July 2023: New In Coagulation
by Donna Castellone, MS, MT(ASCP)S • July 17, 2023
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Brain Bleed Outcomes Improve With Bundled Care Strategy
The INTERACT3 trial demonstrated that lowering blood pressure and bundling it with other simple medical interventions resulting in clinical benefits in ICH. The trial was conducted in Brazil, Chile, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Vietnam and included 7036 patients from 121 hospitals, 36% women and 90% were Chinese with a mean age of 62. These hospitals lacked a pre-exsisting ICH specific protocol. The cause of ICH was presumed to be related to hypertension in 94.3% of people.
Improved function was seen at 12 months with 14% lower odds of worse functional outcome when compared with the usual care group. Additionally, 6 month mortality risk was observed. ICH is less common than acute ischemic stroke, brain bleeds carry a higher mortality risk.
ICH interventions included: lowering BP to a systolic target of 140mmHg or less, correction of hyperglycemia with a target of 6.1-7.8 mmol/L in those without diabetes and 7.8-10.0 mmol/L in those with diabetes, anti-fever treatment, and rapid reversal of warfarin related abnormal anticoagulation.
This child showed that treatments can be used to improve outcomes in resource limited setting.
Tenecteplase Late After Stroke Misses Endpoint: TIMELESS
This study looked at giving patients with a large vessel occlusion stroke Tenecteplase (TNK) up to 24 hours after symptoms. The results of the TIMELESS trial did not show a significant benefit, there did not appear to show a significant increase in ICH.
In those patients who were determine by perfusion imaging who were determined to have had a stroke with a small core and large amount of salvageable brain tissue were included and compared to a placebo controlled study.
This trial looked at administrating TNK in patients with ischemic stroke with large vessel occlusion between 4.5 and 24 hours. It included 458 patients randomly assigned to either TNK or placebo. The primary endpoint showed no significant difference 90 days out. No significant safety issues were observed nor was there a risk for bleeding in the TNK group. Symptomatic ICH occurred in 3.2% of TNK group versus 2.3% of the placebo group. There was a benefit seen in 227 patients with an M1 occlusion at 90 days with a subgroup analysis favorable outcome 45.9% TNK vs 31.4% for placebo. However, this was an exploratory analysis.
Limitations of this study included no information on the timing of the TNK administration, and the small size of the study.
Ticagrelor, DAPT Equal in Preventing Repeat Revascularization
A post hoc analysis of the TWILIGHT trial compared ticagrelor versus ticagrelor plus aspirin in high risk patients post PCI shows both treatments were effective in preventing revascularization after 1 year (7.1% vs 6.6% respectively). This included 6759 patients out of the original 7119 patients enrolled. This evaluation showed three issues. Repeat vascularization were due to events at the target lesion or vessel and most occurred in patients without a concomitant ACS and were essentially stable. The second finding was that these patients were at a three times greater risk for major adverse events and cerebrovascular events and last finding showed that ticagrelor on its own was as equally effective in preventing revascularization when compared to those patients who’s treatment also included aspirin. Monotherapy also reduced the rate of bleeding (3.4% vs 7.1%).
A limitation of this analysis is that the data is validated and adjusted for multiple risk factors and may not be generalizable to broader patients and high risk patients.
Cardiopathy No Basis for Choosing Anticoagulation in ESUS
The ARCADIA trial randomized 1000 patients who presented with embolic stroke of undetermined source (ESUS) who have atrial cardiopathy without overt atrial fibrillation. Anticoagulation using apixaban showed no benefit over aspirin in these patients, nor did it improve the rates of recurrent stroke or safety outcomes such as major hemorrhage and all cause mortality. The trial was stopped early.
Similar results were seen in the NAVIGATE and RE-SPECT trials in ESUS patients and may be due to heterogeneous underlying etiologies and may require different types of antithrombotic therapy to prevent recurrence. One etiology may be atrial cardiopathy.
ARCADIA looked at patients 45 and older (n=105) from 185 sites, mean age 68, 54% female. It was conducted in the US and Canada with a clinical diagnosis of stroke with consensus criteria for ESUS who also ruled out hemorrhagic stroke and had atrial cardiopathy. Patients were randomly assigned to apixaban 5 mg or 2.5 mg twice daily plus aspirin placebo, or apixaban placebo plus aspirin 81 mg daily.
