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Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.


Positive Data Salvaged for Thrombectomy on Basilar Strokes

Positive Data Salvaged for Thrombectomy on Basilar Strokes | MedPage Today

The BEST and BASICS trials have demonstrated that patients with basilar artery occlusion strokes could benefit from endovascular therapy (EVT). Looking at 351 stroke patients with baseline Stroke Scale scored of >10 on the NIH Stroke Scale, EVT was associated with better odds of disability at a zero to moderate rate at 90 days versus best medical management. A subgroup analysis of these trials showed that older patients had especially good outcomes with EVT despite higher mortality rates over the controls (40.3% versus 48.2%). The study shows that some patients who present with basilar artery occlusion strokes do not appear to benefit from mechanical thrombectomy and favor EVT.

Posterior circulation LVO strokes are hard to study given their rarity. These strokes are also characterized by complex symptoms and severity. BEST and BASICS both failed to show a benefit to EVT over medical management in vertebrobasilar occlusion strokes.

Each study was underpowered and results were compiled from both studies. The median age was 68 with one third of the participants being women. Additionally underlying AF was more prevalent at baseline in the EVT arm versus controls.

 

DOACs Top Warfarin in Real-World Valvular Heart Disease Patients

DOACs Top Warfarin in Real-World Valvular Heart Disease Patients | MedPage Today

A retrospective study looked at patients with newly prescribed DOACs and their safety and efficacy in patients with valvular atrial fibrillation (AF) as compared to those on warfarin.

A significant reduction in stroke on patients using DOACs of 3.9 per 100 person years versus 6.0 events in those with warfarin. Bleeding rates were also decreased at 7.1 versus 10.6 events/100 person years.

These results may be used to guide risk benefit of DOACs in patients with a broad definition of valvular heart disease. However the sample of patients with mitral valve regurgitation or stenosis was limited and additional studies are required.

Apixaban and rivaroxaban were both associated with fewer effectiveness and safety events compared to warfarin while dabigatran was linked to reduced bleeding but no better than warfarin for effectiveness. There has been a shift from prescribing warfarin to DOACs in valvular AF. Advantages include DOACs having short half life, no drug food interactions, less drug-drug interactions, convenient dosing and no routine laboratory monitoring. These advantages have led to rapid prescribing in patients with nonvalvular AF resulting in becoming first line of treatment in international guidelines.

The study included 56,000 patients with a mean age of 81, roughly 50% male and female with a CHA2DS2-VASc score ≥3 for 17% of people; HAS-BLED scores ge;2 for 15%. DOAC patients were followed for 134 days and warfarin for 124 days. This was a short follow up and a limitation for the study.

Other study limitations included a lack of data with regard to lifestyle variables, OTC prescriptions, severity of valvular disease.

 

Novel Antithrombotic Misses the Mark in PCI

-Mixed results for glycoprotein VI inhibitor in ISAR-PLASTER

Novel Antithrombotic Misses the Mark in PCI | MedPage Today

The ISAR-PLASTER trial looked at reduction in PCI patients of MI when received revacept infusions along with DAPT. Revacept is a novel lesion-directed competitive inhibitor to the platelet collagen receptor glycoprotein VI. The endpoint was 48-hour death or MI as defined by an increase in hs-Troponin at > 5 times the upper limit. A 334 person trial resulted in only 1 death. This was a phase II double-blind trial that enrolled low-risk stable ischemic heart disease with a median age of 67.4, mostly white males. They were randomized to a single infusion of revacept 160mg, or 80 mg, or placebo on top of DAPT prior to PCI.

At a 160mg dose of revacept there was a significant additional increase in platelet inhibition except with ADP induced platelet aggregation compared with placebo. There was no associated risk with an increase in bleeding.

 

High thrombotic risk in cancer patients receiving immunotherapy

High thrombotic risk in cancer patients receiving immunotherapy | MedUni Vienna (meduniwien.ac.at)

In general cancer patients present with a higher thrombotic risk which may be influenced by patient specific factors, cancer, and its treatment such as surgery. Immune check point inhibitors have been used to treat cancer. These drugs work by activating the immune system against the tumor. Most patients who receive this type of treatment have advanced cancer and it was expected to see a significant risk of thromboembolism in these patients.

