PARADIGM-HF: New Drug Class Outclasses ACE-I in Chronic HF

August 30, 2014

BARCELONA, SPAIN — Patients with chronic heart failure who take a newly developed drug that has effects both within and beyond the renin-angiotensin system, instead of the old-standby ACE inhibitor enalapril, will have fewer HF hospitalizations and die less often from cardiovascular causes, suggests a phase 3 trial that is huge both in size and its potential impact on clinical practice[1].

The risks of those two end points, as a composite as well as individually, fell by about 20% among the trial's patients with NYHA class 2–4 systolic heart failure who took the novel agent LCZ696 (Novartis) instead of the ACE inhibitor. All-cause mortality fell 16% on the novel agent. Follow-up averaged about 27 months.

The results in a general way have been known since April of this year, when Novartis announced that the Prospective Comparison of ARNI with ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, with its >8000 patients, had been halted early after LCZ696 showed clinical superiority and at least comparable safety compared with the ACE inhibitor in an interim analysis. This was followed by an only slightly fuller announcement at a meeting in May, in which coprincipal investigator Dr Milton Packer (University of Texas Southwestern, Dallas) said that the agent "had demonstrated convincing superiority over high doses of enalapril," as reported then by heartwire .

The PARADIGM-HF results were scheduled to be announced today at a press conference here at the European Society of Cardiology (ESC) 2014 Congress to coincide with its publication in the New England Journal of Medicine. The report's first author is the other coprincipal investigator, Dr John JV McMurray (University of Glasgow, Scotland).

Hazard Ratio (95% CI) for Clinical Outcomes in PARADIGM-HF, LCZ696 vs Enalapril

End points HR (95% CI) p
CV death or HF hospitalization* 0.80 (0.73–0.87) <0.001
Death from any cause 0.84 (0.76–0.93) <0.001
CV death 0.80 (0.71–0.89) <0.001
HF hospitalization 0.79 (0.71–0.89) <0.001
*Primary end point

LCZ696 is the first apparently successful drug in the angiotensin receptor-neprilysin inhibitor (ARNI) class, an inhibitor of angiotensin that can also potentiate endogenous natriuretic peptides, which are vasodilators. Chemically, it consists of the angiotensin-receptor blocker (ARB) valsartan affixed to the neprilysin inhibitor sacubitril, notes the paper.

Independent Views

An editorial accompanying the PARADIGM-HF report proposed that LCZ696 "may prove to be the first disruptive agent to the heart-failure treatment algorithm, which has remained essentially unchanged for a decade"[2]. In her methodical comparison of the PARADIGM-HF patients with those in a half-dozen other major heart-failure studies, Dr Mariell Jessup (University of Pennsylvania, Philadelphia) concludes they are comparable to those in the other trials who had "mild to moderately severe" HF. That could help allay concerns that an odd or unrepresentative patient cohort may have been responsible for the standout results of PARADIGM-HF.

The trial "may well represent a new threshold of hope for patients with heart failure," she writes. "The beneficial results seen in PARADIGM-HF may apply to a wide spectrum of patients, even those who are currently receiving the best possible therapy."

Dr John GF Cleland (Harfield Hospital, Imperial College London, UK) was bullish on the new agent when commenting to heartwire . "LCZ696 is one of the great innovations in the management of heart failure in the past quarter century," he said.

"The PARADIGM study shows that, for the management of stable outpatients with heart failure and a reduced left ventricular ejection fraction [HFREF] and, crucially, increased plasma concentrations of natriuretic peptides, LCZ696 is substantially superior to an ACE inhibitor (and by implication angiotensin-receptor blockers), in terms of reducing both morbidity and mortality. Patients also felt better on the newer agent; a small but highly significant effect."

Cleland noted that the morbidity and mortality gains were more pronounced in patients with less severe symptoms, who may be at lower risk "but whose outcome may be more amenable to improvement with this therapy. This is crucially important, since it is the patient who appears stable on existing therapy, in whom a change in treatment may be considered unnecessary, who is most likely to benefit."

