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New in Coagulation

Thursday, July 6, 2017

What's New in Coagulation - July 2017

Written By Donna Castellone, MS, MT (ASCP) SH | LinkedIn

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

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Eat More Chocolate, Have Less Atrial Fibrillation? Hope Springs Eternal

A large prospective study from Denmark showed that people who eat more chocolate have a reduced risk of developing atrial fibrillation (AF). Dark chocolate has been associated with lower rates of cardiovascular events and heart failure. This is thought to be due large flavonoid content. This study enrolled 55,502 subjects between the ages of 50 to 64 from 1993-1997 22,909 consumed chocolate one to three times a month demonstrated a 10% risk of AF. A serving of chocolate is about 1 oz, 8476 ate two to six serving/week while 1239 had one or more servings/day. This is one finding they felt patients would be happy to comply with. With a mean follow up of 13.5 years, the rate was lower in the cohort of patients. This finding was significant for both men and women.

Even if the results were too good to be true, the results warrant further consideration. A limitation of the study may be that chocolate consumers were generally healthier and better educated than other participants. Confounding variables were a history of hypertension and cardiovascular disease or by adjustment for caffeine intake and coffee consumption. Further studies will have to be conducted to see if this may be part of preventative care for AF.

Further Reassurance on Anticoagulants After ICH in AF

The two new meta analyses showed more reassuring data on resuming OAC therapy in patients with AF post intracerebral hemorrhage. The analysis suggests that resuming OAC is at least not extremely dangerous. However the data is observational and need to be confirmed by randomized trials.

Three ICH studies RETRACE, MGH and ERICH looked at 1027 patients on OAC for prevention of cardioembolic stroke and diagnosed with ICH. Investigated was the outcome for resuming OAC 1 year from the ICH including mortality, favorable functional outcome, recurrent ICH and ischemic stroke. The study focused on ICH that were lobar vs nonlobar since location can provide information on underlying cause and recurrence rates.

Limitations of this study included it was observational with a 1 year follow up- but they do support further trials to evaluate resuming OAC after ICH. Many of these patients have AF and are at a higher risk of stroke.

Prasugrel Fails to Show Noninferiority to Clopidogrel in Stroke

Prasugrel failed to show non-inferiority to clopidogrel in reducing vascular events among patients with noncardioembolic ischemic stroke. The PRASTRO-1 study is a phase 3 randomized controlled trial. Prasugrel is a thienopyridine inhibitor of the platelet P2Y12 receptor shows less platelet resistance than clopidrogrel, however the effect in stroke patients haven't been clarified.

This study conducted in 224 Japanese hospitals included 3747 patients randomly assigned to receive 3.75 mg prasugrel or clopidogrel 75mg once daily for 96 weeks. Results showed that a primary outcome event occurred in 73 of 1885 (3.9%) patients receiving prasugrel vs 69 of 1862 (3.7%) patients receiving clopidogrel (RR, 1.05; 95% confidence interval [CI], 0.76 - 1.44).

In patients with large-vessel atherosclerosis or small vessel occlusion prasugrel fulfilled the non-inferior criteria. As a secondary outcome, stroke occurred in 73 patients for both groups, while life threatening bleeding, major bleeding or clinically relevant bleeding occurred in 115 prasugrel patient versus 110 versus those receiving clopidogrel.

Clopidogrel Reloading Appears Safe for AMI Patients

Clopidogrel reloading appears safe for patients with acute myocardial infarction (AMI) who are already taking clopidogrel, according to a registry study. Early initiation of dual antiplatelet therapy is recommended for all patients presenting with AMI, but the optimal strategy for MI patients already receiving clopidogrel remains unclear. This assessment used data from the ACTION Registry-Get With the Guidelines (GWTG). It included 735 hospitals and more than 51,000 patients to investigate the association of clopidogrel reloading with in-hospital bleeding and mortality.

At presentation, 9.3% of patients with ST-segment elevation MI (STEMI) and 18.9% of non-STEMI (NSTEMI) patients were already using a P2Y12 inhibitor, most commonly clopidogrel (91.9%). Among those who continued clopidogrel, three-quarters of STEMI patients and a quarter of NSTEMI patients were reloaded with clopidogrel (≥ 300 mg). Among STEMI patients, clopidogrel reloading was not associated with an increased risk of major bleeding, but was associated with a significant 20% lower risk of in-hospital death.

