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Duloxetine and cardiovascular adverse events: A systematic review and meta-analysis
Journal of Psychiatric Research 124 (2020) 109–114
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Journal of Psychiatric Research journal homepage: www.elsevier.com/locate/jpsychires
Duloxetine and cardiovascular adverse events: A systematic review and meta-analysis
T
Kyounghoon Park, Seonji Kim, Young-Jin Ko, Byung-Joo Park∗ Department of Preventive Medicine, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, South Korea
A R T I C LE I N FO
A B S T R A C T
Keywords: Duloxetine Cardiovascular adverse events Systematic review Risk of Bias 2.0 PRISMA harm checklist
Duloxetine has been increasingly administered, but the associated cardiovascular adverse event risk is not clearly understood. Therefore, we identified the association between duloxetine and cardiovascular adverse events through an analysis of heart rate and blood pressure change. We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and psycINFO in June 2019. The title, abstract, and full text were checked in order to obtain articles. A meta-analysis was conducted with random effect model and quality of articles was evaluated using Cochrane Risk of Bias 2.0. The manuscript has been written according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) harm checklist. A total of 4009 studies were screened by the title and abstract. After reviewing 186 full texts, 17 studies were finally selected for the meta-analysis. Nine of the 17 studied duloxetine given for mood disorders and 8 for pain control. The duration of 14 studies was under 13 weeks. Cardiovascular adverse events (hypertension, myocardial infarction, transient ischemic attack, tachycardia atrial fibrillation, and cerebrovascular accident) were reported. The meta-analysis demonstrated that duloxetine increased heart rate by 2.22 beats/min (95% confidence intervals [CIs]: 1.53, 2.91) and diastolic blood pressure by 0.82 mmHg (95% CI: 0.17, 1.47). Our findings may be the signal for the safety of cardiovascular disease for short-term use of duloxetine. Well-designed pharmacoepidemiological studies evaluating the causal relationship between long-term use of duloxetine and cardiovascular disease is still necessary.
1. Introduction Cardiovascular disease (CVD) is the number one cause of death worldwide, causing 17.9 million deaths in 2016. It encompasses diseases of the blood vessels such as coronary artery disease and cerebrovascular disease (WHO, 2017). The known risk factors for CVD are obesity, hyperlipidemia, hypertension, diabetes, smoking, lack of exercise, and excessive drinking (Lichtenstein et al., 2006). It has also been established that mood disorders such as major depressive disorder (MDD) and bipolar disorder are associated with CVD (Frasure-Smith and Lesperance, 2005). Additionally, the prevalence of MDD is higher in patients with CVD (Niranjan et al., 2012); therefore, risk assessment for CVD with antidepressant use is gaining importance. Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) that blocks serotonin and norepinephrine neuro-transporters (Chalon et al., 2003). In 2017, duloxetine was prescribed more than 16 million times in the U.S. and was the most widely used drug among the SNRIs along with venlafaxine (AHRQ, 2017). Although there are differences in
the neuroanatomy of the regulatory pathways, reuptake inhibition of serotonin and norepinephrine neurotransmission is expected to affect both mood disorders and pain control (Goldstein et al., 2004). However, because the levels of both serotonin and norepinephrine are increased with the use of SNRIs, hypertension, tachycardia, arrhythmias, and other adverse events are more likely than with selective serotonin reuptake inhibitors use (Piña et al., 2018). There are several studies on the cardiovascular-related adverse events of duloxetine. According to an analysis of eight randomized controlled trials (RCTs), the use of duloxetine compared to placebo significantly increased heart rate (HR) (1.6 vs. −0.6 beats/min) and systolic blood pressure (SBP) (1.0 vs. −1.2 mmHg) (Thase et al., 2005). In 2007, results from 42 placebo-controlled trials reported a significant increase in HR (3.20 vs. −0.67 beats/min), SBP (0.65 vs. −0.55 mmHg), and diastolic blood pressure (DBP) (0.88 vs. −0.18 mmHg) (Wernicke et al., 2007). The authors concluded that the results were statistically significant but clinically meaningless. However, the analysis was not a systematic review and many of the studies
∗ Corresponding author. Department of Preventive Medicine, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea. E-mail addresses: [email protected] (K. Park), [email protected] (S. Kim), [email protected] (Y.-J. Ko), [email protected] (B.-J. Park).
https://doi.org/10.1016/j.jpsychires.2020.02.022 Received 4 December 2019; Received in revised form 24 February 2020; Accepted 24 February 2020 0022-3956/ © 2020 Elsevier Ltd. All rights reserved.
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and created a funnel plot to determine the probability of publication bias.
(13 of 42) were not published. Since the indications for duloxetine have expanded and new RCTs are being conducted, systematic reviews and meta-analyses are necessary to reassess the potential cardiovascular-related adverse events of duloxetine. Therefore, we identified RCTs that reported cardiovascularrelated adverse events after comparing duloxetine and placebo. Changes in HR, SBP, and DBP from these studies have been quantitatively summarized.
2.4. Risk of bias in individual studies We used Cochrane ROB (Risk-of-bias tool for randomized trials) version 2.0 from August 22, 2019, to assess for bias (Sterne et al., 2019). This tool was developed to assess the risk of bias in RCTs and consist of 5 domains: 1) the randomization process, 2) the intended interventions, 3) missing outcome data, 4) the measurement of the outcome, and 5) the reported result. Because our main concern was safety, we evaluated outcomes accordingly. This study was written in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) harms checklist (Zorzela et al., 2016). Studies search, selection, data extraction, and risk of bias evaluation were performed independently by two authors (KP and SK), and a conclusion was reached through consensus. A conclusion was reached through discussion with other authors in case there was a disagreement (YJK and BJP).
