THROMBOSIS RESEARCH Supplement XII; 51-59,1990 004~3949/90 $3.00 + .OO Printed In the USA. Copyright (c) 1990 Pergrmon Press pk. All rights reserved.
PREVENTION
OF ACUTE COMPLICATIONS AFTER PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY
M.G. Bourassa, L. Schwartz’, J. Lesperance, C. Eastwoodz, F. Kazim* Department of Medicine and Radiology, Montreal Heart Institute, Department of Medicine, Toronto General Hospital’, and Medical Department, Boehringer Ingelheim Canada* ARwRAcT The prevention of major complications occurring during or early after percutaneous transluminal coronary angioplasty was evaluated in 376 patients in a randomized, double-blind, placebo-controlled multicenter trial. Starting 24 hours before angioplasty, I87 patients received an aspirin-dipyridamole combination and 189 were given placebo. There were no periprocedural deaths. Periprocedural nonQ wave fatal myocardial infarction was diagnosed in 34 patients (9.0%). myocardial infarction occurred in 16 patients: 3 (1.6%) in the aspirin-dipyridamole group and 13 (6.y) in the placebo group (p = 0.0113). Non-Q wave myocardial infarction occurred in 18 patients: 6 (3.2%) in the active drug group and 12 (6.3%) in the placebo group (p = 0.1538). Emergency myocardial revascularization was performed in 9 patients in each treatment arm. Q wave myocardial infarction occurred following revascularization in 5 patients (55.5%) in the placebo group and in only 2 (22.2%, p = 0.1670) in the aspirindipyridamole group. Thus the incidence of periprocedural Q and non-Q wave myocardial infarction is high in patients not on antiplatelet therapy (13.2%) and is markedly lower in those on the aspirin-dipyridamole combination (4.8%, p = 0.0044). Short-term antiplatelet therapy before and after angioplasty can be recommended for patients who do not have contraindications to this medication.
INTRODUCI’ION Major clinical complications occurring during, or early after, percutaneous transluminal coronary angioplasty (PTCA) include death, non-fatal myocardial infarction and emergency revascularization for impending infarction (l-4) The role of antiplatelet therapy in reducing their occurrence was recognized only recently (5,6). The purpose of this report is to evaluate the effect of an aspirin-dipyridamole combination therapy in the prevention of major complications occurring less than 48 hours after PTCA. PATIENTS AND METHODS Patients Patients were enrolled between November 1983 and December 1986 at two participating centers, the Toronto General Hospital and the Montreal Heart Institute. Consecutive patients Keywords:randomized
clinical trial, antiplatelet
agents,
revascularization.
51
Q and non-Q wave myocardial
infarction,
myocardial
52
PREVENTION OF PTCA COMPLICATIONS
Suppl. XII, 1990
scheduled for coronary angioplasty during this period were candidates for the study. However, only patients in whom at least one lesion with stenosis of 70% diameter or greater, who were scheduled for angioplasty, met the inclusion criteria. Moreover, patients were excluded if they presented with any of the conditions listed in Table 1. After signing a written informed consent, patients were randomized into the active drug or placebo arm of the study using a center-specific computer-generated allocation schedule. TABLE
1
Exclusion Criteria for Study Candidates
Age less than 21 years
Documented variant angina
Previous coronary angioplasty
Documented duodenal ulcer
Hypersensitivity to aspirin, dipyridamole or tartrazine
Upper GI tract bleeding in past 6 months History of a hemorrhagic disorder
Non-interruptible anticoagulant or antiplatelet therapy at least 7 days prior to entry
Severe uncontrolled systemic illness History of asthma
Nasal polyps
Studv medication The study was a randomized, double-blind, placebo-controlled trial. The active treatment comprised an oral aspirin-dipyridamole combination (330 mg and 75 mg respectively, t.i.d.) beginning 24 hours before PTCA. Eight hours pre-PTCA, oral dipyridamole was replaced with intravenous dipyridamole (10 mg/hour) for 24 hours while oral aspirin was continued. At 16 hours post-PTCA the oral combination was reinstituted every 8 hours. Patients in the placebo arm received matching oral and intravenous placebos during the same period. If complications occurred during or within 48 hours after the procedure, or if no lesion was successfully dilated (i.e. reduced from 70% or greater obstruction to 50% or less), study medication was discontinued and appropriate medical or surgical therapy was given. In patients with successful angioplasty, the medication was maintained until the date of the follow-up angiogram at 4-7 months. AneioDlastv Drocedure Diltiazem was given orally in 60 mg doses 12 and 4 hours before angioplasty. Heparin (10,000 IU i.v.> was given at the onset of the procedure and continued at 200 III/hour for 3 hours. After the groin sheaths were removed at 4 hours, heparin was resumed at a rate of 500 IU/ hour for 12 hours. Low molecular weight dextran was started at the beginning of angioplasty and was continued until a total of 500 ml had been administered. Glyceryl trinitrate (200 pg) was given intravenously just before dilatation. The angioplasty procedure was performed using the steerable technique with an attempt to obtain the best cosmetic result by selecting a balloon size appropriate to the artery.
