What's New In Coagulation - August 2017

Want to be in the know? Check out our monthly compilation of the latest studies, guidelines, and discussions in coagulation.

Please note - many linked teasers require registered account/subscription in order to view the full articles. Medscape registration is free of charge.

Novel Agent Reduces Antithrombin Levels to Treat Hemophilia

Fitusiran (Alnylam) is an investigation RNA agent that works by reducing levels of circulating antithrombin. This allows for sufficient thrombin generation, and works downstream bypassing FVIII (hemophilia A) and FIX (hemophilia B). A results of a phase 2 open label extension study of 33 hemophilia A and B patients without inhibitors received the agent monthly by injection at either 50 or 80 mg monthly.

The RNAi works by targeting specific messenger RNA by prevention translation into antithrombin. The drug works by the RNAi mechanism which regulates AT levels, and is metabolized by the liver. Additionally bleeding events in patients without inhibitors were contolled and evaluated when AT exceeded 75%. The bleeding rate was 1.7 versus 2 with those on patients previously on prophylaxis and 12 for those on demabnd therapy. These were all managed with factor replacement and with activated prothrombin complex in patients with inhibitors. Most adverse events reported (70%) were not related to the study drug. Two may have been related to the drug which included a seizure and elevated liver enzymes.

Emicizumab Replaces Factor VIII Function in Hemophilia A

The HAVEN 1 trial which gave emicizumab as a once-weekly subcutaneous injection reduced or prevented bleeds in people with hemophilia A and inhibitors to factor VIII. This is a bispecific monoclonal antibody that bridges activated factor IX and factor X and thereby replaces the missing factor VIII which resulted in a significantly lower rate of bleeding among patients with inhibitors. Up to 30% of hemophilia patients develop inhibitors to FVIII which make it ineffective, this doesn't happen with emicizumab. The trial enrolled patients 12 years and older with FVIII inhibitors who were assigned to either athe emicizumab group or no prophylaxis. Each group had a variable range of Bethesda titer ranging from 5 to 1570 BU in the emicizumab group versus 18 to 4500 BU in the no prophylaxis group.

Over 24 weeks, 62.9% of patients in group A receiving emicizumab had no bleeds, the primary end point of the trial, compared with only 5.6% of those people not receiving the drug. On prophylaxis, 85.8% had zero to three bleeds vs 11.2% without prophylaxis.There was an 87% reduction in the annualized bleeding rate between the groups - 2.9 bleeds/year (95% CI 1.69-5.02) with prophylaxis vs 23.3 bleeds/year (95% CI 12.33 - 43.89) without prophylactic emicizumab (P<0.0001).

The secondary endpoint was the reduction of all bleeds (80%) with emicizumab, 92% for spontaneous bleeds and 89% reduction with joint bleeds. In a comparison of emicizumab prophylaxis vs prior BPA prophylaxis within individual patients, emicizumab produced a 79% reduction in the annualized bleed rate: 70.8% had no bleeds when on emicizumab, compared with only 12.5% when on prior BPA prophylaxis (P=0.0003). Emicizumab prophylaxis was associated with statistically significant and clinically meaningful improvement in health-related quality of life and physical health scores.

There has been signficicant strides in hemophilia treatment. FVIII replacement therapies and gene therapies target replacement of the natural molecule while functioning as FVIII. With a goal in eliminating FVIII inhibitors in these patients.

Rapid Reversal of Dabigatran Anticoagulation With Idarucizumab

Idarucizumab a monoclonal antibody has demonstrated reversal of dabigatran. It works by rapid onset and by binding free and thrombin bound dabigatran. Patients in this study, RE-VERSE AD, required reversal of anticoagulation because of uncontrolled bleeding or because they needed emergency surgery or an invasive procedure within 2.5 hours. In 202 patients 93.4% achieved hemostasis with only 6.6% that had only mildly or moderate hemostasis.

