FOURIER - Evolocumab in patients with CVD

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Bottom line:

  • In patients with ASCVD & high CV risk (~5%/year), evolocumab reduced the risk of CV events (NNT 67 over 2.2 years, i.e. ~150/year) with a ~2% risk of injection-site reactions & no other safety concerns.

  • LDL-lowering with evolocumab did not reduce the risk of death.

  • Although FOURIER is a high-quality trial that conclusively demonstrates that lowering LDL with a PCSK9 inhibitor reduces CV risk, it's not clear from this study for whom this reduction is clinically important enough to justify the substantial cost of these drugs.

  • EBBINGHAUS substudy: Evolocumab did not differ in placebo in change in cognitive function over 19 months.

 

Context

  • There's been substantial controversy around the LDL hypothesis in the past few years
    • For the longest time, statins were the only lipid-lowering agents with robust evidence of efficacy in reducing the risk of CV events
    • In 2013, American guidelines flipped their recommended approach from "treat to LDL target" to "treat to risk, whereas Canadian guidelines maintained the treat-to-target approach (though emphasis shifted further from non-statins such as fibrates & niacin)
    • In 2015, the IMPROVE-IT trial of ezetimibe in post-ACS patients, though underwhelming some with its fairly unimpressive absolute risk reduction in CV events, provided support for the LDL hypothesis by offering another class of agents which reduces CV risk seemingly via LDL reduction
    • PCSK9 inhibitors, potent LDL-lowering agents, were thus positioned as a "third pillar" for the LDL hypothesis
  • Previous meta-analyses, based almost exclusively on statin trials, demonstrated a reduction of CV events with lipid-lowering proportional to LDL reduction; relative risk reduction (RRR) per 1-mmol/L LDL reduction (estimates from Cholesterol Treatment Trialists' Collaboration meta-analysis):
    • Death ~10-15%
    • Major vascular events (MI, stroke, coronary revascularization) ~20-25%
      • Non-fatal MI or coronary death ~20-25%
      • Coronary revascularization ~20-25%
      • Stroke ~10-20%
  • The open-label OSLER trial, the largest RCT of evolocumab prior to FOURIER, found a statistically significant reduction in CV events (NNT 82 @ 11 months) with the ~60% reduction in LDL with evolocumab over placebo, but was based on a very small number of outcome events

Patients (n=27,564)

  • Included:
    1. Age 40-85 y
    2. Atherosclerotic cardiovascular disease (ASCVD), history of any of the following:
      • MI
      • Non-hemorrhagic stroke (TIA does not count)
      • Symptomatic PAD (claudication + ABI <0.85, peripheral artery revascularization or amputation due to atherosclerotic disease)
    3. LDL (most recent) >1.8 mmol/L or non-HDL >2.6 mmol/L after 2+ weeks of stable lipid-lowering therapy (max-tolerated statin, "preferentially" high-intensity with equivalent of atorvastatin 20+ mg/d +/- ezetimibe)
    4. Fasting triglycerides <4.5 mmol/L
    5. Additional risk factors: 1+ major or 2+ minor
      • Major:
        • Age 65+
        • MI/non-hemorrhagic stroke in prior 6 months
        • Multiple MI/non-hemorrhagic stroke or PAD+MI/non-hemorrhagic stroke
        • Current daily smoker
        • Diabetes
      • Minor
        • Hx non-MI-related coronary revascularization
        • Residual CAD 40+% stenosis in 2+ large vessels
        • HDL (most recent) <1.0 mmol/L
        • LDL (most recent) >3.4 mmol/L or non-HDL >4.1 mmol/L
        • Metabolic syndrome
  • Key exclusion criteria (list of all 25 in supplemental appendix)
    1. Any hx hemorrhagic stroke
    2. MI/stroke within 4 weeks
    3. Planned/expected cardiac surgery or revascularization within 3 months
    4. HF NYHA III-IV or last-known LVEF <30%
    5. Uncontrolled/recurrent VT
    6. BP >180/110 mm Hg
    7. eGFR <20
    8. Uncontrolled hypo- or hyperthyroid
  • Average study patient
    • Age 62.5 y
    • Male 75%
    • North American 17%
    • Type of ASCVD:
      • MI 81% (most recent median 3.4 y before enrolment)
      • Non-hemorrhagic stroke 19% (most recent median 3.2 y before enrolment)
      • PAD 13%
    • CV risk factors
      • Current smoker 28%
      • HTN 80%
      • Diabetes 37%
    • Labs
      • Total cholesterol 4.3 mmol/L
      • HDL 1.1 mmol/L
      • LDL 2.4 mmol/L
      • Triglycerides 1.5 mmol/L
      • Lipoprotein(a) 37 nmol/L
    • Meds
      • Statins: High-intensity 69%, moderate-intensity 30%, low-intensity <1%
      • Ezetimibe 5%
      • Antiplatelet 92%
      • ACEI/ARB 78%
      • Beta-blocker 76%

