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vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation
Patients who filled a prescription for a standard dose non vitamin K antagonist oral anticoagulant (novel oral anticoagulants, NOACs) were excluded. To control for baseline differences in the population, a propensity score for receipt of either of the four treatment alternatives was calculated to apply an inverse probability treatment weight.
InterventionInitiated anticoagulant treatment (dabigatran 110 mg, rivaroxaban 15 mg, apixaban 2.5 mg, and warfarin).
Main outcome measuresPatients were followed in the registries from onset of treatment for the primary effectiveness outcome of ischaemic stroke/systemic embolism and for the principal safety outcome of any bleeding events.
ResultsAmong 55644 patients with atrial fibrillation who met inclusion criteria, the cohort was distributed according to treatment: apixaban n=4400; dabigatran n=8875; rivaroxaban n=3476; warfarin n=38893. The overall mean age was 73.9 (SD 12.7), ranging from a mean of 71.0 (warfarin) to 83.9 (apixaban). During one year of follow up, apixaban was associated with higher (weighted) event rate of ischaemic stroke/systemic embolism (4.8%), while dabigatran, rivaroxaban, and warfarin had event rates of 3.3%, 3.5%, and 3.7%, respectively. In the comparison between a non vitamin K antagonist oral anticoagulant and warfarin in the inverse probability of treatment weighted analyses and investigation of the effectiveness outcome, the hazard ratios were 1.19 (95% confidence interval 0.95 to 1.49) for apixaban, 0.89 (0.77 to 1.03) for dabigatran, and 0.89 (0.69 to 1.16) for rivaroxaban. For the principal safety outcome versus warfarin, the hazard ratios were 0.96 (0.73 to 1.27) for apixaban, 0.80 (0.70 to 0.92) for dabigatran, and 1.06 (0.87 to 1.29) for rivaroxaban.
ConclusionIn this propensity weighted nationwide study of reduced dose non vitamin K antagonist oral anticoagulant regimens, apixaban 2.5 mg twice a day was associated with a trend towards higher rates of ischaemic stroke/systemic embolism compared with warfarin, while rivaroxaban 15 mg once a day and dabigatran 110 mg twice a day showed a trend towards lower thromboembolic rates. The results were not significantly different. Rates of bleeding (the principal safety outcome) were significantly lower for dabigatran, but not significantly different for apixaban and rivaroxaban compared with warfarin.
IntroductionAtrial fibrillation is associated with an increased risk of ischaemic stroke and mortality. During the past five years, large randomised trials have established that non vitamin K antagonist oral anticoagulants (novel oral anticoagulants, NOACs) have a similar efficacy to warfarin but have a superior safety profile, largely driven by a substantial reduction in associated risk of intracranial haemorrhage.1 These findings have subsequently changed guidelines to either include NOACs as an option for stroke prophylaxis2 or to recommend these agents as first choice of drug.3 The findings of clinical trials have been confirmed in various observational cohort studies based on data from clinical practice.4567
While meticulous dose adjustments are not required for NOACs as they are for warfarin, a clinical evaluation of appropriate (constant) dose is still necessary. Various degrees of renal function entails recommendations to offer these drugs in a reduced dosing regimen, but different cut off values for age, body weight, or interacting drugs also require consideration for appropriate dose selection.8 Indeed, both age and chronic kidney disease in patients with atrial fibrillation intensifies the risk of stroke and increases the risk of bleeding during antithrombotic treatment.9 Elderly patients with atrial fibrillation (such as those aged 80) and patients with impaired renal function were included in the landmark trials of NOACs, but these important subgroups comprised only a small proportion of the patient populations.
