Early Versus Standard Care Invasive Examination and Treatment of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome: VERDICT Randomized Controlled Trial
This article has been corrected.
VIEW CORRECTIONAbstract
Background:
The optimal timing of invasive coronary angiography (ICA) and revascularization in patients with non-ST-segment elevation acute coronary syndrome is not well defined. We tested the hypothesis that a strategy of very early ICA and possible revascularization within 12 hours of diagnosis is superior to an invasive strategy performed within 48 to 72 hours in terms of clinical outcomes.
Methods:
Patients admitted with clinical suspicion of non-ST-segment elevation acute coronary syndrome in the Capital Region of Copenhagen, Denmark, were screened for inclusion in the VERDICT trial (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography) (ClinicalTrials.gov NCT02061891). Patients with ECG changes indicating new ischemia or elevated troponin, in whom ICA was clinically indicated and deemed logistically feasible within 12 hours, were randomized 1:1 to ICA within 12 hours or standard invasive care within 48 to 72 hours. The primary end point was a combination of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or hospital admission for heart failure.
Results:
A total of 2147 patients were randomized; 1075 patients allocated to very early invasive evaluation had ICA performed at a median of 4.7 hours after randomization, whereas 1072 patients assigned to standard invasive care had ICA performed 61.6 hours after randomization. Among patients with significant coronary artery disease identified by ICA, coronary revascularization was performed in 88.4% (very early ICA) and 83.1% (standard invasive care). Within a median follow-up time of 4.3 (interquartile range, 4.1–4.4) years, the primary end point occurred in 296 (27.5%) of participants in the very early ICA group and 316 (29.5%) in the standard care group (hazard ratio, 0.92; 95% CI, 0.78–1.08). Among patients with a GRACE risk score (Global Registry of Acute Coronary Events) >140, a very early invasive treatment strategy improved the primary outcome compared with the standard invasive treatment (hazard ratio, 0.81; 95% CI, 0.67–1.01; P value for interaction=0.023).
Conclusions:
A strategy of very early invasive coronary evaluation does not improve overall long-term clinical outcome compared with an invasive strategy conducted within 2 to 3 days in patients with non-ST-segment elevation acute coronary syndrome. However, in patients with the highest risk, very early invasive therapy improves long-term outcomes.
Clinical Trial Registration:
URL: https://www.clinicaltrials.gov. Unique identifier: NCT02061891.
Clinical Perspective
What Is New?
•
VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography) is a large-scale randomized controlled trial evaluating the value of a very early invasive strategy conducted within 12 hours of diagnosis on long-term clinical outcome in patients with non-ST-segment elevation acute coronary syndrome.
•
An invasive strategy performed within 4.7 hours after diagnosis was not associated with improved outcome compared to an invasive strategy conducted within 2 to 3 days.
•
However, in the prespecified subgroup of patients with a GRACE risk score (Global Registry of Acute Coronary Events) >140, a very early invasive treatment strategy improved outcome compared with a standard invasive treatment strategy.
What Are the Clinical Implications?
•
Very early coronary evaluation and intervention can safely be performed in patients with non-ST-elevation myocardial infarction with high-risk clinical features, including dynamic ECG changes and cardiac troponin elevation.
•
The findings of the VERDICT trial do not support an advantage of routine invasive strategy performed within <12 hours in all-comer patients compared with a more delayed invasive approach.
•
In highest risk patients with a GRACE risk score >140 a very early invasive strategy improved clinical outcomes, a finding consistent with results from the TIMACS (Timing of Intervention in Acute Coronary Syndromes) trial.
