Brian A. Baker

The Association of Cigarette Smoking With Enhanced Platelet Inhibition by Clopidogrel

OBJECTIVES The purpose of this study was to examine the effect of cigarette smoking on the platelet response to clopidogrel. BACKGROUND Response variability to clopidogrel therapy has been demonstrated. Clopidogrel is metabolically activated by several hepatic cytochrome P450 (CYP) isoenzymes, including CYP1A2. Cigarette smoking induces CYP1A2 and may, therefore, enhance the conversion of clopidogrel to its active metabolite. METHODS Among 259 consecutive patients undergoing elective coronary stenting; 120 were on chronic clopidogrel therapy and were not loaded; and 139 were clopidogrel naïve and were loaded with 600 mg. There were 104 current smokers (CS) and 155 nonsmokers (NS). The adenosine diphosphate (ADP)-stimulated platelet aggregation (PA) was assessed by conventional aggregometry. The ADP-stimulated total and active glycoprotein (GP) IIb/IIIa expression were assessed with flow cytometry. Low PA was defined as the lowest quartile of 5 micromol/l ADP-induced post-treatment PA. RESULTS Current smokers on chronic clopidogrel therapy displayed significantly lower PA and ADP-stimulated active GP IIb/IIIa expression compared with NS (p < or = 0.0008 for both). Similarly, CS treated with 600 mg of clopidogrel displayed greater platelet inhibition and lower active GP IIb/IIIa expression compared with NS (p < or = 0.05). In a multivariate Cox regression analysis, current smoking was an independent predictor of low PA (p = 0.0001). CONCLUSION Clopidogrel therapy in CS is associated with increased platelet inhibition and lower aggregation as compared with NS. The mechanism of the smoking effect deserves further study and may be an important cause of response variability to clopidogrel therapy.

Depression and risk of sudden cardiac death after acute myocardial infarction: testing for the confounding effects of fatigue.

OBJECTIVES This study examined the impact of depressive symptoms and social support on 2-year sudden cardiac death (SCD) risk, controlling for fatigue symptoms. METHODS Myocardial infarction (MI) patients (N = 671) participating in the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial completed measures of depression, hostility, and social support. RESULTS After controlling for significant biological predictors, psychosocial predictors of increased SCD risk in the survival analysis were greater social network contacts (RR = 1.04; 95% CI = 1.01-1.06; p < .007), lower social participation (RR = 0.98; 95% CI = 0.96-1.00; p < .05), and, in placebo-treated patients, elevated depressive symptoms (RR = 2.45; 95% CI = 1.14-5.35; p < .02). Fatigue was associated with SCD (RR = 1.31; 95% CI = 1.11-1.53; p < .001), and, when included in the model, diminished the influence of depression (RR = 1.73; 95% CI = 0.75-3.98; p = .20). When the cognitive-affective depressive symptoms were examined separately from somatic symptoms, there was a trend for an association between cognitive-affective symptoms and SCD in placebo-treated patients after controlling for fatigue (RR = 1.09; 95% CI = 0.99-1.19, p < .06). CONCLUSIONS Symptoms of depression and fatigue overlap in patients with MI. The trend for the cognitive-affective symptoms of depression to be associated with SCD risk, even after controlling for dyspnea/fatigue, suggests that the association between depression and mortality after AMI cannot be entirely explained as a confound of cardiac-related fatigue. The independent contribution of social participation suggests a role of both depressive symptomatology and social factors in influencing mortality risk after MI.

A pharmacodynamic comparison of prasugrel vs. high-dose clopidogrel in patients with type 2 diabetes mellitus and coronary artery disease: results of the Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 Trial

Aims Patients with diabetes mellitus (DM) have increased platelet reactivity and reduced platelet response to clopidogrel compared with patients without DM. Prasugrel, a more potent antiplatelet agent, is associated with greater reductions in ischaemic events compared with clopidogrel, particularly in patients with DM. The aim of this study was to perform serial pharmacodynamic assessments of prasugrel with high-dose clopidogrel in patients with DM. Methods and results Optimizing anti-Platelet Therapy In diabetes MellitUS (OPTIMUS)-3 was a prospective, randomized, double-blind, crossover study in patients with type 2 DM and coronary artery disease (CAD). Patients (n= 35) were randomly assigned to either prasugrel 60 mg loading dose (LD)/10 mg maintenance dose (MD) or clopidogrel 600 mg LD/150 mg MD over two 1-week treatment periods separated by a 2-week washout period. Platelet function was assessed by VerifyNow® P2Y12 assay, light transmission aggregometry, and vasodilator-stimulated phosphoprotein phosphorylation at 0, 1, 4, and 24 h and 7 days. Greater platelet inhibition by VerifyNow® P2Y12 was achieved by prasugrel compared with clopidogrel at 4 h post-LD (least squares mean, 89.3 vs. 27.7%, P< 0.0001; primary endpoint). The difference in platelet inhibition between prasugrel and clopidogrel was significant from 1 h through 7 days (P < 0.0001). Similar results were obtained using all other platelet function measures. Prasugrel resulted in fewer poor responders at all time points irrespective of definition used. Conclusion In patients with type 2 DM and CAD, standard-dose prasugrel is associated with greater platelet inhibition and better response profiles during both the loading and maintenance periods when compared with double-dose clopidogrel. Clinical trial identifier: www.clinicaltrials.gov—NCT00642174

