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Figure. Kaplan-Meier Mortality Curves in the Invasive and Conservative Therapy Groups
Figure. Kaplan-Meier Mortality Curves in the Invasive and Conservative Therapy Groups

Hazard ratios (HRs) with their 95% confidence intervals (CIs) as well as P values were calculated from unadjusted and adjusted Cox proportional hazards models relating treatment group with mortality. Adjustment was performed for sex, age, diabetes, arterial hypertension, smoking, hypercholesterolemia, previous myocardial infarction, previous coronary artery bypass surgery, Killip class, and pain-to-randomization interval.

1.
Eagle KA, Goodman SG, Avezum A, Budaj A, Sullivan CM, López-Sendón J.GRACE Investigators.  Practice variation and missed opportunities for reperfusion in ST-segment-elevation myocardial infarction: findings from the Global Registry of Acute Coronary Events (GRACE).  Lancet. 2002;359(9304):373-377PubMedArticle
2.
Antman EM, Hand M, Armstrong PW,  et al; 2004 Writing Committee Members.  2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction.  Circulation. 2008;117(2):296-329PubMedArticle
3.
Schömig A, Mehilli J, Antoniucci D,  et al; Beyond 12 hours Reperfusion Alternative Evaluation (BRAVE-2) Trial Investigators.  Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset: a randomized controlled trial.  JAMA. 2005;293(23):2865-2872PubMedArticle
4.
Parodi G, Ndrepepa G, Kastrati A,  et al; Beyond 12 hours Reperfusion Alternative Evaluation (BRAVE-2) Trial Investigators.  Ability of mechanical reperfusion to salvage myocardium in patients with acute myocardial infarction presenting beyond 12 hours after onset of symptoms.  Am Heart J. 2006;152(6):1133-1139PubMedArticle
Research Letter
February 4, 2009

Mechanical Reperfusion and Long-term Mortality in Patients With Acute Myocardial Infarction Presenting 12 to 48 Hours From Onset of Symptoms

JAMA. 2009;301(5):487-488. doi:10.1001/jama.2009.32

To the Editor: Nearly one-third of patients with acute ST-segment elevation myocardial infarction (STEMI) do not receive early reperfusion therapy, mostly due to late presentation after symptom onset.1 Current guidelines do not recommend primary percutaneous coronary intervention (PCI) in patients with STEMI who present later than 12 hours from symptom onset.2 The Beyond 12 hours Reperfusion Alternative Evaluation (BRAVE-2) Trial3,4 demonstrated that an invasive treatment is associated with substantial myocardial salvage and reduction in infarct size in patients with STEMI presenting from 12 to 48 hours after symptom onset. No studies to date have investigated the long-term prognosis after PCI in these patients. In this study, we present the results of the 4-year follow-up of the patients enrolled in the BRAVE-2 trial.3

Methods

The BRAVE-2 trial was an international, multicenter, open-label, randomized controlled study conducted from May 2001 to December 2004; it included 365 patients with STEMI who were assessed between 12 and 48 hours from symptom onset. Details of the primary study have been previously reported.3 The patients were assigned to either an invasive PCI strategy (n = 182) or a conservative treatment strategy (n = 183). The primary end point was final infarct size measured by single-photon emission computed tomography with technetium 99m sestamibi 5 to 10 days after randomization. The present study focused on the prespecified analysis of 4-year outcomes with mortality as the primary outcome.

All analyses were performed as intention-to-treat. Percentage data are presented as Kaplan-Meier estimates. Cox proportional hazards models were used to assess differences in 4-year outcomes, adjusted for sex, age, diabetes, arterial hypertension, smoking, hypercholesterolemia, previous myocardial infarction, previous coronary artery bypass surgery, Killip class, and pain-to-randomization interval; proportional hazards assumptions were met. S-PLUS version 4.5 (Insightful Corp, Seattle, Washington) was used for all statistical analyses. A 2-tailed P < .05 was considered to indicate statistical significance.

