Efficacy of prostaglandin E1 in the treatment of lower extremity ischemic ulcers secondary to peripheral vascular occlusive disease

Efficacy of prostaglandin E1 in the treatment of lower extremity ischemic ulcers secondary to peripheral vascular occlusive disease Results of a prospective randomized, double-blind, multicenter clinical trial James J. Schuler, M.D., D. P r e s t o n Flanigan, M.D., James W. H o l c r o f t , M.D., Joseph J. U r s p r u n g , Ph.D., J. Scott M o h r l a n d , Ph.D., and J u d y Pyke, M.S.,

Chicago, Ill., Davis, Calif., and Kalamazoo, Mich. Most previous reports suggesting beneficial effects ofprostaglandin E1 (PGEI) have been retrospective and uncontrolled. Therefore, this study was undertaken to assess the efficacy of PGE1 in the treatment ofischemic ulcers in patients with peripheral vascular occlusive disease (PVOD). One hundred twenty patients with one to three ischemic ulcers not healing for 3 weeks with standard care were randomized to receive either PGE1 (20 ng/kg/min) or a placebo for 72 hours through a central venous catheter. Ulcers were measured and photographed, and the rest pain was evaluated before and after infusion and at 1- and 2-month follow-up intervals. Fifty-seven patients with 95 ulcers received PGE1. Seventeen ulcers healed (18%); 22 ulcers decreased in size (23%); 37 ulcers remained unchanged or increased in size (39%); five new ulcers developed during the study (5%); and 14 ulcers had inadequate follow-up (15%). Sixty-three patients with 115 ulcers received a placebo. Nineteen ulcers healed (16%); 38 ulcers decreased in size (33%); 45 ulcers remained unchanged or increased in size (39%); three new ulcers developed during the study (3%); and 10 ulcers had inadequate follow-up (9%). None of the above differences between the drug-treated group and the placebo-treated group was statistically significant. This study did not demonstrate efficacy for intravenously administered PGE~ in the healing of ischemic ulcers in patients with PVOD. (J VASC SURG 1984; 1:160-70.)

The treatment o f ischemic ulcers and rest pain of the lower extremities continues to be one o f the most important problems in the management o f peripheral vascular occlusive disease. This is especially true for those patients in whom lower extremity revascularization is not indicated or in whom conventional revascularization with bypass techniques is judged unlikely to be o f long-term benefit. Treatment with various vasodilators has been shown to be ineffective and may in fact increase the degree o f From the Division of Vascular Surgery, Department of Surgery, University of Ilfinois, Collegeof Medicine at Chicago, Ill., the Department of Surgery, Universityof California, Davis, Calif., and the Upjohn Co., Kalamazoo,Mich. Presented at the Thirty-first Scientific Meeting of the North American Chapter, International Society for Cardiovascular Surgery, San Francisco, Calif., june 16-17, 1983. Reprint requests: D. Preston Flanigan, M.D., Chief, Division of Vascular Surgery, Department of Surgery, 518-J, Universityof Illinois at Chicago, P.O. Box 6998, Chicago, IL 60680. 160

ischemia by causing systemic hypotension, the shunting o f blood from the area o f ischemia to more normal tissue, or both. 1.., Conventional anticoagulation and antiplatelet therapy has likewise not been beneficial. Because o f this lack o f an effective nonsurgicaI method for treating lower extremity arterial occlusive disease, the prostaglandins I2 (PGI2) and E1 (PGE1), which are potent vasodilators and inhibitors o f platelet aggregation, have been evaluated in various clinical trials. Carlson and Olsson 3 in 1976 and Pardy et al. 4 in 1980 reported healing o f ischemic ulcers and reduction in rest pain in small series of patients following the intravenous infusion o f PGE1. Ecklund et al., ~ however, failed to demonstrate a significant long-term (2-month) difference in ulcer healing in a placebo-controlled double-blind study using intravenously administered PGE1 in 22 patients with peripheral vascular occlusive disease,

Volume 1 Number 1 January 1984

EJ~cacy of prostaglandin E 1

161

Table 1. Principal investigators Investigator

Center

Investigator

Center

j. Alpert W. H. Baker W. Blackshear, Jr. G. E. Bone R. E. Casali F. J. Daghar R. S. Dilley D. P. Flanigan W. J. Fouty B. L. Gewertz L. Gillespie, Jr. J. Goldstone

Newark, N.J. Maywood, Ill. Tampa, Fla. Dallas, Tex. Little Rock, Ark. Baltimore, Md. Indianapolis, Ind. Chicago, Ill. Washington, D.C. Chicago, Ill. Washington, D.C. Tucson, Ariz.

