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

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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) 

 

Consequences of inadequate direct oral anticoagulant (DOAC) dosing

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Yao X, et al. Non-vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. J Am Coll Cardiol 2017;69:2779-90.

Bottom line:

  • Many patients with non-valvular AF receiving a DOAC receive inappropriate doses.

  • In patients with an indication to reduced the DOAC dose, "overdosing" (using regular doses) is associated with a 2-fold higher risk of major bleeding vs using appropriate reduced doses.

  • In patients taking apixaban without an indication to reduce the dose, "underdosing" (using reduced doses) apixaban is associated with a ~5-fold increased risk of stroke/systemic embolism.

 

Design summary

  • Cohort study using administrative claims database & linked lab data
  • Included: US patients enrolled with Medicare Advantage with non-valvular AF treated with apixaban, dabigatran or rivaroxaban between Oct 2010-Sept 2015 who had serum creatinine results available within 1 year
  • Excluded: Valvular heart disease, other indication for DOAC, eGFR <15 (calculated using CKD-EPI)
  • Account for bias & confounding: Propensity score matching to balance baseline characteristics, statistical adjustment with Cox proportional hazards regression, numerous sensitivity analyses (such as changing criteria for apixaban dose reduction to age >80 + SCr >132 umol/L, dabigatran dose reduction criteria to eGFR <50), different matching criteria, subgroup analyses based on baseline criteria & individual DOACs, analysis of ICH as individual outcome, & analysis of 'falsification outcomes')
    • Note on the point of evaluating falsification outcomes: Falsification outcomes are outcomes that should not be associated with the presence/absence of an exposure. This is used to identify residual confounding after matching & statistical adjustment (i.e. if there's an association with an outcome that the exposure shouldn't affect, it implies residual confounding).

Results for PICO 1: Normal renal function (no need for DOAC dose reduction), n=13,392

  • Overall, 16.5% of patients underdosed
  • Increased risk of stroke/systemic embolism with reduced dose ("underdosed") vs normal dose of apixaban
    •  2.6% vs 0.5% per year, hazard ratio (HR) 4.87 (1.30-18.26)
  • No statistically significant difference in stroke/systemic embolism with reduced vs normal doses of dabigatran or rivaroxaban, though confidence intervals are very wide
  • No statistically significant difference in major bleeding with reduced vs normal doses of any DOAC

PICO 2: Renal impairment (indication for DOAC dose reduction), n=1,473

  • Overall, 48.5% of patients were overdosed
  • Definition of indication for dose reduction: Apixaban (SCr >132 umol/L), dabigatran (eGFR <30), rivaroxaban (eGFR <50)
  • Increased risk of major bleeding with normal ("overdosing") vs reduced dose of any DOAC
    • 11.3% vs 5.1% per year, HR 2.19 (1.07-4.46)
  • No difference of stroke/systemic embolism with normal vs reduced dose of any DOAC
    • 2.32% vs 1.85%, HR 1.66 (0.40-6.88)

Caveats

  • Due to a limited sample size & low outcome event rates, many analyses were underpowered, particularly when evaluating DOACs individually.
  • Due to limitations with available data, study definitions for criteria to reduce DOAC dose were not entirely consistent with drug label (e.g. weight for apixaban)
  • The analyses only partially accounted for known drug interactions (e.g. amiodarone, digoxin), & could not account for unknown or novel drug interactions (e.g. P-glycoprotein interaction between dabigatran & simvastatin).

