by Donna Castellone, MS, MT (ASCP) SH •
February 02, 2023
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation. Please Note: many linked teasers require account/subscription in order to view full articles.
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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.
In the CLARITY-AD trial, which looked at the utility of the anti-amyloid agent lecanemab for Alzheimer, a fatal bleeding event was recorded. A 65 year old patient on the drug with cerebral amyloid angiopathy died after being given tPA for an acute ischemic stroke that occurring during the trial. The patient also had underlying conditions. The participant was homozygous for the APOE4 allele and had an includion of lecanemab 4 days prior to the stroke. Prior to the stroke, MRI results showed mild small-vessel disease, with no microhemorrhages, edema, or amyloid-related imaging abnormalities (ARIA).
A CT prior to tPA administration revealed no hemorrhage. Hypertension developed 50 minutes into the infusion resulting in extensive, multifocal intraparenchymal hemorrhages without systemic bleeding. Patient received cryo and tranexamic acid. These findings may be associated with tpa infusion in a patient with CV amyloid who received lecanemab. The death occurred during the trials extension phase and was not counted in the trials 13 deaths.
CLARITY's main finding was that lecanemab was associated with a statistically significant albeit modest reduction in clinical decline after 18 months in people with early Alzheimer's disease.
A meta-analysis that included 66 randomized trials which included 38,574 patients, looked at the incidence of VTE in JAK inhibitors versus tumor necrosis factor (TNF) occurred in patients with immune-mediated inflammatory disease. Risk was also dependent on duration of exposure, particularly after 12 months.
Implications For Practice
The link between JAK inhibitors and increased risk of VTE appears to be soft, but increases predominantly in those taking the medication for longer than 12 months.
Caution is advised for individuals at higher-risk for VTE and MACE who take JAK inhibitors, particularly over longer periods.
Controlling lipids and addressing risk factors are key to reducing VTE risk in high-risk patients taking JAK inhibitors.
Antiphospholipid syndrome (APS) is an autoimmune disease predominantly affecting women. They are treated with medications to reduce the risk of blood clots and also normalization of platelet counts. Despite these treatments, patients do not feel as well as their laboratory tests reveal.
A study of 139 patients were given three questionnaires upon arrival to their appointment in which they rated physical function, cognitive function and pain intensity. Results showed that half of the patients had a physical score of less than 45 and a cognitive function score of 40. This suggests impairment in day to day physical and cognitive activity. These scores could be suggestive of more severe disease but also with potentially modifiable lifestyles including obesity and smoking. Even patients on serotonin reuptake inhibitors reported worse physical and cognitive function an higher pain intensity.
A study that included 832 patient who were on a DOAC, received IV thrombolysis (Alteplase in the majority, a few receiving Tenecteplase) within 48 hours for ischemic stroke. The DOACs that had most commonly been ingested prior to stroke were dabigatran (Pradaxa, 41%), rivaroxaban (Xarelto, 31%), and apixaban (Eliquis, 20%).
Results showed that this did not raise the risk of bleeding in these patients. Patients had a median age of 73 and 43.5% were women. Time from stroke onset to thrombolysis was 138 minutes. These patients experienced a lower incidence of symptomatic ICH within 36 hours compared with controls without anticoagulant use in the prior 48 hours. This finding was counterintuitive and needs to be considered when updating future stroke guidelines for recent DOAC ingestion and IV thrombolysis.
Patients on DOACs when compared to controls were older, hypertensive, greater pre-stroke disability and more severe strokes, waited longer for treatment and more likely to have large vessel occlusion.
The study did not use randomization and was a limitation leaving room for potential confounding and bias. However, information from the study can helpful for these patients.
Results from the SELECT study showed that patients who received endovascular thrombectomy (EVT) were more likely to achieve functional independence at 90 days. It was associated with decreased mortality however there was an increased level of ICH. It also benefited select stroke patients presenting beyond 24 hours of the time they were last known well.
In 2018 the American Heart Association/American Stroke Association increased the treatment window for stroke patients from 6 up to 24 hours. This was based on better imaging techniques that identify people with salvageable brain tissue. Timely treatment is important. A meta-analysis showed that every hour of EVT delay translated to a loss of 0.81 healthy life years.
