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Vol. 293 No. 4, January 26, 2005 |
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Original Contribution |
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JAMA-EXPRESS
Effects of Reviparin, a Low-Molecular-Weight Heparin, on Mortality, Reinfarction, and Strokes in Patients With Acute Myocardial Infarction Presenting With ST-Segment Elevation
The CREATE Trial Group Investigators*
JAMA. 2005;293:427-435.
ABSTRACT
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Context Although reperfusion therapy, aspirin,  -blockers, and angiotensin-converting enzyme inhibitors reduce mortality when used early in patients with acute myocardial infarction (MI), mortality and morbidity remain high. No antithrombotic or newer antiplatelet drug has been shown to reduce mortality in acute MI.
Objective To evaluate the effects of reviparin, a low-molecular-weight heparin, when initiated early and given for 7 days in addition to usual therapy on the primary composite outcome of death, myocardial reinfarction, or strokes at 7 and 30 days.
Design, Setting, and Patients A randomized, double-blind, placebo-controlled trial (Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation [CREATE]) of 15 570 patients with ST-segment elevation or new left bundle-branch block, presenting within 12 hours of symptom onset at 341 hospitals in India and China from July 2001 through July 2004.
Intervention Reviparin or placebo subcutaneously twice daily for 7 days.
Main Outcome Measure Primary composite outcome of death, myocardial reinfarction, or stroke at 7 and 30 days.
Results The primary composite outcome was significantly reduced from 854 (11.0%) of 7790 patients in the placebo group to 745 (9.6%) of 7780 in the reviparin group (hazard ratio [HR], 0.87; 95% CI, 0.79-0.96; P = .005). These benefits persisted at 30 days (1056 [13.6%] vs 921 [11.8%] patients; HR, 0.87; 95% CI, 0.79-0.95; P = .001) with significant reductions in 30-day mortality (877 [11.3%] vs 766 [9.8%]; HR, 0.87; 95% CI, 0.79-0.96; P = .005) and reinfarction (199 [2.6%] vs 154 [2.0%]; HR, 0.77; 95% CI, 0.62-0.95; P = .01), and no significant differences in strokes (64 [0.8%] vs 80 [1.0%]; P = .19). Reviparin treatment was significantly better when it was initiated very early after symptom onset at 7 days (<2 hours: HR, 0.70; 95% CI, 0.52-0.96; P = .03; 30/1000 events prevented; 2 to <4 hours: HR, 0.81; 95% CI, 0.67-0.98; P = .03; 21/1000 events prevented; 4 to <8 hours: HR, 0.85; 95% CI, 0.73-0.99; P = .05; 16/1000 events prevented; and  8 hours: HR, 1.06; 95% CI, 0.86-1.30; P = .58; P = .04 for trend). There was an increase in life-threatening bleeding at 7 days with reviparin and placebo (17 [0.2%] vs 7 [0.1%], respectively; P = .07), but the absolute excess was small (1 more per 1000) vs reductions in the primary outcome (18 fewer per 1000) or mortality (15 fewer per 1000).
Conclusions In patients with acute ST-segment elevation or new left bundle-branch block MI, reviparin reduces mortality and reinfarction, without a substantive increase in overall stroke rates. There is a small absolute excess of life-threatening bleeding but the benefits outweigh the risks.
INTRODUCTION
Approximately 15.5 million cardiovascular deaths occur every year.1 Of these, about half are likely to be due to acute myocardial infarction (MI), with the majority occurring in low- and middle-income countries. Aspirin,2 thrombolytic therapy,3 -blockers,4 and angiotensin-converting enzyme (ACE) inhibitors5 improve prognosis in acute MI. Primary percutaneous coronary angioplasty (PCI) offers benefits over thrombolytic therapy,6 but access to primary PCI is limited and not affordable to the majority of patients in the world.
Combinations of newer antiplatelet regimens,7-8 or direct thrombin inhibitors,9-10 appear to reduce reinfarction but do not reduce mortality.7-10 Moreover, these agents are expensive and increase bleeding. Although intravenous unfractionated heparin is commonly used after acute MI, especially in patients receiving fibrin-specific thrombolytic agents, this practice is based on a few trials that indicated modest improvements in coronary patency.11-14 However, no reduction in mortality or reinfarction has been documented and there appears to be an increase in bleeding. In the Third International Study of Infarct Survival (ISIS-3)15 and Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico (GISSI-2)16 trial groups, subcutaneous heparin reduced in-hospital mortality and reinfarction to a small extent, when given with fibrin-specific and nonspecific thrombolytic agents, but these differences did not persist at 1 month. In a subsequent large trial,17 intravenous heparin tended to be worse than subcutaneous heparin, when given with streptokinase. Trials of enoxaparin (vs placebo or unfractionated heparin) indicate fewer reinfarctions,8 but none observed mortality reductions,18 and there are concerns of substantial increases in strokes when enoxaparin and some fibrin-specific agents such as tenectoplase are used in elderly patients.19
Therefore, the net benefit-risk ratio of using any thrombin inhibitor in acute MI is not clear. A meta-analysis of the trials comparing enoxaparin vs unfractionated heparin suggests a lower rate of reinfarction, with no impact on mortality but an increase in major bleeding and strokes.18 Given that unfractionated heparin does not reduce mortality or reinfarction (vs usual care) but increases bleeding, trials of low-molecular-weight heparin (LMWH) vs unfractionated heparin are difficult to interpret for both efficacy or safety. However, given the promising data with LMWH in patients with ST-segment elevation acute MI, a large definitive trial is urgently needed.
We conducted 2 similar trials, the Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation (CREATE) trial and the Estudios Cardiologicas Latin America Study Group trial,18 aimed at reliably evaluating the role of high-dose glucose, insulin, and potassium (GIK) in 20 000 patients and also described in the accompanying article.20 In the 2 largest countries (India and China), we simultaneously evaluated reviparin (an LMWH) in 15 570 patients (CREATE trial) using a factorial design. The goal of this part of the trial was to evaluate the impact of reviparin on the composite outcome of death, myocardial reinfarction, and stroke (first coprimary outcome) or the first coprimary outcome with the addition of recurrent ischemia with electrocardiogram changes (second coprimary outcome) at 7 and 30 days. The impact on individual components of the composite outcomes, especially mortality, were evaluated. A combined efficacy and safety outcome of death, myocardial reinfarction, strokes, and life-threatening bleeding at 30 days was used to assess the balance between efficacy and safety.
