Treatment of adults with intracranial hemorrhage on apixaban or rivaroxaban with prothrombin complex concentrate products

To analyze the efficacy and safety of activated prothrombin complex concentrates (aPCC) and four-factor prothrombin complex concentrates (4F-PCC) to prevent hematoma expansion in patients taking apixaban or rivaroxaban with intracranial hemorrhage (ICH). In this multicenter, retrospective study, sixty-seven ICH patients who received aPCC or 4F-PCC for known use of apixaban or rivaroxaban between February 2014 and September 2018 were included. The primary outcome was the percentage of patients who achieved excellent/good or poor hemostasis after administration of aPCC or 4F-PCC. Secondary outcomes included hospital mortality, thromboembolic events during admission, and transfusion requirements. Excellent/good hemostasis was achieved in 87% of aPCC patients, 89% of low-dose 4F-PCC [<?30 units per kilogram (kg)], and 89% of high-dose 4F-PCC (≥?30 units per kg). There were no significant differences in excellent/good or poor hemostatic efficacy (p?=?0.362). No differences were identified in transfusions 6 h prior (p?=?0.087) or 12 h after (p?=?0.178) the reversal agent. Mortality occurred in five patients, with no differences among the groups (p?=?0.838). There were no inpatient thromboembolic events. Both aPCC and 4F-PCC appear safe and equally associated with hematoma stability in patients taking apixaban or rivaroxaban who present with ICH. Prospective studies are needed to identify a superior reversal agent when comparing andexanet alfa to hospital standard of care (4F-PCC or aPCC) and to further explore the optimal dosing strategy for patients with ICH associated with apixaban or rivaroxaban use.

     

Four factor prothrombin complex concentrate for warfarin reversal in patients with left ventricular assist devices

Continuous flow left ventricular assist devices (CF-LVAD) require therapeutic anticoagulation which is often interrupted for procedures or bleeding. Prior to the availability of four factor prothrombin complex concentrate (4F-PCC) in the United States, warfarin was held and its effects reversed by vitamin K or fresh frozen plasma. We evaluated the use of 4F-PCC for temporary warfarin reversal in patients with CF-LVADs and assessed outcomes. This analysis is a retrospective study of CF-LVAD patients who received 4F-PCC for warfarin reversal in the setting of bleeding or need for urgent or elective procedures. Primary outcome assessments included feasibility of administration in elective versus emergent situations, safety measured as incidence of thrombotic events, and change in INR after administration. In total, 37 CF-LVAD patients received 49 4F-PCC administrations. The average 4F-PCC dose was 1842 units (range 518–4292 units), or 22 units/kg (range 5.8–58 units/kg). 4F-PCC significantly decreased the mean INR from 2.9 to 1.7 (p?<?0.0001) in 47 of 49 administrations; two patients did not have post infusion INR testing. No cases of new confirmed or suspected pump thrombosis, stroke, venous thromboembolism, arterial thrombosis, or myocardial infarction were observed within 30 days of administration of 4F-PCC. 4F-PCC administration for temporary warfarin reversal was demonstrated to be feasible, effective, and, safe in CF-LVAD patients and judged to be 96% effective in patients for whom data were available. We observed no thrombotic events attributed to use of 4F-PCC.     

Anticoagulant Reversal in Gastrointestinal Bleeding: Review of Treatment Guidelines

Background

Patients receiving anticoagulant therapies, such as vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs), commonly experience gastrointestinal (GI) bleeding as a complication and may require anticoagulant reversal prior to endoscopic treatment. Anticoagulant reversal agents include prothrombin complex concentrates (PCCs; including 3 or 4 coagulation factors), plasma, vitamin K, and target-specific DOAC reversal agents (e.g., idarucizumab and andexanet alfa).

