Reocclusion
Prophylaxis with Dipyridamole Combined with Acetylsalicylic Acid Following PTA H. W. Heiss, M.D., F.I.C.A. H. Just, M.D. D. Middleton, M.D.* and G. Deichsel, M.D.*
FREIBURG and BIBERACH, WEST GERMANY
Abstract After primary successful PTA, 199 patients were randomized into one of three treatment groups, namely, placebo or a combination of 75 mg dipyridamole with either 330 mg (high dose) or 100 mg (low dose) acetylsalicylic acid (ASA) tid. The duration of treatment was six months. Of the 199 patients admitted to the study, 156 completed the six-month trial period. Not all patients had a second angiogram, and in these cases clinical findings were used in the evaluation. Evaluation of the combined angiographic and clinical results showed improvement or no deterioration in 37% of patients in the placebo group compared with 49% in the low-dose and 61% in the high-dose ASA groups respectively. The only statistically significant difference observed was between the placebo group and the group treated with dipyridamole and high-dose ASA (p = 0.01). This difference remained statistically significant at p 0.039 if only the angiographic findings were considered for group comparison. It cannot, however, be concluded from this study that 75 mg dipyridamole in combination with 100 mg ASA tid is more effective in preventing reocclusion after PTA than in combination with 330 mg ASA tid. =
-
-..........--
Introduction Percutaneous transluminal angioplasty (PTA) is a valuable procedure for the local treatment of occlusive arteriosclerotic vascular disease. Risks and complications associated with From the
Department of Internal Medicine III,
Medical Clinic,
University of Freiburg,
Biberach, West Germany
263
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
and *Dr. Karl Thomae GmbH,
264
.
this intervention are low.’’2 The procedure may, moreover, be performed repeatedly. It supports the therapeutic regimen for patients with occlusive arterial disease, which includes physical, medical, and surgical strategies. The influence of this intervention on the natural course of occlusive arteriosclerotic disease has not yet been fully clarified. In addition the efficacy of any therapy in preventing recurrence of femoral and popliteal arteriosclerotic lesions following PTA has not been shown convincingly in clinical studies. In the past few years special attention has been paid to drugs that inhibit platelet aggregation. Among these, acetylsalicylic acid (ASA) has been most widely used. It causes irreversible inhibition of platelet cyclooxygenase and thereby prevents the formation of thromboxane A2 (TXA2), a potent platelet aggregator. Depending on the dose of ASA used, however, the cyclooxygenase in the endothelial cells is also inhibited. This mechanism leads to a reduction of the formation of prostaglandin, which is a potent vasodilator and exerts pronounced antithrombotic activity. This undesirable effect may be diminished by the addition of dipyridamole (DPM), which has been known for many years as an antithrombotic agent. It is a phosphodiesterase inhibitor and delays the breakdown of platelet cyclic adenosine monophosphate (AMP). Furthermore, it inhibits the uptake of adenosine, which is physiologically released from the endothelium. Similar to prostacyclin, it enhances platelet cyclic AMP levels, which contribute to an antiaggregatory stabilization of the platelets.3-’ It has been shown in pharmacology and clinical pharmacologic studies9 that ASA potentiates the effect of DPM in a dose-dependent way. It was, therefore, justifiable to administer a combination of ASA with DPM to patients who had undergone PTA in order to prevent the recurrence of the obliterative arteriosclerotic disease at the site of the angioplasty. Evidence for the efficacy of the combination of DPM with ASA is available in the prophylaxis of myocardial reinfarction,’° following coronary bypass surgery,&dquo; in the prevention of stroke, 12 and from therapeutic studies in arterial occlusive dis-
ease. 6,7
investigated, therefore, the efficacy of different fixed combinations of DPM and ASA, namely, 75/330 mg and 75/100 mg respectively, versus placebo in a randomized, doubleblind, angiographically controlled study. The different doses of ASA were chosen because Sinzinger et all3 had shown that both 20 and 1,000 mg of aspirin per day significantly reduces platelet uptake ratio to the same extent. Long-term administration of 20 mg ASA also almost completely inhibited formation of thromboxane B2 (TXB2), whereas platelet aggregation as stimulated by adenosine diphosphate (ADP) was not significantly changed. The aim of the study was, therefore, to compare the effects of the three treatments in preventing the recurrence of femoral or popliteal lesions following successful angioplasty. In addition, we wanted We
apparent difference between the two doses of ASA used in the combination with DPM, namely, 990 mg and 300 mg per day. Preliminary results, which to determine whether there was any
prompted the additional statistical analysis of all data accumulated in the study, by Heiss et all4 in 1987.