METHODS
The CREATE trial used a partial 2 x 2 factorial design comparing reviparin with placebo administered for 7 days (double-blind) and comparing GIK with control (open) administered for 24 hours, in addition to usual care. Patients in India and China were randomized to both parts of the trial (n = 15 570 patients), whereas those from other countries were only included in the GIK component. All centers obtained local ethics committee approval and, in addition, the project office obtained approval from the institutional review board of the Hamilton Health Sciences and McMaster University, Hamilton, Ontario.
Following written or witnessed oral informed consent, patients presenting with suspected acute MI and ST-segment elevation or new left bundle-branch block within 12 hours of symptom onset and without contraindications to heparin (active or high risk of bleeding, recent major surgery or trauma within 2 weeks, systolic blood pressure 180 mm Hg, severe anemia, hemorrhagic stroke <12 months, oral anticoagulant therapy, heparin-induced thrombocytopenia, pregnancy, or other diseases limiting life expectancy less than 1 month) or GIK (type 1 diabetes mellitus, renal impairment, or hyperkalemia) were randomized (Figure 1).
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Figure 1. CREATE-ECLA Partial Factorial Study Flow Diagram
CREATE indicates Clinical Trial of Reviparin and Metabolic Modulation in Acute Myocardial Infarction Treatment Evaluation; ECLA, Estudios Cardiologicas Latin America study group; GIK, glucose, insulin, and potassium; UFH, unfractionated heparin; LMWH, low-molecular-weight heparin.
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Study drugs were recommended to be initiated prior to or within 15 minutes of thrombolytic therapy. Patients who weighed less than 50 kg received 3436 IU Ph Eur antiXa units of reviparin (provided by Abbott GmbH & Company KG, Ludwigshafen, Germany) every 12 hours subcutaneously, patients who weighed between 50 to 75 kg received 5153 IU every 12 hours, and patients who weighed more than 75 kg received 6871 IU every 12 hours. In patients undergoing primary PCI, open-label unfractionated heparin was used during the procedure, with study medication being initiated 1 hour after removal of the sheath. Nonstudy thrombin inhibitors were not allowed, unless there was a clinical need, in which case patients who were blinded to study medication were discontinued of study drug. All other proven therapies were permitted based on the physician’s judgement.
Study Organization
Data from 274 centers in China and 67 centers in India were sent to the National Coordinating Office (NCO) at the Beijing Hypertension League Offices, Beijing, China, or to the NCO at St John’s Academy of Medical Sciences, Bangalore, India, respectively. Randomization to reviparin or placebo was grouped in blocks, with the block size kept confidential and the randomization list stratified by center. All patients in China were randomized by telephone to Beijing. In India, patients were initially randomized using sealed opaque envelopes (n = 5127), but this procedure was changed to central telephone randomization for subsequent patients (n = 2933). Despite extensive precautions, randomization errors occurred in 173 (1.1%) of 15 570 patients. These patients were included in the originally intended allocation for analyses.
The NCOs entered the data into a Web-based database that was connected online to the Population Health Research Institute, McMaster University and Hamilton Health Sciences, Hamilton, Ontario. Extensive consistency and edit checks at the NCO and the Population Health Research Institute, and at site visits ensured high data completeness (99.9%).
Follow-up at 30 days was obtained by having patients return for a no-cost visit. For approximately 200 patients in which follow-up was difficult to obtain, even after telephone calls and mailings, research staff visited the patients’ homes. Patients were not paid to participate in the trial but were offered transportation costs and, as noted, a no-cost 30-day follow-up visit. Centers were reimbursed based on each follow-up visit completed.
Outcome Measures
The first coprimary outcome was a composite of death, reinfarction, or stroke at 7 days, while the second coprimary outcome was the first outcome with the addition of ischemia with electrocardiogram changes, also at 7 days. Secondary outcomes included the components of these coprimary outcomes, any ischemia at 7 days, and 30-day outcomes, which included the same composites.
Total mortality was included in the composite efficacy outcomes. Causes of death were categorized by the local investigator without knowledge of treatment allocation. Reinfarction was defined as recurrent typical chest pain with new clear persistent ischemic (ST reelevation or depression) electrocardiogram changes within 24 hours; or after 24 hours, recurrent typical chest pain with characteristic new electrocardiogram changes (new Q waves, ST elevation or depression with evolution) or a further increase in enzyme levels (to twice the upper limit of normal if it had returned to baseline or if already elevated, with a further elevation by 50%). Refractory ischemia was defined as recurrent chest pain on optimal medical therapy (at least 2 anti-anginals) and further subcategorized as those patients with or without documented new electrocardiogram changes. Strokes were defined as focal neurological deficits that persisted for more than 24 hours. These were further categorized as probable/definite hemorrhagic, ischemic, or type unknown. Computed tomographic scans, magnetic resonance imaging, or autopsy were available in 102 (70.8%) of 144 patients with strokes. Major bleeding was defined as bleeding requiring the transfusion of at least 2 units of blood, intracranial or fatal. Major bleeding was subcategorized as life-threatening (fatal, needing surgical intervention, transfusion of 4 units of blood, drop in hemoglobin of >5 g/dL, or intracranial) or non–life-threatening. Intracranial bleeding and fatal bleeding were already included in the efficacy composite outcomes. All efficacy and safety outcomes were adjudicated by blinded central committees in each country.
Interim Analysis
An independent data and safety monitoring board regularly reviewed the accumulating data. Three formal interim analyses occurred when 25%, 50%, and 75% of the data were available. For the first 2 interim analyses, the boundary for benefit had to exceed a difference of 4 SDs ( 2 = 16; P<.0001) for the first coprimary outcome for the reviparin group, on 2 successive examinations of the data about 3 months apart. For the third analysis, the boundary was 3.5 SDs (2 = 12.3; P<.00047).
