ODYSSEY OUTCOMES - Alirocumab added to max-tolerated statins after ACS

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Bottom line: In patients with ACS in the past 12 months & LDL-C >1.8 mmol/L on max-tolerated statin therapy, alirocumab reduced the risk of major adverse cardiovascular events (composite of death/MI/stroke) by 1.6% (NNT 63), versus placebo over 2.8 years. Alirocumab increased local injection-site reactions compared to placebo (NNH 59).

Context: FOURIER trial and prior evidence

Patients (n=18,924)

  • 1315 sites in 57 countries (15% from Canada/US), enrolling from Nov 2012 to Nov 2015

  • Included

    • 40+ y/o

    • Hospitalized for ACS 1-2 months ago

    • LDL-C 1.8+ mmol/L, non-HDL-C 2.6+ mmol/L, or ApoB 0.80+ g/L after 2+ weeks on stable high-intensity statin (atorvastatin 40-80 mg/d, rosuvastatin 20-40 mg/d), or max-tolerated statin (including no statin if documented intolerance)

  • Excluded

    • Uncontrolled HTN (>180/110 mm Hg)

    • HF with NYHA functional class 3-4

    • Hx hemorrhagic stroke

    • Fasting triglycerides >4.5 mmol/L

    • ALT/AST >3x ULN

  • Baseline characteristics

    • Age 59 y, female (25%), white (79%)

    • Randomized median 2.6 months (IQR 1.7-4.3) after ACS

    • Index ACS: STEMI (35%), NSTEMI (48%), UA (17%)

    • Prior MI (19%), PCI (17%), stroke (3%), HF (15%)

    • Smoker (24%), HTN (65%), DM (29%), FHx premature CAD (36%)

    • Labs: LDL-C 2.4 mmol/L, HDL-C 1.2, non-HDL-C 3.2, apoB 0.8 g/L, Lp(a) 40 mg/dL

    • Meds: Statin (97.5%; high-intensity 89%), ezetimibe (3%)

      • Antiplatelet (99%), ACEI/ARB (78%), beta-blocker (85%)

Intervention & control

  • I: Alirocumab 75 mg subcut every 2 weeks

    • Uptitrated to 150 mg every 2 weeks to target an LDL-C 0.65-1.3 mmol/L, or switch to placebo if <0.4 mmol/L

  • C: Matching placebo

Results @ median 2.8 years

Efficacy

  • 1o outcome (CHD death, non-fatal MI, fatal or non-fatal ischemic stroke, UA hospitalization): Alirocumab 9.5% vs placebo 11.1% (NNT=63, or NNT=~175/year)

    • Hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.78-0.93

    • No significant difference in efficacy between pre-defined subgroups

    • Non-fatal MI: 6.6% vs 7.6% (HR 0.86, 95% CI 0.77-0.96)

    • Non-fatal ischemic stroke: 1.2% vs 1.6% (HR 0.73, 0.57-0.93)

    • UA hospitalization: 0.4% vs 0.6% (HR 0.61, 0.41-0.92)

  • Composite of all-cause death, MI, stroke: 10.3% vs 11.9% (HR 0.86, 95% CI 0.79-0.93)

  • All-cause death: 3.5% vs 4.1% (HR 0.85, 95% CI 0.73-0.98)

    • Note: To minimize type 1 error in the secondary outcomes, the investigators performed hierarchical testing, which means they tested for statistical significance of several outcomes in a pre-defined sequence, and stopped testing once they reach an outcome that was not statistically significantly different. The difference between groups for CHD death was not different, & the hierarchical testing therefore stopped before all-cause death.

    • Regardless, the mortality findings are not statistically robust with a fragility index of only 6, & do not correspond with a reduction in CV death. For comparison to statin data, the fragility index for mortality was 33 in the 4S trial, 81 in the HPS trial.

