Objectives This study sought to perform an indirect comparison analysis of dabigatran etexilate (2 doses), rivaroxaban, and apixaban for their relative efficacy and safety against each other. ...Background Data for warfarin compared against the new oral anticoagulants (OACs) in large phase III clinical trials of stroke prevention in atrial fibrillation (AF) are now available for the oral direct thrombin inhibitor, dabigatran etexilate, in 2 doses (150 mg twice daily BID, 110 mg BID), and the oral Factor Xa inhibitors, rivaroxaban and apixaban. A “head-to-head” direct comparison of drugs is the standard method for comparing different treatments, but in the absence of such head-to-head direct comparisons, another alternative to assess the relative effect of different treatment interventions would be to perform indirect comparisons, using a common comparator. Nonetheless, any inter-trial comparison is always fraught with major difficulties, and an indirect comparison analysis has many limitations, especially with the inter-trial population differences and thus, should not be overinterpreted. Methods Indirect comparison analysis was performed using data from the published trials. Results There was a significantly lower risk of stroke and systemic embolism (by 26%) for dabigatran (150 mg BID) compared with rivaroxaban, as well as hemorrhagic stroke and nondisabling stroke. There were no significant differences for apixaban versus dabigatran (both doses) or rivaroxaban; or rivaroxaban versus dabigatran 110 mg BID in preventing stroke and systemic embolism. For ischemic stroke, there were no significant differences between the new OACs. Major bleeding was significantly lower with apixaban compared with dabigatran 150 mg BID (by 26%) and rivaroxaban (by 34%), but not significantly different from dabigatran 110 mg BID. There were no significant differences between apixaban and dabigatran 110 mg BID in safety endpoints. Apixaban also had lower major or clinically relevant bleeding (by 34%) compared with rivaroxaban. When compared with rivaroxaban, dabigatran 110 mg BID was associated with less major bleeding (by 23%) and intracranial bleeding (by 54%). There were no significant differences in myocardial infarction events between the dabigatran (both doses) and apixaban. Conclusions Notwithstanding the limitations of an indirect comparison study, we found no profound significant differences in efficacy between apixaban and dabigatran etexilate (both doses) or rivaroxaban. Dabigatran 150 mg BID was superior to rivaroxaban for some efficacy endpoints, whereas major bleeding was significantly lower with dabigatran 110 mg BID or apixaban. Only a head-to-head direct comparison of the different new OACs would fully answer the question of efficacy/safety differences between the new drugs for stroke prevention in AF.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
AbstractObjectiveTo determine the incidence of hospital admissions and associated mortality rates for non-covid medical conditions during the covid-19 pandemic.DesignNationwide, population based ...cohort study.SettingDenmark from 13 March 2019 to 27 January 2021.ParticipantsAll Danish residents >1 year of age.Main outcomes measuresPopulation based healthcare registries that encompass the entire Danish population were used to compare hospital admission and mortality rates during the covid-19 pandemic (from 11 March 2020 to 27 January 2021) with the prepandemic baseline data (from 13 March 2019 to 10 March 2020). Hospital admissions were categorised as covid-19 when patients were assigned a diagnosis code for covid-19 within five days of admission. All patients were followed until migration, death, or end of follow-up, whichever came first. Rate ratios for hospital admissions were computed using Poisson regression and were directly standardised using the Danish population on 1 January 2019 as reference. 30 day mortality rate ratios were examined by Cox regression, adjusted for age and sex, and covid-19 diagnosis was used as a competing risk.Results5 753 179 residents were identified during 567.8 million person weeks of observation, with 1 113 705 hospital admissions among 675 447 people. Compared with the prepandemic baseline period (mean hospital admission rate 204.1 per 100 000/week), the overall hospital admission rate for non-covid-19 conditions decreased to 142.8 per 100 000/week (rate ratio 0.70, 95% confidence interval 0.66 to 0.74) after the first national lockdown, followed by a gradual return to baseline levels until the second national lockdown when it decreased to 158.3 per 100 000/week (0.78, 0.73 to 0.82). This pattern was mirrored for most major diagnosis groups except for non-covid-19 respiratory diseases, nervous system diseases, cancer, heart failure, sepsis, and non-covid-19 respiratory infections, which remained lower throughout the study period. Overall 30 day mortality rates were higher during the first national lockdown (mortality rate ratio 1.28, 95% confidence interval 1.23 to 1.32) and the second national lockdown (1.20, 1.16 to 1.24), and these results were similar across most major diagnosis groups. For non-covid-19 respiratory diseases, cancer, pneumonia, and sepsis, the 30 day mortality rate ratios were also higher between lockdown periods.ConclusionsHospital admissions for all major non-covid-19 disease groups decreased during national lockdowns compared with the prepandemic baseline period. Additionally, mortality rates were higher overall and for patients admitted to hospital with conditions such as respiratory diseases, cancer, pneumonia, and sepsis. Increased attention towards management of serious non-covid-19 medical conditions is warranted.
