Effect of Renal Function on Anticoagulation Therapy in Asian Patients

Prevention of strokes using anticoagulants is the main target of the management of atrial fibrillation (AF). To achieve this, warfarin and other oral anticoagulants have been prescribed and are now mainstream therapy for AF. However, it has been reported that there are regional differences in the safety profile of warfarin, namely, Asians or East Asians have a higher risk of bleeding events, including intracranial hemorrhage, than non-Asians despite a lower PT-INR control.^1–3 Therefore, clinicians in Asia are always concerned about the risk of bleeding side-effects, and warfarin is often under-prescribed or under-dosed in the real world.^4–6 Non-vitamin K antagonist oral anticoagulants (NOACs) have been recently introduced and have demonstrated many clinical advantages compared with warfarin in patients with nonvalvular AF (NVAF). However, it has also been reported that the efficacy and safety profile of each NOAC differs regionally and with individual characteristics (ie, age, body weight (BW), renal function, etc). Therefore, it is important to analyze the efficacy and safety of anticoagulants according to region and individual characteristics.

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Regional Differences in Renal Function Between Asian and Non-Asian Patients

In general, BW in Asians is lower than in non-Asians. In fact, the mean (median) BW of patients in (East) Asia was significantly lower than that of those from non-(East) Asia in recent global clinical trials of NOACs, and the difference was not negligible: 20 kg in RELY, 16 kg in ROCKET AF, and 17 kg in ARISTOTLE (Figure 1A).^1–3 BW is an important factor in estimating renal function, and the creatinine clearance (CCr) is estimated using Cockcroft-Gault equations that are calculated by the serum creatinine level, age, BW, and sex of the patient. Renal function is crucial in patients with NVAF receiving anticoagulation therapy. Impaired renal function increases the risk of strokes and bleeding in patients with AF compared with those with a preserved renal function, irrespective of whether the patients are treated with warfarin or NOACs.^7–10

Figure 1.

(A) Difference in body weight in the global clinical trials of anticoagulation (RELY, ROCKET-AF, and ARISTOTLE). (B) Percentage of patients in each renal function level (creatinine clearance ≥80, 50–80, and <50 ml/min) in the global clinical trials of anticoagulation (RELY, ROCKET-AF, and ARISTOTLE). The results are shown separately for (East) Asian and non-(East) Asian patients.

Figure 1B shows the percentage of patients in each renal function level (CCr ≥80, 50–80, and <50 ml/min) in the clinical trials (RELY, ROCKET-AF, and ARISTOTLE).^1–3 The mean CCr was lower, and a mild or moderate renal impairment (CCr <80 ml/min) was more frequently observed in (East) Asians than in non-(East) Asians because of the substantially lower BW in (East) Asians, but the (East) Asian patients were younger than the non-(East) Asian patients in these trials.^1–3

The efficacy and safety of anticoagulation are influenced by renal function, and it is lower in Asian patients than in non-Asian patients. Therefore, it is important to assess efficacy and safety according to renal function in Asian AF patients.

In this issue of the Journal, Hori et al analyze the Asian patients in the RE-LY trial to evaluate the relationship between the baseline renal function or CHADS₂ score category and the efficacy and safety outcomes.¹¹ In their study, 2,782 Asian patients from 10 Asian countries were evaluated, with a mean age of 68 years, mean BW of 66.3 kg, and mean CCr of 65.3 ml/min. They conclude that the bleeding and stroke rates in Asian patients varied according to renal function and CHADS₂ score, but the relative efficacy and safety of dabigatran over warfarin were preserved when analyzed by subcategories.

Renal Function Deterioration in AF Patients Receiving Anticoagulation Therapy

There is another important topic concerning the relationship between renal function and anticoagulation: the change in renal function during anticoagulation. Roldán et al¹² evaluated the changes in glomerular filtration rate (GFR) during long-term follow-up of patients receiving anticoagulation with acenocoumarol. After excluding patients with a baseline GFR <30 ml/min/1.73 m², a mean GFR decrease >10 ml/min/1.73 m² was observed in 181 of 863 patients (21%) during a median follow-up of 875 days. Böhm et al evaluated the changes in GFR for up to 30 months in patients enrolled in the RELY trial, and reported that the GFR declined in all treatment groups (dabigatran 220 mg/day, 300 mg/day, and warfarin).¹³ Interestingly, they also found that the decline in the GFR was significantly greater with warfarin than with either dose of dabigatran.

We recently evaluated the time course of renal function in 807 consecutive NVAF patients treated with NOACs and with a CCr ≥50 ml/min.¹⁴ During a mean follow-up of 382±288 days, 751 (93%) patients maintained a CCr ≥50 ml/min (group A), whereas the CCr declined to <50 ml/min in the remaining 56 (7%) patients (group B). We showed that renal function deterioration was not uncommon in patients receiving anticoagulation and that patients with a higher CHADS₂ score were more prone to develop impaired renal function. In addition, renal function deterioration during anticoagulation was associated with more frequent adverse events, including major bleeding events in NVAF patients.

Figure 2 shows the CHADS₂ score and risk factors for chronic kidney disease. Some of those (age, hypertension, and diabetes mellitus) are identical to the risk factors used to calculate the CHADS₂ score.¹⁵ Therefore, we should keep in mind that many AF patients with a CHADS₂ score ≥1 have risks not only for stroke, but also for renal function deterioration, which may lead to an increasing concentration of anticoagulation drugs and bleeding events.

Figure 2.

Relationship between CHADS₂ score and risk factors for renal function deterioration.

Anticoagulation using NOACs could confer a greater benefit to Asian NVAF patients than non-Asian patients, including a substantially reduced incidence of intracranial hemorrhages compared with warfarin. To put the NOAC treatment to safer, practical use, we need to monitor the laboratory data, including the renal function, carefully during anticoagulation therapy.

Disclosures

K.K. received lecture fees from Bayer, Boehringer Ingelheim, Bristol-Myers, Pfizer, Daiichi-Sankyo, and Esai. K.M. received lecture fees from Bristol-Myers.

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