Suppl. XII, 1990
PREVENTION
OF PTCA COMPLICATIONS
ECG and enzvmic data Resting ECGs were recorded routinely before and approximately 24 hours after angioplasty. Additional ECGs were obtained when clinically indicated. Creatine kinase (CK) was determined at least once within 24 hours after angioplasty and was repeated as clinically indicated. Whenever CK levels were elevated above normal values, the CK-MB fraction was measured. Pre- and post-angioplasty ECGs were interpreted independently by two experienced cardiologists, who were blinded as to treatment allocation. Using Minnesota code criteria (7,8), post-angioplasty ECGs were classified for each patient as: indeterminate, if the pre- or post-afigioplasty ECG showed bundle branch block or if a pre- or post-angioplasty tracing was not recorded; unchanged, compared with the pre-angioplasty tracing; showing new ST-T wave changes; showing new significant Q waves. Discrepancies between the two interpreters were resolved by consensus. Identical methods of enzymatic determinations and identical normal CK values (225 U/liter or less for males and 110 U/liter or less for females) were used at both centers (9). Enzymatic increases were defined as abnormal when CK values were at least twice the upper normal limit br when the CK value was above normal and the CK-MB fraction was 8% or greater. Patients were classified into three subgroups: the Q wave myocardial infarction group included patients with new significant Q waves on post-PTCA ECGs and significant enzyme elevations; the non-Q wave myocardial infarction group included patients with new ST-T changes on post-PTCA ECGs with significant enzyme rises, or significant enzyme rises without ECG changes after PTCA; and patients with unchanged or indeterminate ECGs or nonspecific ST-T changes with normal enzymes after PICA formed the third group. Death and complications were considered to be procedure-related if they occurred within 48 hours after PTCA. Major procedure-related complications included Q or non-Q wave myocardial infarction, the need for revascularization by coronary bypass surgery or by repeat PTCA as a separate procedure, within 48 hours after the index PTCA. Aneiorrraohic data The angiographic technique was standardized. Orthogonal views of target lesions with at least one of these views reflecting the most severe aspect of stenosis were recorded. Transverse angulations were recorded for each coronary injection, and angiographic success was determined by visual estimation. A segment was considered to be successfully dilated when a lumen stenosis of 70% diameter or greater present before angioplasty, was reduced to less than 50% immediately after angioplasty. Statistical analvsis The chi-square statistic and, when appropriate, Students t-test were used in the univariate analysis of differences between treatment groups in the distribution of baseline and outcome variables. RESULTS
Baseline data and orimarv success rate Selected clinical and angiographic characteristics of the 376 patients are shown in Table 2. The mean age was 52.0 f 9.0 years and 79.5% of patients were male. A history of hypertension was noted in 73 patients and 24 suffered from diabetes mellitus. The mean serum cholesterol
54
PREVENTION OF PTCA COMPLICATIONS
Suppl. XII, 1990
TABLE 2
Clinical and Angiographic Number Number of patients Age (years) Males/females History of hypertension Diabetes Cholesterol (mmol/liter) Triglycerides (mmol/liter) Angina class*: I-II III-Iv Unstable angina Prior myocardial infarction Extent of coronary artery disease: single vessel multivessel Patients having: single lesion PTCA multi-lesion PTCA
52.0 + 9.0 299/77 73 24 5.73 f 1.20 2.29 f 1.31 175 174 56 93
Characteristics (%)
(79.5%/20.5%) (19.4%) (6.4%)
(50.1%) (49.9%) (14.9%) (24.7%)
245 131
(65.2%) (34.8%)
272 97
(73.7%) (26.3%)
Values represent means f SD. Canadian Cardiovascular Society angina classification. ??
was 5.73 f 1.20 mmol/litre
and mean serum triglycerides 2.29 + 1.31 mmol/litre. Of the patients with angina, the severity was class I or II in 50.1% of the patients and class III or IV in 49.9%. Of all patients, 14.9% had unstable angina and 24.7% were diagnosed as having prior myocardial infarction. Finally, 65.2% had single vessel disease and 34.8% multivessel disease. Segments attempted at PTCA involved the left anterior descending artery in 51% of the patients, the right coronary artery in 31% and left circumflex artery in 18%. Single lesion angioplasty was attempted in 73.7% of the patients and multilesion angioplasty in 26.3%. Seven patients did not have any lesion attempted., Among the remaining 369 patients, 329 had at least one lesion successfully dilated, resulting in a primary success rate/patient of 89.1%. Of the 489 segments attempted, 374 were successfully dilated giving a primary success rate/ segment of 76.5%. Incidence of orocedure-related 0 and non-0 wave mvocardial infarction There were no procedural deaths among the 376 patients. Sixteen patients (4.3%) suffered a periprocedural Q wave myocardial infarction (Table 3). Nine were managed conservatively during the acute episode. In the other seven patients, the Q wave infarction was documented following emergency myocardial revascularization. Eighteen patients (4.8%) were strongly suspected of having suffered a non-Q wave myocardial infarction. Eight developed new STT changes and significant enzyme rises, whereas the other 10 only had significant enzyme elevations. A nonfatal myocardial infarction was, therefore, diagnosed in 34 patients (9.0%) during or early after PTCA.
