Mineralocorticoid receptor antagonists (MRAs) in HFrEF or post-MI LV dysfunction (EPHESUS, EMPHASIS, RALES)

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EPHESUS: Pitt B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21.

EMPHASIS-HF: Zannad F, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21.

RALES: Pitt B, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999;341:709-17.

Bottom-line:

  • In patients with HFrEF with NYHA functional class 2-4, MRAs reduced the risk of death (NNT 18-60 per year) and hospitalization (NNT 24-30 per year), but increased the risk of hyperkalemia.

  • Proper monitoring of renal function & serum potassium (e.g. 1 week after start/dose change, monthly x3 months, then q3-6 months) is critical to ensure that harms do not outweigh benefits of this important therapy.

Patients, Interventions, Controls & Duration of Follow-Up

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Results

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Additional Results/Analyses

Generalizability & internal validity

  • RALES set the indication for mineralocorticoid antagonists in HFrEF NYHA class III-IV; EPHESUS expanded it to HFrEF or LV dysfunction+diabetes post-MI; EMPHASIS-HF further expanded the indication to HFrEF NYHA II with high risk for HF hospitalization.

  • Assessed together, these 3 trials evaluated MRAs in all stages in a varity of etiologies for HFrEF, as early as 3 days post-MI, with background therapy ranging from the full gamut to only ACEI + diuretic therapy.

  • Trials employed routine monitoring for renal & potassium abnormalities:

    • EPHESUS: Serum potassium 48h after treatment start, then at weeks 1, 4, 5, 12 of treatment, then q3 months

    • RALES: Serum potassium q4 weeks x3 months, then q3 months x1 year, then q6 months

  • Internal validity: Low risk of bias in all 3 trials

SHIFT - Ivabradine for heart failure with reduced ejection fraction

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Swedberg K, et al. Ivabradine and outcomes in chronic heart failure (SHIFT): A randomised placebo-controlled study. Lancet 2010;376:875-85.

Bottom-line: In patients with HFrEF and a resting heart rate >70 bpm despite maximally-tolerated beta-blocker therapy, ivabradine reduced the risk of hospital admissions (NNT 25), mainly by reducing HF-related hospitalization, over ~2 years.

When using ivabradine, monitoring HR via pulse and EKG at baseline and at follow-up is critical to ensure benefit, and to minimize symptomatic bradycardia (NNH 25) and atrial fibrillation (NNH 100). It appears that the higher the baseline HR, the greater the benefit (and likely the lower risk of bradycardia).

 

Patients (n=6558)

  • Inclusion

    • Age 18+ y

    • Stable symptomatic HF for at least 4 weeks

    • LVEF 35% or lower

    • HF hospitalization in the last 12 months

    • Normal sinus rhythm with HR 70+ bpm on 12-lead EKG after 5 min of rest on 2 consecutive visits

  • Exclusion

    • HF etiology of congenital heart disease or primary severe valvular disease

    • MI in last 2 months

    • CRT implanted in last 6 months

    • Implantable pacemaker that's pacing >40% of the day

    • Permanent AF/flutter

    • Symptomatic hypotension

    • Drugs: Use of diltiazem or verapamil, class I antiarrhythmics or strong CYP 3A4 inhibitors

  • Screened 7411 -> randomized 6558

  • "Average" patient in the trial

    • Age 60 y

    • Male 76%

    • Duration of HF 3.5 y

    • HF etiology: Ischemic 68%

    • NYHA class: II (~50%), III (~50%)

    • PMHx

      • MI 56%

      • HTN 67%

      • Diabetes 30%

      • AF/flutter 8%

    • BP 122/76 mm Hg

    • HR 80 bpm

    • LVEF 29%

    • eGFR 75 mL/min*1.73 m^2

    • Meds

      • Beta-blocker ~90% (26% on target dose, 56% on at least 1/2 target dose)

