Effects of antidepressants on QT interval in people with mental disorders.

INTRODUCTION: Drug-induced QT prolongation is associated with higher cardiovascular mortality. MATERIAL AND METHODS: We conducted a protocol-based comprehensive review of antidepressant-induced QT prolongation in people with mental disorders. RESULTS: Based on findings from 47 published randomized controlled trials (RCTs), 3 unpublished RCTs, 14 observational studies, 662 case reports of torsades de pointes, and 168 cases of QT prolongation, we conclude that all antidepressants should be used only with licensed doses, and that all patients receiving antidepressants require monitoring of QT prolongation and clinical symptoms of cardiac arrhythmias. Large observational studies suggest increased mortality associated with all antidepressants (RR = 1.62, 95% CI: 1.60-1.63, number of adults: 1,716,552), high doses of tricyclic antidepressants (OR = 2.11, 85% CI 1.10-4.22), selective serotonin reuptake inhibitors (OR = 2.78, 95% CI: 1.24-6.24), venlafaxine (OR = 3.73, 95% CI: 1.33-10.45, number of adults: 4,040), and nortriptyline (OR = 4.60, 95% CI: 1.20-18.40, number of adults: 5,298). CONCLUSIONS: Evidence regarding the risk of QT prolongation in children is sparse.

Comparative Clinical Outcomes of Edoxaban in Adults With Nonvalvular Atrial Fibrillation.

BACKGROUND: A critical appraisal of all pooled evidence regarding novel oral anticoagulants (NOACs) for stroke prevention regardless of publication status or study design has not been conducted yet. Being the latest addition to NOACs, the data on edoxaban are especially scarce. STUDY QUESTION: What are the comparative clinical outcomes of edoxaban versus warfarin and other NOACs apixaban, dabigatran, or rivaroxaban in adults with nonvalvular atrial fibrillation? DATA SOURCES: Randomized controlled trials (RCTs), observational studies, and network meta-analyses were identified in PubMed, EMBASE, the Cochrane Library, Pharmapendium, Elsevier Clinical Pharmacology, and the clinicaltrials.gov trial registry in June 2018. STUDY DESIGN: Rapid review per a priori developed protocol, direct frequentist random-effects meta-analysis of aggregate data, grading the quality of evidence per the Grading of Recommendations Assessment, Development and Evaluation working group approach. RESULTS: Direct 4 RCTs (23,021 patients) suggest that edoxaban is noninferior to warfarin in prevention of stroke and systemic embolism [pooled relative risk (RR): 0.65, 95% confidence interval (CI): 0.23-1.81, 2 RCTs] and reduces the risk of cardiovascular mortality (RR: 0.87, 95% CI: 0.78-0.97, 1 RCT), major cardiovascular morbidity (RR: 0.90, 95% CI: 0.82-0.98, 2 RCTs), and major bleeding events (RR: 0.80, 95% CI: 0.71-0.91, 1 RCT) but increases the risk of gastrointestinal bleeding (RR: 1.21, 95% CI: 1.01-1.46, 1 RCT) and anemia (RR: 1.45, 95% CI: 1.05-1.99, 3 RCTs). Edoxaban is superior to warfarin in patients with increased risk of bleeding with warfarin because of variants in CYP2C9 and VKORC1 genes. Indirect evidence does not allow valid conclusions regarding comparative superiority of NOACs. The quality of evidence was downgraded because of reporting bias, small number of events, and indirectness in comparisons. CONCLUSIONS: Edoxaban is a welcome addition to the NOAC's armamentarium. However, the comparative data with other novel NOACs are mostly nonexisting, and urgently needed for better individual patient assessment.

Exercise for Preventing Hospitalization and Readmission in Adults With Congestive Heart Failure.

