Tolvaptan in Acute Heart Failure: Abandon, or Explore Targeted Therapy?

October 10, 2016

ORLANDO, FL — The oral vasopressin-2 receptor antagonist tolvaptan (Samsca, Otsuka American Pharmaceutical) indeed promotes significant loss of fluid volume in patients with acute decompensated heart failure (ADHF), congestion, and dyspnea, but little beyond that of clinical benefit, according to two newly reported randomized trials[1,2].

Together, the studies of tolvaptan on top of standard loop diuretics illustrate what's been described as a disconnect between fluid loss, or its proxy weight loss, and clinical benefit in HF patients with acute decompensation, and to many observers are a call to finally ditch the drug as a potential treatment in ADHF.

But others see signals in the studies and some prior trials that preserve hope tolvaptan could prove to be a welcome addition to current treatments in select patient groups, such as those with right heart failure, that should be the focus of future trials with the drug.

All along, hopes were that volume reduction with tolvaptan would alleviate congestion and symptoms in acute HF, allow less reliance on loop diuretics, preserve renal function, and maybe benefit clinical outcomes down the road.

The new studies, Targeting Acute Congestion with Tolvaptan in Congestive Heart Failure (TACTICS-HF), looked at the drug's effects on symptoms by 24 hours and 48 hours, and the Study to Evaluate Challenging Responses to Therapy in Congestive Heart Failure (SECRET of CHF) tracked dyspnea responses at 8 and 16 hours on the first day.

Both trials were presented recently here at the Heart Failure Society of America (HFSA) 2016 Scientific Meeting, and TACTICS-HF was published at about the same time in the Journal of the American College of Cardiology.

They follow earlier tolvaptan trials that followed ADHF patients primarily for clinical outcomes. The study triad EVEREST A, EVEREST B, and EVEREST long-term trial found no significant effect of tolvaptan on a 7-day clinical composite or on all-cause mortality, cardiovascular death, or HF hospitalization. But there were modest improvements in dyspnea scores at day 1, global clinical status, fluid volume, and edema.

Dr John Teerlink

Vasopressin-2 receptor antagonists "are very useful for hyponatremia" from whatever cause, Dr John Teerlink (San Francisco Veterans Affairs Medical Center/University of California, San Francisco) told heartwire from Medscape. Hyponatremia can result from the rampant hormonal activation that is part of heart failure, he observed.

"There's no doubt that the biological plausibility is very compelling," he said, regarding the use of vasopressin-2 receptor antagonists in ADHF. Tolvaptan in the trials "seemed to improve dyspnea a little, but not nearly as much, proportional to what we see in fluid loss."

Apparently, "it matters what kind of water you're losing" according to Teerlink. Vasopressin-2 receptor antagonists promote aquaresis, or electrolyte-free water excretion. Other volume-reduction methods, such as diuretics and ultrafiltration, he observed, reduce fluid that is either hypertonic or physiologic in electrolytes.

"I'm not sure which of those forms of [fluid] loss are going to have an impact on long-term outcomes," said Teerlink, who is not an investigator with either TACTICS-HF or SECRET of CHF. But "I think we've learned that losing free water does not seem to improve long-term outcomes."

Weight Loss vs Symptoms

Dr Clyde Yancy

Indeed, "now we have nearly 5000 patients with acute decompensated heart failure exposed to tolvaptan in randomized controlled trials, with no evidence of a benefit on morbidity or mortality. But there is a consistent signal of weight loss and decongestion that is not associated with clinical benefit," observed Dr Clyde W Yancy (Northwestern University, Chicago, IL), summing up the tolvaptan trials as featured discussant for TACTICS-HF at the HFSA sessions.

The two presented trials "make it clear that the biology of this weight loss is dissonant from the clinical outcome," he continued. "Promoting weight loss alone, particularly via aquaresis, does not appear to have clinical impact." Therefore, "hyponatremia may simply be an epiphenomenon" in ADHF, and so it may not be worthwhile in future studies to use hyponatremia as a treatment target.

"We should continue to think about arginine-vasopressin as a target of therapy for heart failure via alternative means. Targeting it further with antagonistic compounds may be a question that's now resolved and may no longer be reasonable."

Indeed, TACTICS-HF builds on trials of other decongestive treatments in ADHF, such as loop diuretics and ultrafiltration, "that demonstrate the disconnect between short-term fluid and weight loss and improvements in longer-term clinical outcomes," observe the authors of the TACTICS report, led by Dr G Michael Felker (Duke University, Durham, NC).

"To date, only chronic therapy with neurohormonal antagonists has been shown to definitively improve clinical outcomes in patients with heart failure," they write. Given the drug's cost, at least in the US, "the added value of tolvaptan in this clinical setting would not appear justified based on available data, nor would our data seem to support an expansion of the role of tolvaptan in patients with acute heart failure beyond the current FDA indication for hyponatremia."

TACTICS-HF "proves clearly that there is no benefit to the use of tolvaptan, and its use should be discouraged based upon lack of efficacy and cost," agreed an accompanying editorial from Drs Randall C Starling and James B Young (Cleveland Clinic Lerner College of Medicine of the Case Western Reserve University)[3].

