HOPE, EUROPA, PEACE - ACEIs in CAD & other high-risk patients without HF or LV systolic dysfunction

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Generalizability: Who do these results apply to?

  • HOPE represents a population of patients at high risk of CVD, the majority of whom had stable CAD
  • EUROPA and PEACE represent a stable CAD population
  • All 3 trials specifically excluded patient with clinical HF or LVEF <40% (though HOPE went to lesser lengths to obtain objective evidence of preserved EF)

Interventions

  • I: ACEI
    • HOPE: Ramipril for up to 5 y (median 4.5 y)
      • Initial: 2.5 mg PO HS x1 week,
      • Then increased to 5 mg PO HS x1 week,
      • Then increased to 10 mg PO HS for the duration of the trial
      • Adherence: 79% still taking at final follow-up visit
    • EUROPA: Perindopril for a mean 4.2 years
      • Initial: 4 mg PO daily x2 weeks (started @ 2 mg if age 70+ y),
      • Then increased to 8 mg PO daily
      • Dose could be reduced to 4 mg daily if higher dose not tolerated
      • Adherence: 81% still taking at 3 y follow-up visit
    • PEACE: Trandolapril for a median 4.8 years
      • Initial: 2 mg PO daily x6 months,
      • Then increased to 4 mg PO daily if tolerated
      • Adherence: 74% still taking at 3 y follow-up visit
  • C: Matching placebo

Results

Individually, HOPE and EUROPA demonstrated statistically significant results in their primary outcome, whereas PEACE did not. Results of PEACE originally seemed contradictory, however, a pooled analysis of these trials demonstrated consistent benefits.

Note: The following results are approximately calculated using the pooled relative risks & absolute risk in each study's placebo group.

  • Statistically significant reduction in:
    • Primary outcome (from PEACE, used for pooled analysis): Odds ratio (OR) 0.82, 95% confidence interval 0.76-0.88
      • 10.7% vs 12.8% (NNT 48)
    • All-cause mortality: OR 0.86 (0.79-0.94)
      • HOPE: 10.5% vs 12.2% (NNT 59)
      • EUROPA: 5.9% vs 6.9% (NNT 100)
      • PEACE: 7.0% vs 8.1% (NNT 91)
    • Non-fatal MI: OR 0.82 (0.75-0.91)
      • HOPE: 6.1% vs 7.5% (NNT 72)
      • EUROPA: 5.1% vs 6.2% (NNT 91)
      • PEACE: 4.3% vs 5.3% (NNT 100)
    • Stroke (fatal or non-fatal): OR 0.77 (0.66-0.89)
      • HOPE: 3.8% vs 4.9% (NNT 91)
      • EUROPA: 1.3% vs 1.7% (NNT 250)
      • PEACE: 1.7% vs 2.2% (NNT 200)
    • Hospital admission for HF: OR 0.77 (0.67-0.90)
      • HOPE: 2.6% vs 3.4% (NNT 125)
      • EUROPA: 1.3% vs 1.7% (NNT 250)
      • PEACE: 2.5% vs 3.2% (NNT 143)
    • Revascularization with CABG: OR 0.87 (0.79-0.96)
      • HOPE: 8.2% vs 9.4% (NNT 84)
      • EUROPA: 4.1% vs 4.7% (NNT 167)
      • PEACE: 6.2% vs 7.1% (NNT 112)
  • No statistically significant difference in revascularization with PCI: OR 0.97 (0.89-1.06)
  • Subgroup analyses showed consistent benefit with no significant difference in relative risk reduction between the following subgroups:
    • Low vs high annual CV risk
    • Revascularized or not (p=0.078 for interaction, both groups statistically significantly beneficial)
    • Optimal medical management (ASA+statin+beta-blocker), partially optimized, or not (p=0.357)
    • BP >140/90 vs <140/90

Issues with internal validity?

  • No; all 3 trials were randomized, allocation concealed, double-blind trials with low loss-to-follow-up (<2%) that adhered to the intention-to-treat principle
  • Run-in phase: All 3 trials had a run-in phase prior to randomization lasting 2-4 weeks

ACTION - Nifedipine for stable CAD

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Poole-Wilson PA, et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): Randomized controlled trial. Lancet 2004;364:849-57.

Bottom line: In patients with stable angina already treated with at least 1 maintenance anti-anginal drug, nifedipine for 4.5-6 years did not reduce major CV events.

