American Heart Journal
Volume 141, Issue 1 , Page E2, January 2001

Direct thrombin inhibitors in acute coronary syndromes and during percutaneous coronary intervention: Design of a meta-analysis based on individual patient data☆☆☆★

  • Direct Thrombin Inhibitor Trialists’ Collaborative Group*

Direct Thrombin Inhibitor Trialists’ Collaborative Group

Received 27 June 2000; accepted 20 September 2000.

Article Outline

Abstract 

Background More than 30 randomized trials involving more than 40,000 patients with acute coronary syndrome and undergoing percutaneous coronary intervention have evaluated the efficacy and safety of direct thrombin inhibitors relative to unfractionated heparin. However, few trials have been large enough to provide reliable estimates of treatment effects on major cardiovascular outcomes. Therefore uncertainty remains regarding the benefits of direct thrombin inhibitors on major cardiovascular outcomes such as death or myocardial infarction and the balance of any such benefits against the risk of major bleeding. Objectives By combining data on individual patients from all the major studies, we sought to obtain reliable estimates of the treatment effects of direct thrombin inhibitors on death, myocardial infarction, major bleeding, and secondary outcomes including refractory or recurrent ischemia and need for revascularization. We examined these outcomes at the completion of active treatment and during long-term follow-up, as well as in clinically important subgroups. Methods Individual patient data, including baseline demographics, previous history of vascular disease, conventional vascular risk factors, qualifying diagnosis, prognostic markers including biochemical markers of extent of myocardial injury, cointerventions, and fatal and nonfatal cardiovascular outcomes, have been obtained from 14 randomized studies, constituting more than 95% of the available randomized evidence. These data will undergo exhaustive data checking for completeness and consistency and will then be merged into a master database for analysis. Analyses will undergo extensive scrutiny by trialists of the direct thrombin inhibitor studies before incorporation into a manuscript. (Am Heart J 2001;141:e2.)

 

The use of statistical methods to combine results of individual trials addressing the same or similar questions can provide more reliable estimates of the treatment effects of an intervention than those derived from individual studies. This approach is increasingly used as a basis for decision making in clinical medicine. However, meta-analyses that rely solely on data extracted from published reports may give estimates of treatment effects that are not confirmed subsequently when all of the relevant evidence is analyzed.1, 2

An alternative method for combining the results of clinical trials is a meta-analysis based on individual patient data. This approach, which has been described as the “yardstick” against which all systematic reviews should be measured,1, 3 has a number of important benefits compared with meta-analyses based on published aggregate data.1 These include the ability to obtain more complete outcome data for all patients, perform detailed checking of the data and ensure the quality of randomization and follow-up, perform survival and other time-to-event analyses that may lead to improvement in the reliability of the estimated treatment effect, and undertake analyses in clinically important subgroups to explore potential differences in treatment effects.

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Theoretic basis for the use of direct thrombin inhibitors in acute coronary syndrome and during percutaneous coronary intervention 

Thrombin plays a central role in the initiation and propagation of occlusive intravascular thrombus, and therapies aimed at inhibiting thrombin generation and activity are widely used for the prevention and treatment of arterial thrombosis.4 The major goal of antithrombotic therapy is to prevent the development and propagation of thrombi, control symptoms of ischemia, and prevent further complications of acute coronary syndromes including myocardial infarction and death. Unfractionated heparin and low-molecular-weight heparin exert their antithrombotic action primarily by antithrombin III-mediated inhibition of thrombin and factor Xa and are effective therapies for the management of acute coronary syndromes.5 However, an important limitation of both unfractionated heparin and low-molecular-weight heparin is their inability to inhibit fibrin-bound thrombin, which represents a potent prothrombotic reservoir and provides a potent ongoing stimulus for local thrombus growth.