An open-label preliminary trial of sertraline for treatment of major depression after acute myocardial infarction (the SADHAT Trial) ☆ ☆☆ ★

BACKGROUND Depression occurs frequently in patients with acute myocardial infarction and is associated with increased mortality rates. It is not known whether serotonin reuptake inhibitors would be safe and effective for patients with depression after myocardial infarction and whether such treatment would reduce mortality rates. METHODS AND RESULTS We conducted a multicenter, open-label, pilot study of sertraline treatment in patients with major depressive disorder identified 5 to 30 days after admission for acute myocardial infarction. Outcome measures included cardiovascular and hemostatic function, adverse events, and mood ratings. Twenty-six patients were enrolled in the study. During treatment there were no significant changes in heart rate, blood pressure, cardiac conduction, or left ventricular ejection fraction, and there was a trend toward reduced ventricular ectopic activity. There were no changes in coagulation measures. Bleeding time increased in 12 patients, decreased in 4 patients, and was unchanged in 2 patients. Three (12%) patients withdrew from treatment prematurely because of adverse events. Significant improvements in mood ratings occurred over the course of treatment. CONCLUSIONS Sertraline treatment was associated with clinical improvement and was well tolerated in >85% of the patients in this open-label treatment trial for patients with major depression after myocardial infarction. These results encourage further controlled trials to establish the effects of treatment for this high-risk population.

POOR ADHERENCE TO PLACEBO OR AMIODARONE THERAPY PREDICTS MORTALITY : RESULTS FROM THE CAMIAT STUDY

OBJECTIVE This study examined the relationship between adherence, mortality, and psychosocial factors. METHODS Subjects were 1141 patients participating in the Canadian Amiodarone Myocardial Infarction Arrhythmia Trial. Poor adherence to study medication (amiodarone or placebo), measured by pill count over 2 years, was defined as the lower 20th percentile of the pill count distribution. Predictors of adherence were also studied and included demographic and cardiac variables and, in a subset of participants (N = 671), measures of depression, distress, hostility, and social support. RESULTS In survival analysis controlling for cardiac and demographic variables, poor adherence in the placebo and amiodarone groups was associated with an increased risk of sudden cardiac death (relative risk (RR) = 2.11, 95% confidence interval (CI) = 1.03-4.56, p < .05; and RR = 3.15, 95% CI = 1.34-7.44, p < .01, respectively), total cardiac mortality (RR = 2.04, 95% CI = 1.12-3.72, p < .02; and RR = 2.49, 95% CI = 1.32-4.72, p < .01, respectively), and all-cause mortality (RR = 2.25, 95% CI = 1.27-3.97, p < .001; and RR = 2.34, 95% CI = 1.32-4.17, p < .004, respectively). Logistic regression analysis identified two predictors of poor adherence to placebo: age > 70 years (odds ratio = 2.18, 95% CI = 1.11-4.29, p < .03) and social activities in the month before the index heart attack (odds ratio = 1.02, 95% CI = 1.00-1.04, p < .05). CONCLUSIONS Poor adherence is associated with a greater risk of mortality. The relationship between adherence and social activities suggests a higher motivation to adhere to treatment in individuals more engaged in enjoyable activities.

