Deep venous thrombosis: rate of spontaneous lysis and thrombus extension.

AIM: Although recanalization occurs after an episode of venous thrombosis, the exact timing for this process, the rate of clearing at the different venous segments and the nature of the mechanisms involved and their progression are not well known. Recognition of these competing events is important in understanding the natural history and the mechanisms responsible for lysis of the thrombus and for the development of the post-thrombotic syndrome METHODS: During the course of 5 consecutive years, 110 patients (126 legs) with deep vein thrombosis (DVT) were prospectively followed using ultrasonic duplex. Follow-up studies were performed at intervals of 1 and 7 days, 1 month, every 3 months for the 1(st) year, and yearly thereafter. Mean duration of follow-up was 329 days. RESULTS: When only legs with initial complete occlusion are considered, the prevalence of occlusion progressively decreases to 33% after 6 months, 17% after the 1(st) year, and 0% after 3 years. Recanalization of individual segments occurred even more rapidly. After 3 months, recanalization of completely occluded segments was present in 93% of common femoral veins, 79% of superficial femoral veins (proximal segment), 84% of popliteal veins, and 72% of posterior tibial veins. The rate of recanalization was highest for multisegmental disease. Propagation of thrombi to adjacent venous segments occurred in 15% of the limbs. Propagation was usually limited to 1 or 2 adjacent segments. CONCLUSION: Lysis occurred early and was progressive. After 1 year most legs have recanalized. After 3 years recanalization occurred in all legs although residual thrombosis (partial obstruction) was still present in 50% of the limbs. Propagation of the thrombus was a limited process.

Clinical and duplex ultrasound follow-up after balloon angioplasty for atherosclerotic renal artery stenosis.

The purpose of this study was to investigate changes in blood pressure and renal function after percutaneous renal artery balloon angioplasty in hypertensive patients with atherosclerotic renal artery stenosis. Renal artery lesions were assessed by duplex ultrasound before and after renal artery balloon angioplasty. Renal arteries were classified as normal, < 60% stenosis, > or =60% stenosis, and occluded according to previously validated duplex criteria. Data regarding risk factors for atherosclerosis and years of hypertension were collected. Systolic and diastolic blood pressure, creatinine, and number of medications were obtained before and after intervention. The immediate technical outcome of renal artery angioplasty was classified based on the arteriographic result as follows: success (residual stenosis < or =30%), partial success (residual stenosis 31-50%), or unsuccessful (residual stenosis > 50%). For bilateral procedures, success required both renal arteries to be classified as technical successes; a technical success on one side only was classified as partial success. The blood pressure response to intervention was classified as follows: cure (diastolic blood pressure < or =95 mm Hg on no medications), improved (control of blood pressure with a significant reduction in number of medications or control of previously elevated blood pressure without a change in medications), or failed (all other responses). The study group included 28 patients (14 men, 14 women) with a mean age of 65 years. The preintervention and the first postintervention evaluations occurred within 180 days of the procedure. All patients were hypertensive, and all except one were under medical treatment. Mean duration of hypertension was 9.1 +/-8.8 years. There were 38 interventional procedures (28 unilateral, 10 bilateral) involving 41 renal arteries; seven arteries had two procedures done. Before angioplasty, all renal arteries had lesions of > or =60% diameter reduction by duplex scanning. Endovascular stents were deployed following angioplasty in 14 (34%) of the procedures. The technical result was classified as a success in 24 (63%), a partial success in 12 (32%) of the procedures, and two procedures (5%) were classed as technical failures. There were statistically significant reductions in blood pressure following successful and partially successful procedures, but cure of hypertension was achieved in only 11% of cases. There were no significant changes in creatinine in any of the technical result groups. Of the 38 renal arteries evaluated with duplex ultrasound following intervention, 39% were found to have stenosis of > or =0% involving a treated renal artery, including one postintervention occlusion. Cure of hypertension was rare in this patient population with atherosclerotic renal artery stenosis. More than one third of the treated renal arteries showed > or =0% lesions recurring after the procedure. Thirteen percent of those with technical success and 17% of those with partial technical success had creatinine improvement of at least 20% over the baseline value. Significant clinical and anatomic improvement were relatively uncommon following balloon angioplasty in this series of patients.

Screening for carotid disease and surveillance for carotid restenosis.

