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The organization to assess strategies for ischemic syndromes (OASIS) pilot study: evaluation of acute and long-term therapies for patients with acute coronary syndromes without ST elevation
The Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study: Evaluation of Acute and Long-Term Therapies for Patients With Acute Coronary Syndromes Without ST Elevation Sonia S. Anand,
MD
The objectives of the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study (phase 2) were (1) to compare the efficacy, safety, and feasibility of recombinant hirudin versus unfractionated heparin as short-term therapy in patients with acute coronary syndromes without ST elevation and (2) to compare the efficacy and safety of long-term therapy with warfarin and aspirin versus standard therapy with aspirin alone in the same patient population. Investigators at 31 Canadian centers randomized 909 patients to receive either medium-dose hirudin, low-dose hirudin, or unfractionated heparin. The incidence of the 7-day primary composite outcome of cardiovascular death, new myo-
cardial infarction (MI), or refractory angina was significantly lower among patients who received hirudin than among those assigned to unfractionated heparin. A subset of these patients was subsequently randomized to long-term, low-intensity (international normalized ratio [INR] <1.5) or moderate-intensity (INR 2–2.5) anticoagulant treatment with warfarin or to standard therapy. In this substudy, promising results were observed in favor of moderate-intensity warfarin. These findings provided the rationale for the design and conduct of the largescale, phase III OASIS-2 trial. 䊚1999 by Excerpta Medica, Inc. Am J Cardiol 1999;84:13M–19M
cute coronary syndromes represent a continuum of acute myocardial ischemia (MI), spanning A from acute transmural infarction with ST-segment el-
the OASIS Pilot Study were (1) to compare the benefits of low-dose and medium-dose hirudin with those of conventional unfractionated heparin as short-term intravenous antithrombotic therapy in combination with aspirin and (2) to compare the efficacy of longterm, low-intensity or moderate-intensity anticoagulant therapy with warfarin plus aspirin versus standard therapy with aspirin alone. Hirudin, a 65-amino acid protein derived from the saliva of the medicinal leech, is now available in recombinant form. This direct thrombin inhibitor can inhibit both clot-bound and circulating thrombin.4 In contrast, unfractionated heparin requires a cofactor (either antithrombin III or heparin cofactor II) to inhibit fluid-phase thrombin and has little effect on clot-bound thrombin. Another disadvantage of unfractionated heparin is that it binds to and is neutralized by circulating plasma proteins. As a result, bioavailability varies among patients, leading to a less-predictable dose response as measured by the activated partial thromboplastin time.5
evation to unstable angina characterized by ischemia without ST elevation. In the majority of patients with acute coronary syndromes, the cause is thought to be a nonocclusive coronary thrombosis superimposed on a ruptured atherosclerotic plaque.1 The current standard of practice is to administer short-term antithrombotic therapy with intravenous heparin and aspirin.2 Although this strategy does decrease the short-term incidence of cardiovascular events, over the long term, patients with acute coronary syndromes continue to have recurrent ischemic events such as cardiovascular death, new MI, and stroke.3 In addition, a large proportion of patients require readmission to the hospital for recurrent acute ischemic events. The current belief is that the long-term recurrence of acute ischemic events is caused by an ongoing thrombotic stimulus. We therefore designed the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study to address both the acute and chronic management of patients who have acute coronary syndrome without ST elevation. The goals of From the Department of Preventive Cardiology and Therapeutics, McMaster University, Hamilton, Ontario, Canada. Address for reprints: Sonia S. Anand, MD, Department of Preventive Cardiology and Therapeutics–Population Health, 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2. Dr. Anand is a recipient of a Medical Council of Canada Clinician-Scientist Award.
©1999 by Excerpta Medica, Inc. All rights reserved.
DESIGN AND METHODS Patients were eligible for the OASIS Pilot Study if they were admitted to the hospital within 12 hours of experiencing an episode of chest pain suspected to be caused by unstable angina or by acute MI without ST elevation. Symptoms had to be associated with either current electrocardiographic evidence of ischemia or a history of documented coronary artery disease. Patients were excluded from the study if they had con0002-9149/99/$20.00 PII S0002-9149(99)00396-3
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TABLE I Baseline Characteristics of Patients Randomized to Intravenous Antithrombotic Therapy in the OASIS Pilot Study, According to Treatment Allocation Heparin n Total Age ⫾ mean SD (yr) Women MI without ST elevation Abnormal ECG Associated acute MI Heparin given before randomization Previous MI Hyperlipidemia Known hypertension Diabetes Current smoker Median hours between onset of chest pain and randomization (range)
Low-Dose Hirudin %
n
371
100.0 65 ⫾ 11.3 126 34.0 50 13.5 311 83.8 66 17.8 101 27.2 167 45.0 148 39.9 169 45.6 70 18.9 101 27.2 6 (0.3–19.0)
%
271
