Extended-release ranolazine: critical evaluation of its use in stable angina

Coronary heart disease is the major cause of morbidity and mortality throughout the world, and is responsible for approximately one of every six deaths in the US. Angina pectoris is a clinical syndrome characterized by discomfort, typically in the chest, neck, chin, or left arm, induced by physical exertion, emotional stress, or cold, and relieved by rest or nitroglycerin. The main goals of treatment of stable angina pectoris are to improve quality of life by reducing the severity and/or frequency of symptoms, to increase functional capacity, and to improve prognosis. Ranolazine is a recently developed antianginal with unique methods of action. In this paper, we review the pharmacology of ranolazine, clinical trials supporting its approval for clinical use, and studies of its quality of life benefits. We conclude that ranolazine has been shown to be a reasonable and safe option for patients who have refractory ischemic symptoms despite the use of standard medications (for example, nitrates, beta-adrenergic receptor antagonists, and calcium channel antagonists) for treatment of anginal symptoms, and also provides a modestly improved quality of life

QT interval prolongation and torsades de pointes in a patient undergoing treatment with vorinostat: A case report and review of the literature

Vorinostat is a histone deacetylase inhibitor used in the treatment of recurrent or persistent cases of cutaneous T-cell lymphoma (CTCL). A retrospective review of 116 patients from phase I and II clinical trials who had a baseline and at least one subsequent ECG revealed that four patients had Grade 2 and one patient had Grade 3 QTc interval prolongation; however, a MEDLINE search found no reported cases of torsades de pointes (TdP) in patients treated with vorinostat. We describe the case of a 49 year-old male with a history of CTCL actively undergoing treatment with vorinostat. During day 1 of hospitalization, he developed a pulseless polymorphic ventricular tachycardia requiring resuscitation. He was found to have a QTc of 826 ms. Following correction of potassium and magnesium, QTc gradually decreased and no further ventricular arrhythmia was noted. Other factors implicated in this case included concurrent sertraline and doxepin therapy (both drugs have been associated with the development of TdP in overdose). The mechanism of development of TdP in this patient is postulated to be related to vorinostat use in combination with hypokalemia and concomitant treatment with medications associated with QTc prolongation. This case highlights the importance of post-market surveillance

Methodology of a reevaluation of cardiovascular outcomes in the RECORD trial: study design and conduct

Background In 2010, after regulatory review of rosiglitazone licensing, the US Food and Drug Administration (FDA) requested a reevaluation of cardiovascular end points in the RECORD trial.<p></p> Methods Automated screening of the original clinical trial database and manual case report form review were performed to identify all potential cardiovascular and noncardiovascular deaths, and nonfatal myocardial infarction (MI) and stroke events. Search techniques were used to find participants lost to follow-up, and sites were queried for additional source documents. Suspected events underwent blinded adjudication using both original RECORD end point definitions and new FDA end point definitions, before analysis by the Duke Clinical Research Institute.<p></p> Results The reevaluation effort included an additional 328 person-years of follow-up. Automated screening identified 396 suspected deaths, 2,052 suspected MIs, and 468 suspected strokes. Manual review of documents by Duke Clinical Research Institute clinical events classification (CEC) coordinators identified an additional 31 suspected deaths, 49 suspected MIs, and 28 suspected strokes. There were 127 CEC queries issued requesting additional information on suspected deaths; 43 were closed with no site response, 61 were closed with a response that no additional data were available, and additional data were received for 23. Seventy CEC queries were issued requesting additional information for suspected MI and stroke events; 31 were closed with no site response, 20 were closed with a response that no additional data were available, and 19 resulted in additional data.<p></p> Conclusions Comprehensive procedures were used for rigorous event reascertainment and readjudication in a previously completed open-label, global clinical trial. These procedures used in this unique situation were consistent with other common approaches in the field, were enhanced to address the FDA concerns about the original RECORD trial results, and could be considered by clinical trialists designing event readjudication protocols for drug development programs that have been completed.<p></p&gt

Results of a reevaluation of cardiovascular outcomes in the RECORD trial

Background The US Food and Drug Administration (FDA) required a reevaluation of cardiovascular (CV) outcomes in the RECORD trial. This provided an opportunity to assess the implications of event adjudication by 2 groups and quantify the differences as well as to use new FDA end point definitions in development.<p></p> Methods Original data were used to systematically identify all potential deaths, myocardial infarctions (MIs), and strokes. Site investigators were approached for additional source documents and information about participants lost to follow-up. Suspected events were adjudicated using standard procedures, and the results were compared with the original trial outcomes.<p></p> Results Follow-up for mortality was 25,833 person-years, including an additional 328 person-years identified during the reevaluation effort. A total of 184 CV or unknown-cause deaths (88 rosiglitazone, 96 metformin/sulfonylurea), 128 participants with an MI (68 rosiglitazone, 60 metformin/sulfonylurea), and 113 participants with a stroke (50 rosiglitazone, 63 metformin/sulfonylurea) were included. The hazard ratio (HR) for rosiglitazone versus metformin/sulfonylurea for the end point of CV (or unknown cause) death, MI, or stroke was 0.95 (95% CI 0.78-1.17) compared with 0.93 (95% CI 0.74-1.15) for the original RECORD results. Treatment comparisons for MI (HR 1.13, 95% CI 0.80-1.59) and mortality (HR 0.86, 95% CI 0.68-1.08) were also the same compared with the original RECORD results. Sensitivity analyses were also consistent with the original RECORD results. Analyses using the FDA definitions showed similar results.<p></p> Conclusions Only a modest number of additional person-years of follow-up were ascertained from this reevaluation of CV end points in RECORD. Observed HRs and CIs from these analyses using the original RECORD or new FDA end point definitions showed similar treatment effects of rosiglitazone compared with the original RECORD results.<p></p&gt