Author + information
- David Antoniucci, MD* ()
- ↵*Reprint requests and correspondence:
Dr. David Antoniucci, Division of Cardiology, Careggi Hospital, Viale Morgagni, Florence I-50135, Italy
More than 30 years ago the hypothesis of an interventional approach in patients with unstable angina or non–ST-segment elevation myocardial infarction (NSTEMI) was considered only after a “cooling-off” period. This negative attitude was in part justified by the lack of effective antithrombotic adjunctive therapies and devices in the management of lesion containing thrombus and the subsequent early hazard of percutaneous coronary intervention (PCI). The delay—many days or weeks after hospital admission—to interventional treatment could result in an apparent stabilization of the acute coronary syndrome (ACS) with a high incidence of early recurrent ischemia or nonfatal myocardial infarction (MI) in the more favorable cases or in a definitive “cooling” of the patients.
During this long period many trials comparing an early invasive strategy with a conservative strategy in patients with unstable angina or NSTEMI have produced conflicting results that have delayed the current general consensus regarding the benefit of an early invasive strategy, which is more evident in high-risk patients and mainly driven by the decrease in MI and the need for percutaneous or surgical coronary revascularization. This troubled history might be explained at least in part by the design of most studies that randomized patients before cardiac catheterization and the use of a wide temporal windows—from 24 to 48 h to 5 days—for the definition of “early” intervention. Randomization before cardiac catheterization resulted in the enrolment of a high percentage (>30%) of patients who did not receive coronary revascularization, because of mild or absent atherosclerotic coronary artery disease in most of them, making the comparison of an early invasive strategy versus a conservative or a delayed invasive strategy in selected patients distorted by the high number of patients at low risk of events whatever the strategy adopted. The use of temporal windows as long as 24 to 48 h to several days for the definition of an early treatment hides the potential benefit of a true “early” treatment (within 24 h of patient presentation) and contributes to maintaining considerable uncertainty about the optimal timing of cardiac catheterization and revascularization for patients with unstable angina or NSTEMI.
The study by Sorajja et al. (1) in this issue of the Journal overcame these 2 critical points and provides important data on the impact of delay to PCI on clinical outcome in the large cohort of patients with ACS enrolled in the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial who underwent PCI (2). Patients who underwent PCI (7,749 patients) were stratified by time from hospital presentation to PCI into 3 groups: <8 h, 8 to 24 h, and >24 h. A delay to PCI >24 h after clinical presentation was associated with >50% increase in 30-day and 1-year mortality as compared with patients who were treated earlier. Moreover, true “early” PCI was associated with a decreased rate of nonfatal MI. The incremental risk of death attributable to PCI delay >24 h was greatest in high-risk patients.
The study results are consistent with those of the ISAR-COOL (Intracoronary Stenting With Antithrombotic Regimen Cooling-Off) trial (3). This elegant study is the only randomized trial comparing early intervention (delay to PCI <6 h) with prolonged (3 to 5 days) maximized antithrombotic therapy before intervention in patients with ACS. The study involved 410 patients, and the primary end point was the composite of death or large MI at 30 days. The primary end point rate was 11.6% in patients allocated to delayed intervention and 5.9% in patients receiving early intervention (p = 0.04). Very importantly, the difference between groups was driven by the events that occurred before cardiac catheterization, whereas the rates of post-procedural events were identical in the 2 groups. This study has been criticized, mainly because of the small number of patients, and the results were in the opposite direction of the study hypothesis that was used for the calculation of the sample size (prolonged antithrombotic treatment before intervention would result in a relative risk reduction of death and MI of 60% as compared with early intervention). Nevertheless, the study has several strengths, such as the strict criteria used for the definition of ACS and the temporal windows for intervention and the optimal antithrombotic treatment in both arms that included heparin, glycoprotein IIb/IIIa inhibitors, a 600-mg loading dose of clopidogrel, and aspirin.
