Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Ranolazine is currently employed as antianginal (chronic angina - not for acute angina/Acute Coronary Syndrome) and anti-ischemic drug in therapeutics. The drug in chronic angina patients according to guidelines is given as a substitute of beta blocker in patient having a lack of symptomatic improvement / unacceptable side effect - after initial treatment with beta-blocker or for those patients for whom there exist a contraindication for prescribing beta blocker or as a combination with beta-blocker following demonstration of lack of efficacy with single therapy of beta- blocker alone. The drug has a novel mechanism of action - inhibition of late phase of inward sodium channel in the cardiac myocytes (ischemic areas). Typically the inhibition occurs at the cardiac depolarization phase, thereby the amount of intracellular sodium and calcium (indirectly through Na+ - Ca 2+ exchange) are reduced in the cardiac myocytes. The calcium being the prime ion regulating contraction, a decreased amount of it leads to reduction in ventricular tension and oxygen consumption by the cardiac myocytes.

In mechanism specific to HFpEF, preclinical studies has shown that oxidative stress causes an increase in sensitivity of myocardial fibre to calcium. Ranolazine by decreasing calcium reduces the contractility and dysfunction of myocardial fibres. Other mechanisms supporting ranolazine include its indirect action against the key protein of HF namely Ca (2+)/calmodulin-dependent protein kinase IIδ (CaMKIIδ). This protein acts by increasing late sodium channels and accumulation of intracellular calcium. Ranolazine, as demonstrated in animal experiment counteract the negative effect of protein by inhibiting late sodium channels and improving diastolic dysfunction. Sanguinely, ranolazine also has a good safety profile, as vividly seen over its period of clinical utilization.

A randomized double-blind trial would be performed evaluating ranolazine over placebo in patients of HFpEF. The null hypothesis of our study is that the change in the biomarker concentration with the treatment of ranolazine will be the same as that of placebo over a period of 6 months in patients of HFpEF. We have employed stringent criteria for the diagnosis of HFpEF.  The diagnosis of HFpEF requires the following conditions to be satisfied: (i) signs or symptoms of heart failure; (ii) normal or mildly abnormal systolic LV function; (iii) evidence of diastolic LV dysfunction. Normal or mildly abnormal systolic LV function implies both an Left Ventricular Ejection Fraction (LVEF) > 50% and an LV end-diastolic volume index (LVEDVI) < 97 mL/m2. The diastolic LV dysfunction is evidenced by Tissue doppler E/E‟ greater than 15. If E/E‟ is between 8 to 15, then the diagnosis should be confirmed by the plasma level of NT-proBNP > 220 pg/ml. The duration of evaluation of the study will be over a period of 6 months and the primary outcome is the change in biomarker concentration. In addition, a spectrum of secondary outcome ranging from the 6-minute walk test to Quality of life (KCCQ - Kansas City Cardiomyopathy Questionnaire) will be assessed for bringing about more scientific knowledge from the study. The HFpEF variety of heart failure is in-amenable to therapy. There is a dire need for a safe and efficacious drug. So this trial would help in evaluating ranolazine as a potential therapy for HFpEF.