were
reported
Patients and Methods Between January, 1981, and September, 1985, 199 patients (134 men, 65 women) between thirty-five and eighty-five years of age who had given informed consent were admitted to the study. Patients with arteriosclerotic lesions or occlusions in stage I, II, or III of the Fontaine
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
265
classification were considered for the study in joint meetings of angiologists, radiologists, and vascular surgeons. The inclusion criterion was a lesion with greater than 50 % narrowing of the lumen diameter on monoplane angiography located in the femoropopliteal segment of the artery. Only patients with primary successful PTA were randomized into the treatment groups. Excluded from the study were patients with one or more of the following criteria: hemodynamically relevant occlusions or stenoses of more than 50 % in the pelvic region; a pathologic platelet count; hemorrhagic or allergic diatheses; gastrointestinal ulcers, gastritis, or
duodenitis; tor
severe
cardiac, pulmonary, renal,
or
hepatic insufficiency; diseases of the locomo-
system; and long-term immobilization.
The current medication of the patients was discontinued seven days prior to angioplasty. During the study, no drugs that could affect platelet or coagulation parameters were administered. Patients were randomized one to two hours following successful angioplasty into one of the three treatment groups, which were placebo, 75 mg DPM plus 330 mg ASA, or 75 mg DPM plus 100 mg ASA tid. The capsules were identical and given in a double-blind way. The duration of treatment and observation period after PTA was six months. The following investigations were performed to evaluate the efficacy of the preparations: angiography; walking distance; duration of the negative reaction in the exercise oscillogram; systolic pressure in the radial, posterior tibial, and dorsalis pedis arteries on both sides by Doppler sonography; pressure differences in the corresponding radiotibial and radiodorsal artery; and plethysmography of both lower limbs, which was, however, started first with patient number 47. The first angiogram was taken four to six weeks prior to angioplasty (in a few cases three to four months before commencement of treatment). The second angiogram was obtained immediately after angioplasty and the third six months later. The study population is described in more detail with regard to age and sex distribution, clinical stage before angioplasty, and distribution of risk factors in Tables I to III. TABLE I
Age and Sex Distribution of 199
Patients
TABLE ][I
Clinical
Stage Before Angioplasty
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
266 :~ ,
TABLE III I Distribution of Risk Factors
’
’
. ’
significant difference between the treatment groups regarding age, sex, height, body weight, condition of the occlusive arterial disease, and distribution of risk factors su;.h as cigarette smoking, diabetes mellitus, hypertension, and hypercholesterolemia. There
was no
Completion
TABLE IV and Termination
of Study
Angiogram: evaluation according to control angiogram at termination of trial. Clinical findings: evaluation according to clinical findings at termination of trial
without
angiogram.