M. A. Hardy R. W. Hobson J. W. Holcroft L. A. Jacobs M. E. Kuehner J. A. Pinkerton S. B. Reele R. A. Rhodes J. J. Schuler W. Schumer B. L. Thiele S. E. Wilson

Bronx, N.Y. Newark, N.J. Sacramento, Calif. Allen Park, Mich. Marshfield, Wis. Kansas City, Mo. Kalamazoo, Mich. Cleveland, Ohio Chicago, Ill. North Chicago, Ill. Seattle, Wash. Los Angeles, Calif.

although significant short-term benefit in the PGE1treated group was demonstrated. In light of these reports suggesting a beneficial eff,)At of PGE1, a prospective randomized, doubleblind, placebo-controlled, multicenter clinical trial was undertaken to assess the efficacy of intravenously administered PGE1 in the healing ofischemic ulcers and relief of ischemic rest pain of the lower extremities. PATIENTS AND M E T H O D S Patient entry. Between December 1980 and October 1982, 24 principal investigators at 22 cen~ers entered into the study 123 patients with ischemic ulceration of the lower extremities. The performance of the study at each individual center was under the direction of a peripheral vascular surgeon who functioned as the principal investigator for that center. The participating centers and principal inVestigators are listed in Table I. Patient selection and data collection were the responsibility of the principa~ ~nvesngators. The data were forwarded to the Upjohn Company, Kalamazoo, Michigan, and statistical analysis was performed by three of the authors (j.P., J.S.M., and J.J.S.). Patient eligibility. Male or postmenopausal female patients with one to three ischemic ulcers of the lower extremities with greatest diameters -<4 cm ~or 0.5 cm in greatest depth that had been present for at least 3 weeks and did not show clinical signs of healing with conventional care were eligible for ~ntry into the study. It was anticipated that the majority of patients with ischemic ulcerations would also have ischemic rest pain, but rest pain alone did *not qualify a patient for entry into the study. Patients with ischemic ulcers were entered into the study if in the opinion of the principal investigator s',lrgical procedures were unsuitable, had previously failed or produced limited success, were not indi-

cated, were refused by the patient, or could without undue risk of further tissue loss be judiciously postponed and performed at a later date if necessary. Exclusion criteria included the following: patients with cancer; premenopausal women; patients less than 18 years of age; those unable to understand and grant truly informed consent; patients participating in other experimental drug studies; patients with recent or unstable angina pectoris, pericardial effusion, idiopathic subaortic stenosis, congestive heart failure, recent myocardial infarction, or severe hypertension (diastolic blood pressure > 115 mm Hg); patients with chronic obstructive pulmonary disease or acute respiratory infection; those with poorly controlled diabetes mellitus; patients with active hepatic, biliary, or peptic ulcer disease or with ulcerative colitis or regional enteritis; those with any hematologic or coagulation disorder; patients with leg ulcers who had associated chronic venous insufficiency; patients with an ulcer that had tendon, periosteum, or a joint space in its base because of its location; patients with ulcers overlying the calcaneus; and patients with ulcers associated with gross infection or gangrene in other areas. Patients were allowed to continue use of their regular prescribed medications such as digoxin, diuretics, antihypertensive medications, and insulin. Patients taking other vasodilator agents or antiplatelet agents such as aspirin or dipyridamole were excluded from the study. A complete medical history and physical examination with special emphasis on examination of peripheral pulses and clinical estimation of the degree of ischemia (pallor, dependent rubor, or poo r capillary filling) were performed for all patients. A description of the ulcers in addition to measurements were recorded, and all ulcers were photographed. On the assumption of an elliptical shape, ulcer area was calculated by the formula

162

Schuler et al.

3.14 × BDIAM/2 × NDIAM/2 where BDIAM is the broadest diameter and NDIAM is the narrowest diameter of the ulcer. A 12-1ead ECG and chest x-ray examination were also performed. Baseline laboratory evaluation included routine urinalysis; complete blood count; platelet COtlnt; prothrombin time; partial thromboplastin time; and routine tests of serum electrolytes, amylase, bilirubin, cholesterol, creatinine, glucose, uric acid, albumin, globulin, alkaline phosphatase, lactate dehydrogenase, and serum glutamic-oxaloacetic transaminase levels. Segmental lower extremity Doppler blood pressures were done before and after each infusion and at 1- and 2-month follow-up. It was anticipated that the majority of patients with ischemic ulcers would also have ischemic rest pain. Rest pain was evaluated objectively on a scale of 0 (no analgesic medication required) to 5 (narcotic analgesics required seven or more times per week for control of rest pain) and subjectively by the patient on a scale of 0 (no pain) to 7 (excruciating, unbearable pain). Side effects and intercurrent medical events were recorded, and selected laboratory tests were repeated at intervals during the study. Allocations. On completion of the preliminary assessment, the obtaining of informed consents, and the decision that protocol requirements had been met, patients were assigned identification numbers; the pharmacist at each participating center followed a random code of drug assignment supplied by the Upjohn Project Coordinator (J.J.U.). Randomization was performed on a per center basis to eliminate the possibility of some centers treating a majority of patients with drugs while other centers treated a majority of patients with placebos. The patient, the principal investigator, and all other personnel involved in patient care were blinded as to the nature of the infusion received. Only the pharmacist charged with preparing the infusion solution was aware of whether the patient was receiving PGE1 or a placebo, and the pharmacist was not aware of the patients' status at presentation or the subsequent clinical course. To ensure patient safety, the principal investigators were given a 24-hour phone number for the pharmacist and project coordinator should the randomization code need to be broken in the event of an adverse reaction to the infusion. Regimens. PGEI was supplied without charge by the Upjohn Company as 0.5 ml of active drug in 1 ml of sterile ethanol, which was diluted with 0.9% saline solution to a concentration of 2.5 /~gm/ml. The placebo consisted of an equal volume of ethanol in normal saline solution. The infusions were given

