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Surgery or Balloon Angioplasty for Peripheral Vascular Disease: A Randomized Clinical Trial
Vascular Inte~ention
Surgery or Balloon Angioplasty for Peripheral Vascular Disease: A ~and6mized Clinical Trial1 Gerald L. Wolf, PhD, MD Samuel E. Wilson, MD Anne P. Cross, PhD Robert H. Deupree, PhD William B. Stason, MD, MS and the Principal Investigators and their Associates of Veterans Administration Cooperative Study Number 199 Index terms: Arteries, surgery, 92.452, 984,452,986,452 Arteries, transluminal angioplasty, 92.1282, 984,1282,986.1282
JVIR 1993;4:639-648 Abbreviations: ABI = ankle-brachial index, BIRLS = beneficiary identification and records locator subsystem, BP = bypass surgery, PTA = percutaneous transluminal angioplasty, SIP = Sickness Impact Profile, VAMC = Veterans Administrative Medical Center
PURPOSE: Surgical revascularization and angioplasty (PTA)are effective therapies for patients with peripheral arterial disease, but there are no data on long-term survival, limb salvage, and hemodynamic status from a randomized study of such patients. A multicenter, prospective trial compared PTA with bypass surgery (BP) in 263 men who had iliac, femoral, or popliteal artery obstruction. PATIENTS AND METHODS: Lesions in the iliac versus the femoropopliteal artery and rest pain versus claudication were separately randomized to the two treatment interventions. One hundred twenty-sixpatients underwent BP, 129 patients underwent PTA, and eight patients were not treated for lower extremity ischemia. RESULTS: Three operative deaths occurred in the BP group and none in the PTA group. For the entire study, average annual mortality was higher in the BP group, but survival was not significantly different on life-tableanalysis (P = .O8). Primary success favored BP, while limb salvage favored PTA, but differences were not statistically significant (P = .O8 and .35, respectively). Patients with iliac disease or claudication fared better, but there was no statistical difference in response to PTA or BP. CONCLUSION: Patients in both treatment groups had prompt and sustained increases in hemodynamics and quality of life. This study of patients randomly assigned to BP or PTA shows no significant difference in outcomes during a median follow-upof 4 years.
transluminal angioplasty (PTA), conceived by Dotter almost 30 years ago and made practical by Gruntzig in 1975, has a widely accepted role in the treatment of peripheral vascular occlusive disease (1-9). Angiographic guidelines are generally accepted with regard to descriptions of lesions likely to respond to PTA. For example, iliac lesions and shorter stenoses are considered more remediable than femoral lesions and longer occlusions. On the other hand, bypass surgery (BP) has been the standard for treatment of moderate to severe peripheral arterial disease for more than 30 years (10-17). No randomized clinical trial has compared the results and durability of PTA with those of BP performed for these occlusions. This study was designed in 1983 PEncuTANEous
' From the Center for Imaging and Pharmaceutical Research and the Department of Radiology, Harvard University, Massachusetts General Hospital, 149 13th St, Charlestown, MA 02129-2060 (G.L.W.); Department of Surgery, University of California, Irvine (S.E.W.);Department of Biostatistics, Bristol-Myers-Squibb (A.P.C.) Wallingford, Conn; Biostatistics, Cooperative Studies Program Coordinating Center, West Haven Veterans Administration Medical Center, Conn (R.H.D.); Health Economics Research, Waltham, Mass (W.B.S.). Received November 2, 1992; revision requested February 1, 1993; revision received March 2; accepted March 8. Supported by the Cooperative Studies Program of the Medical Research Service, Department of Veteran Affairs Central Office, Washington, DC. Address reprint requests to G.L.W. " SCVIR, 1993
under the auspices of the Department of Veterans Affairs Cooperative Studies Program to compare the hemodynamic results, complicatioris, longterm patency, amputation rate, and mortality in patients randomly assigned to treatment with either PTA or BP. An interim report published earlier (18) had incomplete follow-up, utilized different measures of success, and found some statistically significant differences favoring BP that were not evident a t the end of the study. The interim report also did not include the hemodynamic or qualityof-life outcomes or a n analysis of risk factors predicting incomplete revascularization. This report summarizes the experimental design and major clinical findings after a median follow-up of approximately 4 years.
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METHODS Eligibility Male patients with symptomatic peripheral arterial disease were screened for disease amenable to treatment with either PTA or BP by means of complete physical examination, ankle-brachial index (ABI), laboratory tests, and peripheral angiography. Vascular anatomy from the infrarenal aorta to below the trifurcation of the popliteal artery at midcalf was examined with angiography in the anteroposterior projection as well as at least one oblique projection of the iliac arteries and the femoral bifurcation. At the completion of the work-up, the anatomic and physiologic data were independently reviewed by the radiologist and the vascular surgeon to identify the single lesion considered to be the principal cause of the patient's symptoms and to determine whether this lesion was suitable for treatment by means of PTA and BP. Inclusion criteria were as follows: (a)angiographic demonstration of at least 80% diameter stenosis or a total occlusion of the iliac, femoral, or popliteal artery less than 10 cm long; (b) ABI of less than 0.90 at rest; (c)intermittent claudication when walking less than two blocks with rest pain or impending gangrene; and (d)agreement by the radiologist and surgeon that the patient was an acceptable candidate for either procedure. Thus, these patients had chronic limb ischemia of category 2-5 according to the criteria of the Society for Vascular Surgery and the International Society of Cardiovascular Surgery (19). Exclusion criteria were as follows: (a) patient already scheduled for major amputation; (b)emergency surgery contemplated; ( c ) short-term heparin or long-term antiplatelet therapy contraindicated; ( d )life expectancy less than 3 years due to comorbidity; (el patients unlikely to be available for follow-up due to personality, mental health, or geographic distance from a participating Veter-
ans Administration Medical Center (VAMC); ( f )patient not a candidate for BP or PTA; ( g )patient or physician refuses randomized intervention choice; or ( h )patient is female. Eight VAMCs began the study in June 1983, but two were dropped due to low patient accession and were replaced by a better performing VAMC in March 1985. All eligible patients were invited to participate in the study. The subjects consented both to randomized treatment assignment and to follow-up angiography 3 years after intervention and were informed of their right to withdraw at any time without prejudice. About 60% of the patients who met the eligibility criteria consented to participate, and a total of 263 men were enrolled in the study between June 1,1983, and July 31, 1987.
Randomization After consent was obtained, the participating hospital contacted the study biostatistician by phone for treatment assimment. Randomization was stratized by center and for each of four disease categories: iliac disease with claudication, iliac disease with rest pain, femoropopliteal disease with claudication, or femoropopliteal disease with rest pain. Impending gangrene or limb threat was considered to be a rest-pain equivalent for randomization purposes. This produced a 2 x 2 x 2 factorial randomization scheme (PTA vs BP, iliac vs femoropopliteal disease, claudication vs rest pain) within each medical center. All patients were followed up until conclusion of the study on July 31,1989. Of the 263 consenting patients, 133 were randomly assigned to surgery and 130 to PTA. Eleven patients did not receive the assigned treatment. While awaiting their intervention, six patients assigned to surgery suffered an intervening event that precluded surgery. One patient assigned to surgery refused any intervention, and another insisted on PTA. One patient assigned to surgery did not have a significant pressure gradient across his arterial lesion and
received no treatment. Two patients assigned to PTA refused and underwent surgery. These changes resulted in 126 patients who underwent surgery, 129 patients who underwent PTA, and eight patients who were not treated for lower extremity ischemia.
Intervention All participating centers had surgeons experienced in operations for iliac and femoropopliteal disease and radiologists who had performed at least 20 peripheral PTA procedures prior to the study. In general, the techniques and performance of the intervention were left to the discretion of the physicians at each site. Prophylactic antibiotics and intraoperative heparinization were suggested for surgical patients, and administration of 5,000 U of intravenous heparin was suggested for those undergoing PTA after the lesion had been crossed. All centers were affiliated with universities and residents and fellows participated in the care of these patients according to local policies. Each subject was randomized based on the principal lesion in a designated artery. However, many patients had additional lesions in the ipsilateral or contralateral leg. Only the intervention for the study lesion was randomized; all other interventions were performed according to the judgment of the clinical team and the consent of the patient.
