Renal impairment, race affect maintenance warfarin dosing in Asian patients

Race and renal function both influence maintenance warfarin dosing in a multi-ethnic Southeast Asian population, suggests a study in Singapore. Specifically, impaired renal function is associated with lower warfarin maintenance doses, while South Asians may require a larger dose than Chinese and Malays.

However, “the magnitude of impact of impaired renal function on warfarin dosing was less pronounced in South Asian patients compared to their Chinese and Malay counterparts,” the investigators said. [Proc Singap Healthc 2024;doi:10.1177/20101058241253458]

This retrospective cohort analysis was conducted on patients seen for warfarin titration at the anticoagulation clinic (ACC) of the National Heart Centre Singapore from 1 January 2010 to 31 December 2019. The investigators explored the impact of renal impairment and ethnicity on warfarin dosing in a total of 3,610 multi-ethnic Asian patients.

Of the participants, 70.7 percent had no/mild renal impairment (eGFR ≥60 ml/min/1.73 m²), 24.7 percent had moderate renal impairment (eGFR 30 ml/min/1.73 m²), and 4.5 percent had severe renal impairment (eGFR <30 ml/min/1.73 m²).

Patients with moderate renal impairment needed a 19-percent lower dose of maintenance warfarin (β, 0.81, 95 percent confidence interval [CI], 0.79‒0.84; p<0.001), while those with severe renal impairment required a 30-percent lower dose (β, 0.70, 95 percent CI, 0.66‒0.75; p<0.001) than individuals with normal kidney function.

With regard to ethnicity, majority of the patients (84.4 percent) were Chinese, while the rest were Malay (9.5 percent) and South Asian (6.1 percent). Compared with Chinese patients, South Asians required an 83-percent larger maintenance warfarin dose (β, 1.83, 95 percent CI, 1.73‒1.94; p<0.001), while Malays needed an 18-percent larger dose (β, 1.18, 95 percent CI, 1.12‒1.23; p<0.001).

On the other hand, South Asians with impaired renal function required a 16-percent lower dose than patients with normal renal function of the same race, whereas Malays and Chinese needed 21-percent and 23-percent lower doses.

“In this large multi-ethnic Asian study, renal function and ethnicity significantly affected maintenance warfarin dosing,” the investigators said. “South Asian patients required larger doses but were less affected by renal impairment compared with Chinese and Malays.”

Pharmacokinetics

It remains unclear how renal impairments affect the pharmacokinetics of nonrenally cleared drugs, but earlier studies using animal models have shown the downregulation of hepatic cytochrome P450 in chronic renal failure, according to the investigators.

One specific study showed that the S-Warfarin enantiomer, which is exclusively eliminated by CYP2C9, was markedly increased in patients with end-stage renal failure. This indicated a reduction in hepatic CYP2C9 activity in renal failure. [Clin Pharmacol Ther 2003;73:475-477]

“[The current] study highlights the significant differences in maintenance warfarin doses between races that is further attenuated by renal function,” the investigators said.

“It is common practice for healthcare institutions to have warfarin initiation protocols that may take into consideration clinical factors such as age, size of the patient, liver function, etc, followed thereafter by dosing based on individual patient’s International Normalised Ratio,” they added. [Chest 2012;141:e152S-e184S]