_
~~
~
z
Results Of the 199 patients admitted to the three treatment groups, 156 completed the six-month trial period. The reasons for withdrawal of the remaining 43 patients are given in Table IV. Not all patients had a second angiogram, and in these cases the clinical findings were used in the assessment. the results of the combined evaluation of patency assessed angiographically and clinically are given in Table V. If only the angiographic findings are taken into consideration there is still a significant difference between the combination of DPM 75/ASA 330 mg and placebo as shown in Table VI. ’
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
267 TABLE V Total Number of Patients Assessed by Angiography or Substituted Clinical Findings from Those Cases Who Did Not Undergo Reangiography (this subgroup includes 1 SS patients who completed treatment according to trial protocol as well as 15 patients who discontinued treatment prior to the planned 6 months study period)
study design was a three-group comparison. As shown in Tables V and VI there was an significant difference at p = 0.039 and p = 0.106 level in the evaluation of the angiographic plus the clinical data and in the angiographic data alone, respectively. In the twogroup comparison between DPM 75/ASA 330 and placebo there was a statistically significant 0.011 in favor of the DPM/ASA group in the angiographic difference of p = 0.039 and p and the angiographic plus clinical data, respectively. No statistically significant difference was found between placebo and DPM 75/ASA 100 or between DPM 75/ASA 100 and DPM The overall
=
75/ASA 330. Other parameters, such as the pressure difference between the posterior tibial, dorsalis pedis, and radial arteries as measured by Doppler sonography, walking distance, exercise oscillography, plethysmography, and clinical findings, showed no statistically significant difference among the three groups. Discussion
Acetylsalicylic acid (ASA) has been employed as an antithrombotic agent for some timer and even today it is still an open question whether ASA is clinically effective in preventing arterial thrombosis. There exists a so-called &dquo;aspirin-dilemma; ’ 19 which states that ASA inhibits the two opposing biologically effective eicosanoids thromboxane A, and prostacyclin
(PGI2) . The use of DPM compensates at least in part for the increased tendency for platelet aggregation, which results from the decreased prostacyclin systhesis by ASA. The favorable results in clinical studies by Hess et al6’’ and by Chesebro et all encouraged us to pursue this concept
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
268
study by Chesebro et al concerned the management of patients who had undergone coronary bypass surgery. These patients were treated preoperatively with DPM and postoperatively with a combination of DPM plus ASA. A similar study in a small number of patients by Pantely et al2° did not produce such favorable results. Most probably this study was at a disadvantage in that the treatment with 75 mg DPM plus 325 mg ASA was first started on the third postoperative day. In an open study by Zeitler et al21 no difference in the incidence of recurrence following PTA was seen when the two treatments, ASA alone and ASA plus heparin, were compared. Ehresmann et a122 also did not observe any difference between treatment with ASA and placebo with regard to the clinical stage, according to Fontaine, in a large number of patients following further. The
vascular surgery. The only study that can be compared partially with the present investigation was performed by Hess et al,6 although a placebo control group was not included and only some of the results were angiographically confirmed. The 101 patients treated received either 330 mg ASA or a fixed combination of 330 mg ASA plus 75 mg DPM orally tid, beginning twenty-four hours before and up to fourteen days after PTA. The combination group 330 mg ASA plus 75 mg DPM proved to be more effective (p < 0.1) than ASA alone. In a further study by Hess et al,7 240 patients were admitted to a double-blind trial to determine the long-term effect of platelet-function-inhibiting agents on occlusive arterial disease in the lower extremities. Patients were randomized into one of three treatment groups: 330 mg ASA; 75 mg DPM and 330 mg ASA; or matching placebo tid. The duration of treatment was two years. Results were evaluated by repeated angiography at end point. Qualitative evaluation of angiograms 1 and 2 showed a difference in the formation of new occlusions and in the grade of stenosing changes among the three treatment groups. Significantly more occlusions occurred in the placebo group than in the active treatment groups and in these there was also a trend for stenotic lesions to regress more. The difference between the DPM/ASA group and the placebo group was significant (p < 0.01), but there was no significant difference between the ASA group and the placebo group. The difference between the two active treatment groups was significant (p < 0.01) in favor of the combination DPM/ASA.
Conclusions The angiographic findings in the present study also showed a significant difference between DPM 75/ASA 330 and placebo in favor of the combination but not between the placebo and the DPM group with low-dose ASA (100 mg). The study supports, therefore, the previous findings of Hess et al,7 where the use of 75 mg DPM in combination with 330 mg ASA tid prevented the recurrence and progression of stenosis in peripheral arterial disease. The results do not support a contention that a reduction of the ASA dose from 990 mg per day to 300 mg per day is of benefit for reducing recurrence of arterial lesions after angioplasty. This may eventually hold true for ASA doses lower than 300 mg per day.