Follow-upand Outcome Measures At each participating hospital, a full-time nurse clinician recorded the patient data at entry and at intervals up to 6 years after randomization. The qualifying angiogram, a postangioplasty image, and representative angiograms obtained to document the status of the study lesion were coded locally on an angiographic score sheet and sent to a central angiographic laboratory. Nurse clinicians were trained to obtain ABIs in a standard manner (20-221, and preand postintervention ABI scores were
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recorded on separate forms along with a clinical judgment of patency of the study lesion. Some patients had incompressible arteries with unevaluable ABI. It was usually possible to position the blood pressure cuff higher on the leg but still below the intervention site. This value was then used for that patient, but it was not included in the ABI data base. The ABI was recorded at discharge, at 1month, and at routine follow-up visits at 3-month intervals unless an intercurrent hospitalization or an unscheduled outpatient visit occurred. At each contact with the VAMC, whether as an inpatient or outpatient, the study nurse completed a physical examination, ABI measurement, a functional performance questionnaire, and a record of all current medications. New events were recorded and classified in relation to the study lesion, other vascular disease, and all nonvascular causes. The nurse also determined if any intervening care had been received outside the study environment. Prior to the intervention and at each follow-up visit or rehospitalization, the patient completed an activity form describing his usual activities. To evaluate health status further, the Sickness Impact Profile (SIP) (23-25) was administered bv the nurse at the time of randomization and at 1month, 1 year, and 2 years following intervention. All patients in the study were also followed up with use of the beneficiary identification and records locator subsystem (BIRLS) database to document deaths not reported to the study team. BIRLS is a data file maintained by the Veterans Administration that records death benefits paid to survivors. This file has been repeatedly verified to be 98%-100% accurate for survival information.
Definitions A study death was any death that occurred within 30 days of the primary intervention or as a direct consequence of the primary intervention. A major amputation included above the knee, below the knee, or a Symes
foot amputation. Primarypatency was defined as a sustained increase of 0.15 or more in ABI without further intervention at the site of the vascular lesion randomized to treatment. Immediate intervention failures were those for which the threshold increase in ABI was not achieved within 24 hours, while early failures were those that occurred within 30 days of the primary intervention. Limb salvage was the retention of the leg without a major amputation or death.
Statistical Analyses The minimum period of follow-up was 2 years; the maximum period of follow-up was 6 years; and the median follow-up was 4.1 years. Lifetable estimates of cumulative event rates in the two intervention groups were calculated for the entire maximum follow-up interval of 6 years. Analyses based on clinical measurements such as ABI and event rates within subgroups were calculated for the median follow-up of 4 years. Cumulative survival rates and success rates for each combined endpoint variable were calculated by using the actuarial life-table method. Intervals were calculated from the date of randomization. Following the recommendation of Rutherford et a1 (19), data were censored at the time of a terminating event, that is, patient drop-out, last contact, or death, as appropriate. Differences in cumulative success rates between the two treatment groups were tested by means of the log-rank statistic (26). All analyses were according to original treatment assignment, that is, intent-to-treat or treatment policy (27). Differences in the distribution of baseline characteristics between the two treatment groups were tested with the X 2 statistic and, when appropriate, the t statistic (28). Differences in serial ABIs between PTA and BP patients were analyzed at each time of evaluation. All P values are for two-tailed tests of statistical significance. The sample size of 263 patients provided 90% power to detect an odds ratio of 2.3 for failure of PTA
versus BP at the 5% level of significance (29).
RESULTS Comparability of Study Groups In designing the study, we anticipated that the anatomic level of the arterial disease, as well as the severity of symptoms, would affect clinical outcomes. Table 1compares study groups with respect to demographic and clinical characteristics at entry that might affect outcome. The distributions of these factors were similar for the two intervention groups. Severity of arterial disease at the time of randomization, as measured by the ABI index, was similar for each treatment within lesion location (iliac or femoropopliteal) and symptom (claudication or rest pain) categories (Table 2). As expected, patients with rest pain had significantly lower perfusion pressures than those with claudication for both the iliac (P < .001) and the femoropopliteal (P = .026) locations of the study lesion. Initial Outcomes Two hundred fifty-two (96%)of the patients received their assigned treatment, and there was little difference in the outcomes by intent to treat or by treatment received. Nineteen BP patients whose operations failed within 30 days and six patients who did not receive the assigned operation because of an intervening event were considered surgical failures. Twentyfive PTA failures occurred within the same 30-day period. The radiologist was unable to cross the study lesion in 10 patients, and in eight patients the balloon could not be inflated sufficiently to dilate the lesion. In 17 of these patients with immediate PTA failures, prompt and successful BP was performed during the same hospitalization. Five additional PTA patients experienced an acute thrombosis of the treated lesion, and two required a major amputation of the study leg despite technically successful angioplasties.
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Journal of Vascular and Interventional Radiology
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Two hundred nineteen of the 263 patients achieved primary patency from their assigned intervention. Overall, 39 of the 130 PTA patients required additional vascular procedures during their initial hospitalization: 17 because of treatment failure and 22 because a technically successful angioplasty did not result in adequate revascularization. Factors independently associated with the need for additional vascular procedures included the Dresence of rest ~ a i n, . hypertension, and multiple arterial lesions (Table 3). For those with technically successful angioplasty, the additional intervention did not affect the primary patency outcome unless revascularization of the treated site was required. Similarly, the rules of counting for limb survival (19) require that either major amputation or death signals the end of limb survival, irrespective of whether the treated site was patent or occluded. A substantial and durable increase in average ABI occurred after intervention in both study groups (Fig 1). The serial change in ABI was not significantly different between treatment groups. Treated patients who chose to withdraw from the study (n = 8), were lost to follow-up (n = 20), or died (42 in surgery group, 31 in PTA group, difference is not significant) were censored on the date of their last examination. Life-table analysis of patient survival is presented in Figure 2. Survival status was known in 94% of subjects. Although the surgical cohort experienced more late deaths, the overall difference is not significant (P = .081). Figure 3a compares primary patency resulting from PTA and BP by treatment assigned for the entire cohort. The same outcome is shown for each treatment group in Figure 3b. Primary patency was higher with the BP surgery, but this difference did not meet conventional levels of significance in the entire patient set or any subset. Figure 4a compares limb survival when a major amputation or death is the termination criterion, and Figure 4b depicts
.
Table 1 Demographics of Study Groups According to Treatment Assigned Surgery PTA P Patient Characteristic (n = 133) (n = 130) Value Age (Y)* 62.0 t 1.28 60.9 t 1.18 Height (inch)* 68.6 k 0.56 68.7 k 0.61 Weight (lb)* 169.0 2 5.2 168.0 2 4.8 Race (%) White 74.4 80.0 Black 24.1 17.7 Other 1.5 2.3 Blood pressure (mm Hg) Systolic* 138.0 -C 3.4 137.0 2 3.4 Diastolic* 80.0 k 2.0 79.0 t 1.8 Smoking history Never (%) 2 0 Currently (%) 79 78 19 22 Previous (%) Pack-years* 47 2 5.6 50 t 6.6 Co-morbidity history (%) Angina 18 27 Myocardial infarct 19 22 Congestive heart failure 7 5 Stroke 15 12 Diabetes 29 30 Alcoholism 22 15 Previous vascular surgery (%) Coronary 7 9 Carotid 7 7 Vascular disease 21 19 * Note.-Values given as mean t two standard errors of the mean.
.221 ,909 386
.414 .721 .487
.392 ,101 .557 ,649 520 .799 .I31 .461 .960 ,684
Table 2 Comparison of ABI at Randomization by Location of the Study Lesion and Presenting Symptom Iliac Femoropopliteal Treatment Group Claudication Rest Pain Claudication Rest Pain Surgery No. patients 59 23 35 16 ABI 0.60k0.06 0.36k0.04 0.53+0.04 0.45t0.09 PTA 38 11 59 22 No. patients 0.44k0.15 0.3220.05 0.52k0.05 0.56k0.04 ABI Note.-ABI values given as mean k two standard errors of the mean.
the response within subgroups. Angioplasty does slightly better at all time points for the entire study group but is not significantly different from BP for the entire subject set or any subset. A balanced design was used to randomize patients into four groups by the location of their study lesion (iliac or femoropopliteal) and by whether claudication or rest pain was
the presenting symptom. Table 4 compares primary patency and limb survival for BP and PTA occurring within these four groups after 4 years of follow-up. Claudicants had better outcomes than patients with rest pain. Patients with iliac disease had better outcomes with either intervention than did patients with femoropopliteal disease. In none of these
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1. 2. Figures 1,2. (1) Serial change in ABI by intent-to-treat. The number of patients with an evaluable index who remained in the study at each follow-up interval is shown at the bottom of the graph. The decrease in numbers of patients during late time periods is due to death, intervention failure, or late entry. For example, the last patient entered had only 24 months of follow-up. (2) Life-table analysis of survival by intent-to-treat. These survival curves include all deaths. Statistical comparison by means of the log-rank test shows no significant difference over the study period. No data point had a standard error greater than 10%.
Table 3 Risk Factors for 39 Patients Assigned to PTA Who Required Additional Vascular Procedures No. of Additional Procedure (%) P Value Risk Factor Patients Observed* Predictedt Univariatet Multivariate" Rest pain 97 22.7 (22) 20.0 .002 ,005 Absent Present 33 51.5 (17) 49.2 Hypertension Absent 70 18.6 (13) 18.8 .002 ,034 Present 60 43.3 (26) 36.7 Arterial lesions Single 75 21.3 (16) 18.4 .012 .037 Multiple 55 41.8 (23) 37.4 * Actual number of PTA patients in category who underwent additional vascular procedures. Percentage predicted with use of multiple regression analysis. x2 statistic for independent difference between risk factor absent and risk factor present. multivariate statistic for interdependence of risk factors determined from multiple logistic regression analysis.
subsets was there a statistical difference in outcome between PTA and BP, although the smaller sample sizes reduce the power of these comparisons. Changes in SIP scores provide a measure of the effects of treatment on the functional status of the patient (20-22). Healthy control subjects average 5.2 on the SIP (23). Baseline total SIP scores in our study
averaged 15.8 in the BP group and 15.6 in the PTA group. Statistically significant improvements were achieved in total SIP scores in both treatment groups (P < .0001 for BP and P < .003 for PTA) 1month following the procedures, but the differences between BP and PTA were not significant (Table 5). More than half of BP and PTA patients had complete SIP follow-up data for 2 years. For
these patients, improvements in SIP scores persisted for both treatments and were not significantly different from one another. Physical and psychologic subscores of the SIP showed similar patterns.
