Stroke Prevention Strategies Discussed

MIAMI BEACH, FLA.—One of the most frequently asked questions in the rapidly evolving field of anticoagulation for stroke prevention is, “Which agent is best?” noted Michael D. Ezekowitz, MB, ChB, DPhil, of Lankenau Medical Center, Wynnewood, Pa., at TCT 2012.

That is difficult to answer, he explained, because the amount of information on the major agents is limited and variable.

The novel anticoagulants share several features, including rapid onset and offset of action, oral administration, no need for routine monitoring and no antidote. Importantly, said Ezekowitz, the “big three” trials—ROCKET AF (rivaroxaban; Xarelto, Bayer), RE-LY (dabigatran; Pradaxa, Boehringer Ingelheim) and ARISTOTLE (apixaban; Eliquis, Bristol-Myers Squibb/Pfizer)—show that all three agents are generally safer than warfarin.

Ezekowitz reviewed the trial highlights. In RE-LY, published in 2009 (Connolly SJ, et al. N Engl J Med. 2009;361:1139-1151), the results showed that the higher dose of dabigatran (150 mg) was superior to warfarin with regard to stroke or systemic embolism (1.11% per year vs. 1.71% per year; P<.001) and equivalent with regard to major bleeding (3.32% per year vs. 3.57% per year; P=.32).

The lower dose (110 mg), meanwhile, showed noninferiority compared with warfarin with regard to stroke or systemic embolism (1.54% per year with 110 mg dabigatran; P<.001 for noninferiority) and superiority with regard to major bleeding (2.87% per year with dabigatran; P=.003). Both doses more than halved the rate of intracranial bleeding compared with warfarin. The 150-mg dose did increase major gastrointestinal bleeding (P<.001).  Gastrointestinal complaints, Ezekowitz noted, occur in about 10% of patients and lead to discontinuation in about 2.1%.

In the ROCKET AF trial, rivaroxaban was also noninferior for stroke/systemic embolism (P<.001 for noninferiority) and reduced intracranial hemorrhage (P<.001). Again, however, there were GI signals, Ezekowitz said.

With apixaban, all the efficacy and safety parameters were either significantly better than warfarin or trended in that direction, he added.

One of the novel agents should be considered for new AF patients, Ezekowitz said, although apixaban awaits FDA approval. The only exceptions are patients with a creatinine clearance less than 15 mL/min (ck unit) or a mechanical heart valve or hemodynamic mitral stenosis, as well as those who are pregnant or nursing, in labor or delivering, or children. In addition, the new agents should be not be used in conjunction with aspirin or clopidogrel, and if triple therapy is required, warfarin should be the default anticoagulant.

Factors to consider in choosing the most appropriate agent include the fact that dabigatran comes with the most data and is the only new anticoagulant that at the higher dose reduces ischemic stroke, Ezekowitz said. On the other hand, it is associated with GI complaints and, unlike rivaroxaban and apixaban, must be taken twice daily. 

Cryptogenic stroke: Don’t assume it’s the PFO

David E. Thaler, MD, PhD, of Tufts Medical Center, Boston, advocated “clear thinking” about the cause of cryptogenic stroke in PFO patients and thus the potential benefit of medical therapy. Although more than one-third of strokes are cryptogenic, it is impossible to know in individual cases whether the PFO is pathogenic or simply incidental, he said.

Other stroke mechanisms may be present. A 2011 study published in Stroke by Mono et al showed that even when the PFO was causal for the first stroke, 35% of subsequent ischemic events were unrelated to it. Interestingly, Thaler pointed out, in patients with a history of thromboembolic events, an atrial arrhythmia often goes undetected for at least a month after the event.

To the common objection that PFO stroke patients tend to be younger, without conventional vascular risk factors, Thaler offered evidence that, on the contrary, such risk factors begin to build after the early thirties, suggesting that aggressive primary prevention should start early.

Thaler told TCT Daily that even if PFO closure works, and is used, there will still be patients with non-PFO-related index strokes who may be lulled into a false sense of security and so ignore secondary prevention treatments. Patients must continue to be treated with antithrombotics, probably statins, and vascular risk factor modification even if they are successfully closed, he added.