Clinical Pharmacology Unit (G.M., P.M.) and Cardio Center (V.C.), Campus Bio-Medico University Hospital, Rome; Units of Drug Sciences (G.M., E.S.), Radiation Oncology (C.G.), Oncology (G.A.), and Hematology (O.A.), Department of Medicine and Center for Integrated Research, University Campus Bio-Medico, Rome; Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome (F.M.); and Mediservice S.r.l., Agrate Brianza (Monza) (G.R.), Italy
Clinical Pharmacology Unit (G.M., P.M.) and Cardio Center (V.C.), Campus Bio-Medico University Hospital, Rome; Units of Drug Sciences (G.M., E.S.), Radiation Oncology (C.G.), Oncology (G.A.), and Hematology (O.A.), Department of Medicine and Center for Integrated Research, University Campus Bio-Medico, Rome; Hematology and Stem Cell Transplant Unit, IRCCS Regina Elena National Cancer Institute, Rome (F.M.); and Mediservice S.r.l., Agrate Brianza (Monza) (G.R.), Italy.
J Pharmacol Exp Ther. 2019 Aug;370(2):197-205. doi: 10.1124/jpet.119.258178. Epub 2019 May 17.
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 -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.
我们曾报道过蒽环类和非蒽环类化疗药物可导致无心血管危险因素的癌症患者出现舒张功能障碍。舒张功能障碍早在末次化疗周期后 1 周即可出现，并表现为超声心动图显示心肌舒张功能受损或 B 型利钠肽（BNP）或肌钙蛋白持续升高。抗心绞痛药物雷诺嗪具有心脏松弛作用，我们认为这对于治疗癌症药物引起的早期舒张功能障碍具有重要价值；因此，我们将 24 例化疗后舒张功能障碍的低危患者随机（1:1）分为雷诺嗪组或研究者选择的常见心血管药物组，如β受体阻滞剂和/或血管紧张素转换酶抑制剂或袢利尿剂（最佳标准治疗，BST）。治疗 5 周后，12 例雷诺嗪组患者的舒张功能障碍均恢复正常，而 12 例 BST 组患者中仅有 3 例未改善；然而，雷诺嗪组的不良事件（非严重）明显多于 BST 组（4/12 例比 1/12 例）。雷诺嗪没有降低血压，而 BST 降低了收缩压并导致舒张压有降低趋势。大多数随机分组患者因化疗相关贫血而出现心动过速。血红蛋白恢复有助于这些患者的心率正常化；然而，雷诺嗪组的一些患者因 BNP 水平升高而出现心动过速，并通过降低 BNP 水平的作用使心率恢复正常。这项小型试验描述了雷诺嗪缓解化疗相关舒张功能障碍的潜在作用；然而，这些发现的临床意义需要通过具有足够样本量的研究来确定。意义：抗心绞痛药物雷诺嗪具有心脏松弛作用，可能缓解舒张功能障碍。在一项临床药理学研究中，将 24 例患者随机（1:1）分为接受雷诺嗪或常见心血管药物组，以治疗蒽环类或非蒽环类化疗药物引起的早期舒张功能障碍。雷诺嗪缓解了这些患者的舒张功能障碍。雷诺嗪在癌症患者中的安全性与一般人群相似。与常见心血管药物相比，雷诺嗪在不降低血压的情况下缓解舒张功能障碍。然而，这项研究的样本量太小，无法考虑雷诺嗪对蒽环类或非蒽环类化疗药物引起的早期舒张功能障碍的癌症患者的潜在临床价值。这方面的信息需要通过具有足够样本量的研究获得。
