed phase 3 English-language studies in patients with hypercholesterolaemia, published between 1 January 2005 and 20 October 2015. Congress proceedings from 16 November 2012 to 16 November 2015 were also reviewed.

RESULTS:

We identified 12 studies of alirocumab and nine of evolocumab, including over 10 000 patients overall. Most studies enrolled patients with hypercholesterolaemia and used anti-PCSK9 antibodies with statins. The ODYSSEY FH I, FH II and HIGH FH alirocumab studies and the RUTHERFORD-2 evolocumab study exclusively recruited patients with heterozygous familial hypercholesterolaemia. Two evolocumab studies focused mainly on homozygous familial hypercholesterolaemia (HoFH): TESLA Part B and TAUSSIG (a TESLA sub-study); only data for HoFH are reported here. All comparator studies demonstrated a reduction in LDL cholesterol (LDL-C) with the anti-PCSK9 antibodies. No head to head studies were conducted between alirocumab and evolocumab. Up to 87% of patients receiving alirocumab and up to 98% receiving evolocumab reached LDL-C goals. Both antibodies were effective and well tolerated across a broad population of patients and in specific subgroups, such as those with type 2 diabetes.

CONCLUSIONS:

Using anti-PCSK9 antibodies as add-on therapy to other lipid-lowering treatments or as monotherapy for patients unable to tolerate statins may help patients with high cardiovascular risk to achieve their LDL-C goals.