Physicians' Academy for Cardiovascular Education

ARNI stabilises the course of heart failure, substantial effects in addition to recommended therapy

Eur Heart J en Circulation 2014

Recently, two papers have been published that are further looking into the PARADIGM-HF data. PARADIGM-HF was a randomised double-blind trial that compared the angiotensin-neprilysin inhibitor LCZ696 (400 mg daily) with the angiotensin- converting enzyme (ACE) inhibitor enalapril (20 mg daily) in over 8000 patients with heart failure (HF) with mild-to-moderate symptoms. LCZ696 was found to be superior to enalapril with regard to all-cause and cardiovascular (CV) mortality [1].
Apart from prolonging survival, preventing nonfatal worsening of the disease is a major goal in the management of chronic HF. M Packer et al. (Circulation [2]) looked into the effect of LCZ696 as compared to enalapril, on the nonfatal progression of HF in surviving patients. 835 patients died in the enalapril group (annualised rate: 7.5%) and 711 in the LCZ696 group (6.0%).
McMurray et al describe in European Heart Journal [3] their statistical efforts to be able to make an indirect comparison of LCZ696 performance vs. a putative placebo. Their statistical approach benefits from the available data of placebo-controlled trials of the active-comparator of PARADIGM-HF, namely enalapril (SOLVD-T), as well as an angiotensin-receptor blocker (CHARM-Alternative), both in HF with reduced ejection fraction (HF-REF).
We here briefly discuss the main findings of both analyses, and some of the discussion points raised in the accompanying editorial comments [4,5].

M Packer et al. Circulation 2014

  • Fewer LCZ696-treated patients showed worsening of HF requiring addition of a new drug, intravenous therapy, or an increase of the daily dose of diuretic > 1 month than enalapril-treated patients (520 vs 604 patients, HR: 0.84, 95%CI: 0.74-0.94, P=0.003).
  • Fewer LCZ696-treated patients were evaluated and treated for worsening HF in the emergency department but discharged without hospital admission (102 vs. 150 on enalapril, HR: 0.66, 95%CI: 0.52-0.85, P=0.001).
  • Already at 30 days following randomisation, a significantly lower risk of hospitalisation for HF was seen in patients treated with LCZ696, as compared to enalapril (HR: 0.60, 95%CI: 0.38-0.94, P=0.037).
  • At 8 and 12 months, more surviving patients in the enalapril group were considered by their physician to be worse (at least 1 NYHA class), than in the LCZ696 group, despite greater intensification of treatment and mortality of severely ill patients in the enalapril group.


Conclusion Packer et al.

Combined inhibition of the angiotensin-receptor and neprilysin with LCZ696 lowered the risk of worsening HF more than did guideline-recommended ACE inhibition with enalapril. Fewer patients treated with LCZ696 needed intensification of outpatient therapy or the use of additional treatment due to worsening of HF. Fewer emergency department visits and hospitalisation for HF were needed in patients treated with LCZ696, as compared to enalapril.

Editorial comment [4]

Krum notes that in the PARADIGM-HF main results paper, the clinical impact of the novel intervention was missing, which has now been addressed by focussing entirely on the clinical course and resource use of surviving patients. “These data are all the more impressive given that more patients died in the enalapril group than the LCZ-696 group over the course of the PARADIGM-HF study.“ (…)
“The clinical efficacy benefits of LCZ696 do, however, have to be weighed against the side-effect profile of the new drug. (…) Symptomatic postural hypotension was greater in the LCZ696 group compared with enalapril and may limit clinical utility. (…) It has to be remembered that this increase in hypotension occurred despite a very carefully controlled run-in period whereby patients were exposed to both ACE inhibitor and LCZ-696, sequentially. Patients not tolerating this run-in for hypotension (or other reasons) were removed from the trial before randomization. Therefore, in the real world it may be expected that this adverse event will occur with even greater frequency and certainly needs to be carefully followed in post- marketing surveillance if/when the drug is approved”.

