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New in Coagulation

Thursday, December 7, 2017

What's New in Coagulation - December 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.

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

Thrombectomy Up to 24 Hours Effective in Certain Strokes

Results from the DAWN trail revealed that thrombectomy 6 hours post onset of symptoms in patients with acute ischemic stroke can still be beneficial in patients who demonstrate by imaging they have salvageable brain tissue identified by a small infarct core. Disability outcomes were better in this cohort and showed that treatment should not be time dependent. Patients who presented later than 6 hours were identified as having salvageable brain tissue on the basis of "clinical-core mismatch": that is, patients who have a clinical deficit disproportionate to that expected from imaging the infarct. The trial enrolled 206 patients who had been known to be well 6-24 hours prior. They were randomly assigned to thrombectomy plus standard care or to standard care alone.

Mismatch is defined as patients with symptoms of a severe stroke indicated a large are of brain tissue isn't functioning, but when the brain is imaged only a small core is damaged. When a vessel in the brain becomes blocked, a small area of brain dies off initially. This is what we call the core. But a larger area supplied by this vessel is threatened. This is referred to as the penumbra. The penumbra area will also eventually die if left untreated, but it can survive for several hours if the collateral circulation is good. This clinical core mismatch is a critical predictor of treatment response and should not be based only on time alone as an indication for thrombectomy.

FDA Clears Rivaroxaban (Xarelto) for Extended VTE Prevention

Rivaroxaban (Xarelto, Janssen) 10 mg once daily has been cleared by the US Food and Drug Administration (FDA) for reducing the ongoing risk for recurrent venous thromboembolism (VTE) following at least 6 months of initial anticoagulation therapy, the company said today. Rivaroxaban is a factor Xa oral anticoagulant used to treat and prevent DVT and PE, and used in patients with AF for stroke prevention. The new indication allows physicians to prescribe the drug at 10mg daily in patients at risk for VTE. Rivaroxaban was noted to be more effective than aspirin in prevention of VTE without an increased risk of bleeding.

Antibody-Enhanced DES May Shorten DAPT in ACS, Claims REDUCE

The REDUCE trial looked at dual-antiplatelet therapy (DAPT) after PCI in patients with acute coronary syndromes. Despite the study being underpowered, it showed that this might sometimes be shortened to as little as 3 months using a polymer drug-eluting stent (DES) loaded with sirolimus and an endothelium-promoting antibody. However, results need to be confirmed in large randomized trials and questions were also raised regarding its mixed-bag composite primary end point. Others took issue with the declaration of noninferiority for 3-month DAPT, which was compared with 12-month DAPT in the diverse ACS cohort, when some predefined secondary end points for shorter DAPT "went in the wrong direction" even if they fell short of significance.

The novel COMBO stent (OrbusNeich) used in REDUCE not only elutes restenosis-fighting sirolimus, it also administers an antibody agent that attracts endothelial progenitor cells. They promote reendothelialization at the PCI target site, which is supposed to reduce the risk of thrombosis. This device is CE marked. The message from REDUCE is that the ultrashort 3-month DAPT duration is noninferior to a more conventional 12-month course of DAPT specifically in patients with ACS getting a DES. The trial's 1496 patients included about one-half with ST-segment-elevation MI (STEMI) and about half with either unstable angina or non-STEMI.

At 12 months for the 751 patients randomized in hospital to the short DAPT course and the 745 randomized to the longer DAPT duration showed an 8.2% and 8.4% rate for the primary end point, respectively (odds ratio 0.97, 95% CI 0.67-1.41, Pnoninferiority <0.001).

The primary end point was a composite of all-cause mortality, MI, stent thrombosis, stroke, target-vessel revascularization (TVR), and Bleeding Academic Research Consortium (BARC) 2, 3, or 5 bleeding. Patients were entered over 2 years at 36 hospitals in Europe and Asia.

New Practice Discharges More Pulmonary Embolism Patients

With a combination of risk stratification, treatment with rivaroxaban (Xarelto, Janssen Pharmaceuticals), and rapid follow-up, more patients with pulmonary embolism can be discharged from the emergency department instead of being admitted to the hospital, new research indicates. This helps to save money and time while protecting patients.