2. Methods and materials 2.1. Search strategy We searched Medline/PubMed, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), ClinicalTrials.gov, and PsycINFO databases in June 2019 to find studies that met our inclusion criteria. We constructed a PICOT-SD (Patients, Intervention, Comparison, Outcome, Time, Setting and Design) to discover keywords. Any indication for duloxetine prescription (P, I) compared with a placebo or no medication (C), outcome-related safety (O), published after the 1990s (T), community- or hospital-based (S), and designated RCTs (D). The outcome (O) keywords used were related to the overall safety (safety, complication, adverse event, etc.) and included CVD. When we conducted the pilot study, we confirmed that the search was insufficient when the outcome keywords were limited to specific diseases or conditions such as CVD, hypertension, and blood pressure. Therefore, terms for specific diseases, conditions, and safety were included as keywords used for searching. The keywords were created by combining keyword subject searches (such as Medical Subject Headings) and free text words (Table S1). The retrieved studies were sorted using EndNote X9 and Excel. There was no language restriction.
3. Results After removing 717 duplicates from the 4726 studies retrieved, 3823 studies were additionally removed after reviewing the title and abstract because they were not RCTs involving duloxetine. For the 186 studies selected, the full texts were evaluated for eligibility. Those sharing study samples (n = 10), those without parallel design and open-label studies (n = 56), studies comparing duloxetine to other antidepressants or analgesics only (n = 32), and studies whose full texts were impossible to find (n = 8) were excluded. Additionally, 15 studies were obtained from the ClinicalTrials.gov database. In the end, 95 studies were selected. The studies were then divided, by indications, into mood disorder, (n = 35) pain control, (n = 41) urinary incontinence, (n = 12) and others (n = 9). In the end, we conducted a metaanalysis with 17 studies (Goldstein et al., 2004; Detke et al., 2004; Arnold et al., 2005; Raskin et al., 2005; Perahia et al., 2006, 2009; Allgulander et al., 2008; Chappell et al., 2008; Skljarevski et al., 2009, 2010; Gaynor et al., 2011; Wu et al., 2011; Vollmer et al., 2014; Atkinson et al., 2014; Emslie et al., 2014; Strawn et al., 2015; Upadhyaya et al., 2019). Sixteen studies on HR change, 12 studies on SBP change, and 13 studies on DBP change were included (Fig. 1).
2.2. Study selection and data collection After removing duplicate studies, the titles and abstracts of the RCTs related to duloxetine were searched for any information on the adverse events of duloxetine. Thereafter, the RCTs studies that compared duloxetine to a placebo or to no treatment were selected through full-text reviews. Because information on adverse events of duloxetine was often unknown before the full texts were checked, the exclusion was not made before the final selection of the studies through full-text reviews. The exclusion criteria were studies that shared patient data from other RCTs, compared duloxetine with other antidepressants or analgesics only, open-labeled studies, and those that switched duloxetine and placebo treatments during the study period. Unlike other databases, ClinicalTrials.gov provided the results of clinical trials in text form without providing abstracts or titles. Therefore, among the studies that were searched in ClinicalTrials.gov, studies not found in other databases and presented information on the adverse events of duloxetine were included. We then collected data from the selected studies: authors; publication year; indication for duloxetine; study period; number of subjects taking duloxetine; number of subjects in the control group; age and sex of the subjects; the daily dose of duloxetine; any reported adverse event related to CVD during the study course (e.g., hypertension, myocardial infarction, heart failure, and stroke); and the change from baseline of HR, SBP, and DBP for subjects taking duloxetine and those taking a placebo.
3.1. General characteristics of studies included in the meta-analysis Nine of the 17 studies were conducted for mood disorders and 8 studies for controlling pain. Fourteen of the studies lasted less than 13 weeks and the daily doses of duloxetine were 30, 60, 80, and 120 mg. Nine studies were conducted using a single dose, and in eight studies, the treatment dose was increased during the study. The sample size of the study group ranged from 331 to 59. The proportion of women in all groups was larger than men. Thirteen studies were conducted on those aged between 30s and 50s, and four studies on 10s. Many cardiovascular-related adverse events were reported. Hypertension was the most common adverse event, but myocardial infarction, transient ischemic attack, tachycardia, atrial fibrillation, and cerebrovascular accident were also reported (Table 1). 3.2. Meta-analysis for HR, SBP, and DBP change from baseline compared to a placebo
2.3. Statistical analyses A meta-analysis of the mean difference of HR, SBP, and DBP change from baseline between duloxetine and placebo was performed. Additionally, we conducted subgroup analyses of the subjects' ages and drug indications. Since the heterogeneity of each group was expected to be high, a random effects model was used and the heterogeneity between groups was calculated as Higgins I2. We also applied Egger's test
Compared to the placebo group, the duloxetine group showed a 2.22 beats/min (95% confidence interval [CI]: 1.53, 2.91) increase in HR (Fig. 2). SBP increased by 0.62 mmHg (95% CI: -0.24, 1.52) although insignificant, statistically (Fig. 3). DBP increased by 0.82 mmHg (95% CI: 0.17, 1.47) (Fig. 4). The heterogeneity of the included studies 110
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Fig. 1. Flow chart of systematic review and meta-analysis.
was calculated by Higgins I2 and was not very high (HR: 27%; SBP: 21%; DBP: 24%). Meta regression was performed to estimate the association of differences according to daily dose (if the daily dose changed, the median value was used) and publication year. However, there were not significant slope values with daily dose (HR: -0.01; 95% CI: -0.04, 0.03/SBP: 0.02; 95% CI: -0.02, 0.06/DBP: -0.002; 95% CI: -0.03, 0.03) and publication year (HR: -0.01; 95% CI: −0.19, 0.18/SBP: -0.03; 95% CI: -0.24, 0.17/DBP: 0.02; 95% CI: -0.13, 0.17). We conducted the Egger's test on each result (HR: 0.31; SBP: 0.85; DBP: 0.68), and the Funnel plot results for the study are included in supplement (Figs. S1–S3).
