Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Brain Bleeds Double the Risk of Arterial Ischemic Events
A study pooled four U.S. population-based cohort studies -- the Atherosclerosis Risk in Communities (ARIC) study, Cardiovascular Health Study (CHS), Northern Manhattan Study (NOMAS), and Reasons for Geographic and Racial Differences in Stroke (REGARDS) study -- and involved a total of 47,866 eligible participants (57.7% women, mean age 62 years). This included 318 intracerebral hemorrhages (ICH) 7,648 arterial ischemic events over a median follow-up of 12.7 years.
Results showed that ICH was associated with an increased risk for later arterial ischemic events when compared with the general population. The events were consistent across the four studies. Also, twice the risk of MI was seen. The increased risk was comparable among black and white individuals. It is possible that ICH may be a novel risk marker for arterial ischemic events. Similar findings liked ICH with subsequent MI and ICH, however those studies did not have control groups without ICH.
There is the unresolved question of whether there is a net benefit of starting statins after ICH in patients at risk for ischemic events. This study seems to revisit that as a strategy worth investigation as well as including specific anti-inflammatory therapies and phosphodiesterase-3 inhibitors, that may safely address the risk of ischemic events after intracerebral hemorrhage.
Limitations to this study include the differences in the definition of exposure and outcomes in the four cohorts including surveillance bias due to the evolving approaches to the management of vascular risk factors between 1980s up to late 2000s.
Post-Vax Clot Case Supports Angiomax Use
A case study report in a 40 year old women who presented with a headache, sinus pressure, myalgias, and sore throat post administration of the J & J vaccine. Results found the patient to have thrombocytopenia, elevated D-dimer, normal fibrinogen and elevated serum transaminase. CT imagining showed cerebral venous sinus thrombosis, and the patient had a confirmatory ELISA test pointing to vaccine-induced thrombotic thrombocytopenia (VITT) of thrombosis with thrombocytopenia syndrome (TTS).
The patient was given bivalirudin at 0.15 mg/kg/hr with coagulation-based titration along with IV immune globulin and prednisone. The patient's platelet count steadily rose from 20 x 109/L at admission to 115 x 109/L at discharge after 6 days in the hospital and then 182 x 109/L on outpatient follow-up (day 9). Her headache resolved without clinical sequelae of thrombosis or evidence of bleeding.
The CDC guidance as well as the UK Expert Haematology Panel and a German group all recommend treatment with heparin alternatives. However, bivalirudin doesn’t have any advantage over argatroban or fondaparinux. However, some patients have been treated with LMWH and done well suggesting that there may be a different physiology that classical HIT.
Versiti releases new test for detecting blood clots after vaccine
Versiti test determines the presence and function of platelet activating antibodies for use in testing VITT. This can occur within 3-20 days post administration of COVID-19 vaccine. The antibodies are similar to those seen in HIT. They have been granted three multi center contracts to coordinate nationwide clinical trials to establish optimal treatment plans for clot prevention in COVID-19 patients. This collaborative effort may change the standard of care in hospitalized patients. Interim results found that full dose anticoagulation given to patients not in the ICU demonstrated a reduction in patients requiring ventilation.
Blood Thinners Continue at End of Life, Despite Risks
Anticoagulation is often continued in patients with AF even when patients have advanced dementia. Up to 1/3 of elderly people received anticoagulation during the last 6 months of their life according to Medicare records. The benefits of these drugs are the lowest in this group. Use may be due to a lack of clear guidelines for clinicians regarding stopping and starting anticoagulation. Patients with dementia have limited life expectancy and should focus on quality of life but avoiding the potential morbidity of stroke may be a goal.
