Correspondence
Comparison of Early Invasive and Conservative Strategies in Patients with Unstable Coronary Syndromes
N Engl J Med 2001; 345:1573-1575November 22, 2001
- Article
To the Editor:
In the randomized Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction 18 (TACTICS–TIMI 18) trial, Cannon et al. (June 21 issue)1 compared the effects of early invasive and conservative strategies in patients with acute coronary syndromes. Two potential biases were not discussed in their report.
First, the definitions of myocardial infarction are not provided in the report, in the article outlining the study protocol,2 or in the article cited as providing “standard TIMI definitions.”3 One must consult the TIMI 11B trial,4 whose results were published in 1999, for these definitions. For patients who had undergone percutaneous transluminal coronary angioplasty less than 24 hours previously, levels of the MB isoform of creatine kinase had to be at least three times the upper limit of normal and increased by at least 50 percent over the previous value; for those who had undergone coronary artery bypass grafting less than 24 hours previously, creatine kinase MB levels had to be at least five times the upper limit of normal and increased by at least 50 percent over the previous value; whereas for those who had not undergone revascularization, creatine kinase MB levels had to be above normal and increased by at least 50 percent over the previous value. These differences in definitions alone will alter the probabilities of myocardial infarction in the invasive-strategy and conservative-strategy groups in the TACTICS–TIMI 18 trial.
Second, the duration of the tirofiban infusion was 48 hours, whereas in an earlier study,5 the benefits of this agent were established with use of a mean duration of infusion of 71 hours. In addition, 94 percent of patients in the invasive-strategy group received tirofiban during percutaneous revascularization, as compared with only 59 percent of patients in the conservative-strategy group. Though these differences may reflect “real world” practice, we believe that all these factors may introduce a bias in favor of the invasive strategy and that these issues should be clearly discussed in the light of the study's findings.
5 ReferencesDiego Perez de Arenaza, M.D.
Ameet Bakhai, M.B., B.S.
Marcus Flather, M.B., B.S.
Royal Brompton and Harefield National Health Service Trust, London SW3 6NP, United Kingdom
d.perez@rbh. nthames. nhs. uk 1
Cannon CP ,Weintraub WS ,Demopoulos LA , et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med 2001;344:1879-1887
Full Text | Web of Science | Medline2
Cannon CP ,Weintraub WS ,Demopoulos LA ,Robertson DH ,Gormley GJ ,Braunwald E . Invasive versus conservative strategies in unstable angina and non-Q-wave myocardial infarction following treatment with tirofiban: rationale and study design of the international TACTICS-TIMI 18 Trial. Am J Cardiol 1998;82:731-736
CrossRef | Web of Science | Medline3
Cannon CP ,McCabe CH ,Wilcox RG , et al. Oral glycoprotein IIb/IIIa inhibition with orbofiban in patients with unstable coronary syndromes (OPUS-TIMI 16) trial. Circulation 2000;102:149-156
Web of Science | Medline4
Antman EM ,McCabe CH ,Gurfinkel EP , et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction. Circulation 1999;100:1593-1601
Web of Science | Medline5
The Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study Investigators
Full Text | Web of Science | Medline
To the Editor:
The most important sentence of the article by Cannon et al. is incorrect and misleading. The final sentence of the Conclusions section of the abstract states, “These data support a policy involving broader use of the early inhibition of glycoprotein IIb/IIIa in combination with an early invasive strategy in such patients.” In fact, these data imply nothing whatsoever about the benefits of glycoprotein IIb/IIIa inhibitors in patients with unstable coronary syndromes, since 99 percent of the patients in both treatment groups received tirofiban. A more accurate sentence would have been as follows: These data support a policy of early invasive intervention in patients with unstable coronary syndromes treated with aspirin, heparin, and glycoprotein IIb/IIIa inhibitors.
Peter Campbell, M.B., Ch.B.
Christchurch Hospital, Christchurch, New Zealand
peterc1@cdhb.govt. nz To the Editor:
Cannon et al. report that in patients with unstable coronary syndromes, those who had elevated levels of troponin T at presentation derived greater benefit from an early invasive strategy than those who did not have elevated levels of troponin T. In the invasive-strategy group, the relative reduction in the risk of the primary end point of death, nonfatal myocardial infarction, or rehospitalization for an acute coronary syndrome was 33 percent among patients with elevated troponin T levels and 9 percent among patients without elevated troponin T levels. The authors suggest that measurement of troponin T could be incorporated into approaches for the triage of patients with respect to an early invasive strategy.
Patients with diabetes and coronary artery disease have higher mortality rates than nondiabetic patients with coronary artery disease1 and, therefore, may also be viewed as being at high risk. In Figure 2 of their article, Cannon et al. show that in patients with diabetes, the invasive strategy was associated with a relative reduction in the risk of the primary end point of 27 percent, as compared with a reduction of 13 percent in patients without diabetes. In both diabetic patients and those with elevated troponin T levels, the reductions in the risk of the primary end point were significant (95 percent confidence intervals did not cross unity). Although not commented on by the authors, their data suggest that the presence of diabetes could also be incorporated into the risk-based stratification for early invasive management.
