COMPASS - ASA + rivaroxaban (or riva alone) vs ASA alone in stable CVD

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Eikelboom JW, et al. Rivaroxaban with or without aspirin in stable cardiovascular disease. NEJM 2017

Note: This was a factorial trial; the other intervention under study - pantoprazole vs placebo - will be reported later in a separate report.

Bottom line:

  • In patients with stable CAD/PAD, addition of rivaroxaban 2.5 mg PO BID to low-dose ASA resulted in a reduction in cardiovascular events, primarily driven by all-cause mortality & stroke (NNT ~144 each), and an increase in major & minor bleed (NNH 84 & 28, respectively) over an average duration of 1.9 years;

    • In patients with PAD, rivaroxaban + ASA also reduces the risk of major adverse limb events (NNT 100).

  • Monotherapy with rivaroxaban 5 mg PO BID did not reduce events compared to ASA monotherapy, but increased major & minor bleeds (NNH 112 & 39).

Patients (n=27,402)

  • Included either CAD or PAD:
    • CAD (MI within 20 years, multivessel CAD with symptoms or history of angina, multivessel PCI, multivessel CABG), plus
      • Age >65 y
      • Atherosclerosis in at least 2 vascular beds
      • At least 2 more risk factors (current smoking, diabetes, eGFR <60, non-lacunar stroke >1 month earlier)
    • PAD (with either claudication, previous revasc [including carotid], or amputation)
  • Exclusion
    • High bleeding risk
    • Recent stroke, or previous hemorrhagic or lacunar stroke
    • Severe HF
    • eGFR <15
    • Use of DAPT, anticoagulation, or other antithrombotic therapy
  • Baseline characteristics
    • Age 68 y
    • Female 22%
    • CV history
      • Previous MI 62% (mean 7.1 years ago)
      • CAD 90% (multivessel 62%; enrolled within 2 weeks of CABG ~5%)
      • PAD 27%
    • Risk factors: Tobacco use 21%, HTN 75%, diabetes 38%
    • eGFR: <30 (<1%), 30-59 (22%), 60+ (77%)
    • Meds: ACEI/ARB ~70%, BB 70%, lipid-lowering ~90%

Interventions

  • Intervention1: Enteric-coated ASA 100 mg/d + rivaroxaban 2.5 mg PO BID
  • Intervention2: Rivaroxaban 5 mg PO BID
  • Control: Enteric-coated ASA 100 mg/d

Results @ mean 1.9 years (max 3.92 years)

Subgroup analyses published in separate papers:

  • CAD (91% of study population, n=24,824)
    • Of the 69% with prior MI, timing: <1 y (5%), 1-5 y (29%), >5 y (34%)
    • 4-5% received DAPT during trial follow-up, & most in rivaroxaban groups D/Ced rivaroxaban
    • Efficacy & safety results virtually identical to full trial
    • Additional analyses:
      • Post-hoc defined coronary event composite (MI, coronary death, sudden death, resuscitated cardiac arrest, or unstable angina): ASA+riva vs ASA HR 0.83 (0.81-0.98)
      • Stent thrombosis: ASA+riva vs ASA HR 1.08 (0.72-1.61)
      • Coronary revascularization: ASA+riva vs ASA HR 0.95 (0.84-1.07)
      • Post-hoc landmark analysis suggests that efficacy HR consistent between years 1, 2 & >2, whereas bleeding risk is front-loaded & decreases after year 1
      • Further subgroups suggest that relative risk reduction similar across most subgroups, including those with vs without prior PCI, optimal use of 2o CV prevention vs not, & different risk categories. Notably, however, significant p-value for interaction suggesting no/less benefit in patients with history of CABG.
  • PAD or carotid disease (27% of study population, n=7470)
    • Efficacy & safety results virtually identical to full trial
    • Additional analyses:
      • Prespecified limb outcomes - Major adverse limb event or major amputation: ASA+riva 1% vs ASA 2%: HR 0.54 (0.35-0.82)
      • Composite of 1o outcome + limb outcome: ASA+riva 6% vs ASA 9% (NNT 34), HR 0.69 (0.56-0.85)
  • Modified ISTH definition of major bleed included standard ISTH major bleed components (fatal bleed, symptomatic bleed into a critical organ, bleeding into a surgical site requiring re-operation) plus bleeding that led to hospitalization (including ED visits without overnight stay)