Direct thrombin inhibitors, of which hirudin and bivalirudin are the most widely studied, are able to inactivate both free and fibrin-bound thrombin and have the potential to block thrombin activity.6 However, unlike unfractionated heparin and low-molecular-weight heparin, direct thrombin inhibitors are unable to inhibit coagulation enzymes that are more proximal in the clotting pathway (such as factor Xa). In vitro and in vivo studies suggest that direct thrombin inhibitors are more potent antithrombotic agents than unfractionated heparin and are more effective in preventing platelet deposition and thrombus growth on deep wall injury at both low- and high-shear rate conditions.7 However, direct thrombin inhibitors have been associated with a higher risk of bleeding in some experimental models.8

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Limitations of published data 

To date, more than 30 randomized trials involving more than 40,000 patients have evaluated the efficacy and safety of direct thrombin inhibitors in patients with acute coronary syndrome with ST elevation, without ST elevation, or undergoing percutaneous coronary interventions,9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 and several additional trials are currently in progress.42, 43 The results of several studies suggest that direct thrombin inhibitors are superior to unfractionated heparin for the prevention of death or myocardial infarction in patients with acute coronary syndromes, but others have failed to demonstrate a significant treatment benefit. A preliminary meta-analysis of the 3 largest hirudin trials indicates that hirudin is superior to unfractionated heparin for the prevention of death or myocardial infarction at the completion of intravenous therapy (odds ratio [OR] 0.78, P = .0004).32 The aggregate data from trials in which bivalirudin was compared with unfractionated heparin show nonsignificant 25% risk reduction at 7 days or during hospitalization with bivalirudin (OR 0.75, 95% confidence interval [CI] 0.54-1.05, P = .09).44 Bivalirudin appeared to have a lower risk of major bleeding (OR 0.41, 95% CI 0.32-0.52, P < .001).

Although these data regarding the use of direct thrombin inhibitors in acute coronary syndromes are promising, they have not been sufficient to alter clinical practice. However, these data also have several limitations. First, the key composite clinical outcome of death or myocardial infarction has not been reported in all the trials. Second, when available, the outcome of death or myocardial infarction is reported at different time points in different studies. Lack of data from all the studies at the completion of active therapy may be “masking” a true treatment benefit of direct thrombin inhibitors and limits the power of conventional meta-analysis to detect a moderate yet clinically important treatment benefit (for example a 10% or 20% risk reduction). Third, the ability to explore subgroups with use of published data is limited, and it remains unclear whether there may be subgroups of high-risk patients in whom there may be a more favorable risk/benefit ratio with the use of direct thrombin inhibitors.

To further explore the efficacy and safety of direct thrombin inhibitors relative to unfractionated heparin in acute coronary syndrome and during percutaneous coronary intervention, and in high-risk subgroups, individual patient data from each of the major trials are being obtained. This approach will allow a comparison of the efficacy and safety of direct thrombin inhibitors and unfractionated heparin for the key composite outcome of death or myocardial infarction from all the studies. Effects on these outcomes can be examined at consistent time points including the completion of active therapy and during long-term follow-up, on the basis of use of time-to-event data, in subgroups of individual classes of direct thrombin inhibitors including hirudin, semisynthetic hirudin analogs and low-molecular-weight direct thrombin inhibitors, and among important prognostic subgroups of patients.

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Objectives 

Primary objectives 

The primary objectives of this meta-analysis are to address the following questions: (1) What are the best estimates of the overall effects of direct thrombin inhibitors compared with unfractionated heparin at the completion of treatment for the prevention of death or myocardial infarction? (2) Are the absolute treatment benefits of direct thrombin inhibitors at the completion of treatment maintained during longer-term follow-up at 30 days and at 6 months? (3) What are the risks of major, life-threatening, and intracranial bleeding during hospitalization associated with direct thrombin inhibitors compared with unfractionated heparin? (4) What are the proportional and absolute treatment benefits of the direct thrombin inhibitors in key subgroups of patients according to treatment indication (acute coronary syndrome with ST elevation, acute coronary syndrome without ST elevation, percutaneous coronary intervention), cointervention with thrombolytic therapy, propensity to undergo percutaneous coronary intervention, and treatment allocation (hirudin, bivalirudin, low-molecular-weight direct thrombin inhibitors)?

Secondary objectives 

Secondary analyses will examine the consistency of the data in clinically important subgroups of patients and will address the following issues: (1) the proportional and absolute clinical benefits of the direct thrombin inhibitors on secondary outcomes (eg, stroke, recurrent ischemia, need for cardiac catheterization, need for revascularization), (2) the proportional and absolute clinical benefits of the direct thrombin inhibitors on major nonfatal vascular events and vascular death in subgroups on the basis of dose intensity (presence or absence of bolus dose, rate of initial infusion, target activated partial thromboplastin time), duration of therapy, prerandomization patient characteristics (age, sex, diabetes), and baseline clinical features (heart rate, blood pressure, electrocardiographic changes, myocardial infarction at enrollment, creatine kinase, or troponin) at enrollment, (3) evidence of clinical rebound of events during the first 48 to 72 hours after cessation of direct thrombin inhibitor therapy, and (4) risks of major bleeding stratified by prerandomization baseline patient characteristics, baseline clinical features, direct thrombin inhibitor agent, dose intensity, and cointerventions.

