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New in Coagulation

February 5, 2018

What's New in Coagulation - February 2018

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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What COMPASS and RE-DUAL Mean for Aspirin and Triple Therapy

A commentary was presented on the results of the two studies: COMPASS and RE-DUAL and their impact on aspirin and triple therapy.

The COMPASS was a large study conducted in patients with coronary artery disease of peripheral artery disease. Patients had 3 different treatments: low dose aspirin, 5mg 2/day rivaroxaban, or 2.5mg 2/day rivaroxaban with low dose aspirin. The results showed the most benefit was derived from the low dose rivaroxaban and aspirin treatment with a 20-25% risk reduction in cardiovascular events, however 70% increase in bleeding. Noted were a reduction in mortality and stroke. This mortality benefit was also seen in the ATLAS trial which also used a low dose of rivaroxaban. However it is important to understand the cost of utilization of these drugs over a long period of time.

The largest cost reduction came from the reduction of ischemic stroke incidences including hospital costs, chronic care facilities and additional procedures. The findings support inhibiting both pathways with both drugs.

The RE-DUAL study looked at two doses of dabigatran you alluded to compared with warfarin. The key here was that both of the dabigatran doses (110 mg and 150 mg) were combined with a single agent-just clopidogrel or ticagrelor (mostly clopidogrel). Then the warfarin group got triple therapy with aspirin added on top. The results showed that in the group that did not receive aspirin had less bleeding with no significant increase in stroke. There was a slight increase in the low dose dabigatran group in thrombosis in stented patients, however the results were not significant. The subgroup analysis showed consistent results; that removing aspirin appears to be okay if you are adding a full dose of oral anticoagulant plus a full dose of P2Y12 inhibitor. It appears the addition of aspirin increases the bleeding risk.

Increased Stroke Risk Following Cardiac Procedures

Results from a national database reveal that the risk of stroke is increased the year following cardiac procedures. This may be due to concurrent vascular risk factors present and risks for stroke post cardiac surgery. Data was collected from 21 states to calculate the risk of stroke following cardiac procedures, noncardiac surgery and medical admissions. They compared: transcatheter (TAVR) versus surgical aortic valve replacement (SAVR) and coronary artery bypass graft (CABG) versus percutaneous coronary intervention (PCI).

Rates for ischemic stroke were higher in the cardiac procedures versus noncardiac. Re admission post ischemic stroke were 86% higher after TAVR and a 6 fold increase of hemorrhagic stroke. The risk of ischemic and hemorrhage stroke were similar between CABG and PCI. This may suggest that TAVR techniques may need to be addressed to reduce stroke outcomes.

Patients may benefit from having a risk index calculator for stroke risk following cardiac and non-cardiac surgeries.

FDA Clears Medtronic's Riptide Clot Aspiration System

The FDA has approved Medtronics' Riptide aspiration system. This is used to retrieve blood clots and flow in patients with acute ischemic stroke. The intended use is for use in "the revascularization of patients with acute ischemic stroke secondary to intracranial large-vessel occlusive disease (within the internal carotid, middle cerebral - M1 and M2 segments, basilar and vertebral arteries) within 8 hours of symptom onset."

This treatment can be used in patients in whom tPA therapy fails. The system includes the Medtronic Arc Catheter, Riptide Aspiration Tubing, Riptide Aspiration Pump and collection canister.

The AHA/ASA updated their guidelines on endovascular treatment for acute ischemic stroke recommending its use in certain patients. This was based on information from clinical trials.

After a Clot, Shorter Treatment With Compression Stockings May Be OK

The current recommendation for patients with blood clots in their veins is to wear compression stockings for 2 years. This is to prevent pain and swelling. A new study demonstrated that time may be reduced to six months. Patients with DVT wore stockings for six months, after the 6 months 428 patients continued to wear them for 2 years, while 437 stopped wearing them sooner, even at 6 months based on the doctors risk assessment. Patients in the 2 year group, up to 28% (n=116) developed post thrombotic syndrome similar to the 29% (n=125) in the group that stopped sooner. As a result, there may be patients who can stop wearing stockings at 6 months.

NOACs for Atrial Fibrillation: Important Drug/Drug Interactions

There are known drug interactions associated with DOACs, which include both direct Xa inhibitor and direct thrombin inhibitors.

