September 2022: New In Coagulation

by Donna Castellone, MS, MT (ASCP) SH • September 01, 2022

The interpretations below are provided by Donna Castellone, MS, MT (ASCP) SH for Aniara Diagnostica.

Our Monthly complilation of the latest studies, guidelines and discussions in coagulation.
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Vaccinated Have Lower Heart, Stroke Risk From COVID

A study from Korea demonstrated that people who were fully vaccinated against COVID-19 had a lower risk of AMI and ischemic stroke as a result from complications of acute infection. The study was conducted retrospectively in patients diagnosed from July 2020 to December 2021. They compared 62,727 unvaccinated patients versus 168,310 vaccinated patients. Outcomes were reduced with the 31-120 day time frame and was observed among various subgroups. It did not reach statistical significance for people with a previous history or those with severe or critical COVID-19. The findings are not different than a previous study on post-acute cardiovascular manifestations.

U.S. Department of Veterans Affairs prior to widespread vaccine availability, investigators had estimated strokes from 30 days after infection as occurring at a rate of 4.03 per 1,000 people at 12 months; post-COVID myocardial infarctions were reported at 2.91 per 1,000 people at 12 months. The Korean data showed the stroke rate in the unvaccinated as 4.59 per million person-days. The MI rate was 1.60 per million person-days in the 31 to 120 days post COVID-19 diagnosis.

CDC: More Clots, Kidney Failure in Kids After COVID

In children ages 0-17 with laboratory confirmed COVID-19 were found to be significantly more likely to develop certain conditions within 331-365 days of diagnosis. Post COVID symptoms appear 4 weeks post infection. These included acute PE, myocarditis and cardiomyopathy, VTE, acute and unspecified renal failure, as well as Type 1 diabetes. Additional links to COVID-19 were persistent cardiac arrhythmias, bleeding disorders, smell and taste disturbances, malaise and fatigue. Diabetes appears to be novel in this population. Data was collected from a large medical claims database.

Information form 781,419 US children were matched 1:3 with peers who had a healthcare encounter that was not COVID from March 2021 - January 2022. There was a mean age of 12 and equally split between boys and girls. Bias included unknown conditions prior to the COVID infection and whether conditions were chronic or transient. Additionally, some children may have had undocumented COVID.

Potent DAPT After CABG Halves Vein Graft Failure

A meta-analysis that included four randomized trials: TAP-CABG, DACAB, TARGET, and POPular CABG. In included a total of 1316 patients and 1668 saphenous vein grafts. Median age was 67 with 15% being women. Graft failure was defined as an occlusion or stenosis great than 50% and bleeding events were classified using BARC criteria.

Post CABG, doubling up on antiplatelet agents decreased graft failure but increased bleeding risk. Using ticagrelor and aspirin versus just aspirin halved the risk of saphenous graft failure. However, bleeding was threefold more likely in patients receiving DAPT. The all cause mortality risk was double with DAPT, however only 13 deaths occurred in the trials and was not statistically significant.

This analysis suggests that a patient's individual risk of graft failure, ischemic events and bleeding should be evaluated carefully when determining to add ticagrelor to aspirin after CABG surgery.

Type of AF Among Predictors of DOAC Overdosing, Underdosing

Up to 25% of patients with AF are receiving inappropriate DOAC dosing. Factors such as advanced age, chronic kidney disease and permanent AF all contribute to this issue. It was also associated with DOACs being prescribed at reduced doses, nonuse of statins and concomitant use of amiodarone. All of this can lead to stroke, embolism, bleeding or death. Despite there being specific dosage reduction criteria for each DOAC, this can still be seen as a clinical challenge.

A multicenter observational study included 2004 patients with AF with defined DOAC dosing. Patients with moderate to severe mitral valve regurgitation and those with mechanical heart valved were excluded. Patients median age was 72, 58% were female. Rivaroxaban was prescribed in 987 patients, 658 were on apixaban, 239 edoxaban and 120 were on dabigatran. Of this cohort 24.9% did not receive the appropriate DOAC. Additionally, 12% received an inappropriately low dose while 12.9% received a high dose. Factors that contributed to DOAC dosing included advanced age, single marital status, chronic kidney disease and the presence of permanent AF.

