Selective Serotonin Reuptake Inhibitors in Patients with Depression and Coronary Heart Disease: a meta-analysis.

Transcription

1 Selective Serotonin Reuptake Inhibitors in Patients with Depression and Coronary Heart Disease: a meta-analysis. Carmine Pizzi, MD 1, Anne Wilhelmina Saskia Rutjes, PhD 2,3 Grazia Maria Costa, MD 4, Fiorella Fontana, MD 1, Andrea Mezzetti, MD 2, Lamberto Manzoli, MD MPH 2,5. (1) Department of Internal Medicine, Aging and Nephrological Diseases, University of Bologna, Italy; (2) Clinical Research Center, Ce.S.I., University "G. d'annunzio" Foundation, Chieti, Italy; (3) Division of Clinical Epidemiology and Biostatistics, Institute of Social and Preventive Medicine (ISPM), University of Bern, Switzerland; (4) Department of Cardiovascular Disease, University of Bologna, Italy; (5) Section of Epidemiology and Public Health, University G. d Annunzio of Chieti, Italy.

2 Background Coronary heart disease (CHD) is the leading cause of death, major morbidity and disability in Europe and the United States. Among CHD patients, approximately 40% experience depressive symptoms and about 20-25% develop major depression, which in turn is the fourth leading cause of global disease burden.

3 Background Indeed, the occurrence of depression in patients with CHD has shown to substantially increase the likelihood of a poorer cardiovascular prognosis. Although antidepressants are generally effective in reducing depression, their use in CHD patients is controversial. Some studies have shown an increased CHD risk associated with depression and the use of tricyclic antidepressant medication. As a consequence, selective serotonin reuptake inhibitors (SSRIs) currently represent the mainstay of pharmacological treatment for depressed CHD patients. However, some studies supported the efficacy and safety of SSRIs for such patients, while other observational analyses reported an association between SSRI and serious cardiovascular events. Therefore, uncertainty remains on the effects of SSRIs in patients with depression and CHD.

4 Aim of the Study We carried out a meta-analysis to summarize the evidence on the effects of SSRI versus placebo or no antidepressants in terms of allcause mortality and readmission for CHD in patients with CHD and depression.

5 Methods Study Population Studies evaluating the health effects of any SSRI on depressed individuals with CHD were retrieved through a search in MEDLINE (Pubmed), EMBASE, PsycINFO and CENTRAL, and the Cochrane Controlled Clinical Trial Register ( from inception to April 30, We did not apply any language restriction. Search terms were SSRI* or selective serotonin reuptake inhibitor* or citalopram or dapoxetine or escitalopram or fluoxetine or fluvoxamine or paroxetine or sertraline or zimelidine, depress*, coronary heart disease* or heart disease or cardiovascular disease* or myocardial infarction or angina or acute coronary syndrome in all fields. In addition, we searched the following clinical trial registries: and screened the bibliographies of related systematic reviews and articles meeting inclusion criteria. To locate unpublished material and avoid systematic (ie, publication) bias, we searched the Food and Drug Administration or other sources. Case-control and cohort studies, as well as randomized controlled trials (RCTs) were considered for inclusion. Studies without a control group or with active control groups (other antidepressant medications) were excluded.

6 Methods The primary outcomes related to safety: readmission for CHD (including myocardial infarction, unstable angina, and stroke) and all-cause mortality. Secondary outcomes pertained to SSRI efficacy in reducing depression: mean reduction in depression symptoms between baseline and the end of the follow-up; response rate (defined as the percentage of individuals who had at least a 50% reduction in their baseline depression score during follow-up); and remission rate (proportion of patients whose depression score decreased below a certain cutoff indicating normality during the follow-up). All validated instruments were accepted to evaluate depression symptoms. When a study used more than one depression scale, we applied an a priori determined hierarchy (based upon diffusion in the field), and extracted data on the depression scale that was highest on this ordered list: Hamilton Depression 17-item rating scale (HAMD-17), Hamilton Depression 24-item rating scale (HAMD- 24) [24], Beck Depression Inventory (BDI), other validated depression scale.

