FOURIER
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Clinical Question
Among patients with clinical atherosclerotic disease and LDL >70 despite high- or moderate-intensity statin therapy, does the addition of PCSK9 inhibitor evolocumab reduce major cardiovascular events compared to placebo?
Bottom Line
Among patients with clinical atherosclerotic disease and LDL > 70 despite high- or moderate-intensity statin therapy (70% high intensity), the addition of evolocumab resulted in an absolute 1.5% reduction in major cardiovascular events (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) at median follow-up 26 months, driven primarily by reductions in nonfatal MI, stroke, and revascularization. There was no overall or CV-specific mortality benefit with evolocumab. Other than a modest 2% incidence in injection-site reactions, there was no increase in key adverse events including new-onset diabetes or neurocognitive effects in patients receiving evolocumab.
Major Points
Multiple large RCTs including 4S, MIRACL, and PROVE IT-TIMI 22 have established the role of statin therapy in reducing future cardiovascular events and mortality in patients with established atherosclerotic disease. The subsequent IMPROVE-IT trial demonstrated that the addition of ezetimibe to statin therapy further reduces CV events in this population, suggesting that maximal LDL reduction is the key mechanism in improving outcomes in patients with established atherosclerotic disease.
The PCSK9 inhibitors alirocumab and evolocumab have recently been approved as effective LDL reducing agents. PCSK9 inhibitors work by inhibiting the action of PCSK9, an enzyme that results in internalization and destruction of LDL receptors. In the trials OSLER and ODYSSEY LONG TERM, use of these agents was shown to reduce LDL by an additional 60% in patients on background moderate- or high-intensity statin therapy with very good tolerability. A prospective randomized trial investigating whether the resultant LDL reduction seen with these agents in addition to statin therapy results in an improvement in CV outcomes was needed.
The 2017 Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) trial randomized patients with established atherosclerotic disease on background moderate- or high-intensity statin therapy (70% high intensity) to the PCSK9 inhibitor evolocumab versus placebo and assessed for a primary outcome of major CV events (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization). At median follow-up 26 months, evolocumab was associated with an absolute 1.5% reduction in major cardiovascular events (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization), driven primarily by reductions in nonfatal MI, stroke, and revascularization. Treatment of 74 patients with evolocumab over 2 years would be expected to prevent one CV death, MI, or stroke. LDL was reduced by 59% from a median of 92 to 30 in the evolocumab group. There was no overall or CV-specific mortality benefit with evolocumab, although CV death rates were notably low (< 2%) in both groups. Effects of evolocumab were consistent regardless of baseline LDL level or intensity of background statin use. Other than a modest 2% incidence in injection-site reactions (which led to no excess drug discontinuations vs. placebo), there was no increase in key adverse events including new-onset diabetes or neurocognitive effects in patients receiving evolocumab.
In summary, evolocumab in addition to moderate- or high-intensity statin therapy in patients with established atherosclerotic disease results in a modest reduction in CV events including MI and stroke although notably without a reduction in overall or CV-specific mortality. Importantly, PCSK9 inhibition was well-tolerated without excess new-onset diabetes or neurocognitive effects despite dramatic LDL reduction. The effect of FOURIER on clinical practice remains to be seen, but given the significant cost of PSCK9 inhibitors and lack of established mortality benefit, their routine addition to standard-of-care statin therapy in patients with established atherosclerosis is likely to be reserved (at least initially) for those perceived to be at particularly high risk for CV events, including patients with poorly controlled LDL levels despite maximally-tolerated statin therapy. There is also further evidence provided that treatment of LDL to below current targets appears to be beneficial and well-tolerated.