Recurrent stroke occurred in 4.4% of patients treated with apixaban and aspirin. No significant difference was seen in secondary outcomes of recurrent ischemic stroke or systemic embolism (4.1 vs 4.4%) as well as recurrent stroke of any type and death from any cause (7.3 vs 6.8%). When safety was evaluated the rates of major hemorrhage were low (0.7 vs 0.8%). An increase was seen in ICH in patients treated with aspirin (1.1 vs 0%).
ANDEXXA Phase IV trial stopped early after achieving pre-specified criteria on hemostatic efficacy versus usual care
Andexanet alfa (ANDEXXA) is used in patients on oral FXa inhibitors (apixaban and rivaroxaban) was a Phase IV trial to evaluate the efficacy and treatment in patients with ICH. ANDEXXA is specifically designed to rapidly reverse the anticoagulation effects of direct oral FXa inhibitors due to life-threatening or uncontrolled bleeding. The treatment has been granted accelerated approval in the US and is conditionally approved in the EU. The decision was to stop the trial early was made by the independent Data and Safety Monitoring Board (DSMB) because it achieved pre-specified stopping criteria of superior hemostatic efficacy which included the ability to limit the expansion of a potentially life threatening bleed when compared to usual care. The decision was made after an interim assessment was made of 450 patients who demonstrated ANDEXXA's reversal benefit.
Regulatory filings will now be initiated to convert for full label approval in the US and EU.
Prehospital Tranexamic Acid Won't Stave Off Disability After Severe Trauma
Six month outcomes were looked at in patients in advanced trauma, when tranexamic acid (TXA) initiated prior to hospital admission in the PATCH-Trauma trial. TXA is an antifibrinolytic drug FDA approved for heavy menstrual bleeding an short term prevention in hemophilia patients. It is used off label to improve clotting in trauma and surgery. Results were similar in patients who received tranexamic acid (53.7%) versus placebo (53.5%). A small positive effect was seen in the tranexamic group prior to the 6 months this included mortality at 28 days: 17.3% vs 21.8% and mortality at 6 months: 19% vs 22.9%.
In trauma the use of TXA is supported by the CRASH-2 trial which reduced 28 day mortality in patients with suspected bleeding when it was administrated 3 hours after injury. While CRASH-3 showed that TXA reduced mortality in mild to moderate traumatic brain injury but not in severe injury. However, both trials were conducted in countries lacking organized region wide systems of trauma care and no difference was seen in hospitals that had advanced trauma systems.
PATCH-Trauma also looks at trauma investigation beyond survival alone. The trial had 15 emergency medical services and 21 hospitals in Australia, New Zealand and Germany from 2014-2021. Patients were eligible if the first dose of TXA could be administered within 3 hours after injury. There were 1310 trauma patients (mean age 44 and 70% men) split into patients receiving TXA or matched placebo.
There were no increase in DVT seen, however vascular occlusive events were higher in the TXA group (23.6-19.7%). While other serious adverse events were comparable between groups.
Daily Low-Dose Aspirin Upped Incidence of Anemia in Older Adults
A secondary analysis of the ASPREE trial showed that daily low dose aspirin increased incident anemia in otherwise healthy older adults. The incidence of anemia increased with age, up to 17% in patients over 65.
The post-hoc analysis in the US and Australia, randomly assigned 19,114 participants ages 70 and older, or 65 for Black and Hispanic adults, 56% were women and 93% were white. Over 4.7 years, the incidence of anemia was 51.2 events per 1000 person years in the aspirin group versus 42.9 events in the placebo group. The probability of those having anemia within 5 years was 23.5% in patients on aspirin versus 20.3% on placebo. A decrease of 3.6 g/L in hemoglobin was seen in the placebo group with a 0.4 g/L lower baseline in the aspirin group. Ferritin levels less than 45 mg/L were seen in the aspirin group at year 3. A significant bleed was seen in 3% of the aspirin group versus 2.1% of those in the placebo group. The ASPREE trial showed associations between use of low dose aspirin and increases in overall mortality and deaths from cancer in the elderly.
