PARADIGM-HF: Some Say, 'A New Day in Heart Failure'

September 02, 2014

BARCELONA, SPAIN — "This is a new day in heart failure," said Dr Clyde Yancy (Northwestern University, Chicago, IL). "This is a step closer to taking the failure out of heart failure."

Yancy's acclamation to heartwire referred to the seeming knockdown success of the novel drug studied in PARADIGM-HF [1]. It surpassed the classic ACE inhibitor enalapril at diminishing cardiovascular mortality in the convincingly huge trial that has been the talk of the town, so to speak, here at the European Society of Cardiology2014 Congress .

Other thought leaders in heart failure and the broader realm of cardiology seem just as excited at the prospect, still only a hope, of the awkwardly named LCZ696 (Novartis) taking over as the new cornerstone of chronic HF therapy.

"Often I am very critical of clinical studies, but I'm having difficulty being critical of this one. I'm really quite encouraged," said Dr Mark Creager (Brigham and Women's Hospital, Boston, MA) when interviewed after the trial was presented here two days ago.

"Given the data that were presented and also reported [the same day] in the New England Journal of Medicine, right now those of us in the field have to be pretty enthusiastic." As for himself, Creager said he is "cautiously optimistic."

Dr Elliot Antman (also of Brigham and Women's Hospital) liked the trial's subgroup analyses, which are typically taken with a grain of salt but in this case pointed to similar outcomes in a broad variety of patients. "It's a pretty impressive, consistent result in all those subgroups. None are really powered to show a particular interaction, but it was very gratifying to see the general consistency."

One of the trial's contributions was to introduce what seems a successful heart-failure medication with a mechanism that extends well outside the renin-angiotensin system (RAS), observed Dr Mariell Jessup (University of Pennsylvania, Philadelphia). She said it makes sense that maybe for heart failure, "we've wrung all we can" out of RAS inhibitors.

PARADIGM-HF randomized >8000 patients with depressed LV systolic function, almost all of whom were in NYHA class 2–3, to treatment with LCZ696 or enalapril on top of other evidence-based therapies. Molecularly, LCZ696 includes moieties of valsartan and sacubitril, from which it is classified as an angiotensin receptor-neprilysin inhibitor (ARNI).

The trial's short story: patients who received the novel agent compared with the vintage one showed 20% drops in CV death or HF hospitalization and in CV death as a solo end point (p<0.001 for both) over two to three years, as heartwire reported August 30. All-cause mortality dropped 0.80% (p<0.001).

"Doubling the Benefit of Enalapril"

"The magnitude of the advantage of LCZ696 over enalapril on cardiovascular mortality was at least as large as that of enalapril over placebo during long-term treatment [in the early large trials], meaning that LCZ696 effectively doubled the survival benefit of enalapril," said PARADIGM-HF co–principal investigator Dr Milton Packer (University of Texas Southwestern, Dallas) when presenting the trial.

"This robust finding provides strong support for using LCZ696 instead of ACE inhibitors or angiotensin-receptor blockers in the treatment of chronic heart failure."

The discussant following Packer's presentation, Dr Michel Komajda (Groupe Hospitalier Pitié-Salpêtrière, Paris, France), openly wondered whether the PARADIGM-HF results are enough to make "a major change in the international guidelines for the management of heart failure."

PARADIGM-HF, he said, "is the first contemporary trial to propose [a new drug for] substitution rather than an add-on strategy in chronic heart failure. The magnitude of the risk reduction, as the number of patients needed to treat to prevent outcomes, suggest that LCZ696 is cost-effective. However, pricing will be key, and economic studies are therefore eagerly awaited."

And PARADIGM-HF is only one trial. "As enthusiastic as we are, and as insistent as I and others are to move quickly to implementation, we must do so responsibly. No trial can answer all the questions," Yancy said. "The simple approach is to rush to treatment, but the right approach is to work toward implementation, where we continue to study this therapy and work to answer the important questions that are still pending."

And also to look more deeply into PARADIGM-HF results: "There will obviously be a lot more analysis," said the trial's other co–principal investigator, Dr John JV McMurray (University of Glasgow, Scotland). Even the primary New England Journal of Medicine paper could only go so far. "We wrote up and submitted the paper six days after we got the final data, and [it took] five days to answer the reviewer's comments. As you can imagine, comprehending, understanding, and drilling down into every item is quite difficult when you have a relatively short time to write," he said.

"It will be interesting to see how the clinical community responds once the dust has settled, the package has been submitted, and the drug finally gets a proper name," observed Dr Kenneth Dickstein (University of Bergen, Stavanger University Hospital, Norway). "But I must admit that I was encouraged and pleasantly surprised by these findings."