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
269
Acknowledgment We wish to thank Mrs. Christiane Müller of Dr. Karl Thomae GmbH for data and assisting with the statistical analysis.
documenting the
H. W Heiss, M. D. , F.I. C. A. Professor of Medicine Department of Internal Medicine III Medical Clinic, University of Freiburg Hugstetterstrasse 55 D-7800 Freiburg, West Germany
References 1. Mahler F, Nachbur B, Probst P: Die perkutane Katheterbehandlung arterieller Stenosen und Gefäßverschlüsse der unteren Extremität. Schweiz Rundschau Med 68:1250-1253, 1979. 2. Schneider E, Gruntzig A, Bollinger A: Langzeitergebnisse nach perkutaner transluminaler Angioplastie der Extremitätenarterien. Vasa 10:97 (abstr). 3. Moncada S, Gryglewski RJ, Bunting S, et al: An enzyme isolated from arteries transforms prostaglandin endoperosides to an unstable substance that inhibits platelet aggregation. Nature 263:663-665, 1976. 4. Moncada S, Korbut R: Dipyridamole and other phosphodiesterase inhibitors act as antithrombotic agents by potentiating endogenous prostacyclin. Lancet 1:12861289, 1978. 5. Harber LA: In vivo evaluation of antithrombotic therapy in man. In: Platelets, Thrombosis and Inhibitors, ed. by didisheim P, Shimamoto T, Yamazaki H. Thromb Diath Haemorrh (Suppl 60):481-486, 1974. 6. Hess H, Müller-Faßbender H, Ingrisch H, et al: Verhütung von Wiederverschlüssen nach Rekanalisation obliterierter Arterien mit der Kathetermethode. Dtsch Med Wochenschr 103:1994-1997, 1978. 7. Hess H, Mietaschk A, Deichsel G: Drug-induced inhibition of platelet function delays progression of peripheral occlusive arterial disease. Lancet 1:415-419, 1985. 8. Harker LA, Kadatz RA: Mechanism of action of dipyridamole. Thromb Res Suppl IV: 39-46, 1983. 9. Tindall H, Paton RC, McNicol CP: Aspirin, dipyridamole and platelet survival in patients with diabetes mellitus. Clin Sci 63:205-209, 1982. 10. Klimt CR, Knatterud GL, Stamler J, et al: Persantine aspirin reinfarction study. Part II. Secondary coronary prevention with Persantine and aspirin. J Am Coll Cardiol 7:251-269, 1986. 11. Chesebro JH, Fuster V, Elveback LR, et al: Effect of dipyridamole and aspirin on late vein-graft patency af-
ter coronary
bypass operations.
N
Engl
J Med
310:209-214, 1984.
European Stroke Prevention Study (ESPS): Principal end points. Lancet 2:1351-1354, 1987. Sinzinger H, Silberbauer K, Kaliman J, et al: 20 mg aspirin daily—evidence for a clinical future of this extremely low dose in arterial disease? Vasa 17:10, 1988. Heiss HW, Mathias K, Beck AH, et al: Rezidivprophylaxe mit Acetylsalicylsäure und Dipyridamol nach perkutaner transluminaler Angioplastie der Beinarte-
12. The 13.
14.
15.
16. 17.
18.
19.
20.
21.
22.
rien bei obliterierender Arteriosklerose. CorVas 1:2534, 1987. Carven LL: Experiences with aspirin with non-specific prophylaxis of coronary thrombosis. Miss Valley Med J 75:38-41, 1953. O’Brian JR: The adhesiveness of native platelets and its prevention. J Clin Path 14:140-144, 1961. O’Brian JR: Effects of salicylates on human platelets. Lancet 1:779-783, 1968. Weiss HJ, Aledort LM: Imparied platelet connectivetissue reaction in man after aspirin ingestion. Lancet 2:495-497, 1967. De Gaetano H, Cerletti C, Bertele V: Pharmacology of antiplatelet drugs and clinical trials on thrombosis prevention : A difficult link. Lancet 2:974-977, 1982. Pantely GA, Scott H, Goodnight SH Jr, et al: Failure of antiplatelet and anticoagulant therapy to improve patency of grafts after coronary-artery bypass: A controlled, randomized study. N Engl J Med 301:962-966, 1979. Zeitler E, Reichold J, Schoop W, et al: Einfluß von Acetylsalicylsäure auf das Früshergebnis nach perkutaner Rekanalisation arterieller Obliterationen nach Dotter. Dtsch Med Wochenschr 98:1285-1288, 1973. Ehresmann U, Alemanny A, Loew D: Prophylaxe von Rezidivverschlüssen nach Ravaskularisationseingriffen mit Acetylsalicylsäre. Med Welt 28:1157-1162, 1977.