1 ReferencesRichard E. Gilbert, M.D., Ph.D.
University of Melbourne, Fitzroy, VIC 3065, Australia1
Kurbaan AS ,Bowker TJ ,Ilsley CD ,Sigwart U ,Rickards AF . Difference in the mortality of the CABRI diabetic and nondiabetic populations and its relation to coronary artery disease and the revascularization mode. Am J Cardiol 2001;87:947-950
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Perez de Arenaza et al. point out that the definition of myocardial infarction that we used is the same one that has been used in all prior (and ongoing) TIMI trials, as well as in all Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trials and in the Fragmin and Fast Revascularization during Instability in Coronary Artery Disease II trial.1 In our study, a blinded clinical-events committee applied this definition equally to each group. The number of events after percutaneous coronary revascularization was actually quite similar in the conservative-strategy and invasive-strategy groups (14 and 11, respectively). Thus, no apparent imbalance was present in this aspect of the definition of myocardial infarction. Nonprocedural myocardial infarctions accounted for over 80 percent of the total number of myocardial infarctions, and it was the differences in the number of these nonprocedural events (42 in the invasive-strategy group and 62 in the conservative-strategy group) that drove the overall result.
Regarding the definition of myocardial infarction after percutaneous coronary revascularization, most debate has focused on the lack of importance of an elevation in creatine kinase MB levels to one to three times the upper limit of normal, and many have argued that the appropriate cutoff point after percutaneous coronary revascularization is even higher than the one we have used (e.g., more than five times the upper limit of normal or even more than eight times the upper limit of normal).2 In another analysis of the data, we found that patients with creatine kinase MB levels that were one to three times the upper limit of normal after percutaneous coronary revascularization had six-month mortality rates that were similar to those of patients with no elevation in creatine kinase MB. In contrast, patients who had an elevation in creatine kinase MB levels to more than the upper limit of normal not immediately after percutaneous coronary revascularization and those with postprocedural levels that were more than three times the upper limit of normal had significantly higher mortality rates.3 Thus, we believe we used the standard definition of myocardial infarction appropriately.
Regarding the differential use of glycoprotein IIb/IIIa inhibition during percutaneous coronary revascularization, despite the availability (at no cost) of tirofiban for all procedures, as we reported in a footnote to Table 5, patients who did not receive tirofiban had outcomes similar to those of patients who were treated with tirofiban. Thus, this appears to have had little or no effect on the overall results of the trial.
The first sentence of our Discussion section is, in fact, the one that Dr. Campbell proposes. In contrast, in the TIMI IIIB trial,4 we did not see a benefit of an invasive strategy in patients who did not receive glycoprotein IIb/IIIa inhibitors. Accordingly, we conclude that the implications of the current trial are that these data support the broader use of the complete strategy that was tested — namely, early inhibition of glycoprotein IIb/IIIa in combination with an early invasive strategy.
We agree with Dr. Gilbert that diabetes is an important risk factor. We did not observe a statistically significant difference between patients with diabetes and those without diabetes with respect to the relative benefit of an early invasive strategy. Nonetheless, the greater absolute difference in the rate of the primary end point among patients with diabetes (7.6 percent, vs. 2.2 percent in patients without diabetes) does suggest that diabetes is a clinically useful indicator that an early invasive strategy will have a large benefit.
4 ReferencesChristopher P. Cannon, M.D.
Eugene Braunwald, M.D.
Brigham and Women's Hospital, Boston, MA 02115
cpcannon@partners.org 1
Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet 1999;354:708-715
CrossRef | Web of Science | Medline2
Stone GW ,Mehran R ,Dangas G ,Lansky AJ ,Kornowski R ,Leon MB . Differential impact on survival of electrocardiographic Q-wave versus enzymatic myocardial infarction after percutaneous intervention: a device-specific analysis of 7147 patients. Circulation 2001;104:642-647
CrossRef | Web of Science | Medline3
Sadanandan S, Cannon CP, DiBattiste PM, et al. Outcomes of patients with spontaneous versus post-PCI CK-MB elevation: data from TACTICS-TIMI 18 trial. Circulation (in press). abstract.
4
Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction: results of the TIMI IIIB trial. Circulation 1994;89:1545-1556
Web of Science | Medline
- Citing Articles (2)
Citing Articles
1
Juan Sanchís, Vicente Bertomeu González, Vicent Bodí, Julio Núñez, Catherine Lauwers, Juan M. Ruiz-Nodar, José L. Díez, Vicente Bertolín, Ernesto Casabán, Alejandro Navarro, Araceli Frutos, Javier Carratalá, Àngel Llàcer. (2006) Estrategia invasiva en pacientes con diabetes avanzada y síndrome coronario agudo sin elevación del segmento ST. Hallazgos angiográficos y evolución clínica. Resultados del estudio PREDICAR. Revista Española de Cardiología 59:4, 321-328
CrossRef2
KAA Fox, PA Poole-Wilson, RA Henderson, TC Clayton, DA Chamberlain, TRD Shaw, DJ Wheatley, SJ Pocock. (2002) Interventional versus conservative treatment for patients with unstable angina or non-ST-elevation myocardial infarction: the British Heart Foundation RITA 3 randomised trial. The Lancet 360:9335, 743-751
CrossRef
