Search

Purpose: Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, though uncertainty exists regarding their immune-related safety. The objective of this study was to assess the comparative safety profile (odds ratio) of ICIs and estimate the absolute rate of immune-related serious adverse events (irSAEs) in cancer patients undergoing treatment with ICIs. Methods: We searched for randomized trials till February 2021, including all ICIs for all cancers. Primary outcome was overall irSAEs, and secondary outcomes were pneumonitis, colitis, hepatitis, hypophysitis, myocarditis, nephritis, and pancreatitis. We conducted Bayesian network meta-analyses, estimated absolute rates and ranked treatments according to the surface under the cumulative ranking curve (SUCRA). Results: We included 96 trials (52,811 participants, median age 62 years). Risk of bias was high in most trials. Most cancers were non-small cell lung cancer (28 trials) and melanoma (15 trials). The worst-ranked ICI was ipilimumab (SUCRA 14%; event rate 848/10,000 patients) while the best-ranked ICI was atezolizumab (SUCRA 82%; event rate 119/10,000 patients). Conclusion: Each ICI showed a unique safety profile, with certain events more frequently observed with specific ICIs, which should be considered when managing cancer patients. [ABSTRACT FROM AUTHOR]

Background: Depressive disorders are recognized as a common neuropsychiatric disorder of Parkinson's disease (PD). Reported frequencies vary widely among studies and depend on the diagnostic criteria, the methods of ascertainment used, and the population sampled. Objective: We aimed to evaluate the frequency of depressive disorders in PD and to investigate the relationship with PD clinical variables. Methods: A systematic review and meta-analysis of observational studies (community-based, prospective and retrospective cohort, case-control, and cross-sectional studies) reporting the frequency of depressive disorders in PD patients. Results: Electronic database search wielded 3,536 articles; an additional 91 were identified through citation chaining. 163 full-text articles were assessed for eligibility. Of these, 49 met the inclusion criteria for our analysis. The pooled frequency of depressive disorders was 30.7% (95% confidence interval [CI] 25.6 to 36.2; I2 = 95%; 49 studies; combined n = 10,039). The pooled frequency of major depressive disorder was 14.0% (95% CI 10.5 to 18.5; I2 = 88%; 23 studies; combined n = 5,218). Subgroup/meta-regression analyses were conducted to investigate the relationship between frequency and study inclusion criteria, methodology used for diagnosis, and study design. We found a statistically significant correlation between study design and depressive disorders frequency (ranging from 8% in the community-based study to 44% in the retrospective studies) and a statistically significant positive correlation between mean baseline PD duration and major depressive disorder frequency. Conclusion: The current meta-analysis found a global frequency of depressive disorders of 30.7% and major depressive disorder of 14.0%. Study design influenced the frequency of depressive disorders in PD. Mean baseline PD duration and major depressive disorder frequency were positively correlated. [ABSTRACT FROM AUTHOR]

Background: Some patients with chronic coronary syndromes undergo invasive procedures but the efficacy of such interventions remains to be robustly established by randomised sham-controlled trials (RCTs).Purpose: To determine the sham effect in patients with chronic coronary syndromes enrolled in RCTs by performing a systematic review and meta-analysis.Methods: In April 2022, we performed a literature search for published patient-blind RCTs (CENTRAL, MEDLINE®, PsycINFO, and reference lists) with sham procedures, reporting the pre-post effects in the invasive sham arm among patients with Canadian cardiovascular society (CCS) angina or angina equivalents.Results: 16 RCTs were included with 546 patients in the sham arm. Pooled results showed that sham interventions were associated with: improvement of 7% (95% CI 2-11%; I2 = 0%) in exercise time; decrease of 0.78 (95% CI - 1.10 to - 0.47; I2 = 75%) in CCS angina class; decrease of 53% (95% CI 24-71%; I2 = 96%) and 25% (95% CI 20-29%; I2 = 0%) in anginal episodes and nitroglycerine (NTG) use, respectively. Pooled results also showed an improvement in the physical functioning, angina frequency, treatment satisfaction, and disease perception domains of the Seattle Angina Questionnaire (SAQ).Conclusion: Sham interventions in patients with chronic coronary syndromes were associated with a significant decrease in anginal episodes, NTG use, and CCS angina class and increased SAQ quality of life and exercise time. These results highlight the need for previous non sham-controlled trials to be interpreted with caution, and the importance of new invasive interventions to be evaluated versus a sham procedure. [ABSTRACT FROM AUTHOR]