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
Prophylaxis with Dipyridamole Combined with Acetylsalicylic Acid Following PTA H. W. Heiss, M.D., F.I.C.A. H. Just, M.D. D. Middleton, M.D.* and G. Deichsel, M.D.*
FREIBURG and BIBERACH, WEST GERMANY
Abstract After primary successful PTA, 199 patients were randomized into one of three treatment groups, namely, placebo or a combination of 75 mg dipyridamole with either 330 mg (high dose) or 100 mg (low dose) acetylsalicylic acid (ASA) tid. The duration of treatment was six months. Of the 199 patients admitted to the study, 156 completed the six-month trial period. Not all patients had a second angiogram, and in these cases clinical findings were used in the evaluation. Evaluation of the combined angiographic and clinical results showed improvement or no deterioration in 37% of patients in the placebo group compared with 49% in the low-dose and 61% in the high-dose ASA groups respectively. The only statistically significant difference observed was between the placebo group and the group treated with dipyridamole and high-dose ASA (p = 0.01). This difference remained statistically significant at p 0.039 if only the angiographic findings were considered for group comparison. It cannot, however, be concluded from this study that 75 mg dipyridamole in combination with 100 mg ASA tid is more effective in preventing reocclusion after PTA than in combination with 330 mg ASA tid. =
-
-..........--
Introduction Percutaneous transluminal angioplasty (PTA) is a valuable procedure for the local treatment of occlusive arteriosclerotic vascular disease. Risks and complications associated with From the
Department of Internal Medicine III,
Medical Clinic,
University of Freiburg,
Biberach, West Germany
263
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
and *Dr. Karl Thomae GmbH,
264
.
this intervention are low.’’2 The procedure may, moreover, be performed repeatedly. It supports the therapeutic regimen for patients with occlusive arterial disease, which includes physical, medical, and surgical strategies. The influence of this intervention on the natural course of occlusive arteriosclerotic disease has not yet been fully clarified. In addition the efficacy of any therapy in preventing recurrence of femoral and popliteal arteriosclerotic lesions following PTA has not been shown convincingly in clinical studies. In the past few years special attention has been paid to drugs that inhibit platelet aggregation. Among these, acetylsalicylic acid (ASA) has been most widely used. It causes irreversible inhibition of platelet cyclooxygenase and thereby prevents the formation of thromboxane A2 (TXA2), a potent platelet aggregator. Depending on the dose of ASA used, however, the cyclooxygenase in the endothelial cells is also inhibited. This mechanism leads to a reduction of the formation of prostaglandin, which is a potent vasodilator and exerts pronounced antithrombotic activity. This undesirable effect may be diminished by the addition of dipyridamole (DPM), which has been known for many years as an antithrombotic agent. It is a phosphodiesterase inhibitor and delays the breakdown of platelet cyclic adenosine monophosphate (AMP). Furthermore, it inhibits the uptake of adenosine, which is physiologically released from the endothelium. Similar to prostacyclin, it enhances platelet cyclic AMP levels, which contribute to an antiaggregatory stabilization of the platelets.3-’ It has been shown in pharmacology and clinical pharmacologic studies9 that ASA potentiates the effect of DPM in a dose-dependent way. It was, therefore, justifiable to administer a combination of ASA with DPM to patients who had undergone PTA in order to prevent the recurrence of the obliterative arteriosclerotic disease at the site of the angioplasty. Evidence for the efficacy of the combination of DPM with ASA is available in the prophylaxis of myocardial reinfarction,’° following coronary bypass surgery,&dquo; in the prevention of stroke, 12 and from therapeutic studies in arterial occlusive dis-
ease. 6,7
investigated, therefore, the efficacy of different fixed combinations of DPM and ASA, namely, 75/330 mg and 75/100 mg respectively, versus placebo in a randomized, doubleblind, angiographically controlled study. The different doses of ASA were chosen because Sinzinger et all3 had shown that both 20 and 1,000 mg of aspirin per day significantly reduces platelet uptake ratio to the same extent. Long-term administration of 20 mg ASA also almost completely inhibited formation of thromboxane B2 (TXB2), whereas platelet aggregation as stimulated by adenosine diphosphate (ADP) was not significantly changed. The aim of the study was, therefore, to compare the effects of the three treatments in preventing the recurrence of femoral or popliteal lesions following successful angioplasty. In addition, we wanted We
apparent difference between the two doses of ASA used in the combination with DPM, namely, 990 mg and 300 mg per day. Preliminary results, which to determine whether there was any
prompted the additional statistical analysis of all data accumulated in the study, by Heiss et all4 in 1987.
