CONSENSUS - Enalapril in severe HF

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The Consensus Trial Study Goup. Effects of enalapril on mortality in severe congestive heart failure. N Engl J Med 1987;316:1429-35.

Bottom line: In patients with NYHA class IV HF (presumably with reduced EF), enalapril reduced the risk of death (NNT 6-7) & reduced symptom burden at 6 & 12 months.

 

Patients (n=253)

  • Inclusion
    • Clinical diagosis of HF
      • Hx of heart disease
      • Symptoms of dyspnea and/or fatigue
      • Signs of fluid retention
    • Symptomatic at rest (NYHA functional class IV)
    • Cardiomegaly on CXR, defined as heart size
      • Men: >600 mL/m^2
      • Women: >550 mL/m^2
    • No assessment of myocaridal function performed (? LVEF)
  • Exclusion
    • NYHA <IV after optimization with diuretics & digoxin
    • Hemodynamically important aortic/mitral stenosis
    • MI <2 months
    • Unstable angina
    • Planned cardiac surgery
    • 1o pulmonary disease or right HF due to pulmonary disease
    • SCr >300 umol/L
  • "Average" patient
    • Age 70
    • Female 30%
    • HF duration: <18 months (25%), 18 months to 4 y (~25%), >4 y (50%)
    • PMHx
      • CAD 73%, previous MI 48%
      • Cardiomyopathy 15%
      • Valvular heart disease ~20%
      • AF ~50%
    • BP 120/75 mm Hg
    • SCr 130 umol/L
    • K 4.0 mmol/L
    • Meds
      • Furosemide 90% (mean dose 200 mg)
      • Spironolactone 55% (mean dose 80 mg)
      • Digoxin 93%
      • Nitrate 45%, hydralazine 2%
      • Anticoagulant 33%

Interventions & co-interventions

  • I: Enalapril
    • Initial dose 5 mg PO BID (started in hospital)
    • Then increased to 10 mg PO BID after 1 week
    • Then the dose could be increased up to 20 mg PO BID
    • Mean dose @ end of study: 18.4 mg/day (~10 mg PO BID)
  • C: Matching placebo
  • Co-interventions
    • Optimized on diuretics +/- digoxin at start of trial
    • Other non-ACEI vasodilators permitted, including nitrates, alpha-1 blockers, hydralazine

Results @ 6 months

  • Death, statistically significant reduction
    • @ 6 months (primary outcome): 26% vs 44% (NNT 6 - relative risk reduction (RRR) 40%)
    • @ 1 year: 36% vs 52% (NNT 7 - RRR 31%)
  • Improvement in NYHA functional class: 42% vs 22% (NNT 5)
  • Study drug discontinuation: 17% vs 14% (NSS)

Issues with internal validity?

  • Possible exaggeration of benefit due to early termination for mortality in enalapril group in unplanned interim analysis
  • Otherwise well-designed: Randomized, allocation-concealed, blinded trial with low loss-to-follow-up analyzed according to the intention-to-treat principle

EMPA-REG - Empagliflozin for CV risk reduction in T2DM with hx of CVD

in ,

Zinman B, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med 2015;373:2117-28.

Bottom line: In patients with T2DM and CVD, empagliflozin (at either dose of 10 mg or 25 mg daily) reduced the risk of death (NNT 39) & CV events (NNT 63) over 3 years.

 

