October 2024: New In Coagulation
by Donna Castellone • October 02, 2024
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Clot Removal Device Correction: Inari Medical Updates Use Instructions for ClotTriever XL Catheter due to Reports of Patient Injury and Death from Device Entrapment and Pulmonary Emboli
- Avoid pulling the ClotTriever XL Catheter caudal to cranial through upper extremity or jugular vein access.
- To prevent advancing clot from veins into heart/pulmonary arteries, ensure that the ClotTriever XL Catheter is slowly retracted distally away from the heart, while maintaining sheath position and visualization under fluoroscopy.
- Operation of a thrombectomy catheter may cause embolization of some thrombus and/or thrombotic particulate, physician discretion advised. The potential for extensive and/or difficult to treat pulmonary thromboembolism should be carefully considered when ClotTriever XL Catheter is used to engage and remove thrombus from large vessels such as the inferior vena cava (IVC).
- To minimize risk of embolization of blood clots, use of a device that entraps clots is recommended.
- In the presence of excessive clot volume, it is recommended to sequentially remove portions of thrombus. Avoid removal of the entire clot in one pass.
- Current: Not indicated for the removal of predominantly fibrous, firmly adherent, or calcified material.
- Additions:
- Review of patient history and pre-procedure imaging may aid in identifying patients with these lesion types.
- Contraindicated in patients with suspected tumor thrombus.
Warnings section additions
Prior to Use section addition
Procedure section (ClotTriever Sheath use with ClotTriever XL Catheter) addition
Contraindications updates and additions
The FDA recommends that users consider the device be contraindicated for the removal of fibrous, firmly adherent or calcified material. A clot capture device has not yet been demonstrated to be effective in the venous vasculature. Updated training will be arranged with customers. Updated instructions were implemented after serious advents events were caused when the device became entrapped or blocking the lung arteries. There have been 4 injuries and 6 reports of death.
Customers in the U.S. with questions about this recall should contact their local sales representative, Inari Customer Care at 877-923-4747, or the Quality department at QA@inarimedical.com.
Delayed Bleeding: The Silent Risk for Seniors
Robert D. Glatter, MD; Richard D. Shih, MD; Christina L. Shenvi, MD, PhD, MBA
The Journal of Emergency Medicine looked at the incidence of delayed ICH among older patients taking anticoagulants and present to the ED with blunt head trauma. Patients presented with negative initial head CTs however after a second CT about 7% became positive. If diagnosis was based on initial CT the patient was sent home. Current practice is to not perform two CT, so the study prospectively enrolled patients and followed patients over time and followed medical records to identify delayed bleeding.
Prior prospective studies have shown that the rate of delayed bleeding on anticoagulants was between 0.2-1.0%. In this study it was 0.4%. There were 14 delayed bleeds out of 6000 patients with head trauma only one required neurosurgery. This questions if the 7% rate is high and should all patients be admitted. Delayed bleeding doesn't always occur within the first 24 hours. Another consideration is that initial studies patients were only on warfarin which has shifted to DOACs. The rate of ICH are lower in DOACs, lower rate for neurosurgical intervention and lower rates of discharge to a skilled nursing home. International guidelines from Austria and Scandinavia both recommend 24-hour observation if a patient is on an anticoagulant.
Anticoagulants alone are not the cause for bleeding, age and comorbidities need to be considered including frailty, heart disease, and AF. Follow up for the study was difficult and follow up calls at 14 and 60 days fell between 30-35%. Chart reviews occurred at 60 and 90 days.
Based on a negative CT scan, admitting patients for observation may be difficult based on insurance. It will be important to evaluate them to determine if they are at a risk for another fall causing a second bleed. Additional supporting information for admission could include dehydration, need for PT assessment and inability to take care of themselves. Clinical human judgement is important. Patients should also be informed if they have a worse headache, nausea or vomiting or weakness in one are, or vision changes they should return to the ED.
Childhood ITP: School, Sports, Treatment
Jennifer DiRaimo
Dr. Lambert, the PDSA Medical Advisor offers guidance on strategies on managing ITP in school, sports and treatments. In these patients, underlying causes of immune dysregulation involved in platelet count reduction may cause these patients to respond differently to treatments resulting in trying different treatments to get the best result. Treatment is reserved for children who have difficulty in controlling bleeding in brain or other internal organs or if they cannot participate in daily activities or quality of life is impacted. The risk for treating must out-weigh the risks associated with not treating. Most ITP children have only mild bleeding symptoms such as petechia and bruising.