4. Discussion Our study showed that, compared to the control group, the use of duloxetine increased HR and DBP. However, this change was considered clinically meaningless because it was minimal. The American Heart Association guideline released in 2017 also reported that an increase of SBP above 10 mmHg could clinically increase the risk of CVD (Whelton et al., 2017). However, valdecoxib and sibutramine, which were withdrawn from the market due to the risk of CVD, had an increase of 1–3 mmHg in SBP or DBP compared to the control group (Blankfield and Iftikhar, 2015). Moreover, the increases in SBP of 2 mmHg and in DBP of 1 mmHg were reported to increase the risk of heart attack by 10% and the risk of stroke by 7% in middle-aged subjects (Lewington et al., 2002). Because most RCTs were conducted for < 13 weeks and each study group's sample size was < 350, it was not feasible to fully observe all cardiovascular-related adverse events caused by duloxetine. Like the Framingham risk score, assessing for the occurrence of CVD requires long study periods (D'Agostino et al., 2008). And according to the rule of three, with 300 study subjects, only adverse events with an incidence rate of 1 percent can be found with a probability of 95% (Eypasch et al., 1995). Our findings may provide evidence for the short-term safety of duloxetine use with regards to CVD adverse events. However, the long-term safety of duloxetine must be evaluated in longer observational studies. For the observational studies reviewed, there were conflicting results in the relationship between duloxetine and cardiovascular disease. Xue et al. (2012) published a cohort study in 2012 that showed cardiovascular-related events (acute myocardial infarction, sudden death, hypertensive crisis, arrhythmia, and coronary revascularization) were not related to duloxetine (incidence rate ratio: 0.51; 95% confidence interval [CI]: 0.32, 0.81). However, another cohort study by Leong et al. (2017) reported that SNRIs had a higher risk of acute myocardial infarction, stroke, or cardiovascular-related adverse outcomes compared to SSRIs (hazard ratio: 1.13; 95% CI: 1.06, 1.21). Leong et al.’s cohort study had a 16-year observation period, while the cohort study
3.3. Subgroup analyses by age and indication Subgroup analyses were performed by age and duloxetine indication. For age, the analysis was conducted in two groups—one in teenagers (HR: 2.31; 95% CI: 0.61, 4.02/SBP: 0.83; 95% CI: -0.41, 2.08/ DBP: 1.27; 95% CI: 0.26, 2.28) and the other in the 30s–50s age range (HR: 2.20; 95% CI: 1.41, 2.98/SBP: 0.51; 95% CI: -0.86, 1.87/DBP: 0.63; 95% CI: -0.20, 1.46). The results obtained were similar, except for changes in DBP. The results were similarly divided by the indication: mood disorder (HR: 1.91; 95% CI: 0.81, 3.00/SBP: 0.58; 95% CI: -0.50, 1.66/DBP: 0.58; 95% CI: -0.11, 1.26) and pain control (HR: 2.60; 95% CI: 1.75, 3.44/SBP: 0.76; 95% CI: -0.98, 2.51/DBP: 1.47; 95% CI: 0.01, 2.93).
3.4. Risk of bias ROB was low in almost all the studies because they were doubleblind placebo-controlled trials. Some studies did not provide all of the vital signs data; however, this was considered low ROB as they were not presented because of their statistical insignificance (Table S2).
111
112
Atkinson et al. (32) Emslie et al. (33) Strawn et al. (34) Upadhyaya et al. (35)
2014 2014 2015 2019
MDD MDD GAD fibromyalgia
MDD and APPS GAD Multiple Sclerosis
CLBP
MDD recurrence
MDD GAD fibromyalgia CLBP
DPNP
MDD fibromyalgia
MDD
Indication
10 10 10 13
weeks weeks weeks weeks
8 weeks 15 weeks 6 weeks
13 weeks
52 weeks
8 weeks 10 weeks 27 weeks 13 weeks
12 weeks
8 weeks 12 weeks
8 weeks
Study duration
80/120/placebo 60–120/placebo 60–120/placebo 20/60/120/placebo
117(61)/103(51) 116(47)/108(60)/122(69) 135(70)/137(75) 91(73)/93(65)
§
60–120/placebo 30/60/placebo § 30–120/placebo § 30–60/placebo
262(180)/266(184) 108(50)/102(56) 118(86)/121(93)
115(71)/121(73)
146(100)/142(106)
93(62)/103(77)/99(65) 320(−)/331(−) 162(149)/168(159) 59(36)/116(67)/112(65)/117(64)
116(68)/116(55)/116(63)
86(48)/91(56)/89(57) 118(118)/116(116)/120(120)
95(70)/93(70)/93(69)
Sample size (female)†
60/placebo 60–120/placebo 60/placebo
§
60–120/placebo
§
60–120/placebo
§
§
§
60/120/placebo
40/80/placebo 60/120/placebo
80/120/placebo
Study group*
13.1/13.3 12.9/12.9/13.1 12.6/12.2 15.74/15.33
46.2/45.7 37.3/38.0 50.8/52.7
51.8/51.2
47.1/48
46.5/44/44.7 41.6 (total) 50.75/50.23 52.9/53.3/54.9/54
58.3/59/59.2
41/41/40 49.6 (total)
43.1/44.7/43.7
Mean age† Duloxetine: 3 patients HTN (80 mg) 1 patient HTN (120 mg) Placebo: 1 patient HTN No cardiovascular-related adverse events reported Duloxetine: 1 patient HTN Placebo: 1 patient HTN Duloxetine: 1patient atrial fibrillation (60 mg) 4 patients HTN (60 mg) 6 patients HTN (120 mg) Placebo: 1 patient cerebrovascular accident 1 patient chest pain 7 patents HTN No cardiovascular-related adverse events reported No cardiovascular-related adverse events reported HTN reported (No number presented) Duloxetine: 1event TIA (120 mg) 1event MI (120 mg) HTN reported (No number presented) Duloxetine: 1 patient MI 1 patient TIA 3 patients HTN Placebo: 2 patients HTN Duloxetine: 1 patient HE 1 patient TIA Placebo: 1 patient MI No cardiovascular-related adverse events reported No cardiovascular-related adverse events reported Duloxetine: 3.3% patient diastolic HTN 2.6% patient systolic HTN 2.7% patient tachycardia Placebo: 1.1% patient diastolic HTN 1.2% Systolic HTN 0.9% tachycardia No cardiovascular-related adverse events reported No cardiovascular-related adverse events reported No cardiovascular-related adverse events reported No cardiovascular-related adverse events reported
Reported cardiovascular-related adverse events
companies companies companies companies
Pharmaceutical Pharmaceutical Pharmaceutical Pharmaceutical
companies companies companies companies
Pharmaceutical companies Pharmaceutical companies Pharmaceutical companies
Pharmaceutical companies
Pharmaceutical companies
Pharmaceutical Pharmaceutical Pharmaceutical Pharmaceutical
Pharmaceutical companies
Pharmaceutical companies Pharmaceutical companies
Pharmaceutical companies
Funding source
MDD Major Depressive Disorder; DPNP Diabetic Peripheral Neuropathic Pain; GAD Generalized Anxiety Disorder; CLBP Chronic Low Back Pain; APPS associated painful physical symptoms; HTN hypertension; TIA transient ischemic accident; MI myocardial infarction; HE hypertensive encephalopathy *Duloxetine daily dose(mg) †Categorized by study group §Drug dose increased in the study duration.
