Letter Regarding Article by Nallamothu et al, “Times to Treatment in Transfer Patients Undergoing Primary Percutaneous Coronary Intervention in the United States”
To the Editor:
We agree with Nallamothu et al1 and Herrmann2 that the long treatment delays in patients transferred for primary angioplasty emphasize the need for process improvement in the United States. We do not agree that current evidence supports fibrinolytic therapy as the treatment of choice for most patients in whom total door-to-balloon time is >120 minutes.
In 5 recent trials, the transfer of patients with STEMI presenting to noninterventional hospitals for primary PCI rather than fibrinolysis has resulted in reduced rates of death, reinfarction, and stroke.2 The additional treatment delays (time to PCI minus time to lytic therapy) in these studies have ranged from 48 to 111 minutes.2 The relative outcomes of primary PCI and fibrinolysis when additional treatment delays to primary PCI are greater than this are unknown.
Recent studies have demonstrated that incremental delays to mechanical reperfusion have a major impact on mortality within the first 2 to 3 hours of symptom onset when significant myocardial salvage is possible.3,4 After 2 to 3 hours, incremental reperfusion delays have little impact on myocardial salvage or mortality.3,4 Consequently, short door-to-balloon times are important for mortality reduction in patients presenting early (<2 to 3 hours) but not late after symptom onset.3,4 In addition, delays in reperfusion have an impact on mortality in high-risk patients but have little or no effect on mortality in low-risk patients.3 Moreover, the benefits of primary PCI versus fibrinolysis in reducing reinfarction, intracranial bleeding, and stroke are time independent.2,3
Therefore, we propose the following approach to reperfusion therapy in patients presenting at noninterventional hospitals. In agreement with current American College of Cardiology/American Heart Association guidelines, patients with cardiogenic shock and contraindications to fibrinolysis should be transferred for primary PCI. Patients at high risk who present within 2 to 3 hours of symptom onset should be transferred for primary PCI unless an additional treatment delay of >60 to 90 minutes is likely, in which case fibrinolytic therapy should be administered and transfer initiated. Low-risk patients (eg, inferior infarction) or those who present beyond 2 to 3 hours, when incremental treatment delays have little impact on mortality, should be transferred for primary PCI without fibrinolytic therapy. This approach allows all patients to realize the substantial benefits of primary PCI over fibrinolytic therapy in reducing reinfarction, intracranial hemorrhage, and stroke, and pending the completion of ongoing trials of facilitated PCI, it is the most rational approach to maximize survival in high-risk patients presenting early after symptom onset.
Dr Grines has received research grants from Berlex; Pfizer; GlaxoSmithKline; Aventis; Guidant, Eli Lilly, SciMed, Johnson&Johnson, and Amersham Health (Senior PAMI); Otsuka; Esperion Therapeutics; Innercool Therapies; and AstraZeneca. Dr Grines has consulted for or served on the advisory boards of Innercool Therapies, Pfizer, Sanofi-Synthelabo, Inc, Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership, and the GlaxoSmithKline Global Cardiovascular Advisory Board. Dr Stone has consulted for or served on the advisory boards of Guidant, Abbott, and Boston Scientific.
Nallamothu BK, Bates ER, Herrin J, Wang Y, Bradley EH, Krumholz HM; NRMI Investigators. Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the United States: National Registry of Myocardial Infarction (NRMI)-3/4 analysis. Circulation. 2005; 111: 761–767.
Herrmann H. Transfer for primary angioplasty: the importance of time. Circulation. 2005; 111: 718–720.
Brodie BR, Stone GW, Cox DA, Stuckey TD, Turco M, Tcheng JE, Berger P, Mehran R, McLaughlin M, Constantini C, Lansky AS, Grines CL. Impact of treatment delays on outcomes of primary percutaneous coronary intervention for acute myocardial infarction: analysis from the CADILLAC trial. Am Heart J. In press.
Stone GW, O’Neill WW, Dixon S, Cox DA, Webb JG, Brodie B, Griffin JJ, Martin J, Gibbons R, Fahy M, Mehran R, Grines C. Predictors of infarct size by technetium-99m sestamibi imaging after angioplasty in acute myocardial infarction [abstract]. J Am Coll Cardiol. 2005; 45: 208A.
The 2004 American College of Cardiology/American Heart Association Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (STEMI) state that primary percutaneous coronary intervention (PPCI) is the preferred reperfusion strategy when a door-to-balloon time of <90 minutes is possible. PPCI should be performed in patients who are fibrinolytic ineligible or in cardiogenic shock, even when longer delays may occur.
The guidelines also state that patients who present to a facility without the capability for PPCI within 90 minutes should undergo fibrinolysis unless contraindicated. This recommendation is based on preclinical, single-center registry and randomized clinical trial data showing increasing infarct size and increasing mortality rates when reperfusion is delayed. For example, Drs Brodie, Grines, and Stone1 have recently demonstrated that myocardial infarct size and major adverse cardiac event rates are lower in patients when door-to-balloon times are <90 minutes as compared with longer times, and they concluded that their data provided “validation for current guideline recommendations.” We recently found similar results while also observing that this relationship is important regardless of whether patients presented within 2 hours of symptom onset or later.2
Although randomized clinical trial data demonstrate the superiority of PPCI over fibrinolysis, registry reports have often shown no difference in mortality between strategies. The probable explanation is that in registry reports, the routine use of rescue PCI and predischarge angiography with revascularization in many patients decreases reinfarction rates. Moreover, reports consistently demonstrate equivalent clinical results between strategies in patients with inferior STEMI (60% of patients)3 and in younger patients because of low mortality overall.
Five trials have suggested that transfer for PPCI is superior to on-site lytic therapy, but the results need to be evaluated within the context of trial design. Streptokinase, used in 50% of patients, is inferior when compared with fibrin-specific agents. Some protocols also called for higher-than-currently-recommended heparin dosing and repeat fibrinolytic therapy rather than rescue PCI for failed reperfusion. Most important, randomization-to-balloon times were 90 to 100 minutes. In contrast, the NRMI data we reported demonstrated that only 4% of US transfer patients received PPCI within 90 minutes, and only 15% were treated within 120 minutes. Rather than arguing from an ideological perspective that patients should undergo PPCI, we would suggest that process improvements be made by institutions that want to deliver evidence-based PPCI therapy but have unacceptably long door-to-balloon times.
O’Neill WW, Grines CL, Dixon SR, Griffin JJ, Martin JL, Cox DA, Webb JG, Brodie BR, Mehran R, Gibbons RJ, Held J, Stone GW. Does a 90-minute door-to-balloon time matter? Observations from four current reperfusion trials. J Am Coll Cardiol. 2005; 45: 225A.
McNamara RL, Wang Y, Herrin J, Curtis J, Bradley EH, Magid DJ, Peterson E, Blaney M, Frederick P, Krumholz HM. Does time from symptom onset to hospital presentation influence importance of time from door-to-balloon? J Am Coll Cardiol. 2005; 45: 11A. Abstract.
Stone GW, Grines CL, Browne KF, Marco J, Rothbaum D, O’Keefe J, Hartzler GO, Overlie P, Donohue B, Chelliah N, Vlietstra R, Puchrowicz-Ochocki S, O’Neill WW. Influence of acute myocardial infarction location on in-hospital and late outcome after primary percutaneous transluminal coronary angioplasty versus tissue plasminogen activator therapy. Am J Cardiol. 1996; 78: 19–25.