by Donna Castellone, MS, MT (ASCP) SH •
August 10, 2021
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.
To Master Stroke Thrombectomy, It Takes Way More Than 50 Cases
Competency a "touchy subject" for training programs, trainees, and new graduates
At seven French centers it was found that interventional neuroradiologist demonstrated better performance metrics with increased experience with thrombectomy. Skills were improved up to around their 80-100th procedure post training. Training guidelines state trainees should perform 50 EVT procedures before performing alone. However, this can take years to accumulate. It was found that in 2016 fewer than 12 stroke thrombectomies were performed by operators.
Procedural time: increasing individual experience was independently associated with shorter procedure durations. Recanalization status: increasing experience was independently associated with better Thrombolysis in Cerebral Infarction scores. First-pass recanalization: there was no effect of operator experience on first-pass complete reperfusion. Complications: operator experience made no difference in the rates of perforation or arterial dissection.
EVT treatment will continue to grow and evolve and the volume relationship may change with new technologies and approaches. In a retrospective analysis of 26 operators, there were 4516 procedures performed from 2015-2020. Boulouis and colleagues performed a retrospective analysis of individual thrombectomy procedural data for 36 operators, 4012 procedures with sufficient operator data were included in the analysis with a median of 97.5 procedures per operators. Results of this study demonstrate the importance of expertise in stroke care.
Stroke Thrombectomy: Removing Clot on First Attempt Is Key
A single attempt for clot retrieval in patients with acute ischemic stroke has the best outcome. When multiple attempts at clot retrieval were performed they were associated with an increase in emboli to new territory and greater infarct growth.
Stroke data was looked at for 419 patients treated with mechanical thrombectomy. It was demonstrated that symptomatic ICH rates increased with the number of clot retrieval attempts ranging from 5.8% after one attempt with up to a 10% rate when there are four or more attempts. However, successful recanalization despite multiple attempts is better than no recanalization. The study showed that 45% of people who had up to third attempts still had a favorable outcome. Favorable outcomes were achieved among 62% of those needing just one attempt, vs 55% among those needing two attempts, 49% of those requiring three attempts, and 42% of those requiring four or more attempts. Migration of emboli to a new territory correlated to the number of attempts with it at 1% after one try and up to 28.2% when there were four or more attempts.
There are no guidelines on the limit of attempts prior to changing strategy and a randomized trial is needed to address this issue and define the best strategy after the first attempt fails.
How Much Thrombotic Risk Is OK for Novel CKD Anemia Drug?
Roxadustat (FibroGen) a chronic kidney disease (CKD) related anemia drug used in patients on and off dialysis will be reviewed for safety by the FDA. If approved it would be the first in class oral anemia treatment. Current available options for anemia include iron, erythropoiesis stimulating agents and RBC transfusions. Roxadustat works as a reversible inhibitor of hypoxia inducible factor prolyl hydroxylases. Roxadustat already demonstrated efficacy in six phase III studies, three in a non-dialysis dependent population and another three in a dialysis-dependent population.
The principle issue is the drug’s safety in regards to thrombotic events. When compared to placebo, Roxadustat showed an estimated risk difference for serious thrombotic events of 1.1 events/100 patient years with a relative risk of 1.45 and driven by risks for myocardial infarction and stroke. DVT and PE weren't as common. In the non-dialysis population, the risk for a major adverse cardiovascular event (MACE) including MI, stroke, or all-cause mortality was comparable to placebo, but a slight increase was seen in a window of 7 days post treatment driven by all cause death. While the dialysis group had comparable MACE profile to darbepoetin alfa. Other notable adverse events included seizures, acute kidney injury, hyperkalemia, fracture, gastrointestinal hemorrhage, and hyponatremia.
However, not all of these risks are unique to roxadustat, as ESAs are also known to carry an increased risk of death, MI, stroke, congestive heart failure, thrombosis of vascular access, as well as other thrombotic events.
