Impact of Sacubitril/Valsartan Compared With Ramipril on Cardiac Structure and Function After Acute Myocardial Infarction: The PARADISE-MI Echocardiographic Substudy.

BACKGROUND: Angiotensin-converting enzyme inhibitors attenuate left ventricular (LV) enlargement after acute myocardial infarction (AMI). Preclinical data suggest similar benefits with combined angiotensin receptor neprilysin inhibition, but human data are conflicting. The PARADISE-MI Echo Study (Prospective ARNI Versus ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After Myocardial Infarction) tested the effect of sacubitril/valsartan compared with ramipril on LV function and adverse remodeling after high risk-AMI. METHODS: In a prespecified substudy, 544 PARADISE-MI participants were enrolled in the Echo Study to undergo protocol echocardiography at randomization and after 8 months. Patients were randomized within 0.5 to 7 days of presentation with their index AMI to receive a target dose of sacubitril/valsartan 200 mg or ramipril 5 mg twice daily. Echocardiographic measures were performed at a core laboratory by investigators blinded to treatment assignment. The effect of treatment on change in echo measures was assessed with ANCOVA with adjustment for baseline value and enrollment region. The primary end points were change in LV ejection fraction (LVEF) and left atrial volume (LAV), and prespecified secondary end points included changes in LV end-diastolic and end-systolic volumes. RESULTS: Mean age was 64±12 years; 26% were women; mean LVEF was 42±12%; and LAV was 49±17 mL. Of 544 enrolled patients, 457 (84%) had a follow-up echo at 8 months (228 taking sacubitril/valsartan, 229 taking ramipril). There was no significant difference in change in LVEF (P=0.79) or LAV (P =0.62) by treatment group. Patients randomized to sacubitril/valsartan demonstrated less increase in LV end-diastolic volume (P=0.025) and greater decline in LV mass index (P=0.037), increase in tissue Doppler e'lat (P=0.005), decrease in E/e'lat (P=0.045), and decrease in tricuspid regurgitation peak velocity (P=0.024) than patients randomized to ramipril. These differences remained significant after adjustment for differences in baseline characteristics. Baseline LVEF, LV end-diastolic volume, LV end-systolic volume, LV mass index, LAV, and Doppler-based diastolic indices were associated with risk of cardiovascular death or incident heart failure. CONCLUSIONS: Treatment with sacubitril/valsartan compared with ramipril after AMI did not result in changes in LVEF or LAV at 8 months. Patients randomized to sacubitril/valsartan had less LV enlargement and greater improvement in filling pressure. Measures of LV size, systolic function, and diastolic properties were predictive of cardiovascular death and incident heart failure after AMI in this contemporary, well-treated cohort. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02924727.

Effect of Sacubitril/Valsartan vs Standard Medical Therapies on Plasma NT-proBNP Concentration and Submaximal Exercise Capacity in Patients With Heart Failure and Preserved Ejection Fraction: The PARALLAX Randomized Clinical Trial.

