by Donna Castellone, MS, MT (ASCP) SH •
May 09, 2022
Our Monthly complilation of the latest studies, guidelines and discussions in coagulation. Please Note: many linked teasers require account/subscription in order to view full articles.
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The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.
The Perioperative Ischemic Evaluation-3 (POISE-3) trial (n=9535) randomly assigned patients undergoing noncardiac surgery. Patients were 45 years of age or older, with a bleeding risk and having vascular complication. The studies were conducted at 114 hospitals(only inpatients) across six continents to double-blind treatment. They received tranexamic acid (1-g IV bolus) or placebo at the start and end of surgery.
The POISE-3 trial showed that a dose of the antifibrinolytic drug tranexamic acid reduced major or critical organ bleeding by 24% when compared with a placebo. However non-inferiority was not achieved for the primary safety endpoint which was a composite of myocardial injury, nonhemorrhagic stroke, peripheral artery thrombosis, or symptomatic proximal venous thromboembolism at 30 days. The risk benefit will have to be considered in the reduction in the incidence of composite bleeding outcome events and the cardiovascular events.
Surgical bleeding accounts for 40% of all transfusions and POISE-3 results carry the potential for clinical benefits for the utilization of tranexamic acid in non cardiac surgery.
Patients with moderate COVID 19 who were given aspirin early in their treatment had a lower risk of dying compared to patients who were not based on a study from George Washington University. It included data from 112,269 patients enrolled from January 2020 until September 2021 and included 64 health systems in the US. They found a 1.6% reduction in mortality when aspirin was given on the first day of hospitalization. Patients were also less prone to developing blood clots.
Asundexian is a new class of anti-clotting drug that works by inhibiting Factor XI. When compared in patients with atrial fibrillation who were taking apixaban, asundexian caused fewer bleeding events.
The Pacific-AF trial looked at bleeding outcomes from two different doses (20mg and 50 mg) in patients with AF and compared them to similar doses of apixaban. The trial included 755 patients average age of 74 years old. Patients on asudexian had a 67% lower risk of bleeding on both doses compared to patients on apixaban.
When data from more than a million ischemic-stroke patients was analyzed it was noted that 54.5% of stroke patients received monotherapy and 44.9% received dual antiplatelet therapy (DAPT) which is the suggested treatment. DAPT includes both aspirin and clopidogrel for secondary prevention when used short term to prevent recurrence in minor ischemic stroke. This is based on guidelines from the American Heart Association and American Stroke Association.
Patients were evaluated at five time periods of therapy and had a median age of 68 and 51% were men. Nearly two-thirds were non-Hispanic white, while 21% were non-Hispanic Black, 8% Hispanic, 3% Asian and 4% of another race. Results showed that 54.5% received aspirin monotherapy, 12.4% received clopidogrel monotherapy and 30.8% received DAPT. DAPT increased across the five time periods based on the clinical trial updates that were published. Additionally, there are huge disparities around the country and in rural parts of the country. It can also take a long time for a guideline to make their way into clinical practice.
One in four patients have presented with a small leak after a left atrial appendage occlusion (LAAO) with the Watchman 2.5 device 45 days post procedure. The leaks were 5mm or less. At 1 year their risk adjusted rate of stroke or TIA were 15% higher than when compared with patients that had no leaks. This group also had an 11% higher rate of major bleeding versus those that had no leaks. The study looked at 51,222 patients who had transesophageal echocardiogram and were followed for a year.
Bentracimab is being investigated in a phase 2b study as a reversal agent for the antiplatelet drug ticagrelor. It significantly restored platelet function when compared with placebo when measured on multiple assays by binding and eliminating free ticagrelor. This appears to be a promising agent for ticagrelor which is a reversable P2Y12 recThe eptor antagonist which is different than clopidogrel an presugrul which are irreversible platelet inhibitors.
Bentracimab is a recombinant human monoclonal antibody fragment that binds to free ticagrelor with high affinity and specificity which allows ADP to then bind to the P2Y12 receptor and activate platelets. The bentracimab/ticagrelor complex is eliminated from the bloodstream.
In a phase 2b study 205 volunteers (50-80 years old) were were pretreated with ticagrelor and aspirin for 48 hours and randomized 3:1 ratio to bentracimab or placebo. Platelet function was evaluated by Verity Now P2Y12 tests 4 hours post dose. Reversal of platelet inhibition was achieved that was statistically significant between the drug and the placebo and the effect was consistent across all ages and subgroups.
