Annotated Abstracts of Journal Articles
2013, 3rd Quarter
Annotations by Jeff Huffman, MD, FAPM
ANNOTATION (Jeff Huffman)
The Finding: The authors found that a stepped-care depression care management program in patients with recent acute coronary syndrome was associated with significantly greater depression improvement over 6 months compared to enhanced usual care; the intervention also appeared to be cost neutral.
Strengths and Weaknesses: Strengths included careful design, multiple academic and community sites, and measurement of costs. Weaknesses included that this was not a full ‘integrated care’ design (i.e., study prescribers made medication decisions), and no discussion of impact on medical outcomes, at least in this report. There was, consistent with other trials, a relatively modest overall improvement of depression symptoms (approximately 10 point improvement on BDI vs. 7 points in usual care), though the effect size in this trial was bigger than many others.
Relevance: This trial provides another example—in this case using psychotherapy delivered from a centralized location to subjects across the country in addition to locally prescribed medication—of a care management paradigm that may be broadly applicable and effective in a very high-risk population for whom depression is linked to mortality.
Importance: Controversy remains about whether depression can be successfully managed after acute coronary syndrome (ACS) and the costs and benefits of doing so.
Objective: To determine the effects of providing post-ACS depression care on depressive symptoms and health care costs.
Design: Multicenter randomized controlled trial. SETTING Patients were recruited from 2 private and 5 academic ambulatory centers across the United States.
Participants: A total of 150 patients with elevated depressive symptoms (Beck Depression Inventory [BDI] score =10) 2 to 6 months after an ACS, recruited between March 18, 2010, and January 9, 2012.
Interventions: Patients were randomized to 6 months of centralized depression care (patient preference for problem-solving treatment given via telephone or the Internet, pharmacotherapy, both, or neither), stepped every 6 to 8 weeks (active treatment group; n = 73), or to locally determined depression care after physician notification about the patient’s depressive symptoms (usual care group; n = 77).
Main Outcome Measures: Change in depressive symptoms during 6 months and total health care costs.
Results: Depressive symptoms decreased significantly more in the active treatment group than in the usual care group (differential change between groups, -3.5 BDI points; 95% CI, -6.1 to -0.7; P = .01). Although mental health care estimated costs were higher for active treatment than for usual care, overall health care estimated costs were not significantly different (difference adjusting for confounding, -$325; 95% CI, -$2639 to $1989; P = .78).
Conclusions: For patients with post-ACS depression, active treatment had a substantial beneficial effect on depressive symptoms. This kind of depression care is feasible, effective, and may be cost-neutral within 6 months; therefore, it should be tested in a large phase 3 pragmatic trial.
Trial Registration: clinicaltrials.gov Identifier: NCT01032018.
ANNOTATION (Jeff Huffman)
The Finding: Among SSRIs, citalopram and escitalopram were associated with significant dose-dependent increases in QTc (e.g., increase in citalopram from 10 to 20 mg associated with ~7ms increase in QTc; increase from 20mg to 40mg associated with ~10ms increase); this finding was not replicated in other SSRIs, and bupropion was associated with slight QTc decrease.
Strengths and Weaknesses: The strengths of this work include the fact that this was a very large dataset and an unselected/real-world population; the major limitation is that this sort of data analysis does not allow any kind of random assignment of medication or dose, and medications and dose changes may have been made for specific clinical reasons not accounted for in the analysis.
Relevance: This analysis indeed suggests a small but statistically significant effect of citalopram and escitalopram—but not other SSRIs—on QTc and suggests that patients at high risk for arrhythmia should generally be placed on one of these other SSRIs.
Objective: To quantify the impact of citalopram and other selective serotonin reuptake inhibitors on corrected QT interval (QTc), a marker of risk for ventricular arrhythmia, in a large and diverse clinical population.
Design: A cross sectional study using electrocardiographic, prescribing, and clinical data from electronic health records to explore the relation between antidepressant dose and QTc. Methadone, an opioid known to prolong QT, was included to demonstrate assay sensitivity.
Setting: A large New England healthcare system comprising two academic medical centres and outpatient clinics.
Participants: 38,397 adult patients with an electrocardiogram recorded after prescription of antidepressant or methadone between February 1990 and August 2011.
Main Outcome Measures: Relation between antidepressant dose and QTc interval in linear regression, adjusting for potential clinical and demographic confounding variables. For a subset of patients, change in QTc after drug dose was also examined.