DISCUSSION The major justification for performing a randomized clinical trial is to obtain unbiased estimates of the effects of treatment. One usually compares a new treatment with proved methods, but the new treatment must be mature enough to remain stable during the evaluation period. The current study was proposed to the Veterans Administration Cooperative Studies Program in 1979, took more than 2 years to plan (including the identification of appropriate participating centers), began patient intake in June 1983, concluded intake in July 1987, and concluded follow-up in July 1989. It is the first randomized clinical trial comparing PTA with surgery. Fortunately, both angioplasty and BP techniques remained relatively stable during enrollment. More recently, new guide wires and balloon catheters have been developed for use in PTA of the lower extremity. Incre-
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Journal of Vascular and Interventional Radiology
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mental benefits of these innovations will need to be established in future studies. The patients were randomly assigned to the two treatment groups within participating hospitals by using the major site of arterial disease and the severity of symptoms as stratifying variables. The randomization procedure created two groups that were similar in their demographics, severity of their disease, and comorbidities. The patients were elderly and had a high prevalence of other vascular diseases and comorbidities; nearly 80% were current smokers. Men who smoke heavily tend to experience rapid progression of peripheral vascular disease from claudication to intervention (24,25). The ABI scores of the study patients show that they had moderate to severe disease at the time of randomization. To be eligible, all patients had to be candidates for both BP and PTA. Intervention failures occurred in both groups. Most PTA failures resulted from inability to pass the study lesion with the guide wire or inability to dilate the lesion sufficiently to raise the ABI by at least 0.15. This occurred more commonly in femoropopliteal cohorts. Inability to achieve at least a 0.15 increase in ABI from a balloon properly positioned across the study lesion may have resulted from the use of polyethylene materials available in the mid 1980s: from underinflation, elastic recoil, or unrecognized acute thrombosis; or the randomized study lesion may not have been the only significant lesion accounting for the depressed ABI. In this regard, it is important to stress that the experimental design of the study was not allowed to interfere with acceptable care of the patient. Thus, clinical circumstances created a potential for bias against angioplasty success in this trial. There was only one postoperative death and a total of three study-related deaths, all in the surgery group. The incidence of acute thrombosis or other acute failure of intervention within 30 days was similar in the two groups, and all
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b. Figure 3. Life-table analysis of primary patency. Following the convention of Rutherford (19), each patient fails to sustain primary patency on the date of his death, when he requires another intervention at the experimentally assigned site, when he fails to maintain an ABI of 0.15 or more above baseline, or has a major amputation of the study extremity. Patients were censored as of the date of their last examination if they withdrew, were lost to follow-up, or were reported dead by the BIRLS data base. (a)Life-table analysis for the entire group. (b) Primary patency by means of the lifetable method for disease subsets that were separately randomized. Fern-Pop = femoropopliteal.
of these patients received further treatment. Few major differences were found between centers despite
the fact that surgery and PTA both require a high degree of technical skill. An unsuccessful attempt at
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and amputation rates favored angioplasty. Thus, the advantage of surgery with respect to primary patency SURGERY does not fully characterize patient 5 outcome. This could be due to a late adverse effect of surgery (30). Two groups of patients deserve special mention. Eight patients assigned to surgery did not receive any Log Rank p-value 0.354 intervention due to patient refusal, erroneous diagnosis, or an interven0 SURGERY PTA ing event that precluded surgery. a Five of these patients died early in .. 133 ill 99 72 34 18 1 SWIGERV their follow-up. At the other extreme 130 106 91 61 32 14 1 PTA I I I I I I I I I I I I I I I I I I I I I ~ ~ are ~patients ~ with an unsuccessful 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 PTA attempt. Procedures in these MONTHS F R O M D A T E O F R A N D O M I Z A T I O N patients were declared failures, but all patients underwent successful and durable surgical interventions. This combination of PTA plus surgery inh PTA creased the length of hospital stay l-,-,-,-1-l-1-1-1-1 and resource consumption for the angioplasty group. SURGERY Differences in patient selection criteria make comparisons between our results and those in published reports difficult. For example, our patients were required to have a discrete vascular lesion less than 10 cm in length that was suitable for either PTA or BP as the principal cause of their symptoms. Surgical series do not impose this type of restriction. Moreover, 73% of our patients had claudication rather than rest pain, a symptom level that many surgeons do not consider to be an appropriate indication for surgical intervention (17,31-33). With these caveats, our results appear to be similar to those of other surgical studies. Studies of aortoiliac surgery that include claudicants report primary patency rates of 74%-95% at 4 years (10-14) and limb Figure 4. Life-table analyses of limb survival. The same criteria were applied as in survival of 86% (12). Our iliac BP Figure 3 except that only death or major amputation were failure criteria. (a)Outcome patients experienced 77% primary for the entire patient set. (b)Comparison of BP and PTA for separately randomized patency and 88% limb salvage. For disease subsets. Fern-Pop = femoropopliteal. femoropopliteal surgery, primary patency is reported to be 52%-68% and limb survival 73%-75% at 4 years PTA had little impact on ultimate rates for PTA, however, are reduced (14,151. Our femoropopliteal BP paoutcomes, but it did prolong mean by our strict definition of technical tients had 57% primary patency and duration of hospitalization for pafailure. When analyzed by level of 77% limb survival for the same petients in the PTA group. arterial disease and presenting symp- riod. Our operative mortality was less Long-term primary patency rates tom, it is clear that the surgical benthan 1%, while that in published rewere slightly better for surgery than efit was confined to the iliac claudiports was 1%-6% (10-13). for angioplasty. The primary patency cant group. Cumulative mortality Most reported PTA series do not ...
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Journal of Vascular and Interventional Radiology
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utilize stringent criteria of outcome success for all patients in whom PTA is attempted (5-9). Becker et al(3) analyzed technical success and patency in PTA clinical reports and estimated 92% technical success and 72% 5-year patency for iliac PTA, with 81% technical success and 67% 4-5year patency for femoropopliteal PTA. Similarly, Adar et al (4) adjusted outcomes from 12 selected reports on PTA of the lower extremity, noting early success in 89% + 2.5 of treatments for claudication with 62% 2 9 patency rates at 3 years, while patients treated for limb salvage had 77% + 4 early success and 43% 2 7 3-year patency. Our overall technical success was 87%; for iliac PTA, primary patency was 67% and limb salvage was 86%; for femoropopliteal PTA, primary patency was 58% and limb salvage was 92%. There were no operative or early deaths. Available benchmarks suggest outcomes consistent with a high standard of care in our patients whether assigned to PTA or BP. After the first 30 days, the life-table decrements following either PTA or BP are nearly parallel. This may suggest relentless progression of a chronic disease. This final report of Cooperative Study Program No. 199 differs in important aspects from our earlier interim publication (18). Here we adopt the criteria of Rutherford (19) for measuring primary patency and limb survival. Formerly, we utilized studyrelated deaths, major amputations of a study limb, and failure to increase ABI by more than 0.2. The earlier report also had a median follow-up of only 2 years. When more explicit definitions of intervention success and longer follow-up are used, the statistically significant preference for BP in the entire group (P = .0375) and in patients with iliac disease (P = .037) that was noted in the earlier report is no longer evident. Indeed, at this final accounting, there was no statistically significant difference between results with PTA and BP in any of the four separately randomized subgroups-that is, iliac claudication, iliac rest pain, femoropopliteal
Table 4 Primary Patency and Limb Survival by Assigned Intervention, Study Lesion Location, and Preoperative Symptom Category after a Median Follow-upof 4 Years Surgery PTA P Outcome n %* n %* Valuet Primary patency Iliac Claudication 59 85.2 + 4.9 .055 59 70.8 -+ 6.60 Rest pain 23 57.0 2 11.3 .66 22 57.6 + 10.8 Femoral/popliteal Claudication 35 57.7 2 9.8 38 59.5 4 8.1 .43 Rest pain 16 56.3 2 12.4 11 52.5 t 15.6 .86 Overall
133
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130
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.14
59 23
94.7 + 3.0 72.5 2 9.6
59 22
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38 11
92.7 t 5.0 90.9 t 8.7
.38 .12
Overall 133 84.0 t 3.5 130 88.5 t 3.1 Note.-n = patients at risk by intention-to-treat. * Percentage ( + standard error) is estimated from life-table analysis. P values are presented for the log-rank test.
