October 2021: New In Coagulation

by Donna Castellone, MS, MT (ASCP) SH • October 07, 2021

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.

DAPT for 1 Month Falls Short in Acute Coronary Syndrome

DAPT for 1 Month Falls Short in Acute Coronary Syndrome | MedPage Today

There was a difference seen in the results of the 1 month DAPT strategy used in the STOPDAPT-2 ACS trial that didn't match the safety and efficacy of the original STOPDAPT-2 study which looked at 12 months of DAPT. STOPDAPT-2 ACS enrolled 2,988 patients with ACS and pooled the results with those from patients with ACS in STOPDAPT-2, for a total study population of 4,136 patients. For a composite endpoint of CV death, MI, stroke, stent thrombosis or major or minor bleeding the event rate was 3.2% in the 1 month DAPT group versus 2.83 in the 12 month group. MI was significantly higher in the 1 month DAPT versus 12 months (1.59% versus 0.85%).

The original STOPDAPT-2 trial showed both non-inferiority and superiority of 1-month DAPT followed by clopidogrel monotherapy through 1 year against 12 months of DAPT post-percutaneous coronary intervention. In the first trial, only 38% of the patients had ACS; all received a permanent-polymer, cobalt-chromium, everolimus-eluting stent.

There was a reduction in major bleeding events.


Edoxaban: A Mixed Bag for TAVR Patients Needing Anticoagulation

Edoxaban: A Mixed Bag for TAVR Patients Needing Anticoagulation | MedPage Today

The ENVISAGE-TAVI AF trial was a randomized trial that investigated the use of DOAC post TAVR. The 1,426 study participants had a mean age of 82.1 and 47.5% were women. This was an intermediate-risk cohort given a mean STS score of 4.9%. The mean CHA2DS2-VASC score was 4.5, and 99% of people had Afib prior to TAVR. It was conducted at 173 centers in 14 countries.

Edoxaban demonstrated noninferiority against standard vitamin K antagonists in terms of efficacy. Ischemic stroke and all cause mortality rates were also lower. The DOAC passed the test of efficacy but failed over bleeding rates. ENVISAGE bleeding rate was 9.7 versus 7.0 per 100 person years. As a result, more bleeds put a limit on potential patient eligibility for edoxaban. Factors that may account for the excess bleeds is the suboptimal treatment in the warfarin arm being less than 70% of the time in the therapeutic INR range, as well as the higher incidence of drug discontinuation in the warfarin group. Also, concomitant antiplatelet therapy contributed to additional bleeding.

The ATLANTIS trial showed apixaban was no better than antiplatelet therapy or warfarin after TAVR and the ischemic event rates were higher comparing apixaban versus standard care.

The trial ultimately adds high-quality evidence on what the "sweet spot" is regarding the dosing and duration of anticoagulation for each patient such that they achieve the greatest reduction of ischemic events while minimizing bleeding.


The Pill Linked to Higher Risk of Blood Clots After Knee Surgery

The Pill Linked to Higher Risk of Blood Clots After Knee Surgery | MedPage Today

Women on birth control pills had a higher incidence of blood clots when undergoing knee arthroscopy and ACL reconstruction with VTE more than doubling in this population. Smoking and obesity further increased the risk. The estrogen and progesterone in combination oral contraception pills increase the risk of clots and that clots are problematic after orthopedic surgery. Additional risk factors such as smoking obesity, lack of mobility and genetic predisposition should be considered in addition to the type and duration of oral contraceptive pills and the incidence of VTE.

A large healthcare database to tracked 64,165 female patients ages 16 to 40 who underwent simple knee arthroscopy and ACL reconstruction from 2010 to 2015. They focused on post-surgery blood clots both DVT and/or PE that occurred within 90 days of the procedures. They found the risk of VTE increased with OC compared with no OC. The risk was further increased with additional risk factors.

The overall risk of clots was 0.95% in patients without obesity and oral contraception use and rose to 1.62% in those who were obese. Among smokers, the risk of clots was 1.24% which grew to 4.04% when these patients also used oral contraceptives. Patients may benefit from stopping their OC one month prior to surgery or consider postoperative anticoagulation. There doesn't seem to be an increased risk in upper extremity surgery. It would be helpful to understand which types of OC pose the highest risk since many vary in dosage and type of hormone.


Is Heparin-Based Thromboprophylaxis Necessary for Obstetric Patients?

