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

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.

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

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

FOURIER Steering Committee and Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. NEJM [online ahead of print]

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

Reducing LDL & improving CV outcomes - systematic review

Silverman MG, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: A systematic review and meta-analysis. JAMA 2016;316:1289-97.

Clinical question: Does reduction of CV outcomes with lipid-lowering therapy correlate with degree of LDL-lowering?

Bottom line:

• The value of this study is mechanistic; it does not provide clinical guidance. 

• The analysis demonstrates that CV outcome reduction of proven lipid-lowering drugs is closely associated with degree of LDL-lowering. This supports the lipid hypothesis, i.e. that lipid-lowering drugs which lower CV risk outcomes (statins, bile acid sequestrants, & ezetimibe) do so primarily by lowering LDL.

• This study does not validate a particular lipid target, nor does it support using interventions with neutral, harmful or conflicting evidence (fibrates, niacin, or CETP inhibitors) to achieve a lipid target.

Search

• Databases: MEDLINE, Embase
• Timeframe: 1966 to July 2016
• Inclusion criteria:
  • Randomized controlled trials (RCTs)
  • Compared (1) LDL-lowering intervention to control/placebo or (2) more vs less intensive statin therapy
  • Reported cardiovascular outcomes including MI
  • Duration of at least 6 months
  • At least 50 events
• Exclusion criteria: Trial with populations with "significant competing risks", including heart failure & chronic kidney disease
• Additional measures for comprehensiveness:
  • References lists of identified studies, review and meta-analyses
  • Reviewed abstracts of major cardiovascular meetings held in past 2 years (no mention of which)
  • Contacted content experts

Results of systematic review

• Included 49 RCTs (n=312,175)
  • Statin (25 trials)
  • Fibrate (9 trials)
  • Diet (4 trials)
  • CETP inhibitor (3 trials)
  • Niacin (3 trials)
  • Bile acid sequestrants (2 trials)
  • PCSK9 inhibitor (2 trials)
  • Ezetimibe (1 trial)
  • Ileal bypass surgery (1 trial)

Results of the meta-analysis

• Mean follow-up 4.3 years
• Mean ~absolute reduction in LDL vs placebo in trials
  • PCSK9 inhibitor -1.85 mmol/L
  • Ileal bypass -1.6 mmol/L
  • Bile acid sequestrant -0.90 mmol/L
  • Statin -0.85 mmol/L (all drugs & doses pooled)
  • Diet -0.75 mmol/L
  • Niacin -0.35 mmol/L
  • Ezetimibe -0.3 mmol/L
  • Fibrate -0.25 mmol/L
• ~23% relative risk reduction (RRR) in major vascular events per 1 mmol/L reduction in LDL with any interventions except CETP inhibitors

Considerations & limitations

• Generalizability & internal validity
  • Investigators excluded studies that included patients with "significant competing risk", which includes some of the landmark "negative" statin trials (CORONA, GISSI-HF, 4D, etc)
    • Results of this analysis don't apply to the subpopulations of these studies (primarily heart failure & chronic kidney disease)
    • The analysis may overestimate the true relative risk reduction since this exclusion criterion primarily excluded "negative" studies.
  • Numerous differences in populations between trials, including
    • Era (e.g. 1st fibrate/niacin trial conducted in 60s, most statin trials conducted in 1990s-2000s)
    • Primary vs secondary prevention
    • LDL before initiation of study treatment & background CV therapies
• Results
  • Although interventions produced comparable RRRs in CV outcomes per 1-mmol/L reduction in LDL, actual achievable LDL reduction & therefore realistic CV reductions with each agent are quite different
  • This study evaluated a composite CV outcome, which bundles together outcomes of different severity & importance to patients. Different interventions may have the same effect on a composite CV outcome, but not specific components. For example, statins reduce every type of CV event (death, MI, stroke, revascularization), whereas fibrates only reduce non-fatal MI, but not death or stroke.

OSLER - Evolocumab (PCSK9 inhibitor) for LDL lowering

Sabatine MS, et al. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med 2015;372:1500-9.

Bottom line: In patients previously enrolled in a phase 2/3 trial of evolocumab due to elevated LDL in the context of HeFH, statin intolerance, or maximum-tolerated statin therapy, addition of evolocumab lowered LDL by ~60% versus standard therapy alone. This LDL reduction resulted in a reduction in CV events (NNT 82 at 11 months), which may be an inaccurate estimate due to high risk of performance and detection bias.

