Dual Antiplatelet Therapy With Cilostazol Cuts Recurrent Stroke

Pauline Anderson

February 07, 2019

HONOLULU — Stroke patients have almost half the risk of a recurrent event if they take a combination of cilostazol plus aspirin or clopidogrel rather than aspirin or clopidogrel alone, a new study shows.

Importantly, patients on the combination therapy had a risk of severe bleeding similar to those on monotherapy. However, headaches and cardiac adverse events such as palpitations and tachycardia were relatively frequent early complications of cilostazol, which is a phosphodiesterase 3 (PDE3) inhibitor.

The results suggest adding cilostazol to aspirin or clopidogrel could be beneficial in some high-risk patients who can tolerate headache or palpitations, lead author Kazunori Toyoda, MD, PhD, Deputy Director General, National Cerebral and Cardiovascular Center, Osaka, Japan, told Medscape Medical News.

Dr Kazunori Toyoda

Findings of the Cilostazol Stroke Prevention Study for Antiplatelet Combination (CSPS.com) were presented here at the International Stroke Conference (ISC) 2019.

Although previous research showed that aspirin and clopidogrel reduce early recurrence of ischemic stroke, the benefits seem to be short-lived, and are offset by a risk of major bleeding with long-term use, the researchers note.

The new multicenter open-label, parallel-group trial included patients ages 20 to 85 years at 292 sites in Japan, deemed at high risk for recurrent stroke. They had a history of noncardioembolic ischemic stroke up to 6 months earlier and were taking aspirin or clopidogrel alone as antiplatelet therapy.

As well, study participants had to have at least one of the following risk factors: 50% or more stenosis of a major intracranial artery; 50% or greater stenosis of an extracranial artery; and two or more of the following factors: over age 65 years, diabetes, hypertension, chronic kidney disease, peripheral artery disease, being a smoker, history of ischemic stroke (excluding the index one for this trial), and history of ischemic heart disease.

Participants were randomly assigned to receive aspirin or clopidogrel alone, or a combination of cilostazol plus aspirin or clopidogrel over about 4 years.

The trial was stopped early owing to a delay in recruiting patients after enrollment of 1884 of an anticipated 4000 patients. Toyoda noted that the study used brand name cilostazol (Pletal, Otsuka Pharmaceutical), the cost of which may have affected enrollment.

The primary outcome was recurrence of ischemic stroke. Secondary outcomes included the following: any stroke (ischemic or hemorrhagic); hemorrhagic stroke (intracerebral or subarachnoid); ischemic stroke or transient ischemic attack (TIA); death from any cause; composite of stroke, myocardial infarction (MI), and vascular death; and all vascular events, including stroke, MI, and others.

Safety outcomes included severe or life-threatening bleeding (GUSTO classification), intracranial hemorrhage, any adverse events, serious adverse events, and bleeding adverse events.

The final analysis included 932 patients in the dual therapy group and 947 in the monotherapy group. Toyoda noted that baseline characteristics of the two groups were almost identical. Their mean age was about 70 years, about 30% were women, and all were Japanese.

Intracranial artery stenosis was detected in about 29% in both groups and extracranial artery stenosis in about 13% of all patients.

Highly Significant

The annual rate of ischemic stroke was 2.2% per year for dual therapy and 4.5% per year for monotherapy (hazard ratio [HR] 0.49; 95% confidence interval [CI], 0.31 - 0.76; P = .001). The difference was statistically "highly significant," noted Toyoda.

The composite of stroke, MI, and vascular death was also cut by half in the dual therapy group compared with the monotherapy group. There were 38 such events in the dual therapy group compared with 78 in the monotherapy group (HR 0.52; 95% CI, 0.35 - 0.77; P = .0008).

Dual therapy also reduced the risk of any stroke, ischemic stroke, or TIA and all vascular events by almost half.