A cohort study of 672 patients who had received this treatment for 8.5 months were included. Preliminary data was published in Blood on the incidence, risk factors and clinical outcomes of thrombotic complications in patients receiving immunotherapy. During the course of treatment 13% develop VTE and 2% develop thrombosis in the arterial system such as a heart attack, stroke or acute peripheral arterial occlusion. The risk is independent of the type of cancer and the immunotherapy used. Occurrence of VTE was associated with a poorer prognosis and a shorter time before tumor progression.

This study can serve as the basis for future studies to identify patients who could benefit from thrombosis prophylaxis to prevent VTE.

 

Haphazard Aspirin Add-On: Not a Great Risk-Reward Tradeoff for DOAC Users

Haphazard Aspirin Add-On: Not a Great Risk-Reward Tradeoff for DOAC Users | MedPage Today

Patients on DOACs were often also prescribed aspirin without a clear indication resulted in having a higher risk of bleeding without a reduction in thrombosis. This was seen in patients with AF, or VTE with no history of MI or valve replacement. Up to 33.8% of patients were treated with concomitant aspirin.

An observational study of 1047 matched pairs showed that when they were compared (DOAC monotherapy versus combination) over a 12 month period, results showed:

  • All bleeding: 31.6 vs 26.0 per 100 patient-years (P=0.01)
  • Nonmajor bleeding: 26.1 vs 21.7 per 100 person-years (P=0.02)
  • Major bleeding: 4.95 vs 3.59 per 100 person-years (P=0.09)
  • Thrombotic events: similar at 2.5 vs 2.3 per 100 patient-years (P=0.80)
  • Hospitalizations: 9.1 vs 6.5 per 100 patient years (P=0.02)
  • Mortality: 3.8 vs 3.4 per 100 patient-years (P=0.76)

Monotherapy may be sufficient in several groups of patients as well as clinical scenarios and needs to be studied.

This observational study included 3280 adults (51% men; mean age 68) with AF or VTE with no clear indication for aspirin. All were on a DOAC (apixaban, dabigatran, edoxaban or rivaroxaban). Exclusion criteria included patients with a history of MI, coronary artery disease or PAD.

Limitations of the study included unmeasured confounding variables and changes in aspirin use during follow up. Additionally, since the rates of thrombosis and bleeding were low the study may be underpowered resulting in making conclusion difficult.

 

Arterial Thromboembolism Risk Varies Across Cancer Types, Ages

Arterial Thromboembolism Risk Varies Across Cancer Types, Ages (medscape.com)

Both MI and stroke appeared to be increased in a population based study in patients with cancer, however the risk varies. The 6 month incidence of arterial thromboembolism (ATE) was 4.09% in men older than 75 with diabetes and bladder cancer versus 0.12% of women with breast cancer younger than 65 without comorbidities. ATE was also linked to more than a threefold higher risk of all cause mortality.

About 3% of patients will develop a VTE with cancer, however the risk for ATE is not as defined and appears to be restricted to specific types of cancer.

A Danish registry-based health data for 458,462 patients (median age, 69 years; 51% women) with a first-time cancer diagnosis between 1997 and 2017 and 1.3 million matched individuals in the general population. Among patients with solid cancer, cancer stage at diagnosis was localized in 34%, regional in 27%, distant metastasis in 22%, and unknown in 17%. The cumulative incidence of ATE, which included MI, stroke, and PAD was 1.50% in patients with cancer and 0.76% in control patients at 6 months post diagnosis versus 2.11% and 1.48% in controls at 12 months but diminished thereafter.

The types of cancer with the highest ATE were bladder 2.49%, lung 2.08% and colon 2.08% all are associated with smoking, the lowest risk was with breast cancer. With regard to age, the 6 month risk for ATE was higher patients between 65 and 75. Other independent predictors included prior ATE, distant metastasis, chemotherapy, male sex, hypertension and diabetes.

