ARNI as First-line Therapy for HF? Not Yet, Debate Suggests

Marlene Busko

August 30, 2016

ROME, ITALY — Like gladiators, two debaters squared off to convince the audience here at the European Society of Cardiology (ESC) 2016 Congress that the angiotensin-receptor-neprilysin inhibitor (ARNI) sacubitril/valsartan (Entresto, Novartis; formerly called LCZ369) should (according to the pro side) or should not (according to the con side) replace ACE inhibitors as first-line therapy for patients with chronic heart failure with reduced ejection fraction (HFrEF)[1].

When it was over, based on a show of hands, roughly a quarter of this international audience indicated that they had already prescribed this agent to their patients and a third would like to do so if this therapy were available to them.

"The US data would suggest that . . . there are people coming on board thinking about [prescribing this new agent], which I think is a good thing," session cochair Dr Clyde Yancy (Northwestern University, Chicago, IL) told heartwire from Medscape. "Remember, we are trying to replicate the results of a highly controlled, very well-structured clinical trial [PARADIGM-HF] in an unselected [clinical-practice] patient population. . . . So I think haste in this regard is not where we want to be," he said.

The debater for the pro side, Prof John McMurray (University of Glasgow, Scotland), who was also lead investigator in the landmark PARADIGM-HF trial, presented arguments for why PARADIGM-HF "indisputably" showed that sacubitril/valsartan was better than the ACE inhibitor enalapril to treat the patients with heart failure, although he didn't explain why this first-in-class agent should also be a first-line treatment.

Arguing for the con side, Dr Giuseppe Rosano (St George's University, London, United Kingdom), cochair of the ESC scientific program committee, agreed that this agent is an option for patients with symptomatic, chronic class 2 or 3 heart failure with the same features as those in PARADIGM-HF, but "not as first-line therapy for the time being," he stressed.

According to Yancy, the takeaway message from this debate is, once again, "Let's do the right thing for the right patient at the right time." Specifically, "if the patient has a good blood pressure, is tolerating a good dose of an ACE inhibitor, has recently been hospitalized, or has a mildly elevated BNP…that's the patient who should take the compound, and let's do that," he said.

Correct Order of Therapy Remains Controversial

The American guidelines for treating patients with HF with reduced ejection fraction specifically recommend starting with an ACE inhibitor (or if this is not tolerated, prescribing an angiotensin-receptor blocker [ARB]) plus an evidence-based beta-blocker, Yancy explained, introducing the debate. If the patient's symptoms resolve, no further action is required. "But only if symptoms persist, and after a mineralocorticoid receptor antagonist [MRA] has been added, would one consider an ARNI to replace an ACE inhibitor," he said.

However, "others have already suggested in the literature that we should consider the introduction of the combination of sacubitril/valsartan at the topmost tier of therapy in patients with reduced-ejection-fraction HF," Yancy continued. Thus, this debate should help shed light on the controversial issue of the correct order of treatment with and ACE inhibitor and with an ARNI.

ARNI Should Be First-line Therapy

"Without any doubt," sacubitril/valsartan is superior to enalapril to reduce the rates of CV death, all-cause death, HF hospitalization, all-cause hospitalization, and the likelihood of a deterioration in health-related quality of life in patients with HFrEF," McMurray stated emphatically. "Would you not want a better treatment for your patients, your family, or yourself?" he asked.

Moreover, PARADIGM-HF found a statistically significant reduction in the primary end point of CV mortality within days of randomization. "Do you really want to put your patient on the inferior treatment, to wait to switch them to the better treatment?" he continued.

McMurray then countered some common reasons for a reluctance to prescribe an ARNI for a patient with HF.

First, although this ARNI inhibits the enzyme neprilysin that is involved in clearing amyloid beta peptides in the brain, which are associated with Alzheimer's disease, "there is no consistent experimental evidence that neprilysin is involved in dementia," he said.

Second, although PARADIGM-HF is only one trial, the very low P value for the primary end point in this trial is equivalent to having four or five trials with a P value <0.05; similarly, the low P value for CV mortality in PARADIGM-HF is equal to having two to three trials with a P value <0.05, he said.

