Reperfusion therapies in patients with acute ischaemic stroke and atrial fibrillation: data on safety and effectiveness from a multi-centre cohort study.

BACKGROUND: Intravenous thrombolysis (IVT) and/or endovascular therapy (EVT) are currently considered best practices in acute stroke patients. Data regarding the efficacy and safety of reperfusion therapies in patients with atrial fibrillation (AF) are conflicting as regards haemorrhagic transformation, mortality, and functional outcome. This study sought to investigate for any differences, in terms of safety and effectiveness, between AF patients with acute ischaemic stroke (AIS) treated and untreated with reperfusion therapies. METHODS: Data from two multicenter cohort studies (RAF and RAF-NOACs) on consecutive patients with AF and AIS were analyzed to compare patients treated and not treated with reperfusion therapies (IVT and/or EVT). Multivariable logistic regression analysis was performed to identify independent predictors for outcome events: 90-day good functional outcome and mortality. A propensity score matching (PSM) analysis compared treated and untreated patients. RESULTS: Overall, 441 (25.4%) were included in the reperfusion-treated group and 1,295 (74.6%) in the untreated group. The multivariable model suggested that reperfusion therapies were significantly associated with good functional outcome. Rates of mortality and disability were higher in patients not treated, especially in the case of higher NIHSS scores. In the PSM comparison, 173/250 patients (69.2%) who had received reperfusion therapies had good functional outcome at 90 days, compared to 146/250 (58.4%) untreated patients (p = 0.009, OR: 1.60, 95% CI:1.11-2.31). CONCLUSIONS: Patients with AF and AIS treated with reperfusion therapies had a significantly higher rate of good functional outcome and lower rates of mortality compared to those patients with AF and AIS who had undergone conservative treatment.

P2Y12 inhibitors plus aspirin for acute treatment and secondary prevention in minor stroke and high-risk transient ischemic attack: A systematic review and meta-analysis.

BACKGROUND: Aspirin is a cornerstone of preventive treatment for stroke recurrence, but during the last few years the role of dual antiplatelet therapy (DAPT) is much more emerging. OBJECTIVE: This systematic review aimed to compare early use of P2Y12 inhibitors (clopidogrel/ticagrelor) plus aspirin to aspirin alone for acute treatment and secondary prevention in acute non-cardioembolic minor ischemic stroke or TIA. METHODS: A systematic search on MEDLINE and EMBASE was performed. Treatment effects were estimated with RRs and 95% CI. We used RevMan 5.4 for data analyses. We assessed methodological quality of selected studies according to Rob2 tools and quality of evidence with GRADE approach. RESULTS: Four RCTs were included, enrolling 21,459 patients. Compared to aspirin alone, DAPT was superior in reducing stroke recurrence (RR 0.74, 95% CI 0.67-0.82, P <0.00001, absolute risk difference by 2%, NNT 50) and disabling stroke defined as mRS>2 (RR 0.84, 95% CI 0.75-0.95, P = 0.004), with no impact on all causes of mortality (RR 1.30, 95% CI 0.90-1.89, P = 0.16). An increased risk of major bleeding was emerged (RR 2.54, 95% CI 1.65-3.92, P <0.0001, absolute risk difference by 0,4%, NNH 250), in particular with ticagrelor, but there was no correlation between therapy duration and bleeding risk, as appeared from one-month (RR 3.06, 95% CI 1.64 to 5.69) and three-month (RR 2.09, 95% CI 1.18 to 3.69) follow-up analysis. CONCLUSIONS: Early administration of P2Y12 inhibitors plus aspirin in patients with acute non-cardioembolic minor ischemic stroke or TIA reduced the incidence of ischemic stroke recurrence, impacting more significantly than the increased bleeding risk and influencing patients' quality of life by reducing disabling stroke.

D-dimer to rule out venous thromboembolism during pregnancy: A systematic review and meta-analysis.

