Cilostazol: A Drug for Leg Pain From Narrowed Arteries

Cilostazol is a tablet taken by people whose leg arteries have narrowed so much that walking brings on cramping pain in the calf, thigh or buttock, pain that goes away after a few minutes of rest. Doctors call this pain intermittent claudication, and it is the most common symptom of peripheral artery disease. In the United States cilostazol carries one approved use: walking further before the pain stops a person. In Japan and other parts of Asia it has also been tested, in large trials, as a way to prevent a second stroke. This page sets out what the drug does, what the walking and stroke trials found in both directions, what the U.S. Food and Drug Administration label says about its heart-failure warning, side effects and drug interactions, and what is still unknown.

Table of Contents

  1. What Cilostazol Is
  2. How Cilostazol Works
  3. The Walking-Distance Trials
  4. What the Pooled Reviews Found
  5. Side Effects and Stopping Treatment
  6. The Heart-Failure Boxed Warning
  7. Other Warnings and Contraindications on the Label
  8. Drug Interactions and Dose Changes
  9. Stroke-Prevention Trials in Japan
  10. Stroke Research Outside Japan
  11. What Is Not Known
  12. Key Research Papers
  13. Connections
  14. Featured Videos

What Cilostazol Is

Cilostazol is a small synthetic molecule taken by mouth. The U.S. Food and Drug Administration (FDA) approved it on 15 January 1999 as a new molecular entity, according to the agency's Drugs@FDA record for the original application. Generic versions are now sold by several companies.

The current U.S. Food and Drug Administration label (DailyMed, generic cilostazol tablets, 2025 version) words the approved use this way: cilostazol tablets "are indicated for the reduction of symptoms of intermittent claudication, as demonstrated by an increased walking distance." It does not list stroke prevention or any other use.

The label gives the dose as 100 mg twice a day, taken at least half an hour before or two hours after breakfast and dinner. The label explains the timing in its pharmacology section: a high-fat meal raised the peak blood level by about 90% and the total amount absorbed by about 25%. The label states that some people respond within 2 to 4 weeks, that up to 12 weeks may be needed before a benefit appears, and that the drug is to be stopped if symptoms have not improved after 3 months. It lowers the dose to 50 mg twice a day when certain other medicines are taken at the same time (see Drug Interactions below).

Cilostazol does not open a blocked artery and is not a treatment for leg pain at rest. The label states that it "has not been studied in patients with rapidly progressing claudication or in patients with leg pain at rest, ischemic leg ulcers, or gangrene," and that its long-term effects on limb preservation and hospital admission have not been evaluated.

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How Cilostazol Works

Inside platelets and the muscle cells of blood-vessel walls, a messenger molecule called cyclic adenosine monophosphate (cAMP) acts as a brake: when its level rises, platelets become less sticky and vessel muscle relaxes. An enzyme called phosphodiesterase-3 (PDE3) breaks this messenger down. Cilostazol blocks phosphodiesterase-3.

The label describes the result in two parts. Cilostazol and several of its breakdown products block phosphodiesterase-3, so cyclic adenosine monophosphate builds up "in platelets and blood vessels, leading to inhibition of platelet aggregation and vasodilation, respectively." In other words, it has an anti-clotting (antiplatelet) effect and a vessel-widening (vasodilator) effect. The label adds that the platelet effect is reversible: after long-term use, it began to fade 48 hours after the last dose and was back to baseline by 96 hours, with no rebound. Bleeding time was not affected in the studies the label describes.

A 2002 pharmacology review by Schrör describes further actions in laboratory and animal work: cilostazol blocks the reuptake of adenosine, slows the growth and movement of smooth-muscle cells in vessel walls, and has positive effects on the force and rate of the heartbeat. The review states that "most, if not all" of these actions run through cyclic adenosine monophosphate. The heart effects are visible in people: the label reports that heart rate rose by an average of 5.1 beats per minute on 50 mg twice daily and 7.4 beats per minute on 100 mg twice daily.

