Ranolazine for Refractory Angina in a Heart Transplant Recipient With Cardiac Allograft Vasculopathy

To the Editor: Cardiac allograft vasculopathy (CAV) is a leading cause of long-term mortality in patients who have undergone cardiac transplantation (1Chih S Chong AY Mielniczuk LM Bhatt DL Beanlands RS Allograft vasculopathy: The Achilles’ heel of heart transplantation.J Am Coll Cardiol. 2016; 68: 80-91Crossref PubMed Scopus (160) Google Scholar). Because of allograft denervation, these patients rarely present with typical chest pain. Nevertheless, reinnervation is possible and allows angina to develop in the presence of myocardial ischemia (2Stark RP McGinn AL Wilson RF Chest pain in cardiac-transplant recipients. Evidence of sensory reinnervation after cardiac transplantation.N Engl J Med. 1991; 324: 1791-1794Crossref PubMed Scopus (202) Google Scholar). Ranolazine has been used to treat refractory angina in patients with coronary artery disease (3Rayner-Hartley E Sedlak T Ranolazine: A contemporary review.J Am Heart Assoc. 2016; 5: e003196Crossref PubMed Scopus (54) Google Scholar). It inhibits the late sodium current in cardiac myocytes, and that reduces calcium overload in these cells, thereby reducing diastolic left ventricular wall tension and myocardial oxygen demand. We report our experience with the use of ranolazine in a patient with refractory angina from CAV. A 32-year-old man with diabetes, dyslipidemia, and chronic kidney disease underwent orthotopic heart transplantation for dilated cardiomyopathy. He remained asymptomatic until 12 years after the procedure, when he developed chest pain attributed to CAV. He was felt not to be a candidate for retransplantation because of comorbidities. Over the next 5 years, he underwent seven percutaneous coronary interventions for recurrent functionally limiting angina despite maximally tolerated medical therapy. His medications for CAV included aspirin, clopidogrel, pravastatin 60 mg daily, metoprolol 100 mg three times daily, amlodipine 10 mg daily, and hydralazine 100 mg three times daily, in addition to sirolimus and tacrolimus for immunosuppression. His pain was further managed with extended-release hydromorphone 9 mg twice daily and short-acting hydromorphone 2 mg as needed for breakthrough pain. Eight months after his seventh procedure, he again exhibited Canadian Cardiovascular Society class III angina. At that point, he was started on ranolazine 250 mg twice daily, which was uptitrated to 500 mg twice daily. Over the next month, his pain subsided until complete resolution, which allowed him to achieve New York Heart Association class I activity. He remained pain-free for 3 months until he suffered a myocardial infarction after discontinuing clopidogrel for an elective urologic procedure. Despite another percutaneous coronary intervention and ongoing ranolazine therapy, his angina returned and has been comanaged with palliative care using escalating doses of hydromorphone. TERISA and CARISA are two of the largest double-blind placebo-controlled trials to show a significant reduction in angina frequency after 8–12 weeks of ranolazine therapy in patients with coronary artery disease (4Kosiborod M Arnold SV Spertus JA et al.Evaluation of ranolazine in patients with type 2 diabetes mellitus and chronic stable angina: Results from the TERISA randomized clinical trial (Type 2 Diabetes Evaluation of Ranolazine in Subjects With Chronic Stable Angina).J Am Coll Cardiol. 2013; 61: 2038-2045Crossref PubMed Scopus (172) Google Scholar,5Chaitman BR Pepine CJ Parker JO et al.Effects of ranolazine with atenolol, amlodipine, or diltiazem on exercise tolerance and angina frequency in patients with severe chronic angina: A randomized controlled trial.JAMA. 2004; 291: 309-316Crossref PubMed Scopus (616) Google Scholar). Heart transplant recipients were not included in these studies. To our knowledge, our case is the first to report the use of ranolazine to treat refractory angina in a heart transplant recipient with CAV. Use of ranolazine was described in a patient who underwent kidney transplant, but its combination with diltiazem and tacrolimus led to acute allograft injury caused by altered tacrolimus metabolism (6Patni H Gitman M Hazzan A Jhaveri KD Ranolazine, tacrolimus, and diltiazem might be a hazardous combination in a transplant patient.Ren Fail. 2012; 34: 251-253Crossref Scopus (2) Google Scholar). Traditional therapies for CAV include aspirin, statins, vasodilators (calcium channel blockers, angiotensin-converting enzyme inhibitors), immunosuppressants (mycophenolic acid, azathioprine, mammalian target of rapamycin inhibitors, calcineurin inhibitors), revascularization (percutaneous coronary intervention, coronary artery bypass grafting), and retransplantation (1Chih S Chong AY Mielniczuk LM Bhatt DL Beanlands RS Allograft vasculopathy: The Achilles’ heel of heart transplantation.J Am Coll Cardiol. 2016; 68: 80-91Crossref PubMed Scopus (160) Google Scholar). Spinal cord stimulation has also been effective in the infrequently reported cases of refractory angina after cardiac transplantation (7Maritano M Centofanti P La Torre M et al.New therapeutic option for cardiac ischemia in transplant vasculopathy: Spinal cord stimulation.J Heart Lung Transplant. 2004; 23: 368-370Abstract Full Text Full Text PDF PubMed Scopus (2) Google Scholar,8Singh H Merry AF Ruygrok P Ruttley A Treatment of recurrent chest pain in a heart transplant recipient using spinal cord stimulation.Anaesth Intensive Care. 2008; 36: 242-244Google Scholar). As our case demonstrates, ranolazine could represent an alternative noninvasive therapy that may offer at least temporary relief in patients with CAV-related refractory angina. The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.

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