Gaynor et al. (29) Wu et al. (30) Vollmer et al. (31)
2011 2011 2014
Perahia et al. (23) Allgulander et al. (24) Chappell et al. (25) Skljarevski et al. (26)
2006 2008 2008 2009
Skljarevski et al. (28)
Raskin et al. (22)
2005
2010
Goldstein et al. (6) Arnold et al. (21)
2004 2005
Perahia et al. (27)
Detke et al. (20)
2004
2009
Author
Year
Table 1 General characteristics of studies included in this systematic review and meta-analysis.
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Fig. 2. Changes in heart rates in duloxetine vs placebo treatment.
Fig. 3. Changes in systolic blood pressure in duloxetine vs placebo treatment.
Fig. 4. Changes in diastolic blood pressure in duloxetine vs placebo treatment.
of selective reporting. We have tried to conduct a comprehensive search; however, not all published studies were included. In addition, the included studies presented only changes for the entire group, not individual changes. However, compared to previous studies (Thase et al., 2005; Wernicke et al., 2007), this was a well-organized study using the PRISMA-harms checklist that provided evidence to support existing data regarding the short-term safety of duloxetine use. Although vital signs were measured by other researchers when examining the cardiovascular-related adverse events of duloxetine, all results were not published because of statistical insignificance, a major obstacle for us in generating evidence through systematic review and meta-analysis. It could be concluded that although many RCTs have been conducted to evaluate the efficacy and safety of duloxetine, they were insufficient due to their short observational periods and small study samples. Therefore, well-designed pharmaco-epidemiological
by Xue et al. was a 3-year study, supported by a pharmaceutical company. Additionally, Lee et al. (2018) conducted a signal detection study that reported that duloxetine had signals related to cardiac disorder (reporting odds ratios [ROR]: 3.12; 95% CI: 2.88, 3.38) and vascular hypertensive disorders (ROR: 2.07; 95% CI: 1.91, 2.25). As many CVD related adverse events have been identified in our study, we suggest that more studies are conducted to determine the risk of cardiovascularrelated adverse events with duloxetine. This study has several strengths. We applied the latest PRISMA harms checklist to improve the transparency of the reporting and used the risk of bias tool version 2.0 to evaluate the objectivity of study inclusion. Also, in order to incorporate as many studies as possible, a preliminary study was conducted to confirm the validity of our search strategy and to modify the keywords. Our systematic review has a limitation that there is a potential risk 113
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studies are necessary to establish the long-term safety of duloxetine.
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Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Declaration of competing interest No conflict of interest with any authors. Appendix A. Supplementary data Supplementary data to this article can be found online at https:// doi.org/10.1016/j.jpsychires.2020.02.022. References Agency for Healthcare Research and Quality, 2017. Prescribed drugs. https://meps.ahrq. gov/mepstrends/hc_pmed/, Accessed date: 2 January 2020. Allgulander, C., Nutt, D., Detke, M., Erickson, J., Spann, M., Walker, D., et al., 2008. A non-inferiority comparison of duloxetine and venlafaxine in the treatment of adult patients with generalized anxiety disorder. J. Psychopharmacol. 22 (4), 417–425. Arnold, L.M., Rosen, A., Pritchett, Y.L., D'Souza, D.N., Goldstein, D.J., Iyengar, S., et al., 2005. A randomized, double-blind, placebo-controlled trial of duloxetine in the treatment of women with fibromyalgia with or without major depressive disorder. Pain 119 (1–3), 5–15. Atkinson, S.D., Prakash, A., Zhang, Q., Pangallo, B.A., Bangs, M.E., Emslie, G.J., et al., 2014. A double-blind efficacy and safety study of duloxetine flexible dosing in children and adolescents with major depressive disorder. J. Child Adolesc. Psychopharmacol. 24 (4), 180–189. Blankfield, R.P., Iftikhar, I.H., 2015. Food and drug administration regulation of drugs that raise blood pressure. J. Cardiovasc. Pharmacol. Therapeut. 20 (1), 5–8. Chalon, S.A., Granier, L.A., Vandenhende, F.R., Bieck, P.R., Bymaster, F.P., Joliat, M.J., et al., 2003. Duloxetine increases serotonin and norepinephrine availability in healthy subjects: a double-blind, controlled study. Neuropsychopharmacology 28 (9), 1685–1693. Chappell, A.S., Bradley, L.A., Wiltse, C., Detke, M.J., D'Souza, D.N., Spaeth, M., 2008. A six-month double-blind, placebo-controlled, randomized clinical trial of duloxetine for the treatment of fibromyalgia. Int. J. Gen. Med. 1, 91–102. D'Agostino, RB Sr, Vasan, R.S., Pencina, M.J., Wolf, P.A., Cobain, M., Massaro, J.M., et al., 2008. General cardiovascular risk profile for use in primary care: the Framingham Heart Study. Circulation 117 (6), 743–753. Detke, M.J., Wiltse, C.G., Mallinckrodt, C.H., McNamara, R.K., Demitrack, M.A., Bitter, I., 2004. Duloxetine in the acute and long-term treatment of major depressive disorder: a placebo- and paroxetine-controlled trial. Eur. Neuropsychopharmacol 14 (6), 457–470. Emslie, G.J., Prakash, A., Zhang, Q., Pangallo, B.A., Bangs, M.E., March, J.S., 2014. A double-blind efficacy and safety study of duloxetine fixed doses in children and adolescents with major depressive disorder. J. Child Adolesc. Psychopharmacol. 24 (4), 170–179. Eypasch, E., Lefering, R., Kum, C.K., Troidl, H., 1995. Probability of adverse events that have not yet occurred: a statistical reminder. BMJ 311 (7005), 619–620. Frasure-Smith, N., Lesperance, F., 2005. Reflections on depression as a cardiac risk factor. Psychosom. Med. 67 (Suppl. 