Suppl. XII, 1990
Incidence
PREVENTION
of Non-fatal
OF PTCA COMPLICATIONS
TABLE 3 Myocardial Infarction
During or Early After PTCA
Aspirin/ Placebo dipyridamole (n = 187) (n = 189) Number (%) Number (%) Q wave myocardial Without
revascularization
revascularization
Total
Non-Q wave myocardial New ST-T changes Abnormal
(Pearson
x2)
1 (0.5)
8 (4.2)
2 (1.1)
13 (6.9)
3 (1.6)
13 (6.9)
0.0113
infarction
with abnormal
CK only
Total
Total infarctions
p value
infarction
emergency
After emergency
55
(both types)
CKl(O.5)
7 (3.7)
5 (2.7)
5 (2.6)
6 (3.2)
I2 (6.3)
0.1538
9 (4.8)
2503.2)
0.0044
Finally, emergency myocardial revascularization was performed in 18 patients (4.8%) of whom I4 had coronary bypass surgery and 4 had repeat PTCA as a separate procedure. Effect of antiolatelet theranv on orocedure-related comolications Of the 376 patients, 187 were randomized to the aspirin-dipyridamole arm and 189 to placebo. The two groups were well matched for all major clinical, angiographic and procedural characteristics. The only significant baseline difference was a higher percentage of females in the aspirin-dipyridamole arm (25% US16% in the placebo arm, p = 0.05). As it has been suggested that aspirin is less effective in females (lo), this may have introduced a bias against treatment efficacy in the aspirindipyridamole arm. The effect of antiplatelet therapy on procedure-related complications is shown in Table 3. Three patients in the aspirin-dipyridamole group had a Q wave myocardial infarction as opposed to 13 in the placebo group. Likewise, 6 patients in the aspirin-dipyridamole group had a non-Q wave infarction in comparison to I2 in the placebo group. Thus, 9 patients (4.8%) in the aspirin-dipyridamole group and 25 patients (13.2%) in the placebo group had a nonfatal myocardial infarction @ = 0.0044). In addition, 9 patients in each group underwent coronary artery bypass surgery or repeat PTCA within 48 hours of the reference PTCA.
PREVENTION
OF PTCA COMPLICATIONS
Suppl. XII, 1990
The number of emergency revascularizations was almost identical (4.8%) in both treatment groups. However, only 2 of 9 patients (22.2%) undergoing early revascularization in the active treatment arm suffered a documented Q wave infarction compared with 5 of 9 (55.5%) in the placebo group. This difference was not statistically significant @ = 0.1670). DISCUSSION This randomized clinical trial demonstrates that aspirin-dipyridamole combination therapy begun 24 hours before PTCA and continued for at least 48 hours after the procedure, is associated with a markedly reduced incidence of Q and non-Q wave myocardial infarction during and early after PTCA. Antiplatelet therapy did not alter the number of emergency myocardial revascularizations after PTCA. However, the incidence of Q wave myocardial infarction in patients undergoing early revascularization in the aspirin-dipyridamole group was only 22% compared with 55% in patients receiving placebo. The role of antiplatelet therapy in reducing the incidence of Q and non-Q wave myocardial infarction during or early after PTCA is supported by previous experimental and clinical data. Balloon angioplasty in animal models has been shown to induce endothelial denudation, platelet adhesion to the subendothelial matrix and platelet thrombus formation (11). Whereas mild arterial injury is associated with only mild platelet accumulation, deep injury extending into the media almost always leads to a non-occlusive or occlusive mural thrombus (12). Reductions in platelet accumulation and mural thrombus formation can be demonstrated experimentally following antiplatelet therapy (13,14). A recent retrospective clinical study has shown that aspirin alone or a combination of aspirin and dipyridamole administered before PTCA were both associated with a decreased incidence and extent of acute coronary thrombosis complicating PTCA (15). Finally, a recent preliminary report also demonstrated marked efficacy of an aspirin-dipyridamole combination and of ticlopidine in reducing procedure-related acute complications after PTCA (6). Our data also support the concept that antiplatelet therapy effectively reduces the incidence of myocardial infarction in these patients. The number of emergency myocardial revascularizations was almost identical in the placebo group and in the group receiving antiplatelet therapy. However, the indications for emergency revascularization were not standardized in this study, but were left to the investigators judgement. Of the 9 patients who suffered a periprocedural Q wave myocardial infarction and did not undergo emergency revascularization for various reasons, 8 had an onset of the event less than 4 hours after the initial PTCA. In addition, there was a marked increase in the number of emergency revascularization procedures during the course of the study which contrasted with the steady incidence of major periprocedural complications. Only 4 patients underwent emergency revascularization during the first half of the study, compared with 14 during the second half. Thus several factors besides study medication influenced the decision to perform emergency revascularization in these patients. In our study, antiplatelet therapy was started before PTCA, as data available at the time indicated that greater effectiveness was obtained by pre-treatment (13,14). Intravenous dipyridamole was used during PTCA in order to ensure complete absorption of the drug during vessel injury. At the doses used in this study, the dipyridamole infusion was well tolerated and there were no apparent side-effects which might have unblinded the investigators (5). Whether this route of dipyridamole administration has advantages over oral administration, in combination with aspirin, during the procedure will require further study. Our study was not designed to test the efficacy of aspirin alone, or of low UShigh doses of