      • ACEI ~80%, ARB 14%

      • Mineralocorticoid antagonist ~60%

      • Diuretic 84%

      • Digoxin 22%

      • Devices: ICD 3%, CRT 1%

Intervention & control

  • I: Ivabradine

    • Initial dose of 5 mg PO BID

    • After 14 days:

      • If HR >60 bpm, increased to 7.5 mg PO BID

      • If HR 50-60 bpm, kept on 5 mg PO BID

      • If HR <50 bpm or symptomatic bradycardia, dose reduced to 2.5 mg PO BID

    • At each subsequent follow-up, above algorithm used to titrate between 2.5-7.5 mg PO BID

  • C: Matching placebo

Results @ median 1.9 years

  • HR

    • @ 1 month: Ivabradine 64 bpm, placebo 75 bpm

    • @ 2-3 years: 67 vs 75 bpm

  • Significant reduction with ivabradine in:

    • Serious adverse events: Ivabradine 45%, placebo 48% (p=0.025)

    • Primary outcome (CV death or hospital admission for HF): 24% vs 29% (hazard ratio 0.82, 0.75-0.90), NNT 20

    • Hospital admission: 38% vs 42% (HR 0.90, 0.82-0.96), NNT 25

      • For HF: 16% vs 21%

    • Unclear effect on death

      • No statistically significant difference in death (16% vs 17%. HR 0.90, 0.80-1.02) or CV death: 14% vs 15% (HR 0.91, 0.80-1.03)

      • Reduction in death from HF: 3% vs 5% (HR 0.74, 0.58-0.94)

    • Significant increase with ivabradine in:

      • Symptomatic bradycardia: 5% vs 1%, NNH 25

      • Asymptomatic bradycardia: 6% vs 1%, NNH 20

      • Atrial fibrillation: 9% vs 8%, NNH 100

      • Blurred vision: 1% vs <1%, NNH 100

      • Phosphenes: 3% vs 1%, NNH 50

  • Subgroup analyses demonstrated a significant interaction between baseline HR 77 bpm or greater versus <77 bpm and effect on the primary outcome. Greater relative benefit was seen in patients with a higher baseline HR.

Generalizability

  • Patients included in this trial overall had HFrEF of ischemic and non-ischemic origin with NYHA functional class II or III

  • Use of background medical therapies for HFrEF was fairly good, although very few patients were optimized on beta-blockers, with the most common reasons cited as hypotension and fatigue

Internal validity

  • Low risk of allocation, performance and detection bias

    • Computer-generated randomization with central, automated allocation and blinding with use of identical placebo)

  • Low risk of attrition bias

    • Loss-to-follow-up <1%

    • Intention-to-treat analysis

Other studies

  • The BEAUTIFUL trial, which came out before SHIFT, evaluated the use of ivabradine in patients with CAD and LV dysfunction with a heart rate of 60 bpm or greater

    • Patients were quite similar to those in the SHIFT trial with a mean HR of 72 bpm and 84% with HFrEF NYHA class II or III

    • In the overall population studied in BEAUTIFUL, ivabradine did not reduce the risk of CV events

    • In a subgroup of patients with HR >70 bpm (mimicking the SHIFT population), there was no reduction in the primary outcome or any HF-related outcome.

  • A pooled analysis of BEAUTIFUL and SHIFT showed results consistent with the SHIFT trial in patients with HFrEF and HR of 70 bpm or more.

  • The SIGNIFY trial, which was published after SHIFT, evaluated ivabradine in patients with CAD without HF with a HR of 70 bpm or greater

    • Patients had stable CAD, no HF, a mean HR of 77 bpm, and a mean LVEF of 56%

    • All analyses of SIGNIFY demonstrated no benefit on CV outcomes, with a possible increase in HF-related hospital admission (HR 1.20, 0.99-1.46), and an increased risk of the primary CV outcome in patients with angina CCS class II-IV at baseline

    • In this population, ivabradine increased the risk of adverse events (NNH 14), symptomatic bradycardia (NNH 15), phosphenes (NNH 20) and blurred vision (NNH 125)

    • SIGNIFY therefore solidifed that ivabradine has no role in CAD without HF.

