Copyright © 2000 by the European Society of Cardiology.
Geographic variability in outcomes within an international trial of glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes. Results from PURSUIT
a Thoraxcenter, University Hospital Rotterdam, Rotterdam, The Netherlands
b Duke Clinical Research Institute, Durham, NC, U.S.A.
c National Institute of Cardiology, Warsaw, Poland
d Queen's Medical Centre, Nottingham, U.K.
e Cleveland Clinic Foundation, Cleveland, OH, U.S.A.
f Hungarian Institute of Cardiology, Budapest, Hungary
revised June 7, 1999; accepted June 9, 1999
Abstract
Aims Variations in outcome of patients from different geographic regions have been observed in many large international trials. We analysed the factors that might contribute to the geographic variations in patient outcome and treatment effect as observed in the PURSUIT trial.
Methods In PURSUIT, 9461 patients with acute coronary syndromes without persistent ST-elevation were randomized to the platelet inhibitor eptifibatide or placebo for 72h in 27 countries in four geographic regions: Western (n=3697) and Eastern Europe (n=1541) as well as North (n=3827) and Latin America (n=396). The primary end-point was the 30-day composite of death or myocardial infarction. In the initial univariate analysis, the treatment effect appeared greater in N. America than in W. Europe, while no benefit was apparent in L. America and E. Europe. However, the confidence intervals were wide and overlapping. To study these differences, a subdivision in an early and late patient outcome and treatment effect was made. Accordingly, we analysed the rate of death or infarction at 72h censored for percutaneous coronary intervention and the rate between 3 and 30 days, respectively. Additional analyses were performed with different definitions of myocardial infarction using progressively higher thresholds of CK(-MB) elevation. Multivariable analysis was used to evaluate the relation between region and outcome and to determine the adjusted odds ratios for the eptifibatide treatment effect.
Results Major differences in baseline demographics were apparent among the four regions; in particular, more patients from E. Europe had characteristics associated with impaired outcome. Interventional treatment also varied considerably, with more patients from N. America undergoing revascularization. Despite differences in the 72h event rate, eptifibatide showed a consistent trend towards a reduction in the composite end-point among all four regions and for all definitions of infarction. Relative reductions ranged from 17–42% in W. Europe, 23–35% in N. America, 0–33% in E. Europe, and 55–82% in L. America. After multivariable adjustment, the pattern of benefit with eptifibatide was consistent among the regions. In patients undergoing percutaneous coronary intervention during study drug infusion in W. Europe (n=266) and N. America (n=931), the relative reduction in myocardial infarction during medical therapy ranged from 56–75% in W. Europe and 14–67% in N. America, while the reduction in procedure-related events ranged from 12–44% and 25–61% for different definitions of infarction. After multivariable adjustment neither benefit nor rebound were apparent after study drug discontinuation, or after 3 days in all regions, except in L. America. In general, the differences in outcome and treatment effect were greatest when the protocol definition of myocardial infarction (CK(-MB) >1 upper normal limit) was applied. Under stricter definitions, these differences became smaller and disappeared with the investigator’s assessment.
Conclusion The analysis suggests that the apparent differences in patient outcome and eptifibatide treatment effect can be explained largely by differences in baseline demographics and adjunctive treatment strategies as well as by the methodology of myocardial infarction definition and the adjudication process.
Key Words: Unstable angina, myocardial infarction, acute coronary syndromes, platelet glycoprotein IIb/IIIa receptor inhibition, geographic variation
f1 Correspondence: K. Martijn Akkerhuis, MD, Cardialysis B.V., P.O. Box 2125, 3000 CC Rotterdam, The Netherlands.