Data from 15,217 Medicare nursing home residents with AF and advanced dementia with a moderate stroke risk and who died from 2014-2017 was reviewed. The mean age was 88 with 68% of patients being women. Greater odds of anticoagulant use were tied to:
- Nursing home length of stay of at least 1 year: OR 2.68
- Not having Medicaid: OR 1.59
- CHA2DS2-VASc score above 7: OR 1.38
- Pressure ulcers: OR 1.37
- ATRIA score above 7: OR 1.25
- Difficulty swallowing: OR 1.12
- Weight loss: OR 1.09
Studies using decision making aids as well as dose reduction should be performed in this population. This research was limited by its cross sectional design as well as being only conducted on patients in nursing home with AF and advanced dementia.
Baby Aspirin on Par With Full Dose to Prevent Repeat Heart Events
The ADAPTABLE trial was a cardiology based pragmatic trial that looked at 81mg dose of aspirin versus 325 mg for secondary cardiovascular prevention. The trial included 15,076 patients identified via electronic health records as having CVD and one risk factor. They were enrolled and followed for 16.2 months via electronic means.
Results demonstrated that death from any cause and hospitalization for MI or stroke were similar 7.28% at 81 mg and 7.51% with the higher dose, while hospitalization for major bleeding with transfusion of a blood product occurred in 0.63% and 0.60% respectively. It was concluded that patients doing well on their current dose should be fine to stay there, with no mandate to switch. For patients starting or restarting aspirin, the 81 mg dose is probably right due to better tolerability. There were 42% of the group that was randomized to 325 mg who switched to the 81mg dose upon physician recommendation.
TALOS-AMI: Switching From Ticagrelor to Clopidogrel Safe Post-PCI
Results from the TALOS-AMI trial supported replacing ticagrelor with clopidogrel as part of dual antiplatelet therapy (DAPT) 30 days post stenting for MI. The study randomized 2697 acute MI patients who had received 1 month of DAPT with ticagrelor and aspirin without any events, were moved to either aspirin and clopidogrel or kept on ticagrelor and aspirin. Mean age was 60, 54% presented with ST-segment elevation MI, and 28% had multivessel PCI. Adherence to therapy was greater than 97% in both groups. The primary endpoint was a composite of CV death, MI, stroke and bleeding. Bleeding was reduced from 5.0% vs 3.0%, with rate of CV death, MI and stroke 3.1% vs. 2.1% in the clopidogrel group.
Limitations of the study included that it was unblinded and conducted only in South Korea. Koreans have higher prevalence of the CYP2CI9 loss-of-function allele, which can diminish clopidogrel efficacy.
HOST-EXAM: Clopidogrel Beats Aspirin as Monotherapy After StentingHOST-EXAM: Clopidogrel Beats Aspirin as Monotherapy After Stenting (medscape.com)
The HOST-EXAM trial looked at 5530 patients with drug eluting stent after completing 6-18 months of dual antiplatelet therapy and then continuing with long term monotherapy of either clopidogrel 75 mg or 100mg of aspirin monotherapy for 24 months. This randomized therapy compared ischemic events and major bleeding. The primary endpoint of all cause death, nonfatal MI, stroke, readmission due to ACS and bleeding occurring in 5.7% in the clopidogrel group and 7.7% in the aspirin group resulting in a 27% risk reduction in the clopidogrel group.
The secondary composite thrombotic endpoint of cardiac death, nonfatal MI, stroke, readmission due to ACS, or definite or probable stent thrombosis occurred in 3.7% of patients in the clopidogrel group and 5.5% of patients in the aspirin group, bleeding occurred in 2.3% of patients with clopidogrel and 3.3% in the aspirin group.
Specific endpoints that were reduced with clopidogrel included nonfatal MI (0.7% vs 1.0%), stroke (0.7% vs 1.6%), hemorrhagic stroke (0.2% vs 0.6%), readmission for ACS (2.5% vs 4.1%), and major bleeding (1.2% vs 2.0%). All-cause death was numerically higher in the clopidogrel group (1.9% vs 1.3%), although this was a nonsignificant difference.
