Angiotensin Receptor Neprilysin Inhibition versus Individualized RAAS Blockade: Design and Rationale of the PARALLAX Trial

Figures

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  Figure 1. Study design of PARALLAX trial. Patients will be stratified according to therapy prior to study inclusion. Patients with ACEi therapy will be randomized to enalapril or sacubitril/valsartan; patients with ARB therapy will be randomized to valsartan or sacubitril/valsartan, and patients with neither therapy will be randomized to placebo or sacubitril/valsartan. *Patients in the ACEi and ARB strata must have a history of hypertension. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor blocker; b.i.d., twice daily; RAAS, renin–angiotensin–aldosterone system; sac/val, sacubitril/valsartan.

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  Figure 2. Uptitration in the PARALLAX trial. Baseline doses of study medication will depend on the dosage of medication prior to randomization. Patient with low‐dose RAAS therapy will be randomized to enalapril 2.5 mg b.i.d., valsartan 40 mg b.i.d., or sacubitril/valsartan 24/26 mg b. i. d. (Dose level 1). They will be uptitrated to Dose level 2, which is doubling of Dose level 1, after 2 weeks. Patients with high dose RAAS therapy will directly start with Dose level 2. After 2 weeks on dose level 2, patients will be uptitrated to Dose level 3, which is a doubling of Dose level 2. ACEi, angiotensin‐converting enzyme inhibitor; ARB, angiotensin II receptor blocker; b.i.d., twice daily; RAASi, renin–angiotensin–aldosterone system inhibitor.

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  Figure 3. Graphical illustration of the sequentially rejective testing procedure. H1: Sacubitril/valsartan is no better than the comparator in change from baseline in log‐transformed NT‐proBNP at Week 12 (Primary). H2: Sacubitril/Valsartan is no better than the comparator in change from baseline in 6 min walking distance (6MWD) at Week 24. (Primary). H3: Sacubitril/valsartan is no better than the comparator in change from baseline in Kansas City Cardiomyopathy Questionnaire (KCCQ) Clinical Summary Score (CSS) (mean score) at Week 24. H4: Sacubitril/valsartan is no better than the comparator in NYHA class change from baseline at Week 24. In order to control the family‐wise type‐I error rate at the one‐sided 0.025 significance level, a sequentially rejective multiple testing procedure will be employed, whereby H1 and H2 will be tested first at initially assigned level of one‐sided (9/10) × α = 0.0225 and one‐sided (1/10) × α = 0.0025, accordingly. If H1 and/or H2 are rejected, the alpha for the rejected null hypotheses will be propagated to H3, such that, H3 will be tested at the updated alpha level (one‐sided 0.025 if both H1 and H2 are rejected; one‐sided 0.0225 if H1 is rejected but H2 is…