.33
Limb survival Iliac Claudication Rest pain Femoral/popliteal Claudication Rest pain
Table 5 SIP Scores during 2 Years of Follow-up Follow-up Interval Baseline 1month 1year 2 years Total score*
n 128 115 95 76
BP Mean (SD) 15.8 (11.2) 12.2 (8.8) 10.6 (10.2) 9.6 (8.1)
Median 13 11 7 7.5
n 130 120 98 75
PTA Mean (SD) 15.6 (11.3) 11.3 (9.4) 10.8 (10.2) 11.2 (10.2)
Median 12 9 8 8
74
-5.7 (9.4)
5
75
-4.7 (12.8)
4
* Change after 2 years of follow-up in patients with complete data.
claudication, or femoropopliteal rest pain-or in the entire study population. Functional status was measured in our population at baseline, 1month following treatment, and at yearly intervals with the SIP. This instrument is administered by a trained interviewer, and scoring provides a total score, as well as physical and psychosocial subscores, measured on an interval scale from 0 (no impairment) to 100 (maximum impairment). Changes in the SIP score have
been validated to reflect functional status response to treatment (23-25). Patients with other chronic diseases have had total scores similar to baseline values in our patients with peripheral vascular disease (mean, 15.71, for example, a patient with chronic renal disease undergoing hemodialysis (mean, 13.9) (341, with low back pain (mean, 20.8) (35,361, or with rheumatoid arthritis (mean 21.0) (37). A gratifying and sustained improvement in SIP scores was observed in our study following either
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P T A o r BP, but n o significant difference was evident between t h e two interventions. O u r study demonstrates t h e value of controlled trials t o evaluate new technologies. When planning for o u r study began 11years ago, considerable uncertainty surrounded clinical indications for P T A o r BP. Since that time, much of this uncertainty h a s been dispelled by clinical experience a n d uncontrolled trials. O u r conclusion that t h e two procedures a r e equally effective in treating patients with discrete, large-vessel disease of t h e lower extremity is now widely held. T h i s conclusion would have been reached much sooner a n d with greater validity, however, had a randomized study such a s ours been completed sooner. New technologies for treating peripheral vascular disease, including laser angioplasty a n d mechanical atherectomy, a r e currently being introduced into clinical practice (38-40). We believe that randomized controlled trials of these technologies a r e feasible a n d would help considerably to define indications for their use i n t h e treatment of peripheral vascular disease. We urge t h a t such studies be performed.
Acknowledgments: The Principal Investigators were Gerald L. Wolf, PhD, MD, Pittsburgh VA Medical Center, Study Co-Chairman; Henry Berkowitz, MD, Philadelphia VA Medical Center, Study Co-Chairman, 1983-1985; Samuel E. Wilson, MD, Los Angeles (Wadsworth) VA Medical Center, Study Co-Chairman, 1985-1988; Anne Cross, PhD, Study Biostatistician, (Data Coordinating Center) West Haven VA Center, 1983-1988; S. Ramamurthy, MD, Fred Littooy, MD, Hines VA Medical Center; Edward Cockerill, MD, Michael Dalsing, MD, Kathryn Reilly, MD, Indianapolis VA Medical Center; Timothy Tytle, MD, Alex Jacocks, MD, Oklahoma City VA Medical Center; Robert LeVeen, MD, Leonard Perloff, MD, Philadelphia VA Medical Center; William Fields, MD, Mitchell Goldman, MD, Michael Sobel, MD, Richmond VA Medical Center; Anton Pogany, MD, David Effany, MD, San Francisco VA Medical Center; John Harley, MD, Eugene Zierler, MD, George Fortner, MD, Seattle VA Medical Center; David Stern,
MD, George Peters, MD, Geoffrey White, MD, Los Angeles (Wadsworth) VA Medical Center; Andrew B. Crummy, MD, Charles Acher, MD, Madison VA Medical Center; Carol Fye, RPh, MS, (Pharmacy Coordinating Center) Albuquerque VA Medical Center; Ping Huang, PhD, Staff Assistant, Cooperative Studies Program. The contribution of all the nurse clinicians is appreciated along with the technical expertise of Beverly Farrar, Janis Gottlieb, Steven Wright, and Joan Derrico. Secretarial assistance was provided by J. Jones and V. Williams. Boston Scientific Corporation defrayed some PTA catheter costs.
References 1. Dotter CT, Rosch J , Anderson JM, et al. Transluminal iliac artery dilation: nonsurgical catheter treatment of atheromatous narrowing. JAMA 1974; 230:117-124. 2. Gruntzig A, Kumpe DA. Technique of percutaneous transluminal angioplasty with the Gruntzig balloon catheter. AJR 1979; 132:547-552. 3. Becker GJ, Katzen BT, Dake MD. Noncoronary angioplasty. Radiology 1989; 170:921-940. 4. Adar R, Critchfield GC, Eddy DM. A confidence profile analysis of the results of femoropopliteal percutaneous transluminal angioplasty in the treatment of lower-extremity ischemia. J Vasc Surg 1989; 10: 57-67. 5. Colapinto RF, Harries-Jones EP, Johnston KW. Percutaneous transluminal angioplasty of peripheral vascular disease: a two-year experience. J Cardiovasc Intervent Radio1 1989; 3:213-218. 6. Waltman AC. Percutaneous transluminal angioplasty: iliac and deep femoral arteries. AJR 1980; 135: 921-925. 7. Kadir S, White RL Jr, Kaufman SL, et al. Long-term results of aortoiliac angioplasty. Surgery 1983; 94:lO-14. 8. Krepel VM, van Andel GJ, van Erb WF, Breslau PJ. Percutaneous transluminal angioplasty of the femoropopliteal artery: initial and long-term results. Radiology 1985; 156:325-328. 9. van Andel GJ, van Erb WFM, Krepel VM, Breslau PJ. Percutaneous transluminal dilatation of the iliac artery: long-term results. Radiology 1985; 156:321-323. 10. Crawford ES, Bomberger RA, Glae-
ser DH, Saleh SA, Russel WL. Aortoiliac occlusive disease: factors influencing survival and function following reconstructive operation over a 25-year period. Surgery 1981; 90:1055-1066. Malone JM,Moore WS, Gladstone J . Life expectancy following aortofemoral arterial grafting. Surgery 1977; 81:551- 555. Maini BS, Mannick JA. Effect of arterial reconstruction on limb salvage: a ten year appraisal. Arch Surg 1978; 113:1297-1304. Piotrowski J J , Pearce WH, Jones DN, et al. Aortobifemoral bypass: the operation of choice for unilateral iliac occlusion? J Vasc Surg 1988; 8:211-218. Veith FJ, Gupta SK, Samson RH, et al. Progress in limb salvage by reconstructive surgery combined with new or improved adjunctive procedures. Ann Surg 1981; 194:386-401. Veith FJ, Gupta SK, Ascer E, et al. Six-year prospective multicenter randomized comparison of autologous saphenous vein and expanded polytetrafluoroethylene grafts in infrainguinal arterial reconstructions. J Vasc Surg 1986; 3:104-114. Rutherford RB, Jones DN, Bergentz SE, et al. Factors affecting the patency of infrainguinal bypass. J Vasc Surg 1988; 8:236-246. Veith FJ, Gupta SK, Ascer E. Femoral, popliteal, and tibia1 occlusive disease. In: Wilson SE, Veith FS, Hobson RW, Wilson RA, eds. Vascular surgery: principles and practice. New York, IVY: McGraw Hill, 1987; 353-375. Wilson SE, Wolf GL, Cross AP. Percutaneous transluminal angioplasty versus operation for peripheral arteriosclerosis. J Vasc Surg 1989; 9:l-9. Rutherford RB. Standards for evaluating results of interventional therapy for peripheral vascular disease. Circulation 1991; 83(suppl I): 11-111. Yao JST, Bergan JJ. Application of ultrasound to arterial and venous diagnosis. Surg Clin North Am 1974; 23-38. Franek A, Johansen KH, Dilley RB, Bernstein EF. Noninvasive physiologic tests in the diagnosis and characterization of peripheral arterial occlusive disease. Am J Surg 1973; 126:205-214. Barnes RW. Noninvasive diagnos-
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23.
24.
25.
26.
27.
