Pharmacology of ranolazine versus common cardiovascular drugs in patients with early diastolic dysfunction induced by anthracyclines or nonanthracycline chemotherapeutics: A phase 2b minitrial
2019
We have reported that anthracyclines and nonanthracycline chemotherapeutics caused diastolic dysfunction in cancer patients without cardiovascular risk factors. Diastolic dysfunction occurred as early as one week after the last chemotherapy cycle and manifested as impaired myocardial relaxation at echocardiography or persistent elevations of B-type natriuretic peptide (BNP) or troponin. The antianginal drug, ranolazine, shows cardiac relaxant effects that we considered of value to treat early diastolic dysfunction induced by cancer drugs; therefore, 24 low risk patients with post-chemotherapy diastolic dysfunction were randomized (1:1) to ranolazine or investigator9s choice of common cardiovascular drugs, like β blockers and/or angiotensin converting enzyme inhibitors or loop diuretics (best standard therapy, BST). After 5-weeks 12 of 12 patients on ranolazine recovered from diastolic dysfunction, while 3 of 12 patients on BST failed to improve; however, not serious adverse events were apparently more frequent for ranolazine than BST (4/12 versus 1/12). Ranolazine did not lower blood pressure while BST reduced systolic pressure and caused a trend toward a reduced diastolic pressure. The majority of patients presented at randomization with tachycardia due to chemotherapy-related anemia. Hemoglobin recovery contributed to normalizing heart rate in these patients; however, some patients in ranolazine arm developed tachycardia through chronotropic effects of high BNP levels and returned to a normal heart rate through the effects of ranolazine on decreasing BNP levels. This minitrial describes potential effects of ranolazine on relieving chemotherapy-related diastolic dysfunction; however, clinical implications of these findings need to be characterized by studies with an adequate sample size. SIGNIFICANCE STATEMENT The antianginal drug, ranolazine, causes cardiac relaxant effects that might relieve diastolic dysfunction. We report on a clinical pharmacology study in which 24 patients were randomized (1:1) to receive ranolazine or common cardiovascular drugs for treatment of early diastolic dysfunction induced by anthracycline-based or nonanthracycline chemotherapy. Ranolazine showed effects on relieving diastolic dysfunction in these patients. The safety profile of ranolazine in cancer patients was similar to that characterized for the general population. Compared to common cardiovascular drugs, ranolazine relieved diastolic dysfunction without lowering blood pressure. The sample size of this study was nonetheless too small to permit considerations about the potential clinical value of ranolazine for oncologic patients with early diastolic dysfunction induced by anthracyclines or nonanthracycline chemotherapeutics. This information should be obtained by studies with an adequate sample size.
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