Results: Dose-response association with QTc prolongation was identified for citalopram (adjusted beta 0.10 (SE 0.04), P<0.01), escitalopram (adjusted beta 0.58 (0.15), P<0.001), and amitriptyline (adjusted beta 0.11 (0.03), P<0.001), but not for other antidepressants examined. An association with QTc shortening was identified for bupropion (adjusted beta 0.02 (0.01) P<0.05). Within-subject paired observations supported the QTc prolonging effect of citalopram (10 mg to 20 mg, mean QTc increase 7.8 (SE 3.6) ms, adjusted P<0.05; and 20 mg to 40 mg, mean QTc increase 10.3 (4.0) ms, adjusted P<0.01).
Conclusions: This study confirmed a modest prolongation of QT interval with citalopram, and identified additional antidepressants with similar observed risk. Pharmacovigilance studies using electronic health record data may be a useful method of identifying potential risk associated with treatments.
ANNOTATION (Jeff Huffman)
Patients randomized to 6 weeks of escitalopram (titrated to 20mg/day) had significantly lower rates of mental stress-induced ischemia when retested at the end of the trial (~65% vs. 83%), though not significantly lower rates of exercise-induced ischemia, versus placebo.
Strengths and Weaknesses: Strengths of the trial included assessment of covariates and use of imputation to account for missing data, and the overall novelty of the project (stress-induced ischemia has been linked to cv prognosis but there have been few studies of treatments). Weaknesses include relatively small sample size (n=127) and lack of data on clinical outcomes.
Relevance: Overall, this suggests that escitalopram reduces mental-stress induced ischemia in nondepressed (mean baseline BDI of cohort=9) heart disease patients; whether this is due to effects of SSRIs on small cardiac vessels, platelets, or psychological factors is unclear, but this is a very intriguing finding that should prompt additional study given potential benefit on major adverse events.
Importance: Mental stress can induce myocardial ischemia and also has been implicated in triggering cardiac events. However, pharmacological interventions aimed at reducing mental stress-induced myocardial ischemia (MSIMI) have not been well studied.
Objective: To examine the effects of 6 weeks of escitalopram treatment vs placebo on MSIMI and other psychological stress-related biophysiological and emotional parameters.
Design, Setting, and Participants: The REMIT (Responses of Mental Stress Induced Myocardial Ischemia to Escitalopram Treatment) study, a randomized, double-blind, placebo-controlled trial of patients with clinically stable coronary heart disease and laboratory-diagnosed MSIMI. Enrollment occurred from July 24, 2007, through August 24, 2011, at a tertiary medical center.
Interventions: Eligible participants were randomized 1:1 to receive escitalopram (dose began at 5 mg/d, with titration to 20 mg/d in 3 weeks) or placebo over 6 weeks.
Main Outcomes and Measures: Occurrence of MSIMI, defined as development or worsening of regional wall motion abnormality; left ventricular ejection fraction reduction of 8% or more; and/or horizontal or down-sloping ST-segment depression of 1 mm or more in 2 or more leads, lasting for 3 or more consecutive beats, during 1 or more of 3 mental stressor tasks.
Results: Of 127 participants randomized to receive escitalopram (n = 64) or placebo (n = 63), 112 (88.2%) completed end point assessments (n = 56 in each group). At the end of 6 weeks, more patients taking escitalopram (34.2% [95% CI, 25.4%-43.0%]) had absence of MSIMI during the 3 mental stressor tasks compared with patients taking placebo (17.5% [95% CI, 10.4%-24.5%]), based on the unadjusted multiple imputation model for intention-to-treat analysis. A significant difference favoring escitalopram was observed (odds ratio, 2.62 [95% CI, 1.06-6.44]). Rates of exercise-induced ischemia were slightly lower at 6 weeks in the escitalopram group (45.8% [95% CI, 36.6%-55.0%]) than in patients receiving placebo (52.5% [95% CI, 43.3%-61.8%]), but this difference was not statistically significant (adjusted odds ratio; 1.24 [95% CI, 0.60-2.58]; P = .56).
Conclusions and Relevance: Among patients with stable coronary heart disease and baseline MSIMI, 6 weeks of escitalopram, compared with placebo, resulted in a lower rate of MSIMI. There was no statistically significant difference in exercise-induced ischemia. Replication of these results in multicenter settings and investigations of other medications for reducing MSIMI are needed.