Is Heparin-Based Thromboprophylaxis Necessary for Obstetric Patients? | MedPage

VTE is one of the leading causes of maternal mortality, making up about 9% of pregnancy-related deaths in the U.S. Medical societies including the American College of Obstetricians and Gynecologists (ACOG) and the Society of Maternal-Fetal Medicine (SMFM) currently recommend a risk-stratified approach to VTE prevention during pregnancy. In hospitals that had a standardized protocol, patients were 15 times more likely to receive heparin based thromboprophylaxis. In obstetric patients this did not reduce the risk of VTE but may have increased the risks of other postpartum complications. This was seen in a single center retrospective study.

The study included all patients who delivered at their single tertiary care center from 2013 to 2018. Deliveries before 2016 were categorized as pre-protocol, while deliveries from 2016 to 2018 were categorized as post-protocol. After the protocol went into effect, patients with specific risk factors, including those with pre-pregnancy obesity, older maternal age, history of VTE, and others, received low-molecular-weight heparin 40 mg subcutaneously once a day. Patients with a BMI of 40 or higher received a 40-mg dose twice daily.

The risk of postpartum wound superficial hematomas doubled in the post protocol group. There was no difference in deep wound hematomas between the pre and post group. Unplanned surgical procedures increased post protocol and more patients required RBC transfusions.

Despite international recommendations for routine use of heparin based thromboprophylaxis evidence is lacking its expanded use in the general obstetric population. There are no randomized trials showing benefit or harm of heparin for VTE in pregnant patients without significant risk factors.


Are DOACs Any Better Than Warfarin for Dementia Risk?

Are DOACs Any Better Than Warfarin for Dementia Risk? | MedPage Today

New onset dementia occurs at a rate of 4.87 per 100 person years in people with nonvalvular AF with no previous dementia. There were no advantages in the protection of dementia in patient who took DOACs versus warfarin. This was consistent in both vascular and Alzheimer dementia. An exception was seen in people 65 to 74 with prior stroke, there was a lower risk of dementia in patients on DOACs when compared to warfarin. Edoxaban was associated with a lower risk, but dabigatran and apixaban didn't reduce the incident dementia over warfarin.

This was a retrospective study included people 40 years or older (mean age 71.8, 58% men) with oral anticoagulant-naive nonvalvular AF who were new users of warfarin (n=25,948) and DOACs (n=46,898) from 2014 to 2017 with a follow-up of 1.3 years on average.

Guidelines in the US recommends AF patients take DOACs or non-Vitamin K oral anticoagulants versus warfarin for stroke prevention. The choice of DOAC is uncertain due to limited data.

The rate of AF associated dementia has fallen over the last 3 decades with increased anticoagulant use and increased time in therapeutic range adding to the protection.

Compared with patients treated with warfarin, those treated with DOACs were older and had a higher CHA2DS2-VASc score. The study also had some issues as to if patients adhered to their prescribed oral anticoagulant. It is also possible that dementia was underdiagnosed. The population was Korean and these patients on DOACs received a reduced dose in half the cases. Using off-label underdosed DOACs may be associated with an increased risk of ischemic stroke and further investigation is required to determine the clinical impact.


Renal Decline Slower With Rivaroxaban Than Warfarin in AF Patients

Renal Decline Slower With Rivaroxaban Than Warfarin in AF Patients | Medscape

A study looked at 11600 non-valvular atrial fibrillation and the impact of OAC on kidney function. The team included 5338 rivaroxaban patients, who had a mean age of 72.6 years and of whom 61% were male, alongside 6314 patients treated with warfarin. The latter had an average age of 73.2 years and 58% were male.

Rivaroxaban was associated with a 37% reduction in the risk of doubling serum creatinine clearance versus warfarin. The analysis of the RE-LY trial showed that AF patients treated with dabigatran had a slower rate of decline in renal function versus warfarin. VKA could have an adverse effect on renal function as they inhibit the phosphorylation of VK dependent enzymes. Adverse renal outcomes were defined as a doubling of sCr levels, an ≥30% decline in eGFR, and incident ESRD (end-stage renal disease), which included a code in the health record for ESRD, stage 5 chronic kidney disease, chronic dialysis, or an eGFR lt;15 ml/min/1.73m2. Patients treated with rivaroxaban were less likely to have adverse events that those treated with warfarin.


What's the Right TIMING for NOAC After Ischemic Stroke?