To offset some of the increased thrombotic risk, the FDA suggested less aggressive dosing schemes such as starting at lower doses, smaller dose increments during titration and lower hemoglobin targets. These strategies haven't been proven effective in a clinical trial setting.
Genotype-Based Strategy Reduces Thrombotic Events After Watchman Implant
A CYP2C19 loss of function polymorphism can contribute to a variation in clopidogrel metabolism. In patients using a Watchman heart device with this genetic predisposition the use of aspirin and a half dose of a DOAC significantly reduced device-related thrombosis (DRT) as well as thrombotic events when compared with DAPT.
When 758 patients were evaluated for DRT after implantation with a Watchman device they were compared between patients who were genotyped (n=401) versus those not genotyped (n=357) and receiving DAPT. Of the 401 patients 25.7% had reduced metabolism of clopidogrel, of those 98 were given aspirin plus half dose of DOAC. Only 1 DRT was observed versus seven patients who did not undergo genetic testing. Bleeding rates between the two groups were not significantly different between the two groups, as well as all-cause mortality or cardiovascular mortality.
Is Aspirin Overused in Older Patients With Diabetes?
It was previously advised for millions of adults over the age of 70 to take aspirin for primary prevention, however that has changed in particular in patients with diabetes at a low risk of CVD. A cross sectional study looked at aspirin use in primary and secondary prevention of CVD in adults > 60 years of age for primary prevention without bleeding. Older people with diabetes were found to be two times more likely to use aspirin for primary prevention as those without diabetes. More than 20% of individuals with low cardiovascular risk use daily aspirin, with up to 50% in people over 80. These rates of aspirin utilization is poorly justified and maybe causing more harm than good.
Guidelines from the American Diabetes Association and ACA were changed based on evidence from the ASCEND, ASPREE and ARRIVE trials. As a result, both organization discourage the use of aspirin for primary prevention in people over 70 years with or without diabetes. Overall, aspirin use — for primary or secondary prevention — in older US adults was 46.7%. For those with diabetes it was 61.7%, compared to 42.2% in those without diabetes. These findings are from data on preventive aspirin in 7103 adults over age of 60.
Ticagrelor Beneficial for Moderate Stroke: New THALES Analysis
The results of the THALES trial demonstrated that when ticagrelor with aspirin versus aspirin alone reduced vascular events with a small increase in bleeding risk in the overall population. An exploratory analysis looked at whether ticagrelor also benefits moderate as well as minor stroke patients. Results showed that both cohorts of stroke patients benefited from ticagrelor plus aspirin. The study included 9983 patients of which 3312 patients had moderate stroke and 6671 had minor stroke. Patients received a loading dose of 180mg of ticagrelor, followed by 90 mg twice daily on days 2-30, with placebo within 24 hours. All patients received aspirin on day one (300-325 mg) followed by 75-100mg day 2-30.
Bleeding has always been a concern when using dual platelet antitherapy, however this current analysis showed that there was no difference in efficacy or risk of bleeding between the higher and lower risk patients. The observed primary outcome event rate for patients with moderate stroke was 7.6% for those in the ticagrelor group and 9.1% for those in the placebo group. The primary outcome event rate for patients with less severe stroke was 4.7% for those in the ticagrelor group and 5.7% for those in the placebo group. Severe bleeding occurred in eight patients (0.5%) in the ticagrelor group and in four patients (0.2%) in the placebo group among those with moderate stroke, compared with 16 patients (0.5%) and three patients (0.1%), respectively, among those with minor severe stroke.
At present, dual antiplatelet therapy is not recommended for patients with larger infarction because of concerns with bleeding.
Intensive BP-Lowering for ICH Potentially Deadly in Chronic Kidney Disease
The ATACH-2 trial which included 1000 participants showed patients with an eGFR that pointed toward kidney dysfunction were at a higher risk for death and disability after an ICH versus those with a normal eGRF. In patients with mild to moderate loss of kidney function undergoing intensive blood pressure reduction for ICH the odds of death or disability was more than three times greater versus those using standard blood pressure reduction.
