By Annette M. Boyle
WASHINGTON — Use of novel anticoagulants has risen sharply both at the VA and in the Army in the last three years, freeing more atrial fibrillation patients from food restrictions and regular checks for coagulation time, as required when using warfarin.
The Food and Drug Administration approved dabigatran, the first of the new anticoagulants (ACs), in October 2010 and it was first available for use by VA/DoD patients in February 2011. VA providers put 1,500 patients on the oral anticoagulant in its first year. In fiscal year 2013, 12,000 veterans were on dabigatran and the other two approved novel anticoagulants, rivaroxaban and apixaban.
The use of novel ACs has risen steadily, increasing across the Army, as well, where the medications are being adopted as a first-line treatment for patients with appropriate indications, according to Col. Randolph Modlin, MD, chief of cardiology at Walter Reed National Military Medical Center and Lt. Col. Todd Villines, MD, cardiology consultant to the Office of the Surgeon General.
Today, the drugs account for only 7% percent of anticoagulants used at the VA, according to a VA spokesperson. About 190,000 VA patients receive anticoagulant treatment for multiple conditions, with the vast majority of them on warfarin, which has FDA approval for a number of indications.
Of all oral anticoagulations dispensed at Army MTFs, the novel oral anticoagulants (Dabigatran, Rivaroxaban and Apixaban) represent 19.3% or greater of total prescriptions, with the rest being forms of warfarin, said Lt. Col. Ricardo J. Nannini, PharmD, MBA, Deputy Army pharmacy consultant.
Nannini noted that the statistics, which were validated through the DoDs Pharmacoeconomic Center, have some limitations and that they “may give the appearance that warfarin (brand orgeneric) is prescribed more frequently and/or to a greater number of uniqueutilizers than the novel oral anticoagulants. In other words, prescriptions (expressed as 30-day equivalents) for novel oral anticoagulants may represent greater than 19.3% of total prescriptions for oral anticoagulants at MTF pharmacy points of service.”
Dabigatran and apixaban have so far gained approval only for stroke prevention in atrial fibrillation. Rivaroxaban is approved for atrial fibrillation and secondary venous thromboembolism (VTE) prevention and for short-term use in primary VTE prophylaxis in patients undergoing hip or knee replacement surgery.
The anticoagulant field remains quite dynamic, though, with both dabigatran and apixaban currently seeking expanded FDA approval for venous thromboembolism, and edoxaban, the newest drug in the factor Xa inhibitor class, recently filing for both atrial fibrillation and VTE indications. In addition, several more Xa inhibitors are in development, as are a number of direct thrombin inhibitors, an IXa inhibitor plus other enzymes and inhibitors that affect the coagulation cascade.
“While we will continue to need warfarin, as a well-proven agent, to treat many conditions requiring systemic anticoagulation, we see the use of novel ACs continuing to grow as providers become more familiar with the medications, and patient acceptance continues to increase,” according to a statement prepared by Modlin and Villines for U.S. Medicine.
Use in patients with atrial fibrillation (AF), in particular, seems likely to increase as the novel ACs “have demonstrated equivalent therapeutic results with a lower incidence of complications from the medication. The relative safety and ease of use of these medications have allowed us to pursue converting these patients from warfarin to the novel ACs in an effort to decrease the volume of patients in the anticoagulation clinics,” Modlin and Villines said.
In particular, the novel ACs have consistently shown a markedly lower rate of intracranial hemorrhage (ICH) compared to warfarin. “A meta-analysis of prospective randomized controlled trials combining all of the novel AC agents as a class revealed an overall mortality benefit of novel drugs as compared to warfarin in AF patients, mainly driven by a lower rate of ICH and overall lower rates of stroke. As a result, novel AC agents have a class I indication for the prevention of stroke/systemic embolism in non-valvular AF patients with many international guidelines now listing them as the preferred agent in patients in whom novel AC agents are appropriate,” Modlin and Villines said.
It’s unlikely that the novel ACs will entirely replace warfarin, however. Recent research published in the New England Journal of Medicine, the Re-ALIGN study, suggests that patients who have had aortic valve replacements may do better with warfarin rather than the novel ACs. The new agents are also contraindicated in patients with renal impairment.1
The novel anticoagulants cost considerably more than warfarin, but a recent study in the journal Stroke found that the new agents are cost-effective alternatives to warfarin for patients with non-valvular atrial fibrillation, increased risk of stroke and good kidney function. In the analysis, the researchers found all the new drugs had incremental cost-effectiveness ratios (ICER) below the $50,000 willingness to pay threshold. That study relied upon the clinical trials used to gain approval for novel ACs with a hypothetical cohort modeled for 30 years, according to the VA spokesperson, while only two years of outcome data from clinical trials is currently available. In addition, for the VA at least, the cost of warfarin is significantly lower than the cost assumed in the model.2
Still, outside of the VA, which has a well-developed pharmacist-managed system of anticoagulation clinics, the use of the novel ACs seems likely to reduce overall patient-care costs. The Army also has anticoagulation clinics at its larger facilities but has found that “the costs for the medical resources to staff an anticoagulation clinic, perform lab testing and hospitalize patients are saved with the use of the novel ACs,” according to Modlin and Villines.
Unlike warfarin, the newer agents do not require blood testing on at least a monthly basis to monitor the international normalized ratio (INR) for coagulation and frequent adjustment of medication levels to keep anticoagulation in the therapeutic range. In addition, “though the new agents are not free from dietary considerations, there is no interaction with vitamin K containing foods as there is with warfarin. The novel agents are associated with fewer potential drug interactions and less inter- and intra-patient variability,” the VA spokesperson said.
Some concerns about the novel ACs persist, however. “The novel agents have shorter durations of action than warfarin and may be simply discontinued to manage many bleeding events. However, the concern of lack of reversal agent and optimal management strategy in life-threatening bleeding events remains a primary reason for hesitancy to use the novel agents,” the VA spokesperson told U.S. Medicine. As with any new drug or class of drugs, the lack of long-term safety data and scarcity of data on the impact of real world situations such as missed doses and non-adherence also continue to trouble some providers.
1 Eikelboom JW, Brueckmann M, Van de Werf F. Dabigatran versus warfarin in patients with mechanical heart valves: reply. J Thromb Haemost. 2014 Jan 10. [Epub ahead of print]
2 Harrington AR, Armstrong EP, Nolan PE, Malone DC. Cost-effectiveness of apixaban, dabigatran, rivaroxaban, and warfarin for stroke prevention in atrial fibrillation. Stroke. 2013;44:1676-81.