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 health care systems much different than United States. |
| 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 health care cost structure than United States. |
| 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 United States. Bolus hypotension may have been a significant contributor to adverse events. |
| EVEREST, Gheorghiade | 2007 (n = 4133) | Composite of global clinical status and body weight on 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 on 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 endpoint 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 on 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 and 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 6 hr, 24 hr, 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 IV 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 |
BiPAP = bilevel positive airway pressure; BP = blood pressure; CPAP = continuous positive airway pressure; EF = ejection fraction; IV = intravenous; LOS = length of stay; NIPPV = noninvasive positive pressure ventilation; VAS = visual analog scale; WHF = worsening heart failure; WRF = worsening renal function.