Proportion of Patients (%) Who Were "Responders" to Tolvaptan in TACTICS-HF

Time of assessment (h) Tolvaptan (%) Placebo (%) P
24* 16 20 0.32
48 45 36 0.14
72 30 18 0.022
*Primary end point
Responders=patient experienced dyspnea relief, absence of death/worsening heart failure

TACTICS-HF randomized 257 patients with ADHF to receive tolvaptan or placebo double-blind on top of fixed-dose furosemide. It showed no significant difference in the number of patients deemed "responders" at 24 hours, the primary end point, or at 48 hours by showing dyspnea relief or absence of death or worsening HF.

At neither point was the rate of dyspnea relief, on its own, significantly greater in the tolvaptan group. And yet patients on active therapy lost significantly more fluid and weight.

Targeting Subgroups, Targeting Biomarkers

Secondary findings in the SECRET of CHF trial and prior studies of tolvaptan suggest there may be subgroups of patients with ADHF that respond better to tolvaptan than the study populations as a whole. And at the HFSA sessions, it was suggested that certain biomarkers might help to identify those patients.

As presented at the HFSA sessions by Dr Marvin A Konstam (Tufts University, Boston, MA), SECRET of CHF randomized 250 patients with ADHF at 37 sites in the US to receive either tolvaptan or placebo on top of standard therapy.

The trial prospectively aimed to enroll a population with an increased prevalence of hyponatremia, renal insufficiency, or diuretic resistance, Konstam said, and therefore possibly more likely to respond to tolvaptan (as hinted by earlier trials). Patients had to have been hospitalized with dyspnea within the prior 36 hours and have two of the following features: eGFR <60 mL/min/1.73m2; serum Na <134 mEq/L; or urine output <125 mL/h over 2 hours given >40 mg IV furosemide.

Both patient groups, 119 given tolvaptan and 125 who received placebo, lost weight during the trial. But weight loss was significantly greater in the tolvaptan group both early after the start of therapy and for the next 3 days. Any changes in renal function were similar in the two groups.

Proportion of Patients (%) "Markedly or Moderately Better" on the 7-point Likert Dyspnea Scale in SECRET of CHF

Time of assessment (h) Tolvaptan (%) Placebo (%) P
8* 37.9 33.3 0.46
16 44.9 43.1 0.78
24 52.1 48.8 0.60
48 73.5 64.3 0.14
72 81.2 66.3 0.02
*Primary end point

The rate of patient-assessed "markedly or moderately" improved dyspnea, as measured by the 7-point Likert scale, did not differ between the two groups at either 8 hours or 16 hours or through day 2; there was a moderately significant benefit for tolvaptan at 72 hours, a secondary finding.

In a prespecified subgroup analysis, however, there were significant interactions between jugular venous pressure (JVP) (P=0.001) and presence of ascites (P=0.009) for the primary Likert score end point, according to Konstam. Patients without elevated JVP and those without ascites had significantly better dyspnea scores on tolvaptan at 8 and 16 hours.

"The subgroup finding of earlier benefit with tolvaptan in patients without jugular venous distension or ascites suggests differential mechanisms for dyspnea in patients with vs without right heart failure, and a more gradual dyspnea benefit in those with right heart failure," he said.

"Additional work is warranted" to explore vasopressin-receptor antagonists in heart failure, "and particularly, to distinguish patients with and without right heart failure in future acute heart-failure trials," according to Konstam.

"Larger studies of course are required for proper analysis of subgroups and perhaps to narrow the field of patients who may respond and eliminate those who may not," according to Dr Mona Fiuzat (Duke University and the US Food and Drug Administration), discussant for Konstam's presentation.

"Clearly, patients with right heart failure responded differently to this drug," she agreed. And it may be possible to use "biomarkers like serum sodium, copeptin, and other markers that may help us narrow the patient population for which the drug may work best."

Although "improvements in dyspnea and weight loss did not translate to longer-term clinical outcomes," she said, patient-reported outcomes (PRO) "are relevant, important, and adequate for approval of indications. We should utilize data from smaller studies such as this to identify the signals for phase 3 studies that utilize PRO end points."

A secondary observation from the trial, that apparently increasing rates of dyspnea improvement with tolvaptan became significantly different by 72 hours, implied "a temporal separation between fluid removal and dyspnea relief," according to Konstam. That may imply that any effect the drug may have on symptoms is delayed and therefore greater in some ways than the trial's prospectively defined end points could have detected.

TACTICS-HF researchers made a similar observation. "Tolvaptan therapy resulted in greater net fluid loss at early time points; however, it was not until the 48- and 72-hour time points that this translated into a trend toward dyspnea relief (albeit not statistically significant)," they write. "This finding may reflect the time needed for distribution of fluid out of extravascular spaces (such as alveoli) back into the circulation."

Both TACTICS-HF and SECRET of CHF were reported as investigator-initiated and funded by Otsuka Pharmaceuticals. Teerlink reports receiving research grants from Amgen, Bayer, Bristol-Myers Squibb, Cardio3 Bioscience, Medtronic, and Novartis and serving as a consultant or on an advisory board for Myer Squibb, Cytokinetics, Mast Therapeutics, Novartis, Relypsa, and ZS Pharma. Yancy had no relevant financial relationships. Felker reports receiving research funding from Otsuka, Novartis, Roche Diagnostics, Amgen, and Merck and consulting for Novartis, Amgen, Trevena, Cytokinetics, Bristol-Myers Squibb, Stealth Biotherapeutics, and GlaxoSmithKline; disclosures for the coauthors are listed in the abstract. Starling and Young report that they have no relevant financial relationships. Konstam discloses that he has no relevant financial relationships. Fiuzat reports research funding from Otsuka for TACTICS-HF.

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