Suppl. XII, 1990
PREVENTION
OF PTCA COMPLICATIONS
57
aspirin in the prevention of PTCA complications. It is possible that low dose aspirin (80 mg/ day> might be as effective as the dose used in our study (990 mg/day) (16,17), and it remains to be established whether aspirin alone is as effective as aspirin-dipyridamole combinations. REFERENCES 1 DORROS, G., COWLEY, M.J., SIMPSON, J., BENTIVOGLIO, L.G., BLOCK, PC., BOURASSA, M., DETRE, K.M., GOSSELIN, A.J., GRUNTZIG, A.R., KELSEY, S.F., KENT, K.M., MOCK, M.B., MULLIN, SM., MYLER, R.K., PASSAMANI, E.R., STERTZER, S.H. and WILLIAMS, D.O. Percutaneous transluminal coronary angioplasty: report of complications from the National Heart, Lung, and Blood Institute PTCA Registry. Circulation, 67, 723-730, 1983. 2 DETRE, K., HOLUBKOV, R., KELSEY, S., COWLEY, M., KENT, K., WILLIAMS, D., MYLER, R., FAXON, D., HOLMES, D., BOURASSA, M., BLOCK, P., GOSSELIN, A., BENTIVOGLIO, L., LEATHERMAN, L., DORROS, G., KING, S., GALICHIA, J., AL-BASSAM, M., LEON, M., ROBERTSON, T. and PASSAMANI, E. Percutaneous transluminal coronary angioplasty in 1985-1986 and 1977-1981. The National Heart, Lung and Blood Institute Registry. NEngl JMed, 318, 265-270, 1988. 3 MABIN, T.A., HOLMES, D.R., SMITH, H.C., VLIETSTRA, R.E., REEDER, G.S., BRESNAHAN, J.F., BOVE, A.A., HAMMES, L.N., ELVEBACK, L.R. and ORSZULAK, T.A. Follow-up clinical Circulation, results in patients undergoing percutaneous transluminal coronary angioplasty. 71, 754-760, 1985. 4 BREDLAU, C.E., ROUBIN, G.S., LEIMGRUBER, P.P., DOUGLAS, J.S., KING, S.B. and GRUENTZIG, A.R. In-hospital morbidity and mortality in patients undergoing elective coronary angioplasty. Circulation 72, 1044-1052, 1985. 5 SCHWARTZ, L., BOURASSA, M.G., LESPERANCE J., ALDRIDGE, H.E., KAZIM, F., SALVATORI, V.A., HENDERSON, M., BONAN, R. and DAVID, P.R. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. NEngi JMed 318, 1714-1719, 1988. 6 WHITE, C.W., CHAITMAN, B., LASSAR, T.A., MARCUS, M.L., CHISHOLM, R.J., KNUDSON, M., MORTON, B., ROY, L., KHAJA, F., VANDORMAEL, M., REITMAN, M. and the Ticlopidine Study Group. Antiplatelet agents are effective in reducing the immediate complications of PTCA: results from the ticlopidine multicenter trial (abstract). Circulation, 76(Suppl), IV-400, 1987. 7 BLACKBURN, H., KEYS, A., SIMONSON, E., RAUTAHARJU, P. and PUNSAR, S. The electrocardiogram in population studies: a classification system. Circulation 22, 1160-1175, 1960. 8 The Coronary Drug Project Research Group. The Coronary Drug Project: methods, and baseline results. Circulation, 47 (Suppl I), l-50, 1973. 9 HOMBURGER, H.A. and JACOB, G.L. Creatine kinase radioimmunoassay electrophoresis compared in the diagnosis of acute myocardial infarction.
design,
and isoenzyme Clin Gem, 26,
PREVENTION OF PTCA COMPLICATIONS
58 861-866,
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1980.
10 Canadian Co-operative Study Group. A randomized trial of aspirin and sulfinpyrazone in treated stroke. NEngl JMed, ZB, 5359, 1978.11 STEELE, P.M., CHESEBRO, J.H., STANSON, A.W., HOLMES, D.R., DEWANJEE, M.K., BADIMON, L. and FUSTER, V. Balloon angioplasty: natural history of the pathophysiological response to injury in a pig model. Circ Res, 57, 105-112, 1985. 12 LAM, J.Y.T., CHESEBRO, J.H., STEELE, P.M., DEWANJEE, M.K., BADIMON, L. and FUSTER,. V. Deep arterial injury during experimental angioplasty: relation to a positive indium-111 labeled platelet scintigram, quantitative platelet deposition and mural thrombosis. JAm Co11Cardiol, 8, 1380-1386, 1986. 13 STEELE, P.M., CHESEBRO, J.H., HOLMES, D.R., BADIMON, L. and FUSTER, V. Balloon angioplasty in pigs: comparative effects of platelet-inhibitor drugs (Abstract). Circulation, 70
(St@@ZZI,11-361, 1984. 14 LAM,J.Y.T., CHESEBRO, J.H., STEELE, P.M., BADIMON, L. and FUSTER, V. Antithrombotic therapy for arterial angioplasty: efficacy of common platelet-inhibitors in a porcine model, Circulation, in press 1990. 15 BARNATHAN, ES., SCHWARTZ, J.S., TAYLOR, L., LASKEY, W.K., KLEAVELAND, J.P., KUSSMAUL, W.G. and HIRSCHFELD, J.W. Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circuldtion, 76, 125-134,
1987. 16 LEMBO, N.J., BLACK, A.J., ROUBIN, G.S., MUFSON, L.H., WILENTZ, J.R., DOUGLAS, J.S. and KING, S.B. Does the addition of dipyridamole to aspirin decrease acute coronary angioplasty fzomplications? The result of a prospective randomized clinical trial (Abstract).
JAm Co11Cardiol, 11, 237A, 1988. 17 MUFSON, L., BLACK, A., ROUBIN, G., WILENTZ, J., MEAD, S., MCFARLAND, K., WEINTRAUB, W., DOUGLAS, J.S. and KING, S.B. A randomized trial of aspirin in PTCA: Effect of high versus low dose aspirin on major complications and restenosis (Abstract). JAm Co11
Cardiol, 11, 236A, 1988.