In patients who experience a stroke, chronic kidney disease (CKD) is common and associated with worse outcomes. Although intensive blood-pressure lowering is a common treatment for ICH, this approach has raised concerns in the setting of CKD. The INTERACT2 trial suggests intensive blood pressure lowering provided slightly greater benefits than standard lowering among patients with ICH. But in the original ATACH-2 trial intensive BP lowering didn't improve functional outcomes of ICH but did increase the risk for renal adverse events.
A post hoc analysis of data from the ATACH-2 trial included 974 patients with ICH of less than 60 mL and systolic blood pressure (SBP) of greater than 180 mm Hg. They were randomly assigned within 4.5 hours of ICH to intensive or standard BP lowering with a target of 110 to 139 mmHg for the intensive group and 140 to 179 mm Hg for the standard group. There were 46% of the population that had the highest eGFR, 37% in the middle group and 16% with the lowest eGFR. The primary endpoint was death or severe disability at 90 days. Patients with a decreased eGFR were older, likely to have hypertension, dyslipidemia, AF or diabetes. Renal function was linked to outcomes of ICH, and rate of death or disability was 49.7% in the lowest eGFR category, 40% in the middle category and 31.7% in the highest category. The odds ratio in the lowest eGFR category was as high as 2.02 when compared with those in the highest category.
The findings in this study show a significant interaction between intensive BP lowering and poor function recovery shown in the current study raises caution in the intensity of treatment in this subgroup of patients.
Lower Post-TAVR Mortality Seen on DOAC vs VKA When OAC Indicated
Based on data from a large multicenter registry of more than 24,000 patients it was noted that following a transcatheter aortic valve replacement (TAVR), direct oral anticoagulants (DOACs) are preferable to vitamin K antagonists (VKAs) in patients who are candidates for oral anticoagulants. The primary endpoint of mortality at 3 years was 35.6% for VKA and 31.2% with DOAC, resulting in a 37% greater hazard ratio for death in those treated with VKA. The rate of major bleeding was also higher 12.3% VKA vs 8.4% DOAC as well as the rates for ischemic stroke, ACS and hemorrhage stroke were all higher in VKA patients but not statistically significant.
There is also concern about the risks and benefits of oral anticoagulation in TAVR patients. These patients are elderly and at a higher risk for bleeding with anticoagulation making it a concern in this population.
Ticagrelor or Prasugrel for Patients With Acute Coronary Syndrome Treated With Percutaneous Coronary Intervention
A Prespecified Subgroup Analysis of a Randomized Clinical Trial
J. J. Coughlan, MB, BCh1,2; Alp Aytekin, MD1; Shqipdona Lahu, MD1; et al
Importance It is unclear whether ticagrelor or prasugrel hydrochloride is superior for patients with acute coronary syndrome (ACS) treated with percutaneous coronary intervention (PCI).
Objective To assess the safety and efficacy of ticagrelor vs prasugrel for patients with ACS treated with PCI.
Design, Setting, and Participants A prespecified analysis was performed of a postrandomization subgroup of 3377 patients who presented with ACS and were treated with PCI in the investigator-initiated, multicenter, phase 4, open-label Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 5 randomized clinical trial, conducted from September 1, 2013, to February 28, 2018. Statistical analysis was performed from September 1, 2020, to January 30, 2021. Analysis was performed according to the intention-to-treat principle.
Interventions Patients were randomly assigned to a ticagrelor-based or prasugrel-based strategy. This analysis focuses on the subgroup of patients who underwent PCI that was formed after randomization.
Main Outcomes and Measures The primary end point was a composite consisting of all-cause death, myocardial infarction, or stroke at 12 months. The safety end point was Bleeding Academic Research Consortium (BARC) type 3 to 5 bleeding.