Interventions

  • I: Evolocumab
    • Either 140 mg q2 weeks or 420 mg q1 month (per patient preference)
  • C: Placebo

Results @ 2.2 years

  • Lipid parameters
    • LDL, median
      • Baseline: 2.4 mmol/L
      • @ week 48: Evolocumab 0.8 mmol/L, placebo  (-1.45 mmol/L vs placebo, ~60% reduction)
        • <0.65 mmol/L: 42% vs 0%
        • <1.0 mmol/L: 67% vs 0.5%
        • <1.8 mmol/L: 87% vs 18%
    • ApoB reduced by 46% with evolocumab
    • Lp(a) reduced by 27% with evolocumab
  • Efficacy
    • No difference in death: 3.2% vs 3.1%, hazard ratio (HR) 1.04 (0.91-1.19)
    • Reduction in composite primary outcome (CV death, MI, stroke, hospitalization for unstable angina, coronary revascularization): 9.8% vs 11.3% (NNT 67), HR 0.85 (0.79-0.92)
      • Reduction in Cholesterol Treatment Trialists "major vascular events": 9.2% vs 11.0% (NNT 56), HR 0.83 (0.77-0.90)
      • Reduction in "key" secondary composite efficacy outcome (CV death, MI, stroke): 5.9% vs 7.4% (NNT 67), HR 0.80 (0.73-0.88)
        • CV death: 1.8% vs 1.7%, p=0.62
        • MI: 3.4% vs 4.6% (NNT 84), HR 0.73 (0.65-0.82)
        • Stroke: 1.5% vs 1.9% (NNT 250), HR 0.79 (0.66-0.95)
        • Hospitalization for unstable angina: 1.7% in both groups, p=0.89
        • Coronary revascularization: 5.5% vs 7.0% (NNT 67), HR 0.78 (0.71-0.86)
  • Safety:
    • Only statistically-significant difference: Injection-site reaction: 2.1% vs 1.6% (NNH 200)
    • Serious adverse events: ~25% in both groups
    • Permanent drug discontinuation: 12% vs 13%
    • Any adverse event: 77.4% in both groups
    • Specific adverse events
      • Allergic reaction: ~3% in both groups
      • Neurocognitive event: 1.6% vs 1.5%
      • Cataract: 1.7% vs 1.8%
      • ALT/AST >3x ULN: 1.8% in both groups
      • New-onset diabetes (in those without diabetes at baseline): 8.1% vs 7.7%, non-significant relative risk (RR) 1.05
      • Muscle-related event: 5% in both groups
        • CK >5x ULN: 0.7% in both groups
        • Rhabdomyolysis: 0.1% in both groups
    • Development of evolocumab-binding antibodies in evolocumab group: 0.3% (none were neutralizing antibodies)
  • Results consistent within all tested subgroups (including q2 week vs monthly dosing); RRR similar regardless of baseline LDL

Generalizability

  • Main consideration that should limit over-generalizing the findings of this trial: High cost of evolocumab (Repatha; ~$8000/year in Canada)
    • NNT to prevent 1 CV event/year ~150 in FOURIER
    • Cost of preventing 1 non-fatal CV event with evolocumab (treating 150 patients/year): ~1.2 million
  • Population:
    • Patients in this trial were at very high CV risk (~5%/year) owing to requirement of existing ASCVD + additional risk factors. Extrapolating the NNT/year to lower-risk groups:
      • Secondary prevention or high-risk primary prevention (>2%/year): ~300 (cost ~$2.4 million/non-fatal CV event prevented)
      • Intermediate risk (1-2%/year): 450 (cost ~$3.6 million/non-fatal CV event prevented)
      • Low-risk primary prevention (<1%/year): 800-1500 (cost $7-12 million/non-fatal CV event prevented)
    • Authors did not report the % of patients with FH; if similar to other PCSK9 inhibitor trials, it is likely a small minority of enrolled patients (~3-5%). FOURIER doesn't address long-term effectiveness of lowering LDL with PCSK9 inhibitors in FH & its cost-effectiveness
  • Co-interventions
    • Only ~70% were on equivalent of atorvastatin 20 mg/d or more. It's not clear how aggressive clinicians were in trying to optimize statins before enrolling their patients into FOURIER
    • Only 5% were receiving ezetimibe at baseline. In many jurisdictions, a trial of ezetimibe to lower LDL is a prerequisite to initiating a PCSK9 inhibitor. Although the reduction in CV events is modest with ezetimibe, wider use likely would have resulted in a lower baseline CV risk & further reduced the absolute benefit (& increased the NNT) from PCSK9 inhibitors