This supports the restriction of low dose aspirin in those with an evidence based indication. The US Preventive Services Task Force recommends against low dose aspirin for primary prevention in adults 60 years and older.
Clot Risk More Common in Survivors of Severe COVID Versus Flu
When compared with patients presenting with influenza and sepsis in 380,000 patients there was one difference seen in patients hospitalized with COVID-19. These patients showed and increased risk of VTE at one year. There were no other increased risk of selected ischemic and non-ischemic cerebrovascular and cardiovascular disorders, neurological disorders, RA or mental health conditions. It is important to note that a higher proportion of patients hospitalized for COVID-19 died during hospitalization as compared to those with influenza or sepsis which may explain the lower risk of outcomes in these patients.
The study included all adults hospitalized for COVID from April 2020- October 2021 (n=26,499) and were compared to those hospitalized with sepsis or influenze (N=299,989) in Canada. There was also a comparator group for hospitalized for sepsis in Ontario (n=52,878). The cohort had a median age of 75, and 54% were women, with those in the COVID group had a median age of 61, with 46% women, only 7% of the COVID group were fully or partially vaccinated.
JOURNAL CLUB
COVID-19-Related Adrenal Haemorrhage
Multicentre UK Experience and Systematic Review of the Literature
Yasir S. Elhassan; Fizzah Iqbal; Wiebke Arlt; Stephanie E. Baldeweg; Miles Levy; Paul M. Stewart; John Wass; Sue Pavord; D. Aled Rees; Cristina L. Ronchi
Clin Endocrinol. 2023;98(6):766-778.
Abstract
Objective: Adrenal haemorrhage (AH) is an uncommon, usually incidental imaging finding in acutely unwell patients. AH has been reported during coronavirus disease 2019 (COVID-19) infection and following ChAdOx1 nCoV-19 (Oxford-AstraZeneca) vaccination. The Society for Endocrinology (SfE) established a task force to describe the UK experience of COVID-19-related AH.
Design: A systematic literature review was undertaken. A survey was conducted through the SfE clinical membership to identify patients with COVID-19-related AH using a standardized data collection tool.
Results: The literature search yielded 25 cases of COVID-19-related AH (19 bilateral; 13 infection-related, and 12 vaccine-related). Eight UK centres responded to the survey with at least one case. A total of 18 cases were included in the descriptive study, including 11 from the survey and 7 UK-based patients from the systematic review. Seven patients (4 males; median age 53 (range 26–70) years), had infection-related AH (four bilateral). Median time from positive COVID-19 test to AH detection was 8 (range 1–30) days. Eleven cases of vaccine-related AH (eight bilateral) were captured (3 males; median age 47 (range 23–78) years). Median time between vaccination (nine Oxford-AstraZeneca and two Pfizer- BioNTech) and AH was 9 (range 2–27) days; 9/11 AH occurred after the first vaccine dose. Acute abdominal pain was the commonest presentation (72%) in AH of any cause. All 12 patients with bilateral AH and one patient with unilateral AH required glucocorticoid replacement.
Conclusion: Adrenal haemorrhage with consequential adrenal insufficiency can be a complication of COVID- 19 infection and vaccination. Adrenal function assessment is mandatory to avoid the potentially fatal consequences of unrecognized adrenal insufficiency.
Quantitative Risk for Single Positive Lupus Anticoagulant
Results With Different Anticoagulants
Waleed Khan; Christopher A. Tormey, MD; Henry M. Rinder, MD; Alexa J. Siddon, MD
Am J Clin Pathol. 2023;159(5):417-419.
Abstract
Objectives: Clinical experts recommend against testing for lupus anticoagulant (LAC) during anticoagulation. Methods: We quantitated the risk of a single-positive dilute Russell viper venom time (dRVVT) result or partial thromboplastin time–based phospholipid neutralization (PN) result on anticoagulation.
Results: Any anticoagulation led to a fourfold greater likelihood of single-positive results, primarily by rivaroxaban (odds ratio [OR] = 8.6) and warfarin (OR = 6.6), resulting in a positive dRVVT test with a normal PN test. Heparin and apixaban were twofold more likely to show single-positive results, but enoxaparin did not show significant single positivity.
Conclusions: Our results quantitatively support experts' avoidance of LAC testing during anticoagulation.