    Patients

    • Inclusion
      • Adults with T2DM
        • No glucose-lowering agents in previous 12 weeks: 7-9%
        • Receiving glucose-lowering agents, stable x12 weeks: 7-10%
      • Established CVD, defined as any of the following:
        • MI >2 months ago
        • CAD (confirmed with angiography)
        • Stroke >2 months ago
        • PAD documented by
          • Limb revascularization or amputation
          • Peripheral artery stenosis >50% on angiography or non-invasive evaluation
          • ABI <0.9 on at least 1 side
    • Key exclusion criteria
      • Cancer within last 5 y
      • Stroke/TIA within 2 months
      • Planned cardiac surgery or PCI in next 3 months
      • BMI >45
      • Blood dyscrasias or any disorder causing hemolysis or unstable RBCs
      • eGFR <30 mL/min/1.73 m^2
      • ALT, AST or ALP >3x ULN
    • 11,531 individuals screened across 590 sites in 42 countries -> 7028 randomized -> 7020 analyzed
    • "Average" patient
      • Age 63 y
      • Male 72%
      • White 72%, Asian 22%, Black 5%, other 1%
      • Geography: Europe 41%, North America 20%, Asian 19%, Latin America 15%, Africa 4%
      • CV risk factors
        • CAD 76% (multivessel 47%)
        • MI 46%
        • CABG 24%
        • Stroke 24%
        • PAD 20%
      • Time since T2DM dx: >10 y (57%), 5-10 y (25%), 1-5 y (16%)
      • Wt 87 kg, BMI 31
      • BP 136/77
      • Lipids: total 4.2, LDL 2.2, HDL 1.1 mmol/L
      • A1c 8%
      • Meds
        • Metformin 74%
        • Insulin 49%
        • Sulfonylurea 43%
        • DPP-4 inhibitor 11%
        • Antihypertensives 95%
          • ACEI 80%
          • Beta-blocker 64%
        • ASA 83%
        • Statin 76%

    Interventions & co-interventions (median 2.6 y)

    • I: Empagliflozin 10 mg or 25 mg
      • A1c lowered by 0.5-0.6% at 12 weeks vs placebo
    • C: Matching placebo
    • Co-interventions:
      • 1st 12 weeks after randomization: No change to glycemic management unles fasting glucose >13.3 mmol/L
      • After 12 weeks: Adjustment to glucose-lowering therapy according to local guidelines

    Results @ median 3.1 y

    • Results for both doses of empaglifozin were similar, and therefore pooled
    • Statistically significant reduction in:
      • The primary outcome (CV death, MI, stroke): Hazard ratio (HR) 0.86, 95% confidence interval 0.74-0.99 (p=0.04)
        • 10.5% vs 12.1% (NNT 63)
      • Death: HR 0.68 (0.57-0.82)
        • 5.7% vs 8.3% (NNT 39)
      • HF hospitalization: HR 0.65 (0.50-0.85)
        • 2.7% vs 4.1% (NNT 72)
    • No statistically significant difference:
      • MI: HR 0.87 (0.70-1.09) - 4.8% vs 5.4%
      • Stroke: HR 1.18 (0.89-1.56) - 3.5% vs 3.0%
      • Coronary revascularization: HR 0.86 (0.72-1.04) - 7.0% vs 8.0%
    • Safety
      • Serious adverse events: 38.2% vs 42.3% (NNT 25, p<0.001)
      • Premature discontinuation: 23.4% vs 29.3%
      • Hypovolemia: 5.1% vs 4.9%
      • Acute kidney injury: 1.0% vs 1.6%
      • UTI: 18.0% vs 18.1% (complicated 1.7% vs 1.8%)
      • Genital infection: 6.4% vs 1.8% (NNH 22)
      • DKA: 0.1% vs <0.1%
      • Hypoglycemia (glucose <3.9 mmol/L or requiring assistance): 27.8% vs 27.9%
    • Numerous subgroup analyses were performed, which demonstrated inconsistent subgroup interactions with the primary outcome and CV death

    Issues with internal validity?

    • No: Randomized, allocation-concealed, blinded trial with low loss-to-follow-up (<0.1%) analyzed using intention-to-treat principles 
    • Run-in: 2-week open-label placebo run-in

    Additional considerations

    • The reduction of CV events became apparent after only 3 months. Previous trials of diabetes drugs or glycemic control goals have never demonstrated a benefit this early, suggesting that the apparent benefit of empagliflozin may have resulted from another mechanism. 
    • The reduction int the primary CV event resulted mainly from a reduction in CV death, but not MI or stroke. This further argues against glycemic control as the beneficial mechanism of empagliflozin.

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

    in

    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

    in ,

    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).