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Methods 

Selection of trials 

Collaboration has been established among coordinators of both published and unpublished, unconfounded, properly randomized trials (1) involving patients with acute coronary syndrome with or without ST elevation or patients undergoing percutaneous coronary intervention, in which (2) a direct thrombin inhibitor is compared with unfractionated heparin, and where (3) data on key irreversible outcomes including death and myocardial infarction have been recorded. Trials have only been included if randomization was performed in a manner that precluded knowledge of the next treatment (for example, trials where allocation is alternate were not included), and where 1 treatment group differed from another only by the treatments of interest (ie, unconfounded trials).

Potentially eligible trials were identified by formal computer-aided searches (Medline database, EMBASE, Cochrane database of clinical trials), by scrutiny of the reference lists of trials and review articles, abstracts, meeting proceedings, and trial registries, and by inquiry of other investigators and the manufacturers of thrombin inhibitors. Individual patient data have only been requested from the larger randomized trials, involving at least 200 patients and at least 100 patients in the control arm. (See Table I for a list of included studies.) All trials meeting these criteria have been included in the meta-analysis.

Table I. Randomized trials comparing a direct thrombin inhibitor versus unfractionated heparin for which individual patient data has been obtained
StudyDesignEligibilityNo.ExperimentalControlPrimary outcomeTiming of primary outcome
ARGAMI-2 (1998)Phase II double-blindACS with ST elevation; tPA or SK1201Argatroban (low or high dose)UFHDeath, MI, stroke, pump failure, or intervention for ischemia30 d
GUSTO-2A (1994)Phase III double-blindACS with or without ST elevation; SK or tPA2564Hirudin 3-5 dUFH 3-5 dDeath or MI30 d
GUSTO-2B (1996)Phase III double-blindACS with or without ST elevation; SK or tPA12142Hirudin 3-5 dUFH 3-5 dDeath or MI30 d
HELVETICA (1995)Phase III double-blindUSA with CAD and planned PCI1154Hirudin 24 h, then hirudin or placebo 72 hUFH 24 h, then placebo 72 hDeath, MI, CABG, bailout, or repeat PCI30 wk
HERO-1 (1997)Phase II double-blindACS with ST elevation; SK412Bivalirudin 72 hUFH 72 hAngiographic patency90-120 min
Hirulog Angioplasty Study (1995)Phase III double-blindACS scheduled for urgent PCI4312Bivalirudin 24 hUFH 24 hDeath, MI, vessel closure, ABP, urgent revascularizationIn-hospital
HIT-3 (1994)Phase III double-blindACS plus tPA302Hirudin 48-72 hUFH 48-72 hDeath or in-hospital MI30 d
HIT-4 (1999)Phase III double-blindACS with ST elevation; SK1208Hirudin 5-7 dUFH 5-7 dAngiographic patency90 min
Klootwijk et al (1999)Phase II single-blind*USA300Efegatran 48 hUFH 48 hECG evidence of ischemia48 h
OASIS-1 (1997)Phase II open-labelACS without ST elevation909Hirudin 72 hUFH 72 hCV death, MI, or refractory angina7 d
OASIS-2 (1999)Phase III double-blindACS without ST elevation10141Hirudin 72 hUFH 72 hCV death or MI7 d
TIMI-9A (1994)Phase III double-blindACS plus ST elevation; tPA or SK757Hirudin 96 hUFH 96 hDeath, MI, CCF, shock, or LVEF <40%30 d
TIMI-9B (1996)Phase III double-blindACS plus ST elevation; tPA or SK3002Hirudin 96 hUFH 96 hDeath, MI, CCF, shock, or LVEF <40%30 d
TRIM (1997)Phase II double-blindACS without ST elevation1209Inogatran 72 hUFH 72 hDeath, MI, refractory or recurrent angina7 d
*This trial was conducted in two phases: dose finding and randomized.

