sefulness of Antithrombotic Therapy in Resting Angina Pectoris or Non-Q-Wave Myocardial Infarction in Preventing Death and Myocardial Infarction (a Pilot Study from the Antithrombotic Therapy in Acute Coronary Syndromes Study Group) Marc Cohen, MD, Philip C. Adams, MB, BS, Linda Hawkins, RN, Matt Bach, MD, and Valentin Fuster, MD
In a prospective pilot trial of antithrombotic therapy in the acute coronary syndromes (ATACS) of resting and unstable angina pectoris or non-Q-wave myocardial infarction, 3 different antithrombotic regimens in the prevention of recurrent ischemic events were compared for efficacy. Ninety-three patients were randomized to receive aspirin (325 m&day), or full-dose heparin followed by warfarin, or the combination of aspirin (80 mg/day) plus heparin and then warfarin. Trial antithrombotic therapy was added to standardized antianginal medication and continued for 3 months or until an end point was reached. Analysis, by intention-to-treat, of the 3-month end points, revealed the following: recurrent ischemia occurred in 7 patients (22%) after aspirin, in 6 patients (25%) after heparin and warfarin, and in 16 patients (43%) after aspirin combined with heparin and then warfarin; coronary revascularization occurred in 12 patients (38%) after aspirin, in 12 patients (50%) after heparin and warfarin, and in 22 patients (60%) after aspirin combined with heparin and then warfarin; myocardial infarction occurred in 1 patient (3%) after aspirin, in 3 patients (13%) after heparin and warfarin, and in no patient after aspirin combined with heparin and then warfarin; no deaths occurred after aspirin or after aspirin combined with heparin and then warfarin, but 1 patient (4%) died after warfarin alone; major bleeding occurred in 3 patients (9%) after aspirin, in 2 patients (8%) after heparin nd warfarin, and in 3 patients (8%) after aspirin combined with heparin and then warfarin.
From the Division of Cardiology, Department of Medicine, Mount Sinai School of Medicine of the City University of New York, New York, New York; The Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; and Beth Israel Medical Center, New York, New York. Part of this work was performed while Dr. Adams was a BritishAmerican Research Fellow of the British Heart Foundation and the American Heart Association. Address for reprints: Marc Cohen, MD, Division of Cardiology, Box 1030, Mount Sinai Hospital, New York, New York 10029.
Recurrent myocardial ischemia occurred at 3 f 3 days after randomization. In those who had coronary angioplasty or bypass surgery, revascularization was performed at 6 f 4 days. During trial therapy, no patient died, had a Q-wave myocardial infarction or a major bleed. Most bleeding complications consisted of blood transfusions during or immediately after bypass surgery. Only 25% of patients enrolled were discharged on trial therapy because of revascularization and withdrawals. Thus, irrespective of the antithrombotic regimen used, and even with aggressive combination therapy, a substantial fraction of patients with unstable angina or non-Q-wave myocardial infarction have recurrent myocardial ischemia and are referred for coronary revascularization. Antithrombotic therapy, coupled with early intervention after recurring ischemia, was associated with a low rate of death or myocardial infarction within the first 3 months. (Am J Cardiol 1990;66: 1287- 1292)
he beneficial role of antithrombotic therapy with either antiplatelet agentsle4 or anticoagulants3+s in patients with unstable angina pectoris has been established. Theroux et al” compared combination antithrombotic therapy with aspirin plus heparin versus placebo in unstable angina. By design, trial therapy was continued for only 5 to 6 days, and several patients had rebound myocardial ischemic pain after heparin was stopped.q Based upon (1) pathoanatomic observations implicating plaque rupture and thrombosis,1°m13 (2) limitations in the aforementioned trials, and (3) the potential for a lower medical failure rate with the use of a more aggressive antithrombotic regimen, we studied the efficacy of aspirin combined with anticoagulant therapy in patients with unstable angina or non-Q-wave infarction, or both, administered over a 3-month trial period. This study assessed whether aspirin combined with anticoagulant therapy was superior to either agent alone in reducing the frequency of recurrent myocardial ischemia and the need for coronary angioplasty or bypass surgery.
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TABLE First
I Screening Six Months
Process
for
Patient
Selection:
ScreeningCategories
No.
Screened (all patients with unstable angina or “rule-out MI”) Met inclusion criteria (rest angina or non-Q-wave infarction) Excluded In protocol already Left bundle branch block Coronary bypass surgery within 1 year Coronary angioplasty within 6 months Q-wave Ml within 6 weeks Tachyarrhythmia Hypertension Heart failure Peptic ulcer or previous CVA Bleeding tendency Allergy to trial therapy Anemia Other serious illness Need anticoagulants Need chronic aspirin or steroids Eligible Private physician refused Patient refused Randomized
300
CVA = cerebrovascular
patients.
accident;
MI = myocardial
Subgroup No.
118 77 2 5
10 4 2 4 6 8 5 3
1 5 14 4 4 41 6 8 27 (66% infarction:
of those
eligible)
No. = number
of
METHODS Patient selection: The study was conducted at Mount Sinai Hospital and Beth Israel Hospital after approval by the respective institutional review boards concerned with human research. From March 20, 1987, to March 14, 1989, all patients with cardiac pain, resting pain, or non-Q-wave infarction were screened. Men and women between the ages of 21 and 75 years were eligible if they met both of the following inclusion criteria. First, they must have presented to the hospital with ischemic pain caused by either unstable angina or nonQ-wave infarction defined as follows: (1) recent onset (-l-mm ST-segment deviation) or (2) prior history of myocardial infarction, positive exercise test results or coronary arteriogram, or typical exertional chest pain relieved by rest or nitroglycerin, or both. Exclusion criteria consisted of the following: evolving Q-wave myocardial infarction, left bundle branch block, angina precipitated by obvious provoking factors (e.g., heart failure, tachyarrhythmia, hypertension [systolic 1160 mm Hg, diastolic 1100 mm Hg]), current use of
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or contraindications to anticoagulation, coronary angioplasty within 6 months or coronary bypass surgery within 1 year, or patient unable or unwilling to give consent. Patients with occasional aspirin use were not excluded from this trial. Data obtained during screening in the first 6 months of the trial were recorded (Table I). Fifty-four percent of patients eligible for the study were randomized. Study protocol: After consent was obtained, patients were randomized to 1 of 3 therapies: ASPIRIN ALONE: Upon randomization, aspirin 325 mg orally was followed by aspirin 325 mg/day. HEPARIN FOLLOWED BY WARFARIN ALONE: An intravenous loading dose of heparin 100 U/kg bolus was followed by a continuous infusion to maintain the activated partial thromboplastin time at 2.0 X control for 3 to 4 days. If coronary arteriography did not appear imminent because of recurring pain by the third day, warfarin was started and titrated to maintain the prothrombin time at 1.5 to 2.0 X control (international normalized ratio at 3.0 to 4.5), and heparin was discontinued. ASPIRIN, PLUS HEPARIN AND THEN WARFARIN: Aspirin 325 mg orally and a bolus of intravenous heparin 100 U/kg were followed by aspirin 80 mg/day, plus a continuous heparin infusion, as in limb 2. By the third day, warfarin was started and titrated, as in limb 2, and heparin was discontinued. Aspirin, 80/mg, was continued along with warfarin. By design, every effort was made to continue the trial therapy for 12 weeks, unless an end point or a withdrawal criterion was reached (see below). After 12 weeks, the decision to continue administration of aspirin or warfarin was made by the private physician. In addition to the trial therapy, all patients received standard antianginal medical therapy with oral nitrates plus p blockers or calcium antagonists, or both. If pain recurred on this regimen, intravenous nitroglycerin was administered. The dosages of the 3 antianginal drugs were maximized within 48 hours of admission to reduce the systolic blood pressure to < 120 to 130 mm Hg, and to reduce the heart rate to 165 beats/min. Aspirin containing medication other than that used in the trial drugs was prohibited. Trial therapy was ended by design for the following reasons: (1) an end point occurred (recurrent ischemia, myocardial infarction, death or bleeding); (2) the patient was found to have normal or nonobstructive coronary artery disease, or a negative exercise tolerance test; (3) coronary revascularization or angioplasty was performed; and (4) noncompliance with medication. Patients who needed revascularization were continued on trial medications until the day of the procedure. Study end points: There were 3 primary end points: RECURRENTMYOCARDIALISCHEMIA: This was defined as the presence of recurrent angina at rest with ischemic electrocardiographic changes occurring despite full medical therapy. Full medical therapy was defined as receiving a minumum of 2 antianginal medications, resulting in a baseline resting heart rate of 565 beats/ min and a systolic pressure 5120 to 130 mm Hg.