Results The ticagrelor group comprised 1676 patients (1323 men [78.9%]; mean [SD] age, 64.4 [12.0] years), and the prasugrel group comprised 1701 patients (1341 men [78.8%]; mean [SD] age, 64.7 [12.0] years). The primary end point occurred for 162 patients (9.8%) in the ticagrelor group and 120 patients (7.1%) in the prasugrel group (hazard ratio [HR], 1.41; 95% CI, 1.11-1.78; P =.005). Myocardial infarction occurred in 88 patients (5.3%) in the ticagrelor group compared with 55 patients (3.8%) in the prasugrel group (HR, 1.67; 95% CI, 1.19-2.34; P =.003). The safety end point, BARC type 3 to 5 bleeding, occurred in 84 of 1672 patients (5.3%) in the ticagrelor group and 78 of 1680 patients (4.9%) in the prasugrel group (HR; 1.10; 95% CI, 0.81-1.50; P =.54).
Conclusions and Relevance Among patients presenting with ACS who were treated with PCI, the incidence of the primary composite end point occurred less frequently for patients who received prasugrel compared with those who received ticagrelor. The incidence of bleeding events was comparable between the 2 groups. These results suggest that, for patients presenting with ACS who undergo PCI, a prasugrel-based strategy is superior to a ticagrelor-based strategy. However, because these observations are based on a postrandomization subgroup, these findings should be regarded as hypothesis generating and dedicated randomized clinical trials may be warranted to confirm these findings.
Efficacy and Safety of Revacept, a Novel Lesion-Directed Competitive Antagonist to Platelet Glycoprotein VI, in Patients Undergoing Elective Percutaneous Coronary Intervention for Stable Ischemic Heart Disease
The Randomized, Double-blind, Placebo-Controlled ISAR-PLASTER Phase 2 Trial
Katharina Mayer, MD1; Ralph Hein-Rothweiler, MD2; Stefanie Schüpke, MD1,3; et alMarion Janisch, MD1; Isabell Bernlochner, MD3,4; Gjin Ndrepepa, MD1; et al
Importance The assessment of new antithrombotic agents with a favorable safety profile is clinically relevant.
Objective To test the efficacy and safety of revacept, a novel, lesion-directed antithrombotic drug, acting as a competitive antagonist to platelet glycoprotein VI.
Design, Setting, and Participants A phase 2 randomized clinical trial; patients were enrolled from 9 centers in Germany from November 20, 2017, to February 27, 2020; follow-up ended on March 27, 2020. The study included patients with stable ischemic heart disease (SIHD) undergoing elective percutaneous coronary intervention (PCI).
Interventions Single intravenous infusion of revacept, 160 mg, revacept, 80 mg, or placebo prior to the start of PCI on top of standard antithrombotic therapy.
Main Outcomes and Measures The primary end point was the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin to at least 5 times the upper limit of normal within 48 hours from randomization. The safety end point was bleeding type 2 to 5 according to the Bleeding Academic Research Consortium criteria at 30 days.
Results Of 334 participants (median age, 67.4 years; interquartile range, 60-75.1 years; 253 men [75.7%]; and 330 White participants [98.8%]), 120 were allocated to receive the 160-mg dose of revacept, 121 were allocated to receive the 80-mg dose, and 93 received placebo. The primary end point showed no significant differences between the revacept and placebo groups: 24.4%, 25.0%, and 23.3% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P =.98). The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, with a median 26.5 AU × min (interquartile range, 0.5-62.2 AU × min) in the revacept, 160 mg, group; 43.5 AU × min (interquartile range, 22.8-99.5 AU × min) in the revacept, 80 mg, group; and 41.0 AU × min (interquartile range, 31.2-101.0 AU × min) in the placebo group (P= .02), while adenosine 5'-diphosphate–induced aggregation was not affected. Revacept did not increase Bleeding Academic Research Consortium type 2 or higher bleeding at 30 days compared with placebo: 5.0%, 5.9%, and 8.6% in the revacept, 160 mg, revacept, 80 mg, and placebo groups, respectively (P = .36).
Conclusions and Relevance Revacept did not reduce myocardial injury in patients with stable ischemic heart disease undergoing percutaneous coronary intervention. There were few bleeding events and no significant differences between treatment arms.