ARGAMI, Argatroban Compared With Heparin in Myocardial Infraction Treated With rt-PA; ACS, acute coronary syndrome; tPA, tissue plasminogen inhibitor; SK, streptokinase; UFH, unfractionated heparin; MI, myocardial infarction; GUSTO, Global Use of Strategies to Open Occluded Arteries; HELVETICA, Hirudin in a European Restenosis Prevention Trial Versus Heparin Treatment in PTCA Patients; USA, unstable angina; CAD, coronary artery disease; PCI, percutaneous coronary intervention; CABG, coronary artery bypass graft; HERO, Hirulog Early Reperfusion/Occlusion; ABP, aortic balloon pump; HIT, Hirudin for the Improvement of Thrombolysis; ECG, electrocardiogram; OASIS, Organization to Assess Strategies for Ischemic Syndromes; CV, cardiovascular; TIMI, Thrombolysis and Thrombin Inhibition in Myocardial Infarction; CCF, congestive cardiac failure; LVEF, left ventricular ejection fraction; TRIM, Thrombin Inhibition in Myocardial Ischemia.

Justification for restricting individual patient data collection to the larger studies 

There are several important reasons for concentrating efforts on obtaining individual patient data from the larger trials: (1) Large trials are less subject to publication bias. (2) Large trials have enrolled the majority (95%) of patients and therefore the amount of data missed by not including the smaller trials is limited. (3) Restricting the data requests to larger trials decreases the amount of work involved in central data collection and handling. (4) The larger studies usually have ongoing data management and computing support, allowing the data to be more readily converted into the format required by the systematic overview.

Outcomes 

The effects of the direct thrombin inhibitors are being assessed in terms of their effects on major vascular events: nonfatal myocardial infarction, nonfatal stroke, recurrent ischemia, need for revascularization, cardiovascular death, all deaths, and major, life-threatening, and intracranial bleeding. Transient ischemic attacks of the eye or brain will not be counted as outcomes.

Wherever possible, causes of death are being subdivided into “nonvascular” and “vascular” (that is, definitely or probably vascular). Vascular death includes all deaths attributed to cardiovascular, cerebrovascular, thromboembolic, hemorrhagic, other vascular, or unknown vascular causes.

Although there are differences among the studies in the definitions of vascular outcomes and major bleeding, the original definitions will be retained because retrospective reclassification of events may lead to bias. Exploratory analyses may, however, be carried out where outcomes can be redefined to make a definition consistent across trials.

Data collection and management 

Individual patient data 

From trials involving at least 200 patients overall as well as at least 100 controls, a few key details of trial design are being requested (Table II).

Table II. Summary trial design
1. Were study participants randomly allocated to treatment groups?
2. What was the method of randomization? (eg, central computer-assisted randomization, central–sealed envelopes, local–sealed envelopes, other)
3. Was the randomization process concealed? (concealment is defined as having no chance of determining the group of alloca-tion before enrollment in the trial)
4. Were those providing care blinded to the assigned therapy?
5. Were the recipients of care (patients) blinded to their assigned treatments?
6. Were persons responsible for reporting outcomes blinded to the assigned therapy?
7. Were study outcomes adjudicated?
8. If study outcomes were adjudicated, were study adjudicators blinded to treatment allocation?
9. Were all outcomes recorded at the last day of follow-up?
10. If no, please provide duration (days) of follow-up for individual outcomes (new myocardial infarction, stroke, recurrent angina, revascularization, bleeding).
This includes information relating to the exact method of treatment allocation, whether controls received unfractionated heparin or another form of active comparator and whether patients, investigators, or event adjudicators were blinded to treatment allocation.

Individual patient data are being obtained regarding baseline entry characteristics, the allocated treatments, dates of randomization, dates of scheduled and actual end of treatment, dates of last follow-up, and dates of outcome event(s). A list of key variables being collected for each patient is included in Table III.