PREVENTION
OF ACUTE COMPLICATIONS AFTER PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY
M.G. Bourassa, L. Schwartz’, J. Lesperance, C. Eastwoodz, F. Kazim* Department of Medicine and Radiology, Montreal Heart Institute, Department of Medicine, Toronto General Hospital’, and Medical Department, Boehringer Ingelheim Canada* ARwRAcT The prevention of major complications occurring during or early after percutaneous transluminal coronary angioplasty was evaluated in 376 patients in a randomized, double-blind, placebo-controlled multicenter trial. Starting 24 hours before angioplasty, I87 patients received an aspirin-dipyridamole combination and 189 were given placebo. There were no periprocedural deaths. Periprocedural nonQ wave fatal myocardial infarction was diagnosed in 34 patients (9.0%). myocardial infarction occurred in 16 patients: 3 (1.6%) in the aspirin-dipyridamole group and 13 (6.y) in the placebo group (p = 0.0113). Non-Q wave myocardial infarction occurred in 18 patients: 6 (3.2%) in the active drug group and 12 (6.3%) in the placebo group (p = 0.1538). Emergency myocardial revascularization was performed in 9 patients in each treatment arm. Q wave myocardial infarction occurred following revascularization in 5 patients (55.5%) in the placebo group and in only 2 (22.2%, p = 0.1670) in the aspirindipyridamole group. Thus the incidence of periprocedural Q and non-Q wave myocardial infarction is high in patients not on antiplatelet therapy (13.2%) and is markedly lower in those on the aspirin-dipyridamole combination (4.8%, p = 0.0044). Short-term antiplatelet therapy before and after angioplasty can be recommended for patients who do not have contraindications to this medication.
INTRODUCI’ION Major clinical complications occurring during, or early after, percutaneous transluminal coronary angioplasty (PTCA) include death, non-fatal myocardial infarction and emergency revascularization for impending infarction (l-4) The role of antiplatelet therapy in reducing their occurrence was recognized only recently (5,6). The purpose of this report is to evaluate the effect of an aspirin-dipyridamole combination therapy in the prevention of major complications occurring less than 48 hours after PTCA. PATIENTS AND METHODS Patients Patients were enrolled between November 1983 and December 1986 at two participating centers, the Toronto General Hospital and the Montreal Heart Institute. Consecutive patients Keywords:randomized
clinical trial, antiplatelet
agents,
revascularization.
51
Q and non-Q wave myocardial
infarction,
myocardial
52
PREVENTION OF PTCA COMPLICATIONS
Suppl. XII, 1990
scheduled for coronary angioplasty during this period were candidates for the study. However, only patients in whom at least one lesion with stenosis of 70% diameter or greater, who were scheduled for angioplasty, met the inclusion criteria. Moreover, patients were excluded if they presented with any of the conditions listed in Table 1. After signing a written informed consent, patients were randomized into the active drug or placebo arm of the study using a center-specific computer-generated allocation schedule. TABLE
1
Exclusion Criteria for Study Candidates
Age less than 21 years
Documented variant angina
Previous coronary angioplasty
Documented duodenal ulcer
Hypersensitivity to aspirin, dipyridamole or tartrazine
Upper GI tract bleeding in past 6 months History of a hemorrhagic disorder
Non-interruptible anticoagulant or antiplatelet therapy at least 7 days prior to entry
Severe uncontrolled systemic illness History of asthma
Nasal polyps
Studv medication The study was a randomized, double-blind, placebo-controlled trial. The active treatment comprised an oral aspirin-dipyridamole combination (330 mg and 75 mg respectively, t.i.d.) beginning 24 hours before PTCA. Eight hours pre-PTCA, oral dipyridamole was replaced with intravenous dipyridamole (10 mg/hour) for 24 hours while oral aspirin was continued. At 16 hours post-PTCA the oral combination was reinstituted every 8 hours. Patients in the placebo arm received matching oral and intravenous placebos during the same period. If complications occurred during or within 48 hours after the procedure, or if no lesion was successfully dilated (i.e. reduced from 70% or greater obstruction to 50% or less), study medication was discontinued and appropriate medical or surgical therapy was given. In patients with successful angioplasty, the medication was maintained until the date of the follow-up angiogram at 4-7 months. AneioDlastv Drocedure Diltiazem was given orally in 60 mg doses 12 and 4 hours before angioplasty. Heparin (10,000 IU i.v.> was given at the onset of the procedure and continued at 200 III/hour for 3 hours. After the groin sheaths were removed at 4 hours, heparin was resumed at a rate of 500 IU/ hour for 12 hours. Low molecular weight dextran was started at the beginning of angioplasty and was continued until a total of 500 ml had been administered. Glyceryl trinitrate (200 pg) was given intravenously just before dilatation. The angioplasty procedure was performed using the steerable technique with an attempt to obtain the best cosmetic result by selecting a balloon size appropriate to the artery.