Introduction: The summary of product characteristics of vaccines administered intramuscularly, including the vaccine for coronavirus SARS-CoV-2 (COVID-19) and Influenza, warned for risks of bleeding in patients treated with oral anticoagulants. We aimed to estimate the incidence of major bleeding events in this setting and to compare these risks against other vaccination routes. Methods: This systematic review included all prospective and retrospective studies enrolling anticoagulated patients that received intramuscular vaccination, published until December 2020 in CENTRAL, MEDLINE and EMBASE. The outcomes of interest were major bleeding and haematoma related with vaccination. The incidence of the outcomes was estimated through a random-effects meta-analysis using the Freeman-Turkey transformation. The results are expressed in percentages, with 95%-confidence intervals (95%CI), limited between 0 and 100%. When studies compared intramuscular vaccination vs. other route, the data were compared and pooled using random-effects meta-analysis. Risk ratios (RR) with 95%CI were reported. Results: Overall 16 studies with 642 patients were included. No major bleeding event was reported. The pooled incidence of haematomas following vaccination (mostly against Influenza) in patients treated with oral anticoagulants (mostly warfarin; no data with DOACs / NOACs) was 0.46% (95%CI 0-1.53%). Three studies evaluated the intramuscular vs. subcutaneous route of vaccination. Intramuscular vaccines did not increase the risk of haematoma (RR 0.53, 95%CI 0.10-2.82) compared with subcutaneous route. Conclusions: Intramuscular vaccination in anticoagulated patients is safe with very low incidence of haematomas and the best available evidence suggests that using the intramuscular route does not increase the risk of haematomas compared with the subcutaneous route. [ABSTRACT FROM AUTHOR]

Background: Psychotic symptoms are highly frequent in Parkinson's disease (PD) patients and are associated with poor prognosis. They include hallucinations, delusions, and minor psychotic phenomena, including sense of presence, passage hallucinations, and illusions. Objective: To evaluate the frequency of psychosis in PD patients. Methods: A systematic review and meta-analysis of clinical trials, prospective and retrospective cohort studies, case-control studies, and cross-sectional studies reporting the frequency of psychosis, hallucinations, and delusions in PD. Results: Electronic database search wielded 3536 articles, an additional 91 were identified through citation chaining. Of these, 163 were fully inspected, 57 removed, and 106 included as relevant for neuropsychiatric events frequency, with 32 meeting our inclusion criteria (psychosis and/or specific psychotic phenomena). The pooled frequency of psychosis was 20.7% (95% CI 14.5 to 28.6; I2 = 94%, 15 studies; combined n = 2919). None of the pre-defined meta-regressions or subgroup analyses were statistically significant or helped explain the statistical heterogeneity. The pooled frequency of any form of hallucination was 21.6% (95% CI 14.7 to 30.6; I2 = 95%; 18 studies; combined n = 3161). Duration of PD at baseline and mean baseline Hoehn & Yahr stage helped explain the statistical heterogeneity in the meta-analysis of hallucinations. Conclusion: Based on the available evidence, around a fifth of PD patients experience psychosis or hallucinations. The risk of developing hallucinations is likely moderated by the disease duration, Hoehn & Yahr stage, and the cognitive status. [ABSTRACT FROM AUTHOR]

Nonsteroidal anti‐inflammatory drugs (NSAIDs) were thought to increase the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) virus entrance into cells. Hence, it was suggested in the media that NSAIDs could lead to a higher risk of infection and/or disease severity. To determine the existence or absence of this association, we aimed to systematically evaluate the risk of SARS‐CoV‐2 infection and mortality and the risk of severe coronavirus disease 2019 (COVID‐19) associated with previous exposure to NSAIDs. MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL), and EMBASE were searched in February 2021 for controlled studies. The results were calculated through random‐effect meta‐analyses and reported in terms of odds ratios (ORs) with 95% confidence intervals (CIs). Heterogeneity was assessed with I2 test. Eleven studies were included, comprising a total of 683 715 patients. NSAID exposure did not increase the risk of having a positive test for SARS‐CoV‐2 infection (OR, 0.97; 95%CI, 0.85‐1.11, I2 = 24%; 5 studies). The exposure to NSAIDs did not increase the risk of severe/critical COVID‐19 disease (OR, 0.92; 95%CI, 0.80‐1.05; I2 = 0%; 5 studies) nor all‐cause mortality among patients with COVID‐19 (OR, 0.86; 95%CI, 0.75‐0.99; I2 = 14%, 4 studies). Our data did not suggest that exposure to NSAIDs increases the risk of having SARS‐CoV‐2 infection or increases the severity of COVID‐19 disease. Also, the fragility of the studies included precludes definite conclusions and highlights the need for further robust data. [ABSTRACT FROM AUTHOR]

