Novel Compound Holds Big Promise as HF Therapy: Maybe Not ‘Too Good to be True,’ but Alzheimer’s Issue Raises Red Flag

ACCEL | A new drug, still called LCZ696, combines two blood pressure-lowering medications: one of the most widely used angiotensin II receptor blockers (valsartan) and an agent from a new class of drugs called an angiotensin receptor neprilysin inhibitor (ARNI) known as sacubitril. The ARNI raises the level of endogenous natriuretic peptides by preventing their enzymatic breakdown in chronic heart failure (HF) patients.

At the 2014 meeting of the European Society of Cardiology (ESC), investigators presented the results of PARADIGM-HF, which stands for Prospective Comparison of ARNi with ACE-I (angiotensin-converting enzyme inhibitor) to Determine Impact on Global Mortality and Morbidity in Heart Failure. A total of 8,442 patients with class II, III, or IV HF and an ejection fraction <40% were randomized to receive either the combo agent of LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy.1

CSWN June 2015 Information Graphic

The primary outcome was a composite of death from cardiovascular (CV) causes or HF hospitalization, but the trial was designed to detect a difference in the rates of death from cardiovascular causes.

After a median follow-up of 27 months—and after enrollment had been completed—the trial was stopped early due to an overwhelming benefit favoring LCZ696. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1,117 patients (26.5%) in the enalapril group (hazard ratio [HR] in the LCZ696 group: 0.80; 95% confidence interval [CI]: 0.73-0.87; p<0.001). This means the trial was stopped after reaching the clinical events deemed necessary for statistical significance: the study design estimated a need for 1,229 deaths from CV causes, to provide an 80% power to detect a relative reduction of 15% in the risk of death from CV causes. In point of fact, there had been a total of 1,251 such deaths when the pre-specified boundary for halting the trial had been crossed. (Specifically, 558 [13.3%] LCZ696 and 693 [16.5%] enalapril patients died from CV causes [HR: 0.80; 95% CI: 0.71-0.89; p<0.001).

Results also showed that a total of 711 patients (17.0%) receiving LCZ696 versus 835 patients (19.8%) receiving enalapril died (HR for death from any cause: 0.84; 95% CI: 0.76-0.93; p<0.001). LCZ696 also reduced the risk of HF hospitalization by 21% (p<0.001) versus enalapril and decreased the symptoms and physical limitations of HF (p=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.

(Editor’s note: A trial evaluating this agent for patients with HF and preserved ejection fraction is underway called PARAGON HF.)

Too Good To Be True?

Skepticism is healthy and was certainly evident after the trial’s presentation at ESC.14. Indeed, a recent paper with additional data was accompanied by an editorial simply titled, “LCZ696: Too Good to Be True?”2 The author was Robert M. Califf, MD, Professor of Cardiology at Duke University, now on leave after being named the Food and Drug Administration (FDA) Deputy Commissioner for Medical Products and Tobacco.

Missing from the PARADIGM-HF main results was the clinical impact of the novel intervention over the period of follow-up post-randomization. Some of those details have been subsequently published.3-6 In brief, compared with enalapril, patients on LCZ696 were less likely to:

  • show symptomatic deterioration
  • need intensification of oral therapy/addition of intravenous (IV) therapy
  • visit the emergency department
  • be admitted to the hospital
  • go to the intensive care unit (ICU) when admitted and less likely to need IV therapy require devices/surgery for worsening/end-stage HF (although not statistically significant)
  • die prematurely (either suddenly or from worsening HF)
  • show biomarker evidence of cardiac wall-stress and myocyte injury.

In short, LCZ696 slows progression of HF, delaying/preventing nonfatal and fatal worsening. Also, benefits were consistent regardless of the baseline NYHA functional class. There are still questions as to whether the effects seen in PARADIGM-HF will also be seen to the same extent outside of the clinical trial setting. There was a single-blind run-in period during which all patients received enalapril, followed by a single-blind run-in period during which all patients received LCZ696. This was done to ensure an acceptable side-effect profile of the study drugs at target doses.

A total of 9,419 patients entered the roll-in period with 977 (10.4%) discontinuing study participation. While there were multiple reasons for patients not making it to randomization, not being able to tolerate the therapy was a factor. So it is not possible to know whether an individual patient will tolerate LCZ696 at the time of treatment initiation—and the key toxicities (hyperkalaemia and hypotension) tend to occur early and thus were screened out in the PARADIGM-HF run-in phase.

In another editorial comment accompanying some of these new data, Henry Krum, MBBS, PhD, Head of the Clinical Pharmacology Unit and Director of the Monash University (Australia) Centre of Cardiovascular Research and Education in Therapeutics, noted that in the real-world adverse events may very well occur with even greater frequency with LCZ696 and will require careful review during post-marketing surveillance should the drug be approved.7 There are still mechanistic issues that need to be worked out and PARADIGM-HF was not a mechanistic study, so it can’t explain why the new combination works so well. PARADIGM-HF, he said, should rather be viewed as a pragmatic study asking the question of whether the newer agent is clinically superior to current best practice management of systolic chronic HF patients. With the new data, Dr. Krum wrote, “LCZ696 clearly meets any and all reasonable criteria for clinical superiority versus conventional therapy.”

Alzheimer’s Question

Finally, another issue was raised recently: could long-term use of this new drug increase the risk of Alzheimer’s disease?8 The issue revolves around the ability of LCZ696 to inhibit an enzyme that fights sticky plaques in the brain. The paper, published in the European Heart Journal, cautioned that previous studies suggest that an ARNI might accelerate progression of Alzheimer’s.

According to The Wall Street Journal (February 26, 2015), the question was enough for Novartis to amend one of its continuing trials of the drug to add measures of cognitive function to the trial. Trial investigators have also said that the drug might even help improve cognitive function through increased blood flow.

How this plays out will be interesting. The Wall Street Journal noted that analysts see LCZ696 as a potential blockbuster that could generate as much as $5 billion in sales by 2020. The U.S. FDA granted priority review to the drug in February 2015, meaning the drug could be approved as early as August. Canada also has decided to expedite the drug’s review. One thing is sure: we’ll be hearing a lot more about LCZ696—or whatever they ultimately decide to call it.


  1. McMurray JJ, Packer M, Desai AS, et al. N Engl J Med. 2014;371:993-1004.
  2. Califf RM. Eur Heart J. 2015;36:410-2.
  3. McMurray J, Packer M, Desai A, et al. Eur Heart J. 2015;36:434-9.
  4. Packer M, McMurray JJ, Desai AS, et al. Circulation. 2015;131:54-61.
  5. McMurray JJ, Packer M, Desai AS, et al. Eur J Heart Fail. 2014;16:817-25.
  6. McMurray JJ, Packer M, Desai AS, et al. Eur J Heart Fail. 2013;15:1062-73.
  7. Krum H. Circulation. 2015;131:11-2.
  8. Vodovar N, Paquet C, Mebazaa A, et al. Eur Heart J. 2015;36:902-5.

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