Vitamin E-induced Coagulopathy in a Young Patient
A Case Report
Ritika Abrol; Reshma Kaushik; Deepak Goel; Sonu Sama; Rajeev Mohan Kaushik; Mansi Kala
J Med Case Reports. 2023;17(107)
Abstract
Background: High-dose vitamin E intake is known to inhibit vitamin K-derived coagulation factor synthesis, which can cause serious bleeding events such as gastrointestinal bleeding and intracranial hemorrhage. We report a case of coagulopathy induced by marginally increased levels of vitamin E.
Case Presentation: A 31-year-old Indian man presented with oral bleeding, black tarry stools, and bruising over his back. He had been taking non-steroidal anti-inflammatory drugs for low backache and vitamin E for hair loss. He had mild anemia with normal platelet count, thrombin time, and prolonged bleeding time, activated partial thromboplastin time, and prothrombin time. Serum fibrinogen was slightly raised. Mixing studies with pooled normal plasma, aged plasma, and adsorbed plasma were suggestive of deficiency of multiple coagulation factors due to acquired vitamin K deficiency. Serum phylloquinone was normal, while prothrombin induced by vitamin K absence-II level was increased. Serum alpha- tocopherol was slightly raised. Upper gastrointestinal endoscopy showed multiple gastroduodenal erosions. A final diagnosis of vitamin E toxicity-related coagulopathy was made. The patient responded well to pantoprazole, vitamin K supplementation, multiple fresh frozen plasma transfusions, and other supportive treatments besides the discontinuation of vitamin E supplementation. The coagulation parameters normalized, and the patient was discharged with complete resolution of symptoms and remained asymptomatic during the follow-up for 6 months.
Conclusions: Vitamin E-related inhibition of vitamin K-dependent factors with coagulopathy may occur even at marginally increased levels of serum vitamin E. This risk becomes significant in patients receiving other drugs that may increase the risk of bleeding.
Cost Effectiveness of Strategies to Manage Atrial Fibrillation in Middle- and High-Income Countries: A Systematic Review
Charles Okafor, Joshua Byrnes, Simon Stewart, Paul Scuffham, Clifford Afoakwah
Pharmacoeconomics 2023 May 19.
Abstract
Background: Atrial fibrillation (AF) remains the most common form of cardiac arrhythmia. Management of AF aims to reduce the risk of stroke, heart failure and premature mortality via rate or rhythm control. This study aimed to review the literature on the cost effectiveness of treatment strategies to manage AF among adults living in low-, middle- and high-income countries.
Methods: We searched MEDLINE (OvidSp), Embase, Web of Science, Cochrane Library, EconLit and Google Scholar for relevant studies between September 2022 and November 2022. The search strategy involved medical subject headings or related text words. Data management and selection was performed using EndNote library. The titles and abstracts were screened followed by eligibility assessment of full texts. Selection, assessment of the risk of bias within the studies, and data extraction were conducted by two independent reviewers. The cost-effectiveness results were synthesised narratively. The analysis was performed using Microsoft Excel 365. The incremental cost effectiveness ratio for each study was adjusted to 2021 USD values.
Results: Fifty studies were included in the analysis after selection and risk of bias assessment. In high- income countries, apixaban was predominantly cost effective for stroke prevention in patients at low and moderate risk of stroke, while left atrial appendage closure (LAAC) was cost effective in patients at high risk of stroke. Propranolol was the cost-effective choice for rate control, while catheter ablation and the convergent procedure were cost-effective strategies in patients with paroxysmal and persistent AF, respectively. Among the anti-arrhythmic drugs, sotalol was the cost-effective strategy for rhythm control. In middle-income countries, apixaban was the cost-effective choice for stroke prevention in patients at low and moderate risk of stroke while high-dose edoxaban was cost effective in patients at high risk of stroke. Radiofrequency catheter ablation was the cost-effective option in rhythm control. No data were available for low-income countries.
Conclusion: This systematic review has shown that there are several cost-effective strategies to manage AF in different resource settings. However, the decision to use any strategy should be guided by objective clinical and economic evidence supported by sound clinical judgement.