Allowing these children to participate and or avoid certain activities is a challenge. A study of 102 patients showed that there was minimal risk associated with organized sports participation with low risk. Only 1 child with a low platelet count (<20,000) required further treatment. Most injuries occurred in unstructured play. Gym class participation is acceptable. Too many restrictions can impact the child’s quality of life. A child may have even short-term treatment to increase platelet counts during a sports season. If there is chronic ITP, a risk benefit should be applied when determining what activities can be safely encouraged.
Secondary causes of ITP should be explored if a child is refractory or unresponsive to therapies. Treatment then would be targeted for a more successful response. Every effort should be made to normalize a childschild’s life as well as being able to mitigate risk to minimize injury.
Adding anti-clotting drugs to stroke care ineffective, clinical trial finds
Patients who have a stroke due to a blood clot are at risk of developing a new clot.
At 57 sites, doctors tested the addition of anticoagulant drugs to dissolve blood clots. Results showed that two drugs did not improve outcomes. The Multi-arm Optimization of Stroke Thrombolysis (MOST) clinical trial was to test the efficacy of adding argatroban, a blood thinner, or eptifibatide, which inhibits blood platelets from sticking together, to the routine intravenous thrombolysis treatment. Patients (n=500) received either argatroban, epifibatide or placebo. Data showed that neither drug was beneficial with the probability of it being beneficial as < 1%. Even more concerning was that argatroban and eptifibatide were linked with greater incidences of disability and mortality three-month post treatment. This lack of improvement caused the trial to be stopped.
DOAC Monotherapy Bests Dual Antithrombotic Therapy for Afib Plus Coronary Disease
The EPIC-CAD trial looked at patients with AF and stable coronary artery disease and compared edoxaban versus dual antithrombotic therapy weighing bleeding and ischemic events. The trial included 1040 South Korean patients who required anticoagulation due to AF with stable CAD ( 6-12 months post acute coronary syndrome). Mean age was 72.1 and 22.9% were women, mean CHA2DS2-VASc score was 4.3. Patients were randomized to edoxaban or dual antithrombotic therapy (edoxaban with aspirin or a P2Y12 inhibitor).
Results showed that the 12 month composite death from MI, stroke, embolism, unplanned revascularization or major or clinically relevant non major bleeding occurred in 6.8% of patients on edoxaban monotherapy and 16.2% assigned to dual antithrombotic therapy. Major bleeding or clinically nonmajor bleeding occurred in 4.7% in edoxaban monotherapy and 14.2% of dual antithrombotic therapy.
These results reinforces the ESC and American Heart Association/American College of Cardiology guidelines of oral anticoagulation alone 6-12 months after PCI or acute coronary syndrome. The timing of when to transition to a single agent after the early post-event period remains unclear.
Limitations include the trial was underpowered for thrombotic events. The rates of bleeding and thrombotic events differ between Asian and n on-Asian patients.
Oral Anticoagulation and TAVR Together: A Recipe for Trouble
Results from the RIGHT trial showed that there was no advantage for continuing anticoagulation after PCI for ST-elevation MI (STEMI) at one year for either ischemic or bleeding outcomes. There were 53 sites in China that took part in the study which included 2989 patients. Initially patients were treated during and up to 4 hours after procedures with bivalirudin. Patients (n=1494) were allocated to prolonged anticoagulation or (n=1495) which could be UFH, LMWH or bivalirudin or to a no anticoagulation placebo group. The primary efficacy endpoint was occurrence of a major adverse cardiovascular event (MACE) at 30 days (all-cause death, nonfatal MI or stroke, stent thrombosis or revascularization of a vessel) while the primary safety endpoint was major bleeding at 30 days.
MACE occurred in an equal percentage of patients in both the prolonged anticoagulation and no anticoagulation groups (both 2.5%). Major bleeding also occurred in similar percentages of patients in both the groups, at 0.5% vs 0.7%, respectively. The cumulative incidence of MACE at 1 year was 47% lower with enoxaparin than with no anticoagulant use. There were no apparent differences, however, for UFH or bivalirudin.