Current treatment guidelines recommend a dual antiplatelet regimen of 6 to 12 months after stenting, with monotherapy thereafter. But the optimal single-antiplatelet agent for long-term maintenance therapy has been unclear. Results are similar to the CAPRIE trial that was conducted 20 years ago comparing clopidogrel versus aspirin for secondary prevention, however the dose of aspirin was 325 mg.
The study was conducted in Asia and the results did not include patients in which there was a greater degree of racial diversity and where obesity rates are higher. There is a known difference in bleeding thrombosis balance between Asians and Caucasians, but there is less clopidogrel resistance in Caucasians.
Early Aspirin Withdrawal After PCI: More Benefit for Women?
A TWILIGHT study sub analysis has shown that, in the high-risk population undergoing percutaneous coronary intervention (PCI) enrolled in the study, the benefits of early aspirin withdrawal and continuation on ticagrelor monotherapy were similar in women and men. There may be additional benefits for women due to the risk reduction of bleeding.
In the main results from the TWLIGHT study ticagrelor monotherapy when compared to continued monotherapy led to reduced bleeding without an increase risk in ischemic events after PCI. This study included 7119 patients with a high risk of ischemic or bleeding events who had undergone successful PCI with one drug eluting stent and compated 3 moths of dual antiplatelet therapy to aspirin or placebo for an additional 12 months plus open label ticagrelor. The current analysis looked at the variations in relation to sex.
The study included 23.9% women who were older than the man and more likely to have comorbidities of diabetes, chronic kidney disease, anemia, and hypertension versus men who were more likely to be current smokers with a higher incidence of coronary heart disease. The ischemic endpoint of death/stroke or MI was similar in men (4.0%) and women (3.5%), and this did not change after adjustment for baseline characteristics. The absolute risk reduction in bleeding was greater in women (3.6%) vs men (2.9%).
There were limitations in the analysis since the study was not powered to show the difference between men versus women and were only applicable to those at high risk of bleeding post PCT. Despite the differences being minimal, it still can be considered that there may be additional factors that may be important and contribute to an increased risk for bleeding which may be more serious types of bleeding in women.
Direct Oral Anticoagulant Reversal Agent Not Always on Hand at Trauma Centers, Acute Care Hospitals
Data from 4000 US hospitals revealed that only 11.7% had andexanet alfa on hand for the reversal agent for Xa inhibitors. Idarucizumab, the reversal agent for dabigatran, was available in 59.9% of hospitals. Xa reversal agents are less likely to be available in stock at acute care hospitals and trauma centers despite them being used more almost 20 times more frequently. Both of these DOACs are considered safer than warfarin, however people still may bleed. Results of the Medicare database looked at 5,340 hospitals, of which 4,276 met the researchers' inclusion criteria. Among those hospitals, 2,562 (59.9%) carried idarucizumab and 499 (11.7%) carried andexanet alfa. Among the 528 trauma centers, 503 (95.3%) stocked idarucizumab and 151 (28.6%) stocked andexanet alfa.
Many bleeds can be treated with prothrombin complex concentrates but specifically targeted medication is recommended. These findings may be due to the fact that andexanet alfa is more expensive. Andexanet alfa costs about $22,000 per patient as compared to about $6,000 for 4-factor prothrombin complex concentrate.
Therapeutic Rivaroxaban Dose: Risk Outweighs Benefit in Stable COVID
Rivaroxaban is used in patients with AF, DVT, and PE. It is also being used in some centers to prevent thromboembolic events in COVID-19 patients, but there is no data on optimum duration or dosage.
The ACTION trial looked at 615 stable hospitalized COVID-19 patients with elevated d-dimer levels using therapeutic rivaroxaban at 20mg/once daily. Unstable patients received enoxaparin twice daily. Baseline characteristics of the patients enrolled showed that more than 90% were classified as stable, with around 75% needing oxygen support; 90% were already on anticoagulants (most on standard prophylaxis), 8% were taking antiplatelet medication, and 83% were on systemic corticosteroids.