The phase 3 trial REVERS-IT looked at 122 patients who required urgent surgery or invasive procedures and require rapid restoration of platelet function. Effective hemostasis was achieved in more than 90% of cases.
It was found that the risk for a first pulmonary embolism in patients who test positive for COVID-19 were 33 times higher when compared with a control group after adjusting for multiple potential confounders as found by a University in Sweden. The study consisted of 51% were women with a mena age of 40 with over 1 million participants. The risk for a first DVT was five times higher while the risk for bleeding was twice as high. The study also found the risk for DVT up to three months and PE up to six months with bleeding up to two months. An excess risk was found in patients with more severe COVID. These finding support thromboprophylaxis to avoid thrombotic events for high risk patients.
When the risk of outcomes were compared from different pandemic waves, the incidence or risks were higher in the first of COVID which could be explained by the improvements in treatment against COVID and the widespread use of thromboprophylaxis after the first wave.
Limitations to the study included registry based information which may be incomplete or inaccurate. Venous thromboembolism may have been underdiagnosed in patients with COVID and critically ill patients may be too unstable for diagnostic evaluation of VTE or evaluation may be delayed due to other issues. The control participants registry data was from 1997 which might have more often been falsely classified as first events resulting in an underestimation of risks. There was also limited COVID testing during the first wave. Since vaccines were given to elderly people first, and they are at an increased risk for VTE and bleeding, vaccines provided them with a protective effect decreasing the rates during the third wave of the pandemic.
An association between thrombosis and infections have been demonstrated in previous studies, however this study was much higher. This maybe attributed to several pathophysiological alterations in COVID 19 which includes the direct effect of the virus on endothelial cells, an exaggerated inflammatory response, down regulation of angiotensin converting enzyme 2 receptors, and activation of the coagulation system.
The incidence of PE was disproportionately higher possible due to thrombosis in the pulmonary vessels from local inflammation while the increased risk of bleeding could be due to endothelial dysfunction, coagulopathy or DIC.
A study that looked at prevention of complication of leaflet thrombosis post transcatheter aortic valve replacement (TAVR) using the DOAC edoxaban was not found to be significantly more efficient in preventing complications when compared with DAPT of aspirin and clopidogrel. Analysis of the primary endpoint, leaflet thrombosis occurred among 9.1% of patients on edoxaban and 19.1% of those on DAPT. Incidence of new cerebral lesions on brain MRI were numerically greater among patients in the edoxaban group 25.0% compared with those on DAPT 20.6%.
The study included 229 individuals from five centers and 111 were randomized to received edoxaban and 118 were assigned to received DAPT with an average age of 80 with 55% were women. There were 31% diagnosed with diabetes, 29% with coronary artery disease and 25% with chronic lung disease. The incidence of any or major bleeding events were not different between two groups.
Two cardiovascular adverse events vaccine-induced immune thrombotic thrombocytopenia (VITT) and myocarditis were discussed in a position statement highlighting specific considerations and recommendations on COVID-19 vaccination for subjects with a previous history or predisposition of VTE or a risk of myocarditis. These two adverse risks were identified during post-marketing surveillance.
There were two adenovirus-vector vaccines (AVV) implicated in the cause of VITT ChAdOx1S nCoV-19 (Oxford/AstraZeneca and Serum Institute of India) and Ad26.COV2.S (Janssen; Johnson & Johnson). The incidence is unknown and it is a rare complication. A report has shown that there were 54 cases of thrombosis among more than 14 million recipients. Cerebral venous thrombosis is the most common occurrence, however thrombocytopenia alone may also occur.
However the incidence of cerebral venous thrombosis among patients hospitalized for COVID was 207 per million cases which is much higher than the incidence of vaccine induced thrombosis of 0.9-3.8 per million cases.
Benefits of vaccines surpass the potential risks of side effects and these recommendations were made to cardiologists:
Previous history of VTE or predisposition to VTE are not contraindications for COVID-19 vaccination, regardless of the type of vaccine. No study has shown an increased risk of VITT or other thrombotic complications after vaccination in these individuals.