The RE-VERSE AD study enrolled 503 patients which included 301 patients with uncontrolled bleeding and 202 requiring urgent surgery. Patients were treated based on clinical presentation. Reversal was assessed by dilute thrombin time and ecarin clotting time. At 72 hours after idarucizumab infusion, 22.9% of the previously bleeding and 66.8% of the procedural patients had restarted anticoagulation or antiplatelet therapy. By 90 days, antithrombotic therapy had been restarted in 72.8% and 90.1% of the patients, Thrombotic events occurred in fewer than 5% of patients within 30 days. Mortality was 13.5% in patients with bleeds and 12.6% in those with invasive procedures.

Defying Hopes, Dual Antiplatelets May Be Needed With LAA-Closure Devices in AF

Post implantation of left atrial appendage (LAA) occlude devices sometimes had thrombi. In two large studies this was observed, and patients with atrial fibrillation deemed at high risk for bldding complications on OAC. They looked at 450 patients implanted with the Amplatzer Amulet and found thrombus in about 5% of cases. This resulted in an eightfold increased risk of ischemic stroke or TIA.

Device thrombosis was significantly more likely if the patient had a history of ischemic stroke, and the risk of it being detected in the months after implantation plunged if discharge medications included dual antiplatelet therapy (DAPT). The question remains if these can replace antithrombotic therapy and how do they perform against the NOAC; which have demonstrated a benefit to patients with AF and stroke risk. Mostly they are considered as an alternative for patients who are contraindicated for long term OAC.

One of the issues regarding the LAA occluders is that there is no agreement on treatment with antiplatelet and or OAC administration,versus no treatment.

Life-threatening bleeding - what's the right call?

At a session based on how to manage bleeding patients, cases were presented on how to handle bleeding patients. Presented by Dr. Nester, the first cas was a 74 year old man on warfarin after suffering a DVT with a headache. A head CT scan confirms an acute subdural hematoma with an INR of 3.5. If Kcentra is available, then plasma is not required. Is this true or false? The answer is true. This is FDA approved for use in patients on warfarin who present with life threatening bleeding. The use of four factor PCC contains factors II, FII, IX and X versus 3 factor PCC which needs to be administered with plasma so that there is sufficient FVII to reverse the warfarin.

A 65 year male on dabigatran with AF presents with GI bleeding from a perforated ulcer requires urgent surgery asked the question the if the aPTT is a useful test to determine anticoagulation? The audience was split 50/50. The aPTT is affected by dabigatran. Testing for Xa inhibitors; for rivaroxaban depending on reagent the INR can be sensitive. Testing can be performed using a anti-Xa assay, which can be helpful if the laboratory offers the test. Next a discussion on how to treat this patient. Idarucizumab is a reversal reagent specific for dabigatran. To reverse Xa inhibitors, specific reversal with andexanet alfa is in clinical trials, so presently 4 factor PCC is used.

Other cases a patient with alcoholic cirrhosis with esophageal varicies The man's hemoglobin is 8, his PT/INR is 1.9; the PTT is 42 seconds, and the platelet count, 50,000/µL. How would you treat this patient? Another patient is a 73 year old male with a ruptured abdominal aortic aneurysm and a 13% HCT- how is the person transfused? What is the protocol? What is the best option for patient success? How are these trauma patients treated?

The next case looks at a 30-year-old woman delivers a baby and has massive blood loss estimated to be 1,700 mL upon delivery of the placenta. The clinical team triggers its hemorrhagic protocol, which is different than what is recommended for trauma due to thrombocytopenia being less common. In these patients it appers that fibrinogen levels should be maintained about 200 mg/dL.

Bleeding Common Years After TAVR, and Deadly

A study looked transcatheter aortic valve replacement (TAVR) which demonstrated that nearly one in three patients experience bleeding up to 5 years after TAVR. Bleeds were gastrointestinal and pericardial. Mortality rates rose from 49% in patients without a bleed to 59% with access site bleeding and 73% with nonaccess site bleeding. The Bern TAVR registry followed 926 patients that underwent TAVR from 2007-2014 for an average of 2.75 years.

Use of single-antiplatelet therapy increased from 10% at 1 month to 57% at 5 years, and oral anticoagulants from 7% to 21%, while over the same period, dual-antiplatelet use dropped from 60% to 7% and oral anticoagulants plus single- or dual-antiplatelets from 22% to 6%. Notably, antithrombotic therapy during follow-up was not associated with post-discharge, nonaccess-site bleeding events in univariate or multivariate analysis.