Dual Antiplatelet Therapy Versus Aspirin in Patients With Stroke or Transient Ischemic Attack
Background and Purpose: Antiplatelet therapy is key for preventing thrombotic events after transient ischemic attack or ischemic stroke. Although the role of aspirin is well established, there is emerging evidence for the role of short-term dual antiplatelet therapy (DAPT) in preventing recurrent stroke.
Methods: We conducted a systematic review and study-level meta-analyses of randomized controlled trials comparing outcomes of early initiation of short-term DAPT (aspirin+P2Y12 inhibitor for up to 3 months) versus aspirin alone in patients with acute stroke or transient ischemic attack. Primary efficacy outcome was risk of recurrent stroke and primary safety outcome was incidence of major bleeding. Secondary outcomes studied were risk of any ischemic stroke, hemorrhagic stroke, major adverse cardiovascular events, and all-cause death. Pooled risk ratios (RRs) and CIs were calculated using a random-effects model.
Results: Four trials with a total of 21 459 patients were included. As compared to aspirin alone, DAPT had a lower risk of recurrent stroke (RR, 0.76 [95% CI, 0.68–0.83]; P<0.001; I2=0%) but a higher risk of major bleeding events (RR, 2.22 [95% CI, 1.14–4.34], P=0.02, I2=46.5%). Patients receiving DAPT had a lower risk of major adverse cardiovascular events (RR, 0.76 [95% CI, 0.69–0.84], P<0.001, I2=0%) and recurrent ischemic events (RR, 0.74 [95% CI, 0.67–0.82], P<0.001, I2=0%).
Conclusions: As compared to aspirin alone, short-term DAPT within 24 hours of high-risk transient ischemic attack or mild-moderate ischemic stroke reduces the risk of recurrent stroke at the expense of higher risk of major bleeding.
Bone density and quality in patients treated with direct-acting oral anticoagulants versus warfarin
Jeferson Zanovelli Nalevaikoa, Júlia Vieira Oberger Marquesb, Matheus Felipe Oliveirac, Arthur William Passos Raetschc, Gustavo Lenci Marques a, Ricardo Rasmussen Petterle d, Carolina Aguiar Moreirab, Victória Zeghbi Cochenski Borbab
Introduction Direct-acting oral anticoagulants (DOACs) are therapeutic alternatives to warfarin that act independently of vitamin K, thus not affecting bone matrix formation. The aim of this study was to compare bone mineral density (BMD) and microarchitecture in patients treated with DOACs versus warfarin.
Methods Cross-sectional, observational study in patients using oral anticoagulants for >1 year and a paired control group (CG). Based on the type of anticoagulant used, the patients were grouped into a DOAC (DOACG) or warfarin (WG) group. All patients filled out a questionnaire and underwent BMD evaluation and trabecular bone score (TBS) measurement.
Results In all, 150 patients were included (50 patients in each group). The mean age was 60.49 ± 7.48 years, and most participants were men (64%). The most frequent comorbidities were hypertension, dyslipidemia, and hyperglycemia (comparison between groups p > 0.05). Low bone mass was diagnosed in 42%, 50%, and 66% of the patients in the CG, DOACG, and WG, respectively (p = 0.012). On logistic regression analysis, BMD was associated with body mass index (BMI; odds ratio [OR] 0.846, 95% confidence interval [CI] 0.763–0.926, p = 0.001), creatinine level (OR 0.024, 95%CI 0.001–0.434, p = 0.017), and TBS value (OR 17.777, 95%CI 4.526–96.903, p = 0.000). The mean TBS decreased progressively from the CG to the DOACG and WG (1.328 ± 0.112, 1.264 ± 0.138, and 1.203 ± 0.112, respectively, p < 0.001). On multivariate linear regression, negative predictors of TBS included warfarin use (−0.06, 95%CI -0.11 to −0.02, p = 0.006), BMI (−0.01, 95%CI -0.01 to −0.00, p < 0.001), and hyperglycemia (−0.07, 95%CI -0.11 to −0.03, p = 0.003), while positive predictors were an active IPAQ classification (0.06, 95%CI 0.01–0.11, p = 0.029) and family history of hip fracture (0.07, 95%CI 0.01–0.14, p = 0.029).