were
reported
Patients and Methods Between January, 1981, and September, 1985, 199 patients (134 men, 65 women) between thirty-five and eighty-five years of age who had given informed consent were admitted to the study. Patients with arteriosclerotic lesions or occlusions in stage I, II, or III of the Fontaine
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
265
classification were considered for the study in joint meetings of angiologists, radiologists, and vascular surgeons. The inclusion criterion was a lesion with greater than 50 % narrowing of the lumen diameter on monoplane angiography located in the femoropopliteal segment of the artery. Only patients with primary successful PTA were randomized into the treatment groups. Excluded from the study were patients with one or more of the following criteria: hemodynamically relevant occlusions or stenoses of more than 50 % in the pelvic region; a pathologic platelet count; hemorrhagic or allergic diatheses; gastrointestinal ulcers, gastritis, or
duodenitis; tor
severe
cardiac, pulmonary, renal,
or
hepatic insufficiency; diseases of the locomo-
system; and long-term immobilization.
The current medication of the patients was discontinued seven days prior to angioplasty. During the study, no drugs that could affect platelet or coagulation parameters were administered. Patients were randomized one to two hours following successful angioplasty into one of the three treatment groups, which were placebo, 75 mg DPM plus 330 mg ASA, or 75 mg DPM plus 100 mg ASA tid. The capsules were identical and given in a double-blind way. The duration of treatment and observation period after PTA was six months. The following investigations were performed to evaluate the efficacy of the preparations: angiography; walking distance; duration of the negative reaction in the exercise oscillogram; systolic pressure in the radial, posterior tibial, and dorsalis pedis arteries on both sides by Doppler sonography; pressure differences in the corresponding radiotibial and radiodorsal artery; and plethysmography of both lower limbs, which was, however, started first with patient number 47. The first angiogram was taken four to six weeks prior to angioplasty (in a few cases three to four months before commencement of treatment). The second angiogram was obtained immediately after angioplasty and the third six months later. The study population is described in more detail with regard to age and sex distribution, clinical stage before angioplasty, and distribution of risk factors in Tables I to III. TABLE I
Age and Sex Distribution of 199
Patients
TABLE ][I
Clinical
Stage Before Angioplasty
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
266 :~ ,
TABLE III I Distribution of Risk Factors
’
’
. ’
significant difference between the treatment groups regarding age, sex, height, body weight, condition of the occlusive arterial disease, and distribution of risk factors su;.h as cigarette smoking, diabetes mellitus, hypertension, and hypercholesterolemia. There
was no
Completion
TABLE IV and Termination
of Study
Angiogram: evaluation according to control angiogram at termination of trial. Clinical findings: evaluation according to clinical findings at termination of trial
without
angiogram.
