DOSE - Diuretic strategies (low vs high dose & IV bolus vs continuous infusion) for acutely decompensated HF

Bottom line: In patients with acutely decompensated HF patients not in cardiogenic shock,

  • Higher versus lower doses of loop diuretics did not significantly affect primary efficacy & safety outcomes
    • However, secondary outcomes consistently demonstrated a lower risk of serious adverse events (NNT 9), more rapid resolution of dyspnea & congestion, & greater weight loss (extra -1.2 kg in first 72h), at the cost of an increased risk of AKIN stage 1 AKI (NNH 12)
  • Continuous IV administration of loop diuretics does not appear to have any advantage over q12h IV boluses.

Patients (n=300)

  • Included
    • Presented for acutely decompensated HF (ADHF) within 24h
      • Diagnosed based on 1+ symptoms (SOB, orthopnea, edema) & 1+ sign (crackles, peripheral edema, ascites, pulmonary vascular congestion on CXR) of HF
    • Hx of chronic HF (any LV ejection fraction [LVEF])
    • Receiving an oral loop diuretic equivalent to furosemide 80-240 mg/d +/- chronic thiazide diuretic
  • Excluded
    • SBP <90 mm Hg
    • SCr >265 umol/L
    • Requiring IV vasodilators or inotropes
  • Average baseline characteristics
    • Age 66 y
    • Male ~74%
    • Median time from presentation to randomization ~15h
    • Ischemic CM 57%
    • Hospitalized for HF within 1 y ~75%
    • Home dose of furosemide PO ~130 mg/d
    • Clinical characteristics
      • Orthopnea ~90%
      • SBP 120 mm Hg
      • SpO2 96%
      • JVP 8+ cm 91%
      • LVEF 35% (27% with EF 50%+)
      • NT-proBNP ~680-8200 pg/mL
      • Sodium 138
      • SCr 133 umol/L
    • Meds
      • ACEI/ARB ~65%
      • BB ~85%
      • MRA ~27%

Interventions

  • Dose comparison
    • High dose: Daily IV dose = 2.5x total home PO dose
    • Low dose: Daily IV dose = total home PO dose
  • Administration method comparison
    • Continuous IV infusion
    • IV bolus dose divided as q12h administration
  • Assigned treatment continued for up to 72h, after which treatment was open-label at discretion of treating physician
    • At 48h, could either
      • Increase dose by 50%
      • Maintain same strategy
      • D/C IV & switch to open-label PO
  • At 48h:
    • Change to PO diuretics: High 31%, low 17% (p<0.001)
    • Need for dose increase
      • High 9%, low 24% (p=0.003)
      • Continuous 11%, bolus 21% (p=0.01)
  • Median dose over first 72h
    • High 773 mg, low 358 mg
    • Continuous 480 mg (160 mg/d), bolus 592 mg (~200 mg/d)

Results

At 72h

  • Primary efficacy outcome: Global assessment of symptoms (serial 0-100 visual analogue scale measurements tallied using area under the curve [AUC] from baseline to 72h, HIGHER=better)
    • High 4430, low 4171 (p=0.06)
    • Continuous 4373, bolus 4236 (p=0.47)
  • Dyspnea AUC (higher=better)
    • High 4668, low 4478 (p=0.04)
    • Continuous 4699, bolus 4456 (p=0.36)
  • Free from congestion (JVP <8 cm [<3 cm ASA], no orthopnea & trace/np peripheral edema)
    • High 18, low 11 (p=0.09)
    • Continuous 15%, bolus 14% (p=0.78)
  • Wt change (kg)
    • High -3.9, low -2.7 (p=0.01)
    • Continuous -3.6, bolus -3.0 (p=0.20)
  • Primary safety outcome: Change in SCr (umol/L) from baseline to 72h
    • High +7.1, low +3.5 (p=0.21)
    • Continuous +6.2, bolus +4.4 (p=0.45)
  • SCr increase >26 umol/L
    • High 23%, low 14% (p=0.04)
    • Continuous 19%, bolus 17% (p=0.64)

At 60 days

  • Serious adverse event
    • High 38%, low 50% (p=0.03)
    • Continuous 44%, bolus 44% (p=0.92)
  • Composite of death, hospitalization or ED visit: 42% overall, no difference between groups

No difference between groups in median length of stay (5 days for all)

Generalizability

  • Included a mix of HFrEF & HFpEF patients at high risk of HF hospitalization with moderate to high home doses of loop diuretics, a reasonable proportion of whom were receiving good HF medical therapy
  • Outcomes were clinically important and easily measurable and translatable to practice

Internal validity

  • Low risk of bias
    • 2x2 factorial randomization using permuted blocks
    • Allocation concealed
    • Double-blind, dummy-dummy design (saline placebos with identical appearance)
    • ITT analysis
    • Threshold for significance p<0.025 for coprimary outcomes (global assessment of wellbeing & change in SCr from baseline to 72h) 

 

ACE inhibitors & ARBs in HFpEF

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).

TOPCAT - Spironolactone in HFpEF

Pitt B, et al. Spironolactone for heart failure with preserved ejection fraction. NEJM 2014;370:1383-92.

Bottom line: In patients with HFpEF, spironolactone did not reduce the risk of death or hospitalization over 3.3 years. Spironolactone does not noticeably improve quality of life in HFpEF.

Consistent with other "negative" studies in HFpEF, the results of TOPCAT supports the notion that patients with "HFpEF" should receive symptomatic treatment for HF, & interventions to reduce morbidity & mortality according to the underlying etiology. In this context, spironolactone remains useful for patients with HFpEF & resistant hypertension. The label of "HFpEF" does not yet offer an actionable management plan.