Background: Gait impairments are common and highly disabling for Parkinson's disease (PD) patients. With the development of technology-based tools, it is now possible to measure the spatiotemporal parameters of gait with a reduced margin of error, thereby enabling a more accurate characterization of impairment. Objective: To summarize and critically appraise the characteristics of technology-based gait analysis in PD and to provide mean and standard deviation values for spatiotemporal gait parameters. Methods: A systematic review was conducted using the databases CENTRAL, MEDLINE, Embase, and PEDro from their inception to September 2019 to identify all observational and experimental studies conducted in PD or atypical parkinsonism that included a technology-based gait assessment. Two reviewers independently screened citations and extracted data. Results: We included 95 studies, 82.1% (n = 78) reporting a laboratory gait assessment and 61.1% (n = 58 studies) using a wearable sensor. The most frequently reported parameters were gait velocity, stride and step length, and cadence. A statistically significant difference was found when comparing the mean values of each of these parameters in PD patients versus healthy controls. No statistically significant differences were found in the mean value of the parameters when comparing wearable versus non-wearable sensors, different types of wearable sensors, and different sensor locations. Conclusion: Our results provide useful information for performing objective technology-based gait assessment in PD, as well as mean values to better interpret the results. Further studies should explore the clinical meaningfulness of each parameter and how they behave in a free-living context and throughout disease progression. [ABSTRACT FROM AUTHOR]

Objective: Despite the progression of treatments over decades, heart failure (HF) is a disease with high morbidity, mortality and economic burden. Influenza infection is an important trigger for cardiovascular (CV) events, including HF. Influenza vaccination has been seen to reduce the risk of CV mortality in patients with coronary disease, but the effect in patients with HF is still unclear. Therefore, we conducted a systematic review to evaluate the effect of influenza vaccination in the morbimortality of patients with HF.Methods: MEDLINE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Health Technology Assessment and PsycINFO databases (December 2018) were searched for longitudinal studies evaluating influenza vaccination compared with a non-vaccination control group in patients with HF. The risk of bias was assessed according to the ROBINS-I tool. We performed a random-effects meta-analysis to estimate the pooled HRs with 95% CIs, and heterogeneity was evaluated using the I2 statistics.Results: Six cohort studies evaluating 179 158 patients with HF were included in the meta-analysis. Influenza vaccination was associated with a lower risk of all-cause mortality (HR=0.83; 95% CI 0.76 to 0.91; I2=75%). The effect of the influenza vaccination was not statistically significant in a pooled analysis of CV mortality (HR=0.92, 95% CI 0.73 to 1.15; 2 studies) and of all-cause hospitalisations (HR=1.01, 95% CI 0.92 to 1.11; 2 studies). The majority of outcomes in the included studies had a serious risk of bias and almost all evaluated outcomes had very low Grading of Recommendation, Assessment, Development and Evaluation (GRADE) evidence.Conclusions: Influenza vaccination was associated with a significant decrease in all-cause mortality risk in patients with HF. [ABSTRACT FROM AUTHOR]