The study looked at patients with a diagnosis of DVT or PE over 16 months. Physicians were educated on the risk stratification, but not required to implement it. It involved 2318 patients, with 1073 treated prior to the protocol rollout versus 1245 treated after. Eligibility of patients included assessment for risk, biomarkers, measures of heart strain and PE or DVT as demonstrated with ultrasound.

Overall, the rate of discharge from the emergency department increased from 10.5% to14.8% after the roll-out. But at one of the two hospitals, the increase in discharge rates was more pronounced - from 12.2% to 19.9%. More patients with pulmonary embolism or deep vein thrombosis were discharged on rivaroxaban after the protocol roll-out than before (58.9% vs 24.2%; P < .001). However, changes in 7-day mortality, major bleeding, and hospital readmissions were not significantly different before and after the roll-out. Of great importance is the 1 week follow up.

VTE Prophylaxis Warranted in Pregnant Women With Rare Thrombophilias

There is a 5-6 fold risk of VTE during pregnancy, and in patients with a positive history are at a high risk. Guidelines vary in their recommendation for prophylaxis in pregnancy. An observational study looked at 36 women with thrombophilia who had not received anticoagulants and without a history of VTE. Patients were observed ante or postpartum.

The highest risk was found in patients with AT deficiency (7.3% had VTE antepartum, 11.1% postpartum); protein C deficiency (3.2% and 5.4%, respectively); protein S deficiency (0.9% and 4.2%); and homozygous factor V Leiden (2.8% and 2.8%). Risk of antepartum or postpartum VTE was below 3% for women with heterozygous factor V Leiden, heterozygous prothrombin G20210A mutations, and those with compound heterozygous V Leiden and prothrombin G20210A mutations.

Women with antithrombin deficiency or protein C deficiency should be considered for ante- and postpartum VTE prophylaxis, while those with protein S deficiency should be considered only for postpartum prophylaxis.Those with more common types generally do not need preventive treatment.

Threefold Increased Stroke Risk Tied to Certain Antipsychotics

The risk of stroke is increased in older adults taking atypical antipsychotics that induce rapid metabolic changes such as weight gain and that alter lipid profiles. A three fold increased risk was found in patients taking second-generation antipsychotics who experienced a high level or an intermediate level of metabolic changes compared to their counterparts taking medications that were associated with a lower risk for metabolic changes.

It is also noted that in this population the prevalence of obesity, type 2 diabetes mellitus (T2DM), hyperlipidemia, and metabolic syndrome is increased in patients with schizophrenia, bipolar disorder, and unipolar depression, a fact that "may largely explain the increased rate of cardiovascular disease [CVD] and mortality seen in this population, as compared to the general public. There are differences in the metabolic profiles between the various medications and understanding the severity and clinical impact is important.

The study included 1008 consecutive patients who received antipsychotic medication for the first time from January 2002 to December 2007. For inclusion, patients were required to be aged 30 years or older (up to 90 years old) on index date. In addition, continuous information had to have been available for at least 1 year prior to the index date, and patients had to have been enrolled in a health plan for longer than 6 months and to have had two or more pharmacy claims during the first 6 months of treatment.

The "primary exposure of interest" was antipsychotic therapy, which the researchers defined as therapy with any antipsychotic drug that was received by the patient for the first time in his or her life. Medication was categorized based on side effects of developing metabolic abnormalities associated with CVD. They were classified as low (n=223) intermediate (n=465) and high risk (n=320). High risk also included those taking a combination of two or more antipsychotics concomitantly (n=31). Mean age was 68.7.

The primary outcome measure was time to the composite of acute MI, acute coronary syndrome, ischemic stroke, peripheral artery disease, or a new revascularization procedure. The composite secondary outcome was time to the composite primary outcome plus all-cause mortality, as well as onset of T2DM. The most frequent diagnoses were dementia (63.4%), schizophrenia (9.6%), major depression (12.4%), and bipolar disorder (11.6%).

