What's New in Coagulation - October 2017

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

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Recalled in US: Three Lots of Alteplase (Activase), Vial Leakage Hazard

Lots 3128243, 3141239, and 3166728 of alteplase 100mg (Activase, Genentech/Roche) shipped to US hospitals from January 6, 2017 to May 19, 2017 have been recalled. This is due to vials of water for injection may be cracked or leaking and are no longer sterile. However, there have not been any reports of adverse events associated with the recall. The indication for use in the US with Alteplase is for acute ischemic stroke given within 3 hours of onset, acute MI and acute massive PE. All recalled products should be returned.

MAUDE: Post-TAVR Leaflet Thrombosis Not Benign

Leaflet thrombosis has already been highlighted as a link with stroke or transient ischemic attack (TIA), and now a new study suggests leaflet thrombosis after transcatheter aortic-valve replacement (TAVR) is also associated with cardiogenic shock and death. In 5691 TAVR related adverse events there were 30 cases of structural valve dysfunction due to leaflet thrombosis. Of that group there were nine deaths, 3 had stroke/TIA and 2 developed cardiogenic shock. The RESOLVE and SAVORY registries analysis of 890 patients revealed subclinical leaflet thrombosis is far more common in transcatheter than surgical aortic valves (13.4% vs 3.6%) and in patients on dual antiplatelet therapy (DAPT) than on oral anticoagulation (14.9% vs 3.6%). All of this needs to be considered, however actual incidence is unknown. But data supports routine post TAVR follow-up is needed to ensure that early signs of valve dysfunction are evaluated.

Notably, 60% of leaflet-thrombosis cases occurred in the first year following TAVR, but 40% of events occurred later, even 5 years after implantation. Leaflet thrombosis was managed with escalation of antiplatelet or anticoagulant therapy in eight cases, valve-in-valve TAVR in three, and surgery in 14, but also with diuretics in one, thrombus aspiration in one, balloon aortic valvuloplasty in two, and no intervention in two.

New ESC Guideline on Peripheral Arterial Disease

New guidelines reveal that patients with peripheral arterial disease (PAD) should receive multidisciplinary management from a "vascular team" that involves specialties outside of cardiovascular medicine and surgery due to the complex nature of this disorder. PAD includes atherosclerosis of the extracranial carotid and vertebral, mesenteric, renal, upper- and lower-extremity arteries. All of this place patients at increased risk of fatal and nonfatal cerebrovascular events, MI, and cardiac death. These guidelines look at the use of antithrombotic drugs and have updated the recommendations on the management disorders including carotid artery disease, lower extremity disease, and renal artery disease as well as managing patient with comorbidities including heart failure, AF and valvular heart disease. A multidisciplinary approach must be used to ensure long-term management and reassessment of patients.

Recommendation for 2017 include several new or revised concepts in the way in which clinicians should approach their management of PAD:

  1. All patients should be screened for heart failure based on brain natriuretic peptide levels and transthoracic echocardiography, and patients with stable PAD and other conditions requiring anticoagulants, such as AF, should be given anticoagulation alone (both class IIa).
  2. In CAD, the recommendation that embolic-protection devices should be used in asymptomatic patients with 60% to 99% carotid stenosis during carotid stenting has been strengthened from class IIb to IIa, while surgery should now be reserved for those with a high stroke risk, among other changes from the 2011 guidelines.
  3. New for 2017 is that coronary angiography should be performed before elective carotid surgery in CAD patients. Also, although routine prophylactic revascularization should not be given to all CAD patients with asymptomatic carotid stenosis of 70% to 99% undergoing CABG (class III), it may be considered for those with 70% to 99% carotid stenosis in the presence of "one or more characteristics that may be associated with an increased risk of ipsilateral stroke in order to reduce stroke risk beyond the perioperative period" (class IIb) and in patients with bilateral 70% to 99% occlusions or 70% to 99% occlusion plus a contralateral occlusion (class IIb).
  4. There are a number of changes and novel recommendations in the field of LEAD, such as refinements to the management of aorto-iliac and infrapopliteal lesions, and new class I recommendations to give statins to LEAD patients and to administer anticoagulation to LEAD patients with AF, if they have a CHA2DS2-VASc score >2.
  5. Upper-extremity artery disease also sees changes, with the 2011 recommendation to perform revascularization for symptomatic subclavian artery stenosis weakened from class I to class IIa, and the previous class I recommendation to perform endovascular treatment first for subclavian stenosis revascularization switched to a class IIa recommendation to carry out stenting or surgery, among other changes.
  6. Other recommendations added to the guidelines for the first time include the use of D-dimers to rule out acute mesenteric ischemia in patients with mesenteric artery disease (class IIb) and a class III recommendation not to delay renutrition in cases of symptomatic chronic mesenteric ischemia.
  7. It is also recommended that renal artery disease patients with fibromuscular dysplasia receive balloon angioplasty without bailout stenting, which is a class IIa recommendation. There is less confidence in the use of stenting for renal-artery patients who have symptomatic atherosclerotic stenosis >60%, with the recommendation weakened from class IIb in 2011 to class III in the current version of the guidelines.
  8. In terms of novel and revised concepts in patient management, the guidelines emphasize the importance of the "vascular team" in the multidisciplinary management of PAD patients, including initiatives to improve awareness of PAD and the use of the best pharmacological and nonpharmacological interventions to optimize outcomes.
  9. Within CAD, the need for risk stratification for asymptomatic patients is highlighted, as well as the view that the revascularization of severe carotid stenosis in CABG patients should not be performed systematically but on a case-by-case basis.
  10. The themes of the individualization of therapy and the use of the latest management strategies are also given weight in the treatment of LEAD patients, including the blanket prescription of statins and supervised exercise therapy in patients with claudication, even after revascularization.
  11. It is underlined that PAD patients often have comorbid cardiac conditions, such as heart failure and AF, and vice versa.