Introduction
Editorial, see p 2751
Clinical outcomes in patients with non-ST segment elevation acute coronary syndrome (NSTE-ACS) have progressively improved within the last 2 decades with a trend toward a smaller improvement in recent years.1 An important contemporary challenge in the management of patients with NSTE-ACS is to define the optimal timing of invasive coronary angiography (ICA) and revascularization. Several large-scale trials have explored the impact of timing on mainly short-term clinical outcomes to further improve clinical outcome.2–8 The coronary pathology found in patients with acute coronary syndrome varies substantially, ranging from structurally normal vessels, nonobstructive atherosclerotic disease to severe multivessel obstructive, including occlusive coronary artery disease (CAD). The relative importance between antithrombotic and anti-inflammatory medical therapy and coronary revascularization, specifically in terms of timing to achieve the highest clinical benefit of treatment, is not clearly defined.9 An early invasive strategy conducted within 12 hours of diagnosis could be helpful to identify patients with imminent or established vessel closure, in whom prompt revascularization might result in salvage of ischemic myocardium.10 In contrast, a prolonged antithrombotic and lipid-lowering pretreatment could stabilize the coronary plaques and thus optimize conditions for a subsequent revascularization.
Current guidelines from the American Heart Association and the European Society of Cardiology for the treatment of patients with NSTE-ACS recommend an early invasive strategy within 24 hours of hospital admission, specifically in patients with ≥1 high-risk criterion (eg, abnormal cardiac troponin compatible with myocardial infarction, dynamic ECG changes, or a GRACE risk score >140).11,12 The recommendation to conduct ICA within 24 hours of hospital admission is logistically demanding for many healthcare systems, requiring either an onsite catheterization laboratory or a fast-responding interhospital patient transportation service. The scientific evidence base specifically supporting the <24-hour invasive recommendation is primarily provided by the TIMACS trial (Timing of Intervention in Acute Coronary Syndromes), which investigated 3031 patients with an acute coronary syndrome >60 years of age.5 In this trial, invasive examination conducted within 14 hours was not advantageous in terms of the primary end point of short-term (6 months) clinical outcome (death, myocardial infarction, or stroke), except for patients with a GRACE risk score (Global Registry of Acute Coronary Events) >140. In contrast, a significant beneficial effect on the secondary end point of refractory myocardial ischemia was observed. It is unknown to what extent patients might benefit from an invasive strategy conducted even earlier than 14 hours.
We therefore conducted the VERDICT trial in all-comer patients presenting with acute coronary syndrome and ≥1 high-risk criterion (eg, troponin rise or ischemia in ECG). We tested the hypothesis that a strategy of very early ICA and revascularization if needed conducted within 12 hours from the time point of the diagnosis is superior to a standard care invasive strategy, which implies ICA within 48 to 72 hours in terms of long-term clinical outcome.
Methods
Study Design
The VERDICT trial was a prospective, multicenter, open label, parallel group, randomized controlled trial assessing the optimal timing of coronary invasive management strategy in terms of long-term clinical outcome in patients with NSTE-ACS. Patients were randomized 1:1 to either an early invasive coronary angiography and possible revascularization within 12 hours from time of diagnosis or a standard care invasive strategy performed within 48 to 72 hours. The trial was conducted as a pragmatic clinical study embedded in routine clinical practice at the participating hospitals. Clinical outcomes were assessed when all patients had been followed for ≥18 months after randomization. The VERDICT trial also included a postrandomization, observational study, in which participants underwent coronary computerized tomography angiography before invasive examination when logistically possible. Coronary computerized tomography angiography findings remained blinded throughout the entire study period, and the results are not included in this report. The study was approved by the Danish National Committee on Health Research Ethics (no. H-4-2010-039) and the Danish Data Protection Agency and registered at ClinicalTrials.gov NCT02061891. Written informed consent was obtained from all participants. None of the funders has taken any part in study design, study conduct, data analysis, data interpretation, or writing of this article. The corresponding author has had full access to all data of the study and has the final responsibility for the decision to submit the report for publication. The data that support the findings of this study are available from the corresponding author on reasonable request.