Direct Xa inhibitors most commonly used in the US are rivaroxaban and apixaban. The drugs that have the greatest impact are ketoconazole and protease inhibitors, in particular ritonavir. These drugs can increase the area under the plasma drug concentration/time curve almost twofold. They double the risk for bleeding. There are also drugs that can increase the metabolism of Xa inhibitors. They include carbamazepine, phenytoin, St John's wort, and rifampin resulting in decreased efficacy.

Dabigatran is the only direct thrombin inhibitor used in the US. When verapamil is administered with dabigatran, the area under the curve is increased by 54%, while amiodarone results in an increase by 60%. Drugs that are formally contraindicated for use with dabigatran include cyclosporine, ketoconazole, itraconazole, and dronedarone. Certain drugs were also found to reduce the efficacy of DTI's by increasing metabolism include carbamazepine, phenytoin, and rifampin and the herb St John's wort.

A retrospective study from the Taiwan NHI database looked at over 91,000 patients with atrial fibrillation receiving at least one DOAC over of 5 year period. Data from this study provided a real world experience with possible interactions. There was a total of 4770 major bleeding events. Atorvastatin, digoxin, and diltiazem had a non-statistically significant lower risk for bleeding when they were used with the DOACs. Amiodarone had a relative risk (RR) for bleeding of 1.37 (P = 01) and was associated with significantly more bleeding events, demonstrating that the risk "probably exceeds any benefit that such a combination could deliver." Fluconazole had an RR of 2.35 (P < .01).

Of note, in this study, some of the drugs that would be anticipated to lower the effect of the DOACs actually increased the likelihood of bleeding. Those drugs were rifampin (RR, 1.57) and phenytoin (RR, 1.54). Rifampin and phenytoin should in theory increase metabolism of the NOACs, which should lead to lower levels, more rapid clearance, and decreased efficacy. That finding needs to be further studied.

The most important outcome was the interaction of amiodarone with the DOAC's, and should be avoided. This drug also interacts with warfarin, however this interaction is measurable with the PT/INR and enables dose adjustments of warfarin. This may suggest warfarin may be better used in these patients.

First Cardiopulmonary Bypass Anticoagulation Guidelines Issued

The Society of Thoracic Surgeons (STS), the Society of Cardiovascular Anesthesiologists (SCA), and the American Society of ExtraCorporeal Technology (AmSECT) have published the first clinical practice guidelines for anticoagulation therapy during cardiopulmonary bypass (CPB). These guidelines discuss the safety of anticoagulation practices during heart surgery. Surveys have shown that there is huge variability in how clinicians not only use heparin, but monitor it and reverse it. Additionally, variability exists in the utilization of alternative anticoagulation such as bivalirudin. There are no existing strategies for patients who cannot take heparin.

The guidelines were based on 96 papers published between 2000-2015, included were 17 sentinel papers also included that were published prior to 2000. There are 2 class 1 recommendations:

• A functional whole blood test of anticoagulation, in the form of a clotting time, should be measured and demonstrate adequate anticoagulation before initiation of and at regular intervals during CPB.

• Discontinuation of protamine and implementation of resuscitative measures, including reinstitution of CPB with adequate anticoagulation, may be lifesaving for patients at high risk for anaphylactic response to protamine who have pulmonary hypertension and circulatory collapse.

Additional recommendations include:

• Heparin dosing calculations may differ so long as the result achieves the desired target level of anticoagulation.

• It's reasonable to maintain an activated clotting time (ACT) above 480 seconds during CPB. However, ACT is a "gross and imperfect," test and the testing platform affects the target value of ACT.

• Heparin reversal should be carefully calculated with low doses of protamine, so long as heparin rebound is controlled for.

Regarding heparin reversal, there is insufficient data to support any alternative reversal agents beside protamine.

A class IIa recommendation is that bivalirudin is an option in patients requiring CPB with a diagnosis of HIT. An additional class IIb recommendation in patients with renal dysfunction states using plasmapheresis, argatroban or heparin with antiplatelet agents may be considered, however there is a risk of increased bleeding.


Randomized Controlled Trial of Early Versus Delayed Statin Therapy in Patients With Acute Ischemic Stroke

ASSORT Trial (Administration of Statin on Acute Ischemic Stroke Patient)

Shinichi Yoshimura, MD, PhD; Kazutaka Uchida, MD; Takashi Daimon, PhD; Ryuzo Takashima, BA; Kazuhiro Kimura, PhD; Takeshi Morimoto, MD, PhD, MPH

Stroke. 2017;48(11):3057-3063.