Importance: There is limited evidence on the benefits of sacubitril/valsartan vs broader renin angiotensin system inhibitor background therapy on surrogate outcome markers, 6-minute walk distance, and quality of life in patients with heart failure and mildly reduced or preserved left ventricular ejection fraction (LVEF >40%). Objective: To evaluate the effect of sacubitril/valsartan on N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, 6-minute walk distance, and quality of life vs background medication-based individualized comparators in patients with chronic heart failure and LVEF of more than 40%. Design, Setting, and Participants: A 24-week, randomized, double-blind, parallel group clinical trial (August 2017-October 2019). Of 4632 patients screened at 396 centers in 32 countries, 2572 patients with heart failure, LVEF of more than 40%, elevated NT-proBNP levels, structural heart disease, and reduced quality of life were enrolled (last follow-up, October 28, 2019). Interventions: Patients were randomized 1:1 either to sacubitril/valsartan (n = 1286) or to background medication-based individualized comparator (n = 1286), ie, enalapril, valsartan, or placebo stratified by prior use of a renin angiotensin system inhibitor. Main Outcomes and Measures: Primary end points were change from baseline in plasma NT-proBNP level at week 12 and in the 6-minute walk distance at week 24. Secondary end points were change from baseline in quality of life measures and New York Heart Association (NYHA) class at 24 weeks. Results: Among 2572 randomized patients (mean age, 72.6 years [SD, 8.5 years]; 1301 women [50.7%]), 2240 (87.1%) completed the trial. At baseline, the median NT-proBNP levels were 786 pg/mL in the sacubitril/valsartan group and 760 pg/mL in the comparator group. After 12 weeks, patients in the sacubitril/valsartan group (adjusted geometric mean ratio to baseline, 0.82 pg/mL) had a significantly greater reduction in NT-proBNP levels than did those in the comparator group (adjusted geometric mean ratio to baseline, 0.98 pg/mL) with an adjusted geometric mean ratio of 0.84 (95% CI, 0.80 to 0.88; P < .001). At week 24, there was no significant between-group difference in median change from baseline in the 6-minute walk distance with an increase of 9.7 m vs 12.2 m (adjusted mean difference, -2.5 m; 95% CI, -8.5 to 3.5; P = .42). There was no significant between-group difference in the mean change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (12.3 vs 11.8; mean difference, 0.52; 95% CI, -0.93 to 1.97) or improvement in NYHA class (23.6% vs 24.0% of patients; adjusted odds ratio, 0.98; 95% CI, 0.81 to 1.18). The most frequent adverse events in the sacubitril/valsartan group vs the comparator group were hypotension (14.1% vs 5.5%), albuminuria (12.3% vs 7.6%), and hyperkalemia (11.6% vs 10.9%). Conclusions and Relevance: Among patients with heart failure and left ventricular ejection factor of higher than 40%, sacubitril/valsartan treatment compared with standard renin angiotensin system inhibitor treatment or placebo resulted in a significantly greater decrease in plasma N-terminal pro-brain natriuretic peptide levels at 12 weeks but did not significantly improve 6-minute walk distance at 24 weeks. Further research is warranted to evaluate potential clinical benefits of sacubitril/valsartan in these patients. Trial Registration: ClinicalTrials.gov Identifier: NCT03066804.

Baseline characteristics of patients in the PARALLAX trial: insights into quality of life and exercise capacity in heart failure with preserved ejection fraction.

AIMS: We sought to describe the baseline characteristics of PARALLAX [a randomized controlled trial of sacubitril/valsartan vs. individualized medical therapy in heart failure (HF) with mildly reduced and preserved ejection fraction (HFpEF)]; compare PARALLAX to recent HFpEF trials; and examine the clinical characteristics associated with quality of life (QOL) and 6-min walk test distance (6MWD). METHODS AND RESULTS: A total of 2566 patients with HF and left ventricular ejection fraction (LVEF) >40% were randomized, of whom 96% had an LVEF ≥45%. Multivariable linear regression was used to determine characteristics associated with Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS) and 6MWD. Mean age was 73 ± 8 years, 51% were female, and comorbidities were common. Of the QOL measures tested in PARALLAX, the Short Form Health Survey-36 physical functioning score was most closely correlated with 6MWD (R = 0.41, P < 0.001), and outperformed the KCCQ physical limitation score (R = 0.33) and KCCQ-CSS (R = 0.31) on multivariable analyses. Female sex, higher body mass index, history of coronary artery disease, lower LVEF, and higher N-terminal pro-B-type natriuretic peptide (NT-proBNP) were associated with worse (lower) KCCQ-CSS; older age, female sex, higher body mass index, diabetes, coronary artery disease, chronic obstructive pulmonary disease, prior HF hospitalization, lower LVEF, and higher NT-proBNP were associated with shorter 6MWD (P < 0.05 for all associations). CONCLUSIONS: PARALLAX is the largest HFpEF study to date to examine 6MWD together with QOL. The KCCQ-CSS and 6MWD were modestly correlated, and several factors were associated with worse values of both. These results provide insight into the association between QOL and exercise capacity in HFpEF.

Angiotensin receptor neprilysin inhibition versus individualized RAAS blockade: design and rationale of the PARALLAX trial.