Aim

To review current US, as well as international, guidelines for anticoagulant reversal agents in patients on VKAs or DOACs presenting with GI bleeding prior to endoscopy, guideline-based management of coagulation defects, timing of endoscopy, and recommendations for resumption of anticoagulant therapy following hemostasis. Supporting clinical data were also reviewed.

Methods

This is a narrative review, based on PubMed and Internet searches reporting GI guidelines and supporting clinical data.

Results

GI-specific guidelines state that use of reversal agents should be considered in patients with life-threatening GI bleeding. For VKA patients presenting with an international normalized ratio >?2.5, guidelines recommend PCCs (specifically 4F-PCC), as they may exhibit greater efficacy/safety compared with fresh frozen plasma in reversal of VKA-associated GI bleeding. For DOAC patients, most guidelines recommend targeted specific reversal agents in the setting of GI bleeding; however, PCCs (primarily 4F-PCC) are often listed as another option. Resumption of anticoagulant therapy following cessation of GI bleeding is also recommended to reduce risks of future thromboembolic complications.

Conclusions

The utility of anticoagulant reversal agents in GI bleeding is recognized in guidelines; however, such agents should be reserved for use in truly life-threatening scenarios.

     

Death and disability from warfarin-associated intracranial and extracranial hemorrhages

Objectives

Little is known about the outcomes of patients who have hemorrhagic complications while receiving warfarin therapy. We examined the rates of death and disability resulting from warfarin-associated intracranial and extracranial hemorrhages in a large cohort of patients with atrial fibrillation.

Methods

We assembled a cohort of 13,559 adults with nonvalvular atrial fibrillation and identified patients hospitalized for warfarin-associated intracranial and major extracranial hemorrhage. Data on functional disability at discharge and 30-day mortality were obtained from a review of medical charts and state death certificates. The relative odds of 30-day mortality by hemorrhage type were calculated using multivariable logistic regression.

Results

We identified 72 intracranial and 98 major extracranial hemorrhages occurring in more than 15,300 person-years of warfarin exposure. At hospital discharge, 76% of patients with intracranial hemorrhage had severe disability or died, compared with only 3% of those with major extracranial hemorrhage. Of the 40 deaths from warfarin-associated hemorrhage that occurred within 30 days, 35 (88%) were from intracranial hemorrhage. Compared with extracranial hemorrhages, intracranial events were strongly associated with 30-day mortality (odds ratio 20.8 [95% confidence interval, 6.0-72]) even after adjusting for age, sex, anticoagulation intensity on admission, and other coexisting illnesses.

Conclusions

Among anticoagulated patients with atrial fibrillation, intracranial hemorrhages caused approximately 90% of the deaths from warfarin-associated hemorrhage and the majority of disability among survivors. When considering anticoagulation, patients and clinicians need to weigh the risk of intracranial hemorrhage far more than the risk of all major hemorrhages.     

Assessment of patients post reversal with idarucizumab

Idarucizumab, a fully humanized Fab antibody fragment, is indicated for reversal of dabigatran’s anticoagulant activity. Idarucizumab neutralizes the anticoagulant effects of dabigatran by binding to dabigatran and its metabolite. In the full analysis of 503 patients, idarucizumab fully reversed the anticoagulant effect of dabigatran in more than 98% of patients. Real-world clinical experience with idarucizumab for dabigatran reversal remains limited. We report 11 real-world clinical cases in which idarucizumab was administered for dabigatran reversal in the setting of bleed (bleeding cohort n?=?5) or emergent procedure (emergent procedure cohort, n?=?6). Coagulation tests and clinical outcomes were assessed before and after idarucizumab administration. Clinical outcomes included thromboembolic events and hemostasis. The median (IQR) aPTT (seconds) before versus after idarucizumab was 40.4 (36.1) versus 27.3 (6.2) (bleeding cohort) and 50.1 (13.4) versus 26.5 (8.1) (emergent procedure cohort). The median (IQR) INR before and after idarucizumab was 2.0 (1.1) versus 1.2 (0.1) (bleeding cohort) and 1.1 (0.5) versus 1.1 (0.3) (emergent procedure cohort). Hemostasis was achieved in 4/5 patients in the bleeding cohort and 5/6 patients in the emergent procedure cohort. Thrombotic events occurred in four patients with a median time (IQR) from idarucizumab administration of 7.4 (4.3–14.7) days. Idarucizumab achieved adequate dabigatran reversal as evident by normalization of aPTT, INR, and achieving hemostasis. However, our data demonstrates a high thrombotic risk associated with dabigatran reversal with idarucizumab than previously reported.     