Considerations

  • Risk of bias
    • Low for allocation, performance, detection, attrition bias
      • Computer-generated randomization (reported in Lancet substudies)
      • Allocation concealed by using central web-based randomization (reported in Lancet substudies)
      • Blinding of all participants, clinicians & investigators
      • 0.2% lost to follow-up, ~16% discontinued study drug before last follow-up (but continued follow-up)
      • ITT analysis
    • Trial stopped early after 1st interim analysis for efficacy of ASA + rivaroxaban
    • Run-in phase (active ASA & placebo rivaroxaban BID) to ensure patient able to adhere to trial regimen (~8% excluded after run-in)
  • Generalizability
    • This trial applies to patients with previous MI or clear history of angina/ischemia/coronary revascularization + angiographically-proven CAD, or with PAD
      • Unclear how these results may translate to use of higher doses of rivaroxaban once daily (i.e. rivaroxaban 15-20 mg once daily as used in AF +/- PCI)

Beta-blockers post-MI or in stable CAD

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Summary:

High-quality but outdated evidence (with likely overestimated benefit) from RCTs, corroborated by contemporary observational studies, supports the use of beta-blockers in patients post-MI without HF or LV dysfunction to reduce the risk of death;

  • Acutely post-MI, beta-blockers reduce deaths due to arrhythmias & re-infarction. In the long-term where patients with normal LV function & low risk of ventricular arrhythmias, the main mechanism for mortality reduction of beta-blockers would be by reducing re-infarctions;
  • Much uncertainty remains due to the indirectness of old evidence and high risk of bias of newer observational studies; only a contemporary, adequately-powered RCT of patients without HFrEF post-MI will provide clarity.

The evidence for post-MI beta-blocker use (in those without HF or LV dysfunction) is limited to an average of 3 years, after which the benefit of continued use is unclear;

  • After 3 years, clinicians should re-assess the benefit/risk of continuing beta-blockers based on presence/control of angina, arrhythmias and risk factors for re-infarction, as well as tolerability and patient willingness to continue taking the beta-blocker.

Beta-blockers do not appear to reduce CV events in patients with uncomplicated stable CAD (no prior MI, LV dysfunction or HFrEF), so they should only be used in the presence of a compelling indication (such as angina, for which a calcium-channel blocker could also be used as first-line therapy).

 

Current guideline recommendations

Acute coronary syndrome (ACS; AHA 2013 STEMI guidelines, AHA 2014 NSTE-ACS guidelines, AHA 2011 secondary prevention guidelines)

  • Start an oral beta-blocker on the first day of no contraindications (STEMI Class I recommendation, Level of evidence B; NSTE-ACS I, A)
  • Use a beta-blocker in all patients with prior-MI & EF 40% or less unless contraindicated" (I, A)
  • Continue during & after hospitalization in all patients with STEMI and with no contraindications" (I, B); also reasonable to continue in patients with NSTE-ACS with normal LV function" (IIa, C)
  • Continued for 3 years after an ACS in all patients with normal LV function (I, A)
    • It is also reasonable to continue beyond (I, B)

For stable coronary artery disease (CAD)/ischemic heart disease (IHD; CCS 2014 stable IHD guidelines)

  • Use a beta-blocker in all patients with stable IHD & LV dysfunction (strong recommendation, high-quality evidence) or prior MI (conditional recommendation, moderate-quality evidence)
  • Use either a beta-blocker or calcium-channel blocker for stable angina if none of the above (conditional recommendation, moderate-quality evidence)
  • Consider a beta-blocker for all other patients with coronary or other vascular disease" (AHA 2011 secondary prevention guidelines; IIb, C)

The focus of this article will be patients with CAD without HF/LV dysfunction. We have covered beta-blocker use for post-MI LV dysfunction & HFrEF elsewhere.

