Bruce S. Cutler

Pentoxifylline efficacy in the treatment of intermittent claudication: Multicenter controlled double-blind trial with objective assessment of chronic occlusive arterial disease patients

The efficacy, safety, and tolerance of pentoxifylline (Trental, Hoechst-Roussel Pharmaceuticals, Inc.) in the treatment of intermittent claudication associated with chronic occlusive arterial disease (COAD) were evaluated in a double-blind, placebo-controlled, parallel-group, multicenter clinical trial involving a total of 128 outpatients. The response to treatment was ascertained at regular intervals during the trial by measuring the distance walked prior to the onset of claudication when patients were subjected to a standardized treadmill test. Pentoxifylline given orally in doses up to 1200 mg/day was significantly more effective than placebo in increasing both the initial and absolute claudication distances in patients with COAD. Reduction of lower limb paresthesias also suggested greater clinical improvement in the pentoxifylline treated patients. These results support the hypothesis that pentoxifylline reduces blood viscosity by improving red cell flexibility, and thereby enhances blood flow in patients with COAD. White the precise mode of therapeutic action requires clarification, pentoxifylline was well tolerated with minimal unwanted effects.

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.

Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease

PURPOSE This study evaluated the effects of cilostazol on walking distances in patients with intermittent claudication (IC) caused by peripheral arterial occlusive disease. METHODS The study was a multicenter, randomized, double-blind, placebo-controlled trial. Two hundred thirty-nine patients with IC were randomly assigned to receive cilostazol (100 mg b.i.d.) or a placebo for 16 weeks. All patients underwent serial, variable-grade, constant-speed treadmill testing. Absolute claudication distance (ACD), assessed at the end of the 12-hour dosing interval (trough), was the primary end point. Secondary end points included ACD assessed 3 to 4 hours after dosing (peak) and initial claudication distances (trough and peak). Functional status measures, including the Medical Outcomes Scale (SF-36) and Walking Impairment Questionnaire, were used to assess subjective changes over the 16-week treatment period. Ankle-brachial indexes were calculated from Doppler-measured systolic pressures at every visit with treadmill testing. RESULTS Patients treated with cilostazol demonstrated significant improvements over the placebo patients in ACD at all three time points tested after baseline (weeks 8, 12, and 16). Peak treadmill testing at weeks 8 and 12 also showed significant improvement in walking distances for cilostazol-treated patients over placebo-treated patients. At week 16, patients in the cilostazol group had a 96.4-meter (47%) increase in ACD compared with 31.4 meters (12.9%) for the placebo group (p < 0.001). In the SF-36, significant improvement was observed in the physical component subscale and the composite physical component score. In the Walking Impairment Questionnaire, improvements were significant in patient reports of walking speed and specific measures of walking difficulty. Ankle-brachial indexes improved in the cilostazol group (0.64 +/- 0.02 to 0.70 +/- 0.02) compared with the placebo group (0.68 +/- 0.02 to 0.69 +/- 0.02) (p < 0.0125). The most frequent adverse events were headache, abnormal stools (e.g. loose stools), diarrhea, and dizziness. CONCLUSIONS Cilostazol significantly increased ACD at all measured time points and initial claudication distances at most time points. This agent may represent a new treatment option for patients with intermittent claudication.

Noninvasive evaluation of cardiac risk before elective vascular surgery.

The prognostic utility for predicting cardiac events was determined for dipyridamole-thallium scintigraphy, exercise stress testing (when possible; n = 69) and multiple clinical variables in 100 consecutive patients admitted for elective surgical repair of peripheral vascular disease. After initial noninvasive evaluation, 11 patients were referred for coronary angiography and the remaining 89 patients had surgery without further cardiac studies. Fifteen patients (17%) had a postoperative myocardial infarction, one of which was fatal. Of these 15 patients, 14 had thallium redistribution and 3 had positive ST segment depression during stress testing. Among the many variables tested, the presence of redistribution on serial dipyridamole-thallium images was the most significant predictor of serious cardiac events. All 11 patients who had coronary angiography had both redistribution and multivessel coronary artery disease. Four of these 11 patients died during follow-up and 6 had coronary artery bypass surgery. It is concluded that dipyridamole-thallium imaging has significant prognostic utility in predicting postoperative myocardial infarction and death in patients with severe peripheral vascular disease, and is superior to exercise testing or clinical variables in determining cardiac risk. The odds for a serious cardiac event were 23 times greater in a patient with thallium redistribution than in a patient without redistribution, strongly suggesting that myocardial imaging may be used as a primary screening test before elective vascular surgery.