The therapeutic group showed numerically lower rates of thromboembolic events (relative risk [RR], 0.75; 95% CI, 0.45 - 1.26), but also numerically higher rates of 30-day mortality (RR, 1.49; 95% CI, 0.90 - 2.46). There was also a significant increase in major or clinically relevant bleeding in the therapeutic group (8.4% vs 2.3%), giving a RR of 3.64.
Clinical outcomes were not improved but bleeding was increased when compared to in hospital prophylactic anticoagulation. Based on these results, this dose should not be used.
Sex Differences Among Patients With High Risk Receiving Ticagrelor With or Without Aspirin After Percutaneous Coronary Intervention A Subgroup Analysis of the TWILIGHT Randomized Clinical Trial
Birgit Vogel, MD1; Usman Baber, MD, MS1,2; David J. Cohen, MD, MSc3,4; et alSamantha Sartori, PhD1; Samin K. Sharma, MD1; Dominick J. Angiolillo, MD, PhD5; Serdar Farhan, MD1; Ridhima Goel, MD1; Zhongjie Zhang, MPH1; Carlo Briguori, MD, PhD6; Timothy Collier, MSc7; George Dangas, MD, PhD1; Dariusz Dudek, MD, PhD8,9; Javier Escaned, MD, PhD10; Robert Gil, MD, PhD11; Ya-ling Han, MD, PhD12; Upendra Kaul, MD13; Ran Kornowski, MD14; Mitchell W. Krucoff, MD15; Vijay Kunadian, MBBS, MD16; Shamir R. Mehta, MD, MSc17; David Moliterno, MD18; E. Magnus Ohman, MD15; Gennaro Sardella, MD19; Bernhard Witzenbichler, MD20; C. Michael Gibson, MD, MS21; Stuart Pocock, PhD7; Kurt Huber, MD22,23; Roxana Mehran, MD1
Importance Shortened dual antiplatelet therapy followed by potent P2Y12 receptor inhibitor monotherapy reduces bleeding without increasing ischemic events after percutaneous coronary intervention (PCI).
Objective To explore sex differences and evaluate the association of sex with outcomes among patients treated with ticagrelor monotherapy vs ticagrelor plus aspirin.
Design, Setting, and Participants This was a prespecified secondary analysis of TWILIGHT, an investigator-initiated, placebo-controlled randomized clinical trial conducted at 187 sites across 11 countries. Study participants included patients who underwent successful PCI with drug-eluting stents, were planned for discharge with ticagrelor plus aspirin, and who had at least 1 clinical and at least 1 angiographic feature associated with high risk of ischemic or bleeding events. Data were analyzed from May to July 2020.
Interventions At 3 months after PCI, patients adherent to ticagrelor and aspirin without major adverse event were randomized to either aspirin or placebo for an additional 12 months along with ticagrelor.
Main Outcomes and Measures The primary end point was Bleeding Academic Research Consortium (BARC) type 2, 3, or 5 bleeding at 12 months after randomization. The primary ischemic end point was a composite of death, myocardial infarction, or stroke.
Results Of 9006 enrolled patients, 7119 underwent randomization (mean [SD] age, 63.9 [10.2] years; 5421 [76.1%] men). Women were older (mean [SD] age, 65.5 [9.6] years in women vs 63.4 [10.3] years in men) with higher prevalence of chronic kidney disease (347 women [21.2%] vs 764 men [14.7%]). The primary bleeding end point occurred more often in women than men (hazard ratio [HR], 1.32; 95% CI, 1.06-1.64; P=.01). After multivariate adjustment, incremental bleeding risk associated with female sex was no longer significant (adjusted HR, 1.20; 95% CI, 0.95-1.52; P=.12). Ischemic end points were similar between sexes. Ticagrelor plus placebo vs ticagrelor plus aspirin was associated with lower risk of BARC type 2, 3, or 5 bleeding in women (adjusted HR, 0.62; 95% CI, 0.42-0.92; P=.02) and men (adjusted HR, 0.57; 95% CI, 0.44-0.73; P<.001; P for interaction=.69). Ischemic end points were similar between treatment groups in both sexes.
