Safe to Start Sacubitril/Valsartan Predischarge in Acute Heart Failure: TRANSITION

September 18, 2018

NASHVILLE, Tenessee — Concerns about sacubitril/valsartan (Entresto, Novartis) promoting hypotension in patients with chronic heart failure (HF) started almost as soon as the pivotal PARADIGM-HF results were unveiled 4 years ago.

Now, a randomized trial has demonstrated the feasibility and safety of initiating sacubitril/valsartan prior to discharge from a hospitalization for acute decompensated heart failure instead of the less exotic approach of starting it soon after discharge.

In the TRANSITION study, uptitration of sacubitril/valsartan to target twice-daily dosages of either 100 mg or 200 mg was achieved and maintained in about 62% of patients who started before discharge, compared with 68% for those starting the drug after discharge. The difference was not significant.

Adverse events prompting a halt to therapy occurred at the same low rates in both groups of the trial, which had randomized about 1000 patients. In particular, rates of hypotension and hyperkalemia were both less than 1% whether the drug was initiated before or after discharge.

The study suggests lei most patients with acute decompensation of HF with reduced ejection fraction, once they are stabilized, "tolerate sacubitril/valsartan quite well," regardless of when uptitration starts, Dmytro Butylin, MD, Novartis, Basel, Switzerland, told | Medscape Cardiology.

He said TRANSITION researchers had expected that those initiating the drug after leaving the hospital and the more vulnerable group starting it closer to acute decompensation would respond differently.

But, "we observed no differences in the safety profiles, and there were no new safety signals" throughout the 10-week postdischarge period covered in his presentation, Butylin said. Planned patient follow-up will be 6 months.

"We can be reasonably confident that there's no reason to delay initiating this new therapy."

Butylin presented the trial here at the Heart Failure Society of America 22nd Annual Scientific Meeting in lieu of the scheduled presenter, Rolf Wachter, MD, University Hospital Leipzig, Germany. He is cardiometabolic global medical affairs director for his company and a coauthor of the TRANSITION protocol.

Those Hypotension Concerns

In PARADIGM-HF, the trial that led to the regulatory approval of sacubitril/valsartan internationally and guided its labeling, patients taking the novel drug showed a 20% drop in the primary end point of CV death or HF hospitalization and in CV death on its own, compared with patients assigned to enalapril, a standard-therapy ACE inhibitor. There was also a 16% fall in all-cause mortality; all three differences were significant at < .001.

Speaking as a comoderator of Butylin's presentation, Clyde W. Yancy, MD, MSc, from Northwestern University, Chicago, said when the PARADIGM-HF findings were unveiled about 4 years ago, "we expressed great concern about the risk of hypotension" with sacubitril/valsartan.

"It could be very important for the everyday practitioner who wants to start these therapies" to hear whether that was a problem in TRANSITION," he said, calling it "a really excellent study."

Table. Top Reported Adverse Events by Timing of Sacubitril/Valsartan Initiation*
Adverse Event Predischarge Initiation (%) Postdischarge Initiation (%)
Hyperkalemia 11.1 11.3
Hypotension 12.3 9.1
Cardiac failure 6.8 8.5
Dizziness 5.6 4.2
Renal impairment 5.0 3.0

*all differences nonsignificant


Butylin replied that hypotension was observed in about 12% of the predischarge-initiation group and 9% of those starting the drug after discharge, but in no case did hypotension lead to permanent discontinuation of the therapy.

"It's a moderate risk of hypotension, which can be easily managed," Butylin said in an interview. "It's the same frequency of hypotension you'd see if you were initiating beta blockers in the hospital, or angiotensin receptor blockers [ARBs] or ACE inhibitors."

"First of its Kind"

The other comoderator, James L. Januzzi Jr, MD, Massachusetts General Hospital, Boston, said the TRANSITION data on the in-hospital initiation of sacubitril/valsartan "is the first of its kind to emerge."

A trial of about the same size that is comparing sacubitril/valsartan with enalapril for in-hospital administration after HF decompensation will be reported "soon," he said. That study, called PIONEER-HF, also has a placebo-control group and measures changes in natriuretic peptides for the primary outcome.