Dipyridamole thallium 201 scintigraphy to detect coronary artery disease before abdominal aortic surgery

Dipyridamole thallium 201 scintigraphy (DTS) was used to screen 116 consecutive patients referred for aortic reconstructive surgery for coronary artery disease (CAD). Thallium redistribution was found to have the best statistical correlation with postoperative myocardial infarction (MI). No MIs occurred after aortic operations among 60 patients with normal scans compared with 8 of 31 patients with abnormal ones. The odds of a patient with abnormalities found by DTS having a postoperative MI were 12 times greater than for those with a normal scan. No symptom or combination of symptoms of CAD was as good as an abnormal DTS in identifying patients at risk. The incidence of MI was 7.0% for patients with symptomatic CAD and 8.5% for those who were asymptomatic. Cardiac complications gradually declined as surgeons gained confidence in the use of DTS, to the point where no postoperative MIs occurred during the final year of the study. DTS approaches the ideal preoperative test for CAD in patients with peripheral vascular disease. The test does not require exercise, is minimally invasive, safe, and of sufficient sensitivity to detect myocardial ischemia in the absence of symptoms. Furthermore, it is cost-effective; only those patients with an abnormal scan and an imperative need for aortic surgical treatment need further cardiac evaluation.

Comparative early and late cardiac morbidity among patients requiring different vascular surgery procedures

PURPOSE The evaluation of coronary artery disease (CAD) in patients undergoing vascular surgery can provide information with respect to perioperative and long-term risk for CAD-related events. However, the extent to which the required surgical procedure itself imparts additional risk beyond that dictated by the presence of CAD determinants remains in question. The purpose of this study was to quantify the relative contributions of specific vascular procedures and CAD markers on perioperative and long-term cardiac risk. METHODS The study cohort comprised 547 patients undergoing vascular surgery from two medical centers who underwent clinical evaluation, dipyridamole thallium testing, and either aortic (n = 321), infrainguinal (n = 177), or carotid (n = 49) vascular surgery between 1984 and 1991. Perioperative and late cardiac risk of fatal or nonfatal myocardial infarction (MI) was compared for the three procedures before and after adjustment for the influence of comorbid factors. These adjusted estimates may be regarded as the component of risk because of type of surgery. RESULTS Perioperative MI occurred in 6% of patients undergoing aortic and carotid artery surgery, and in 13% of patients undergoing infrainguinal procedures (p = 0.019). Significant (p < 0.05) predictors of MI were history of angina, fixed and reversible dipyridamole thallium defects, and ischemic ST depression during testing. Although patients undergoing infrainguinal procedures exhibited more than twice the risk for perioperative MI compared with patients undergoing aortic surgery (relative risk: 2.4[1.2 to 4.5, p = 0.008]), this value was reduced to insignificant levels (1.6[0.8 to 3.2, p = 0.189]) after adjustment for comorbid factors. There was little change in comparative risk between carotid artery and aortic procedures before (1.0[0.3 to 3.6, p = 0.95]) or after (0.6[0.2 to 2.3, p = 0.4]) covariate adjustment. The 4-year cumulative event-free survival rate was 90% +/- 2% for aortic, 74% +/- 5% for infrainguinal, and 78% +/- 7% for carotid artery procedures (p = 0.0001). Predictors of late MI included history of angina, congestive heart failure, diabetes, fixed dipyridamole thallium defects, and perioperative MI. Patients undergoing infrainguinal procedures exhibited a threefold greater risk for late events compared with patients undergoing aortic procedures (relative risk: 3.0[1.8 to 5.1, p = 0.005]), but this value was reduced to 1.3(0.8 to 2.3, p = 0.32) after adjustment. Long-term risk among patients undergoing carotid artery surgery was less dramatically altered by risk factor adjustment. CONCLUSION In current practice, among patients referred for dipyridamole testing before operation, observed differences in cardiac risk of vascular surgery procedures may be primarily attributable to readily identifiable CAD risk factors rather than to the specific type of vascular surgery. Thus the cardiac and diabetic status of patients should be given careful consideration whenever possible, regardless of surgical procedure to be performed.