1), S19–S25. Gaynor, P.J., Gopal, M., Zheng, W., Martinez, J.M., Robinson, M.J., Marangell, L.B., 2011. A randomized placebo-controlled trial of duloxetine in patients with major depressive disorder and associated painful physical symptoms. Curr. Med. Res. Opin. 27 (10), 1849–1858. Goldstein, D.J., Lu, Y., Detke, M.J., Wiltse, C., Mallinckrodt, C., Demitrack, M.A., 2004. Duloxetine in the treatment of depression: a double-blind placebo-controlled comparison with paroxetine. J. Clin. Psychopharmacol. 24 (4), 389–399. Lee, Y.K., Shin, J.S., Kim, Y., Kim, J.H., Song, Y.-K., Oh, J.M., et al., 2018. Antidepressants-related cardiovascular adverse events using the adverse event reporting system. Psychiatr. Res. 268, 441–446.
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Duloxetine and cardiovascular adverse events: A systematic review and meta-analysis
T
Kyounghoon Park, Seonji Kim, Young-Jin Ko, Byung-Joo Park∗ Department of Preventive Medicine, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, South Korea
A R T I C LE I N FO
A B S T R A C T
Keywords: Duloxetine Cardiovascular adverse events Systematic review Risk of Bias 2.0 PRISMA harm checklist
Duloxetine has been increasingly administered, but the associated cardiovascular adverse event risk is not clearly understood. Therefore, we identified the association between duloxetine and cardiovascular adverse events through an analysis of heart rate and blood pressure change. We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, ClinicalTrials.gov, and psycINFO in June 2019. The title, abstract, and full text were checked in order to obtain articles. A meta-analysis was conducted with random effect model and quality of articles was evaluated using Cochrane Risk of Bias 2.0. The manuscript has been written according to the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) harm checklist. A total of 4009 studies were screened by the title and abstract. After reviewing 186 full texts, 17 studies were finally selected for the meta-analysis. Nine of the 17 studied duloxetine given for mood disorders and 8 for pain control. The duration of 14 studies was under 13 weeks. Cardiovascular adverse events (hypertension, myocardial infarction, transient ischemic attack, tachycardia atrial fibrillation, and cerebrovascular accident) were reported. The meta-analysis demonstrated that duloxetine increased heart rate by 2.22 beats/min (95% confidence intervals [CIs]: 1.53, 2.91) and diastolic blood pressure by 0.82 mmHg (95% CI: 0.17, 1.47). Our findings may be the signal for the safety of cardiovascular disease for short-term use of duloxetine. Well-designed pharmacoepidemiological studies evaluating the causal relationship between long-term use of duloxetine and cardiovascular disease is still necessary.
1. Introduction Cardiovascular disease (CVD) is the number one cause of death worldwide, causing 17.9 million deaths in 2016. It encompasses diseases of the blood vessels such as coronary artery disease and cerebrovascular disease (WHO, 2017). The known risk factors for CVD are obesity, hyperlipidemia, hypertension, diabetes, smoking, lack of exercise, and excessive drinking (Lichtenstein et al., 2006). It has also been established that mood disorders such as major depressive disorder (MDD) and bipolar disorder are associated with CVD (Frasure-Smith and Lesperance, 2005). Additionally, the prevalence of MDD is higher in patients with CVD (Niranjan et al., 2012); therefore, risk assessment for CVD with antidepressant use is gaining importance. Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) that blocks serotonin and norepinephrine neuro-transporters (Chalon et al., 2003). In 2017, duloxetine was prescribed more than 16 million times in the U.S. and was the most widely used drug among the SNRIs along with venlafaxine (AHRQ, 2017). Although there are differences in
the neuroanatomy of the regulatory pathways, reuptake inhibition of serotonin and norepinephrine neurotransmission is expected to affect both mood disorders and pain control (Goldstein et al., 2004). However, because the levels of both serotonin and norepinephrine are increased with the use of SNRIs, hypertension, tachycardia, arrhythmias, and other adverse events are more likely than with selective serotonin reuptake inhibitors use (Piña et al., 2018). There are several studies on the cardiovascular-related adverse events of duloxetine. According to an analysis of eight randomized controlled trials (RCTs), the use of duloxetine compared to placebo significantly increased heart rate (HR) (1.6 vs. −0.6 beats/min) and systolic blood pressure (SBP) (1.0 vs. −1.2 mmHg) (Thase et al., 2005). In 2007, results from 42 placebo-controlled trials reported a significant increase in HR (3.20 vs. −0.67 beats/min), SBP (0.65 vs. −0.55 mmHg), and diastolic blood pressure (DBP) (0.88 vs. −0.18 mmHg) (Wernicke et al., 2007). The authors concluded that the results were statistically significant but clinically meaningless. However, the analysis was not a systematic review and many of the studies
∗ Corresponding author. Department of Preventive Medicine, Seoul National University College of Medicine, 103, Daehak-ro, Jongno-gu, Seoul, 03080, South Korea. E-mail addresses: [email protected] (K. Park), [email protected] (S. Kim), [email protected] (Y.-J. Ko), [email protected] (B.-J. Park).
https://doi.org/10.1016/j.jpsychires.2020.02.022 Received 4 December 2019; Received in revised form 24 February 2020; Accepted 24 February 2020 0022-3956/ © 2020 Elsevier Ltd. All rights reserved.