Limitations of the study were due to bias in an observational study and patients were only included from cardiology outpatient clinics. There also was no follow up data limiting outcome data.

Updates on Treatment/Prevention of VTE in Cancer Patients

New guidelines were published for the treatment and prevention of VTE in patients with cancer and in those with cancer and COVID-19. Cancer patients have an increased risk of VTE and with the combination of COVID-19 its effect on VTE risk and treatment was of concern. These were released by the International Initiative on Thrombosis and Cancer and covers new evidence on the treatment and prophylaxis of cancer-associated thrombosis included those with cancer and COVID-19.

The treatment and prevention of VTE for cancer patients infected with SARS-CoV-2 remain the same as for those patients without COVID. All should be evaluated for the risk of VTE. Hospitalized cancer patients with COVID should be give pharmacologic prophylaxis at the same dose and anticoagulant type for hospitalized cancer patients who do not have COVID-19. VTE prophylaxis is not advised for cancer patients with COVID, nor recommended for ambulatory patients with COVID.

Initially treatment for an established VTE should include LMWH for 10 days when the creatinine clearance is at least 30 mL/min. UFH or fondaprinux can be used if LMWH is contraindicated. This should be taken once daily unless characteristics may benefit from twice daily dosing (enoxaparin at 1 mg/kg) which include a high risk of bleeding moderate renal failure or the need for technical intervention. Those with a low risk of GI bleeding can be given rivaroxaban or apixaban during the first 10 days.

Long term maintenance is beyond 6 months and LMWH are preferred over vitamin K antagonists. DOACs are also recommended for patients providing there is no risk of inducing a drug to drug interaction or impaired GI absorption or upper GI cancer which shows an increased risk of GI bleeding. Therapy should be used for a minimum of six months. If a VTE reoccurs an option would be to include LMWH by 20-25% or switch to a DOAC, or if on a DOAC switch to LMWH, if on a Vitamin K antagonist they could be switched to LMWH or DOAC.

In patients with reduced mobility, prophylaxis is recommended with either LMWH or fondaparinux. DOACs are not recommended. In patients with metastatic pancreatic cancer, LMWH or DOACs are indicated provided they are at a low risk of bleeding. LWMH is not recommended for patients with metastatic lung cancer even if they are at a low risk of bleeding.

Treatment for VTE in unique situation include patients with a brain tumor for whom treatment of an established VTE includes LMWH or DOAC. LMWH or UFH should be used postoperatively in patients undergoing neurosurgery. In children with symptomatic catheter-related thrombosis treatment should be for a minimum of 3 months. LMWH is recommended in children with acute lymphoblastic leukemia.

More Upper GI Bleeding Linked to Warfarin Versus DOACs

When compared to DOACs warfarin was associated with higher rates of upper GI bleeding but not lower GI bleeding. When over 7000 patients were investigated the rates of upper GI bleeding was 1.7 events per 100 person years as compared to 0,8 events with DOACs compared with lower GI bleeding at 1.0 vs 1.6 events respectively. Data was obtained from electronic medical records. Patients who experienced GI bleeding were older, had more comorbidities including hypertension and congestive heart failure and had more concomitant medications. Overall, mean age was 67-73, and 53-59% were men.

Warfarin was associated with the highest bleeding rate when compared to apixaban (2.3 vs 1.5 events). DOACs may be beneficial in patients most at risk of upper GI bleeding as seen in those with a history of peptic ulcer disease. While GO has been established in DOAC and warfarin users, the rates of upper and lower GI bleeding have not been addressed. These drugs spend proportionally longer time in the lower GI tract. Upper GI bleeding was higher in men on warfarin versus DOACs and compared with women, while rates of lower GI bleeding were similar.

VTE Risk Substantially Lower in Breakthrough COVID Cases

COVID-19 raised the overall 30 risk of DVT or PE to an incidence of 50.99 per 1000 person years in infected outpatients versus 2.37 cases in unaffected patients. The event of VTE are higher in unvaccinated patients with a 27.94 risk when compared to vaccinated patients with a 5.95 fold risk.

Other factors associated with risk include males, obesity and those with V Leiden in particular in older patients. These patients may benefit from preventative anticoagulants. The OVID and ETHIC trials showed that routine use of enoxaparin to prevent VTE provided no benefit in symptomatic outpatient with COVID-19. Antiplatelet use of aspirin or apixaban also did not benefit symptomatic outpatients in the ACTIV-4B trial.