Although cardiovascular comorbidity at baseline was higher for patients receiving low-risk antipsychotics (more previous MI and T2DM), significantly more patients in the high-risk group (14.8%) developed obesity with antipsychotic therapy, compared to the low-risk group (2.4%).Similarly, 15.9% of the high-risk and 6.7% of the low-risk groups developed T2DM, vs 5.8% of the low-risk group.

On the basis of the crude cumulative incidence of outcome measures, stroke was the cardiovascular event most associated with risk level in the antipsychotics: 10.5% and 17.2% in the intermediate- and high-risk groups, respectively, vs 9.0% in the low risk group (P < .01).

Compared to the low-risk group, high- and intermediate-risk agents also were associated with diabetes (5.8% vs 6.7% and 15.9% respectively [P < .01]), weight gain (2.4% vs 4.9% and 14.8% respectively [P < .01]), MI (1.8% vs 3.01% and 5.0%, respectively [ P = .11]), and all-cause mortality (21.5% vs 25.6% and 26.3%, respectively [P = .41]).

The higher risk for major cardiovascular events among those taking intermediate- or high-risk agents "appears" to be mostly driven by the enhanced risk of stroke among our population, something that might be due to the high prevalence of patients with dementia or related to potential direct or indirect effects of antipsychotics.

New RE-DUAL PCI Data: Dabigatran Dual Therapy Benefit Consistent

The RE-DUAL PCI study demonstrated that dual antithrombotic therapy with dabigatran and a P2Y12 inhibitor reduces the risk of bleeding better than triple therapy with warfarin in a range of patients with atrial fibrillation (AF) undergoing PCI. The benefit of dabigatran dual therapy was consistent with the main results in:

  • Patients with and without acute coronary syndrome (ACS) as the index event.
  • Those receiving drug-eluting stents (DES) or bare-metal stents.
  • Patients treated with either P2Y12 inhibitor, clopidogrel or ticagrelor.
  • The risk reduction in clinically relevant non major bleeding was 11.5% and 5.5% with twice daily 110mg and 150mg dabigatran, versus warfarin, P2Y12 inhibitor and aspirin. Notably, aspirin therapy duration was just 1 to 3 months in the study and ACS was the index indication for PCI in 50% of patients. DES were used in 83% of patients and at similar rates in ACS and non-ACS patients. The study demonstrated clinically relevant nonmajor bleeding were lower in ACS patients treated with 110-mg (14.7% vs 27.8%) and 150-mg (20.5% vs 27.1%) dabigatran dual therapy than in those treated with triple therapy and similar results were seen in non-ACS patients in dabigatran versus triple therapy.

    A trend- however nonsignificant (p=0.20) for a higher risk of MI in ACS patients on those with a lower dose of dabigatran dual therapy (6.3% vs 3.4%). While the patients on the 150mg dose presented with the same risk of MI as those on warfarin triple therapy. (3.3% vs 3.0%; P for interaction=0.82).

    Bare-Metal Stents vs DES

    In 404 patients with bare-metal stents clinically relevant nonmajor bleeding fell from 26.3% with triple therapy to 12.8% with 110-mg dabigatran dual therapy and from 25.2% with triple therapy to 14.6% with 150-mg dabigatran dual therapy. While those with DES (N=2251) rates of this bleeding outcome fell from 27.6% to 15.8% and from 26.3% to 21.4%, respectively.

    When looking at ticagrelor versus clopidogrel in dual therapy- 12% of both arms received ticagrelor. Patients receiving ticagrelor were more likely than those receiving clopidogrel to have ACS as the index reason for PCI, to be oral anticoagulation naïve, and to have dual-antiplatelet clinical complexity factors.

    The risk of clinically relevant nonmajor bleeding events was lower with ticagrelor in the 110-mg (21.2% vs 37.4%) and 150-mg (23.1% vs 34.2%) dabigatran groups than in the warfarin triple-therapy group. As well as the risk of looking at the events in patients on clopidogrel and dabigatran versus triple therapy. (14.5% vs 25.8%) or 150-mg dabigatran vs triple therapy (19.7% vs 24.7%).