A retrospective analysis of the periprocedural management of oral anticoagulants in patients undergoing interventional radiology procedures

Limited evidence is available to guide periprocedural management of oral anticoagulants in the setting of interventional radiology (IR) procedures. For direct oral anticoagulants, therapy interruption (TI) is based on medication half-life and procedural bleeding risk. Periprocedural management of warfarin includes INR monitoring, and possible bridging with parenteral anticoagulants. It is unknown if these recommendations apply to IR procedures. To evaluate bleeding complications and thromboembolic events following periprocedural management of the factor Xa (FXa) inhibitors or warfarin in patients undergoing IR procedures. We performed a retrospective, observational study at NYU Langone Health (NYULH) of all adult patients who underwent an IR procedure from January 2015 to July 2017 and were receiving apixaban, rivaroxaban, or warfarin. Patients who were pregnant or who had a mechanical heart valve were excluded. At NYULH, TI is not required for FXa inhibitors, and an INR?<?3 is recommended for patients on warfarin undergoing low risk procedures. For moderate/high risk procedures, TI for 48 h or 72 h with reduced renal function, is recommended for FXa inhibitors, and an INR?<?1.5 is recommended for patients on warfarin. We evaluated 350 IR procedures, with a total of 174 low bleeding risk and 176 moderate/high bleeding risk. The 30-day major bleeding rate was 0.9%, clinically relevant non-major bleeding rate was 3%, minor bleeding rate was 1% and thromboembolic event rate was 1%. The periprocedural oral anticoagulation management strategy at NYULH appears safe given the low 30-day incidence of bleeding and thromboembolic events.     

Post-Discharge Prophylaxis With Rivaroxaban Reduces Fatal and Major Thromboembolic Events in Medically Ill Patients

BackgroundHospitalized acutely ill medical patients are at risk for fatal and major thromboembolic events. Whether use of extended-duration primary thromboprophylaxis can prevent such events is unknown.ObjectivesThe purpose of this study was to evaluate whether extended-duration rivaroxaban reduces the risk of venous and arterial fatal and major thromboembolic events without significantly increasing major bleeding in acutely ill medical patients after discharge.MethodsMARINER (A Study of Rivaroxaban [JNJ-39039039] on the Venous Thromboembolic Risk in Post-Hospital Discharge Patients) studied acutely ill medical patients with additional risk factors for venous thromboembolism (VTE). Medically ill patients with a baseline creatinine clearance ≥50 ml/min were randomized in a double-blind fashion to rivaroxaban 10 mg or placebo daily at hospital discharge for 45 days. Exploratory efficacy analyses were performed with the intent-to-treat population including all data through day 45. Time-to-event curves were calculated using the Kaplan-Meier method. A blinded independent committee adjudicated all clinical events.ResultsIn total, 4,909 patients were assigned to rivaroxaban and 4,913 patients to placebo. The mean age was 67.8 years, 55.5% were men, mean baseline creatinine clearance was 87.8 ml/min, and mean duration of hospitalization was 6.7 days. The pre-specified composite efficacy endpoint (symptomatic VTE, myocardial infarction, nonhemorrhagic stroke, and cardiovascular death) occurred in 1.28% and 1.77% of patients in the rivaroxaban and placebo groups, respectively (hazard ratio: 0.72; 95% confidence interval: 0.52 to 1.00; p = 0.049), whereas major bleeding occurred in 0.27% and 0.18% of patients in the rivaroxaban and placebo groups, respectively (hazard ratio: 1.44; 95% confidence interval: 0.62 to 3.37; p = 0.398).ConclusionsExtended-duration rivaroxaban in hospitalized medically ill patients resulted in a 28% reduction in fatal and major thromboembolic events without a significant increase in major bleeding. (A Study of Rivaroxaban [JNJ-39039039] on the Venous Thromboembolic Risk in Post-Hospital Discharge Patients [MARINER]; NCT02111564)     

