Download McMurray JV, Packer M, Desai AS, et al. Angiotensin

McMurray JV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Eng J Med.
2014; 371:993-1004.
This randomized, double-blind, parallel-group, active-control trial randomized 8,442 adult patients with heart failure (NYHA Class IIIV) from 47 different countries to therapy with either a combination angiotensin-receptor blocker and neprilysin inhibitor (LCZ696) or
enalapril 10 mg BID. Primary outcome included time to first occurrence of composite endpoint of cardiovascular death or HF
hospitalization. Researchers determined that inhibition of both angiotensin II receptors and neprilysin was more effective in reducing
morbidity and mortality relative to the control therapy (21.8% vs 26.5%; HR 0.80, P = <0.001), with a greater incidence of
hypotension (588 vs 388; P <0.001) but no significant increase in serious angioedema. Researchers therefore concluded that
combination therapy with LCZ696 proved superior to ACE inhibition alone in reducing the risk of death and re-hospitalization due to
HF.
Cardiology ACCP PRN Journal Club: PARADIGM-HF Newsletter
1) What impact do you feel the run-in phase/wash-out period might have played in the results of this
trial? What impact will this have on the role of this therapy? Do you feel this was ethical?
This consideration has been heavily discussed as it relates to not only the PARADIGM-HF trial but also to
clinical study design as a whole. Arguments in favor of such a design cite the clinical applicability of a run-in
period, that is, patients intolerant to certain therapies will be transitioned to another viable option in actual
practice settings. This design also has clinical precedent within the variety of trials, such as SOLVD Treatment
Trial showing mortality benefit with enalapril.1Similarly, the FDA has supported the use of the double-blind
run-period design utilized in PARADIGM-HF as a means of enhancing credibility.
Dissenters to this approach have questioned the variability in length of therapy administration for the runin period (i.e. the run-in period for LCZ696 was twice as long as that of the control therapy). Similarly, one
can argue that removing patients intolerant to therapy circumvents intention-to-treat study design by
preventing a normal progression toward the mean of those who would have otherwise had a negative benefit. It
may be said that the randomization of patients to either enalapril or LCZ696 at the outset of the trial with
appropriate cross-over (following adequate wash-out period) at the investigators’ discretion is vastly different
than was done in this trial. To the best of my knowledge, it is unknown whether patients intolerant to ACE-I
therapy would have an attenuated response to neprilysin inhibition (NI) given inter-patient variability in
neurohormonal function.
As it relates to the impact this trial would have on the role of LCZ696 in clinical practice, I would opine
that we are relegated to utilizing this drug in patient’s having already been known to tolerate ACE-I therapy
and mimic the dose titration protocol undertaken in this trial.
There is no absolute as it relates to the utilization of drug run-in periods within clinical trial design and is
certainly an area of on-going controversy. I would not suspect any ethical dilemmas with such a design as long
patients were appropriately consented for trial participation. For additional information, I would direct readers
to a paper by Pablos-Méndez and colleagues which addresses this issue in clinical trial design.2
2) Would this medication be use to modify BNP or other markers?
Upon further review, NI results in higher levels of urinary cGMP and plasma BNP (by roughly 50 pg/mL)
with lower levels of NT-proBNP, which likely reflects a reduction in cardiac wall stress secondary to the use
of this therapy. BNP, acting as a substrate for neprilysin, will therefore give the clinician further information
on the drug’s mechanism of action, while NT-proBNP may be said to be a marker of response to therapy.3
1
The SOLVD Investigators. N Eng J Med. 1992; 327: 685-691.
Pablos-Méndez A, et al. JAMA. 1998; 279: 222-225.
3
Packer M, et al. Circulation. 2015; 131:--2
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3) Were patients allowed to be on ARA's during the trial and what impact would this have had in terms
of safety and efficacy?
Baseline characteristics of participating patients saw 54.2% in the LCZ696 arm and 57% in the control
arm receiving therapy with a mineralocorticoid antagonist. Of note, background heart failure medications
remained unchanged for the duration of this study.
Any possible effects on efficacy and safety with concomitant aldosterone antagonist/neprilysin inhibition
would be speculative and drawn in the absence of reproducible clinical data. What is known from existing
research is that the administration of spironolactone and other mineralocorticoid receptor antagonists results in
an attenuation of nuclear factor kappaB (NF-ĸB), a transcription factor expressed in most nucleated cells
which is responsible for facilitating the transcription of many genes implicated in cell cycling,
immune/inflammatory responses, and pro/anti apoptotic processes.4 Further studies have shown that
aldosterone exposure stimulates cardiac myocyte apoptosis in vivo in cultured cells.5
Vasopeptidase inhibitors such as LCZ696 effect concentrations of vasodilator peptides such as bradykinin
and/or adrenomedullin, the latter of which has been shown to reduce hypoxia-induced apoptosis in cultured
cardiomyocytes.6 To suggest an augmentation of such effects with concomitant administration in patients with
ischemic cardiomyopathy is highly speculative but thought-provoking nonetheless. I would be interested to see
if future studies isolate the role of aldosterone antagonist therapy with neprilysin inhibition in patients with
HFrEF.
4) Do you feel that the dosing of each was a fair comparison? Do you feel like the new medication
should have been compared to valsartan (valsartan/placebo and valsartan/active drug)?
To a certain degree, the suggestion that the benefit observed with LCZ696 is attributable simply to a
superiority of an ARB over an ACE-I does not correlate with the totality of evidence on the subject in patients
with HFrEF. As evidence, the HEAVEN trial randomized 141 patients who were previously stabilized on
ACE-I therapy and possessed mild/moderate heart failure and an EF < 45% to valsartan 160 mg daily and
enalapril 10 mg BID (both doses utilized in PARADIGM-HF). The study found no difference in patient’s 6minute walk test, left ventricular size/function, and overall patient quality of life.7
I would agree that the ideal scenario from a design perspective would be a direct comparator study of an
ARB versus an ARB plus NI, so as to select for any possible incremental contribution of the added therapy.
The reason(s) as why this was not done is/are not entirely clear. One could make a reasonable argument that
the investigators wished to directly compare neprilysin inhibition to the cornerstone of existing heart failure
therapy in the form of an ACE inhibitor. To this end, researchers could thus argue the overwhelmingly positive
results are strengthened given LCZ696’s comparison to the primary treatment option. To a lesser degree,
competing interests on the part of Novartis, who also manufactures valsartan under the trade name Diovan®,
may have prevented this Swiss-based pharmaceutical company from directly comparing two of its own
products head-to-head. This conclusion does not seem as likely given valsartan’s current generic availability
(and thus Novartis’ loss of market exclusivity for the branded Diovan® product).
4
Sonder S, et al. Apoptosis. 2006; 11:2159-2165.
de Angelis N, et al. J Mol Cell Cardiol.2002; 34: 1655-1665.
6
Yin H, et al. Hypertension. 2004; 43: 109-116.
7
Willinheimer R, et al. Int J Cardiol. 2002; 85: 261-270.
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