Rates of in-hospital major bleeding and mortality among NSTEMI patients were similar for those treated with and without the loading dose. Even among subgroups at highest risk of bleeding, clopidogrel reloading was not associated with major bleeding. "Clopidogrel reloading is necessary in primary PCI patients with STEMI and possibly in non-STEMI ACS patients with early invasive strategy," Dr. Kim told Reuters Health by email. The paper shows us that 1/4 of STEMI patients and 3/4 of non-STEMI patients did not reload in current US practice.

TPA Challenge Predicts Need for Massive Transfusion in Trauma Patients

Using a modified thromboelastography (TEG) assay with tissue plasminogen activator (tPA) added to a patient's blood can identify trauma patients who require massive transfusion. The test is for research use only, but it may be a predictor of patients who need massive transfusion. Presently scoring systems are used, which also require ultrasound imagining. Using the TEC and tPA is based on the evidence that hemorrhagic shock released tPA and increased circulating tPA activity due to persistent depletion of inhibitors which results in hyperfibrinolysis. Using the TEG and the tPA could mimic this and help predict risk.

Among the 324 trauma patients included in the study, 17% required massive transfusion and 13% died, with 33% of those deaths attributed to uncontrolled hemorrhage or circulatory arrest.

The low-dose tPA challenge percent clot lysis 30 minutes after reaching maximum amplitude (Lt-TEG LY30) had the best performance of all assays and scores assessed, with an AUROC of 0.86 and sensitivity of 84% and specificity of 82% at its optimal cut points, but it required 50 minutes to obtain results.

The high-dose tPA time to maximum amplitude (Ht-TEG TMA) had the shortest time to provide results (16 minutes) while retaining an acceptable sensitivity of 80% and specificity of 74%. In logistic regression analysis, INR and Ht-TEG TMA independently predicted massive transfusion. An Ht-TMA <16 minutes in a patient with an INR > 1.1 had a positive predictive value (PPV) of massive transfusion of 49%, whereas an INR ≤1.1 and an Ht-TMA >16 minutes had a negative predictive value (NPV) of a massive transfusion of 98%.

Inappropriate NOAC Dosing Common, May Be Compromising Safety

A large US cohort study revealed that there was inappropriate dosing of non–vitamin K antagonist oral anticoagulants (NOACs) for atrial fibrillation (AF). Doses appeared to be reduced even when there weren’t renal indication as well as failure to decrease the dose when there was renal dysfunction. The study looked at 15,000 patients with AF in which over 2/5ths required a dose reduction due to renal indications while 10% were underdosed, putting patients at either a risk for a bleed or thrombosis.

A renal indication for a NOAC dose reduction was defined as a dabigatran prescription with an estimated glomerular filtration rate (eGFR) <30 mL/min/1.73 m2, rivaroxaban with an eGFR <50 mL/min/1.73 m2, or apixaban with an SCr ≥1.5 mg/dL. There were 1473 patients with renal indications for dose reduction, however 43% got standard doses and were potentially overdosed. Their rate of major bleeding had a hazard ration of 2.9%. The remaining 13,392 patients, 13.3% were underdosed with a stroke rate of 1.43, with those patients on apixaban had a significantly increase risk of stroke but no increased risk of bleeding.

Potential reasons for inappropriate dosing include older age. Also, the desire to reduce the risk of bleeding can result in poor outcomes.

Bristol-Myers Squibb Pulls One Lot of Apixaban Over Tablet Mix-up

One lot of apixaban 5-mg tablets is being voluntarily recalled after a consumer complained that a bottle labeled as Eliquis 5 mg actually contained 2.5-mg tablets putting these patients at a risk for stroke due to decreased dosing. In patients who take the drug for DVT and PE this could lead to increased risk of growing or moving the clot.

No reports of related injuries or illnesses have been reported, according to the company. The recall is being conducted with the US Food and Drug Administration. The tablets are different. The 2.5 mg dose is yellow with a 893 and 2.5 on the other side, the 5 mg is oval and pink with a 894 on one side and a 5 on the other.

