Dr Jiexin Deng | Optimising Warfarin Treatments for Chinese Patients

Warfarin is a commonly prescribed oral blood thinner used for the prevention and treatment of thromboembolic conditions. The wide variability in these conditions, that may range from deep vein thrombosis to heart valve replacement, adds to the complexity in determining dosing requirements among patients. Dr Jiexin Deng and colleagues at Zhengzhou Cardiovascular Hospital and Huaihe Hospital of Henan University in China have investigated the suitability of various pharmacogenetic algorithms based on different ethnicities to assist with warfarin dosing for the Chinese population, hoping to improve clinical outcomes and reduce the incidence of unwanted side effects.

Identifying Therapeutic Dosages: A Balancing Act

Anticoagulation medications prevent or treat abnormal blood clot formation by inhibiting clotting factors or platelet activity. In recent years, direct oral anticoagulants (DOACs), such as apixaban, dabigatran, and rivaroxaban, have increasingly been used as alternatives to warfarin for anticoagulation treatments. However, warfarin is still the most suitable option, especially for older patients, those with greater morbidity, who do not respond to DOACs, who do not have access to DOACs due to high copay costs, and those who require the replacement of a damaged heart valve with a mechanical or biological valve. While warfarin has been successfully used to control blood clotting for decades and is considered safe, efficient, and cost-effective, the therapeutic window of warfarin is narrow. This means that there is a small margin during which clinical benefits are maximised while risks are minimised. Additionally, dosing requirements vary between patients by up to 60%, based upon their clinical characteristics such as age, height, weight, co-medication, and ethnicity, as well as on their genetic makeup. The main genes affecting warfarin dose/response encode for VKORC1 (Vitamin K Epoxide Reductase Complex Subunit 1) and CYP2C9 (Cytochrome P450 Family 2 Subfamily C Member 9). While VKORC1 affects drug response, CYP2C9 affects the amount of drug in the body. In this instance, due to differences in genotype prevalence and body weight/height, Asian individuals are more sensitive to the effects of warfarin and therefore require lower doses to achieve the desired benefits whilst still avoiding abnormal bleeding. Inaccurate dosing can lead to severe adverse reactions and suboptimal disease management; indeed, warfarin is one of the most common causes of serious drug-related harm.

Treatment with warfarin is routinely initiated with higher starting doses for the first few days, followed by lower maintenance doses based on population averages. This is followed by regular monitoring of the international normalized ratio (INR) that checks whether medication levels are within the therapeutic range, enabling any appropriate adjustments of the maintenance dose. Hence, health-harming incidents are kept to a minimum, but the patient is placed at ongoing risk, since the optimal dosage may take weeks or months to achieve. The use of pharmacogenetic algorithms can aid in speeding up this process.

Recently, predictive algorithms based on clinical and genetic factors have been developed to assist clinicians in prescribing warfarin by recommending individually tailored doses, and two authoritative algorithms recommended by the pharmacogenetics Implementation Consortium (CPIC) are currently available. The two algorithms were developed by Gage et al. and the International Warfarin Pharmacogenetics Consortium. However, these have been developed using data mainly from Western populations, which proves problematic when trying to plan medication regimes for people of other ethnicities, who may have different genotype frequencies in the population.

In Henan University, Dr Jiexin Deng (along with associates from hospitals in Zhengzhou and Kaifeng, in China) investigated the suitability of various pharmacogenetic algorithms based on different ethnicities to assist with warfarin dosing for the Chinese population. They also assessed algorithms developed using only Chinese subjects, to determine whether it might be more appropriate to use data from local populations to facilitate the development of customised model-based treatment planning tools.

Assessing Warfarin Dose Predictions

To begin with, Dr Deng and colleagues identified 15 algorithms which had been developed using only data from the Chinese population.  The researchers then proceeded to calculate and compare dosage predictions from the Chinese algorithms and those algorithms developed based on Western populations, while accounting for factors such as age, weight, height, and genotypes.

Specifically, the team conducted quantitative assessments comparing the Chinese and Western dosing prediction algorithms for a typical 60-year-old Chinese individual who is 1.65 m tall and weighs 65 kg with the most frequent gene variants found in the Chinese population. Consistent with reports that Asian patients are more sensitive to warfarin anticoagulation and require lower doses to minimize the risk of adverse bleeding, it was found that most Chinese dosing algorithms predicted doses that are 10–20% lower than the ones predicted by the IWPC and Gage algorithms. To evaluate prediction deviations, doses were then predicted and compared for Chinese individuals aged 45- to 70-years-old and who are 1.65 m in height and 50–75 kg in weight, with the most frequent gene variants. The extent from which these predictions deviated from the Western algorithms was largest in those of younger age with a smaller body weight.