BACKGROUND: The usefulness of D-dimer measurement to rule out venous thromboembolism (VTE) during pregnancy is debated. OBJECTIVES: We performed a systematic review and meta-analysis to investigate the safety of D-dimer to rule out acute VTE in pregnant women with suspected pulmonary embolism and/or deep vein thrombosis. METHODS: Two reviewers independently identified studies through PubMed and Embase until June 2021, week 1. We supplemented our search by manually reviewing reference lists of all retrieved articles, clinicalTrials.gov, and reference literature. Prospective or retrospective studies in which a formal diagnostic algorithm was used to evaluate the ability of D-dimer to rule out VTE during pregnancy were eligible. RESULTS: We identified 665 references through systematic database and additional search strategies; 45 studies were retrieved in full, of which four were included, after applying exclusion criteria. Three studies were prospective, and one had a retrospective design. The 3-month thromboembolic rate in pregnant women left untreated after a negative D-dimer was 1/312 (0.32%; 95% CI, 0.06-1.83). The pooled estimate values were 99.5% for sensitivity (95% CI, 95.0-100.0; I², 0%) and 100% for negative predictive value (95% CI, 99.19-100.0; I², 0%). The prevalence of VTE and the yield of D-dimer were 7.4% (95% CI, 3.8-12; I², 83%) and 34.2% (95% CI, 15.9-55.23; I², 89%) respectively. CONCLUSION: Our results suggest that D-dimer allows to safely rule out VTE in pregnant women with suspected VTE and a disease prevalence consistent with a low/intermediate or unlikely pretest probability.

External validation of the YEARS diagnostic algorithm for suspected pulmonary embolism.

BACKGROUND: Validated diagnostic algorithms are used to manage patients with suspected pulmonary embolism (PE). The recently published YEARS study proposed a simplified diagnostic strategy to reduce the use of computed tomography pulmonary angiography. OBJECTIVES: To externally validate this strategy in an independent cohort. METHODS: We analyzed data from three previous prospective cohort studies of outpatients with suspected PE. We retrospectively applied the YEARS algorithm. The three YEARS clinical criteria are: clinical signs of deep vein thrombosis, hemoptysis, and PE as the most likely diagnosis. If zero YEARS criteria are met, a D-dimer < 1000 ng/mL will rule out PE. If ≥1 YEARS criteria are met, a D-dimer < 500 ng/mL will rule out PE. RESULTS: Of the 3314 patients, 731 (22.1%) had PE. Applying the YEARS diagnostic algorithm, 1423 (42.9%) patients could have had PE ruled out without imaging. Of these patients, 17 (1.2%; 95% confidence interval 0.8-1.9) were diagnosed with PE at initial testing. All 17 had no YEARS item and a D-dimer < 1000 ng/mL. All 17 had a D-dimer level above their age-adjusted cutoff. Among the 272 patients with no YEARS criteria and a D-dimer < 1000 ng/mL but above their age-adjusted D-dimer cutoff, PE was diagnosed in 6.3% (17/272; 95% confidence interval 3.9-9.8). CONCLUSION: We provide external validation of the YEARS diagnostic algorithm in an independent cohort. The rule appears to safely exclude PE. However, caution is required in patients with no YEARS item and a D-dimer < 1000 ng/mL but above their age-adjusted D-dimer cutoff.

Drug-Drug Interactions between Direct Oral Anticoagulants and Hepatitis C Direct-Acting Antiviral Agents: Looking for Evidence Through a Systematic Review.

BACKGROUND: Direct oral anticoagulants (DOACs), as substrates of cytochrome P450 (CYP) 3A4 and/or P-glycoprotein, are susceptible to drug-drug interactions (DDIs). Hepatitis C direct-acting antiviral agents (DAAs), via P-glycoprotein or CYP3A4 inhibition, may increase DOAC exposure with relevant bleeding risk. We performed a systematic review on DDIs between DOACs and DAAs. METHODS: Two reviewers independently identified studies through electronic databases, until 7 July 2020, supplementing the search by reviewing conference abstracts and the ClinicalTrials.gov website. RESULTS: Of 1386 identified references, four articles were finally included after applying the exclusion criteria. Three phase I clinical studies in healthy volunteers assessed interactions between dabigatran and glecaprevir/pibrentasvir, odalasvir/simeprevir, or sofosbuvir/velpatasvir/voxilaprevir, showing an increase in the dabigatran area under the concentration-time curve (AUC) by 138%, 103%, and 161%, respectively. CONCLUSIONS: DOACs and DAAs are under-investigated for DDI risk. Real-world studies are needed to assess the clinical relevance of the pharmacokinetic interactions with dabigatran and describe the actual spectrum of possible DDIs between DAAs and other DOACs.

Aspirin Plus Clopidogrel vs Aspirin Alone for Preventing Cardiovascular Events Among Patients at High Risk for Cardiovascular Events.

Clinical Question: Among patients at high risk for or with established cardiovascular disease (ie, history of peripheral artery disease, stroke, or coronary artery disease without a coronary stent), is the addition of clopidogrel to aspirin associated with lower risk of mortality and cardiovascular events compared with aspirin alone? Bottom Line: Clopidogrel plus aspirin is associated with a reduced risk for myocardial infarction and ischemic stroke and an increased risk for major bleeding compared with aspirin alone among patients at high risk for or with an established cardiovascular disease but without a coronary stent. However, combined therapy is not associated with lower mortality.