The recalled lot is HN0063, Exp 09/2019, NDC 0003-0894-2 and was distributed in February 2017 to wholesalers and retail pharmacies across the US. They have been notified to contact the drug maker to return and replace any recalled product.

Consumers with the recalled Eliquis are asked to contact their physician and Bristol-Myers Squibb at 800-332-2056 or via its website for more information.

Oral Anticoagulants (Still) Underused in Paroxysmal AF: UK Data

In the UK, patients with paroxysmal atrial fibrillation (AF) have been found to be less likely treated with oral anticoagulants. There were more patients that were treated in the later years than in the earlier years. The analysis included > 175,000 patients between 2000-2015. In 2000 these patients were half as likely to receive OAC than other patients with AF- where are in 2015 that number dropped to 20%.

Both UK and European guidelines recommend that all AF patients at increased risk of stroke be offered anticoagulants, regardless of their type of AF. There doesn't seem to data as to why the treatment gap exists.

Of a subgroup of 4,419,659 patients in the Health Improvement Network, based on 648 UK primary-care practices, 179,343 had AF, yielding a total of 848,852 AF patient records across the 16 years of the study. The group performed 16 sequential cross-sectional analyses set to May 1 for each year from 2000 to 2015, with the study population comprising all AF patients aged 35 years and over. Exposure was defined as a diagnosis of paroxysmal AF or "other AF," the latter including persistent or permanent AF. During this time, the amount of patients diagnosed with paroxysmal AF increased from 7.4% - 14.0%.

Among patients eligible for oral anticoagulant therapy, the proportion of paroxysmal AF patients prescribed the drugs increased significantly from 18.8% to 56.2%, while the proportion of other AF patients prescribed anticoagulants rose significantly from 34.2% to 68.4%. Consequently, the treatment gap decreased from 15.4% to 13.2%.

Aspirin Bleeding Risk in Over 75s Higher Than Thought

In patients 75 years or older taking aspirin for prevention of stroke of MI have been shown to have a higher risk of disabling or fatal bleeding and should also be prescribed a proton pump inhibitor (PPI) to protect against GI bleeding. Data shows that the bleeding in this group is more likely to be disabling than the stroke. Up to 80% of bleeds caused anti-platelet agents can be prevented by PPIs. Being > 75 years of high should be considered a high risk population.

Additional evidence has raised the question if these patients should be put on aspirin for prevention, or even after an event. It appears that the evidence suggests that there is no compelling evidence that aspirin is beneficial form greater than 28 days past an event. Most of the trial evidence is on younger patients. There needs to be a balance in older patients regarding the benefit of antiplatelet agents and the risk of bleeding.

The Oxford Vascular Study looked at bleeding events in 3166 patients (50% age 75 years or older) treated with antiplatelet drugs (mainly aspirin based) after a first transient ischemic attack, ischemic stroke, or MI in the Oxford Vascular Study, a population-based study of the incidence and outcome of all acute vascular events in a population of 92,728 individuals, irrespective of age, registered at nine general practices in Oxfordshire, United Kingdom. Results showed that 405 patients had bleeding events with a 3.36% annual risk with a major risk at 1.46%. In patients age 85 years or older the risk was 4.1%.

Oral Anticoagulants, With Cautions, Can Continue During CIED Lead Extractions

If caution is used, there may not be a need to discontinue OAC prior to extracting unwanted cardiac implantable electronic devices. A retrospective study from a high volume extraction center showed that withdrawing OCA and bridging patient on heparin did not decrease bleeding risk. Findings of this study will need to be confirmed with prospective clinical trials. The findings were the same regardless of the OAC used (including warfarin).

However it is important to have fast access to a surgeon in case of serious complications during the procedure. The lead extractions are usually performed percutaneously but can turn into a surgical procedure if there are complications. There are no guidelines on how to manage anticoagulation.

Ultrasound "Drill" Dissolves Deep Blood Clots with Impeccable Precision

A new technology for dissolving venous blood clots has been developed. This collaboration fir dissolving DVTs is between North Carolina State University and the University of North Carolina at Chapel hill. They have developed an ultrasound drill which dissolves clots better than other methods.