  • None of the trials (BEAUTIFUL, SHIFT, SIGNIFY) enrolled patients with HFpEF. The role of ivabradine in HFpEF is therefore unknown.

 

 

AF-CHF - Rhythm vs rate control in AF with HFrEF

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Roy D, et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med 2008;358:2667-77.

Bottom-line: In individuals with both AF & HFrEF, a rhythm-control strategy is not superior to an aggressive rate-control strategy targeting resting HR <80 bpm. More patients starting with the rhythm-control strategy will require a strategy change (NNH 9), but neither strategy works for everybody.

 

Patients (n=1376)

  • Inclusion
    • AF
      • Episode with EKG documentation lasting at least 6h or requiring cardioversion in previous 6 months, or
      • Episode lasting 10+ minutes in previous 6 months & previous cardioversion for AF
    • HF
      • NYHA II-IV in previous 6 months, or
      • Hospitalized for HF in previous 6 months, or
      • LVEF 25% or less
    • LVEF 35% or less measured in last 6 months
  • Exclusion
    • Persistent AF >12 months
    • Reversible cause of AF or HF
    • Decompensated HF in previous 48h
    • Use of antiarrhythmics for other arrhythmias
    • 2o-3o AVB with bradycardia <50 bpm
    • Hx long QT syndrome
    • Dialysis-dependent renal failure
  • "Typical" patient
    • Age 66 y
    • Male 78-85%
    • NYHA class III-IV 32%
    • HF etiology: Ischemic (48%), hypertensive (10%), valvular (5%)
    • Prior hospitalization for AF (50%), HF (55%)
    • AF paroxysmal (1/3), persistent (2/3)
    • PMHx
      • Previous stroke/TIA 10%
      • HTN 49%
      • Diabetes 22%
    • AF on EKG (55-60%)
    • LVEF 27%
    • Concomitant meds
      • ACEI 86%, ARB 11%
      • Mineralocorticoid antagonist 45%
      • OAC 85-90%
      • ASA 40%
      • Lipid-lowering 43%
    • ICD 7%

Interventions

  • I: Rhythm control: Aggressive pharmacotherapy + electrical cardioversion to prevent and cardiovert AF
    • Drug of choice: Amiodarone, then sotalol or dofetilide as required
    • Drugs @ 1 year: Amiodarone (82%), sotalol (2%), dofetilide (<1%)
      • Beta-blocker (80%), digoxin (~50%), anticoagulant (88%)
    • Electrical cardioversion
      • 1st recommended <6 weeks after enrollment not converting to NSR with pharmacological rhythm control alone
    • 2nd recommended <3 months after enrollment if still not in NSR
    • Subsequent cardioversions PRN
  • C: Rate control: Adjusted doses of beta-blocker & digoxin to achieve resting HR <80 bpm & <110 bpm during 6-min walk test (tested @ month 4 & 12, then yearly)
    • Drugs @ 1 year: Beta-blocker (88%), digoxin (75%), verapamil/diltiazem (3%)
      • Amiodarone (7%), sotalol or dofetilide (<1%), anticoagulant (92%)
  • Interventions common to both groups:
    • Max-tolerated doses of beta-blockers (for HFrEF management)
    • Anticoagulation

Results @ mean 3 y f/u

  • Death: 32% vs 33% (p=0.68)
    • CV death (primary outcome): 27% vs 25% (p=0.53)
  • Hospitalization: 64% vs 59% (p=0.06)
    • AF hospitalization: 14% vs 9% (p=0.001)
  • Worsening HF: 28% vs 31% (p=0.17)
  • Switched to other intervention: 21% vs 10%
  • AF on EKG at study visit:
    • Month 4, years 1-3: ~20% vs ~60% (during f/u, >55% in rhythm-control group had at least 1 AF recurrence)
    • Year 4: ~25% vs ~70%

