Gastrointestinal bleeding (GIB) rates for direct oral anticoagulants (DOACs) and warfarin have been extensively compared. However, population-based studies comparing GIB rates among different DOACs ...are limited.
To compare rates of GIB among apixaban, dabigatran, and rivaroxaban.
Nationwide population-based cohort study.
Landspítali-The National University Hospital of Iceland and the 4 regional hospitals in Iceland.
New users of apixaban, dabigatran, and rivaroxaban from 2014 to 2019.
Rates of GIB were compared using inverse probability weighting, Kaplan-Meier survival estimates, and Cox regression.
In total, 2157 patients receiving apixaban, 494 patients receiving dabigatran, and 3217 patients receiving rivaroxaban were compared. For all patients, rivaroxaban had higher overall rates of GIB (3.2 vs. 2.5 events per 100 person-years; hazard ratio HR, 1.42 95% CI, 1.04 to 1.93) and major GIB (1.9 vs. 1.4 events per 100 person-years; HR, 1.50 CI, 1.00 to 2.24) compared with apixaban. Rivaroxaban also had higher GIB rates than dabigatran, with similar point estimates, although the CIs were wider and included the possibility of a null effect. When only patients with atrial fibrillation were included, rivaroxaban was associated with higher rates of overall GIB than apixaban (HR, 1.40 CI, 1.01 to 1.94) or dabigatran (HR, 2.04 CI, 1.17 to 3.55). Dabigatran was associated with lower rates of upper GIB than rivaroxaban in both analyses.
Unmeasured confounding and small subgroup analyses.
Rivaroxaban was associated with higher GIB rates than apixaban and dabigatran regardless of treatment indication.
Icelandic Centre for Research and Landspítali-The National University Hospital of Iceland.
While overall gastrointestinal bleeding (GIB) rates have been extensively compared between warfarin and direct oral anticoagulants (DOACs), it is still unclear whether upper and lower GIB rates ...differ between these types of drugs. This study aimed to compare upper and lower GIB rates between warfarin and DOACs in a nationwide cohort.
Data on all patients in Iceland who received a prescription for oral anticoagulation from 2014 to 2019 were collected and their personal identification numbers linked to the electronic medical record system of the National University Hospital of Iceland and the 4 regional hospitals in Iceland. Inverse probability weighting was used to yield balanced study groups and rates of overall, major, upper, and lower GIB were compared using Cox regression. All GIB events were manually confirmed by chart review.
Warfarin was associated with higher rates of upper GIB (1.7 events per 100 person-years vs 0.8 events per 100 person-years; hazard ratio HR, 2.12; 95% confidence interval CI, 1.26-3.59) but similar rates of lower GIB compared with DOACs. Specifically, warfarin was associated with higher rates of upper GIB compared with apixaban (HR, 2.63; 95% CI, 1.35-5.13), dabigatran (5.47; 95% CI, 1.87-16.05), and rivaroxaban (HR, 1.74; 95% CI, 1.00-3.05). Warfarin was associated with higher rates of major GIB compared with apixaban (2.3 events per 100 person-years vs 1.5 events per 100 person-years; HR, 1.79; 95% CI, 1.06-3.05), but otherwise overall and major GIB rates were similar in warfarin and DOAC users.
Warfarin was associated with higher rates of upper but not overall or lower GIB compared with DOACs. Warfarin was associated with higher rates of major GIB compared with apixaban.
The new Fiix prothrombin time (Fiix-PT) and its derived Fiix-normalized ratio (Fiix-NR) is affected only by reductions in coagulation factors (F) II and X, the two factors responsible for the ...antithrombotic effect of vitamin K antagonists (VKA). Due to insensitivity to reductions in the short half-life FVII, the Fiix-NR rises later than standard PT-INR during warfarin initiation. To describe a warfarin initiation nomogram adapted for monitoring with Fiix-NR, anticoagulation development was assessed during use of standard PT-INR based initiation nomogram and after adapting the initiation nomogram for Fiix-NR monitoring. Normalized ratios were retrospectively assessed in consecutive warfarin naïve patients during their first 60 days of warfarin intake for one year prior to (PT-INR period) and for one year after replacing the PT-INR with the Fiix-NR (Fiix-NR period). The INR target was NR 2.0–3.0. We evaluated 160 patients monitored with PT-INR and dosed with the PT-nomogram, 57 monitored with Fiix-INR but dosed with PT-nomogram, and 163 Fiix-NR monitored patients dosed using a new Fiix nomogram. Mean PT-INR over 2.0 was reached on day 7 during the PT-period and remained around 2.5 thereafter. When the PT-nomogram continued in use during Fiix-monitoring significantly more patients became overanticoagulated during days 11–29. After the nomogram was modified to respond to rising Fiix-NR with larger initial dose reduction, the mean Fiix-NR reached over 2 on day 8–9 and remained around 2.5 thereafter. When warfarin is monitored with Fiix-NR, an adjusted dosing nomogram should be used during initiation to prevent early overanticoagulation.