Clinical Effectiveness of Anticoagulation Therapy Among Older Patients With Heart Failure and Without Atrial Fibrillation: Findings From the ADHERE Registry Linked to Medicare Claims

BackgroundPatients with heart failure are at higher risk for thromboembolic events, even in the absence of atrial fibrillation, but the effect of anticoagulation therapy on outcomes is uncertain.Methods and ResultsWith data from a clinical registry linked to Medicare claims, we estimated the adjusted associations between anticoagulation and 1-year outcomes with the use of inverse probability of treatment weighting. Eligible patients had an ejection fraction ≤35%, had no concurrent atrial fibrillation, were alive at discharge, and had not received anticoagulation therapy before admission. Of 13,217 patients in 276 hospitals, 1,140 (8.6%) received anticoagulation therapy at discharge. Unadjusted rates of thromboembolic events and major adverse cardiovascular events did not differ by receipt of anticoagulation therapy. Patients discharged on anticoagulation therapy had lower unadjusted rates of all-cause mortality (27.2% vs 32.3%; P < .001) and readmission for heart failure (29.4% vs 35.4%; P < .001) and higher rates of bleeding events (5.2% vs 2.8%; P < .001). After adjustment for probability of treatment and discharge medications, there were no differences in all-cause mortality (hazard ratio 0.92; 95% confidence interval 0.80–1.06) or readmission for heart failure (0.91, 0.81–1.02), but patients receiving anticoagulation therapy were at higher risk for bleeding events (2.09, 1.47–2.97).ConclusionsAnticoagulation therapy at discharge is infrequent among older patients with heart failure and without atrial fibrillation. There were no statistically significant propensity-weighted associations between anticoagulation therapy and 1-year outcomes, except for a higher risk of bleeding.     

The clinical impact of bleeding during oral anticoagulant therapy

Although the risk for bleeding during long-term warfarin therapy is established, little is known about the clinical impact following warfarin-associated bleeding and the management of anticoagulant resumption after a bleed. We performed a retrospective chart review of patients who suffered a warfarin-associated bleed that required hospitalization or that occurred during hospitalization. We determined the proportion of patients who required a blood product transfusion, a surgical or other invasive procedure or admission to an intensive care unit, and the duration of hospitalization. We also determined the case-fatality rate of bleeding and described post-bleed resumption of anticoagulation. We studied 142 patients (70 women) hospitalized with warfarin-associated bleeding with a mean age of 73 years. The most prevalent sites of bleeding were the gastrointestinal tract (40.8%) and urinary tract (14.1%). Of all bleeding episodes, 72 (50.1%) were classified as major bleeds. There were 66 (46.4%) patients who required either endoscopy, surgery or admission to an intensive care unit, and the mean duration of hospitalization was 23 days. The case fatality rate of major bleeding was 9.5%. Among patients in whom warfarin was restarted, 8.3% suffered recurrent bleeding. Warfarin-associated bleeding appears to confer considerable morbidity related to transfusion and hospitalization, approximately 1 in 10 major bleeds are fatal, and 1 in 12 patients will re-bleeding after warfarin resumption.     