Generalizability

  • Representative of individuals with HFrEF and moderately good use of HFrEF medical therapies & low ICD use
  • Rhythm-control intervention consistent with real world use; rate-control intervention similar to "intensive" intervention from AFFIRM trial

Internal validity

  • Unclear risk of allocation bias
    • Allocation concealment not described + some moderately-large baseline differences in certain characteristics (e.g. male 78% vs 85%, AF on baseline EKG 54% vs 61%)
  • Unclear risk of performance & detection bias
    • Predefined treatment protocols accounted for most potential differences in interventions
    • Rhythm-control group required more AF-related hospitalizations, likely cardioversion-related
    • Higher rate of cross-over in rhythm-control group
    • Once outcomes reported, adjudicated by committee unaware of treatment allocation
  • Unclear risk of attrition bias
    • 5-6% loss-to-follow-up, which could be enough to hide differences between groups in main outcomes

WARCEF - Warfarin vs ASA in HFrEF in sinus rhythm

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Homma S, et al. Warfarin and aspirin in patients with heart failure and sinus rhythm. N Engl J Med 2012;366:1859-69.

Bottom-line: In patients with HFrEF in sinus rhythm and without any additional risk factors for cardiac embolism, warfarin reduced the risk of ischemic stroke, and increased the risk of major and minor hemorrhages and HF hospitalization (possibly from anemia or cessation/reduction of HF meds during bleeding events).

For every 1000 patients with HFrEF in sinus rhythm, treatment warfarin instead of ASA would result in 7 fewer ischemic strokes, 11 extra HF hospitalizations, 9 extra major and 43 extra minor bleeds per year. Thus for most patients represented here, the risks far outweigh the benefits.

 

Patients (n=2305)

  • Inclusion
    • Age 18+ y
    • HFrEF
      • NYHA class I-IV
      • LVEF 35% or less assessed in the past 3 months
    • Normal sinus rhythm
    • Modified Ranking scale (mRS) <5 (i.e. no more than moderately severe disability)
    • Planned treatment with a beta-blocker plus ACEI/ARB/hydralazine+nitrate
  • Exclusion:
    • Clear indication for either warfarin or ASA
    • High risk of cardiac embolism
      • AF
      • Mechanical heart valve
      • Endocarditis
      • Intracardiac thrombus (mobile or pedunculated)
  • Screened ? -> randomized & analyzed 2305
  • Typical trial patient
    • Age 61 y
    • Male 80%
    • North American ~50%
    • NYHA class I (14%), II (55%), III (30%), IV (~1%)
    • mRS 0 (41%), 1 (31%), 2 (23%), 3-4 (5%)
    • Ischemic HF etiology 43%
    • PMHx
      • Stroke/TIA 13%
      • MI 48%
      • Current smoker 17%
      • ETOH consumption >2 onces/day - 25%
      • HTN 61%
      • Diabetes 32%
      • AF 4%
    • BMI 29
    • BP 124/74 mm Hg
    • HR 72 bpm
    • LVEF 25%
    • Meds
      • ACEI/ARB 98%
      • Beta-blocker 90%
      • Mineralocorticoid antagonist 60%
      • Diuretic 80%
      • Nitrate 25%
      • Statin 83%
      • Prior to randomization: ASA (59%), other antiplatelet (7%), oral anticoagulant (8%)
    • ICD 18%

Interventions

  • Warfarin with target INR 2.75 (range 2.0 to 3.5)
    • Mean INR during trial 2.5 +/- 1, time in target range=63%
    • Spent 66% of follow-up on study treatment
  • ASA 325 mg PO once daily
    • Spent 68% of follow-up on study treatment