Nevertheless, contemporary guidelines suggest a reduced dosing regimen for dabigatran (110 mg twice a day) if patients are aged 80 or have an estimated glomerular filtration rate (eGFR) of 30 50 mL/min; rivaroxaban (15 mg once a day) if eGRF is 15 49 mL/min; apixaban (2.5 mg twice a day) if two of the three following criteria are present: age 80 or an eGRF 15 29 mL/min or body weight 60 kg; or edoxaban (30 mg once a day) if eGFR is 15 50 mL/min.10 While subgroup analyses including patients with varying degree of renal function showed comparable efficacy with warfarin,11 evidence on reduce dose regimens of non vitamin K antagonist oral anticoagulants from "real world" clinical practice is scarce. In response to this lack of evidence about reduce dose regimens for stroke prevention in atrial fibrillation, fake hermes brown belt whosale we conducted a nationwide cohort study to examine effectiveness and safety compared with warfarin. To ascertain appropriateness of prescribing, we particularly focused on subgroups of elderly patients and those with impaired renal function, given their potential "indication for dose reduction" when NOACs are used.
MethodsThis was an observational cohort study of a nationwide population of unselected patients with atrial fibrillation who had not previously taken an oral anticoagulant. Patients were identified from nationwide registries in Denmark.
Data sourcesIn Denmark, individuals are assigned a unique identification number allowing linkage on an individual level between databases. Study data were obtained from three nationwide administrative databases: the Danish national prescription registry, which holds information on purchase date, Anatomical Therapeutic Chemical (ATC) classification code, and package size for every prescription claim since 1994; the Danish civil registration system, which holds information on sex, date of birth, and vital and emigration status; and the Danish national patient register, which includes admission/discharge date, and discharge ICD (international classification of diseases) diagnosis codes for hospital admissions since 1977.
Patient populationEligible patients were identified as those with a first time prescription claim for an NOAC defined as: apixaban (introduced 10 December 2012), dabigatran (introduced 1 August 2011), or rivaroxaban (introduced 1 February 2012), as well as individuals who started warfarin treatment (since 1 August 2011) up to 28 February 2016. Patients who had taken any oral anticoagulant within the previous year were excluded to establish a naive cohort. All NOACs were restricted to reduced doses approved for stroke prevention in atrial fibrillation (in Europe) as follows: apixaban 2.5 mg, dabigatran 110 mg, and rivaroxaban 15 mg. To focus on non valvular atrial fibrillation, we excluded patients with previous hospital diagnoses indicating valvular atrial fibrillation (mitral stenosis or mechanical heart valves). We further excluded all those patients with an indication for oral anticoagulant treatment other than atrial fibrillation (history of pulmonary embolism, deep venous thrombosis, or recent hip/knee surgery). This allowed for an indirect identification of eligible patients with atrial fibrillation as all other reasons for initiation of an oral anticoagulation were ruled out. We therefore assumed that initiation of treatment indicated stroke prophylaxis for atrial fibrillation.
Patient involvementNo patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for recruitment, design, or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.
Ascertainment of outcome measures and comorbidityWe used the Danish national patient register to follow included patients from onset of treatment until 30 April 2016 for the occurrence of a combined endpoint of "ischaemic hermes belt price replica stroke or systemic embolism" and ischaemic stroke separately. All cause mortality was included as a single endpoint because oral anticoagulants significantly reduce the risk of stroke and death compared with control or placebo,12 while NOACs significantly reduce all cause mortality compared with warfarin.13 Safety outcomes were recorded as haemorrhagic stroke and major and gastrointestinal bleeding and reported in a combined endpoint as "any bleeding" and specific for haemorrhagic stroke. Major bleeding was defined as bleeding with anaemia, haemothorax, haematuria, epistaxis, and bleeding in the eye (see table A in appendix 1). We used ICD 10 (international classification of diseases, 10th revision) to identify outcomes. The coding accuracy of the selected outcomes has previously been validated and found sufficiently accurate for epidemiological research.1415
For quantifying thromboembolic risk, we combined comorbidity information into the CHA2DS2 VASc score16; similarly, to assess the risk of bleeding we calculated the HAS BLED score (table B in appendix 2).17
Within each NOAC agent, there are differences in criteria for recommendation of a reduced dose; nevertheless, elderly people and those with renal impairment are subgroups of patients who require special attention regarding choice of NOAC and dose.18 Therefore, we analysed these subgroups as having a potential "indication for dose reduction." We identified those with adult polycystic kidney disease, chronic glomerulonephritis, chronic tubulointestinal nephropathy, diabetic nephropathy, non end stage chronic kidney disease, hypertensive nephropathy, and nephropathy of unknown aetiology and categorised them as having chronic kidney disease (table A in appendix 1). While we did not have access to individual eGFR or creatinine clearance directly at the time of treatment initiation, a reasonable clinical assumption is that the aforementioned diseases would affect the renal function to such an extent that it could confer a clinical recommendation to reduce the dose of any NOAC.