Participants
Patients from 9 hospitals in the Capital Region of Copenhagen, Denmark, admitted with chest pain and clinical suspicion of acute coronary syndrome were screened for inclusion. Patients in whom ICA was deemed clinically indicated and logistically possible within 12 hours from time of diagnosis were offered participation in the study according to inclusion and exclusion criteria. Inclusion criteria were ≥18 years of age, clinical suspicion of acute coronary syndrome, and ≥1 of the following high-risk criteria: (1) ECG changes indicating new ischemia (new ST segment depression, horizontal or down sloping ≥0.05 mV in 2 consecutive leads, or T-wave inversion >0.01 mV in 2 leads with prominent R wave or R/S ratio >1); and (2) an increase in coronary markers of ischemia (troponin). Exclusion criteria were pregnancy, patient inability to understand trial information, an indication for acute ICA (very high-risk NSTE-ACS,12 including ongoing ischemia despite intravenous nitroglycerin infusion, hemodynamic or electric instability, acute heart failure, mechanical complication, or cardiac arrest), expected survival <1 year, and known intolerance to platelet inhibitors, heparin, or x-ray contrast, which could not be remedied medically. All included patients provided written informed consent.
Randomization and Clinical Management Strategy
Patients accepting participation were prospectively randomized 1:1 to a very early or a standard invasive treatment strategy. Randomization was performed centrally by study personnel at the 2 invasive centers at Rigshopitalet and Gentofte University Hospitals using an electronic case report form by means of permuted-block randomization and stratified by including site. All patients randomized to the very early invasive strategy were transferred immediately from the referring hospital to the invasive center for ICA and possible revascularization, except during the night, when patient transfer was postponed to the early morning for logistical reasons. Patients randomized to a deferred invasive strategy were transferred within 48 to 72 hours to the invasive center.
Procedures
Medical Treatment
At time of hospitalization and before randomization, all patients received oral β-blockers, statins, a loading dose of either clopidogrel 600 mg or ticagrelor 180 mg according to local practice, aspirin 300 mg, and fondaparinux 2.5 mg administered subcutaneously daily unless contraindicated.
Coronary Angiography and Revascularization
ICA was performed according to guidelines and clinical practice at the individual invasive center.
Procedural diagnostic methods, procedural medication, and coronary revascularization were performed at the discretion of the interventional cardiologist, which in some patients included staged invasive procedures. Patients undergoing percutaneous coronary intervention (PCI) received unfractionated heparin to obtain an activated clotting time between 250 and 300 seconds. Any addition of bivalirudin or glycoprotein IIB/IIIA inhibitors was at the discretion of the operator. Complete revascularization was encouraged but not mandatory. Patients with a coronary anatomy not suited for partial or complete revascularization by PCI were presented at the heart team conference intending to perform revascularization by coronary bypass graft surgery (CABG) within 1 to 2 weeks.
Study Outcomes
The primary end point was a combination of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or hospital admission for heart failure. Secondary end points were invasive procedure complications during index hospitalization (procedure related death, bleeding by the BARC criteria13 [Bleeding Academic Research Consortium], procedure-related nonfatal acute myocardial infarction, stroke, or transient ischemic attack) in addition to the occurrence of each of the following events at any time after randomization: death, nonfatal acute myocardial infarction, admission for refractory myocardial ischemia, repeat coronary revascularization, or hospital admission for heart failure. For end point definitions, see online-only Data Supplement. All end points were recorded by review of patients’ electronic and hard copy medical files and adjudicated by an event committee blinded to management strategy allocation.
Statistical Analyses
The primary hypothesis of the study was that very early invasive evaluation and possible coronary revascularization would reduce the primary outcome by ≥25%. Power calculations were conducted based on previous studies in patients with NSTE-ACS, in whom the expected event rate of the primary end point was 15% within 1 year and 50% at 4 years of the primary combined end point. The trial was event-driven. To demonstrate a relative risk reduction of 25% with a power of 80%, we estimated that 711 patients in each group would need to be included within a 6-year period, with a minimum follow-up of 1 year, to accrue ≥375 primary events. Inclusion was stopped in June 2016 (at which time point >2100 patients were included) and >400 events had occurred.
