Pharmacology of Ranolazine versus Common Cardiovascular Drugs in Patients with Early Diastolic Dysfunction Induced by Anthracyclines or Nonanthracycline Chemotherapeutics: A Phase 2b Minitrial

Abstract

We have reported that anthracyclines and nonanthracycline chemotherapeutics caused diastolic dysfunction in cancer patients without cardiovascular risk factors. Diastolic dysfunction occurred as early as 1 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 the investigator's choice of common cardiovascular drugs, such as b-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, whereas 3 of 12 patients on BST did not improve; however, adverse events (not serious) were apparently more frequent for ranolazine than for BST (4/12 vs. 1/12). Ranolazine did not lower blood pressure, whereas BST reduced systolic pressure and caused a trend toward a reduced diastolic pressure. Most patients at randomization showed tachycardia resulting from chemotherapy-related anemia. Hemoglobin recovery contributed to normalizing heart rate in these patients; however, some patients in the 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 the 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. In a clinical pharmacology study, 24 patients were randomized (1:1) to receive ranolazine or common cardiovascular drugs to treat early diastolic dysfunction induced by anthracycline-based or nonanthracycline chemotherapy. Ranolazine relieved diastolic dysfunction in these patients. The safety profile of ranolazine in cancer patients is similar to that of the general population. Compared with 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.

Efficacy of Ranolazine to Improve Diastolic Performance in Heart Failure with Preserved Ejection Fraction: A Systematic Review and Meta-analysis

“…[26][27][28] One study targeted type 2 diabetes patients with HF syndrome. 29,30 Another study recruited patients with hypertrophic cardiomyopathy with a left ventricular thickness of 15 mm. 31 A more detailed description of study characteristics is attached in Supplementary Table 1.…”

Ranolazine: An Old Drug with Emerging Potential; Lessons from Pre-Clinical and Clinical Investigations for Possible Repositioning

“…To our knowledge, the efficacy and safety of ranolazine or other Na v channel blockers in oncology have not been assessed in clinical trials. However, ranolazine may reduce the cardiotoxicity of anticancer therapy (trastuzumab, doxorubicin) in mice, thus paving the way to a clinical trial [138,[202][203][204]. A controlled trial is needed regarding the potential of ranolazine on relieving chemotherapy-related diastolic dysfunction and its safety profile in cancer patients compared to that of the general population [204].…”

The cancer patient and cardiology

“…Conversely, although mean BNP/NT‐proBNP levels were increased in patients post‐cancer therapy, these biomarkers did not consistently predict LV dysfunction (OR 1.7, 95% CI 0.7–4.2). It was recently suggested that post‐cancer therapy elevations of NT‐proBNP might herald early diastolic dysfunction rather than LV systolic dysfunction 82 …”

“…It was recently suggested that post-cancer therapy elevations of NT-proBNP might herald early diastolic dysfunction rather than LV systolic dysfunction. 82 Troponin elevation was also useful to monitor the efficacy of preventive therapy, with lower levels seen with angiotensin-converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB) therapy (OR 9.8, 95% CI 2.6-37.1) and, to a lesser extent, beta-blocker therapy (OR 2.1, 95% CI 1.3-3.6). 81 However, a multicentre prospective study, the International CardioOncology Society (ICOS)-one trial, did not demonstrate prevention of troponin elevations by ACE inhibitor therapy, 83 84 and Carvedilol Effect in Preventing Chemotherapy-Induced Cardiotoxicity (CECCY) 85 trials demonstrated an attenuation of the troponin response to anthracycline therapy by beta-blocker therapy.…”