By Van Selby, MD
Assistant Professor of Medicine, University of California, San Francisco Cardiology Division, Advanced Heart
Failure Section
Dr. Selby reports no financial relationships relevant to this field of study.
SYNOPSIS: In patients hospitalized for acute heart failure, adding tolvaptan to furosemide lead to increased weight and fluid loss, but did not improve dyspnea at 24 hours.
SOURCE: Felker GM, Mentz RJ, Cole RT, et al. Efficacy and safety of tolvaptan in patients hospitalized with acute heart failure. J Am Coll Cardiol 2017;69:1399-1406.
Tolvaptan is an oral vasopressin-2 receptor antagonist that inhibits antidiuretic hormones and promotes free water elimination (aquaresis). Although it has been shown to increase fluid loss in patients suffering from acute heart failure (AHF), no clinical trial has shown clear improvements in symptoms or long-term outcomes. However, subgroup analyses of several trials suggested that patients with hyponatremia and those who received tolvaptan earlier in their hospital course may have experienced clinical benefit.
To determine whether more targeted use of tolvaptan in AHF could improve outcomes, the creators of the Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure (TACTICS-HF) trial randomized 257 patients hospitalized for AHF to oral tolvaptan (30 mg) vs. placebo in addition to a fixed-dose furosemide regimen. All patients were identified within 24 hours of hospitalization and were required to demonstrate dyspnea at rest or, with minimal exertion, elevated natriuretic peptide levels and at least one additional sign or symptom of congestion. Patients also were required to exhibit a serum sodium level < 140 mmol/L. The primary endpoint was the proportion of patients with at least moderate improvement in dyspnea at both eight and 24 hours (“responders”).
For the primary outcome of dyspnea relief, there was no significant difference between those randomized to tolvaptan vs. placebo (50% responders for tolvaptan and 47% for placebo at 24 hours; P = 0.80). Patients randomized to tolvaptan experienced significantly greater weight and fluid loss at 48 hours compared to those who received placebo. Tolvaptan also was associated with an increased incidence of worsening renal function (39% vs. 27%; P = 0.037). There was no difference in hospital length of stay or post-discharge event rates. The authors concluded that adding tolvaptan to a standard furosemide regimen does not significantly improve dyspnea at 24 hours despite greater weight and fluid loss.
COMMENTARY
Tolvaptan currently is approved for the treatment of hyponatremia, and there has been substantial interest in expanding its use to AHF. The pathophysiologic basis is sound, with the hope that adding a potent aquaretic would reduce the required dose of loop diuretics, avoiding some of the drawbacks of loop diuretics such as resistance and neurohormonal activation as well as preserving renal function. The TACTICS-HF trial built on data from previous trials, attempting to target subgroups in whom there was previously a suggestion of benefit. Unfortunately, TACTICS-HF (as well as the SECRET of CHF, another negative trial of tolvaptan for AHF published alongside TACTICS-HF) only adds to a growing list of trials showing that although tolvaptan effectively promotes fluid loss, this does not translate to clinically meaningful improvements.
It is not entirely clear why there is such a disconnect between fluid loss and clinical improvement in patients treated with tolvaptan. It may be that the type of fluid removed is important. In other words, losing free water is not as beneficial as losing fluid with a more physiologic electrolyte balance. That said, even trials of alternative fluid removal strategies, such as aggressive loop diuretics or ultrafiltration, have failed to show clear improvements in long-term outcomes despite successful volume removal. AHF clearly remains an incompletely understood syndrome. As a result, identifying effective therapies has proven very challenging.
Overall, TACTICS-HF was a well-conducted trial with few major limitations. The dose of furosemide used was relatively low compared to what has been used in previous trials, and may have reduced the proportion of patients who were adequately decongested. The study also was powered inadequately to identify differences in survival and rehospitalization. Another consideration in all AHF trials is the difficulty determining an appropriate primary endpoint. Although TACTICS-HF missed the primary endpoint of dyspnea relief at 24 hours, there was a non-statistically significant trend toward reduced dyspnea in the tolvaptan group at 48 and 72 hours. A similar delayed effect was seen in the SECRET of CHF. This may reflect the time needed for fluid to distribute out of the lungs and extravascular space into circulation before a patient experiences clinical benefit. In any case, the primary outcome of both trials was negative, and these secondary findings only can be considered hypothesis-generating.
Based on the results of TACTICS-HF and prior clinical trials, routine use of tolvaptan in AHF cannot be recommended at this time, especially given the high price of the drug. It is possible that further studies targeting even more specific subgroups of AHF patients will identify a role for tolvaptan. For now, we must continue searching for an intervention that clearly improves outcomes in patients hospitalized for AHF.