Both the review and the label report a change in blood fats. After 12 weeks on 100 mg twice daily, the label records triglycerides falling by 29.3 mg/dL (15%) and high-density lipoprotein (HDL) cholesterol rising by 4.0 mg/dL (about 10%) compared with placebo. Why the drug lets people walk further is not settled; the label describes the vessel and platelet effects but does not tie the walking benefit to one of them.

The liver breaks cilostazol down, mainly through the enzyme cytochrome P450 3A4 (CYP3A4) and to a lesser extent cytochrome P450 2C19 (CYP2C19). Two breakdown products are active; one of them, 3,4-dehydro-cilostazol, is 4 to 7 times as active as cilostazol itself. The label gives a half-life of about 11 to 13 hours for cilostazol and its active products, with about a twofold build-up on regular dosing.

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The Walking-Distance Trials

Walking in these trials is measured on a treadmill. Two distances are recorded: how far a person walks before the pain starts (pain-free or initial claudication distance) and how far they walk before the pain forces them to stop (maximal or absolute claudication distance).

The approval rested on eight randomized, placebo-controlled, double-blind trials lasting 12 to 24 weeks and involving 2,274 patients. The label reports that, across the eight trials, maximal walking distance on 100 mg twice daily rose by 28% to 100% from baseline, while in the placebo groups it changed by −10% to 41%. The placebo figures matter: in several trials, people on dummy tablets also walked further, because of practice on the treadmill and the attention of being in a study.

Strandness 2002. In this 24-week trial, 394 people aged 40 or older with stable claudication took cilostazol 100 mg twice daily, 50 mg twice daily, or placebo. On the higher dose, maximal walking distance improved 21% more than on placebo and pain-free walking distance 22% more. The 50 mg dose gave 7% and 11% improvements, which did not reach statistical significance.

Dawson 2000. This trial compared cilostazol with pentoxifylline, the other drug with a U.S. label for claudication, and with placebo, in 698 people at 54 U.S. clinics. After 24 weeks, maximal walking distance rose by a mean of 107 metres (54%) on cilostazol 100 mg twice daily, 64 metres (30%) on pentoxifylline and 65 metres (34%) on placebo. Cilostazol did better than both; pentoxifylline did no better than placebo. Deaths and serious adverse events were similar in the three groups.

Thompson 2002. A pooled analysis of 2,702 patients in eight placebo-controlled trials reported that cilostazol increased maximal walking distance by 50% and pain-free walking distance by 67%. The gain was similar in men and women, in people aged 65 and over and younger, and in people with and without diabetes. Headache, bowel complaints and palpitations were more common than on placebo.

The percentages in these trials sound large because people with claudication often start from short distances. The pooled reviews in the next section turn the results into metres.

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What the Pooled Reviews Found

The 2021 Cochrane review. Brown and colleagues pooled 16 double-blind randomized trials with 3,972 participants, treated for 6 to 26 weeks at doses of 100 to 300 mg a day. Compared with placebo:

The reviewers downgraded the certainty of every result by one level "because publication bias was strongly suspected," meaning trials with disappointing results may never have been published. Quality of life could not be pooled because the trials measured it in different ways; the reviewers describe only "a possible indication" of improvement. Too few trials reported amputation, operations to reopen arteries, or heart attacks and strokes for any conclusion on those outcomes.

Against pentoxifylline, the review found no clear difference in walking distance (pain-free distance 20.0 metres in favour of cilostazol, 95% confidence interval −2.57 to 42.57, one study; maximal distance 13.4 metres, 95% confidence interval −43.50 to 70.36, two studies), but headache was more common on cilostazol (odds ratio 2.20). This differs from the single Dawson trial above, which found cilostazol clearly better; the review rated the comparison as low to very low certainty.

The 2022 network meta-analysis. Liang and colleagues combined 29 randomized trials with 5,352 patients, including trials from Chinese databases, and compared cilostazol, pentoxifylline and beraprost. Against placebo, cilostazol increased maximal walking distance by 62.93 metres (95% confidence interval 44.06 to 81.79) and pain-free distance by 23.92 metres, and it ranked first of the three drugs for both.