TABLE
II Clinical
Characteristics
of the
Study
Population
Demographics Age (mean yrs) Malegender Previous angina or MI interval from onset of angina Cigarette smoker Systemic hypertension Diabetes mellitus Medication before admission Nltrates p blockers Calcium antagonists Recent aspirin In-Hospital
or first MI (mos.)
Heparin/ Warfarin n = 24(%)
Aspirin + Hep/Warf n = 37 (%)
Total Group n = 93 (%)
62 18 24 35 15 17 11
(47) (53) (34)
61 16 (68) 22 (92) 72 14 (58) 11146) 8 (33)
63 22 30 40 22 18 15
(59) (49) (41)
62 56 (60) 76 (82) 47 51(55) 46 (49) 34 (37)
13 (41) 8 (25)
12 (50) 8 (33)
19 (51) 7U9)
44 (47) 23 (25)
12 (37) 8 (25)
12 (50) 7 (2%
17 (46) 14 (38)
41(M) 29 (31)
14 22 (69) ll(34)
11 17(71) ll(46)
12 28 (76) 13 (35)
12 67 (72) 34 (37)
28 (88) 12(37) 27 (84) 18 (56)
21(88) 11 (46) 22 (92) 15 (63)
30 13 29 25
79 36 78 58
(56) (75)
(59) (81)
Data
Time between randomization and last resting ST-T changes at randomization Present with non-Q infarct (%) Treatment during hospitalization Nitrates p blockers Calcium antagonists Coronary Arteriography Percentage* with diseased vessels (>70%) 0 1 3 3 Left main PTCA CABG Non-obs Duration
Aspirin n=32(%)
pain
(hours)
2(11) 4 (22) 5 (28) 6 (33) artery
CAD or neg ETT on trial therapy (days)
l(6) 7 (22)
5(16) 8 (25) 29
(81) (35) (78) (65)
(85) (39) (84) (62)
(13) (13) (27) (40)
2 (8)
6 (10)
6 (24) 4(16) l(W
12 (21) 13 (22) 23 (40)
l(7) 4U7) 8 (33) 302) 16
9 (24) 13 (35) 4(11) 8
2 2 4 6
2 03)
of those 58 patients who underwent arteriography. All other percentages are percentages of the total population (n = 93). CABG = coronary artery bypassgratttlng; Hep/Warf = heparin hollowed by warfarin; neg E T T = negative maxlmal exercise tolerance test: Non-obs artery disease: PTCA = percutaneous transluminal coronary angioplasty; other abbrewtions as in Table I.
4 20 26 15 17
(7) (22) (28) (16)
* Percentage
MYOCARDIAL INFARCTION: This was defined as chest pain associated with new and persistent ST-T-wave changes or Q waves, accompanied either by a rise in serum creatine kinase to >2 times the upper limit of normal or by an increase of 150% in creatine kinase activity above the preceding sample but at least 1.5 times the upper limit of normal. Perioperative myocardial infarction was identified by a combination of electrocardiographic criteria and enzyme criteria. However, in this setting, the creatine kinase MB isoenzyme must be X0 p/ml (normal is 46 p/ml). Only those infarctions considered as events clearly separate from the initial cardiac event that qualified the patient for randomization were considered as end points. TOTAL DEATHS: All deaths, regardless of etiology, were end points. A death occurring 2 units of blood was considered a major bleed. Follow-up and protocol deviations: Trial therapy and study end points were monitored daily during the hospital stay. After discharge, patients were reevaluated at 6 and 12 weeks using the interval history, any readmission hospital records, 12-lead electrocardiogram, hematocrit, stool for occult blood, and prothrombin time. Trial therapy was initiated in 13 hours of randomization in all patients. One patient was not included in this analysis; she signed out against medical advice before trial therapy was begun. Protocol deviations occurred in 17 patients; their follow-up, however, is included in the analysis: 2 patients were inappropriately randomized; 2 were noncompliant and stopped their trial therapy prematurely; and private physicians referred 13 patients for revascularization despite their being asymptomatic on trial therapy. Trial therapy was continued until the time of their revascularizations. In-hospital follow-up was complete. After hospital discharge, 5 patients were lost to follow-up, and no determination could be made regarding their vital or clini-
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TABLE
TABLE IV Complications
III End Points Aspirin n=32 W)
Primary end points Recurrent ischemia
(pain
Heparin/ Warfarin n=24 W)
Aspirin + Hep/Warf n=37 (%I
Total Group n=93
Aspirin n=32
Heparin/ Warfarin n=24
Aspirin + Hep/Warf n=37
(%)
W)
(%)
(“A)
16 (43)
29(31)
0 l(3)
0 0
0 l(3)
0
1
0
0
0
0 1
1 1
3 (9) 3
0
3 (8) 2
5
7 (22)
6 (25)
l(3) 0 0 0
3(13)
0
4 (4)
26%
0
2(2)
l(4) l(4)
0 0
l(l) l(l)
+ KG) MI (total) Perioperative infarction Death (total) Death off trial therapy Secondary end points Recurrent chest pain PTCA or CABG
16 (50) 12 (38)
Pawn + ECG = chest pain accompanied abbreviations as in Tables I and Ii.