  • HF hospitalization: 1.9% in both groups

Safety

  • Premature discontinuation: Alirocumab 14.2% vs placebo 15.8%

  • Adverse events

    • Serious (SAEs): 23.3% vs 24.9%

    • Local injection-site reaction: 3.8% vs 2.1% (NNH 59)

    • No difference in neurocognitive adverse effects, new-onset diabetes, diabetes worsening, or myopathy

  • Neutralizing antidrug antibodies: 0.5% vs <0.1%

Effect on LDL-C (ITT analysis that includes patients who D/Ced alirocumab/switched to placebo)

  • Baseline: 2.4 in both groups

  • Month 4: Alirocumab 1.0 vs placebo 2.4 (-58%)

  • Month 12: 1.2 vs 2.5 (-52%)

  • Month 48: 1.7 vs 2.7 (-37%)

Internal validity

  • Low risk of allocation, performance, detection & attrition bias:

    • Computer-generated randomized sequence with centralized allocation of study drug/placebo kits;

    • Patients & clinicians blind to study intervention & lipid panel;

    • Central, blinded outcome adjudication;

    • Loss-to-follow-up 0.2% for death & 0.9% for primary outcome;

    • Analyses based on intention-to-treat principle.

  • Pre-randomization run-in with placebo injection x2-16 weeks to ensure patients could use autoinjector & tolerate stable statin regimen.

REVEAL: Anacetrapib in ASCVD

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The HPS3/TIMI55-REVEAL Collaborative Group. Effects of anacetrapib in patients with atherosclerotic vascular disease. N Engl J Med 2017;377:1217-27.

Bottom line: In patients with ASCVD & a risk of coronary events ~3%/year, anacetrapib reduced the risk of major coronary events (NNT 100 over 4.1 years, or NNT 410/year).

Anacetrapib's CV benefit is proportional to its LDL-C reduction, & may be unrelated to its effect on HDL-C.

Context

  • Lower HDL-C concentrations are associated with greater risk of CV disease; however, no trial has yet to show benefit of increasing HDL-C with pharmacological therapy;
  • Mechanism: Cholesteryl ester transfer protein (CETP) transfer triglycerides & cholesteryl esters between LDL or VLDL to HDL. Inhibiting CETP results in greater HDL-C serum concentrations & lower LDL-C & non-HDL-C serum concentrations;
  • Previous trials of CETP inhibitors have all failed to demonstrate clinical benefit, & some even caused harm:
    • ILLUMINATE: RCT of 15,067 patients at high risk of ASCVD. Torcetrapib increased the risk of CV events versus placebo over 550 days (6.2% vs 5.0% [NNH 84); hazard ratio [HR] 1.25, 1.09-1.44), as well as death (1.2% vs 0.8% [NNH 250], HR 1.58, 1.14-2.19);
    • dal-OUTCOMES: RCT of 15,871 patients with recent ACS. Dalcetrapib did not reduce the risk of CV events versus placebo over 31 months (8.3% vs 8.0%; HR 1.04, 0.93-1.16);
    • ACCELERATE: RCT of 12,092 patients with ASCVD stopped early for futility. Evacetrapib did not reduce CV events versus placebo over 26 months (12.9% vs 12.8%; HR 1.01, 0.91-1.11).
  • In October 2017, the maker of anacetrapib announced that it would not seek market approval, essentially ensuring that no CETP inhibitor would reach clinical use.

Patients (n=30,449)

  • Inclusion
    • Age >50 years
    • Hx of ASCVD (MI, cerebrovascular aatherosclerotic disease, PAD, or diabetes with symptomatic CAD)
  • Exclusion
    • ACS or stroke <3 months ago
    • Planned CABG/PCI
    • "Clinically significant liver, kidney, inflammatory muscle, or other disease"
    • Current tx with a fibrate, niacin, "or any drug contraindicated with anacetrapib or atorvastatin"
    • Previous statin-related adverse reaction
    • Known poor adherence to clinic visits or medications
  • Baseline characteristics
    • Age 67 y
    • Male 88%
    • PMHx
      • ASCVD: CAD 88%, cerebrovascular disease 22%, PAD 8%
      • Diabetes 37%
      • HF 6%
    • BP 131/78 mm Hg
    • HDL-C 1.0 mmol/L
    • LDL-C 1.6 mmol/L
    • Non-HDL-C 2.4 mmol/L

Interventions

  • Intervention: Anacetrapib 100 mg once daily
  • Control: Matching placebo
  • Co-intervention for all: Atorvastatin to reduce LDL-C <2.0 mmol/L

Results @ median 4.1 years

  • Effect on lipids (difference vs placebo) @ year 2:
    • HDL-C: +104% (+1.1 mmol/L)
    • LDL-C, non-HDL-C, ApoB: -18% (LDL-C -0.3 mmol/L)
    • Lp(a) -25%
  • Effect on BP: +0.7/0.3 mm Hg with anacetrapib vs placebo
  • Note 1: The reduction in major coronary events only became apparent after day 3; additionally, the relative risk reduction (RRR) increased over time (e.g. from 2% at year 1 up to 17% after year 4)
  • Note 2: Annualized NNT for major coronary events: ~410/year