Table III. Summary of individual patient data collection
Baseline data
Unique anonymous patient identifier
Date of birth
Sex
History of coronary disease or cardiac failure
History of coronary revascularization
History of hypertension
History of diabetes
History of high lipid levels
Current smoker
Weight and height
Prerandomization data
Pharmacologic therapies
Date of qualifying event
Type of qualifying event
Biochemical markers of myocardial damage
Killip class
Heart rate and blood pressure
Creatinine level
Randomization data
Date of randomization
Treatment allocation
Postrandomization data
Treatment dose
Treatment duration
Pharmacologic cointerventions
Vital status at last follow-up
Primary cause of death
Stroke
New myocardial infarction
Recurrent ischemia at rest
Cardiac catheterization
Percutaneous coronary intervention
Thrombolysis
CABG
Major bleeding
Life-threatening bleeding
Intracranial bleeding

Data are being transferred in electronic format (floppy disk, data tapes, or direct electronic transfer). For each study, consistency and completeness checks will be carried out, followed by preliminary analyses to ensure agreement with the main published result. Discrepancies in any of these steps are being resolved through direct contact with the data management personnel of the trials. The complete set of information on each trial will be referred to the investigator for confirmation. Only once this process has been satisfactorily completed will the primary data analysis be performed.

Statistical analysis 

The fundamental assumptions that underlie a systematic review of many trials are not statistical but medical. The first is that moderate mortality differences (in the order of 10%-20%) are clinically important and worthwhile. A second is that although the same types of treatment would probably not produce exactly the same size of therapeutic effect in different circumstances it would tend to produce effects that point in the same direction.

In our analysis, treatment effects will be compared with control only within one trial to avoid completely any direct comparison of patients in one trial with patients in another. Therefore differences in patient characteristics among the trials from which data are being combined do not matter as long as the patients are broadly similar (for example, they all have a diagnosis of unstable coronary artery disease and are expected to benefit from antithrombin therapy). There may still be wide variability in the event rates in the control group among the trials because of differences in the type of patients enrolled in the study; however, the stratified approach of only comparing events and patients within a trial compares only like with like and is not affected by differences in patient characteristics among the trials.

Outcome data from the different trials will be combined by use of the Peto-Yusuf modification of the Mantel-Haenszel method.45 This method entails calculating the observed (number of events in the treatment group) minus the expected (average number of events for treatment and control groups) events and determining the variance for each. Grand totals are calculated for each, and the ratio of the two is used to estimate the OR. The OR and its 95% CI are calculated for each trial. Trials will be also examined for statistical evidence of heterogeneity. The chi-square tests for heterogeneity will be approximated by summing the N separate chisquare test statistics (O – E2/V) for each trial and subtracting the overall chi-square value (GT2/SIV) from this, using N – 1 degrees of freedom.

It is recognized that other statistical methods are commonly used to combine data from individual trials (eg, the DerSimonian and Laird method), but we propose, in the first instance, to use the modification of the Mantel-Haenszel method because of its simplicity, widespread acceptance, and lack of other assumptions (other than that the effects of a treatment in different trials are likely to be in the same direction). Secondary analyses will, however, compare results obtained with the modified Mantel-Haenszel method with results obtained with a random effects model. In addition, time-to-event analyses will be performed with a Cox proportional hazards model with adjustment with use of Cox regression.

Proposed analyses 

Each of these analyses will be performed unadjusted as well as adjusted for key baseline variables, and in key subgroups according to treatment allocation and qualifying diagnosis: (1) proportion of death or myocardial infarction, death, myocardial infarction, recurrent ischemia, and revascularization at completion of active treatment, at 7 days, 30 days, and 6 months; (2) time to event analysis for death or myocardial infarction, death, myocardial infarction, recurrent ischemia, and revascularization up to 6 months; (3) proportion of death or myocardial infarction, death, myocardial infarction, recurrent ischemia, and revascularization during the 72-hour period after cessation of active therapy and between the end of 72 hours after cessation and 6 months; (4) proportion of death or myocardial infarction, death, myocardial infarction, recurrent ischemia, and revascularization during active treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention compared and in those not undergoing percutaneous coronary intervention, in patients receiving thrombolytic therapy (and by lytic agent), and those not receiving thrombolytic therapy; (5) proportion of death or myocardial infarction, death, myocardial infarction, recurrent ischemia, and revascularization in subgroups of patients according to baseline patient and clinical characteristics (age, sex, diabetes, creatine kinase, or troponin rise, electrocardiogram changes, dose intensity); (6) proportion of major, life-threatening, and fatal bleeding during treatment or within 24 hours of cessation of antithrombotic therapy and during subsequent follow-up and in the presence or absence of a concomitant surgical or other invasive procedure; and (7) proportion of major bleeding, minor bleeding, and patients requiring transfusion by baseline patient and clinical characteristics (age, sex, diabetes, creatine kinase, or troponin rise, electrocardiogram changes, treatment doses).

