Annelieke M. Roest

Anxiety and Risk of Incident Coronary Heart Disease: A Meta-Analysis

OBJECTIVES The purpose of this study was to assess the association between anxiety and risk of coronary heart disease (CHD). BACKGROUND Less research has focused on the association of anxiety with incident CHD in contrast to other negative emotions, such as depression. METHODS A meta-analysis of references derived from PubMed, EMBASE, and PsycINFO (1980 to May 2009) was performed without language restrictions. End points were cardiac death, myocardial infarction (MI), and cardiac events. The authors selected prospective studies of (nonpsychiatric) cohorts of initially healthy persons in which anxiety was assessed at baseline. RESULTS Twenty studies reporting on incident CHD comprised 249,846 persons with a mean follow-up period of 11.2 years. Anxious persons were at risk of CHD (hazard ratio [HR] random: 1.26; 95% confidence interval [CI]: 1.15 to 1.38; p < 0.0001) and cardiac death (HR: 1.48; 95% CI: 1.14 to 1.92; p = 0.003), independent of demographic variables, biological risk factors, and health behaviors. There was a nonsignificant trend for an association between anxiety and nonfatal MI (HR: 1.43; 95% CI: 0.85 to 2.40; p = 0.180). Subgroup analyses did not show any significant differences regarding study characteristics, with significant associations for different types of anxiety, short- and long-term follow-up, and both men and women. CONCLUSIONS Anxiety seemed to be an independent risk factor for incident CHD and cardiac mortality. Future research should examine the association between anxiety and CHD with valid and reliable anxiety measures and focus on the mechanisms through which anxiety might affect CHD.

Quarterly Focus Issue: Prevention/OutcomesClinical Research: Cardiovascular RiskAnxiety and Risk of Incident Coronary Heart Disease: A Meta-Analysis

OBJECTIVES The purpose of this study was to assess the association between anxiety and risk of coronary heart disease (CHD). BACKGROUND Less research has focused on the association of anxiety with incident CHD in contrast to other negative emotions, such as depression. METHODS A meta-analysis of references derived from PubMed, EMBASE, and PsycINFO (1980 to May 2009) was performed without language restrictions. End points were cardiac death, myocardial infarction (MI), and cardiac events. The authors selected prospective studies of (nonpsychiatric) cohorts of initially healthy persons in which anxiety was assessed at baseline. RESULTS Twenty studies reporting on incident CHD comprised 249,846 persons with a mean follow-up period of 11.2 years. Anxious persons were at risk of CHD (hazard ratio [HR] random: 1.26; 95% confidence interval [CI]: 1.15 to 1.38; p < 0.0001) and cardiac death (HR: 1.48; 95% CI: 1.14 to 1.92; p = 0.003), independent of demographic variables, biological risk factors, and health behaviors. There was a nonsignificant trend for an association between anxiety and nonfatal MI (HR: 1.43; 95% CI: 0.85 to 2.40; p = 0.180). Subgroup analyses did not show any significant differences regarding study characteristics, with significant associations for different types of anxiety, short- and long-term follow-up, and both men and women. CONCLUSIONS Anxiety seemed to be an independent risk factor for incident CHD and cardiac mortality. Future research should examine the association between anxiety and CHD with valid and reliable anxiety measures and focus on the mechanisms through which anxiety might affect CHD.

Prognostic Association of Anxiety Post Myocardial Infarction With Mortality and New Cardiac Events: A Meta-Analysis

