Editorials
New Oral Anticoagulants (NOAC) Studies in the Ideal and the Real World – Needs of Prospective Observational Studies –
2015 Volume 79 Issue 5 Pages 962-963
Details
2015 Volume 79 Issue 5 Pages 962-963
The anticoagulant warfarin has been conventionally used for prophylaxis of cerebral infarction (cardioembolism) with atrial fibrillation (AF). The prescription rate of warfarin increased after 2000 in particular. In fact, warfarin was used in 87% of patients with AF in the J-RHYTHM registration study at Japanese institutions.1 That registry study demonstrated that a PT-INR=1.6–2.6 is a safe and effective target for preventing thromboembolic events in nonvalvular AF (NVAF) patients in Japan, particularly those aged ≥70 years’ although INR=2.6–2.99 is also effective, it is associated with a trend toward an increased risk of major hemorrhage. Warfarin has been the gold standard of stroke prevention for patients with AF. However, it is associated with many limitations: high risks of drug-drug (vitamin K) and drug-food (such as natto [traditional Japanese fermented soybeans]) interactions, long half-life, complicated induction and interruption, and the need for frequent PT-INR monitoring.
Article p 1018
Recently, new oral anticoagulants (NOACs) have been used as alternatives to warfarin anticoagulation in NVAF. A randomized trial, RE-LY,2 evaluated 110 mg and 150 mg twice-daily doses of dabigatran in such patients. Compared with warfarin, both doses of dabigatran were associated with similar and lower rates of stroke and systemic embolism, and with lower and similar rates of major hemorrhage, respectively. The randomized, double-blind ARISTOTLE clinical trial showed that apixaban was superior to warfarin in preventing stroke or systemic embolism in AF patients, caused less bleeding, and resulted in lower mortality.3 The ROCKET-AF double-blind clinical trial showed that rivaroxaban was not inferior to warfarin in the prevention of subsequent stroke or systemic embolism in AF patients.4 A randomized double-blind, double-dummy trial found that 2 different once-daily regimens of edoxaban were not inferior to warfarin with respect to the prevention of stroke or systemic embolism in AF patients and were associated with significantly lower rates of bleeding and cardiovascular disease mortality.5 A systematic review and meta-analysis of subgroups showed that NOACs were generally associated with a lower risk of intracranial bleeding than warfarin, although no more effective than warfarin for prevention of ischemic stroke and systemic embolic event in the overall NVAF population.6
The latest editions of guidelines for the management of AF have been published in Western countries and Japan.7–9 They reflect a necessarily tentative response to NOAC trial results. The patients recruited for these large clinical trials had to meet strict criteria and in the large-scale clinical trials of NOACs, diseases that are relatively frequent in the real world were excluded (Table). The ages of the subjects in the large-scale clinical trials (median age 70–73) also differ from those in the real world, where AF patients include a relatively large percentage of octogenarians or nonagenarians. To close the gaps between large-scale clinical trials and the real world, prospective observational studies are necessary.10
| Common exclusion criteria |
| Acute stroke, moderate or severe mitral stenosis, severe renal failure, high risk of bleeding. |
| Other exclusion criteria |
| Acute coronary syndrome, coronary revascularization, active endocarditis, use of dual antiplatelet therapy, other indications for anticoagulation therapy, an inability to adhere to study procedures, severe stroke <6 months prior, active liver disease, sustained uncontrolled hypertension (≥180/100 mmHg), use of dual antiplatelet therapy, severe anemia/thrombocytopenia, pregnancy, and so on. |
In this issue of the Journal, Saji et al11 report the results of their nationwide anonymous survey conducted to establish the clinical outcomes of Japanese patients who developed NOAC-associated cerebral hemorrhage. They found that 55% of stroke centers had not encountered even 1 patient with NOAC-associated cerebral hemorrhage, suggesting that the incidence is low. Patients taking rivaroxaban had a significantly higher risk of hemorrhagic stroke or hematoma than those taking dabigatran, but had a lower risk of subdural hematoma than those taking dabigatran. These findings underscore the importance of evaluating treatment with NOACs in the real world.
The national chart audit of Canadian AF patients showed that primary care physicians did not undertake stroke and bleeding risk assessments in 15% and 25% of patients, respectively.12 Oral anticoagulation was used in 93% of patients, most commonly warfarin. The estimated time in the therapeutic range (TTR) was 73% overall; however, only 55% of warfarin patients had a TTR >70%. The estimation of stroke risk matched well with the CHADS2 score estimate in 87% of cases; however, estimated bleeding risk matched in only 64% of cases, and with an apparent overestimation in 26%. According to the European Primary Care Cardiovascular Society, NOACs are at least as safe as warfarin.13 The NOAC guidelines also have more reliable methods of determining stroke and bleeding risks, to guide treatment choice and improve management of risk factors better; for instance, the exclusion of low-dose aspirin as an option for most patients, the use of good therapeutic control if warfarin is used, and the availability of a range of new rapid-onset, short-acting, anticoagulants with few interactions and no monitoring requirements.13 The ORBIT-AF was an out-patient registry conducted for AF patients14 and showed that two-thirds of patients with AF who were previously not recommended for oral anticoagulants were newly recommended under the 2014 guidelines.
It is also important for patients with asymptomatic or untreated AF to consult a doctor. A person with a high risk of AF should undergo electrocardiography regularly. However, the present Japanese medical examination does not include electrocardiography and no risk chart to predict incident AF as a substitute for an electrocardiogram. Quite recently, a Japanese cohort study showed that hypertension is a risk for incident AF.15 Compared with normal blood pressure and normal weight, systolic prehypertension with overweight is associated with increased risk of incident AF (P for interaction=0.04). We hope that an AF prediction tool such as the Framingham Heart Study will be available in Japan as soon as possible.
I thank Dr Masatoshi Koga for his useful discussion.
This study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (Nos. 25293147 and 26670320), and Intramural Research Fund of the National Cerebral and Cardiovascular Center (22-1-2).
None.