Meta-Analysis of Reversal Agents for Severe Bleeding Associated With Direct Oral Anticoagulants

BackgroundDirect oral anticoagulants (DOACs) have shown a positive benefit-risk balance in both clinical trials and real-world data, but approximately 2% to 3.5% of patients experience major bleeding annually. Many of these patients require hospitalization, and the administration of reversal agents may be required to control bleeding.ObjectivesThe aim of this study was to investigate clinical outcomes associated with the use of 4-factor prothrombin complex concentrates, idarucizumab, or andexanet for reversal of severe DOAC-associated bleeding.MethodsThe investigators systematically searched for studies of reversal agents for the treatment of severe bleeding associated with DOAC. Mortality rates, thromboembolic events, and hemostatic efficacy were meta-analyzed using a random effects model.ResultsThe investigators evaluated 60 studies in 4,735 patients with severe DOAC-related bleeding who were treated with 4-factor prothrombin complex concentrates (n = 2,688), idarucizumab (n = 1,111), or andexanet (n = 936). The mortality rate was 17.7% (95% confidence interval [CI]: 15.1% to 20.4%), and it was higher in patients with intracranial bleedings (20.2%) than in patients with extracranial hemorrhages (15.4%). The thromboembolism rate was 4.6% (95% CI: 3.3% to 6.0%), being particularly high with andexanet (10.7%; 95% CI: 6.5% to 15.7%). The effective hemostasis rate was 78.5% (95% CI: 75.1% to 81.8%) and was similar regardless of the reversal agent considered. The rebleeding rate was 13.2% (95% CI: 5.5% to 23.1%) and 78% of rebleeds occurred after resumption of anticoagulation. The risk of death was markedly and significantly associated with failure to achieve effective hemostasis (relative risk: 3.63; 95% CI: 2.56 to 5.16). The results were robust regardless of the type of study or the hemostatic scale used.ConclusionsThe risk of death after severe DOAC-related bleeding remains significant despite a high rate of effective hemostasis with reversal agents. Failure to achieve effective hemostasis strongly correlated with a fatal outcome. Thromboembolism rates are particularly high with andexanet. Comparative clinical trials are needed.     

Lack of Evidence to Support Thromboprophylaxis in Hospitalized Medical Patients with Cancer

Background

The administration of anticoagulant thromboprophylaxis for all patients with cancer who are hospitalized for acute medical illness is considered standard practice and strongly recommended in clinical guidelines. These recommendations are extrapolated from randomized controlled prophylaxis trials not specifically conducted in cancer cohorts. Because hospitalized patients with cancer constitute a unique population with increased risk of venous thromboembolic events and major hemorrhage, validation of the efficacy and safety of primary thromboprophylaxis in this population is critical. We sought to summarize the rates of venous thromboembolic events and major bleeding episodes among hospitalized patients with cancer who were receiving anticoagulant therapy compared with placebo.

Methods

A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials. Two reviewers independently extracted data onto standardized forms. The primary end points were all venous thromboembolic events. Secondary end points included major bleeding episodes and symptomatic venous thromboembolic events. Pooled analysis with relative risk using a random effect model was used as the primary measurement.

Results

A total of 242 citations were identified by the literature search. Of these, 3 placebo-controlled randomized trials included venous thromboembolic events as a primary outcome and were analyzed according to cancer subgroups. The pooled relative risk of venous thromboembolic events was 0.91 (95% confidence interval, 0.21-4.0; I²: 68%) among hospitalized patients with cancer who were receiving thromboprophylaxis compared with placebo. None of the trials reported the rates of symptomatic venous thromboembolic events or major bleeding episodes according to cancer status.

Conclusions

The risks and benefits of primary thromboprophylaxis with anticoagulant therapy in hospitalized patients with cancer are not known. This is especially relevant because numerous Medicare-type pay-for-performance incentives mandate prophylaxis specifically in patients with cancer.     