Results @ mean 3.5 y

  • No statistically significant difference in
    • Primary outcome (death, ischemic stroke, intracerebral hemorrhage): Warfarin 26.4% vs ASA 27.5%, hazard ratio (HR) 0.93 (95% confidence interval 0.79-1.10)
    • Secondary outcome (primary outcome, MI, HF hospitalization): 39.1% vs 37.4%, HR 1.07 (0.93-1.23)
    • Death: 23.5% vs 22.6%
  • Statistically significant
    • Reduction with warfarin in
      • Ischemic stroke: 2.5% vs 4.7%, HR 0.52 (0.33-0.82, NNT 46)
        • Per year: 0.7% vs 1.4% (NNT 143/year)
    • Increase with warfarin in
      • HF hospitalization: 20.9% vs 17.5%, HR 1.21 (1.00-1.47, NNH 30)
        • Per year: 6.8% vs 5.7% (NNH 91/year)
      • Major hemorrhage: 1.8%/year vs 0.9%/year, HR 2.05 (1.36-3.12, NNH 112/year)
      • Minor hemorrhage: 11.6%/year vs 7.3%/year, HR 1.56 (1.34-1.81, NNH 24/year)

Generalizability

  • The study population represents a typical HFrEF population of both ischemic & non-ischemic etiology with good to excellent use of background therapy for systolic dysfunction
    • 43% of patients had ischemic cardiomyopathy, therefore qualifying for ASA for secondary prevention
    • 57% had non-ischemic cardiomyopathy, for which antiplatelet therapy would not be indicated routinely. Since this trial has no placebo group, it's not able to answer whether these patients need any antithrombotic therapy at all in the absence of another indication.
  • The target INR in this trial (2.75, range 2.0-3.5) was higher than typically used in practice for AF (2.5, range 2.0-3.0), but similar to that used for mechanical mitral or high-risk aortic valves (3.0, range 2.5-3.5), however the mean INR during the trial was 2.5. Similarly, the ASA dose (325 mg/d) was higher than that typically used for AF/secondary prevention (75-100 mg/d). Thus, bleeding in both groups is likely to be higher than with regimens used in practice, particularly in the ASA group.

Issues with internal validity?

  • No: Centrally randomized, allocation-concealed, double-dummy double-blind trial with blinded outcome adjudication, and low loss-to-follow-up (1.5%) analyzed using intention-to-treat population.

Other studies

  • 3 other RCTs (WASH 2004, HELAS 2006, WATCH 2009) with a total of 1358 patients compared warfarin to ASA in patients with HF. Meta-analysis of all 4 trials demonstrates results consistent with WARCEF: Warfarin cut the risk of ischemic stroke by ~half, & ~doubled the risk of major & minor bleeds compared to ASA.

ACE inhibitors post-MI (CCS-1, CONSENSUS II, GISSI-3, ISIS-4, SMILE; AIRE, SAVE, TRACE)

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Bottom line:

  • Short-term use of ACE inhibitors reduces the risk of death post-MI regardless of HF signs/symptoms or LVEF at time of initiation (NNT 125-200).

    • Note: The previously-reviewed HOPE trial then supports continuing ACE inhibitors in patients without HF or LV dysfunction. 

  • In patients with either clinical HF or reduced LVEF post-MI, long-term use of ACE inhibitors reduce the risk of death (NNT 14-20) and severe HF.

 

Short-term use of ACEI in MI all-comers:

  • Oral captopril versus placebo among 13,634 patients with suspected acute myocardial infarction: Interim report from the Chinese Cardiac Study (CCS-1). Lancet 1995;345:686-7.
  • ISIS-4 (Fourth International Study of Infarct Survival) Collaborative Group. ISIS-4: A randomised factorial trial assessing early oral captopril, oral mononitrate, and intravenous magnesium sulphate in 58,050 patients with suspected acute myocardial infarction. Lancet 1995;345:669-85.
  • Swedberg K, et al. Effects of the early administration of enalapril on mortality in patients with acute myocardial infarction: Results of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). N Engl J Med 1992;327:678-84.
  • Gruppo Italiano per lo Study della Sopravvivenza nell'infarcto Miocardico. GISSI-3: Effects of lisinopril and transdermal glyceryl trinitrate singly and together on 6-week mortality and ventricular function after myocardial infarction. Lancet 1994;343:1115-22.
  • The Survival of Myocardial Infarction Long-Term Evaluation (SMILE) Study Investigators. The effect of the angiotensin-converting-enzyme inhibitor zofenopril on mortality and morbidity after anterior myocardial infarction. N Engl J Med 1995;332:80-5.