One method relies on lateral emission of ultrasound waves, however the damage is not limited to only blood clots, it can also damage blood vessels. The diamond ripped drill technique dissolves clots by chewing through them which reduces the damage to blood vessels but the clots are in larger pieces and require blood thinning drugs.

The new technology improves upon the limitations of both of these existing methods, the new ultrasound tool is forward-facing, like a drill, but still breaks down clots into very fine particles. The device works via a low-frequency intravascular ultrasound that breaks up blood clots that lead to DVT. An injection tube for microbubbles at the clot site dissolves the clot with extreme precision, reducing damage done to the blood vessel and reducing the amount of time it takes to complete the treatment.

Testing will begin in animal models.


Antiphospholipid Syndrome: Role of Vascular Endothelial Cells and Implications for Risk Stratification and Targeted Therapeutics

Michel T. Corban, MD; Ali Duarte-Garcia, MD; Robert D. McBane, MD; Eric L. Matteson, MD, MPH; Lilach O. Lerman, MD, PHD; Amir Lerman, MD

J Am Coll Cardiol. 2017;69(18):2317-2330.

Abstract and Introduction

Abstract:Antiphospholipid syndrome (APS) is an autoimmune disease characterized by venous thromboembolism, arterial thrombosis, and obstetric morbidities in the setting of persistently positive levels of antiphospholipid antibodies measured on 2 different occasions 12 weeks apart. Patients with APS are at increased risk for accelerated atherosclerosis, myocardial infarction, stroke, and valvular heart disease. Vascular endothelial cell dysfunction mediated by antiphospholipid antibodies and subsequent complement system activation play a cardinal role in APS pathogenesis. Improved understanding of their pathogenic function could help in the risk stratification of patients with APS and provide new molecular therapeutic targets.

Risk of Acute Myocardial Infarction With NSAIDs in Real World Use

Bayesian Meta-analysis of Individual Patient Data

Michele Bally; Nandini Dendukuri; Benjamin Rich; Lyne Nadeau; Arja Helin-Salmivaara; Edeltraut Garbe; James M Brophy

BMJ. 2017;357(j1909)

Abstract and Introduction

Objective: To characterise the determinants, time course, and risks of acute myocardial infarction associated with use of oral non-steroidal anti-inflammatory drugs (NSAIDs).

Design: Systematic review followed by a one stage bayesian individual patient data meta-analysis.

Data sources: Studies from Canadian and European healthcare databases.

Review methods: Eligible studies were sourced from computerised drug prescription or medical databases, conducted in the general or an elderly population, documented acute myocardial infarction as specific outcome, studied selective cyclo-oxygenase-2 inhibitors (including rofecoxib) and traditional NSAIDs, compared risk of acute myocardial infarction in NSAID users with non-users, allowed for time dependent analyses, and minimised effects of confounding and misclassification bias.

Exposure and outcomes: Drug exposure was modelled as an indicator variable incorporating the specific NSAID, its recency, duration of use, and dose. The outcome measures were the summary adjusted odds ratios of first acute myocardial infarction after study entry for each category of NSAID use at index date (date of acute myocardial infarction for cases, matched date for controls) versus non-use in the preceding year and the posterior probability of acute myocardial infarction.

Results: A cohort of 446,763 individuals including 61,460 with acute myocardial infarction was acquired. Taking any dose of NSAIDs for one week, one month, or more than a month was associated with an increased risk of myocardial infarction. With use for one to seven days the probability of increased myocardial infarction risk (posterior probability of odds ratio >1.0) was 92% for celecoxib, 97% for ibuprofen, and 99% for diclofenac, naproxen, and rofecoxib. The corresponding odds ratios (95% credible intervals) were 1.24 (0.91 to 1.82) for celecoxib, 1.48 (1.00 to 2.26) for ibuprofen, 1.50 (1.06 to 2.04) for diclofenac, 1.53 (1.07 to 2.33) for naproxen, and 1.58 (1.07 to 2.17) for rofecoxib. Greater risk of myocardial infarction was documented for higher dose of NSAIDs. With use for longer than one month, risks did not appear to exceed those associated with shorter durations.