7 Results Characteristics and methodological quality of eligible studies Of the 1413 papers initially retrieved (Figure 1), we identified eleven studies that evaluated the health effects of SSRI in depressed patients with cardiovascular diseases. Of those, four had to be excluded; one trial because of the absence of a control group; one trial because an active control group receiving other antidepressants was used; one cohort study because of misclassification of SSRI drugs (venlafaxine and clomipramine were considered as SSRI); and one case-control study because it did not include any of the outcomes considered. Seven reports on six studies were eligible and included in the analyses. Four studies concerned randomized controlled trials. One trial randomized 50 patients before assessing inclusion criteria, then limited the analysis to the 17 patients with depression. It was therefore considered as incorrectly randomized (thus, observational) and excluded from the main analysis. Another study was a re-analysis of the data of a subset of patients participating in a randomized controlled trial (RCT), evaluating the effects of cognitive behavior therapy, supplemented with SSRI when indicated.

8 Results Overall, data were available on a total of 2461 patients from North America, Europe, Australia and India, with a mean age that was similar in all trials and close to 58 years (Table 1). Inclusion criteria varied, although all patients were previously admitted for CHD. Depression was established using validated methodology in all studies, which had been performed from 1994 up to 2006, with a mean follow-up duration varying from a minimum of 12 weeks to a maximum of 29 months Table 2 summarizes the methodological characteristics of the included studies. Only Lespérance and colleagues reported the use of adequate methods of sequence generation and concealment of allocation. The remaining three randomized trials did not provide any details on sequence generation or method of concealment. In the study by Taylor et al., we judged the groups to be comparable at baseline for confounding factors, except for age and gender. Taylor and colleagues did not model according to the original design, in which patients were randomized to either cognitive behavior therapy or usual care, which is a limitation in their analysis. They however adequately adjusted the analysis for all relevant confounders except gender. Most studies reported adequate blinding of patients. Although the trials by Strik and colleagues and Mohapatra and colleagues were described as double blinded trials, it was unclear whether therapists, outcome assessors or both were blinded.

9 Results Main outcomes Readmission for coronary heart diseases and all-cause mortality When the studies with incorrect randomization were excluded, the metaanalysis of the remaining three RCTs evaluating the association between SSRI use and risk of CHD readmission did not show a significant difference in the rate of CHD readmissions between SSRI patients and controls (Figure 2; p=0.24). Two of the three RCTs showed RRs that were reduced, but not significant. Conversely, when all studies were considered, patients assuming SSRI showed a significantly lower rate of CHD readmissions during the follow-up as compared with controls (Table 2 RR=0.63; 95% CI: ). Similarly, when all studies that assessed all-cause mortality were combined, a significantly lower risk of death (Figure 3 RR=0.56; 95% CI: ) was observed for SSRI patients, but this association was no longer significant when the two studies with incorrect randomization were excluded (p=0.26). Three of the five studies examining mortality showed reduced RRs for the SSRI group, but only the largest study achieved significance

10 Results Secondary outcomes Remission and response after therapy, and reduction of depression symptoms Four studies compared the remission rate for depression in patients assuming SSRIs versus controls (Figure 4, 5 and 6): all trials reported RRs that were elevated; significantly in two studies. No relevant differences emerged excluding the trial with incorrect randomization: compared with control, the assumption of SSRI determined a 35% increase in the rate of remissions during the follow-up (95% CI: 15%- 60%), and such a difference was highly significant (p<0.001). Likewise, SSRI patients showed an increased likelihood of responding to therapy 36% higher than controls (p=0.010) and a significantly greater reduction in depression symptoms (SMD=0.41; p=0.007). All of the five studies evaluating the effects of SSRI on depression symptoms showed a higher reduction for the treatment group, but this result was significant only in three trials.