Journal of VASCULAR SURGERY

by a central venous catheter inserted through the subclavian or internal jugular vein route beginning~ at a rate of 0.7 n g / k g / m i n and increased to 20 n g / k g / m i n or until significant side effects occurred. The infusion was maintained at this dose rate or the maximal dose tolerated without side effects for 64 to 66 hours and then decreased over a period of 6 to 8 hours for a total infusion time of 72 hours. Infusior~, rates for the placebo-treated group were the same as for the drug-treated group to ensure an equal volume of infusion in both groups of patients. Thirty patients were randomized to receive one 72-hour infusion followed by repeat evaluation of ulcer healing, rest pain, and other parameters after the infusion and at 1 and 2 months following infusion. Ninety-three patients were randomized to receive three 72-hour infusions at 2-week intervals with, evaluation of ulcer healing and rest pain beforei~nd after each infusion and at 1- and 2-month intervals following the infusions. Withdrawal. Patients were withdrawn from the study at their request, when amputation was required prior to the 2-month follow-up evaluation; or when, in the opinion of the principal investigator, the patient was clearly a treatment failure and other methods of treatment (usually revascularization) were required. Patients who experienced intercurrent medical events or infusion-related side effects of a severity that precluded further infusion or follow-up were likewise withdrawn from the study at the discretion of the principal investigator. Events and analysis. Follow-up data were examined for the three events of ulcer healing or significant change in size of ulcers, the relief of re~ pain, and the incidence of side effects or medical events occurring during the course of the study.~ifferences between the two groups of patients with regard to sex and racial distribution; presence or absence of diabetes mellitus, hypertension, previous sympathectomy, or vascular reconstruction; the ire cidence of intercurrent medical events or death; and the incidence of ulcer healing were analyzed by chisquare analysis and Yates' correction for continu-' ity when applicable. Differences between the two groups with respect to changes in ulcer size, pain score, and medication use were analyzed by Student's unpaired t test; and differences within the groups regarding the same parameters were analyzed by Student's paired t test. RESULTS Enrollment. Twenty-two centers entered 12~ patients into the study between December 1980 and October 1982. The number of patients entered~er

Volume 1 Number 1 January 1984

Efficacy ofprostaglandin E1

163

SO0-

gO. PQ=-I 80PL~,CI[IIO 70"

60-

40-

80-

20-

10"

0

® HEALED ~X

| ~ REDUCTIt~I

I~'SUI-'rs

~

ZNCREASED NEW ~

OF"

|

IHAOE~UATE'FOU.OW"UP PEVELOPE1~

"rR~'A'rM~'I~IT

Fig. 1. Final result of PGE1 vs. placebo treatment showing percent of ulcers that healed completely, were reduced by 20% or more in surface area, remained unchanged or increased by 20% or more, developed during the course of treatment, and had inadequate follow-up. The differences between treated group and placebo group were not significant.

center ranged from 1 to 16, with a mean of 5.6 patients entered per center. Follow-up observation was concluded in December 1982. Of these 123 paTients, 60 were randomized to receive PGE1, and 63 were randomized to receive a placebo. No attempt was made to quantify the number of patients who were screened for entry to the study but were excluded for various reasons. Exclusions from evaluation. Final analysis at the Conclusion of the study revealed that three patients initially entered into the PGE~-treated group had to ebe'k~:kcluded because one had ulcers secondary to Raynaud's syndrome, one had no ulcers, and the third had a pressure-induced ulcer on a previous below-knee amputation stump. This left 57 patients ~la the PGEl-treated group and 63 patients in the placebo group available for final analysis. Homogeneity of groups. Randomization produced comparable treatment groups. Forty-nine of 57 patients (86%) assigned to the PGE~ group and 48 of 63 patients (76%) assigned to the placebo group were men. Thirty-four of 57 patients (60%) in the PGEa group had diabetes mellitus, whereas 35 of 63 patients (56%) in the placebo group were diabetic. Thirty-four of 57 patients (60%) in the PGE~ group and 28 of 63 patients (44%) in the placebo group were hypertensive. Fifty-three percent of the PGEl-treated patients and 41% of the placebo-treated patients had a single isd~'mic ulcer, whereas 47% of the PGE1 group and