100.0 64 ⫾ 11.2 95 35.1 36 13.3 235 86.7 53 19.6 82 30.3 116 42.8 114 42.1 128 47.2 55 20.3 66 24.4 7 (0.0–15.0)
Medium-Dose Hirudin n
%
267
100.0 64 ⫾ 12.0 84 31.5 34 12.7 212 79.4 46 17.2 89 33.3 128 47.9 116 43.4 118 44.2 53 19.9 72 27.0 7 (0.3–12.6)
ECG ⫽ electrocardiogram; MI ⫽ myocardial infarction; OASIS ⫽ Organization to Assess Strategies for Ischemic Syndromes. Reprinted with permission from Circulation.6
traindications to heparin or hirudin, a history of stroke during the previous year, or renal impairment. Short-term treatment: Patients were first randomized, in a 4:3:3 ratio, to receive 72 hours of treatment with either intravenous unfractionated heparin (as a 5,000-U bolus, followed by a 1,200-U/h infusion), low-dose hirudin (lepirudin [HBW 023]) (as a 0.20 mg/kg bolus, followed by a 0.1 mg/kg per hour infusion), or medium-dose hirudin (as a 0.4 mg/kg bolus, followed by a 0.15 mg/kg per hour infusion). The target activated partial thromboplastin time (aPTT) for all 3 groups was 60 –100 seconds. Randomization to heparin or hirudin was open, whereas randomization to low-dose or medium-dose hirudin was blinded. All events occurring within 35 days of randomization, including death, MI, refractory angina, readmission for unstable angina, major bleeding, and stroke, were adjudicated by a central committee of clinicians blinded to the treatment allocation. Long-term treatment: All eligible patients initially randomized to heparin or hirudin were given the opportunity to participate in the long-term warfarin substudy, with the exception of those (1) who experienced major bleeding during or within 48 hours after the initial intravenous infusion; (2) who had a clear indication for long-term warfarin therapy; and (3) in whom coronary artery bypass grafting (CABG) surgery was already planned within 1 week of hospital discharge. In Phase 1, patients were randomized to receive either warfarin, in a fixed dose of 3 mg/day aimed at achieving a low-intensity level of anticoagulation (international normalized ratio [INR], ⬍1.5), or standard therapy. All patients were encouraged to take aspirin. Treatment was started 5–7 days after the cessation of intravenous antithrombotic treatment and continued for 6 months. In Phase 2, patients were randomly assigned to treatment with either warfarin, in a dose that produced moderate-intensity anticoagulation (target INR, 2–2.5) or standard therapy, start-
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ing 12–24 hours after initiation of the intravenous antithrombotic infusion and continuing for 3 months. All patients were encouraged to take aspirin.
RESULTS Between July 1994 and April 1996, 909 patients were randomized to hirudin or unfractionated heparin at 31 clinical centers in Canada. Key characteristics of these patients at baseline are outlined in Table I. Within 6 –72 hours of starting intravenous antithrombotic therapy, the majority of patients in all groups achieved aPTT values within the therapeutic range. The mean activated partial thromboplastin time during the first 12–24 hours was 79 seconds in the heparin group, as compared with 73 seconds in the medium-dose hirudin group and 66 seconds in the low-dose hirudin group (Figure 1). Between 24 and 74 hours, however, mean activated partial thromboplastin time values in the heparin and medium-dose hirudin groups were similar and tended to be higher than the corresponding values in the low-dose hirudin group. Patients treated with heparin required significantly more dose adjustments than did those who received hirudin (2 vs 0, respectively). Clinical outcomes: The primary outcome cluster was cardiovascular death, new MI, or refractory angina at 7 days. Secondary combined outcomes included cardiovascular death, new MI, or refractory/severe angina, and cardiovascular death, new MI, refractory/ severe angina, or revascularization.6 Refractory angina was defined as a new episode of ischemic chest pain with documented electrocardiographic changes in patients on optimal medical therapy, which required an additional intervention such as cardiac catheterization, thrombolytic therapy, or an intra-aortic balloon pump within 24 hours. At 7 days, the rate of cardiovascular death, new
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FIGURE 1. aPTT response to heparin, medium-dose hirudin, and low-dose hirudin in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study. During the first 24 hours, mean aPTT levels were significantly higher with heparin than with hirudin and were significantly higher with medium-dose hirudin than with low-dose hirudin. aPTT ⴝ activated partial thromboplastin time; STD ⴝ standard deviation. (Reprinted with permission from Circulation.6)
MI, or refractory angina was 6.5% in patients treated with heparin, as compared with 4.4% in patients treated with low-dose hirudin, and 3% in patients treated with medium-dose hirudin (p ⫽ 0.05 for medium-dose hirudin vs heparin; Table II and Figure 2). The proportion of patients who experienced cardiovascular death, new MI, or refractory/severe angina was 15.6% in the heparin group, 12.2% in the lowdose hirudin group, and 9.4% in the medium-dose hirudin group (p ⫽ 0.02 for medium-dose hirudin vs heparin). This pattern was also observed when revas-
cularization was added to the outcome cluster at 7 days. The major impact of hirudin on outcome cluster events was observed in the prevention of new MIs (relative risk reduction, 60%; p ⫽ 0.045 for mediumdose hirudin vs heparin). In addition, CABG was required by fewer patients receiving low-dose hirudin (3.7%) or medium-dose hirudin (1.1%) than by patients treated with heparin (4.0%). The safety profile of hirudin was acceptable. In contrast to previous hirudin trials, we did not observe any hemorrhagic strokes. In addition, the incidence of