We critically appraised all available evidence regarding exercise interventions for improving patient survival and reducing hospital admissions in adults with chronic heart failure (HF). We searched 4 databases up to April 2018 and graded the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation working group approach. We reviewed 7 meta-analyses and the publications of 48 randomized controlled trials (RCTs). In HF with reduced ejection fraction, low-quality evidence suggests that exercise prevents all-cause hospitalizations [Relative risk (RR), 0.77; 95% confidence interval (CI), 0.63 to 0.93; 1328 patients in 15 RCTs] and hospitalizations due to HF (RR, 0.57; 95% CI, 0.37 to 0.88; 1073 patients in 13 RCTs) and improves quality of life (standardized mean difference, -0.37; 95% CI, -0.60 to -0.14; 1270 patients in 25 RCTs) but has no effect on mortality. In HF with preserved ejection fraction, low-quality evidence suggests that exercise improves peak oxygen uptake (mean difference, 2.36; 95% CI, 1.16 to 3.57; 171 patients in 3 RCTs) and quality of life (mean difference, -4.65; 95% CI, -8.46 to -0.83; 203 patients in 4 RCTs). In patients after heart transplantation, low-quality evidence suggests that exercise improves peak oxygen uptake (standardized mean difference, 0.68; 95% CI, 0.43 to 0.93; 284 patients in 9 RCTs) but does not improve quality of life. In order to reduce hospitalization and improve quality of life for adults with HF and reduced ejection fraction, clinicians should recommend exercise interventions. For adults with HF and preserved ejection fraction and in those undergoing heart transplantation, clinicians may recommend exercise interventions in order to improve peak oxygen uptake.

Comparative Effectiveness and Safety of Rivaroxaban in Adults With Nonvalvular Atrial Fibrillation.

BACKGROUND: All evidence regarding benefits and harms of rivaroxaban for stroke prevention has not been appraised yet. STUDY QUESTION: What are the comparative effectiveness and safety of rivaroxaban in adults with nonvalvular atrial fibrillation? DATA SOURCES: Randomized controlled trials (RCTs), meta-analyses, and observational studies were identified in several databases in October 2018. STUDY DESIGN: Rapid review with evidence appraisal using the Grading of Recommendations Assessment, Development and Evaluation working group approach. RESULTS: Two direct RCTs (23,021 patients) suggest that rivaroxaban is noninferior to warfarin in the prevention of stroke and systemic embolism (pooled relative risk [RR] 0.73, 95% confidence interval [CI], 0.43-1.24), reduces risk of hemorrhagic stroke (RR 0.59, 95% CI, 0.38-0.92), fatal bleeding (RR 0.49, 95% CI, 0.31-0.76), and cardiac arrest (RR 0.45, 95% CI, 0.25-0.82, 2 RCTs), but increases risk of major gastrointestinal bleeding (RR 1.46, 95% CI, 1.19-1.78). In observational studies, rivaroxaban is associated with lower risk of ischemic stroke (RR 0.87, 95% CI, 0.77-0.99, 222,750 patients), acute myocardial infarction (RR 0.61, 95% CI, 0.48-0.78, 73,739 patients), and intracranial hemorrhage (RR 0.64, 95% CI, 0.45-0.92, 197,506 patients) but higher risk of gastrointestinal bleeding (RR 1.30, 95% CI, 1.19-1.42, 188,968 patients) and higher risk of mortality when compared with warfarin in European studies (RR 1.19, 103,270 patients in the UK; RR 2.02, 22,358 patients in Denmark) but lower risk of mortality in Taiwan (RR 0.58, 40,000 patients). Network meta-analyses and observational studies suggest that rivaroxaban is associated with higher risk of bleeding when compared with apixaban (RR 2.14, 72,586 patients), dabigatran (RR 1.24, 67,102 patients), and edoxaban (RR 1.32, 71,683 patients). CONCLUSIONS: Research on the long-term comparative effectiveness, safety, and effects on quality of life between rivaroxaban and other novel oral anticoagulants is urgently needed.

Blood pressure targets for hypertension in patients with type 2 diabetes.

BACKGROUND: Clinical guidelines vary in determining optimal blood pressure targets in adults with diabetes mellitus. METHODS: We systematically searched PubMed, EMBASE, Cochrane Library, and clinicaltrials.gov in March 2018; conducted random effects frequentist meta-analyses of direct aggregate data; and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. RESULTS: From eligible 14 meta-analyses and 95 publications of randomized controlled trials (RCT), only 6 RCTs directly compared lower versus higher blood pressure targets; remaining RCTs aimed at comparative effectiveness of hypotensive drugs. In adults with diabetes mellitus and elevated systolic blood pressure (SBP), direct evidence (2 RCTs) suggests that intensive target SBP <120-140 mmHg decreases the risk of diabetes-related mortality [relative risk (RR) =0.68; 95% confidence interval (CI), 0.50-0.92], fatal (RR =0.41; 95% CI, 0.20-0.84) or nonfatal stroke (RR =0.60; 95% CI, 0.43-0.83), prevalence of left ventricular hypertrophy and electrocardiogram (ECG) abnormalities, macroalbuminuria, and non-spine bone fractures, with no differences in all-cause or cardiovascular mortality or falls. In adults with diabetes mellitus and elevated diastolic blood pressure (DBP) ≥90 mmHg, direct evidence (2 RCTs) suggests that intensive DBP target ≤80 versus 80-90 mmHg decreases the risk of major cardiovascular events. Published meta-analyses of aggregate data suggested a significant association between lower baseline and attained blood pressure and increased cardiovascular mortality. CONCLUSIONS: We concluded that in adults with diabetes mellitus and arterial hypertension, in order to reduce the risk of stroke, clinicians should target blood pressure at 120-130/80 mmHg, with close monitoring for all drug-related harms.