Long-term use of ACEI started shortly post-MI with LV dysfunction or clinical HF:

  • Pfeffer MA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction: Results of the Survival and Ventricular Enlargement trial. N Engl J Med 1992;327:669-77.
  • The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet 1993;342:821-8.
  • Trandolapril Cardiac Evaluation (TRACE) Study Group. A clinical trial of the angiotensin-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995;333:1670-6.

Issues with internal validity?

  • No: All but 1 trial double-blind (GISSI-3) with measurement of objective outcome (all-cause mortality) and consistency between all trials.

Patients

5 trials enrolled "all-comer" acute MI patients, regardless of the presence/absence of clinical HF or LVEF

About 20% of patients in the "all comer" trials had clinical HF. LVEF was not routinely measured & is not reported in the original trial reports

3 trials enrolled patients early after an MI if they had either clinical HF (AIRE) or reduced LVEF (SAVE, TRACE) for enrolment

The majority of patients in the 2 trials of patients with LV dysfunction (SAVE, TRACE) did not have any clinical signs of HF at baseline despite an average LVEF ~30%

Generalizability: Who do these results apply to?

  • Taken together, these 8 trials enrolled any patient within ~2 weeks of an MI with or without clinical HF or LV dysfunction in the fibrinolytic/pre-early invasive management era, as long as they did not have an absolute contraindication to ACEI such as SBP <90, AKI or hyperkalemia (exclusion criteria common to 2+ trials)
  • Baseline use of concomitant medications (ASA, beta-blockers, etc) was variable, & overall suboptimal (ASA use ranged 55-94%)

Interventions

  • Captopril studies
    • CCS-1: 6.25 mg PO test dose, followed by 12.5 mg PO TID x28 days
    • ISIS-4: 6.25 mg PO test dose, then 12.5 mg 2h later, then 25 mg 10h later, then 50 mg PO BID x28 days
      • 17% discontinued captopril before discharge
    • SAVE: Initial dose 6.25-12.5 mg PO TID, titrated up to 25 mg PO TID by hospital discharge, then increased to 50 mg PO TID & continued for trial duration (mean 3.3 y)
  • Enalaprilat/enalapril (CONSENSUS II)
    • Enalaprilat 1 mg IV over 2h, then enalapril 2.5 mg PO BID, doubled daily as tolerated up to 20 mg PO BID on day 5 onward & continued for trial duration (41-180 days)
  • Lisinopril (GISSI-3)
    • 5 mg PO daily x2 days, then 10 mg PO daily x6 weeks
    • 18% discontinued by week 6
  • Ramipril (AIRE)
    • 2.5 mg PO BID x2 days, then 5 mg PO BID for trial duration (mean 1.25 y)
      • 86% discharged on 10 mg/d
  • Trandolapril (TRACE)
    • 1 mg PO daily x2 days, then 2 mg PO daily x4 weeks, then 4 mg PO daily for trial duration (2-5.1 y)
  • Zofenopril (SMILE)
    • 7.5 mg PO BID x1 day, doubled daily to target 30 mg PO BID, continued for total 6 weeks

Results

The 5 all-comer trials all evaluated outcomes in the short term, & all but CONSENSUS II (which initiated ACEI therapy as IV) demonstrated a reduction in the incidence of death +/- HF with NNT ~125-200 for death at 4-6 weeks

The trials of patients with clinical HF/LV dysfunction post-MI all evaluated outcomes beyond 1 year, with all trials demonstrating a mortality benefit that ranged from NNT 14-20 at ~1-5 y. Superficially, the greatest absolute benefit was seen in the AIRE trial, which enrolled only patients with clinical HF