Suppl. XII, 1990
PREVENTION
OF PTCA COMPLICATIONS
ECG and enzvmic data Resting ECGs were recorded routinely before and approximately 24 hours after angioplasty. Additional ECGs were obtained when clinically indicated. Creatine kinase (CK) was determined at least once within 24 hours after angioplasty and was repeated as clinically indicated. Whenever CK levels were elevated above normal values, the CK-MB fraction was measured. Pre- and post-angioplasty ECGs were interpreted independently by two experienced cardiologists, who were blinded as to treatment allocation. Using Minnesota code criteria (7,8), post-angioplasty ECGs were classified for each patient as: indeterminate, if the pre- or post-afigioplasty ECG showed bundle branch block or if a pre- or post-angioplasty tracing was not recorded; unchanged, compared with the pre-angioplasty tracing; showing new ST-T wave changes; showing new significant Q waves. Discrepancies between the two interpreters were resolved by consensus. Identical methods of enzymatic determinations and identical normal CK values (225 U/liter or less for males and 110 U/liter or less for females) were used at both centers (9). Enzymatic increases were defined as abnormal when CK values were at least twice the upper normal limit br when the CK value was above normal and the CK-MB fraction was 8% or greater. Patients were classified into three subgroups: the Q wave myocardial infarction group included patients with new significant Q waves on post-PTCA ECGs and significant enzyme elevations; the non-Q wave myocardial infarction group included patients with new ST-T changes on post-PTCA ECGs with significant enzyme rises, or significant enzyme rises without ECG changes after PTCA; and patients with unchanged or indeterminate ECGs or nonspecific ST-T changes with normal enzymes after PICA formed the third group. Death and complications were considered to be procedure-related if they occurred within 48 hours after PTCA. Major procedure-related complications included Q or non-Q wave myocardial infarction, the need for revascularization by coronary bypass surgery or by repeat PTCA as a separate procedure, within 48 hours after the index PTCA. Aneiorrraohic data The angiographic technique was standardized. Orthogonal views of target lesions with at least one of these views reflecting the most severe aspect of stenosis were recorded. Transverse angulations were recorded for each coronary injection, and angiographic success was determined by visual estimation. A segment was considered to be successfully dilated when a lumen stenosis of 70% diameter or greater present before angioplasty, was reduced to less than 50% immediately after angioplasty. Statistical analvsis The chi-square statistic and, when appropriate, Students t-test were used in the univariate analysis of differences between treatment groups in the distribution of baseline and outcome variables. RESULTS
Baseline data and orimarv success rate Selected clinical and angiographic characteristics of the 376 patients are shown in Table 2. The mean age was 52.0 f 9.0 years and 79.5% of patients were male. A history of hypertension was noted in 73 patients and 24 suffered from diabetes mellitus. The mean serum cholesterol
54
PREVENTION OF PTCA COMPLICATIONS
Suppl. XII, 1990
TABLE 2
Clinical and Angiographic Number Number of patients Age (years) Males/females History of hypertension Diabetes Cholesterol (mmol/liter) Triglycerides (mmol/liter) Angina class*: I-II III-Iv Unstable angina Prior myocardial infarction Extent of coronary artery disease: single vessel multivessel Patients having: single lesion PTCA multi-lesion PTCA
52.0 + 9.0 299/77 73 24 5.73 f 1.20 2.29 f 1.31 175 174 56 93
Characteristics (%)
(79.5%/20.5%) (19.4%) (6.4%)
(50.1%) (49.9%) (14.9%) (24.7%)
245 131
(65.2%) (34.8%)
272 97
(73.7%) (26.3%)
Values represent means f SD. Canadian Cardiovascular Society angina classification. ??
was 5.73 f 1.20 mmol/litre
and mean serum triglycerides 2.29 + 1.31 mmol/litre. Of the patients with angina, the severity was class I or II in 50.1% of the patients and class III or IV in 49.9%. Of all patients, 14.9% had unstable angina and 24.7% were diagnosed as having prior myocardial infarction. Finally, 65.2% had single vessel disease and 34.8% multivessel disease. Segments attempted at PTCA involved the left anterior descending artery in 51% of the patients, the right coronary artery in 31% and left circumflex artery in 18%. Single lesion angioplasty was attempted in 73.7% of the patients and multilesion angioplasty in 26.3%. Seven patients did not have any lesion attempted., Among the remaining 369 patients, 329 had at least one lesion successfully dilated, resulting in a primary success rate/patient of 89.1%. Of the 489 segments attempted, 374 were successfully dilated giving a primary success rate/ segment of 76.5%. Incidence of orocedure-related 0 and non-0 wave mvocardial infarction There were no procedural deaths among the 376 patients. Sixteen patients (4.3%) suffered a periprocedural Q wave myocardial infarction (Table 3). Nine were managed conservatively during the acute episode. In the other seven patients, the Q wave infarction was documented following emergency myocardial revascularization. Eighteen patients (4.8%) were strongly suspected of having suffered a non-Q wave myocardial infarction. Eight developed new STT changes and significant enzyme rises, whereas the other 10 only had significant enzyme elevations. A nonfatal myocardial infarction was, therefore, diagnosed in 34 patients (9.0%) during or early after PTCA.
