Preventive Strategies against Bleeding due to Nonvitamin K Antagonist Oral Anticoagulants

Dabigatran etexilate (DE), rivaroxaban, and apixaban are nonvitamin K antagonist oral anticoagulants (NOACs) that have been compared in clinical trials with existing anticoagulants (warfarin and enoxaparin) in several indications for the prevention and treatment of thrombotic events. All NOACs presented bleeding events despite a careful selection and control of patients. Compared with warfarin, NOACs had a decreased risk of intracranial hemorrhage, and apixaban and DE (110 mg BID) had a decreased risk of major bleeding from any site. Rivaroxaban and DE showed an increased risk of major gastrointestinal bleeding compared with warfarin. Developing strategies to minimize the risk of bleeding is essential, as major bleedings are reported in clinical practice and specific antidotes are currently not available. In this paper, the following preventive approaches are reviewed: improvement of appropriate prescription, identification of modifiable bleeding risk factors, tailoring NOAC’s dose, dealing with a missed dose as well as adhesion to switching, bridging and anesthetic procedures.

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Complex antithrombotic therapy and bleeding risk in patients with peripheral arterial disease

European Heart Journal ◽

10.1093/ehjci/ehaa946.2396 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

A Tseng ◽

S Bhatt ◽

M Girardo ◽

D Liedl ◽

P Wennberg ◽

...

Keyword(s):

Peripheral Arterial Disease ◽

Triple Therapy ◽

Major Bleeding ◽

Antithrombotic Therapy ◽

Oral Anticoagulants ◽

Bleeding Risk ◽

Arterial Disease ◽

Risk Of Bleeding ◽

Increased Risk ◽

Peripheral Arterial

Abstract Introduction Antiplatelet therapy is the cornerstone of treatment for many atherosclerotic vascular pathologies including peripheral arterial disease (PAD). Patients with PAD often have comorbid conditions that require complex antithrombotic therapy, i.e. combined antiplatelet and anticoagulation. Methods All adult patients undergoing ankle brachial index (ABI) measurements were included in the study. ABI values between 1.00 and 1.40 were considered normal, and values below 1.00 or above 1.40 were considered PAD. Demographic, comorbidity and outcome data were obtained using diagnostic codes from the electronic health record. Three medication classes were analyzed: aspirin, non-aspirin oral antiplatelets (e.g. P2Y12 inhibitors) and oral anticoagulants (warfarin and the direct oral anticoagulants). Medication use was determined for patients who had been on a medication for at least one year. Cox proportional hazard analysis for the time to first bleeding event was analyzed. Bleeding was defined as any bleeding requiring medical evaluation (including clinically-relevant non-major bleeding and major bleeding). Results In all, 40,144 patients were included in the analysis (mean age 66±15, 43% female). Patients with PAD were more likely to be on double therapy (one antiplatelet with anticoagulation) (28% vs 19%) and triple therapy (dual antiplatelet with anticoagulation) (10% vs 4%). Unadjusted hazard ratios for bleeding risk showed increased risk of bleeding for patients with PAD (1.18, 95% confidence interval [CI]: 1.08–1.29), though the association is no longer present after adjustment for antithrombotic therapy. Adjusting for age, sex and PAD class, compared to no antithrombotic therapy, there was increased risk of bleeding for monotherapy (1.91, 95% CI: 1.61–2.26), double therapy (3.40, 95% CI: 2.89–4.00) and triple therapy (5.00, 95% CI: 4.21–5.96). Among medications, aspirin and anticoagulant use was independently associated with the greatest increase in risk of bleeding. Conclusion Patients in PAD are at increased risk of bleeding secondary to antithrombotic therapy. Complex antithrombotic therapy with double or triple therapy confer additional bleeding risk, particularly regimens containing aspirin and oral anticoagulants. Funding Acknowledgement Type of funding source: None

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Patients Taking Direct Oral Anticoagulants (DOAC) Undergoing Oral Surgery: A Review of the Literature and a Proposal of a Peri-Operative Management Protocol

Healthcare ◽

10.3390/healthcare8030281 ◽

2020 ◽

Vol 8 (3) ◽

pp. 281

Author(s):

Saturnino Marco Lupi ◽

Arianna Rodriguez y Baena

Keyword(s):

Vitamin K ◽

Oral Surgery ◽

Dabigatran Etexilate ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Thrombin Inhibitor ◽

