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

in

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

MRA PICT.png

Results

MRA O.png

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

ACE inhibitors & ARBs in HFpEF

in

CHARM-Preserved: Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved trial. Lancet 2003;362:777-81.

I-PRESERVE: Massie BM, et al. Irbesartan in patients with heart failure and preserved ejection fraction. N Engl J Med 2008;359:2456-67.

PEP-CHF: The perindopril in elderly people with chronic heart failure (PEP-CHF) study. Eur Heart J 2006;27:2338-45.

Bottom-line: In patients with HFpEF & well-controlled hypertension, ACE inhibitors and ARBs do not reduce the risk of hospitalization or death.

However, since uncontrolled hypertension is one of the predominant causes of HFpEF and an important risk factor for HF progression, most patients with HFpEF will end up receiving an ACEI/ARB anyway to control BP.

 

Patients & Generalizability

These trials generally enrolled older individuals with clinical HF and a LVEF >40-45%. Notably, these trials excluded multiple conditions that may be classified as "HFpEF", namely valvular heart diseases such as aortic stenosis, pericardial disease and certain cardiomyopathies.

Due to the exclusion criteria noted above, most of the cases of HFpEF in these trials were caused by hypertension (I-PRESERVE, PEP-CHF) or ischemia (CHARM-Preserved). it is thus worth mentioning that BP was well-controlled on average at baseline in all of these trials.

Interventions

  • I: ACE inhibitor or ARB
    • CHARM-Preserved: Initially, candesartan 4-8 mg PO once daily, doubled q2 weeks to target 32 mg PO daily by week 6
      • At 6 months: 67% on target dose
    • I-PRESERVE: Initially, irbesartan 75 mg PO once daily, doubled q1-2 weeks to target 300 mg PO daily
      • 88% achieved target dose
    • PEP-CHF: Initially, perindopril 2 mg PO once daily, increased to 4 mg PO daily after 2 weeks
      • ~90% on 4 mg daily at 1 year
  • C: Matching placebo

Results

Internal validity

  • All 3 trials are randomized, allocation-concealed, double-blind trials with loss-to-follow-up <2% and intention to treat analysis
  • Other considerations:
    • I-PRESERVE employed 1 to 2-week single-blind placebo run-in phase. Patients that remained clinically stable in this phase were randomized
    • PEP-CHF: Trial recruitment stopped early due to expected futility

Other studies

  • Meta-analysis of 13 RCTs of RAAS inhibition (including ACE inhibitors, ARBs and mineralocorticoid antagonists) in HFpEF (Herz 2016;41:76-86): When all pooled together,
    • No statistically significant difference in
      • Hospitalizations: HR 0.99 (0.96-1.03)
      • CV death: HR 0.98 (0.89-1.09)
      • Death: HR 0.99 (0.92-1.07)
      • 6-minute walk test distance
    • Statistically significant reduction in HF hospitalization (HR 0.89, 0.82-0.97), though this was driven by TOPCAT trial of mineralocorticoid antagonists. The lack of a reduction on death or all-cause hospitalization suggests that the reduction in HF-related hospitalization is offset by an increase in other events (e.g. syncope or falls from hypotension, hyperkalemia).

SHIFT - Ivabradine for heart failure with reduced ejection fraction

in

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.

 

 

Association between serum triglycerides (non-fasting) & pancreatitis

in

Pedersen SB, et al. Nonfasting mild-to-moderate hypertriglyceridemia and risk of acute pancreatitis. JAMA Intern Med 2016

Bottom-line: Serum triglyceride concentrations increase the risk of pancreatitis in a "dose-dependent" manner (i.e. the higher the concentration, the greater the risk).

The absolute risk increase of mild-moderate triglyceride elevations remains small. With a risk of pancreatitis of ~1% over 10 years, individuals with a triglyceride concentration of ~5-10 mmol/L are unlikely to benefit from medical management to lower triglycerides (e.g. fibrates).

 

Design summary

  • Registry-based cohort study conducted in the Netherlands.
  • Patients: Included 116,550 individuals, 434 of whom developed acute pancreatitis (0.3%) over a median 6.7 years of follow-up.
  • Exposure: Non-fasting serum triglyceride concentration, separated into 6 categories ranging from <1 mmol/L to 5+ mmol/L.
    • Individuals with a triglyceride concentration 5+ mmol/L represented <2% of the general population in this study.
  • Co-variables included age, sex, BMI, alcohol intake/week, education level, smoking status, hypertension, diabetes, statin use, birth year, HDL.
  • Outcome: Death or hospitalization with ICD-8/10 code for acute or chronic pancreatitis.

Results

  • Adjust events per 10,000 person-years based on serum triglyceride concentration (hazard ratio, 95% confidence interval versus <1.00 mmol/L):
    • <1.00 mmol/L: 2.7 = 0.3% over 10 years
    • 1-1.99 mmol/L: 4.3 (HR 1.7, 1.0-2.7)
    • 2-2.99 mmol/L: 5.5 (HR 2.4, 1.4-4.2)
    • 3-3.99 mmol/L: 6.3 (HR 3.2, 1.6-6.5)
    • 4-4.99 mmol/L: 7.5 (HR 4.6, 1.8-12)
    • 5 mmol/L or greater: 12 = 1.2% over 10 years (HR 11, 4.7-26)

Additional observations

  • Previous smaller studies showed that triglyceride concentrations needed to be >20 to >34 mmol/L in order to significantly increase the risk of acute pancreatitis

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

in ,

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