Consequently, the guidelines recommend that patients considered for heart transplantation or cardiac assist device implantation undergo a full vascular assessment, while those having transcatheter aortic-valve implantation or other structural interventions should be screened for PAD.

Apixaban Advantage Before AF Cardioversion Hinted in EMANATE Trial

A randomized trial tentatively pointing to fewer strokes vs standard therapy when a direct oral anticoagulant (DOAC) is used before cardioversion for atrial fibrillation (AF) may edge the field forward in a few ways. Prior DOAC studies in the same clinical setting, the current trial used apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) and was limited to anticoagulant-naïve patients or those with <48 hours anticoagulant exposure. The EMANATE trial (n=1500) supported an accelerated cardioversion schedule in which the procedure can be performed as soon as 2 hours after the start of bolus-dosed apixaban, with or without transesophageal echocardiography (TEE) or CT to show or rule out potentially embolic atrial thrombus.

They used a 5 or 10 mg bolus as opposed to 3-4 weeks of anticoagulation before cardioversion. No strokes were seen in 753 patients getting apixaban, however there were 6/747 with strokes in those receiving standard anticoagulants. Overall there were three and six major bleeds, respectively, and two deaths on apixaban vs one among controls. No cases of extracranial systemic emboli were seen. Among the 342 patients who received apixaban bolus dosing with accelerated cardioversion, there was one death, one major bleed, and four clinically relevant nonmajor bleeds.

The trial nonetheless supports using apixaban as anticoagulant pretreatment in patients.

ESC Guideline Update on Dual Antiplatelet Therapy in CAD

A new guideline update has been issues by The European Society of Cardiology on dual antiplatelet therapy (DAPT)-aspirin plus a P2Y12 inhibitor-in coronary artery disease (CAD). The focus of this document is based on central decision making about the type and duration of DAPT versus the previous guideline which addressed more individualized patient focus. This is due to the use of the PRECISE DAPT score. This score takes into account age, renal function, history of bleeding, and allows accurate quantification of bleeding risk resulting in more individual decisions to be made. The document highlights who should and should not receive long-term treatment, while outlining how to maximize the expected benefits over the risks. For example, if the bleeding risk is higher, DAPT should be shorter.

Key messages in the update include the following:

  • For ACS patients, the default DAPT duration should be 12 months, irrespective of the revascularization strategy (medical therapy, PCI, or CABG surgery). Six months of DAPT should be considered in patients at high bleeding risk (PRECISE-DAPT score ≥25). Therapy longer than 12 months may be considered in ACS patients who have tolerated DAPT without a bleeding complication.
  • The need for a short DAPT regimen should no longer justify the use of bare-metal stents instead of newer-generation drug-eluting stents. DAPT duration should be guided by an assessment of the individual patient's ischemic vs bleeding risks and not by the stent type.
  • Irrespective of the type of metallic stent implanted, the duration of DAPT in stable CAD patients treated with PCI should be 1 to 6 months depending on the bleeding risk. A longer DAPT duration may be considered in patients whose ischemic risk is greater than the risk of bleeding.
  • There are insufficient data to recommend DAPT in stable CAD patients treated with CABG.
  • The addition of DAPT to oral anticoagulation therapy increases the risk of bleeding complications by two- to threefold. The indication for oral anticoagulation should be reassessed and treatment continued only if there is a compelling indication such as atrial fibrillation, a mechanical heart valve, or recent history of recurrent deep venous thrombosis or pulmonary embolism. The duration of triple therapy (DAPT plus oral anticoagulation) should be limited to 6 months or omitted after hospital discharge, depending on the ischemic and bleeding risks.
  • Clopidogrel is recommended as the default P2Y12 inhibitor in patients with stable CAD treated with PCI, patients with an indication for oral anticoagulation, and ACS patients in whom ticagrelor (Brilinta/Brilique, AstraZeneca) or prasugrel (Effient/Efient , Eli Lilly/Daiichi Sankyo) are contraindicated. Ticagrelor or prasugrel is recommended for ACS patients unless there are drug-specific contraindications.
  • The decision on when to initiate a P2Y12 inhibitor depends on both the specific drug and the specific disease (stable CAD vs ACS).

Data Bolster Dual Antithrombotic Therapy in AF PCI Patients

Based on the results of the RE-DUAL PCI study, AT patients are at a lower risk of bleeding after PCI when treated with dabigatran and a P2Y12 inhibitor but not aspirin. The absolute reduction in major or clinically relevant nonmajor bleeding according to ISTH criteria was 11.5% with 110-mg dabigatran twice daily plus clopidogrel or ticagrelor (Brilinta/Brilique, AstraZeneca) compared with triple therapy with warfarin, clopidogrel or ticagrelor, and aspirin (15.4% vs 26.9%; P7<0.001 for noninferiority and superiority). The absolute risk reduction (ARR) in the primary end point was 5.5% with dabigatran at the 150-mg twice-daily dose vs triple therapy (20.2% vs 25.7%; P<0.001 for noninferiority).

There did not appear to be an increase in thrombotic events after aspirin was withdrawn between 1-3 months Dabigatran was noninferior to triple therapy for the composite of death, thromboembolic event or unplanned revascularization (13.7% vs. 13.4%). The AUGUSTUS ongoing trial, uses apixaban versus warfarin and aspirin versus no aspirin should provide more information regarding stopping aspirin while on apixaban. Additional supportive evidence for dropping aspirin was seen in the WOEST and PIONEER AF-PCI study with lower doses of rivaroxaban.

In RE-DUAL PCI, 2725 patients (mean age 70.8 years) with nonvavular AF undergoing PCI received aspirin and other standard therapies for the procedure and were randomized within 5 days (average 1.1 days) into one of the three long-term antithrombotic strategies based on age and location. Because patients aged 80 years or older outside the US and aged 70 years or older in Japan are not eligible for the 150-mg dabigatran dose, 427 elderly patients were assigned to dabigatran 110-mg dual therapy or warfarin triple therapy. Overall, about 75% of patients were men, a third had diabetes, half had ACS as the indication for PCI, and most received clopidogrel, with only 12% of patients receiving ticagrelor. In the triple-therapy group, aspirin was given for 1 month after implantation with a bare-metal stent and for 3 months with a drug-eluting stent. The mean time in the target INR range was 64%.

Over a mean follow-up of 14 months, rates of TIMI major bleeding were lower with dual than with triple therapy, as was the rare outcome of intracranial hemorrhage. There were also nonsignificant increases in thromboembolic end points, however the study did not have sufficient power to examine these differences.

Commentary: Kawasaki Disease: High- OR Low-Dose Aspirin?

Intravenous immunoglobulin and aspirin are standard of care for Kawasaki disease, due that 15%-25% of children who are untreated will develop coronary artery aneurysms or dilation. Whether higher-dose aspirin should be given to achieve anti-inflammatory effects beyond the antithrombotic effects of lower-dose aspirin is unclear as is if it reduces cardiovascular morbidity. In a retrospective outcome study in which children 0-10 years of age received low dose versus high dose aspirin were compared. They looked at 3-5 mg/kg/day versus 80mg/kg/day. Investigators were interested in coronary artery abnormality. The study took a noninferiority approach in that the two treatment doses would be considered noninferior if the difference in the risk for coronary artery abnormalities was ≤5%. The analysis cohort included 1213 children, 848 of whom were treated at high-dose aspirin institutions. In general, the treatment groups were not different at enrollment for age, sex, or duration of fever before treatment.