Background: Functional mobility (FM) is a person's ability to move to accomplish activities of daily living; it bridges the concepts of mobility and functional ability. There is frequently a loss of FM in Parkinson's disease (PD). Several instruments have been used to assess this concept in PD; however, there is no consensus on which are the most appropriate. Objective: We aimed to identify and critically appraise which measurement instruments have been used to assess FM. Methods: A systematic review was conducted using the databases CENTRAL, MEDLINE, Embase, and PEDro from their inception to January 2019 to identify all observational and experimental studies conducted in PD or atypical parkinsonism that included an FM assessment. Two reviewers independently screened citations, extracted data, and assessed clinimetric properties. Results: We included 95 studies that assessed FM in PD. Fifty‐five (57.9%) studies mentioned FM in the article, and 39 (41.1%) specified the measurement tools used to evaluate FM. FM was the primary outcome in 12 (12.6%) studies. The Timed Up and Go test was the most frequently used measurement tool. Only one study presented a definition of FM. Several overlapping terms were used, the most common being mobility. Conclusion: Several studies reported the use of FM measurement tools in PD, though with frequent misconceptions, an inadequate context of use, or suboptimal assessment. We propose the establishment of the concept of FM applied to PD, followed by the adequate clinimetric validation of existing measurement tools to provide a comprehensive and reliable evaluation of FM in PD. [ABSTRACT FROM AUTHOR]

Introduction: Influenza vaccination may be beneficial in coronary disease patients; however the infection and vaccination are associated with acute inflammation, a trigger of cardiovascular events. We aimed to review the risk of myocardial infarction (MI) associated with Influenza infection and the safety of vaccination in self-controlled case series (SCCS). Methods: We performed a systematic review with meta-analysis of SCCS studies to evaluate the risk of MI associated with Influenza infection/vaccination. Database search was performed in August/2018. The data were reported using the incident rate ratio (IRR) and 95% confidence interval (95%CI). Results: three studies for Influenza infection and two studies for Influenza vaccination were eligible. The risk of MI following an Influenza infection was significantly increased in the first 3 days (IRR 5.79; 95%CI: 3.59–9.38) and between 4-7 days (IRR 4.52; 95%CI: 2.80–7.32). In the first 4 weeks following the Influenza vaccination, there was a significant decrease of MI risk (IRR 0.84, 95%CI: 0.78–0.91). Conclusions: Short-term MI risk in Influenza infection is significantly increased, with a low-to-moderate confidence in the pooled evidence. The Influenza vaccine was safe regarding the short-term risk for MI, and the risk reduction is possibly related to a healthy period bias. [ABSTRACT FROM AUTHOR]

Introduction: Ibrutinib is an oral covalent inhibitor of Bruton's tyrosine kinase approved for the treatment of patients with chronic lymphocytic leukemia (CLL), mantle cell lymphoma and Waldenstrӧm’s macroglobulinemia. Ibrutinib has an increased risk of atrial fibrillation but the mechanism is unknown, and hypertension may play a role in the pathogenesis of this adverse drug reaction. Methods: We aimed to review the risk of hypertension and atrial fibrillation as adverse events associated with ibrutinib through a systematic review with meta-analysis of randomized controlled trials (RCTs) retrieved in December 2018 on MEDLINE, EMBASE, CENTRAL and ClinicalTrials.gov. The data were pooled using random-effects meta-analyses using the risk ratio (RR) with the 95% confidence interval (95%CI). The confidence on the pooled estimates was ascertained through the grading of recommendations assessment, development, and evaluation (GRADE) approach. Results: There were 8 eligible RCTs (2580 patients), all reporting safety data of interest. Ibrutinib was associated with a significant increase in the risk of hypertension with a RR of 2.82 (95%CI 1.52–5.23) with moderate quality evidence. Ibrutinib increased significantly the risk of atrial fibrillation with a RR of 4.69 (95%CI 2.17–7.64) with high quality evidence. Conclusions: Ibrutinib was associated with significantly increased risks of both hypertension and atrial fibrillation. [ABSTRACT FROM AUTHOR]