Duplex scanning is being used now to screen patients with suspected carotid artery disease, as the sole diagnostic test before carotid endarterectomy, and for follow-up surveillance after carotid surgery. Although the role of screening in patients with neurologic symptoms generally is accepted, noninvasive screening of asymptomatic patients remains controversial. The basic rationale for screening is to detect disease that can be treated to improve the patient's outcome. Although debate over the value of endarterectomy for asymptomatic carotid stenosis will continue, there is abundant evidence from natural history studies and clinical trials indicating that patients with asymptomatic high-grade (80% to 99% by duplex) stenoses can benefit from surgery if it can be performed with an acceptably low perioperative complication rate. Therefore, screening appears to be justified in patients with asymptomatic neck bruits and patients being evaluated for peripheral arterial or coronary artery disease. Those who are found to have moderate stenoses (50% to 79%) should be followed up at 6-month intervals to detect disease progression that may require surgery. Patients with less than 50% carotid stenoses can be followed up annually. Early restenosis is relatively common after carotid endarterectomy, occurring in about 20% of patients followed up with serial duplex scans, but it appears to have a benign natural history in the majority of patients. Reoperation is indicated only for symptomatic recurrent lesions and selected high-grade asymptomatic restenoses. An early postoperative surveillance examination is justified to provide a baseline study. The frequency of subsequent follow-up examinations will be determined by the status of the contralateral nonoperated carotid artery or the development of neurologic symptoms.

Measurement of abdominal aortic aneurysms with three-dimensional ultrasound imaging: preliminary report.

OBJECTIVE: Accurate measurements of abdominal aortic aneurysms (AAAs) are required for surgical planning and monitoring over time. We have examined the feasibility of using a three-dimensional (3-D) ultrasound imaging system to derive quantitative measurements of interest from AAAs. METHODS: A normal aorta, a small AAA, and an AAA repaired with an endovascular stent graft were scanned with a 3-D ultrasound imaging system. For each case, a 3-D surface reconstruction was generated from manual outlines of a sequence of two-dimensional ultrasound images, registered in 3-D space with a magnetic tracking system. The surfaces were resampled in planes perpendicular to the vessel center axis to calculate cross-sectional area and maximum diameter as a function of distance along the length of the aorta. RESULTS: Cross-sectional area and maximum diameter were plotted along the length of the aneurysmal aortas from the renal arteries to the aortic bifurcation. The overall maximum diameter was found for both aneurysms. For the small AAA, the distances of the aneurysm from the renal arteries and the bifurcation were measured. For the repaired AAA, the location of the stent graft relative to the renal arteries was measured. CONCLUSIONS: 3-D surface reconstructions from ultrasound images show promise for quantitatively characterizing the geometry of AAAs both before surgery and after endovascular repair.

Serial measurement of cross-sectional area in peripheral vein grafts using three-dimensional ultrasound.

Frequent surveillance of bypass grafts placed in the lower limbs can provide early detection of stenoses. A three-dimensional (3-D) ultrasound (US) imaging system has been used to produce serial surface reconstructions of regions of interest in vein grafts in the lower extremities. Using anatomical reference points, data sets from serial studies are registered in a common 3-D coordinate system. Cross-sectional area measurements are extracted from the surface reconstructions in planes normal to the vessel center axis. These measurements are compared at matched sites over time to track changes in the vessel configuration. The quantitative measurements are paired with surface displays of the vessels for a complete depiction of the changing geometry. Example studies from three patients are shown, for time periods up to 38 weeks. The cross-sectional area measurements highlight regions of remodeling and developing stenoses within the grafts.

Identification of factors predictive of lower extremity vein graft thrombosis.

