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hardly conclusive. Are these results suffi cient to support continuation of a large phase III development programme? Thankfully, the sponsor’s view was affi rmative. With the need so enormous, and the potential benefi t suggested (although not proven) by these phase II results, the eff ort is indeed justifi ed despite the substantial uncertainty. In a few months, we will learn whether tarenfl urbil will be the fi rst anti-amyloid intervention to be effi cacious in a pivotal trial.

The best news is that several other promising anti-amyloid programmes are moving forwards, despite the methodological diffi culties of seeing clear effi cacy in phase II studies.2 Further, biomarker techniques are improving, allowing more rational selection of drug doses to target secretases;7 these advances should increase the likelihood that such programmes will succeed. The realistic possibility that pharmacological control over the amyloid cascade will be achieved, and the enormous eff ect this would have on world health, should continue to drive these eff orts.

Paul S AisenDepartment of Neurosciences, University of California at San Diego, 9500 Gilman Drive, M/C 0949, San Diego, CA 92093, USA paisen@ucsd.edu

While working at Georgetown University, I was a site investigator for the Myriad Pharmaceuticals phase III trial of tarenfl urbil. I was not involved in the Phase II trial, and I have never been a consultant to Myriad.

1 Wilcock GK, Black SE, Hendrix SB, et al. Effi cacy and safety of tarenfl urbil in mild to moderate Alzheimer’s disease; a randomised phase II trial. Lancet Neurol 2008; 7: 483–493

2 Aisen PS. The development of anti-amyloid therapy for Alzheimer’s disease: from secretase modulators to polymerisation inhibitors. CNS Drugs 2005; 19: 989–96.

3 Wolfe MS. Gamma-secretase: structure, function, and modulation for Alzheimer’s disease. Curr Top Med Chem 2008; 8: 2–8.

4 Siemers ER, Dean RA, Friedrich S, et al. Safety, tolerability, and eff ects on plasma and cerebrospinal fl uid amyloid-beta after inhibition of gamma-secretase. Clin Neuropharmacol 2007; 30: 317–25.

5 Weggen S, Eriksen JL, Das P, et al. A subset of NSAIDs lower amyloidogenic Abeta42 independently of cyclooxygenase activity. Nature 2001; 414: 212–16.

6 Eriksen JL, Sagi SA, Smith TE, et al. NSAIDs and enantiomers of fl urbiprofen target gamma-secretase and lower Abeta 42 in vivo. J Clin Invest 2003; 112: 440–49.

7 Bateman RJ, Munsell LY, Morris JC, Swarm R, Yarasheski KE, Holtzman DM. Human amyloid-beta synthesis and clearance rates as measured in cerebrospinal fl uid in vivo. Nat Med 2006; 12: 856–61.

Cilostazol shows promise as an alternative to aspirin for patients with ischaemic stroke

The most widely prescribed antiplatelet drug to reduce the long-term risk of major vascular events in patients who have had arterial ischaemic stroke is aspirin.1 Aspirin is reasonably safe and aff ordable2 but has only modest eff ectiveness; the reduction in relative risk (RRR) of major vascular events is only about 13% (95% CI 6–19%).2 Aspirin also might not be safe to use in populations that are at high risk of intracerebral haemorrhage (eg, Asians).2,3 Among the alternative antiplatelet drugs, dipyridamole is not more eff ective than aspirin (–2%, –18% to 12%) and clopidogrel might only be marginally more eff ective than aspirin (8·7%, 0·3–16·3%); the combination of aspirin and extended-release dipyridamole is more eff ective than aspirin alone (18%, 9–26%) but is more likely to cause headache.2 Cilostazol is an antiplatelet drug that has been shown to reduce the risk of major vascular events compared with placebo (39%, 9–59%) in a randomised trial of 1095 Japanese patients with ischaemic stroke.4 However, the burning question is: how does cilostazol compare with another “gold standard” antiplatelet drug, such as aspirin, and not just with a placebo? In this issue of The Lancet Neurology,5 Huang and colleagues report the results of a randomised, double-blind, pilot trial that

compared cilostazol with aspirin in 720 patients from China with recent (within 1–6 months) ischaemic stroke.5

Compared with standard-dose aspirin (100 mg per day), random assignment to cilostazol (100 mg twice per day) was associated with a reduction in the relative risk of the primary outcome—recurrent stroke—by 38% (95% CI –26% to 70%) after an average of little more than a year on treatment.5 These results are consistent with the expected outcome, based on a previous comparison of cilostazol with placebo4 (ie, a RRR of about 25% with cilostazol vs aspirin), but they are also consistent with cilostazol being up to 26% less eff ective than aspirin and 70% more eff ective than aspirin, in relative terms. The extremely wide confi dence intervals around the point estimate of the RRR show the small number of primary outcome events (12 in the cilostazol group [3·6%] vs 20 in the aspirin group [6·4%]) owing to the small number of patients randomised, their moderate risk profi le (patients who were at the highest risk of recurrent stroke—those in their fi rst month after ischaemic stroke—were excluded), and the short follow-up. Unfortunately, the trial design did not include sample-size calculations or the more statistically robust

Published OnlineMay 5, 2008DOI:10.1016/S1474-4422(08)70095-4

See Articles page 494

outcome event—the composite of stroke, myocardial infarction, or vascular death.