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and created a funnel plot to determine the probability of publication bias.
(13 of 42) were not published. Since the indications for duloxetine have expanded and new RCTs are being conducted, systematic reviews and meta-analyses are necessary to reassess the potential cardiovascular-related adverse events of duloxetine. Therefore, we identified RCTs that reported cardiovascularrelated adverse events after comparing duloxetine and placebo. Changes in HR, SBP, and DBP from these studies have been quantitatively summarized.
2.4. Risk of bias in individual studies We used Cochrane ROB (Risk-of-bias tool for randomized trials) version 2.0 from August 22, 2019, to assess for bias (Sterne et al., 2019). This tool was developed to assess the risk of bias in RCTs and consist of 5 domains: 1) the randomization process, 2) the intended interventions, 3) missing outcome data, 4) the measurement of the outcome, and 5) the reported result. Because our main concern was safety, we evaluated outcomes accordingly. This study was written in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) harms checklist (Zorzela et al., 2016). Studies search, selection, data extraction, and risk of bias evaluation were performed independently by two authors (KP and SK), and a conclusion was reached through consensus. A conclusion was reached through discussion with other authors in case there was a disagreement (YJK and BJP).
2. Methods and materials 2.1. Search strategy We searched Medline/PubMed, EMBASE, CENTRAL (Cochrane Central Register of Controlled Trials), ClinicalTrials.gov, and PsycINFO databases in June 2019 to find studies that met our inclusion criteria. We constructed a PICOT-SD (Patients, Intervention, Comparison, Outcome, Time, Setting and Design) to discover keywords. Any indication for duloxetine prescription (P, I) compared with a placebo or no medication (C), outcome-related safety (O), published after the 1990s (T), community- or hospital-based (S), and designated RCTs (D). The outcome (O) keywords used were related to the overall safety (safety, complication, adverse event, etc.) and included CVD. When we conducted the pilot study, we confirmed that the search was insufficient when the outcome keywords were limited to specific diseases or conditions such as CVD, hypertension, and blood pressure. Therefore, terms for specific diseases, conditions, and safety were included as keywords used for searching. The keywords were created by combining keyword subject searches (such as Medical Subject Headings) and free text words (Table S1). The retrieved studies were sorted using EndNote X9 and Excel. There was no language restriction.
3. Results After removing 717 duplicates from the 4726 studies retrieved, 3823 studies were additionally removed after reviewing the title and abstract because they were not RCTs involving duloxetine. For the 186 studies selected, the full texts were evaluated for eligibility. Those sharing study samples (n = 10), those without parallel design and open-label studies (n = 56), studies comparing duloxetine to other antidepressants or analgesics only (n = 32), and studies whose full texts were impossible to find (n = 8) were excluded. Additionally, 15 studies were obtained from the ClinicalTrials.gov database. In the end, 95 studies were selected. The studies were then divided, by indications, into mood disorder, (n = 35) pain control, (n = 41) urinary incontinence, (n = 12) and others (n = 9). In the end, we conducted a metaanalysis with 17 studies (Goldstein et al., 2004; Detke et al., 2004; Arnold et al., 2005; Raskin et al., 2005; Perahia et al., 2006, 2009; Allgulander et al., 2008; Chappell et al., 2008; Skljarevski et al., 2009, 2010; Gaynor et al., 2011; Wu et al., 2011; Vollmer et al., 2014; Atkinson et al., 2014; Emslie et al., 2014; Strawn et al., 2015; Upadhyaya et al., 2019). Sixteen studies on HR change, 12 studies on SBP change, and 13 studies on DBP change were included (Fig. 1).
2.2. Study selection and data collection After removing duplicate studies, the titles and abstracts of the RCTs related to duloxetine were searched for any information on the adverse events of duloxetine. Thereafter, the RCTs studies that compared duloxetine to a placebo or to no treatment were selected through full-text reviews. Because information on adverse events of duloxetine was often unknown before the full texts were checked, the exclusion was not made before the final selection of the studies through full-text reviews. The exclusion criteria were studies that shared patient data from other RCTs, compared duloxetine with other antidepressants or analgesics only, open-labeled studies, and those that switched duloxetine and placebo treatments during the study period. Unlike other databases, ClinicalTrials.gov provided the results of clinical trials in text form without providing abstracts or titles. Therefore, among the studies that were searched in ClinicalTrials.gov, studies not found in other databases and presented information on the adverse events of duloxetine were included. We then collected data from the selected studies: authors; publication year; indication for duloxetine; study period; number of subjects taking duloxetine; number of subjects in the control group; age and sex of the subjects; the daily dose of duloxetine; any reported adverse event related to CVD during the study course (e.g., hypertension, myocardial infarction, heart failure, and stroke); and the change from baseline of HR, SBP, and DBP for subjects taking duloxetine and those taking a placebo.