Subgroup analyses 

Many different subgroups will be performed and presented and, among these, the play of chance alone is likely to yield misleading tests of significance. Therefore the effects of treatment among specific categories of patient or of trial may best be assessed indirectly by approximate extrapolation from the apparent effects of treatment among all patients in a wide class of trials.

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Organizational structure 

Coordination 

The Canadian Cardiovascular Collaboration and Duke Clinical Research Institute are jointly coordinating this project. A management committee representing the collaborating investigators and the coordinating centers oversees the conduct of this project. The study secretariat is based at the Canadian Cardiovascular Collaboration, but data tapes are being shared between the 2 coordinating centers, with both Duke and the Canadian Cardiovascular Collaboration maintaining an overall database across all conditions.

Confidentiality and publication policy 

All data will be held securely and will remain confidential. The results of all analyses will be presented to investigators for scrutiny and comments. All reports will be published in the name of collaborating trialists and will be circulated to collaborators for comments and approval before submission. A list of collaborators is provided in the Appendix. The results of primary analyses are expected to be available by the end of 2000.

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Appendix 

Coordinating Centers: Canadian Cardiovascular Collaboration and Duke Clinical Research Institute Study Chairs: S. Yusuf, C. Granger Project Officers: J. W. Eikelboom, D. Kong Members: S. Mehta, J. Pogue, P. Tait Direct Thrombin Inhibitor Trialists Argatroban Compared With Heparin in Myocardial Infarction Treated With rt-PA (ARGAMI)-2: S. Behar, M. Benderly, H. Hod, E. Kaplinsky Aventis: N. Barrett, R. Bilke, M. Luz, M. Marhoefer, L. Roi Cardialysis: H. Boersma Clinical Trials and Evaluation Unit, London: M. Flather Clinical Trial Service Unit, Oxford: C. Baigent Efegatran Study: M. L. Simoons Global Use of Strategies to Open Occluded Arteries (GUSTO)-II: R. Califf, C. Granger, K. Pieper, E. J. Topol Research Centre, Hamilton Health Sciences Corporation: J. Weitz Hirudin in a European Restenosis Prevention Trial Versus Heparin Treatment in PTCA Patients (HELVETICA): P. W. Serruys Hirulog Early Reperfusion/Occlusion (HERO)-1: H. D. White Hirulog Angioplasty Study: J. A. Bittl Hirudin for the Improvement of Thrombolysis (HIT)-3 and 4: K. L. Neuhaus, U. Zeymer National Health and Medical Research Council Clinical Trials Centre: J. Simes Novartis: P. Close, S. Edwards, P. Gallo, M. Henis Organization to Assess Strategies for Ischemic Syndromes (OASIS)-1 and 2: S. Anand, S. Yusuf Quintiles: W. Kimball The Medicines Company: G. C. Cupit, C. Meanwell, J. Villiger Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI)-9A and 9B: E. M. Antman, M. Gibson, S. Murphy Thrombin Inhibition in Myocardial Ischemia (TRIM): L. Grip, P. Held