 

Early/short-term use during ACS

  • COMMIT provides the best-available evidence in a contemporary population
    • Double-blind RCT of 45,852 patients with suspected MI (87% with STEMI, mean 10h from symptom onset) with no planned PCI
    • Randomized to metoprolol (5 mg IV x3 over 15 min, then 200 mg/d until discharge or up to 4 weeks) or placebo
    • There was no difference in the co-primary outcomes
      • Death, re-MI, VF, or other arrest) in hospital: Metoprolol 9.4%, placebo 9.9% (odds ratio [OR] 0.96, 0.90-1.01)
      • Death: Metoprolol 7.7%, placebo 7.8% (OR 0.99, 0.92-1.05)
    • Increased risk of cardiogenic shock (metoprolol 5.0% vs placebo 3.9%, NNH 91, OR 1.30), but
    • Decreased risk of re-MI (2.0% vs 2.5%, NNT 200, OR 0.82) & VF (2.5% vs 3.0%, NNT 200, OR 0.83)

 

Should beta-blockers be used post-MI in patients with normal LV function?

  • A 1999 systematic review with meta-analysis remains the best-available evidence on this topic
    • Major caveats:
      • Included trials were published between 1966-1991, which precedes widespread use of many ACS therapies, including PCI & statins (most of the trials also preceded use of fibrinolytics, ASA)
      • Patients were not systematically assessed for HF or LV dysfunction, so it is unclear how many of these patients had normal LV function
      • Maximum average follow-up of 3 years
    • Over 2 years, use of a beta-blocker decreased the risk of death (NNT 42, OR 0.77, 0.69-0.85)
  • A newer systematic review, which attempted to determine the efficacy of statins in the modern era, had numerous issues limiting clinical utility:
    • Arbitrarily classified trials as being in the "reperfusion era" if >50% of patients underwent revascularization with PCI/CABG, reperfusion with a fibrinolytic, or received ASA+statin
    • Results of the "reperfusion era" analysis dominated by COMMIT, which was a trial of short-term metoprolol use
    • There were no "reperfusion era" trials with beta-blocker duration >1 year
  • Observational studies show conflicting results on beta-blocker use after MI
    • A 2017 cohort of 179,810 patients with MI found a reduction in 1-year mortality in unadjusted comparisons (4.9% versus 11.2% without beta-blockers), but not in adjusted analyses using propensity score matching or instrumental variables
      • Notably, 95% of participants in this study received a beta-blocker on discharge, leading to very high risk of selection bias
    • A 2015 systematic review of 10 cohort studies with 40,973 patients who underwent PCI for MI found a reduction in death with beta-blocker use (relative risk (RR) 0.58, 0.48-0.79)
      • The relative risk reduction was numerically greater for those with reduced EF (RR 0.60, 0.36-1.00) compared to those with EF >40% (RR 0.79, 0.59-1.07)
    • A 2015 cohort study (that did not exclude patients with HFrEF or LV dysfunction) not included in the above review  found that beta-blocker use after an MI reduced the relative risk of death (HR ~0.6) at a median 2.1 years 
    • Notably, a 2012 cohort study using the REACH registry that initially led to questioning the utility of beta-blockers post-MI was underpowered to identify a clinically meaningful difference

 

How long should beta-blockers be continued post-MI?

  • Average duration of beta-blocker use in the 1999 systematic review was 2-3 years
  • A 2016 cohort study of 2679 patients with MI without HF or LV dysfunction demonstrated a reduction in the risk of death at 30 days (hazard ratio (HR) 0.46, 0.26-0.82)
    • This study was underpowered to identify a clinically-important difference in death at 1 year (HR 0.77, 0.46-1.30) or 5 years (HR 1.19, 0.65-2.18)
  • There is no evidence that discontinuing beta-blockers after a certain duration post-MI is safe or beneficial

 

What about patients with stable CAD (without prior MI, or HFrEF/LV dysfunction)?