Statistical analysesCharacteristics of the study population were reported as percentages, means (standard deviation), or medians (interquartile range). Person years of follow up were calculated from the date of first prescription claim to the occurrence of first endpoint, death, emigration, or end of follow up, whichever came first. Incidence rates were calculated as number of events divided by person time. To determine the risk of outcomes among NOAC users compared with warfarin (reference) users, we calculated cause specific hazard ratios using Cox regression models. Failure curves were used to depict how risks of events evolved over time. Specifically, we used the Aalen Johansen estimator to calculate absolute risk of events taking into account the competing risk of death16 and the Kaplan Meier estimator hermes belts Knockoff for all cause mortality. To allow an unbiased comparison across different treatment regimens, we applied an inverse probability of treatment weighted approach. This is particularly suitable when there are several treatment alternatives in this case, dabigatran, apixaban, rivaroxaban, and warfarin.1920 The weights were derived to obtain estimates representing population average treatment effects with optimal balance between the treatment populations21 by using generalised boosted models based on 10000 regression trees as done previously.4 The underlying propensity models included age (continuous); binary indicators for sex and hospital diagnosis of atrial fibrillation, ischaemic stroke, vascular disease, ischaemic heart disease, hypertension, diabetes, cancer, chronic obstructive lung disease, heart failure or left ventricular dysfunction, recent prescription of aspirin, blockers, non steroidal anti inflammatory drugs, statins, loop and non loop diuretics, amiodarone, dronedarone, vasodilators, calcium channel blockers, and verapamil; and the CHA2DS2 VASc and HAS BLED scores included as continuous variables.
The examined treatment regimens should be contrasted on comparable populations and any patient must have positive probability for any treatment (positivity Hermes belts replica paris assumption), hence substantial overlap between the propensities for each treatment should be present. In agreement with best methodological practice, this was assessed by graphical inspection of the weight distributions (appendix 2).22 Additionally, we evaluated balance between treatment populations by standardised differences of all baseline covariates, using a threshold of 0.1 to indicate imbalance.23
Sensitivity analysesTo further explore the potential for bias from baseline differences and the propensity of receiving treatment with an NOAC, we performed sensitivity analyses using an ordinary crude and Cox multivariate adjusted analysis to compare the results obtained from the weighted analyses. We also performed a sensitivity analysis using standardised morbidity ratio24 weights to address the (hypothetical) casual situation of all patients receiving warfarin treatment rather than an NOAC.
To allow for a thorough prognostic evaluation and given the divergence of age across oral anticoagulant exposure groups, we supplemented the main analysis by a sensitivity analysis stratified on age category for instance, age 80. While not all of these patients would have renal deficiencies severe enough to acquire a diagnosis, advanced age significantly affects renal function2526; thus, assessment of comparative effectiveness and safety between NOAC and warfarin in these age groups is of clinical value given the age dependency on renal function (opting for reduce dose NOAC regimen). We also conducted a sensitivity analysis restricted to patients with a hospital diagnosis of atrial fibrillation to increase likelihood of treatment indication. Finally, as the introduction of each NOAC could have influenced patient selection, we repeated the main analysis confined to the time period where all three NOACs were available in Denmark that is, from 12 December 2012, when apixaban (latest market drug) was available in Denmark.
The analyses were performed with Stata version 14 (StataCorp) and R version 3.1.1 (R Foundation for Statistical Computing). A two sided P
ResultsWe identified 88141 patients in the study period who were eligible for inclusion by either fillinga prescription for low dose regimen NOAC or warfarin (only 2.5 mg available in Denmark). After we excluded reasons for oral anticoagulant treatment other than atrial fibrillation (n=31852) and previous use of phenprocoumon within the past year for unknown reasons (n=645), we identified a study population (n=55644) of patients who had not been taking oral anticoagulants within the previous year and who were starting treatment with either reduced dose NOAC or warfarin (fig A in appendix 3).