"At first blush, PARADIGM-HF looks like a therapeutic home run for patients with heart failure and will likely lead to a change in our current practice guidelines in the future," Dr Douglas L Mann (Washington University School of Medicine, St Louis, MO) told heartwire . Patients who took the ARNI showed "dramatic effects" on the clinical end points, and the benefits were seen "in most of the subgroups that were examined, with the notable exceptions of black patients and patients with an ejection fraction >35%," he observed. "The drug LCZ696 also appeared to be safe and well tolerated."

There were 428 blacks randomized in the trial; whites were the only listed ethnic group showing a significant LCZ696 effect for the primary end point or CV death.

"One curious observation was that there was no apparent benefit for heart-failure patients who had not been treated previously with an ACE inhibitor," Mann also noted. Whether it stems from a statistical issue with the same size or whether it points to less benefit from starting ACE-inhibitor–naive patients on LCZ696 instead of an ACE inhibitor, he noted, should be studied further.

The trial randomized 8399 patients with NYHA class 2–4 heart failure with an LV ejection fraction <35% and elevated natriuretic peptides who completed at least four weeks of treatment with an ACE inhibitor or ARB equivalent to enalapril at 10 mg/day. They were maintained as possible on stable doses of beta-blockers, preferably with aldosterone inhibitors. They were assigned to either 200-mg LCZ696 or 10-mg enalapril, both twice daily, on top of the other guidelines-based therapy.

Over a median of 27 months, the rate of CV death or HF hospitalization was 21.8% among LCZ696 patients and 26.5% for those taking enalapril; all-cause mortality was 13.3% and 16.5%, respectively.

Side Effects and Related Events in PARADIGM-HF

End points LCZ696 (n=4187), % Enalapril (n=4212) % p
Drug discontinued 17.8 19.8 0.02
Symptomatic hypotension 14.0 9.2 <0.001
Serum creatinine >2.5 mg/dL 3.3 4.5 0.007
Serum K >6.0 mmol/L 4.3 5.6 0.007
Cough 11.3 14.3 <0.001

There were no significant differences between the LCZ696 and enalapril groups in prevalence of angioedema at any severity. Packer previously observed for heartwire that the new drug was designed specifically to avoid that complication. That was based primarily on experience with another agent with similar properties, omapatrilat, which was associated with a worrisome risk of angioedema partly responsible for the drug's withdrawal as a potential treatment for hypertension and heart failure drug a dozen years ago.

Mann observed that less than 1% of patients in PARADIGM-HF were in NYHA class 4, so the study can say little about the drug's use in that group. "Given that treatment with LCZ696 resulted in a significant increase in symptomatic hypotension, this may limit use of this drug in patients with more advanced heart failure."

He also noted that only about 7% of patients in either group were on cardiac resynchronization therapy (CRT), raising questions about whether patients in the trial were on optimal HF therapy when randomized.

Still, Mann said, "PARADIGM-HF is an important trial that will likely have a profound impact on the way we treat patients with symptomatic heart failure."

According to Cleland, "the two big remaining issues are: When are we going to be able to prescribe LCZ696, and how much will it cost? Assuming cost is not prohibitive, national programs should be put in place to treat all relevant patients who have HFREF with LCZ696," he said.

"This means switching millions of patients worldwide and perhaps more than 100 000 in the UK alone," according to Mann. "Most of these patients will currently be managed in primary care. The safety of initiating LCZ696 in the hospital during an admission for an exacerbation of heart failure has not been established, although there is no obvious safety concern other than a greater risk of hypotension."

PARADIGM HF is funded by Novartis Pharmaceuticals.PARADIGM HF is funded by Novartis Pharmaceuticals. Packer reports receiving "personal fees" from Novartis, AMAG, Amgen, BioControl, CardioKinetix, CardioMEMS, Cardiorentis, Daiichi Sankyo, Janssen, and Sanofi. McMurray reports that his institution is paid by Novartis for his involvement in the PARADIGM-HF and ATMOSPHERE trials and that he has received reimbursement from the company for travel related to the trials. Disclosures for the other authors are available at the journal’s site. Jessup reports she has no relevant conflicts of interest. Mann says he has no working relationships with Novartis, nor has he with any company currently with an FDA-approved device. Cleland discloses that he is the UK national leader for the Novartis-funded RELAX-AHF-2 and PARAGON trials.


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