Individuals who received the first dose of ChAdOx1 nCoV-19 and did not develop VITT should complete the vaccination schedule of two doses. There is no evidence that the second dose (or even the booster) increases the risk of thrombotic complications. A review of the AstraZeneca safety database in Europe and the United Kingdom showed an incidence of 8.1 cases of VITT per million for the first dose and of only 2.3 cases per million for the second dose.
Individuals who received an adenovirus-vectored vaccine and developed VITT should not receive a second dose. Transition to an mRNA vaccine schedule is recommended. Furthermore, available evidence does not support performing any clinical, laboratory, or imaging tests in asymptomatic individuals before or after vaccination.
Myocarditis that is associated with vaccines is mild and self-limited and the protection of the vaccine outweighs the risk. It has been associated with the mRNA vaccines from Pfizer and Moderna. In one study it was found that there were 54 cases of myocarditis in 2.5 million individuals that were monitored. Another study reported an incidence rate of 0.35 cases per 100,000 within 21 days after the first dose and 2.10 cases per 100,000 individuals after the second dose.
There was a high prevalence of VTE in hospitalized COVID-19 patients with severe disease. Data on long term outcomes is unavailable. Data from a prospective observational study looked at data from 48 patients who had developed COVID related VTE during a hospital stay. There were no instances of symptomatic VTE recurrence after their initial VTE diagnosis. There were 5 patients who presented with bleeding due to anticoagulant use. Most were given LMWH (85%), 13% received a DOAC while 4% received UFH. The study was limited to a single center and a small sample size.
JAMA Cardiol. Published online April 13, 2022. doi:10.1001/jamacardio.2022.0480
Importance Long-term use of oral anticoagulants (OACs) is necessary for stroke prevention in patients with atrial fibrillation (AF). The effectiveness and safety of OACs in extremely older patients (ie, aged 80 years or older) with AF and at high risk of bleeding needs to be elucidated.
Objective To examine the effects of very low-dose edoxaban (15 mg) vs placebo across 3 age strata (80-84 years, 85-89 years, and ≥90 years) among patients with AF who were a part of the Edoxaban Low-Dose for Elder Care Atrial Fibrillation Patients (ELDERCARE–AF) trial.
Design, Setting, and Participants This prespecified subanalysis of a phase 3, randomized, double-blind, placebo-controlled trial was conducted from August 5, 2016, to December 27, 2019. Patients with AF aged 80 years or older who were not considered candidates for standard-dose OACs were included in the study; reasons these patients could not take standard-dose OACs included low creatinine clearance (<30 mL per minute), low body weight (≤45 kg), history of bleeding from critical organs, continuous use of nonsteroidal anti-inflammatory drugs, or concomitant use of antiplatelet drugs. Eligible patients were recruited randomly from 164 hospitals in Japan and were randomly assigned 1:1 to edoxaban or placebo.
Interventions Edoxaban (15 mg once daily) or placebo.
Main Outcomes and Measures The primary efficacy end point was the composite of stroke or systemic embolism. The primary safety end point was International Society on Thrombosis and Hemostasis–defined major bleeding.
Results A total of 984 patients (mean [SD] age: age group 80-84 years, 82.2 [1.4] years; age group 85-89 years, 86.8 [1.4] years; age group ≥90 years, 92.3 [2.1] years; 565 women [57.4%]) were included in this study. In the placebo group, estimated (SE) event rates for stroke or systemic embolism increased with age and were 3.9% (1.2%) per patient-year in the group aged 80 to 84 years (n=181), 7.3% (1.7%) per patient-year in the group aged 85 to 89 years (n=184), and 10.1% (2.5%) per patient-year in the group aged 90 years or older (n=127). A 15-mg dose of edoxaban consistently decreased the event rates for stroke or systemic embolism with no interaction with age (80-84 years, hazard ratio [HR], 0.41; 95% CI, 0.13-1.31; P=.13; 85-89 years, HR, 0.42; 95% CI, 0.17-0.99; P = .05; ≥90 years, HR, 0.23; 95% CI, 0.08-0.68; P = .008; interaction P = .65). Major bleeding and major or clinically relevant nonmajor bleeding events were numerically higher with edoxaban, but the differences did not reach statistical significance, and there was no interaction with age. There was no difference in the event rate for all-cause death between the edoxaban and placebo groups in all age strata.