Mechanisms that could account for increased thrombotic risk in cancer patients may include the ability of tumors to secret tissue factor, mucin and cysteine protease. Certain cancer therapies thalidomide, cisplatin and ponatinib. One issue is that there is not a good scoring system for thrombosis. Elevated absolute neutrophile and soluble P-selecting have been identified as potential biomarkers for cancer-associated ATE but have not been prospectively validated.

 

Stroke 'Not a Common Complication' in COVID-19: New Studies

Stroke 'Not a Common Complication' in COVID-19: New Studies (medscape.com)

Very low rates of stroke were found in patients hospitalized with COVID-19. Results were based on two large international studies. One study found a rate of 2.2% among hospitalized COVID patients and the other at 1.48%. Stroke has been known to be a serious complication of COVID-19 with a higher than expected occurrence in young people. However, in the study, in those patients admitted to the ICU, stroke was not a common complication and ischemic stroke did not increase the risk of death.

In this study, researchers analyzed a database of 2699 patients who were admitted to the intensive care unit (ICU) with COVID-19 in 52 countries and found that 59 of these patients (2.2%) subsequently sustained a stroke with most of them (46%) being hemorrhagic with a fivefold increased risk for death, 32% ischemic and 22% unspecified. There was no association between ischemic stroke and mortality.

A large Korean study had a rate of 1.2% stroke in patients without COVID admitted to ICU's. While reports from the AHA showed an overall rate of ischemic stroke of 0.75%, however the studies are reported on two different populations. However both studies identified less that the rate of COVID-related stroke.

The other study, which includes 119,967 COVID-19 hospitalizations and represents the largest sample reporting the concomitant diagnoses of stroke and SARS-CoV-2 infection to date. This observation, retrospective study was across 6 continents, 70 countries and 457 stroke centers. There was a 1.48% stroke rate across 119,967 COVID-19 hospitalizations. SARS-CoV-2 infection was noted in 3.3% (1722) of all stroke admissions, which numbered 52,026.

Results showed a global decline in the number of stroke patients admitted to the hospital as well as acute stroke treatments, such as thrombolysis, during the first wave of the COVID-19 pandemic. This is believe to be attributed to a reduction of patients presenting to the hospital for fear of contracting the coronavirus.

 


 

JOURNAL CLUB

 

Effect of CYP2C19 Genotype on Ischemic Outcomes During Oral P2Y12 Inhibitor Therapy: A Meta-Analysis

Naveen L. Pereira, Charanjit Rihal, Ryan Lennon, Gil Marcus, Sanskriti Shrivastava, Malcolm R. Bell, Derek So, Nancy Geller, Shaun G. Goodman, Ahmed Hasan, Amir Lerman, Yves Rosenberg, Kent Bailey, M. Hassan Murad, and Michael E. Farkouh

J Am Coll Cardiol Intv. 2021 Apr, 14 (7) 739–750

Effect of CYP2C19 Genotype on Ischemic Outcomes During Oral P2Y12 Inhibitor Therapy: A Meta-Analysis | JACC: Cardiovascular Interventions

Abstract

Objectives: The aim of this study was to examine the effect of CYP2C19 genotype on clinical outcomes in patients with coronary artery disease (CAD) who predominantly underwent percutaneous coronary intervention (PCI), comparing those treated with ticagrelor or prasugrel versus clopidogrel.

Background: The effect of CYP2C19 genotype on treatment outcomes with ticagrelor or prasugrel compared with clopidogrel is unclear.

Methods: Databases through February 19, 2020, were searched for studies reporting the effect of CYP2C19 genotype on ischemic outcomes during ticagrelor or prasugrel versus clopidogrel treatment. Study eligibility required outcomes reported for CYP2C19 genotype status and clopidogrel and alternative P2Y12 inhibitors in patients with CAD with at least 50% undergoing PCI. The primary analysis consisted of randomized controlled trials (RCTs). A secondary analysis was conducted by adding non-RCTs to the primary analysis. The primary outcome was a composite of cardiovascular death, myocardial infarction, stroke, stent thrombosis, and severe recurrent ischemia. Meta-analysis was conducted to compare the 2 drug regimens and test interaction with CYP2C19 genotype.