Conclusion Patients using anticoagulants have lower BMD and TBS values compared with controls. This negative effect on bone was more pronounced with warfarin, but was also seen with DOACs.
Anticoagulation in Elective Spine Cases
Rates of Hematomas Versus Thromboembolic Disease
Dharani Rohit Thota, BA; Carlos A. Bagley, MD; Mazin Al Tamimi, MD; Paul A. Nakonezny, PhD; Michael Van Hal, MD
Study Design: Retrospective cohort study with propensity matched cohorts.
Objective: The purpose of this study was to evaluate the association of anticoagulation with VTE and hematoma complications after spine surgery.
Summary of Background Data: One of the major complications of surgery is VTE which can range in presentation. Spine surgery is an especially complex balance between minimizing the risk of a VTE event and also the increased risk of a hematoma which can lead to devastating neurological outcomes.
Methods: The elective spine surgery cases at a single academic center between 2015 and 2017 were identified. A total of 3790 patients were initially identified. Two hundred sixty patients were excluded. The cohort was then matched using a propensity score. This matched a single patient who did not receive anticoagulation to a single patient who did within the institution. This left a total of 1776 patients with 888 patients in each arm.
Results: The incidence of VTE, PE, and unplanned reoperation for hematoma in this cohort was 0.96%, 0.34%, and 1.13%, respectively. Predicted odds of VTE and PE were not significantly different; however, the odds of an unplanned reoperation for hematoma (odds ratio [OR] = 7.535, 95% confidence interval [CI]: 2.004–28.340, P = 0.002) were greater for those who received pharmacological anticoagulation in our institutional cohort.
Conclusion: In this study, anticoagulation does not lead to lower rates of VTE events, but it increases the risk of symptomatic hematomas which require a return trip to the OR. While this was not a randomized controlled trial, we attempted to correct for this with propensity matching. Future randomized control trials would be needed.
Abelacimab for Prevention of Venous Thromboembolism
Verhamme, P., Yi, BA., Segers, A., Salter, J., Bloomfield, D., Büller, HR., Raskob, GE., Weitz, JI.
Background The role of factor XI in the pathogenesis of postoperative venous thromboembolism is uncertain. Abelacimab is a monoclonal antibody that binds to factor XI and locks it in the zymogen (inactive precursor) conformation.
Methods In this open-label, parallel-group trial, we randomly assigned 412 patients who were undergoing total knee arthroplasty to receive one of three regimens of abelacimab (30 mg, 75 mg, or 150 mg) administered postoperatively in a single intravenous dose or to receive 40 mg of enoxaparin administered subcutaneously once daily. The primary efficacy outcome was venous thromboembolism, detected by mandatory venography of the leg involved in the operation or objective confirmation of symptomatic events. The principal safety outcome was a composite of major or clinically relevant nonmajor bleeding up to 30 days after surgery.
Results Venous thromboembolism occurred in 13 of 102 patients (13%) in the 30-mg abelacimab group, 5 of 99 patients (5%) in the 75-mg abelacimab group, and 4 of 98 patients (4%) in the 150-mg abelacimab group, as compared with 22 of 101 patients (22%) in the enoxaparin group. The 30-mg abelacimab regimen was noninferior to enoxaparin, and the 75-mg and 150-mg abelacimab regimens were superior to enoxaparin (P<0.001). Bleeding occurred in 2%, 2%, and none of the patients in the 30-mg, 75-mg, and 150-mg abelacimab groups, respectively, and in none of the patients in the enoxaparin group.
Conclusions This trial showed that factor XI is important for the development of postoperative venous thromboembolism. Factor XI inhibition with a single intravenous dose of abelacimab after total knee arthroplasty was effective for the prevention of venous thromboembolism and was associated with a low risk of bleeding.