Suppl. XII, 1990
Incidence
PREVENTION
of Non-fatal
OF PTCA COMPLICATIONS
TABLE 3 Myocardial Infarction
During or Early After PTCA
Aspirin/ Placebo dipyridamole (n = 187) (n = 189) Number (%) Number (%) Q wave myocardial Without
revascularization
revascularization
Total
Non-Q wave myocardial New ST-T changes Abnormal
(Pearson
x2)
1 (0.5)
8 (4.2)
2 (1.1)
13 (6.9)
3 (1.6)
13 (6.9)
0.0113
infarction
with abnormal
CK only
Total
Total infarctions
p value
infarction
emergency
After emergency
55
(both types)
CKl(O.5)
7 (3.7)
5 (2.7)
5 (2.6)
6 (3.2)
I2 (6.3)
0.1538
9 (4.8)
2503.2)
0.0044
Finally, emergency myocardial revascularization was performed in 18 patients (4.8%) of whom I4 had coronary bypass surgery and 4 had repeat PTCA as a separate procedure. Effect of antiolatelet theranv on orocedure-related comolications Of the 376 patients, 187 were randomized to the aspirin-dipyridamole arm and 189 to placebo. The two groups were well matched for all major clinical, angiographic and procedural characteristics. The only significant baseline difference was a higher percentage of females in the aspirin-dipyridamole arm (25% US16% in the placebo arm, p = 0.05). As it has been suggested that aspirin is less effective in females (lo), this may have introduced a bias against treatment efficacy in the aspirindipyridamole arm. The effect of antiplatelet therapy on procedure-related complications is shown in Table 3. Three patients in the aspirin-dipyridamole group had a Q wave myocardial infarction as opposed to 13 in the placebo group. Likewise, 6 patients in the aspirin-dipyridamole group had a non-Q wave infarction in comparison to I2 in the placebo group. Thus, 9 patients (4.8%) in the aspirin-dipyridamole group and 25 patients (13.2%) in the placebo group had a nonfatal myocardial infarction @ = 0.0044). In addition, 9 patients in each group underwent coronary artery bypass surgery or repeat PTCA within 48 hours of the reference PTCA.
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Suppl. XII, 1990
The number of emergency revascularizations was almost identical (4.8%) in both treatment groups. However, only 2 of 9 patients (22.2%) undergoing early revascularization in the active treatment arm suffered a documented Q wave infarction compared with 5 of 9 (55.5%) in the placebo group. This difference was not statistically significant @ = 0.1670). DISCUSSION This randomized clinical trial demonstrates that aspirin-dipyridamole combination therapy begun 24 hours before PTCA and continued for at least 48 hours after the procedure, is associated with a markedly reduced incidence of Q and non-Q wave myocardial infarction during and early after PTCA. Antiplatelet therapy did not alter the number of emergency myocardial revascularizations after PTCA. However, the incidence of Q wave myocardial infarction in patients undergoing early revascularization in the aspirin-dipyridamole group was only 22% compared with 55% in patients receiving placebo. The role of antiplatelet therapy in reducing the incidence of Q and non-Q wave myocardial infarction during or early after PTCA is supported by previous experimental and clinical data. Balloon angioplasty in animal models has been shown to induce endothelial denudation, platelet adhesion to the subendothelial matrix and platelet thrombus formation (11). Whereas mild arterial injury is associated with only mild platelet accumulation, deep injury extending into the media almost always leads to a non-occlusive or occlusive mural thrombus (12). Reductions in platelet accumulation and mural thrombus formation can be demonstrated experimentally following antiplatelet therapy (13,14). A recent retrospective clinical study has shown that aspirin alone or a combination of aspirin and dipyridamole administered before PTCA were both associated with a decreased incidence and extent of acute coronary thrombosis complicating PTCA (15). Finally, a recent preliminary report also demonstrated marked efficacy of an aspirin-dipyridamole combination and of ticlopidine in reducing procedure-related acute complications after PTCA (6). Our data also support the concept that antiplatelet therapy effectively reduces the incidence of myocardial infarction in these patients. The number of emergency myocardial revascularizations was almost identical in the placebo group and in the group receiving antiplatelet therapy. However, the indications for emergency revascularization were not standardized in this study, but were left to the investigators judgement. Of the 9 patients who suffered a periprocedural Q wave myocardial infarction and did not undergo emergency revascularization for various reasons, 8 had an onset of the event less than 4 hours after the initial PTCA. In addition, there was a marked increase in the number of emergency revascularization procedures during the course of the study which contrasted with the steady incidence of major periprocedural complications. Only 4 patients underwent emergency revascularization during the first half of the study, compared with 14 during the second half. Thus several factors besides study medication influenced the decision to perform emergency revascularization in these patients. In our study, antiplatelet therapy was started before PTCA, as data available at the time indicated that greater effectiveness was obtained by pre-treatment (13,14). Intravenous dipyridamole was used during PTCA in order to ensure complete absorption of the drug during vessel injury. At the doses used in this study, the dipyridamole infusion was well tolerated and there were no apparent side-effects which might have unblinded the investigators (5). Whether this route of dipyridamole administration has advantages over oral administration, in combination with aspirin, during the procedure will require further study. Our study was not designed to test the efficacy of aspirin alone, or of low UShigh doses of