28.
tic techniques in peripheral vascular disease. Am Heart J 1979; 97:241258. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The Sickness Impact Profile: development and final revision of a health status measure. Med Care 1981; 19:787-805. Bergner M, Bobbitt RA, Pollard WE, Martin DP, Gilson BS. The Sickness Impact Profile: validation of a health status measure. Med Care 1976; 14:57-67. Pollard WE, Bobbitt RA, Bergner M, Martin DP, Gilson BS. The Sickness Impact Profile: reliability of health status measure. Med Care 1976; 14:146-155. Walker SH, Duncan DB. Estimation of the probability of an event as a function of several independent variables. Biometrika 1967; 54:167179. Peduzzi P, Detre K, Wittes J, Holford T. Intent-to-treat analysis and the problem of crossovers: an example from the Veterans Administration coronary bypass surgery study. J Thorac Cardiovasc Surg 1991; 101:481-487. Snedecor GW, Cochran WG. Statistical methods. 6th ed. Ames, Iowa:
Iowa State University Press, 1967. 29. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br J Cancer 1976; 34:585-612. 30. Bergan JF, Wilson SE, Wolf GL, Deupree R. Unexpected, late cardiovascular effects of surgery for peripheral vascular disease. Arch Surg 1992; 127:1119-1124. 31. Ahlmen M, Sullivan M, Archenholtz B, Svensson G. Measuring health in rheumatic disorders by means of a Swedish version of the Sickness Impact Profile: results from a population survey. Scand J Rheumatol 1986; 15:193-300. 32. Cronewett JL, Warner KG, Zelenock GB, et al. Intermittent claudication: current results of nonoperative management. Arch Surg 1984; 119: 430-436. 33. Wilson SE, Schwartz I, Williams RA, Owens ML. Occlusion of the superficial femoral artery: what happens without operation. Am J Surg 1980; 140:112-118. 34. Hart LG, Evans RW. The functional status of ESRD patients as measured by the Sickness Impact Profile. J Chron Dis 1987; 40:117130.
35. Deyo RA, Diehl RK. Measuring physical and psychosocial function in patients with low back pain. Spine 1983; 9:635-642. 36. Deyo RA. Comparative validity of the Sickness Impact Profile and shorter scales for functional assessment in low back pain. Spine 1983; 9:635-642. 37. Ahlmen M, Sullivan M, Bjelle A. Team versus non-team outpatient care in rheumatoid arthritis: a comprehensive outcome evaluation including an overall health measure. Arthritis Rheum 1988; 31:471-479. 38. Koto MM, Kadir S, Bennett JD, Beam CA. Aortoiliac angioplasty: is there a need for other types of percutaneous intervention? JVIR 1992; 3:67-71. 39. Triller J, Do DD, Maddern G, Mahler F. Femoropopliteal artery occlusion: clinical experience with the Kensey catheter. Radiology 1992; 182:257-261. 40. Belli AM, Cumberland DC, Procter AE, Welsh CL. Follow-up of conventional angioplasty versus laser thermal angioplasty for total femoropopliteal artery occlusions: results of a randomized trial. JVIR 1991; 2:485-488.
Surgery or Balloon Angioplasty for Peripheral Vascular Disease: A ~and6mized Clinical Trial1 Gerald L. Wolf, PhD, MD Samuel E. Wilson, MD Anne P. Cross, PhD Robert H. Deupree, PhD William B. Stason, MD, MS and the Principal Investigators and their Associates of Veterans Administration Cooperative Study Number 199 Index terms: Arteries, surgery, 92.452, 984,452,986,452 Arteries, transluminal angioplasty, 92.1282, 984,1282,986.1282
JVIR 1993;4:639-648 Abbreviations: ABI = ankle-brachial index, BIRLS = beneficiary identification and records locator subsystem, BP = bypass surgery, PTA = percutaneous transluminal angioplasty, SIP = Sickness Impact Profile, VAMC = Veterans Administrative Medical Center
PURPOSE: Surgical revascularization and angioplasty (PTA)are effective therapies for patients with peripheral arterial disease, but there are no data on long-term survival, limb salvage, and hemodynamic status from a randomized study of such patients. A multicenter, prospective trial compared PTA with bypass surgery (BP) in 263 men who had iliac, femoral, or popliteal artery obstruction. PATIENTS AND METHODS: Lesions in the iliac versus the femoropopliteal artery and rest pain versus claudication were separately randomized to the two treatment interventions. One hundred twenty-sixpatients underwent BP, 129 patients underwent PTA, and eight patients were not treated for lower extremity ischemia. RESULTS: Three operative deaths occurred in the BP group and none in the PTA group. For the entire study, average annual mortality was higher in the BP group, but survival was not significantly different on life-tableanalysis (P = .O8). Primary success favored BP, while limb salvage favored PTA, but differences were not statistically significant (P = .O8 and .35, respectively). Patients with iliac disease or claudication fared better, but there was no statistical difference in response to PTA or BP. CONCLUSION: Patients in both treatment groups had prompt and sustained increases in hemodynamics and quality of life. This study of patients randomly assigned to BP or PTA shows no significant difference in outcomes during a median follow-upof 4 years.
transluminal angioplasty (PTA), conceived by Dotter almost 30 years ago and made practical by Gruntzig in 1975, has a widely accepted role in the treatment of peripheral vascular occlusive disease (1-9). Angiographic guidelines are generally accepted with regard to descriptions of lesions likely to respond to PTA. For example, iliac lesions and shorter stenoses are considered more remediable than femoral lesions and longer occlusions. On the other hand, bypass surgery (BP) has been the standard for treatment of moderate to severe peripheral arterial disease for more than 30 years (10-17). No randomized clinical trial has compared the results and durability of PTA with those of BP performed for these occlusions. This study was designed in 1983 PEncuTANEous
' From the Center for Imaging and Pharmaceutical Research and the Department of Radiology, Harvard University, Massachusetts General Hospital, 149 13th St, Charlestown, MA 02129-2060 (G.L.W.); Department of Surgery, University of California, Irvine (S.E.W.);Department of Biostatistics, Bristol-Myers-Squibb (A.P.C.) Wallingford, Conn; Biostatistics, Cooperative Studies Program Coordinating Center, West Haven Veterans Administration Medical Center, Conn (R.H.D.); Health Economics Research, Waltham, Mass (W.B.S.). Received November 2, 1992; revision requested February 1, 1993; revision received March 2; accepted March 8. Supported by the Cooperative Studies Program of the Medical Research Service, Department of Veteran Affairs Central Office, Washington, DC. Address reprint requests to G.L.W. " SCVIR, 1993
under the auspices of the Department of Veterans Affairs Cooperative Studies Program to compare the hemodynamic results, complicatioris, longterm patency, amputation rate, and mortality in patients randomly assigned to treatment with either PTA or BP. An interim report published earlier (18) had incomplete follow-up, utilized different measures of success, and found some statistically significant differences favoring BP that were not evident a t the end of the study. The interim report also did not include the hemodynamic or qualityof-life outcomes or a n analysis of risk factors predicting incomplete revascularization. This report summarizes the experimental design and major clinical findings after a median follow-up of approximately 4 years.
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METHODS Eligibility Male patients with symptomatic peripheral arterial disease were screened for disease amenable to treatment with either PTA or BP by means of complete physical examination, ankle-brachial index (ABI), laboratory tests, and peripheral angiography. Vascular anatomy from the infrarenal aorta to below the trifurcation of the popliteal artery at midcalf was examined with angiography in the anteroposterior projection as well as at least one oblique projection of the iliac arteries and the femoral bifurcation. At the completion of the work-up, the anatomic and physiologic data were independently reviewed by the radiologist and the vascular surgeon to identify the single lesion considered to be the principal cause of the patient's symptoms and to determine whether this lesion was suitable for treatment by means of PTA and BP. Inclusion criteria were as follows: (a)angiographic demonstration of at least 80% diameter stenosis or a total occlusion of the iliac, femoral, or popliteal artery less than 10 cm long; (b) ABI of less than 0.90 at rest; (c)intermittent claudication when walking less than two blocks with rest pain or impending gangrene; and (d)agreement by the radiologist and surgeon that the patient was an acceptable candidate for either procedure. Thus, these patients had chronic limb ischemia of category 2-5 according to the criteria of the Society for Vascular Surgery and the International Society of Cardiovascular Surgery (19). Exclusion criteria were as follows: (a) patient already scheduled for major amputation; (b)emergency surgery contemplated; ( c ) short-term heparin or long-term antiplatelet therapy contraindicated; ( d )life expectancy less than 3 years due to comorbidity; (el patients unlikely to be available for follow-up due to personality, mental health, or geographic distance from a participating Veter-
ans Administration Medical Center (VAMC); ( f )patient not a candidate for BP or PTA; ( g )patient or physician refuses randomized intervention choice; or ( h )patient is female. Eight VAMCs began the study in June 1983, but two were dropped due to low patient accession and were replaced by a better performing VAMC in March 1985. All eligible patients were invited to participate in the study. The subjects consented both to randomized treatment assignment and to follow-up angiography 3 years after intervention and were informed of their right to withdraw at any time without prejudice. About 60% of the patients who met the eligibility criteria consented to participate, and a total of 263 men were enrolled in the study between June 1,1983, and July 31, 1987.