Thromboembolic events among adult patients with primary immune thrombocytopenia in the United Kingdom General Practice Research Database

Background

The risk of thromboembolic events in adults with primary immune thrombocytopenia has been little investigated despite findings of increased susceptibility in other thrombocytopenic autoimmune conditions. The objective of this study was to evaluate the risk of thromboembolic events among adult patients with and without primary immune thrombocytopenia in the UK General Practice Research Database.

Design and Methods

Using the General Practice Research Database, 1,070 adults (≥18 years) with coded records for primary immune thrombocytopenia first referenced between January 1^st 1992 and November 30^th 2007, and having at least one year pre-diagnosis and three months post-diagnosis medical history were matched (1:4 ratio) with 4,280 primary immune thrombocytopenia disease free patients by age, gender, primary care practice, and pre-diagnosis observation time. The baseline prevalence and incidence rate of thromboembolic events were quantified, with comparative risk modelled by Cox’s proportional hazards regression.

Results

Over a median 47.6 months of follow-up (range: 3.0–192.5 months), adjusted hazard ratios of 1.58 (95% CI, 1.01–2.48), 1.37 (95% CI, 0.94–2.00), and 1.41 (95% CI, 1.04–1.91) were found for venous, arterial, and combined (arterial and venous) thromboembolic events, respectively, when comparing the primary immune thrombocytopenia cohort with the primary immune thrombocytopenia disease free cohort. Further event categorization revealed an elevated incidence rate for each occurring venous thromboembolic subtype among the adult patients with primary immune thrombocytopenia.

Conclusions

Patients with primary immune thrombocytopenia are at increased risk for venous thromboembolic events compared with patients without primary immune thrombocytopenia.     

Variations in Perioperative Warfarin Management: Outcomes and Practice Patterns at Nine Hospitals

Background

Before surgery, most patients receiving oral anticoagulation require temporary cessation of treatment. Physicians sometimes substitute heparin or low-molecular-weight heparin for oral anticoagulation in the perioperative setting (“bridging therapy”). We sought to characterize rates of bridging therapy use at 9 clinical centers to determine the extent to which the use of bridging is explained by clinical characteristics of patients (vs physician style) and to determine the 30-day incidence of thrombotic and bleeding complications.

Methods

This was a prospective, multicenter, observational study. Periprocedural bridging anticoagulation was classified as none, prophylactic-dose heparin/low-molecular-weight heparin, or full-dose heparin/low-molecular-weight heparin. We collected data on patient and surgery characteristics, anticoagulation management, and thromboembolic and bleeding events.

Results

A total of 492 of 497 consecutive patients completed the study; 54%, 14%, and 33% of patients had no, prophylactic, and full (therapeutic) doses, respectively, of heparin/low-molecular-weight heparin postprocedure. Two hospitals treated more than 80% of their patients with full-dose heparin, whereas the remaining 7 hospitals used full-dose heparin in an average of 22% of cases (P <.001); this variation persisted after adjustment for patient characteristics. There were 4 thromboembolic events (0.8%) and 16 major bleeding events (3.2%). Full-dose heparin/low-molecular-weight heparin postprocedure was associated with a higher likelihood of major bleeding: adjusted odds ratio 4.4 (95% confidence interval, 1.5-14.7).

Conclusion

Management of anticoagulation after an invasive procedure varies widely and is not explained by clinical characteristics of patients alone. The risk of major bleeding is strongly associated with the use of postoperative therapeutic doses of heparin/low-molecular-weight heparin.     