Results: Of 1,335 studies identified, 7 RCTs were included (15,949 patients, mean age 62 years; 77% had PCI, 98% had acute coronary syndromes). Statistical heterogeneity was minimal, and risk for bias was low. Ticagrelor and prasugrel compared with clopidogrel resulted in a significant reduction in ischemic events (relative risk: 0.70; 95% confidence interval: 0.59 to 0.83) in CYP2C19 loss-of-function carriers but not in noncarriers (relative risk: 1.0; 95% confidence interval: 0.80 to 1.25). The test of interaction on the basis of CYP2C19 genotype status was statistically significant (p = 0.013), suggesting that CYP2C19 genotype modified the effect. An additional 4 observational studies were found, and adding them to the analysis provided the same conclusions (p value of the test of interaction <0.001).

Conclusions: The effect of ticagrelor or prasugrel compared with clopidogrel in reducing ischemic events in patients with CAD who predominantly undergo PCI is based primarily on the presence of CYP2C19 loss-of-function carrier status. These results support genetic testing prior to prescribing P2Y12 inhibitor therapy.

 

Adverse Events Associated With the Addition of Aspirin to Direct Oral Anticoagulant Therapy Without a Clear Indication

Jordan K. Schaefer, MD1; Josh Errickson, PhD2; Yun Li, PhD3; et alXiaowen Kong, MA4; Tina Alexandris-Souphis, RN4; Mona A. Ali, PharmD5; Deborah Decamillo, RN, BSN4; Brian Haymart, RN, MS4; Scott Kaatz, DO, MSc6; Eva Kline-Rogers, RN, MS4; Jay H. Kozlowski, MD7; Gregory D. Krol, MD8; Sahana R. Shankar4; Suman L. Sood, MD, MSCE1; James B. Froehlich, MD, MPH4; Geoffrey D. Barnes, MD, MSc4 Author Affiliations Article Information

JAMA Intern Med. Published online April 19, 2021. doi:10.1001/jamainternmed.2021.1197

Adverse Events Associated With the Addition of Aspirin to Direct Oral Anticoagulant Therapy Without a Clear Indication | Atrial Fibrillation | JAMA Internal Medicine | JAMA Network

Abstract

Importance It is unclear how many patients treated with a direct oral anticoagulant (DOAC) are using concomitant acetylsalicylic acid (ASA, or aspirin) and how this affects clinical outcomes.

Objective To evaluate the frequency and outcomes of prescription of concomitant ASA and DOAC therapy for patients with atrial fibrillation (AF) or venous thromboembolic disease (VTE).

Design, Setting, and Participants This registry-based cohort study took place at 4 anticoagulation clinics in Michigan from January 2015 to December 2019. Eligible participants were adults undergoing treatment with a DOAC for AF or VTE, without a recent myocardial infarction (MI) or history of heart valve replacement, with at least 3 months of follow-up.

Exposures Use of ASA concomitant with DOAC therapy.

Main Outcomes and Measures Rates of bleeding (any, nonmajor, major), rates of thrombosis (stroke, VTE, MI), emergency department visits, hospitalizations, and death.