This was a retrospective study that looked at 18,818 COVID-19 outpatients matched with 93,179 uninfected patients with a mean age of 64 and 56% were women. In the matched set 40% were fully vaccinated the remainder were unvaccinated or partially vaccinated. Those who had COVID there were 67 cases of VTE versus six cases in the fully vaccinated patients. This reinforces the need for vaccination.

High-dose tranexamic acid may reduce need for RBC transfusion during cardiac surgery

In patients who required a RBC transfusion during cardiac surgery who received a high dose of tranexamic acid resulted in the modest reduction in patients requiring that transfusion. The OPTIMAL trail enrolled 3079 patients undergoing cardiac surgery with cardiopulmonary bypass to receive either high dose or lor dose tranexamic acid with the endpoint being RBC transfusion. The primary safety endpoint was 30 day postoperative rate of mortality and adverse events. There were 1525 in the high dose arm with the remaining in the low dose group. RBC transfusion occurred in 21j.8% of high dose patients and 26% in the low dose. Adverse events occurred in 17.6% of the high dose, while 16.8% occurred in the low dose.


Comparison of Unguided De-Escalation Versus Guided Selection of Dual Antiplatelet Therapy After Acute Coronary Syndrome: A Systematic Review and Network Meta-Analysis

Toshiki Kuno, Tomohiro Fujisaki, Satoshi Shoji, Yuki Sahashi. Yusuke Tsugawa, Masao Iwagami, Hisato Takagi, Alexandros Briasoulis. Pierre Deharo, Thomas Cuisset, Azeem Latib

28 Jul 2022Circulation: Cardiovascular Interventions. 2022;0:10.


The benefit of dual antiplatelet therapy (DAPT) for reducing ischemic events is greatest in the early period of acute coronary syndrome, and recent randomized controlled trials have investigated the unguided de-escalation strategy of changing potent P2Y12 inhibitors to less potent or reduced-dose P2Y12 inhibitors 1 month after acute coronary syndrome. However, it remains unclear which strategy is more effective and safer: the uniform unguided de-escalation strategy versus the personalized guided selection of DAPT with genotype or platelet function tests.

PubMed, EMBASE, and Cochrane Central were searched for articles published from database inception to September 10, 2021. Randomized controlled trials investigating DAPT using clopidogrel, low-dose prasugrel, standard-dose prasugrel, ticagrelor, unguided de-escalation strategy, and guided selection strategy for patients with acute coronary syndrome were included. Hazard ratios and relative risk estimates were extracted from each study. The estimates were pooled using a random-effects network meta-analysis. The primary efficacy outcome was major adverse cardiovascular events, defined as a composite of cardiovascular death, myocardial infarction, or stroke. The primary safety outcome was major or minor bleeding. Secondary outcomes were all-cause death, cardiovascular death, myocardial infarction, stroke, stent thrombosis, and major bleeding.

This study included 19 randomized controlled trials with 69 746 patients. Compared with guided selection of DAPT, unguided de-escalation of DAPT was associated with a decreased risk of the primary safety outcome (hazard ratio, 0.48 [95% CI, 0.33–0.72]) without increased risks of major adverse cardiovascular events (hazard ratio, 0.82 [95% CI, 0.53–1.28]) or any secondary outcomes. The results were similar when the guided selection strategy was divided into platelet function–guided and genotype-guided strategies.

Compared with guided selection of DAPT, unguided de-escalation of DAPT decreased bleeding without increasing ischemic events in patients after acute coronary syndrome. If a strategy of de-escalation is chosen, these findings do not support the routine use of personalized guiding tests.