Bleeding risk with concurrent use of anticoagulants and ibrutinib: A population-based nested case-control study

Data regarding the safety of co-administration of ibrutinib with anticoagulants in real-life settings are scarce. Using a nationwide database, we conducted a nested case-control study in a cohort of new users of ibrutinib to assess the risk of clinically relevant bleeding (CRB) associated with anticoagulation. Cases were patients with a diagnosis of CRB, defined as hospitalization with a diagnosis of bleeding. The date of CRB constituted the index date. Up to four controls were matched on sex, age at index date and duration of follow-up. The risk of CRB associated with anticoagulation in patients receiving ibrutinib was estimated using conditional logistic regression models, providing odds ratios (OR) adjusted for risk factors of bleeding. Among 614 cases and 2407 matched controls, the risk of CRB was significantly higher in patients receiving both ibrutinib and anticoagulants (adjusted OR [aOR] 2.54, confidence interval [CI] 95% [1.94; 3.32]). When considering anticoagulant class, aOR was 1.99 (CI 95% [1.19; 3.33]) for VKA, 2.48 (CI 95% [1.76; 3.47]) for direct oral anticoagulants and 3.40 (CI 95% [2.01; 5.75]) for parenteral anticoagulants. In conclusion, this study found a 2.5-fold increased risk of CRB in patients receiving both ibrutinib and anticoagulants in real-life settings, and similar aOR among oral anticoagulants.     

Clot Lysis Time Predicts Stroke During Anticoagulant Therapy in Patients with Atrial Fibrillation

BackgroundFormation of dense fibrin clots has been reported in both atrial fibrillation (AF) and ischemic stroke. We have previously demonstrated that such clot properties can predict thromboembolism and major bleeding in AF patients treated with vitamin K antagonists (VKAs). In this longitudinal cohort study, we evaluated whether impaired fibrinolysis is associated with clinical outcomes in AF.MethodsIn 236 patients with AF receiving VKAs, we measured ex vivo plasma clot lysis time (CLT), a measure of global fibrinolysis along, with von Willebrand factor antigen (vWF), plasminogen activator inhibitor 1 antigen (PAI-1), and other fibrinolysis modulators. The primary outcome were ischemic cerebrovascular events. Secondary end points were death and major bleeding.ResultsDuring a median follow-up time of 4.3 (interquartile range 3.7-4.8) years, annual rates of death, ischemic cerebrovascular events, and major bleeding were 1.48%, 2.96%, and 3.45%, respectively. Patients with CLT in the fourth quartile (> 115 min) had 8-fold higher stroke or transient ischemic attack (TIA) rates compared with the other patients (8.67% vs 1.1%; P < 0.0001). CLT correlated with PAI-1 and vWF (r = 0.59; P < 0.0001 for both). In the multivariate Cox regression analysis adjusted for potential confounders, the independent predictors of stroke or TIA were CLT > 115 minutes (hazard ratio [HR] 7.67, 95% confidence interval [CI] 2.78-21.17; P < 0.0001), PAI-1 (HR 1.16, 95% 1.05-1.28; P = 0.003), and CHA₂DS₂-VASc score ≥3 (HR 5.18, 95% 1.76-15.29; P = 0.003). CLT was not associated with death or major and minor bleeding events.ConclusionsImpaired fibrinolysis may predict thromboembolic events in AF patients receiving VKA.     

High platelet reactivity after P2Y<Subscript>12</Subscript>-inhibition in patients with atrial fibrillation and coronary stenting

High platelet reactivity (HPR) after P2Y₁₂-inhibition in patients undergoing coronary stenting is associated with an increased risk for thromboembolic events and coronary death. So far it is not known how HPR affects the clinical outcome of different treatment strategies in patients with atrial fibrillation (AF) undergoing coronary stenting. In this single centre, observational study the antiplatelet effect of P2Y₁₂-inhibitors in AF patients undergoing coronary stenting was investigated using impedance aggregometry. Patients received either dual antiplatelet therapy (DAPT) or triple therapy (TT). HPR was defined as the ratio of ADP-to TRAP-induced aggregation (r-ADP-agg) ≥50 %. Thromboembolic and bleeding events were assessed within the first 30 days after stenting. Out of 910 screened patients 167 patients were available for the present analysis. HPR was found in 5 of 43 (12 %) patients treated with DAPT and in 18 of 124 (15 %) patients treated with TT. In patients receiving TT, HPR was not a risk factor for thromboembolic events compared to patients with adequate response to P2Y₁₂-inhibitors (6 vs. 8 %, p = 0.712). There was a trend for less bleeding events in patients with HPR compared to r-ADP-agg <50 % in the TT group (0 vs. 16 %, p = 0.077). Our data suggest that HPR after P2Y₁₂-antagonism in patients receiving TT due to AF and coronary stenting might protect from bleeding without increasing thromboembolic risk. Future studies will need to investigate if patients with AF receiving coronary stenting benefit from a reduction of antithrombotic therapy.     