Guidelines
AHA/ACCP Cholesterol Clinical Practice Guidelines (2018, adapted)[1]
- Following patient-clinician discussion of benefit, safety, and cost, it is reasonable to add PCSK9 inhibitor in patients with clinical ASCVD at very high risk who are on maximally tolerated LDL-lowering therapy with LDL ≥70 mg/dL or non-HDL level of ≥100 mg/dL. (Class of recommendation: moderate benefit, level of evidence A)
- Based on 2018 data, PCSK9 inhibitors appear to be a low-value intervention (>$150,000 per QALY). (Level of evidence B, non-randomized)
Design
- Multicenter, randomized, double-blind, trial
- N=24,081
- Evolocumab (n=13,784)
- Placebo (n=13,780)
- Setting: 1242 sites in 49 countries
- Enrollment: February 2013 - June 2015
- Median follow-up: 26 months
- Analysis: Intention-to-treat
- Primary outcome: Major CV events (CV death, MI, stroke, hospitalization for unstable angina, or coronary revascularization)
Population
Inclusion Criteria
- Age ≥ 40 and ≤ 85
- Clinically evidence atherosclerotic disease (1 required):
- MI
- Non-hemorrhagic stroke
- Symptomatic PAD (claudication with ABI ≤ 0.85 or revascularization or amputation)
- Major risk factor for CV events (1 required, or 2 minor risk factors met):
- Diabetes
- Age ≥ 65 at randomization
- MI or non-hemorrhagic stroke within 6 months
- Additional MI or non-hemorrhagic stroke
- Current daily smoker
- History of PAD if qualified by MI or stroke
- Minor risk factor for CV events (2 required if no major risk factor met):
- History of non-MI-related coronary revascularization
- Residual CAD with stenosis ≥ 40% in ≥ 2 large vessels
- Most recent HDL < 40 for men or < 50 for women
- Most recent hsCRP > 2
- Most recent LDL ≥ 130 or ≥ 70 after two weeks of lipid lowering therapy
- Presence of metabolic syndrome
- Most recent fasting TG ≤ 400
Exclusion Criteria
- MI or stroke within 4 weeks
- NYHA class III or IV heart failure or LVEF < 30%
- Hemorrhagic stroke
- Uncontrolled or recurrent ventricular tachycardia
- Planned cardiac surgery or revascularization within 3 months
- SBP > 180mmHg or DBP > 110mmHg
- Use of CETP inhibition, mipomersen, or lomitapide within 12 months prior to randomization
- Prior use of PCSK9 inhibitor other than evolocumab or use of evolocumab < 12 weeks prior
- Uncontrolled or inadequately treated hyperthyroidism or hypothyroidism
- Severe renal or liver dysfunction
- CK > 5 times ULN
- Life expectancy < 3 years
- Active malignancy
- Active infection
- Premenopausal woman not receiving birth control
Baseline Characteristics
From the evolocumab group
- Demographics: age 63, male 75% white 85%
- Region: Europe 63%, North America 17%, Asia 14%, Latin America 7%
- Type of atherosclerosis: MI 81%, stroke 20%, PAD 14%
- CV risk factors: HTN 80%, DM 37%, smoker 28%
- Medications: High-intensity statin 70%, moderate-intensity statin 30%, ezetimibe 5%, ASA 93%, beta blocker 76%, ACE/ARB 78%
- Lipids: LDL 92, total cholesterol 168, HDL 44, TG 134, Lp(a) 37
Interventions
- Patients randomized in 1:1 ratio to receive subcutaneous evolocumab
- Randomization stratified by screening LDL < 85 vs. > 85
- Evolocumab dosed either as 140mg every 2 weeks or 420mg every month (per patient preference)
- A central clinical-events committee adjudicated all potential efficacy and safety endpoint events and cases of new-onset diabetes
Outcomes
Evolocumab vs. placebo
Primary Outcome
- Cardiovascular death, MI, stroke, hospitalization for unstable angina, coronary revascularization
- 1344 (9.8%) vs. 1563 (11.3%) [HR 0.85, 95% CI 0.79-0.92, p<0.001]
Secondary Outcomes
- Cardiovascular death, MI, stroke
- 816 (5.9%) vs. 1013 (7.4%) [HR 0.80, 95% CI 0.73-0.88, p<0.001]
- Cardiovascular death
- 251 (1.8%) vs. 240 (1.7%) [HR 1.05, 95% CI 0.88-1.25, p=0.62]
- All-cause death
- 444 (3.2%) vs. 426 (3.1%) [HR 1.04, 95% CI 0.91-1.19, p=0.54]
- Myocardial infarction
- 468 (3.4%) vs. 639 (4.6%) [HR 0.73, 95% CI 0.65-0.82, p<0.001]
- Stroke
- 207 (1.5%) vs. 262 (1.9%) [HR 0.79, 95% CI 0.66-0.95, p=0.01]
- Coronary revascularization
- 759 (5.5%) vs. 965 (7.0%) [HR 0.78, 95% CI 0.71-0.86, p<0.001]
Subgroup Analysis
The effect of evolocumab with regard to the primary endpoint and key secondary composite endpoint were consistent across major subgroups, including those based on age, sex, type of atherosclerotic vascular disease, evolocumab dosing regime, intensity of baseline statin use, and baseline LDL level.
Adverse Events
- Any adverse event
- 10,664 (77.4%) vs. 10,644 (77.4%) [p=NS]
- Serious adverse event
- 3410 (24.8%) vs. 3404 (24.7%) [p=NS]
- Injection site reaction
- 296 (2.1%) vs. 219 (1.6%) [p<0.001]
- Muscle-related event
- 682 (5.0%) vs. 656 (4.8%) [p=NS]
- New-onset diabetes
- 677 (8.1%) vs. 644 (7.7%) [p=NS]
- Neurocognitive event
- 217 (1.6%) vs. 202 (1.5%) [p=NS]
- LFT elevation
- 240 (1.8%) vs. 242 (1.8%) [p=NS]
- CK elevation
- 95 (0.7%) vs. 99 (0.7%) [p=NS]
Criticisms
- Median follow-up time of 26 months limits assessment of the effects of evolocumab on cardiovascular events or mortality over the long-term
- Very low CV mortality rates (< 2%) in both groups may result in underpowering to detect a mortality benefit with evolocumab, although the numerical direction of effect is in favor of statin therapy making this possibility remote
Funding
- The trial sponsor Amgen was involved with the design of the trial and data collection (but not data analysis).