Triggering of myocardial infarction by heat exposure is modified by medication intake

Kai Chen, Robert Dubrow, Susanne Breitner, Kathrin Wolf, Jakob Linseisen, Timo Schmitz, Margit Heier, Wolfgang von Scheidt, Bernhard Kuch, Christa Meisinger, Annette Peters, KORA Study Group & Alexandra Schneider

Nature Cardiovascular Research August 1, (2022)

Acute myocardial infarction (MI) can be triggered by heat exposure, but it remains unknown whether patients taking certain cardiovascular medications have elevated vulnerability. Based on a validated and complete registration of all 2,494 MI cases in Augsburg, Germany, during warm seasons (May to September) from 2001 to 2014, here we show that heat-related non-fatal MI risk was elevated among users of anti-platelet medication and beta-receptor blockers, respectively, but not among non-users, with significant differences between users and non-users. We also found that these effect modifications were stronger among younger patients (25–59 years), who had a lower prevalence of pre-existing coronary heart disease (CHD, a potential confounder by indication), than among older patients (60–74 years), who had a higher prevalence of pre-existing CHD. Users of these medications may be more vulnerable than non-users to non-fatal MI risk due to heat exposure. Further research is needed to disentangle effect modification by medication use from effect modification by pre-existing CHD.

Analysis of Prescriptions for Dual Antiplatelet Therapy After Acute Ischemic Stroke

Ying Xian, MD, PhD1; Haolin Xu, MS2; Roland Matsouaka, PhD2; et alDaniel T. Laskowitz, MD, MHS3; Lesley Maisch, BA4; Deidre Hannah, MSN, RN4; Eric E. Smith, MD, MPH5; Gregg C. Fonarow, MD6; Deepak L. Bhatt, MD, MPH7; Lee H. Schwamm, MD8; Brian Mac Grory, MB, BCh, BAO3; Wuwei Feng, MD, MS3; Emil Loldrup Fosbøl, MD, PhD9; Eric D. Peterson, MD, MPH10; Mark Johnson, MD1

JAMA Netw Open. 2022;5(7):e2224157. doi:10.1001/jamanetworkopen.2022.24157


Importance After the publication of the CHANCE (Clopidogrel in High Risk Patients With Acute Nondisabling Cerebrovascular Events) and POINT (Platelet-Oriented Inhibition in New Transient Ischemic Attack and Minor Ischemic Stroke) clinical trials, the American Heart Association/American Stroke Association (AHA/ASA) issued a new class 1, level of evidence A, recommendation for dual antiplatelet therapy (DAPT; aspirin plus clopidogrel) for secondary prevention in patients with minor ischemic stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤3). The extent to which variations in DAPT prescribing patterns remain and the extent to which practice patterns in the US are consistent with evidence-based guidelines are unknown.

Objective To evaluate the discharge DAPT prescribing patterns after publication of the new AHA/ASA guidelines and assess the extent of hospital-level variation in the use of DAPT for secondary prevention in patients with minor stroke (NIHSS score ≤3), as indicated by guidelines, and in patients with nonminor stroke (NIHSS score >3), for whom the risks and benefits of DAPT have not been fully established.

Design, Setting, and Participants This multicenter retrospective cohort study involved 132 817 patients from 1890 hospitals participating in the AHA/ASA Get With The Guidelines–Stroke program. Patients who were hospitalized for acute ischemic stroke and prescribed antiplatelet therapy at discharge between October 1, 2019, and June 30, 2020, were included.

Exposures Minor ischemic stroke (NIHSS score ≤3) vs nonminor ischemic stroke (NIHSS score >3).

Main Outcomes and Measures The primary outcome was DAPT prescription at discharge. The extent to which variations in DAPT use were explained at the hospital level was assessed by calculating the median odds ratio (OR), which was derived using multivariable logistic regression analysis and compared the likelihood that 2 patients with identical clinical features admitted to 2 randomly selected hospitals (1 with higher propensity and 1 with lower propensity for DAPT use) would receive DAPT at discharge. Associations between hospital-level DAPT use among patients with minor vs nonminor stroke were evaluated using Pearson ρ correlation coefficients.