Heparin, enoxaparin & fondaparinux in ACS

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NSTE-ACS

Heparin: Systematic review of 6 RCTs (3 were double-blind) published 1988-1995

  • P: NSTE-ACS patients treated with ASA (n=1353)
  • I: Heparin bolus + infusion x2-7 days
  • C: Placebo/no treatment
  • O:
    • Death/MI: Heparin 7.9%, control 10.4% (NNT 40), OR 0.67 (0.45-0.99)
    • Recurrent angina: OR 0.94 (0.58-1.54)
    • Revascularization: OR 1.25 (0.76-2.06)
    • Major bleed: OR 1.88 (0.60-5.87)

 

Enoxaparin (A to Z, ESSENCE, SYNERGY, TIMI 11B)

 

Fondaparinux: OASIS 5 - Double-blind non-inferiority RCT

  • P: NSTE-ACS (n=20,078)
    • Clopidogrel given to 2/3
  • I: Fondaparinux 2.5 mg  once daily up to 8 days or until discharge
  • C: Enoxaparin 1 mg/kg q12h (if CrCl <30: 1 mg/kg q24h) x2-8 days or until "clinically stable"
  • O @ day 9:
    • Primary outcome (death/MI/refractory ischemia): Fondaparinux 5.8%, enoxaparin 5.7%, HR 1.01 (0.90-1.13)
      • Death: 1.8% vs 1.9%
      • MI: 2.6% vs 2.7%
      • Refractory ischemia: 1.9% for both
    • Major bleed: 2.2% vs 4.1% (NNT 53), HR 0.52 (0.44-0.61)
  • O @ 180 days:
    • Primary outcome: 12.3% vs 13.2% (NNT 112), HR 0.93 (0.86-1.00)
      • Death: 5.8% vs 6.5%
    • Major bleed: 4.3% vs 5.8%, HR 0.72 (0.64-0.82)
  • Benefit & safety preserved in 1/3 of patients who underwent PCI during initial ACS hospitalization (in fondaparinux group, heparin given during PCI)

 

STEMI

Enoxaparin: (ASSENT 3, EXTRACT TIMI 25)

  • ASSENT 3
    • P: STEMI undergoing fibrinolysis with TNK (n6095)
    • I: Enoxaparin 30 mg IV bolus, then 1 mg/kg subcutaneously q12h continued for max 7 days
    • C: Heparin bolus, then infusion for at least 48h (also 3rd group given abciximab & no anticoagulant)
    • O @ 30 days:
      • Primary outcome (death, in-hospital re-infarction or refractory ischemia): Enoxaparin 11.4%, heparin 15.4% (NNT 25)
        • Death: 5.4% vs 6.0% (p=0.25)
        • Re-infarction: 2.7% vs 4.2%
        • Refractory ischemia: 4.6% vs 6.5%
      • ICH: 0.9% in both groups
      • Major bleed, non-ICH: 3.0% vs 2.2% (NNH 125)
  • EXTRACT TIMI 25
    • P: STEMI undergoing fibrinolysis (n=20,506)
    • I: Enoxaparin 30 mg IV bolus, then 1 mg/kg subcutaneously q12h continued for max 8 days or until discharge
      • If >75 y/o: No bolus, 0.75 mg/kg q12h
      • If CrCl <30 mL/min: 1 mg/kg q24h
    • C: Heparin infusion to aPTT 1.5-2.0x above normal, given for at least 48h
    • O @ 30 days:
      • Primary outcome (death/MI): Enoxaparin 9.9%, heparin 12.0% (NNT 48), RR 0.83 (0.77-0.90)
        • Death: 6.9% vs 7.5%
        • MI: 3.0% vs 4.5%
      • Urgent revascularization: 2.1% vs 2.8%
      • Major bleed: 2.1% vs 1.4% (NNH 143), RR 1.53 (1.23-1.89)

 

Fondaparinux: OASIS 6 - Double-blind RCT

  • P: STEMI (n=12,092)
  • I: Fondaparinux 2.5 mg daily (first dose IV if lytic/PCI) for up to 8 days or until discharge
  • C: Stratified by indication for placebo
    • No indication for heparin: Placebo
    • Indication for heparin (fibrin-specific thrombolytic or scheduled for 1o PCI): Heparin x1-2 days
  • O @ 30 days (only presenting data for those with indication for heparin)
    • Primary outcome (death/MI): Fondaparinux 8.3%, heparin 8.7%, HR 0.96 (0.81-1.13)
    • Major bleed: Fondaparinux 2.1%, heparin 2.3%, HR 0.93 (0.67-1.30)