    Patients

    • Inclusion:
      • Age 35+ y
      • Angina stable for at least 1 month
      • Needing treatment of angina (note: not necessarily uncontrolled or symptomatic at baseline)
      • Plus one of the following
        1. Hx of MI
        2. No hx of MI, but angiographically-confirmed CAD
        3. No hx of MI or angiography, but CAD by positive exercise test or perfusion defect
    • Exclusion
      • Overt HF
      • LVEF <40%
      • Any majr CV event or intervention in the past 3 months
      • Planned coronary angiography or intervention
      • Clinically significant valvular or pulmonary disease
      • Unstable insulin-dependent diabetes
      • Any GI disorder that could impair absorption of long-acting nifedipine formulation
      • Any other condition other than CAD that could limit life expectancy
      • Symptomatic orthostatic hypotension, or supine SBP <90 mm Hg
      • SBP 200+ mm Hg, DBP 105+ mm Hg
      • Renal dysfunction (SCr >2x ULN)
      • Liver dysfunction (ALT/AST >3x ULN)
    • From 1996-1998, ? screened -> 7797 randomized -> 7665 analyzed
    • "Average" patient
      • Age 63.5 y
      • Male 80%
      • Enrollment criterion met
        • Hx of MI ~50%
        • No MI, angiographically-confirmed CAD 33%
        • No MI or angiography, but positive exercise or perfusion defect 17%
      • Current NYHA class II-III symptoms 46%
      • Hx of angina attacks 93%
      • Baseline vitals
        • BP 137/80
        • HR 64
      • Mean LVEF 48%
      • Concomitant meds
        • Any anti-anginal drug 99%
          • Beta-blocker 79%
          • Nitrate (daily maintenance) 38%
          • Nitrate PRN use 56%
        • ASA 86%
        • Statin 63%
        • Any BP lowering 30% - ACEI 20%

    Generalizability: Who do these results apply to?

    • Normotensive individuals with CAD without LV dysfunction, most of whom with a previous MI (of unreported age, but at least 3 months ago), already taking at least 1 daily anti-anginal drug.
    • Does not apply to patients with:
      • Recent MI
      • Angina at rest or with minimal activity
      • Optimized secondary prevention therapy
      • Overt HF or reduced LVEF
      • Patients with uncontrolled HTN

    Interventions

    • I: Nifedipine
      • Initial dose: 30 mg PO once daily
      • If initial dose tolerated, increased to 60 mg PO once daily within 6 weeks
      • Dose could be reduced or interrupted
    • C: Matching placebo
    • The following drugs couldn't be used during the study:
      • Non-study calcium-channel blocker (if on prior to study, 2-week washout before study enrollment)
      • Digoxin (unless used for supraventricular arrhythmias such as afib) or other positive inotropes
      • Antiarrhythmics, class I or III (exceptions: amiodarone or sotalol)
      • Cimetidine
      • Anticonvulsants
      • Antipsychotics
      • Rifampicin

    Results @ planned follow-up of 4.5-6 y (97% of patients met minimal planned follow-up)

    • Effect on vitals
      • BP reduced by ~5/3 mm Hg (not reported; estimated from Figure 2)
        • Patients with BP <140/90: 65% vs 53%
      • HR increased by 1 bpm
    • No statistically significant difference in primary composite outcome and multiple components of this outcome
      • Primary outcome (time to first occurrence of either all-cause death, MI, refractory angina, new over HF, debilitating stroke, or peripheral revascularization): ~22% in both groups (hazard ratio 0.97, 95% confidence interval 0.88-1.07, p=0.54)
      • Death: 8% vs 7.6% (HR 1.07, 95% CI 0.91-1.25)
      • Debilitating stroke: 2% vs 2.6% (HR 0.78, 0.58-1.05)
      • MI: 7.0% vs 6.7% (HR 1.04, 0.88-1.24)
      • Refractory angina (defined as angina at rest, prolonged administration of IV nitrates or equivalent plus a coronary angiogram <1 week after onset of symptoms): 3.9% vs 4.5% (HR 0.86, 0.69-1.07)
      • PCI: 10.1% vs 10.9% (HR 0.92, 0.80-1.06)
    • Certain components of the primary composite outcome were statistically reduced with nifedipine
      • New overt HF: 2.2% vs 3.2% (HR 0.71, 0.54-0.94)
      • Coronary angiography: 23.4% vs 27.8% (HR 0.82, 0.75-0.90)
      • CABG: 7.7% 9.7% (HR 0.79, 0.68-0.92)
    • Subgroups: Of 11 subgroup analyses, only separation of patients based on BP 140/90 or greater vs <140/90 had a significant test for interaction (p=0.015), suggesting benefit of nifedipine in patients with CAD + HTN

    Issues with internal validity?

