Gaps in Acute Heart Failure Therapy
Despite significant advances in understanding the pathophysiology of HF, treatment of ADHF has changed little in the past decade. The mainstays of parenteral pharmacological treatments, such as diuretics, vasodilators and positive inotropes, improve haemodynamics but have not been shown to improve outcomes.48 The optimal diuretic regimen remains at the discretion of the clinician as the Diuretic Optimization Strategies Evaluation (DOSE) trial did not show clear benefits for low-dose or high-dose diuretics and bolus or continuous infusion.49 Contemporary trial of a common clinical practice, low-dose dopamine in ADHF, failed to show clinical benefits in the Renal Optimization Strategies Evaluation (ROSE) trial.50 Though intravenous nitrates and nitroprusside are widely used in practice, data demonstrating their safety and efficacy are sparse. The vasodilator nesiritide was widely used based on improvement in dyspnoea from the Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial, but it fell out of favour after safety concerns were raised.51 Confirmatory trials demonstrated safety but also no significant clinical benefits.50,52 Ironically, given the number of trials, nesiritide has one of the largest bodies of evidence demonstrating safety compared with other pharmacological therapies for ADHF. Novel agents for ADHF that improve outcomes are urgently needed. The most promising of these is serelaxin, a peptide hormone with vasodilatory effect. In the Relaxin in Acute Heart Failure (RELAX-AHF) trial, serelaxin significantly reduced the primary endpoint of dyspnoea in patients with both HFrEF and HF with preserved ejection fraction (HFpEF).53,54 Unexpectedly there was a large reduction in the non-predefined endpoint of mortality (HR 0.63, 95 % CI 0.42–0.93), and a larger trial is looking to confirm this finding (NCT01870778). Another phase III trial is ongoing to evaluate ularitide, a synthetic natriuretic peptide, in ADHF (NCT01661634). Omecamtiv mecarbil, a novel inotrope-like agent, is awaiting phase III trial though phase II did not achieve the primary endpoint of reducing dyspnoea.55
From a non-pharmacological standpoint, contemporary ultrafiltration devices used for rapid fluid removal promised rapid decongestion in treatment of ADHF. The Ultrafiltration versus intravenous Diuretics for Patients Hospitalized for Acute Decompensated Congestive Heart Failure (UNLOAD) and Continuous Ultrafiltration for Congestive Heart Failure (CUORE) trials showed reduced readmission rates with ultrafiltration compared with diuretics (HR 0.56, 95 % CI 0.28–0.51 and HR 0.14, 95 % CI 0.04–0.48, respectively).56,57 However, the Cardiorenal Rescue Study in Acute Decompensated Heart Failure (CARRESS-HF) trial evaluating patients with ADHF and renal dysfunction showed only excess adverse events in the ultrafiltration group (72 versus 57 %, p=0.03), driven by worsened renal function, bleeding complications and intravenous catheter-related complications.58 Unfortunately, a larger trial to evaluate the role of ultrafiltration on readmissions for HF has been terminated due to patient recruitment challenges (NCT01474200). The ESC Guideline does not provide specific recommendation for ultrafiltration, and the ACCF/AHA Guideline gives it an equivocal Class IIB/LOE B recommendation. The ideal patient population who would benefit from ultrafiltration remains uncertain until more definitive data from larger trials are available.
Future clinical trials of therapies for ADHF should target HFpEF and HFrEF separately in addition to stratifying patients based on severity of decompensation and co-morbidities. Pressure to expand inclusion criteria to enrol enough patients to power studies for mortality benefits may ultimately dilute findings by increasing patient heterogeneity.