Beta-blockers post-MI or in stable CAD

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Summary:

High-quality but outdated evidence (with likely overestimated benefit) from RCTs, corroborated by contemporary observational studies, supports the use of beta-blockers in patients post-MI without HF or LV dysfunction to reduce the risk of death;

  • Acutely post-MI, beta-blockers reduce deaths due to arrhythmias & re-infarction. In the long-term where patients with normal LV function & low risk of ventricular arrhythmias, the main mechanism for mortality reduction of beta-blockers would be by reducing re-infarctions;
  • Much uncertainty remains due to the indirectness of old evidence and high risk of bias of newer observational studies; only a contemporary, adequately-powered RCT of patients without HFrEF post-MI will provide clarity.

The evidence for post-MI beta-blocker use (in those without HF or LV dysfunction) is limited to an average of 3 years, after which the benefit of continued use is unclear;

  • After 3 years, clinicians should re-assess the benefit/risk of continuing beta-blockers based on presence/control of angina, arrhythmias and risk factors for re-infarction, as well as tolerability and patient willingness to continue taking the beta-blocker.

Beta-blockers do not appear to reduce CV events in patients with uncomplicated stable CAD (no prior MI, LV dysfunction or HFrEF), so they should only be used in the presence of a compelling indication (such as angina, for which a calcium-channel blocker could also be used as first-line therapy).

 

Current guideline recommendations

Acute coronary syndrome (ACS; AHA 2013 STEMI guidelines, AHA 2014 NSTE-ACS guidelines, AHA 2011 secondary prevention guidelines)

  • Start an oral beta-blocker on the first day of no contraindications (STEMI Class I recommendation, Level of evidence B; NSTE-ACS I, A)
  • Use a beta-blocker in all patients with prior-MI & EF 40% or less unless contraindicated" (I, A)
  • Continue during & after hospitalization in all patients with STEMI and with no contraindications" (I, B); also reasonable to continue in patients with NSTE-ACS with normal LV function" (IIa, C)
  • Continued for 3 years after an ACS in all patients with normal LV function (I, A)
    • It is also reasonable to continue beyond (I, B)

For stable coronary artery disease (CAD)/ischemic heart disease (IHD; CCS 2014 stable IHD guidelines)

  • Use a beta-blocker in all patients with stable IHD & LV dysfunction (strong recommendation, high-quality evidence) or prior MI (conditional recommendation, moderate-quality evidence)
  • Use either a beta-blocker or calcium-channel blocker for stable angina if none of the above (conditional recommendation, moderate-quality evidence)
  • Consider a beta-blocker for all other patients with coronary or other vascular disease" (AHA 2011 secondary prevention guidelines; IIb, C)

The focus of this article will be patients with CAD without HF/LV dysfunction. We have covered beta-blocker use for post-MI LV dysfunction & HFrEF elsewhere.

 

Early/short-term use during ACS

  • COMMIT provides the best-available evidence in a contemporary population
    • Double-blind RCT of 45,852 patients with suspected MI (87% with STEMI, mean 10h from symptom onset) with no planned PCI
    • Randomized to metoprolol (5 mg IV x3 over 15 min, then 200 mg/d until discharge or up to 4 weeks) or placebo
    • There was no difference in the co-primary outcomes
      • Death, re-MI, VF, or other arrest) in hospital: Metoprolol 9.4%, placebo 9.9% (odds ratio [OR] 0.96, 0.90-1.01)
      • Death: Metoprolol 7.7%, placebo 7.8% (OR 0.99, 0.92-1.05)
    • Increased risk of cardiogenic shock (metoprolol 5.0% vs placebo 3.9%, NNH 91, OR 1.30), but
    • Decreased risk of re-MI (2.0% vs 2.5%, NNT 200, OR 0.82) & VF (2.5% vs 3.0%, NNT 200, OR 0.83)

 

Should beta-blockers be used post-MI in patients with normal LV function?