Applicability and interpretation of electrocardiographic stress testing in patients with peripheral vascular disease

Abstract Electrocardiographically monitored arterial stress testing was performed before surgery in 130 patients with peripheral vascular disease. When limitations of claudication or pain at rest precluded treadmill exercise, arm ergometry was employed. The electrocardiographically monitored arterial stress test proved a cost-effective, easily applicable means of screening for coronary artery disease in this group of patients. Unlike statistical analyses of historical risk factors, the electrocardiographically monitored arterial stress test evaluates the current functional state of the myocardium. We believe that preoperative electrocardiographic exercise testing should be employed more widely and should be considered in any patient facing major surgery in whom coronary artery disease is suspected on the basis of past history or known risk factors. In patients who have an ischemic response to exercise, particularly at less than 75 percent of the maximum predicted heart rate, coronary angiography and possibly coronary revascularization should be considered before elective major surgery is performed.

Results of a multicenter study of the modified hook-titanium Greenfield filter

Initial efforts to modify the stainless steel Greenfield filter for percutaneous insertion led to development of a titanium Greenfield filter, which could be inserted by use of a 12F carrier. This device functioned well as a filter but had an unacceptable 30% rate of migration, tilting, and penetration. Therefore a titanium Greenfield filter with modified hooks was developed and has been tested in 186 patients at 10 institutions. Successful placement occurred in 181 (97%); placement of the remainder was precluded by unfavorable anatomy. A contraindication to anticoagulation was the most frequent indication for insertion (75%). All but two were inserted percutaneously, predominantly via the right femoral vein (70%). Initial incomplete opening was seen in four patients (2%), which was corrected by guide wire manipulation and asymmetry of the legs in 10 (5.4%). Insertion site hematoma occurred in one patient, and apical penetration of the cava during insertion occurred in a second patient. Both events were without sequelae. Follow-up examinations were performed at 30 days at which time 35 deaths had occurred. Recurrent embolism was suspected in six patients (3%) and two of three deaths were confirmed by autopsy. Filter movement greater than 9 mm was seen in 13 patients, (11%) and increase in base diameter greater than or equal to 5 mm was seen in 17 patients (14%). CT scanning showed evidence of caval penetration in only one patient (0.8%). Insertion site venous thrombosis was seen in 4/46 (8.7%) patients screened. The modified hook titanium Greenfield filter is inserted percutaneously or operatively through a sheath, eliminating concern for misplacement from premature discharge.(ABSTRACT TRUNCATED AT 250 WORDS)

Prediction of late cardiac events by dipyridamole thallium imaging in patients undergoing elective vascular surgery

Dipyridamole thallium scintigraphy has previously been shown to have prognostic value in the preoperative assessment of patients scheduled to undergo vascular surgery, but its effect on the long-term outcome is less well-defined. In the largest series to date, dipyridamole thallium scanning was performed in 360 patients before elective vascular surgery and survivors were followed for a mean of 31 months. In the 327 patients who underwent vascular surgery, operative death and nonfatal myocardial infarction occurred in 4.9 and 6.7%, respectively. A cardiac event (nonfatal myocardial infarction or cardiac death) occurred in 14.4% of patients with a transient thallium defect, as opposed to 1% with a normal scan (p < 0.001). Logistic regression analysis revealed that the best predictor of a perioperative event was the presence of a reversible thallium defect, elevating the risk by 4.3-fold. Late cardiac events occurred in 53 (15.2%) surgical survivors or nonsurgically treated patients. Patients with a fixed perfusion abnormality had a 24% late event rate, compared with 4.9% in those with a normal dipyridamole thallium study (p < 0.01). Cox analysis demonstrated that a fixed thallium defect was the strongest factor for predicting a late event and increased the relative risk by almost fivefold. A history of congestive heart failure was the only significant variable that contributed additional value to that of a fixed defect alone. Life-table analysis confirmed the strong relation of a fixed defect to cardiac event free survival (p < 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)

Asymptomatic deep venous thrombosis in the trauma patient: Is an aggressive screening protocol justified?

The incidence and sequelae of deep venous thrombosis (DVT) in trauma patients are unclear because the majority of patients who develop DVT are asymptomatic. This study evaluated the incidence, risk factors, and efficacy of prophylaxis for DVT in trauma patients over a 5-year period. Trauma patients at high risk for DVT were evaluated biweekly with lower extremity venous duplex scans. The DVT prophylaxis was instituted on admission with low-dose heparin therapy and pneumatic compression. The incidence of asymptomatic DVT identified by duplex screening was 10% (45 of 458); one pulmonary embolus occurred. Five variables were significant from bivariate and multiple logistic regression analysis: age (p = 0.005), Injury Severity Score (p = 0.005), length of stay (p = 0.004), Trauma and Injury Severity Score (p = 0.01), and spinal injury (p = 0.014). This analysis documents that trauma patients with these risk factors are at increased risk for the development of asymptomatic DVT, despite prophylaxis, and warrant surveillance with venous duplex sonography.