Good INR Control on Warfarin Doesn’t Necessarily Predict Future Success, Outcomes

Many patients with good INR control on warfarin won’t maintain a high time in therapeutic range (TTR) even a year later, making past TTR a poor predictor of clinical outcomes in patients with A-fib, a new study shows. Its investigators say the findings could have implications for the decision to switch warfarin-treated patients to a direct oral anticoagulant (DOAC).

Of patients who consistently took a vitamin K antagonist (VKA) for at least 6 months after starting treatment, only 35.4% had a high TTR (70% or higher). And among those patients with a high TTR who were still on treatment a year later, only 55.7% maintained a high level of control, according to researchers led by Anders Nissen Bonde, MD (Copenhagen University Hospital Herlev and Gentofte, Hellerup, Denmark).

Moreover, patients with poor suboptimal INR control during the first 6 months of treatment were not at an increased risk of stroke/thromboembolism or major bleeding in the following year compared with those who started with a high TTR, Bonde et al report in a study published online ahead of the September 18, 2018, issue of the Journal of the American College of Cardiology.

European A-fib guidelines contain a recommendation stating that VKA-treated patients may be considered for DOAC therapy if the TTR is not sufficient, whereas US guidelines more definitively state that a switch to a DOAC is recommended in patients who are unable to maintain a therapeutic INR level. The implication, one that is consistent with the beliefs of many physicians, is that patients who are well controlled on warfarin should continue taking warfarin.

But that line of thinking may need to be reconsidered in light of these new data, Bonde told TCTMD.

“Just because a patient has been INR-stable in the past, it does not guarantee that the patient will be INR-stable in the future,” he said. “Previous INR control is not necessarily a good predictor of future outcomes, and just because a patient has been stable in INRs in the past, it should not exclude patients from switching to a DOAC.”

Different Takeaways

Commenting for TCTMD, Alan Go, MD (Kaiser Permanente Division of Research, Oakland, CA), said the study findings are not surprising and support the idea “that if you’re going to take warfarin or a vitamin K antagonist, you need to stay in good control for it to be effective.”

But Go didn’t agree with the conclusion that a stable TTR should not necessarily dissuade physicians from switching a patient from warfarin to a DOAC. “I would take a different approach and say that it isn’t just using the past level of control but really thinking about different characteristics about the patient, including patient preferences, for deciding what’s the best long-term way to prevent stroke,” he said. “I think it’s more complex than just using the past 6 months of control level on warfarin.”

The study “really argues for why it’s important to have system-level ways to improve control of warfarin if you’re going to use it,” Go said. “What I mean by that is [that] coordinated anticoagulation management systems have been very effective in being able to keep large populations of patients with A-fib who are taking warfarin in good control.”

Bonde countered by saying that “of course everyone should do their best to keep patients stable, but it’s very, very hard to pick out those patients who will continue to be INR stable and it’s a very huge effort, and it might in the end be more cost-effective to switch them [to a DOAC].”

For the current study, Bonde et al examined Danish nationwide registry data on patients with A-fib who were treated with a VKA between January 1, 1997, and August 22, 2011—the day the first DOAC, dabigatran (Pradaxa; Boehringer Ingelheim), became available in Denmark. The analysis included 4,772 patients who were still on treatment 6 months after starting. Median TTR in that initial period was 82.7% in the high TTR group and 49.2% in the low TTR group.

During a year of follow-up, the mortality rate was lower in those patients who had a high versus low TTR in the initial treatment period (3.0% vs 4.7%), but, the authors say, “because cumulative incidences of stroke/thromboembolism and bleeding were similar in the groups, and because patients with prior TTR ≥ 70% had less cancer, less chronic kidney disease, and less alcohol abuse, this finding is likely not to be related to anticoagulation control.”

When accounting for changes in TTR during the year of follow-up, however, having a TTR below 70% was associated greater risks of stroke/thromboembolism (HR 1.91; 95% CI 1.30-2.82) and major bleeding (HR 1.34; 95% CI 1.02-1.76).

Premature to Abandon TTR in Decision-Making?

In an accompanying editorial, Antonio Raviele, MD (ALFA-Alliance to Fight Atrial Fibrillation, Venice, Italy), highlights the continued importance of decisions about whether to use VKAs or DOACs by laying out the pros and cons of each class of agents. On the plus side, DOACs have a lower intracranial hemorrhage risk, a more predictable response, more rapid onset and offset of effect, and fewer food-drug and drug-drug interactions compared with VKAs. But working against DOACs are the inability to catch poor drug compliance because of the lack of routine monitoring—as is done with VKAs—and also higher costs.

Raviele acknowledges that “the use of clinical parameters able to predict TTR in a single patient is very limited,” but notes that a tool incorporating clinical variables—the SAMe-TT2R2 score—has been implemented in clinical practice and recommended by European guidelines as a way to identify patients who are likely to maintain good INR control.

“Although we do not know whether the use of this score would have changed the results reported by Bonde et al, it is reasonable to advocate its implementation in daily routine, with the aim of improving the anticoagulation control and clinical outcome of patients taking VKAs.”

Even though the study seems to suggest that the practice of using a high TTR to select patients who are likely to maintain good INR control should be stopped, “it is likely that better patient education, more frequent INR monitoring, prompt VKA dose adjustment, and the accurate selection of appropriate candidates for VKA therapy on the basis of TTR predictors would yield a better outcome than that found in the Danish study,” Raviele concludes. “I therefore think that such efforts should be made before a final decision is taken on this issue. It is indisputable that restricting the use of DOACs only to patients who are really poor candidates for warfarin would markedly improve the cost-effectiveness and the economic sustainability of these drugs.”

From Go’s perspective, a key question raised by the study is how best to personalize stroke prevention therapy in patients with A-fib. He noted that there are now many options available, including VKAs, DOACs, and nondrug options like percutaneous left atrial appendage closure and surgery.

“I think one of the key areas that we need to figure out in this field is what kinds of patient characteristics help determine the best response to any one of those options,” Go said. “It’s not that one’s bad or one’s good. It’s really tailoring the right therapy to the right patient.”