Clopidogrel plus aspirin versus aspirin alone for preventing cardiovascular events.

BACKGROUND: Aspirin is the prophylactic antiplatelet drug of choice for people with cardiovascular disease. Adding a second antiplatelet drug to aspirin may produce additional benefit for people at high risk and people with established cardiovascular disease. This is an update to a previously published review from 2011. OBJECTIVES: To review the benefit and harm of adding clopidogrel to aspirin therapy for preventing cardiovascular events in people who have coronary disease, ischaemic cerebrovascular disease, peripheral arterial disease, or were at high risk of atherothrombotic disease, but did not have a coronary stent. SEARCH METHODS: We updated the searches of CENTRAL (2017, Issue 6), MEDLINE (Ovid, 1946 to 4 July 2017) and Embase (Ovid, 1947 to 3 July 2017) on 4 July 2017. We also searched ClinicalTrials.gov and the WHO ICTRP portal, and handsearched reference lists. We applied no language restrictions. SELECTION CRITERIA: We included all randomised controlled trials comparing over 30 days use of aspirin plus clopidogrel with aspirin plus placebo or aspirin alone in people with coronary disease, ischaemic cerebrovascular disease, peripheral arterial disease, or at high risk of atherothrombotic disease. We excluded studies including only people with coronary drug-eluting stent (DES) or non-DES, or both. DATA COLLECTION AND ANALYSIS: We collected data on mortality from cardiovascular causes, all-cause mortality, fatal and non-fatal myocardial infarction, fatal and non-fatal ischaemic stroke, major and minor bleeding. The overall treatment effect was estimated by the pooled risk ratio (RR) with 95% confidence interval (CI), using a fixed-effect model (Mantel-Haenszel); we used a random-effects model in cases of moderate or severe heterogeneity (I2 ≥ 30%). We assessed the quality of the evidence using the GRADE approach. We used GRADE profiler (GRADE Pro) to import data from Review Manager to create a 'Summary of findings' table. MAIN RESULTS: The search identified 13 studies in addition to the two studies in the previous version of our systematic review. Overall, we included data from 15 trials with 33,970 people. We completed a 'Risk of bias' assessment for all studies. The risk of bias was low in four trials because they were at low risk of bias for all key domains (random sequence generation, allocation concealment, blinding, selective outcome reporting and incomplete outcome data), even if some of them were funded by the pharmaceutical industry.Analysis showed no difference in the effectiveness of aspirin plus clopidogrel in preventing cardiovascular mortality (RR 0.98, 95% CI 0.88 to 1.10; participants = 31,903; studies = 7; moderate quality evidence), and no evidence of a difference in all-cause mortality (RR 1.05, 95% CI 0.87 to 1.25; participants = 32,908; studies = 9; low quality evidence).There was a lower risk of fatal and non-fatal myocardial infarction with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 0.78, 95% CI 0.69 to 0.90; participants = 16,175; studies = 6; moderate quality evidence). There was a reduction in the risk of fatal and non-fatal ischaemic stroke (RR 0.73, 95% CI 0.59 to 0.91; participants = 4006; studies = 5; moderate quality evidence).However, there was a higher risk of major bleeding with clopidogrel plus aspirin compared with aspirin plus placebo or aspirin alone (RR 1.44, 95% CI 1.25 to 1.64; participants = 33,300; studies = 10; moderate quality evidence) and of minor bleeding (RR 2.03, 95% CI 1.75 to 2.36; participants = 14,731; studies = 8; moderate quality evidence).Overall, we would expect 13 myocardial infarctions and 23 ischaemic strokes be prevented for every 1000 patients treated with the combination in a median follow-up period of 12 months, but 9 major bleeds and 33 minor bleeds would be caused during a median follow-up period of 10.5 and 6 months, respectively. AUTHORS' CONCLUSIONS: The available evidence demonstrates that the use of clopidogrel plus aspirin in people at high risk of cardiovascular disease and people with established cardiovascular disease without a coronary stent is associated with a reduction in the risk of myocardial infarction and ischaemic stroke, and an increased risk of major and minor bleeding compared with aspirin alone. According to GRADE criteria, the quality of evidence was moderate for all outcomes except all-cause mortality (low quality evidence) and adverse events (very low quality evidence).