Coronary artery abnormality was found in 21% of children, but half were considered transient since they were no longer present post 6 week evaluation, but persisted in 12.9% of children. Frequency was similar in both high and low dose aspirin (20.5 vs.22.2%). Abnormalities persisted in 13.2% of high dose patients compared with 12.3% of low dose patients. The investigators concluded that with respect to coronary artery abnormalities or secondary outcomes, low-dose aspirin is not inferior to high-dose aspirin treatment of Kawasaki disease.

Commentary: Menopausal Hormone Therapy: Why Mortality Outcomes are 'Vital'

This is a discussion looking the Women's Health Initiative (WHI) hormone therapy trials that looked at all-cause and cause-specific mortality during the intervention phases and cumulative follow-up for an average of 18 years. The two parallel trials included more than 27,000 women. One trial looked at estrogen plus progestin and the other at estrogen alone. During the follow-up, more than 7000 deaths occurred. This is more than twice as many deaths as included in our earlier analyses.

Why is all-cause mortality an important endpoint to examine? With an intervention such as hormone therapy, with a complex pattern of benefits and risk, all-cause mortality provides a critically important summary measure, showing the net effect of the intervention on serious and life-threatening health outcomes. Hormone therapy has known benefits, including a reduction in symptoms and in hip fracture and other fractures. Hormone therapy has also been linked to risks such as venous thromboembolism, stroke, and, with estrogen plus progestin, increased risk for breast cancer. In terms of mortality in the overall study population, which comprised women ages 50-79 years (mean age, 63 years), we found a neutral effect of hormone therapy in both trials during both the intervention phase and the cumulative 18-year follow-up period for all-cause mortality and for mortality from cardiovascular disease and cancer.

We used a preplanned analysis to look at the results by age group, however, and in women who were 50-59 years of age, we saw a signal for reduced mortality with hormone therapy during the intervention phase of both trials. In the pooled analysis of the two trials, the hazard ratio was 0.69 with a P value of 0.01 for differences across age groups. This suggested significant differences depending upon age, with more favorable results in the younger women. With the cumulative 18-year follow-up, however, the test for trend by age groups was attenuated and no longer statistically significant.

The study showed that there was a significantly reduced risk in the estrogen-alone trial for dementia mortality, with a hazard ratio of 0.74 and a P value of .01. Looking at estrogen plus progestin, we found a neutral effect on dementia mortality. Results were also neutral for cancer mortality in both trials. For breast cancer mortality, the results diverged between the two trials, with an increased risk with estrogen plus progestin and a decreased risk with estrogen alone. Clinical implications of these findings endorse the use of hormone therapy for moderate to severe menopausal symptoms who do not have contraindications to treatment. However, the findings did not support hormone therapy for the prevention of cardiovascular disease since results were neutral.


Effect of Pulmonary Arteriovenous Malformations on the Mechanical Properties of the Lungs

Cécile Rotenberg; Marcel Bonay; Mostafa El Hajjam; Sandra Blivet; Alain Beauchet; Pascal Lacombe; Thierry Chinet

BMC Pulm Med. 2017;17(64)


Background: Pulmonary arteriovenous malformations (PAVMs) are present in approximately 15-50% individuals with hereditary hemorrhagic telangiectasia (HHT). They may be isolated but more often are multiple. The goal of this study was to evaluate the influence of PAVMs on lung mechanical properties.

Methods: We reviewed the files of all adult patients (age ≥ 18 years) referred to our Center for evaluation of HHT between 2005 and 2013. The diagnosis of HHT was based on the Curacao criteria and/or the presence of a pathogenic mutation. Exclusion criteria included: chronic cardiac or lung disease (i.e. asthma or COPD), suspicion of pulmonary hypertension on echocardiography, current or past smoking (>10 pack-years), history of thoracic surgery, previous treatment of PAVMs by embolotherapy, lung infection or thromboembolic disease in the past 3 months, pregnancy and obesity (BMI > 30 kg/m2). Chest high resolution CT-scan and pulmonary function tests were performed the same day in all patients as part of our routine work-up.

Results: One hundred and fifty-five patients with HHT were included (age: 44.4 ± 16.7 yrs - mean ± SD -; males: 39%). Eighty-eight patients had no PAVM, 45 had 1-3 PAVMS and 22 had at least 4 PAVMs. Thirty-eight patients had unilateral PAVMs and 29 bilateral PAVMs. We found no statistical relationship between the number, the size and the laterality of PAVMs and results of lung flows and volumes.