3.1. General characteristics of studies included in the meta-analysis Nine of the 17 studies were conducted for mood disorders and 8 studies for controlling pain. Fourteen of the studies lasted less than 13 weeks and the daily doses of duloxetine were 30, 60, 80, and 120 mg. Nine studies were conducted using a single dose, and in eight studies, the treatment dose was increased during the study. The sample size of the study group ranged from 331 to 59. The proportion of women in all groups was larger than men. Thirteen studies were conducted on those aged between 30s and 50s, and four studies on 10s. Many cardiovascular-related adverse events were reported. Hypertension was the most common adverse event, but myocardial infarction, transient ischemic attack, tachycardia, atrial fibrillation, and cerebrovascular accident were also reported (Table 1). 3.2. Meta-analysis for HR, SBP, and DBP change from baseline compared to a placebo
2.3. Statistical analyses A meta-analysis of the mean difference of HR, SBP, and DBP change from baseline between duloxetine and placebo was performed. Additionally, we conducted subgroup analyses of the subjects' ages and drug indications. Since the heterogeneity of each group was expected to be high, a random effects model was used and the heterogeneity between groups was calculated as Higgins I2. We also applied Egger's test
Compared to the placebo group, the duloxetine group showed a 2.22 beats/min (95% confidence interval [CI]: 1.53, 2.91) increase in HR (Fig. 2). SBP increased by 0.62 mmHg (95% CI: -0.24, 1.52) although insignificant, statistically (Fig. 3). DBP increased by 0.82 mmHg (95% CI: 0.17, 1.47) (Fig. 4). The heterogeneity of the included studies 110
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Fig. 1. Flow chart of systematic review and meta-analysis.
was calculated by Higgins I2 and was not very high (HR: 27%; SBP: 21%; DBP: 24%). Meta regression was performed to estimate the association of differences according to daily dose (if the daily dose changed, the median value was used) and publication year. However, there were not significant slope values with daily dose (HR: -0.01; 95% CI: -0.04, 0.03/SBP: 0.02; 95% CI: -0.02, 0.06/DBP: -0.002; 95% CI: -0.03, 0.03) and publication year (HR: -0.01; 95% CI: −0.19, 0.18/SBP: -0.03; 95% CI: -0.24, 0.17/DBP: 0.02; 95% CI: -0.13, 0.17). We conducted the Egger's test on each result (HR: 0.31; SBP: 0.85; DBP: 0.68), and the Funnel plot results for the study are included in supplement (Figs. S1–S3).
4. Discussion Our study showed that, compared to the control group, the use of duloxetine increased HR and DBP. However, this change was considered clinically meaningless because it was minimal. The American Heart Association guideline released in 2017 also reported that an increase of SBP above 10 mmHg could clinically increase the risk of CVD (Whelton et al., 2017). However, valdecoxib and sibutramine, which were withdrawn from the market due to the risk of CVD, had an increase of 1–3 mmHg in SBP or DBP compared to the control group (Blankfield and Iftikhar, 2015). Moreover, the increases in SBP of 2 mmHg and in DBP of 1 mmHg were reported to increase the risk of heart attack by 10% and the risk of stroke by 7% in middle-aged subjects (Lewington et al., 2002). Because most RCTs were conducted for < 13 weeks and each study group's sample size was < 350, it was not feasible to fully observe all cardiovascular-related adverse events caused by duloxetine. Like the Framingham risk score, assessing for the occurrence of CVD requires long study periods (D'Agostino et al., 2008). And according to the rule of three, with 300 study subjects, only adverse events with an incidence rate of 1 percent can be found with a probability of 95% (Eypasch et al., 1995). Our findings may provide evidence for the short-term safety of duloxetine use with regards to CVD adverse events. However, the long-term safety of duloxetine must be evaluated in longer observational studies. For the observational studies reviewed, there were conflicting results in the relationship between duloxetine and cardiovascular disease. Xue et al. (2012) published a cohort study in 2012 that showed cardiovascular-related events (acute myocardial infarction, sudden death, hypertensive crisis, arrhythmia, and coronary revascularization) were not related to duloxetine (incidence rate ratio: 0.51; 95% confidence interval [CI]: 0.32, 0.81). However, another cohort study by Leong et al. (2017) reported that SNRIs had a higher risk of acute myocardial infarction, stroke, or cardiovascular-related adverse outcomes compared to SSRIs (hazard ratio: 1.13; 95% CI: 1.06, 1.21). Leong et al.’s cohort study had a 16-year observation period, while the cohort study
3.3. Subgroup analyses by age and indication Subgroup analyses were performed by age and duloxetine indication. For age, the analysis was conducted in two groups—one in teenagers (HR: 2.31; 95% CI: 0.61, 4.02/SBP: 0.83; 95% CI: -0.41, 2.08/ DBP: 1.27; 95% CI: 0.26, 2.28) and the other in the 30s–50s age range (HR: 2.20; 95% CI: 1.41, 2.98/SBP: 0.51; 95% CI: -0.86, 1.87/DBP: 0.63; 95% CI: -0.20, 1.46). The results obtained were similar, except for changes in DBP. The results were similarly divided by the indication: mood disorder (HR: 1.91; 95% CI: 0.81, 3.00/SBP: 0.58; 95% CI: -0.50, 1.66/DBP: 0.58; 95% CI: -0.11, 1.26) and pain control (HR: 2.60; 95% CI: 1.75, 3.44/SBP: 0.76; 95% CI: -0.98, 2.51/DBP: 1.47; 95% CI: 0.01, 2.93).
3.4. Risk of bias ROB was low in almost all the studies because they were doubleblind placebo-controlled trials. Some studies did not provide all of the vital signs data; however, this was considered low ROB as they were not presented because of their statistical insignificance (Table S2).