The cohort included 301 patients with a median age of 69 years, half were female. Patients presented more than 24 hours after last known being well. They presented with occlusions in the internal carotid artery or middle cerebral artery. Wake up stroke occurred in 20% of cases and 80% had unwitnessed stroke onset. In the study, 61% received EVT and 39% were managed medically. IV thrombolysis was given to 4% of patients in the EVT group and 5% in medical management.
Prospective studies are required to confirm these findings. A randomized trial in patients presenting beyond 24 hours would be challenging.
Subgroup analysis of the STOPDAPT-2 and STOPDAPT-2 ACS trials found that replacing DAPT with just clopidogrel resulted in a lower risk of bleeding while giving comparable protection against cardiovascular events. The analysis looked at the benefit to risk ratio in patients who had a high bleeding risk or had a complex PCE. This is a follow-up to the 2019 trial that initially tested 1 versus 12 month DAPT in PCI patients with a drug eluting stent. The second study compared the same DAPT strategies in patients undergoing PCI to treat ACS. Both studies were conducted in Japan and the experimental are received this treatment for 1 month followed by clopidogrel monotherapy versus the control arm receiving DAPT for 12 months. Previous studies have suggested that East Asians have a higher risk of bleeding but anti-ischemic benefits from DAPT.
The substudies combined data from 5997 patients in the two trials. The first one looked at 1893 patients who presented with a high bleeding risk and compared them to 4104 who did not. Results showed that results of reaching a primary endpoint after 1 year was not significantly different in 1 month versus 12 months standard DAPT and was found to also be the same in those without an elevated bleeding risk.
The second substudy looked at 999 patients with complex PCI compare to 4998 who did not. Primary endpoint was lower in those who had a complex PCI. Those on the one month DAPT with a high bleeding risk had a lower risk of bleeding events, but a higher risk of cardiovascular events but was not significant.
The study may not be transferable to all patients. It may be difficult to have a person on monotherapy. One point from the study is that bleeding risk trumps PCI complexity. More data is needed in order to reliably be able to shorten DAPT duration in all patients to tailor therapy in specific populations to ensure the best risk to benefit in treatment.
Thrombotic antiphospholipid syndrome (APS) is an autoimmune disorder in which patients present with recurrent arterial and or venous thrombosis. It can be the cause of 50,000-100,000 strokes, 100,000 cased of MI and 30,000 occurrences of DVT annually. Standard treatment is warfarin but this requires monitoring and can be difficult to manage, therefore using DOACs in this cohort was promising.
A systematic review and meta analysis of randomized controlled trials that compared DOACs versus vitamin K antagonists was conducted. Four main trials (n=472) looked at this in APS, three trials used rivaroxaban and one used apixaban. Results showed that vitamin K was associated with an increased risk of arterial thrombotic events and a risk primarily driven by a significant increase in the risk of stroke. The risk of bleeding or subsequent VTE were not significantly different between groups. These results probably suggest that DOACs are not the optimal regimen for patients with thrombotic antiphospholipid syndrome. A subgroup analysis showed no difference in any groups and similar trends towards worse outcomes in all subgroups (single positive, double positive, triple positive).
Reasons why DOACs would be less effective than vitamin K antagonists is not known. A hypothesis is that these patients have some more components of inflammation and are more prone to blood clots, and because vitamin K antagonists work at several parts of the coagulation cascade, they might be more successful compared with the more targeted DOAC therapy.
The PREVENT CLOT randomized trial (n=12,000) compared aspirin versus low molecular heparin (LMWH) in patients with traumatic bone fractures. The study was conducted at 21 trauma centers in the US and Canada from 2017-2021, Patients presented with pelvic fractures, leg or arm fractures requiring surgery. Patients had a mean age of 44.6 with 62.3% being men. They were randomly assigned to enoxaparin or aspirin and continued to receive thromboprophylaxis according to standard of care for their hospital. Duration of thromboprophylaxis was not mandated.