Recovery of Platelet Function After Discontinuation of Prasugrel or Clopidogrel Maintenance Dosing in Aspirin-Treated Patients With Stable Coronary Disease : The Recovery Trial

OBJECTIVES The goal of this study was to assess the offset of the antiplatelet effects of prasugrel and clopidogrel. BACKGROUND Guidelines recommend discontinuing clopidogrel at least 5 days and prasugrel at least 7 days before surgery. The pharmacodynamic basis for these recommendations is limited. METHODS Aspirin-treated patients with coronary artery disease were randomly assigned to either prasugrel 10 mg or clopidogrel 75 mg daily for 7 days. Platelet reactivity was measured before study drug administration and for up to 12 days during washout. The primary endpoint was the cumulative proportion of patients returning to baseline reactivity after study drug discontinuation. RESULTS A total of 56 patients were randomized; 54 were eligible for analysis. Platelet reactivity was lower 24 h after the last dose of prasugrel compared with clopidogrel. After prasugrel, ≥75% of patients returned to baseline reactivity by washout day 7 compared with day 5 after clopidogrel. Recovery time was dependent on the level of platelet reactivity before study drug exposure and the initial degree of platelet inhibition after study drug discontinuation but not on treatment assignment. CONCLUSIONS Recovery time after thienopyridine discontinuation depends on the magnitude of on-treatment platelet inhibition, resulting, on average, in a more delayed recovery with prasugrel compared with clopidogrel. The offset of prasugrel was consistent with current guidelines regarding the recommended waiting period for surgery after discontinuation. (Prasugrel/Clopidogrel Maintenance Dose Washout Study; NCT01014624).

Autonomic correlates of antidepressant treatment using heart-rate variability analysis.

Objective: To assess the 24-hour temporal-domain heart-rate variability correlates of treatment with fluoxetine or doxepinfor depression. Method: A randomized evaluation of fluoxetine and doxepin measured a 50% change in the Hamilton Depression Rating Scale (HDRS) score as a response to therapy and was correlated with measures of standard deviation of the mean of all 5-minute segments of normal electrocardiographic R-R intervals (SDANN), standard deviation of all normal R-R intervals (SDNN), root mean square of successive differences in R-R intervals (r-MSSD), and percentage difference between adjacent normal R-R intervals that are greater than 50 msec (pNN50)from 24-hour electrocardiogram (ECG) tapes. Results: Ten out of 14 patients responded. Response was associated with an increase in SDANN of 17% (P < 0.05). Nonresponse was associated with a 17% decrease in SDANN and a 22% decrease in SDNN (both P < 0.05). No other measures correlated with therapeutic response. No heart-rate variability (HRV) differences between the 2 drug therapies were observed. Conclusion: Twenty-four-hour HRV measures may be useful in assessing response to antidepressant therapy.

Electrocardiographic effects of fluoxetine and doxepin in patients with major depressive disorder.

Cardiovascular adverse effects are amongst the most serious observed with antidepressant drugs and are often due to effects on cardiac conduction and refractoriness. However, such electrophysiologic effects may not be evident when using conventional electrocardiographic measures. Forty patients with major depressive disorder (according to DSM-III-R criteria) were enrolled in a 6-week double-blind parallel group study of fluoxetine (N = 20) or doxepin (N = 20). Cardiac conduction (QRS duration) and repolarization (corrected QT interval, QTc), were measured using signal-averaged electrocardiograms and 12-lead electrocardiogram at baseline and after 2, 4, and 6 weeks of treatment. Patients taking doxepin (mean daily dosage at 6 weeks 169 +/- 42 mg) were similar to those taking fluoxetine (37 +/- 18 mg) for demographic variables and improvement in depression scores but volunteered more side effects (p = 0.011), especially dry mouth (p < 0.001) and dizziness/lightheadedness (p = 0.005). After 6 weeks, doxepin increased heart rate (69 +/- 12 to 81 +/- 13 beats per minute; p = 0.0003) and prolonged QTc (from 417 +/- 36 to 439 +/- 28 msec; p < 0.03); overall QRS duration was not prolonged but was correlated with serum doxepin concentrations (r = 0.78, p < 0.0001). Fluoxetine had no effect on QTc (428 +/- 24 msec at baseline vs. 430 +/- 24 msec at 6 weeks) or QRS duration (97 +/- 12 msec at baseline vs. 94 +/- 12 msec at 6 weeks). The standard 12-lead electrocardiogram showed no significant change in QRS or QTc for either drug. Using a sensitive measure of electrocardiographic effects, doxepin prolongs repolarization and may slow cardiac conduction. Fluoxetine has no measurable electrocardiographic effects, which suggests an increased safety margin for cardiac adverse effects. The ability of the signal-averaged electrocardiogram to resolve small changes in the electrocardiogram is useful in the assessment of drugs with subtle electrophysiologic effects.

Outcomes of Patients With Acute Myocardial Infarction Undergoing Percutaneous Coronary Intervention Receiving an Oral Anticoagulant and Dual Antiplatelet Therapy: A Comparison of Clopidogrel Versus Prasugrel From the TRANSLATE-ACS Study.

