“Over the next 10 years, patients who require anticoagulation will have more and, we hope, better therapeutic options,” said David Garcia, MD, Albuquerque, USA. He then examined the current situation with novel anticoagulant medication in the late stages of development and the potential benefits of genetic testing.
Concerning Pharmacogenetics, there is clear evidence that two genetic polymorphisms exist that have a large impact on the required warfarin dose. Potential benefits from genetic testing could therefore be a more accurate initial dosing, fewer blood draws and doctor visits, and less frequent dose adjustments. Less bleedings, less thrombo-embolism and fewer hospitalizations are also expectations for pharmacogenetic testing.
“However, many questions remain”, said Garcia. “Is routine pharmacogenetic testing affordable, and is the turnaround time rapid enough? Will PG testing reduce the need for frequent PT measurement during initiation of VKA?”
To Garcia, although the science of pharmacogenetics has substantially improved, the understanding of the inter-individual dose variability seen with VKA, the hypothesis that genotyping can improve patient-important outcomes, remains unproven. The evidence from four small RCTs he regards as inconclusive at best, models with genotyping and clinical risk factors explain about 50% of dose variability. “Ongoing trials will give much more accurate information” said Garcia. “Current estimates suggest that pharmacogenomic testing is not cost effective, since early INR response may provide much of the information obtained by genotyping.”
On the therapeutic side, the future has room for improvement too. Garcia stated: “The current vitamin K antagonists (VKA) have many limitations, which prevent them from being perfect anticoagulants. They show a narrow therapeutic index and drug/diet interaction, and therefore require frequent monitoring. Their long half-life and slow onset of action complicate the management of bleeding patients and patients with high INR.”
So it is not surprising that there is a high level of interest in novel anticoagulants such as the Thrombin-targeting dabigatran or the factor Xa-targeting rivaroxaban and apixaban. “From a public health perspective, it is hoped that one or more of the agents in development will increase the number of at-risk patients who receive optimal antithrombotic therapy. Currently, many patients who stand to benefit from anticoagulant treatment do not receive it because of the burdens associated with long-term vitamin K antagonists. New drugs are expected to be a step forward, not only because the need for frequent monitoring and dose adjustment could disappear, but also because peri-operative “bridging therapy” using parenteral agents may well become unnecessary.
“ADVANCE–2 and RE-LY suggest that we may find doses of these novel agents where efficacy will be preserved at the same time that bleeding risk is reduced”, said Garcia.
However, even with all the promising properties of the novel agents, some topics remain open for Garcia, like the situation in patients with renal insufficiency or mechanical heart valves, cost issues, the possibility of assessing the anticoagulant effects in laboratories, and therapy reversal strategies in emergency situations.
“Forecasting the death of vitamin K antagonists may be premature”, said Garcia, “Innovations such as patient-self testing, computerized dose adjustment, and specialized anticoagulant management teams, continue to make VKAs more effective and safer than ever.”
Report by Thomas Klein, MD, MSc (Nov. 2009)