OBJECTIVE: The objective of this study was to assess the prognostic value of hemodynamic parameters measured with duplex ultrasound scan, together with other important graft and patient characteristics, in predicting lower extremity vein graft thrombosis. METHODS: A total of 165 lower extremity vein grafts were entered prospectively into a postoperative duplex ultrasound scan surveillance program with examinations performed at 1, 2, 3, 4, 6, 9, 12, 18, and 24 months, and annually thereafter. Duplex scan-derived blood flow velocity measurements were recorded at 1562 patient visits over 7 years. Graft patency was determined after each visit, and an analysis of factors predictive of vein graft thrombosis was performed with Poisson regression. RESULTS: Thirty-two episodes of first-time graft thrombosis occurred, 23 of which were permanent. One-, 3-, and 5-year secondary graft patency rates were 90%, 86%, and 79%, respectively. In multivariate analyses, duplex scan velocity measurements predictive of lower extremity graft thrombosis included the maximum velocity ratio (Vr) in association with a graft stenosis and the mean graft peak systolic velocity (MGV) within nonstenotic portions of the body of the graft. The incidence of graft thrombosis among grafts without inflow/outflow stenoses, with Vr less than 3.5, and with MGV 50 cm/s or more, was 2.9% per year. Incidence rates were considerably higher among grafts with a of Vr of 3.5 or more (incidence rate ratio = 7.0; 95% CI, 3.4-14.6) or an MGV less than 50 cm/s (incidence rate ratio = 6.5; 95% CI, 3.3-13.1). In grafts without identifiable inflow, outflow, or graft stenoses, there was no association between MGV and the risk of graft thrombosis. CONCLUSION: Duplex scan velocity measurements are valid predictors of impending graft thrombosis. A Vr of 3.5 or more and an MGV less than 50 cm/s are the best predictive measures. Repair of correctable graft lesions with a Vr of 3.5 or more, or inflow, outflow, or graft lesions associated with an MGV less than 50 cm/s are recommended. Grafts without detectable inflow, outflow, or graft stenoses, regardless of MGV, may be safely followed.

Therapeutic thrombin injection of pseudoaneurysms: a multicenter experience.

The standard non-invasive treatment of pseudoaneurysms has been ultrasound-guided compression (UGC). Problems with UGC include pain at the site of compression, long compression times and incomplete closure. Each of these difficulties is exacerbated with large pseudoaneurysms. Recently, ultrasound-guided injection of pseudoaneurysms with thrombin has gained popularity. The goal of this study was to report a multicenter registry using this technique and in so doing detail the clinical utility and safety of this emerging procedure. The medical records of all patients diagnosed with pseudoaneurysm in the vascular laboratory who underwent thrombin injection over the past year were reviewed for patient characteristics and clinical outcome. There were 91 patients (55 male) with a mean age of 69 years. Three patients also had an arteriovenous fistula. The majority of patients were receiving one or more antiplatelet agents and/or anticoagulants. All patients underwent pseudoaneurysm injection with bovine thrombin. The mean aneurysm diameter was 3.3 cm, with a range of 1.5-6.3 cm. Successful thrombosis of the pseudoaneurysm was achieved in 89/91 (98%) of cases. Anticoagulation with heparin was used in one of the unsuccessful cases. In two cases, UGC was used to close a small active region that did not completely thrombose after thrombin injection. There were two patients who had recurrence of pseudoaneurysm the day after successful injection and thrombosis of the pseudoaneurysm. There were no local complications after injection; however, one patient suffered a pulmonary embolus that was thought to be unrelated to the procedure. In conclusion, thrombin injection for the treatment of pseudoaneurysms is safe and effective, even in patients receiving anticoagulation. This procedure should be considered as the initial therapeutic approach for peripheral pseudoaneurysms.

Cross-beam vector Doppler ultrasound for angle-independent velocity measurements.

Combining Doppler measurements taken along multiple intersecting ultrasound (US) beams is one approach to obtaining angle-independent velocity. Over 30 laboratories and companies have developed such cross-beam systems since the 1970s. Early designs focused on multiple single-element probes. In the late 1980s, combining multiple color Doppler images acquired from linear-array transducers became a popular modality. This was further expanded to include beam steering and the use of subapertures. Often, with each change in design, came a new twist to calculating the velocity. This article presents a review of most proposed cross-beam systems published to date. The emphasis is on the basic design, the approach used to determine the angle-independent velocity, the advantages of the design, and the disadvantages of the design. From this, requirements needed to convert the idea of angle-independent vector Doppler into a commercial system are suggested.

A comparison of cilostazol and pentoxifylline for treating intermittent claudication.

PURPOSE: We performed a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the relative efficacy and safety of cilostazol and pentoxifylline. PATIENTS AND METHODS: We enrolled patients with moderate-to-severe claudication from 54 outpatient vascular clinics, including sites at Air Force, Veterans Affairs, tertiary care, and university medical centers in the United States. Of 922 consenting patients, 698 met the inclusion criteria and were randomly assigned to blinded treatment with either cilostazol (100 mg orally twice a day), pentoxifylline (400 mg orally 3 times a day), or placebo. We measured maximal walking distance with constant-speed, variable-grade treadmill testing at baseline and at 4, 8, 12, 16, 20, and 24 weeks. RESULTS: Mean maximal walking distance of cilostazol-treated patients (n = 227) was significantly greater at every postbaseline visit compared with patients who received pentoxifylline (n = 232) or placebo (n = 239). After 24 weeks of treatment, mean maximal walking distance increased by a mean of 107 m (a mean percent increase of 54% from baseline) in the cilostazol group, significantly more than the 64-m improvement (a 30% mean percent increase) with pentoxifylline (P <0.001). The improvement with pentoxifylline was similar (P = 0.82) to that in the placebo group (65 m, a 34% mean percent increase). Deaths and serious adverse event rates were similar in each group. Side effects (including headache, palpitations, and diarrhea) were more common in the cilostazol-treated patients, but withdrawal rates were similar in the cilostazol (16%) and pentoxifylline (19%) groups. CONCLUSION: Cilostazol was significantly better than pentoxifylline or placebo for increasing walking distances in patients with intermittent claudication, but was associated with a greater frequency of minor side effects. Pentoxifylline and placebo had similar effects.