10 (42) 12 (50)
23 (62) 22 (60)
by electrocardiographic
49 (52) 48 (50) changes;
other
cal status by the end of the 1Zweek trial period. Two of these patients were in the aspirin-alone group, and 3 were in the heparin-alone group. Characteristics of the study population: Clinical characteristics, including baseline demographics as well as data acquired after randomization, are listed in Table II. The study population (n = 93) consisted of a group that was at high risk for coronary artery disease. More than two-thirds of the study group had 11 coronary risk factor before admission, and 82% had either a previous myocardial infarction or a history of stable angina, In 18% of patients, the qualifying episode of resting pain was their first manifestation of coronary disease. Sixty-seven percent of the patients recalled having had an earlier episode of resting pain within the 4 weeks before the qualifying episode of resting pain. Trial therapy was initiated at a mean of 12 f 10 hours after the last episode of resting pain. Patients were distributed among the 3 treatment groups as follows: aspirin alone-32 patients; heparin and warfarin alone-24 patients; and aspirin plus heparin and then warfarin-37 patients. At randomization, 72% of the study group had ischemic electrocardiographic changes. Statistical analysis: Continuous variables are presented as mean f standard deviation. Multiple comparisons among the 3 treatment groups were not undertaken because of the relatively small sample size. The 5 patients who were lost to follow-up after hospital discharge were distributed among the 3 treatment groups and were counted as having experienced no end points during the 3-month follow-up. RESULTS Primary
end points:
EMIA,INFARCTION,OR
RECURRENT DEATH: Despite
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On trial therapy Major bleeding (total) Minor bleeding (total) Hematuria + stool guaiac Off trial therapy (related to PTCA or CABG) Major bleeding (total) Wound bleed and transfusion Requiring surgical repair GI bleed and transfusion Minor bleeding (total) Related to CABG GI = gastrointestinal;
0 0 0 0
other abbreviations
2(8)
Total Group n=93 W)
2(2)
8(9)
2 0 l(4)
0 0
2 1 l(l)
1
0
1
1
as in Table Il.
trial antithrombotic therapy and before any revascularization procedure. In both cases they were non-Q-wave infarctions. Two additional patients developed myocardial infarction during coronary bypass surgery and both were in the heparin- and warfarin-alone group. During the trial therapy, there were no deaths. However, after hospital discharge, there was 1 fatality: a noncompliant patient who had stopped her trial medication prematurely (warfarin alone) experienced sudden death 2 weeks after discharge. Secondary
end points:
RECURRENT
CHEST
PAIN
AND
Recurrent chest pain (with or without electrocardiographic changes) occurred in 49 patients, 52% of the total population at a mean of 3 f 3 days after initiation of the trial therapy (Table III). At the time of recurrent pain, 86% of these 49 patients were on a minimum of 2 antianginal drugs, including intravenous nitroglycerin. No significant difference in the incidence of recurrent pain was observed among the 3 treatment groups. In the 49 patients with recurrent pain, revascularization by either coronary angioplasty or coronary bypass surgery was undertaken in 67%, whereas, in the 44 patients without recurrent pain, 13 (29%) underwent revascularization. Ten of the 13 patients without recurrent pain, who were revascularized, had severe multivessel disease. For the population as a whole (n = 93), the mean duration from randomization to diagnostic catheterization was 4 f 3 days, and the mean duration from randomization to revascularization was 6 f 4 days. Forty-one of the 46 patients who underwent revascularization were operated on during the initial hospitalization and the remaining 5 were revascularized during the first 3 months after discharge. A total of 15 patients (16%) had either nonobstructive coronary artery disease or negative maximal stress test results, and their trial therapy was discontinued. Only 25 of the original 93 patients (26%) were discharged on trial therapy. MAJOR BLEEDING COMPLICATIONS: There were no episodes of spontaneous major bleeding during the trial therapy in any of the 3 groups (Table IV). Two patients experienced minor bleeding during the trial therapy, ne-
REVASCULARIZATION:
-
-
cessitating withdrawal of therapy in 1 patient. No major bleeding occurred as a result of diagnostic cardiac catheterization. Off of trial therapy, 8 patients experienced major bleeding, all of which was related to revascularization. One patient required surgical repair of the femoral artery puncture site after coronary angioplasty. The remaining 7 patients experienced major bleeding in relation to coronary bypass surgery: 5 of the 7 required >2 units of blood transfusion for perioperative blood loss, 1 underwent reoperation for a slipped ligature, and another had a perioperative gastrointestinal bleed. Patients in the aspirin plus heparin and then warfarin group did not experience a greater frequency of either spontaneous bleeding or perioperative bleeding. During the same time period, 49% of all patients undergoing coronary bypass surgery at this hospital required blood transfusion. The average blood requirement for these patients was 2.3 units. In contrast, of the 27 patients who underwent bypass surgery in our study, only 7 (26%) required blood, and their average requirement was 2.8 units.
minimize the need for invasive diagnostic catheterization and revascularization procedures? (2) In view of the dynamic intraarterial processes precipitating the acute coronary syndromes, does more aggressive antithrombotic therapy with platelet inhibition plus anticoagulation offer more benefit than either agent alone? (3) Is one antithrombotic regimen better at reducing perioperative complications in patients presenting with unstable angina? Our study was designed to enroll highrisk patients with either resting angina or non-Q-wave infarction and to continue medical therapy (antianginal plus trial antithrombotic therapy) for 3 months after presentation. In addition, our analysis included events occurring during or after crossover to revascularization, and provided pilot data on the relative efficacy and safety of combination antithrombotic therapy administered over a 3-month trial period. Several findings emerged. We observed a disappointingly high rate of recurrent chest pain prompting catheterization and revascularization in all 3 treatment groups. Specifically, aggressive combination therapy did not reduce the frequency of recurrent pain and of subsequent coronary angioplasty DISCUSSION or coronary bypass surgery, compared to that seen with Unstable angina pectoris represents a broad spec- single antithrombotic therapy. In all, between the 51% trum, ranging from progressive or accelerating angina of patients withdrawing from trial therapy because of to the higher risk subset of resting angina with revers- revascularization, and the 16% of patients with nonobible electrocardiographic changes.r4 Previous placebo- structive coronary disease or negative stress test results, controlled therapeutic trials established a beneficial role only 26% of the original cohort were discharged on the for antithrombotic therapy with aspirin alone or with trial therapy and even fewer reached the 3-month folheparin or warfarin alone in progressive or accelerating low-up on therapy. Despite our intention to attempt to