Power
Anticipating a 12% rate for the first coprimary outcome of death, reinfarction, or stroke at 7 days in the placebo group with 15 000 patients, there was 93% power to detect a 15% relative risk reduction with reviparin.
Statistical Analysis
All analyses presented are by intention-to-treat. Where randomization errors occurred (1.1%), analyses are based on the group they were originally allocated to rather than the treatment actually administered. This resulted in the opposite treatment being administered to 0.55%; our analytical approach led to a very slight underestimation of the treatment effect. The study was considered significant at P .05 for both coprimary outcomes, or if the first coprimary outcome was P.046 or the second coprimary was P.01, which preserved the overall  level at .05. Outcomes were compared using hazard ratios (HRs) and the 95% confidence intervals (CIs) derived from a Cox proportional hazards regression model; the proportional hazards assumption was confirmed. Data were also presented using Kaplan-Meier curves. Practically no adjustments of the final P values were required given the extreme statistical boundaries used for interim analyses. Subgroup hypotheses were analyzed using tests for trend or interactions in the Cox proportional hazards regression analyses. Two prespecified subgroup hypotheses were postulated: first, that treatment would be effective both in those patients undergoing and not undergoing reperfusion therapy; and second, that reviparin would be more effective with earlier treatment. Statistical analyses were performed with SAS version 8.2 (SAS Institute Inc, Cary, NC).
RESULTS
A total of 15 570 patients were randomized to receive either reviparin or placebo. Seven-day data were available in all patients (100%) and 30-day vital status was known in 15 565 patients (99.96%). A total of 7780 patients received reviparin and 7790 received placebo.
Table 1 summarizes key baseline characteristics. More than 75% of the patients were randomized within 8 hours of symptom onset (median duration, 4.9 hours). A total of 13 030 patients (83.7%) were in Killip class I (no pulmonary rales or third heart sound). Thrombolytic therapy was used in 11 355 patients (73%) and primary PCI in 949 patients (6.1%), with any reperfusion strategy in 12 245 patients (79%) (59 patients received both). Aspirin was used in 15 084 patients (96.9%), clopidogrel or ticlopidine in 8555 (54.9%), -blockers in 10 259 (65.9%), ACE inhibitors in 11 314 (72.7%), and lipid-lowering medications in 10 374 (66.6%). The number of patients that evolved electrocardiographic Q-waves was 12 064 (77.5%) overall, with no significant difference between the 2 groups. The number of patients undergoing PCI after thrombolytic therapy was 156 (2.7%) in the reviparin group compared with 201 (3.5%) in the placebo group (P = .02).
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Table 1. Baseline Characteristics and Interventions in Hospital of Patients Receiving Reviparin or Placebo*
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Adherence and Timing of Therapy
A total of 7626 patients (98.0%) allocated to reviparin and 7647 (98.2%) allocated to placebo received study drugs (Figure 1). The time from randomization to administration of the first dose of study drug was less than 1 hour in 85% of patients. In 2745 patients (17.6%), the study drug was initiated before thrombolytic therapy; in 8512 patients (54.7%), the study drug was administered after thrombolytic therapy, with about a third (n = 2750) receiving it less than 30 minutes, another third within 30 to 60 minutes (n = 2294), and another third more than 60 minutes (n = 3468). Prerandomization heparin was used in 1466 patients (9.4%) and nonstudy heparin or LMWH after randomization was used in 739 patients (9.5%) in the reviparin group compared with 799 (10.3%) in the placebo group. A total of 11 893 patients (76%) received allocated study drug for 7 days, with 14 231 (91.4%) receiving it for at least 2 days.
Efficacy Outcomes
Both coprimary outcomes were significantly reduced at 7 days with reviparin (Table 2). The composite efficacy of death, myocardial reinfarction, or strokes was reduced from 854 patients (11.0%) in the placebo group to 745 (9.6%) in the reviparin group (HR, 0.87; 95% CI, 0.79-0.96; P = .005) (Figure 2). The second coprimary outcome, which included recurrent ischemia with electrocardiogram changes, was also significantly reduced from 982 patients (12.6%) to 864 (11.1%) (HR, 0.87; 95% CI, 0.80-0.96; P = .004). Significant reductions in mortality and myocardial reinfarction were also observed, with favorable trends toward lower rates of recurrent ischemia. However, there was no significant difference in strokes. There was a mix of a small but significant excess of hemorrhagic strokes (23 patients [0.3%] vs 10 [0.1%]; P = .03), with little difference in other types of strokes (38 patients [0.5%] vs 39 [0.5%]).
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Table 2. Efficacy of Reviparin vs Placebo at 7 Days
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Figure 2. Primary Outcome of Death, Myocardial Reinfarction, or Stroke Over 7 Days for Patients Receiving Either Placebo or Reviparin
HR indicates hazard ratio; CI, confidence interval. There is an early separation of the curves with continuing divergence over the entire 7-day period.
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At 30 days, both composite outcomes were similarly reduced (Table 3). The reductions in mortality and myocardial reinfarction were highly significant (Figure 3), with no significant excess in strokes (Figure 4). The number of patients with a composite outcome of death, reinfarction, or disabling strokes at 30 days were signficantly reduced from 1034 patients (13.3%) in the placebo group to 904 (11.6%) in the reviparin group (HR, 0.87; 95% CI, 0.79-0.95; P = .002).
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Table 3. Efficacy of Reviparin vs Placebo at 30 Days
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Figure 3. Cumulative Mortality and Myocardial Reinfarction for Up to 30 Days for Patients Receiving Either Placebo or Reviparin
HR indicates hazard ratio; CI, confidence interval. There were 52 reinfarctions within 24 hours in the placebo group and 40 reinfarctions within 24 hours in the reviparin group.
