Single Risk Factor Heightens Stroke Risk in AF Patients: Danish Analysis

April 07, 2015

BIRMINGHAM, UK — Patients with atrial fibrillation (AF) who have no other additional risk factors, aside from gender in the case of females, are at a very low risk for stroke and bleeding, according to registry data from Denmark.

But with just one additional risk factor, there is a significant increase in the risk of stroke and mortality if the patient is not receiving oral anticoagulation therapy, report investigators[1]. For untreated men and women with a CHA2DS2-VASc score of 1 and 2, respectively, the risk of stroke increased more than twofold and the risk of death increased more than threefold compared with individuals without any risk factors.

"The bottom line, maybe as the take-away point, is that rather than a categorical approach to risk stratification in AF and treatment decisions on that basis, we should be moving toward a strategic approach of initially identifying the low-risk patients with the CHA2DS2-VASc score," lead investigator Dr Gregory Lip (University of Birmingham, UK) told heartwire . "Step two would be to offer effective stroke prevention to those with one or more risk factors for stroke. The benefit on mortality and stroke reduction far and away exceeds the small increase in serious bleeds."

The results of the study were published in the April 14, 2015 issue of the Journal of the American College of Cardiology.

"Do What You Like"

The European Society of Cardiology (ESC) currently recommends a two-step approach to managing patients with AF. Similar to Lip's thought, the first step is to identify patients at low risk for stroke on the basis of the CHA2DS2-VASc score. For men and women with a CHA2DS2-VASc score of 0 and 1, respectively, no antithrombotic therapy is recommended for these low-risk patients. For those with one or more additional risk factors for stroke, clinicians can "consider" antithrombotic therapy for reducing risk while antithrombotic therapy is a class 1 recommendation for those with two or more risk factors.

Across the pond in the US, the American College of Cardiology (ACC)/American Heart Association (AHA)/Heart Rhythm Society (HRS) guidelines recommend oral anticoagulation for those with a CHA2DS2-VASc score >2 and no treatment for those with a CHA2DS2-VASc score of 0. For those in the middle—those with a CHA2DS2-VASc score of 1—physicians can give no therapy, aspirin, or anticoagulation.

"In other words, do what you like," said Lip.

With the present study, Lip and colleagues wanted to examine the risk for stroke and mortality among AF patients with a single risk factor. In the study, researchers identified low-risk patients with an incident hospital diagnosis of nonvalvular AF between 1998 and 2012 by linking data from the Danish Civil Registration System, the Danish National Patient Register, and the Danish National Prescription Registry. In total, 39 400 patients were included in the analysis. Of the low-risk patients—those with a CHA2DS2-VASc score of 0 or 1—23 572 received no treatment, 5353 received aspirin, and 10 475 were started on warfarin.

Overall, the stroke event rates at 1 year for AF patients with no risk factors and not receiving treatment was 0.49 per 100 person-years and 0.47 per 100 person-years at 5.9 years. For those with one risk factor, the corresponding stroke event rates were 1.55 and 1.24 per 100 person-years, respectively. The 1-year ischemic stroke rates were 1.39 per 100 person-years among the untreated AF patients with one risk factor and 0.94 among those who received warfarin.

"If you have a single risk factor, the annual risk of ischemic stroke is in the range of 1% to 2% per year," said Lip. "These days, that's a real risk, because we're now managing warfarin so much better in our understanding of a good time-in-therapeutic range. We can also pick out the patients we think are going to do well on warfarin. And of course, we have the [novel oral anticoagulants] NOACs. With the NOACs, if used appropriately, the efficacy is at least as good as, or even better than, warfarin."

Event Rates per 100 Person-Years: Follow-Up at 1 Year

End point No treatment Aspirin Warfarin
AF patients with no risk factors
Stroke 0.49 0.78 0.88
Ischemic stroke 0.43 0.78 0.75
Bleeding 1.08 1.52 1.66
Intracranial hemorrhage 0.15 0.10 0.16
Death 3.87 3.12 2.20
AF patients with one risk factor
Stroke 1.55 1.45 1.06
Ischemic stroke 1.50 1.45 1.02
Bleeding 2.74 2.31 2.42
Intracranial hemorrhage 0.36 0.20 0.44
Death 11.3 5.66 4.00

To heartwire , Lip said the "tipping point" for initiating treatment for stroke prevention is approximately 1% per year. If the risks are higher than this 1% threshold, physicians should start the patient with warfarin or one of the NOACs. In the Danish cohort, even with just a single additional risk factor the risk of stroke exceeds the 1% tipping point, he said.

"We're also talking about a significant mortality risk if these patients are untreated," said Lip. "The risk of stroke and the risk of mortality are substantially reduced if they are treated with anticoagulants. So very loosely, for the net clinical benefit balancing the benefit of stroke and mortality against the small risk of serious bleeding, including intracranial hemorrhage, the data clearly support treatment even with just a single risk factor."

He added that it's "probably simplistic" to assume that each of the risk factors making up the CHA2DS2-VASc score carry equals weight. Their analysis showed the 1-year stroke rates were higher for individuals with vascular disease compared with individuals with hypertension or heart failure. In addition, while age 65 to 74 years gets 1 point on the CHA2DS2-VASc score, it would be wrong to assume a 65-year-old AF patient had the same risk as a 74-year-old patient, said Lip.

Getting to the Heart of the Exact Stroke Rate

In an editorial[2], Dr Menno Huisman (Leiden University Medical Center, the Netherlands) focuses on the estimation of stroke risk among AF patients from different cohorts. He points out that the CHA2DS2-VASc score has been retrospectively validated in different patient populations and this has led to markedly different estimates of stroke risk.

The large differences in these estimates of stroke risk among the patients with a CHA2DS2-VASc score of 1 has led to the debate about whether or not these patients should receive oral anticoagulation. For example, Huisman points out that estimations of the annual stroke rate range from 0.6% to more than 2.0% if such patients remain untreated.

"We are therefore left with uncertainty as to the true stroke rate in untreated patients with a CHA2DS2-VASc score of 1," according to Huisman. "This uncertainty should be incorporated into guidelines, thus enabling clinicians to build it into the decision process when confronted with their next patient presenting with nonvalvular atrial fibrillation. On the basis of current evidence, there is still equipoise as to whether a patient with a CHA2DS2-VASc score of 1 carries a low or a high stroke risk."

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. Disclosures for the coauthors are listed in the article. Huisman has received research grants from Boehringer Ingelheim and GlaxoSmithKline and has provided lectures and consultations for Bristol-Myers Squibb and Boehringer Ingelheim.

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