11 TABLE 1. Characteristics of published studies investigating the health effects of selective serotonin reuptake inhibitors (SSRI) versus placebo or no intervention. First Author RCT Strik McFarlane Glassman Lespérance Design RCT, Double blind RCT, Double blind RCT, Double blind RCT, Double blind Main inclusion criteria From 3 to 12 months after myocardial infarction (MI), with DSM-III-R criteria for major depressive episode met, and HAMD-17>17. After discharge for MI, scoring >=15 (twice) at the Inventory to Diagnose Depression (IDD): minor or major depression. After discharge for MI (74%) or unstable angina (26%), with DSM-IV criteria for major depression met and BDI>10. After discharge for CHD, with DSM-IV criteria for major depression met for >=4 weeks and HAMD-24>=20. Observational or RCT with high risk of bias in the randomization process Sample Size Intervention Fluoxetine vs placebo Sertraline vs placebo Sertraline vs placebo 4 arms: (1) Psychotherapy + Citalopram; (2) Psychotherapy + placebo; (3) Citalopram; (4) placebo. Dose in each arm Flexible-dose: from 20 to 40 or 60 mg/d depending on clinical response. Mean dose / mg/d. Fixed-dose: 50 mg/d. Flexible-dose: from 50 to 200 mg/d depending on clinical response. Mean dose = / mg/d. Flexible-dose: from 20 to 40 mg/d. Mean dose / mg/d. Taylor After admission for acute myocardial infarction, with DSM-IV criteria for depression met for >=14 days, or >=7 days if prior major depression, and HAMD-17>24 or change in BDI<50% in the first 5 weeks Sertraline (49.5%) or Paroxetine (29%), or Fluoxetine (13%) or another SSRI (8.6%) vs no intervention Flexible-dose: i.e. Sertraline, from 50 to 200 mg/d depending on clinical response. Mohapatra After MI, during their hospital stay, with DSM-IV criteria for depression 38 Sertraline vs no intervention Flexible-dose: from 50 to 200 mg/d depending on clinical response.

12 TABLE 2. General characteristics of the sample. Adequate sequence generation? Allocation concealment? Adequate blinding of patients? Adequate blinding of therapists? Adequate blinding of outcome assessors? Intention-totreat analysis performed? Strik, 2000?? +?? + McFarlane, 2001?? +?? Glassman, 2002 Taylor, 2005 Mohapatra, 2005 Lespérance, 2007?? +? + + +????

13 Figure 1. Flow of the included studies in each stage of the bibliographic search potentially relevant reports identified and screened 1349 reports excluded by title/abstract reading 64 reports retrieved for detailed evaluation 53 reports excluded for not satisfying inclusion criteria 11 potentially appropriate studies for inclusion in meta-analysis 2 trials excluded because of absence of a valid control group 1 cohort study excluded because of misclassification of SSRI 1 case-control study excluded because it did not include any of the outcomes considered 7 reports reporting the results of 6 randomized controlled trials included in the meta-analysis: 4 RCTs included in the main analysis 2 RCT with high risk of bias in the randomization process included in secondary analyses

14 Meta-analysis evaluating the risk of CHD readmission of patients assuming selective serotonin reuptake inhibitors (SSRI), as compared with placebo or no intervention. Study or Subgroup RCT Strik 2000 Glassmann All 2002 Lesperance 2007 Subtotal (95% CI) Risk Ratio IV, Random, 95% CI 0.17 [0.02, 1.29] 0.77 [0.51, 1.16] 1.00 [0.33, 3.03] 0.74 [0.44, 1.23] Heterogeneity: Tau² = 0.05; Chi² = 2.34, df = 2 (P = 0.31); I² = 15% Test for overall effect: Z = 1.16 (P = 0.24) Year Risk Ratio IV, Random, 95% CI Observational or RCT with high risk of bias in randomization Taylor 2005 Mohapatra 2005 Subtotal (95% CI) 0.53 [0.32, 0.89] 0.44 [0.18, 1.05] 0.50 [0.32, 0.79] Heterogeneity: Tau² = 0.00; Chi² = 0.13, df = 1 (P = 0.72); I² = 0% Test for overall effect: Z = 3.01 (P = 0.003) Total (95% CI) 0.63 [0.46, 0.86] Heterogeneity: Tau² = 0.01; Chi² = 4.24, df = 4 (P = 0.37); I² = 6% Test for overall effect: Z = 2.95 (P = 0.003) Favours SSRI Favours Control

