Intensive therapy with aspirin, clopidogrel (Plavix), and dipyridamole (Persantine) had no better 90-day functional outcome in terms of stroke or TIA recurrence and severity as indicated by score shifting on an ordinal modified Rankin Scale analysis (adjusted common odds ratio 0.93, 95% CI 0.70-1.23) compared with aspirin and dipyridamole dual therapy or clopidogrel alone as indicated in U.K. guidelines.
The same was true for fatal stroke (aOR 1.62, 95% CI 0.67-3.93) and for most subgroups, although triple therapy tended to be better for milder strokes (NIHSS ≤3, P=0.026 for interaction but no significant treatment effect in that group alone).
"Stick with the guideline," Philip Bath, MBBS, MD, of the University of Nottingham, England, concluded in presenting the findings here at the International Stroke Conference. "What our study says is the sweet spot ... is not at three drugs. It's somewhere at one or two, and perhaps nearer two than one."
Bleeding risk was clearly increased with triple therapy, with an adjusted common OR of 2.49 in the ordinal analysis for bleeding occurrence and severity at 90 days (95% CI 2.00-3.10). The net risk-to-benefit ratio came up neutral across all endpoints and combination endpoints considered.
The findings were "fairly definitive" and consistent with prior antiplatelet prophylaxis evidence across multiple other conditions, commented Mark Alberts, MD, of the Hartford Hospital, and spokesperson for the American Stroke Association on the press conference panel.
"The more antiplatelet treatments you add on and the longer the treatment, you increase risk of hemorrhagic or bleeding complications, not just in the brain but throughout the body, such as gastrointestinal hemorrhage," he said.
In terms of generalizability, the findings fit with U.S. guidelines too, Alberts said, although even dual therapy is not typical in U.S. stroke care.
U.K. guidelines switched during the TARDIS trial as clopidogrel went generic to recommend monotherapy with that drug over dual aspirin and dipyridamole and then aspirin monotherapy as third line.
While triple therapy looked better on efficacy when compared with the aspirin/dipyridamole combo than against clopidogrel alone, Bath cautioned against concluding that clopidogrel is more effective than the dual therapy combination.
Physicians' choice between those two types of U.K. guideline-directed therapy was not randomized, he noted. The trial protocol allowed physicians to chose between the two strategies for their standard therapy group but were locked into that choice to minimize selection.
TARDIS, the first vascular prevention trial to prospectively adopt ordinal outcomes on primary endpoints, included 3,069 patients, shy of the planned 4,100 due to early termination. It was an international, open-label but blinded-endpoint trial with "very inclusive" entry criteria: age over 50, 48 or more hours after stroke onset, acute non-cardioembolic ischemic stroke of any severity or acute TIA with an ABCD2 score of at least 4 or more than one event in the prior week.
Bath noted that the findings were interim but "very close to the final lock" on the data. "I don't think anything fundamental will change."
Bath disclosed having no relevant conflicts of interest.
International Stroke ConferenceSource Reference: Bath P, et al "Intensive versus guideline antiplatelet therapy for preventing recurrence in patients with acute ischaemic stroke or TIA: main results from the triple antiplatelets for reducing dependency in ischaemic stroke (TARDIS) trial" ISC 2017; Abstract LB4.