Abstract and Introduction

Background and Purpose: Several studies suggested that statins during hospitalization were associated with better disability outcomes in patients with acute ischemic stroke, but only 1 small randomized trial is available.

Methods: We conducted a multicenter, open-label, randomized controlled trial in patients with acute ischemic strokes in 11 hospitals in Japan. Patients with acute ischemic stroke and dyslipidemia randomly received statins within 24 hours after admission in the early group or on the seventh day in the delayed group, in a 1:1 ratio. Statins were administered for 12 weeks. The primary outcome was patient disability assessed by modified Rankin Scale at 90 days.

Results: A total of 257 patients were randomized and analyzed (early 131, delayed 126). At 90 days, modified Rankin Scale score distribution did not differ between groups (P=0.68), and the adjusted common odds ratio of the early statin group was 0.84 (95% confidence interval, 0.53-1.3; P=0.46) compared with the delayed statin group. There were 3 deaths at 90 days (2 in the early group, 1 in the delayed group) because of malignancy. Ischemic stroke recurred in 9 patients (6.9%) in the early group and 5 patients (4.0%) in the delayed group. The safety profile was similar between groups.

Conclusions: Our randomized trial involving patients with acute ischemic stroke and dyslipidemia did not show any superiority of early statin therapy within 24 hours of admission compared with delayed statin therapy 7 days after admission to alleviate the degree of disability at 90 days after onset.

Effect of New Oral Anticoagulants on Prescribing Practices for Atrial Fibrillation in Older Adults

Raymond B. Fohtung, MD; Eric Novak, MS; Michael W. Rich, MD

J Am Geriatr Soc. 2017;65(11):2405-2412.

Abstract and Introduction

Objectives: To determine the effect of new oral anticoagulants (NOACs) on prescribing practices in older adults with atrial fibrillation (AF).

Design: Retrospective observational cohort study.

Setting: Academic medical center in St. Louis, Missouri.

Participants: Individuals aged 75 and older with AF admitted to the hospital from October 2010 through September 2015 (N = 6,568, 50% female, 15% non-white).

Measurements: Information on NOACs and warfarin prescribed at discharge was obtained from hospital discharge summaries, and linear regression was used to examine quarterly trends in their use. Multivariable logistic regression was used to assess independent predictors of anticoagulant use.

Results: NOAC use increased over time (correlation coefficient (r) = 0.87, P < .001), warfarin use did not change (r = -0.16, P = .50), and overall anticoagulant use (NOACs and warfarin) increased (r = 0.68, P = .001). NOAC use increased over time in all age groups (75-79, 80-84, 85-89) except aged 90 and older, but increasing age attenuated the rate of NOAC uptake. There was no consistent relationship between age and warfarin or overall anticoagulant use, except that individuals aged 90 and older had consistently lower use. Overall, fewer than 45% of participants were prescribed an anticoagulant. In multivariable analysis, younger age, white race, female sex, higher hemoglobin, higher creatinine clearance, being on a medical service, hypertension, stroke or transient ischemic attack, no history of intracranial hemorrhage, and a modified HAS-BLED score of less than 3 increased the likelihood of receiving NOACs.

Conclusion: Prescription of anticoagulants for AF increased in older adults primarily because of an increase in the use of NOACs. Nonetheless, fewer than 45% of participants were prescribed an anticoagulant. Additional research is needed to optimize prescribing practices for older adults with AF.

Knowledge Translation of the PERC Rule for Suspected Pulmonary Embolism

A Blueprint for Reducing the Number of CT Pulmonary Angiograms

Michael J. Drescher, MD; Jeremy Fried, MD; Ryan Brass, MD; Amanda Medoro, MD; Timothy Murphy, MD; Joao Delgado, MD

Western J Emerg Med. 2017;18(6):1091-1097.

Abstract and Introduction

Introduction: Computerized decision support decreases the number of computed tomography pulmonary angiograms (CTPA) for pulmonary embolism (PE) ordered in emergency departments, but it is not always well accepted by emergency physicians. We studied a department-endorsed, evidence-based clinical protocol that included the PE rule-out criteria (PERC) rule, multi-modal education using principles of knowledge translation (KT), and clinical decision support embedded in our order entry system, to decrease the number of unnecessary CTPA ordered.

