Friday, January 4, 2019


Written by Pendell Meyers, with edits by Steve Smith

The VERDICT trial was recently published. This is yet another study looking at the optimal timing of cardiac catheterization in the setting of NSTEMI.

Here are the key summary points of this RCT:

Reference: Kofoed et al. Early Versus Standard Care Invasive Examination and Treatment of Patients With Non-ST-Segment Elevation Acute Coronary Syndrome VERDICT Randomized Controlled Trial. Circulation. 2018;138:2741–2750.

Stated hypothesis: “that a strategy of very early invasive coronary angiography (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.”

Multiple sites in Denmark
Inclusion: suspected ACS patients without STEMI criteria, with at least 1 of the following high-risk criteria: (1) ECG changes indicating new ischemia (new ST segment depression, horizontal or down-sloping of at least 0.05 mV in 2 consecutive leads, or T-wave inversion of at least 0.01 mV in 2 leads with prominent R wave or R/S ratio greater than 1); and (2) an increase in coronary markers of ischemia (troponin). There is no comment in the paper about patients with subtle ST elevation, theoretically they could have been included.
Exclusion: “an indication for acute ICA (very high-risk NSTE-ACS, including ongoing ischemia despite intravenous nitroglycerin infusion, hemodynamic or electric instability, acute heart failure, mechanical complication, or cardiac arrest)”

Intervention arms:
“Very early invasive evaluation” Arm: cath within 12 hours
“Standard invasive care” Arm: cath within 48-72 hours

Primary Endpoint: Combination of all-cause death, nonfatal recurrent myocardial infarction, hospital admission for refractory myocardial ischemia, or hospital admission for heart failure

Key Results:
2147 patients randomized
1075 in the “very early invasive” group, who had cath at a median of 4.7 hours after randomization (remember that randomization takes significant time, and in this study they did not state how long after symptoms onset or after presentation this was) 1072 in the “standard invasive care” group, who had cath at a median of 61.6 hours

With 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) greater than 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). Of note, approximately 50% of patients had a GRACE score of at least 140.

Note: GRACE score of 140 correlates to an in-hospital mortality of 3%
Click here for GRACE score risk categories
Example patient with GRACE score of 140:
60 yo M with heart rate 96, systolic BP 120, creatinine 1.2, some ST depression, positive troponin and no evidence of CHF.

My Thoughts:
First of all, remember who these patients are: these are ACS patients who do not meet STEMI criteria but who have either or both of positive troponin and/or “new ST segment depression, horizontal or down sloping 0.05 mV in 2 consecutive leads, or T-wave inversion of at least 0.1 mV in 2 leads with prominent R wave or R/S ratio greater than 1).”  Most importantly, they excluded those with refractory ischemia (refractory to maximal antiplatelet and antithrombotic therapy as well as IV nitroglycerine), hemodynamic or electric instability, acute heart failure, mechanical complication, or cardiac arrest, because emergent angiography is already indicated in such patients.

Example patients who must get emergent cath according to these guidelines:

Case 1: A patient with clinically diagnosed ACS, even without any ECG findings, who gets maximal medical management and still complains of any residual pain (or anginal equivalent) upon 20-30 minute reevaluation.

Case 2: A patient with clinically diagnosed ACS presents with chest pain and has "ischemic ST depression" (in this example, let's assume the provider is not entertaining posterior Occlusion MI for some reason, just "ischemia"). Upon receiving medical therapy, he states that his pain is now gone, or maybe "just a little soreness leftover," however repeat ECGs show persistent ischemic ST depression, equal to that on arrival, even 20 minutes after pain has improved. This patient, even if he is not interpreted to have ongoing symptoms, has definite ECG evidence of ongoing ischemia. He therefore has persistent ischemia refractory to medical management. He must get emergent cath according to our guidelines regardless of his symptomatic improvement.

Case 3: A patient with a "nondiagnostic ECG" and ongoing pain thought to probably be GERD or chest wall pain, but the 2nd or 3rd troponin returns positive. Pain remains ongoing. If this patient has received maximal medical therapy and continues to have pain or rising troponin, the guidelines mandate an emergent cath.

Keep in mind that all patients received aspirin, heparin, and clopidogrel/ticagrelor in addition to the nitroglycerin drip mentioned above (this combination satisfies the ACC/AHA and European definition of "maximal medical therapy", after which continued ischemia by symptoms or ECG findings requires emergent cath). Therefore all these patients were required to become completely pain free AND their ECG findings must have resolved completely, or else they would have been excluded because of ongoing evidence of ischemia.