Effects of atypical antipsychotic drugs on QT interval in patients with mental disorders.

BACKGROUND: Drug-induced QT prolongation is associated with higher risk of cardiac arrhythmias and cardiovascular mortality. We investigated the effects of atypical antipsychotic drugs on QT interval in children and adults with mental disorders. METHODS: We conducted random-effects direct frequentist meta-analyses of aggregate data from randomized controlled trials (RCT) and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our search in PubMed, EMBASE, the Cochrane Library, clinicaltrials.gov, and PharmaPendium up to October 2017 identified studies that examined aripiprazole, quetiapine, risperidone, olanzapine, ziprasidone and brexpiprazole. RESULTS: Low quality evidence suggests that aripiprazole (four meta-analyses and twelve RCTs), brexpiprazole (one systematic review and four RCTs) or olanzapine (five meta-analyses and twenty RCTs) do not increase QT interval. Low quality evidence suggests that ziprasidone (five meta-analyses and 11 RCTs) increases QT interval and the rates of QT prolongation while risperidone (four meta-analyses, 70 RCTs) and quetiapine (two meta-analyses and seven RCTs) are associated with QT prolongation and greater odds of torsades de pointes ventricular tachycardia especially in cases of drug overdose. CONCLUSIONS: The main conclusion of our study is that in people with mental disorders and under treatment with atypical antipsychotic drugs, in order to avoid QT prolongation and reduce the risk of ventricular tachycardia clinicians may recommend aripiprazole, brexpiprazole or olanzapine in licensed doses. Long-term comparative safety needs to be established.

Comparative Effectiveness of Disease Management With Information Communication Technology for Preventing Hospitalization and Readmission in Adults With Chronic Congestive Heart Failure.

OBJECTIVES: Critical appraisal of all available evidence regarding the role of noninvasive communication technology for improving patient survival and reducing hospital admissions in adults with chronic heart failure (HF). DESIGN: Systematic literature review and grading of the quality of evidence according to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group approach. SETTING AND PARTICIPANTS: Four databases were searched in March 2018 to find 2 high-quality meta-analyses and published and unpublished data from 58 randomized controlled trials (RCTs) that compared noninvasive communication technology with usual care in community-dwelling adults with HF. MEASURES: Direct meta-analysis of aggregate data with random effects models. RESULTS: Moderate-quality evidence suggests that there are no differences in all-cause mortality between telemonitoring and usual care, whereas complex telemonitoring that includes transmission of patient parameters and analysis by health care professionals decreases all-cause mortality (relative risk [RR] 0.78, 95% confidence interval [CI] 0.62, 0.99; 2885 people in 12 RCTs). Moderate-quality evidence suggests that telemonitoring prevents HF-related hospitalizations (RR 0.74; 95% CI 0.62, 0.88; 4001 people in 11 RCTs). Moderate-quality evidence suggests that structured telephone support decreases all-cause mortality (RR 0.86; 95% CI 0.77, 0.97; 9535 people in 24 RCTs) and HF-related hospitalizations (RR 0.83; 95% CI 0.73, 0.94; 7030 people in 16 RCTs). Use of a mobile personal digital assistant prevents HF-related hospitalizations (RR 0.58; 95% CI 0.44, 0.77; 674 people in 3 RCTs). The evidence regarding the comparative effectiveness of specific telecommunication devices is insufficient. The results from many completed studies are not available. CONCLUSIONS: Clinicians should offer noninvasive monitoring with communication technology applications to all HF patients. Future research should examine comparative effectiveness of technology applications in patient subpopulations.

Comparative effectiveness and safety of empagliflozin on cardiovascular mortality and morbidity in adults with type 2 diabetes.