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Figure 4. Total Stroke and Probable/Definite Hemorrhagic Stroke Up to 30 Days for Patients Receiving Either Placebo or Reviparin
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Subgroups
The benefits of reviparin were greatest with earlier treatment after symptom onset at 7 days (<2 hours: HR, 0.70; 95% CI, 0.52-0.96; P = .03; 30 events prevented per 1000 patients; 2 to <4 hours: HR, 0.81; 95% CI, 0.67-0.98; P = .03; 21 events prevented per 1000 patients; 4 to <8 hours: HR, 0.85; 95% CI, 0.73-0.99; P = .05; 16 events prevented per 1000 patients; and 8 hours: HR, 1.06; 95% CI, 0.86-1.30; P = .58; P = .04 for trend). Similarly, at 30 days, a 30% relative risk reduction was observed in those patients randomized less than 2 hours compared with 20% in those randomized between 2 to 4 hours, 15% between 4 and 8 hours, and little benefit for those randomized more than 8 hours (P = .01 for trend) (Figure 5). Similar trends were observed for mortality and myocardial reinfarction but not for strokes. Consistent benefits at 7 days were observed in those patients undergoing reperfusion therapy (HR, 0.90; 95% CI, 0.81-1.01) and in those not receiving this therapy (HR, 0.79; 95% CI, 0.65-0.95; P = .23 for interaction) for the first coprimary outcome, with similar results for the second coprimary outcome (HR, 0.90; 95% CI, 0.81-1.00; and HR, 0.81; 95% CI, 0.68-0.97; respectively). Similar results with benefits in both subgroups were also observed by 30 days. In the subgroup of patients (n = 949) undergoing primary PCI, trends toward fewer events were observed (28 [5.8%] of 481 patients vs 34 [7.3%] of 468; HR, 0.79; 95% CI, 0.48-1.31; for the first coprimary outcome, and 35 [7.3%] of 481 vs 47 [10.0%] of 468; HR, 0.71; 95% CI, 0.46-1.10; for the second coprimary outcome). In the patients who received tissue plasminogen activator or primary PCI (which approximates the usual practice in many North American centers), there were 31 (5.8%) of 532 individuals assigned to reviparin with death, myocardial reinfarction, stroke, or recurrent ischemia compared with 40 (7.7%) of 520 individuals assigned to placebo (HR, 0.75; 95% CI, 0.47-1.19), suggesting that the benefits of reviparin were independent of the type of reperfusion therapy.
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Figure 5. Death, Myocardial Reinfarction, and Stroke in the 2 Prespecified Groups at 30 Days
There is an increasing benefit with earlier treatment (P = .01 for trend) but the effects in those patients with or without reperfusion therapy did not significantly differ from each other (P = .31 for interaction). The boxes indicate hazard ratios, and their size is proportional to the number of patients in each group.
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Safety
There was a significant increase in the rates of life-threatening or major bleeding at 7 days (Table 4). The most common sites were gastrointestinal (19 vs 9 patients) and intracranial (22 vs 10 patients). The increased bleeding risk tended to be greater in those patients undergoing reperfusion therapy (1.1% receiving reviparin vs 0.4% receiving placebo), whereas the rates were low in the 3325 patients without reperfusion therapy (0.1% vs 0.1%, respectively). Intracranial hemorrhage also tended to be higher with reviparin in those patients undergoing reperfusion therapy (0.4% vs 0.1%) compared with those not undergoing such treatment (0.1% vs 0.1%). However, fatal bleeding and intracranial bleeding were already included in the analysis of death or strokes, as part of the efficacy outcome. Therefore, the number of patients with life-threatening bleeding not associated with death or strokes was 17 (0.2%) receiving reviparin vs 7 (0.1%) receiving placebo (P = .07).
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Table 4. Major or Life-Threatening Bleeding at 7 Days Comparing Reviparin With Placebo
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Benefit and Risk Balance
The composite outcome of death, myocardial reinfarction, strokes, and life-threatening bleeding (Figure 6) occurred in 762 patients (9.8%) in the reviparin group compared with 861 (11.1%) in the placebo group (HR, 0.88; 95% CI, 0.80-0.97; P = .01), with similar results at 30 days (934 [12.0%] vs 1065 [13.7%] patients; HR, 0.87; 95% CI, 0.80-0.95; P = .002), which suggests that for every 1000 patients treated with reviparin, 17 fewer major adverse outcomes would be prevented.
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Figure 6. Primary Outcome of Death, Myocardial Reinfarction, or Stroke, and Life-Threatening Bleeding in Patients Receiving Either Placebo or Reviparin
HR indicates hazard ratio; CI, confidence interval. There is a substantially greater benefit from reviparin in preventing major vascular events (18 fewer per 1000 patients) compared with the small excess in other life-threatening bleeding (1 more per 1000 patients).
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COMMENT
The CREATE trial demonstrated a clear and significant reduction in both coprimary outcomes at 7 and 30 days. Furthermore, there were significant reductions in death and myocardial reinfarction, with no significant excess in strokes. There was a small but significant early increase in life-threatening bleeding, but this only slightly offset the reductions in mortality or myocardial reinfarction. Overall, there were 17 fewer major events (death from any cause, reinfarction, strokes, or life-threatening bleeding) per 1000 patients who were administered reviparin (P = .002). Thus, the overall benefits of reviparin in acute MI clearly outweighs its risks.
Reductions in recurrent myocardial reinfarction and recurrent ischemic events observed in the CREATE trial with reviparin are consistent with the results of previous trials of LMWH, such as the ASSENT-3 study,8, 15 which used enoxaparin, or those studies evaluating direct thrombin inhibitors.9-10 However, unlike these trials, the CREATE trial has also observed significant reductions in mortality. Although there was an excess of early intracranial bleeding, there was no significant excess of overall strokes with the absolute excess being small (2 per 1000 patients treated). Eighty percent of patients with intracranial hemorrhagic died; therefore, these deaths due to strokes were included in the analysis of deaths, which was still significantly lower with reviparin. The rates of intracranial hemorrhage and strokes in our trial (0.3% and 0.8%, respectively) in the reviparin group at 7 days were lower than previous trials of enoxaparin used in conjunction with fibrin-specific thrombolytic agents, such as tenecteplase (for intracranial hemorrhage and total strokes, 0.88% and 1.62%, respectively, in the ASSENT-3 study8; and 2.2% and 2.9%, respectively, in the ASSENT-Plus study14). Therefore, given the clearly lower mortality and myocardial reinfarction rates with no excess in overall stroke rates, the combination of reviparin with less expensive nonspecific thrombolytic therapy is a reasonable option in patients with acute MI receiving other effective therapies.
