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

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.

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%

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)

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)

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