Introduction: Sofosbuvir is a new direct-acting pyrimidine nucleotide analogue antiviral drug that has shown remarkable efficacy in the treatment of hepatitis C in clinical trials. However, observational anecdotal data have recently suggested an increased risk of serious bradycardia among patients treated with sofosbuvir and amiodarone.Objective: We aimed to estimate and characterize the cardiac safety of sofosbuvir by performing a systematic review of randomized controlled trials (RCTs).Methods: We conducted a systematic review of RCTs (PROSPERO 2016: CRD42016033109) comparing sofosbuvir and non-sofosbuvir regimens in patients with chronic hepatitis C by searching the MEDLINE, Embase, and Cochrane Library databases up to January 2017. Non-published data were obtained from the sofosbuvir marketing authorization holder. Random-effects meta-analysis was performed to derive pooled estimates of relative risks (RRs) and corresponding 95% confidence intervals (CIs).Results: Six trials, enrolling 2346 patients (1625 treated with sofosbuvir), were included. The overall risk of bias across studies was moderate. The risk of reported cardiac events (RR 0.87; 95% CI 0.41-1.85), arrhythmias (RR 0.93; 95% CI 0.34-2.51), bradycardia (RR 0.47; 95% CI 0.04-5.20), and tachycardia (RR 0.91; 95% CI 0.20-4.20) were not significantly different between sofosbuvir and non-sofosbuvir regimens. The risks of reported syncope, presyncope, loss of consciousness, or palpitations were similar among those receiving sofosbuvir regimens and controls.Conclusions: The pooled data from RCTs did not show an increased risk of cardiac outcomes, including arrhythmias (and bradycardia), among sofosbuvir-treated patients, although the overall quality of the evidence supporting this conclusion was very low. Registration: PROSPERO 2016:CRD42016033109 at http://www.crd.york.ac.uk/PROSPERO/ . [ABSTRACT FROM AUTHOR]

Background Tetrabenazine is the only US Food and Drug Administration-approved drug for Huntington's disease, and deutetrabenazine was recently tested against placebo. A switching-trial from tetrabenazine to deutetrabenazine is underway, but no head-to-head, blinded, randomized controlled trial is planned. Using meta-analytical methodology, the authors compared these molecules. Methods RCTs comparing tetrabenazine or deutetrabenazine with placebo in Huntington's disease were searched. The authors assessed the Cochrane risk-of-bias tool, calculated indirect treatment comparisons, and applied the Grading of Recommendations Assessment, Development, and Evaluation ( GRADE) framework. Results The evidence network for this report comprised 1 tetrabenazine trial and 1 deutetrabenazine trial, both against placebo. Risk of bias was moderate in both. Participants in the tetrabenazine and deutetrabenazine trials did not differ significantly on motor scores or adverse events. Depression and somnolence scales significantly favored deutetrabenazine. Conclusion There is low-quality evidence that tetrabenazine and deutetrabenazine do not differ in efficacy or safety. It is important to note that these results are likely to remain the only head-to-head comparison between these 2 compounds in Huntington's disease. [ABSTRACT FROM AUTHOR]

Background Atrial fibrillation (AF) is the most prevalent sustained arrhythmia, and risk factors are well established. Caffeine exposure has been associated with increased risk of AF, but heterogeneous data exist in the literature. Objective To evaluate the association between chronic exposure to caffeine and AF. Design Systematic review and meta-analysis of observational studies. Data sources PubMed, CENTRAL, ISI Web of Knowledge and LILACS to December 2012. Reviews and references of retrieved articles were comprehensively searched. Study selection Two reviewers independently searched for studies and retrieved their characteristics and data estimates. Data synthesis Random-effects meta-analysis was performed, and pooled estimates were expressed as OR and 95% CI. Heterogeneity was assessed with the I2 test. Subgroup analyses were conducted according to caffeine dose and source (coffee). Results Seven observational studies evaluating 115 993 individuals were included: six cohorts and one case- control study. Caffeine exposure was not associated with an increased risk of AF (OR 0.92, 95% CI 0.82 to 1.04, I²=72%). Pooled results from high-quality studies showed a 13% odds reduction in AF risk with lower heterogeneity (OR 0.87; 95% CI 0.80 to 0.94; I2=39%). Low-dose caffeine exposure showed OR 0.85 (95% CI 0.78 to 92, I²=0%) without significant differences in other dosage strata. Caffeine exposure based solely on coffee consumption also did not influence AF risk. Conclusions Caffeine exposure is not associated with increased AF risk. Low-dose caffeine may have a protective effect. [ABSTRACT FROM AUTHOR]

Introduction: Botulinum toxin (BoNT) is the first line therapy for cervical dystonia (CD), with most patients receiving many treatment sessions, and so come to recognize and expect the benefits and harms of BoNT, making it difficult to separate which adverse events (AEs) are driven by BoNT and which come from patients' expectations.Methods: Using the results of three Cochrane systematic reviews of randomized controlled trials (RCTs) we pooled results to calculate the risk of general and specific AEs associated with BoNT, and the proportion of AEs that cannot be pharmacologically attributed to BoNT.Results: Fifteen RCTs, enrolling 1604 patients, were included. BoNT was associated with an increased risk of AEs, but 79% of this increased risk cannot be pharmacologically attributed to BoNT.Conclusions: Patients with CD attach a considerable expectation of harm due to BoNT, reflected in the large proportion of non-pharmacologically-mediated AEs. [ABSTRACT FROM AUTHOR]