Results Of the study cohort of 3280 patients (1673 [51.0%] men; mean [SD] age 68.2 [13.3] years), 1107 (33.8%) patients without a clear indication for ASA were being treated with DOACs and ASA. Two propensity score–matched cohorts, each with 1047 patients, were analyzed (DOAC plus ASA and DOAC only). Patients were followed up for a mean (SD) of 20.9 (19.0) months. Patients taking DOAC and ASA experienced more bleeding events compared with DOAC monotherapy (26.0 bleeds vs 31.6 bleeds per 100 patient years, P= .01). Specifically, patients undergoing combination therapy had significantly higher rates of nonmajor bleeding (26.1 bleeds vs 21.7 bleeds per 100 patient years, P=.02) compared with DOAC monotherapy. Major bleeding rates were similar between the 2 cohorts. Thrombotic event rates were also similar between the cohorts (2.5 events vs 2.3 events per 100 patient years for patients treated with DOAC and ASA compared with DOAC monotherapy, P=.80). Patients were more often hospitalized while undergoing combination therapy (9.1 vs 6.5 admissions per 100 patient years, P=.02).

Conclusion and Relevance Nearly one-third of patients with AF and/or VTE who were treated with a DOAC received ASA without a clear indication. Compared with DOAC monotherapy, concurrent DOAC and ASA use was associated with increased bleeding and hospitalizations but similar observed thrombosis rate. Future research should identify and deprescribe ASA for patients when the risk exceeds the anticipated benefit.

 

Assessing the Risks of Bleeding vs Thrombotic Events in Patients at High Bleeding Risk After Coronary Stent Implantation
The ARC–High Bleeding Risk Trade-off Model

Philip Urban, MD1; John Gregson, PhD2; Ruth Owen, MSc2; et alRoxana Mehran, MD3; Stephan Windecker, MDML4; Marco Valgimigli, MD, PhD4; Olivier Varenne, MD, PhD5,6; Mitchell Krucoff, MD7; Shigeru Saito, MD8; Usman Baber, MD, MSc3; Bernard Chevalier, MD9; Davide Capodanno, MD, PhD10,11; Marie-Claude Morice, MD12; Stuart Pocock, MSc, PhD2

Author Affiliations

JAMA Cardiol. 2021;6(4):410-419. doi:10.1001/jamacardio.2020.6814

Assessing the Risks of Bleeding vs Thrombotic Events in Patients at High Bleeding Risk After Coronary Stent Implantation: The ARC–High Bleeding Risk Trade-off Model | Cardiology | JAMA Cardiology | JAMA Network

Abstract

Importance Patients who are candidates for percutaneous coronary intervention (PCI) and are at high bleeding risk constitute a therapeutic challenge because they often also face an increased risk of thrombotic complications.

Objectives To develop and validate models to predict the risks of major bleeding (Bleeding Academic Research Consortium [BARC] types 3 to 5 bleeding) and myocardial infarction (MI) and/or stent thrombosis (ST) for individual patients at high bleeding risk and provide assistance in defining procedural strategy and antithrombotic regimens.

Design, Setting, and Participants This prognostic study used individual patient data from 6 studies conducted from July 1, 2009, to September 5, 2017, for 6641 patients at more than 200 centers in Europe, the US, and Asia who underwent PCI and were identified as being at high bleeding risk using the Academic Research Consortium criteria. In 1 year of follow-up (excluding periprocedural events), individual patient risks of MI and/or ST and major bleeding were evaluated using 33 baseline variables. To validate these models, a subgroup of 1458 patients at high bleeding risk from the ONYX ONE trial were analyzed. Statistical analysis was performed from February 1, 2019, to April 30, 2020.

Exposures All patients underwent PCI with bare metal, drug-coated, or drug-eluting stent implants.

Main Outcomes and Measures Forward, stepwise multivariable proportional hazards models were used to identify highly significant predictors of MI and/or ST and BARC types 3 to 5 bleeding.