Descriptive statistics were summarized using median and quartiles for continuous variables and number/percentages for discrete variables. Time-to-event outcomes were presented as cumulative events (Kaplan–Meier estimates for end points including death and the Aalen–Johansen method for other end points). Comparison was with the log-rank test for events including death and Gray’s test for end points with a competing risk.14 For all time-to-event outcomes, univariable Cox regression was used to derive a hazard ratio and a CI. Presence or absence of hospital complications were presented as percentages and compared with the χ2 test. Analysis of prespecified subgroups used univariable Cox regression and comparisons were tests for interaction. The prespecified subgroups were previous myocardial infarction, previous PCI, previous CABG, known heart failure, known valvular heart disease, GRACE risk score ≤140 versus >140,15 troponin (normal versus increased [>URL]), pathological ST-depression or T-wave inversion on ECG, Killip class (>1), estimated glomerular filtration rate (>45, 45–30, <30 mL/min/1.73m16), anemia (Hgb <8.3 mmol/L men, <7.3 mmol/L women at hospitalization), and atrial fibrillation. The subgroups by Killip Class and glomerular filtration were omitted from presentation because of few patients with poor renal function and with Killip class >1. Statistical analyses were conducted with R version 3.5.1.16
Results
From November 2010 to June 2016, 2147 patients met inclusion criteria and consented to be randomized in the VERDICT trial. Patients in allocated treatment strategy groups were similar regarding age, sex, medical history, previous coronary revascularization procedures, and NSTE-ACS risk criteria (Table 1). Among patients allocated to a very early invasive strategy, 33 patients (3.1%) did not undergo ICA compared with 66 patients (6.2%) in the standard invasive strategy group (P<0.001) (Table 2). The reason was that more patients in the standard invasive strategy group had ICA canceled by the treating physician at the referring hospital (Figure 1). In the very early invasive strategy group, 1042 patients had ICA performed a median of 4.7 (interquartile range, 3.0–12.2) hours after randomization, whereas 1006 patients assigned to standard care invasive strategy had ICA performed after 61.6 (interquartile range, 39.4–87.8) hours. Procedural and angiographic findings are reported in Table 2. Procedural times were slightly longer and radiation doses slightly higher in the standard strategy group compared with corresponding values of the very early invasive group. Slightly more patients in the early strategy group underwent PCI compared with the standard strategy group (Table 3).
| Variable | Very Early (n=1075) | Standard (n=1072) | P Value |
|---|---|---|---|
| Male sex, n (%) | 716 (66.6) | 696 (64.9) | 0.43 |
| Age in years, mean (SD) | 63.6 (12.1) | 63.6 (12.5) | 0.89 |
| Body mass index, kg/m2, mean (SD) | 26.9 (4.7) | 27.2 (4.8) | 0.19 |
| Prior smoker, n (%) | 403 (37.5) | 407 (38.0) | 0.67 |
| Current smoker, n (%) | 342 (31.8) | 323 (30.1) | 0.88 |
| Diabetes mellitus, n (%) | 158 (14.7) | 173 (16.1) | 0.38 |
| Hypertension, n (%) | 543 (50.5) | 578 (53.9) | 0.12 |
| Obstructive lung disease, n (%) | 175 (16.3) | 164 (15.3) | 0.57 |
| Renal disease, n (%) | 95 (8.8) | 103 (9.6) | 0.58 |
| Estimated glomerular filtration rate, ml/min per 1.73 m2 (SD) | 90.5 (23.7) | 91.2 (23.7) | 0.49 |
| Previous stroke, n (%) | 94 (8.7) | 82 (7.6) | 0.39 |