Internal validity

  • Low risk of
    • Allocation bias: Allocated centrally by computer
    • Performance bias: Use of matching placebo, allocation concealment maintained
    • Detection bias: Outcomes adjudicated by central committee unaware of treatment assignment & lipid levels
    • Attrition bias: <0.1% lost to follow-up; analyzed by intention-to-treat
    • Selective outcome reporting bias: All outcomes of interest reported

Additional considerations

    • How does evolocumab compare to other lipid-lowering agents?
      • Statins: The effect of evolocumab on outcomes is consistent with the RRR/1-mmol/L LDL reduction with statin monotherapy, except for evolocumab's neutral effect on mortality. The 95% CI for death in FOURIER rules out the 10-15% RRR seen with statins in the Cholesterol Treatment Trialists' Collaboration meta-analysis
      • Beyond low/moderate-intensity statin:
        • High-intensity statin: Maximizing statin dose & lowering LDL by an extra 20-25% (e.g. going from atorvastatin 10 mg/d to 80 mg/d) further reduces the relative risk of a major vascular event by 15% (& are cost-effective for doing this). As with evolocumab, high-intensity statins have not demonstrated a lower risk of death versus moderate-intensity statins
        • Other than evolocumab, only ezetimibe has evidence for reducing CV outcomes beyond statin monotherapy. Fibrates, niacin & CETP inhibitors all failed as add-on to statin therapy
    • What does FOURIER mean for lipid targets?
      • Although debate will continue regarding the clinical significance of benefits from increasing lipid-lowering intensity, FOURIER & IMPROVE-IT consistently demonstrate that "lower is better" for LDL, with no clear safe lower limit
      • FOURIER inclusion criteria required patients to have LDL >1.8 mmol/L, but patients achieved similar absolute & relative risk reductions with evolocumab regardless of baseline LDL (from 1.8-2.0 mmol/L to >2.8 mmol/L)
      • Despite most patients in the evolocumab group achieving an LDL <1.8 mmol/L (and most reaching <1.0 mmol/L, half the Canadian LDL target), their CV risk remained elevated at ~4-5%/year. This is a reminder that dyslipidemia is but 1 of many CV risk factors & that achieving LDL targets cannot be the only means of reducing an individual's CV risk

    EBBINGHAUS substudy

    • Subgroup study of FOURIER (n=1974, 7.2% of study population; 1204 analyzed in primary analysis) evaluating the effect of evolocumab vs placebo on cognitive function using the Cambridge Neuropsychological Test Automated Battery (CANTAB) done at baseline, week 24, annually, & then at the end of the trial
    • Primary outcome (spatial working member strategy index of executive function, score ranges from 4-28, lower = better)
      • Baseline: 17.8
      • Last follow-up (median 19 months): Evolocumab 17.5, placebo 17.6
      • Change from baseline: -0.21 vs -0.29 (p<0.001 for non-inferiority)
    • Secondary outcomes:
      • Working memory (score 0-270, lower = better)
        • Last follow-up: Evolocumab 20.3 vs placebo 20.1
        • Change from baseline: -0.52 vs -0.93 (p=0.36 for difference)
      • Episodic memory (score 0-70, lower = better)
        • Last follow-up: Evolocumab 24.9 vs placebo 23.6
        • Change from baseline: -1.53 in both groups (p=0.49 for difference)
      • Psychomotor speed (median time, lower = better)
        • Baseline: 356.7 vs 355.1
        • Last follow-up: 361.8 vs 355.7
        • Change from baseline: +5.2 vs +0.9 (p=0.06 for difference)
    • Subgroup analyses suggested that evolocumab was worse than placebo in patients with baseline LDL <85 mg/dL, but better than placebo in those with baseline LDL >85 mg/dL (p=0.01 for interaction), though this was not supported by subgroup analysis of secondary outcomes