Results A total of 6641 patients (4384 men [66.0%]; median age, 77.9 years [interquartile range, 70.0-82.6 years]) were included in this study. Over 365 days, nonperiprocedural MI and/or ST occurred in 350 patients (5.3%), and BARC types 3 to 5 bleeding occurred in 381 patients (5.7%). Eight independent baseline predictors of risk of MI and/or ST and 8 predictors for risk of BARC types 3 to 5 bleeding were identified. Four of these predictors were in both risk models. Both risk models showed moderate discrimination: C statistic=0.69 for predicting MI and/or ST and 0.68 for predicting BARC types 3 to 5 bleeding. Applying these same models to the validation cohort gave a similar strength of discrimination (C statistic=0.74 for both MI and/or ST and BARC types 3-5 bleeding). Patients with MI and/or ST had a mortality hazard ratio of 6.1 (95% CI, 4.8-7.7), and those with BARC types 3 to 5 bleeding had a mortality hazard ratio of 3.7 (95% CI, 2.9-4.8) compared with patients free of both events. Taking these data into account, the risk scores facilitate investigation of the individual patient trade-off between these 2 risks: 2931 patients (44.1%) at high bleeding risk in the 6 studies had a greater risk of MI and/or ST than of BARC 3 to 5 bleeding, 1555 patients (23.4%) had a greater risk of BARC 3 to 5 bleeding than of MI and/or ST, and 2155 (32.4%) had a comparable risk of both events.

Conclusions and Relevance In a large cohort of patients at high bleeding risk undergoing PCI, 2 prognostic models have been developed to identify individual patients’ risk of major coronary thrombotic and bleeding events. In future clinical practice, using an application on a smartphone to evaluate the trade-off between these 2 quantifiable risks for each patient may help clinicians choose the most appropriate revascularization strategy and tailor the duration and intensity of antithrombotic regimens.

 

Early Apixaban use Following Stroke in Patients With Atrial Fibrillation

Arthur J. Labovitz, MD; David Z. Rose, MD; Michael G. Fradley, MD; John N. Meriwether, MD; Swetha Renati, MD; Ryan Martin, MD; Thomas Kasprowicz, MD; Ryan Murtagh, MD; Kevin Kip, PhD; Theresa M. Beckie, PhD, MN, RN; Marcus Stoddard, MD; Andrea C. Bozeman, APRN; Tara McTigue, RN; Bonnie Kirby, RN, MSN; Nhi Tran, MS; W. Scott Burgin, MD

Stroke. 2021;52(4):1164-1171.

Early Apixaban use Following Stroke in Patients With Atrial Fibrillation

Abstract

Background and Purpose: It is unknown when to start anticoagulation after acute ischemic stroke (AIS) from atrial fibrillation (AF). Early anticoagulation may prevent recurrent infarctions but may provoke hemorrhagic transformation as AF strokes are typically larger and hemorrhagic transformation-prone. Later anticoagulation may prevent hemorrhagic transformation but increases risk of secondary stroke in this time frame. Our aim was to compare early anticoagulation with apixaban in AF patients with stroke or transient ischemic attack (TIA) versus warfarin administration at later intervals.

Methods: AREST (Apixaban for Early Prevention of Recurrent Embolic Stroke and Hemorrhagic Transformation) was an open-label, randomized controlled trial comparing the safety of early use of apixaban at day 0 to 3 for TIA, day 3 to 5 for small-sized AIS (lt;1.5 cm), and day 7 to 9 for medium-sized AIS (ge;1.5 cm, excluding full cortical territory), to warfarin, in a 1:1 ratio at 1 week post-TIA, or 2 weeks post-AIS.

Results: Although AREST ended prematurely after a national guideline focused update recommended direct oral anticoagulants over warfarin for AF, it revealed that apixaban had statistically similar yet generally numerically lower rates of recurrent strokes/TIA (14.6% versus 19.2%, P=0.78), death (4.9% versus 8.5%, P=0.68), fatal strokes (2.4% versus 8.5%, P=0.37), symptomatic hemorrhages (0% versus 2.1%), and the primary composite outcome of fatal stroke, recurrent ischemic stroke, or TIA (17.1% versus 25.5%, P=0.44). One symptomatic intracerebral hemorrhage occurred on warfarin, none on apixaban. Five asymptomatic hemorrhagic transformation occurred in each arm.

Conclusions: Early initiation of anticoagulation after TIA, small-, or medium-sized AIS from AF does not appear to compromise patient safety. Potential efficacy of early initiation of anticoagulation remains to be determined from larger pivotal trials.