Objective: To assess the association of anxiety after myocardial infarction (MI) with cardiac prognosis. Methods: A meta-analysis of references derived from MEDLINE, EMBASE, and PSYCINFO (1975–March 2009) was performed without language restrictions. End point was cardiac outcome defined as all-cause mortality, cardiac mortality, and cardiac events. The authors selected prospective studies with at least 6 months follow-up, and anxiety had to be assessed within 3 months after MI with reliable and valid instruments. Results: Twelve papers met selection criteria. These studies described follow-up (on average, 2.6 years) of 5750 patients with MI. Anxious patients were at risk of adverse events (odds ratio (OR) fixed, 1.36; 95% confidence interval (CI), 1.18–1.56; p < .001). Anxiety was also specifically associated with all-cause mortality (OR fixed, 1.47; 95% CI, 1.02–2.13; p = .04), cardiac mortality (OR fixed, 1.23; 95% CI, 1.03–1.47; p = .02), and new cardiac events (OR fixed, 1.71; 95% CI, 1.31–2.23; p < .001). Conclusions: Post-MI anxiety is associated with a 36% increased risk of adverse cardiac outcomes in bivariate analyses. Because the existing literature is small and contains several limitations, more research is needed to evaluate the association of anxiety and prognosis in patients with MI and to assess the extent to which this association is independent of clinical variables, such as disease severity, and other psychological variables, especially depression. BMI = body mass index; CABG = coronary artery bypass graft; CHD = coronary heart disease; CI = confidence interval; CBAHF = Cognitive Behavioral Assessment Hospital Form; ENRICHD = Enhancing Recovery in Coronary Heart Disease Patients; FEM = fixed effects model; GAD = generalized anxiety disorder; HADS = Hospital Anxiety and Depression Scale; HR = hazard ratio; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MIND-IT = Myocardial Infarction and Depression Intervention Trial; NA = not available; OR = odds ratio; REM = random effects model; STAI = State Trait Anxiety Inventory; STPI = State Trait Personality Inventory; UA = unstable angina.

Gender differences in major depressive disorder: Results from the Netherlands study of depression and anxiety

BACKGROUND Although an overall gender difference in prevalence of major depressive disorder (MDD) has been well established, several questions concerning gender differences in the clinical manifestation of depression remain. This study aims to identify gender differences in psychopathology, treatment, and public health consequences in patients with MDD. METHODS Baseline data from the Netherlands Study of Depression and Anxiety (NESDA) were used, including 1115 participants (364 men, 751 women, mean age 41 years) with a DSM-IV diagnosis of current MDD. Characteristics studied included symptom profiles, comorbidity, treatment, and public health consequences. RESULTS Women reported a younger age of onset of single (27.8 years vs. 31.6 years; p=0.001) and recurrent MDD (24.8 years vs. 27.6 years; p=0.014), a higher comorbidity of panic disorder with agoraphobia (24.9% vs. 17.3%; p=0.006) and life-time overall anxiety disorder (77.6% vs. 71.4%; p=0.029) than men. More men than women suffered from comorbid alcohol dependence or abuse (48.1% vs. 24.5%; p<0.001). An increased prevalence of atypical depression in women (24.6% vs. 17.3%; p=0.009) was found. Women were treated more frequently by an alternative caretaker (20.6% vs. 14.8%; p=0.025), men more often in mental health care organizations (61.0% vs. 53.7%; p=0.025). No gender differences in frequency of medication use or counseling were found. LIMITATIONS Cross sectional design. CONCLUSIONS Main gender differences in the clinical presentation of MDD concerned a younger age of onset, higher anxiety and lower alcohol use comorbidity and higher prevalence of atypical depression in women. These differences were accompanied by differences in health care use.

Myocardial infarction and generalised anxiety disorder: 10-year follow-up

BACKGROUND Few studies have addressed the relationship between generalised anxiety disorder and cardiovascular prognosis using a diagnostic interview. AIMS To assess the association between generalised anxiety disorder and adverse outcomes in patients with myocardial infarction. METHOD Patients with acute myocardial infarction (n = 438) were recruited between 1997 and 2000 and were followed up until 2007. Current generalised anxiety disorder and post-myocardial infarction depression were assessed with the Composite International Diagnostic Interview. The end-point consisted of all-cause mortality and cardiovascular-related readmissions. RESULTS During the follow-up period, 198 patients had an adverse event. Generalised anxiety disorder was associated with an increased rate of adverse events after adjustment for age and gender (hazard ratio: 1.94; 95% confidence interval: 1.14-3.30; P = 0.01). Additional adjustment for measures of cardiac disease severity and depression did not change the results. CONCLUSIONS Generalised anxiety disorder was associated with an almost twofold increased risk of adverse outcomes independent demographic and clinical variables and depression.