Overall, about 40% of nonaccess-site bleeding events occurred more than 30 days after the index TAVR. Among 285 patients who had bleeding, a recurrent event occurred in 53 cases, or nearly 20%.Compared with no bleeding, the adjusted risk of mortality was significantly higher with access-site bleeding (HR 1.34; 95% CI 1.01-1.76) and nonaccess-site bleeding (HR 2.08; 95% CI 1.60-2.71).

Chronic kidney disease and Society of Thoracic Surgeons (STS) score were independent correlates of nonaccess-site bleeding, reflecting the greater burden of age and coexisting comorbidities over time rather than in the immediate aftermath of TAVR. Importantly, nonaccess-site bleeding raised the risk of death more than 1.5-fold compared with access-site bleeding in 746 patients who underwent transfemoral TAVR, prompting the investigators to comment that "use of this route of access may not suffice to offset the detrimental effects of bleeding complications."

Both the investigators and editorialists commented that while selection of oral antithrombotic therapy is critical in the mid- and long-range period after TAVR, there is a paucity of robust randomized data to inform clinical decision-making.

Treatment of VTE Varies Widely

A new study has shown that treatment of VTE is varied which speaks to the need for individualized therapy. In the GARFIELD-VTE study 10,677 patients with confirmed VTE from 415 sites in 20 countries consisted of two cohorts considered representative of national VTE settings. They were recruited 1 year apart and standard of treatment has changed. About 50% of patients are treated with DOACs, 15% LWMH and 40% on VKA. Patients chosen to be placed on DOACs, are those without cancer and those without previous bleeding events. Patients with PE are still given heparin due to the lack of evidence in this higher risk population. Patients from the study will be followed for 3 years to determine long term outcomes in real world settings.

The median age in the registry is 60 years; 15% of patients have underlying cancer, 35% of patients had transient risk factors for VTE and about 45% to 50% of patients with unprovoked venous thrombosis. Two-thirds of events were deep venous thrombosis (DVT), and one-third were pulmonary embolism (PE). Patients were evenly divided between the sexes, had a median age of 60.2 years (interquartile range 46.1-71.7 years), and were predominantly white (69.1%), followed by Asian (19.6%) and black (4.6%).

Shorter Compression Stocking Time May Be OK for Some With DVT

A study has shown that in patients that have DVT, elastic compression stocking (ECS) therapy can shorten duration of treatment. However there are patients who can still benefit from 2 full years of therapy of stocking use to prevent post thrombotic syndrome.

Adult participants were randomly assigned to ECS therapy (n=432) or an individualized-therapy group (n=432) for 2 years. Investigators assessed PTS severity using the Villalta scale at 3, 6, 12, and 24 months. There was no significant difference in PTS between the groups with 28,9% for individualized treatment versus 27.8% for standard therapy.

There were also questionnaires for health-related quality of life (HRQoL), costs, and adherence to therapy. Participants had to have had adequate treatment within 24 hours of diagnosis. Among the exclusion criteria were previous ipsilateral DVT, contraindications for compression, treatment with thrombolysis, or a recurrent DVT within 6 months of inclusion in the study.

The groups were well matched for age (56-58 years), body mass index (28 kg/m2), and gender (50% male). Eight percent to 11% had a history of a contralateral DVT, two-thirds of each group had an unprovoked DVT, half were left-sided, half were in a popliteal vein, one-quarter in a femoral vein, and just over 20% in a common femoral vein.

About 90% of participants in each group were receiving vitamin K antagonists, about 20% direct oral anticoagulants, 15% to 20% low-molecular-weight heparin, and the rest investigational anticoagulants. In both groups, people were on anticoagulant therapy for 6 months (range 179-217 days). Most participants (90.5%) completed the study.