Results Among 132 817 patients (median [IQR] age, 68 [59-78] years; 68 768 men [51.8%]), 4282 (3.2%) were Asian, 11 254 (8.5%) were Hispanic, 27 221 (20.5%) were non-Hispanic Black, 84 468 (63.6%) were non-Hispanic White, and 5592 (4.2%) were of other races and/or ethnicities (including American Indian or Alaska Native, Native Hawaiian or Pacific Islander, and unable to determine). Overall, 86 551 patients (65.2%) presented with minor ischemic stroke, and 46 266 patients (34.8%) presented with nonminor ischemic stroke. After the 2019 AHA/ASA guideline updates, 40 661 patients (47.0%) with minor stroke (NIHSS median [IQR] score, 1 [0-2]) and 19 703 patients (42.6%) with nonminor stroke (NIHSS median [IQR] score, 6 [5-9]) received DAPT at discharge. Despite guideline recommendations, 45 890 patients (53.0%) with minor stroke did not receive DAPT. After accounting for patient characteristics, substantial hospital-level variations were found in the use of DAPT in those with minor stroke (median [IQR] hospital-level DAPT prescription rate, 44.8% [33.7%-57.7%]; range, 0%-91.7%; median OR, 2.03 [95% CI, 1.97-2.09]) when comparing 2 patients with identical risk factors discharged from 2 randomly selected hospitals, 1 with higher propensity and 1 with lower propensity for DAPT use. The use of DAPT in patients with nonminor stroke also varied significantly (median [IQR] hospital-level DAPT prescription rate, 41.4% [30.0%-53.8%]; range, 0%-100%; median OR, 1.90 [95% CI, 1.83-1.97]). Overall, hospitals that were more likely to prescribe DAPT for minor strokes were also more likely to prescribe DAPT for nonminor strokes (Pearson ρ=0.72; P<.001).

Conclusions and Relevance This cohort study found that despite updated AHA/ASA guidelines, more than 50% of patients with minor acute ischemic stroke did not receive DAPT at discharge. In contrast, more than 40% of patients with nonminor stroke received DAPT despite lack of evidence in this setting. These findings suggest that enhancing adherence to evidence-based DAPT practice guidelines may be a target for quality improvement in the treatment of patients with ischemic stroke.

Drug Interactions Affecting Oral Anticoagulant Use

Philip L Mar 1, Rakesh Gopinathannair 2, Brooke E Gengler 3, Mina K Chung 4, Arturo Perez 1, Jonathan Dukes 5, Michael D Ezekowitz 6, Dhanunjaya Lakkireddy 2, Gregory Y H Lip 7 8, Mike Miletello 9, Peter A Noseworthy 10, James Reiffel 11, James E Tisdale 12 13, Brian Olshansky 14, from the American Heart Association Electrocardiography & Arrhythmias Committee of the Council of Clinical Cardiology

Circ Arrhythm Electrophysiol . 2022 Jun;15(6):e007956.
doi: 10.1161/CIRCEP.121.007956. Epub 2022 May 27.

Oral anticoagulants (OACs) are medications commonly used in patients with atrial fibrillation and other cardiovascular conditions. Both warfarin and direct oral anticoagulants are susceptible to drug-drug interactions (DDIs). DDIs are an important cause of adverse drug reactions and exact a large toll on the health care system. DDI for warfarin mainly involve moderate to strong inhibitors/inducers of cytochrome P450 (CYP) 2C9, which is responsible for the elimination of the more potent S-isomer of warfarin. However, inhibitor/inducers of CYP3A4 and CYP1A2 may also cause DDI with warfarin. Recognition of these precipitating agents along with increased frequency of monitoring when these agents are initiated or discontinued will minimize the impact of warfarin DDI. Direct oral anticoagulants are mainly affected by medications strongly affecting the permeability glycoprotein (P-gp), and to a lesser extent, strong CYP3A4 inhibitors/inducers. Dabigatran and edoxaban are affected by P-gp modulation. Strong inducers of CYP3A4 or P-gp should be avoided in all patients taking direct oral anticoagulant unless previously proven to be otherwise safe. Simultaneous strong CYP3A4 and P-gp inhibitors should be avoided in patients taking apixaban and rivaroxaban. Concomitant antiplatelet/anticoagulant use confers additive risk for bleeding, but their combination is unavoidable in many cases. Minimizing duration of concomitant anticoagulant/antiplatelet therapy as indicated by evidence-based clinical guidelines is the best way to reduce the risk of bleeding.