Suppl. XII, 1990
PREVENTION
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57
aspirin in the prevention of PTCA complications. It is possible that low dose aspirin (80 mg/ day> might be as effective as the dose used in our study (990 mg/day) (16,17), and it remains to be established whether aspirin alone is as effective as aspirin-dipyridamole combinations. REFERENCES 1 DORROS, G., COWLEY, M.J., SIMPSON, J., BENTIVOGLIO, L.G., BLOCK, PC., BOURASSA, M., DETRE, K.M., GOSSELIN, A.J., GRUNTZIG, A.R., KELSEY, S.F., KENT, K.M., MOCK, M.B., MULLIN, SM., MYLER, R.K., PASSAMANI, E.R., STERTZER, S.H. and WILLIAMS, D.O. Percutaneous transluminal coronary angioplasty: report of complications from the National Heart, Lung, and Blood Institute PTCA Registry. Circulation, 67, 723-730, 1983. 2 DETRE, K., HOLUBKOV, R., KELSEY, S., COWLEY, M., KENT, K., WILLIAMS, D., MYLER, R., FAXON, D., HOLMES, D., BOURASSA, M., BLOCK, P., GOSSELIN, A., BENTIVOGLIO, L., LEATHERMAN, L., DORROS, G., KING, S., GALICHIA, J., AL-BASSAM, M., LEON, M., ROBERTSON, T. and PASSAMANI, E. Percutaneous transluminal coronary angioplasty in 1985-1986 and 1977-1981. The National Heart, Lung and Blood Institute Registry. NEngl JMed, 318, 265-270, 1988. 3 MABIN, T.A., HOLMES, D.R., SMITH, H.C., VLIETSTRA, R.E., REEDER, G.S., BRESNAHAN, J.F., BOVE, A.A., HAMMES, L.N., ELVEBACK, L.R. and ORSZULAK, T.A. Follow-up clinical Circulation, results in patients undergoing percutaneous transluminal coronary angioplasty. 71, 754-760, 1985. 4 BREDLAU, C.E., ROUBIN, G.S., LEIMGRUBER, P.P., DOUGLAS, J.S., KING, S.B. and GRUENTZIG, A.R. In-hospital morbidity and mortality in patients undergoing elective coronary angioplasty. Circulation 72, 1044-1052, 1985. 5 SCHWARTZ, L., BOURASSA, M.G., LESPERANCE J., ALDRIDGE, H.E., KAZIM, F., SALVATORI, V.A., HENDERSON, M., BONAN, R. and DAVID, P.R. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. NEngi JMed 318, 1714-1719, 1988. 6 WHITE, C.W., CHAITMAN, B., LASSAR, T.A., MARCUS, M.L., CHISHOLM, R.J., KNUDSON, M., MORTON, B., ROY, L., KHAJA, F., VANDORMAEL, M., REITMAN, M. and the Ticlopidine Study Group. Antiplatelet agents are effective in reducing the immediate complications of PTCA: results from the ticlopidine multicenter trial (abstract). Circulation, 76(Suppl), IV-400, 1987. 7 BLACKBURN, H., KEYS, A., SIMONSON, E., RAUTAHARJU, P. and PUNSAR, S. The electrocardiogram in population studies: a classification system. Circulation 22, 1160-1175, 1960. 8 The Coronary Drug Project Research Group. The Coronary Drug Project: methods, and baseline results. Circulation, 47 (Suppl I), l-50, 1973. 9 HOMBURGER, H.A. and JACOB, G.L. Creatine kinase radioimmunoassay electrophoresis compared in the diagnosis of acute myocardial infarction.
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1980.
10 Canadian Co-operative Study Group. A randomized trial of aspirin and sulfinpyrazone in treated stroke. NEngl JMed, ZB, 5359, 1978.11 STEELE, P.M., CHESEBRO, J.H., STANSON, A.W., HOLMES, D.R., DEWANJEE, M.K., BADIMON, L. and FUSTER, V. Balloon angioplasty: natural history of the pathophysiological response to injury in a pig model. Circ Res, 57, 105-112, 1985. 12 LAM, J.Y.T., CHESEBRO, J.H., STEELE, P.M., DEWANJEE, M.K., BADIMON, L. and FUSTER,. V. Deep arterial injury during experimental angioplasty: relation to a positive indium-111 labeled platelet scintigram, quantitative platelet deposition and mural thrombosis. JAm Co11Cardiol, 8, 1380-1386, 1986. 13 STEELE, P.M., CHESEBRO, J.H., HOLMES, D.R., BADIMON, L. and FUSTER, V. Balloon angioplasty in pigs: comparative effects of platelet-inhibitor drugs (Abstract). Circulation, 70
(St@@ZZI,11-361, 1984. 14 LAM,J.Y.T., CHESEBRO, J.H., STEELE, P.M., BADIMON, L. and FUSTER, V. Antithrombotic therapy for arterial angioplasty: efficacy of common platelet-inhibitors in a porcine model, Circulation, in press 1990. 15 BARNATHAN, ES., SCHWARTZ, J.S., TAYLOR, L., LASKEY, W.K., KLEAVELAND, J.P., KUSSMAUL, W.G. and HIRSCHFELD, J.W. Aspirin and dipyridamole in the prevention of acute coronary thrombosis complicating coronary angioplasty. Circuldtion, 76, 125-134,
1987. 16 LEMBO, N.J., BLACK, A.J., ROUBIN, G.S., MUFSON, L.H., WILENTZ, J.R., DOUGLAS, J.S. and KING, S.B. Does the addition of dipyridamole to aspirin decrease acute coronary angioplasty fzomplications? The result of a prospective randomized clinical trial (Abstract).
JAm Co11Cardiol, 11, 237A, 1988. 17 MUFSON, L., BLACK, A., ROUBIN, G., WILENTZ, J., MEAD, S., MCFARLAND, K., WEINTRAUB, W., DOUGLAS, J.S. and KING, S.B. A randomized trial of aspirin in PTCA: Effect of high versus low dose aspirin on major complications and restenosis (Abstract). JAm Co11
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