    However, in this study ticagrelor versus clopidogrel comparison was not randomized, and differences did occur in the clinicial characteristics of both groups. The comparison was not adjusted for these differences.

    Real-world Study Reassures on Dabigatran Stroke, ICH Rates

    A real work study looked at the overall bleeding risks and intracranial hemorrhage rates in 25,000 patients with atrial fibrillation comparing dabigatran and warfarin. It covered all ages and regions of the US. The findings support that dabigatran is associated with a lower overall risk of stroke versus warfarin in both ischemic and hemorrhagic stroke.

    Dabigatran was associated with a decreased rate of ICH, increased risk of GI bleed and a possible increased risk of MI. (that is 1%/year versus 0.5% with warfarin). The risk is non-significant. All of these real world findings matched the results in initial the RE-LY trial. This real world study evaluated outcomes of these two drugs in populations seen in clinical practice. The results also showed that older patients and those with kidney disease had higher GI bleeding rates with dabigatran.

    These results provide reassurance about overall bleeding risks and provide insights to assist in making decisions regarding stroke prevention strategies for patients with AF.


    Antiplatelet Agents for the Treatment and Prevention of Coronary Atherothrombosis

    Carlo Patrono, MD; Joao Morais, MD; Colin Baigent, BM, BC; JeanPhilippe Collet, MD; Desmond Fitzgerald, MD; Sigrun Halvorsen, MD; Bianca Rocca, MD; Agneta Siegbahn, MD; Robert F. Storey, MD; Gemma Vilahur, PD

    J Am Coll Cardiol. 2017;70(14):1760-1776.


    Antiplatelet drugs provide first-line antithrombotic therapy for the management of acute ischemic syndromes (both coronary and cerebrovascular) and for the prevention of their recurrence. Their role in the primary prevention of atherothrombosis remains controversial because of the uncertain balance of the potential benefits and risks when combined with other preventive strategies. The aim of this consensus document is to review the evidence for the efficacy and safety of antiplatelet drugs, and to provide practicing cardiologists with an updated instrument to guide their choice of the most appropriate antiplatelet strategy for the individual patient presenting with different clinical manifestations of coronary atherothrombosis, in light of comorbidities and/or interventional procedures.

    Efficacy and Safety of Mechanical Thrombectomy in Older Adults With Acute Ischemic Stoke

    Fabrizio Sallustio, MD; Giacomo Koch, PhD; Caterina Motta, MD; Marina Diomedi, MD; Fana Alemseged, MD; Vittoria C. D'Agostino, MD; Simone Napolitano, MD; Domenico Sama, MD; Alessandro Davoli, MD; Daniel Konda, MD; Daniele Morosetti, MD; Enrico Pampana, MD; Roberto Floris, MD; Roberto Gandini, MD

    J Am Geriatr Soc. 2017;65(8):1816-1820.

    Abstract and Introduction


    Objectives To evaluate the safety and efficacy of endovascular therapy in elderly adults treated for acute ischemic stroke.

    Design Retrospective cohort study.

    Setting Comprehensive Stroke Center, University of Tor Vergata, Rome, Italy.

    Participants Elderly adults treated for acute ischemic stroke (N = 219).

    Measurements Participants were divided into two groups based on their age (n = 62, ≥80; n = 157, <80). Baseline and procedural characteristics, safety outcomes such as intracranial hemorrhage (ICH) and mortality and efficacy outcomes such as successful reperfusion and 3-month good clinical outcome of the two groups were compared. Mutivariable analysis was performed to identify predictors of clinical outcome.

    Results Intravenous thrombolysis was more frequent (67.7% vs 52.8%, P = .04), and onset to reperfusion time was shorter (318.7 ± 128.7 vs 282 ± 53.5, P = .02) in participants aged 80 and older, but no between-group differences were found in terms of successful reperfusion (69% vs 63%, P = .4), good clinical outcome (30.6% vs 34.3%, P = .6), any (37% vs 37.5%, P > .99) or symptomatic (11% vs 14%, P = .6) ICH, or mortality (40.3% vs 29.2%, P = .14). Multivariable analysis revealed that, in the older group, onset National Institute of Health Stroke Scale (NIHSS) score (odds ratio (OR) = 0.65, 95% confidence interval (CI) = 0.44–0.96, P = .03) and 24-hour clinical improvement (OR = 141.13, 95% CI = 2.96-6,720.7, P = .01) were independent predictors of 3-month functional independence.