TABLE II Seven-Day Individual and Composite Efficacy Outcomes in the OASIS Pilot Study
Total randomized Cluster outcomes Primary outcome CV death, new MI, refractory angina Secondary outcomes CV death, new MI, refractory/severe angina CV death, new MI, refractory/severe angina, revascularization
Heparin
Low-Dose Hirudin
MediumDose Hirudin
n
n
n
%
%
%
371 100.0 271 100.0 267 100.0
24
6.5
12
4.4
8
3.0
58
15.6
34
12.5
25
9.4
27
7.3
10
3.7
9
Heparin vs Low-Dose Hirudin
Heparin vs Medium-Dose Hirudin
Heparin vs Combined Hirudin
RR (95% CI)
p
RR (95% CI)
p
RR (95% CI)
p
—
—
—
—
—
—
0.68 0.267 0.46 0.047 0.57 0.057 (0.35–1.34) (0.21–1.02) (0.32–1.02)
0.80 0.270 0.60 0.020 0.70 0.039 (0.54–1.19) (0.39–0.93) (0.50–0.98) 3.4 0.51 0.054 0.46 0.035 0.49 0.011 (0.25–1.03) (0.22–0.97) (0.27–0.86)
CI ⫽ confidence interval; CV ⫽ cardiovascular; MI ⫽ myocardial infarction; OASIS ⫽ Organization to Assess Strategies for Ischemic Syndromes; RR ⫽ relative risk. Reprinted with permission from Circulation.6
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FIGURE 2. Seven-day event rates with hirudin versus heparin in patients with unstable angina enrolled in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study (n ⴝ 909). CVD ⴝ cardiovascular disease; MI ⴝ myocardial infarction; revasc ⴝ revascularization. (Reprinted with permission from Circulation.6)
major bleeding was low and was similar in all 3 treatment groups.6 Clinical recurrences after completion of short-term therapy: Patients treated with hirudin had fewer ische-
mic events while receiving the intravenous infusion than did those treated with unfractionated heparin. The beneficial impact of low-dose hirudin was similar to that of medium-dose hirudin at the end of the 72-hour infusion. Although the initial differences observed between unfractionated heparin and hirudin persisted after the cessation of the intravenous infusion, an increase in the number of recurrent ischemic episodes was seen in the low-dose hirudin group approximately 30 hours after treatment was stopped. In contrast, no rebound of ischemic events was observed in patients treated with medium-dose hirudin, suggesting that medium-dose hirudin may be more efficacious than low-dose hirudin and unfractionated heparin in cooling off the clot and minimizing further thrombotic stimuli (Figure 3). Reactivation of coagulation markers after cessation of short-term treatment: Specific coagulation parame-
ters, including D-dimer, prothrombin fragment 1.2, thrombin–antithrombin complex, and fibrinopeptide A, were measured in a subset of patients in the OASIS Pilot Study. D-dimer, which is formed when plasmin cleaves cross-linked fibrin, is a marker of endogenous fibrinolysis. Because D-dimer has a relatively long half-life, it is the most informative coagulation marker to study when comparing treatment effects. Both lowdose hirudin and medium-dose hirudin were more effective in suppressing D-dimer levels during the intravenous infusion than was heparin. Moreover, D16M THE AMERICAN JOURNAL OF CARDIOLOGY姞
dimer levels increased, soon after the heparin infusion was stopped. In contrast, significant increases in Ddimer levels did not occur until about 12 hours after the cessation of low-dose hirudin and were not observed at all after withdrawal of medium-dose hirudin. These findings suggest that clot breakdown continues to occur after the cessation of 72 hours of intravenous antithrombotic therapy and that medium-dose hirudin was the most effective of the 3 regimens in temporizing thrombus activity (Figure 4). Warfarin versus standard therapy: In Phase 1 of the OASIS Pilot Study, 309 of 601 eligible patients (51%) were randomized a second time to receive a fixed, low-intensity dose of warfarin or standard therapy. All patients were encouraged to take aspirin. Baseline characteristics of patients enrolled in Phase 1 of the warfarin substudy are summarized in Table III. The median duration between entry into the study and initiation of warfarin therapy was 6 days. The mean INR was 1.68 (⫾ 0.67) at the time of hospital discharge and 1.48 (⫾ 0.63) after 6 months. The average dose of warfarin in Phase 1 was 3 mg/day. No significant difference in the primary outcome of cardiovascular death, new MI, or refractory angina was observed between patients treated with warfarin and those who received standard therapy (Table IV).7 In addition, the number of rehospitalizations for unstable angina was similar in both groups. Bleeding complications occurred more frequently in patients randomized to warfarin than in those who received standard therapy. The results of Phase 1 of the warfarin substudy, as well as concurrent evidence from post-MI patients (Coumadin Aspirin Reinfarction Study [CARS]8 and
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FIGURE 3. Mean number of angina episodes experienced over time by each treatment group in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study. (Reprinted with permission from Circulation.6)
FIGURE 4. D-Dimer levels (adjusted for baseline) over time in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Coagulation Substudy. Note that both medium and low doses of hirudin produced greater suppression of D-dimer levels than did heparin, but that less rebound occurred with medium-dose hirudin after the infusion was stopped (*p <0.001). SE ⴝ standard error.
