ESC 2009: No Significant Reduction in Progression of Symptomatic Intracranial Stenosis With Cilostazol vs Clopidogrel

Susan Jeffrey

June 16, 2009

June 16, 2009 (Stockholm, Sweden) — Results of a randomized trial show no significant reduction in the progression of symptomatic intracranial stenosis with cilostazol (Pletal, Otsuka Pharmaceuticals) plus aspirin over clopidogrel (Plavix, Bristol-Myers Squib/Sanofi-Aventis) plus aspirin.

Although there was a numerical decrease in the primary outcome of progression of symptomatic lesions on magnetic resonance imaging (MRI) with cilostazol, this difference did not reach statistical significance. However, there was also an increase in the number of patients who showed regression in symptomatic lesions with cilostazol, and when progression and regression were considered together in a trend analysis, it did become statistically significant, the authors note.

Ischemic cardiovascular events and asymptomatic new lesions on MRI were actually fewer in the aspirin plus clopidogrel group, the researchers noted, but serious bleeding complications were more frequent with the clopidogrel combination.

Taking into account results from the previously reported CARESS trial, "aspirin plus clopidogrel may be the most effective therapy in prevention of recurrent embolic events from intracranial stenosis," lead author Sun U. Kwon, MD, PhD, associate professor in the department of neurology at Asan Medical Center, University of Ulsan Medical College, in Seoul, South Korea, told Medscape Neurology.

However, he added that the aspirin-plus-cilostazol combination may also be helpful in long-term management of these patients.

Results of the Trial of Cilostazol in Symptomatic Intracranial Arterial Stenosis II (TOSS-2) were presented here at the European Stroke Conference 2009.

Alternative Antiplatelet Therapy?

Cilostazol is a phosphodiesterase 3 (PDE3) inhibitor already approved in the United States for the treatment of symptoms of intermittent claudication associated with peripheral vascular disease. A previous pilot study of cilostazol, called the Cilostazol vs Aspirin for Secondary Ischemic Stroke Prevention (CASISP) trial, suggested that the drug may be as effective as aspirin in preventing recurrent strokes, but with significantly lower rates of bleeding (Huang Y et al. Lancet Neurol. 2008;7:494-499).

Cilostazol acts by preventing inactivation of the intracellular second-messenger cyclic AMP and irreversibly inhibits platelet aggregation and vasodilation, the CASISP authors noted in their report. It has also been shown to delay the onset of atherosclerosis, protect endothelium, and inhibit the proliferation of arterial smooth-muscle cells, they noted. Other trials in this research program have shown that cilostazol reduced the progression of carotid intima-media thickness and angiographic restenosis after coronary stenting.

Another previous trial, TOSS, showed that cilostazol reduced progression of symptomatic intracranial atherosclerotic stenosis (ICAS) on magnetic resonance angiography (MRA) and transcranial Doppler. "Because of the small sample size and short-term follow-up, no reduction of clinical events by the addition of cilostazol was observed," Dr. Kwon noted.

To confirm the TOSS results, TOSS-2 enrolled 456 acute ischemic stroke patients with symptomatic ICAS within 14 days of stroke onset from 20 centers in 4 countries: Korea, Hong Kong, Thailand, and the Philippines. Patients were randomized to receive either 100 mg twice daily of cilostazol plus dummy clopidogrel or 75 mg per day of clopidogrel plus dummy cilostazol, in addition to background therapy of 75 to 125 mg per day of aspirin.

Symptomatic ICAS was defined as stenosis of the M1 segment of the middle cerebral artery or basilar artery on MRI, with acute ischemic lesions on MRI in the vascular territory of the stenosed artery. Patients with embolic sources in the heart or extracranial arteries were excluded.

The primary outcome was progression of symptomatic ICAS on MRA. Secondary end points included the occurrence of new ischemic lesions on MRI, all stroke events, and major bleeding complications.

Baseline characteristics, including stroke severity, location of symptomatic stenosis, and risk factors were similar between the groups, Dr. Kwon reported. Follow-up MR angiograms were available in 87% of the cilostazol group and 92% of the clopidogrel group, he noted.

