ARBs in HFrEF (ELITE I & II, CHARM-Alternative, CHARM-Added & Val-HeFT)

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ARB HFrEF PIC.png

Results

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Safety

  • CHARM-Alternative
    • Any adverse event or lab abnormality: Candesartan 21.5% vs placebo 19.3% (p=0.23)
      • Hypotension leading to D/C: 3.7% vs 0.9% (NNH 36)
      • SCr increase leading to D/C: 6.1% vs 2.7% (NNH 30)
      • Hyperkalemia: 1.9% vs 0.3% (NNH 63)
  • CHARM-Added
    • Any adverse event or lab abnormality: Candesartan 24.2% vs placebo 18.3% (NNH 17)
      • Hypotension leading to D/C: 4.5% vs 3.1%
      • SCr increase leading to D/C: 7.8% vs 4.1%
      • Hyperkalemia: 3.4% vs 0.7%
  • Val-HeFT
    • Drug D/C: Valsartan 9.9% vs placebo 7.2% (NNH 37)
      • Dizziness 1.6% vs 0.4%
      • Hypotension: 1.3% vs 0.8%
      • Renal impairment: 1.1% vs 0.2%

Generalizability of trials adding ARB to ACEI

  • CHARM-Alternative specifically enrolled patients intolerant of ACEI & therefore not receiving these agents, whereas 93% of patients enrolled in Val-HeFT received ACEI therapy
    • Results of CHARM-Added were similar to those of Val-HeFT (HR 0.85 for primary outcome & 0.83 for HF hospital admission)
  • Patients in both trials had overall poor optimization of other HF meds (35-55% on beta-blockers, 5-25% on mineralocorticoid receptor antagonist) at baseline.

Internal validity

  • Low risk of allocation, performance, detection and attrition bias, as all trials were randomized, allocation concealed, double-blind trials with blinded outcome adjudication, loss-to-follow-up <1% and intention-to-treat analysis.

Statin dose & CV events

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Bottom-line:

  • In patients with CAD, high-dose statin therapy vs low/moderate statin doses further reduces the risk of CV events by an ~15% (relative risk reduction).

  • In Japanese patients with CAD, moderate-dose statin reduces the risk of CV events and death versus a very low dose by ~19% (relative risk reduction).

 

    Summary of 6 largest trials (n=52,666) 

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    Latest trial: REAL-CAD summarized below:

    • Design: RCT with open-label, blinded-outcome-adjudication design
    • 13,054 randomized -> 12,413 analyzed in ITT population
    • Included: 
      • Age 20-80 y/o +
      • CAD (history of ACS, prior PCI/CABG, or angiographic coronary artery stenosis >75%) +
      • LDL-C >2.6 mmol/L (excluded if LDL-C >3.0 mmol/L on pitavastatin 1 mg/d during run-in phase)
    • Excluded: Known FH, contraindication to statin, HF NYHA 3-4 or LVEF <30%
    • Baseline characteristics:
      • Age 68 y, male 83%
      • Prior MI 52% (mean 5 years ago), HF 5%, ischemic stroke 7%
      • Statin before run-in: 91%, ASA 92%, ACEI/ARB 67%, beta-blocker 42%
      • LDL-C: before run-in 2.4 mmol/L, after run-in on pitavastatin 1 mg/d: 2.2 mmol/L
    • Interventions: Pitavastatin 4 mg/d (equivalent to ~atorvastatin 20-40 mg/d)
      • Reduced LDL-C by an additional 0.4 mmol/L (18%) vs lower dose
    • Control: Pitavastatin 1 mg/d (equivalent to ~atorvastatin 5 mg/d)
    • Follow-up: 3.9 years (median)

    Results from 5 largest RCTs

    statin dose outcomes.png

    Results from REAL-CAD

    • Primary outcome (CV death, MI, ischemic stroke or unstable angina requiring hospitalization):
      • Higher dose 4.3%, lower dose 5.4% - 1.1% absolute risk reduction (ARR)
      • HR 0.81, 95% CI 0.69-0.95
    • Death: 3.3% vs 4.2% - 0.9% ARR; HR 0.81, 0.69-0.98
    • MI: 0.6% vs 1.2% - 0.6% ARR; HR 0.57, 0.38-0.83
    • Any muscle complaints: 1.9% vs 0.7% - 1.2% absolute risk increase
    • No difference in rhabdo (<0.1%), CK increase >5xULN (0.7% vs 0.6%) or liver enzyme elevations (2.9% vs 2.7%, p=0.46)

    Meta analysis comparing high- to moderate-dose statins @ mean 2.5 years

    • Systematic review of 10 databases (including MEDLINE, Embase, CENTRAL) to Dec 2010
    • Included 10 RCTs enrolling 41,778 patients
    • Results
      • Statistically significant reduction with higher dose in
        • Coronary death or MI: Relative risk 0.90 (0.84-0.96), low heterogeneity (I^2=0%) in 9 trials
        • Stroke (excluding TIA): RR 0.86 (0.77-0.96), I^2=0% in 10 trials
          • Non-fatal MI: RR 0.82 (0.76-0.90), I^2=0% in 5 trials
      • No statistically significant difference in
        • Death: RR 0.92 (0.83-1.03), I^2=38% in 10 trials
      • Lab abnormalities, elevated
        • Liver enzymes, for ALT: RR 1.57 (1.29-1.91)
        • CK: RR 2.86 (2.02-4.04)
      • Subgroup analysis limited to 3 trials of patients with recent ACS (A-Z, PROVE-IT, Colivicchi et al) found possible reduction in death with higher dose (RR 0.75, p=0.005)

    Article links

    de Lemos JA, et al. Early intensive vs a delayed conservative simvastatin strategy in patients with acute coronary syndromes: Phase Z of the A to Z Trial. JAMA 2004;292:1307-16.

