Daniel Caldeira

Non-vitamin K antagonist oral anticoagulants and major bleeding-related fatality in patients with atrial fibrillation and venous thromboembolism: a systematic review and meta-analysis

Objective Non-vitamin K antagonist oral anticoagulants (NOACs) are efficacious and safe antithrombotic drugs but the non-availability of an antidote for potential fatal haemorrhagic events is clinically perceived as a strong limitation. We aimed at evaluating the risk of haemorrhage-related fatalities associated with NOACs in patients requiring long-term anticoagulation. Methods MEDLINE, Cochrane Library and Web of Science databases were searched in November 2014 for atrial fibrillation (AF) or venous thromboembolism (VTE) phase III randomised controlled trials (RCT) comparing NOACs with vitamin K antagonists (VKAs) or low molecular weight heparin (LMWH) followed by VKAs. Pooled OR and 95% CIs were estimated through meta-analysis. Heterogeneity was assessed with the I2 test. Results Eleven studies were included: 5 on AF and 6 on VTE. A total of 100 324 patients were evaluated in 4 rivaroxaban, 3 dabigatran, 2 apixaban and 2 edoxaban studies. NOAC-treated patients had a 47% odds reduction compared with VKA (OR 0.53; 95% CI 0.42 to 0.68; I2=0%; 3 events avoided per 1000 patients) and 64% odds reduction compared with LMWH–VKA (OR 0.36; 95% CI 0.15 to 0.84; I2=0%; 1 event avoided per 1000 patients) regarding fatal bleeding risk. Case fatality due to major bleeding was lower in NOAC-treated patients both in AF (OR 0.68; 95% CI 0.48 to 0.96; I2=37%; 1 death avoided per 39 major bleedings) and VTE (OR 0.54; 95% CI 0.22 to 1.32; I2=0%) patients. AF survivors of major bleeding events treated with NOACs had lower mortality compared with patients treated with VKAs (OR 0.57; 95% CI 0.45 to 0.73; I2=0%; 78 events avoided per 1000 survivors to major bleeding). Conclusions These data suggest that NOACs decrease the risk of fatality cases related to major bleeding events, particularly in AF patients. These results support the safety profile of NOACs even without having a widely available drug-specific antidote.

Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis

Objective To systematically review longitudinal studies evaluating use of angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) and risk of pneumonia. Design Systematic review and meta-analysis. Data sources Medline through PubMed, Web of Science with conference proceedings (inception to June 2011), and US Food and Drug Administration website (June 2011). Systematic reviews and references of retrieved articles were also searched. Study selection Two reviewers independently selected randomised controlled trials and cohort and case-control studies evaluating the use of ACE inhibitors or ARBs and risk of pneumonia and retrieved characteristics of the studies and data estimates. Data synthesis The primary outcome was incidence of pneumonia and the secondary outcome was pneumonia related mortality. Subgroup analyses were carried according to baseline morbidities (stroke, heart failure, and chronic kidney disease) and patients’ characteristics (Asian and non-Asian). Pooled estimates of odds ratios and 95% confidence intervals were derived by random effects meta-analysis. Adjusted frequentist indirect comparisons between ACE inhibitors and ARBs were estimated and combined with direct evidence whenever available. Heterogeneity was assessed using the I2 test. Results 37 eligible studies were included. ACE inhibitors were associated with a significantly reduced risk of pneumonia compared with control treatment (19 studies: odds ratio 0.66, 95% confidence interval 0.55 to 0.80; I2=79%) and ARBs (combined direct and indirect odds ratio estimate 0.69, 0.56 to 0.85). In patients with stroke, the risk of pneumonia was also lower in those treated with ACE inhibitors compared with control treatment (odds ratio 0.46, 0.34 to 0.62) and ARBs (0.42, 0.22 to 0.80). ACE inhibitors were associated with a significantly reduced risk of pneumonia among Asian patients (0.43, 0.34 to 0.54) compared with non-Asian patients (0.82, 0.67 to 1.00; P<0.001). Compared with control treatments, both ACE inhibitors (seven studies: odds ratio 0.73, 0.58 to 0.92; I2=51%) and ARBs (one randomised controlled trial: 0.63, 0.40 to 1.00) were associated with a decrease in pneumonia related mortality, without differences between interventions. Conclusions The best evidence available points towards a putative protective role of ACE inhibitors but not ARBs in risk of pneumonia. Patient populations that may benefit most are those with previous stroke and Asian patients. ACE inhibitors were also associated with a decrease in pneumonia related mortality, but the data lacked strength.