The risk of hemorrhage among patients with warfarin-associated coagulopathy.

OBJECTIVES: Among warfarin-treated patients with international normalized ratio (INR) >5, we sought to determine the risk of major bleeding within 30 days. BACKGROUND: For warfarin-treated patients, the risk of bleeding increases as the INR rises, particularly if the INR exceeds 4. The 30-day risk of hemorrhage among outpatients with excessively prolonged INR values is unknown. METHODS: To assess anticoagulation care in the U.S., a cohort of 6,761 patients taking warfarin was prospectively assembled from 101 participating sites (43% were community-based cardiology practices). From this cohort, 1,104 patients were identified with a first episode of INR >5. RESULTS: A total of 979 met eligibility criteria; complete follow-up information was available for 976 (99.7%). Ninety-six percent (n = 937) of patients had an INR value between 5 and 9; 80% of INR values were <7. Thirteen patients (1.3%) experienced major hemorrhage during the 30-day follow-up period; among patients whose INR was >5 and <9, 0.96% experienced major hemorrhage. None of the bleeding events was fatal. Intervention with vitamin K was uncommon (8.7%). Warfarin doses were withheld for the majority of patients. Fifty percent of patients who were managed conservatively and retested on day 4 or 5 had an INR of 2.0 or less. CONCLUSIONS: For warfarin-treated outpatients presenting with an INR >5 and <9, the 30-day risk of major bleeding is low (0.96%). Intervention with vitamin K among asymptomatic patients presenting with an INR <9 is not routine practice in the U.S.     

Adverse Events After Initiating Angiotensin-Converting Enzyme Inhibitor/Angiotensin II Receptor Blocker Therapy in Individuals with Heart Failure and Multimorbidity

BackgroundCurrent clinical practice guidelines recommend routine kidney function and serum potassium testing within 30 days of initiating angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) therapy. However, evidence is lacking on whether routine follow-up testing reduces therapy-related adverse events in adults with heart failure and if multimorbidity influences the association between laboratory testing and these adverse events.MethodsWe conducted a retrospective cohort study among adults with heart failure from 4 US integrated health care delivery systems. Multimorbidity was defined using counts of chronic conditions. Patients with outpatient serum creatinine and potassium tests in the 30 days after starting ACEI or ARB therapy were matched 1:1 to patients without follow-up tests. We evaluated the association of follow-up testing with 30-day all-cause mortality and hospitalization with acute kidney injury or hyperkalemia using Cox regression.ResultsWe identified 3629 matched adults with heart failure initiating ACEI or ARB therapy between January 1, 2005, and December 31, 2012. Follow-up testing was not significantly associated with 30-day all-cause mortality (adjusted hazard ratio [aHR] 0.45, 95% confidence interval [CI] 0.14; 1.39) and hospitalization with hyperkalemia (aHR 0.73, 95% CI, 0.33; 1.61). However, follow-up testing was significantly associated with hospitalization with acute kidney injury (aHR, 1.40, 95% CI, 1.01; 1.94). Interaction between multimorbidity burden and follow-up testing was not statistically significant in any of the outcome models examined.ConclusionsRoutine laboratory monitoring after ACEI or ARB therapy initiation was not associated with risk of 30-day all-cause mortality or hospitalization with hyperkalemia across the spectrum of multimorbidity burden in a cohort of patients with heart failure.