Previous trials of unfractionated heparin in patients with acute ST elevation MI who are receiving streptokinase or tissue plasminogen activator and aspirin have not demonstrated a reduction in major vascular events at 1 month, despite increased bleeding.15-16 In these trials, there was a small reduction in hospital mortality and reinfarction, but these differences did not persist at 1 month. This lack of benefit may have been because of the inherent limitations of unfractionated heparin or delays in therapy after a thrombolytic agent (>4 hours in ISIS-315 and >12 hours in GISSI-216). In the GUSTO trial,17 there was no significant impact on mortality but an increase in reinfarction with intravenous heparin compared with subcutaneous heparin when used in conjunction with streptokinase.13 Intravenous heparin is commonly used in some countries for approximately 24 to 48 hours after a fibrin-specific thrombolytic agent, largely based on the results of some but not all trials that demonstrated differences in angiographic patency.11-14 However, this difference in patency was very small in the only trial that used an adequate dose of aspirin.14 Even collectively, these trials were too small to reliably evaluate the impact on mortality, reinfarction, or strokes, but was associated with an increase in major bleeding in 1 study.21 Thus, despite the common use of intravenous heparin with a fibrin-specific thrombolytic agent, the net benefit-risk ratio on clinical outcomes is uncertain.
Low-molecular-weight heparin has been evaluated in ST elevation acute MI in several small- and moderate-sized studies. No trial has demonstrated a significant reduction in mortality, perhaps because of the small size, shorter duration of treatment, and higher rates of intracranial bleeding. A meta-analysis of 6 randomized controlled trials of enoxaparin vs unfractionated heparin in approximately 8000 patients indicates a reduction in myocardial reinfarction with enoxaparin (3.2% vs 5.1%, respectively; odds ratio [OR], 0.61; 95% CI, 0.48-0.76), no impact on mortality (5.8% vs 6.1%, respectively; OR, 0.97; 95% CI, 0.81-1.17), an increase in major bleeding (3.2% vs 2.3%, respectively; OR, 1.38; 95% CI, 1.05-1.81), and hemorrhagic strokes (1.29% vs 0.89%, respectively; OR, 1.30; 95% CI, 0.84-2.03)18 compared with unfractionated heparin.
Prior data comparing LMWH with placebo are also sparse (only 1376 patients) and indicate little impact on mortality (6.4% vs 6.8%, respectively; OR, 0.75; 95% CI, 0.36-1.55).18 However, the CIs were wide and are consistent with the CREATE trial results. In these trials, there was a significant reduction in reinfarction (3.2% with LMWH vs 6.0% with placebo; OR, 0.54; 95% CI, 0.33-0.91), but much higher rates of major bleeding (3.6% vs 1.0%, respectively; OR, 3.0; 95% CI, 1.50-6.00). The results of the CREATE trial, which involved 4 times the number of patients compared with any previous trials of LMWH, demonstrates significant reductions in death and myocardial reinfarction. Although there was increased bleeding, this adverse event was much smaller than that observed with trials of other LMWHs, newer antiplatelet drugs, or direct thrombin inhibitors.7-10,18
Interestingly, the reductions in death and myocardial reinfarction at 7 and 30 days were greater with earlier treatment but no such trend was observed with strokes alone. This suggests that at least some of the benefits of reviparin may be related to improved rates of coronary patency and increased myocardial salvage. Because the benefits are related to the time of initiation of treatment and the adverse effects are not, the benefit-risk balance is likely to be most favorable if treatment is initiated with 8 hours or even earlier. In the CREATE trial, administering 1000 patients with reviparin who presented 8 hours or less at the hospital for 7 days prevented 20 major vascular events, at a cost of only 2 other life-threatening bleeding.
Reperfusion therapy was administered in 78.6% of patients in our trial and benefits were noted among those patients receiving or not receiving such therapy. In particular, there was an apparent consistent benefit in those patients undergoing primary PCI, suggesting that prolonged antithrombin therapy after the procedure may well be beneficial.
The CREATE trial was conducted in India and China, the 2 largest countries in the world, which are projected to have approximately 50% of the global burden of coronary heart disease. Our results may be applicable to other countries for several reasons. First, the rates of use of proven pharmacological treatments, such as aspirin (97%), -blockers (66%), ACE inhibitors (73%), lipid-lowering therapy (67%), and reperfusion therapy (79%), were high. Second, although streptokinase and urokinase were the thrombolytic agents most commonly used, there was a consistent trend toward benefit in the 1052 patients undergoing primary PCI or receiving tissue plasminogen activator (HR, 0.65; 95% CI, 0.37-1.13). Furthermore, there was a clear benefit among those patients not receiving reperfusion therapy (HR, 0.79; 95% CI, 0.65-0.95). Therefore, reviparin was effective irrespective of the ancillary treatments used. Third, the duration of hospitalization may be shorter by a day or 2 in some Western countries, but the benefits in the CREATE trial emerged early and patients can self-inject reviparin after hospital discharge, as has been performed in deep vein thrombosis prophylaxis. Therefore, use of an LMWH, such as reviparin, for a week should be practical and effective in most settings. Finally, the high adherence to the protocol and very high rates of complete follow-up provides high confidence in the validity and broad applicability of our findings.
In common with all trials of antithrombotic and thrombolytic therapy, we observed a significant increase in bleeding rates for those events classified as either life-threatening or other major bleeding. We deliberately chose our primary outcome to include total mortality, myocardial reinfarction, and stroke, because these outcomes include intracranial bleeding and other fatal bleeding, and provide an estimate of the balance between benefit and risks. A further analysis of the outcome of death, reinfarction, strokes, and life-threatening bleeding at 30 days indicates a significant risk reduction of 0.87 (95% CI, 0.80-0.95; P = .002), suggesting a moderate overall benefit with reviparin when added to conventional therapies. Treatment of 1000 patients for 7 days prevented 18 deaths or reinfarctions, with an excess of 1 other life-threatening bleeding (net benefit of 17 events per 1000 patients).