Put in everyday terms, the pooled gain is roughly 25 to 60 metres of extra walking on a treadmill, on top of whatever placebo gave. Whether that is meaningful depends on the person. For someone who can manage 150 metres, it is a noticeable share. Supervised walking programmes, the main non-drug treatment, are described on the Peripheral Arterial Disease page.

The 2024 U.S. multisociety guideline for lower extremity peripheral artery disease, written for the American College of Cardiology and the American Heart Association with nine other societies, updated the 2016 recommendations with new evidence. Its abstract does not set out the rating for cilostazol; the full text was not available to this page and is not quoted here.

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Side Effects and Stopping Treatment

The label pools eight placebo-controlled trials (1,301 people on cilostazol, 973 on placebo, median treatment about four months). The most common reactions on 100 mg twice daily, compared with placebo, were:

Headache was the most frequent reason for stopping in those trials: 3.5% of people on 100 mg twice daily stopped because of it, against 0.3% on placebo. Palpitations and diarrhoea each led 1.1% of people on cilostazol to stop, against 0.1% on placebo.

Over longer periods, more people stopped. In the Dawson trial, 16% withdrew from cilostazol and 19% from pentoxifylline over 24 weeks. In the CASTLE long-term safety study (described in the next section), more than 60% of participants had stopped the study drug by 36 months; the study abstract reports this for the whole study and does not split it by drug.

A small British trial in people after a lacunar stroke (LACI-1, 57 participants) started cilostazol at a lower dose and raised it over two weeks. Most participants reached the full dose (64%) or more than half of it (87%). Headache and palpitations rose at first and then declined.

The label also lists reports received after approval, where frequency and cause cannot be measured. They include bleeding in the stomach and gut, lungs, skin and brain (intracranial, cerebral, extradural and subdural haemorrhage); aplastic anaemia, pancytopenia and other blood-count disorders; a heart-rhythm disorder called torsade de pointes and QTc prolongation in people with heart conditions such as complete heart block, heart failure or slow heart rhythm; liver dysfunction and jaundice; interstitial pneumonia; Stevens-Johnson syndrome; and rises in blood sugar, uric acid and blood pressure.

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The Heart-Failure Boxed Warning

Cilostazol carries a boxed warning, the strongest kind on a U.S. drug label. It reads: "Cilostazol tablets are contraindicated in patients with heart failure of any severity. Cilostazol and several of its metabolites are inhibitors of phosphodiesterase III. Several drugs with this pharmacologic effect have caused decreased survival compared to placebo in patients with class III-IV heart failure."

The warning is based on the drug family, not on a cilostazol trial in heart failure. One of the family trials is PROMISE, published in 1991. In 1,088 people with severe chronic heart failure, oral milrinone, another phosphodiesterase inhibitor, was linked with a 28% increase in deaths from all causes compared with placebo, a 34% increase in deaths from heart and vessel causes, and a 53% increase in deaths among those with the most severe symptoms. The researchers wrote that the mechanism "is unknown." The label applies the contraindication to heart failure "of any severity," wider than the class III-IV patients in whom the deaths were seen.

The CASTLE study. When cilostazol was approved, the FDA required a long-term safety study. CASTLE randomized 1,435 people with claudication and no heart failure to cilostazol or placebo. During time on treatment there were 18 deaths on cilostazol and 19 on placebo (hazard ratio 0.99, 95% confidence interval 0.52 to 1.88); heart and vessel deaths were 14 in each group. Serious bleeding affected 18 people on cilostazol and 22 on placebo. The authors found "no safety signal," but also wrote that the study was "underpowered to detect a small adverse impact" on survival. The label adds that the data appear to rule out a 75% increase in the risk of death, which was the study's starting hypothesis.

Later research. A Taiwanese national insurance study of 47,506 people with diabetes who were admitted for heart failure compared each person's drug use just before admission with an earlier period. Use of cilostazol was linked with higher odds of heart-failure admission (odds ratio 1.35, 95% confidence interval 1.14 to 1.59). This design shows an association, not cause. In the other direction, a 2025 U.S. crossover trial (CLIP-HFpEF) gave cilostazol or placebo for one-week periods to 23 people with heart failure with preserved ejection fraction, a form in which the heart pumps normally but fills stiffly. Health-status scores improved by 4.8 points and a heart-strain blood marker fell on cilostazol. This was a short, small study; it does not change the label, which still lists heart failure of any severity as a contraindication.