Patients (n=4465)

• Inclusion
  • Patients who completed one of the 12 phase 2 & 3 RCTs of evolocumab without discontinuation due to an adverse event
  • No unstable medical condition
  • Basic patient populations enrolled in phase 2 & 3 trials:
    • MENDEL-1 & 2: LDL 2.6-4.9 mmol/L without background lipid lowering
    • GAUSE-1: LDL >2.6 mmol/L, statin intolerant
    • GAUSE-2: LDL 2.6-4.9 mmol/L, statin intolerant
    • DESCARTES, THOMAS1&2: LDL >1.9 mmol/L with statin (DESCARTES: +/- ezetimibe)
    • LAPLACE-TIMI 57: LDL >2.1 mmol/L with statin +/- ezetimibe
    • LAPLACE-2: LDL >2.0 mmol/L with "intensive" statin, >2.6 mmol/L on "non-intensive" statin, or >3.9 mmol/L without statin at baseline, added to statin +/- ezetimibe
    • RUTHERFORD-1 & 2: HeFH with LDL >2.6 mmol/L with statin +/- ezetimibe
    • YUKAWA-1: "High-risk" Japanese patients with LDL 3.0 mmol/L or greater while receiving statin
• 4465 randomized (74.1% of eligible from phase 2 & 3 trials)
• "Average" patients (baseline of phase 2 & 3 trials)
  • 58 y
  • Male 51%
  • White 85%
  • North American 47%
  • CV risk factors
    • Smoker 15%
    • Known CAD 20%, MI 9%, PCI 11%, CABG 7%
    • Cerebrovascular or peripheral-artery disease 9%
    • Family hx of premature CAD 24%
    • HTN 52%
    • Diabetes 13%
    • Known FH 10%
  • Lipids: Total cholesterol 5.1, LDL 3.1, HDL 1.3, trig 1.35 mmol/L
  • Meds
    • Statin 70%, high-intensity 27%
    • Ezetimibe 14%

Issues with generalizability (external validity)?

• Yes: The patients in OSLER 1 & 2 represent a highly-selected patient population enrolled into early phase 2/3 mechanistic efficacy trials who were adherent and tolerant to their allocated therapy in the phase 2/3 trial
  • In care of real-world patients with greater likelihood of comorbid conditions and frailty, we'd expect lower eficacy, adherence, tolerability and safety than estimated from these trials.

Interventions

• I: Evolocumab x56 weeks + standard of care lipid-lowering therapy per local guidelines
  • OSLER-1: 420 mg q1 month
  • OSLER-2: Patient's choice of 140 mg q2weeks or 420 mg q1month
  • In-person clinic visit q3 months
• C: No evolocumab x48 weeks + standard of care lipid-lowering therapy per local guidelines
  • Telephone contact only
• After trial: Open-label evolocumab for all patients completing OSLER-1&2

Results @ median ~11 months

• LDL reduction
  • Change from baseline to week 12 of OSLER for evolocumab+standard therapy vs standard therapy alone = 61%
    • @ baseline: Median 3.1 mmol/L in both groups
    • @ week 12 of OSLER trial (variable time from baseline): Median 1.2 vs 3.1 mmol/L
  • <1.8 mmol/L target: 73.6% vs 3.8%
• Statistically significant reduction in composite CV outcome (death, MI, unstable angina requiring hospitalization, coronary revascularization, stroke/TIA, or HF requiring hospitalization): Hazard ratio 0.47 (0.28-0.78)
  • 0.95% vs 2.18% (NNT 82)
  • Not clearly driven by any single component of the composite outcome (e.g. MI or stroke)
• No patients developed neutralizing antibodies against evolocumab

Issues with internal validity?

• Yes: Randomized, allocation-concealed, open-label (participants, clinicians and investigators aware of allocated treatment) non-placebo controlled trial with ? lost-to-follow-up analyzed using intention-to-treat population
  • High risk of performance and detection bias, particularly relating to "soft" CV outcomes such as hospitalizations and decision to revascularize
• Notably, this is actually a pooled report of 2 RCTs: OSLER-1 is an extension of 5 phase-2 trials, and OSLER-2 is an extension of 7 phase-3 trials