Revealing Causal Heterogeneity Using Time Series Analysis of Ambulatory Assessments: Application to the Association Between Depression and Physical Activity After Myocardial Infarction

Objective Studies in psychosomatic medicine are characterized by analyses that typically compare groups. This nomothetic approach leads to conclusions that apply to the average group member but not necessarily to individual patients. Idiographic studies start at the individual patient and are suitable to study associations that differ between time points or between individuals. We illustrate the advantages of the idiographic approach in analyzing ambulatory assessments, taking the association between depression and physical activity after myocardial infarction as an example. Methods Five middle-aged men who had myocardial infarction with mild to moderate symptoms of depression were included in this study. Four of these participants monitored their physical activity and depressive symptoms during a period of 2 to 3 months using a daily self-registration form. The time series of each individual participant were investigated using vector autoregressive modeling, which enables the analysis of temporal dynamics between physical activity and depression. Results We found causal heterogeneity in the association between depression and physical activity. Participants differed in the predominant direction of effect, which was either from physical activity to depression (n = 1, 85 observations, unstandardized effect size = −0.183, p = .03) or from depression to physical activity (n = 2, 65 and 59 observations, unstandardized effect sizes = −0.038 and −0.381, p < .001 and p = .04). Also, the persistency of effects differed among individuals. Conclusions Vector autoregressive models are suitable in revealing causal heterogeneity and can be easily used to analyze ambulatory assessments. We suggest that these models might bridge the gap between science and clinical practice by translating epidemiological results to individual patients. Abbreviations PEP = Psycho-Educational Prevention Module BDI = Beck Depression Inventory PCI = percutaneous coronary intervention CABG = coronary artery bypass graft LVEF = left ventricular ejection fraction BMI = body mass index VAR = vector autoregressive modeling

Somatic/affective symptoms, but not cognitive/affective symptoms, of depression after acute coronary syndrome are associated with 12-month all-cause mortality

BACKGROUND Symptom dimensions of post myocardial infarction (MI) depression may be differently related to prognosis. Somatic/affective symptoms appear to be associated with a worse cardiac outcome than cognitive/affective symptoms. We examined the relationship between depressive symptom dimensions following acute coronary syndrome (ACS) and both disease severity and all-cause mortality. METHODS Patients (n=913) who had unstable angina pectoris or MI were recruited from 12 coronary care units between 1997 and 1999. Measurements included sociodemographic and clinical data and the Beck Depression Inventory (BDI). Endpoint was all-cause mortality at 12-month follow-up. RESULTS Principal component analysis revealed two components, somatic/affective and cognitive/affective symptoms of depression. Somatic/affective symptoms of depression (odds ratio (OR): 1.49; 95% confidence interval (CI): 1.23-1.81; p<0.001) but not cognitive/affective symptoms (OR: 0.92; 95% CI: 0.75-1.12; p=0.40) were related to a higher Killip class. Fifty-one patients died during the follow-up period. When controlling for index event, history of MI, Killip class, diabetes, gender and age, there was a significant association between the somatic/affective component (OR: 1.92; 95% CI: 1.36-2.71; p<0.001) and mortality. The cognitive/affective component was not related to mortality (OR: 1.07; 95% CI: 0.75-1.52; p=0.73). LIMITATIONS Time to death was not available. CONCLUSIONS This study showed that only somatic/affective depressive symptoms were associated with disease severity and all-cause mortality in ACS patients. More research is needed to evaluate the differential associations of somatic/affective and cognitive/affective depressive symptoms with cardiac outcomes and the underlying mechanisms.

Toward evidence-based medical statistics

The Food and Drug Administration (FDA) uses a p < 0.05 null‐hypothesis significance testing framework to evaluate “substantial evidence” for drug efficacy. This framework only allows dichotomous conclusions and does not quantify the strength of evidence supporting efficacy. The efficacy of FDA‐approved antidepressants for the treatment of anxiety disorders was re‐evaluated in a Bayesian framework that quantifies the strength of the evidence. Data from 58 double‐blind placebo‐controlled trials were retrieved from the FDA for the second‐generation antidepressants for the treatment of anxiety disorders. Bayes factors (BFs) were calculated for all treatment arms compared to placebo and were compared with the corresponding p‐values and the FDA conclusion categories. BFs ranged from 0.07 to 131,400, indicating a range of no support of evidence to strong evidence for the efficacy. Results also indicate a varying strength of evidence between the trials with p < 0.05. In sum, there were large differences in BFs across trials. Among trials providing “substantial evidence” according to the FDA, only 27 out of 59 dose groups obtained strong support for efficacy according to the typically used cutoff of BF ≥ 20. The Bayesian framework can provide valuable information on the strength of the evidence for drug efficacy. Copyright

