With Poor NOAC Adherence, Monitoring Seen as Partial Solution

April 15, 2015

STANFORD, CA — A study on the use of dabigatran (Pradaxa, Boehringer Ingelheim) reveals considerable site-level variation in adherence to the novel oral anticoagulant (NOAC) among patients with atrial fibrillation treated within a large US healthcare system[1].

At 67 sites of care within the Veterans Health Administration (VHA), adherence to dabigatran ranged from 42% to 93%. Investigators did observe better adherence to dabigatran among clinical sites that had a system in place for selecting appropriate dabigatran candidates, sites that included pharmacy-led patient education, and sites that regularly monitored the patients.

"We've had a shift from warfarin to these new drugs, and the use of the new oral anticoagulants was largely predicated on obviating the need for regular monitoring," senior investigator Dr Mintu Turakhia (Stanford University, CA) told heartwire from Medscape. That argument, however, is "completely flawed," he said. "We have been operating under a false assumption."

Instead, the data show that the clinical sites managing AF patients treated with dabigatran, and likely other NOACs, play a crucial role in determining clinical outcomes, no different from what would be the case in patients managed and monitored with warfarin.

"We have actually identified modifiable factors that are associated with poor adherence, and it's not the usual culprits of socioeconomic status or multiple comorbidities," continued Turakhia. "These are things that we can fix. My hope is that large healthcare systems and policy stakeholders rethink the delivery of care around NOACs."

The results of the study are published in the April 14, 2015 issue of the Journal of the American Medical Association.

Dr Stuart Connolly (McMaster University, Hamilton, Canada), who was not involved in the analysis but was the lead investigator of the RE-LY trial testing dabigatran against warfarin, said that adherence to medication for chronic prevention remains a "huge problem."

"Patients have to take these drugs and they often don't understand why they're taking them," Connolly told heartwire . "They don't have any symptoms, so if they stop the drug it's not like they develop a symptom. They feel just fine. This is not specific to dabigatran or any other drug in particular. It's a general truth of chronic cardiovascular disease prevention."

Even NOAC-Treated Patients Need Support

When the NOACs were approved, one of their major advantages was that they did not require routine testing to assess the anticoagulation effect. There are currently three factor Xa inhibitors approved for the prevention of stroke and non–central-nervous-system systemic embolism in patients with AF: edoxaban (Savaysa, Daiichi-Sankyo), rivaroxaban (Xarelto, Bayer), and apixaban (Eliquis, Bristol Myers-Squibb). Dabigatran, a direct thrombin inhibitor, was approved by the US Food and Drug Administration in 2011.

Previous studies have shown that poor adherence to the NOACs is associated with worse clinical outcomes, and the pivotal trials with the factor Xa inhibitors have also shown improved treatment effects in the on-treatment analysis compared with the intention-to-treat analysis. "And there's a biologic reason," said Turakhia. "If you take the drug correctly, it will work better than having gaps in anticoagulation."

To heartwire , he said there hasn't been a lot of thought concerning adherence with the NOACs. "Everybody assumes there was no reason to even look at it," said Turakhia. "Why should you? It's a pill. It shouldn't require management. I think that's one thing we sort of turned on its head. A lot of how well patients do is actually explained at the site level."

In the present study, the researchers identified 4863 total patients who filled a prescription for dabigatran between 2010 and 2012. Of these, 74% were adherent to the medication. Of the 67 sites included the study, the researchers called 41 sites to conduct a qualitative interview about their practices when prescribing dabigatran to AF patients.

Nearly all the sites had a pharmacist review the indications and contraindications to ensure appropriate use after it was ordered by the physician. Just one in four sites assessed adherence to warfarin and other medications as a criterion for selecting appropriate dabigatran patients. Overall, 73% of the VHA sites included mandatory pharmacist-led education before starting dabigatran, and 68.3% of the sites included pharmacy-led monitoring of adverse events and adherence. For one-third of the hospitals, monitoring was the domain of the prescribing doctor.

Regarding adherence, the proportion of patients taking dabigatran was higher at sites that performed appropriate patient selection (75% vs 69% at sites without a patient-selection protocol in place), those that included education (76% vs 66% at those that did not), and those that monitored patients (77% vs 65%). These associations were statistically significant in a model that included adjustment for multiple variables.

When the NOACs were rolled out, it was suggested that some level of education and patient management was needed, but there were no firm guiding recommendations, noted Turakhia.

"Education is something we kind of forget about," he said. "It tells me that having an additional care structure in place, typically a pharmacist-led intervention, does better than doctors and nurses in terms of educating their patients. It could be a simple thing of explaining to them why they can't miss any doses."

To the researchers, the results of the study suggest a need to "rethink" the management and monitoring of patients treated with the NOACs. For example, physicians are reimbursed for warfarin management even if the patient does not come to the office, but there is no such provision for managing patients treated with NOACs. The implementation of mandatory pharmacy-led education and monitoring would also go a long way to improving outcomes among patients treated with dabigatran and the other new drugs.

"This is not hypertension, where if you don't take your hydrochlorothiazide for a couple of days, probably nothing is going to happen to you," Turakhia told heartwire . "There are great concerns of what happens when you disrupt anticoagulation with drugs that have a much shorter half-life."

Adherence Is Tough With All Chronic Conditions

Dr Gregory Lip (University of Birmingham, UK), who commented on the analysis for heartwire , said the study makes an important observation about variable adherence among this high-risk patient population. He echoed concerns about the short half-life with the NOACS so "adherence to treatment should always be emphasized as missing a couple of doses can lead to a patient being unprotected."

Earlier this year, Lip and Danish colleagues published a similar study looking at dabigatran adherence in AF patients in the first year after diagnosis[2]. They performed the analysis because there was a perception that a lack of routine monitoring with the NOACs, unlike that with warfarin, might worsen adherence to the medication. Overall, they showed that 76.8% of patients were adherent to dabigatran within this first year (also defined as having >80% of days covered).

To heartwire , Lip noted that sicker patients, including those with a higher risk of stroke and bleeding, exhibited better adherence, a finding they attributed to more frequent contact with the healthcare system. Lip added that patient selection is also important, noting there are some options for physicians looking to identify patients who might do well with warfarin, such as AF patients with a high SAMe-TT2R 2 score[3].

Regarding the issue of pharmacy-led interventions to improve adherence, Connolly said there are some programs that do get patients taking their medications but they tend to be labor intensive and complex and involve multiple interactions with patients. Such interventions do have an impact, albeit a small one, on adherence, said Connolly. These pharmacy-led education and monitoring programs aimed at improving adherence have never been studied before with dabigatran, but with medications for diabetes, hypertension, hyperlipidemia, and other chronic conditions.

"I think there may be something in it, but they have to be carefully assessed," he told heartwire . "These interventions cost money, and you have to ask, 'How much better adherence are we getting for the dollars that we spend, and is it actually worth it?' "

Turakhia reports consulting for Precision Health Economics, Medtronic, and St Jude Medical. The coauthors report no relevant financial relationships. Lip has served as a consultant for Bayer, Astellas, Merck, AstraZeneca, Sanofi, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Medtronic, Biotronik, Portola, and Boehringer Ingelheim and has been on the speaker's bureau for Bayer, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim, Medtronic, Daiichi-Sankyo, and Sanofi. Connolly reports grants and personal fees from Boehringer-Ingelheim, grants and personal fees from Bristol-Myers Squibb/Pfizer, grants from Merck, grants and personal fees from Sanofi and Bayer, personal fees from Portola, grants from St Jude Medical, grants from Boston Scientific, and an institutional research grant from Boehringer-Ingelheim.


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