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New in Coagulation

Monday, November 6, 2017

What's New in Coagulation - November 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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NOAC-Drug Interactions Linked to Increased Bleeding

A study looked at a nationwide cohort of patients with nonvalvular atrial fibrillation and bleeding risk for 12 commonly prescribed medications that share common metabolic pathways with the NOACs (dabigatran, rivaroxaban, and apixaban). The medications selected were P-glycoprotein competitors (digoxin, verapamil, diltiazem, amiodarone, and cyclosporine), CYP3A4 inhibitors (fluconazole and ketoconazole, itraconazole, voriconazole, or posaconazole), or both (atorvastatin, erythromycin or clarithromycin, dronedarone, rifampin, and phenytoin), which may have a potential drug-drug interaction with NOACs. Bleeding was defined as hospitalization, ED visit with ICH, GI, or other bleeding. Several drugs can increase the risk of bleeding when taken with the NOAC's. These include amiodarone (increase in 13.94), fluconazole (138.46), rifampin (36.90) and phenytoin (52.31). This, however, was not seen when atorvastatin was combined with a NOAC, actually a lower risk of bleeding was observed. All of these risks need to be evaluated in patients that are taking these drugs together. Interactions were the same for all three NOACs.

Stopping Long-term Aspirin Linked to CV-Event Spike

A large population based study showed that after 3 years of follow up, patients who stopped taking aspirin for reasons other than surgery or bleeding have a 37% higher rate of hospitalization for MI, stroke, or cardiovascular death. That is, one in every 74 patient who discontinued aspirin had an additional CV event in 1 year. The study included equal males/females with a mean age of 73 years and 54% used aspirin for secondary prevention versus the rest for long term aspirin without prior hospitalization for CVD. Being off aspirin was associated with an increased risk of CV events in patients using aspirin for primary prevention (HR 1.28; 95% CI 1.22-1.34) and secondary prevention (HR 1.46; 95% CI 1.41-1.51). Patients who were older and had prior CVD were at higher elevated risk for CV events when off aspirin, while treatment with other antiplatelet or oral anticoagulant drugs was associated with a lower CV event-risk when off aspirin. There may be a rebound effect a few days after stopping aspirin, where blood clotting is stimulated as opposed to inhibited. This may also be supported by the finding that CV events didn't occur in patient supported by other anti-platelet drugs or OACs.

Stroke, Cardiac Events Increased After First Stroke in Young

The incidence of recurrent stroke has been demonstrated to be increased in the age group of 18-45 years in the one year period post first ischemic stroke. Cardiac events are also increased however the risk is not as high as the stroke risk. Overall there has been a risk in the incidence of stroke in young people and accounts for 10% of all strokes.

A study identified 12,812 patients in the Nationwide Readmissions Database aged 18 to 45 years who were admitted with an index ischemic stroke in 2013. At the time of hospitalization, the prevalence of vascular risk factors was significant; 48.8% had hypertension, 32% had hypercholesterolemia, and 36.3% were smokers. More than half of patients were discharged to home or self-care after the index hospitalization, and 6.3% died.The risk for recurrent stroke was overall three times higher than the risk for cardiac events, with a rate of 2913.3 readmissions per 100,000 index hospitalizations at 90 days for stroke vs 1132.2 for cardiac events.Among patients without any vascular risk factors at the time of index hospitalization, the respective rates were 2534.9 vs 676 per 100,000 index hospitalizations.

The presence of diabetes or hypercholesterolemia was associated with an increased risk for recurrent stroke and post stroke cardiac events. However hypertension was not associated with any increased risk in younger patients, whereas it has the strongest association for recurrent stroke in adults.

'Alarming' Increase in Stroke Risk Factors

Data observed from the Nationwide Inpatient Sample based on 922,451 hospitalization for acute ischemic stroke reveals that despite many preventative initiatives conventional risk factors appear to be on the rise. These include hypertension, diabetes, dyslipidemia, drug abuse, and smoking as well as chronic renal failure, coronary artery disease and carotid stenosis. These observations occurred over a ten year period (2004-2014) with an observed prevalence of a doubling of raised cholesterol.