After 7 months of treatment, follow-up MRA showed a slightly lower rate of progression and a higher rate of regression in the symptomatic stenosis with cilostazol vs clopidogrel, which showed a statistically significant difference when considered in trend analysis, Dr. Kwon said.

Table 1. TOSS-2: Symptomatic Intracranial Stenosis With Cilostazol vs Clopidogrel Combination Treatment

End Point Cilostazol, n (%) Clopidogrel, n (%) P
Progression (primary outcome) 20 (9.90) 32 (15.46) .049
No change 121 (59.90) 126 (60.87)
Regression 61 (30.20) 49 (23.67)

More patients in the cilostazol group had new asymptomatic ischemic lesions at the follow-up MRA than those receiving clopidogrel, as well as in the territory of the symptomatic ICAS, but this difference was not statistically significant.

Table 2. TOSS-2: Asymptomatic Intracranial Stenosis With Cilostazol vs Clopidogrel Combination Treatment

End Point Cilostazol, n (%) Clopidogrel, n (%) P
Any new ischemic lesion 34 (18.68) 23 (12.04) .0775
New ischemic lesions in the territory of symptomatic ICAS 22 (12.09) 17 (8.90) .321

There was no statistical difference in the occurrence of clinical events by treatment group, although events tended to be more frequent in the cilostazol group.

Table 3. TOSS-2: Clinical Events by Treatment

End Point Cilostazol, n (%) Clopidogrel, n (%) P
Total cardiovascular events 15 (6.46) 10 (4.83) .283
Nonfatal stroke 11 (4.74) 6 (2.67) .324
Ischemic stroke in the territory of symptomatic ICAS 9 (3.88) 5 (2.22) .417
Nonfatal MI 3 (1.3) 1 .04) .624
Vascular death 1 (0.43) 2 (0.89) .607

Bleeding complications were higher with clopidogrel, but again, not statistically significantly different between groups.

Table 4. TOSS-2: Major Bleeding Complications by Treatment

End Point Cilostazol, n (%) Clopidogrel, n (%) P
Major bleeding complications 2 (0.86) 6 (2.67) .163
Life-threatening hemorrhage 1 (0.43) 2 (0.89)
Other major bleeding 1 (0.43) 4 (1.78)

"Therefore, cilostazol combination therapy did not show significant reduction in the progression of symptomatic ICAS," Dr. Kwon concluded. "However, it had a favorable effect on the overall change in symptomatic ICAS."

Asymptomatic new ischemic lesions on follow-up MRI tended to be less frequent in the clopidogrel group, he added. "However, overall cardiovascular events, including major bleeding, tended to be similar in both groups."

Follow-Up Too Short?

Asked for comment on the findings, Ralph Sacco, MD, from the Miller School of Medicine at the University of Miami, in Florida, who comoderated the late-breaking trial session here, pointed out that with follow-up of only 7 months, the trial may have been too short to see a statistical difference between the groups.

"They were looking at progression of intracranial athero, and Asians have a lot more intracranial disease, which is what makes this interesting," he told Medscape Neurology. "I think 2 things: the follow-up may have been too short to see any effect, and there are still some technical issues with the adequacy of MRA for really being able to track intracranial disease. There are still false positives and negatives, and I think I'd really want to be sure that the technique that we're using is valid and solid enough to clearly define progression vs regression."

In terms of treatment of these patients right now, the choice is between conventional antiplatelets, including aspirin, clopidogrel, and extended-release dipyridamole, Dr. Sacco said.

More will be known about how to approach these patients from a National Institutes of Health–funded study that has just begun called Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis (SAMMPRIS), he noted. The trial is comparing angioplasty with stenting vs aggressive medical management in patients with a transient ischemic attack (TIA) or nonsevere stroke within the previous 30 days attributed to a 70% to 99% stenosis of a major intracranial artery.

This investigator-initiated study was funded by Otsuka International Asia Arab and other local companies of Otsuka, including Korea Otsuka Pharmaceutical Company, which provided the study drug. Dr. Kwon reports he has not received honoraria or consulting fees more than $3000 per year from any company.

XVIII European Stroke Conference: Large Clinical Trials Session 5. Presented May 27, 2009.