EU Regulator Backs Use Of Pfizer's Gene Therapy for Rare Bleeding Disorder
Gene therapy for hemophilia B has been recommended by the European Medicines Agency by granting it a 'conditional marketing authorization' for approval of unmet needs of patients. The drug Beqvez has been approved in the United States and Canada it will be called Durveqtix in the EU. The therapy will stimulate production of Factor IX by the patient's body instead of weekly or monthly infusions of FIX. The gene therapy was found to eliminate bleeding in 60% of patients versus 29% who receive infusions.
Will OCEANIC-AF Sink Factor XI Inhibitors?
The OCEANIC-AF trial looked at Factor XI inhibition in patients with AF to try to stop clots and while not having the risk for bleeding. Previously warfarin was used for AF which attacked several parts of the coagulation cascade and was effective in preventing clots, however it also promoted bleeding. Direct thrombin or factor X inhibitors (edoxaban, rivaroxaban and apixaban) inhibited specific factors and improved the bleeding risk.
This trial used asundexian, a small molecule that affected factor XIa inhibition. This would allow normal hemostasis as well as clot formation, however it would stop the propagation of thrombus formation and not become pathologic. This was what was hoped with DOACs which has helped however bleeding is still a concern in particular GI bleeding.
Factor XIa inhibition with asundexian was done in healthy volunteers and then a phase 2 study was conducted. The PACIFIC-AF study compared the drug (at 20 and 50mg) in relation to apixaban. Factor XI assay monitored the inhibition of factor XI activity to demonstrate inhibition and then to assess if there was less bleeding when compared to apixaban. Results showed that 92% of Factor XI activity was inhibited with the 50 mg dose and slightly less with the 20 mg dose but significantly less than with apixaban. A phase 3 study using the 50mg dose to determine if there is a reduction in stroke, embolism and a reduction in bleeding.
The OCEANIC-AF trial was a 1:1 randomization, double-blind study, looking for the primary efficacy endpoint of stroke or systemic embolism and being noninferior to apixaban. If there was sufficient power, bleeding and net clinical benefit would be assessed. There were 14,000 patients enrolled in 11 months, however there was a hazard with asundexian actually increasing the rate of stroke or systemic embolism so the trial was stopped for inferiority. The cumulative incidence for stroke was 1.3% with asundexian and 0.4% with apixaban. The hazard ratio was around 3.7 for asundexian compared with apixaban. As a result, asundexian is inferior to apixaban for stroke or systemic embolism. This may be due to the dose of the drug; the does may need to result in near-complete inhibition of factor XI activity.
Bone marrow cancer drug shows success in treatment of rare blood disorder
An NIH clinical trial of 144 adults with hereditary hemorrhagic telangiectasia (HHT) was conducted at 11 US medical centers. Patients presented with moderate to severe nosebleeds requiring iron infusions or blood transfusions. Researchers gave 95 of the participants 4 mg of pomalidomide daily, though the dosage was reduced to 3 mg or 2 mg daily in patients with adverse reactions — mostly constipation, rashes, and lower than average white blood cell counts. The remaining 49 patients received a daily sugar pill designed to look exactly like the pomalidomide pill, in addition to their usual care.
Pomalidomide is thought to work by blocking theh growth of abnormal blood vessels. It may also cause the blood vessels to have a more normal structure or thicker walls making them less fragile.
A validated bleeding assessment tool specific to HHT was used to score each patient's nosebleed severity. The number of units of RBC transfused or iron transfused were recorded. The trial results showed that patients experienced a significant reduction in the severity of nosebleeds, needed fewer of the blood transfusions and iron infusions that HHT often demands, and showed improved quality of life. After 43 months, an interim analysis found that results met the threshold for efficacy which closed the study. Pomalidomide which is used to treat bone marrow cancer and Kaposi sarcoma is safe and effective in treating hereditary hemorrhagic telangiectasia (HHT).