The study population was distributed by type of oral anticoagulant: 69.9% received warfarin, 7.9% apixaban, 15.9% dabigatran, and 6.3% rivaroxaban. The population average time of follow up (with respect to all cause mortality) was 2.3 years, with the apixaban group having the shortest mean follow up of one year. The study population age varied markedly across exposure to each drug for example, the average age for apixaban users was 83.9, while for warfarin the average age was 71.0 (table 1). Patients treated with either apixaban or rivaroxaban had a higher prevalence of renal diseases (9.5% and 9.1%, respectively) than patients treated with dabigatran (3.9%) or warfarin (8.3%). In general, the patients treated with apixaban had more comorbidities such as heart failure, previous thromboembolism, diabetes, and presence of vascular diseases. Therefore, the estimated risk of stroke, as summarised by the mean CHA2DS2 VASc score, was highest in patients treated with apixaban (4.3), and slightly lower for dabigatran (3.8) and rivaroxaban (3.6), and lowest for warfarin treated patients (3.0). A similar pattern (but with less pronounced differences) for risk of bleeding, as summarised by the mean HASBLED score, was observed with an overall population average score of 2.4.
Table 1 Characteristics of patients with atrial fibrillation who had not previously received oral anticoagulant by treatment groups. Values are numbers (percentages) unless stated otherwise
View this table:View popupView inline
With inverse probability of treatment weight to account for baseline differences, the standardised differences were less than 0.09 (compared with 1.01 before imposing estimated weights). Comparisons of individual propensity score distributions showed sufficient overlap, and suggest that application of the weights of inverse probability of treatment, resulted in a cohort in which the distribution of variables were comparable between treatment groups; hence comparisons between treatment groups were feasible (appendix 2).
Patients who filled a prescription for a standard dose non vitamin K antagonist oral anticoagulant (novel oral anticoagulants, NOACs) were excluded. To control for baseline differences in the population, a propensity score for receipt of either of the four treatment alternatives was calculated to apply an inverse probability treatment weight.
InterventionInitiated anticoagulant treatment (dabigatran 110 mg, rivaroxaban 15 mg, apixaban 2.5 mg, and warfarin).
Main outcome measuresPatients were followed in the registries from onset of treatment for the primary effectiveness outcome of ischaemic stroke/systemic embolism and for the principal safety outcome of any bleeding events.
ResultsAmong 55644 patients with atrial fibrillation who met inclusion criteria, the cohort was distributed according to treatment: apixaban n=4400; dabigatran n=8875; rivaroxaban n=3476; warfarin n=38893. The overall mean age was 73.9 (SD 12.7), ranging from a mean of 71.0 (warfarin) to 83.9 (apixaban). During one year of follow up, apixaban was associated with higher (weighted) event rate of ischaemic stroke/systemic embolism (4.8%), while dabigatran, rivaroxaban, and warfarin had event rates of 3.3%, 3.5%, and 3.7%, respectively. In the comparison between a non vitamin K antagonist oral anticoagulant and warfarin in the inverse probability of treatment weighted analyses and investigation of the effectiveness outcome, the hazard ratios were 1.19 (95% confidence interval 0.95 to 1.49) for apixaban, 0.89 (0.77 to 1.03) for dabigatran, and 0.89 (0.69 to 1.16) for rivaroxaban. For the principal safety outcome versus warfarin, the hazard ratios were 0.96 (0.73 to 1.27) for apixaban, 0.80 (0.70 to 0.92) for dabigatran, and 1.06 (0.87 to 1.29) for rivaroxaban.
ConclusionIn this propensity weighted nationwide study of reduced dose non vitamin K antagonist oral anticoagulant regimens, apixaban 2.5 mg twice a day was associated with a trend towards higher rates of ischaemic stroke/systemic embolism compared with warfarin, while rivaroxaban 15 mg once a day and dabigatran 110 mg twice a day showed a trend towards lower thromboembolic rates. The results were not significantly different. Rates of bleeding (the principal safety outcome) were significantly lower for dabigatran, but not significantly different for apixaban and rivaroxaban compared with warfarin.