angina.1y2,4,7 With regard to the higher risk patients continue antithrombotic therapy for 3 months, our rate with resting unstable angina pectoris or non-Q-wave of failure of medical therapy-that is, need for revascumyocardial infarction, several trials of antithrombotic larization-was similar to that of Theroux, Neri Sertherapy have been reported 3,6,8but the trial therapy was neris and their co-workers-about 50%. Of interest, limited only to the first week after presentation.6,8 The- Ouyang et a1,15in 1984, observed a similar rate of medroux et a1,3 for example, compared antithrombotic ther- ical failure and revascularization, about 40 to 50%, with apy with either aspirin or heparin, or both, versus place- maximal antianginal therapy. Therefore, while the addibo, in the high-risk subset of patients presenting with tion of conventional antithrombotic therapy to antiangipain either at rest or with minimal effort and with elec- nal medication has had a beneficial impact on the rate trocardiographic changes. They observed that, in this of death and myocardial infarction,le7 it has not altered high-risk subset, as well, antithrombotic therapy was the natural history of resting unstable angina or non-Qmore effective than placebo was in reducing the rate of wave infarction in the face of the need for definitive myocardial infarction or death. Furthermore, only hep- revascularization. arin, or the combination of aspirin plus heparin, signifiRevascularization in the setting of unstable angina is cantly reduced the rate of refractory angina. However, associated with a higher complication rate.16.‘9 Our by design, all patients in this study3 were referred for study is the first to analyze perioperative ischemic catheterization and the trial therapy was ended 5 to 6 events and bleeding prospectively in patients with unstadays after randomization. Subsequently, several pa- ble angina undergoing revascularization while on differtients experienced rebound myocardial ischemic pain af- ent antithrombotic regimens. Specifically, 2 of the 3 inter heparin was stopped,9 and, at 3-month follow-up, farctions in our heparin- or warfarin-alone group oc48% of the original study population underwent coro- curred during coronary bypass surgery. In contrast, nary revascularization.3 More recently, Neri Serneri et none of the patients treated with aspirin experienced a al* compared different antithrombotic regimens in a perioperative infarction, or died. Earlier investigators small group of patients with refractory angina. They ob- have already noted the beneficial effect of aspirin given served a significant reduction in episodes of silent isch- before revascularization.20,21 emia in patients randomized to a continuous heparin inThe combination of aspirin plus heparin and then fusion but not in patients randomized to aspirin or to warfarin was associated with the lowest rate of infarcthe thrombolytic agent tissue plasminogen activator.8 tion or death, although the relatively small sample size Despite these trials, several questions remain: (1) Is of our study groups must be kept in mind. The prelirrrithere an effective “medical” regimen for this acute cor- nary report of Wallentin and the RISK study group4 is onary syndrome that can substantially reduce the inci- the first study with enough power to observe a statistidence of recurrent myocardial ischemia and thereby cally significant benefit of combination therapy over THE AMERICAN
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placebo and over short-term heparin-alone therapy. It might be anticipated that the routine use of antithrombotics, especially the combination of aspirin with anticoagulants, would produce more adverse effects than either aspirin or heparin alone. In fact, we did not observe any spontaneous major bleeding during the trial therapy or major bleeding related to diagnostic catheterization. The lower rate of bleeding observed in the present study, compared to that observed by Theroux et aL3 could be explained in two ways. They accepted a decrease in hematocrit levels alone as a criterion for a “serious bleed,” and they used a dose of 650 mg/day of aspirin. In the present study, 325 mg was used in the aspirin-alone limb, and 80 mg in the combination limb. In addition, the combination of low-dose aspirin plus heparin and then warfarin did not result in an increased rate of blood transfusion during coronary bypass surgery. Study limitations: First, patients were prospectively enrolled and randomized, but the trial therapy was not blinded. However, the main end points were identified by daily interviews of the patients, and by review of the daily progress notes in the chart and of serial cardiac enzymes. These daily notes were written by the patients’ personal physicians and by nurses who were unaware of the general progress of the study and the emerging trends. Second, different dosages of aspirin were used in the 2 aspirin-containing limbs. In parallel with the study of Lewis et al,’ we used 325 mg/day in the aspirinalone limb, as the standard. For the combination limb, a dose of 80 mg of aspirin was chosen because this low dose would minimize aspirin-related adverse effects, which are dose-dependent. Third, our patient population was relatively small. In our ongoing trial, we are evaluating only 2 limbs, aspirin versus aspirin plus heparin and then warfarin, and will aim to enroll several hundred patients to achieve an adequate power to detect significant differences in treatment effect, REFERENCES 1. Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE III, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Sabharwal SC, Chesler E, DeMots H. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Eng/ J Med 1983;309:396-403. 2. Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky G, Kostuk WJ, Melendez LJ, Myers MG, Sackett DL, Sealey BJ, Tamer PH. Aspirin, sulfinpyrazone or both in unstable angina: results of a Canadian multicenter trial. N Engl J Med 1985;313:1369-1375.
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3. Theroux P, Ouimet H, McCans J, Latour JG, Joly P, Levy G, Pelletier E, Juneau M, Stasiak J, DeGuise P, Pelletier GB, Rinzler D, Waters DD. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med 1988:319:11051111. 4. Wallentin L for the RISK study group in southeast Sweden. Aspirin 75 mg and/or heparin after an episode of unstable coronary artery disease-risk for myocardial infarction and death in a randomized placebo-controlled study (abstr). Circulation 1989;8O(suppl II):Il-419. 5. Wood P. Acute and subacute coronary insufficiency. Br Med .I 1961;1:17791782. 6. Telford A, Wilson C. Trial of heparin versus atenolol in prevention of myocardial infarction in the intermediate coronary syndrome. Lancet 1981;1:1225-1228. 7. Williams DO, Kirby MG, McPherson K. Anticoagulant treatment in unstable angina. Br J Chin Pratt 1986;40:114-116. 8. Neri Serneri GG, Gensini GF, Poggesi L, Trotta F, Modesti PA, Boddi M, Ieri A, Margheri M, Casolo GC, Bini M, Rostagno C, Carnovali M, Abbate R. Effect of heparin, asprin, or alteplase in reduction of myocardial ischemia in refractory unstable angina. Lancer 1990,335:615-618. 9. Ouimet H, Theroux P, McCans .I, Waters D. Rebound caused by withdrawal of heparin in the acute phase of unstable angina (abstr). Circulation 1989; 8O(suppl II):&266. 10. Bresnahan DR, Davis DL, Holmes DR Jr, Smith HC. Angiographic occurrence and clinical correlates of intraluminal coronary artery thrombus: role of unstable angina. / Am Co11 Cardiol 1985;56:403-406, 11. Wilerson JT, Hillis LD, Winniford M, Buja LM. Speculation regarding mechanisms responsible for acute ischemic heart disease syndromes. J Am Co/l Cardiol 1986;8:245-250. 