BACKGROUND: Based on a single placebo-controlled randomized clinical trial, empagliflozin is licensed to reduce cardiovascular death in diabetes and comorbid cardiovascular disease. METHODS: We examined the comparative effectiveness of empagliflozin on mortality and cardiovascular morbidity in type 2 diabetes. We conducted random-effects direct frequentist meta-analyses of aggregate data and appraised the quality of evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. Our search in PubMed, EMBASE, the Cochrane Library, clinicaltrials.gov, and PharmaPendium up to May 2017 identified 11 meta-analyses, multiple publications, and unpublished data from 29 randomized controlled trials (RCTs). RESULTS: Empagliflozin reduces all-cause mortality [relative risk (RR) of death, 0.69; 95% confidence interval (CI): 0.58-0.82; number needed to treat (NNT) to postpone mortality in one patient, 39; 95% CI: 26-79; 1 RCT of 7,020 patients) in patients with but not without (RR, 0.90; 95% CI: 0.36-2.23; 14 RCTs of 7,707 patients) established cardiovascular disease when compared with placebo. Empagliflozin reduces cardiovascular mortality (RR, 0.62; 95% CI: 0.50-0.78; NNT, 45; 95% CI: 30-90; 1 RCT of 7,020 patients) in patients with but not without (RR, 0.98; 95% CI: 0.29-3.33; 10 RCTs of 5,429 patients) established cardiovascular disease when compared with placebo. There are no differences in cardiovascular morbidity and mortality and all-cause mortality between empagliflozin and metformin (4 RCTs of 1,344 patients), glimepiride (1 RCT of 1,549 patients), linagliptin (2 RCTs of 1,348 patients), or sitagliptin (3 RCTs of 1,483 patients). Two network meta-analyses concluded that sodium-glucose cotransporter 2 (SGLT2) inhibitors, mostly due to empagliflozin, decrease all-cause and cardiovascular mortality but increase the risk of nonfatal stroke, genital infection, and volume depletion. CONCLUSIONS: We conclude that empagliflozin reduces all-cause and cardiovascular mortality in patients with established cardiovascular disease and type 2 diabetes. Sparse direct evidence suggests no difference in mortality between empagliflozin and metformin, glimepiride, linagliptin, or sitagliptin. Long-term comparative safety needs to be established.

Benefits and Harms of Sacubitril in Adults With Heart Failure and Reduced Left Ventricular Ejection Fraction.

The quality of evidence regarding patient-centered outcomes in adults with heart failure (HF) after sacubitril combined with valsartan has not been systematically appraised. We searched 4 databases in February 2017 and graded the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation working group approach. We reviewed 1 meta-analysis and multiple publications of 2 randomized controlled trials (RCT) and 1 unpublished RCT. In adults with HF and reduced ejection fraction, low-quality evidence from 1 RCT of 8,432 patients suggests that sacubitril combined with valsartan reduces all-cause (number needed to treat [NNT] to prevent 1 event [NNTp] = 35) and cardiovascular mortality (NNTp = 32), hospitalization (NNTp = 11), emergency visits (NNTp = 69), and serious adverse effects, leading to treatment discontinuation (NNTp = 63) and improves quality of life when compared with enalapril. In adults with HF and preserved ejection fraction, very low-quality evidence from 1 RCT of 301 patients suggests that there are no differences in mortality, morbidity, or adverse effects between sacubitril combined with valsartan and valsartan alone. In conclusion, in adults with HF and reduced ejection fraction, to reduce cardiovascular mortality and hospitalizations and improve quality of life, clinicians may recommend sacubitril combined with valsartan over angiotensin-converting enzyme inhibitors.

Additional Improvements in Clinical Response From Adjuvant Biologic Response Modifiers in Adults With Moderate to Severe Systemic Lupus Erythematosus Despite Immunosuppressive Agents: A Systematic Review and Meta-analysis.