Results showed that aspirin met noninferiority criteria against enoxaparin for all cause mortality at 90 days. Both treatments had similar incidents of bleeding, nonfatal PE and other serious adverse events. Only DVT was found to be significantly worse with aspirin. Patients preferred to take aspirin versus injections of LMWH. This is the largest trial to date that provides evidence that aspirin is a viable alternative to more expensive prophylaxis.
The phase III study XTEND-1 trial showed that treatment with efanesoctocog alfa prevented bleeding episodes in patients with severe hemophilia A. This class of factor VIII replacement therapy was used in 133 patients. They received one dose weekly prophylactically for 52 weeks with an annualized bleeding rate of 0 and the mean annualized bleeding rate was 0.71. Additionally a subgroup of 78 patients who were switched from pre-study standard care FVIII prophylaxis to efanesoctocog alfa decreased the bleeding rate from 2.96 to 0.69 which was a 77% reduction. A smaller group of 26 men received on demand treatment with efanesoctocog alfa for 26 weeks followed by 1 week of prophylaxis for 26 weeks resulted in a reduced bleeding rate when switched to prophylaxis.
Using weekly prophylaxis maintained sustained FVIII levels resulting in improvements in clinical outcomes and quality of life. The drug is currently under FDA review.
One of the issues with providing sustained factor VIII activity in these patients is the factor imposed half life ceiling of von Willebrand factor (VWF). The interaction between FVIII and VWF limits the half life of current FVIII replacement products to 8-19 hours. To maintain levels close to the normal range of between 40 and 50 IU require frequent administration. Since efanesoctocog alfa circulated independently of VWF it extends the protection of bleeds with weekly dosing. In this study its half-life was 47 hours resulting in protective levels with weekly dosing.
Jiayi Ma; Naga P. Chalasani; Linus Schwantes-An; Einar Stefán Björnsson
Aliment Pharmacol Ther. 2023;57(1):52-71.
Patients with cirrhosis were long thought to be coagulopathic. However, this paradigm has changed in recent years and currently, cirrhosis is recognised as a prothrombotic state. Due to the increasing incidence of cirrhosis from nonalcoholic steatohepatitis which is closely associated with cardiac disease, patients with cirrhosis increasingly require therapy with anticoagulants and antiplatelet agents. However, their potential for causing catastrophic and life-threatening bleeding in patients with cirrhosis leads to hesitancy about their use in patients with cirrhosis. Overall, traditional anticoagulation is safe for all Child-Pugh classes while newer direct oral anticoagulants (DOACs) are mostly safe in Child-Pugh class A/B and contraindicated in severe hepatic impairment. For different indications, published data to date suggest that anticoagulation is overall safe for patients with cirrhosis who have venous thromboembolism, atrial fibrillation and portal vein thrombosis, and does not increase the risk of variceal bleeding. Moreover, DOACs appear to have similar safety profiles as traditional anticoagulants. Finally, most studies suggest that antiplatelet agents are also safe to use in patients with cirrhosis although they are mostly contraindicated in severe hepatic impairment. For both anticoagulants and antiplatelet agents, severe thrombocytopaenia presents a relative contraindication to their use. More prospective trials and large cohort studies are needed to advance our understanding of the safety and nuances of DOACs and antiplatelet agents in patients with advanced cirrhosis.
Candrika D Khairani, Antoine Bejjani, Gregory Piazza, David Jimenez, Manuel Monreal, Saurav Chatterjee, Vittorio Pengo, Scott C Woller, Josefina Cortes-Hernandez, Jean M Connors, Yogendra Kanthi, Harlan M Krumholz, Saskia Middeldorp, Anna Falanga, Mary Cushman, Samuel Z Goldhaber, David A Garcia, Behnood Bikdeli
J Am Coll Cardiol, 2023 Jan 3;81(1):16-30.
Background: The efficacy and safety of direct oral anticoagulants (DOACs) for patients with thrombotic antiphospholipid syndrome remain controversial.
Objectives: The authors performed a systematic review and meta-analysis of randomized controlled trials that compared DOACs with vitamin K antagonists (VKAs).