The study of Sorajja et al. (1), based on a very large cohort of patients who received PCI, strongly supports the results of the ISAR-COOL (Intracoronary Stenting With Antithrombotic Regimen Cooling Off) trial and avoids the confounding effect of the substantial percentage of low- or very-low-risk patients who received medical therapy after cardiac catheterization (32% in the entire cohort of the ACUITY trial) (2). As expected, major differences in MI and death rates were revealed in high-risk patients. Even among the low-risk patients there was a significantly higher 1-year mortality rate among those who had PCI >24 h after clinical presentation than among patients who had earlier PCI: no deaths at 1 year in the Thrombolysis In Myocardial Infarction (TIMI) risk score 1 to 2 subgroup with a time-to-PCI <8 h, and >2% in the subgroup with a time-to-PCI >24 h. This point is really important, because it outlines a major limitation of risk-scoring before cardiac catheterization in the individual patient and at the same time weakens a strategy of deferring for expedited cardiac catheterization only patients with a high risk score. A low TIMI risk score might correspond to a very-high-risk angiographic profile. This event is frequent and confirmed also by early coronary angiography in the PCI-ACUITY patient cohort (1). Nearly one-half of patients who underwent coronary angiography within 24 h of presentation had a baseline target vessel TIMI flow grade ≤2. A strategy of plaque passivation before PCI could be effective in decreasing PCI complications in the portion of patients who spontaneously or with an intensive antithrombotic treatment may experience improved coronary flow. Also in this subset of patients with an initial favorable course, the incidence of recurrent refractory ischemia is high—as is MI even after successful emergency PCI—whereas a remarkable portion of patients will not respond to antithrombotic therapy: in the ACUITY PCI study, 38% of patients who underwent coronary angiography with a delay >24 h still had a baseline target vessel TIMI flow grade <3 (1). Another important finding provided by this study is that the benefit in terms of mortality and MI provided by early PCI at 1 month is maintained at 1-year follow-up, whereas most of the previous studies provide short follow-up data.
At first sight the results of this study conflict with those of a contemporary umpteenth randomized trial comparing an early invasive strategy with a delayed invasive strategy in ACS patients, the TIMACS (Timing of Intervention in Acute Coronary Syndromes) trial (4). This study, which enrolled 3,031 patients with ACS, compared an early invasive strategy (coronary angiography performed within 24 h) with a delayed invasive strategy (coronary angiography performed >36 h after randomization). The difference between groups in the primary study end point (6-month death, MI, stroke) rate was not significant (9.6% of patients in the early-intervention group, and 11.3% in the delayed intervention group) (hazard ratio [HR]: 0.85; 95% confidence interval [CI]: 0.68 to 1.06, p = 0.15). As in previous trials with similar results, the lack of significant difference in outcome between the 2 strategies might be explained by the fact that the study could be underpowered for the primary end point (the study was stopped prematurely because of recruitment challenges), involved mainly low-intermediate-risk patients with a subsequent low rate of PCI (<60% of patients underwent PCI), with a median time to PCI of 16 h in the early invasive strategy group. These possible explanations are made plausible because early intervention improved the primary outcome in the one-third of patients who were at high risk (HR: 0.65; 95% CI: 0.48 to 0.89) and the secondary outcome (composite of death, MI, and refractory ischemia) in the entire cohort of patients (HR: 0.72; 95% CI: 0.58 to 0.89, p = 0.003) (4).
This study by the ACUITY investigators adds to the body of knowledge about how best to care for patients presenting with ACS. Refined adjunctive antithrombotic therapies and, eventually, thrombectomy devices overcome the potential hazard of early PCI in ACS patients. Acute coronary syndrome patients, particularly those with positive troponins and/or dynamic electrocardiographic changes, should be immediately triaged to catheterization laboratory-based diagnosis and treatment.
↵* Editorials published in the Journal of the American College of Cardiology reflect the views of the authors and do not necessarily represent the views of JACC or the American College of Cardiology.
- American College of Cardiology Foundation
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