Results showed 92.5% of patients with acute ischemic stroke had one or more risk factors. Overall the age- and sex-adjusted prevalence of hypertension was 79%; diabetes, 34%; dyslipidemia, 47%; smoking, 15%; an drug abuse, 2%. In addition, 13% of patients had carotid stenosis, 12% had chronic renal failure, and 27% had coronary artery disease.

Hispanic participants with ischemic stroke had diabetes and that many risk factors are higher also in the black population. Half of the 75 million patients in the US have uncontrolled blood pressure and about 20% have A1C levels greater than 9.0 mg/dL.

It is important to focus on risk factor control and to implement evidence based interventions to reduce stroke risk. Data also needs to be interpreted in the appropriate context.

Real-World Reassurance on Bleeding Risk With DOACs in VTE

When compared with warfarin, an observation analysis of approximately 60,000 patients with VTE has demonstrated that there was no increased incidence of bleeding risk using the DOACs: dabigatran, apixaban and rivaroxaban. There actually was a trend towards a lower bleeding rate. Several randomized clinical trains have been focused on efficacy and have also similar findings, however these results provide evidence to support safety of the drugs in the real world.

Patients were included in the study if they presented with a VTE within 30 days prior to their first prescription for warfarin or a DOAC. They were matched with 5 patients given warfarin based on age, sex, and scored based on demographic information, comorbid conditions and medications. Included were 12,489 patients who received one of the new anticoagulant drugs (95% rivaroxaban) and 47,036 patients who received warfarin. Outcomes included hospital admission or emergency department visit for major bleeding and all-cause mortality within 90 days after starting treatment.

The results showed that 1967 (3.3%) of patients had a major bleed and 1029 (1.7%) died after a follow up of 85.2 days. The risk for major bleeding was similar for warfarin and the DOAC's 0.92; 95% confidence interval [CI], 0.82 - 1.03).

Since most patients were given rivaroxaban, the study was unable to demonstrate safety between the different agents, however they found no evidence of heterogeneity across centers, between patients with and without chronic kidney disease, across age groups, or between male and female patients.

Presently, DOAC's are contraindicated in patients with chronic kidney disease due to the high bleeding risk, so further data is needed. This study assessed the safety of the new anticoagulant drugs in patients with an estimated glomerular filtration rate less than 50 mL/min found the bleeding risks to be strongly related to percentage renal excretion of the agent.

While rivaroxaban and apixaban (which have renal excretion below 50%) showed a reduced risk for major bleeding vs warfarin, dabigatran (which has a higher renal excretion) showed no reduction in the risk for major bleeding.


Successful Intravenous Thrombolysis for Ischemic Stroke After Reversal of Dabigatran Anticoagulation With Idarucizumab

Sergio Agosti; Laura Casalino; Enrico Rocci; Gabriele Zaccone; Eugenia Rota

J Med Case Reports. 2017;11(224)


Background: Non-vitamin K antagonist oral anticoagulants, including dabigatran, are currently widely used for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation. Recently, idarucizumab, a monoclonal antibody fragment for immediate reversal of dabigatran-induced anticoagulation, has been introduced into the market to be used in life-threatening bleeding or urgent surgery, allowing for rapid normalization of clotting parameters. The use of idarucizumab is not yet well established in patients presenting with acute ischemic stroke on dabigatran who are candidates for thrombolytic therapy.

Case Presentation: We report the case of a 71-year-old hypertensive Caucasian woman with non-valvular atrial fibrillation treated with dabigatran 150 mg twice daily, who presented with acute ischemic stroke causing right-sided hemiparesis and aphasia. Two hours after presentation to the emergency department, a decision was made to administer idarucizumab for achieving complete reversal of any potential anticoagulant effect of dabigatran and, in the absence of any contraindications, our patient underwent successful thrombolysis. At discharge, our patient was able to walk unassisted and had only residual aphasia. Twenty days later, she had completely recovered motor function of her right side, with further progressive improvement of aphasia. Repeat cranial computed tomography confirmed the absence of hemorrhage, and anticoagulant therapy with dabigatran 150 mg twice daily was resumed.