IntroductionAtrial fibrillation is associated with an increased risk of ischaemic stroke and mortality. During the past five years, large randomised trials have established that non vitamin K antagonist oral anticoagulants (novel oral anticoagulants, NOACs) have a similar efficacy to warfarin but have a superior safety profile, largely driven by a substantial reduction in associated risk of intracranial haemorrhage.1 These findings have subsequently changed guidelines to either include NOACs as an option for stroke prophylaxis2 or to recommend these agents as first choice of drug.3 The findings of clinical trials have been confirmed in various observational cohort studies based on data from clinical practice.4567
While meticulous dose adjustments are not required for NOACs as they are for warfarin, a clinical evaluation of appropriate (constant) dose is still necessary. Various degrees of renal function entails recommendations to offer these drugs in a reduced dosing regimen, but different cut off values for age, body weight, or interacting drugs also require consideration for appropriate dose selection.8 Indeed, both age and chronic kidney disease in patients with atrial fibrillation intensifies the risk of stroke and increases the risk of bleeding during antithrombotic treatment.9 Elderly patients with atrial fibrillation (such as those aged 80) and patients with impaired renal function were included in the landmark trials of NOACs, but these important subgroups comprised only a small proportion of the patient populations.
Nevertheless, contemporary guidelines suggest a reduced dosing regimen for dabigatran (110 mg twice a day) if patients are aged 80 or have an estimated glomerular filtration rate (eGFR) of 30 50 mL/min; rivaroxaban (15 mg once a day) if eGRF is 15 49 mL/min; apixaban (2.5 mg twice a day) if two of the three following criteria are present: age 80 or an eGRF 15 29 mL/min or body weight 60 kg; or edoxaban (30 mg once a day) if eGFR is 15 50 mL/min.10 While subgroup analyses including patients with varying degree of renal function showed comparable efficacy with warfarin,11 evidence on reduce dose regimens of non vitamin K antagonist oral anticoagulants from "real world" clinical practice is scarce. In response to this lack of evidence about reduce dose regimens for stroke prevention in atrial fibrillation, fake hermes brown belt whosale we conducted a nationwide cohort study to examine effectiveness and safety compared with warfarin. To ascertain appropriateness of prescribing, we particularly focused on subgroups of elderly patients and those with impaired renal function, given their potential "indication for dose reduction" when NOACs are used.
MethodsThis was an observational cohort study of a nationwide population of unselected patients with atrial fibrillation who had not previously taken an oral anticoagulant. Patients were identified from nationwide registries in Denmark.
Data sourcesIn Denmark, individuals are assigned a unique identification number allowing linkage on an individual level between databases. Study data were obtained from three nationwide administrative databases: the Danish national prescription registry, which holds information on purchase date, Anatomical Therapeutic Chemical (ATC) classification code, and package size for every prescription claim since 1994; the Danish civil registration system, which holds information on sex, date of birth, and vital and emigration status; and the Danish national patient register, which includes admission/discharge date, and discharge ICD (international classification of diseases) diagnosis codes for hospital admissions since 1977.
Patient populationEligible patients were identified as those with a first time prescription claim for an NOAC defined as: apixaban (introduced 10 December 2012), dabigatran (introduced 1 August 2011), or rivaroxaban (introduced 1 February 2012), as well as individuals who started warfarin treatment (since 1 August 2011) up to 28 February 2016. Patients who had taken any oral anticoagulant within the previous year were excluded to establish a naive cohort. All NOACs were restricted to reduced doses approved for stroke prevention in atrial fibrillation (in Europe) as follows: apixaban 2.5 mg, dabigatran 110 mg, and rivaroxaban 15 mg. To focus on non valvular atrial fibrillation, we excluded patients with previous hospital diagnoses indicating valvular atrial fibrillation (mitral stenosis or mechanical heart valves). We further excluded all those patients with an indication for oral anticoagulant treatment other than atrial fibrillation (history of pulmonary embolism, deep venous thrombosis, or recent hip/knee surgery). This allowed for an indirect identification of eligible patients with atrial fibrillation as all other reasons for initiation of an oral anticoagulation were ruled out. We therefore assumed that initiation of treatment indicated stroke prophylaxis for atrial fibrillation.
