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Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM- HF Investigators and Committees. N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077 01.12.2014 Johannes Schmid Alexander Triebl

Angiotensin-Neprilysin Inhibition versus Enalapril in

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Page 1: Angiotensin-Neprilysin Inhibition versus Enalapril in

Angiotensin-Neprilysin Inhibition versus Enalapril in Heart Failure

McMurray JJ, Packer M, Desai AS, Gong J, Lefkowitz MP, Rizkala AR, Rouleau JL, Shi VC, Solomon SD, Swedberg K, Zile MR; PARADIGM-

HF Investigators and Committees.

N Engl J Med. 2014 Sep 11;371(11):993-1004. doi: 10.1056/NEJMoa1409077

01.12.2014Johannes SchmidAlexander Triebl

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Research Question

Is treatment with the angiotensin receptor neprilysininhibitor LCZ696superior to enalaprilin the prevention of death from cardiovascular causes orhospitalisation due to heart failurein patients with heart failure with reduced ejectionfraction?

P

O

C

I

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Study design

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Study design

• “Randomized, double-blind, parallel group, active-controlled, two-arm, event-driven trial”

• Multi-center• Single blind run-in period• Double blind treatment after randomization• Sponsored by Novartis

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Study design

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; 15:1062‐73.

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P-I-C-O

• Inclusion criteria– Ejection fraction ≤ 40 % (changed to ≤ 35 %, 15.12.2010)– NYHA class II, III or IV symptoms– BNP ≥ 150 pg/mL or NT-proBNP ≥ 600 pg/mL– ...

• Exclusion criteria– RRsys < 100 mm Hg (at screening) or < 95 (at randomization)– eGFR < 30 mL/min/1.73 m2 (at screening or at randomization)– Decrease in eGFR > 25 % between screening and randomization– Serum [K+] > 5.2 mM at screening or > 5.4 mM at randomization– Unacceptable side effects– …

Study design

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P-I-C-O

• LCZ696:– Sacubitril (inhibitor of ANP/BNP-degrading

enzyme Neprilysin)– Valsartan (angiotensin II receptor type I blocker)– 1:1 (mol) mixture

• Target dose: 200 mg 2x/d

• Dose adjustment possible at each visit(3 dose levels: 50, 100, 200 mg)

Study design

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P-I-C-O

• Enalapril:– ACE inhibitor– Reduces risk of death in heart failure

• Target dose: 10 mg 2x/d

• Dose adjustment possible at each visit(3 dose levels: 2.5, 5, 10 mg)

Study design

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P-I-C-O

• Primary outcome:– Death from cardiovascular causesor– First hospitalization for heart failure

• Secondary outcomes– Time to death from any cause– Change from baseline to 8 months in the clinical summary score on the

KCCQ (Kansas City Cardiomyopathy Questionnaire)– Time to a new onset of atrial fibrillation– Time to the first occurence of a decline in renal function (end-stage

renal disease or decrease in eGFR of > 50 % or > 30 mL/min/1.73 m2

from baseline)

Study design

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• Randomisation– Interactive voice response system (IVRS),

using a “validated system that automates the random assignment of patient numbers to randomization numbers” (linked to treatment arms)

– Strictly confidential until unblinding

• Blinding– Unique medication number provided at each visit by the system

(to enable dose adjustment)– Study drugs “are all identical in packaging, labeling, schedule of

administration, appearance, and odor”– For each dose level either LCZ696 + Placebo (Enalapril appearance)

or Enalapril + Placebo (LCZ696 appearance)

Study design

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Statistical analysis plan• Sample size, duration:

– Sample size calculated based on mortality from cardiovascular causes(CHARM-trial): 7 %

– Power of 80 % to detect a relative risk reduction of 15 % (two-sided α levelof 5 %)

– Power 97 % for the primary endpoint (CV mortality + HF hospitalisation)– Follow 8000 patients until 2410 patients have reached the primary endpoint

(for ~ 34 months)– Three interim efficacy analyses with stopping criteria

• Intention to treat

• Primary/secondary endpoints: Cox proportional hazards models,one-sided α level of 2,5 %

• Additional exploratory analyses

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• Trial was stopped on 31.03.2014 after the third interimanalysis (median follow up: 27 months)

• Prespecified criteria:

“...statistical stopping guideline for a compelling benefit required a one-sided nominal P value of [...] less than 0.001 at the second and third analyses in favor of LCZ696 for both death from cardiovascular causes and the primary end point.”

Results

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From 08.12.2009 to 23.11.2012, 10521 patients at 1043 centers in 47 countries entered the run in period(8 Pat. skipped enalapril phase)

(censored at last visit)

Intention to treat analysis

Results

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• Baseline characteristics

Results

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Results

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Results

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Results

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Results

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Effect size

• CER = 1117/4212 = 0.265 = 26.5 %

• EER = 914/4187 = 0.218 = 21.8 %

• ARR = CER – EER = 0.265 – 0.218 = 0.047 = 4.7 %

• RRR = ARR/CER = 0.047/0.265 = 0.177 = 17.7 %

• NNT = 1/ARR = 1/0.047 = 21.3 = 22

Primary endpoint

totaloccurred not occurred

Enalapril 1117 3095 4212LCZ696 914 3273 4187

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Critical reading• Multiple authors state serious conflicts of interest (employee of

Novartis, personal fees)• Adverse event rate: Patients who had adverse events at run in

phase did not enter randomisation(12%)

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Critical reading• Multiple authors state serious conflicts of interest (employee of

Novartis, personal fees)• Adverse event rate: Patients who had adverse events at run in

phase did not enter randomisation

• Incoherent patient numbers between paper and supplement table

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Critical reading

• No reporting of per protocol analyses (planned in the protocol)

• Atrial fibrillation not listed as secondary outcome in the protocol

• Study centers not listed in paper, appendix or protocol

• Only detailed reading of study protocol states the use ofplacebos along with the verum

• Statistician did not recieve authorship

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Thank you for your attention