| History of cardiovascular disease | 302 (28.1) | 305 (28.5) | 0.89 |
| Known valve disease, n (%) | 35 (3.3) | 53 (4.9) | 0.06 |
| Previous acute myocardial infarction, n (%) | 186 (17.3) | 186 (17.4) | 1.00 |
| Previous percutaneous coronary intervention, n (%) | 151 (14.0) | 163 (15.2) | 0.48 |
| Previous coronary artery bypass grafting, n (%) | 57 (5.3) | 57 (5.3) | 1.00 |
| Global Registry of Acute Coronary Events risk score | |||
| Mean (SD) | 141.3 (29.8) | 140.8 (31.4) | 0.72 |
| >140, n (%) | 520 (49.3) | 505 (48.7) | 0.78 |
| ECG with new ischemia, n (%) | 413 (38.9) | 412 (39.2) | 0.94 |
| Elevated troponin, n (%) | 871 (81.2) | 847 (79.2) | 0.26 |
| Variable | Very Early (n=1075) | Standard (n=1072) | P value |
|---|---|---|---|
| Procedural details | |||
| Coronary angiography, n (%) | 1042 (96.9) | 1006 (93.8) | 0.0009 |
| Femoral access, n (%) | 898 (83.5) | 857 (79.9) | 0.15 |
| Median angiography time, min (interquartile range) | 10.0 (7.0 -18.0) | 13.0 (9.0- 20.0) | 0.0005 |
| Radiation (mSv), median (interquartile range) | 2.3 (1.6–4.1) | 2.7 (1.8–5.4) | 0.008 |
| Angiographic characteristics | |||
| No coronary stenosis, n (%) | 311 (29.8) | 302 (30.0) | 0.97 |
| Left main coronary artery, 1,2,3-Vd, n (%) | 0.66 | ||
| Left main coronary artery stenosis | 70 (6.7) | 58 (5.8) | |
| 1-Vd | 351 (33.7) | 342 (34.0) | |
| 2-Vd | 174 (16.7) | 159 (15.8) | |
| 3-Vd | 117 (11.2) | 131 (13.0) | 0 |
| ≥1 Occluded coronary artery, n (%) | 277 (26.6) | 249 (24.8) | 0.36 |
| Left anterior descending artery stenosis, n (%) | 480 (46.1) | 456 (45.3) | 0.77 |
| Left circumflex artery stenosis, n (%) | 345 (33.1) | 333 (33.1) | 1.00 |
| Right coronary artery stenosis, n (%) | 376 (36.1) | 378 (37.6) | 0.51 |
mSv indicates mili Sievert; and VD, vessel disease.
| Variable | Very Early (n=1075) | Standard (n=1072) | P Value |
|---|---|---|---|
| Percutaneous coronary intervention performed, n (%) | 498 (46.3) | 442 (41.2) | 0.019 |
| ≥1 Drug-eluting stent | 425 (85.3) | 383 (86.7) | 0.62 |
| ≥1 Bare metal stent | 28 (5.6) | 19 (4.3) | 0.43 |
| Balloon angioplasty alone | 35 (7.0) | 28 (6.3) | 0.76 |
| Staged percutaneous coronary intervention, n (%) | 8 (0.7) | 8 (0.7) | 1.00 |
| Complete revascularization by percutaneous coronary intervention, n (%) | 379 (76.1) | 347 (78.5) | 0.05 |
| Number of treated lesions, n (%) | 0.65 | ||
| 1 | 385 (77.3) | 354 (80.1) | |
| 2 | 85 (17.1) | 71 (16.1) | |
| 3 | 21 (4.2) | 13 (2.9) | |
| ≥4 | 5 (1.0) | 2 (0.5) | |
| Number of stents, n (%) | 0.48 | ||
| 0 | 46 (9.2) | 37 (8.4) | |
| 1 | 298 (59.8) | 286 (64.7) | |
| 2 | 111 (22.3) | 94 (21.3) | |
| ≥3 | 42 (16.0) | 25 (5.7) | |
| Coronary artery bypass grafting, n (%) | 132 (12.2) | 132 (12.3) | 1.00 |
| Antiplatelet and antithrombotic medication at time of discharge | |||
| Aspirin, n (%) | 878 (81.7) | 891(83.1) | 0.99 |
| Ticagrelor, n (%) | 500 (46.5) | 500 (46.6) | 1.00 |
| Clopidogrel, n (%) | 228 (21.2) | 236 (22.0) | 0.97 |
| Prasugrel, n (%) | 22 (2.0) | 17 (1.6) | 0.42 |
| Warfarin/direct oral anticoagulant, n (%) | 78 (7.2) | 70 (6.5) | 0.90 |
The median follow-up time after randomization of the patients was 4.3 (interquartile range 4.1–4.4) years. There was no significant difference in the primary composite end point of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or hospital admission for heart failure between the very early invasive and standard invasive groups (27.5% versus 29.5%; hazard ratio, 0.92; 95% CI, 0.78–1.08; P=0.29) (Table 4, Figure 2).