Conclusions and Relevance Results of this subanalysis of the ELDERCARE–AF randomized clinical trial revealed that among Japanese patients aged 80 years or older with AF who were not considered candidates for standard OACs, a once-daily 15-mg dose of edoxaban was superior to placebo in preventing stroke or systemic embolism consistently across all 3 age strata, including those aged 90 years or older, albeit with a higher but nonstatistically significant incidence of bleeding.
A Secondary Analysis of the TRIUMPH Randomized Clinical Trial
Sonali R. Gnanenthiran, MBBS, PhD1; Nelson Wang, MD, MPhil1; Gian Luca Di Tanna, PhD1; et alAbdul Salam, PhD2; Ruth Webster, PhD1,3; H. Asita de Silva, DPhil4; Rama Guggilla, MBBS, MMed5; Stephen Jan, PhD1; Pallab K. Maulik, PhD2; Nitish Naik, MD6; Vanessa Selak, PhD7; Simon Thom, MD8; Dorairaj Prabhakaran, MD9; Aletta E. Schutte, PhD1; Anushka Patel, PhD1; Anthony Rodgers, PhD1; for the TRIUMPH Study Group
JAMA Cardiol. Published online April 13, 2022. doi:10.1001/jamacardio.2022.0471
Importance Cumulative exposure to high blood pressure (BP) is an adverse prognostic marker. Assessments of BP control over time, such as time at target, have been developed but assessments of the effects of BP-lowering interventions on such measures are lacking.
Objective To evaluate whether low-dose triple combination antihypertensive therapy was associated with greater rates of time at target compared with usual care.
Design, Setting, and Participants The Triple Pill vs Usual Care Management for Patients With Mild-to-Moderate Hypertension (TRIUMPH) trial was a open-label randomized clinical trial of low-dose triple BP therapy vs usual care conducted in urban hospital clinics in Sri Lanka from February 2016 to May 2017. Adults with hypertension (systolic BP >140 mm Hg and/or diastolic BP >90 mm Hg or in patients with diabetes or chronic kidney disease, systolic BP >130 mm Hg and/or diastolic BP >80 mm Hg) requiring initiation (untreated patients) or escalation (patients receiving monotherapy) of antihypertensive therapy were included. Patients were excluded if they were currently taking 2 or more blood pressure–lowering drugs or had severe or uncontrolled blood pressure, accelerated hypertension or physician-determined need for slower titration of treatment, a contraindication to the triple combination pill therapy, an unstable medical condition, or clinically significant laboratory values deemed by researchers to be unsuitable for the study. All 700 individuals in the original trial were included in the secondary analysis. This post hoc analysis was conducted from December 2020 to December 2021.
Intervention Once-daily fixed-dose triple combination pill (telmisartan 20 mg, amlodipine 2.5 mg, and chlorthalidone 12.5 mg) therapy vs usual care.
Main Outcomes and Measures Between-group differences in time at target were compared over 24 weeks of follow-up, with time at target defined as percentage of time at target BP.
Results There were a total of 700 randomized patients (mean [SD] age, 56  years; 403 [57.6%] women). Patients allocated to the triple pill group (n=349) had higher time at target compared with those in the usual care group (n=351) over 24 weeks' follow-up (64% vs 43%; risk difference, 21%; 95% CI, 16-26; P<.001). Almost twice as many patients receiving triple pill therapy achieved more than 50% time at target during follow-up (64% vs 37%; P<.001). The association of the triple pill with an increase in time at target was seen early, with most patients achieving more than 50% time at target by 12 weeks. Those receiving the triple pill achieved a consistently higher time at target at all follow-up periods compared with those receiving usual care (mean [SD]: 0-6 weeks, 36.3% [30.9%] vs 21.7% [28.9%]; P<.001; 6-12 weeks, 5.2% [31.9%] vs 33.7% [33.0%]; P<.001; 12-24 weeks, 66.0% [31.1%] vs 43.5% [34.3%]; P<.001).
Conclusions and Relevance To our knowledge, this analysis provides the first estimate of time at target as an outcome assessing longitudinal BP control in a randomized clinical trial. Among patients with mild to moderate hypertension, treatment with a low-dose triple combination pill was associated with substantially higher time at target compared with usual care.