References
- N Engl J Med. 1998;339:436–443
[Abstract/Free Full Text] - Van de Werf F, Topol EJ, Lee KL. Variations in patient management and outcomes for acute myocardial infarction in the United States and other countries. Results from the GUSTO trial. JAMA. 1995;273:1586–1591[Abstract]
- Rouleau JL, Moyé LA, Pfeffer MA. A comparison of management patterns after acute myocardial infarction in Canada and the United States. N Engl J Med. 1993;328:779–784
[Abstract/Free Full Text] - Barbash GI, Modan M, Goldbourt U, White HD, Van de Werf F. Comparative case fatality analysis of the International Tissue Plasminogen Activator/Streptokinase mortality trial: variation by country beyond predictive profile. J Am Coll Cardiol. 1993;21:281–286[Abstract]
- Lancet. 1993;342:759–766[CrossRef][ISI][Medline]
- Harrington RA. Design and methodology of the PURSUIT trial: evaluating eptifibatide for acute ischemic coronary syndromes. Am J Cardiol. 1997;80:34B–38B[CrossRef][Medline]
- Ryan TJ, Anderson JL, Antman EM. ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation. 1996;94:2341–2350
[Free Full Text] - Boersma E, Pieper K, Wilcox RG. The risk of adverse outcome in patients with acute coronary syndromes without ST elevation is mainly determined by baseline clinical factors. J Am Coll Cardiol. 1999;33:359A
- Armstrong PW, Fu Y, Chang W-C. Acute coronary syndromes in The GUSTO-IIb trial: Prognostic insights and impact of recurrent ischemia. Circulation. 1998;98:1860–1868
[Abstract/Free Full Text] - N Engl J Med. 1996;335:775–782
[Abstract/Free Full Text] - Lee KL, Woodlief LH, Topol EJ. Predictors of 30-day mortality in the era of reperfusion for acute myocardial infarction. Results from an international trial of 41,021 patients. Circulation. 1995;91:1659–1668
[Abstract/Free Full Text] - N Engl J Med. 1998;338:1488–1497
[Abstract/Free Full Text] - Van Miltenburg-van Zijl AJM, Simoons ML, Veerhoek RJ, Bossuyt PMM. Incidence and follow-up of Braunwald subgroups in unstable angina pectoris. J Am Coll Cardiol. 1995;25:1286–1292[Abstract]
- Serruys PW, de Jaegere P, Kiemeneij F. A comparison of balloon-expandable-stent implantation with balloon angioplasty in patients with coronary artery disease. N Engl J Med. 1994;331:489–495
[Abstract/Free Full Text] - N Engl J Med. 1994;330:956–961
[Abstract/Free Full Text] - N Engl J Med. 1997;336:1689–1696
[Abstract/Free Full Text] - Lancet. 1997;349:1429–1435[CrossRef][ISI][Medline]
- Lancet. 1997;349:1422–1428[CrossRef][ISI][Medline]
- Circulation. 1997;96:1445–1453
[Abstract/Free Full Text] - Alexander JH, Alexander K, Kong DF, Tung CY, Whellan D. Session highlights from the American Heart Association Scientific Sessions: November 9–12, 1997. Am Heart J. 1998;135:157–180[CrossRef][ISI][Medline]
- Klootwijk P, Meij S, Melkert R, Lenderink T, Simoons ML. Reduction of recurrent ischemia with abciximab during continuous ECG-ischemia monitoring in patients with unstable angina refractory to standard treatment (CAPTURE). Circulation. 1998;98:1358–1364
[Abstract/Free Full Text] - Akkerhuis M, Boersma H, Harrington RA, Deckers JW, Califf RM, Simoons ML. In patients with acute coronary syndromes without ST-segment elevation, eptifibatide particularly reduces complications in those undergoing an early percutaneous intervention: a report of the PURSUIT study (Abst). Eur Heart J. 1998;19:3421
- Harrington RA, Lincoff AM, Califf RM. Characteristics and consequences of myocardial infarction after percutaneous coronary intervention: Insights from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). J Am Coll Cardiol. 1995;25:1693–1699[Abstract]
- Abdelmeguid AE, Topol EJ. The myth of the myocardial infarctlet during percutaneous coronary revascularization procedures. Circulation. 1996;94:3369–3375
[Free Full Text] - Topol EJ, Ferguson JJ, Weisman HF. Long-term protection from myocardial ischemic events in a randomized trial of brief integrin ß3blockade with percutaneous coronary intervention. JAMA. 1997;278:479–484[Abstract]
- Simoons, ML, Van den Brand, M, Lincoff, M, Minimal myocardial damage during coronary intervention is associated with impaired outcome, Eur Heart J
- Califf RM, Abdelmeguid AE, Kuntz RE. Myonecrosis after revascularization procedures. J Am Coll Cardiol. 1998;31:241–251
[Abstract/Free Full Text] - Alexander JH, Sparapani RA, Mahaffey KW. 30-day and 6-month mortality is proportional to magnitude of peak creatine kinase elevation the non-ST-segment elevation acute coronary syndromes. Circulation. 1998;98:I-3306
