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Confident prediction of who will or will not experience side effects from a cornerstone heart failure therapy continues to elude researchers, even as they showed that some real-world patients were more likely not to tolerate even the lowest starting dose.

For the LIFE trial, 445 people with New York Heart Association class IV symptoms entered a run-in period of 3-7 days taking sacubitril/valsartan (Entresto) 24/26 mg twice a day. Ultimately, 18% dropped out at a median 6 days due to intolerance -- mostly symptomatic hypotension, and renal dysfunction in some cases -- before ever reaching the study's randomization phase.

Investigators found several multivariable predictors of angiotensin receptor-neprilysin inhibitor (ARNI) intolerance at 50 mg twice a day:

• Lower mean arterial pressure
• Lower serum chloride
• Presence of an implantable cardioverter-defibrillator or cardiac resynchronization device
• Moderate or greater mitral regurgitation
• Nonuse of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) at screening
• Use of insulin at screening

Anyone with just one or no risk factors was unlikely to fail run-in, whereas people meeting four or more of these criteria had a nearly 50% probability of sacubitril/valsartan intolerance, according to a group led by Justin Vader, MD, of Washington University School of Medicine in St. Louis. The manuscript was published in the July 2022 issue of .

ARNI therapy has won strong recommendations from the latest U.S. and European heart failure guidelines on the basis of the landmark PARADIGM-HF trial and other studies.

"However, whether sacubitril/valsartan indeed is the right choice for patients with advanced heart failure was not addressed by these large clinical trials as most patients they enrolled were relatively stable. The patients we worry the most about, those with advanced heart failure, are brittle and are often barely able to tolerate neurohormonal blockade," according to Marc Samsky, MD, and Sounok Sen, MD, both of Yale University School of Medicine in New Haven, Connecticut.

"Intolerance to this medication should also be a reminder to clinicians that sacubitril/valsartan is not a panacea for all heart failure; indeed, its benefit has only been proven in a subset of patients who might not represent a real-world population," the pair wrote in an .

Vader's group noted that PARADIGM-HF had a sequential two-phase run-in design that required participants be stable on the ACE inhibitor enalapril before getting a higher dose of sacubitril/valsartan.

PARADIGM-HF's enalapril phase took out 25-30% of people due to hypotension and worsening renal function, and sacubitril/valsartan took out approximately 30% of the remaining candidates. This suggests "that sacubitril/valsartan is associated with dose-limiting side effects even in patients who are able to tolerate optimal guideline-directed medical therapy doses of enalapril," Vader and colleagues said.

"What does this mean for the practicing heart failure clinician? Based on the results of LIFE, initiation of sacubitril/valsartan might be considered the equivalent of adding another plate to the already precariously dowel rod–balanced stack of dishes," according to Samsky and Sen.

"For patients who might otherwise be suitable recipients of therapies known to be life-prolonging such as left ventricular assist device implantation or cardiac transplantation, sacubitril/valsartan intolerance should be a signal for expedited referral for these therapies, as continued pharmaceutical management might even impair their candidacy," the editorialists urged.

Reported last year, the main finding of LIFE was that sacubitril/valsartan not only did not improve N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels in people with heart failure and reduced ejection fraction -- it even trended toward increased risk of heart failure hospitalization over an ARB alone.

The study was a disappointment and left some wary of prescribing the ARNI to those with advanced heart failure.

"Given that the LIFE trial did not include a prior run-in period, in which patients were required to be hemodynamically stable on an optimal dose of an ACE inhibitor before their first exposure to sacubitril/valsartan, the LIFE trial provides an opportunity to assess the tolerability of sacubitril/valsartan in a clinically applicable, real-world setting," Vader and colleagues maintained.

Nevertheless, they acknowledged that their analysis relied on a relatively small number of people who did not complete the run-in period. Moreover, NT-proBNP levels at the time of run-in were not collected and could not be accounted for in the present study.

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