Bleeding related to oral anticoagulants: Trends in US emergency department visits, 2016- 2020
Andrew I Geller, Nadine Shehab, Maribeth C Lovegrove, Nina J Weidle, Daniel S Budnitz
Thromb Res, 2023 May;225:110-115.
Abstract
Background: Clinical trials suggest lower rates of major bleeding with direct-acting oral anticoagulants (DOACs) than with warfarin, but anticoagulant-related bleeding remains one of the most common outpatient adverse drug events.
Methods: We estimated the number of emergency department (ED) visits and subsequent hospitalizations for oral anticoagulant-related bleeding in 2016-2020 based on active surveillance in a nationally representative, size-stratified probability sample of 60 U.S. hospitals. We estimated rates of ED visits using a nationally-projected retail prescription dispensing database.
Results: Based on 19,557 cases, oral anticoagulant-related bleeding resulted in an estimated 1,270,259 (95 % Confidence Interval [CI], 644,686-1,895,832) ED visits for the five years 2016-2020, of which 47.8 % (95 % CI, 40.6 %- 55.0 %) resulted in hospitalization. Oral anticoagulant-related bleeding resulted in an estimated 230,163 (95% CI, 109,598 -350,728) ED visits in 2016 and 301,433 (95% CI, 138,363-464,503) in 2020. During 2016-2020, ED visits for DOAC- related bleeding increased by an average of 27.9 % (95 % CI, 24.0 %-32.0 %; p < .001) per year, while ED visits for warfarin-related bleeding decreased by an average of 8.8 % (95 % CI, -10.7 % to -7.0 %; p = .001) per year. The estimated rate of bleeding visits per 100 patients dispensed oral anticoagulants at least once in 2016-2020 was highest for patients aged ≥ 80 years (13.1; 95 % CI, 6.2-20.0) and lowest for those aged <45 years (4.0; 95 % CI, 2.6-5.5); it was 5.9 visits per 100 patients dispensed DOACs [95 % CI, 2.5-9.2] and 13.0 visits per 100 patients dispensed warfarin [95 % CI, 7.4-18.7].
Conclusions: Although the rates of ED visits for anticoagulant-related bleeding may be lower for DOACs than for warfarin, persistently large numbers of patients requiring ED visits for anticoagulant-related bleeding despite increased use of DOACs and declining use of warfarin suggest that efforts to improve appropriate prescribing and monitoring of anticoagulants remain important.
Pharmacist Practice Patterns Regarding Direct Oral Anticoagulants for Treatment of Venous Thromboembolism
David M Kaylor, Andrew J Johnson, Sarah L Berardi, Vanessa M VanArsdale, Meredith H Niemann
Hosp Pharm 2023 Apr;58(2):200-204.
Abstract
Background: Direct oral anticoagulants (DOACs) are increasingly prescribed for the treatment of venous thromboembolism (VTE). However, little is known regarding pharmacists' practice patterns and preferences in clinical areas of contention, such as initiation dosing, obesity, and renal impairment.
Objective: To determine pharmacist trends in practice regarding DOACs for the treatment of VTE overall and within areas of clinical controversy.
Methods: An electronic survey was distributed to pharmacists in the United States through national and state pharmacy organizations. Responses were collected for 30 days.
Results: One hundred fifty-three complete responses were submitted. The majority of pharmacists preferred apixaban (90.2%) for the oral treatment of venous thromboembolism. When initiating apixaban or rivaroxaban for a new VTE, 76% and 64% of pharmacists surveyed, respectively, state the duration of the initiation dose phases are reduced if the patient received parenteral anticoagulation. Fifty-eight percent of pharmacists used body mass index to evaluate the appropriateness of DOACs in obese patients whereas 42% used total body weight. Preference for rivaroxaban (31.4%) was higher in this population compared to the global population (10%). Apixaban was preferred for patients with renal impairment (92.2%). However, as creatinine clearance as calculated by the Cockcroft-Gault equation (CrCl) reduced to <15 milliliters/minute (mL/min), preference for warfarin increased (36%).
Conclusion: This national survey of pharmacists demonstrated an overall preference for apixaban and significant variability in practice patterns regarding DOACs for patients with new VTE, patients with obesity, and patients with renal impairment. Further research is warranted to evaluate the efficacy and safety of DOAC initiation dosing phase modifications. Prospective evaluations of DOACs in obese and renal dysfunction populations would confirm the safety and efficacy of DOACs in these populations.