12. Hoher M, Homhach V, Hannekum A, Huge1 W, Hopp HW, Hirche H. Coronary angioscopy during cardiac catheterization and cardiac surgery. Int .I Card Imaging 1988;3:153-159. 13. Fuster V, Badimon L, Cohen M, Ambrose J, Badimon JJ, Chesebro JH. Insights into the pathogen& of acute coronary syndromes. Circulation 1988; 77:1213-1220. 14. Farhi JI, Cohen M, Fuster V. The broad spectrum of unstable angina pectoris and its implications for future controlled trials. Anz J Cardiol 1986;58:547-550. 15. Ouyang P, Brinker JA, Mellits ED, Weisfeldt ML, Gerstenblith G. Variables predictive of successful medical therapy in patients with unstable angina: selection by multivariate analysis from clinical, electrocardiographic, and angiographic evaluations. Circulation 1984;70:367-376. 16. McCormick JR, Schick EC, McCabe CH, Kronmal RA, Ryan TJ. Determinants of operative mortality and long-term survival in patients with unstable angina: the CASS experience. J Thorac Cardiouasc Surg 1985;89:683-688, 17. Mabin TA, Holmes DR Jr, Smith HC, Vliestra RE, Bove AA, Reeder GS, Chesebro JH, Bresnahan JF, Orsulak TA. Intracoronary thrombus: role in coronary occlusion complicating percutaneous transluminal coronary angioplasty. J Am Coil Cardiol 1985;5:198-202. 16. Quigley PJ, Erwin J, Maurer BJ, Walsh MJ, Gearty GF. Percutaneous transluminal coronary angioplasty in unstable angina: comparison with stable angina. Br Heart J 1986;55:227-230. 19. DeFeyter PJ, Suryapranata H, Serruys PW, Beatt K, van Domburg R, van den Brand M, Tijssen JJ, Azar AJ, Hugenholtz PG. Coronary angioplasty for unstable angina: immediate and late results in 200 consecutive patients with identification of risk factors for unfavorable early and late outcome. J Am Coil Cardiol 1988;12:324-333. 20. Goldman S, Copeland J, Moritz T, Henderson W, Zadina K, Ovitt T, Doherty J, Read R, Chesler E, Sako Y, Lancaster L, Emery R, Sharma GVRK, Josa M, Pacold I, Montoya A, Parikh D, Sethi G, Holt J, Kirklin J, Shabetai R, Moores W, Aldridge J, Masud Z, DeMots H, Floten S, Haakenson C, Harker LA. Improvement in early saphenous vein graft patency after coronary artery bypass surgery with antiplatelet therapy: results of a Veterans Administration Cooperative Study. Circulation 1988;77:1324-1332. 21. Schwartz L, Bourassa MG, Lesperance J, Aldridge HE, Kazim F, Salvatori VA, Henderson M, Bona” R, David PR. Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty. N Engl J Med 1988;318:1714-1719.
In a prospective pilot trial of antithrombotic therapy in the acute coronary syndromes (ATACS) of resting and unstable angina pectoris or non-Q-wave myocardial infarction, 3 different antithrombotic regimens in the prevention of recurrent ischemic events were compared for efficacy. Ninety-three patients were randomized to receive aspirin (325 m&day), or full-dose heparin followed by warfarin, or the combination of aspirin (80 mg/day) plus heparin and then warfarin. Trial antithrombotic therapy was added to standardized antianginal medication and continued for 3 months or until an end point was reached. Analysis, by intention-to-treat, of the 3-month end points, revealed the following: recurrent ischemia occurred in 7 patients (22%) after aspirin, in 6 patients (25%) after heparin and warfarin, and in 16 patients (43%) after aspirin combined with heparin and then warfarin; coronary revascularization occurred in 12 patients (38%) after aspirin, in 12 patients (50%) after heparin and warfarin, and in 22 patients (60%) after aspirin combined with heparin and then warfarin; myocardial infarction occurred in 1 patient (3%) after aspirin, in 3 patients (13%) after heparin and warfarin, and in no patient after aspirin combined with heparin and then warfarin; no deaths occurred after aspirin or after aspirin combined with heparin and then warfarin, but 1 patient (4%) died after warfarin alone; major bleeding occurred in 3 patients (9%) after aspirin, in 2 patients (8%) after heparin nd warfarin, and in 3 patients (8%) after aspirin combined with heparin and then warfarin.
From the Division of Cardiology, Department of Medicine, Mount Sinai School of Medicine of the City University of New York, New York, New York; The Royal Victoria Infirmary, Newcastle upon Tyne, United Kingdom; and Beth Israel Medical Center, New York, New York. Part of this work was performed while Dr. Adams was a BritishAmerican Research Fellow of the British Heart Foundation and the American Heart Association. Address for reprints: Marc Cohen, MD, Division of Cardiology, Box 1030, Mount Sinai Hospital, New York, New York 10029.
Recurrent myocardial ischemia occurred at 3 f 3 days after randomization. In those who had coronary angioplasty or bypass surgery, revascularization was performed at 6 f 4 days. During trial therapy, no patient died, had a Q-wave myocardial infarction or a major bleed. Most bleeding complications consisted of blood transfusions during or immediately after bypass surgery. Only 25% of patients enrolled were discharged on trial therapy because of revascularization and withdrawals. Thus, irrespective of the antithrombotic regimen used, and even with aggressive combination therapy, a substantial fraction of patients with unstable angina or non-Q-wave myocardial infarction have recurrent myocardial ischemia and are referred for coronary revascularization. Antithrombotic therapy, coupled with early intervention after recurring ischemia, was associated with a low rate of death or myocardial infarction within the first 3 months. (Am J Cardiol 1990;66: 1287- 1292)
he beneficial role of antithrombotic therapy with either antiplatelet agentsle4 or anticoagulants3+s in patients with unstable angina pectoris has been established. Theroux et al” compared combination antithrombotic therapy with aspirin plus heparin versus placebo in unstable angina. By design, trial therapy was continued for only 5 to 6 days, and several patients had rebound myocardial ischemic pain after heparin was stopped.q Based upon (1) pathoanatomic observations implicating plaque rupture and thrombosis,1°m13 (2) limitations in the aforementioned trials, and (3) the potential for a lower medical failure rate with the use of a more aggressive antithrombotic regimen, we studied the efficacy of aspirin combined with anticoagulant therapy in patients with unstable angina or non-Q-wave infarction, or both, administered over a 3-month trial period. This study assessed whether aspirin combined with anticoagulant therapy was superior to either agent alone in reducing the frequency of recurrent myocardial ischemia and the need for coronary angioplasty or bypass surgery.
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TABLE First
I Screening Six Months
Process
for
Patient
Selection:
ScreeningCategories
No.
Screened (all patients with unstable angina or “rule-out MI”) Met inclusion criteria (rest angina or non-Q-wave infarction) Excluded In protocol already Left bundle branch block Coronary bypass surgery within 1 year Coronary angioplasty within 6 months Q-wave Ml within 6 weeks Tachyarrhythmia Hypertension Heart failure Peptic ulcer or previous CVA Bleeding tendency Allergy to trial therapy Anemia Other serious illness Need anticoagulants Need chronic aspirin or steroids Eligible Private physician refused Patient refused Randomized
300
CVA = cerebrovascular
patients.
accident;
MI = myocardial
Subgroup No.
