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Novel Oral Anticoagulants Dosed Differently in Real World Than in Clinical Trials

Discrepancies highlighted at 2015 European Society of Cardiology

The use of novel oral anticoagulants (NOACs) has risen steadily in recent years, but a session at the 2015 European Society of Cardiology (ESC) Congress raised the issue of NOAC under-dosing in current clinical practice — which could potentially lead to inadequate treatment in patients and increase their risk for ischemic stroke.

Consultant GlobalData reports that current clinical use of NOACs and whether they would become the new standard of care in the next few years was one of the key topics at the ESC meeting. Four NOACs are available worldwide: Boehringer Ingelheim’s Pradaxa (dabigatran), Bristol-Myers Squibb’s Eliquis (apixaban), Bayer and Johnson & Johnson’s Xarelto (rivaroxaban), and Daiichi Sankyo’s Lixiana (edoxaban).

An animated session led by Dr. Jonathan Halperin of Mount Sinai Hospital in New York and Dr. Samuel Goldhaber of Harvard Medical School in Boston highlighted the discrepancy between the doses of NOACs used in real-world clinical practice and those used in the pivotal clinical trials. This was based on information collected from global registries, such as GLORIA-AF, GARFIELD-AF, RE-COVERY DVT/PE, and XALIA. The experts also highlighted observations from the Danish registry, a Turkish study, a Medicare analysis, and prescription data from the United Kingdom to substantiate their claim that the lower of the approved doses of the NOACs was being used in the majority of patients globally, although the clinical evidence actually recommends reserving this dose only for high-risk patients (such as those with renal insufficiency).

In the U.S., underutilization of NOACs is a commonly acknowledged issue due to the approved lower doses of these drugs. For example, the FDA-approved 75-mg dose of Pradaxa for patients with severe renal impairment is lower than the 110-mg dose approved for the same patients throughout the rest of the world. According to the FDA, the decision about the 75-mg dose is based on pharmacokinetic and pharmacodynamic modeling rather than safety and efficacy data, since the pivotal RE-LY trial demonstrated the noninferiority of Pradaxa compared with warfarin for both the 110-mg and 150-mg doses. However, during the ESC session, Drs. Halperin and Goldhaber raised concerns about the FDA’s decision and whether overprotection from bleeding was increasing patients’ clotting probability and exposing them to a greater risk of ischemic stroke-based events.

Overall, GlobalData notes, it is clear from the discussion that this anomaly stems mostly from physicians’ reluctance to take responsibility for possible complications, such as gastrointestinal bleeding, that may arise from using higher doses of the NOACs. Also, there is still a tendency among health care providers to resort to using the tried-and-tested warfarin for high-risk patients, even though the drug does not perform very well in these cases.

GlobalData believes that more real-world safety data, especially in the high-risk patient population, can potentially address the issue of under-dosing and under-treatment with the NOACs. The launch of NOAC antidotes in the near future will help tilt the scales more in favor of the use of these drugs, the consultant adds.

The 2015 European Society of Cardiology Congress, possibly the most influential cardiology event in the world, was held in London from August 29 to September 2. Approximately 32,000 participants from all over the world attended the conference, including more than 26,000 key opinion leaders and other experts in the field of cardiology, as well as 5,000 pharmaceutical industry representatives.

Source: GlobalData; September 2015.

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