Patient involvementNo patients were involved in setting the research question or the outcome measures, nor were they involved in developing plans for recruitment, design, or implementation of the study. No patients were asked to advise on interpretation or writing up of results. There are no plans to disseminate the results of the research to study participants or the relevant patient community.
Ascertainment of outcome measures and comorbidityWe used the Danish national patient register to follow included patients from onset of treatment until 30 April 2016 for the occurrence of a combined endpoint of "ischaemic hermes belt price replica stroke or systemic embolism" and ischaemic stroke separately. All cause mortality was included as a single endpoint because oral anticoagulants significantly reduce the risk of stroke and death compared with control or placebo,12 while NOACs significantly reduce all cause mortality compared with warfarin.13 Safety outcomes were recorded as haemorrhagic stroke and major and gastrointestinal bleeding and reported in a combined endpoint as "any bleeding" and specific for haemorrhagic stroke. Major bleeding was defined as bleeding with anaemia, haemothorax, haematuria, epistaxis, and bleeding in the eye (see table A in appendix 1). We used ICD 10 (international classification of diseases, 10th revision) to identify outcomes. The coding accuracy of the selected outcomes has previously been validated and found sufficiently accurate for epidemiological research.1415
For quantifying thromboembolic risk, we combined comorbidity information into the CHA2DS2 VASc score16; similarly, to assess the risk of bleeding we calculated the HAS BLED score (table B in appendix 2).17
Within each NOAC agent, there are differences in criteria for recommendation of a reduced dose; nevertheless, elderly people and those with renal impairment are subgroups of patients who require special attention regarding choice of NOAC and dose.18 Therefore, we analysed these subgroups as having a potential "indication for dose reduction." We identified those with adult polycystic kidney disease, chronic glomerulonephritis, chronic tubulointestinal nephropathy, diabetic nephropathy, non end stage chronic kidney disease, hypertensive nephropathy, and nephropathy of unknown aetiology and categorised them as having chronic kidney disease (table A in appendix 1). While we did not have access to individual eGFR or creatinine clearance directly at the time of treatment initiation, a reasonable clinical assumption is that the aforementioned diseases would affect the renal function to such an extent that it could confer a clinical recommendation to reduce the dose of any NOAC.
Statistical analysesCharacteristics of the study population were reported as percentages, means (standard deviation), or medians (interquartile range). Person years of follow up were calculated from the date of first prescription claim to the occurrence of first endpoint, death, emigration, or end of follow up, whichever came first. Incidence rates were calculated as number of events divided by person time. To determine the risk of outcomes among NOAC users compared with warfarin (reference) users, we calculated cause specific hazard ratios using Cox regression models. Failure curves were used to depict how risks of events evolved over time. Specifically, we used the Aalen Johansen estimator to calculate absolute risk of events taking into account the competing risk of death16 and the Kaplan Meier estimator hermes belts Knockoff for all cause mortality. To allow an unbiased comparison across different treatment regimens, we applied an inverse probability of treatment weighted approach. This is particularly suitable when there are several treatment alternatives in this case, dabigatran, apixaban, rivaroxaban, and warfarin.1920 The weights were derived to obtain estimates representing population average treatment effects with optimal balance between the treatment populations21 by using generalised boosted models based on 10000 regression trees as done previously.4 The underlying propensity models included age (continuous); binary indicators for sex and hospital diagnosis of atrial fibrillation, ischaemic stroke, vascular disease, ischaemic heart disease, hypertension, diabetes, cancer, chronic obstructive lung disease, heart failure or left ventricular dysfunction, recent prescription of aspirin, blockers, non steroidal anti inflammatory drugs, statins, loop and non loop diuretics, amiodarone, dronedarone, vasodilators, calcium channel blockers, and verapamil; and the CHA2DS2 VASc and HAS BLED scores included as continuous variables.
