NO BENEFIT OF TRIPLE ANTI-PLATELET THERAPY FOR STROKE-TIA

Triple antiplatelet therapy was not superior to guideline-recommended treatment with aspirin/dipyridamole or clopidogrel alone in preventing recurrent strokes in patients who had sustained a recent ischemic stroke or transient ischemic attack (TIA) in the TARDIS trial.

The trial was presented at the International Stroke Conference (ISC) 2017.

Although triple therapy did show a trend toward recurrent cerebral events, it was also associated with increased major bleeding, leading to a neutral net risk benefit, lead investigator, Philip Bath, MD, University of Nottingham, United Kingdom, reported.

"Our conclusion is that triple therapy does not offer benefits over guideline-recommended strategies of clopidogrel or aspirin/dipyridamole. So we should just stick with the guideline treatment," Dr Bath said.

American Heart Association/American Stroke Association spokesperson Mark Alberts, MD, chief of neurology at Hartford Hospital, Connecticut, said, "TARDIS is a very well conducted study which shows that more is not better in terms of antiplatelet drugs in secondary stroke prevention."

Dr Bath explained that it is well known that patients who have recently had an ischemic stroke or TIA are at increased risk for another such event in the next days or weeks.

"Current guidelines in the UK recommend use of clopidogrel or aspirin plus dipyridamole in these patients to reduce the risk of recurrent stroke, but we wanted to look at whether using all three agents together would lead to a greater risk reduction and whether the bleeding risk would be acceptable."

The TARDIS trial was therefore conducted. It randomly assigned patients within 48 hours of a noncardioembolic ischemic stroke or TIA to intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) or guideline-recommended antiplatelets (clopidogrel alone or combined aspirin and dipyridamole) given for 1 month.

Aspirin was given at a loading dose of 300 mg (day 0), then 75 mg daily (days 1 to 30). Clopidogrel was given at a loading dose of 300 mg (day 0), then 75 mg daily (days 1 to 30), and dipyridamole was dosed at 200 mg twice daily or 150 mg three times daily.

The study used a novel primary endpoint for a secondary prevention trial taking into account both the number and severity of future strokes, with the use of an ordinal shift modified Rankin Scale (mRS) score.

This scale is used routinely in acute stroke trials, but this is the first secondary prevention study to include this endpoint, Dr Bath noted. The trial also used an ordinal safety outcome to assess both the number and severity of bleeds.

The Independent Data Monitoring Committee recommended stopping the trial in March 2016 because a definitive result had been reached. At this point, 3096 (of a planned 4100) patients were enrolled from 106 sites in 4 countries (95% from the United Kingdom).

Because the UK guidelines changed during the study (from recommending aspirin plus dipyridamole to clopidogrel as first-line antiplatelet treatment for these patients), the control group consisted of either of these two options.

"The study started with aspirin/dipyridamole as the control, but after the guidelines changed we had to allow clopidogrel to be used, so generally the control group switched over to clopidogrel in the latter part of the trial," Dr Bath explained

Dr Alberts noted that in the United States, monotherapy with either aspirin or clopidogrel is generally recommended for these patients and the combination of aspirin plus dipyridamole is not often used.

Baseline characteristics of the TARDIS population showed that the mean age of participants was 69 years; 63% were male, 11% had had a prior stroke, and 19% had diabetes. The index event was ischemic stroke in 70% of patients and TIA in 30%.

Results showed the primary endpoint (ordinal stroke/TIA) was not significantly different between the two groups.

Table 1. TARDIS: Efficacy Endpoints at Day 90

Endpoint	Odds Ratio (95% Confidence Interval)	PValue
Ordinal stroke/TIA	0.93 (0.70 - 1.23)	.61
Fatal stroke	1.62 (0.67 - 3.93)	.29

The primary safety endpoint showed a significant increase in bleeding. More bleeding events and more severe bleeding occurred with triple therapy. There were very few fatal bleeding episodes (7 with intensive therapy vs 4 with control), a nonsignificant difference.

Table 2. TARDIS: Safety Endpoints at Day 90

Endpoint	Odds Ratio (95% Confidence Interval)	P Value
Ordinal bleeding	2.49 (2.00 - 3.10)	< .001
Fatal bleeding	2.32 (0.64 - 8.36)	.20
Major bleeding	2.04 (1.16 - 3.60)	.013
Fatal/major intracerebral hemorrhage	3.33 (1.08 - 10.31)	.037

Subgroup analysis suggested that triple therapy was superior to control in terms of the primary efficacy endpoint in patients with mild stroke (National Institutes of Health Stroke Scale [NIHSS] score ≤ 3) but inferior in patients with more severe stroke (NIHSS score > 3). But the mild stroke group still showed an increase in bleeding with triple therapy, so there was still no net benefit, Dr Bath said.

Subgroup analysis also suggested that triple therapy appeared superior to aspirin/dipyridamole but inferior to clopidogrel alone in terms of efficacy and that more bleeding occurred with triple therapy than with aspirin/dipyridamole but less bleeding occurred with triple therapy than with clopidogrel alone.

Net Risk/Benefit Neutral 

When all the efficacy and safety data are analyzed together, there was a neutral effect on net risk benefit.

Table 3. Net Risk/Benefit

Outcome	Triple Therapy (%)	Control (%)	Odds Ratio (95% Confidence Interval)	PValue
Stroke/major bleeding	5.9	4.9	1.21 (0.88 - 1.67)	.23
Death, stroke, myocardial infarction, major bleeding	7.1	6.8	1.04 (0.79 - 1.38)	.77

"There was a nonsignificant reduction in recurrent ischemic events and a significant increase in bleeding," Dr Bath commented. "But the absolute numbers of strokes and bleeds are comparable so the net clinical benefit is neutral."

Dr Alberts added: "We are trying to identify the sweet spot — maybe a subgroup of patients who are at increased risk for ischemic events and who may benefit from intensive therapy for a short time after a stroke rather than indefinitely."

He noted that another trial — POINT, which is currently underway in the United States — is also looking at this question and is randomly assigning patients to clopidogrel plus aspirin vs aspirin alone starting within 12 hours of a small stroke or TIA.

The TARDIS trial was funded by the British Heart Foundation and the UK National Institute for Health Research Health Technology Assessment programme.

International Stroke Conference (ISC) 2017. Abstract LB4. Presented February 23, 2017.