    • No: Randomized, allocation-concealed, blinded (patients, clinicians, investigators) trial with unclear loss-to-follow-up (~5% terminated study earlier than intended) analyzed using a modified intention-to-treat population (all patients who took at least 1 dose of study drug)
    • Note: No run-in phase

    Additional considerations

    • A deeper look at secondary outcomes and subgroup analyses does not clearly support either the role of nifedipine as a antihypertensive drug in patients with CAD, or as an effective anti-anginal.

      • Antihypertensive: Subgroup analysis demonstrated potential benefit in patients with BP 140/90 mm Hg or greater, but there was no statistically significant reduction in debilitating stroke in the overall study population (the outcome most closely associated with HTN in observational studies).

      • Anti-anginal: Though a reduction in the need for coronary angiography and CABG both suggest a reduction in myocardial ischemia, there was no reduction in the proportion of patients with MI, refractory angina, or PCI.

    • The results of this study conflict with those of the previously-covered CAMELOT trial of amlodipine, which argues against a class effect of dihydropyridine calcium-channel blockers in CAD.

    CAMELOT - Amlodipine, enalapril or placebo in CAD

    in

    Nissen SE, et al. Effect of antihypertensive agents on cardiovascular events in patients with coronary disease and normal blood pressure: the CAMELOT study: a randomized controlled trial. JAMA 2004;292:2217-25.

    Bottom line: In patients with symptomatic, angiographically-confirmed CAD without heart failure symptoms or LV dysfunction, amlodipine, but not enalapril, reduced the risk of ischemia-driven outcomes, including coronary revascularization (NNT 26) and hospitalization for angina (NNT 20), consistent with its anti-anginal mechanism.

    Notably, neither amlodipine or enalapril reduced "hard" clinical outcomes, including death, MI or stroke, compared to placebo over the duration of this trial. This likely reflects a low/intermediate-risk population (e.g. risk of MI ~1.5%/year in placebo group) due to high use of other interventions that reduce CV risk, and short study duration.

     

     

    Patients

    • Inclusion:
      • Adults aged 30-79 requiring coronary angiography for evaluation for chest pain or PCI
      • 1 or more lesions in native coronary artery with >20% stenosis
      • Diastolic BP <100 mm Hg by manual BP measurement (could be taking antihypertensives at time of measurement)
    • Exclusion:
      • Moderate-severe HF
      • LVEF <40%
      • Left main coronary artery stenosis >50%
    • 2865 screened -> 1997 randomized -> 1991 analyzed
    • "Average" patient:
      • 58 y
      • Male 75%
      • White 89%
      • Number of coronary arteries with stenosis >20% - 1 (~30%), 2 (~33%), 3 (~35%)
      • BP 129/77
      • PMHx
        • MI 37-40%
        • PCI 26-30%
        • Angina CCS class 4 - 8-9%
        • HTN 60%
        • Diabetes 17-19%
      • Concomitant meds
        • ASA 95%
        • Statin 83%
        • Beta-blocker ~75%
        • Diuretic 26-33%

    Generalizability: Who do these results apply to?

    • These results apply to patients with angina and angiographically-confirmed CAD without hypertension, most of whom did not have a previous MI, with no/minimal HF symptoms & normal LVEF
    • These results do not apply to patients who:
      • Qualify for the HOPE or EUROPA trials
      • Have HFrEF, or who are post-MI with LV dysfunction

    Interventions

    • Intervention 1: Amlodipine
      • Initial dose: 5 mg PO daily
      • If initial dose tolerated, doubled to 10 mg PO daily at end of week 2
      • If intolerable adverse effect, dose halved & uptitration tried at a later point
      • Titrated to full target dose: 86.7%
      • BP reduced by ~5/2 mm Hg
    • Intervention 2: Enalapril
      • Initial dose: 10 mg PO daily
      • If initial dose tolerated, doubled to 20 mg PO daily at end of week 2
      • If intolerable adverse effect, dose halved & uptitration tried at a later point
      • Titrated to full target dose: 84.3%
      • BP reduced by ~5/2 mm Hg
    • Control: Placebo
    • Co-interventions:
      • Diuretics, alpha-1 blockers, & beta-blockers were permitted
      • Non-study ACEI, ARB & CCBs were not permitted (discontinued over 2-6-week period before study initiation)