The examined treatment regimens should be contrasted on comparable populations and any patient must have positive probability for any treatment (positivity Hermes belts replica paris assumption), hence substantial overlap between the propensities for each treatment should be present. In agreement with best methodological practice, this was assessed by graphical inspection of the weight distributions (appendix 2).22 Additionally, we evaluated balance between treatment populations by standardised differences of all baseline covariates, using a threshold of 0.1 to indicate imbalance.23
Sensitivity analysesTo further explore the potential for bias from baseline differences and the propensity of receiving treatment with an NOAC, we performed sensitivity analyses using an ordinary crude and Cox multivariate adjusted analysis to compare the results obtained from the weighted analyses. We also performed a sensitivity analysis using standardised morbidity ratio24 weights to address the (hypothetical) casual situation of all patients receiving warfarin treatment rather than an NOAC.
To allow for a thorough prognostic evaluation and given the divergence of age across oral anticoagulant exposure groups, we supplemented the main analysis by a sensitivity analysis stratified on age category for instance, age 80. While not all of these patients would have renal deficiencies severe enough to acquire a diagnosis, advanced age significantly affects renal function2526; thus, assessment of comparative effectiveness and safety between NOAC and warfarin in these age groups is of clinical value given the age dependency on renal function (opting for reduce dose NOAC regimen). We also conducted a sensitivity analysis restricted to patients with a hospital diagnosis of atrial fibrillation to increase likelihood of treatment indication. Finally, as the introduction of each NOAC could have influenced patient selection, we repeated the main analysis confined to the time period where all three NOACs were available in Denmark that is, from 12 December 2012, when apixaban (latest market drug) was available in Denmark.
The analyses were performed with Stata version 14 (StataCorp) and R version 3.1.1 (R Foundation for Statistical Computing). A two sided P
ResultsWe identified 88141 patients in the study period who were eligible for inclusion by either fillinga prescription for low dose regimen NOAC or warfarin (only 2.5 mg available in Denmark). After we excluded reasons for oral anticoagulant treatment other than atrial fibrillation (n=31852) and previous use of phenprocoumon within the past year for unknown reasons (n=645), we identified a study population (n=55644) of patients who had not been taking oral anticoagulants within the previous year and who were starting treatment with either reduced dose NOAC or warfarin (fig A in appendix 3).
The study population was distributed by type of oral anticoagulant: 69.9% received warfarin, 7.9% apixaban, 15.9% dabigatran, and 6.3% rivaroxaban. The population average time of follow up (with respect to all cause mortality) was 2.3 years, with the apixaban group having the shortest mean follow up of one year. The study population age varied markedly across exposure to each drug for example, the average age for apixaban users was 83.9, while for warfarin the average age was 71.0 (table 1). Patients treated with either apixaban or rivaroxaban had a higher prevalence of renal diseases (9.5% and 9.1%, respectively) than patients treated with dabigatran (3.9%) or warfarin (8.3%). In general, the patients treated with apixaban had more comorbidities such as heart failure, previous thromboembolism, diabetes, and presence of vascular diseases. Therefore, the estimated risk of stroke, as summarised by the mean CHA2DS2 VASc score, was highest in patients treated with apixaban (4.3), and slightly lower for dabigatran (3.8) and rivaroxaban (3.6), and lowest for warfarin treated patients (3.0). A similar pattern (but with less pronounced differences) for risk of bleeding, as summarised by the mean HASBLED score, was observed with an overall population average score of 2.4.
Table 1 Characteristics of patients with atrial fibrillation who had not previously received oral anticoagulant by treatment groups. Values are numbers (percentages) unless stated otherwise
View this table:View popupView inline
With inverse probability of treatment weight to account for baseline differences, the standardised differences were less than 0.09 (compared with 1.01 before imposing estimated weights). Comparisons of individual propensity score distributions showed sufficient overlap, and suggest that application of the weights of inverse probability of treatment, resulted in a cohort in which the distribution of variables were comparable between treatment groups; hence comparisons between treatment groups were feasible (appendix 2).
The Wall