111
112
Atkinson et al. (32) Emslie et al. (33) Strawn et al. (34) Upadhyaya et al. (35)
2014 2014 2015 2019
MDD MDD GAD fibromyalgia
MDD and APPS GAD Multiple Sclerosis
CLBP
MDD recurrence
MDD GAD fibromyalgia CLBP
DPNP
MDD fibromyalgia
MDD
Indication
10 10 10 13
weeks weeks weeks weeks
8 weeks 15 weeks 6 weeks
13 weeks
52 weeks
8 weeks 10 weeks 27 weeks 13 weeks
12 weeks
8 weeks 12 weeks
8 weeks
Study duration
80/120/placebo 60–120/placebo 60–120/placebo 20/60/120/placebo
117(61)/103(51) 116(47)/108(60)/122(69) 135(70)/137(75) 91(73)/93(65)
§
60–120/placebo 30/60/placebo § 30–120/placebo § 30–60/placebo
262(180)/266(184) 108(50)/102(56) 118(86)/121(93)
115(71)/121(73)
146(100)/142(106)
93(62)/103(77)/99(65) 320(−)/331(−) 162(149)/168(159) 59(36)/116(67)/112(65)/117(64)
116(68)/116(55)/116(63)
86(48)/91(56)/89(57) 118(118)/116(116)/120(120)
95(70)/93(70)/93(69)
Sample size (female)†
60/placebo 60–120/placebo 60/placebo
§
60–120/placebo
§
60–120/placebo
§
§
§
60/120/placebo
40/80/placebo 60/120/placebo
80/120/placebo
Study group*
13.1/13.3 12.9/12.9/13.1 12.6/12.2 15.74/15.33
46.2/45.7 37.3/38.0 50.8/52.7
51.8/51.2
47.1/48
46.5/44/44.7 41.6 (total) 50.75/50.23 52.9/53.3/54.9/54
58.3/59/59.2
41/41/40 49.6 (total)
43.1/44.7/43.7
Mean age† Duloxetine: 3 patients HTN (80 mg) 1 patient HTN (120 mg) Placebo: 1 patient HTN No cardiovascular-related adverse events reported Duloxetine: 1 patient HTN Placebo: 1 patient HTN Duloxetine: 1patient atrial fibrillation (60 mg) 4 patients HTN (60 mg) 6 patients HTN (120 mg) Placebo: 1 patient cerebrovascular accident 1 patient chest pain 7 patents HTN No cardiovascular-related adverse events reported No cardiovascular-related adverse events reported HTN reported (No number presented) Duloxetine: 1event TIA (120 mg) 1event MI (120 mg) HTN reported (No number presented) Duloxetine: 1 patient MI 1 patient TIA 3 patients HTN Placebo: 2 patients HTN Duloxetine: 1 patient HE 1 patient TIA Placebo: 1 patient MI No cardiovascular-related adverse events reported No cardiovascular-related adverse events reported Duloxetine: 3.3% patient diastolic HTN 2.6% patient systolic HTN 2.7% patient tachycardia Placebo: 1.1% patient diastolic HTN 1.2% Systolic HTN 0.9% tachycardia No cardiovascular-related adverse events reported No cardiovascular-related adverse events reported No cardiovascular-related adverse events reported No cardiovascular-related adverse events reported
Reported cardiovascular-related adverse events
companies companies companies companies
Pharmaceutical Pharmaceutical Pharmaceutical Pharmaceutical
companies companies companies companies
Pharmaceutical companies Pharmaceutical companies Pharmaceutical companies
Pharmaceutical companies
Pharmaceutical companies
Pharmaceutical Pharmaceutical Pharmaceutical Pharmaceutical
Pharmaceutical companies
Pharmaceutical companies Pharmaceutical companies
Pharmaceutical companies
Funding source
MDD Major Depressive Disorder; DPNP Diabetic Peripheral Neuropathic Pain; GAD Generalized Anxiety Disorder; CLBP Chronic Low Back Pain; APPS associated painful physical symptoms; HTN hypertension; TIA transient ischemic accident; MI myocardial infarction; HE hypertensive encephalopathy *Duloxetine daily dose(mg) †Categorized by study group §Drug dose increased in the study duration.
Gaynor et al. (29) Wu et al. (30) Vollmer et al. (31)
2011 2011 2014
Perahia et al. (23) Allgulander et al. (24) Chappell et al. (25) Skljarevski et al. (26)
2006 2008 2008 2009
Skljarevski et al. (28)
Raskin et al. (22)
2005
2010
Goldstein et al. (6) Arnold et al. (21)
2004 2005
Perahia et al. (27)
Detke et al. (20)
2004
2009
Author
Year
Table 1 General characteristics of studies included in this systematic review and meta-analysis.
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Fig. 2. Changes in heart rates in duloxetine vs placebo treatment.
Fig. 3. Changes in systolic blood pressure in duloxetine vs placebo treatment.
Fig. 4. Changes in diastolic blood pressure in duloxetine vs placebo treatment.
of selective reporting. We have tried to conduct a comprehensive search; however, not all published studies were included. In addition, the included studies presented only changes for the entire group, not individual changes. However, compared to previous studies (Thase et al., 2005; Wernicke et al., 2007), this was a well-organized study using the PRISMA-harms checklist that provided evidence to support existing data regarding the short-term safety of duloxetine use. Although vital signs were measured by other researchers when examining the cardiovascular-related adverse events of duloxetine, all results were not published because of statistical insignificance, a major obstacle for us in generating evidence through systematic review and meta-analysis. It could be concluded that although many RCTs have been conducted to evaluate the efficacy and safety of duloxetine, they were insufficient due to their short observational periods and small study samples. Therefore, well-designed pharmaco-epidemiological
by Xue et al. was a 3-year study, supported by a pharmaceutical company. Additionally, Lee et al. (2018) conducted a signal detection study that reported that duloxetine had signals related to cardiac disorder (reporting odds ratios [ROR]: 3.12; 95% CI: 2.88, 3.38) and vascular hypertensive disorders (ROR: 2.07; 95% CI: 1.91, 2.25). As many CVD related adverse events have been identified in our study, we suggest that more studies are conducted to determine the risk of cardiovascularrelated adverse events with duloxetine. This study has several strengths. We applied the latest PRISMA harms checklist to improve the transparency of the reporting and used the risk of bias tool version 2.0 to evaluate the objectivity of study inclusion. Also, in order to incorporate as many studies as possible, a preliminary study was conducted to confirm the validity of our search strategy and to modify the keywords. Our systematic review has a limitation that there is a potential risk 113
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studies are necessary to establish the long-term safety of duloxetine.
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