For the primary outcome of prevention of PTS, the individualized-treatment group experienced only 1.1% more PTS compared with the standard-treatment group (28.9% vs 27.8%, respectively), resulting in a hazard ratio of 1.13 (95% CI 0.88-1.46), which was not a significant difference, showing noninferiority of the individualized treatment-Proportions of participants affected by recurrent DVT plus pulmonary embolism were about the same in the individualized- (7.9%) and standard- (8.5%) therapy groups.There were slightly more deaths in the individualized- vs standard-therapy group (3.9% and 1.7%, respectively). Most of the deaths in each group were considered related to underlying malignancy (2.8% and 1.2%, respectively) and not to recurrent thrombosis.


Non-Vitamin K Antagonist Oral Anticoagulant Dosing in Patients With Atrial Fibrillation and Renal Dysfunction

J Am Coll Cardiol. 2017;69(23):2779-2790.

Xiaoxi Yao, PHD; Nilay D. Shah, PHD; Lindsey R. Sangaralingham, MPH; Bernard J. Gersh, MB, CHB, DPHIL; Peter A. Noseworthy, MD

Abstract and Introduction

Background: Dose reduction of non–vitamin K antagonist oral anticoagulants (NOACs) is indicated in patients with atrial fibrillation (AF) with renal impairment. Failure to reduce the dose in patients with severe kidney disease may increase bleeding risk, whereas dose reductions without a firm indication may decrease the effectiveness of stroke prevention.

Objectives: The goal of this study was to investigate NOAC dosing patterns and associated outcomes, i.e., stroke (ischemic stroke and systemic embolism) and major bleeding in patients treated in routine clinical practice.

Methods:Using a large U.S. administrative database, 14,865 patients with AF were identified who initiated apixaban, dabigatran, or rivaroxaban between October 1, 2010, and September 30, 2015. We examined use of a standard dose in patients with a renal indication for dose reduction (potential overdosing) and use of a reduced dose when the renal indication is not present (potential underdosing). Cox proportional hazards regression was performed in propensity score-matched cohorts to investigate the outcomes.

Results: Among the 1,473 patients with a renal indication for dose reduction, 43.0% were potentially overdosed, which was associated with a higher risk of major bleeding (hazard ratio: 2.19; 95% confidence interval: 1.07 to 4.46) but no statistically significant difference in stroke (3 NOACs pooled). Among the 13,392 patients with no renal indication for dose reduction, 13.3% were potentially underdosed. This underdosing was associated with a higher risk of stroke (hazard ratio: 4.87; 95% confidence interval: 1.30 to 18.26) but no statistically significant difference in major bleeding in apixaban-treated patients. There were no statistically significant relationships in dabigatran- or rivaroxaban-treated patients without a renal indication.

Conclusions: In routine clinical practice, prescribed NOAC doses are often inconsistent with drug labeling. These prescribing patterns may be associated with worse safety with no benefit in effectiveness in patients with severe kidney disease and worse effectiveness with no benefit in safety in apixaban-treated patients with normal or mildly impaired renal function.

Prevalence of Pulmonary Embolism Among Systemic Lupus Erythematosus Discharges

A Decade of Analysis of the National Hospital Discharge Survey

Srinadh Annangi, MBBS; Tirumala Rao Dammalapati, MBBS; Snigdha Nutalapati, MD; Marshaleen N. Henriques King, MBBS, MSCR, FCCP

J Clin Rheumatol. 2017;23(4):200-206.

Abstract and Introduction

Introduction: Pulmonary embolism (PE) is a life threatening preventable medical condition involving sudden occlusion of arteries within the lungs. Systemic lupus erythematosus (SLE) is an inflammatory disorder and therefore independently poses a risk of PE. We aimed to determine the association of SLE and PE using National Hospital Discharge Survey data, a national representative sample of hospital discharges throughout the United States.

Methods: Retrospective population-based analysis was done using National Hospital Discharge Survey data for the period 2001 to 2010. International Classification of Diseases, Ninth Revision (ICD-9) coding was used to identify SLE (ICD-9 code 710.0) and PE (ICD-9 codes 415.11, 415.12, 415.13, and 415.19) mentioned in any of the discharge diagnosis. Patients 15 years or older were included in the study. Regression analysis was done including hyperlipidemia, heart failure, lower-limb injury or surgery, hypertension, diabetes cerebrovascular disease, and cancer.