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Other Warnings and Contraindications on the Label

The label lists two contraindications: heart failure of any severity, and allergy to cilostazol or any ingredient of the tablets (for example anaphylaxis or angioedema, a swelling of the face, lips or throat).

Its warnings and precautions section reports:

On pregnancy, the label reports that cilostazol caused birth defects in rats at doses above five times the maximum human dose, and that there are no adequate studies in pregnant women. It passes into milk in rats, and the label states that either nursing or cilostazol is to be discontinued. Its safety and effectiveness in children have not been established. No dose change is listed for mild liver impairment or for kidney impairment; moderate and severe liver impairment and dialysis have not been studied. Smoking lowered cilostazol exposure by about 20% in a population analysis.

The label lists the expected signs of overdose as severe headache, diarrhoea, low blood pressure, fast heart rate and possibly abnormal heart rhythms.

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Drug Interactions and Dose Changes

Because the liver clears cilostazol mainly through cytochrome P450 3A4 and partly through cytochrome P450 2C19, medicines that block those enzymes raise the amount of cilostazol or its active products in the blood. The label sets a single rule for both groups: the dose is reduced to 50 mg twice daily when cilostazol is taken with strong or moderate cytochrome P450 3A4 blockers or with cytochrome P450 2C19 blockers.

The label's measured effects:

Other combinations the label reports: clopidogrel did not significantly raise cilostazol levels; cilostazol did not change how warfarin is broken down after a single warfarin dose; quinidine did not change cilostazol levels; and cilostazol raised lovastatin exposure by about 70%, which the label does not expect to be clinically significant. With aspirin, short-term use together increased the blocking of platelet clumping in the laboratory but did not change clotting tests or bleeding time compared with aspirin alone; the label states that the effects of long-term combined use in the general population are unknown.

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Stroke-Prevention Trials in Japan

All three of the large stroke trials below were run in Japan, in Japanese patients who had already had an ischaemic stroke (a stroke caused by a blocked artery, not by bleeding). The two larger, later trials were funded by the manufacturer. Stroke prevention is not an approved use in the United States. The Stroke page covers the condition itself.

The Cilostazol Stroke Prevention Study (published 2000). Researchers enrolled 1,095 people one to six months after a stroke between 1992 and 1996 and gave cilostazol 100 mg twice daily or placebo. Among 1,052 eligible patients, cilostazol was linked with a 41.7% relative reduction in repeat strokes (95% confidence interval 9.2% to 62.5%). The authors reported no clinically significant adverse drug reactions.

The second Cilostazol Stroke Prevention Study (published 2010). This double-blind trial at 278 Japanese sites compared cilostazol 100 mg twice daily with aspirin 81 mg once daily in 2,757 people aged 20 to 79 who had had a non-cardioembolic stroke (a stroke not caused by a clot travelling from the heart) within the previous 26 weeks. Over a mean of 29 months, any stroke occurred at a yearly rate of 2.76% on cilostazol and 3.71% on aspirin (hazard ratio 0.743, 95% confidence interval 0.564 to 0.981). Bleeding events (bleeding into or around the brain, or bleeding needing hospital admission) were fewer on cilostazol: 0.77% against 1.78% (hazard ratio 0.458). Headache, diarrhoea, palpitations, dizziness and fast heart rate were more frequent on cilostazol. The authors concluded that cilostazol "seems to be non-inferior, and might be superior" to aspirin. Aspirin's own record is set out on the Aspirin and Stroke Prevention page.