    Results @ 2 years

    • Statistically significant reduction in the primary outcome with amlodipine, but not enalapril, versus placebo
      • Amlodipine vs placebo: Hazard ratio 0.69 (0.54-0.88)
      • Enalapril vs placebo: HR 0.85 (0.67-1.07)
      • Amlodipine 16.6%, enalapril 20.2%, placebo 23.1%
    • Beneficial effects of amlodipine versus placebo on primary outcome driven by softer, "ischemic" outcomes
      • Coronary revascularization: 11.8% vs 15.7% (NNT 26, p=0.03)
      • Hospitalization for angina: 7.7% vs 12.8% (NNT 20, p=0.002)
    • No statistically significant difference between groups in "hard" clinical outcomes (listed as amlodipine, enalapril, placebo):
      • All-cause mortality, MI or stroke: 3.3%, 3.4%, 4.7%
        • All-cause mortality: 1.1%, 1.2%, 0.9%
        • Non-fatal MI: 2.1%, 1.6%, 2.9%
        • Stroke or TIA: 0.9%, 1.2%, 1.8%
      • Hospitalization for HF: 0.5%, 0.6%, 0.8%
    • Safety:
      • Discontinued study medication: 29.3%, 35.1%, 31.1% (differences between groups not statistically significant, p=0.07)
      • Hypotension: 3.3%, 9.5%, 3.2% (NNH 16 for enalapril vs placebo)
      • Cough: 5.1%, 12.5%, 5.8% (NNH 15 for enalapril vs placebo)
      • Peripheral edema: 32.4%, 9.5%, 9.6% (NNH 5 for amlodipine vs placebo)

    Issues with internal validity?

    • No: Randomized, allocation-concealed, blinded (patients, clinicians & outcome adjudicators) trial with low loss-to-follow-up (<0.5%) analyzed using the intent-to-treat population.
    • Notes:
      • Minor baseline imbalances in baseline characteristics, e.g. age (amlodipine 57.3 y vs enalapril 58.5 y) & history of MI (amlodipine 37.4% versus enalapril 40.3%) do not suggest compromised allocation concealment or impact results
      • 2-week placebo run-in period to exclude non-adherent patients (took <80% of doses).

    CORONA & GISSI-HF - Statins in heart failure

    in ,

    Bottom line: Issues with generalizability strongly limit the applicability of CORONA and GISSI-HF to the real world.

    CORONA selected an ischemic HFrEF population at lower risk of coronary events (>6 months from most recent MI), and was unable to rule out the 25-30% relative risk reduction in coronary events consistently demonstrated in statin RCTs.

    GISSI-HF, on the other hand, may have washed out any effect in ischemic HFrEF by also enrolling patients with no CAD and at low risk for an atherosclerotic CV event. However, it is reasonable to conclude from GISSI-HF that patients with HF of non-ischemic origin likely will not benefit from statin therapy unless at high risk due to other coronary risk factors (i.e. traditional threshold of Framingham 10-year risk >20%).

     

    (1) CORONA

    Kjekshus J, et al. Rosuvastatin in older patients with systolic heart failure. N Engl J Med 2007;357:2248-61.

      Patients

      • Inclusion
        • 60+ y/o
        • Chronic HFrEF with NYHA II-IV symptoms & LVEF <40% (<35% if NYHA II symptoms)
        • HF of ischemic etiology, as reported by investigators
        • Not already on statin & not thought to have absolute indication/contraindication by patient's physician
        • Stable on optimal therapy x 2+ weeks
      • Exclusion
        • Decompensated HF
        • Need for inotropes
        • MI in past 6 months
        • PCI, CABG, ICD or biventricular pacemaker in past 3 months (or planned)
        • Multifactorial HF
          • Clinically significant uncorrected primary valvular heart disease or malfunctioning prosthetic valve
          • HoCM
          • Acute endomyocarditis/myocarditis
          • Pericardia disease
          • Systemic disease (e.g. amyloidosis)
        • Significant competing causes of morbidity & mortality
          • Liver disease or ALT >2x ULN
          • SCr >221 micromol/L
          • TSH >2x ULN
          • Chronic muscle disease or unexplained CK >2.5x ULN
          • "Any other condition that would substantially reduce life expectancy or limit compliance"
      • ? screened -> 5459 entered placebo run-in -> 5011 randomized
      • "Average" patient
        • 73 y
        • Male 59%
        • HF characteristics
          • NYHA class II (37%), III (62%)
          • EF 31%
        • PMHx
          • MI 60%
          • Past/current angina 72%
          • CABG/PCI 26%
          • AFib 24%
          • ICD <3%
        • Lipids: Total cholesterol 5.35, LDL 3.54, HDL 1.23 mmol/L
        • Meds
          • Loop diuretic 75%
          • Digoxin 33%
          • ACEI or ARB 92%
          • Beta-blocker 75%

      Issues with external validity (generalizability)?