Doppler and ultrasound methods for diagnosis.

With the availability of ultrasonic duplex scanning we now have a method of safely screening those patients who may be thought to have renal artery stenosis as the basis for hypertension or renal failure. Modern instrumentation combined with an experienced technologist makes this a reasonable and accurate screening test. One of its major advantages is that it can be used for repeat studies to document the outcome of any form of intervention designed to remove or bypass areas of stenosis. We no longer need to wonder if a reconstruction has been successful or not. Another great advantage is its role in documenting both the degree of narrowing and its effect on kidney size. It is now known, because of information obtained with this technology, that high-grade renal artery stenoses are accompanied by a decrease in kidney size. It is also possible to document disease progression with atherosclerotic involvement of the renal arteries. With more widespread use of this method, we will be able to obtain useful information on how renal artery disease should be treated and monitored.

Markers of plasma coagulation and fibrinolysis after acute deep venous thrombosis.

OBJECTIVE: Plasma markers of coagulation and fibrinolysis have proved sensitive in the initial diagnosis of acute deep venous thrombosis (DVT). The purpose of this study was to examine the evolution and utility of measuring D-dimer and prothrombin fragment 1+2 (F 1+2) levels after an acute DVT. METHODS: Subjects with DVT confirmed by ultrasonography had quantitative plasma D-dimer and F 1+2 levels determined before anticoagulation. Ultrasound scan and coagulation studies were repeated at 3, 7, and 14 days; 1 month; and every 3 months for 1 year. RESULTS: Sixty-one patients with a median initial thrombus score of 3 (interquartile range, 2-7) were followed up for 266 days (interquartile range, 91.5-364 days). Initial D-dimer levels were elevated in 92.7% of patients and were associated with thrombus extent (P =.003), whereas F 1+2 levels were increased in 94.5% of patients and were lower in patients with isolated calf vein thrombosis (P =.001). Initial D-dimer (P =.002) and F 1+2 levels (P =.009) were significantly higher in the 26 (43%) patients with recurrent thrombosis during follow-up. Initial D-dimer levels of 2000 ng/mL or greater were predictive of recurrent events after both proximal and isolated calf vein thrombosis. Although interval increases in these markers had little value in detecting recurrent thrombotic events, D-dimer levels of 1000 ng/mL or greater and 500 ng/mL or greater had respective sensitivities of 89.3% and 100% in detecting early and late recurrences. Corresponding specificities were 35.6% and 53.9%. CONCLUSIONS: Initial D-dimer levels are determined by total thrombus load and remain elevated long after an acute DVT. F 1+2 levels are less sensitive to thrombus score and return to baseline more quickly. Initial levels of these markers may have some utility in predicting the risk of ultrasound scan-documented recurrences, whereas increased D-dimer levels are a sensitive but nonspecific marker of these events.

Deep venous thrombosis and superficial venous reflux.