The Cilostazol Stroke Prevention Study for Antiplatelet Combination (published 2019). This open-label trial at 292 Japanese hospitals took 1,879 people with high-risk non-cardioembolic stroke, meaning a major artery narrowed by at least 50% or two or more vascular risk factors. Half stayed on aspirin or clopidogrel alone; half added cilostazol 100 mg twice daily. Over a median of 1.4 years, a repeat ischaemic stroke occurred in 29 of 932 people (3%) on the combination and 64 of 947 (7%) on one drug (hazard ratio 0.49, 95% confidence interval 0.31 to 0.76). Severe or life-threatening bleeding occurred in 8 and 13 people (hazard ratio 0.66, 95% confidence interval 0.27 to 1.60, not a significant difference). The trial was stopped at 1,884 of a planned 4,000 patients because recruitment was slow, and patients and doctors knew which treatment was given.

These results come from one country and one population. The authors of the 2020 review below note that most cilostazol stroke trials relate to Asia-Pacific patients.

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Stroke Research Outside Japan

The 2020 systematic review. McHutchison and colleagues in Edinburgh and Nottingham pooled 20 randomized trials with 10,505 people, 18 of them in ischaemic stroke; most were done in Asia-Pacific countries. Compared with placebo, aspirin or clopidogrel, cilostazol was linked with fewer repeat ischaemic strokes (odds ratio 0.68, 95% confidence interval 0.57 to 0.81), fewer haemorrhagic strokes (odds ratio 0.43), fewer deaths (odds ratio 0.64) and less bodily bleeding (odds ratio 0.73), but more headache and palpitations. The reduction was larger with treatment longer than six months and in trials where more than 40% of strokes were lacunar (small, deep strokes from diseased small arteries). The review describes cilostazol as used in Asia-Pacific countries for stroke prevention "but rarely used elsewhere," and calls for more trials in Western countries. Data were too thin to judge effects on thinking, brain scans, function or tolerance.

The Lacunar Intervention Trial-2 (LACI-2, United Kingdom, 2023). This open-label feasibility trial at 26 British stroke centres randomized 363 people after a lacunar stroke to isosorbide mononitrate, cilostazol 200 mg a day, both, or neither, on top of usual stroke-prevention care, for one year. Cilostazol alone did not significantly reduce the main combined outcome of vascular events, dependence, cognitive impairment and death (adjusted hazard ratio 0.77, 95% confidence interval 0.57 to 1.05). Cilostazol was linked with less dependence (adjusted hazard ratio 0.31). The two drugs together reduced the combined outcome (adjusted hazard ratio 0.58). The authors reported no safety concerns, and 257 of 272 people (94.5%) took at least half their allocated drug. They concluded that both drugs need testing in large phase 3 trials. The Vascular Dementia page covers the small-vessel disease behind lacunar strokes.