Objective: Evaluate the frequency of cardiovascular adverse events reported in randomized controlled trials (RCT) in Restless Leg Syndrome (RLS).Methods: Databases were searched up to October 2015. Randomized, double-blind, placebo-controlled trials of patients with RLS were included if quantitative data were extractable. The primary outcome was cardiovascular adverse events defined as cardiac diseases, blood pressure abnormalities, syncope, cerebrovascular diseases, thromboembolic events, and sudden death. The pooled estimated prevalence of cardiovascular (CV) adverse events (AE) and respective 95% confidence interval (CI) was determined by using a meta-analysis.Results: In sum, 28 RCT (2515 participants in the placebo arm and 4223 participants in the intervention arm) reported CV AE. The pooled estimated prevalence of CV AE was 0.61% (95% CI 0.31 to 0.91; I2 = 0%) in the placebo arm and 0.68% (95%CI 0.40 to 0.96; I2 = 18.25%) in the intervention arm. The frequency of major CV events (myocardial infarction, stroke and peripheral artery disease) was 0.49% (95%CI 0.22 to 0.77; I2 = 0%) and 0.33% (95% CI 0.16 to 0.50; I2 = 0%) in the placebo and intervention arm, respectively.Conclusions: The frequency of major cardiovascular events in the RLS trials is not negligible, particularly when considering the young age of these patients. [ABSTRACT FROM AUTHOR]

Objective: To estimate the magnitude of the nocebo response in Parkinson's disease and explore possible associations with study characteristics.Methods: Databases were searched up to February 2017. Placebo-controlled, parallel-group randomized controlled trials investigating pharmacological interventions in people with Parkinson's disease were included. Data were derived from the last measured within-group response in the placebo and intervention arms of randomized controlled trials, after independent extraction. A random-effects model was used to pool study data. The main outcome was the nocebo response, measured as the proportion of placebo-treated participants experiencing any adverse events (AEs). We also measured the proportion of patients with serious AEs (SAEs), and the rates of study dropouts (including due to AEs) and death. PROSPERO registration number is CRD42017070471.Results: We included 236 randomized controlled trials, with a combined population of 17,381 participants allocated to placebo. The nocebo response was 56.0% (95% CI, 51.7%-60.4%; 148 trials; I2 = 98%). SAEs were reported in 4.0% (95% CI, 3.4%-4.6%, 157 trials; I2 = 73%) of placebo-treated patients, dropouts in 14.0% (95% CI, 12.5%-15.5%, 225 trials; I2 = 91%), dropouts due to AEs in 5.7% (95% CI, 5.1%-6.4%, 219 trials; I2 = 73%). Deaths occurred in 0.6% (95% CI, 0.5%-0.7%, 227 trials; I2 = 0%). Similar proportions were identified in patients in intervention arms.Conclusions: The magnitude of the nocebo response in parallel-designed randomized controlled trials in Parkinson's disease is substantial and should be considered in the interpretation of safety results and in the design and interpretation of future clinical trials. [ABSTRACT FROM AUTHOR]