PURPOSE: The role of biologic disease-modifying drugs in patients with systemic lupus erythematosus (SLE) remains controversial. METHODS: Following systematic review and meta-analysis protocol, we searched PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov in January 2017 to identify all studies of people with SLE treated with biologic response modifiers. We performed direct frequentist random effects meta-analyses, calculated pooled relative risk and number needed to treat to achieve an outcome in 1 patient (NNT) as reciprocal to statistically significant absolute risk difference, and graded the quality of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation criteria. FINDINGS: Seven meta-analyses, 33 publications of randomized controlled trials (RCTs), and 5 observational studies met inclusion criteria. All studies enrolled previously treated adults with moderate to severe SLE despite conventional immunosuppression. In patients with extrarenal SLE, adjunctive belimumab (10 mg/kg) increases the rates of clinical response (moderate quality evidence from 2 RCTs, 1125 patients, NNT = 8 [95% CI, 6-16]), whereas adjunctive rituximab or abatacept are ineffective. In adults with lupus nephritis, adjunctive rituximab (4000 mg, very-low-quality evidence from 1 RCT, 144 patients, NNT = 5 [95% CI, 3-18]), but not abatacept, improves renal function. Belimumab and rituximab do not increase the risk of serious intolerable adverse effects leading to treatment discontinuation. Rigerimod, blisibimod, sifalimumab, and anifrolumab show promising results in early RCTs, whereas epratuzumab and tabalumab have an unfavorable benefit-to-harm balance. IMPLICATIONS: In adults with moderate to severe SLE despite conventional immunosuppressive agents, adjunctive belimumab in extrarenal SLE and off-label rituximab in lupus nephritis may offer additional modest benefits.

Patient-centered Outcomes with Concomitant Use of Proton Pump Inhibitors and Other Drugs.

PURPOSE: We performed a systematic review of patient-centered outcomes after the concomitant use of proton pump inhibitors (PPIs) and other drugs. METHODS: We searched 4 databases in July 2016 to find studies that reported mortality and morbidity after the concomitant use of PPIs and other drugs. We conducted direct meta-analyses using a random-effects model and graded the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation working group approach. FINDINGS: We included data from 17 systematic reviews and meta-analyses, 16 randomized controlled trials, and 16 observational studies that examined the concomitant use of PPIs with medications from 10 drug classes. Low-quality evidence suggests that the use of PPIs is associated with greater morbidity when administered with antiplatelet drugs, bisphosphonates, antibiotics, anticoagulants, metformin, mycophenolate mofetil, or nelfinavir. Concomitant PPIs reduce drug-induced gastrointestinal bleeding and are associated with greater docetaxel and cisplatin response rates in patients with metastatic breast cancer. For demonstrated statistically significant relative risks and benefits from concomitant PPIs, the magnitudes of the effects are small, with <100 attributable events per 1000 patients treated, and the effects are inconsistent among specific drugs. Among individual PPIs, the concomitant use of pantoprazole or esomeprazole, but not omeprazole or lansoprazole, is associated with an increased risk for all-cause mortality, nonfatal myocardial infarction, or stroke. Clopidogrel is associated with a greater risk for myocardial infarction compared with prasugrel. Conflicting results between randomized controlled trials and observational studies and high risk for bias in the body of evidence lessened our confidence in the results. IMPLICATIONS: Available evidence suggests a greater risk for adverse patient outcomes after the concomitant use of PPIs and medications from 9 drug classes and warns against inappropriate drug combinations.

Benefits and harms of atypical antipsychotics for agitation in adults with dementia.

We evaluated the most current evidence regarding the benefits and harms of atypical antipsychotics in adults with dementia. In June 2016, following a protocol developed a priori, we systematically searched several databases for published and unpublished data from randomized controlled trials (RCT), observational studies, and meta-analyses; conducted direct meta-analyses using a random effects model; and graded the quality of evidence according to the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. One high-quality meta-analysis and published and unpublished data from 8 RCTs and 12 large observational studies met inclusion criteria. When compared with placebo, aripiprazole, risperidone, and olanzapine but not quetiapine result in modest (standardized mean difference <0.5 standard deviations) improvement in neuropsychiatric symptoms. Aripiprazole, risperidone, quetiapine, and olanzapine are associated with increased odds of acute myocardial infraction, and risperidone and olanzapine are associated with increased odds of hip fracture. Observational studies suggest no differences in all-cause mortality between atypical antipsychotics. Observational studies suggest that atypical antipsychotics are associated with lower risk of all-cause mortality and extrapyramidal symptoms but higher risk of stroke when compared with conventional antipsychotics. To manage agitation in adults with progressive dementia, clinicians may recommend atypical antipsychotics with continuous monitoring of behavioral symptoms, informing patients and their families or caregivers of the significant risk of adverse effects and baseline risk of acute myocardial infraction and bone fractures.