Review Of The Literature ◽

Risk Of Bleeding ◽

Management Protocol ◽

Increased Risk

Patients on anticoagulant therapy for the prevention of cardiovascular accidents present an increased risk of bleeding following dental and oral surgery. Four recently introduced non-vitamin K antagonist oral anticoagulants, namely dabigatran etexilate (direct thrombin inhibitor), rivaroxaban, apixaban, and edoxaban (Xa factor direct inhibitor), are widely spreading for convenience of use compared to the older drug class. Dental management of patients taking these drugs has substantial differences compared to patients on vitamin K antagonist therapy. Anticoagulation is not assessed directly through a hematological test, but indirectly by renal function. The interventions must be scheduled at the time of minimum blood concentration of the drug. Bleeding can occur even after several days following the surgery. The interaction with drugs administered for dental care must be carefully evaluated. The peri-operative diet can influence the risk of bleeding. Local measures favoring coagulation must be adopted. The interventions with higher risk must be divided into multiple less invasive interventions. Although antidotes exist for these drugs, their use does not seem necessary for dental interventions that have been planned optimally. Furthermore, in this review of the literature a decision protocol is proposed for the evaluation of the suspension of the anticoagulant drug before oral surgery. Cessation of any anticoagulant should only be made in consultation with the patient’s general practitioner/cardiologist, who will weigh up the risk of bleeding from the proposed procedure with the risk of thrombosis/stroke in each individual patient.

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Slightly elevated international normalized ratio predicts bleeding episodes in patients treated with direct oral anticoagulants

Journal of International Medical Research ◽

10.1177/0300060519894439 ◽

2020 ◽

Vol 48 (6) ◽

pp. 030006051989443

Author(s):

Priya Bhardwaj ◽

Louise Breum Petersen ◽

Tomas Sorm Binko ◽

Jan Roland Petersen ◽

Gitte Gleerup Fornitz

Keyword(s):

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Bleeding Risk ◽

International Normalized Ratio ◽

Direct Factor ◽

Risk Of Bleeding ◽

Increased Risk ◽

Direct Factor Xa Inhibitors ◽

Bleeding Episodes

Introduction Patients treated with direct oral anticoagulants (DOACs) are at increased bleeding risk. It is therefore of increasing interest to identify predictors of bleeding episodes to increase safety during treatment with DOACs. Methods This retrospective cohort study systematically reviewed medical records of 235 patients treated with either apixaban, rivaroxaban or dabigatran for non-valvular atrial fibrillation or venous thromboembolism and collected data on the international normalized ratio (INR) and all bleeding episodes. Results INR ≥ 1.5 was significantly associated with increased risk of minor and major bleeding events in patients treated with direct factor Xa inhibitors. This association was not present in patients treated with dabigatran. However, a high negative predictive value was identified for INR < 1.5 for all drugs. The relative risks of bleeding episodes in patients with INR ≥ 1.5 and INR < 1.5 were 5.1 and 0.20, respectively. Conclusions Our results demonstrate a strong correlation between INR and risk of bleeding episodes during DOAC treatment. INR < 1.5 was a strong negative predictor for low bleeding risk independent of indication or choice of drug, and INR ≥ 1.5 was associated with increased risk of bleeding episodes in patients treated with direct factor Xa-inhibitors.

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Abstract 17598: More Than One in Five Older Veterans are Hospitalized for Bleeding Following Initiation of Warfarin for Atrial Fibrillation

Circulation ◽

10.1161/circ.132.suppl_3.17598 ◽

2015 ◽

Vol 132 (suppl_3) ◽

Author(s):

John A Dodson ◽

Andrew Petrone ◽

David Gagnon ◽

Mary E Tinetti ◽

Harlan M Krumholz ◽

...