15 Meta-analysis evaluating the risk of death for any cause of patients assuming selective serotonin reuptake inhibitors (SSRI), as compared with placebo or no intervention. Study or Subgroup RCT Strik 2000 McFarlane 2001 Glassmann All 2002 Subtotal (95% CI) Heterogeneity: Not applicable Risk Ratio IV, Random, 95% CI Not estimable Not estimable 0.39 [0.08, 2.01] 0.39 [0.08, 2.01] Test for overall effect: Z = 1.12 (P = 0.26) Year Risk Ratio IV, Random, 95% CI Observational or RCT with high risk of bias in randomization Taylor 2005 Mohapatra 2005 Subtotal (95% CI) 0.59 [0.37, 0.95] 0.19 [0.01, 3.87] 0.57 [0.36, 0.92] Heterogeneity: Tau² = 0.00; Chi² = 0.53, df = 1 (P = 0.47); I² = 0% Test for overall effect: Z = 2.31 (P = 0.02) Total (95% CI) 0.56 [0.35, 0.88] Heterogeneity: Tau² = 0.00; Chi² = 0.72, df = 2 (P = 0.70); I² = 0% Test for overall effect: Z = 2.53 (P = 0.01) Favours SSRI Favours control

16 Meta-analysis evaluating the standardized mean difference in depression symptoms change between baseline and the end of follow-up, of patients assuming selective serotonin reuptake inhibitors (SSRI), as compared with placebo or no intervention. Study or Subgroup RCT Strik 2000 McFarlane 2001 Glassmann All 2002 Lesperance 2007 Subtotal (95% CI) Std. Mean Difference IV, Random, 95% CI 0.38 [-0.16, 0.92] 1.34 [0.48, 2.19] 0.14 [-0.06, 0.35] 0.29 [0.05, 0.52] 0.34 [0.06, 0.63] Heterogeneity: Tau² = 0.04; Chi² = 7.63, df = 3 (P = 0.05); I² = 61% Test for overall effect: Z = 2.38 (P = 0.02) Year Std. Mean Difference IV, Random, 95% CI Observational or RCT with high risk of bias in randomization Mohapatra 2005 Subtotal (95% CI) Heterogeneity: Not applicable 1.14 [0.06, 2.23] 1.14 [0.06, 2.23] Test for overall effect: Z = 2.06 (P = 0.04) 2005 Total (95% CI) 0.41 [0.11, 0.70] Heterogeneity: Tau² = 0.06; Chi² = 10.17, df = 4 (P = 0.04); I² = 61% Test for overall effect: Z = 2.69 (P = 0.007) Favours control Favours SSRI

17 Meta-analysis evaluating the likelihood of remission from depression of patients assuming selective serotonin reuptake inhibitors (SSRI), as compared with placebo or no intervention. Study or Subgroup RCT Strik 2000 Glassmann All 2002 Lesperance 2007 Subtotal (95% CI) Total events Risk Ratio M-H, Random, 95% CI 1.75 [0.58, 5.29] 1.27 [1.07, 1.50] 1.59 [1.09, 2.32] 1.32 [1.14, 1.54] Heterogeneity: Tau² = 0.00; Chi² = 1.54, df = 2 (P = 0.46); I² = 0% Test for overall effect: Z = 3.61 (P = ) Year Risk Ratio M-H, Random, 95% CI Observational or RCT with high risk of bias in randomization Mohapatra 2005 Subtotal (95% CI) Total events Heterogeneity: Not applicable 2.73 [0.87, 8.59] 2.73 [0.87, 8.59] Test for overall effect: Z = 1.71 (P = 0.09) 2005 Total (95% CI) 1.35 [1.15, 1.60] Total events Heterogeneity: Tau² = 0.00; Chi² = 3.10, df = 3 (P = 0.38); I² = 3% Test for overall effect: Z = 3.58 (P = ) Favours control Favours SSRI

18 Meta-analysis evaluating the likelihood of responding to the therapy of patients assuming selective serotonin reuptake inhibitors (SSRI), as compared with placebo or no intervention. Risk Ratio Risk Ratio Study or Subgroup M-H, Random, 95% CI Year M-H, Random, 95% CI Strik [0.88, 3.92] 2000 Lesperance [1.02, 1.70] 2007 Total (95% CI) 1.36 [1.07, 1.73] Total events Heterogeneity: Tau² = 0.00; Chi² = 0.74, df = 1 (P = 0.39); I² = 0% Test for overall effect: Z = 2.53 (P = 0.01) Favours Control Favours SSRI

19 Conclusions The present meta-analysis showed that, in patients with CHD and depression, the administration of SSRIs versus placebo or negative control significantly improved depression symptoms, and might also reduce mortality and CHD readmission rates. Although these findings suggest that SSRI can be safely and effectively used for depressed CHD patients, high-quality evidence is limited and further adequately powered randomized controlled trials are urgently needed.