Efficacy and Safety Considerations With Dose-Reduced Direct Oral Anticoagulants: A Review

Behnood Bikdeli 1 2 3 4, Farbod Zahedi Tajrishi 5, Parham Sadeghipour 6 7, Azita H Talasaz 8 9, John Fanikos 10, Giuseppe Lippi 11, Deborah M Siegal 12, John W Eikelboom 13, Manuel Monreal 14, David Jimenez 15, Jean M Connors 16, Walter Ageno 17, Geoffrey D Barnes 18, Gregory Piazza 1 2, Dominick J Angiolillo 19, Sahil A Parikh 4 20, Ajay J Kirtane 4 20, Renato D Lopes 21 22, Deepak L Bhatt 1, Jeffrey I Weitz 23 24, Roxana Mehran 25, Harlan M Krumholz 3 26 27, Samuel Z Goldhaber 1 2, Gregory Y H Lip 28 29

JAMA Cardiol. 2022 Jul 1;7(7):747-759.doi: 10.1001/jamacardio.2022.1292.


Importance: Dose-reduced regimens of direct oral anticoagulants (DOACs) may be used for 2 main purposes: dose-adjusted treatment intended as full-intensity anticoagulation (eg, for stroke prevention in atrial fibrillation [AF] in patients requiring dose reduction) or low-intensity treatment (eg, extended-duration treatment of venous thromboembolism [VTE]). We reviewed randomized clinical trials (RCTs) to understand the scenarios in which dose-adjusted or low-intensity DOACs were tested and reviewed the labeled indications by regulatory authorities, using data from large registries to assess whether the use of dose-reduced DOACs in routine practice aligned with the findings of RCTs.

Observations: Among 4191 screened publications, 35 RCTs that used dose-adjusted DOACs were identified for dabigatran, apixaban, rivaroxaban, and edoxaban. Of these 35 RCTs, 29 were related to stroke prevention in AF. Efficacy and safety results for dose-adjusted DOACs in large RCTs of AF were similar to those found for full-dose DOACs. To our knowledge, dabigatran, apixaban, and rivaroxaban have not been studied as dose-adjusted therapy for acute VTE treatment. Low-intensity DOACs were identified in 37 RCTs. Low-intensity DOACs may be used for extended-duration treatment of VTE (apixaban and rivaroxaban), primary prevention in orthopedic surgeries (dabigatran, apixaban, and rivaroxaban), primary prevention in ambulatory high-risk cancer patients (apixaban and rivaroxaban) or (postdischarge) high-risk medical patients (rivaroxaban), in stable atherosclerotic vascular disease, or after a recent revascularization for peripheral artery disease in conjunction with aspirin (rivaroxaban). Minor variations exist between regulatory authorities in different regions regarding criteria for dose adjustment of DOACs. Data from large registries indicated that dose-reduced DOACs were used occasionally with doses or for clinical scenarios different from those studied in RCTs or recommended by regulatory authorities.

Conclusions and relevance: Dose adjustment and low-intensity treatment are 2 different forms of dose-reduced DOACs. Dose adjustment is mostly relevant for AF and should be done based on the approved criteria. Dose adjustment of DOACs should not be used for acute VTE treatment in most cases. In contrast, low-intensity DOACs may be used for primary or secondary VTE prevention for studied and approved indications. Attention should be given to routine practice patterns to align the daily clinical practice with existing evidence of safety and efficacy.

Special Considerations for Women of Reproductive Age on Anticoagulation

Tali Azenkot 1, Eleanor Bimla Schwarz 2

J Gen Intern Med 2022 May 31.
doi: 10.1007/s11606-022-07528-y.


Anticoagulation poses unique challenges for women of reproductive age. Clinicians prescribing anticoagulants must counsel patients on issues ranging from menstruation and the possibility of developing a hemorrhagic ovarian cyst to teratogenic risks and safety with breastfeeding. Abnormal uterine bleeding affects up to 70% of young women who are treated with anticoagulation. As such, thoughtful clinical guidance is required to avoid having young women who are troubled by their menses, dose reduce, or prematurely discontinue their anticoagulation, leaving them at increased risk of recurrent thrombosis. Informed by a review of the medical literature, we present current recommendations for assisting patients requiring anticoagulation with menstrual management, prevention of hemorrhagic ovarian cysts, and avoiding unintended pregnancy. The subdermal implant may be considered a first-line option for those requiring anticoagulation, given its superior contraceptive effectiveness and ability to reliably reduce risk of hemorrhagic ovarian cysts. All progestin-only formulations-such as the subdermal implant, intrauterine device, injection, or pills-are generally preferred over combined hormonal pills, patch, or ring. Tranexamic acid, and in rare cases endometrial ablation, may also be useful in managing menorrhagia and dysmenorrhea. During pregnancy, enoxaparin remains the preferred anticoagulant and warfarin is contraindicated. Breastfeeding women may use warfarin, but direct oral anticoagulants are not recommended given their limited safety data. This practical guide for clinicians is designed to inform discussions of risks and benefits of anticoagulation therapy for women of reproductive age.