Endovascular treatment versus medical care alone for ischaemic stroke: systematic review and meta-analysis

Objectives To evaluate the efficacy and safety of endovascular treatment, particularly adjunctive intra-arterial mechanical thrombectomy, in patients with ischaemic stroke. Design Systematic review and meta-analysis. Data sources Medline, Embase, Cochrane Central Register of Controlled Trials, Web of Science, SciELO, LILACS, and clinical trial registries from inception to December 2015. Reference lists were crosschecked. Eligibility criteria for selecting studies Randomised controlled trials in adults aged 18 or more with ischaemic stroke comparing endovascular treatment, including thrombectomy, with medical care alone, including intravenous recombinant tissue plasminogen activator (rt-PA). Trial endpoints were functional outcome (modified Rankin scale scores of ≤2) and mortality at 90 days after onset of symptoms. No language or time restrictions applied. Results 10 randomised controlled trials (n=2925) were included. In pooled analysis endovascular treatment, including thrombectomy, was associated with a higher proportion of patients experiencing good (modified Rankin scale scores ≤2) and excellent (scores ≤1) outcomes 90 days after stroke, without differences in mortality or rates for symptomatic intracranial haemorrhage, compared with patients randomised to medical care alone, including intravenous rt-PA. Heterogeneity was high among studies. The more recent studies (seven randomised controlled trials, published or presented in 2015) proved better suited to evaluate the effect of adjunctive intra-arterial mechanical thrombectomy on its index disease owing to more accurate patient selection, intravenous rt-PA being administered at a higher rate and earlier, and the use of more efficient thrombectomy devices. In most of these studies, more than 86% of the patients were treated with stent retrievers, and rates of recanalisation were higher (>58%) than previously reported. Subgroup analysis of these seven studies yielded a risk ratio of 1.56 (95% confidence interval 1.38 to 1.75) for good functional outcomes and 0.86 (0.69 to 1.06) for mortality, without heterogeneity among the results of the studies. All trials were open label. Risk of bias was moderate across studies. The full results of two trials are yet to be published. Conclusions Moderate to high quality evidence suggests that compared with medical care alone in a selected group of patients endovascular thrombectomy as add-on to intravenous thrombolysis performed within six to eight hours after large vessel ischaemic stroke in the anterior circulation provides beneficial functional outcomes, without increased detrimental effects. Systematic review registration PROSPERO CRD42015019340.

Skin antiseptics in venous puncture-site disinfection for prevention of blood culture contamination: systematic review with meta-analysis.

Blood cultures drawn by venous puncture are common clinical procedures for the detection of bacteraemia. Blood culture contamination (BCC) can lead to clinical misinterpretation and unnecessary expenses. We aimed to systematically review randomised controlled trials (RCTs) with skin antiseptics for prevention of contamination in venous-puncture drawn blood cultures. We conducted database search using CENTRAL (Cochrane Library issue April 2010), MEDLINE, EMBASE and mRCT, in June 2010. All RCTs testing skin antiseptics in venous-puncture drawn blood cultures were retrieved. Relative risk (RR) of the BCC outcome was analysed by random effects method using confidence interval (CI) of 95%. Studies were assessed by one review author and checked by another. Six studies were identified. Single-trial comparisons showed that alcoholic iodine tincture was better than non-alcoholic povidone-iodine, and isopropyl/acetone/povidone-iodine showed superiority against isopropyl/povidone-iodine. Meta-analysis demonstrated that alcoholic chlorhexidine was better than non-alcoholic povidone-iodine (RR: 0.33; 95% CI: 0.24-0.46) in 4757 blood cultures from two trials. Alcoholic solutions were better than non-alcoholic products (0.53; 0.31-0.90) in 21,300 blood cultures from four studies. Two trials with 13,418 blood cultures showed that iodine tincture was not superior to povidone-iodine in BCC prevention (0.79; 0.54-1.18). Alcoholic iodine was not different from non-alcoholic iodine (0.79; 0.53-1.17). Comparison of chlorhexidine vs iodine compounds was not conclusive. Alcohol alone was not inferior to iodinated products for prevention of contamination in venous-puncture drawn blood cultures. The association of alcohol and povidone-iodine did not seem to be useful. Alcoholic chlorhexidine solutions reduced blood culture false positives compared with aqueous povidone-iodine.

Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis

Objective In recent years, safety alerts have been made warning of the risk of serious drug-induced liver injury (DILI) caused by cardiovascular drugs. The new oral anticoagulants (NOACs) have now reached the market. However, safety concerns have been raised about their hepatic safety. Therefore we aimed to evaluate NOAC liver-related safety. Methods Systematic review and meta-analysis of phase III randomised controlled trials (RCTs). Medline and CENTRAL were searched to September 2013. Reviews and reference lists were also searched. Two reviewers independently searched for studies and retrieved data estimates. Primary outcome was DILI (transaminases elevations >3× upper limit of normal (ULN) with total bilirubin >2× ULN). NOACs were compared against any control group. Random-effects meta-analysis was performed, and pooled estimates were expressed as relative risk (RR) and 95% CI heterogeneity was evaluated with I2 test. Results Twenty-nine RCTs evaluating 152 116 patients (mean follow-up of 16 months) were included. All RCTs were rated as having low risk of bias. NOAC were not associated with an increased risk of DILI (RR 0.90, 95% CI 0.72 to 1.13, I2=0%). Similar results were obtained for individual NOAC (rivaroxaban, apixaban, dabigatran, darexaban, edoxaban) and considering the different control groups (vitamin K antagonists, low molecular weight heparin (LMWH) and placebo). The risk of transaminases elevations (>3×ULN) was lower among NOAC-treated patients, in particular in comparison with LMWH-treated patients (RR 0.71, 95% CI 0.59 to 0.85; I2=27%) Conclusions NOACs are not associated with an increased risk of DILI. The unexpected ‘protective’ effect of NOAC is probably due to LMWH-associated hepatotoxicity.

Caffeine does not increase the risk of atrial fibrillation: a systematic review and meta-analysis of observational studies

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.

Educational Strategies to Reduce Serum Phosphorus in Hyperphosphatemic Patients With Chronic Kidney Disease: Systematic Review With Meta-analysis

OBJECTIVE To systematically review educational strategies for phosphorus reduction in patients with hyperphosphatemia and chronic kidney disease (CKD). DESIGN Systematic review with meta-analysis. DATA SOURCES CENTRAL, MEDLINE, EMBASE, and mRCT databases were assessed in June 2010. STUDY SELECTION Randomized controlled trials evaluating educational strategies related to diet in hyperphosphatemic patients with CKD. DATA EXTRACTION AND SYNTHESIS METHOD: Study characteristics, phosphorus levels, and calcium-phosphorus product levels were retrieved. Jadad scale was used for quality assessment. Mean difference (MD) and 95% confidence intervals (CIs) were calculated by random effects method. RESULTS Seven randomized controlled trials were retrieved with a total of 524 patients with hyperphosphatemia and CKD. Educational strategies reduced phosphorus levels with an MD of -0.72 mg/dL (95% CI: -1.11 to -0.33, P < .01). Sensitivity analysis of trials with follow-up of <4 months did not show any benefit of the intervention, but educational intervention for ≥ 4 months showed an MD of -1.07 (95% CI: -1.49 to -0.64, P < .01). Calcium-phosphorus product level was improved in 227 evaluated patients from 5 trials with an MD of -5.22 mg(2)/dL(2) (95% CI: -9.48 to -0.98, P = .02, and I(2) = 58%). Sensitivity analysis removed the source of heterogeneity and resulted in an MD of -3.02 (95% CI: -6.51 to 0.47, P = .09). CONCLUSIONS Education helped reduce phosphorus levels in hyperphosphatemic patients with CKD, particularly those on dialysis.