Background
Although epistaxis is one of the most common side effects of oral anticoagulation, it is unclear whether epistaxis rates vary between different oral anticoagulants (OAC).
Objective
To ...compare rates of clinically relevant epistaxis between OAC.
Methods
Epistaxis event rates were compared between new users of apixaban, dabigatran, rivaroxaban, and warfarin in a nationwide population‐based cohort study over a 5‐year study period, 2014–2019. Data was collected from the Icelandic Medicine Registry and the five major hospitals in Iceland. Inverse probability weighting (IPW) was used to yield balanced baseline characteristics, and epistaxis rates were compared using Kaplan–Meier survival estimates and Cox regression.
Results
During the study period, 2098 patients received apixaban, 474 dabigatran, 3106 rivaroxaban, and 1403 warfarin. In total, 93 patients presented with clinically relevant epistaxis, including 11 (12%) major epistaxis events and one fatal epistaxis episode. Furthermore, seven patients (9%) with non‐major epistaxis later presented with major bleeding during the follow‐up period. Warfarin use was associated with higher rates of epistaxis compared to apixaban (2.2 events per 100‐person years (events/100‐py) vs. 0.6 events/100‐py, hazard ratio HR 4.22, 95% confidence interval CI 2.08–8.59, p < 0.001), rivaroxaban (2.2 events/100‐py vs. 1.0 events/100‐py, HR 2.26, 95% CI 1.28–4.01, p = 0.005), and dabigatran (2.2 events/100‐py vs. no events, HR n/a, p < 0.001).
Conclusion
Warfarin treatment was associated with higher rates of clinically relevant epistaxis compared to direct oral anticoagulants.
Previous observational studies have yielded conflicting results on whether medication adherence differs between patients receiving warfarin and direct oral anticoagulants (DOACs). Importantly, no ...study has adequately accounted for warfarin dosing being continuously modified based on INR values while dosing of DOACs is fixed. We aimed to compare non-adherence between new users of apixaban, dabigatran, rivaroxaban and warfarin in a population-based cohort.
New users of apixaban, dabigatran, rivaroxaban and warfarin from 2014 to 2019 living in the Icelandic capital area were included. Non-adherence was defined as proportion of days covered below 80%. Inverse probability weighting was used to yield balanced study groups and non-adherence was compared using logistic regression. Factors associated with non-adherence were estimated using multivariable logistic regression.
Overall, 1266 patients received apixaban, 247 dabigatran, 1566 rivaroxaban and 768 warfarin. The proportion of patients with non-adherence ranged from 10.5% to 16.7%. Dabigatran was associated with significantly higher odds of non-adherence compared with apixaban (OR 1.57, 95% CI 1.21 to 2.04, p<0.001), rivaroxaban (OR 1.45, 95% CI 1.12 to 1.89, p=0.005) and warfarin (OR 1.63, 95% CI 1.23 to 2.15, p<0.001). The odds of non-adherence were similar for apixaban, rivaroxaban and warfarin. Apart from the type of oral anticoagulants (OACs) used, female sex, hypertension, history of cerebrovascular accident and concomitant statin use were all independently associated with lower odds of non-adherence.
Dabigatran was associated with higher odds of non-adherence compared with other OACs. Non-adherence was similar between apixaban, rivaroxaban and warfarin users. Female sex and higher comorbidity were associated with better medication adherence.
•In this nationwide cohort study, apixaban, dabigatran, and rivaroxaban had similar rates of any stroke or systemic embolism.•Rivaroxaban had higher rates of major bleeding than apixaban and ...dabigatran but lower rates of myocardial infarction than dabigatran.