Results

Four-year follow-up was complete in all but 44 of 365 patients (20 patients in the invasive group and 24 patients in the conservative group). Among the patients who did not complete the 4-year follow-up, median duration of follow-up was 44 months (interquartile range [IQR], 39-46 months) in the invasive group vs 44 months (IQR, 38-46 months) in the conservative group (P = .36). Death occurred in 20 patients (11.1%; 95% confidence interval [CI], 7.3%-16.7%) in the invasive group and 34 patients (18.9%; 95% CI, 13.9%-25.4%) in the conservative group (unadjusted hazard ratio [HR], 0.57; 95% CI, 0.33-0.99; P = .047; adjusted HR, 0.55; 95% CI, 0.31-0.97; P = .04) (Figure).

Myocardial reinfarction occurred in 12 patients (6.8%; 95% CI, 3.9%-11.7%) in the invasive group and 10 patients (5.6%; 95% CI, 3.0%-10.1%) in the conservative group (unadjusted HR, 1.20; 95% CI, 0.52-2.78; P = .66). Stroke occurred in 3 patients (1.6%) in the invasive group and 2 patients (1.1%) in the conservative group (P = .65). Subsequent revascularization of the infarct-related artery was performed in 45 patients in the invasive group and 125 patients in the conservative group (25.8% vs 69.1%; P < .001).

Comment

To our knowledge, this is the first study to address the prognostic effect of PCI in patients with STEMI who present between 12 and 48 hours from symptom onset, showing that PCI may reduce 4-year mortality in these patients. The divergence in mortality curves suggests that the clinical benefit from PCI needs time to become evident. These findings, in addition to those demonstrating reduction of infarct size,3 may support the use of invasive PCI treatment in this subset of patients.

However, the major limitation of this study is that the trial was underpowered to demonstrate a mortality advantage of PCI (the power of the study to show statistical significance for the observed difference in mortality was 57%). Given the wide CIs and the risk of inflation of type I error by comparisons of multiple outcomes in the BRAVE 2 trial, these results should be seen as hypothesis generating. Larger trials are required to confirm this effect and clarify its magnitude.

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Article Information

Author Contributions: Dr Kastrati 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: Kastrati, Schömig.

Acquisition of data: Mehilli, Antoniucci.

Analysis and interpretation of data: Ndrepepa, Kastrati.

Drafting of the manuscript: Ndrepepa, Kastrati.

Critical revision of the manuscript for important intellectual content: Mehilli, Antoniucci, Schömig.

Statistical analysis: Ndrepepa, Kastrati.

Obtained funding: Schömig.

Administrative, technical, or material support: Mehilli, Antoniucci, Schömig.

Study supervision: Antoniucci, Schömig.

Financial Disclosures: None reported.

Funding/Support: The primary trial was supported by grants KKF 10-02 and KKF 04-03 from Deutsches Herzzentrum, Munich, Germany, as well as by unrestricted research grants from Lilly Deutschland GmbH, Bad Homburg, Germany, and Guidant Advanced Cardiovascular Systems Inc, Santa Clara, California.

Role of the Sponsor: The funding sources had no role 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 Contributions: Stefanie Schulz, MD, Deutsches Herzzentrum, Munich, Germany, provided help with the statistical analysis, for which she received no compensation. We appreciate the contributions of all the investigators of the BRAVE-2 trial.

References
1.
Eagle KA, Goodman SG, Avezum A, Budaj A, Sullivan CM, López-Sendón J.GRACE Investigators.  Practice variation and missed opportunities for reperfusion in ST-segment-elevation myocardial infarction: findings from the Global Registry of Acute Coronary Events (GRACE).  Lancet. 2002;359(9304):373-377PubMedArticle
2.
Antman EM, Hand M, Armstrong PW,  et al; 2004 Writing Committee Members.  2007 Focused Update of the ACC/AHA 2004 Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction.  Circulation. 2008;117(2):296-329PubMedArticle
3.
Schömig A, Mehilli J, Antoniucci D,  et al; Beyond 12 hours Reperfusion Alternative Evaluation (BRAVE-2) Trial Investigators.  Mechanical reperfusion in patients with acute myocardial infarction presenting more than 12 hours from symptom onset: a randomized controlled trial.  JAMA. 2005;293(23):2865-2872PubMedArticle
4.
Parodi G, Ndrepepa G, Kastrati A,  et al; Beyond 12 hours Reperfusion Alternative Evaluation (BRAVE-2) Trial Investigators.  Ability of mechanical reperfusion to salvage myocardium in patients with acute myocardial infarction presenting beyond 12 hours after onset of symptoms.  Am Heart J. 2006;152(6):1133-1139PubMedArticle
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