Methods: We searched PubMed, EMBASE, and Cochrane Central Register of Controlled Trials through April 9, 2022. The 2 main efficacy outcomes were a composite of arterial thrombotic events and venous thromboembolic events (VTEs). The main safety outcome was major bleeding. Random effects models with inverse variance were used.
Results: Our search retrieved 253 studies. Four open-label randomized controlled trials involving 472 patients were included (mean control-arm time-in-therapeutic-range 60%). All had proper random sequence generation and adequate allocation concealment. Overall, the use of DOACs compared with VKAs was associated with increased odds of subsequent arterial thrombotic events (OR: 5.43; 95% CI: 1.87-15.75; P < 0.001, I2 = 0%), especially stroke, and the composite of arterial thrombotic events or VTE (OR: 4.46; 95% CI: 1.12-17.84; P = 0.03, I2 = 0%). The odds of subsequent VTE (OR: 1.20; 95% CI: 0.31-4.55; P = 0.79, I2 = 0%), or major bleeding (OR: 1.02; 95% CI: 0.42-2.47; P = 0.97; I2 = 0%) were not significantly different between the 2 groups. Most findings were consistent within subgroups.
Conclusions: Patients with thrombotic antiphospholipid syndrome randomized to DOACs compared with VKAs appear to have increased risk for arterial thrombosis. No significant differences were observed between patients randomized to DOACs vs VKAs in the risk of subsequent VTE or major bleeding.
Leonie S Penner, Sean P Gavan, Darren M Ashcroft, Niels Peek, Rachel A Elliott
Br J Clin Pharmacol, 2022 Nov;88(11):4789-4811.
Aims: To examine the risk of gastrointestinal (GI) bleeding, major bleeding, stroke and systemic embolism associated with prescribing nonsteroidal anti-inflammatory drugs (NSAIDs) to adults receiving oral anticoagulant (OAC) therapy.
Methods: We conducted a population-based cohort study in adults receiving OAC therapy using linked primary care (Clinical Practice Research Datalink GOLD) and hospital (Hospital Episodes Statistics) electronic health records. We used cause-specific Cox regression models with time-dependent NSAID treatment in a propensity score matched population to estimate the increased risk of GI bleeding, stroke, major bleeding and systemic embolism associated with NSAID use.
Results: The matched cohort contained 3177 patients with OAC therapy alone and 3177 with at least 1 concomitant NSAID prescription. Compared with OAC therapy alone, concomitant prescription of NSAIDs with OACs was associated with increased risk of GI bleeding (hazard ratio [HR] 3.01, 95% confidence interval [CI] 1.63 to 5.55), stroke (HR 2.71, 95% CI 1.48 to 4.96) and major bleeding (HR 2.77, 95% CI 1.84 to 4.19). The association with systemic embolism did not reach statistical significance (HR 3.02, 95% CI 0.82 to 11.07). Sensitivity analyses indicated that the results were robust to changes in exclusion criteria and the choice of potential confounding variables.
Conclusion: When OACs are coprescribed with NSAIDs, the risk of adverse bleeding events increases and, simultaneously, the protective effect of OACs to prevent strokes reduces. There is a need for interventions that reduce hazardous prescribing of NSAIDs in people receiving OAC therapy.
Ainhoa Gomez Lumbreras, Thomas J Reese, Guilherme Del Fio, Malinda S Tan, Jorie M Butler, Jason T Hurwitz, Mary Brown, Kensaku Kawamoto, Henrik Thiess, Maria Wright, Daniel C Malone
JMIR Form Res, 2022 Oct 19;6(10):e40018.
Background: Warnings about drug-drug interactions (DDIs) between warfarin and nonsteroidal anti-inflammatory drugs (NSAIDs) within electronic health records indicate potential harm but fail to account for contextual factors and preferences. We developed a tool called DDInteract to enhance and support shared decision-making (SDM) between patients and physicians when both warfarin and NSAIDs are used concurrently. DDInteract was designed to be integrated into electronic health records using interoperability standards.