59% of the placebo group had two or more ischemic ulcers. Three patients in the PGE1 group (5%) and nine patients in the placebo group (14%) had undergone previous sympathectomy. Thirteen patients in the PGE1 group (23%) and 17 patients in the placebo group (27%) had undergone previous vascular reconstruction (bypass), and at the time of entry into the study eight patients in the PGE1 group (14%) and four patients in the placebo group (6%) had patent lower extremity bypass grafts. None of the above-mentioned differences were statistically significant as assessed by chi-square analysis. The initial mean ankle-brachial index (ABI) in the PGEl-treated patients was 0.54 _+ 0.43 as compared with 0.51 + 0.39. This difference was likewise not significant as assessed by Student's unpaired t test. Withdrawals from the study. Twenty-eight of 57 patients (49%) in the PGE~ group and 34 of 63 patients (54%) in the placebo group completed the study.

Three patients in the PGE1 group (5%) and one patient (2%) in the placebo group were lost to follow-up. Six patients in the PGE~ group (10%) and two patients in the placebo group (3%) were withdrawn because of side effects believed to be drug related at the time of their occurrence or intercurrent medical events that precluded their continuation in the study. Three patients in the PGE1 group (5%) and five patients in the placebo group

164

Journal of VASCULAR SURGERY

Schuler et al.

~10,

PGI¢-I ,,-AcBo

Iz *,1 U ¢ II; a.

ao

|O

// i

TREATHENT

GROUP

Fig. 2. Percent of patients in two groups with at least one ulcer completely healed during course of study.

(8%) were withdrawn either because of technical difficulties with catheter placement and maintenance or at the patients' request. Seventeen patients in the PGE1 group (30%) and 21 patients in the placebo group (33%) were withdrawn because aggravation or exacerbation of their ischemic ulcers and rest pain caused their principal investigator to deem them failures of treatment and elect to perform amputation (12 patients in the PGE1 group and nine patients in the placebo group) or operative revascularization (four patients in the PGEl-treated group and six patients in the placebo group). None of the above-mentioned differences between the treatment groups regarding reasons for withdrawal from the study was statistically significant as assessed by chi-square analysis and Yates's correction for continuity when applicable. Infusions per patient. In the final analysis 40 patients received one infusion, 18 patients received two infusions, and 62 patients received three infusions. There was no significant difference between the PGEl-treated group and the placebo group with regard to the number of infusions received per patient. Healing of ischemic ulcers. The 57 patients in the PGEl-treated group had a total of 95 ulcers. Seventeen ulcers healed (18%); 22 ulcers decreased in size by greater than 20% of surface area (23%); 37 ulcers remained unchanged or increased in size (39%); five new ulcers developed during the course

of treatment and follow-up (5%); and 14 ulcers (15%) had inadequate follow-up or occurred in patients who were withdrawn from the study before an accurate assessment of heating or nonhealing could be made. The 63 patients who received a placebo had a total of 115 ulcers. Nineteen ulcers healed (16%); 38 ulcers decreased in size by greater than 20% of surface area (33%); 45 ulcers remained unchanged or increased in size (39%); three new ulcers developed during the course of treatment and follow-up (3%); and 10 ulcers (9%) had inadequate follow-up (Fig. 1). Overall, 13 of 57 PGEl-treated patients (22.8%) and 14 of 63 placebo patients (22.2%) experienced heating of at least one isch~lic ulcer (Fig. 2). None of these differences was statistically significant. Thirty-five percent of the PGEl-treated patients and 27% of the placebo-treated patients experienc,d a 20% or greater reduction in total ulcer surface area, whereas 65% of the treated group and 73% of the placebo group had either no change or an increase in total ulcer surface area greater than 20% following the first infusion or at the time of the first follow-up visit (Fig. 3). At the final follow-up visit; 50% of treated patients and 54% of placebo patients had experienced a reduction in total ulcer surface area greater than 20% as compared with 50% of treated patients and 46% of placebo patients whose ulcer surface area remained unchanged or increased by 20% or more (Fig. 4). These differences were

Volume 1 Number 1 January 1984

Efficacy of prostagIandin E 1

165

gO.

IO.

V///A

70"

IIO.

f///~

50'

40

---~ 20'

,~I"////L

------;2;2f / / / / ~

I0'