Tolerability is among the major issues with the novel agent that clinicians have questioned, Januzzi said. Clinical practice on both sides of the Atlantic has been slow to adopt sacubitril/valsartan over ACE inhibitors or angiotensin receptor blockers, although that's usually attributed to its much greater cost.

The rate of treatment discontinuation was 4.5% for patients starting the drug before discharge and 3.5% for those starting after discharge, Butylin explained; the difference was nonsignificant.

The analysis, he said, suggests that uptitration of the drug, regardless of randomization group, was tolerated best in younger patients without renal dysfunction, hypertension, atrial fibrillation, or a lot of comorbidities, especially a history of HF. Assignment to predischarge or postdischarge initiation was not related to tolerability.

It's important that the patients be stabilized, defined as achieving at least 24 hours without the need for diuresis, and normovolemic before starting the uptitration, Butylin said.

Interestingly in the trial, he noted, 24% of participants had no prior exposure to an ACE inhibitor or ARB.

Januzzi pointed out that "the guidelines are pretty prescriptive about making sure patients are stabilized on an ACE inhibitor or ARB before considering transition" to sacubitril/valsartan.

However, he noted, the 2017 American College of Cardiology Expert Consensus Decision Pathway for Optimization of Heart Failure Treatment makes an allowance for considering such de novo sacubitril/valsartan in "well-informed patients who, within a framework of shared-decision making, accept the uncertainty about effectiveness and safety as well as potentially greater out-of-pocket costs."

But the document was "fairly mute about what to do in the hospital," Januzzi said. He added there may now be occasion for accommodating de novo and prehospital initiation of the drug in future guidelines.

Speaking from the audience after Butylin's presentation, John Teerlink, MD, San Francisco VA Medical Center and University of California, San Francisco, said that in a 2017 report, he and his coauthor "thought it was reasonable to initiate sacubitril/valsartan early on in ACE inhibitor-naïve patients, but that it would take time and practice for people to be comfortable with that."

Addressing the rest of the audience, Teerlink said, "I hope that most of you by now have that level of comfort, because this is clearly life-saving therapy."

Uptitration Schedule

Patients in TRANSITION had NYHA class 3–4 heart failure and an LVEF of 40 or less after stabilization following an episode of acute decompensation; patients with newly diagnosed HF made up 29% of the cohort.

The 1002 patients from 19 countries were randomly assigned to either predischarge or postdischarge initiation of the drug, in both cases after a 36-hour ACE-inhibitor/ARB washout period, if needed. After some patients dropped out because of "protocol violations," there were 493 and 490 remaining in each group, respectively.

At the physicians' discretion, open-label sacubitril/valsartan was given twice daily at either 50 mg, escalating to 100 mg and again to 200 mg as tolerated, or at 100 mg twice daily with escalation to double that dose as tolerated.

Within 10 weeks of randomization, 45% of predischarge patients and 50.4% of postdischarge patients met the primary end point, which was achievement and toleration of 200 mg twice daily (P = .092).

Sacubitril/valsartan was tolerated and maintained at the twice-daily dosage of either 100 mg or 200 mg in 62.5% and 68.0% of predischarge and postdischarge patients, respectively (P = .07).

At least one serious adverse event was reported in 18.9% and 17.7% of the predischarge and postdischarge groups, respectively. For cardiac failure, the rates were 7.0% and 7.7%, respectively, and for acute kidney injury they were 1.2% and 1.4%, respectively.

There were 13 deaths in the predischarge group and 10 in the postdischarge group (P = .674); none were judged to be related to the treatment.

TRANSITION was funded by Novartis. Butylin is an employee of Novartis. Wachter reports being on advisory boards for and/or receiving speaker's honoraria from Boehringer Ingelheim, Bayer, CVRx, Medtronic, Novartis, Pfizer, Sanofi, Servier; and receiving research grants from Boehringer Ingelheim, European Union and Bundesministerium für Bildung und Forschung. Januzzi reports receiving research grants from Roche Diagnostics, Siemens, Singulex, Abbott, and Prevencio. Yancy and Teerlink disclose that they have no conflicts.

Heart Failure Society of America (HFSA) 22nd Annual Scientific Meeting: Abstract 31. Presented September 5, 2018.

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