Objective: The purpose of this study was to conduct a formative evaluation of a DDInteract that incorporates patient and product contextual factors to estimate the risk of bleeding.
Methods: A randomized formative evaluation was conducted to compare DDInteract to usual care (UC) using physician-patient dyads. Using case vignettes, physicians and patients on warfarin participated in simulated virtual clinical encounters where they discussed the use of taking ibuprofen and warfarin concurrently and determined an appropriate therapeutic plan based on the patient's individualized risk. Dyads were randomized to either DDInteract or UC. Participants completed a postsession interview and survey of the SDM process. This included the 9-item Shared Decision-Making Questionnaire (SDM-Q-9), tool usability and workload National Aeronautics and Space Administration (NASA) Task Load Index, Unified Theory of Acceptance and Use of Technology (UTAUT), Perceived Behavioral Control (PBC) scale, System Usability Scale (SUS), and Decision Conflict Scale (DCS). They also were interviewed after the session to obtain perceptions on DDInteract and UC resources for DDIs.
Results: Twelve dyad encounters were performed using virtual software. Most (n=11, 91.7%) patients were over 50 years of age, and 9 (75%) had been taking warfarin for more than 2 years (75%). Regarding scores on the SDM-Q-9, participants rated DDInteract higher than UC for questions pertaining to helping patients clarify the decision (P=.03), involving patients in the decision (P=.01), displaying treatment options (P<.001), identifying advantages and disadvantages (P=.01), and facilitating patient understanding (P=.01) and discussion of preferences (P=.01). Five of the 8 UTAUT constructs showed differences between the 2 groups, favoring DDInteract (P<.05). Usability ratings from the SUS were significantly higher (P<.05) for physicians using DDInteract compared to those in the UC group but showed no differences from the patient's perspective. No differences in patient responses were observed between groups using the DCS. During the session debrief, physicians indicated little concern for the additional time or workload entailed by DDInteract use. Both clinicians and patients indicated that the tool was beneficial in simulated encounters to understand and mitigate the risk of harm from this DDI.
Conclusions: Overall, DDInteract may improve encounters where there is a risk of bleeding due to a potential drug-drug interaction involving anticoagulants. Participants rated DDInteract as logical and useful for enhancing SDM. They reported that they would be willing to use the tool for an interaction involving warfarin and NSAIDs.
Sahrish Shah, Meritxell Urtecho, Mohammed Firwana, Tarek Nayfeh, Bashar Hasan, Ahmad Nanaa, Samer Saadi, David N Flynn, Rami Abd-Rabu, Mohamed O Seisa, Noora S Rajjoub, Leslie C Hassett, Alex C Spyropoulos, James D Douketis, M Hassan Murad
Mayo Clin Proc Innov Qual Outcomes, 2022 Oct 21;6(6):564-573.
Objective: To summarize the available evidence about the perioperative management of patients who are receiving long-term antiplatelet therapy and require elective surgery/procedures.
Methods: This systematic review supports the development of the American College of Chest Physicians guideline on the perioperative management of antiplatelet therapy. A literature search of MEDLINE, EMBASE, Scopus and Cochrane databases was conducted from each database's inception to July 16, 2020. Meta-analyses were conducted when possible.
Results: In patients receiving long-term antiplatelet therapy and undergoing elective noncardiac surgery, the available evidence did not show a significant difference in major bleeding between a shorter vs longer antiplatelet interruption, with low certainty of evidence (COE). Compared with patients who received placebo perioperatively, aspirin continuation was associated with increased risk of major bleeding (relative risk [RR], 1.31; 95% CI, 1.15-1.50; high COE) and lower risk of major thromboembolism (RR, 0.74; 95% CI, 0.58-0.94; moderate COE). During antiplatelet interruption, bridging with low-molecular-weight heparin was associated with increased risk of major bleeding compared with no bridging (RR, 1.86; 95% CI, 1.24-2.79; very low COE). Continuation of antiplatelets during minor dental and ophthalmologic procedures was not associated with a statistically significant difference in the risk of major bleeding (very low COE).