Randomization After consent was obtained, the participating hospital contacted the study biostatistician by phone for treatment assimment. Randomization was stratized by center and for each of four disease categories: iliac disease with claudication, iliac disease with rest pain, femoropopliteal disease with claudication, or femoropopliteal disease with rest pain. Impending gangrene or limb threat was considered to be a rest-pain equivalent for randomization purposes. This produced a 2 x 2 x 2 factorial randomization scheme (PTA vs BP, iliac vs femoropopliteal disease, claudication vs rest pain) within each medical center. All patients were followed up until conclusion of the study on July 31,1989. Of the 263 consenting patients, 133 were randomly assigned to surgery and 130 to PTA. Eleven patients did not receive the assigned treatment. While awaiting their intervention, six patients assigned to surgery suffered an intervening event that precluded surgery. One patient assigned to surgery refused any intervention, and another insisted on PTA. One patient assigned to surgery did not have a significant pressure gradient across his arterial lesion and
received no treatment. Two patients assigned to PTA refused and underwent surgery. These changes resulted in 126 patients who underwent surgery, 129 patients who underwent PTA, and eight patients who were not treated for lower extremity ischemia.
Intervention All participating centers had surgeons experienced in operations for iliac and femoropopliteal disease and radiologists who had performed at least 20 peripheral PTA procedures prior to the study. In general, the techniques and performance of the intervention were left to the discretion of the physicians at each site. Prophylactic antibiotics and intraoperative heparinization were suggested for surgical patients, and administration of 5,000 U of intravenous heparin was suggested for those undergoing PTA after the lesion had been crossed. All centers were affiliated with universities and residents and fellows participated in the care of these patients according to local policies. Each subject was randomized based on the principal lesion in a designated artery. However, many patients had additional lesions in the ipsilateral or contralateral leg. Only the intervention for the study lesion was randomized; all other interventions were performed according to the judgment of the clinical team and the consent of the patient.
Follow-upand Outcome Measures At each participating hospital, a full-time nurse clinician recorded the patient data at entry and at intervals up to 6 years after randomization. The qualifying angiogram, a postangioplasty image, and representative angiograms obtained to document the status of the study lesion were coded locally on an angiographic score sheet and sent to a central angiographic laboratory. Nurse clinicians were trained to obtain ABIs in a standard manner (20-221, and preand postintervention ABI scores were
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recorded on separate forms along with a clinical judgment of patency of the study lesion. Some patients had incompressible arteries with unevaluable ABI. It was usually possible to position the blood pressure cuff higher on the leg but still below the intervention site. This value was then used for that patient, but it was not included in the ABI data base. The ABI was recorded at discharge, at 1month, and at routine follow-up visits at 3-month intervals unless an intercurrent hospitalization or an unscheduled outpatient visit occurred. At each contact with the VAMC, whether as an inpatient or outpatient, the study nurse completed a physical examination, ABI measurement, a functional performance questionnaire, and a record of all current medications. New events were recorded and classified in relation to the study lesion, other vascular disease, and all nonvascular causes. The nurse also determined if any intervening care had been received outside the study environment. Prior to the intervention and at each follow-up visit or rehospitalization, the patient completed an activity form describing his usual activities. To evaluate health status further, the Sickness Impact Profile (SIP) (23-25) was administered bv the nurse at the time of randomization and at 1month, 1 year, and 2 years following intervention. All patients in the study were also followed up with use of the beneficiary identification and records locator subsystem (BIRLS) database to document deaths not reported to the study team. BIRLS is a data file maintained by the Veterans Administration that records death benefits paid to survivors. This file has been repeatedly verified to be 98%-100% accurate for survival information.
Definitions A study death was any death that occurred within 30 days of the primary intervention or as a direct consequence of the primary intervention. A major amputation included above the knee, below the knee, or a Symes
foot amputation. Primarypatency was defined as a sustained increase of 0.15 or more in ABI without further intervention at the site of the vascular lesion randomized to treatment. Immediate intervention failures were those for which the threshold increase in ABI was not achieved within 24 hours, while early failures were those that occurred within 30 days of the primary intervention. Limb salvage was the retention of the leg without a major amputation or death.
Statistical Analyses The minimum period of follow-up was 2 years; the maximum period of follow-up was 6 years; and the median follow-up was 4.1 years. Lifetable estimates of cumulative event rates in the two intervention groups were calculated for the entire maximum follow-up interval of 6 years. Analyses based on clinical measurements such as ABI and event rates within subgroups were calculated for the median follow-up of 4 years. Cumulative survival rates and success rates for each combined endpoint variable were calculated by using the actuarial life-table method. Intervals were calculated from the date of randomization. Following the recommendation of Rutherford et a1 (19), data were censored at the time of a terminating event, that is, patient drop-out, last contact, or death, as appropriate. Differences in cumulative success rates between the two treatment groups were tested by means of the log-rank statistic (26). All analyses were according to original treatment assignment, that is, intent-to-treat or treatment policy (27). Differences in the distribution of baseline characteristics between the two treatment groups were tested with the X 2 statistic and, when appropriate, the t statistic (28). Differences in serial ABIs between PTA and BP patients were analyzed at each time of evaluation. All P values are for two-tailed tests of statistical significance. The sample size of 263 patients provided 90% power to detect an odds ratio of 2.3 for failure of PTA
versus BP at the 5% level of significance (29).
RESULTS Comparability of Study Groups In designing the study, we anticipated that the anatomic level of the arterial disease, as well as the severity of symptoms, would affect clinical outcomes. Table 1compares study groups with respect to demographic and clinical characteristics at entry that might affect outcome. The distributions of these factors were similar for the two intervention groups. Severity of arterial disease at the time of randomization, as measured by the ABI index, was similar for each treatment within lesion location (iliac or femoropopliteal) and symptom (claudication or rest pain) categories (Table 2). As expected, patients with rest pain had significantly lower perfusion pressures than those with claudication for both the iliac (P < .001) and the femoropopliteal (P = .026) locations of the study lesion. Initial Outcomes Two hundred fifty-two (96%)of the patients received their assigned treatment, and there was little difference in the outcomes by intent to treat or by treatment received. Nineteen BP patients whose operations failed within 30 days and six patients who did not receive the assigned operation because of an intervening event were considered surgical failures. Twentyfive PTA failures occurred within the same 30-day period. The radiologist was unable to cross the study lesion in 10 patients, and in eight patients the balloon could not be inflated sufficiently to dilate the lesion. In 17 of these patients with immediate PTA failures, prompt and successful BP was performed during the same hospitalization. Five additional PTA patients experienced an acute thrombosis of the treated lesion, and two required a major amputation of the study leg despite technically successful angioplasties.
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Two hundred nineteen of the 263 patients achieved primary patency from their assigned intervention. Overall, 39 of the 130 PTA patients required additional vascular procedures during their initial hospitalization: 17 because of treatment failure and 22 because a technically successful angioplasty did not result in adequate revascularization. Factors independently associated with the need for additional vascular procedures included the Dresence of rest ~ a i n, . hypertension, and multiple arterial lesions (Table 3). For those with technically successful angioplasty, the additional intervention did not affect the primary patency outcome unless revascularization of the treated site was required. Similarly, the rules of counting for limb survival (19) require that either major amputation or death signals the end of limb survival, irrespective of whether the treated site was patent or occluded. A substantial and durable increase in average ABI occurred after intervention in both study groups (Fig 1). The serial change in ABI was not significantly different between treatment groups. Treated patients who chose to withdraw from the study (n = 8), were lost to follow-up (n = 20), or died (42 in surgery group, 31 in PTA group, difference is not significant) were censored on the date of their last examination. Life-table analysis of patient survival is presented in Figure 2. Survival status was known in 94% of subjects. Although the surgical cohort experienced more late deaths, the overall difference is not significant (P = .081). Figure 3a compares primary patency resulting from PTA and BP by treatment assigned for the entire cohort. The same outcome is shown for each treatment group in Figure 3b. Primary patency was higher with the BP surgery, but this difference did not meet conventional levels of significance in the entire patient set or any subset. Figure 4a compares limb survival when a major amputation or death is the termination criterion, and Figure 4b depicts
.
Table 1 Demographics of Study Groups According to Treatment Assigned Surgery PTA P Patient Characteristic (n = 133) (n = 130) Value Age (Y)* 62.0 t 1.28 60.9 t 1.18 Height (inch)* 68.6 k 0.56 68.7 k 0.61 Weight (lb)* 169.0 2 5.2 168.0 2 4.8 Race (%) White 74.4 80.0 Black 24.1 17.7 Other 1.5 2.3 Blood pressure (mm Hg) Systolic* 138.0 -C 3.4 137.0 2 3.4 Diastolic* 80.0 k 2.0 79.0 t 1.8 Smoking history Never (%) 2 0 Currently (%) 79 78 19 22 Previous (%) Pack-years* 47 2 5.6 50 t 6.6 Co-morbidity history (%) Angina 18 27 Myocardial infarct 19 22 Congestive heart failure 7 5 Stroke 15 12 Diabetes 29 30 Alcoholism 22 15 Previous vascular surgery (%) Coronary 7 9 Carotid 7 7 Vascular disease 21 19 * Note.-Values given as mean t two standard errors of the mean.