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What Is Not Known

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Key Research Papers

  1. Brown T, Forster RB, Cleanthis M, Mikhailidis DP, Stansby G, Stewart M. Cilostazol for intermittent claudication. Cochrane Database Syst Rev. 2021;6(6):CD003748. PubMed PMID: 34192807
  2. Dawson DL, Cutler BS, Hiatt WR, Hobson RW 2nd, Martin JD, Bortey EB, et al. A comparison of cilostazol and pentoxifylline for treating intermittent claudication. Am J Med. 2000;109(7):523-30. PubMed PMID: 11063952
  3. Strandness DE Jr, Dalman RL, Panian S, Rendell MS, Comp PC, Zhang P, et al. Effect of cilostazol in patients with intermittent claudication: a randomized, double-blind, placebo-controlled study. Vasc Endovascular Surg. 2002;36(2):83-91. PubMed PMID: 11951094
  4. Thompson PD, Zimet R, Forbes WP, Zhang P. Meta-analysis of results from eight randomized, placebo-controlled trials on the effect of cilostazol on patients with intermittent claudication. Am J Cardiol. 2002;90(12):1314-9. PubMed PMID: 12480040
  5. Liang X, Wang Y, Zhao C, Cao Y. Systematic review the efficacy and safety of cilostazol, pentoxifylline, beraprost in the treatment of intermittent claudication: A network meta-analysis. PLoS One. 2022;17(11):e0275392. PubMed PMID: 36318524
  6. Schrör K. The pharmacology of cilostazol. Diabetes Obes Metab. 2002;4 Suppl 2:S14-9. PubMed PMID: 12180353
  7. Hiatt WR, Money SR, Brass EP. Long-term safety of cilostazol in patients with peripheral artery disease: the CASTLE study (Cilostazol: A Study in Long-term Effects). J Vasc Surg. 2008;47(2):330-336. PubMed PMID: 18155871
  8. Packer M, Carver JR, Rodeheffer RJ, Ivanhoe RJ, DiBianco R, Zeldis SM, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991;325(21):1468-75. PubMed PMID: 1944425
  9. Wu CK, Lin JW, Wu LC, Chang CH. Risk of Heart Failure Hospitalization Associated With Cilostazol in Diabetes: A Nationwide Case-Crossover Study. Front Pharmacol. 2018;9:1467. PubMed PMID: 30666197
  10. Aiad N, du Fay de Lavallaz J, Zhang MJ, Chaikijurajai T, Ye B, Nijjar PS, et al. Cilostazol in patients with heart failure and preserved ejection fraction-The CLIP-HFpEF trial. ESC Heart Fail. 2025;12(2):1437-1446. PubMed PMID: 39552153
  11. Gotoh F, Tohgi H, Hirai S, Terashi A, Fukuuchi Y, Otomo E, et al. Cilostazol stroke prevention study: A placebo-controlled double-blind trial for secondary prevention of cerebral infarction. J Stroke Cerebrovasc Dis. 2000;9(4):147-57. PubMed PMID: 24192020
  12. Shinohara Y, Katayama Y, Uchiyama S, Yamaguchi T, Handa S, Matsuoka K, et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol. 2010;9(10):959-68. PubMed PMID: 20833591
  13. Toyoda K, Uchiyama S, Yamaguchi T, Easton JD, Kimura K, Hoshino H, et al. Dual antiplatelet therapy using cilostazol for secondary prevention in patients with high-risk ischaemic stroke in Japan: a multicentre, open-label, randomised controlled trial. Lancet Neurol. 2019;18(6):539-548. PubMed PMID: 31122494
  14. McHutchison C, Blair GW, Appleton JP, Chappell FM, Doubal F, Bath PM, et al. Cilostazol for Secondary Prevention of Stroke and Cognitive Decline: Systematic Review and Meta-Analysis. Stroke. 2020;51(8):2374-2385. PubMed PMID: 32646330
  15. Blair GW, Appleton JP, Flaherty K, Doubal F, Sprigg N, Dooley R, et al. Tolerability, safety and intermediary pharmacological effects of cilostazol and isosorbide mononitrate, alone and combined, in patients with lacunar ischaemic stroke: The LACunar Intervention-1 (LACI-1) trial, a randomised clinical trial. EClinicalMedicine. 2019;11:34-43. PubMed PMID: 31317131
  16. Wardlaw JM, Woodhouse LJ, Mhlanga II, Oatey K, Heye AK, Bamford J, et al. Isosorbide Mononitrate and Cilostazol Treatment in Patients With Symptomatic Cerebral Small Vessel Disease: The Lacunar Intervention Trial-2 (LACI-2) Randomized Clinical Trial. JAMA Neurol. 2023;80(7):682-692. PubMed PMID: 37222252
  17. Gornik HL, Aronow HD, Goodney PP, Arya S, Brewster LP, Byrd L, et al. 2024 ACC/AHA/AACVPR/APMA/ABC/SCAI/SVM/SVN/SVS/SIR/VESS Guideline for the Management of Lower Extremity Peripheral Artery Disease: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2024;149(24):e1313-e1410. PubMed PMID: 38743805
  18. U.S. Food and Drug Administration. Cilostazol tablets: prescribing information (generic, label version of September 2025). DailyMed. DailyMed label
  19. U.S. Food and Drug Administration. Drugs@FDA: New Drug Application 020863, original approval 15 January 1999. Drugs@FDA record

PubMed Topic Searches

  1. PubMed: cilostazol for intermittent claudication
  2. PubMed: cilostazol for secondary stroke prevention
  3. PubMed: cilostazol and heart failure
  4. PubMed: cilostazol drug interactions
  5. PubMed: cilostazol in lacunar stroke and small vessel disease

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