Rate versus rhythm control in atrial fibrillation and clinical outcomes: Updated systematic review and meta-analysis of randomized controlled trials

Atrial fibrillation is the most frequently occurring sustained cardiac arrhythmia and is associated with a significantly increased risk of thromboembolic events and death. We sought to compare the clinical efficacy of rate and rhythm control strategies in patients with non-postoperative atrial fibrillation. We searched the PubMed database and the Cochrane Central Register of Controlled Trials for randomized controlled trials comparing rate versus rhythm control in patients with atrial fibrillation. Studies were retrieved and we analysed major clinical outcomes. Risk ratios (RRs) and 95% confidence intervals were calculated assuming random effects due to the clinical heterogeneity of the study populations. Eight randomized controlled trials were identified, with a total of 7499 patients with atrial fibrillation. There were no significant differences in the effects of rate and rhythm control on any outcome: all-cause mortality (RR: 0.95; CI: 0.86-1.05), cardiovascular mortality (RR: 0.99; CI: 0.87-1.13), arrhythmic/sudden death (RR: 1.12; CI: 0.91-1.38), ischaemic stroke (RR: 0.89; CI: 0.52-1.53), systemic embolism (RR: 0.89; CI: 0.69-1.14) and major bleeding (RR: 1.10; CI: 0.89-1.36). Updated data pooled from a large population of patients with atrial fibrillation suggests that rate and rhythm control strategies have similar effects on major clinical outcomes. Other factors, including individual preferences, comorbidities, drug tolerance and cost issues, should be considered when choosing the approach for these patients.

Systematic review with meta‐analysis: the risk of major gastrointestinal bleeding with non‐vitamin K antagonist oral anticoagulants

Gastrointestinal (GI) bleeding is a common complication among anticoagulated patients. Non‐vitamin K antagonist oral anticoagulants (NOACs) are associated with increased risk of GI (major and clinically relevant non‐major) bleeding. However, more information is needed regarding severe events.

Tolerability of Angiotensin-Receptor Blockers in Patients with Intolerance to Angiotensin-Converting Enzyme Inhibitors

BackgroundBetween 5% and 20% of patients treated with angiotensin-converting enzyme inhibitors (ACE inhibitors) develop intolerance. Angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) can be used as an alternative treatment.ObjectiveIn this study we aimed to evaluate the tolerability of ARBs in patients with intolerance to ACE inhibitors.Data SourcesThe electronic databases PubMed, MEDLINE/EMBASE via Dialog, CENTRAL, and ISI Web of Knowledge were searched.Study SelectionRandomized controlled trials (RCTs) evaluating ARBs in patients with intolerance to ACE inhibitors were selected.Data SynthesisRisk ratio (RR) and 95% confidence intervals (CIs) were estimated assuming the random effects method. We found 11 RCTs comparing ARBs with ACE inhibitors, diuretics, or placebo, and one RCT comparing high-dose versus low-dose ARB.ResultsARBs had fewer cough events versus ACE inhibitors (RR 0.37; 95% CI 0.28, 0.48). ARBs had drug discontinuation (RR 0.99; 95% CI 0.84, 1.17) and cough risk (RR 1.01; 95% CI 0.74, 1.39) rates similar to placebo. Angioedema risk with ARBs was also similar to placebo (RR 1.62; 95% CI 0.17, 15.79). Compared with placebo, hypotension (RR 2.63; 95% CI 1.77, 3.92), renal dysfunction (RR 2.07; 95% CI 1.45, 2.95) and hyperkalemia (RR 3.37; 95% CI 1.60, 7.11) were more frequent with ARBs.ConclusionsACE inhibitor rechallenge should be discouraged in patients with previous intolerance to ACE inhibitors due to a higher risk of cough. ARBs had cough and angioedema incidences similar to placebo. Despite a significantly higher incidence of hypotension, renal dysfunction and hyperkalemia, discontinuation of ARBs was similar to placebo.