Conclusions and Relevance These findings suggest that the higher bleeding risk in women compared with men was mostly attributable to baseline differences, whereas ischemic events were similar between sexes. In this high-risk PCI population, the benefits of early aspirin withdrawal with continuation of ticagrelor were generally comparable in women and men.
Venous Thromboembolic Events in Patients With COVID-19
Ting Wu; Zhihong Zuo; Deyi Yang; Xuan Luo; Liping Jiang; Zanxian Xia; Xiaojuan Xiao; Jing Liu; Mao Ye; Meichun Deng
Age Ageing. 2021;50(2):284-293.
Background: High incidence of venous thromboembolic complications in coronavirus disease 2019 (COVID-19) patients was noted recently.
Objective: This study aimed to explore the factors associated with prevalence of venous thromboembolism (VTE) in COVID-19 patients.
Methods: A literature search was conducted in several online databases. Fixed effects meta-analysis was performed for the factors associated with prevalence of VTE in COVID-19 patients.
Results: A total of 39 studies were analyzed in this analysis. The incidence of pulmonary embolism and VTE in severe COVID-19 patients were 17% (95% CI, 13–21%) and 42% (95% CI, 25–60%), respectively. VTE were more common among individuals with COVID-19 of advance age. Male COVID-19 patients are more likely to experience VTE. Higher levels of white blood cell (WBC; WMD = 1.34 × 109/L; 95% CI, 0.84–1.84 × 109/L), D-dimer (WMD = 4.21 μg/ml; 95% CI, 3.77–4.66 μg/ml), activated partial thromboplastin time (APTT; WMD = 2.03 s; 95% CI, 0.83–3.24 s), fibrinogen (WMD = 0.49 μg/ml; 95% CI, 0.18–0.79 g/L) and C-reactive protein (CRP; WMD = 21.89 mg/L; 95% CI, 11.44–32.34 mg/L) were commonly noted in COVID-19 patients with VTE. Patients with lower level of lymphocyte (WMD = −0.15 × 109/L; 95% CI, −0.23-−0.07 × 109/L) was at high risk of developing VTE. The incidence of severe condition (OR = 2.66; 95% CI, 1.95–3.62) was more likely to occur among COVID-19 patients who developed VTE.
Conclusion: VTE is a common complication in severe COVID-19 patients and thromboembolic events are also associated with adverse outcomes.
Management of Patients With Venous Thromboembolism After the Initial Treatment Period
Timothy M. Fernandes, MD, MPH; Manreet Kanwar, MD; Richard White, MD J Am Board Fam Med. 2021;34(2):409-419.
Background: Venous thromboembolism (VTE) is a common medical problem seen in primary care settings. The most common long-term adverse sequelae are recurrent thromboembolism and incomplete resolution of the embolic material, which may result in pulmonary hypertension after pulmonary embolism and post-thrombotic changes in the leg after deep vein thrombosis. Although there are detailed guidelines for diagnosing and treating acute VTE, there are few focused articles that provide recommendations for primary care physicians (PCPs) about how to manage VTE patients after completion of the initial period of anticoagulation treatment.
Observations: In this article, we highlight several important clinical decisions that must be addressed after the first 3 months of anticoagulation treatment is complete, with a focus on particular management issues for PCPs.
Conclusions: The 2 most important decisions the PCP must make are to determine, first, if symptoms of acute VTE have indeed resolved, and second, if they have resolved, to assess the long-term risk of recurrent VTE versus the risk of potential bleeding and decide if anticoagulation should be stopped, or if indefinite anticoagulation treatment is indicated. Among higher-risk patients who may benefit from indefinite anticoagulation, the PCP should discuss both the risks and benefits of anticoagulation treatment, empowering the patient to actively participate in this important shared decision-making process.