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References 

  1. Stewart LA, Clarke MJ. Practical methodology of meta-analyses (overviews) using updated individual patient data. Stat Med. 1995;14:2057–2079
  2. Stewart LA, Parmar MKB. Meta-analysis of the literature or of individual patient data: is there a difference?. Lancet. 1993;341:418–422
  3. Chalmers I. The Cochrane Collaboration: preparing, maintaining and disseminating systematic reviews of the effects of health care. Ann N Y Acad Sci. 1993;703:156–165
  4. Weitz JI, Hirsh J. New antithrombotic agents. Chest. 1998;114:715
  5. Eikelboom JW, Anand SS, Malmberg K, et al.  Unfractionated heparin and low-molecular-weight heparin in acute coronary syndrome without ST elevation: a meta-analysis. Lancet. 2000;355:1936–1942
  6. Weitz JI, Hudoba M, Massel D, et al.  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
  7. Heras M, Chesebro JH, Webster MWI, et al.  Hirudin, heparin and placebo during deep arterial injury in the pig: the in vivo role of thrombin in platelet-mediated thrombosis. Circulation. 1990;82:1476–1484
  8. Callas D, Fareed J. Comparative pharmacology of site-directed antithrombin agents: implications in drug development. Thromb Haemost. 1997;74:473–481
  9. Vermeer F, Vahanian A, Fels PW, et al.  Intravenous argatroban versus heparin as co-medication to alteplase in the treatment of acute myocardial infarction: preliminary results of the ARGAMI pilot study [abstract]. J Am Coll Cardiol. 1997;29:185A
  10. Kapilinsky E. Direct antithrombin-argatroban in acute myocardial infarction (ARGAMI-2): in late breaking clinical trials. J Am Coll Cardiol. 1998;32:1–7
  11. GUSTO Investigators . Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes: the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators. Circulation. 1994;90:1631–1637
  12. GUSTO Investigators . A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes: the Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators. N Engl J Med. 1996;335:775–782
  13. White HD, Aylward PE, Frey MJ, et al.  Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO): Hirulog Early Reperfusion/Occlusion (HERO) Trial Investigators. Circulation. 1997;96:2155–2161
  14. Neuhaus KL, von Essen R, Tebbe U, et al.  Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study: a study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausarzte. Circulation. 1994;90:1638–1642
  15. Neuhaus KL, Molhoek GP, Zeymer U, et al.  Recombinant hirudin (Lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial. J Am Coll Cardiol. 1999;34:966–973
  16. Molhoek GP, Laarman GJ, Lok DJ, et al.  Angiographic dose-finding study with r-hirudin (HBW 023) for the improvement of thrombolytic therapy with streptokinase (HIT-SK): interim results. Eur Heart J. 1995;16:33–37
  17. Lidon RM, Theroux P, Lesperance J, et al.  A pilot, early angiographic patency study using a direct thrombin inhibitor as adjunctive therapy to streptokinase in acute myocardial infarction. Circulation. 1994;89:I567–I572
  18. Jang IK, Brown DF, Giugliano RP, et al.  A multicenter, randomized study of argatroban versus heparin as adjunct to tissue plasminogen activator (TPA) in acute myocardial infarction: myocardial infarction with novastan and TPA (MINT) study. J Am Coll Cardiol. 1999;33:1879–1885
  19. Miller J, Barsness GW, Leimberger JD, et al.  Direct thrombin inhibition with efegatran does not suppress heightened thrombin generation during thrombolysis for acute myocardial infarction [abstract]. Circulation. 1997;96:I534
  20. Tabata H, Mizuno K, Etsuda H, et al.  The efficacy of argatroban in the prevention of reocclusion and restenosis after reperfusion therapy in patients acute myocardial infarction [abstract]. Circulation. 1994;90:I375
  21. Theroux P, Perez-Villa F, Waters D, et al.  Randomized double-blind comparison of two doses of hirulog with heparin as adjunctive therapy to streptokinase to promote early patency of the infarct-related artery in acute myocardial infarction [abstract]. Circulation. 1995;91:2132–2139
  22. Cannon CP, McCabe CH, Henry TD, et al.  A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial. J Am Coll Cardiol. 1994;23:993–1003
  23. Lee LV. Initial experience with hirudin and streptokinase in acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 6 trial. Am J Cardiol. 1995;75:7–13
  24. Antman EM. Hirudin in acute myocardial infarction: safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial. Circulation. 1994;90:1624–1630
  25. Antman EM. Hirudin in acute myocardial infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation. 1996;94:911–921