Safety

  • Serious adverse events: Anacetrapib 58.4%, placebo 58.5%
  • Non-serious adverse events: Anacetrapib 5.4%, placebo 5.4%
  • eGFR <60 mL/min: Anacetrapib 11.5%, placebo 10.6%, p=0.04 (NNH 112)

Generalizability & other considerations

  • Key characteristics of included patients
    • Moderate risk for a population with existing ASCVD (risk of major vascular event ~3.5%/year & major coronary event ~3%/year) in control group)
    • Excellent LDL-C control (mean ~1.6 mmol/L), & low baseline HDL-C (mean ~1.0 mmol/L)
  • It's unclear if the coronary event reduction with anacetrapib resulted from the HDL-C increase or LDL-C reduction. However, the benefits in REVEAL are consistent with what would be expected based on the LDL-C reduction:

Internal validity: Low risk of bias

  • Allocation: Randomization by minimization, allocation concealed
  • Performance & detection: Patients, clinicians blinded, matching placebo
  • Attrition: Loss-to-follow-up 0.1%, intention-to-treat analysis
  • Selective outcome reporting: Reporting of all clinical outcomes of interest for both efficacy & safety

GAUSS-3 - Evolocumab vs ezetimibe in true muscle-related statin intolerance

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Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA 2016;315:1580-90

Bottom line:

  • ~43% of patients with perceived statin-related muscle symptoms had intolerance reproducible with a N-of-1 trial;

  • In those with muscle-related statin intolerance reproducible with a N-of-1 trial, evolocumab & ezetimibe were similarly tolerated;

  • LDL-C reductions with these agents were consistent with those from other trials with LDL-C reductions of 50-55% for evolocumab & 15-20% for ezetimibe.

 

Patients (Phase A n=491, Phase B n=218)

  • Included
    • Adults unable to tolerate atorvastatin 10 mg/d & any other statin (any dose) or 3+ statins
    • Baseline LDL-C
      • >2.6 mmol/L + CAD
      • >3.3 mmol/L + 2 CV risk factors
      • >4.1 mmol/L + 1 CV risk factor
      • >4.9 mmol/L (at least possible familial hypercholesterolemia [FH])
  • Baseline characteristics (of Phase B patients)
    • Age 59 y
    • Male 51%
    • CV hx: CAD 31%, cerebrovascular disease/PAD 20%
    • Hx of intolerance to at least 3 statins 82%
    • Worst muscle-related adverse effects: Myalgias 80%, myositis 14%, rhabdomyolysis 6%
    • Mean LDL-C 5.7 mmol/L

Interventions

  • Phase A (confirming statin-related muscle symptoms)
    • I: Atorvastatin 20 mg/d x10 weeks
    • C: Matching placebo x10 weeks
    • Note: Preceded by 4-week washout without any lipid-lowering therapy
  • Phase B (comparison of non-statin lipid-lowering monotherapy for those with reproducible statin-related muscle symptoms in Phase A)
    • I: Evolocumab 420 mg subcutaneously q1 month (+ ezetimibe placebo)
    • C: Ezetimibe 10 mg daily (+ evolocumab placebo)

Results

Phase A: Muscle symptoms with

  • Atorvastatin but not placebo (truly statin-related muscle symptoms) 43%
  • Placebo but not atorvastatin: 27%
  • Both atorvastatin & placebo 10%
  • Neither 18%

Phase B

  • Total muscle-related events: Evolocumab 20.7%, ezetimibe 28.8%, p=0.23
    • Myalgia: 13.8% vs 21.9%
    • Elevated CK: 2.8% vs 1.4%
  • LDL-C reduction
    • Evolocumab lowered by ~53% (-2.7 mmol/L) from baseline
    • Ezetimibe lowered by 17% (-0.8 mmol/L) from baseline
    • ~37% (1.9 mmol/L) difference between groups
    • Maximal LDL-C reduction achieved at ~4 weeks & maintained during 6-month follow-up

 

Considerations (generalizability, internal validity, etc)