Highlights • In elderly patients with atrial fibrillation, NOACs showed a 30% relative risk reduction of stroke or systemic embolism. • The cumulative sample size of the trials in elderly patients reached the minimum sample size required for the risk reduction. • All the evaluated NOACs regimens, except dabigatran 110 mg twice daily, reduced the risk of embolic events in elderly patients with AF. • Apixaban and edoxaban individually, reduced significantly the risk of major bleeding in elderly patients with atrial fibrillation. • In younger patients (<75 years-old), NOACs did not reduce the risk of stroke or systemic embolism but reduced the risk of major bleeding. Abstract Background: Elderly population is known to be associated with polymedication, comorbidities and altered drug pharmacokinetics. However, the most adequate oral anticoagulant, attending to its relative efficacy and safety, remains unclear. Methods: We searched for phase III randomized controlled trials (MEDLINE, Cochrane Library, SciELO collection and Web of Science) comparing novel non-vitamin K antagonist oral anticoagulants (NOACs) with Vitamin K antagonists (VKA) in the elderly population (≥75 years-old) in atrial fibrillation (AF). Risk ratios (RR) were calculated using a random effects model. Trial sequential analysis (TSA) was performed in statistically significant results to evaluate whether cumulative sample size was powered. Results: Four trials rendered data about elderly (≥75 years-old) and younger patients (<75 years-old) with AF. NOACs demonstrated a 30% significant risk reduction (RR 0.70, 95% CI: 0.61 to 0.80) in elderly patients compared to VKA, without heterogeneity across studies (I2 = 0%). The TSA showed that cumulative evidence of this subgroup exceeded the minimum information size required for the risk reduction. In younger patients, VKA and NOACs shared a similar risk of stroke and systemic embolism (RR 0.97, 95% CI: 0.79 to 1.18). Regarding major bleeding risk in the elderly, the overall comparative risk of NOACs was not different from VKA (RR 0.91, 95% CI: 0.72 to 1.16; I2 = 86%). Conclusions: NOACs reduce significantly the risk of stroke and systemic embolism in elderly patients without increasing major bleeding events. The dimension of stroke risk reduction was significantly higher in the elderly than in younger adults. [ABSTRACT FROM AUTHOR]

BACKGROUND: Venous thromboembolism (VTE) is a potentially fatal complication of orthopedic surgery, and until recently, few antithrombotic compounds were available for postoperative thromboprophylaxis. The introduction of the non–vitamin K antagonists oral anticoagulants (NOAC), including apixaban, has extended the therapeutic armamentarium in this field. Therefore, estimation of NOAC net clinical benefit in comparison with the established treatment is needed to inform clinical decision making. OBJECTIVES: Systematic review to assess the efficacy and safety of apixaban 2.5 mg twice a day versus low-molecular-weight heparins (LMWH) for thromboprophylaxis in patients undergoing knee or hip replacement. DATA SOURCES: MEDLINE, Embase, and CENTRAL were searched from inception to September 2016, other systematic reviews, reference lists, and experts were consulted. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTION: All major orthopedic surgery randomized controlled trials comparing apixaban 2.5 mg twice daily with LMWH, reporting thrombotic and bleeding events. DATA EXTRACTION: Two independent reviewers, using a predetermined form. STUDY APPRAISAL AND SYNTHESIS METHODS: The Cochrane tool to assess risk bias was used by two independent authors. RevMan software was used to estimate pooled risk ratio (RR) and 95% confidence intervals (95% CI) using random-effects meta-analysis. Trial sequential analysis (TSA) was performed in statistical significant results to evaluate whether cumulative sample size was powered for the obtained effect. Overall confidence in cumulative evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group methodology. RESULTS: Four studies comparing apixaban 2.5 mg twice daily with LMWH were included, with a total of 11.828 patients (55% undergoing knee and 45% hip replacement). The overall risk of bias across studies was low. In comparison with LMWH (all regimens), apixaban showed a significantly lower risk of VTE events and overall mortality combined (RR: 0.63, 95% CI: 0.42-0.95, I2 = 84%, n = 8346), but not of major VTE events (RR: 0.62, 95% CI: 0.32-1.19, I2 = 63%, n = 9493), or of symptomatic VTE events and VTE-related mortality combined (RR: 1.14, 95% CI: 0.68-1.90, I2 = 0%, n = 11 879). Trial sequential analysis showed that the risk reduction obtained for VTE and mortality was based on underpowered cumulative sample size and effect dimension. Subgroup analysis according to LMWH regimens showed that apixaban reduced the risk of VTE events and overall mortality, and major VTE events, when compared with LMWH once daily, without differences between apixaban and LMWH twice daily. CONCLUSIONS: There is low to moderate evidence that in patients undergoing knee or hip replacement, apixaban seems equally effective and safe to LMWH twice a day. When compared with LMWH once a day, apixaban seems a superior thromboprophylaxis option. However, the results are underpowered which precludes definite answers regarding the true net clinical benefit of apixaban versus LMWH in this clinical context.BACKGROUND: Venous thromboembolism (VTE) is a potentially fatal complication of orthopedic surgery, and until recently, few antithrombotic compounds were available for postoperative thromboprophylaxis. The introduction of the non–vitamin K antagonists oral anticoagulants (NOAC), including apixaban, has extended the therapeutic armamentarium in this field. Therefore, estimation of NOAC net clinical benefit in comparison with the established treatment is needed to inform clinical decision making. OBJECTIVES: Systematic review to assess the efficacy and safety of apixaban 2.5 mg twice a day versus low-molecular-weight heparins (LMWH) for thromboprophylaxis in patients undergoing knee or hip replacement. DATA SOURCES: MEDLINE, Embase, and CENTRAL were searched from inception to September 2016, other systematic reviews, reference lists, and experts were consulted. STUDY ELIGIBILITY CRITERIA, PARTICIPANTS, AND INTERVENTION: All major orthopedic surgery randomized controlled trials comparing apixaban 2.5 mg twice daily with LMWH, reporting thrombotic and bleeding events. DATA EXTRACTION: Two independent reviewers, using a predetermined form. STUDY APPRAISAL AND SYNTHESIS METHODS: The Cochrane tool to assess risk bias was used by two independent authors. RevMan software was used to estimate pooled risk ratio (RR) and 95% confidence intervals (95% CI) using random-effects meta-analysis. Trial sequential analysis (TSA) was performed in statistical significant results to evaluate whether cumulative sample size was powered for the obtained effect. Overall confidence in cumulative evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group methodology. RESULTS: Four studies comparing apixaban 2.5 mg twice daily with LMWH were included, with a total of 11.828 patients (55% undergoing knee and 45% hip replacement). The overall risk of bias across studies was low. In comparison with LMWH (all regimens), apixaban showed a significantly lower risk of VTE events and overall mortality combined (RR: 0.63, 95% CI: 0.42-0.95, I2 = 84%, n = 8346), but not of major VTE events (RR: 0.62, 95% CI: 0.32-1.19, I2 = 63%, n = 9493), or of symptomatic VTE events and VTE-related mortality combined (RR: 1.14, 95% CI: 0.68-1.90, I2 = 0%, n = 11 879). Trial sequential analysis showed that the risk reduction obtained for VTE and mortality was based on underpowered cumulative sample size and effect dimension. Subgroup analysis according to LMWH regimens showed that apixaban reduced the risk of VTE events and overall mortality, and major VTE events, when compared with LMWH once daily, without differences between apixaban and LMWH twice daily. CONCLUSIONS: There is low to moderate evidence that in patients undergoing knee or hip replacement, apixaban seems equally effective and safe to LMWH twice a day. When compared with LMWH once a day, apixaban seems a superior thromboprophylaxis option. However, the results are underpowered which precludes definite answers regarding the true net clinical benefit of apixaban versus LMWH in this clinical context. [ABSTRACT FROM AUTHOR]