Post Coronary Artery Bypass Graft trial)9, indicated that the combination of low-intensity warfarin plus aspirin was no more efficacious than aspirin alone. In light of these findings, we modified our protocol to test the efficacy of moderate-intensity warfarin plus aspirin versus aspirin alone. In Phase 2 of the warfarin substudy, 197 of a possible 308 patients were randomized to receive moderate-intensity warfarin or standard therapy in the presence of aspirin and were then
followed for 3 months. The median time from the start of the intravenous antithrombotic infusion to the receipt of the first dose of warfarin was 26 hours. In patients treated with warfarin (mean daily dose, 4 mg), mean INR was 1.7 by the time of hospital discharge and 2.3 ⫾ 0.6 during the follow-up period. The incidence of cardiovascular death, new MI, and refractory angina was 5.1% in patients treated with warfarin, as compared with 12.1% in patients
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TABLE III Baseline Characteristics of Patients Randomized to Chronic Warfarin or Standard Therapy in the OASIS Pilot Study Variable
Standard Therapy
Warfarin
154 65 ⫾ 12 49 (32%) 128 (83%) 26 (17%) 134 (87%) 56 (36%)
155 63 ⫾ 10 53 (34%) 129 (83%) 26 (17%) 136 (88%) 54 (35%)
99 64 ⫾ 12 30 (30%) 79 (80%) 13 (13%) 79 (80%) 27 (27%)
98 64 ⫾ 12 36 (37%) 82 (84%) 9 (9%) 73 (74%) 26 (26%)
Phase 1 Patients (n) Mean age ⫾ SD (yr) Women Unstable angina* Non–Q-wave MI* Abnormal ECG IV heparin given† Phase 2 Patients (n) Mean age ⫾ SD (yr) Women Unstable angina* Non–Q-wave MI* Abnormal ECG IV heparin given†
ECG ⫽ electrocardiogram; IV ⫽ intravenous; MI ⫽ myocardial infarction; OASIS ⫽ Organization to Assess Strategies for Ischemic Syndromes; SD ⫽ standard deviation. *Diagnosis at randomization. † Prior to randomization. Reprinted with permission from Circulation.7
TABLE IV Results of the OASIS Pilot Warfarin Substudy No. of Patients (%) Event Cluster
Warfarin
Standard Therapy
Phase 1: Low-intensity warfarin (INR 1.5) vs control CV death, MI, refractory angina* CV death, MI, refractory angina, severe angina† Rehospitalization for unstable angina† Major bleeds‡ Minor bleeds Phase 2: Moderate-intensity warfarin (INR 2.3) vs control CV death, MI, refractory angina* CV death, MI, refractory angina, severe angina† Rehospitalization for unstable angina† Major bleeds‡ Minor bleeds
155 10 (6.5) 27 (17.4) 32 (21) 4 (2.6) 22 (14.2) 98 5 (5.1) 10 (10.2) 7 (7.1) 2 (2.0) 28 (28.6)
154 6 (3.9) 21 (13.6) 32 (21) 0 4 (2.6) 99 12 (12.1) 20 (20.2) 17 (17.2) 1 (1.0) 12 (12.1)
RR (95% CI)
p
— 1.66 (0.62–4.44) 1.28 (0.76–2.16) 0.99 (0.64–1.54)
— 0.31 0.40 0.97
5.46 (1.93–15.5) — 0.42 (0.15–1.15) 0.51 (0.25–1.02) 0.42 (0.18–0.96) 2.02 (0.19–21.9) 2.36 (1.37–4.36)
0.001 — 0.08 0.051 0.03 0.56 0.004
CV ⫽ cardiovascular; INR ⫽ international normalized ratio; MI ⫽ myocardial infarction; OASIS ⫽ Organization to Assess Strategies for Ischemic Syndromes. *Primary outcome. † Secondary outcome. ‡ Need for transfusion. Reprinted with permission from Circulation.7
randomized to standard therapy (relative risk reduction, 58%; p ⫽ 0.08). Similar benefits of warfarin were seen consistently across outcome clusters.7 In addition, a 58% reduction in the risk of rehospitalization for unstable angina was observed in favor of warfarin (p ⫽ 0.03). As expected, the proportion of patients who suffered a minor (but not major) bleeding episode was significantly greater in the warfarin group than in the standard therapy group.
CONCLUSIONS The OASIS Pilot Study (phase 2) contributed important information that was subsequently applied in designing the large-scale, phase 3 OASIS-2 trial. From the dose-finding study emerged a strong ratio18M THE AMERICAN JOURNAL OF CARDIOLOGY姞
nale for testing medium-dose hirudin. The apparently greater efficacy of mediu-dose hirudin relative to unfractionated heparin in the treatment of patients with acute coronary syndrome without ST elevation was supported by clinical as well as biochemical data. In addition, the warfarin substudy revealed promising trends in favor of moderate-intensity warfarin (dose adjusted to achieve an INR of 2–2.5) plus aspirin versus aspirin alone. This combination may prove to be an effective long-term therapy for preventing recurrent ischemic events in the acute coronary syndrome population. Thus, the OASIS Pilot Study enhanced our understanding of the pathogenesis of acute coronary syndromes, and provided a strong impetus for testing medium-dose hirudin and moderate-intensity warfarin in an expanded phase 3 trial.
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1. Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro JH. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988; 77:1213–1220. 2. Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis. JAMA 1996;276:811– 815. 3. Yusuf S, Flather M, Pogue J, Hunt D, Varigos J, Piegas L, Avezum A, Anderson J, Keltai M, Budaj A, Fox K, Ceremuzynski L, for the OASIS Registry Investigators. Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. Lancet 1998;352:507–514. 4. Weitz JI, Califf RM, Ginsberg JS, Hirsh J, The´roux P. New antithrombotics. Chest 1995;108(suppl):471– 485. 5. Weitz JI, Huboda M, Massel D, Maraganore H, Hirsh J. Clot bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990;86: 385–391.
6. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Comparison of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation: a pilot study. Circulation 1997;96:769 –777. 7. Anand S, Yusuf S, Pogue J, Weitz J, Flather M, for the OASIS Pilot Study Investigators. Long-term oral anticoagulant therapy in patients with unstable angina or suspected non-Q-wave myocardial infarction. Circulation 1998;98: 1064 –1070. 8. Coumadin Aspirin Reinfarction Trial Investigators. Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Coumadin Aspirin Reinfarction Study (CARS) [see comments]. Lancet 1997; 350;389 – 396. 9. Post Coronary Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein levels and low dose anti-coagulation obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153–162.