AIMS: Although the effect of the angiotensin receptor blocker neprilysin inhibitor (ARNI) sacubitril/valsartan on heart failure (HF) hospitalizations and cardiovascular death has been evaluated, its effects on functional capacity in patients with HF and ejection fraction (EF) >40% has yet to be determined. In addition, no prior studies have compared sacubitril/valsartan with angiotensin-converting enzyme inhibitor therapy. We sought to compare the effect of ARNI to background-medication-based individualized comparators (BMICs) on N-terminal pro-B-type natriuretic peptide (NT-proBNP), functional capacity [6 min walk distance (6MWD)], symptoms, and quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ)] in patients with HF and EF >40% in a randomized clinical trial. METHODS: PARALLAX is a prospective, randomized, controlled, double-blind multicentre clinical trial in patients with chronic symptomatic HF with EF >40%, New York Heart Association (NYHA) class II-IV symptoms, elevated natriuretic peptides, and evidence of structural heart disease. Eligible patients are randomized to sacubitril/valsartan vs. BMIC for cardiovascular and related co-morbidities. BMIC includes (i) enalapril, (ii) valsartan, and (iii) placebo depending on the type of medical therapy prior to enrolment. The primary endpoints are the change in plasma NT-proBNP concentration from baseline to 12 weeks and the change from baseline in 6MWD distance at 24 weeks. The secondary endpoints assess quality of life and symptom burden. CONCLUSIONS: PARALLAX will determine if sacubitril/valsartan compared with standard medical therapy for co-morbidities improves NT-proBNP levels, exercise capacity, quality of life, and symptom burden in HF patients with EF >40%.

Efficacy and safety of the direct renin inhibitor aliskiren and ramipril alone or in combination in patients with diabetes and hypertension.

OBJECTIVE: To assess the antihypertensive efficacy and safety of the combination of the direct renin inhibitor aliskiren and ramipril in patients with diabetes and hypertension. METHODS: In this double-blind, multicentre trial, 837 patients with diabetes mellitus and hypertension (mean sitting diastolic blood pressure [BP] > 95 and < 110 mmHg) were randomised to once-daily aliskiren (150 mg titrated to 300 mg after four weeks; n=282), ramipril (5 mg titrated to 10 mg; n=278) or the combination (n=277) for eight weeks. Efficacy variables were cuff mean sitting diastolic BP (msDBP) and mean sitting systolic BP (msSBP); 24-hour ambulatory BP, plasma renin activity (PRA) and plasma renin concentration (PRC) were also assessed. RESULTS: At week 8, aliskiren, ramipril and aliskiren/ramipril lowered msDBP (mean+/-SEM) by 11.3+/-0.5, 10.7+/-0.5 and 12.8+/-0.5 mmHg, and msSBP by 14.7+/-0.9, 12.0+/-0.9 and 16.6+/-0.9 mmHg, respectively. Aliskiren/ramipril provided superior msDBP reductions to ramipril (p=0.004) or aliskiren (p=0.043) monotherapy; adding aliskiren to ramipril provided an additional mean BP reduction of 4.6/2.1 mmHg. Aliskiren monotherapy was non-inferior to ramipril for msDBP reduction (p=0.0002) and superior for msSBP reduction (p=0.021). All treatments significantly lowered mean 24-hour ambulatory BP. Aliskiren significantly reduced PRA from baseline as monotherapy (by 66%, p<0.0001) or in combination with ramipril (by 48%, p<0.0001), despite large increases in PRC in all treatment groups. Aliskiren was well tolerated as monotherapy or in combination with ramipril. CONCLUSIONS: Combining aliskiren with ramipril provided a greater reduction in msDBP than either drug alone in patients with diabetes and hypertension.

Efficacy, safety, and tolerability of aliskiren monotherapy administered with a light meal in elderly hypertensive patients: a randomized, double-blind, placebo-controlled, dose-response evaluation study.

This randomized, double-blind, placebo-controlled study assessed the efficacy, safety, and tolerability of aliskiren 75, 150, and 300 mg to clarify the dose-response relationship and characterize the optimum aliskiren dose when given with a light meal to elderly hypertensive patients. After washout, 754 patients aged ≥65 years with hypertension (mean sitting systolic blood pressure [msSBP] ≥150 and <180 mm Hg; mean sitting diastolic blood pressure [msDBP] <110 mm Hg) were randomized to aliskiren 75, 150, or 300 mg or placebo for 8 weeks; medication was taken each morning with a light meal. The primary efficacy variable was change in msSBP from baseline to week 8 end point. Change from baseline in msDBP and dose-response curves for aliskiren 75, 150, and 300 mg were also assessed. At week 8 end point, all 3 aliskiren doses provided significantly greater least squares mean reductions in msSBP/msDBP (75 mg, 13/5 mm Hg; 150 mg, 15/6 mm Hg; 300 mg, 14/7 mm Hg) compared with placebo (8/4 mm Hg; P < .05). Aliskiren was generally well tolerated at all doses. There was a significant dose-response relationship for aliskiren, with an estimated minimum effective dose of 81.9 mg. In conclusion, aliskiren 150 and 300 mg provided effective blood pressure control in elderly patients when given with a light meal.