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In the pivotal randomized controlled trials (RCTs) for patients with atrial fibrillation, direct oral anticoagulants (DOACs) had similar or even superior efficacy and safety compared with warfarin. However, RCTs comparing different DOACs are nonexistent and previous observational studies have yielded conflicting results. In this nationwide cohort study, rates of any stroke or systemic embolism (stroke/SE) and major bleeding were compared among new users of apixaban, dabigatran, and rivaroxaban with atrial fibrillation from 2014 to 2019. Inverse probability weighting was used to yield balanced study groups, and outcomes were compared using Cox regression. Stroke/SE rates were similar in patients receiving apixaban, dabigatran, and rivaroxaban. Dabigatran was associated with twofold higher rates of myocardial infarction (MI) than rivaroxaban (1.4 events/100 person-years (py) vs 0.7 events/100-py, hazard ratio HR 2.21, 95% confidence interval CI, 1.00-4.90) and apixaban (1.4 events/100-py vs 0.7 events/100-py, HR 2.26, 95% CI, 0.90-5.67), although the second comparison included the possibility of a null effect. Rivaroxaban was associated with higher major bleeding rates compared with apixaban (2.9 events/100-py vs 1.8 events/100-py, HR 1.64, 95% CI, 1.13-2.37) and dabigatran (2.9 events/100-py vs 1.4 events/100-py, HR 2.18, 95% CI, 1.21-3.93). Specifically, rivaroxaban had higher rates of major gastrointestinal bleeding and other major bleeding than apixaban. In conclusion, although stroke/SE rates were similar for DOACs, rivaroxaban was associated with higher rates of major bleeding than other DOACs and lower rates of MI than dabigatran. These results may help guide oral anticoagulant selection, especially in patients at high risk of bleeding or MI.
Abstract Introduction The prevalence and etiology of occult bleeding among patients on warfarin who are screened systematically for new anemia is largely unknown. We aimed to estimate the usefulness ...of following hemoglobin and mean red cell volume (MCV) with INR in order to screen for developing anemia as an indicator of occult bleeding. Material and methods All patients on warfarin controlled at our institution had measurements of complete blood count (CBC) with INR during 18 months. Patients who fell > 25 g/L and/or decrease of MCV over 5 fL or MCV < 80 fL were contacted with instructions to undergo evaluation of anemia. Results Overall 3218 patients on warfarin were monitored at our institution and 442 (13.7%) had anemia and 235 (7.3%) had unexplained anemia. A total of 163/235 (69%) who were notified contacted their doctors and 82/163 (50%) were referred for investigation with upper and/or lower endoscopies. Gastrointestinal malignancies were found in 11 patients (10 colorectal cancers, 1 esophageal) and pre-cancerous lesions among 14 other patients. Additional 25/82 patients (30%) had upper and/or lower bleeding lesions such as ulcers and angiodysplasia. Based on 3669 years of observation, 73 patients needed to be screened for one year in order to identify one gastrointestinal lesion causing occult bleeding. Conclusions Thirty percent of those endoscoped had malignant or pre-malignant diseases. Regular measurement of CBC concomitantly with INR in patients on warfarin therapy led to detection of otherwise asymptomatic diseases in a significant proportion of patients and might lead to earlier diagnosis of malignant and premalignant disease.
Abstract Vitamin K antagonists (VKA) are monitored with prothrombin time (PT) based assays that are equally sensitive to reductions in factors II, VII or X. We compared the effect of vitamin K ...dependent (VKD) coagulation factors on PT and also on rotational thromboelastometric (ROTEM) parameters. The PT was equally sensitive to reductions in factors II, VII or X but ROTEM parameters correlated poorly with the PT in anticoagulated patients´ plasmas. ROTEM parameters were more affected by mild and moderate reductions in FII or FX than by FVII or FIX which had little influence except at very low coagulant activity. We developed a modified PT that was sensitive only to reductions in factors II and X. The Fiix-PT (Fiix-INR) correlated well with PT (INR) but the Fiix-INR fluctuated less than the INR in an anticoagulated patient reflecting its insensitivity to FVII. The ROTEM results suggest that mild to moderate reductions in factors II or X are more important during clot formation than factors VII or IX. Reductions in FII and X may better reflect anticoagulation with VKA than FVII or IX. The new Fiix-PT may more accurately reflect the degree of therapeutic anticoagulation in patients treated with VKA than the current PT which is subject to a confounding variation caused by FVII.
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