.221 ,909 386
.414 .721 .487
.392 ,101 .557 ,649 520 .799 .I31 .461 .960 ,684
Table 2 Comparison of ABI at Randomization by Location of the Study Lesion and Presenting Symptom Iliac Femoropopliteal Treatment Group Claudication Rest Pain Claudication Rest Pain Surgery No. patients 59 23 35 16 ABI 0.60k0.06 0.36k0.04 0.53+0.04 0.45t0.09 PTA 38 11 59 22 No. patients 0.44k0.15 0.3220.05 0.52k0.05 0.56k0.04 ABI Note.-ABI values given as mean k two standard errors of the mean.
the response within subgroups. Angioplasty does slightly better at all time points for the entire study group but is not significantly different from BP for the entire subject set or any subset. A balanced design was used to randomize patients into four groups by the location of their study lesion (iliac or femoropopliteal) and by whether claudication or rest pain was
the presenting symptom. Table 4 compares primary patency and limb survival for BP and PTA occurring within these four groups after 4 years of follow-up. Claudicants had better outcomes than patients with rest pain. Patients with iliac disease had better outcomes with either intervention than did patients with femoropopliteal disease. In none of these
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1. 2. Figures 1,2. (1) Serial change in ABI by intent-to-treat. The number of patients with an evaluable index who remained in the study at each follow-up interval is shown at the bottom of the graph. The decrease in numbers of patients during late time periods is due to death, intervention failure, or late entry. For example, the last patient entered had only 24 months of follow-up. (2) Life-table analysis of survival by intent-to-treat. These survival curves include all deaths. Statistical comparison by means of the log-rank test shows no significant difference over the study period. No data point had a standard error greater than 10%.
Table 3 Risk Factors for 39 Patients Assigned to PTA Who Required Additional Vascular Procedures No. of Additional Procedure (%) P Value Risk Factor Patients Observed* Predictedt Univariatet Multivariate" Rest pain 97 22.7 (22) 20.0 .002 ,005 Absent Present 33 51.5 (17) 49.2 Hypertension Absent 70 18.6 (13) 18.8 .002 ,034 Present 60 43.3 (26) 36.7 Arterial lesions Single 75 21.3 (16) 18.4 .012 .037 Multiple 55 41.8 (23) 37.4 * Actual number of PTA patients in category who underwent additional vascular procedures. Percentage predicted with use of multiple regression analysis. x2 statistic for independent difference between risk factor absent and risk factor present. multivariate statistic for interdependence of risk factors determined from multiple logistic regression analysis.
subsets was there a statistical difference in outcome between PTA and BP, although the smaller sample sizes reduce the power of these comparisons. Changes in SIP scores provide a measure of the effects of treatment on the functional status of the patient (20-22). Healthy control subjects average 5.2 on the SIP (23). Baseline total SIP scores in our study
averaged 15.8 in the BP group and 15.6 in the PTA group. Statistically significant improvements were achieved in total SIP scores in both treatment groups (P < .0001 for BP and P < .003 for PTA) 1month following the procedures, but the differences between BP and PTA were not significant (Table 5). More than half of BP and PTA patients had complete SIP follow-up data for 2 years. For
these patients, improvements in SIP scores persisted for both treatments and were not significantly different from one another. Physical and psychologic subscores of the SIP showed similar patterns.
DISCUSSION The major justification for performing a randomized clinical trial is to obtain unbiased estimates of the effects of treatment. One usually compares a new treatment with proved methods, but the new treatment must be mature enough to remain stable during the evaluation period. The current study was proposed to the Veterans Administration Cooperative Studies Program in 1979, took more than 2 years to plan (including the identification of appropriate participating centers), began patient intake in June 1983, concluded intake in July 1987, and concluded follow-up in July 1989. It is the first randomized clinical trial comparing PTA with surgery. Fortunately, both angioplasty and BP techniques remained relatively stable during enrollment. More recently, new guide wires and balloon catheters have been developed for use in PTA of the lower extremity. Incre-
~
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mental benefits of these innovations will need to be established in future studies. The patients were randomly assigned to the two treatment groups within participating hospitals by using the major site of arterial disease and the severity of symptoms as stratifying variables. The randomization procedure created two groups that were similar in their demographics, severity of their disease, and comorbidities. The patients were elderly and had a high prevalence of other vascular diseases and comorbidities; nearly 80% were current smokers. Men who smoke heavily tend to experience rapid progression of peripheral vascular disease from claudication to intervention (24,25). The ABI scores of the study patients show that they had moderate to severe disease at the time of randomization. To be eligible, all patients had to be candidates for both BP and PTA. Intervention failures occurred in both groups. Most PTA failures resulted from inability to pass the study lesion with the guide wire or inability to dilate the lesion sufficiently to raise the ABI by at least 0.15. This occurred more commonly in femoropopliteal cohorts. Inability to achieve at least a 0.15 increase in ABI from a balloon properly positioned across the study lesion may have resulted from the use of polyethylene materials available in the mid 1980s: from underinflation, elastic recoil, or unrecognized acute thrombosis; or the randomized study lesion may not have been the only significant lesion accounting for the depressed ABI. In this regard, it is important to stress that the experimental design of the study was not allowed to interfere with acceptable care of the patient. Thus, clinical circumstances created a potential for bias against angioplasty success in this trial. There was only one postoperative death and a total of three study-related deaths, all in the surgery group. The incidence of acute thrombosis or other acute failure of intervention within 30 days was similar in the two groups, and all
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MONTHS FROM DATE OF R A N D O M I Z A T I O N
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b. Figure 3. Life-table analysis of primary patency. Following the convention of Rutherford (19), each patient fails to sustain primary patency on the date of his death, when he requires another intervention at the experimentally assigned site, when he fails to maintain an ABI of 0.15 or more above baseline, or has a major amputation of the study extremity. Patients were censored as of the date of their last examination if they withdrew, were lost to follow-up, or were reported dead by the BIRLS data base. (a)Life-table analysis for the entire group. (b) Primary patency by means of the lifetable method for disease subsets that were separately randomized. Fern-Pop = femoropopliteal.
of these patients received further treatment. Few major differences were found between centers despite
the fact that surgery and PTA both require a high degree of technical skill. An unsuccessful attempt at
Wolf et a1
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Volume 4 Number 5
and amputation rates favored angioplasty. Thus, the advantage of surgery with respect to primary patency SURGERY does not fully characterize patient 5 outcome. This could be due to a late adverse effect of surgery (30). Two groups of patients deserve special mention. Eight patients assigned to surgery did not receive any Log Rank p-value 0.354 intervention due to patient refusal, erroneous diagnosis, or an interven0 SURGERY PTA ing event that precluded surgery. a Five of these patients died early in .. 133 ill 99 72 34 18 1 SWIGERV their follow-up. At the other extreme 130 106 91 61 32 14 1 PTA I I I I I I I I I I I I I I I I I I I I I ~ ~ are ~patients ~ with an unsuccessful 0 3 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57 60 63 66 69 72 75 PTA attempt. Procedures in these MONTHS F R O M D A T E O F R A N D O M I Z A T I O N patients were declared failures, but all patients underwent successful and durable surgical interventions. This combination of PTA plus surgery inh PTA creased the length of hospital stay l-,-,-,-1-l-1-1-1-1 and resource consumption for the angioplasty group. SURGERY Differences in patient selection criteria make comparisons between our results and those in published reports difficult. For example, our patients were required to have a discrete vascular lesion less than 10 cm in length that was suitable for either PTA or BP as the principal cause of their symptoms. Surgical series do not impose this type of restriction. Moreover, 73% of our patients had claudication rather than rest pain, a symptom level that many surgeons do not consider to be an appropriate indication for surgical intervention (17,31-33). With these caveats, our results appear to be similar to those of other surgical studies. Studies of aortoiliac surgery that include claudicants report primary patency rates of 74%-95% at 4 years (10-14) and limb Figure 4. Life-table analyses of limb survival. The same criteria were applied as in survival of 86% (12). Our iliac BP Figure 3 except that only death or major amputation were failure criteria. (a)Outcome patients experienced 77% primary for the entire patient set. (b)Comparison of BP and PTA for separately randomized patency and 88% limb salvage. For disease subsets. Fern-Pop = femoropopliteal. femoropopliteal surgery, primary patency is reported to be 52%-68% and limb survival 73%-75% at 4 years PTA had little impact on ultimate rates for PTA, however, are reduced (14,151. Our femoropopliteal BP paoutcomes, but it did prolong mean by our strict definition of technical tients had 57% primary patency and duration of hospitalization for pafailure. When analyzed by level of 77% limb survival for the same petients in the PTA group. arterial disease and presenting symp- riod. Our operative mortality was less Long-term primary patency rates tom, it is clear that the surgical benthan 1%, while that in published rewere slightly better for surgery than efit was confined to the iliac claudiports was 1%-6% (10-13). for angioplasty. The primary patency cant group. Cumulative mortality Most reported PTA series do not ...