What's the Right TIMING for NOAC After Ischemic Stroke? | Medscape

The TIMING study investigated the safety and efficacy of early versus delayed initiation of NOAC. The study enrolled 888 patients mean age 78 years and 46% were female. They were randomly assigned to early or later treatment. Early treatment began within 4 days of onset and in the delayed treatment group began treatment within 5 to 10 days. The choice of NOAC was based on the clinician. Follow up was 90 days.

In a randomized controlled study, the difference between treatment arms in the risk of a composite outcome that included recurrent ischemic stroke was 1.79%, favoring the group that underwent early initiation of NOAC. The rates of major bleeding was low, there were 11 bleeding events overall, seven which occurred in the early arm.


Aspirin and Heparin Increase Bleeding Risk During EVT

Aspirin and Heparin Increase Bleeding Risk During EVT | Medscape

Patients treated with both acetylsalicylic acid (ASA0 and heparin were associated with an increased risk for symptomatic ICH in patients with ischemic stroke undergoing endovascular therapy (EVT) approximately doubling the risk. There was no evidence for beneficial effect on functional outcome found in the MR CLEAN-MED trial.

Previous research has supported the safety and efficacy of EVT for ischemic stroke. Still, more than 30% of patients do not recover, despite fast and complete recanalization. Incomplete microvascular reperfusion (IMR) could explain this incomplete recovery which can be caused by microthrombi which occlude distal vessels and neutrophil extracellular traps. This occurrence can be reduced through treatment with ASA or heparin but come with an increased risk of ICH.

Patients were randomly assigned to receive or not to receive ASA and within those two groups they were also assigned to receive no heparin, low-dose heparin or moderate-dose heparin. There were 628 patients in the study which included 310 patients on ASA and 318 in the non ASA group, and 332 participants received heparin and 296 received no heparin. The median age was 73 and about 53% were men.

The study's primary outcome was Modified Rankin Scale (mRS) score at 90 days. Secondary outcomes were NIHSS score at 24 hours, NIHSS score at 5 to 7 days, and recanalization grade at 24 hours on CT angiography or MRI. The primary safety outcomes were ICH and death within 90 days.

Patients in the ASA group were less likely to have good functional outcome, and the mortality rate tended to be higher while a worse functional outcome in the heparin group, compared with the no-heparin group and the risk for ICH was significantly higher in the heparin group, compared with the no-heparin group. Patients in the heparin group were also less likely to have a good functional outcome and there was a nonsignificant increase in risk for death among those patients.


Study Describes Bleeding Risk With Anticoagulants for VTE

Study Describes Bleeding Risk With Anticoagulants for VTE | Medscape

A meta-analysis of data from 17,202 patients in 27 studies provided the best available estimates of long-term bleeding risk with different anticoagulation for unprovoked VTE including subgroups at increased risk. These risks included older patients, those on antiplatelet therapy, bleeding history, kidney disease or anemia.

Data was analyzed from 14 RCT and 13 cohort studies to include 9982 patients on VKA and 7220 received a DOAC. All patients received OAC for at least 6 months beyond an initial treatment of 3 months. The incidence of major bleeding per 100 person-years was 1.7 events with VKAs, compared with 1.1 events with DOACs.

Clinical guidelines recommend indefinite anticoagulation for an unprovoked VTE except if patients are at a high risk of bleeding. There is no standardized approach to identify patients at a high risk of bleeding. Bleeding events are two to three times more fatal than recurrent VTE. This analysis indicates there is a clinically meaningful difference in long-term risk for anticoagulant-related major bleeding among patients with a first unprovoked VTE stratified according to presence or absence of the following risk factors: age older than 65 years, creatinine clearance less than 50 mL/min, history of bleeding, concomitant use of antiplatelet therapy, and hemoglobin level less than 100 g/L.





Corticosteroid overuse in adults with immune thrombocytopenia: Cause for concern

Adam Cuker MD, MS, Howard A. Liebman MD, 25 August 2021, Research and Practice in Thrombosis and Hemostasis