Who Is It for?

Assuming LCZ696 is approved by regulators, presumably it would be for the indication reflected in PARADIGM HF entry criteria. But in clinical practice, would it be prescribed more widely in heart failure as a substitute for ACE inhibitors? Packer noted that about 70% of the trial's patients were randomized in NYHA class 2 and <1% were in class 4. "The purpose of using this drug is not to make people feel better. . . . The major advantage of this drug, and it's particularly true in someone with minimal symptoms or mild symptoms, is that the natural course of the disease is changed. . . . I actually would argue that there's greater reason to use this drug in mildly symptomatic patients."

Yancy agreed that "the patient with mild heart failure, a reasonable blood pressure to tolerate this new therapy, already on a beta-blocker and mineralocorticoid [aldosterone]-receptor antagonist and an EF <0.35, appears to be the best candidate." Further research should be done to assess the drug in patients who were underrepresented in PARADIGM HF, "older persons, African Americans, and certainly more patients treated in the US."

Curios and Cautions

Other concerns are that the trial didn't answer every question worth answering: "I was hoping that the reduction in the burden of heart failure and its related symptoms would also lead to a reduction in atrial fibrillation," said Antman. "It didn't seem to happen. It isn't a strong negative, but we can't rely on this drug to actually treat heart failure so effectively that it also reduces the burden of atrial fibrillation."

Jessup also wondered why LCZ696, "if it did all those [other] wonderful things," didn't seem to affect AF. "I was surprised, because we always think that [AF] is part and parcel in worsening heart failure." She proposed that perhaps an AF affect might show up in when patients are followed over the long term.

Treatment longer than the trial's follow-up of a few years could also show additional benefits from the drug. Dr John R Teerlink (University of California, San Francisco and San Francisco Veterans Affairs Medical Center), a US national leader for PARADIGM-HF, said patients who took LCZ696 showed an "intriguing" reduction in worsening renal function. "I would be very interested in seeing whether there are long-term renal benefits with LCZ696, both in this trial and perhaps in other therapeutic areas."

Teerlink also said that adverse effects that were more common with LCZ696 were "anticipated effects and should not represent any new challenge to prescribing physicians."

And in the trial, at least, LCZ696 "was better tolerated than enalapril," Packer said, "and there was no increased risk of serious angioedema."

If the drug is approved, Teerlink said, "I believe that it would be appropriate to replace ACE inhibitors with LCZ696 as a cornerstone chronic heart-failure therapy." But he had a caution about transitioning the drug from trials to clinical practice. He pointed out that a full 20% of the cohort in the drug run-in period dropped out because they couldn't tolerate ACE inhibitors. The remaining 80%, the ones randomized, were those "who would tolerate the medicines well during the trial." Because of this, he said, "the adverse-event rates during randomized treatment most likely underestimate the adverse-event rates that will be seen in practice."

What if the Patient Seems Fine on ACE Inhibitors?

Creager observed that patients in the trial were well managed at baseline, most were on beta-blockers, already they "seemed to be doing well," and still they showed the 20% drop in CV death after taking LCZ696. "So it would be hard not to offer this drug, if it became available, to patients who appear to be doing well with stable heart failure" while on ACE inhibitors, he said. Maybe there would be little room for improvement in symptoms on LCZ696, but their mortality risk would still go down.

But Jessup proposed that patients "who are doing fine may not choose to start a new drug."

According to Antman, "When we make those kinds of decisions in clinical medicine, the science is only one of the things that we have to consider. Another is cost, which is a difficult thing to evaluate because it's not just the cost of the drug, which will undoubtedly be higher if this new drug becomes available clinically, but it's the cost to the healthcare system. If in fact there is a reduction not only in heart-failure symptoms but in mortality and readmissions, it may very well be cost-effective. So maybe the switch would be a good thing to do."

Further ARNI Research

"PARADIGM HF has provided some powerful evidence supporting efficacy for clinical outcomes in patients with LV dysfunction and heart failure, and the drug's pharmacology makes sense," Dickstein said. "The PARAMOUNT trial does suggest a potential role in patients with preserved LV function [HFpEF]. But the bar is higher in PARAGON , an outcomes study in a large HFpEF population; and interestingly the comparator this time is an angiotensin-receptor blocker [valsartan] rather than an ACE inhibitor."

According to Komajda, "It will be very interesting to compare the results of PARADIGM-HF with those of direct inhibition of renin with aliskiren (Tekturna, Novartis) alone or in combination with enalapril in the ATMOSPHERE trial, to see which of the two strategies is the most beneficial."

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