OBJECTIVE: Although superficial venous reflux is an important determinant of post-thrombotic skin changes, the origin of this reflux is unknown. The purpose of this study was to evaluate the frequency and etiologic mechanisms of superficial venous reflux after acute deep venous thrombosis (DVT). METHODS: Patients with a documented acute lower extremity DVT were asked to return for serial venous duplex ultrasound examinations at 1 day, 1 week, 1 month, every 3 months for the first year, and every year thereafter. Reflux in the greater saphenous vein (GSV) and lesser saphenous vein (LSV) was assessed by standing distal pneumatic cuff deflation. RESULTS: Sixty-six patients with a DVT in 69 lower extremities were followed up for a mean of 48 (SD +/- 32) months. Initial thrombosis of the GSV was noted in 15 limbs (21.7%). At 8 years, the cumulative incidence of GSV reflux was 77.1% (SE +/- 0.11) in DVT limbs with GSV involvement, 28.9% (+/- 0.09%) in DVT limbs without GSV thrombosis, and 14.8% (+/- 0.05) in uninvolved contralateral limbs (P <.0001). For LSV reflux, the cumulative incidence in DVT limbs was 23.1% (+/- 0.06%) in comparison with 10% (+/- 0.06%) in uninvolved limbs (P =.06). In comparison with uninvolved contralateral limbs, the relative risk of GSV reflux for DVT limbs with and without GSV thrombosis was 8.7 (P <.001) and 1.4 (P =.5), respectively. The relative risk of LSV reflux in thrombosed extremities compared with uninvolved extremities was 3.2 (P =.07). Despite these observations, the fraction of observed GSV reflux that could be attributable to superficial thrombosis was only 49%. CONCLUSIONS: Superficial venous thrombosis frequently accompanies DVT and is associated with development of superficial reflux in most limbs. However, a substantial proportion of observed reflux is not directly associated with thrombosis and develops at a rate equivalent to that in uninvolved limbs.

Effect of metoprolol and verapamil administered separately and concurrently after single doses on liver blood flow and drug disposition.

Nine healthy males participated in a double-blind, placebo-controlled, randomized, crossover study to determine the effects of verapamil and metoprolol administered alone and concurrently on blood flow through the hepatic artery and portal and hepatic veins and to detect a possible drug interaction between the two agents. Single oral doses of placebo/placebo, metoprolol (50 mg)/placebo, verapamil (80 mg)/placebo, or verapamil/metoprolol were separated by at least 14 days. Liver blood flow through individual hepatic vessels was measured up to 8 hours after dosage administration using a duplex Doppler ultrasound technique. Cardiac output, heart rate, blood pressure, stroke volume, and total peripheral resistance were measured for 3 hours after drug doses were given. In 5 subjects, pharmacokinetic parameters for total drug as well as S- and R-enantiomers were also measured. Verapamil given alone caused a rapid and intense increase in liver blood flow (hepatic artery = 50%, portal vein = 42%, hepatic vein = 55%) 0.75 to 1 hour after administration because of a decrease in total peripheral resistance and an increase in heart rate, stroke volume, and cardiac output. Metoprolol given alone caused a slow but prolonged decrease in liver blood flow (maximum decrease: hepatic artery = -54%, portal vein = -21%, hepatic vein = -27%) 4 hours after administration because of a decrease in heart rate and cardiac output. When the two agents were given together, a composite of the changes noted after separate administration was noted: a brief peak increase in liver blood flow at 0.33 to 1 hour followed by a slow, prolonged decrease that reached its maximum decline 4 to 5 hours postdose. During the combined phase, metoprolol and its enantiomers had an increased AUC and Cmax, while verapamil and its enantiomers had an increased AUC and t1/2. These pharmacokinetic changes were consistent with the magnitude and time course of liver blood flow changes through the hepatic artery and portal or hepatic veins.

Pharmacokinetics of diclofenac sodium in chronic active hepatitis and alcoholic cirrhosis.

The objective of this study was to assess the pharmacokinetics of diclofenac sodium and its five metabolites following administration of a 150 mg oral dose to healthy subjects and patients with either chronic active hepatitis of varying morphology or alcoholic cirrhosis. Six healthy subjects, 6 chronic active hepatitis patients, and 6 alcoholic cirrhosis patients were enrolled in this prospective, open-label, parallel study. Blood samples were drawn at 0, 0.25, 0.5, 0.75, 1, 2, 4, 6, 8, 12, 24, 48, 72, 144, 312, and 480 hours, and urine samples were collected for 144 hours after administration of a single oral dose of diclofenac sodium. The mean area under the serum concentration-time curve extrapolated to infinity, oral clearance, half-life, maximal concentration, and time to peak concentration for diclofenac and its metabolites were determined and compared using analysis of variance. Cirrhotics had a mean +/- SD diclofenac AUC value (19,114 +/- 6806 ng.h/ml) significantly different (p < 0.02) from hepatitis patients (6071 +/- 1867 ng.h/ml) and healthy subjects (7008 +/- 2006 ng.h/ml), whereas healthy subjects and hepatitis patients had similar values. Comparable results were found for 4'-hydroxydiclofenac. The AUC values for 3'-hydroxydiclofenac and 3'-hydroxy-4'methoxydiclofeanc were significantly different when healthy subjects were compared to cirrhotics. However, hepatitis subjects were not significantly different from either group. The results indicate that hepatitis does not alter the pharmacokinetics of diclofenac. Alcoholic cirrhosis increased the mean diclofenac AUC approximately three times compared to normal subjects, indicating that one-third of the usual dose in cirrhotics would produce equivalent AUC values in normal subjects and subjects with alcoholic cirrhosis. However, since pharmacodynamic measurements were not made and no increase in untoward or side effects was noted in the alcoholic cirrhosis patients after a single dose, maintenance doses should be titrated to patients response.