Keyword(s):

Atrial Fibrillation ◽

Oral Anticoagulants ◽

Bleeding Event ◽

Bleeding Risk ◽

Bleeding Events ◽

Time Period ◽

Increased Risk ◽

Anticoagulation Clinics ◽

Comorbidity Burden

Introduction: Clinicians are hesitant to prescribe oral anticoagulants to older adults with atrial fibrillation (AF) due to concerns over bleeding risk. Hypothesis: As many data on bleeding events are from trials of rigorously selected patients, we hypothesized that major bleeding events (requiring hospitalization) would be more common than previously reported. Methods: We created a retrospective cohort of 31,951 Veterans with AF aged ≥75 years who were new referrals to VA anticoagulation clinics (warfarin) from 1/1/02 - 12/31/12. Patients with comorbid conditions requiring warfarin (e.g. pulmonary embolus) were excluded. Data were extracted from the VA electronic medical record and linked with Medicare claims data for subsequent hospitalizations. The primary outcome was any hospitalization for bleeding. We identified bleeding subtypes by source, and compared characteristics of patients with and without bleeding hospitalizations. Results: Mean population age was 81.1 years, 98.1% were male, and 8.4% were nonwhite. Over a median follow-up period of 2.62 years, 7288 patients (22.8%) were hospitalized for bleeding. There were 12,004 total bleeding events; overall, 980 (13.4%) patients experienced multiple events. The most common bleeding sources (first event) were gastrointestinal (50.8%), genitourinary (21.6%), and intracranial (9.4%) (Figure). The median time to first bleeding event was 1.59 years. Patients hospitalized for bleeding were more likely to have coronary disease (48.4% vs. 40.9%, P<0.01); COPD (28.4% vs. 24.7%, P<0.01); chronic kidney disease (17.8% vs. 16.0%, P<0.01); CHF (34.7% vs. 29.5%, P<0.01), and labile INR (63.3% vs. 53.7%, P<0.01). The rate of hospitalization for stroke over the same time period was 5.0%. Conclusions: After initiating warfarin, over one in five older Veterans are hospitalized for bleeding, most commonly from a gastrointestinal source. Comorbidity burden and labile INR place these patients at increased risk.

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External validation of the VTE-BLEED score for predicting major bleeding in stable anticoagulated patients with venous thromboembolism

Thrombosis and Haemostasis ◽

10.1160/th16-10-0810 ◽

2017 ◽

Vol 117 (06) ◽

pp. 1164-1170 ◽

Cited By ~ 33

Author(s):

Frederikus A. Klok ◽

Stefano Barco ◽

Stavros V. Konstantinides

Keyword(s):

Venous Thromboembolism ◽

High Risk ◽

Major Bleeding ◽

External Validation ◽

Chronic Phase ◽

Bleeding Risk ◽

Bleeding Events ◽

Risk Of Bleeding ◽

Increased Risk ◽

Study Population

SummaryOne of the main determinants of establishing the optimal treatment duration of patients with venous thromboembolism (VTE) is the risk of major bleeding during long-term anticoagulant therapy. The 6-variable VTE-BLEED score was recently developed to enable estimation of this bleeding risk. This study aimed at externally validating VTE-BLEED. This was a post-hoc study of the randomised, double-blind, double-dummy, Hokusai-VTE study that compared edoxaban versus warfarin for treatment of VTE. VTE-BLEED was calculated in all 8,240 study patients. The numbers of adjudicated major bleeding events during ‘stable anticoagulation’, i. e. occurring after day 30, in patients with low (total score <2 points) and high risk of bleeding (total score ≥2 points) were compared for the overall study population, patients randomised to edoxaban or warfarin, and for important patient subcategories. During ‘stable’ anticoagulation, major bleeding occurred in 1.02% (40/3,903) and 0.82% (32/3,899) of patients treated with warfarin and edoxaban, respectively. For the overall study population, the risks of bleeding in the low and high risk groups were 0.51% and 2.03%, respectively, for an odds ratio (OR) of 4.04 (95% confidence interval [CI]: 2.51–6.48). ORs were 5.04 (95%CI: 2.62–9.69) and 3.09 (95%CI: 1.54–6.22) for warfarin and edoxaban, respectively. VTE-BLEED was consistently able to identify patients at a 2.5- to 11-fold higher bleeding risk across all the predefined subcategories, as well as for the treatment period between day 30 to day 180, and beyond day 180. In conclusion, patients identified as high risk by VTE-BLEED had a four-fold increased risk of bleeding during the chronic phase of treatment.Supplementary Material to this article is available online at www.thrombosis-online.com.

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Abstract MP13: Comparative Effectiveness of Direct Oral Anticoagulants and Warfarin on Risk of Bleeding Resulting in Hospitalization Among Venous Thromboembolism Patients

Circulation ◽

10.1161/circ.137.suppl_1.mp13 ◽

2018 ◽

Vol 137 (suppl_1) ◽

Author(s):

Pamela L Lutsey ◽

Neil A Zakai ◽

Richard F MacLehose ◽

Faye L Norby ◽

Rob F Walker ◽

...