  • A 2016 systematic review with meta-analysis of cohort studies that included 17,397 patients with angiographically-proven CAD without MI or LV dysfunction found no difference in all-cause death (OR 0.91, 0.79-1.04) at 3-5.4 years
  • A 2014 cohort study of 26,793 patients with newly-diagnosed CAD found that that the effect of beta-blockers on the risk of death/MI differed on MI history (p=0.005 for interaction)
    • Prior MI: HR 0.87 (0.82-0.93)
    • PCI or CABG but no prior MI: HR 1.03 (0.93-1.13)
  • INVEST trial (see previous nerdcat summary): A beta-blocker-based regimen was not superior to a verapamil-based regimen over 2.7 years in patients with CAD+HTN without prior MI

 

CONCERN: Naproxen vs celecoxib in patients with recent upper GI bleed with an indication for low-dose ASA

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Chan FKL, et al. Gastrointestinal safety of celecoxib versus naproxen in patients with cardiothrombotic diseases and arthritis after upper gastrointestinal bleeding (CONCERN): an industry-independent, double-blind, double-dummy, randomised trial. Lancet [epub ahead of print]

Bottom line:

  • Issues in reporting of this trial preclude a fully-informed interpretation of its results

  • In patients receiving a PPI & ASA, recurrent upper GI bleed occurred in ~6% of patients also receiving daily celecoxib at a dose of 100 mg BID compared to ~12% of those receiving naproxen 500 mg BID over 18 months.

 

Patients (n=514)

  • Included
    • Presenting with upper GI bleed while on NSAID + low-dose ASA
    • Follow-up endoscopy confirming ulcer healing 8 weeks after GI bleed
    • Negative for H pylori or successful H pylori eradication
    • Ongoing indication for low-dose ASA ("cardiothrombotic diseases" or "multiple CV risk factors")
    • Chronic arthritis pain anticipated to require regular NSAID use
  • Key exclusion criteria
    • Erosive esophagitis
    • Gastric outlet obstruction
    • Renal failure (SCr >200 umol/L)
    • Use of anticoagulants
  • Typical study patient
    • Age 72 y (>80 y in 24%)
    • Female 46%
    • Indication for NSAID: OA 70%, RA 3%, other 27%
    • Baseline upper GI bleed
      • Gastric origin 55%
      • Required endoscopic therapy ~30%
      • Required blood transfusions 55%
    • ASA indication: Secondary prevention (67%), primary prevention with 10-year CV risk >10% (33%)

Interventions x18 months

  • I: Celecoxib 100 mg PO BID
  • C: Naproxen 500 mg PO BID
  • ~90% in both groups took at least 70% of their doses; ~18% in each group discontinued the study drug before 18 months
  • Co-interventions:
    • Esomeprazole 20 mg PO once daily in all patients
    • ASA 80 mg/d (discontinued in ~30% of patients during trial in both groups)

Results @ median 18 months

  • Efficacy (not designed or powered to evaluate this)
    • Patient's global assessment of disease activity scale (range 1-5, lower=better):
      • Baseline: 3.0 in both groups
      • Month 18: Celecoxib 2.1 versus naproxen 2.3, p=0.386 for difference between groups
    • Quality of life, pain, use of other analgesics: ?
  • Safety
    • Primary outcome - recurrent upper GI bleed (hematemesis/melena or hemoglobin drop >20 g/L+ endoscopically-confirmed ulcers or bleeding erosions): Celecoxib 5.6%, naproxen 12.3% (NNT 15), hazard ratio (HR) 0.44 (0.23-0.82)
      • Fatal recurrent GI bleed: 0 in both groups
    • Major CV event (vascular death, MI or stroke): Celecoxib 4.4% vs naproxen 5.5%, HR 0.78 (0.36-1.73)
  • Discontinued treatment before 18 months: Celecoxib 18% vs naproxen 19%