0

g////~

2OX I~D~I~TllaN

Fig. 3. Percent of patients in two groups who had a 20% or greater reduction in total ulcer surface area as compared with those that remained unchanged or increased by 20% or more following one infusion of PGE1 or placebo. Differences between two groups were not significant. likewise not significant. In addition, there was no statistically significant difference in either the incidence of ulcer healing or the reduction in ulcer surface area between subgroups of patients based on whether they received one, two, or three infusions; the presence or absence of diabetes mellitus or hypertension; or proximal (aortoiliofemorah no palpable popliteal pulse) vs. distal (tibial vessel: palpable popliteal pulse) occlusive disease. The PGE1treated patients initially had a mean Doppler-derived ABI of 0.54 _+ 0.43, which decreased to 0.52 + 0.38 at the time o f final follow-up. The placebo group had an initial ABI of 0.51 -+ 0.39, which decreased to 0.48 + 0.33. These differences were likewise not significant. Relief of rest pain. The severity of rest pain was evaluated subjectively by the patient on a scale of 0 to 7, with 0 indicating the absence of pain, i indicating mild pain, 2 indicating mild to moderate pain, 3 indicating moderate pain, 4 indicating moderate to severe pain, 5 indicating severe pain, 6 indicating severe to excruciating pain, and 7 indicating excruciating, unbearable pain. Forty-six of the 57 patients in the PGE~ group (81%) and 55 of the 63 patients in the placebo group (87%) had some degree of rest pain on admission to the study. This difference was not significant. The mean subjective pain score of the 46 patients in the PGE~ group who had rest pain on admission into the study was

2.9 -+ 1.9 (range from 1 to 7), whereas the mean subjective pain score of the 55 placebo group patients who had rest pain on admission to the study was 3.6 + 1.6 (range from 1 to 7). This difference was not significant as assessed by Student's unpaired t test. The mean decrease in rest pain score at the completion of follow-up in the PGE1 group was 1.9 + 2.1 as compared with 1.5 + 1.8 in the placebo group (Fig. 5). This degree of decrease within each group was not significant as assessed by Student's paired t test, and the difference in the mean amount of decrease between the two groups was not significant as assessed by Student's unpaired t test. The severity o f rest pain was evaluated objectively by recording the amount and type of analgesic medication required for control o f rest pain. This was scored on a scale o f 0 to 5, with 0 indicating no medication required, 1 indicating fewer than three nonnarcotic analgesics required per day, 2 indicating four to six nonnarcotic analgesics required per day, 3 indicating more than six nonnarcotic analgesics required per day, 4 indicating that narcotic analgesics were required five to six times per week, and 5 indicating that narcotic analgesics were required more than six times per week. The mean pain medication score of the 46 patients in the PGE1treated group who had rest pain on admission was 2.7 + 1.9 (range from 1 to 5), whereas the mean pain medication score o f the 55 patients in the

166

Journal of VASCULAR SURGERY

Schuler et al.

100,

gO.

IlO,

70.

IlO,

50

40.

3O

20

10

V///'/~ V////~ V///'~ g///'~ g///'/~ ¢/////~ g///'/~ /a,/

/H

0

~ J f f / J

-/////5

¢////

~/,/_/_d ¢¢/I 1~ ~,'////5 ~/'///.,4~ ¢,////~

ii

/H

Fig. 4. Percent of patients in two groups who had a 20% or greater reduction in total ulcer surface area as compared with those that remained unchanged or increased by 20% or more at final follow-up visit 2 months after last infusion. Differences between two groups were not significant.

placebo group who had rest pain on admission was 3.1 + 1.9 (range from 1 to 5). This difference was not significant as assessed by Student's t test. The mean decrease in pain medication score at the completion o f follow-up was 1.8 + 2.5 in the PGEatreated group and 1.1 + 1.9 in the placebo group (Fig. 6). This degree of decrease within each group was not significant as assessed by Student's paired t test, and the difference in mean amount o f decrease between the two groups was not significant as assessed by Student's unpaired t test. In addition, there was no significant difference in either the pain score or the medication use score between the two groups at any interim follow-up point, nor was there a significant difference in pain or medication score within each group at any interim follow-up point. Likewise, there was no significant difference in pain scores or medication use scores between subgroups o f patients based on whether they received one, two, or three infusions; the presence or absence o f diabetes mellitus or hypertension; or proximal (aortoiliofemoral: no palpable popliteal pulse) vs. distal (tibial vessel: palpable popliteal pulse) occlusive disease• I n t e r c u r r e n t medical events a n d side effects. Three patients in each group died during the course of the study. In the PGE~-treated group one patient died o f pneumonia and another died of a perforated duodenal ulcer, both 5 weeks after their last infusion; another patient died of congestive heart failure

3 days after the end of his last infusion. In the opinion of the principal investigators, these deaths were probably not related to treatment. In the placebo group one patient died of a cerebrovascular accident 3 weeks after his last infusion, another died of pulmonary edema 8 weeks after his last infusion, and the third died of a myocardial infarction 6 weeks after his last infusion. Again, these deaths were judged to be unrelated to the infusions. There were two nonfatal myocardial infarctions and one nonfatal cerebrovascular accident in the placebo group and neither in the PGEl-treated group. There were six serious infectious c o m p ~ a tions in the PGEl-treated group and four in the placebo-treated group. There were two cases of central venous catheter-related sepsis in the PGE1treated group and one in the placebo group. Three infections in the PGE~-treated group were instances of cellulitis a n d / o r wet gangrene originating from ischemic ulcers, and the remaining infection in the PGE~-treated group was pneumonia. In the placebo group there was one episode of esophageal candidiasis, one urinary tract infection, and one infected below-knee amputation stump. These differences with regard to the incidence of death or serious complications were not significant between the groups. Forty-seven of the 57 patients in the PGE1treated group (82%) and 29 of the 63 patients in the placebo group (46%) reported at least one intercur-

Volume 1 Number 1 January 1984

Efficacy of prostaglandin E1

III

167

4.

