Hypotension No Reason to Avoid Sacubitril/Valsartan, Says PARADIGM-HF

September 20, 2016

ORLANDO, FL — The PARADIGM-HF trial was a standout for a variety of reasons, beyond showing significant hospitalization and survival advantages for an entire new drug class compared with mainstay ACE inhibitors in chronic heart failure.

For example, it was the first and so far only large randomized outcomes trial for sacubitril/valsartan (Entresto, Novartis), yet regulators on both sides of the Atlantic quickly gave it their stamp of approval. But a year later, with some irony, a medical community that often shows special fondness for new drug options has given it a lukewarm reception.

It's unclear why clinicians haven't embraced sacubitril/valsartan, classified as an angiotensin-receptor-neprilysin inhibitor (ARNI) and formally known as LCZ369, as a replacement for ACE inhibitors in chronic HF. But it was a frequent question heard here in the halls at the Heart Failure Society of America (HFSA) 2016 Scientific Meeting.

Possible reasons include some proposed at last year's HFSA sessions; among them was the PARADIGM-HF finding of a greater rate of symptomatic hypotension in patients randomized to sacubitril/valsartan (14.0%) compared with those assigned to enalapril (9.2%, P<0.001)[1].

But at this HFSA session[2], a post hoc look at the hypotension that developed in the trial showed some patterns that should alleviate most concerns about the complication as a reason to avoid adopting sacubitril/valsartan over ACE inhibitors, according to the PARADIGM-HF group.

Patients in the trial who took sacubitril/valsartan were no more and possibly less likely to have a severe adverse hypotensive event than those who received enalapril, Dr Orly Vardeny (University of Wisconsin, Madison) told heartwire from Medscape. Certainly, according the analysis she presented, patients who took the ARNI were less likely to be hospitalized with hypotension.

And developing hypotension during the trial's drug run-in periods—unusual for a large randomized trial—didn't seem to affect whether physicians thought their patients tolerated either sacubitril/valsartan or enalapril enough to enter the subsequent randomization phase, according to Vardeny.

In the single-blinded run-in periods, all patients took enalapril for 2 weeks and, if it was tolerated, sacubitril/valsartan for the next 4 to 6 weeks; those considered to have tolerated both drugs advanced to the trial's double-blind randomization phase. The 12% who withdrew, at physicians' discretion, did so usually because of cough, hyperkalemia, renal dysfunction, or hypotension, as PARADIGM-HF investigators originally reported.

But most patients who developed some degree of hypotension while on sacubitril/valsartan in the run-in phase were approved for randomization, Vardeny said. And in that phase of the trial directly comparing the two agents, she added, there was no difference between sacubitril/valsartan and enalapril in rate of permanent drug discontinuation due to hypotension.

"We have to be cautious because it's really a small number of events," she said, but "the percent of patients who were hospitalized for hypotension was higher in the enalapril group compared with the sacubitril/valsartan group." That's regardless of which definition for hypotension was used.

Responses to Hypotension* Events in PARADIGM-HF Randomization Phase by Treatment Group

Response to hypotension event Enalapril, n=4212 (% of 1109 events) Sacubitril/Valsartan, n=4187 (% of 1525 events) P
Hospitalization 12.3 7.5 <0.001
Dose adjustment or temporary interruption 34.3 39 0.014
Permanent discontinuation 2.6 2.6 0.93
Change in other meds 12.7 12.9 0.92
Nondrug therapy 2.1 2.6 0.42
No action 43.6 42.4 0.51
*Hypotension defined as "hypotension or orthostatic hypotension, or postural dizziness, or dizziness, or presyncope, or syncope, or depressed consciousness, or loss of consciousness." Results were similar for the alternative definition of "hypotension or postural hypotension, or postural dizziness."

In addition, she observed, the current analysis suggests the patients who developed hypotension during the run-in phase, once randomized, still fared better with sacubitril/valsartan than with enalapril.

Overall in the trial, as heartwire previously reported, patients taking sacubitril/valsartan showed a 20% drop in the primary end point of CV death or HF hospitalization and in CV death on its own, along with a 16% fall in all-cause mortality (P<0.001 for all three differences), compared with the enalapril group.

In the current analysis, patients who experienced a hypotensive event during run-in with either agent but were randomized, compared with those without a hypotensive event, benefited similarly from sacubitril/valsartan for the primary end point, Vardeny reported. The respective hazard ratios (HR) were 0.81 (95% CI 0.44–1.52) and 0.80 (95% CI 0.73–0.87) with an interaction P=0.84.

"So, bottom line, hypotension did occur [in PARADIGM-HF], it occurred more frequently with sacubitril/valsartan compared with enalapril, but it did not preclude the use of sacubitril/valsartan," she said. "And those who got hypotension still received benefit from the drug relative to enalapril."

Vardeny discloses receiving honoraria for speaking from Novartis.

Follow Steve Stiles on Twitter: @SteveStiles2. For more from theheart.org, follow us on Twitter and Facebook.

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