New ultrasound approaches to dialysis access monitoring.

The failure of dialysis access is a frequent source of morbidity and hospitalization. Traditional methods of graft surveillance include: (1) clinical examination, (2) venous line pressure measurements during dialysis, (3) urea or tracer recirculation measurement, (4) continuous wave (CW) Doppler methods, (5) duplex ultrasonography, and (6) radiograph angiography. All these methods require special training and/or laboratory tests. The purpose of this study was to test a simple continuous-wave Doppler method that could be applied to measure the flow rate in dialysis access every time the patient undergoes dialysis. Twenty dialysis patients, 15 with polytetrafluoroethylene grafts and 5 with arteriovenous fistulae, were studied. Two hundred fifty-three examinations were performed over an 8-month period. Doppler waveforms of the access flow were obtained with the pump on, with the pump off, and with the pump on again. Systolic and diastolic Doppler frequency measurements were made, and the pump-on and pump-off measurements were compared. In an access functioning normally, the Doppler frequencies are higher with the pump off than with the pump on. In 22% of the cases, there were abnormal findings in which the Doppler frequencies were lower with the pump off than with the pump on. This occurs if the needles are incorrectly placed, suggesting that recirculation is occurring. Recirculation also occurs if there is stenosis of the access. Examining the hemodialysis access during each dialysis session with an inexpensive directional Doppler may identify a significant stenosis and improve the efficiency of dialysis by detecting those patients in whom the arterial and venous needles are reversed.

A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial.

BACKGROUND: Effective medication is limited for the relief of intermittent claudication, a common manifestation of arterial occlusive disease. Cilostazol is a potent inhibitor of platelet aggregation with vasodilation effects. OBJECTIVE: To evaluate the safety and efficacy of cilostazol for the treatment of intermittent claudication. METHODS: Thirty-seven outpatient vascular medicine clinics at regional tertiary and university hospitals in the United States participated in this multicenter, randomized, double-blind, placebo-controlled, parallel trial. Of the 663 screened volunteer patients with leg discomfort, a total of 516 men and women 40 years or older with a diagnosis of moderately severe chronic, stable, symptomatic intermittent claudication were randomized to receive cilostazol, 100 mg, cilostazol, 50 mg, or placebo twice a day orally for 24 weeks. Outcome measures included pain-free and maximal walking distances via treadmill testing, patient-based quality-of-life measures, global assessments by patient and physician, and cardiovascular morbidity and all-cause mortality survival analysis. RESULTS: The clinical and statistical superiority of active treatment over placebo was evident as early as week 4, with continued improvement at all subsequent time points. After 24 weeks, patients who received cilostazol, 100 mg, twice a day had a 51% geometric mean improvement in maximal walking distance (P<.001 vs placebo); those who received cilostazol, 50 mg, twice a day had a 38% geometric mean improvement in maximal walking distance (P<.001 vs placebo). These percentages translate into an arithmetic mean increase in distance walked, from 129.7 m at baseline to 258.8 m at week 24 for the cilostazol, 100 mg, group, and from 131.5 to 198.8 m for the cilostazol, 50 mg, group. Geometric mean change for pain-free walking distance increased by 59% (P<.001) and 48% (P<.001), respectively, in the cilostazol, 100 mg, and cilostazol, 50 mg, groups. These results were corroborated by the results of subjective quality-of-life assessments, functional status, and global evaluations. Headache, abnormal stool samples or diarrhea, dizziness, and palpitations were the most commonly reported potentially drug-related adverse events and were self-limited. A total of 75 patients (14.5%) withdrew because of any adverse event, which was equally distributed between all 3 treatment groups. Similarly, there were no differences between groups in the incidence of combined cardiovascular morbidity or all-cause mortality. CONCLUSION: Compared with placebo, long-term use of cilostazol, 100 mg or 50 mg, twice a day significantly improves walking distances in patients with intermittent claudication.