Cornelia Englisch, Florian Moik, Stephan Nopp, Markus Raderer, Ingrid Pabinger, Cihan Ay
RESEARCH ARTICLE| APRIL 13, 2022, Blood Advances
Venous thromboembolism (VTE) is common in cancer patients. While in the general population blood type non-O is associated with increased VTE risk, the impact of ABO blood type on risk of cancer-associated VTE has not been clarified. To determine the influence of ABO blood type on cancer-associated VTE risk, we conducted an analysis within the Vienna Cancer and Thrombosis Study (CATS), a prospective cohort study including patients with newly diagnosed or recurrent cancer observed for the primary outcome VTE. Restricted cubic spline analysis was performed and specific time-restricted subdistribution hazard ratios (SHR) were calculated to investigate the association between non-O blood type and VTE over time. 1,708 patients were included in the analysis (median follow-up time: 24 months; interquartile range: 10-24), and 151 patients developed VTE (8.8%). During the first 3 months of follow-up, there was no association between non-O blood type and VTE risk (SHR: 1.00, 95% CI: 0.60-1.67). Thereafter, non-O blood type was associated with a higher VTE risk (SHR 1.79, 95%CI: 1.12-2.85). Furthermore, non-O blood type was associated with increased VTE risk in patients with intermediate and low thrombotic risk tumor types (SHR 1.73, 95% CI: 1.09-2.73), but not in very high-risk types (pancreatic, gastroesophageal and brain cancer; SHR 0.94, 95% CI: 0.55-1.61). This association was weakened after adjustment for factor VIII. Non-O blood type is a time-dependent predictor of VTE in cancer patients. It is associated with increased VTE risk beyond 3 months of follow-up and in patients with intermediate and low-risk tumor types.
Importance Clopidogrel monotherapy after short dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) has not yet been fully investigated in patients with acute coronary syndrome (ACS).
Objective To test the hypothesis of noninferiority of 1 to 2 months of DAPT compared with 12 months of DAPT for a composite end point of cardiovascular and bleeding events in patients with ACS.
Design, Setting, and Participants This multicenter, open-label, randomized clinical trial enrolled 4169 patients with ACS who underwent successful PCI using cobalt-chromium everolimus-eluting stents at 96 centers in Japan from December 2015 through June 2020. These data were analyzed from June to July 2021.
Interventions Patients were randomized either to 1 to 2 months of DAPT followed by clopidogrel monotherapy (n=2078) or to 12 months of DAPT with aspirin and clopidogrel (n=2091).
Main Outcomes and Measures The primary end point was a composite of cardiovascular (cardiovascular death, myocardial infarction [MI], any stroke, or definite stent thrombosis) or bleeding (Thrombolysis in MI major or minor bleeding) events at 12 months, with a noninferiority margin of 50% on the hazard ratio (HR) scale. The major secondary end points were cardiovascular and bleeding components of the primary end point.
Results Among 4169 randomized patients, 33 withdrew consent. Of the 4136 included patients, the mean (SD) age was 66.8 (11.9) years, and 856 (21%) were women, 2324 (56%) had ST-segment elevation MI, and 826 (20%) had non–ST-segment elevation MI. A total of 4107 patients (99.3%) completed the 1-year follow-up in June 2021. One to 2 months of DAPT was not noninferior to 12 months of DAPT for the primary end point, which occurred in 65 of 2058 patients (3.2%) in the 1- to 2-month DAPT group and in 58 of 2057 patients (2.8%) in the 12-month DAPT group (absolute difference, 0.37% [95% CI, −0.68% to 1.42%]; HR, 1.14 [95% CI, 0.80-1.62]; P for noninferiority=.06). The major secondary cardiovascular end point occurred in 56 patients (2.8%) in the 1- to 2-month DAPT group and in 38 patients (1.9%) in the 12-month DAPT group (absolute difference, 0.90% [95% CI, −0.02% to 1.82%]; HR, 1.50 [95% CI, 0.99-2.26]). The major secondary bleeding end point occurred in 11 patients (0.5%) in the 1- to 2-month DAPT group and 24 patients (1.2%) in the 12-month DAPT group (absolute difference, −0.63% [95% CI, −1.20% to −0.06%]; HR, 0.46 [95% CI, 0.23-0.94]).
Conclusions and Relevance In patients with ACS with successful PCI, clopidogrel monotherapy after 1 to 2 months of DAPT failed to attest noninferiority to standard 12 months of DAPT for the net clinical benefit with a numerical increase in cardiovascular events despite reduction in bleeding events. The directionally different efficacy and safety outcomes indicate the need for further clinical trials.