Corticosteroid overuse in adults with immune thrombocytopenia: Cause for concern

Corticosteroids remain a crucial component of first-line therapy for immune thrombocytopenia (ITP) due to low cost, high initial response rates, and acceptable short-term tolerability. However, extended and recurrent use of corticosteroids is associated with substantial toxicity. Survey studies indicate that >95% of patients with ITP treated with corticosteroids report adverse effects, more than one-third of whom require reduction or discontinuation of treatment. In light of the heavy treatment burden of prolonged corticosteroid exposure, clinical practice guidelines recommend limiting corticosteroid treatment to no more than 6 weeks in adults with ITP receiving initial therapy. For patients who require subsequent therapy, clinical practice guidelines recommend treatments more suitable for long-term disease control such as thrombopoietin receptor agonists, rituximab, other immune-modulating medications, or splenectomy, rather than repeated courses of corticosteroids. Despite these recommendations, real-world evidence suggests that corticosteroids remain the most frequently used treatment for adults with ITP, not only in the first line, but also in the second and third line. In this review, we summarize evidence on the efficacy, safety, and tolerability of corticosteroids; discuss the problem of overuse; and suggest strategies for curtailing the excessive use of corticosteroids in adults with ITP.


Response to rituximab in children and adults with immune thrombocytopenia (ITP)

Emily M. Harris MD, Kirsty Hillier MD, Hanny Al-Samkari MD, Laura Berbert MS, Rachael F. Grace MD, 24 August 2021, Research and Practice in Thrombosis and Hemostasis

Response to rituximab in children and adults with immune thrombocytopenia (ITP)

Rituximab is a monoclonal anti-CD20 antibody used as a second-line treatment for immune thrombocytopenia (ITP). As additional treatments for ITP emerge, identifying the most appropriate patients and optimal timing for rituximab are important but challenging without established predictors of response to therapy.

The purpose of this study was to describe demographic, clinical, and laboratory characteristics of pediatric and adult patients with ITP to identify differences in evaluation before rituximab administration and correlates of platelet response.

This is a retrospective cohort study describing the characteristics of patients with ITP treated with rituximab from 2010 to 2020 at two academic tertiary care centers.

not significantly different between children (58%, n = 24) and adults (55%, n = 40). Response rate was similar in those with primary versus secondary ITP (53% vs 62%). Among patients treated with rituximab, Evans Syndrome was more common in children than adults (42% vs 18%). Immunologic labs assessed before rituximab varied by age and were more commonly evaluated in children (lymphocyte subsets 88% vs 22%). Immunologic markers, including antinuclear antibody, direct antiglobulin testing, immunoglobulin levels, and lymphocyte subsets, did not predict response to rituximab in pediatric or adult patients with ITP.

Pre-rituximab immunologic evaluation varied significantly between adults and children, which could represent institution-specific practice patterns or a more general practice difference. If the latter, underlying immunodeficiency in adults with ITP may be underrecognized. Standardized guidance for pre-rituximab immunologic evaluation is needed.


Reasons for Discontinuing Oral Anticoagulation Therapy for Atrial Fibrillation

Jackie Buck; Julia Fromings Hill; Alison Martin; Cassandra Springate; Bikramaditya Ghosh; Rachel Ashton; Gerry Lee; Andrzei Orlowski

Age Ageing. 2021;50(4):1108-1117.

Reasons for Discontinuing Oral Anticoagulation Therapy for Atrial Fibrillation | Medscape


Introduction: Atrial fibrillation (AF) is the most common cardiac arrhythmia and can lead to significant comorbidities and mortality. Persistence with oral anticoagulation (OAC) is crucial to prevent stroke but rates of discontinuation are high. This systematic review explored underlying reasons for OAC discontinuation.

Methods: A systematic review was undertaken to identify studies that reported factors influencing discontinuation of OAC in AF, in 11 databases, grey literature and backwards citations from eligible studies published between 2000 and 2019. Two reviewers independently screened titles, abstracts and papers against inclusion criteria and extracted data. Study quality was appraised using Gough's weight of evidence framework. Data were synthesised narratively.

Results: Of 6,619 sources identified, 10 full studies and 2 abstracts met the inclusion criteria. Overall, these provided moderate appropriateness to answer the review question. Four reported clinical registry data, six were retrospective reviews of patients' medical records and two studies reported interviews and surveys. Nine studies evaluated outcomes relating to dabigatran and/or warfarin and three included rivaroxaban (n = 3), apixaban (n = 3) and edoxaban (n = 1). Bleeding complications and gastrointestinal events were the most common factors associated with discontinuation, followed by frailty and risk of falling. Patients' perspectives were seldom specifically assessed. Influence of family carers in decisions regarding OAC discontinuation was not examined.

Conclusion: The available evidence is derived from heterogeneous studies with few relevant data for the newer direct oral anticoagulants. Reasons underpinning decision-making to discontinue OAC from the perspective of patients, family carers and clinicians is poorly understood.