Updated guidance for efficacy and safety outcomes for clinical trials in venous thromboembolism in children: communication from the ISTH SSC Subcommittee on Pediatric and Neonatal Thrombosis and Hemostasis
Hilary Whitworth, Ernest K Amankwah, Marisol Betensky, Lana A Castellucci, Adam Cuker, Neil A Goldenberg, Christoph Male, Elliot Rinzler, Ayesha Zia, Leslie Raffini
J Thromb Haemost, 2023 Jun;21(6):1666-1673.
Abstract
Despite the growing number of pediatric antithrombotic clinical trials, standardized safety and efficacy outcome definitions for pediatric venous thromboembolism (VTE) clinical trials have not been updated since 2011. Many recent trials have adapted the recommended definitions, leading to heterogeneity in outcomes and limiting our ability to compare studies. The International Society on Thrombosis and Haemostasis Scientific and Standardization Subcommittee (SSC) on Pediatric and Neonatal Thrombosis and Hemostasis organized a Task Force to update the efficacy and safety outcome definitions for pediatric VTE clinical trials. The outcome definitions used in the recent pediatric antithrombotic trials, definitions recommended for adult studies, and regulatory guidelines were summarized and reviewed by the Task Force as the basis for this updated guidance. Major updates to the efficacy outcomes include the removal of VTE-related mortality as a part of a composite primary outcome and explicit inclusion of all deep venous anatomic sites. Safety outcomes were updated to include a new bleeding severity category: patient important bleeding, no intervention, which encompasses bleeding for which a patient seeks care but there is no change in management. Menstrual bleeding can now be included in any bleeding category when the criteria are met. We hope that these updated outcome definitions will allow the investigators to focus on clinically relevant and patient-important outcomes and provide standardization to facilitate continued high-quality evidence for the use of antithrombotic therapies in children.
Risk for Incident VTE Increased in Adults With Atopic Dermatitis
TOPLINE: Atopic dermatitis (AD) in adulthood appears to be associated with an increased risk for incident venous thromboembolism (VTE).
METHODOLOGY:
- In a cohort analysis, researchers drew from Taiwan's National Health Insurance Research Database to identify 142,429 adults with AD newly diagnosed between 2003 and 2017 and 142,429 matched controls.
- AD patients were subgrouped based on severity of their disease
- Researchers used a Cox regression model to estimate hazard ratios (HRs) for VTE.
- Stratified analyses according to age and sex were performed.
TAKEAWAY:
- Adults with AD had an increased risk for incident VTE (HR, 1.28) compared with adults without AD, although the absolute difference in risk appeared to be small.
- Individual outcome analyses revealed that AD was associated with elevated hazards for deep vein thrombosis (HR, 1.26) and pulmonary embolism (HR, 1.30).
- In a sensitivity analysis that excluded systemic steroid users, the risk for VTE remained significantly increased among patients with AD (HR, 1.45).
IN PRACTICE: This study is too preliminary to have practice application. Because of the study's limitations, "findings should be interpreted cautiously," the researchers write.
LIMITATIONS: The study used a claims database that lacked data on specific VTE risk factors, and ascertainment of AD and VTE was based on ICD codes.
Aspirin vs Clopidogrel for Long-term Maintenance After Coronary Stenting in Patients With Diabetes - A Post Hoc Analysis of the HOST-EXAM Trial
Tae-Min Rhee, MD; Jang-Whan Bae, MD; Kyung Woo Park, MD; et alSeung-Woon Rha, MD; Jeehoon Kang, MD; Heesun Lee, MD; Han-Mo Yang, MD; Soo-Heon Kwak; In-Ho Chae, MD; Won-Yong Shin, MD; Dae-Kyeong Kim, MD; Ju Hyeon Oh, MD; Myung Ho Jeong, MD; Yong Hoon Kim, MD; Nam Ho Lee, MD; Seung-Ho Hur, MD; Junghan Yoon, MD; Jung-Kyu Han, MD; Eun-Seok Shin, MD; Bon-Kwon Koo, MD; Hyo-Soo Kim, MD; for the HOST-EXAM Investigators
Abstract
Importance: Selecting the optimal antiplatelet agent in patients who have received percutaneous coronary intervention is especially important in those with diabetes due to the heightened risk of ischemic events in this population. Studies on the efficacy and safety of clopidogrel vs aspirin for long-term maintenance after percutaneous coronary intervention in patients with diabetes are lacking.