Abstract Background The classification of myocardial infarction into 5 types was introduced in 2007 as an important component of the universal definition. In contrast to the plaque rupture–related ...type 1 myocardial infarction, type 2 myocardial infarction is considered to be caused by an imbalance between demand and supply of oxygen in the myocardium. However, no specific criteria for type 2 myocardial infarction have been established. Methods We prospectively studied unselected hospital patients who had cardiac troponin I measured on clinical indication. The diagnosis and classification of myocardial infarction were established, and the frequency and features of type 2 myocardial infarction were investigated by use of novel developed criteria. Results From January 2010 to January 2011, a total of 7230 consecutive patients who had cardiac troponin I measured were evaluated, and 4499 patients qualified for inclusion. The diagnosis of myocardial infarction was established in 553 patients, of whom 386 (72%) had a type 1 myocardial infarction and 144 (26%) had a type 2 myocardial infarction. Patients in the group with type 2 myocardial infarction were older and more likely to be female, and had more comorbidities. The proportion of patients without significant coronary artery disease was higher in those with type 2 myocardial infarction (45%) than in those with type 1 myocardial infarction (12%) ( P < .001). Tachyarrhythmias, anemia, and respiratory failure were the most prevalent mechanisms causing type 2 myocardial infarction. Conclusions In a cohort of patients with myocardial infarction who were admitted consecutively through 1 year, the category of type 2 myocardial infarction comprised one fourth when diagnosed by the use of newly developed criteria. Approximately half of patients with type 2 myocardial infarction had no significant coronary artery disease.
Abstract Background The classification of myocardial infarction into 5 types was introduced in 2007. The prognostic impact of this universal definition, with particular focus on type 2 myocardial ...infarction, has not been studied prospectively in unselected hospital patients. Methods During a 1-year period, all hospitalized patients having cardiac troponin I measured were considered. The diagnosis of a myocardial infarction was according to the universal definition, and specified criteria were used in the classification of type 2 myocardial infarction. Follow-up was at least 1 year, with mortality as the end point. Results A total of 3762 consecutive patients were studied, of whom 488 (13%) had a myocardial infarction. In 119 patients a type 2 myocardial infarction was diagnosed. After a median of 2.1 years (interquartile range, 1.6-2.5 years), 150 patients had died, with a mortality rate of 49% (58/119) in those with type 2 myocardial infarction and 26% (92/360) in those with type 1 myocardial infarction ( P < .0001). In a multivariable Cox regression analysis the following variables were independently associated with mortality: current or prior smoker, high age, prior myocardial infarction, type 2 myocardial infarction, hypercholesterolemia, high p-creatinine, and diabetes mellitus. The multivariable-adjusted hazard ratio for type 2 myocardial infarction was 2.0 (95% confidence interval, 1.3-3.0). With shock as the only exception, mortality was independent of the triggering conditions leading to type 2 myocardial infarction. Conclusions Mortality in patients with type 2 myocardial infarction is high, reaching approximately 50% after 2 years. Further descriptive and survival studies are needed to improve the scientific evidence on which treatment of type 2 myocardial infarction is based.
