Study of Ranolazine in Heart Failure

Not yet recruiting

• Conditions: Diastolic (congestive) heart failure,

• Registration Number: CTRI/2019/02/017766
• Lead Sponsor: Postgraduate Institute of Medical Education and Research PGIMER Chandigarh

Brief Summary

With the development of better diagnostic criteria, the proportion of cases with HFpEF is increasing compared to HFrEF. HFpEF has five-year mortality of 25%. The HFpEF is more prevalent among women as compared to men (this is in contrast to HFrEF in which the male sex is a strong predictor). There is no approved therapy/ recommendation by guidelines - showing mortality benefits in patients of HFpEF. The treatment of HFpEF are mainly directed towards underlying causative condition rather than HFpEF itself as the clinical trial which evaluated different therapies have shown neutral to wavering results. A patient level meta-analysis for the efficacy of beta blocker in HFpEF did not reduce all cause mortality and cardiovascular death. Similarly, diuretics have only shown to reduce hospitalization when the therapy is guided with the knowledge of pulmonary artery wedge pressure. The procedure of measurement of PAWP is associated with risks and is resource intensive and is not practically feasible in routine clinical settings. The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) trial evaluating aldosterone antagonist has shown improvement in hospitalization but the primary outcome turned out to be a similar rate between spironolactone and placebo.

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.

Detailed Description

Not available

Study Timeline

• Last Update Posted: 2019-02-18
• Study Start: 2019-02-26

Recruitment & Eligibility

• Status: Not Yet Recruiting
• Sex: All
• Target Recruitment: 80

Inclusion Criteria

• Patient of Heart failure with preserved Ejection Fraction (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 36 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 plasma level of NT-proBNP > 220 pg/ml (1).
• Patient of either sex.
• Female participant should not be pregnant (negative urinary pregnancy test) during the time of screening and should be ready to follow at least 2 contraceptive measures.
• Age ≥ 18 years 4.
• Diagnosed as NYHA class II or III heart failure and having symptoms of heart failure at the time of screening and is on treatment with minimum of one drug for HF.
• Should give informed consent for participating in study.

Exclusion Criteria

• 1. Patient already on treatment with ranolazine or have been administered with ranolazine over a period of past 6 months. 2. Patient with Acute Coronary Syndrome, cardiac surgery within period of 6 months. 3. On concomitant strong CYP3A4 inhibitor (e.g. Diltiazem, verapamil) or inducer (e.g., Rifampicin, carbamazepine and St John Wort). 4. Patient who are taking concomitant P glycoprotein inhibitor (e.g Cyclosporine). 5. Patient who have participated in another trial in the past 3 months. 6. Patient with history of cardiac arrhythmia (severe in nature) or is currently undertaking treatment with 2 or more antiarrhythmic drugs 7. Patient with pericardial constriction, cor pulmonale, congenital QT interval prolongation, acquired QT interval prolongation, familial history of QT interval prolongation, implanted pacemaker, implanted LVAD, implanted cardioverter.
• 37 defibrillator, significant pulmonary disease (requiring active treatment with oxygen and steroid), acute decompensated heart failure. 8. Patient with history of Myocardial infarction, CABG surgery in the previous 3 months, and PCI in the previous 1 month. 9. Patient with significant pulmonary disease, COPD (severe in nature). 10. Patient who had been prescribed with ranolazine previously. 11. Patient who have osteoarthritis or any other abnormality/ pathology of limbs which would prevent him from performing in exercise test. 12. Patient with renal creatinine clearance ≤ 30 ml/min (Cockcroft.
• gault formula) or with severe hepatic impairment (Child Pugh class B or Class C). 13. Patient who are not willing for manual follow up at our institute (PGIMER, Chandigarh) for a period of 6 months.

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Change in the biomarker concentration over a period of 6 months as compared to that of baseline in ranolazine vs placebo group. The biomarker which would be measured include NT-proBNP (biomarker for prognosis), Von-willebrand Factor (biomarker for long term mortality) and Syndecan - I (biomarker of fibrosis)	Baseline and 6th month

Secondary Outcome Measures

Name	Time	Method
Cardiovascular mortality	6th month
All-cause mortality	6th month
Echocardiographic parameters:	a. LVEDV in ml
Proportion of patients hospitalized	6th month
NYHA(New York Heart Association ) score	Baseline and 6th month
Composite score of CV death, total HF hospitalizations, total non-fatal strokes and total non-fatal myocardial infarction	6th month
Quality of life score as assessed by employing the Kansas City Cardiomyopathy Questionnaire	Baseline and 6th month
Time to event analysis with all-cause mortality as the endpoint	6th month
Frequency of occurrence of adverse events between ranolazine and placebo group	6th month

Trial Locations

Locations (1)

Advanced Cardiac Center; 🇮🇳 Chandigarh, CHANDIGARH, India

Advanced Cardiac Center

🇮🇳Chandigarh, CHANDIGARH, India

Dr Praveen Kumar M

Principal investigator

8728831787

praveenkumarpgiindia@gmail.com