JOURNAL CLUB
Perioperative Management of Patients Taking Direct Oral Anticoagulants
A Review
James D. Douketis, MD; Alex C. Spyropoulos, MD
Abstract
Importance Direct oral anticoagulants (DOACs), comprising apixaban, rivaroxaban, edoxaban, and dabigatran, are commonly used medications to treat patients with atrial fibrillation and venous thromboembolism. Decisions about how to manage DOACs in patients undergoing a surgical or nonsurgical procedure are important to decrease the risks of bleeding and thromboembolism.
Observations For elective surgical or nonsurgical procedures, a standardized approach to perioperative DOAC management involves classifying the risk of procedure-related bleeding as minimal (eg, minor dental or skin procedures), low to moderate (eg, cholecystectomy, inguinal hernia repair), or high risk (eg, major cancer or joint replacement procedures). For patients undergoing minimal bleeding risk procedures, DOACs may be continued, or if there is concern about excessive bleeding, DOACs may be discontinued on the day of the procedure. Patients undergoing a low to moderate bleeding risk procedure should typically discontinue DOACs 1 day before the operation and restart DOACs 1 day after. Patients undergoing a high bleeding risk procedure should stop DOACs 2 days prior to the operation and restart DOACs 2 days after. With this perioperative DOAC management strategy, rates of thromboembolism (0.2%-0.4%) and major bleeding (1%-2%) are low and delays or cancellations of surgical and nonsurgical procedures are infrequent. Patients taking DOACs who need emergent (<6 hours after presentation) or urgent surgical procedures (6-24 hours after presentation) experience bleeding rates up to 23% and thromboembolism as high as 11%. Laboratory testing to measure preoperative DOAC levels may be useful to determine whether patients should receive a DOAC reversal agent (eg, prothrombin complex concentrates, idarucizumab, or andexanet-α) prior to an emergent or urgent procedure.
Conclusions and Relevance When patients who are taking a DOAC require an elective surgical or nonsurgical procedure, standardized management protocols can be applied that do not require testing DOAC levels or heparin bridging. When patients taking a DOAC require an emergent, urgent, or semiurgent surgical procedure, anticoagulant reversal agents may be appropriate when DOAC levels are elevated or not available.
Tenecteplase vs Alteplase for Patients With Acute Ischemic Stroke
The ORIGINAL Randomized Clinical Trial
Xia Meng, MD; Shuya Li, MD1,; Hongguo Dai, MD; et alGuozhi Lu, MD; Weiwei Wang, MD; Fengyuan Che, MD; Yu Geng, MD; Minghui Sun, MD; Xiyan Li, MSc; Hao Li, PhD1; Yongjun Wang, MD
Abstract
Importance Tenecteplase is a bioengineered variant of alteplase with greater fibrin specificity and a longer half-life, allowing single-bolus administration. Evidence on the treatment effect of tenecteplase 0.25 mg/kg in Chinese patients with acute ischemic stroke (AIS) is limited.
Objective To establish the noninferiority of tenecteplase to alteplase in patients with AIS within 4.5 hours of symptom onset.
Design, Setting, and Participants The ORIGINAL study was a multicenter, active-controlled, parallel-group, randomized, open-label, blinded end point, noninferiority trial conducted between July 14, 2021, and July 14, 2023. Participants were recruited from 55 neurology clinics and stroke centers in China and were eligible if they had AIS with a National Institutes of Health Stroke Scale score of 1 to 25 with measurable neurologic deficit and were symptomatic for at least 30 minutes without significant improvement.
Interventions Patients were randomized (1:1) within 4.5 hours of symptom onset to receive intravenous tenecteplase (0.25 mg/kg) or intravenous alteplase (0.9 mg/kg).
Main Outcomes and Measures The primary outcome was the proportion of patients with a modified Rankin Scale (mRS) score of 0 or 1 (no symptoms or no significant disability) at day 90, tested for noninferiority (risk ratio [RR] margin, 0.937). Safety end points included symptomatic intracerebral hemorrhage (per European Cooperative Acute Stroke Study III definition) and 90-day all-cause mortality.