A Comparison of Western and Chinese Algorithms

Next, the team simulated warfarin concentrations over time and INR responses for a 65-year-old Chinese individual, but with different gene variants. These were then used to assess differences in drug concentration and laboratory results in a typical Chinese individual receiving daily doses of warfarin, as recommended by Western vs. Chinese algorithms.

Simulations of dose and response in a typical Chinese individual using a Chinese algorithm showed that the recommended dose allowed the percentage of time spent within the therapeutic window to be maintained, as opposed to overshooting the therapeutic range when using the Western-based algorithms. Interestingly, most of the Chinese algorithms evaluated predicted doses 10–20% lower than those predicted by the recommended Western-derived algorithms, even while controlling for gene variants. Furthermore, the largest prediction discrepancies between the two algorithm categories were seen in the younger patients with smaller body weights, again supporting the notion that Asian people are more sensitive to the effects of warfarin and thus require less of this medication. Indeed, higher medication doses led to higher bloodstream concentrations, which frequently caused the therapeutic window to be overshot. Dr Deng believes that slower warfarin metabolism due to weight and height differences, as well as differences in gene variant frequencies result in lower dosing requirements in the Chinese population. Rather tellingly, the use of a predictive algorithm based on Chinese patient data should help with these issues.

A Virtual Trial: Maintaining the Balance

Dr Deng and team also reproduced a previously conducted clinical trial, in which a pharmacokinetic/pharmacodynamic (PK/PD) model was developed to guide warfarin dosing based on patients’ clinical and genetic factors. After the feasibility of this approach was established, researchers then created a virtual Chinese patient population on which to base their study, and generated dosing recommendations using Western algorithms. Then, they repeated the simulated trial using Chinese algorithms for comparison. The aim was to determine how predicted dosing differences between the algorithms would translate into anticoagulation effects in a Chinese clinical scenario.

For the first part of these investigations, the clinical dosing group patients were given a specific starting dose for three days, after which the dose was adjusted depending on their test results. In the genetic algorithm dosing group, each patient was given a starting dose according to the IWPC algorithm for three days, and then given a further dose according to the Lenzini algorithm for the next four days, after which the dose was adjusted depending on their laboratory test results, as before. Dr Deng and the team found that the doses recommended by the Western algorithms tended to overshoot the therapeutic range more severely than the clinically derived dosages, and that this usually peaked at around day 15 of treatment. However, while the clinical dosing group remained within therapeutic levels for longer than the genetic dosing group, this occurred only if the dosing regimen were to strictly follow simulated protocol conditions and no adjustments were made by clinicians, which is not frequent in real world scenarios.

When comparing Chinese and Western algorithms, Dr Deng and team found that the Western algorithms caused the levels to rise beyond therapeutic levels after approximately two weeks of treatment, before corrections were needed following adjustments based on the routine patient dosage monitoring protocols. Moreover, the time spent in the therapeutic range was considerably increased when using the Chinese algorithms to predict the appropriate dosage. A particularly pertinent finding related to survival probabilities during the first month of treatment; the researchers found that, if strictly following simulated protocol conditions, the Chinese patients were overwhelmingly more at risk of severe bleeding when dosed according to the Western algorithm than if they were treated according to the Chinese algorithm.

Merging Knowledge to Achieve the Best Outcomes

Bearing in mind that patients who have received heart valve replacements are required to remain on anti-clotting medication for life, it is imperative that the treatment they receive is safe and highly effective. Since warfarin usage is associated with a lower likelihood of cardiovascular events and death in those at risk of blood clotting disorders, this treatment must be fine-tuned and tailored to better suit the intended recipient.

As ethnicity is a critical factor in gene-specific dosing predictions, algorithms must be developed and validated to optimise anti-clotting treatments for patients in non-white populations, to reflect the local patient demographic characteristics. As a result of the crucial insights revealed by this research, Dr Deng and his esteemed colleagues have confirmed that Asian people are more sensitive to warfarin and require lower doses to achieve the intended clinical benefits, while avoiding serious health-damaging consequences. The use of algorithms based upon the patient’s genetics may help to optimise their treatment in a timely manner, particularly if used to improve the accuracy of clinically guided dosing by incorporating patient-specific details into the algorithm. In the future, understanding the differences between Western and Chinese algorithms may provide clinicians with a more ethnically attuned dosage regime from the very start of treatment, allowing the therapeutic range to be reached quickly, further reducing the risk of adverse events whilst accounting for ethnic differences in dosing.