Eligibility and Preference of New Oral Anticoagulants in Patients With Atrial Fibrillation
Comparison Between Patients With Versus Without Stroke
Background and Purpose—Recent randomized clinical trials (RCTs) have evaluated the benefit of new oral anticoagulants in reducing the risk of vascular events and bleeding complications in patients with atrial fibrillation (AF). However, abundant and strict enrollment criteria may limit the validity and applicability of results of RCTs to clinical practice. We estimated the eligibility for participation in RCTs of an unselected group of patients with AF. In addition, we compared features favoring new oral anticoagulant use between patients with versus without stroke. Randomized Evaluation of Long-Term Anticoagulation Therapy
Methods—We applied enrollment criteria of 4 RCTs (RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE-AF-TIMI 48) to 695 patients with AF taking warfarin, prospectively and consecutively collected at a university medical center; 500 patients with and 195 patients without stroke. Time in therapeutic range and bleeding risk scheme (anticoagulation and risk factors in atrial fibrillation) were also measured.
Results—The proportions of patients fulfilling the trial enrollment criteria varied, ranging from 39% to 72.8%, depending on the differences in indications/contraindications among studies and presence/absence of stroke. The main reasons for ineligibility for RCTs were hemorrhagic risk (anticoagulation and risk factors in atrial fibrillation [ATRIA] score) (10.8%–40.5%) and planned cardioversion (5.1%–7.7%) for nonstroke patients, and a low creatinine clearance (5.6%–9.2%) and higher risk of bleeding (15.2%–20.8%) for patients with stroke. When compared with nonstroke patients, patients with stroke showed a lower time in therapeutic range (54.4±42.8% versus 65.4±34.9%, especially with severe disability) and a high hemorrhagic risk (ATRIA score) (3.06±2.30 versus 2.18±2.16) (P<0.05 in both cases).
Conclusions—Patients enrolled in RCTs are partly representative of patients with AF in clinical practice. When time in therapeutic range and bleeding tendency with warfarin use were considered, the use of new oral anticoagulants was preferred in patients with stroke than in nonstroke patients, but they were more likely to be excluded in RCTs.
Results of 4 phase III randomized controlled trials (RCTs) on 4 new oral anticoagulants (NOACs), dabigatran, apixaban, rivaroxaban, and edoxaban, have recently been introduced.1–4 NOACs are either noninferior or superior to warfarin in prevention of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation (AF) but are superior to warfarin in reducing hemorrhagic stroke.
Evidence from these trials forms the basis for national and international guidelines for the management of nearly all such patients in clinical practice. The inclusion and exclusion criteria in randomized trials are defined by steering committee based on feedback from regulatory agencies, eg, the US Food and Drug Administration or European Medicines Agency. However, abundant and strict enrollment criteria may limit the validity and the applicability of results of RCTs to clinical practice. Recent studies of antiplatelet therapy for prevention of ischemic stroke and surgical treatment for intracranial hemorrhage showed that patients with ischemic stroke or intracranial hemorrhage enrolled in RCTs are only partially representative of patients in clinical practice.5,6 Both studies suggested the use of less strict enrollment criteria to enhance generalizability. Moreover, a population-based study showed that compared with randomized control trials on NOACs, patients who were discharged with AF differed in that they were older and more comorbid, more like to have severe/recent stroke, and on polypharmacy, which suggest that the patients enrolled in the randomized trials may deviate from the real-world practice.7
We hypothesized that the current enrollment criteria of the clinical trials of NOACs may not representative of patients with AF, and analysis of eligibility of patients in clinical practice may guide the future direction for drug development. Thus, we estimated the eligibility for participation in landmark trials of NOACs of an unselected group of AF patients with or without stroke or transient ischemic attack (transient ischemic attack [TIA]). In addition, we compared features favoring NOAC use between patients with versus without stroke/TIA.
Patients and Methods
This study used a retrospective cohort design based on data of consecutive patients encountered at a University Medical Center from October 2011 to October 2013.
Patients were included in this study if (1) they had AF, (2) they were taking warfarin with a target international normalized ratio (INR) range of 2.0 to 3.0, and (3) who were followed up for >6 months. Patients with and without ischemic stroke or TIA were included in this study. Patients with ischemic stroke or TIA were identified as having suffered focal symptoms and relevant lesions on diffusion-weighted imaging for patients with stroke and no lesions for patients with TIA. The local institutional review board approved the study, and informed consent was obtained from participants before commencement of the study.