Conclusions: Our case report adds to the evidence that idarucizumab administration is safe in the setting of patients with atrial fibrillation treated with dabigatran who develop acute ischemic stroke requiring thrombolysis.

Saturated Fat Does Not Clog the Arteries
Coronary Heart Disease Is a Chronic Inflammatory Condition, the Risk of Which Can Be Effectively Reduced From Healthy Lifestyle Interventions

Aseem Malhotra; Rita F Redberg; Pascal Meier

Br J Sports Med. 2017;51(15):1111-1112.

Abstract and Introduction

Introduction: Coronary artery disease pathogenesis and treatment urgently requires a paradigm shift. Despite popular belief among doctors and the public, the conceptual model of dietary saturated fat clogging a pipe is just plain wrong. A landmark systematic review and meta-analysis of observational studies showed no association between saturated fat consumption and (1) all-cause mortality, (2) coronary heart disease (CHD), (3) CHD mortality, (4) ischaemic stroke or (5) type 2 diabetes in healthy adults.[1]Similarly in the secondary prevention of CHD there is no benefit from reduced fat, including saturated fat, on myocardial infarction, cardiovascular or all-cause mortality.[2] It is instructive to note that in an angiographic study of postmenopausal women with CHD, greater intake of saturated fat was associated with less progression of atherosclerosis whereas carbohydrate and polyunsaturated fat intake were associated with greater progression.

Replacing Warfarin With a Novel Oral Anticoagulant: Risk of Recurrent Bleeding and Stroke in Patients With Warfarin Ineligible or Failure in Patients With Atrial Fibrillation (The ROAR Study)

Mohit K. Turagam MD; Valay Parikh MD; Muhammad R. Afzal MD; Rakesh Gopinathannair MD; Madhav Lavu MD; Arun Kanmanthareddy MD; Jayasree Pillarisetti MD; Madhu Reddy MD; Donita Atkins RN; Sudharani Bommana MSc; Melissa Jaeger RN; Courtney Jeffery NP; Sanghamitra Mohanty MD; Pasquale SantangeliMD; Jie Cheng MD; Luigi Di Biase MD; Calambur Narasimhan MD; Andrea Natale MD; Dhanunjaya Lakkireddy MD

J Cardiovasc Electrophysiol. 2017;28(8):853-861.

Abstract and Introduction

Background: A significant proportion of patients treated with warfarin for atrial fibrillation (AF) become warfarin ineligible (WI) due to major bleeding events (MBE) or systemic thromboembolism (STE). We report a large multicenter real-world experience of the use of direct oral antagonists (DOACs) in these WI patients.

Methods: We report the outcomes of 263 WI patients treated with DOACs. The primary objective was to evaluate clinical outcomes of STE and MBE with DOACs. Secondary objective was to assess clinical predictors of repeat MBE and STE on DOACs.

Results: Note that 63% (166 of 263) patients had a repeat MBE on DOACs. Repeat MBE was significantly higher in patients with prior gastrointestinal bleeding (74.5% vs. 30%, P < 0.0001). Five percent (12 of 263) developed repeat STE. Higher mean CHA2DS2VASC (6.5 ± 1.7 vs. 3.3 ± 1.6 = 0.001) score was associated with repeat STE. About 34% (57 of 166) of patients had an intervention to manage repeat MBE. LAAO devices were successfully used in 67% (12 of 18) high-risk patients who underwent major interventions to manage MBE.

Conclusion: In WI patients rechallenged with DOACs, a significant proportion developed repeat MBE. LAAO devices seem reasonable in those patients who undergo major interventions to manage MBE with cautious and temporary continuation of DOAC.


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