| Variable | Very Early (n=1075) | Standard (n=1072) | Hazard Ratio (95% CI) | P Value |
|---|---|---|---|---|
| Primary end point | ||||
| All-cause death | 296 (27.5) | 316 (29.5) | 0.92 (0.78–1.08) | 0.29 |
| Nonfatal acute myocardial infarction | ||||
| Hospital admission for refractory myocardial ischemia | ||||
| Hospital admission for heart failure | ||||
| Secondary end points | ||||
| Nonfatal acute myocardial infarction | 90 (8.4) | 120 (11.2) | 0.73 (0.56–0.96) | 0.025 |
| Refractory ischemia | 64 (6.0) | 49 (4.6) | 1.32 (0.91–1.91) | 0.14 |
| Heart failure | 99 (9.2) | 126 (11.8) | 0.78 (0.60–1.01) | 0.06 |
| Death | 131 (12.2) | 135 (12.6) | 0.97 (0.76–1.23) | 0.96 |
| Repeat coronary revascularization | 86 (8.0) | 70 (6.5) | 1.24 (0.91–1.70) | 0.18 |
| Invasive procedural complications* | ||||
| Cardiac arrest | 3 (0.3) | 4 (0.4) | — | 0.99 |
| Bleeding | 19 (1.8) | 19 (1.8) | — | 1.0 |
| Stroke/transient ischemia attack | 6 (0.6) | 4 (0.4) | — | 0.75 |
| Nonfatal acute myocardial infarction | 1 (0.1) | 5 (0.5) | — | 0.21 |
*
Procedural complications were recorded as binary data, and P values are for differences assessed with chi-square test.
Analysis of the primary end point in prespecified patient subgroups is given in Figure 3. No significant difference was noted between the 2 treatment strategies for the primary end point across subgroups, except among patients with a GRACE risk score >140. In this subgroup, a very early invasive treatment strategy improved the primary outcome compared with a standard invasive treatment strategy (hazard ratio, 0.81; 95% CI, 0.67 to 1.01; P for interaction=0.023).
Secondary end points are reported in Table 4 and Figure 4. Procedural complications during the index hospitalization were similar in the 2 treatment strategy groups. Except for nonfatal acute myocardial infarction, all long-term secondary end points were not significantly different between the 2 treatment strategy groups. At 15 days after randomization, no difference in nonfatal acute myocardial infarction was observed between treatment strategy groups. However, over the duration of follow-up, a very early invasive evaluation was associated with a significantly reduced risk of nonfatal acute myocardial infarction compared with standard care invasive strategy (8.4% versus 11.2%; hazard ratio, 0.73; 95% CI, 0.56–0.96; P=0.025) (Figure 4).