Patients received long-term warfarin treatment with a target INR range of 2.0 to 3.0. After stabilization, maintenance dosing within the therapeutic range was achieved by performing periodic INRs. Compliance with warfarin treatment was regularly monitored, and patients received education for warfarin diet by a pharmacist at an anticoagulation service. Dose assessment was performed every 1 to 3 months. For the calculation of the proportion of time in therapeutic range of INR levels, Rosendaal’s method was used.8 INR levels after 1 month of initiation of warfarin were used to define the quality of anticoagulation control (labile INRs during warfarin maintenance). In addition, we excluded INRs during temporary or permanent discontinuation, and during the first 1 month after treatment was restarted.
Once a patient was enrolled, we obtained a medical history, performed a physical examination, and asked about concomitant medications, such as the use of antiplatelet agents, nonsteroidal anti-inflammatory drugs, and cytochrome P450 inhibitors/inducers. Blood tests were performed to measure creatinine clearance and liver disease. Variables that could potentially affect vascular events were recorded for each patient, which included congestive heart failure, hypertension, age >75 y, diabetes mellitus, and prior stroke or TIA (CHADS2) score and hemorrhagic (anticoagulation and risk factors in atrial fibrillation [ATRIA])9 risk schemes. In this study, we used ATRIA score for bleeding risk scheme instead of the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile international normalized ratio, elderly, drugs/alcohol) score, because labile INRs are a key component of the HAS-BLED risk scheme.10
Eligibility for Participation in the NOAC Trials and Preference to NOACs Than Warfarain
We applied the enrollment criteria of 4 NOAC trials (Randomized Evaluation of Long-Term Anticoagulant Therapy [RE-LY],1 Rivaroxaban–Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation [ROCKET-AF],2 Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation Trial [ARISTOTLE],3 Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation [ENGAGE-AF-TIMI 48]) (Table 1; Table I in the online-only Data Supplement). The inclusion and exclusion criteria were applied to each patient, and eligibility for participation in the NOAC trials was measured. In this study, recent or severely disabling stroke was not considered as a contraindication of NOACs trials. In addition, we also evaluated features favoring NOAC use in each patient, which included labile INR (time in therapeutic range [TTR] <66%) and bleeding risk (ATRIA score). A recent meta-analysis of NOACs trials showed a greater relative reduction in major bleeding with NOACs when TTR was <66%.11 In addition, the current guideline suggests that assessment of bleeding risk should be considered in the choice of anticoagulant in patients with AF.12
The differences in the clinical and laboratory parameters were evaluated by one-way ANOVA with post hoc analysis using the Fisher least-square difference or Kruskall–Wallis test for continuous variables, and Pearson χ2, Fisher exact test, or linear by linear association for categorical variables. An independent t test or the Mann–Whitney U test was used to evaluate differences in the factors between the groups. All statistical analyses were performed using commercially available software (SPSS for Window, version 18.0; SPSS Inc., Chicago, IL). A P<0.05 was considered statistically significant.
Six hundred ninety-five patients were included in this study. When compared with
patients without stroke/TIA, patients with stroke/TIA were older and had a lower TTR, especially in those with severe disability (modified Rankin scale) (Figure I in the online-only Data Supplement), and bleeding tendency as measured by ATRIA was much higher in patients with stroke/TIA (P<0.001 in both cases) (Table 2). Creatinine clearance was lower in patients with stroke/TIA than in nonstroke patients (P=0.037).
The proportions of patients fulfilling the trial enrollment criteria varied, ranged from 39.0% to 72.8%, depending on the differences in indications/contraindications of studies (lower in ENGAGE-AF-TIMI 48 than others) and presence or absence of stroke/TIA (Figure). It was higher in patients with stroke (57.4%–72.8%) than in nonstroke patients (40.0%–67.7%). When compared with nonstroke patients, patients with stroke/TIA were more likely to meet inclusion criteria but were more likely to be excluded from the studies.
Characteristics of eligible patients were similar among the studies but differed between with versus without stroke or TIA (Tables 3 and 4). In patients without stroke/TIA, eligible patients were older and had a higher CHADS2 score (P<0.01 in both cases) than ineligible patients. On the contrary, in patients with stroke/TIA, eligible patients were younger, less likely to have symptomatic heart failure, and had a lower CHADS2 and ATRIA score and a higher TTR compared with ineligible patients (P<0.05 in all cases).
The main reasons for contraindications of NOACs were also similar among the studies but differed between with versus without stroke or TIA (Figure; Table II in the online-only Data Supplement). A lower CHADS2 score (10.8%–40.5%) and planned cardioversion (5.1%–7.7%) were the main reasons for ineligibility for RCTs for nonstroke patients and a low creatinine clearance (5.6%–9.2%) and higher risk of bleeding (15.2%–20.8%) for patients with stroke.