Methods: We performed a historically controlled observational before-after study for one year pre- and post-implementation of a departmentally-endorsed protocol. We included patients > 18 in whom providers suspected PE and who did not have a contraindication to CTPA. Providers entered clinical information into a diagnostic pathway via computerized order entry. Prior to protocol implementation, we provided education to ordering providers. The primary outcome measure was the number of CTPA ordered per 1,000 visits one year before vs. after implementation.

Results: CTPA declined from 1,033 scans for 98,028 annual visits (10.53 per 1,000 patient visits (95% CI [9.9-11.2]) to 892 scans for 101,172 annual visits (8.81 per 1,000 patient visits (95% CI [8.3-9.4]) p<0.001. The absolute reduction in PACT ordered was 1.72 per 1,000 visits (a 16% reduction). Patient characteristics were similar for both periods.

Conclusion: Knowledge translation clinical decision support using the PERC rule significantly reduced the number of CTPA ordered.

Risk of Venous Thromboembolism in Patients by Albuminuria and Estimated GFR

David Massicotte-Azarniouch, MD; Anan Bader Eddeen, MSc; Alejandro LazoLanger, MD; Amber O. Molnar, MD; Ngan N. Lam, MD; Megan K. McCallum, MPH; Sarah Bota, MPH; Deborah Zimmerman, MD; Amit X. Garg, MD; Ziv Harel, MD; Jeffery Perl, MD; Ron Wald, MD; Manish M. Sood, MD

Am J Kidney Dis. 2017;70(6):826-833.

Abstract and Introduction

Background: The risk for venous thromboembolism (VTE) is elevated with albuminuria or a low estimated glomerular filtration rate (eGFR). However, the VTE risk due to the combined effects of eGFR and albuminuria are unknown.

Study Design: Population-based cohort study.

Settings & Participants: 694,956 adults in Ontario, Canada, from 2002 to 2012.

Factors: eGFR and albumin-creatinine ratio (ACR).

Outcome: VTE.

Results: 15,180 (2.2%) VTE events occurred during the study period. Both albuminuria and eGFR were independently associated with VTE. The association of albuminuria and VTE differed by level of eGFR (P for ACR x eGFR interaction < 0.001). After considering the competing risk for death, there was a 61% higher rate of VTE in patients with normal eGFRs (eGFRs > 90 mL/min/1.73 m2 and heavy albuminuria (ACR > 300 mg/g) compared with those with normal eGFRs and no albuminuria (subdistribution HR, 1.61; 95% CI, 1.38-1.89). Among those with reduced kidney function (eGFR, 15-29 mL/min/1.73 m2, the risk for VTE was only minimally increased, irrespective of albuminuria (subdistribution HRs of 1.23 [95% CI, 1-1.5] and 1.09 [95% CI, 0.82-1.45] for ACR < 30 and >300 mg/g, respectively).

Limitations: Only single determinations of ACR and eGFR were used. Diagnostic/International Classification of Diseases codes were used to define VTE.

Conclusions: Albuminuria increases the risk for VTE markedly in patients with normal eGFRs compared with those with lower eGFRs.

Thromboembolic Events in PICU: A Descriptive Study

Pam Austin; Sceria Jenkins; Annette Hines

Pediatr Nurs. 2017;43(3):132-137.

Abstract and Introduction

In response to an increased incidence of deep vein thrombosis (DVT) in a pediatric intensive care unit (PICU), nurses and physicians convened at an interprofessional meeting to discuss the problem and planned this descriptive study. The purpose of the study was to describe the characteristics of children who are in the PICU with a central venous access device (CVAD) and develop a DVT. Because prevention and early recognition of DVT decreases morbidity and mortality, identifying at-risk children is important. The study used a descriptive design with a chart review that included 42 charts from 2007-2012 and 34 charts during the 12-month prospective arm (N = 76). Although correlations did not reach statistical significance, the results may have clinical importance. Overall, the age and weight of children with DVT were less than children without DVT. There were six children with DVTs in the sample; the most common admitting diagnosis for children with DVT was respiratory condition/infection, which is consistent with infections as an established risk factor for DVT. Laboratory values were evaluated; children with DVT had lower white blood cell counts, lower hemoglobin levels, and higher hematocrits. Use of a standardized reliable screening tool, promoting adequate hydration status, and interprofessional electronic documentation are clinical recommendations.


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