OBJECTIVES The purpose of this study was to determine whether bleeding risk varies depending on which P2Y12 receptor inhibitor agent is used. BACKGROUND Prior studies have shown significant bleeding risk among patients treated with triple therapy (i.e., oral anticoagulant, P2Y12 receptor inhibitor, and aspirin). METHODS We evaluated patients with acute myocardial infarction (MI) treated with percutaneous coronary intervention (PCI) at 233 hospitals in the United States enrolled in the TRANSLATE-ACS (Treatment with Adenosine Diphosphate Receptor Inhibitors: Longitudinal Assessment of Treatment Patterns and Events After Acute Coronary Syndrome) study (April 2010 to October 2012). Using inverse probability-weighted propensity modeling, we compared 6-month adjusted risks of Bleeding Academic Research Consortium (BARC) bleeding, stratifying by whether or not bleeding was associated with rehospitalization among patients discharged on aspirin + anticoagulant + clopidogrel (triple-C), aspirin + anticoagulant + prasugrel (triple-P), aspirin + clopidogrel (dual-C), or aspirin + prasugrel (dual-P). RESULTS Of 11,756 MI patients, 526 (4.5%) were discharged on triple-C, 91 (0.8%) on triple-P, 7,715 (66%) on dual-C, and 3,424 (29%) on dual-P. Compared with dual-therapy patients, triple-therapy patients had significantly higher any BARC-defined bleeding. Triple-P was associated with a greater risk of any BARC-defined bleeding events compared with triple-C. This finding was driven mostly by an increased risk of bleeding events that were patient-reported only and did not require rehospitalization. There were no significant differences in bleeding requiring rehospitalization between the triple-P and -C groups. CONCLUSIONS Among MI patients, the addition of an oral anticoagulant was associated with a significantly greater risk of any BARC-defined bleeding relative to dual antiplatelet therapy, regardless of which P2Y12 receptor inhibitor was selected. Among patients on triple therapy, prasugrel use was associated with higher patient-reported-only bleeding, but not bleeding requiring rehospitalization, than clopidogrel-treated patients.

Design and rationale for a randomized, controlled trial of interpersonal psychotherapy and citalopram for depression in coronary artery disease (CREATE).

Objective: Recognition that depression is associated with increased morbidity and mortality in coronary artery disease (CAD) patients has augmented the need for evidence-based treatment guidelines. This article presents the design of a multisite, Canadian trial of the efficacy, safety, and tolerability of interpersonal psychotherapy (IPT), an empirically supported, depression-focused therapy, and the selective serotonin reuptake inhibitor citalopram, alone or in combination, in the treatment of major depression in CAD patients. Methods: Two hundred eighty stable CAD patients with a current major depressive episode of at least 4 weeks’ duration, based on the Structured Clinical Interview for Depression (SCID), and who have a baseline score >19 on a centralized, telephone-administered, 24-item Hamilton Depression Rating Scale (HAM-D) will be randomly assigned to receive 12 weekly IPT sessions or 12 weekly sessions of standardized clinical management (CM). Patients are also randomly assigned to receive 20 to 40 mg per day of citalopram or pill-placebo. This results in a 2-by-2 factorial design with four groups: IPT plus pill-placebo, IPT plus citalopram, CM plus pill-placebo, and CM plus citalopram. This permits the evaluation of both IPT and citalopram. Blinded, centralized, 24-item, HAM-D telephone ratings constitute the primary outcome variable. The self-report Beck Depression Inventory-II is the secondary outcome. Analyses will involve the intent-to-treat principle with last observation carried forward for incomplete assessments. Results: Not applicable. Conclusions: The results of this trial will contribute to the development of evidence-based clinical guidelines for managing depression in the context of CAD. CREATE = Canadian Cardiac Randomized Evaluation of Antidepressant and Psychotherapy Efficacy; IPT = interpersonal psychotherapy; CAD = coronary artery disease; SCID = Structured Clinical Interview for Depression; HAM-D = Hamilton Depression Rating Scale; CM = clinical management; SADHART = Sertraline Antidepressant Heart Attack Randomized Trial; ENRICHD = Enhancing Recovery in Coronary Heart Disease; SSRI = selective serotonin reuptake inhibitor; ECG = electrocardiogram; NIMH = National Institute of Mental Health; TDCRP = Treatment of Depression Collaborative Research Program; MMSE = Mini-mental Status Exam; STAR*D = Sequenced Treatment Alternatives to Relieve Depression; IDS = Inventory for Depressive Symptomatology; BDI-II = Beck Depression Inventory-II; IPRI = Interpersonal Relationship Inventory; FPI = Functional Performance Inventory; SAE = serious adverse event; LOCF = last observation carried forward; DSMB = data safety monitoring board.