Results Among the 1489 patients randomized, 1465 patients were included in the full analysis set (732 in the tenecteplase group; 733 in the alteplase group) and 446 (30.4%) were female. The primary outcome occurred in 72.7% (532/732) of patients receiving tenecteplase and 70.3% (515/733) receiving alteplase (RR, 1.03 [95% CI, 0.97-1.09]; noninferiority threshold met). Symptomatic intracerebral hemorrhage occurred in 9 patients (1.2%) in each group (RR, 1.01 [95% CI, 0.37-2.70]). The 90-day mortality rate was 4.6% (34/732) in the tenecteplase group and 5.8% (43/736) in the alteplase group (RR, 0.80 [95% CI, 0.51-1.23]).
Conclusions and Relevance In patients with AIS eligible for intravenous thrombolysis within 4.5 hours after stroke onset, tenecteplase was noninferior to alteplase with respect to excellent functional outcome (mRS score of 0 or 1) at 90 days and had a similar safety profile. Findings from this study support tenecteplase as a suitable alternative to alteplase in this setting.
Thrombectomy for Stroke With Large Infarct on Noncontrast CT:
The TESLA Randomized Clinical Trial
The Writing Committee for the TESLA Investigators; for the TESLA Investigators
Abstract
Importance Recent large infarct thrombectomy trials used heterogeneous imaging modalities and time windows for patient selection. Noncontrast computed tomographic (CT) scan is the most common stroke imaging approach. It remains uncertain whether thrombectomy is effective for patients with large infarcts identified using noncontrast CT alone within 24 hours of stroke onset.
Objective To evaluate the effect of thrombectomy in patients with a large infarct on a noncontrast CT scan within 24 hours of onset.
Design, Setting, and Participants Open-label, blinded–end point, bayesian-adaptive randomized trial with interim analyses for early stopping (futility or success) or population enrichment, which was conducted at 47 US academic and community-based stroke thrombectomy centers. Three hundred patients presenting within 24 hours with anterior-circulation, large-vessel occlusion and large infarct on noncontrast CT scan, with Alberta Stroke Program Early CT Scores of 2 to 5, were randomized to undergo thrombectomy or usual care. Enrollment occurred July 16, 2019 to October 17, 2022; final follow-up, January 25, 2023.
Intervention The intervention patients (n = 152) underwent endovascular treatment using standard thrombectomy devices and usual medical care. Control patients (n = 148) underwent usual medical care alone.
Main Outcomes and Measures The primary efficacy end point was improvement in 90-day functional outcome measured using mean utility-weighted modified Rankin Scale (UW-mRS) scores (range, 0 [death or severe disability] to 10 [no symptoms]; minimum clinically important difference, 0.3). A bayesian model determined the posterior probability that the intervention would be superior to usual care; statistical significance was a 1-sided posterior probability of .975 or more. The primary adverse event end point was 90-day mortality; secondary adverse event end points included symptomatic intracranial hemorrhage and radiographic intracranial hemorrhage.
Results The trial enrolled 300 patients (152 intervention, 148 control; 138 females [46%]; median age, 67 years), without early stopping or enrichment; 297 patients completed the 90-day follow-up. The mean (SD) 90-day UW-mRS score was 2.93 (3.39) for the intervention group vs 2.27 (2.98) for the control group with an adjusted difference of 0.63 (95% credible interval [CrI], −0.09 to 1.34; posterior probability for superiority of thrombectomy, .96). The 90-day mortality was similar between groups: 35.3% (53 of 150) for the intervention group vs 33.3% (49 of 147) for the control group. Six of 151 patients (4.0%) in the intervention group and 2 of 149 (1.3%) in the control group experienced 24-hour symptomatic intracranial hemorrhage. Fourteen patients of 148 (9.5%) in the intervention group vs 4 of 146 (2.7%) in the control group experienced parenchymal hematoma type 1 hemorrhages; 14 (9.5%) in the intervention group vs 5 (3.4%) in the control group experienced parenchymal hematoma type 2 hemorrhages; and 24 (16.2%) in the intervention group vs 9 (6.2%) in the control group experienced subarachnoid hemorrhages.
Conclusions and Relevance Among patients with a large infarct on noncontrast CT within 24 hours, thrombectomy did not demonstrate improvement in functional outcomes. But the width of the credible interval around the effect estimate includes the possibility of both no important effect and a clinically relevant benefit, so the potential role of thrombectomy with this imaging approach and time window will likely require additional study.