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MD
The objectives of the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study (phase 2) were (1) to compare the efficacy, safety, and feasibility of recombinant hirudin versus unfractionated heparin as short-term therapy in patients with acute coronary syndromes without ST elevation and (2) to compare the efficacy and safety of long-term therapy with warfarin and aspirin versus standard therapy with aspirin alone in the same patient population. Investigators at 31 Canadian centers randomized 909 patients to receive either medium-dose hirudin, low-dose hirudin, or unfractionated heparin. The incidence of the 7-day primary composite outcome of cardiovascular death, new myo-
cardial infarction (MI), or refractory angina was significantly lower among patients who received hirudin than among those assigned to unfractionated heparin. A subset of these patients was subsequently randomized to long-term, low-intensity (international normalized ratio [INR] <1.5) or moderate-intensity (INR 2–2.5) anticoagulant treatment with warfarin or to standard therapy. In this substudy, promising results were observed in favor of moderate-intensity warfarin. These findings provided the rationale for the design and conduct of the largescale, phase III OASIS-2 trial. 䊚1999 by Excerpta Medica, Inc. Am J Cardiol 1999;84:13M–19M
cute coronary syndromes represent a continuum of acute myocardial ischemia (MI), spanning A from acute transmural infarction with ST-segment el-
the OASIS Pilot Study were (1) to compare the benefits of low-dose and medium-dose hirudin with those of conventional unfractionated heparin as short-term intravenous antithrombotic therapy in combination with aspirin and (2) to compare the efficacy of longterm, low-intensity or moderate-intensity anticoagulant therapy with warfarin plus aspirin versus standard therapy with aspirin alone. Hirudin, a 65-amino acid protein derived from the saliva of the medicinal leech, is now available in recombinant form. This direct thrombin inhibitor can inhibit both clot-bound and circulating thrombin.4 In contrast, unfractionated heparin requires a cofactor (either antithrombin III or heparin cofactor II) to inhibit fluid-phase thrombin and has little effect on clot-bound thrombin. Another disadvantage of unfractionated heparin is that it binds to and is neutralized by circulating plasma proteins. As a result, bioavailability varies among patients, leading to a less-predictable dose response as measured by the activated partial thromboplastin time.5
evation to unstable angina characterized by ischemia without ST elevation. In the majority of patients with acute coronary syndromes, the cause is thought to be a nonocclusive coronary thrombosis superimposed on a ruptured atherosclerotic plaque.1 The current standard of practice is to administer short-term antithrombotic therapy with intravenous heparin and aspirin.2 Although this strategy does decrease the short-term incidence of cardiovascular events, over the long term, patients with acute coronary syndromes continue to have recurrent ischemic events such as cardiovascular death, new MI, and stroke.3 In addition, a large proportion of patients require readmission to the hospital for recurrent acute ischemic events. The current belief is that the long-term recurrence of acute ischemic events is caused by an ongoing thrombotic stimulus. We therefore designed the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study to address both the acute and chronic management of patients who have acute coronary syndrome without ST elevation. The goals of From the Department of Preventive Cardiology and Therapeutics, McMaster University, Hamilton, Ontario, Canada. Address for reprints: Sonia S. Anand, MD, Department of Preventive Cardiology and Therapeutics–Population Health, 237 Barton Street East, Hamilton, Ontario, Canada L8L 2X2. Dr. Anand is a recipient of a Medical Council of Canada Clinician-Scientist Award.
©1999 by Excerpta Medica, Inc. All rights reserved.
DESIGN AND METHODS Patients were eligible for the OASIS Pilot Study if they were admitted to the hospital within 12 hours of experiencing an episode of chest pain suspected to be caused by unstable angina or by acute MI without ST elevation. Symptoms had to be associated with either current electrocardiographic evidence of ischemia or a history of documented coronary artery disease. Patients were excluded from the study if they had con0002-9149/99/$20.00 PII S0002-9149(99)00396-3
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TABLE I Baseline Characteristics of Patients Randomized to Intravenous Antithrombotic Therapy in the OASIS Pilot Study, According to Treatment Allocation Heparin n Total Age ⫾ mean SD (yr) Women MI without ST elevation Abnormal ECG Associated acute MI Heparin given before randomization Previous MI Hyperlipidemia Known hypertension Diabetes Current smoker Median hours between onset of chest pain and randomization (range)
Low-Dose Hirudin %
n
371
100.0 65 ⫾ 11.3 126 34.0 50 13.5 311 83.8 66 17.8 101 27.2 167 45.0 148 39.9 169 45.6 70 18.9 101 27.2 6 (0.3–19.0)
%
271
100.0 64 ⫾ 11.2 95 35.1 36 13.3 235 86.7 53 19.6 82 30.3 116 42.8 114 42.1 128 47.2 55 20.3 66 24.4 7 (0.0–15.0)
Medium-Dose Hirudin n
%
267
100.0 64 ⫾ 12.0 84 31.5 34 12.7 212 79.4 46 17.2 89 33.3 128 47.9 116 43.4 118 44.2 53 19.9 72 27.0 7 (0.3–12.6)
ECG ⫽ electrocardiogram; MI ⫽ myocardial infarction; OASIS ⫽ Organization to Assess Strategies for Ischemic Syndromes. Reprinted with permission from Circulation.6
traindications to heparin or hirudin, a history of stroke during the previous year, or renal impairment. Short-term treatment: Patients were first randomized, in a 4:3:3 ratio, to receive 72 hours of treatment with either intravenous unfractionated heparin (as a 5,000-U bolus, followed by a 1,200-U/h infusion), low-dose hirudin (lepirudin [HBW 023]) (as a 0.20 mg/kg bolus, followed by a 0.1 mg/kg per hour infusion), or medium-dose hirudin (as a 0.4 mg/kg bolus, followed by a 0.15 mg/kg per hour infusion). The target activated partial thromboplastin time (aPTT) for all 3 groups was 60 –100 seconds. Randomization to heparin or hirudin was open, whereas randomization to low-dose or medium-dose hirudin was blinded. All events occurring within 35 days of randomization, including death, MI, refractory angina, readmission for unstable angina, major bleeding, and stroke, were adjudicated by a central committee of clinicians blinded to the treatment allocation. Long-term treatment: All eligible patients initially randomized to heparin or hirudin were given the opportunity to participate in the long-term warfarin substudy, with the exception of those (1) who experienced major bleeding during or within 48 hours after the initial intravenous infusion; (2) who had a clear indication for long-term warfarin therapy; and (3) in whom coronary artery bypass grafting (CABG) surgery was already planned within 1 week of hospital discharge. In Phase 1, patients were randomized to receive either warfarin, in a fixed dose of 3 mg/day aimed at achieving a low-intensity level of anticoagulation (international normalized ratio [INR], ⬍1.5), or standard therapy. All patients were encouraged to take aspirin. Treatment was started 5–7 days after the cessation of intravenous antithrombotic treatment and continued for 6 months. In Phase 2, patients were randomly assigned to treatment with either warfarin, in a dose that produced moderate-intensity anticoagulation (target INR, 2–2.5) or standard therapy, start-
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ing 12–24 hours after initiation of the intravenous antithrombotic infusion and continuing for 3 months. All patients were encouraged to take aspirin.