Reporting Bias in Clinical Trials Investigating the Efficacy of Second-Generation Antidepressants in the Treatment of Anxiety Disorders: A Report of 2 Meta-analyses

IMPORTANCE Studies have shown that the scientific literature has overestimated the efficacy of antidepressants for depression, but other indications for these drugs have not been considered. OBJECTIVE To examine reporting biases in double-blind, placebo-controlled trials on the pharmacologic treatment of anxiety disorders and quantify the extent to which these biases inflate estimates of drug efficacy. DATA SOURCES AND STUDY SELECTION We included reviews obtained from the US Food and Drug Administration (FDA) for premarketing trials of 9 second-generation antidepressants in the treatment of anxiety disorders. A systematic search for matching publications (until December 19, 2012) was performed using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials. DATA EXTRACTION AND SYNTHESIS Double data extraction was performed for the FDA reviews and the journal articles. The Hedges g value was calculated as the measure of effect size. MAIN OUTCOMES AND MEASURES Reporting bias was examined and classified as study publication bias, outcome reporting bias, or spin (abstract conclusion not consistent with published results on primary end point). Separate meta-analyses were conducted for the 2 sources, and the effect of publication status on the effect estimates was examined using meta-regression. RESULTS The findings of 41 of the 57 trials (72%) were positive according to the FDA, but 43 of the 45 published article conclusions (96%) were positive (P < .001). Trials that the FDA determined as positive were 5 times more likely to be published in agreement with that determination compared with trials determined as not positive (risk ratio, 5.20; 95% CI, 1.87 to 14.45; P < .001). We found evidence for study publication bias (P < .001), outcome reporting bias (P = .02), and spin (P = .02). The pooled effect size based on the published literature (Hedges g, 0.38; 95% CI, 0.33 to 0.42; P < .001) was 15% higher than the effect size based on the FDA data (Hedges g, 0.33; 95% CI, 0.29 to 0.38; P < .001), but this difference was not statistically significant (β = 0.04; 95% CI, -0.02 to 0.10; P = .18). CONCLUSIONS AND RELEVANCE Various reporting biases were present for trials on the efficacy of FDA-approved second-generation antidepressants for anxiety disorders. Although these biases did not significantly inflate estimates of drug efficacy, reporting biases led to significant increases in the number of positive findings in the literature.

Association between anxiety and mortality in patients with coronary artery disease: A meta-analysis

BACKGROUND Depression and anxiety are common in patients with coronary artery disease (CAD). Although depression clearly has been associated with mortality in this population, the relationship between anxiety and mortality is less clear. Accordingly, we performed a series of meta-analyses to (1) examine the relationship between anxiety and mortality in patients with established CAD and (2) determine if this relationship differs in patients with stable CAD compared to those who have just had an acute coronary syndrome (ACS). METHODS AND RESULTS Systematic literature searches identified 44 articles (total N = 30,527) evaluating the prospective relationship between anxiety and mortality in individuals with established CAD. A series of 8 adjusted and unadjusted meta-analyses were performed to examine this relationship across all patients, with sensitivity analyses completed in post-ACS and stable CAD cohorts. In unadjusted analyses, anxiety was associated with a moderate increase in mortality risk (odds ratio 1.21 per SD increase in anxiety). However, when adjusting for covariates, nearly all associations became nonsignificant. In sensitivity analyses, anxiety was associated with an increased risk of poor outcomes in the stable CAD-but not post-ACS-cohort. CONCLUSIONS These analyses confirm that anxiety is associated with increased risk of mortality in patients with CAD; however, this relationship is not as strong as that of depression and may be explained partly by other clinical factors. If anxiety screening is performed, it should be performed during a period of clinical stability and should target anxiety disorders rather than anxiety symptoms alone.