  • A 1999 systematic review with meta-analysis remains the best-available evidence on this topic
    • Major caveats:
      • Included trials were published between 1966-1991, which precedes widespread use of many ACS therapies, including PCI & statins (most of the trials also preceded use of fibrinolytics, ASA)
      • Patients were not systematically assessed for HF or LV dysfunction, so it is unclear how many of these patients had normal LV function
      • Maximum average follow-up of 3 years
    • Over 2 years, use of a beta-blocker decreased the risk of death (NNT 42, OR 0.77, 0.69-0.85)
  • A newer systematic review, which attempted to determine the efficacy of statins in the modern era, had numerous issues limiting clinical utility:
    • Arbitrarily classified trials as being in the "reperfusion era" if >50% of patients underwent revascularization with PCI/CABG, reperfusion with a fibrinolytic, or received ASA+statin
    • Results of the "reperfusion era" analysis dominated by COMMIT, which was a trial of short-term metoprolol use
    • There were no "reperfusion era" trials with beta-blocker duration >1 year
  • Observational studies show conflicting results on beta-blocker use after MI
    • A 2017 cohort of 179,810 patients with MI found a reduction in 1-year mortality in unadjusted comparisons (4.9% versus 11.2% without beta-blockers), but not in adjusted analyses using propensity score matching or instrumental variables
      • Notably, 95% of participants in this study received a beta-blocker on discharge, leading to very high risk of selection bias
    • A 2015 systematic review of 10 cohort studies with 40,973 patients who underwent PCI for MI found a reduction in death with beta-blocker use (relative risk (RR) 0.58, 0.48-0.79)
      • The relative risk reduction was numerically greater for those with reduced EF (RR 0.60, 0.36-1.00) compared to those with EF >40% (RR 0.79, 0.59-1.07)
    • A 2015 cohort study (that did not exclude patients with HFrEF or LV dysfunction) not included in the above review  found that beta-blocker use after an MI reduced the relative risk of death (HR ~0.6) at a median 2.1 years 
    • Notably, a 2012 cohort study using the REACH registry that initially led to questioning the utility of beta-blockers post-MI was underpowered to identify a clinically meaningful difference

 

How long should beta-blockers be continued post-MI?

  • Average duration of beta-blocker use in the 1999 systematic review was 2-3 years
  • A 2016 cohort study of 2679 patients with MI without HF or LV dysfunction demonstrated a reduction in the risk of death at 30 days (hazard ratio (HR) 0.46, 0.26-0.82)
    • This study was underpowered to identify a clinically-important difference in death at 1 year (HR 0.77, 0.46-1.30) or 5 years (HR 1.19, 0.65-2.18)
  • There is no evidence that discontinuing beta-blockers after a certain duration post-MI is safe or beneficial

 

What about patients with stable CAD (without prior MI, or HFrEF/LV dysfunction)?

  • A 2016 systematic review with meta-analysis of cohort studies that included 17,397 patients with angiographically-proven CAD without MI or LV dysfunction found no difference in all-cause death (OR 0.91, 0.79-1.04) at 3-5.4 years
  • A 2014 cohort study of 26,793 patients with newly-diagnosed CAD found that that the effect of beta-blockers on the risk of death/MI differed on MI history (p=0.005 for interaction)
    • Prior MI: HR 0.87 (0.82-0.93)
    • PCI or CABG but no prior MI: HR 1.03 (0.93-1.13)
  • INVEST trial (see previous nerdcat summary): A beta-blocker-based regimen was not superior to a verapamil-based regimen over 2.7 years in patients with CAD+HTN without prior MI