Results: Our regression analysis demonstrated a significant association between SLE and PE, which was independent of sex, race, age, and associated comorbidities (odds ratio [OR], 2.0; 95% confidence interval [CI], 1.99-2.16). Of included comorbidities, primary hypercoagulable disorder has the highest odds of association with PE (OR, 15.37; 95% CI, 15.22-15.51) followed by African American race compared with whites (OR, 1.08, 95% 1.08-1.09), and presence of at least 1 of the comorbidities (OR, 1.06; 95% CI, 1.06-1.06). African American SLE cases have the higher prevalence of PE in all age groups, with the exception of persons 35 to 44 years old.

Conclusions: Significant association exists between SLE and PE regardless of sex, race, age, and associated comorbidities. Females had an overall higher prevalence of SLE-related PE (1.67%) compared with males (1.29%). Stratified according to sex, race, and age groups, the association is highest for females, blacks, and age group 35 to 44 years, respectively.

Recognizing and Treating Venous Stasis Ulcers

Yvette C. Terrie, BS Pharm, RPh

US Pharmacist. 2017;42(2):36-39.

Abstract and Introduction

Venous ulcers, also referred to as venous stasis ulcers (VSUs), are the most common cause of ulcerations that affect the lower extremities. These types of ulcers are experienced by an estimated 1% of the U.S. population. The incidence of VSUs is most prevalent among the elderly population and is also ubiquitous in patients with a medical history of edema in the legs, long-standing varicose veins, or blood clots in either the superficial or the deep veins of the legs. VSUs generally occur in the lower extremities, especially along the medial distal ankle. In general, treatments for VSUs include compression therapy, local wound care and debridement, various types of wound dressings, antibiotics for infected wounds, the use of pharmacologic agents such as pentoxifylline, aspirin, calcium channel blockers, and topical corticosteroids when warranted, as well as surgery and other forms of adjunctive therapy.

Anticoagulation for Pregnant Women With Mechanical Heart Valves

A Systematic Review and Meta-analysis

Rohan D'Souza; Jackie Ostro; Prakesh S. Shah; Candice K. Silversides; Ann Malinowski; Kellie E. Murphy; Mathew Sermer; Nadine Shehata

Eur Heart J. 2017;38(19):1509-1516.

Abstract and Introduction

Aims: To review maternal and foetal outcomes in women with mechanical heart valves (MHVs) treated with vitamin-K antagonists (VKAs), first-trimester heparin followed by VKAs (sequential treatment), low molecular weight heparin (LMWH) and unfractionated heparin (UFH) during pregnancy, in order to inform practice.

Methods and results:Medline, Embase and Central were searched from inception until February 2016. Two reviewers independently screened 1786 titles, reviewed 110 full-texts and extracted data and assessed risk-of-bias from 46 articles. Pooled incidence (95% confidence intervals) was calculated for maternal and foetal outcomes. Included studies had a moderate or high risk-of-bias. With VKAs, sequential treatment and LMWH, maternal mortality occurred in 0.9% (0.4-1.4), 2.0% (0.8-3.1) and 2.9% (0.2-5.7), thromboembolic complications in 2.7% (1.4-4.0), 5.8% (3.8-7.7) and 8.7% (3.9-13.4), livebirths in 64.5% (48.8-80.2), 79.9% (74.3-85.6) and 92.0% (86.1-98.0) and anticoagulant-related foetal/neonatal adverse events (embryopathy or foetopathy) in 2.0% (0.3-3.7), 1.4% (0.3-2.5) and 0%, respectively. When UFH is used throughout pregnancy, 11.2% (2.8-19.6) suffered thromboembolic complications. Foetal loss and adverse events occurred with first-trimester warfarin doses ≤ 5 mg/day, although there were more livebirths [83.6% (75.8-91.4) vs. 43.9% (32.8-55.0)] and fewer foetal anomalies [2.3% (0.7-4.0) vs. 12.4% (3.3-21.6)] with lower doses than with warfarin > 5 mg/day.

Conclusions: VKAs are associated with fewest maternal complications but also with fewest livebirths. Sequential treatment does not eliminate anticoagulant-related foetal/neonatal adverse events. LMWH is associated with the highest number of livebirths. The safety of UFH throughout pregnancy and first-trimester warfarin ≤ 5 mg/day remains unconfirmed.