Keyword(s):

Venous Thromboembolism ◽

Comparative Effectiveness ◽

Proportional Hazards ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Final Analysis ◽

Bleeding Risk ◽

Cox Proportional Hazards ◽

Bleeding Events ◽

Risk Of Bleeding

Background: Direct oral anticoagulants (DOACs), including rivaroxaban, dabigatran, apixaban and edoxaban, have been approved as alternatives to warfarin for the primary treatment of venous thromboembolism (VTE). However, understanding of their comparative effectiveness in practice-based populations is limited. Objective: Among anticoagulant-naïve VTE patients, estimate the association of type of oral anticoagulant (OAC) with the rate of bleeding resulting in hospitalization. Methods: Patients with VTE and prescription for an OAC were identified from the US Truven Health MarketScan® Commercial and Medicare Supplemental databases for the period from 2011-2015. Hospitalization related to bleeding events (inclusive of intracranial, gastrointestinal and other) was defined using a validated algorithm. In head-to-head comparisons, initiators of a specific OAC were matched with up to 5 initiators of the comparing OAC by age, sex, and time since database enrollment. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (95%CI) for bleeding by OAC, adjusted for age, sex, and a comorbidity propensity score (created using prevalence of 20 common diagnoses and procedures). Results: The final analysis included 83,831 VTE patients who were 49.9% female and on average (standard deviation) 59.0 (16.0) years old. Of these, the initial OAC prescribed for 2,604 was apixaban, for 1,669 dabigatran, for 28,518 rivaroxaban, and for 48,514 warfarin. A total of 1,947 bleeding events occurred over an average of 13 months. Compared to new warfarin users, risk of bleeding was lower among patients initiating apixaban [HR (95%CI): 0.55 (0.36, 0.83)] and rivaroxaban [0.80 (0.72, 0.89)], but similar among new dabigatran users [0.96 (0.72, 1.27)]. In head-to-head DOAC comparisons, relative to rivaroxaban, risk of bleeding was lower among users of apixaban [0.57 (0.36, 0.89)] but similar for users of dabigatran [1.05 (0.73, 1.51)]. Due to low numbers we did not conduct analyses of edoxaban or a head-to-head comparison of dabigatran versus apixaban. Conclusion: In this practice-based population of 83,831 patients prescribed OACs for the treatment of VTE, subsequent risk of hospitalized bleeding was lowest among those prescribed apixaban, intermediate among those prescribed rivaroxaban, and highest among those prescribed warfarin and dabigatran. These data demonstrate that differences in bleeding risk exist by DOAC. While risk factors for bleeding might impact choice of warfarin versus the DOACs, the choice between DOACs may be less likely to be based on patient conditions.

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The Impact of Body Weight and Renal Function on the Risk of Bleeding With Direct Oral Anticoagulants in Atrial Fibrillation

Annals of Pharmacotherapy ◽

10.1177/1060028021995201 ◽

2021 ◽

pp. 106002802199520

Author(s):

Hannah Whittemore ◽

Andrew K. Posen ◽

Erika L. Hellenbart ◽

Vicki Groo ◽

Eric Wenzler ◽

...

Keyword(s):

Atrial Fibrillation ◽

Renal Function ◽

Body Weight ◽

Renal Dysfunction ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Events ◽

Risk Of Bleeding ◽

Increased Risk ◽

The Impact

Background: Atrial fibrillation (AF) increases the risk of stroke and direct oral anticoagulants (DOACs) are first-line agents for prevention. Gaps in the literature cause reluctance in prescribing DOACs for patients with renal dysfunction and/or extremes in body weight. Objective: To evaluate the impact body weight and renal function have on major and clinically relevant nonmajor (CRNM) bleeding events and ischemic strokes in AF patients receiving a DOAC. Methods: This retrospective cohort study included adults with nonvalvular atrial fibrillation (NVAF) or atrial flutter (AFL) receiving a DOAC ≥12 months. The primary outcome was a composite of major and CRNM bleeding events. Secondary outcomes included ischemic stroke and risk factors for bleeding events. Results: Of the 233 patients analyzed, 25 patients experienced a bleeding event. Patients who bled weighed 10 kg less ( P = 0.043) than those who did not and had a higher HASBLED score ( P = 0.003). Multivariate logistic regression identified weight ( P = 0.048), serum creatinine (SCr; P = 0.027), and HASBLED score ( P = 0.024) as the significant predictors for experiencing a bleed. Three patients experienced a stroke. Conclusion and Relevance: This study demonstrates an association between higher baseline SCr, elevated HASBLED score, and lower weight, with an increased risk of bleeding in patients with NVAF or AFL receiving a DOAC. These findings add to prescribing considerations when initiating DOACs. Closer monitoring is advised for patients with significant renal dysfunction and/or low body weight, even with renal dose adjustments.