¢ 0 U In Z

I.

V///~

70. ¢/////~ ¢//J~ F'///~ FIN;~.

I N I T'IP,I.

RESULTS

OF

TREATMENT

Fig. 5. Average of patients' subjectiveevaluation of degree of rest pain graded on a scale of 0 to 7 prior to beginning of treatment and at time of final follow-up 2 months after last infusion. These differences were not significant. rent medical event or side effect that may have been related to the infusion. This difference is statistically significant (p < 0.0002). Overall, there were 148 intercurrent medical events in the treated group (an average of 2.6 events per patient). However, the difference in the incidence of side effects severe enough to cause the patient to withdraw from the study (six in the PGEl-treated group and two in the placebo group) was not significant. The PGEa-treated group experienced a significantly higher incidence of cardiac arrhythmias (25% vs. 5%), elevated temperatures in the absence of~nfection (17% vs. 0%), musculoskeletal compl,~ifits (17% vs. 3%), and hand or pedal edema (17% vs. 0%) than did the nontreated group. The cardiac arrhythmias consisted of premature atrial or ventricular contractions and supraventricular tachycardias. These arrhythmias were usually experienced during titration of the patient from the initial dose of 7 n g / k g / m i n of PGE1 up to the final dose of 20 n g / k g / m i n and usually subsided after moderate reduction in dosage. In only two instances were these arrhythmias considered serious enough to cause withdrawal from the study; and no patient with an arrhythmia experienced angina pectoris, myocardial infarction, or congestive heart failure. The gastrointestinal side effects consisted primarily of anorexia, nausea, and occasionally mild, selflimited diarrhea and vomiting. Seventeen percent of the PGEl-treated patients developed low-grade temperatures not associated with an infectious

source; these are believed to be drug-related temperatures. Seventeen percent of the drug-treated group also experienced a sensation of generalized malaise, muscle weakness, myalgias, and occasionally arthralgias, which subsided completely after the infusions were stopped. A peculiar side effect noted in 17% of the drug-treated group but not observed in any patient in the placebo group was the development of a moderate amount of edema of the dotsum of the hands and feet, which was not associated with congestive heart failure or prolonged dependency. This edema subsided rapidly, usually within 24 to 48 hours after the infusion was stopped, and was not serious enough to cause withdrawal from the study. Two patients in the PGEa-treated group developed complications of peptic ulcer disease. One patient had an upper gastrointestinal tract hemorrhage from a duodenal ulcer that responded well to medical management, and the other patient experienced a perforated duodenal ulcer 5 weeks after his last infusion of PGE1 and died shortly after from septic complication of his ulcer repair. In the judgment of the principal investigators involved, these complications were not drug related. DISCUSSION The overall incidence of ulcer healing in both the PGEi-treatcd group (18%) and the placebo group (16%) in this study is somewhat lower than that reported in other clinical trials assessing the efficacy of PGE12 -~ This may be related to a number of

168

Journal of VASCULAR SURGERY

Schuler et al.

PrJE-I

~

/f///#,

......

/f///#,

-//_///. ¢ / / / ....... g///.~ ;~5"J'd'&A f / / / " ~ ~,¢////L ./////~

//1 / / / INITIAL RESULTS

FXK~L OF

TREATMENT

Fig. 6. Average of analgesic medication use required for relief of rest pain graded on a scale of 0 to 5 prior to beginning of treatment and at time of final follow-up 2 months after last infusion. These differences were not significant.

factors, including differences in study design, patient populations, and entry requirements. However, because the percent of healed ulcers and ulcers that decreased in size by more than 20% in this study was essentially the same in both groups and randomization produced comparable groups, it can be concluded that intravenously administered P G G is not efficacious in the healing ofischemic ulcers. Furthermore, because the percent of ulcers that remained unchanged in size or increased in size by more than 20% is likewise quite similar in both groups, it can be concluded that treatment with PGE1 did not have a deleterious effect on ulcer healing. This is especially important in light of other published reports indicating that vasodilator therapy may have a detrimental effect by shunting blood from areas of severe ischemia to more normal tissues. The effect of both PGE1 and placebo infusion on rest pain in this study was extremely variable. Some patients in both groups experienced substantial reduction and others experienced substantial increases in both analgesic medication used and pain scores during the study. The fact that both analgesic use and subjective evaluation of pain tended to decrease over the course of the study may indicate that those patients with more severe degrees of rest pain underwent amputation or revascularization or withdrew for other reasons and thus left those patients with lesser degrees of rest pain still in the study