    Cannon CP, et al. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004;350:1495-504.

    Pedersen TR, et al. High-dose atorvastatin vs usual-dose simvastatin for secondary prevention after myocardial infarction: The IDEAL study: A randomized controlled trial. JAMA 2005;294:2437-45.

    LaRosa JC, et al. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. N Engl J Med 2005;352:1425-35.

    SEARCH Collaborative Group. Intensive lowering of LDL cholesterol with 80 mg versus 20 mg simvastatin dialy in 12 064 survivors of myocardial infarction: A double-blind randomised trial. Lancet 2010;376:1658-69.

    Taguchi I, et al. High-dose versus low-dose pitavastatin in Japanese patients with stable coronary artery disease (REAL-CAD): a randomized superiority trial. Circulation 2018;137:1997-2009.

    MIRACL - High-dose statin early post-ACS

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    Schwartz GG, et al. Effects of atorvastatin on early recurrent ischemic events in acute coronary syndromes: The MIRACL study: A randomized controlled trial. JAMA 2001;285:1711-8.

    Bottom line: In patients with ACS (without Q wave formation & not treated with PCI), high-dose atorvastatin reduced the short-term risk of symptomatic ischemia (NNT 46) or stroke (NNT 125).

    Reporting of safety events was limited, but high-dose atorvastatin increased the likelihood of liver enzyme elevation >3x ULN, which has unknown clinical significance.

     

    Patients (n=3086)

    • Included
      • Age 18+ y
      • Within 24-96h after hospital admission for ACS (unstable angina or non-Q-wave MI)
    • Excluded
      • Total cholesterol >7 mmol/L
      • Coronary revascularization planned or anticipated
      • Hx of Q-wave MI within 4 weeks, CABG within 3 months, PCI within 6 months
      • LBBB or paced ventricular rhythm
      • HF with NYHA functional class IIIb-IV
      • Treatment with other lipid-lowering agents or vitamin E
      • Severe anemia, renal failure requiring dialysis, ALT >2x ULN, insulin-dependent diabetes
    • ? screened -> 3086 randomized & analyzed
    • Typical patient in study
      • Age 65 y
      • Female 35%
      • ACS: UA 46%, non-Q-wave MI 54%
      • PMHx
        • Prior MI 25%, CABG 7%, PCI 3%
        • HF 8%
        • CVA 9%
        • Peripheral vascular disease 9%
        • Smoker 28%
        • HTN 55%
        • Diabetes 23%
      • Meds
        • ASA ~90%, OAC 8%
        • ACEI or ARB ~50%
        • Beta-blocker 77%
        • Used in hospital: Heparin 75%, fibrinolytic 8%

    Intervention

    • I: Atorvastatin 80 mg PO once daily
      • Patients on average took 86% of all doses
      • 11.2% discontinued prematurely
    • C: Matching placebo
      • 10.3% discontinued prematurely

    Results @ 4 months

    • LDL
      • @ baseline: 3.2 mmol/L
      • @ 4 months: Atorvastatin 1.9 mmol/L, placebo 3.5 mmol/L (46% reduction vs placebo)
    • Statistically significant reduction in
      • Primary outcome (death, non-fatal MI, cardiac arrest with resuscitation, or recurrent symptomatic myocardial ischemia requiring emergency rehospitalization): 14.8% vs 17.4% (hazard ratio 0.84, 0.70-1.00), NNT 39
      • Symptomatic ischemia with objective evidence: 6.2% vs 8.4% (HR 0.74, 0.57-0.95), NNT 46
      • Stroke (fatal or non-fatal): 0.8% vs 1.6% (HR 0.50, 0.26-0.99), NNT 125
    • No statistically significant difference in
      • Coronary revascularization: 16.5% vs 16.1%
      • Non-fatal MI: 6.6% vs 7.3%
      • Worsening angina without new objective evidence of ischemia: 5.9% vs 6.8%
      • Death: 4.2% vs 4.4%
      • New/worsening HF requiring hospitalization: 2.6% vs 2.8%
      • Resuscitated cardiac arrest: 0.5% vs 0.6%
    • Safety
      • Liver enzymes >3x ULN at any time: 2.5% vs 0.6% (NNH 53)
      • Myalgias, muscle weakness, CK changes or rhabdo: Not reported

    Generalizability

    • Representative ~intermediate-risk ACS population
      • Despite exclusion of patients Q-wave MI, likely included some STEMI patients, particularly since ~8% received lytic therapy
      • Likely included an ACS population at low-intermediate risk by excluding Q-wave MI, patients planned for revascularization, recent CV event, or any significant non-CV comorbidity
    • Short-term follow-up intended only to evaluate acute effects of high-dose statin therapy; 4-month follow-up precludes meaningful evaluation of long-term benefit, particularly for "secondary prevention"

    Internal validity

    • Allocation & performance bias
      • Insufficient description of random-sequence generation, allocation concealment - likely low risk
    • Low risk of detection bias
      • Assuming proper allocation concealment & blinding, though not sufficiently described
      • Endpoints adjudicated by committee of cardiologists unaware of treatment allocation
    • Low risk of attrition bias
      • Intention-to-treat analysis including all randomized patients
      • <1% lost to follow-up

    Corroborating evidence from other studies

    • A secondary analysis of the PROVE IT trial evaluating the early and late benefit of high-intensity statin (atorvastatin 80 mg/d) versus low-intensity statin (pravastatin 40 mg/d) found a statistically significant improvement in the first 30 days:
      • 30-day risk of composite CV outcome (death, MI or ACS hospitalization): High-intensity 3.0% vs low-intensity 4.2%, HR 0.72 (0.52-0.99)

    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

    ACE inhibitors & ARBs in HFpEF

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    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).