_
~~
~
z
Results Of the 199 patients admitted to the three treatment groups, 156 completed the six-month trial period. The reasons for withdrawal of the remaining 43 patients are given in Table IV. Not all patients had a second angiogram, and in these cases the clinical findings were used in the assessment. the results of the combined evaluation of patency assessed angiographically and clinically are given in Table V. If only the angiographic findings are taken into consideration there is still a significant difference between the combination of DPM 75/ASA 330 mg and placebo as shown in Table VI. ’
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
267 TABLE V Total Number of Patients Assessed by Angiography or Substituted Clinical Findings from Those Cases Who Did Not Undergo Reangiography (this subgroup includes 1 SS patients who completed treatment according to trial protocol as well as 15 patients who discontinued treatment prior to the planned 6 months study period)
study design was a three-group comparison. As shown in Tables V and VI there was an significant difference at p = 0.039 and p = 0.106 level in the evaluation of the angiographic plus the clinical data and in the angiographic data alone, respectively. In the twogroup comparison between DPM 75/ASA 330 and placebo there was a statistically significant 0.011 in favor of the DPM/ASA group in the angiographic difference of p = 0.039 and p and the angiographic plus clinical data, respectively. No statistically significant difference was found between placebo and DPM 75/ASA 100 or between DPM 75/ASA 100 and DPM The overall
=
75/ASA 330. Other parameters, such as the pressure difference between the posterior tibial, dorsalis pedis, and radial arteries as measured by Doppler sonography, walking distance, exercise oscillography, plethysmography, and clinical findings, showed no statistically significant difference among the three groups. Discussion
Acetylsalicylic acid (ASA) has been employed as an antithrombotic agent for some timer and even today it is still an open question whether ASA is clinically effective in preventing arterial thrombosis. There exists a so-called &dquo;aspirin-dilemma; ’ 19 which states that ASA inhibits the two opposing biologically effective eicosanoids thromboxane A, and prostacyclin
(PGI2) . The use of DPM compensates at least in part for the increased tendency for platelet aggregation, which results from the decreased prostacyclin systhesis by ASA. The favorable results in clinical studies by Hess et al6’’ and by Chesebro et all encouraged us to pursue this concept
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
268
study by Chesebro et al concerned the management of patients who had undergone coronary bypass surgery. These patients were treated preoperatively with DPM and postoperatively with a combination of DPM plus ASA. A similar study in a small number of patients by Pantely et al2° did not produce such favorable results. Most probably this study was at a disadvantage in that the treatment with 75 mg DPM plus 325 mg ASA was first started on the third postoperative day. In an open study by Zeitler et al21 no difference in the incidence of recurrence following PTA was seen when the two treatments, ASA alone and ASA plus heparin, were compared. Ehresmann et a122 also did not observe any difference between treatment with ASA and placebo with regard to the clinical stage, according to Fontaine, in a large number of patients following further. The
vascular surgery. The only study that can be compared partially with the present investigation was performed by Hess et al,6 although a placebo control group was not included and only some of the results were angiographically confirmed. The 101 patients treated received either 330 mg ASA or a fixed combination of 330 mg ASA plus 75 mg DPM orally tid, beginning twenty-four hours before and up to fourteen days after PTA. The combination group 330 mg ASA plus 75 mg DPM proved to be more effective (p < 0.1) than ASA alone. In a further study by Hess et al,7 240 patients were admitted to a double-blind trial to determine the long-term effect of platelet-function-inhibiting agents on occlusive arterial disease in the lower extremities. Patients were randomized into one of three treatment groups: 330 mg ASA; 75 mg DPM and 330 mg ASA; or matching placebo tid. The duration of treatment was two years. Results were evaluated by repeated angiography at end point. Qualitative evaluation of angiograms 1 and 2 showed a difference in the formation of new occlusions and in the grade of stenosing changes among the three treatment groups. Significantly more occlusions occurred in the placebo group than in the active treatment groups and in these there was also a trend for stenotic lesions to regress more. The difference between the DPM/ASA group and the placebo group was significant (p < 0.01), but there was no significant difference between the ASA group and the placebo group. The difference between the two active treatment groups was significant (p < 0.01) in favor of the combination DPM/ASA.
Conclusions The angiographic findings in the present study also showed a significant difference between DPM 75/ASA 330 and placebo in favor of the combination but not between the placebo and the DPM group with low-dose ASA (100 mg). The study supports, therefore, the previous findings of Hess et al,7 where the use of 75 mg DPM in combination with 330 mg ASA tid prevented the recurrence and progression of stenosis in peripheral arterial disease. The results do not support a contention that a reduction of the ASA dose from 990 mg per day to 300 mg per day is of benefit for reducing recurrence of arterial lesions after angioplasty. This may eventually hold true for ASA doses lower than 300 mg per day.
Downloaded from ang.sagepub.com at Purdue University on June 10, 2015
269
Acknowledgment We wish to thank Mrs. Christiane Müller of Dr. Karl Thomae GmbH for data and assisting with the statistical analysis.
documenting the
H. W Heiss, M. D. , F.I. C. A. Professor of Medicine Department of Internal Medicine III Medical Clinic, University of Freiburg Hugstetterstrasse 55 D-7800 Freiburg, West Germany
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