118 77 2 5
10 4 2 4 6 8 5 3
1 5 14 4 4 41 6 8 27 (66% infarction:
of those
eligible)
No. = number
of
METHODS Patient selection: The study was conducted at Mount Sinai Hospital and Beth Israel Hospital after approval by the respective institutional review boards concerned with human research. From March 20, 1987, to March 14, 1989, all patients with cardiac pain, resting pain, or non-Q-wave infarction were screened. Men and women between the ages of 21 and 75 years were eligible if they met both of the following inclusion criteria. First, they must have presented to the hospital with ischemic pain caused by either unstable angina or nonQ-wave infarction defined as follows: (1) recent onset (-l-mm ST-segment deviation) or (2) prior history of myocardial infarction, positive exercise test results or coronary arteriogram, or typical exertional chest pain relieved by rest or nitroglycerin, or both. Exclusion criteria consisted of the following: evolving Q-wave myocardial infarction, left bundle branch block, angina precipitated by obvious provoking factors (e.g., heart failure, tachyarrhythmia, hypertension [systolic 1160 mm Hg, diastolic 1100 mm Hg]), current use of
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or contraindications to anticoagulation, coronary angioplasty within 6 months or coronary bypass surgery within 1 year, or patient unable or unwilling to give consent. Patients with occasional aspirin use were not excluded from this trial. Data obtained during screening in the first 6 months of the trial were recorded (Table I). Fifty-four percent of patients eligible for the study were randomized. Study protocol: After consent was obtained, patients were randomized to 1 of 3 therapies: ASPIRIN ALONE: Upon randomization, aspirin 325 mg orally was followed by aspirin 325 mg/day. HEPARIN FOLLOWED BY WARFARIN ALONE: An intravenous loading dose of heparin 100 U/kg bolus was followed by a continuous infusion to maintain the activated partial thromboplastin time at 2.0 X control for 3 to 4 days. If coronary arteriography did not appear imminent because of recurring pain by the third day, warfarin was started and titrated to maintain the prothrombin time at 1.5 to 2.0 X control (international normalized ratio at 3.0 to 4.5), and heparin was discontinued. ASPIRIN, PLUS HEPARIN AND THEN WARFARIN: Aspirin 325 mg orally and a bolus of intravenous heparin 100 U/kg were followed by aspirin 80 mg/day, plus a continuous heparin infusion, as in limb 2. By the third day, warfarin was started and titrated, as in limb 2, and heparin was discontinued. Aspirin, 80/mg, was continued along with warfarin. By design, every effort was made to continue the trial therapy for 12 weeks, unless an end point or a withdrawal criterion was reached (see below). After 12 weeks, the decision to continue administration of aspirin or warfarin was made by the private physician. In addition to the trial therapy, all patients received standard antianginal medical therapy with oral nitrates plus p blockers or calcium antagonists, or both. If pain recurred on this regimen, intravenous nitroglycerin was administered. The dosages of the 3 antianginal drugs were maximized within 48 hours of admission to reduce the systolic blood pressure to < 120 to 130 mm Hg, and to reduce the heart rate to 165 beats/min. Aspirin containing medication other than that used in the trial drugs was prohibited. Trial therapy was ended by design for the following reasons: (1) an end point occurred (recurrent ischemia, myocardial infarction, death or bleeding); (2) the patient was found to have normal or nonobstructive coronary artery disease, or a negative exercise tolerance test; (3) coronary revascularization or angioplasty was performed; and (4) noncompliance with medication. Patients who needed revascularization were continued on trial medications until the day of the procedure. Study end points: There were 3 primary end points: RECURRENTMYOCARDIALISCHEMIA: This was defined as the presence of recurrent angina at rest with ischemic electrocardiographic changes occurring despite full medical therapy. Full medical therapy was defined as receiving a minumum of 2 antianginal medications, resulting in a baseline resting heart rate of 565 beats/ min and a systolic pressure 5120 to 130 mm Hg.
TABLE
II Clinical
Characteristics
of the
Study
Population
Demographics Age (mean yrs) Malegender Previous angina or MI interval from onset of angina Cigarette smoker Systemic hypertension Diabetes mellitus Medication before admission Nltrates p blockers Calcium antagonists Recent aspirin In-Hospital
or first MI (mos.)
Heparin/ Warfarin n = 24(%)
Aspirin + Hep/Warf n = 37 (%)
Total Group n = 93 (%)
62 18 24 35 15 17 11
(47) (53) (34)
61 16 (68) 22 (92) 72 14 (58) 11146) 8 (33)
63 22 30 40 22 18 15
(59) (49) (41)
62 56 (60) 76 (82) 47 51(55) 46 (49) 34 (37)
13 (41) 8 (25)
12 (50) 8 (33)
19 (51) 7U9)
44 (47) 23 (25)
12 (37) 8 (25)
12 (50) 7 (2%
17 (46) 14 (38)
41(M) 29 (31)
14 22 (69) ll(34)
11 17(71) ll(46)
12 28 (76) 13 (35)
12 67 (72) 34 (37)
28 (88) 12(37) 27 (84) 18 (56)
21(88) 11 (46) 22 (92) 15 (63)
30 13 29 25
79 36 78 58
(56) (75)
(59) (81)
Data
Time between randomization and last resting ST-T changes at randomization Present with non-Q infarct (%) Treatment during hospitalization Nitrates p blockers Calcium antagonists Coronary Arteriography Percentage* with diseased vessels (>70%) 0 1 3 3 Left main PTCA CABG Non-obs Duration
Aspirin n=32(%)
pain
(hours)
2(11) 4 (22) 5 (28) 6 (33) artery
CAD or neg ETT on trial therapy (days)
l(6) 7 (22)
5(16) 8 (25) 29
(81) (35) (78) (65)
(85) (39) (84) (62)
(13) (13) (27) (40)
2 (8)
6 (10)
6 (24) 4(16) l(W
12 (21) 13 (22) 23 (40)
l(7) 4U7) 8 (33) 302) 16
9 (24) 13 (35) 4(11) 8
2 2 4 6
2 03)
of those 58 patients who underwent arteriography. All other percentages are percentages of the total population (n = 93). CABG = coronary artery bypassgratttlng; Hep/Warf = heparin hollowed by warfarin; neg E T T = negative maxlmal exercise tolerance test: Non-obs artery disease: PTCA = percutaneous transluminal coronary angioplasty; other abbrewtions as in Table I.
