Abstract
Introduction
Dabigatran etexilate is a direct thrombin inhibitor that has become widely used in New Zealand. It has been available and fully subsidised in New Zealand since July 2011. Of patients who receive oral anticoagulation, 51% are now being treated with dabigatran. Although prescribing trends can be followed for dabigatran etexilate their relationship to outcomes is unknown. However, current prescribing trends for dabigatran etexilate, in relation to outcomes, are largely unknown for New Zealand patients. It is also recommended that patients taking dabigatran etexilate have at least annual renal function monitoring. Little is known about the current level of monitoring in New Zealand and which method of estimating renal function is the most appropriate. Finally, there is limited information in real-world patients relating to dabigatran etexilate exposure and response and the possible role of therapeutic monitoring in the future.
Aims
The aims of this research were:
1. to describe current use, effectiveness and safety of treatment with dabigatran etexilate in the New Zealand population;
2. to investigate the differences between different estimators of renal function and the risk of adverse outcomes for patients with atrial fibrillation when these different estimators are used for dose selection of dosing dabigatran etexilate;
3. to investigate the relationship between dabigatran etexilate exposure and adverse response in real-world patients;
4. to investigate if clinically appropriate renal function testing recommendations were being undertaken in New Zealand primary care for atrial fibrillation patients prescribed dabigatran etexilate.
Methods
This series of retrospective cohort studies used administrative health data and patient records from New Zealand for patients dispensed dabigatran etexilate between 1 July 2011 and 31 December 2015. Statistical analyses were performed using Stata/IC (Version 14.2, StataCorpLP, TX, USA).
Adverse event (haemorrhage) and treatment failure (systemic embolism (SE) or cerebrovascular accident (CVA)) data were extracted and linked to patient specific demographic data. Baseline patient characteristics were analysed with descriptive statistics to examine trends in dabigatran etexilate prescribing. Raw and adjusted hazard ratios including covariates were derived using Cox proportional hazard models.
Renal function was estimated using Cockcroft-Gault, chronic kidney disease epidemiology initiative equation (CKD-EPI) and CKD-EPI adjusted for BSA (CKD-EPI-BSA). Analysis of variance (ANOVA) and the Wilcoxon signed-ranks test were used to compare the difference in renal clearance in relation to age. Discordance rates and weighted Cohen’s kappa coefficient of agreement were used as measures of agreement between the equations. Outcomes of CVA, SE and haemorrhage were extracted and hazard ratios (HR) were derived from Cox proportional hazard models.
Simulated pharmacokinetic parameters were derived using a published population pharmacokinetic model of dabigatran etexilate. Area under the curve calculated for a 24-hour period at steady state (AUCss), the exposure parameter, was derived using these simulations and the dosing data and the exposure-response relationship were investigated. The risk of adverse outcomes at AUCss quartiles was compared using Poisson regression and expressed using incidence rate ratios (IRR) (95% CI) adjusted for known potential confounders.
The proportion of patients who had serum creatinine measurements at close proximity to treatment initiation and 12–months post were assessed with 95% confidence intervals and compared with Fisher’s exact test. Log-rank tests for univariate analysis (gender, age, ethnicity and deprivation) effects on serum creatinine testing at dabigatran etexilate treatment initiation and 12–months post were performed.
Results
In total, 52413 patients were dispensed dabigatran etexilate in New Zealand during the study time frame.
1. Multivariate analysis indicated the risk of haemorrhagic events was significantly increased by ethnicities of Māori (HR; 95%CI: 2.10 (1.54–2.86)) and Pacific Peoples (HR; 95%CI: 2.20 (1.49–3.24)), age greater than 80 years (HR; 95%CI: 1.25 (1.08–1.43)) and more deprived quintile ratings of Q4 (HR; 95%CI: 1.24 (1.08–1.43)) and Q5 (HR; 95%CI: 1.30 (1.12–1.50)). There was an increased risk of thromboembolism and cerebrovascular accident for those greater than 80 years of age (HR; 95%CI: 1.79 (1.49–2.15)).
2. When investigating the effects of different renal function estimators there were 2425 patients identified in the related datasets. Of these there were hospitalisations for 138 (5.7%) haemorrhagic events, 45 (1.9%) CVA/SE and 33 (1.4%) unspecified CVA. The level of agreement between Cockcroft-Gault with CKD-EPI and CKD-EPI-BSA yielded a weighted Kappa statistic of 0.47 and 0.71, respectively. The hazard ratio for a haemorrhagic event was 2.32 (95%CI, 1.22-4.42; p=0.01) when a high dose was given compared to normal dose, based on Cockcroft-Gault.
3. For NVAF patients there was a decreased risk of haemorrhage (0.51, 0.32–0.79) when dabigatran AUCss was in the second quartile range of 1.70–1.96 mg*h/L and thromboembolism/CVA (0.34, 0.16–0.76) when AUCss was in the third quartile range of 1.97–2.26 mg*h/L. An increased risk of haemorrhage (1.68, 1.18–2.38) was observed when AUCss was in the fourth quartile range of 2.27–12.76 mg*h/L.
4. There were also 1948 dabigatran etexilate patients identified with available primary care health data to investigate compliance to renal function monitoring. A total of 1,752 (89.9% [95%CI; 88.5-91.2]) patients had a renal function test at dabigatran etexilate initiation. There were 929 (72.8% [95%CI; 70.2-75.2]) patients who received one or more years supply of dabigatran and of these 207 (22.3% [95%CI; 19.6.6-25.1]) had a serum creatinine test one year after initiation. Demographic univariate analysis yielded insignificant log-rank tests for association with having serum creatinine measurements except for Pacific Peoples (p = 0.0230).
Conclusions
Demographic factors are associated with adverse outcomes in patients treated with dabigatran etexilate. Patients prescribed dabigatran etexilate of Māori and Pacific Peoples ethnicity are at greater risk of harm compared with other ethnicities. Improvement of outcomes might be achieved by increased vigilance of clinical monitoring especially in the Māori and Pacific Peoples populations, the elderly and those who are more deprived.