PTA
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646
Journal of Vascular and Interventional Radiology
September-October 1993
utilize stringent criteria of outcome success for all patients in whom PTA is attempted (5-9). Becker et al(3) analyzed technical success and patency in PTA clinical reports and estimated 92% technical success and 72% 5-year patency for iliac PTA, with 81% technical success and 67% 4-5year patency for femoropopliteal PTA. Similarly, Adar et al (4) adjusted outcomes from 12 selected reports on PTA of the lower extremity, noting early success in 89% + 2.5 of treatments for claudication with 62% 2 9 patency rates at 3 years, while patients treated for limb salvage had 77% + 4 early success and 43% 2 7 3-year patency. Our overall technical success was 87%; for iliac PTA, primary patency was 67% and limb salvage was 86%; for femoropopliteal PTA, primary patency was 58% and limb salvage was 92%. There were no operative or early deaths. Available benchmarks suggest outcomes consistent with a high standard of care in our patients whether assigned to PTA or BP. After the first 30 days, the life-table decrements following either PTA or BP are nearly parallel. This may suggest relentless progression of a chronic disease. This final report of Cooperative Study Program No. 199 differs in important aspects from our earlier interim publication (18). Here we adopt the criteria of Rutherford (19) for measuring primary patency and limb survival. Formerly, we utilized studyrelated deaths, major amputations of a study limb, and failure to increase ABI by more than 0.2. The earlier report also had a median follow-up of only 2 years. When more explicit definitions of intervention success and longer follow-up are used, the statistically significant preference for BP in the entire group (P = .0375) and in patients with iliac disease (P = .037) that was noted in the earlier report is no longer evident. Indeed, at this final accounting, there was no statistically significant difference between results with PTA and BP in any of the four separately randomized subgroups-that is, iliac claudication, iliac rest pain, femoropopliteal
Table 4 Primary Patency and Limb Survival by Assigned Intervention, Study Lesion Location, and Preoperative Symptom Category after a Median Follow-upof 4 Years Surgery PTA P Outcome n %* n %* Valuet Primary patency Iliac Claudication 59 85.2 + 4.9 .055 59 70.8 -+ 6.60 Rest pain 23 57.0 2 11.3 .66 22 57.6 + 10.8 Femoral/popliteal Claudication 35 57.7 2 9.8 38 59.5 4 8.1 .43 Rest pain 16 56.3 2 12.4 11 52.5 t 15.6 .86 Overall
133
68.1 t 4.7
130
64.1 t 4.4
.14
59 23
94.7 + 3.0 72.5 2 9.6
59 22
90.5 2 4.1 74.8 t 9.9
.39 .77
35 16
85.1 2 7.1 59.7 + 12.8
38 11
92.7 t 5.0 90.9 t 8.7
.38 .12
Overall 133 84.0 t 3.5 130 88.5 t 3.1 Note.-n = patients at risk by intention-to-treat. * Percentage ( + standard error) is estimated from life-table analysis. P values are presented for the log-rank test.
.33
Limb survival Iliac Claudication Rest pain Femoral/popliteal Claudication Rest pain
Table 5 SIP Scores during 2 Years of Follow-up Follow-up Interval Baseline 1month 1year 2 years Total score*
n 128 115 95 76
BP Mean (SD) 15.8 (11.2) 12.2 (8.8) 10.6 (10.2) 9.6 (8.1)
Median 13 11 7 7.5
n 130 120 98 75
PTA Mean (SD) 15.6 (11.3) 11.3 (9.4) 10.8 (10.2) 11.2 (10.2)
Median 12 9 8 8
74
-5.7 (9.4)
5
75
-4.7 (12.8)
4
* Change after 2 years of follow-up in patients with complete data.
claudication, or femoropopliteal rest pain-or in the entire study population. Functional status was measured in our population at baseline, 1month following treatment, and at yearly intervals with the SIP. This instrument is administered by a trained interviewer, and scoring provides a total score, as well as physical and psychosocial subscores, measured on an interval scale from 0 (no impairment) to 100 (maximum impairment). Changes in the SIP score have
been validated to reflect functional status response to treatment (23-25). Patients with other chronic diseases have had total scores similar to baseline values in our patients with peripheral vascular disease (mean, 15.71, for example, a patient with chronic renal disease undergoing hemodialysis (mean, 13.9) (341, with low back pain (mean, 20.8) (35,361, or with rheumatoid arthritis (mean 21.0) (37). A gratifying and sustained improvement in SIP scores was observed in our study following either
Wolf et a1
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P T A o r BP, but n o significant difference was evident between t h e two interventions. O u r study demonstrates t h e value of controlled trials t o evaluate new technologies. When planning for o u r study began 11years ago, considerable uncertainty surrounded clinical indications for P T A o r BP. Since that time, much of this uncertainty h a s been dispelled by clinical experience a n d uncontrolled trials. O u r conclusion that t h e two procedures a r e equally effective in treating patients with discrete, large-vessel disease of t h e lower extremity is now widely held. T h i s conclusion would have been reached much sooner a n d with greater validity, however, had a randomized study such a s ours been completed sooner. New technologies for treating peripheral vascular disease, including laser angioplasty a n d mechanical atherectomy, a r e currently being introduced into clinical practice (38-40). We believe that randomized controlled trials of these technologies a r e feasible a n d would help considerably to define indications for their use i n t h e treatment of peripheral vascular disease. We urge t h a t such studies be performed.
Acknowledgments: The Principal Investigators were Gerald L. Wolf, PhD, MD, Pittsburgh VA Medical Center, Study Co-Chairman; Henry Berkowitz, MD, Philadelphia VA Medical Center, Study Co-Chairman, 1983-1985; Samuel E. Wilson, MD, Los Angeles (Wadsworth) VA Medical Center, Study Co-Chairman, 1985-1988; Anne Cross, PhD, Study Biostatistician, (Data Coordinating Center) West Haven VA Center, 1983-1988; S. Ramamurthy, MD, Fred Littooy, MD, Hines VA Medical Center; Edward Cockerill, MD, Michael Dalsing, MD, Kathryn Reilly, MD, Indianapolis VA Medical Center; Timothy Tytle, MD, Alex Jacocks, MD, Oklahoma City VA Medical Center; Robert LeVeen, MD, Leonard Perloff, MD, Philadelphia VA Medical Center; William Fields, MD, Mitchell Goldman, MD, Michael Sobel, MD, Richmond VA Medical Center; Anton Pogany, MD, David Effany, MD, San Francisco VA Medical Center; John Harley, MD, Eugene Zierler, MD, George Fortner, MD, Seattle VA Medical Center; David Stern,
MD, George Peters, MD, Geoffrey White, MD, Los Angeles (Wadsworth) VA Medical Center; Andrew B. Crummy, MD, Charles Acher, MD, Madison VA Medical Center; Carol Fye, RPh, MS, (Pharmacy Coordinating Center) Albuquerque VA Medical Center; Ping Huang, PhD, Staff Assistant, Cooperative Studies Program. The contribution of all the nurse clinicians is appreciated along with the technical expertise of Beverly Farrar, Janis Gottlieb, Steven Wright, and Joan Derrico. Secretarial assistance was provided by J. Jones and V. Williams. Boston Scientific Corporation defrayed some PTA catheter costs.
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Iowa State University Press, 1967. 29. Peto R, Pike MC, Armitage P, et al. Design and analysis of randomized clinical trials requiring prolonged observation of each patient. Br J Cancer 1976; 34:585-612. 30. Bergan JF, Wilson SE, Wolf GL, Deupree R. Unexpected, late cardiovascular effects of surgery for peripheral vascular disease. Arch Surg 1992; 127:1119-1124. 31. Ahlmen M, Sullivan M, Archenholtz B, Svensson G. Measuring health in rheumatic disorders by means of a Swedish version of the Sickness Impact Profile: results from a population survey. Scand J Rheumatol 1986; 15:193-300. 32. Cronewett JL, Warner KG, Zelenock GB, et al. Intermittent claudication: current results of nonoperative management. Arch Surg 1984; 119: 430-436. 33. Wilson SE, Schwartz I, Williams RA, Owens ML. Occlusion of the superficial femoral artery: what happens without operation. Am J Surg 1980; 140:112-118. 34. Hart LG, Evans RW. The functional status of ESRD patients as measured by the Sickness Impact Profile. J Chron Dis 1987; 40:117130.
35. Deyo RA, Diehl RK. Measuring physical and psychosocial function in patients with low back pain. Spine 1983; 9:635-642. 36. Deyo RA. Comparative validity of the Sickness Impact Profile and shorter scales for functional assessment in low back pain. Spine 1983; 9:635-642. 37. Ahlmen M, Sullivan M, Bjelle A. Team versus non-team outpatient care in rheumatoid arthritis: a comprehensive outcome evaluation including an overall health measure. Arthritis Rheum 1988; 31:471-479. 38. Koto MM, Kadir S, Bennett JD, Beam CA. Aortoiliac angioplasty: is there a need for other types of percutaneous intervention? JVIR 1992; 3:67-71. 39. Triller J, Do DD, Maddern G, Mahler F. Femoropopliteal artery occlusion: clinical experience with the Kensey catheter. Radiology 1992; 182:257-261. 40. Belli AM, Cumberland DC, Procter AE, Welsh CL. Follow-up of conventional angioplasty versus laser thermal angioplasty for total femoropopliteal artery occlusions: results of a randomized trial. JVIR 1991; 2:485-488.