Third, there is experience with decompensated HF, since there were 1500 cases of admission to the hospital with worsening HF, and patients in the study drug arm were likely to require intensive care or be readmitted.

Last, the US Food and Drug Administration (FDA) and the European Medicine Agency (EMA) approved this drug for a broad indication: that is, for patients with symptomatic HF and reduced EF.

"To conclude, there's not much of a debate," according to McMurray. "You do have a choice," he said, showing a slide of US presidential candidates Hilary Clinton and Donald Trump and adding "I'll let you guess which one is sacubitril/valsartan."

ARNI Should Not Be First-line Therapy

LCZ696 was more effective than enalapril in reducing the risk of CV death, hospitalization, both, and all-cause mortality specifically in ambulatory patients with chronic heart failure who were treated with an ACE inhibitor, beta-blocker, and MRAs, had elevated BNP levels, and were able to tolerate the ARNI without cough or angioedema, Rosano summarized.

"We need to be cautious at the start, and try to stick with patients who are similar to patients who have been included in PARADIGM-HF," he stressed. He reminded the audience of other problems that occurred when rosiglitazone, a good antiglycemic agent, was prescribed for cardioprotection in patients who differed from those that had been studied or the problem of angioedema in blacks with omapatrilat that appeared only in later trials.

"I think it is good for any drug that we market, to stick with the population in which it has been studied and then as we accumulate evidence, expand to other populations," he said.

PARADIGM-HF was a carefully selected population, where patients at risk of angioedema and cough were excluded during the run-in phase—to keep the possibility of angioedema low, Rosano pointed out.

"I don't think cognition is a big issue in patients who resemble the patients who were enrolled in PARADIGM-HF, but when we go to patients who are at low risk who may be treated for 10 to 15 years, we don't know exactly what the long-term effect is; then, probably, we are going to be a bit cautious," he said.

In PARADIGM-HF, only 0.7% of patients had NYHA class 4 HF and only 5.3% had NYHA class 1 HF, and the rest had NYHA class 2 to 3 HF, with 35% LVEF, he noted. Participants were required to have elevated BNP and use of an ACE inhibitor.

"So it's the combination of prior use of ACE inhibitor, depressed LVEF, and elevated BNP that identified patients at increased risk where the benefit of LCZ696 became evident," according to Rosano.

Follow the Data Trail

"The important statement that needs to be reiterated over and over again is that in the setting where we have very compelling data about a number of agents, the best approach is to follow the way in which the data were acquired," Yancy echoed.

"If blood pressure is marginal, if the patient doesn't really fit all the other elements that were seen within the PARADIGM-HF trial, one should be reluctant to make a change without some sense of certainty that the patient would benefit. We shouldn't walk away from this session ignoring the importance of RAS blockade plus an evidence-based beta-blocker," he said.

"For everyone who always said heart failure is so difficult to treat and there's only two or three things you can do, well that argument has been retired," Yancy continued. "There are many things you can do, and I think we should look at this not as one definitive pathway now, but as a background therapy from which we can do many different things."

"As cardiologists we see only 35% of patients with HF," Rosano said, in reply to a question from the audience. The rest are seen in primary care by internists and geriatricians. "The patients we see are more likely to be the type of patients who should be switched; but if you talk about the totality of patients with HF, first line should still be the ACE inhibitors and beta-blockers."

Rosano invited the audience to attend 4th World Congress on Acute Heart Failure, April 29 to May 2, next year in Paris, where more results from ARNI studies of safety, efficacy, and subgroups will be presented.

Yancy has no relevant financial relationships. McMurray reports nonfinancial and other support from Cardiorentis, Amgen, Novartis, Oxford University/Bayer, GlaxoSmithKline, Theracos, AbbVie, AstraZeneca, and Kidney Research UK/Kings College Hospital/ViforFreseneius Pharma, and other support from DalCor, Pfizer, Merck, and Bristol-Myers Squibb outside the submitted work. Rosano reported no relevant financial disclosures.

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