Conclusion: We found no evidence that PAVMs have a significant influence on lung mechanical properties as measured using routine pulmonary function tests in adult patients with HHT, even in case of numerous, macroscopic or bilateral malformations.

Predicting the Risk of Bleeding During Dual Antiplatelet Therapy After Acute Coronary Syndromes

Joakim Alfredsson; Benjamin Neely; Megan L Neely; Deepak L Bhatt; Shaun G Goodman; Pierluigi Tricoci; Kenneth W Mahaffey; Jan H Cornel; Harvey D White; Keith AA Fox; Dorairaj Prabhakaran; Kenneth J Winters; Paul W Armstrong; E Magnus Ohman; Matthew T Roe

Heart. 2017;103(15):1168-1176.


Objectives: Dual antiplatelet therapy (DAPT) with aspirin + a P2Y12 inhibitor is recommended for at least 12 months for patients with acute coronary syndrome (ACS), with shorter durations considered for patients with increased bleeding risk. However, there are no decision support tools available to predict an individual patient's bleeding risk during DAPT treatment in the post-ACS setting.

Methods: To develop a longitudinal bleeding risk prediction model, we analyzed 9240 patients with unstable angina/non-ST segment elevation myocardial infarction (NSTEMI) from the Targeted Platelet Inhibition to Clarify the Optimal Strategy to Medically Manage Acute Coronary Syndromes (TRILOGY ACS) trial, who were managed without revasculari sation and treated with DAPT for a median of 14.8 months.

Results: We identified 10 significant baseline predictors of non-coronary artery bypass grafting (CABG)-related Global Use of Strategies to Open Occluded Arteries (GUSTO) severe/life-threatening/moderate bleeding: age, sex, weight, NSTEMI (vs unstable angina), angiography performed before randomi sation, prior peptic ulcer disease, creatinine, systolic blood pressure, haemoglobin and treatment with beta-blocker. The five significant baseline predictors of Thrombolysis In Myocardial Infarction (TIMI) major or minor bleeding included age, sex, angiography performed before randomi sation, creatinine and haemoglobin. The models showed good predictive accuracy with Therneau's C-indices: 0.78 (SE = 0.024) for the GUSTO model and 0.67 (SE = 0.023) for the TIMI model. Internal validation with bootstrapping gave similar C-indices of 0.77 and 0.65, respectively. External validation demonstrated an attenuated C-index for the GUSTO model (0.69) but not the TIMI model (0.68).

Conclusions: Longitudinal bleeding risks during treatment with DAPT in patients with ACS can be reliably predicted using selected baseline characteristics. The TRILOGY ACS bleeding models can inform risk -benefit considerations regarding the duration of DAPT following ACS.

Neuroprotection in Stroke: The Importance of Collaboration and Reproducibility

Ain A. Neuhaus; Yvonne Couch; Gina Hadley; Alastair M. Buchan

Brain. 2017;140(8):2079-2092.

Abstract and Introduction

Abstract: Acute ischemic stroke accounts for 6.5 million deaths per year, and by 2030 will result in the annual loss of over 200 million disability-adjusted life years globally. There have been considerable recent advances in the gold standard of acute ischemic stroke treatment, some aspects of which-aspirin to prevent recurrence, and treating patients in specialized stroke wards-are widely applicable. Recanalization of the occluded artery through thrombolysis and/or endovascular thrombectomy is restricted to only a small proportion of patients, due to contra-indications and the costs associated with establishing the infrastructure to deliver these treatments. The use of neuroprotective agents in stroke has been a notable failure of translation from medical research into clinical practice. Yet, with the advent of endovascular thrombectomy and the ability to investigate patients in much greater detail through advanced imaging modalities, neuroprotective agents can and should be re-examined as adjunct therapies to recanalization. In parallel, this requires appropriate planning on behalf of the preclinical stroke research community: there is a need to reinvestigate these therapies in a more collaborative manner, to enhance reproducibility through reduced attrition, improved reporting, and adopting an approach to target validation that more closely mimics clinical trials. This review will describe some of the novel strategies being used in stroke research, and focus on a few key examples of neuroprotective agents that are showing newfound promise in preclinical models of stroke therapy. Our primary aim is to give an overview of some of the challenges faced by preclinical stroke research, and suggest potential ways to improve translational success.