There were no significant treatment by subgroup interactions among the prespecified subgroups, said Toyoda. However, he noted that dual therapy was more effective in patients with intracranial artery stenosis than in patients with extracranial artery stenosis.

"This is a subgroup analysis based on small numbers so it's not particularly scientific, but I would guess that patients who have intracranial artery stenosis are better candidates for this dual therapy as compared to patients with extracranial artery stenosis," he said.

That's not to say, however, that the therapy can't also be effective for extracranial artery stenosis patients, he added.

Severe or life-threatening bleeds occurred in less than 1% per year in both groups (the HR was 0.66 and was statistically insignificant [P = .35]). All of these events (eight in the dual therapy group and 13 in the monotherapy group) were intracranial hemorrhages, noted Toyoda.

Adverse events (AEs) were more common in the dual therapy group. In this group, 27.4% had an AE compared with 23.1% of the monotherapy group. 

In the dual therapy group, 8.9% had a nervous system AE (including 26 patients with headache) compared with 9.6% in the monotherapy group.

As for cardiac AEs, 8.4% of the dual therapy group suffered such an event, including 59 patients with palpitation/tachycardia. Only 1.8% of the monotherapy group had a cardiac AE.

In contrast, serious AEs were more common in the monotherapy group (15.% vs 9.3% in the dual therapy group). Toyoda noted that efficacy endpoints such as stroke were included in these adverse events.

Bleeding AEs occurred in 4.1% of the dual therapy group and 3.5% of the monotherapy group.

Some adverse effects might be avoided by starting with smaller doses of cilostazol (for example, 50 mg instead of 100 mg twice daily) and then gradually increasing it, said Toyoda.

Limitations of the study were that it enrolled only 47% of the target 4000 subjects and it included only Japanese patients. As well, about one fifth of patients in the dual therapy group discontinued medications within 6 months. 

"Headache and palpitations seemed to be the main reason of discontinuation," said Toyoda.

Promising and Safe

Commenting on the study for Medscape Medical News, Karen Furie, MD, Chair, Stroke Council, American Heart Association, and Chair, Neurology, Alpert Medical School of Brown University, Providence, Rhode Island, said given these new data, cilostazol "looks very promising and safe" in dual therapy. However, she would like further evidence.

"I think cilostazol should continue to be evaluated in these combination regimens to see if it truly has a better safety profile than what we're currently using."

A typical dual therapy, Furie said, now might be aspirin and clopidogrel in patients with a minor stroke and intracranial stenosis.

"This trial has the potential to extend that to a larger population of patients who have noncardioembolic stroke, and that would include people with extracranial stenosis and patients with small vessel disease," said Furie.

The field has been moving toward increased use of dual antiplatelet therapy, but the concern has been increased bleeding, she said. "This is largely because biologically it kind of makes sense; if something is more effective at preventing clotting, it's going to increase bleeding."

Furie said she's curious why that didn't happen in this new study. "What was different about these patients? I'd like to understand that more."

She would also like to know more about the role of the different combinations — some people were on cilostazol and clopidogrel while others were on cilostazol and aspirin. "We don't know if it makes a difference which one was taken."

Also, those on monotherapy were on two different doses: 81 mg or 100 mg of aspirin, and 50 or 75 mg of clopidogrel.

"I would be curious to know if that had any effect," said Furie. "Let's say that a lot of subjects were on low-dose aspirin and low-dose clopidogrel. Could that have made monotherapy look worse?"

As this is a preliminary report, Furie said she expects more information will be forthcoming from the trial and that her "lingering questions" will be addressed. "Some of the issues I raise may be put to rest when we have more data."

While the new results are "compelling," Furie said she wants to see another study before she's comfortable prescribing cilostazol in dual therapy.

The study was funded by Otsuka Pharmaceutical Co Ltd. Toyoda and coauthors received scientific consultancy fees for trial design and management. 

International Stroke Conference (ISC) 2019: Abstract LB #3. Presented February 6, 2019.

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