Discussion
In the VERDICT trial, we found that a strategy of routine very early invasive coronary evaluation and revascularization performed a median of 4.7 hours after time of diagnosis did not improve overall long-term clinical outcomes compared with an invasive strategy conducted within 2 to 3 days (median 61.6 hours) among patients presenting with NSTE-ACS. The rate of periprocedural complications was low and similar in the 2 treatment strategy groups. Our trial included patients presenting with either dynamic ECG changes or cardiac troponin elevation, corresponding to clinical high-risk criteria as defined by current guidelines.11,12 Evidently, very early coronary evaluation and intervention may be performed safely but appears to offer no advantage in terms of overall long-term morbidity and mortality in patients with clinical features. However, among the highest risk patients, defined by a GRACE score >140, outcomes were improved with very early invasive therapy.
Early invasive coronary evaluation was conducted much earlier in our trial than in the TIMACS trial5 (median 4.6 hours in VERDICT versus 14 hours in TIMACS), and the standard invasive strategy was conducted somewhat later (median 61.6 hours in VERDICT versus 50 hours in TIMACS). If an early invasive strategy is truly better than a standard invasive strategy, it is reasonable to hypothesize that a beneficial effect on outcomes would be more likely to be detected in the current trial than in TIMACS because the time difference between the 2 strategy groups was considerably larger in the current trial. Moreover, although the follow-up duration was longer in the current trial, we did not observe a difference between the 2 strategy groups for the primary composite end point.
The primary composite end point of the VERDICT trial was defined to detect potential clinical benefits of early myocardial salvage, including death, nonfatal myocardial infarction, refractory ischemia, and heart failure. Thus, our study does not support the hypothesis that prompt coronary revascularization to salvage ischemic jeopardized myocardium is a major determinant of clinical outcomes in unselected patients with NSTE-ACS. Overall, although the VERDICT and TIMACS trials have differences in sample size, timing of invasive strategies, components of the primary composite end point, and duration of clinical follow-up, the overall conclusions of the 2 trials appear rather similar. As in the TIMACS trial, we did not observe any difference in all-cause mortality in the VERDICT trial with a very early invasive strategy. This finding is consistent with a recent meta-analysis that included 5324 patients from 8 previous trials17 and with current guidelines.11,12 Nevertheless, it is noteworthy that both the TIMACS and VERDICT trials found that the subgroup of patients with a GRACE risk score >140 had improved outcome when treated with a very early invasive strategy.2–8,17 These consistent observations support an individualized approach to timing of invasive therapy in NSTE-ACS, in which the highest risk patients are considered for very early intervention in the absence of contraindications
Routine ICA in the treatment of patients with NSTE-ACS has been reported to be associated with a significant reduction in recurrent acute myocardial infarction, refractory angina pectoris, rehospitalization, and a trend toward a reduction in cardiovascular death compared with an individualized, selective invasive strategy.18,19 Still, an important caveat of a routine invasive strategy is an increased risk of bleeding as a consequence of concurrent antithrombotic medical therapy.19 The primary mechanism by which routine ICA is thought to improve clinical outcome in patients with NSTE-ACS is the identification of hemodynamically significant stenosis. Revascularization of these lesions relieves ischemia in addition to avoiding vessel closure at the location of unstable plaques. Furthermore, by ruling out epicardial coronary disease, an invasive investigation can lead to cessation of unnecessary antithrombotic medications and thus prevent potential side effects and complications such as bleeding. The proportion of patients with nonsignificant CAD presenting with NSTE-ACS in previous trials has been reported to vary considerably from 0% to 30% (the VERDICT and TIMACS cohorts).17 This broad range most likely reflects differences of inclusion criteria and local clinical practice. In the VERDICT cohort, we found that approximately two thirds of the patients had significant CAD, one quarter of the patients had ≥1 occluded coronary artery, and >70% of patients with CAD underwent complete coronary revascularization with either PCI or CABG. Additionally, the procedural risk of bleeding was low in both strategy groups. A priori, it appears conceivable that any suggested benefit of an invasive strategy in terms of improved clinical outcomes would be more prominently related to the extent, severity, and timing of revascularization. In patients with an elevated GRACE risk score >140, we found