Introduction Acetaminophen is a commonly prescribed and over-the-count used drug, and is considered to be the preferred treatment choice for anticoagulated patients requiring analgesic drug therapy. However, observational data have suggested that this drug combination may increase the International Normalized Ratio (INR) values and bleeding events in patients taking Vitamin K antagonists (VKAs). Still, the clinical impact of this putative effect remains unknown. Therefore, we performed a systematic review of randomized controlled trials (RCTs) to estimate the impact of concomitant use of acetaminophen and VKA in the INR measurements Methods Systematic review and meta-analysis of RCTs comparing acetaminophen versus placebo or no treatment, in VKA-treated patients and reporting INR estimates. Medline and Cochrane Library were searched up to April 2014. Primary outcome was the mean difference (MD) between the greatest INR elevations in each treatment arm. Random-effects meta-analysis was performed to derive pooled estimates and 95% Confidence Interval (CI). Heterogeneity was evaluated with I2 test. Results Seven RCTs (n=225 patients) were included. Acetaminophen was associated with a mean 0.62 INR increase (95%CI: 0.46 to 0.78; II2=25%) compared to placebo in VKA-treated patients. Studies did not report any major bleeding event. Meta-regression showed a significant 0.17 mean increase of the INR per each daily gram of acetaminophen (95%CI: 0.004 to 0.33). Conclusion Acetaminophen is associated with a statistically significant and possible clinically relevant increase in the INR, with a dose dependent relationship. Patients treated concomitantly with VKA and acetaminophen should be monitored more regularly for possible VKA dosage adjustment. [ABSTRACT FROM AUTHOR]