Conclusions: All NSAIDs, including naproxen, were found to be associated with an increased risk of acute myocardial infarction. Risk of myocardial infarction with celecoxib was comparable to that of traditional NSAIDS and was lower than for rofecoxib. Risk was greatest during the first month of NSAID use and with higher doses.

Rivaroxaban As an Effective Alternative to Warfarin in a Patient With Atrial Fibrillation, Thrombophilia, and Left Atrial Appendage Thrombus

A Case Report

Michele Scarano; Matteo Casale; Cesare Mantini; Egidio Imbalzano; Cristiana Consorti; Daniela Clemente; Giuseppe Dattilo

J Med Case Reports. 2017;11(97)

Abstract and Introduction

Background: Atrial fibrillation is the most common cardiac arrhythmia. It is responsible for up to 20% of all ischemic strokes. Rate control and anticoagulation are crucial for atrial fibrillation management and stroke prevention.

Case Presentation: We present the case of an 84-year-old Italian woman with a left atrial appendage thrombus that developed despite her use of anticoagulant therapy with warfarin for a previous pulmonary embolism. She had atrial fibrillation and heterozygosity for both factor V Leiden and methylenetetrahydrofolate reductase C677T mutation, thus creating resistance to activated protein C. Anticoagulant therapy was switched to heparin for 1 week and then to rivaroxaban. After 3 months of rivaroxaban use, the thrombus disappeared.

Conclusions: This case raises the issue of the ineffectiveness of warfarin therapy in complex cases involving particular thrombophilic conditions and the possibility of using rivaroxaban as a safe and effective alternative.

Snake Bite Mortality in Children: Beyond Bite to Needle Time

MP Jayakrishnan; MG Geeta; P Krishnakumar; TV Rajesh; Biju George

Arch Dis Child. 2017;102(5):445-449.

Abstract and Introduction

Objective: To study the clinical characteristics and predictors of mortality from snake bite envenomation in children.

Design: Prospective observational study with a one-group cohort design.

Setting: Pediatric intensive care unit of a tertiary care hospital in South India.

Subjects: The study cohort consisted of 145 children (55 girls and 90 boys) <12 years of age with snake bite envenomation.

Methods: Demographic and clinical details were recorded in a semistructured pro forma. Children were treated with polyvalent antisnake venom (ASV) as per WHO protocol. Details of treatment, complications and outcomes were recorded. Univariate analysis was done to identify statistical significance, and those variables found to be significant were analysed using binary logistic regression.

Results: Russell's viper was the most common offending snake followed by hump-nosed pit viper. Features of haemotoxicity, neurotoxicity and combined haemotoxicity and neurotoxicity occurred in 68 (47%), 39 (26.9%) and 9 (6%) children, respectively. Acute kidney injury (AKI) occurred in 36 (25%) children. The mortality rate was 10.3%. On univariate analysis, nocturnal bites, severe leucocytosis on day 1, AKI, capillary leak syndrome and a need for more than 20 vials of ASV were significantly associated with mortality. On multivariate analysis, only severe leucocytosis on day 1 (OR 35.29; 95% CI 1.37 to 911.89) and AKI (OR 35.05 95% CI 1.74 to 706.93) were found to be independent predictors of mortality.

Conclusions: This study has identified two hitherto unrecognised risk factors—severe leucocytosis on day 1 and capillary leak syndrome. These findings need to be taken into consideration when planning management strategies for snake bite envenomation in children.

Warfarin Initiation, Atrial Fibrillation, and Kidney Function

Comparative Effectiveness and Safety of Warfarin in Older Adults With Newly Diagnosed Atrial Fibrillation

Min Jun, MScMed(ClinEpi), PhD; Matthew T. James, MD, PhD; Zhihai Ma, MSc; Jianguo Zhang, MSc; Marcello Tonelli, MD, SM; Finlay A. McAlister, MD, MSc; Braden J. Manns, MD, MSc; Pietro Ravani, MD, PhD; Robert R. Quinn, MD, PhD; Natasha Wiebe, MMath, PStat; Vlado Perkovic, MBBS, PhD; Stephen B. Wilton, MD, MSc; Wolfgang C. Winkelmayer, MD, ScD; Brenda R. Hemmelgarn, MD, PhD

Am J Kidney Dis. 2017;69(6):734-743.