- N Engl J Med. 1998;338:1498–1505
[Abstract/Free Full Text] - Mahaffey KW, Akkerhuis M, Boersma H. The identification of MI in clinical trials is difficult and there is substantial difference between the assessment by site investigators and a Clinical Events Committee: results from PURSUIT (Abstr). Eur Heart J. 1998;19:498
- Yusuf S, Wittes J, Probsfield J, Tyroler HA. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA. 1991;266:93–98[Abstract]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P Kaul, L K Newby, Y Fu, D B Mark, S G Goodman, G S Wagner, R A Harrington, C B Granger, F Van de Werf, E M Ohman, et al. Relation between baseline risk and treatment decisions in non-ST elevation acute coronary syndromes: an examination of international practice patterns Heart, July 1, 2005; 91(7): 876 - 881. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W.-C. Chang, W. K Midodzi, C. M Westerhout, E. Boersma, J. Cooper, E. S Barnathan, M. L Simoons, L. Wallentin, E M. Ohman, P. W Armstrong, et al. Are international differences in the outcomes of acute coronary syndromes apparent or real? A multilevel analysis J. Epidemiol. Community Health, May 1, 2005; 59(5): 427 - 433. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M Kramer, L.K. Newby, W.-C. Chang, R.J. Simes, F. Van de Werf, C. B Granger, K. L Lee, H. D White, L. S Piegas, E. J Topol, et al. International variation in the use of evidence-based medicines for acute coronary syndromes Eur. Heart J., December 1, 2003; 24(23): 2133 - 2141. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Di Chiara, F. Chiarella, S. Savonitto, D. Lucci, L. Bolognese, S. De Servi, C. Greco, A. Boccanelli, P. Zonzin, S. Coccolini, et al. Epidemiology of acute myocardial infarction in the Italian CCU network: The BLITZ Study Eur. Heart J., September 2, 2003; 24(18): 1616 - 1629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Prasad, V. Mathew, D. R Holmes Jr., and B. J Gersh Current management of non-ST-segment-elevation acute coronary syndrome: reconciling the results of randomized controlled trials Eur. Heart J., September 1, 2003; 24(17): 1544 - 1553. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. S. Kao, B. C. Aaron, and E. P. Dellinger Trials and Tribulations: Current Challenges in Conducting Clinical Trials Arch Surg, January 1, 2003; 138(1): 59 - 62. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. A. Fox, S. G. Goodman, W. Klein, D. Brieger, P. G. Steg, O. Dabbous, A. Avezum, and GRACE Investigators Management of acute coronary syndromes. Variations in practice and outcome. Findings from the Global Registry of Acute Coronary Events (GRACE) Eur. Heart J., August 1, 2002; 23(15): 1177 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W.-C. Chang, R.A. Harrington, M.L. Simoons, R.M. Califf, A.M. Lincoff, and P.W. Armstrong Does eptifibatide confer a greater benefit to patients with unstable angina than with non-ST segment elevation myocardial infarction?. Insights from the PURSUIT Trial Eur. Heart J., July 2, 2002; 23(14): 1102 - 1111. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. Lauer, P. L. Houghtaling, J. G. Peterson, C. B. Granger, D. L. Bhatt, S. K. Sapp, M. L. Simoons, R. A. Harrington, E. J. Topol, and A. M. Lincoff Attenuation of Rebound Ischemia After Discontinuation of Heparin Therapy by Glycoprotein IIb/IIIa Inhibition With Eptifibatide in Patients With Acute Coronary Syndromes: Observations From the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial Circulation, December 4, 2001; 104(23): 2772 - 2777. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.P Giugliano, J Llevadot, R.G Wilcox, E.P Gurfinkel, C.H McCabe, A Charlesworth, S.L Thompson, E.M Antman, E Braunwald, and for the In TIME II Investigators Geographic variation in patient and hospital characteristics, management, and clinical outcomes in ST-elevation myocardial infarction treated with fibrinolysis. Results from InTIME-II Eur. Heart J., September 2, 2001; 22(18): 1702 - 1715. [Abstract] [PDF]
|
|
|
|
|
|
K.A.A Fox, D.V Cokkinos, J Deckers, U Keil, A Maggioni, and G Steg The ENACT study: a pan-European survey of acute coronary syndromes Eur. Heart J., September 1, 2000; 21(17): 1440 - 1449. [Abstract] [PDF]
|
|
|
|
|
|
H.D. White International differences: selection, noise, or real? Eur. Heart J., March 1, 2000; 21(5): 339 - 342. [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||