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Are Direct Oral Anticoagulants Plasma Concentrations Associated with the Risk of Postoperative Bleeding? Results from the Real Life Cohort

Blood ◽

10.1182/blood.v128.22.3819.3819 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3819-3819

Author(s):

Pável Olivera ◽

Vicente Cortina ◽

Verónica Pons ◽

Tania Canals ◽

Erik Johansson ◽

...

Keyword(s):

High Risk ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Postoperative Bleeding ◽

Plasma Concentrations ◽

Thrombin Inhibitor ◽

Bleeding Events ◽

Risk Of Bleeding ◽

Increased Risk

Abstract Background The perioperative management (PM) of direct oral anticoagulants (DOACs) is controversial. The role of assessing DOAC plasma levels in order to ensure a safe use of these anticoagulants is still unknown. Aims To examine the association between DOACs plasma concentrations obtained before surgery and the risk of postoperative bleeding in the perioperative setting. Methods From June 2014 to December 2015 we have consecutively included 99 patients treated with DOACs and referred to our Unit for PM. Management was performed following the PM recommendations from the Catalan Thrombosis Working Group (Tromboc@t) . Bleeding events were classified following the ISTH criteria. Plasma concentrations were measured in the day of invasive procedure using the Technoclone anti-Xa assay from Technoclone (Vienna-Austria) for Rivaroxaban and Apixaban, and the Direct Thrombin Inhibitor Assay from IL (Bedford-MA-USA) for Dabigatran; in each case, specific calibrators were used. Patients were systematically followed 30 days after the surgical procedure. Results A total of 99 patients were recruited. Median age was 76 years (range: 61-94) and 51 (51.5%) were female. Among them, 23 patients received dabigatran, 40 rivaroxaban and 36 apixaban. As per the risk scores, 66.7% of the patients had a CHA2DS2-VASc score >3, 57.6% had a HAS-BLED score >3, and 51 (51.5%) were considered high-risk procedures. Total bleeding events occurred in 23 patients (47.8% minor, 30.4% non-major clinically relevant, and 21.7% major bleeding). The median plasma NOACs concentration was 38.3 ng/ml (0.8-226 ng/ml), with 32 patients having levels >30 ng/mL. HASBLED score > 3 was associated with an increased risk of bleeding events within 30 days (hazard ratio (HR)= 3.9, 95% CI= 1.14-13.4, P=0.03). Plasma DOAC levels > 30 ng/ml were not significantly associated with an increased risk of bleeding events (HR=2.17, 95% CI=0.862-6.67, P=0.10). Major bleeding (n=5) was probably associated with the risk of the procedure than to the DOAC plasma concentrations. Conclusion In our cohort we found significant association between the individual bleeding risk before surgery with the risk of postoperative bleeding. In spite of that, this study will continue to reevaluate PM in high-risk procedures according to plasma DOAC levels. Disclosures No relevant conflicts of interest to declare.

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Comparison of Bleeding Profiles of Sugammadex and Neostigmine in Orthotopic Liver Transplantation

10.22541/au.163491381.11148574/v1 ◽

2021 ◽

Author(s):

Hong Liang ◽

Launia White ◽

Ryan M Chadha ◽

J Ross Renew

Keyword(s):