Bleeding Decreases the Risk of Stroke in Patients With Atrial Fibrillation

Marcelle D Smit; Isabelle C Van Gelder

Evid Based Med. 2017;22(3):107-108.

Context: Anticoagulation decreases the risk of stroke and other thromboembolic complications in patients with atrial fibrillation (AF) at the cost of an increased risk of major bleeding. If patients experience an anticoagulation-related major bleeding complication, the clinician faces the dilemma of whether to resume anticoagulation treatment or not. Evidence-based recommendations are lacking, and there is a wide variation in treatment of these patients, with anticoagulants, antiplatelets or no anticoagulation at all, while there is even less experience with non-vitamin K oral anticoagulants (NOACs), such as dabigatran. This study aimed to (1) evaluate anticoagulation use after a major bleeding event on dabigatran or warfarin and (2) compare outcomes between patients discontinuing anticoagulation and those restarting dabigatran or warfarin.

Methods: This was a retrospective study using data from a Medicare database between 2010 and 2012, early after the introduction of the NOACs. Patients were included if they were known with AF and had experienced a major bleeding event requiring hospitalisation while using dabigatran (n=404) or warfarin (n=1135) and were discharged alive. Patients who received a prescription for dabigatran or warfarin and patients who never filled a prescription for an oral anticoagulant after the index bleeding event were followed until the end of 2012 or until the occurrence of stroke, recurrent bleeding or death. Covariates and outcome variables were assessed using International Classification of Diseases, Ninth Revision (ICD-9) codes.

Findings: After the bleeding event, 49% of dabigatran and 47% of warfarin users reinitiated anticoagulation. Discontinuation of oral anticoagulation occurred significantly more often in older patients. Risk of ischaemic stroke and all-cause mortality was lower in patients who reinitiated anticoagulation than in those who discontinued anticoagulation: HR 0.66, 95% CI 0.44 to 0.99 for dabigatran; HR 0.76, 95% CI 0.59 to 0.97 for warfarin. Recurrent major bleeding occurred more often in warfarin than in dabigatran users (HR 2.31, 95% CI 1.19 to 4.76) or in those who discontinued anticoagulation (HR 1.56, 95% CI 1.10 to 2.22), while there was no difference in recurrent bleeding between dabigatran users versus those who discontinued anticoagulation (HR 0.65, 95% CI 0.32 to 1.33).

Commentary: Other studies have shown a decreased risk of stroke and mortality when reinitiating oral anticoagulation after a major bleeding event, compared with discontinuing anticoagulation. However, resumption of anticoagulation can lead to an increased risk of recurrent bleeding as was observed with warfarin in the current study, while a number of studies have shown comparable bleeding risk with or without anticoagulation during follow-up. In the current study, all major bleeding events were taken into consideration, while other studies used either intracranial haemorrhage or gastrointestinal bleeding as index event. Strengths of this study include the presentation of real-life data, while an important limitation is the retrospective nature; baseline characteristics and follow-up variables were deducted from ICD-9 codes. Not all variables of interest were available, for example, international normalised ratio levels, dabigatran dosages or comorbidities such as cancer, which could influence decision-making and outcome. Furthermore, only oral anticoagulants were taken into account: patients classified as discontinuing anticoagulation could have been using, for example, low molecular weight heparins. Data regarding antiplatelet use during follow-up, which could be used as alternate anticoagulant, are also lacking. If prescribed in combination with (non-vitamin K) oral anticoagulants, antiplatelets could add to bleeding risk. Most importantly, a selection bias was probably present in this observational study, both concerning the decision to discontinue anticoagulation (more likely in older patients and patients with significant comorbidities) and the decision to prescribe dabigatran (more likely in low-risk patients in these early days of dabigatran and/or lower dabigatran dosage), which could importantly influence outcome. We are therefore in need of randomised clinical trials to avoid this selection bias. The question as to whether anticoagulation should or should not be prescribed after a major bleeding event is currently under investigation in the APACHE-AF trial.