Platelet pharmacogenomics

Summary. Platelet responsiveness to conventional antiplatelet therapy underlies a high interindividual variability influenced by various factors. For instance, antiplatelet therapy does not curtail the expected effects in a relevant number of patients as demonstrated by the occurrence of repeated cardiovascular events including stent thrombosis and/or by inadequate platelet inhibition measured by in vitro platelet function assays. Besides non‐genetic factors such as age, gender, liver and renal function and co‐medication, considerable variation of antiplatelet drug responsiveness can be attributed to genetic factors including polymorphisms and genetic variants of platelet surface proteins and drug metabolizing enzymes. Nowadays, platelet pharmacogenomics has started a new field with the goal to link genetic information of various drug targets to interindividual variability of drug response. Evolving data from large cohort studies suggest a promising role for pharmacogenomics in the context of antiplatelet therapy. Additionally, with the revolution of low cost and high‐throughput genotyping techniques, genetic testing has become affordable for clinical application and individualization of therapy. However, a key issue to define the future role of pharmacogenomics will rely on the benefit and the timeliness of implementing the genetic information into therapeutic decision. Hence, it warrants further investigations to document the prognostic effects of therapeutic alterations in distinct genotypes. Concerning the safety profile of emerging antiplatelet and antithrombotic drugs in certain risk groups it would be fatal to individualize treatment barely on behalf of an atherothrombotic genotype. In contrast, individual risk assessment combining non‐genetic information and pharmacogenetic analysis represents a reasonable concept. Here, we provide a review on current data describing the role of pharmacogenomics in the field of antiplatelet drug treatment in cardiovascular patients with future directions.     

Prevention of Inappropriate Shocks in ICD Recipients: A Review of 10,000 Tachycardia Episodes

Background: The efficacy of dual-chamber ICD arrhythmia classification algorithms is crucial to prevent inappropriate shocks. We report our experience from a meta-analysis of five prospective clinical studies with inclusion phases ranging between 1997 and 2003.
Methods: Dual-chamber ICD using standard dual-chamber arrhythmia classification algorithms were implanted in 802 patients (mean age = 64 ± 11 years, 88% men) in 74 medical centers. The ICD indication was secondary prevention in 95% of patients. Supraventricular tachyarrhythmias (SVT) were previously documented in 26% of patients. All spontaneous tachyarrhythmic events documented by the device memories were analyzed by a adjudicating committee. The episodes lasting >12 seconds and/or treated by the ICD were analyzed.
Results: Over a mean follow-up of 302 ± 113 days, 9,690 events were reported. Mean heart rate at the time of events was 131 ± 45 bpm (100–430). Events were classified as oversensing in 1.4%, sinus tachycardia (ST) in 66%, SVT in 13%, slow (<150 bpm) ventricular tachycardia (VT) in 8.7%, and VT or ventricular fibrillation (VF) in 10.3%. The sensitivity of slow VT detection was 94%, and of VT/VF detection 99.3%. The specificity of sinus rhythm/ST/SVT recognition was 94%, positive predictive value 79.3%, and negative predictive value 99.2%. A total of 1,918 episodes were treated in 330 patients: 1,472 appropriately in 213, and 446 inappropriately in 117 (15% of the overall population) patients. Only 62 episodes were inappropriately treated by shocks in 40 patients, representing 5% of the overall population.
Conclusions: In this conventional ICD population, the overall specificity of standard dual-chamber arrhythmia detection settings reached 94%. This feature allows efficient detection of fast as well as slow VT events with a very low rate of inappropriate shocks.     

Clinical Experience with a New Cardioverter Defibrillator Capable of Biphasic Waveform Pulse and Enhanced Data Storage: Results of a Prospective Multicenter Study

A recently introduced cardioverter defibrillator was implanted in 162 patients with refractory ventricular tachyarrhythmias and/or aborted sudden cardiac death. The new device is capable of delivering monophasic and biphasic defibrillation waveform pulses, arrhythmia detection, and therapy in two independently programmable zones, antibradycardia and postshock pacing. Additionally, the device provides enhanced data logs by storing intracardiac “far-field” electrograms of spontaneous arrhythmic episodes. One hundred sixty-two patients (mean age 55.5 years; mean left ventricular ejection fraction 36%) were enrolled in this multicenter investigation; coronary artery disease was the primary cardiac disease in 63.6% of the patients, idiopathic cardiomyopathy in 23.8%. Ventricular fibrillation was present in 49.7% of the patients; 29.3% of the patients experienced ventricular fibrillation and ventricular tachycardia; monomorphic ventricuiar tachycardia alone was present in 19.1% of the patients. In 26 patients the device was implanted with standard epicardial defibrillation leads (mean defibrillation threshold 11.5±3.7J). One hundred thirty-nine patients underwent testing for implantation of a nonthoracotomy system and in 136 (98%), a nonthoracotomy system could be implanted. Defibrillation thresholds with a biphasic waveform (mean 10.2 ± 4.3 J) were lower than with a monophasic waveform (mean 17.4 ± 5.7 J). Two patients (1.2%) died perioperatively (< 30 days). During study time period follow-up, there were 338 device discharges in 49 patients. Analysis of stored electrograms classified 25% of discharges as inappropriate and due to supraventricular tachyarrhythmias. At a mean follow-up of 10.8 months, cumulative survival from sudden cardiac death was 98.8%, and survival from all-cause mortality was 96.3%. This study demonstates the effectiveness of a new implantable cardioverter defibrillator in preventing arrhythmic death and the superior defibrillation efficacy of biphasic waveform pulses, which results in a higher implantation rate of nonthoracotomy systems, as well as the accurate arrhythmia classification made possible by the stored electrograms.