      • Yes, multiple:
        • Subjective inclusion criteria with unclear rationale (i.e. why the patients' physicians felt that they did not have an indication for a statin despite ischemic HFrEF)
        • Extensive exclusion criteria ensured enrollment of patients without any significant comorbidities (& therefore fewer competing risks for death or hospitalization)

      Interventions

      • I: Rosuvastatin 10 mg PO once daily
      • C: Matching placebo

      Results @ median 2.75 y

      • LDL reduced by 44% from baseline with rosuvastatin
        • @ baseline: 3.54 mmol/L
        • @ 3 months: 1.96
      • No statistically significant difference in primary outcome (composite of CV death, MI or stroke): Hazard ratio 0.92 (95% CI 0.83-1.02)
        • 11.4% vs 12.3% (p=0.12)
      • No statistically significant difference in secondary outcomes
        • All-cause death: 11.6% vs 12.2% (p=0.31)
        • Hospitalizations: 35.6% vs 38% (p=0.09)
          • Note: Statistically significant only when considering overall # of hospitalizations in each group
          • For worsening HF: 11.3% vs 12.3% (p=0.11)
        • Any coronary event: 9.3% vs 10% (p=0.18)
          • MI: 1.9% vs 2.4% (HR 0.84, 0.70-1.00)
      • Safety: 
        • All-cause discontinuation & discontinuation due to adverse events statistically significantly LOWER with rosuvastatin vs placebo
        • No statistically significant difference in myalgias, regardless of definition used (~9% in both groups)

      Issues with internal validity?

      • No; Randomized (using minimization), allocation concealed, blinded (patients, clinicians, investigators) with unknown loss-to-follow-up, analyzed using intention-to-treat population.
      • Run-in phase of single-blind placebo x2-4 weeks to ensure adherence (excluded if took <80% of doses)

       

      (2) GISSI-HF

      Tavazzi L, et al. Effect of rosuvastatin in patients with chronic heart failure (the GISSI-HF trial): a raondomised, double-blind, placebo-controlled trial. Lancet 2008;372:1231-9.

        Patients

        • Inclusion
          • Adults with HF NYHA class II-IV
          • Patients with HFpEF (LVEF >40%) had 1+ hospital admissions for HF in the last year
        • Exclusion
          • Any non-cardiac comorbidity "unlikely to be compatible with a sufficiently long follow-up", including
            • Liver disease
            • SCr >221 micromol/L
            • ALT/AST >1.5x ULN
            • CK >1x ULN
          • ACS within 1 month
          • Planned cardiac surgery in next 3 months
        • 7046 assessed for eligibility -> 4631 randomized -> 4574 analyzed
        • "Average" patient
          • 68 y
          • Male 76%
          • HF characteristics
            • Ischemic 40%, dilated CM 34%, hypertensive 18%
            • NYHA class II (61%), III (36%)
            • On exam: S3 25%, MR murmur 64%, crackles 28%
            • EF 33%, >40% in 10%
          • PMHx
            • MI 33%
            • CABG 13%, PCI 8%
            • AFib 20%
            • ICD 6.5%
          • Lipids: LDL ~3.15, HDL 1.2 mmol/L
          • Med
            • Diuretic 90%
            • Digoxin 40%
            • Nitrate 32%
            • ACEI or ARB 94%
            • Beta-blocker 62%

        Issues with external validity?

        • Yes: Enrolled a broad range of patients with heart failure, with variable risk of atherosclerotic/statin-modifiable events
          • Negative results here may not necessarily reflect lack of benefit in population of interest

        Interventions

        • I: Rosuvastatin 10 mg PO once daily
        • C: Matching placebo

        Results @ median 3.9 y

        • LDL reduced by ~30% in rosuvastatin group
          • @ baseline: 3.16 mmol/L
          • @ 1 y: 2.15 mmol/L
        • No statistically significant difference in either co-primary outcomes
          • All-cause death: 28.8% vs 28.1%, HR 1.03 (95.5% CI 0.92-1.15) 
          • All-cause death or CV hospitalization: 57% vs 56%, HR 1.02 (99% CI 0.92-1.13)
        • Low rate of MI, with no statistically significant difference between groups: 2.7% vs 3.1%, R 0.88 (95% CI 0.63-1.24)
          • Similar results for stroke: 3.6% vs 2.9% (HR 1.25, 0.91-1.73)

        Issues with internal validity?

        • No: Randomized, allocation concealed, blinded (patients, clinicians & investigators) with low (<0.1%) loss-to-follow-up, analyzed using intention-to-treat population
        • No run-in phase

        OSLER - Evolocumab (PCSK9 inhibitor) for LDL lowering

        in ,

        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