Subgroup analysis (reported in supplement of authors' reply to letter to the editor)

  • Primary outcome
    • Continued ASA: Celecoxib 7.2%, naproxen 13.8% (p=.042)
    • Discontinued ASA: 1.4% vs 8.4% (p=.054)
  • CV events: 
    • Continued ASA: Celecoxib 5.5% vs naproxen 6.0% (p=.825)
    • Discontinued ASA: 1.5% vs 4.3% (p=.312)

Internal validity

  • Unclear/high risk of allocation bias
  • Unclear risk of performance/detection bias
    • Proper blinding dependent upon allocation concealment. If sealed opaque envelope method was subverted, then blinding would also be compromised
    • Blinding by "double-dummy" pills not prepared by manufacturer
    • GI & CV outcomes adjudicated by committee blinded to allocated treatment group
  • Attrition bias
    • Premature discontinuation occurred in ~18% of patients in each group
    • Modified intention-to-treat analysis for GI safety outcome only counted outcomes that occurred "during treatment," therefore excluding any outcomes occurring after premature discontinuation

Generalizability

  • Study conducted in single centre in Hong Kong, with enrolment taking ~10 years (2005-2015)
    • Many changes to GI bleed management (e.g. reduced transfusion threshold) & CV disease management (including ASA prescribing patterns in primary prevention). No reporting or comments on such trends in this publication, which complicates application of these trial results.
  • Many aspects of this trial remain unreported, which further complicates application of these results
    • CV risk & indication for ASA?
      • This is the key reporting issue in this trial. The authors do not clearly describe the indication for ASA beyond "cardiothrombotic diseases or multiple coronary risk factors", and do not describe these in their 'baseline characteristics' table. Notably, the authors report that ~30% of patients discontinued ASA during the trial, suggesting that some of these patients had no clear indication for ASA
      • Addendum: The authors reported in a response to letter to the editor that 67% received ASA for secondary prevention, with the remaining 33% receiving ASA for primary prevention in the context of a calculated 10-year risk of a CV event >10%. The benefit of ASA for primary prevention is minimal, & the harms of continuing ASA (especially in these patients who already developed a GI bleed on ASA) likely outweighed any benefit. Furthermore, reported subgroup analyses showed that those who discontinued ASA had a lower risk of CV events, suggesting that mostly the lower-risk primary CV prevention patients discontinued ASA during the trial. 
      • Use of dual antiplatelet therapy (DAPT) was not specifically prohibited during this trial, though its use was not reported
    • Time from initial upper GI bleed to initiating of study NSAID?
      • Addendum: The authors later reported that endoscopy was routinely performed to confirm ulcer healing 8 weeks after the GI bleed, at which point patients were enrolled into this trial.
    • Previous history of NSAID use and efficacy (i.e. previous treatment failures with either study NSAID)?
  • Effect of giving no NSAID or NSAID PRN?
    • The majority of patients with OA who use oral NSAIDs in practice do so on a PRN basis. The GI risk related to this kind of usage pattern is likely lower, and may be a reasonable alternative
    • In a previous trial by the same authors of patients with ASA-related upper GI bleed, recurrence using the same definition was <1% over 1 year in patients receiving ASA+PPI
  • Clinical importance of primary outcome?
    • The primary outcome of this trial was recurrent endoscopically-confirmed upper GI bleed that presented as either hematemesis/melena or a >20 g/L hemoglobin drop. None of the recurrent GI bleeds in this trial resulted in patient death, and most would be classified as "minor bleeds" under most commonly-used bleeding definitions. As such, impact of these recurrent events on quality of life would be a key domain to measure (but it wasn't).
    • If we accept that this is a clinically-important outcome, the risk remains far too high even with celecoxib, particularly given that only 90% took at least 70% of their doses and that 30% discontinued ASA during the trial.

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.