\Anticoagulation is used for stroke prophylaxis in non-valvular atrial fibrillation, amongst other by use of the vitamin K antagonist, warfarin. Quality in warfarin therapy is often summarized by the ...time patients spend within the therapeutic range (percent time in therapeutic range, TTR). The correlation between TTR and the occurrence of complications during warfarin therapy has been established, but the influence of patient characteristics in that respect remains undetermined. The objective of the present papers was to examine the association between mean TTR and complication rates with adjustment for differences in relevant patient cohort characteristics.
A systematic literature search was conducted in MEDLINE and Embase (2005-2015) to identify eligible studies reporting on use of warfarin therapy by patients with non-valvular atrial fibrillation and the occurrence of hemorrhage and thromboembolism. Both randomized controlled trials and observational cohort studies were included. The association between the reported mean TTR and major bleeding and stroke/systemic embolism was analyzed by random-effects meta-regression with and without adjustment for relevant clinical cohort characteristics. In the adjusted meta-regressions, the impact of mean TTR on the occurrence of hemorrhage was adjusted for the mean age and the proportion of populations with prior stroke or transient ischemic attack. In the adjusted analyses on thromboembolism, the proportion of females was, furthermore, included.
Of 2169 papers, 35 papers met pre-specified inclusion criteria, holding relevant information on 31 patient cohorts. In univariable meta-regression, increasing mean TTR was significantly associated with a decreased rate of both major bleeding and stroke/systemic embolism. However, after adjustment mean TTR was no longer significantly associated with stroke/systemic embolism. The proportion of residual variance composed by between-study heterogeneity was substantial for all analyses.
Although higher mean TTR in warfarin therapy was associated with lower complication rates in atrial fibrillation, the strength of the association was decreased when adjusting for differences in relevant clinical characteristics of the patient cohorts. This study suggests that mainly the safety of warfarin therapy increases with higher mean TTR, whereas effectiveness appears not to be substantially improved. Due to the limitations immanent in the meta-regression methods, the results of the present study should be interpreted with caution. Further research on the association between the quality of warfarin therapy and risk of complications is warranted with adjustment for clinically relevant characteristics.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background Atrial fibrillation after thoracic surgery is frequent and increases morbidity and mortality. A number of trials have investigated medical prophylaxis for the prevention of atrial ...fibrillation after surgery for lung cancer. However, the literature is diverse and hence difficult to review. The aim of this study was to evaluate the safety and efficacy of reducing the risk of postoperative atrial fibrillation by the use of medical prophylaxis in patients undergoing surgery for lung cancer. Methods A systematic review and meta-analysis of randomized, controlled trials investigating prophylactic medical interventions to reduce the risk of postoperative atrial fibrillation was performed. Results A total number of 10 trials were identified. A significant reduction in the risk of postoperative atrial fibrillation was found with a relative risk of 0.53 (95% confidence interval, 0.42 to 0.67) and a number needed-to-treat of 8.5 (95% confidence interval, 6.4 to 13.3). Amiodarone was found to be the most effective prophylactic agent with a relative risk of 0.32 (95% confidence interval, 0.19 to 0.50) and a number needed-to-treat of 4.8 (95% confidence interval, 3.7 to 7.6) and regarded as safe, with no severe adverse events registered. The risk of atrial fibrillation was overall reduced from 25.1% to 13.4% ( p < 0.001) and for amiodarone as a single therapy from 30.4% to 9.6% ( p < 0.001). Conclusions Medical prophylaxis with calcium-channel blockers, magnesium sulfate, or amiodarone significantly reduces the risk of developing atrial fibrillation after lung reduction surgery. However, amiodarone and magnesium sulfate were the most effective and safest drugs causing no increased risk of adverse events.