The authors are understandably excited by the smaller number of symptomatic intracerebral haemorrhages in patients in the cilostazol group (n=1) versus those in the aspirin group (n=5), and by the possibility that fi nding brain microbleeds on MRI gradient echo T2 sequences might identify the patients who are at greatest risk of antiplatelet-associated intracerebral haemorrhage. However, caution is required in the interpretation of these results because the number of intracerebral haemorrhages was extremely small (and so the results are imprecise and only hypothesis-generating), and the diagnostic and prognostic usefulness of brain microbleeds is uncertain.6

Although the results are prone to random error, they are unlikely to be substantially infl uenced by bias: selection bias in treatment allocation was minimised by the concealed randomisation process, which resulted in baseline comparability of the treatment groups; performance bias was minimised by otherwise equal treatment of the two groups during the trial; attrition bias is unlikely because only 1·3% of patients were lost to follow-up; and detection bias is unlikely because the assessment of outcome events was made by investigators who were blinded to the treatment allocation.

The trial results are, therefore, likely to be internally valid and biologically plausible. Cilostazol not only inhibits platelet aggregation by selectively blocking phos-phodiesterase type 3 (an enzyme that breaks down cyclic AMP) but it also inhibits the production of thromboxane

B2 and the release of platelet-derived growth factor by activated platelets. Cilostazol also has a vasodilatory action and a favourable eff ect on plasma lipid profi les; moreover, it increases the distance that patients with peripheral arterial disease can walk7 and might be comparable or superior to clopidogrel for the prevention of subacute coronary artery stent thrombosis and restenosis.8,9

The implications of these results for clinicians are that they off er hope for a safer antiplatelet drug that is at least as eff ective as aspirin for use in patients with ischaemic stroke. The implications of these results for researchers are the need to explore the external validity of these pilot study results in a phase III randomised trial that compares cilostazol with aspirin (or with the new gold standard of antiplatelet therapy, pending the results of the PRoFESS trial10) in a large number of high-risk patients with recent ischaemic stroke from a wide range of nations and ethnic groups.

Graeme J HankeyDepartment of Neurology, Royal Perth Hospital, 197 Wellington Street, Perth, Western Australia, 6001gjhankey@cyllene.uwa.edu.au

I have received honoraria from Sanofi -Aventis, Bristol-Myers Squibb, Boehringer Ingelheim, and Pfi zer for serving on advisory boards and speaking at sponsored scientifi c symposia.

1 Röther J, Alberts MJ, Touzé E, et al. Risk factor profi le and management of cerebrovascular patients in the REACH registry. Cerebrovasc Dis 2008; 25: 366–74.

2 O’Donnell MJ, Hankey GJ, Eikelboom JW. Antiplatelet therapy for secondary prevention of noncardioembolic ischemic stroke. A critical review. Stroke 2008; published online Mar 27:DOI10.1161/STROKEAHA.107.497271.

3 Liu M, Wu B, Wang W-Z, Lee L-M, Zhang S-H, Kong L-Z. Stroke in China: epidemiology, prevention and management strategies. Lancet Neurol 2007; 6: 456–64.

4 Gotoh F, Tohgi H, Hirai S, et al. Cilostazol stroke prevention study: a placebo-controlled, double-blind trial for secondary prevention of cerebral infarction. J Stroke Cerebrovasc Dis 2000; 9: 147–57.

5 Huang Y, Cheng Y, Wu J, et al. Cilostazol as an alternative to aspirin after ischaemic stroke: a randomised, double-blind, pilot study. Lancet Neurol 2008; 7: 494–99.

6 Cordonnier C, Al-Shahi Salman R, Wardlaw J. Spontaneous brain microbleeds: systematic review, subgroup analyses and standards for study design and reporting. Brain 2007; 130: 1988–2003.

7 Falconer TM, Eikelboom JW, Hankey GJ, Norman PE. Management of peripheral arterial disease in the elderly: focus on cilostazol. Clin Interven Aging 2008; 3: 17–23.

8 Ahn Y, Heong MH, Heong JW, et al. Randomised comparison of cilostazol vs clopidogrel after drug-eluting stenting in diabetic patients. Cilostazol for diabetic patients in drug-eluting stent (CIDES) trial. Circ J 2008; 72: 35–39.

9 Lee S-W, Park S-W, Kim Y-H, et al. Drug-eluting stenting followed by cilostazol treatment reduces late restenosis in patients with diabetes mellitus. J Am Coll Cardiol 2008; 51: 1181–87.

10 Diener H-C, Sacco R, Yusuf S, for the Steering Committee and PRoFESS Study Group. Rationale, design and baseline data of a randomized, double-blind, controlled trial comparing two antithrombotic regimens (a fi xed-dose combination of extended-release dipyridamole plus ASA with clopidogrel) and telmisartan versus placebo in patients with strokes: the prevention regimen for eff ectively avoiding second strokes trial (PRoFESS). Cerebrovasc Dis 2007; 23: 368–80.

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