4 20 26 15 17
(7) (22) (28) (16)
* Percentage
MYOCARDIAL INFARCTION: This was defined as chest pain associated with new and persistent ST-T-wave changes or Q waves, accompanied either by a rise in serum creatine kinase to >2 times the upper limit of normal or by an increase of 150% in creatine kinase activity above the preceding sample but at least 1.5 times the upper limit of normal. Perioperative myocardial infarction was identified by a combination of electrocardiographic criteria and enzyme criteria. However, in this setting, the creatine kinase MB isoenzyme must be X0 p/ml (normal is 46 p/ml). Only those infarctions considered as events clearly separate from the initial cardiac event that qualified the patient for randomization were considered as end points. TOTAL DEATHS: All deaths, regardless of etiology, were end points. A death occurring 2 units of blood was considered a major bleed. Follow-up and protocol deviations: Trial therapy and study end points were monitored daily during the hospital stay. After discharge, patients were reevaluated at 6 and 12 weeks using the interval history, any readmission hospital records, 12-lead electrocardiogram, hematocrit, stool for occult blood, and prothrombin time. Trial therapy was initiated in 13 hours of randomization in all patients. One patient was not included in this analysis; she signed out against medical advice before trial therapy was begun. Protocol deviations occurred in 17 patients; their follow-up, however, is included in the analysis: 2 patients were inappropriately randomized; 2 were noncompliant and stopped their trial therapy prematurely; and private physicians referred 13 patients for revascularization despite their being asymptomatic on trial therapy. Trial therapy was continued until the time of their revascularizations. In-hospital follow-up was complete. After hospital discharge, 5 patients were lost to follow-up, and no determination could be made regarding their vital or clini-
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TABLE
TABLE IV Complications
III End Points Aspirin n=32 W)
Primary end points Recurrent ischemia
(pain
Heparin/ Warfarin n=24 W)
Aspirin + Hep/Warf n=37 (%I
Total Group n=93
Aspirin n=32
Heparin/ Warfarin n=24
Aspirin + Hep/Warf n=37
(%)
W)
(%)
(“A)
16 (43)
29(31)
0 l(3)
0 0
0 l(3)
0
1
0
0
0
0 1
1 1
3 (9) 3
0
3 (8) 2
5
7 (22)
6 (25)
l(3) 0 0 0
3(13)
0
4 (4)
26%
0
2(2)
l(4) l(4)
0 0
l(l) l(l)
+ KG) MI (total) Perioperative infarction Death (total) Death off trial therapy Secondary end points Recurrent chest pain PTCA or CABG
16 (50) 12 (38)
Pawn + ECG = chest pain accompanied abbreviations as in Tables I and Ii.
10 (42) 12 (50)
23 (62) 22 (60)
by electrocardiographic
49 (52) 48 (50) changes;
other
cal status by the end of the 1Zweek trial period. Two of these patients were in the aspirin-alone group, and 3 were in the heparin-alone group. Characteristics of the study population: Clinical characteristics, including baseline demographics as well as data acquired after randomization, are listed in Table II. The study population (n = 93) consisted of a group that was at high risk for coronary artery disease. More than two-thirds of the study group had 11 coronary risk factor before admission, and 82% had either a previous myocardial infarction or a history of stable angina, In 18% of patients, the qualifying episode of resting pain was their first manifestation of coronary disease. Sixty-seven percent of the patients recalled having had an earlier episode of resting pain within the 4 weeks before the qualifying episode of resting pain. Trial therapy was initiated at a mean of 12 f 10 hours after the last episode of resting pain. Patients were distributed among the 3 treatment groups as follows: aspirin alone-32 patients; heparin and warfarin alone-24 patients; and aspirin plus heparin and then warfarin-37 patients. At randomization, 72% of the study group had ischemic electrocardiographic changes. Statistical analysis: Continuous variables are presented as mean f standard deviation. Multiple comparisons among the 3 treatment groups were not undertaken because of the relatively small sample size. The 5 patients who were lost to follow-up after hospital discharge were distributed among the 3 treatment groups and were counted as having experienced no end points during the 3-month follow-up. RESULTS Primary
end points:
EMIA,INFARCTION,OR
RECURRENT DEATH: Despite
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maximal antianginal therapy, recurrent myocardial ischemia (chest pain and electrocardiographic changes) occurred in 29 patients, 3 1% of the total population (Table III). Although the frequency of this event ranged from 22% in the aspirin-alone group to 43% in the aspirin-plus-heparin group, application of the chi-square statistic revealed no significant differences among the 3 treatment groups in this end point. Recurrent myocardial ischemia occurred at a mean of 3 f 2 days after initiation of trial therapy. Two patients developed myocardial infarction while on THE AMERICAN
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On trial therapy Major bleeding (total) Minor bleeding (total) Hematuria + stool guaiac Off trial therapy (related to PTCA or CABG) Major bleeding (total) Wound bleed and transfusion Requiring surgical repair GI bleed and transfusion Minor bleeding (total) Related to CABG GI = gastrointestinal;
0 0 0 0
other abbreviations
2(8)
Total Group n=93 W)
2(2)
8(9)
2 0 l(4)
0 0
2 1 l(l)
1
0
1
1
as in Table Il.
trial antithrombotic therapy and before any revascularization procedure. In both cases they were non-Q-wave infarctions. Two additional patients developed myocardial infarction during coronary bypass surgery and both were in the heparin- and warfarin-alone group. During the trial therapy, there were no deaths. However, after hospital discharge, there was 1 fatality: a noncompliant patient who had stopped her trial medication prematurely (warfarin alone) experienced sudden death 2 weeks after discharge. Secondary
end points:
RECURRENT
CHEST
PAIN
AND
Recurrent chest pain (with or without electrocardiographic changes) occurred in 49 patients, 52% of the total population at a mean of 3 f 3 days after initiation of the trial therapy (Table III). At the time of recurrent pain, 86% of these 49 patients were on a minimum of 2 antianginal drugs, including intravenous nitroglycerin. No significant difference in the incidence of recurrent pain was observed among the 3 treatment groups. In the 49 patients with recurrent pain, revascularization by either coronary angioplasty or coronary bypass surgery was undertaken in 67%, whereas, in the 44 patients without recurrent pain, 13 (29%) underwent revascularization. Ten of the 13 patients without recurrent pain, who were revascularized, had severe multivessel disease. For the population as a whole (n = 93), the mean duration from randomization to diagnostic catheterization was 4 f 3 days, and the mean duration from randomization to revascularization was 6 f 4 days. Forty-one of the 46 patients who underwent revascularization were operated on during the initial hospitalization and the remaining 5 were revascularized during the first 3 months after discharge. A total of 15 patients (16%) had either nonobstructive coronary artery disease or negative maximal stress test results, and their trial therapy was discontinued. Only 25 of the original 93 patients (26%) were discharged on trial therapy. MAJOR BLEEDING COMPLICATIONS: There were no episodes of spontaneous major bleeding during the trial therapy in any of the 3 groups (Table IV). Two patients experienced minor bleeding during the trial therapy, ne-
REVASCULARIZATION:
-
-
cessitating withdrawal of therapy in 1 patient. No major bleeding occurred as a result of diagnostic cardiac catheterization. Off of trial therapy, 8 patients experienced major bleeding, all of which was related to revascularization. One patient required surgical repair of the femoral artery puncture site after coronary angioplasty. The remaining 7 patients experienced major bleeding in relation to coronary bypass surgery: 5 of the 7 required >2 units of blood transfusion for perioperative blood loss, 1 underwent reoperation for a slipped ligature, and another had a perioperative gastrointestinal bleed. Patients in the aspirin plus heparin and then warfarin group did not experience a greater frequency of either spontaneous bleeding or perioperative bleeding. During the same time period, 49% of all patients undergoing coronary bypass surgery at this hospital required blood transfusion. The average blood requirement for these patients was 2.3 units. In contrast, of the 27 patients who underwent bypass surgery in our study, only 7 (26%) required blood, and their average requirement was 2.8 units.
