Table 4.

Randomized Diagnostic and Phase III Therapeutic AHF Studies over the past 10 years.

Study/Author	Year/ Sample Size	Primary Endpoint	Findings	Limitations
Diagnostic Studies
BASEL Mueller	2004 (n=452)	Time to discharge and cost of treatment	Time to discharge and costs of treatment were reduced in patients with undifferentiated dyspnea who were randomized to rapid, bedside BNP testing	Conducted in Europe- median LOS and healthcare systems much different than US
IMPROVE-CHF Moe	2007 (n=500)	ED LOS and total direct medical costs of treatment	ED LOS and cost of treatment were reduced with addition of NT-proBNP to clinical gestalt for patients with undifferentiated dyspnea	Conducted in Canada which has different healthcare cost structure than US
REDHOT II Singer	2009 (n=447)	Hospital LOS	No statistical difference in length of stay with serial BNP testing	Convenience sample; potentially underpowered
Therapeutic Studies
SURVIVE Mebazaa	2007 (n=1327)	All cause mortality at 180 days	No difference in mortality in patients requiring inotrope therapy with randomization to levosidemendan or dobutamine	Conducted in Europe with a drug (levosimendan) that was never FDA approved in the US. Bolus hypotension may have been a significant contributor to adverse events
EVEREST Gheorghiade	2007 (n=4133)	Composite of global clinical status and body weight at day 7	Compared to placebo tolvaptan had significantly greater improvement in the composite	The composite endpoint was largely driven by changes in body weight
VERITAS McMurray	2007 (n=1435)	Change in dyspnea over 24 hours and incidence of death or WHF at day 7	No significant difference in dyspnea or death/WHF between tezosentan and standard therapy
3CPO Gray	2008 (n=1069)	Death or intubation within 7 days	No difference in mortality with NIPPV versus standard oxygen therapy or either end-point with use of CPAP versus BiPAP	Open label study with extensive crossover to NIPPV in patients randomized to standard oxygen therapy
PROTECT Massie	2010 (n=2033)	Overall treatment success defined as early dyspnea improvement and no death, HF readmission or WRF	No significant difference between Rolofylline and placebo
ASCEND O'Connor	2011 (n=7141)	Dyspnea and rehospitalization/death within 30 days	Prespecified dyspnea endpoint not met; no differences in death between nesiritide and standard care	Patients enrolled long after ED stay; significantly greater proportion with hypotension in nesiritide group
DOSE-AHF Felker	2011 (n=308)	Dyspnea and WRF at 72 hours	No significant difference between bolus/drip or high/low dose furosemide	Patients randomized up to 24 hours after ED presentation; population largely white males with low EF, Not powered for longer term outcomes
RELAX-AHF-1 Teerlink	2013 (n=1161)	Improvement in dyspnea measured by both Likert and VAS at day 5	Significant improvement in VAS by serelaxin compared to placebo	No difference in Likert between serelaxin and placebo; clinical meaning of VAS difference unclear
ROSE-AHF Chen	2013 (n=360)	72-hour urine volume and change in Cystatin-C	No difference between low-dose dopamine or low-dose nesiritide compared to placebo in either endpoint	Not powered for longer term outcomes
REVIVE II Packer	2013 (n=600)	Clinical composite of ‘improved’, ‘unchanged’ or ‘worse’ at 6hrs, 24 hrs, and 5 days	More improvement in levosimendan treated patients with less worsening. However, more hypotension and arrhythmias were observed with a numerically higher number of deaths	Bolus hypotension may have been a significant contributor to adverse events
PRONTO Peacock	2014 (n=104)	Targeted BP control in first 30 minutes of intravenous vasodilator	Clevidipine provided more rapid BP control compared to standard therapy	Open label study, more BP overshoot in clevidipine arm, efficacy was monitored only to 12 hours, not powered for longer term outcomes

WRF=worsening renal function; WHF= worsening heart failure; LOS= length of stay; BP = blood pressure; EF=ejection fraction; ED = emergency department