Conclusion: This systematic review summarizes the current evidence about the perioperative management of antiplatelet therapy and highlights the urgent need for further research, particularly with the increasing prevalence of patients taking 1 or more antiplatelet agents.
Holger Reinecke, Christiane Engelbertz, Rupert Bauersachs, Günter Breithardt, Hans-Herbert Echterhoff, Joachim Gerβ, Karl Georg Haeusler, Bernd Hewing, Joachim Hoyer, Sabine Juergensmeyer, Thomas Klingenheben, Guido Knapp, Lars Christian Rump, Hans Schmidt-Guertler, Christoph Wanner, Paulus Kirchhof, Dennis Goerlich
Circulation, 2022 Nov 6.
Background: Non-vitamin K oral anticoagulants (NOACs) have become the standard therapy for preventing stroke and ischemic thromboembolism in most patients with atrial fibrillation (AF). The effectiveness and safety of NOACs in patients on hemodialysis is not well known.
Methods: From June 2017 until May 2022, the investigator-initiated, prospective, randomized, open, blinded outcome assessment 'A Safety Study Assessing Oral Anticoagulation with ApiXAban versus Vitamin K-Antagonists in Patients with Atrial Fibrillation and End-Stage Kidney Disease on Chronic HemoDIAlysis Treatment' (AXADIA) trial randomized patients with AF on chronic hemodialysis to either apixaban 2.5 mg bid or the vitamin K antagonist (VKA) phenprocoumon (INR 2.0-3.0). The composite primary safety outcome was defined by a first event of major bleeding, clinically-relevant non-major bleeding, or all-cause death. The primary efficacy outcome was a composite of ischemic stroke, all-cause death, myocardial infarction, and deep vein thrombosis and/or pulmonary embolism. Our hypothesis was that apixaban is non-inferior to VKA.
Results: Thirty-nine sites randomized 97 patients (30% women, mean age 75 years, mean CHA2DS2-VASc score 4.5, baseline characteristics balanced between groups), 48 to apixaban and 49 to VKA. The median follow-up time was 429 (range 37-1,370) vs. 506 (range 101-1,379) days, respectively. Adherence to apixaban was >80% in 44 of 48 patients; the median time in therapeutic range on VKA was 50.7%. Composite primary safety outcome events occurred in 22 (45.8%) patients on apixaban and in 25 (51.0%) patients on VKA (HR 0.93, 95% CI 0.53-1.65, p(noninferiority)=0.157). Composite primary efficacy outcome events occurred in 10 (20.8%) patients on apixaban and in 15 (30.6%) patients on VKA (p=0.51, log rank). There were no significant differences regarding individual outcomes (all-cause mortality 18.8% vs. 24.5%; major bleedings 10.4% vs. 12.2%; myocardial infarctions 4.2% vs. 6.1%, respectively).
Conclusions: In this randomized trial comparing apixaban and VKA in patients with AF on hemodialysis with long follow-up, no differences were observed in safety or efficacy outcomes. Even on oral anticoagulation, patients with AF on hemodialysis remain at high risk of cardiovascular events. Larger randomized trials are needed to determine the optimal anticoagulation regimen for patients with AF on hemodialysis.
Tzu-Fei Wang, Kristen M Sanfilippo, James Douketis, Anna Falanga, John Karageorgiou, Anthony Maraveyas, Thomas L Ortel, Gerald Soff, Suresh Vedantham, Jeffrey I Zwicker
J Thromb Haemost, 2022 Dec;20(12):3026-3038.
Patients with cancer have an increased risk of thrombosis requiring anticoagulants and/or antiplatelet agents, and they can also encounter thrombocytopenia due to cancer itself or cancer therapies. They often undergo many procedures such as tissue or bone marrow biopsies, placement of central access lines, diagnostic or therapeutic draining procedures, lumbar puncture, and more. Management of antithrombotic agents or thrombocytopenia around the time of these procedures is highly variable. In this document, the Hemostasis and Malignancy Subcommittee of the International Society on Thrombosis and Haemostasis aims to provide useful practice guidance in the management of antithrombotic agents and thrombocytopenia around the time of common procedures in patients with cancer.