Reviparin has been previously shown to be beneficial in preventing deep vein thrombosis.22 It has a relatively low molecular weight (3900 Da) and high anti-Xa activity.23 The anti-Xa/IIa ratio is about 3.3, which is similar to enoxaparin (3.3) and nadroparin (3.0), but higher than that of dalteparin (2.0) and tinzaparin (1.8).23 However, given that dalteparin and enoxaparin are beneficial in patients with non–ST-elevation MI and unstable angina,24-25 and the data with enoxaparin in ST-elevation MI are promising, it is reasonable to expect some benefits from other LMWHs. However, the exact dose of these agents and their benefits and bleeding risks, especially in the context of thrombolytic agents requires clarification. Therefore, further evaluation for each agent at specific doses is required, before these agents can be widely used in the treatment of acute MI. At least 1 such large trial (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment Thrombolysis in Myocardial Infarction–Study 25) evaluating enoxaparin is under way and should provide complementary information.26 The increased risk of bleeding with various antithrombin therapies (heparin, LMWH, direct thrombin inhibitors), intravenous glycoprotein IIb/IIIa inhibitors as well as new thrombolytic agents emphasizes the need to evaluate both clinical benefits and risks in large trials, rather than reliance on surrogate end points, before these drugs are used in clinical practice.
The incremental benefits of reviparin in patients with ST-segment elevation were moderate but clinically worthwhile. It is of the order of magnitude that has been claimed with accelerated tissue plasminogen activator vs streptokinase but with no excess of overall strokes.13, 22 Moreover, the benefits of reviparin has been more clearly demonstrated than with any other antithrombotic therapy (hirudin or bivalirudin) or intravenous glycoprotein IIb/IIIa inhibitors in the treatment of acute MI. In these trials, the duration of treatment was relatively short (48-96 hours), whereas in the CREATE trial, it was 7 days. There was excellent adherence to our protocol with 61.5% of patients receiving treatment within 6 hours along with thrombolytic agents and continuing reviparin therapy for the full duration of the trial. These factors, the high rates of follow-up and data quality, and the large size of our study likely contributed to the clear results of the CREATE trial. Reviparin is considerably less expensive than other antithrombotic agents, such as bivalirudin, is somewhat cheaper compared with other LMWHs, and can be given subcutaneously. Its use is relatively straightforward and can be used in both developed and developing countries. Therefore, the benefits of reviparin represents a moderate but important globally applicable advance in the management of patients with acute MI.
AUTHOR INFORMATION
Corresponding Author: Salim Yusuf, DPhil, FRCPC, Population Health Research Institute, Hamilton General Hospital and McMaster University, 237 Barton St E, Hamilton, Ontario, Canada L8L 2X2 (yusuf{at}mcmaster.ca).
Author Contributions: Dr Yusuf had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study concept and design: Yusuf, Mehta, Xavier, Pais, Zhu, Liu.
Acquisition of data: Yusuf, Mehta, Xie, Ahmed, Xavier, Pais, Zhu, Liu.
Analysis and interpretation of data: Yusuf, Mehta, Xavier, Pais, Zhu, Liu.
Drafting of the manuscript: Yusuf, Mehta.
Critical revision of the manuscript for important intellectual content: Yusuf, Mehta, Xie, Ahmed, Xavier, Pais, Zhu, Liu.
Statistical analysis: Xie.
Obtained funding: Yusuf.
Administrative, technical, or material support: Ahmed.
Study supervision: Yusuf, Mehta.
List of Centers and Investigators: The following persons participated in the CREATE Study.
International Steering Committee: S. Yusuf (principal investigator and chairman), S. R. Mehta (coprincipal investigator and project director), P. Pais (principal investigator, India), S. Reddy (coprincipal investigator, India), L. Liu (principal investigator, China), R. J. Ahmed, L. Cronin (global study coordinators), D. Xavier (coordinator, India), J. Zhu (coordinator, China), C. Xie (project statistician); Indian Steering Committee: R. Gupta, K.K. Haridas, T. M. Jaison, P. P. Joshi, P.G. Kerkar, A.K. Maity, S.C. Manchanda, S. Naik, P. Pais, D. Prabhakaran, S. Reddy, B. Singh, S. Thanikachalam, D. Xavier; Chinese Steering Committee: X. J. Bai, T. Chen, J. J. Cui, T. X. Cui, S. Y. Fu, H. Ge, Q. L. Li, S. M. Li, W. Li, Y. Q. Li, L. Liu, Y. H. Liu, Z. R. Lu, S. P. Ma, D. Qiao, Y. C. Song, N. L. Sun, L. H. Wang, S. W. Wang, W. Wang, Y. Wang, N. Wu, Y. S. Wu, C. B. Xu, S. C. Xu, Z. M. Xu, G. J. Yang, H. S. Yang, C. Z. Zhang, S. T. Zhang, W. J. Zhang, J. C. Zhou, J. Zhu; Population Health Research Institute, Hamilton, Canada: S. Yusuf, S. R. Mehta, R. J. Ahmed, L. Cronin, S. Pavlov, C. Xie, J. Pogue, F. Zhao, I. Tsuluca, M. Molec, I. Holadyk-Gris, K. Ahmed; Indian National Coordinating Office, Institute of Population Health and Clinical Research, St John's National Academy of Health Sciences, Bangalore, India: P. Pais, D. Xavier, D. Freeda, S. Lidwin; Indian Adjudication Committee: M. Chenniappan, B. Isaac, S. S. Iyengar, T. M. Jaison, P. Joshi, S. P. Kalantri, S. K. Kaushik, P. G. Kerkar, U. K. Mahorkar, J. Narendra, S. K. Paul, M. J. Santhosh, B. K. S. Sastry, B. Singh, S. B. Siwach, K. Varghese; China National Coordinating Office, Beijing Hypertensive League Institute, Beijing, China: L. Liu, J. Zhu, H. Yang, Y. Yang, X. Zhang, H. Tan, J. Tang, X. Li, L. Yan, Y. Zhang, J. Li; Chinese Adjudication Committee: M.Y. Bai, Y. Q. Jiang, S. Y. Lang, X. Y. Shi, Y. C. Song, Z. R. Tian, K. Wang, D. H. Yan, S. Y. Yu; Data and Safety Monitoring Board: P. Sleight (Chair), C. Baigent, J. Hirsh, W. Taylor, G. Tognoni; Abbott GmbH & Company KG (reviparin sponsor): P. Bacher, N. Bender, U. Legler, U. Magin, U. Raschke; China: An Yang: H. Liu; Angang: R. Wang; Anshan: Z. C. Liu, X. Tian, G. Wang, Y. Zhang; Baoding: Z. Nan, J. Zhang; Bazhou: C. Zai; Beijing: W. Chen, M. Gao, D. Hu, S. Jia, D. X. Li, Q. Li, W. Li, S. L. Liu, Y. Sun, B. Wang, G. F. Xie, Z. Xu, X. Yang, M. Zhao, X. Zhao; Beipiao: Z. Fang; Benxi: S. Y. Liu; Cangzhou: Z. Ma; Changchun: Y. Jiang, S. M. Li; Changsha: Z. Zhen; Chendu: F. Huo; Chengde: H. G. Yang; Chengwu: H. Liu; Chifeng: Y. Miao; Chongqing: C. M. Yang; Dalian: X. Chi, Z. X. Liu, S. Zhou; Dandong: Y. Sun; Dashiqiao: F. S. Zhou; Fenyang: R. Guo; Gaoping: K. Jing; Guan: Z. Xu; Haicheng: S. Ren, J. Zhao; Hebei: H. Bai, H. Bai, C. Cheng, J. Cheng, X. Hao, H. Li, W. G. Li, S. Wang, W. Zhang; Heilongjiang: L. Li, Y. Sun; Helongjiang: S. Fu, J. Shao, X. Tan; Henan: S. Chen, J. Fu; Hengshui: Q. Zheng; Huai Ren: J. Ma; Inner Mongolia: H. Chen, H. Ma; Jiamusi: L. Gong; Jiaozhou: Z. Zhang; Jiaxiang: F. Li; Jilin B. Yang; Jinan: L. S. Zhou; Jinlin: Z. Wang; Jinning: X. Sun; Jinzhou: G. Tao; Jiujiang: Q. Wang; Jun: J. Li; Lankao: X. Guo; Lian Yungang: X. Wang; Liaocheng: K. Zai; Liaoning: Q. Cui, S. Fan, H. Li, W. Liu, Q. Meng, G. Qi, Y. Qin, G. Wang, N. Wang, G. Xu, X. Yin, Q. Zhang, S. Zhang, Y. Zhang, Z. Zhang; Liaoyang: R. Liu, F. Wang; Linfen: Y. Zhang; Lingbao: W. K. Li; Lingshou: H. Zhang; Linyi: X. Xu; Longkou: R. Ma; Luoyang: F. Guan, T. Yang; Mongolia: R. Zhqo; Nanjing: J. Huang; Nanle: A. Li; Neimeng: J. Zhou; Panjin: X. You; Qi: L. Hao; Qingdao: F. Zhangfang; Qinyuang: X. Ma; Ruyang: C. Shen; Sanhe: Q. Li; Shangdong: Z. Hou; Shanghai: N. F. Zho; Shangqiu: G. Huang; Shanxi: P. Guo, J. Lou, Q. P. Wang, Z. Wang; Shenyang: X. Jiang, Z. Li, D. Tian, S. Wang, Z. D. Wu, M. G. Yang; Shi Jiazhuang: Z. C. Li; Taian: S. G. Yang; Tangshan: Y. Tu; Taonan: C. He; Tianjin: Y. Cao, Y. Han; Wangdu: J. H. Yang; Wangrong: S. Dong; Wuxiang: D. F. Li; Xiang Cheng: Q. F. Zhang; Xianxian: Z. Fan; Xinjiang: D. Q. An; Xinxiang: J. Liu; Xiping: G. Yang; Xiuwu: X. C. Xu; Xuzhou: Y. Xia; Yantai: H. Xu; Yanzhou: T. Wang; Yichun: D. Li; Yingkou: J. Wei; Yongji: P. Yang; Yuci: C. Y. Liu; Zhengzhou: S. Shang; Zhumadian: Y. G. Zhang; India: Adoni: J. Srinivas, B. Srinivasulu; Ahmedabad: S. Dani, J. Prajapati; Alappuzha: G. Deepak, J. F. Shallam; Ambur: K. J. Nesaraj; Amritsar: A. Kumar, R. K. Sharma; Annamalainagar: S. Balasubramaniyan, N. Chidambaram, R. Rani; Bangalore: S. Chandra, S. Dwivedi, B. Isaac, R. Kishore, B. J. Kumar, Y. Kumble, S. Mehrotra, P. R. Nayak, S. S. Ramesh, M. J. Santhosh, P. K. Shetty, K. Varghese; Bhopal: S. K. Trivedi; Bikaner: R. Beniwal, A. Kalla, R. B. Panwar; Calicut: K. G. Alexander, A. V. Bindu, A. Nambiar; Chennai: D. Barkavi, A. Kalanidhi, T. Pradeep, J. Rajesh, M. Ramesh, S. Shanmugasundaram, S. Thanikachalam; Cochin: K. K. Haridas, P. Kumar; Doraha: G. Sidhu, R. Singh; Ernakulam: K. N. Pradeep; Ghaziabad: A. Kumar, A. Mittal; Gulbarga: J. B. Bijapure, M. S. Rao; Guntur: N. G. Mohanarjun, M.B. Rao; Hyderabad: B. R. Babu, N. Dinesh, R. K. Jain, P. A. Jiwani, S. R. Naik, T.N.C. Padmanabhan, B. S. Raju, R. Rajaram, A. S. V. N. Rao, D. Rao, V. S. P. Rao, B. K. S. Sastry, S. Sinha; Indore: A. Bharani, G. Verma; Jaipur: R. Gupta, R. K. Tongia, S. Kalra, S. Sharma; Jodhpur: R. Mehrotra, S. Sanghvi, O. P. Soni; Kolkata: A. D. Biswas, A. K. Maity, S. K. Paul; Kottayam: J. Boben, G. Jacob, J. Joseph; Lucknow: A. Puri, V. K. Puri, H. Singh; Ludhiana: R. Calton, T. M. Jaison; Meerut: G. K. Aneja; Mumbai: P. G. Kerkar, P. Nyayadhish, P. J. Nathani, S. K. Rane; Nagpur: M. Fulwani, A. S. Jain, P. P. Joshi, A. Khan, U. K. Mahorkar, R. G. Salkar, A. Somani, R. Wadhwani, S. D. Zawar; Nanded: V. E. Shegokar, S. L. Tungikar; Nashik: V. Vijan; New Delhi: B. Singh, R. Trehan; Patiala: A. Garg, H. Singh, S. Verma; Pune: S. Borade, D. Duggal, J. Hiremath; Rohtak: Jagdish, V. K. Katyal, S. B. Siwach; Shimoga: H. R. Devendrappa, J. Narendra, Ratnakar; Thrissur: P. B. Latha, E. B. Manoj, P. P. Mohanan; Trichy: M. Chenniappan, P. Gandhimadhinathan, K. Jeremaiah, B. S. V. Raj, R. Udaysankar; Udaipur: J. K. Chhaparwal, S. K. Kaushik; Vellore: S. T. Chandy, O. George, B. John; Vijayawada: P. Ramesh, V. S. Reddy, P. Srinivas; Vishakapatnam: K. D. Rao, B. R Malipeddi, G. S. R. Murthy; Wardha: R. Joshi, S. P. Kalantri, S. Patil.