  26. Bode C, Steg G, Gulba D, et al.  Clinical and laboratory effects of intravenous PEG-hirudin in patients with unstable angina [abstract]. Circulation. 1997;96:I511
  27. Gulba DC, Kadr H, Zabiela P, et al.  Randomised dose finding of short duration IV plus prolonged SC administration of a long acting variant of hirudin (PEG-hirudin) in patients with unstable angina and non Q-wave infarction [abstract]. Circulation. 1998;98:I505
  28. Jackson CV, Satterwhite J, Roberts E. Preclinical pharmacology of efegatran (LY294468): a novel antithrombin for the treatment of acute coronary syndromes. Clin Appl Thromb/Haemost. 1996;2:258–267
  29. Klootwijk P, Lenderink T, Meij S, et al.  Anticoagulant properties, clinical efficacy and safety of efegatran, a direct thrombin inhibitor, in patients with unstable angina. Eur Heart J. 1999;20:1101–1111
  30. Montalescot G, Choussat R, Philippe F, et al.  Both PEG-hirudin and enoxaparin blunt the rise of von Willebrand factor in patients with unstable angina [abstract]. J Am Coll Cardiol. 1999;33:351A
  31. OASIS Investigators . Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischemia without ST elevation: a pilot study. Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Circulation. 1997;96:769–777
  32. OASIS Investigators . Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularisation procedures in patients with acute myocardial ischaemia without ST elevation: a randomised trial. Organisation to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Lancet. 1999;353:429–438
  33. Simoons M, Lenderink T, Scheffer M, et al.  Efegatran, a new direct thrombin inhibitor: safety and dose response in patients with unstable angina [abstract]. Circulation. 1994;90:I231
  34. Steg PG, Petrauskienne B, Lopez-Sendon J, et al.  A randomized trial of safety and efficacy of long-acting PEG-hirudin in patients with unstable angina and non-Q-wave myocardial infarction [abstract]. Eur Heart J. 1998;19:50
  35. Topol EJ, Fuster V, Harrington RA, et al.  Recombinant hirudin for unstable angina pectoris: a multicenter, randomized angiographic trial. Circulation. 1994;89:1557–1566
  36. TRIM Investigators . A low molecular weight, selective thrombin inhibitor, inogatran, vs heparin, in unstable coronary artery disease in 1209 patients: a double-blind, randomized, dosefinding study. Thrombin inhibition in Myocardial Ischaemia (TRIM) study group. Eur Heart J. 1997;18:1416–1425
  37. Serruys PW, Herrman JP, Simon R, et al.  A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty: Helvetica Investigators. N Engl J Med. 1995;333:757–763
  38. Bittl JA, Strony J, Brinker JA, et al.  Treatment with bivalirudin (Hirulog) as compared with heparin during coronary angioplasty for unstable or postinfarction angina: Hirulog Angioplasty Study Investigators. N Engl J Med. 1995;333:764–769
  39. Rupprecht HJ, Terres W, Ozbek C, et al.  Recombinant hirudin (HBW 023) prevents troponin T release after coronary angioplasty in patients with unstable angina. J Am Coll Cardiol. 1995;26:1637–1642
  40. Sakamoto S, Hirase T, Suzuki S, et al.  Inhibitory effect of argatroban on thrombin–antithrombin III complex after percutaneous coronary angioplasty. Thromb Haemost. 1995;74:710–793
  41. van den Bos AA, Deckers JW, Heyndrickx GR, et al.  Safety and efficacy of recombinant hirudin (CGP 39 393) versus heparin in patients with stable angina undergoing coronary angioplasty. Circulation. 1993;88:2058–2066
  42. White HD. Direct thrombin inhibition and thrombolytic therapy: rationale for the Hirulog and Early Reperfusion/Occlusion (HERO-2) trial. Am J Cardiol. 1998;82:57P–62P
  43. Topol EJ. Evolution of improved antithrombotic and antiplatelet agents: genesis of the comparison of abciximab complications with hirulog (and back-up abciximab) events trial (CACHET). Am J Cardiol. 1998;82:63P–68P
  44. Kong DF, Topol EJ, Bittl JA, et al.  Clinical outcomes of bivalirudin for ischemic heart disease. Circulation. 1999;100:2049–2053
  45. Yusuf S, Peto R, Lewis J, et al.  Beta blockade during and after MI: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27:335–371

☆ Supported by a grant from Hoechst Marion Roussel but designed, conducted, interpreted, and submitted for publication independently of the sponsor.

☆☆ Reprint requests: Salim Yusuf, MD, Preventive Cardiology and Therapeutics Program, McMaster University, HGH—McMaster Clinic, 237 Barton St E, Hamilton, Ontario L8L 2X2, Canada. E-mail: yusufs@fhs.csu.mcmaster.ca

★ *A complete list of participants appears in the Appendix.

PII: S0002-8703(01)63952-8

doi:10.1067/mhj.2001.111954

American Heart Journal
Volume 141, Issue 1 , Page E2, January 2001

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