that a very early invasive treatment strategy resulted in improved clinical outcomes compared with a standard invasive treatment strategy. Recently it was reported that a GRACE risk score >140 is a significant predictor of high-risk CAD defined as left main stenosis >50%, proximal left anterior descending artery lesion >70%, or 2- to 3-vessel disease involving the left anterior descending artery.20 It could therefore be speculated that the improved outcome observed in VERDICT patients with a high GRACE risk score allocated to a very early invasive strategy is explained by a more timely revascularization of severe CAD. This concept is a matter of future analyses of our data and will include the recorded coronary computerized tomography angiography data. As defined in the VERDICT trial, research protocol coronary computerized tomography angiography conducted before ICA might offer a means for very early identification of high-risk CAD in need of revascularization. It is interesting to note that a similar concept is currently being evaluated in the randomized controlled trial RAPID-CTCA currently being conducted in the United Kingdom.21
A very early invasive strategy was associated with a small (2.8%) yet significant reduction in nonfatal acute myocardial infarction compared with a standard invasive strategy. This finding is hypothesis-generating and must be viewed within the context of an overall neutral trial for the primary end point. This finding is also discordant from a recent meta-analysis on the optimal timing of a coronary invasive strategy that included >5000 patients, where no impact on recurrent, nonfatal acute myocardial infarction was detected with a very early invasive strategy.22
Some limitations of the VERDICT trial should be considered. First, the trial was conducted as a pragmatic clinical study embedded in routine clinical practice at the participating hospitals, and it was therefore not logistically possibly to record all patients assessed for eligibility during the enrollment of patients in the trial. However, clinical characteristics and coronary angiography findings in the study cohort enrolled are comparable to patients included in earlier studies on timing of invasive treatment strategy in NSTE-ACS.17 We therefore believe that the results of the VERDICT trial can be extrapolated to the general population of patients with NSTE-ACS. Second, slightly more patients in the standard invasive strategy group had ICA cancelled compared with the very early invasive strategy group, and thus a potential clinical advantage of a standard invasive strategy compared with the very early strategy might be missed. However, this would further bias the results toward the null. Third, ≈12% of patients were referred for CABG performed about 2 weeks after randomization. These patients could thus have limited our ability to show a beneficial effect in the very early invasive group. However, the proportion of patients referred for CABG was similar in the 2 groups. Last, although we prespecified several subgroups to be analyzed with regard to the primary end point, the study was not powered to assess the potential differential impact of a very early invasive strategy in these subgroups.
Conclusions
In conclusion, a strategy of invasive coronary evaluation within 4.7 hours after time of diagnosis does not improve the overall long-term clinical outcomes compared with an invasive strategy conducted within 2 to 3 days in patients with NSTE-ACS.
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© 2018 American Heart Association, Inc.
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Received: 1 August 2018
Accepted: 21 August 2018
Published online: 28 August 2018
Published in print: 11 December 2018
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Dr Kofoed reports grants from the Danish Research Foundation during the conduct of the study, in addition to grants from the Research Council of Rigshospitalet, AP Møller og hustru Chastine McKinney Møllers Fond, the Danish Heart Foundation, and Canon Medical Corporation outside the submitted work. Dr Kober reports grants from the Danish Research Foundation during the conduct of the study. Dr Torp-Pedersen reports grants from Bayer outside the submitted work. Dr Linde reports grants from the Danish Research Foundation and the Research Council of Rigshospitalet during the conduct of the study. Dr Abdulla reports personal fees from Novartis Healthcare outside the submitted work. Dr Engstrøm reports personal fees from Abbott, Astra Zeneca, Bayer, Boston Scientific, and Novo outside the submitted work. The other authors report no conflicts of interest.
Sources of Funding
This study was funded by the Danish Agency for Science, Technology, and Innovation and the Danish Council for Strategic Research (grant no. 09–066994) and the Research Council of Rigshopitalet. None of the funding bodies has taken any part in study design, study conduct, or data analysis and has had no role in writing the article.
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