Abstract and Introduction

Background: The effectiveness and safety of warfarin use among patients with atrial fibrillation (AF) and reduced kidney function are uncertain.

Study Design: Community-based retrospective cohort study (May 1, 2003, to March 31, 2012) using province-wide laboratory and administrative data in Alberta, Canada.

Setting & Participants: 14,892 adults 66 years or older with new AF and a measurement of kidney function. Long-term dialysis patients or kidney transplant recipients were excluded.

Predictor: Propensity scores were used to construct a matched-pairs cohort of patients with AF who did and did not have a warfarin prescription within a 60-day period surrounding their AF diagnosis.

Outcomes: Within 1 year of initiating warfarin therapy (or the matched date for nonusers): (1) the composite of all-cause death, ischemic stroke, or transient ischemic attack (also assessed as separate end points) and (2) first hospitalization or emergency department visit for a major bleeding episode defined as an intracranial, upper or lower gastrointestinal, or other bleeding.

Measurements: Baseline glomerular filtration rate (GFR) was estimated using the CKD-EPI creatinine equation. Patients were matched within estimated GFR (eGFR) categories: ≥90, 60 to 89, 45 to 59, 30 to 44, and >30 mL/min/1.73 m2. Information for baseline characteristics (sociodemographics, comorbid conditions, and prescription drug use) was obtained.

Results: Across eGFR categories, warfarin therapy initiation was associated with lower risk for the composite outcome compared to nonuse (adjusted HRs [95% CI] for eGFR categories ≥ 90, 60–89, 45–59, 30–44, and <30 mL/min/1.73 m2: 0.59 [0.35–1.01], 0.61 [0.54–0.70], 0.55 [0.47–0.65], 0.54 [0.44–0.67], and 0.64 [0.47–0.87] mL/min/1.73 m2, respectively). Compared to nonuse, warfarin therapy was not associated with higher risk for major bleeding except for those with eGFRs of 60 to 89 mL/min/1.73 m2 (HR, 1.36; 95% CI, 1.13–1.64).

Limitations: Selection bias.

Conclusions: Among older adults with AF, warfarin therapy initiation was associated with a significantly lower 1-year risk for the composite outcome across all strata of kidney function. The risk for major bleeding associated with warfarin use was increased only among those with eGFRs of 60 to 89 mL/min/1.73 m2.

Role of Direct Oral Anticoagulants in the Management of Anticoagulation

Rajiv N. Thakkar, MD; Suman W. Rathbun, MD; Scott M. Wright, MD

South Med J. 2017;110(4):293-299.

Abstract and Introduction

Abstract: For decades, vitamin K antagonists (VKAs) have been the oral treatment of choice for many thromboembolic conditions. The limitations of VKAs include the need for monitoring through blood testing, drug interactions, and narrow therapeutic windows. These shortcomings have led to the development of direct oral anticoagulants. These new oral agents act on specific targets in the coagulation cascade (eg, factor Xa, thrombin) and negate some of the shortcomings of VKAs. This article reviews the roles of dabigatran, rivaroxaban, apixaban, and edoxaban in stroke prevention in nonvalvular atrial fibrillation, for prevention of venous thromboembolism after orthopedic surgery, and in the treatment of venous thromboembolism. Direct oral anticoagulants are at least as efficacious and safe as traditional anticoagulation therapy.

Conclusions: Efficacy and safety outcomes of DOACs largely have been at least as good as VKAs, and they may now be considered first-line therapy for all FDA-approved indications. DOACs generally are associated with less intracranial bleeding but slightly more gastrointestinal bleeding compared with VKAs. For patients already taking VKAs, the cost-effectiveness and efficacy benefits of DOACs are likely to be greatest in patients poorly controlled on VKAs. The advantages of DOACs include their limited drug interactions and the fact that there is no need for routine blood testing. Without monitoring, it is hard to assess compliance. Dose adjustment is needed for all DOACs in patients with impaired renal function. Given cost and bleeding risks, the off-label use of DOACs for any other conditions is not recommended.


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