Preference of NOACs could be determined by a low TTR, a high ATRIA score, and a high creatinine clearance. However, there was a negative correlation between creatinine clearance and ATRIA score, as well as a negative correlation between ATRIA and TTR (Table 5). Patients who had features favoring NOAC use (ie, a high ATRIA score) were more likely to have contraindications for NOACs use (ie, a low creatinine clearance). Age was commonly associated with these factors.
The main findings of this study are (1) the proportions of patients fulfilling the trial enrollment criteria were varied greatly depending on the differences in indications/contraindications of studies and presence or absence of stroke/TIA, and (2) patients enrolled in randomized clinical trials are only partly representative of patients with AF in clinical practice. Patients in whom NOACs were preferred, ie, at high bleeding risk and poor anticoagulation control with warfarin, were likely to be excluded in the NOAC trials.
The reasons for ineligibility for participation in NOACs trials were different between patients with stroke and nonstroke patients. The main reasons in nonstroke patients were no need for anticoagulation, such as low CHADS2 scores or planned cardiac surgery/intervention. Valvular heart disease was another reason for exclusion in nonstroke patients in our study. The use of an NOAC in patients with mechanical heart valves was associated with increased rates of thromboembolic and bleeding complications when compared with warfarain.13 On the contrary, all ineligible patients with stroke needed anticoagulation therapy. When compared with eligible patients, they were older and had a high ATRIA score and low TTR. Therefore, our results suggest that patients with stroke enrolled in RCTs are not representative of most patients with stroke and AF. Specifically, many patients who definitely need anticoagulation (a high AF-stroke risk schemes including elderly and heart failure), particularly in whom NOACs were preferred because of the poor quality of anticoagulation therapy (ie, low TTR) and a high risk of bleeding (ie, ATRIA score), were excluded in this study. However, NOACs would be particularly helpful in such conditions.12 High TTR (>70%) is associated with the best efficacy and safety of warfarin,14 and a greater reduction in major bleeding with NOACs versus warfarin was observed in patients with a lower TTR (<66%).11
Why would patients in whom the use of NOACs would be preferred be excluded in the NOAC trials? Although there was no restriction in terms of age (except <18 years) in the trial enrollment criteria, age may be the key factors for the eligibility of the NOAC trials. A population study showed that patients in clinical practice were fairly older compared with participants in RCT on NOACs, and severe impair renal impairment was not infrequent in the elderly, particularly in patients aged >80 years (50% showed a creatinine clearance ≤50 mL/min).7 The annual risk of stroke in untreated patients with AF is age dependent, being 1% in the 50 to 59 age group, 3% in the 60 to 90 age group, 10% in the 70 to 79 age group, and 24% in patients aged 80 to 89.7 Patients at increased age have an increased risk of bleeding often because of a declining renal function and other unknown factors. The RE-LY trial investigators reported a significant interaction between age and NOAC-related bleeding complication, and low dose of dabigatran is currently recommended for patients aged ≥75 years.15 Our results showed that AF-risk schemes, bleeding-risk scheme, and a poor quality of anticoagulation are associated with age as well as renal function. Because of the deterioration in kidney function with age, the target populations for NOACs were excluded in most NOAC trials. Recently, subgroup analysis of RCTs of NOACs in patients with renal impairment showed that NOACs reduced the risk of stroke/systemic embolism and major bleeding regardless of renal function.16,17 Our analysis of eligibility of patients in clinical practice raised the importance of the use of less strict enrollment criteria, and the need for development of NOACs that can be used in elderly patients with AF and renal dysfunction.
The strength of this study was the inclusion of a large number of unselected and consecutively enrolled patients with comprehensive evaluation of the quality of anticoagulation control, risk schemes for AF-related thromboembolic risk and hemorrhage, and renal function. This study also has limitations resulting from a single center at a university hospital in Korea. Additional studies are needed to confirm our results. However, patients’ characteristics in East Asians with AF are similar to those in elsewhere. For example, patients’ features in ROCKET-AF participants2 were comparable with those in J-ROCKET-AF participants (exclusively Japanese),18 which may strengthen the generalization of the results of this study (Table III in the online-only Data Supplement).
In conclusion, our results confirm that patients enrolled on RCTs investigating NOACs are partly representative of patients with AF in clinical practice. Furthermore, we demonstrated that currently used enrollment criteria were not successful in selecting patients in whom NOACs are preferred. Further studies are needed for patients who are likely to have beneficial with NOACs with the use of less strict enrollment criteria.
Sources of Funding
This study was supported by the National Research Foundation of Korea, Ministry of Education, Science and Technology (2011–0019389).
The online-only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.114.005599/-/DC1.
- Received March 27, 2014.
- Revision received July 23, 2014.
- Accepted July 28, 2014.
- © 2014 American Heart Association, Inc.
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