Financial Disclosure: Dr Yusuf has received research grants and honoraria for lectures from Knoll and Abbott Laboratories.
Funding/Support: The study had no external funding. Reviparin and placebo were donated by Abbott Laboratories.
Role of the Sponsor: Abbott Laboratories did not participate in the design and conduct of the study; in the collection, analysis, and interpretation of the data; or in the preparation, review, or approval of the manuscript.
Additional Information: Slides are available at: http://www.phri.ca.
Acknowledgment: We thank the numerous patients who volunteered to participate in this trial, Judy Lindeman, for expert secretarial assistance, and Susan Chrolavicius and Colette Easton, for organizational assistance.
*Authors/Writing Committee: Salim Yusuf, DPhil, Shamir R. Mehta, MD, MSc, Changchun Xie, PhD, Rashid J. Ahmed, BScH (Population Health Research Institute, Hamilton Health Sciences, and McMaster University, Hamilton, Ontario); Denis Xavier, MD, Prem Pais, MD (Institute of Population Health and Clinical Research, St John’s National Academy of Health Sciences, Bangalore, India); Jun Zhu, MD, Lisheng Liu, MD (Cardiovascular Institute and Fu Wai Hospital, Chinese Hypertension League Institute, Beijing, China).
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| FULL TEXT
Beyond Unfractionated Heparin and Warfarin: Current and Future Advances
Hirsh et al.
Circulation 2007;116:552-560.
FULL TEXT
Enoxaparin is superior to unfractionated heparin in patients with ST elevation myocardial infarction undergoing fibrinolysis regardless of the choice of lytic: an ExTRACT-TIMI 25 analysis
Giraldez et al.
Eur Heart J 2007;28:1566-1573.
ABSTRACT
| FULL TEXT
Women, Acute Ischemic Heart Disease, and Antithrombotic Therapy: Challenges and Opportunities
Harrington
Circulation 2007;115:2796-2798.
FULL TEXT
Anticoagulants in heart disease: current status and perspectives
De Caterina et al.
Eur Heart J 2007;0:ehl492v1-34.
FULL TEXT
Update in cardiology.
Rapaport
ANN INTERN MED 2006;145:618-625.
FULL TEXT
Underrepresentation of renal disease in randomized controlled trials of cardiovascular disease.
Coca et al.
JAMA 2006;296:1377-1384.
ABSTRACT
| FULL TEXT
Fondaparinux in ST-Segment Elevation Myocardial Infarction: The Drug, the Strategy, the Environment, or All of the Above?
Califf
JAMA 2006;295:1579-1580.
FULL TEXT
Effects of Fondaparinux on Mortality and Reinfarction in Patients With Acute ST-Segment Elevation Myocardial Infarction: The OASIS-6 Randomized Trial
The OASIS-6 Trial Group*
JAMA 2006;295:1519-1530.
ABSTRACT
| FULL TEXT
Unfractionated and Low-Molecular-Weight Heparin as Adjuncts to Thrombolysis in Aspirin-Treated Patients With ST-Elevation Acute Myocardial Infarction: A Meta-Analysis of the Randomized Trials
Eikelboom et al.
Circulation 2005;112:3855-3867.
ABSTRACT
| FULL TEXT
Warfarin plus Aspirin after Myocardial Infarction or the Acute Coronary Syndrome: Meta-Analysis with Estimates of Risk and Benefit
Rothberg et al.
ANN INTERN MED 2005;143:241-250.
ABSTRACT
| FULL TEXT
Additional articles abstracted in ACP Journal Club
Evid. Based Med. 2005;10:126-126.
FULL TEXT
Rescuing COX-2 Inhibitors From the Waste Bin
Albini and Noonan
JNCI J Natl Cancer Inst 2005;97:859-860.
FULL TEXT
Reviparin in Acute Myocardial Infarction
Buccelletti
JAMA 2005;293:2595-2595.
FULL TEXT
Reviparin in Acute Myocardial Infarction
Yan et al.
JAMA 2005;293:2595-2595.
FULL TEXT
Does Reviparin Improve Outcomes in STEMI?
JWatch Emergency Med. 2005;2005:3-3.
FULL TEXT
LMWH Improves Post-STEMI Outcomes
Journal Watch Cardiology 2005;2005:1-1.
FULL TEXT
Low-Molecular-Weight Heparin After Myocardial Infarction
JWatch General 2005;2005:2-2.
FULL TEXT
Effect of Glucose-Insulin-Potassium Infusion on Mortality in Patients With Acute ST-Segment Elevation Myocardial Infarction: The CREATE-ECLA Randomized Controlled Trial
The CREATE-ECLA Trial Group Investigators*
JAMA 2005;293:437-446.
ABSTRACT
| FULL TEXT
Simple Principles of Clinical Trials Remain Powerful
Califf
JAMA 2005;293:489-491.
FULL TEXT
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