minimize the need for invasive diagnostic catheterization and revascularization procedures? (2) In view of the dynamic intraarterial processes precipitating the acute coronary syndromes, does more aggressive antithrombotic therapy with platelet inhibition plus anticoagulation offer more benefit than either agent alone? (3) Is one antithrombotic regimen better at reducing perioperative complications in patients presenting with unstable angina? Our study was designed to enroll highrisk patients with either resting angina or non-Q-wave infarction and to continue medical therapy (antianginal plus trial antithrombotic therapy) for 3 months after presentation. In addition, our analysis included events occurring during or after crossover to revascularization, and provided pilot data on the relative efficacy and safety of combination antithrombotic therapy administered over a 3-month trial period. Several findings emerged. We observed a disappointingly high rate of recurrent chest pain prompting catheterization and revascularization in all 3 treatment groups. Specifically, aggressive combination therapy did not reduce the frequency of recurrent pain and of subsequent coronary angioplasty DISCUSSION or coronary bypass surgery, compared to that seen with Unstable angina pectoris represents a broad spec- single antithrombotic therapy. In all, between the 51% trum, ranging from progressive or accelerating angina of patients withdrawing from trial therapy because of to the higher risk subset of resting angina with revers- revascularization, and the 16% of patients with nonobible electrocardiographic changes.r4 Previous placebo- structive coronary disease or negative stress test results, controlled therapeutic trials established a beneficial role only 26% of the original cohort were discharged on the for antithrombotic therapy with aspirin alone or with trial therapy and even fewer reached the 3-month folheparin or warfarin alone in progressive or accelerating low-up on therapy. Despite our intention to attempt to angina.1y2,4,7 With regard to the higher risk patients continue antithrombotic therapy for 3 months, our rate with resting unstable angina pectoris or non-Q-wave of failure of medical therapy-that is, need for revascumyocardial infarction, several trials of antithrombotic larization-was similar to that of Theroux, Neri Sertherapy have been reported 3,6,8but the trial therapy was neris and their co-workers-about 50%. Of interest, limited only to the first week after presentation.6,8 The- Ouyang et a1,15in 1984, observed a similar rate of medroux et a1,3 for example, compared antithrombotic ther- ical failure and revascularization, about 40 to 50%, with apy with either aspirin or heparin, or both, versus place- maximal antianginal therapy. Therefore, while the addibo, in the high-risk subset of patients presenting with tion of conventional antithrombotic therapy to antiangipain either at rest or with minimal effort and with elec- nal medication has had a beneficial impact on the rate trocardiographic changes. They observed that, in this of death and myocardial infarction,le7 it has not altered high-risk subset, as well, antithrombotic therapy was the natural history of resting unstable angina or non-Qmore effective than placebo was in reducing the rate of wave infarction in the face of the need for definitive myocardial infarction or death. Furthermore, only hep- revascularization. arin, or the combination of aspirin plus heparin, signifiRevascularization in the setting of unstable angina is cantly reduced the rate of refractory angina. However, associated with a higher complication rate.16.‘9 Our by design, all patients in this study3 were referred for study is the first to analyze perioperative ischemic catheterization and the trial therapy was ended 5 to 6 events and bleeding prospectively in patients with unstadays after randomization. Subsequently, several pa- ble angina undergoing revascularization while on differtients experienced rebound myocardial ischemic pain af- ent antithrombotic regimens. Specifically, 2 of the 3 inter heparin was stopped,9 and, at 3-month follow-up, farctions in our heparin- or warfarin-alone group oc48% of the original study population underwent coro- curred during coronary bypass surgery. In contrast, nary revascularization.3 More recently, Neri Serneri et none of the patients treated with aspirin experienced a al* compared different antithrombotic regimens in a perioperative infarction, or died. Earlier investigators small group of patients with refractory angina. They ob- have already noted the beneficial effect of aspirin given served a significant reduction in episodes of silent isch- before revascularization.20,21 emia in patients randomized to a continuous heparin inThe combination of aspirin plus heparin and then fusion but not in patients randomized to aspirin or to warfarin was associated with the lowest rate of infarcthe thrombolytic agent tissue plasminogen activator.8 tion or death, although the relatively small sample size Despite these trials, several questions remain: (1) Is of our study groups must be kept in mind. The prelirrrithere an effective “medical” regimen for this acute cor- nary report of Wallentin and the RISK study group4 is onary syndrome that can substantially reduce the inci- the first study with enough power to observe a statistidence of recurrent myocardial ischemia and thereby cally significant benefit of combination therapy over THE AMERICAN
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placebo and over short-term heparin-alone therapy. It might be anticipated that the routine use of antithrombotics, especially the combination of aspirin with anticoagulants, would produce more adverse effects than either aspirin or heparin alone. In fact, we did not observe any spontaneous major bleeding during the trial therapy or major bleeding related to diagnostic catheterization. The lower rate of bleeding observed in the present study, compared to that observed by Theroux et aL3 could be explained in two ways. They accepted a decrease in hematocrit levels alone as a criterion for a “serious bleed,” and they used a dose of 650 mg/day of aspirin. In the present study, 325 mg was used in the aspirin-alone limb, and 80 mg in the combination limb. In addition, the combination of low-dose aspirin plus heparin and then warfarin did not result in an increased rate of blood transfusion during coronary bypass surgery. Study limitations: First, patients were prospectively enrolled and randomized, but the trial therapy was not blinded. However, the main end points were identified by daily interviews of the patients, and by review of the daily progress notes in the chart and of serial cardiac enzymes. These daily notes were written by the patients’ personal physicians and by nurses who were unaware of the general progress of the study and the emerging trends. Second, different dosages of aspirin were used in the 2 aspirin-containing limbs. In parallel with the study of Lewis et al,’ we used 325 mg/day in the aspirinalone limb, as the standard. For the combination limb, a dose of 80 mg of aspirin was chosen because this low dose would minimize aspirin-related adverse effects, which are dose-dependent. Third, our patient population was relatively small. In our ongoing trial, we are evaluating only 2 limbs, aspirin versus aspirin plus heparin and then warfarin, and will aim to enroll several hundred patients to achieve an adequate power to detect significant differences in treatment effect, REFERENCES 1. Lewis HD Jr, Davis JW, Archibald DG, Steinke WE, Smitherman TC, Doherty JE III, Schnaper HW, LeWinter MM, Linares E, Pouget JM, Sabharwal SC, Chesler E, DeMots H. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. N Eng/ J Med 1983;309:396-403. 2. Cairns JA, Gent M, Singer J, Finnie KJ, Froggatt GM, Holder DA, Jablonsky G, Kostuk WJ, Melendez LJ, Myers MG, Sackett DL, Sealey BJ, Tamer PH. Aspirin, sulfinpyrazone or both in unstable angina: results of a Canadian multicenter trial. N Engl J Med 1985;313:1369-1375.
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