Liver Transplantation ◽

Retrospective Study ◽

Fast Track ◽

Postoperative Bleeding ◽

Bleeding Risk ◽

Neuromuscular Function ◽

Single Center ◽

Bleeding Events ◽

Risk Of Bleeding ◽

Increased Risk

In the era of “fast-track’ liver transplantation (LT), neuromuscular blockade (NMB) antagonists such as neostigmine or sugammadex are used to achieve the restoration of neuromuscular function. While sugammadex reverses NMB faster than neostigmine, it has been shown to prolong prothrombin time (PT) and activated thromboplastin time (aPTT). However, this agent’s impact on coagulation during LT is not understood. We compare bleeding risk associated with sugammadex versus neostigmine during liver transplantation. This is a single-center, retrospective review of LT patients who received NMB antagonists intraoperatively between 01/01/2015 to 05/31/2018 at Mayo Clinic in Florida. The primary outcomes were postoperative day (POD) 0-1 bleeding events and POD 0 values of aPTT and INR. Total 241 patients were included, with 135 patients in the neostigmine group (NG) and 106 in the sugammadex group (SG). POD 0-1 postoperative bleeding requiring transfusion occurred in 20% of NG versus 10.4% in SG. POD 0-1 re-operation for bleeding occurred in 1.5% in NG vs. 0% in SG. POD 0 mean INR was 2.0±0.4 in both groups. POD 0 mean aPTT was 45.5±7.9 in NG vs. 49.3±9.0 in SG. Our retrospective study suggests that sugammadex is not associated with an increased risk of bleeding compared to neostigmine use.

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Abstract MP4: Ticagrelor Plus Aspirin Versus Aspirin Alone in Acute Ischemic Stroke or TIA - Analysis of Bleeding Events in the THALES Trial

Stroke ◽

10.1161/str.52.suppl_1.mp4 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Carlos Molina ◽

Pierre Amarenco ◽

Per Ladenvall ◽

Maria Aunes ◽

Hans Denison ◽

...

Keyword(s):

Ischemic Stroke ◽

High Risk ◽

Acute Ischemic Stroke ◽

Bleeding Event ◽

Bleeding Risk ◽

Severe Bleeding ◽

Bleeding Events ◽

Risk Of Bleeding ◽

Increased Risk ◽

Aspirin Group

Introduction: In the THALES trial, ticagrelor and aspirin was superior to aspirin alone in reducing the primary endpoint of stroke or death, and subsequent disabling strokes, but increased risk of bleeding, as expected for dual antiplatelet therapy. Aim: Present the bleeding profile of ticagrelor in combination with aspirin in patients with acute cerebrovascular events. Methods: The THALES trial randomized patients with non-cardioembolic, non-severe ischemic stroke (NIHSS≤5) or high-risk TIA to ticagrelor (180mg loading dose on day 1 followed by 90mg twice daily until day 30) or placebo within 24h of symptom onset in 28 countries. All patients received aspirin 300-325mg on day 1 followed by 75-100mg daily until day 30. Primary safety endpoint was time to severe bleeding, defined by GUSTO criteria, within 30 days. Analyses were by intention to treat. (ClinicalTrials.gov number, NCT03354429). Results: Among 11016 patients randomized, 28 (0.5%) in the ticagrelor+aspirin group (T+A) and 7 (0.1%) in the aspirin group (A) had a severe bleeding event; HR 3.99 (1.74-9.14); p=0.001. Among these, 22 (0.4%) (T+A) vs 6 (0.1%) (A) were fatal or intracranial hemorrhages (ICHs) and 6 (0.1%) (T+A) vs 1 (<0.1%) (A) non-fatal events with hemodynamic compromise. ICHs included 10 (0.2%) (T+A) vs 2 (<0.1%) (A) hemorrhagic strokes and 4 (0.1%) (T+A) vs 2 (<0.1%) (A) symptomatic haemorrhagic transformations of ischemic stroke and other ICHs. Most severe bleeding events were spontaneous; 1 (T+A) and 2 (A) were traumatic and 1 in each treatment group were procedural. No predefined subgroup was associated with severe bleeding risk though analyses were limited by a small number of events. Moderate/severe bleeding events occurred in 36 (0.7%) (T+A) vs 11 (0.2%) (A) patients. Bleeding leading to discontinuation occurred in 152 (2.8%) (T+A) vs 32 (0.6%) (A) patients. Conclusion: While the rate of severe bleeding in the patients with acute ischemic stroke or TIA was low, patients randomized to receive ticagrelor more often experienced severe bleeding events. No subgroup with different bleeding risk could be identified. Given the high risk of disability following a subsequent stroke, the benefit of adding ticagrelor to aspirin in reducing subsequent stroke appears to outweigh the risk of bleeding.

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