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study

Maurizio Paciaroni 1 2, Valeria Caso 2, Giancarlo Agnelli 2, Maria Giulia Mosconi 2, Michela Giustozzi 2, David Julian Seiffge 3 4, Stefan T Engelter 3, Philippe Lyrer 3, Alexandros A Polymeris 3, Lilian Kriemler 3, Annaelle Zietz 3, Jukka Putaala 5, Daniel Strbian 5, Liisa Tomppo 5, Patrik Michel 6, Davide Strambo 6, Alexander Salerno 6, Suzette Remillard 6, Manuela Buehrer 6, Odessa Bavaud 6, Peter Vanacker 7 8 9, Susanna Zuurbier 7 8, Laetitia Yperzeele 7 8, Caroline M J Loos 7 8, Manuel Cappellari 10, Andrea Emiliani 10, Marialuisa Zedde 11, Azmil Abdul-Rahim 12, Jesse Dawson 12, Robert Cronshaw 12, Erika Schirinzi 13, Massimo Del Sette 13, Christoph Stretz 14, Narendra Kala 14, Michael Reznik 14, Ashley Schomer 14, Brian Mac Grory 14 15, Mahesh Jayaraman 14, Ryan McTaggart 14, Shadi Yaghi 14, Karen L Furie 14, Luca Masotti 16, Elisa Grifoni 16, Danilo Toni 17, Angela Risitano 17, Anne Falcou 18, Luca Petraglia 17, Enrico Maria Lotti 19, Marina Padroni 19, Lucia Pavolucci 19, Piergiorgio Lochner 20, Giorgio Silvestrelli 21, Alfonso Ciccone 21, Andrea Alberti 2, Michele Venti 2, Laura Traballi 2, Chiara Urbini 2, Odysseas Kargiotis 22, Alessandro Rocco 23, Marina Diomedi 23, Simona Marcheselli 24, Pietro Caliandro 25, Aurelia Zauli 26, Giuseppe Reale 26, Kateryna Antonenko 27, Eugenia Rota 28, Tiziana Tassinari 29, Valentina Saia 29, Francesco Palmerini 30, Paolo Aridon 31, Valentina Arnao 32, Serena Monaco 32, Salvatore Cottone 32, Antonio Baldi 33, Cataldo D'Amore 33, Walter Ageno 34, Samuela Pegoraro 34, George Ntaios 35, Dimitrios Sagris 35, Sotirios Giannopoulos 36, Maria Kosmidou 36, Evangelos Ntais 36, Michele Romoli 37, Leonardo Pantoni 38, Silvia Rosa 39, Pierluigi Bertora 38, Alberto Chiti 40, Isabella Canavero 41 42, Carlo Emanuele Saggese 43, Maurizio Plocco 43, Elisa Giorli 44, Lina Palaiodimou 45, Eleni Bakola 45, Georgios Tsivgoulis 45, Fabio Bandini 46, Antonio Gasparro 47, Valeria Terruso 47, Marina Mannino 47, Alessandro Pezzini 48, Raffaele Ornello 49, Simona Sacco 49, Nemanja Popovic 50, Umberto Scoditti 51, Antonio Genovese 51, Licia Denti 52, Yuriy Flomin 53, Michelangelo Mancuso 54, Elena Ferrari 54, Maria Chiara Caselli 54, Leonardo Ulivi 54, Nicola Giannini 54, Gian Marco De Marchis 3

Stroke 2022 Aug;53(8):2620-2627.doi: 10.1161/STROKEAHA.121.038239. Epub 2022 May 11.


Background: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain.

Methods: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment.

Results: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA2DS2-VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0-1.3] for each point increase; P=0.05) and hypertension (OR, 2.3 [95% CI, 1.0-5.1]; P=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0-1.2] for each year increase; P=0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4-14.2]; P=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4-5.5]; P=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8-1.7]).

Conclusions: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.