Various bleeding risk scores have been proposed to assess the risk of bleeding in patients with atrial fibrillation taking oral anticoagulants. Limited data are available with these scores, in users ...of non-vitamin K antagonist oral anticoagulants.
Using the Danish registries, we evaluated and compared the risk classification properties of the Hypertension, Age, Stroke, Bleeding tendency/predisposition, Labile international normalized ratios, Elderly age/frailty, Drugs such as concomitant aspirin/nonsteroidal anti-inflammatory drugs or alcohol excess (HAS-BLED), Anticoagulation and Risk Factors in Atrial Fibrillation (ATRIA), and Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT) scores for predicting major bleeding in 57,930 atrial fibrillation patients (44.6% female; mean age 73.5 years, standard deviation 11.4 years; mean CHA2DS2-VASc score 3.2, standard deviation 1.8).
At 1-year follow-up, C-statistics for ATRIA, HAS-BLED, and ORBIT were approximately 0.59, with only minor differences between scores. Both ATRIA and ORBIT categorized more patients as “low risk” (both >83%, when compared with HAS-BLED, only 53%), and qualitatively, the receiver operating characteristic curves revealed higher sensitivity (62.8%) for HAS-BLED compared with ATRIA (29.7%) and ORBIT (37.1%). The clinical usefulness of scores was evaluated using decision curve analyses at a 1-year perspective. If the intervention threshold is low (<1.7%), the benefit is toward monitoring all patients. If preference is for a major bleeding risk threshold between 1.7% and 2.0%, most benefit was obtained by using HAS-BLED. The ORBIT and ATRIA scores provided better benefit for thresholds between 2.0% and 6.0%.
This analysis of contemporary bleeding risk score stratification in a “real-world” non-vitamin K antagonist oral anticoagulant users population with atrial fibrillation showed modest predictive values using C-statistics. The scores represent different risk thresholds, with HAS-BLED classifying least patients at low risk and achieving the highest benefit if applying a major bleeding intervention threshold of approximately 2%, whereas benefit from using either ATRIA score or ORBIT score was only evident using higher intervention thresholds.
Abstract Background The bleeding risk among patients with atrial fibrillation is higher early after initiating therapy with vitamin K antagonists (VKAs). Evidence is limited on how prior VKA ...experience affects bleeding risk when initiating novel oral anticoagulant therapy. We investigated this among patients with atrial fibrillation initiating dabigatran therapy. Methods By using nationwide Danish prescription and patient registries, we identified 11,315 first-time dabigatran users with atrial fibrillation. Warfarin controls were matched in a 2:1 ratio according to VKA experience status. The average follow-up time was 13 months. Across the 6 combinations of treatment (dabigatran 110 mg, dabigatran 150 mg, and warfarin) and VKA experience status (naive or experienced), VKA-naïve warfarin initiators had the highest rate of any bleeding event. Cox regressions adjusted for baseline characteristics showed reductions relative to this group ranging from 19% for VKA-experienced dabigatran 110 mg users (hazard ratio HR, 0.81; 95% confidence interval CI, 0.66-1.00) to 41% for VKA-experienced dabigatran 150 mg users (HR, 0.59; 95% CI, 0.46-0.75). Among switchers to dabigatran from warfarin, when comparing with warfarin-persisting users, the rate of any bleeding was nonsignificantly decreased for switchers to dabigatran 150 mg (HR, 0.80; 95% CI, 0.62-1.03) but not for switchers to dabigatran 110 mg (HR, 1.12; 95% CI, 0.90-1.41). Results for major bleeding were similar. Crude rates of fatal, intracranial, and gastrointestinal bleeding were low. Conclusions VKA-naïve warfarin initiators had the highest overall bleeding rate. We found no evidence of marked excess of overall bleeding events when comparing dabigatran with warfarin users, irrespective of prior VKA experience.