Low maternal retinol as a risk factor for schizophrenia in adult offspring.

BACKGROUND: Prenatal micronutrient deficiency has been linked to later development of schizophrenia among offspring; however, no study has specifically investigated the association between vitamin A and this disorder. Vitamin A is an essential nutrient which is required by the early embryo and fetus for gene expression and regulation, cell differentiation, proliferation and migration. Previous work suggests that vitamin A deficiency in the second trimester may be particularly relevant to the etiopathogenesis of neurobehavioral phenotypes some of which are observed in schizophrenia. METHODS: We examined whether low maternal vitamin A levels in the second trimester are associated with the risk of schizophrenia and other schizophrenia spectrum disorders (SSD) in the Prenatal Determinants of Schizophrenia study; third trimester vitamin A levels were also examined in relation to SSD. The cases were derived from a population-based birth cohort; all cohort members belonged to a prepaid health plan. Archived maternal serum samples were assayed for vitamin A in cases (N=55) and up to 2 controls per case (N=106) matched on length of membership in the health plan, date of birth (±28 days), sex, and gestational timing and availability of archived maternal sera. RESULTS: For the second trimester, low maternal vitamin A, defined as values in the lowest tertile of the distribution among controls, was associated with a greater than threefold increased risk of SSD, adjusting for maternal education and age (OR=3.04, 95% CI=1.06, 8.79, p=.039). No association between third trimester maternal vitamin A and SSD was observed. CONCLUSIONS: Although further investigations are warranted, this is the first birth cohort study to our knowledge to report an association between low maternal vitamin A levels and SSD among offspring.

Antihypertensive efficacy and tolerability of aliskiren/hydrochlorothiazide (HCT) single-pill combinations in patients who are non-responsive to HCT 25 mg alone.

OBJECTIVE: Thiazide diuretics such as hydrochlorothiazide (HCT) are a widely used first-line treatment for hypertension, but most patients will not achieve blood pressure (BP) control with HCT alone and so will require combination therapy. In this study the efficacy, safety and tolerability of a single-pill combination (SPC) of the direct renin inhibitor aliskiren with HCT were investigated in patients non-responsive to HCT 25 mg therapy. METHODS: In this study, 722 patients with hypertension and an inadequate response to 4 weeks of HCT 25 mg (mean sitting diastolic BP > or =90 and <110 mmHg) were randomized to once-daily, double-blind treatment for 8 weeks with an SPC of aliskiren/HCT 300/25 mg or 150/25 mg, or continued HCT 25 mg monotherapy. Least-squares mean changes in mean sitting systolic/diastolic BP (msSBP/DBP) from double-blind baseline were analyzed for the ITT population at week 8 endpoint. RESULTS: Aliskiren/HCT 300/25 mg and 150/25 mg SPCs lowered msSBP/DBP from baseline by 16.7/10.7 and 12.9/8.5 mmHg, respectively, both significantly greater reductions than HCT 25 mg alone (7.1/4.8 mmHg; both p < 0.001). Rates of BP control (<140/90 mmHg) were also significantly higher with aliskiren/HCT 300/25 mg (58%) and 150/25 mg (49%) than with HCT (26%; both p < 0.001). Aliskiren/HCT 300/25 mg provided significantly greater msSBP/DBP reductions and rates of BP control than the 150/25 mg SPC dose (all p < 0.05). Aliskiren/HCT SPC treatment showed similar tolerability to HCT alone and a numerically lower incidence of hypokalemia (serum potassium <3.5 mmol/L; aliskiren/HCT, 1.3-2.2%: HCT alone, 3.4%). CONCLUSION: Aliskiren/HCT SPCs provide clinically significant BP reductions and improved BP control rates in patients who are non-responsive to HCT 25 mg monotherapy. Limitations of the study were the mainly Caucasian patient population and the non-responder design.