Krum also points out that the increased occurrence of angioedema with LCZ696 as compared to enalapril, needs careful consideration in weighing risks and benefits. A thus far theoretical concern is that amyloid β is a substrate for neprilysin, and inhibition of neprilysin may block breakdown of this key peptide implicated in Alzheimer disease pathogenesis, although this may be more relevant to disease states with greater longevity than HF.
PARADIGM-HF was “a pragmatic study asking the question of whether the newer agent is clinically superior to current best practice management of systolic chronic HF patients. By any measure, in both the main article and the new data published in this issue of Circulation, the ARNI LCZ696 clearly meets any and all reasonable criteria for clinical superiority versus conventional therapy. “

McMurray et al. Eur Heart J 2014

  • Putative placebo analyses (based on SOLVD-T data) for LCZ696 show that the relative risk reduction of CV death or HF hospitalisation with LCZ696 was 43% (95%CI: 34-50%, P<0.0001).
  • CV death was similarly reduced (34%, 95%CI: 21-44%, P<0.0001) with LCZ696 as compared to a putative placebo, as was hospitalisation for HF (49%, 39-58%, P<0.0001).
  • Qualitatively and quantitatively similar effects were seen with LCZ696 a putative placebo analysis based on the CHARM-Alternative data.
  • In comparison with a putative placebo (CHARM-Alternative), LCZ696 would have avoided or postponed 71 CV deaths or HF hospitalisation events, 31 CV deaths, 59 first HF hospitalisations and 18 all-cause deaths per 1000 patient-years of treatment.


Conclusion McMurray et al.

Because it is unethical to withhold treatment to patients with HF-REF, an indirect statistical approach was employed to compare the effect of LCZ696 with a putative placebo. This showed that LCZ696 gave substantial benefit on a number of important CV outcomes, and all-cause mortality. It is interesting to note that the magnitude of the effect of LCZ696 is similar to the effects previously obtained with other proven pharmacological therapies, when they were compared to placebo. LCZ696 yielded these effects in addition to background beta-blocker and MRA therapy.

Editorial comment [5]

Califf discusses some questions relevant to the findings of McMurray. “First, how believable is the putative placebo analysis”, given that any putative placebo analysis must use historical controls? “The authors have diligently provided evidence that, other than a difference in beta-blocker use (which could perhaps be expected to disadvantage LCZ696 in this comparison), the populations appear more similar than one might expect.”
“Given changes in the population, the natural history of the disease, and the underlying therapeutic milieu, is the effect size of enalapril vs. placebo the same in 2014 as it was in 1994?” (…) “The data support the constancy assumption, but do not (and cannot!) definitively prove it.”
With regard to the design of the trial, Califf pints out that “the run-in phase diminishes the generalizability of the results, especially when extrapolating to clinicians and patients who are considering whether to initiate LCZ696 in practice. At present, it is not possible to know whether the patient will tolerate this drug at the time treatment is initiated, and the key toxicities (hyperkalaemia and hypotension) tend to occur early and thus would be screened out in the run-in phase.”
Early termination of a trial may sometimes lead to overestimation of the effect size, but the investigators have countered that “PARADIGM-HF actually reached its projected number of events and that after the conclusion of the trial's active phase, the legacy effect showed continued separation of the event curves rather than the convergence that might be expected.”
Califf concludes: “Although I believe the effect in practice will be smaller than estimated in this trial with its run-in phase, deficits in use of ICDs and biventricular pacing, and early stopping by a diligent DMC, I also believe that the result is sufficiently large to merit early and widespread adoption in practice.


1. McMurray JJ, Packer M, Desai AS, et al. Dual angiotensin receptor and neprilysin inhibition as an alternative to angiotensin-converting enzyme inhibition in patients with chronic systolic heart failure: rationale for and design of the Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure trial (PARADIGM-HF). Eur J Heart Fail. 2013;15:1062–1073.
2. Packer M, McMurray JJV, Desai AS et al., Angiotensin Receptor Neprilysin Inhibition Compared With Enalapril on the Risk of Clinical Progression in Surviving Patients With Heart Failure. Circulation. 2015;131:54–61. DOI: 10.1161/CIRCULATIONAHA.114.013748.
3. McMurray J, Packer M, Desai A et al., A putative placebo analysis of the effects of LCZ696 on clinical outcomes in heart failure. European Heart Journal doi:10.1093/eurheartj/ehu455  
4. Krum H. Prospective Comparison of ARNi With ACE-I to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) Paragon of a Study or Further Investigation Paramount? Circulation. 2015;131:11-12. DOI: 10.1161/CIRCULATIONAHA. 114.013887.
5. Califf RM. LCZ696: too good to be true? DOI:
Find these articles online:
Packer et al., Circulation 2014
Editorial by Krum in Circulation
McMurray et al. Eur Heart J 2014
Editorial by Califf in Eur Heart J