RESULTS Between July 1994 and April 1996, 909 patients were randomized to hirudin or unfractionated heparin at 31 clinical centers in Canada. Key characteristics of these patients at baseline are outlined in Table I. Within 6 –72 hours of starting intravenous antithrombotic therapy, the majority of patients in all groups achieved aPTT values within the therapeutic range. The mean activated partial thromboplastin time during the first 12–24 hours was 79 seconds in the heparin group, as compared with 73 seconds in the medium-dose hirudin group and 66 seconds in the low-dose hirudin group (Figure 1). Between 24 and 74 hours, however, mean activated partial thromboplastin time values in the heparin and medium-dose hirudin groups were similar and tended to be higher than the corresponding values in the low-dose hirudin group. Patients treated with heparin required significantly more dose adjustments than did those who received hirudin (2 vs 0, respectively). Clinical outcomes: The primary outcome cluster was cardiovascular death, new MI, or refractory angina at 7 days. Secondary combined outcomes included cardiovascular death, new MI, or refractory/severe angina, and cardiovascular death, new MI, refractory/ severe angina, or revascularization.6 Refractory angina was defined as a new episode of ischemic chest pain with documented electrocardiographic changes in patients on optimal medical therapy, which required an additional intervention such as cardiac catheterization, thrombolytic therapy, or an intra-aortic balloon pump within 24 hours. At 7 days, the rate of cardiovascular death, new
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FIGURE 1. aPTT response to heparin, medium-dose hirudin, and low-dose hirudin in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study. During the first 24 hours, mean aPTT levels were significantly higher with heparin than with hirudin and were significantly higher with medium-dose hirudin than with low-dose hirudin. aPTT ⴝ activated partial thromboplastin time; STD ⴝ standard deviation. (Reprinted with permission from Circulation.6)
MI, or refractory angina was 6.5% in patients treated with heparin, as compared with 4.4% in patients treated with low-dose hirudin, and 3% in patients treated with medium-dose hirudin (p ⫽ 0.05 for medium-dose hirudin vs heparin; Table II and Figure 2). The proportion of patients who experienced cardiovascular death, new MI, or refractory/severe angina was 15.6% in the heparin group, 12.2% in the lowdose hirudin group, and 9.4% in the medium-dose hirudin group (p ⫽ 0.02 for medium-dose hirudin vs heparin). This pattern was also observed when revas-
cularization was added to the outcome cluster at 7 days. The major impact of hirudin on outcome cluster events was observed in the prevention of new MIs (relative risk reduction, 60%; p ⫽ 0.045 for mediumdose hirudin vs heparin). In addition, CABG was required by fewer patients receiving low-dose hirudin (3.7%) or medium-dose hirudin (1.1%) than by patients treated with heparin (4.0%). The safety profile of hirudin was acceptable. In contrast to previous hirudin trials, we did not observe any hemorrhagic strokes. In addition, the incidence of
TABLE II Seven-Day Individual and Composite Efficacy Outcomes in the OASIS Pilot Study
Total randomized Cluster outcomes Primary outcome CV death, new MI, refractory angina Secondary outcomes CV death, new MI, refractory/severe angina CV death, new MI, refractory/severe angina, revascularization
Heparin
Low-Dose Hirudin
MediumDose Hirudin
n
n
n
%
%
%
371 100.0 271 100.0 267 100.0
24
6.5
12
4.4
8
3.0
58
15.6
34
12.5
25
9.4
27
7.3
10
3.7
9
Heparin vs Low-Dose Hirudin
Heparin vs Medium-Dose Hirudin
Heparin vs Combined Hirudin
RR (95% CI)
p
RR (95% CI)
p
RR (95% CI)
p
—
—
—
—
—
—
0.68 0.267 0.46 0.047 0.57 0.057 (0.35–1.34) (0.21–1.02) (0.32–1.02)
0.80 0.270 0.60 0.020 0.70 0.039 (0.54–1.19) (0.39–0.93) (0.50–0.98) 3.4 0.51 0.054 0.46 0.035 0.49 0.011 (0.25–1.03) (0.22–0.97) (0.27–0.86)
CI ⫽ confidence interval; CV ⫽ cardiovascular; MI ⫽ myocardial infarction; OASIS ⫽ Organization to Assess Strategies for Ischemic Syndromes; RR ⫽ relative risk. Reprinted with permission from Circulation.6