group. However, because both the rate of withdrawal and reduction in pain were quite similar in both groups, it can be concluded that PGE1 treatment did not significantly relieve or exacerbate ischemic rest pain. Because pain is both a subjective and an organic phenomenon, it is also possible that as the study progressed, patients in both groups became more accustomed to pain and subconsciously decreased both their analgesic use and their subjective evaluation of the pain. The incidence of side effects in other clin~.qal series assessing the efficacy of PGE1 in similar &~dsages varies from 0% to 50%. 3-5 Such disparity in the reported incidence of side effects undoubtedly reflects differences in the definition of what constitutes a side effect as well as the degree o f diligence one applies to observing the patients under treatment and questioning them regarding the occurrence of side effects. In this study any event, regardless of how minor it seemed or whether or not it was judged to be related to the infusion, was recorded and reported. This accounts for the high incidence of reported intercurrent medical events in both the PGEl-treated group (82%) and the placebo group (46%). However, the incidence of death and serious side effects was very low in both groups, and in no patient was death or a serious complication judged to be related to the infusion. However, the incidence

Volume 1 Number 1 January 1984

Efficacy ofprostaglandin E 1

169

o f minor side effects that were well tolerated by the patients was significantly higher in the PGEl-treated group than in the nontreated group. This may reflect the dosage used in the present study (20 n g / k g / min) since other trials have failed to show any effect o f PGEi at lower dosages but have suggested benefit from infusion at dosages used in the present study. It is for this reason that the above-mentioned dosage was chosen and the side effects observed were expected. The two patients in the PGEl-treated group who developed complications o f peptic ulcer disease (bleeding in one, perforation in the other) deserve special mention. Even though the incidence o f this type o f complication is low, not statistically significant, and in neither case judged to be drug related in the opinion of the investigators involved, -the clinical importance o f such complications is sti~stantial. In future studies it appears advisable to carefully screen and exclude those patients with peptic ulcer disease. The possible reasons for the failure o f the present study to demonstrate efficacy are many. The intravenous route o f administration was chosen in this study to avoid the inherent risks o f prolonged arterial catheterization. However, other studies have suggested that the intra-arterial route o f administration may be more beneficial and associated with fewer side effects. 3"6'v Another possibility is that PGE1 may not be the most desirable prostaglandin to use in the treatment of ischemia since prostacyclin (PGI2) is much more potent in its vasodilatory and antiplatelet aggregating effects than is PGE1.4 PGE~ was chosen for the present study because, at the time

o f its inception, available supplies o f PGI2 were quite limited and technical problems relating to the biologic stability o f PGI2 in solution had not been completely resolved. An additional possibility is that the patients selected for study had such severe degrees o f ischemia that no treatment o f whatever nature could reasonably be expected to achieve limb salvage in a high percent o f patients. In light o f the above-mentioned possibilities and the acknowledged lack o f an efficacious nonsurgical treatment modality for patients with end-stage occlusive disease o f the lower extremities, further trials with the intra-arterial route o f administration a n d / o r PGI2 are indicated.

DISCUSSION Dr. Bruce L. Gewertz (Chicago, Ill.). Thc prostaglandin fractions have well-documented, if occasionally contradictory, effects on vascular smooth muscle. The biologic activity of each fraction is dose dependent and highly dependent on the specific arterial circulation. In their article the authors have presented a precise and forthright analysis of the lack of benefit of intravenous PGE1 in patients with far-advanced occlusive disease. While these results confirm my prejudice, my question to the authors is, in view of the high degree of pulmonary inactivation of prostaglandin in humans, which has been estimated as high as 95% with one pass through the pulmonary circulation, as well as the very poor perfusion of these limbs, how do we know that patients received comparable levels of active drug or any active drug at all? Finally, I am still hopeful that intra-arterial adminis-

tration of these agents can be of some use in vasospastic disorders such as nonocclusive mesenteric ischemia or Raynand's syndrome. I wonder if the authors are equally optimistic. Dr. Robert W. Hobson II (Newark, N.J.). We are in agreement with Dr. Schuler's conclusions and no longer would recommend intravenous administration of PGE1 for atherosclerotic peripheral vascular disease. However, the intra-arterial route of administration of the drug may be worthy of additional consideration. I wish to present some data on a comparison of the physiologic effects of intravenous and intra-arterial PGE1 on calf blood flow in patients with atherosclerotic peripheral vascular disease. We measured calf blood flow by venous occlusion plethysmography in patients with severe distal arteriopathy during an intravenous infusion of PGE1 at a dose of 21 mg/kg/min with an intra-arterial infusion

