Cilostazol Stroke Prevention Study - CSPS 2

Sep 16, 2010
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Author/Summarized by Author:
Dharam J. Kumbhani, MD, SM, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Summary Supplemental Reviewer:
Anthony A. Bavry, MD, MPH, FACC
Trial Sponsor:
Otsuka Pharmaceutical
Date Presented:
01/01/2010
Date Published:
01/01/2010
Date Updated:
09/16/2010
Original Posted Date:
09/16/2010
References

Description:

The goal of the trial was to evaluate treatment with cilostazol compared with aspirin among patients with recent cerebral infarction.

Hypothesis:

Cilostazol will be noninferior for safety and efficacy in patients with noncardioembolic stroke, as compared with aspirin.

Study Design

  • Parallel
  • Blinded
  • Randomized

Patients Enrolled: 2,672
Mean Follow Up: 1-5 years

Patient Populations:

  • History of cerebral infarction within the last 26 weeks, confirmed by computed tomography or magnetic resonance imaging
  • Clinical stability prior to randomization
  • Age 20-79 years

    Number enrolled: 2,757 (2,672 analyzed)
    Mean patient age: 63.5 years
    Percentage female: 28%
    Mean duration of follow-up: 29 months

Exclusions:

  • Cerebral infarction due to cardiogenic cerebral embolism
  • Contraindications to aspirin or cilostazol
  • Increased risk of hemorrhage, congestive heart failure, and peptic ulcer
  • Blood, hepatic or renal disorders, or cardiac diseases associated with cardioembolism 
  • Undergone or were scheduled to undergo percutaneous transluminal angioplasty or revascularization for treatment of cerebral infarction
  • Patients on thienopyridine derivatives or any other investigational drug

Primary Endpoints:

  • Recurrence ischemic stroke, cerebral hemorrhage, or SAH

Secondary Endpoints:

  • First occurrence of recurrent ischemic stroke
  • Ischemic cerebrovascular events including cerebral infarction or transient ischemic attack
  • All-cause mortality
  • Composite of completed stroke, angina, myocardial infarction, congestive heart failure, or hemorrhage requiring hospitalization
  • Hemorrhagic events

Drug/Procedures Used:

Patients with a history of noncardioembolic stroke within the last 26 weeks were randomized to cilostazol 100 mg twice daily (n = 1,337) versus aspirin 81 mg daily (n = 1,335).

Concomitant Medications:

Antihypertensive medications (70%), statins (29%), antidiabetic agents (21%)

Principal Findings:

Overall, 2,672 patients were enrolled, 1,337 to the cilostazol arm and 1,335 to aspirin. Baseline characteristics were fairly similar between the two arms. The majority of strokes were lacunar (65%), with about 32% being atherothrombotic. More than one-half of the patients were enrolled within 2 months of their infarct. About 74% had hypertension, and 29% had diabetes mellitus.

The primary efficacy endpoint of recurrent ischemic stroke, cerebral hemorrhage, or subarachnoid hemorrhage (SAH) met the predefined endpoint for noninferiority of cilostazol, as compared with aspirin (2.76%/year vs. 3.71%/year, p = 0.0357). This also met the criteria for superiority (0.0471). The secondary endpoints of recurrent ischemic stroke (2.43%/year vs. 2.75%/year,  p = 0.42) and all-cause mortality (0.42%/year vs. 0.39%/year, p = 0.86) were similar between the cilostazol and aspirin arms. The  safety endpoint of hemorrhagic events was also lower in the cilostazol arm (0.77%/year vs. 1.78%/year, p = 0.0004).

Adverse events were significantly more common in the cilostazol arm, including those leading to study drug discontinuation (19.8% vs. 12.2%). Major side effects included headache, diarrhea, palpitations, dizziness, and tachycardia.

Interpretation:

Among patients with a recent noncardioembolic stroke, cilostazol was noninferior and possibly even superior to aspirin in preventing the composite of recurrent ischemic stroke, hemorrhagic stroke, and SAH. This was achieved despite a reduction in major bleeding, as compared with aspirin. Adverse events were frequent with cilostazol, and drug discontinuation was nearly twice as often as with aspirin.

While these results are very interesting, certain caveats exist. It is unclear if the results of this trial will be generalizable to non-East Asian patients, and those with severe strokes. The censoring at study drug discontinuation also makes it a bit challenging to interpret the efficacy and bleeding results. This is especially important since antiplatelet agents that have traditionally demonstrated an improvement in ischemic outcomes, as compared with aspirin, have also resulted in increased bleeding. Statin use was very low (~30%). It is unclear if differential use of statins between the two arms over the course of the study may contribute at least in part to the difference in the primary efficacy outcome.

Finally, it is helpful to note that this trial was mandated of Otsuka Pharmaceuticals (the manufacturers of cilostazol) by the drug regulatory authorities in Japan, for continued marketing approval of cilostazol for the indication of secondary prevention of ischemic stroke.

 

References:

Shinohara Y, Katayama Y, Uchiyama S, et al., on behalf of the CSPS 2 Group. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol 2010;Sep 11:[Epub ahead of print].

Editorial: Kumbhani DJ, Bhatt DL. Secondary prevention of stroke: can we do better than aspirin? Lancet Neurol 2010;Sep 11:[Epub ahead of print].

Presented by Dr. Yukito Shinohara at the American Stroke Association International Stroke Conference, February 26, 2010, San Antonio, TX.

Keywords: Subarachnoid Hemorrhage, Stroke, Follow-Up Studies, Platelet Aggregation Inhibitors, Diarrhea, Fibrinolytic Agents, Tetrazoles, Marketing, Magnetic Resonance Imaging, Headache, Vasodilator Agents, Bronchodilator Agents, Tachycardia, Dizziness, Cerebral Infarction, Neuroprotective Agents, Hypertension, Diabetes Mellitus, Phosphodiesterase 3 Inhibitors, Cerebral Hemorrhage


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