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FIGURE 2. Seven-day event rates with hirudin versus heparin in patients with unstable angina enrolled in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study (n ⴝ 909). CVD ⴝ cardiovascular disease; MI ⴝ myocardial infarction; revasc ⴝ revascularization. (Reprinted with permission from Circulation.6)
major bleeding was low and was similar in all 3 treatment groups.6 Clinical recurrences after completion of short-term therapy: Patients treated with hirudin had fewer ische-
mic events while receiving the intravenous infusion than did those treated with unfractionated heparin. The beneficial impact of low-dose hirudin was similar to that of medium-dose hirudin at the end of the 72-hour infusion. Although the initial differences observed between unfractionated heparin and hirudin persisted after the cessation of the intravenous infusion, an increase in the number of recurrent ischemic episodes was seen in the low-dose hirudin group approximately 30 hours after treatment was stopped. In contrast, no rebound of ischemic events was observed in patients treated with medium-dose hirudin, suggesting that medium-dose hirudin may be more efficacious than low-dose hirudin and unfractionated heparin in cooling off the clot and minimizing further thrombotic stimuli (Figure 3). Reactivation of coagulation markers after cessation of short-term treatment: Specific coagulation parame-
ters, including D-dimer, prothrombin fragment 1.2, thrombin–antithrombin complex, and fibrinopeptide A, were measured in a subset of patients in the OASIS Pilot Study. D-dimer, which is formed when plasmin cleaves cross-linked fibrin, is a marker of endogenous fibrinolysis. Because D-dimer has a relatively long half-life, it is the most informative coagulation marker to study when comparing treatment effects. Both lowdose hirudin and medium-dose hirudin were more effective in suppressing D-dimer levels during the intravenous infusion than was heparin. Moreover, D16M THE AMERICAN JOURNAL OF CARDIOLOGY姞
dimer levels increased, soon after the heparin infusion was stopped. In contrast, significant increases in Ddimer levels did not occur until about 12 hours after the cessation of low-dose hirudin and were not observed at all after withdrawal of medium-dose hirudin. These findings suggest that clot breakdown continues to occur after the cessation of 72 hours of intravenous antithrombotic therapy and that medium-dose hirudin was the most effective of the 3 regimens in temporizing thrombus activity (Figure 4). Warfarin versus standard therapy: In Phase 1 of the OASIS Pilot Study, 309 of 601 eligible patients (51%) were randomized a second time to receive a fixed, low-intensity dose of warfarin or standard therapy. All patients were encouraged to take aspirin. Baseline characteristics of patients enrolled in Phase 1 of the warfarin substudy are summarized in Table III. The median duration between entry into the study and initiation of warfarin therapy was 6 days. The mean INR was 1.68 (⫾ 0.67) at the time of hospital discharge and 1.48 (⫾ 0.63) after 6 months. The average dose of warfarin in Phase 1 was 3 mg/day. No significant difference in the primary outcome of cardiovascular death, new MI, or refractory angina was observed between patients treated with warfarin and those who received standard therapy (Table IV).7 In addition, the number of rehospitalizations for unstable angina was similar in both groups. Bleeding complications occurred more frequently in patients randomized to warfarin than in those who received standard therapy. The results of Phase 1 of the warfarin substudy, as well as concurrent evidence from post-MI patients (Coumadin Aspirin Reinfarction Study [CARS]8 and
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FIGURE 3. Mean number of angina episodes experienced over time by each treatment group in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Pilot Study. (Reprinted with permission from Circulation.6)
FIGURE 4. D-Dimer levels (adjusted for baseline) over time in the Organization to Assess Strategies for Ischemic Syndromes (OASIS) Coagulation Substudy. Note that both medium and low doses of hirudin produced greater suppression of D-dimer levels than did heparin, but that less rebound occurred with medium-dose hirudin after the infusion was stopped (*p <0.001). SE ⴝ standard error.