    Conclusion These findings suggest that endovascular treatment for stroke in selected elderly adults could be safe and effective. Major determinants of outcome in this subgroup of elderly patients are presentation NIHSS score and 24-hour clinical improvement.

    Anticoagulation in Patients With Atrial Fibrillation in the Setting of Prior Hemorrhage

    Larry B. Goldstein, MD

    Stroke. 2017;48(10):2654-2659.

    An Ongoing Dilemma

    A clinician needs to counsel a patient with atrial fibrillation on the advisability of resuming anticoagulation after a parenchymal brain hemorrhage resulting in a persistent, albeit nondisabling functional impairment. The issue to be addressed is straightforward; the advice to be offered, however, is far from clear. Relevant prospective, randomized controlled trials are lacking,[1,2] and the vagaries of providing recommendations based on observational studies and experience (eminence-based medicine) often lead to choices that are later refuted when adequately tested. This is, in part, because historic event rates in populations can change over time,[3,4] and conclusions from observational studies can be affected by several biases.[5] Causing further uncertainty, the results of case–control and other nonrandomized studies may be contradictory because of differences in cohort characteristics and unmeasured confounding.[6] Yet, the patient cannot await the collection of the high-quality data required to support more definitive guidance.

    Healthcare providers turn to authoritative clinical guidelines to review current evidence-based opinions for patient evaluation and management. The American College of Chest Physicians guidelines indicate that, "In patients with a history of a symptomatic primary intracerebral hemorrhage, we suggest against the long-term use of antithrombotic therapy for the prevention of ischemic stroke."[1] The writers, however, remark that patients might benefit from antithrombotic therapy if they are at relatively low risk of recurrent intracerebral hemorrhage (ICH) and relatively high risk (>7% per year) of thromboembolic events. Similarly, the American Heart Association/American Stroke Association secondary stroke prevention guidelines suggest that, "The decision to restart antithrombotic therapy after intracerebral hemorrhage related to antithrombotic therapy depends on the risk of subsequent arterial or venous thromboembolism, the risk of recurrent ICH, and the overall status of the patient and must, therefore, be individualized to each patient. For patients with a comparatively lower risk of cerebral infarction and a higher risk of recurrent ICH or with very poor overall neurological function, an antiplatelet agent may be considered for prevention of ischemic stroke (class IIb; level of evidence B)."[2] Class IIb reflects a recommendation that may be considered because the benefit of the intervention may be greater than or equal to its risk of important complications. Level of evidence B is assigned when additional studies are needed and when the intervention's usefulness is less well established. Although reasonable, operationalizing the recommendations, including weighing the risks of thromboembolism and recurrent bleeding, and the impact of potential therapies on overall outcome in a specific patient is not trivial.

    Clinicians can struggle even when applying the guideline recommendations in individual patients who are at the relative extremes of thromboembolism risk. For example, the chance of embolic events is particularly high in patients who have rheumatic valvular heart disease (>5% per year)[7] or a mechanical prosthetic heart valve (4% per year; 95% confidence interval [CI], 2.9-5.2% rate of major embolism and 8.6% per year; 95% CI, 7.0-10.4% rate of total embolism) with the risk higher for mitral compared with aortic mechanical prostheses (rate ratio, 1.8; 95% CI, 1.4-2.2 and rate ratio, 2.4; 95% CI, 2.0-2.8 for major and total embolism, respectively) and varying with valve type.[8] This risk, which is likely considerably higher among those who also have atrial fibrillation or a prior thromboembolic event, is dramatically reduced with anticoagulation with a vitamin-K antagonist.[2]] As discussed below, even for these patients, the challenge is to balance the benefit of treatment with the chances of anticoagulation-related recurrent hemorrhage.


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