REFERENCES

i. GillespieJA. The case against vasodilator drugs in occlusive vascular disease of the legs. Lancet I959; 2:995-7. 2. HansteenV, LorensteenE. Vasodilatordrugs in the treatment of peripheral arterial insufficiency.Acta Med Scand [Suppl] 1974; 556:1-62. 3. Carlson LA, Olsson AG. Intravenous prostaglandin E1 in severe peripheral vascular disease. Lancet 1976; 2:810. 4. Pardy JM, Lewis JD, Eastcotr HHG. Preliminaryexperience with prostaglandins E1 and 12 in peripheral vascular disease. Surgery 1980; 88:826-32. 5. Ecklund AE, Eriksson G, Olsson AG. A controlled study showing significant short-term effect of prostaglandin E1 in heating of ischemic ulcers of the lower limb in man. Prostaglandins LeukotrienesMed 1982; 8:265-71. 6. Nielsen PE, Holstein P, Nielson SL. Prostaglandin E1 for impending gangrene. Lancet 1977; 1:192. 7. Sethi GK, Scott SM, Takaro T. Effect of intraarterial infusion of PGE1 in patients with severeischemiaof lower extremity. J Cardiovasc Surg 1980; 21:185-92.

170

Schuler et al.

at a dose o f 0.5 m g / k g / m i n . This 40 : 1 ratio between the two routes o f administration is appropriate because o f the drug's rapid metabolism in its first passage through the pulmonary circulation. A dose-dependent relationship was observed as the intra-arterial dose o f PGE1 was increased beyond 0.1 m g / k g / m i n . Increases in calf blood flow were then sustained and became maximal at 0.5 m g / k g / m i n . Conversely, intravenous infusion resulted in no significant increases in calf blood flow. These later data correlate well with your dinical observations and may offer additional explanation for the ineffectiveness o f PGE~ when administered as an intravenous infusion. However, we believe that the intra-arterial administration of PGE1 may have some clinical applications and should be given additional consideration in future cooperative study protocols. I have some questions. Have the authors had any experience with intra-arterial PGE~? I f so, what results have been noted? Because a multicenter trial on use o f intravenous prostacyclin (PGI2) is now under way, do you have any early data or speculation on the anticipated results o f PGIA? Dr. John J. Ricotta (Rochester, N.Y.). We took PGE~ to the animal laboratory and used it in normal and ischemic canine hind limbs; we found a marked increase in skin blood flow by use o f radioactive and labeled microspheres. This leads me to ask several questions o f Dr. Schuler. First, were there any systemic effects such as flushing or hypotension in your PGE1 patients that would suggest that they actually were getting significant levels o f the drug systemically? Second, do you believe that we are simply not measuring the appropriate parameters? Because skin blood flow seems to be the most commonly affected parameter here, do you think that we should be using transcutaneous oxygen or perhaps laser Doppler monitoring to measure skin blood flow? I would also like to ask what you think o f the intraarterial route of administration and, finally, to learn any thoughts that you have for further studies in terms of the dosage, route o f administration, and duration o f therapy with either PGE~ or PGI2. Dr. Schuler (closing). Regarding Dr. Gewertz's question about how we really know that these patients were receiving active levels o f the drug since the majority of PGE~ is inactivated in one passage through the lungs,

Journal of VASCULAR SURGERY

we can only surmise this on the basis o f the incidence of side effects, such as those described by Dr. Ricotta. These consist primarily o f a generalized sensation of flushing, sometimes rubor of the face and hands, and occasionally other systemic effects indicative o f a generalized drug ef feet. Because of the very short half-fife of PGE1, we have not been able to measure circulating levels of the drug. Regarding Dr. Gewertz's second question, we have had no experience in treating patients whose ulcers are secondary to vasculitis or Raynaud's syndrome. In this study we were evaluating only those patients whose ulcers were secondary to occlusive disease. I am aware o f some ongoing studies in Great Britain and Scandinavia in which there have been some very good early results in the treatment of vasculitic ulcers or ulcers secondary to Raynaud's syndrome, although I am not aware that this has as yet been done in a controlled randomized fashion. In response to Dr. Hobson's questions, we have had no experience with intra-arterial PGE1. We are at preset)t, along with a number of other centers, participating in a prospective randomized study using intravenous PGI2 or prostacyclin. That study has been in progress for only approximately 6 to 8 months, and I am not aware o f any early data or trends. In response to Dr. Ricotta's questions, the percent of patients who had systemic side effects noted, almost all o f which were very minor side effects, was 82% in the PGE~-treated group and 46% in the placebo group. This was a significant difference. However, the incidence of side effects serious enough to cause withdrawal from the study was 10% in the PGE~ group and 3% in the placebo group; this difference was not statistically significant. Dr. Ricotta also asked about measurement o f skin blood flow. When this study was initially undertaken, it was hoped that the majority o f participating centers would be able to measure skin blood flow or skin temperature in some manner. As it turned out, most centers were not able to measure these parameters; therefore, these data were not available on enough patients to lend themselves to,~iy meaningful analysis. We are now participating in the intravenous PGI2 study and are assessing skin perfusion with laser Doppler velocimetry. We do not have enough patients entered yet to say anything about it, but I do think that some method for assessing local skin blood flow is needed in any further study of this kind. ,,

\