Post Coronary Artery Bypass Graft trial)9, indicated that the combination of low-intensity warfarin plus aspirin was no more efficacious than aspirin alone. In light of these findings, we modified our protocol to test the efficacy of moderate-intensity warfarin plus aspirin versus aspirin alone. In Phase 2 of the warfarin substudy, 197 of a possible 308 patients were randomized to receive moderate-intensity warfarin or standard therapy in the presence of aspirin and were then
followed for 3 months. The median time from the start of the intravenous antithrombotic infusion to the receipt of the first dose of warfarin was 26 hours. In patients treated with warfarin (mean daily dose, 4 mg), mean INR was 1.7 by the time of hospital discharge and 2.3 ⫾ 0.6 during the follow-up period. The incidence of cardiovascular death, new MI, and refractory angina was 5.1% in patients treated with warfarin, as compared with 12.1% in patients
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TABLE III Baseline Characteristics of Patients Randomized to Chronic Warfarin or Standard Therapy in the OASIS Pilot Study Variable
Standard Therapy
Warfarin
154 65 ⫾ 12 49 (32%) 128 (83%) 26 (17%) 134 (87%) 56 (36%)
155 63 ⫾ 10 53 (34%) 129 (83%) 26 (17%) 136 (88%) 54 (35%)
99 64 ⫾ 12 30 (30%) 79 (80%) 13 (13%) 79 (80%) 27 (27%)
98 64 ⫾ 12 36 (37%) 82 (84%) 9 (9%) 73 (74%) 26 (26%)
Phase 1 Patients (n) Mean age ⫾ SD (yr) Women Unstable angina* Non–Q-wave MI* Abnormal ECG IV heparin given† Phase 2 Patients (n) Mean age ⫾ SD (yr) Women Unstable angina* Non–Q-wave MI* Abnormal ECG IV heparin given†
ECG ⫽ electrocardiogram; IV ⫽ intravenous; MI ⫽ myocardial infarction; OASIS ⫽ Organization to Assess Strategies for Ischemic Syndromes; SD ⫽ standard deviation. *Diagnosis at randomization. † Prior to randomization. Reprinted with permission from Circulation.7
TABLE IV Results of the OASIS Pilot Warfarin Substudy No. of Patients (%) Event Cluster
Warfarin
Standard Therapy
Phase 1: Low-intensity warfarin (INR 1.5) vs control CV death, MI, refractory angina* CV death, MI, refractory angina, severe angina† Rehospitalization for unstable angina† Major bleeds‡ Minor bleeds Phase 2: Moderate-intensity warfarin (INR 2.3) vs control CV death, MI, refractory angina* CV death, MI, refractory angina, severe angina† Rehospitalization for unstable angina† Major bleeds‡ Minor bleeds
155 10 (6.5) 27 (17.4) 32 (21) 4 (2.6) 22 (14.2) 98 5 (5.1) 10 (10.2) 7 (7.1) 2 (2.0) 28 (28.6)
154 6 (3.9) 21 (13.6) 32 (21) 0 4 (2.6) 99 12 (12.1) 20 (20.2) 17 (17.2) 1 (1.0) 12 (12.1)
RR (95% CI)
p
— 1.66 (0.62–4.44) 1.28 (0.76–2.16) 0.99 (0.64–1.54)
— 0.31 0.40 0.97
5.46 (1.93–15.5) — 0.42 (0.15–1.15) 0.51 (0.25–1.02) 0.42 (0.18–0.96) 2.02 (0.19–21.9) 2.36 (1.37–4.36)
0.001 — 0.08 0.051 0.03 0.56 0.004
CV ⫽ cardiovascular; INR ⫽ international normalized ratio; MI ⫽ myocardial infarction; OASIS ⫽ Organization to Assess Strategies for Ischemic Syndromes. *Primary outcome. † Secondary outcome. ‡ Need for transfusion. Reprinted with permission from Circulation.7
randomized to standard therapy (relative risk reduction, 58%; p ⫽ 0.08). Similar benefits of warfarin were seen consistently across outcome clusters.7 In addition, a 58% reduction in the risk of rehospitalization for unstable angina was observed in favor of warfarin (p ⫽ 0.03). As expected, the proportion of patients who suffered a minor (but not major) bleeding episode was significantly greater in the warfarin group than in the standard therapy group.
CONCLUSIONS The OASIS Pilot Study (phase 2) contributed important information that was subsequently applied in designing the large-scale, phase 3 OASIS-2 trial. From the dose-finding study emerged a strong ratio18M THE AMERICAN JOURNAL OF CARDIOLOGY姞
nale for testing medium-dose hirudin. The apparently greater efficacy of mediu-dose hirudin relative to unfractionated heparin in the treatment of patients with acute coronary syndrome without ST elevation was supported by clinical as well as biochemical data. In addition, the warfarin substudy revealed promising trends in favor of moderate-intensity warfarin (dose adjusted to achieve an INR of 2–2.5) plus aspirin versus aspirin alone. This combination may prove to be an effective long-term therapy for preventing recurrent ischemic events in the acute coronary syndrome population. Thus, the OASIS Pilot Study enhanced our understanding of the pathogenesis of acute coronary syndromes, and provided a strong impetus for testing medium-dose hirudin and moderate-intensity warfarin in an expanded phase 3 trial.
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1. Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro JH. Insights into the pathogenesis of acute ischemic syndromes. Circulation 1988; 77:1213–1220. 2. Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina: a meta-analysis. JAMA 1996;276:811– 815. 3. Yusuf S, Flather M, Pogue J, Hunt D, Varigos J, Piegas L, Avezum A, Anderson J, Keltai M, Budaj A, Fox K, Ceremuzynski L, for the OASIS Registry Investigators. Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without initial ST elevation. Lancet 1998;352:507–514. 4. Weitz JI, Califf RM, Ginsberg JS, Hirsh J, The´roux P. New antithrombotics. Chest 1995;108(suppl):471– 485. 5. Weitz JI, Huboda M, Massel D, Maraganore H, Hirsh J. Clot bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990;86: 385–391.
6. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Comparison of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation: a pilot study. Circulation 1997;96:769 –777. 7. Anand S, Yusuf S, Pogue J, Weitz J, Flather M, for the OASIS Pilot Study Investigators. Long-term oral anticoagulant therapy in patients with unstable angina or suspected non-Q-wave myocardial infarction. Circulation 1998;98: 1064 –1070. 8. Coumadin Aspirin Reinfarction Trial Investigators. Randomised double-blind trial of fixed low-dose warfarin with aspirin after myocardial infarction. Coumadin Aspirin Reinfarction Study (CARS) [see comments]. Lancet 1997; 350;389 – 396. 9. Post Coronary Bypass Graft Trial Investigators. The effect of aggressive lowering of low-density lipoprotein levels and low dose anti-coagulation obstructive changes in saphenous-vein coronary-artery bypass grafts. N Engl J Med 1997;336:153–162.
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