 

Context

  • Heart failure with preserved ejection fraction (HFpEF):

    • Defined as a clinical syndrome of signs & symptoms of HF with normal systolic function (LVEF >50% & LV end-diastolic volume index <97 mL/m^2) & evidence of diastolic LV dysfunction (relaxation, filling, diastolic distensibility or diastolic stiffness)

  • Interventions that reduce morbidity & mortality in HFrEF have not translated to benefits in HFpEF, including ACEIs & ARBs, beta-blockers & digoxin

  • Previous studies have demonstrated inconsistent results for aldosterone antagonists in HFpEF:

    • Aldo-DHF trial: In patients with HFpEF with a good prognosis, spironolactone improved E/e' (echo-derived surrogate for filling pressure), but not VO2 (stress test-derived measure of aerobic exercise capacity)

    • Cohort study: In patients with HFpEF, use of an aldosterone antagonist was not associated with reduced mortality or HF hospitalization

Patients (n=3445)

  • Inclusion

    • Age 50+

    • Clinical HF

    • LVEF >45% (measured within 6 months prior to randomization & after any prior ACS)

    • Controlled SBP (<140, or <160 if receiving 3+ antihypertensives)

    • Either,

      • 1+ HF-related hospitalization in prior 12 months, or

      • BNP >100 pg/mL (or N-terminal pro-BNP >360 pg/mL) within 30 days, not explained by another disease entity

  • Exclusion

    • Pericardial constriction

    • Hemodynamically significant uncorrected primary valvular heart disease

    • Infiltrative or hypertrophic obstructive cardiomyopathy (HoCM)

    • Stroke, MI or CABG in past 90 days

    • AF with resting HR >90 bpm

    • Heart transplant recipient or currently implanted LVAD

    • Chronic pulmonary disease: Requiring home O2 or PO steroids, hospitalization for exacerbation within 12 months, or significant in the opinion of the investigator

  • "Average" patient

    • Age 69 y (age 75+ 27%)

    • Female 52%

    • White 89%

    • HFpEF characteristics

      • Hospitalization in last 12 months 71%

      • NYHA functional class I (3%), II (64%), III (33%), IV (<1%)

      • BNP 236

      • LVEF 56%

    • BP 130/80 mm Hg

    • Meds

      • Diuretic 80%

      • ACEI/ARB 85%

      • Beta-blocker 75%

      • ASA 65%

      • Statin 55%

Intervention

  • I: Spironolactone

    • Initial dose: 15 mg PO daily x4 weeks

    • If initial dose tolerated, increased to 30 mg daily

    • If HF still symptomatic at month 4, increased to 45 mg daily

  • C: Matching placebo

  • Monitoring: Measurement of SCr & serum K required <1 week after start or change of study drug dose

Results @ mean 3.3 years

  • Efficacy

    • Death: Spironolactone 14.6% versus placebo 15.9%, hazard ratio (HR) 0.91 (95% confidence interval 0.77-1.08)

    • Hospitalization for any cause: 44.5% vs 46%, HR 0.94 (0.85-1.04)

    • Primary outcome (CV death, aborted cardiac arrest, HF hospitalization): 18.6% vs 20.4%, HR 0.89 (0.77-1.04)

    • Quality of life

      • Kansas City Cardiomyopathy Questionnaire (KCCQ; 100-point scale, minimal clinically important difference -5): -1.86 vs placebo at 36 months (p=0.02)

      • No statistically or clinically significant differences in EQ5D-VAS or McMaster Overall Treatment Evaluation score

  • Safety

    • Serious adverse event: 48.5% vs 49.6%

    • Discontinuation of study drug: 34.3% vs 31.4%

    • Doubling of SCr: 10.2% vs 7% (NNH 32)

    • Hyperkalemia (serum K >5.5 mmol/L): 18.7% vs 9.1% (NNH 11)

Issues with internal validity?

  • Low risk of bias characteristics: Randomized, allocation-concealed, double-blind trial analyzed using intention-to-treat population

  • Unclear risk of bias: Loss-to-follow-up on vital status ~4%

  • Subgroup analysis: Primary outcome varied based on region (Americas vs Russia/Georgia, p<0.001 for interaction)

    • Americas: Spironolactone 27.3% vs placebo 31.8%, HR 0.82 (0.69-0.98) (NNT=23)

    • Russia/Georgia: 9.3% vs 8.4%, HR 1.10 (0.79-1.51)

    • Credibility of this subgroup effect has been increased by a substudy demonstrating that participants from Russia were far more likely than those from North America to have no detectable serum concentrations of spironolactone metabolites. This indicates that significantly more participants from Russia did not receive the study drug, and raises the potential of misconduct at these study sites. Therefore, the results of the 'Americas' subgroup may be the most accurate reflection of the effect of spironolactone in HFpEF.

    • Secondary outcomes from the Americas subgroup:

      • Death: 20.1% vs 23.5%, HR 0.83 (0.68-1.02)

      • All-cause hospitalization: 59.4% vs 60.7%, HR 0.94 (0.83-1.05)

        • HF hospitalization: 20.8% vs 24.5%, HR 0.82 (0.67-0.99) (NNT=28 over 3.3 years)

        • Hyperkalemia: 25.2% vs 8.9% (NNH=7)

    • Exclusion of the Russia/Georgia participants renders the primary outcome statistically significant, but does not materially affect the effect estimate for the primary or secondary outcomes. Additionally, TOPCAT still fails to demonstrate a significant reduction in death or all-cause hospitalizations.