  • Low risk of bias (allocation, performance, detection, attrition) in both phases due to computer-generated randomization sequence with allocation concealed by centralized allocation and blinding of patients and outcome assessors using matching placebos
  • Phase A of this trial is generalizable to our patients who have a history of perceived intolerance to numerous statins
    • The Phase A results indicate that many of these patients can tolerate a statin with rechallenge, particularly if bias is minimized by way of a N-of-1 double-blind trial design. However, up to 43% of these patients have true statin-related myalgia that is reproducible with a N-of-1 trial;
    • Given the high cost of PCSK9 inhibitors, this raises the question of whether it would be cost-effective to perform N-of-1 trials in patients with history of statin intolerance if it allowed us to get 53% of them back onto a statin rather than a more expensive (and in the case of ezetimibe monotherapy at least, inferior) lipid-lowering therapy?
  • Generalizability of Phase B is limited by the fact that most of us cannot perform N-of-1 trials routinely. Consistent with clinical practice however, it does indicate that some of these of these patients will go on to report muscle symptoms while receiving an alternate lipid-lowering agent and even discontinue these agents. Since Phase B of this trial did not have a placebo group, this cannot show that either of these drugs were truly responsible for the muscle symptoms.

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

    Fibrates for CV prevention

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    References: ACCORD Lipid, FIELD

    Bottom-line:

    • In patients taking a statin, the addition of a fibrate does not significantly reduce the risk of CV events.

    • In patients at intermediate-to-high CV risk who are absolutely not able to take a statin, fibrate therapy reduces the relative risk of non-fatal, but not fatal, CV events by ~20%.

      • In my opinion, ezetimibe & bile-acid sequestrants (& soon possibly PCSK9 inhibitors) should be considered before fibrates in these patients.

    Patients

    Intervention

    • FIELD: Fenofibrate vs matching placebo
      • Fenofibrate given as 200 mg (micronized formulation) PO once daily
      • Non-study lipid-lowering drug: Fenofibrate group 8%, placebo group 17%
      • ~20% in each group discontinued study drug by end of study
    • ACCORD Lipid: Fenofibrate + simvastatin vs simvastatin + matching placebo
      • Fenofibrate given as 160 mg PO once daily
      • Average dose of simvastatin 20 mg/d in both groups (open-label, adjusted to lipid targets)
      • Fenofibrate discontinued in 22%, placebo discontinued in 19% by end of study; ~20% in each group discontinued simvastatin by end of study

    Results @ ~5 years

    Internal validity

    • Both trials at low risk of bias (including allocation, performance, detection, & attrition bias)
      • Central randomization
      • Patients, clinicians, investigators, adjudicators all blinded to treatment allocation
      • Loss-to-follow-up <1%
      • Analyzed using intention-to-treat principles

    Generalizability

    • FIELD represents the effects of fibrate monotherapy in a population with type 2 diabetes at mostly intermediate risk of CV events (estimated ~10-12% over 10 years)
      • Mechanistically, primarily testing the mechanistic effect of lowering triglycerides by ~30% over placebo, as effect on both LDL & HDL modest
    • ACCORD Lipid represents the effects of adding a fibrate to a statin in a higher-risk population of patients with type 2 diabetes (estimated ~25% over 10 years without statin)
      • Again, primarily testing the mechanistic effect of lowering triglycerides, as no discernible effect on LDL or HDL

    Other fibrate studies

    • VA-HIT: In 2531 men with CAD not receiving a statin, gemfibrozil lowered trigs by ~30% more than placebo. At a median 5.1 years, this resulted in a 4.4% absolute risk reduction in MI or coronary death (NNT 23).
    • BIP: In 3090 men with CAD not receiving a statin, bezafibrate increased HDL & lowered trigs by ~15% more than placebo. At a mean 6.2 years, this did not result in a statistically significant effect on MI or sudden death.
    • Subgroup analyses from these various trials have provided more confusion than clarity. For example, some studies demonstrate an interaction by baseline triglycerides (VA-HIT, BIP), but not others (FIELD, ACCORD Lipid). The ACCORD Lipid study, but not the BIP trial, found a subgroup interaction based on the combination of low HDL and high trigs.
    • A systematic review of 18 fibrate trials, including the ones already mentioned here, found results largely consistent with the FIELD trial:
      • No reduction in death or fatal CV events;
      • Reduction in CV events, entirely driven by non-fatal coronary events (i.e. non-fatal MI & coronary revascularization): Relative risk 0.81 (0.75-0.89);
      • 5% relative risk reduction in coronary events per 0.1 mmol/L reduction in triglycerides;
      • Notably, ACCORD Lipid was the only trial included in this systematic review which had routine statin administration.