The aim of this study was to assess the efficacy and safety in an "everyday clinical practice" population of anticoagulant-naïve patients with atrial fibrillation (AF) treated with dabigatran ...etexilate after its post-approval availability in Denmark, compared with warfarin.
Concerns have been raised about an excess of bleeding events or myocardial infarction (MI) among patients treated with the new oral direct thrombin inhibitor, dabigatran etexilate.
From the Danish Registry of Medicinal Product Statistics, we identified a dabigatran-treated group and a 1:2 propensity-matched warfarin-treated group of 4,978 and 8,936, respectively. Comparisons on efficacy and safety outcomes were made on the basis of Cox-proportional hazards models stratified on propensity-matched groups.
Stroke and systemic embolism were not significantly different between warfarin- and dabigatran-treated patients. Adjusted mortality was significantly lower with both dabigatran doses (110 mg b.i.d., propensity-match group stratified hazard ratio aHR: 0.79, 95% confidence interval CI: 0.65 to 0.95; 150 mg b.i.d., aHR: 0.57, 95% CI: 0.40 to 0.80), when compared with warfarin. Pulmonary embolism was lower compared with warfarin for both doses of dabigatran. Less intracranial bleeding was seen with both dabigatran doses (110 mg b.i.d., aHR: 0.24, 95% CI: 0.08 to 0.56; 150 mg b.i.d., aHR: 0.08, 95% CI: 0.01 to 0.40). The incidence of MI was lower with both dabigatran doses (110 mg b.i.d., aHR: 0.30, 95% CI: 0.18 to 0.49; 150 mg b.i.d., aHR: 0.40, 95% CI: 0.21 to 0.70). Gastrointestinal bleeding was lower with dabigatran 110 mg b.i.d. (aHR: 0.60, 95% CI: 0.37 to 0.93) compared with warfarin but not dabigatran 150 mg b.i.d. The main findings were broadly consistent in a subgroup analysis of dabigatran users with ≥1-year follow-up (median follow-up 13.9 months interquartile range: 12.6 to 15.3 months).
In this "everyday clinical practice" post-approval nationwide clinical cohort, there were similar stroke/systemic embolism and major bleeding rates with dabigatran (both doses) compared with warfarin. Mortality, intracranial bleeding, pulmonary embolism, and MI were lower with dabigatran, compared with warfarin. We found no evidence of an excess of bleeding events or MI among dabigatran-treated patients in this propensity-matched comparison against warfarin, even in the subgroup with ≥1-year follow-up.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPUK, ZAGLJ, ZRSKP
Contemporary guidelines suggest anticoagulant treatment decisions in atrial fibrillation (AF) patients to be based on risk stratification for stroke. However, guidelines do not agree on the threshold ...for treatment initiation. We explored the variation in thromboembolic event rates in a non-anticoagulated AF population, according to different guideline threshold and methodological approaches. AF patients between 1998 and 2014 free from anticoagulant treatment were identified. Event rates for ischemic stroke and ischemic stroke/systemic embolism were explored. The overall ischemic stroke rate was 3.20 per 100 person-years ('formal rate assessment'). For patients with a CHA2DS2-VASc score of 1 the ischemic stroke rate was 0.97 when using a 'formal rate assessment', 0.62 when using a 'conditioning on the future' approach, and 0.93 when using a 'censoring approach'. Rates for thromboembolism for the 'European treatment threshold' (CHA2DS2-VASc score of 1, males only) ranged 1.17 to 1.53. Rates for the 'U.S. treatment threshold' (CHA2DS2-VASc of 2) ranged from 1.95 to 2.33. Thromboembolic event rates differed markedly in non-anticoagulated AF patients according to the conflicting European and U.S. guideline treatment thresholds. Second, the choice of methodological approach has implications, thus we recommend using the censoring approach for event rate estimation among AF patients not on treatment.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
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