Objective: To investigate cardiovascular outcomes with clopidogrel vs aspirin in patients with and without diabetes.
Design, Setting, and Participants: This was a post hoc analysis of the HOST-EXAM randomized clinical trial, an investigator-initiated, prospective, randomized, open-label, multicenter trial performed at 37 centers in Korea. Patients who received dual antiplatelet therapy without clinical events for 6 to 18 months after percutaneous coronary intervention with drug-eluting stents were enrolled from March 2014 to May 2018 with follow-up at 6, 12, 18, and 24 months. All 5438 patients in the original trial were included in this analysis, which was conducted from June to October 2021.
Interventions and Exposures: Enrolled patients were randomized 1:1 to clopidogrel or aspirin monotherapy. Subgroup analyses were performed by the presence of diabetes.
Main Outcomes and Measures: The main outcome was primary composite end point of all-cause death, nonfatal myocardial infarction, stroke, readmission due to acute coronary syndrome, and major bleeding (Bleeding Academic Research Consortium type 3 or 5) at 24-month follow-up.
Results: Of 5438 patients (mean [SD] age, 63.5 [10.7] years; 1384 [25.5%] female), 1860 (34.2%) had diabetes (925 in the clopidogrel arm and 935 in the aspirin arm), and 5338 (98.2%) completed follow-up. The rate of the primary composite end point was significantly lower in the clopidogrel group compared to the aspirin group in patients with diabetes (6.3% vs 9.2%; hazard ratio [HR], 0.69; 95% CI, 0.49-0.96;
Conclusion and Relevance In this study, clopidogrel monotherapy was associated with a lower rate of the primary composite end point compared to aspirin monotherapy as long-term maintenance therapy after dual antiplatelet therapy for coronary stenting in both patients with and without diabetes. Clopidogrel might thus be considered rather than aspirin in patients who have undergone coronary stenting and successfully completed dual antiplatelet therapy, regardless of diabetes status.
Reversal and Removal of Oral Antithrombotic Drugs in Patients With Active or Perceived Imminent Bleeding
Davide Cao; Nicolas Amabile; Mauro Chiarito; Victoria T. Lee; Dominick J. Angiolillo; Davide Capodanno; Deepak L. Bhatt; Michael J. Mack; Robert F. Storey; Michael Schmoeckel; C. Michael Gibson; Efthymios N. Deliargyris; Roxana Mehran
Eur Heart J. 2023;44(20):1780-1794.
Abstract
In case of ongoing major bleeding, rapid and effective restoration of normal hemostatic functions with reversal agents on top of standard supportive measures may be required to successfully stop the bleeding. When major bleeding risk can be anticipated (e.g. due to the need for urgent invasive surgical procedures), antithrombotic drug removal and some reversal strategies may be considered before proceeding to surgery to mitigate perioperative bleeding risk. Bold text indicates reversal agents, parentheses indicate antithrombotic drugs that are reversed. Ab, antibody; DOACs, direct oral anticoagulants; VKA, vitamin K antagonists.
Remarkable progress has been made in the pharmacological management of patients with cardiovascular disease, including the frequent use of antithrombotic agents. Nonetheless, bleeding complications remain frequent and potentially life-threatening. Therapeutic interventions relying on prompt antithrombotic drug reversal or removal have been developed to assist clinicians in treating patients with active bleeding or an imminent threat of major bleeding due to urgent surgery or invasive procedures. Early phase studies on these novel strategies have shown promising results using surrogate pharmacodynamic endpoints. However, the benefit of reversing/removing antiplatelet or anticoagulant drugs should always be weighed against the possible prothrombotic effects associated with withdrawal of antithrombotic protection, bleeding, and surgical trauma. Understanding the ischemic-bleeding risk tradeoff of antithrombotic drug reversal and removal strategies in the context of urgent high-risk settings requires dedicated clinical investigations, but challenges in trial design remain, with relevant practical, financial, and ethical implications.