The most important problem with this study is that 4.7 hours after randomization is not “very early”. Remember, the only patients who could theoretically benefit from earlier rather than later cath would be those who have acute obstructive ACS with resultant decreased flow to the myocardium such that immediate and irreversible infarction is occurring. Ongoing occlusion of a major vessel is the obvious prototypical anatomic cause of this condition, and this is found in 25% of NSTEMIs upon delayed cath. In this situation the timing of benefit of reperfusion must be assumed to be very similar to that of STEMI, in which we all understand that the benefit diminishes sharply with time. No one would wait 4.7 hours to cath a STEMI, because we all know from the FTT data that the benefit is hugely diminished at that point. Nevertheless, studies continue to define "very early" cath differently for STEMI than for NSTEMI, as if an occluded NSTEMI operates on different physiology of infarction as occluded STEMI, and we have no evidence or rationale to support this notion. This appears to be due to the persistent belief in a true dichotomous difference between OMI that meets STEMI criteria and OMI that does not meet these criteria. For the significant percentage of NSTEMI patients who truly have ongoing occlusion or near occlusion without collateral circulation, they must receive reperfusion as soon as possible, much quicker than 4.7 hours, until proven otherwise. For the majority of the NSTEMI patients who do not have an occlusion or ongoing transmural ischemia, the difference between early and delayed cath would be primarily due to repeat occlusion or recurrent ischemia during the waiting period.

To confirm our existing understanding of Occlusion MI, this study yet again confirms the fact that 25% of these “NSTEMIs” did in fact have complete occlusion of a coronary artery upon catheterization. Unfortunately, the authors do not provide us with data on outcomes differences: did the STEMI(-) OMI(+) group have more outcome benefit from "early" reperfusion than the STEMI(-) OMI (-) group? My guess, even though "early" was not truly "early," would be that these patients would have proven to have more benefit. The patients with OMI are the patients we need to identify prospectively, and cath sooner than 4.7 hours. One caveat, however, is that these authors did not expressly state that the occluded artery was the culprit artery (many people have preexisting, chronic total occlusions). Future researchers should be sure to tell readers whether occlusions found at cath are culprit lesions (acute thrombotic occlusion) vs. chronic total occlusions, if possible (sometimes this is difficult to ascertain).

Even if they had truly done emergent angiography (less than 1 hour for example), large numbers would be required to show a benefit because 75% (those with open arteries) probably will have only marginal benefit. I would not be surprised if this study did not show benefit, because they are not performing angiograms on the right subgroup. When you emergently cath a group of patients who do not have any refractory symptoms or refractory ECG evidence of ischemia and have a 75% chance of not having an occlusion, you have a low chance of helping those patients. But if you can select out those with ongoing ischemia, as determined by refractory symptoms or refractory ischemic ECG findings (including those of OMI), then spend your emergent cath resources on that small subset of patients, I believe there will be benefit.  These are the subgroup with the highest risk, and all of these similar NSTEMI trials have confirmed that higher risk subgroups do receive benefit from an “early” strategy, even though most studies haven't really performed "early" cath at all.

Finally, it is interesting that 25% of patients had occlusion and yet supposedly had no ongoing symptoms (they were enrolled, therefore were supposed to not have any ongoing symptoms or else they would be excluded and emergently cathed). Yet, ongoing acute coronary occlusion is uncommonly completely asymptomatic. More commonly, I believe that patients minimize their remaining symptoms, and providers ask leading questions hoping that symptoms are gone - the result is an "asymptomatic" patient on paper. However, there is another important possibility to explain why these "occlusions" were supposedly asymptomatic: Were these occlusions chronic and thus asymptomatic? They did not assess collateral circulation, so maybe these were acute or chronic occlusions with good collaterals and no ongoing ischemia. If so, then those occlusions may not benefit from emergent cath, assuming they don't reocclude during the delay. These questions are unanswerable with the data presented in the study, yet they may help us understand what is happening for these patients. Future research should keep these questions in mind.

Learning Points from Kofoed et al:

All ACS patients with persistent evidence of ischemia (persistent symptoms, ECG findings, or troponin) despite medical management need emergent cath. This is in accordance with all guidelines, and was an exclusion criteria in this study for that reason. Keep this in mind!

4.7 hours is not "very early" when it comes to dying myocardium.

Despite not getting truly early cath, half of the cohort (those with GRACE score at least 140) had benefit.

This study is unable to comment on whether patients with STEMI(-) Occlusion MI have benefit from emergent cath, because that is not the population studied and this subgroup is not commented on.

This study is just the most recent in a long long line of similar literature. Context is everything for understanding this study. See below for an excerpt from the OMI Manifesto which summarizes the existing literature and provides details on each study:


“Haven’t there been RCTs showing no benefit for early vs. delayed intervention for NSTEMI patients? If so, why didn’t the subtle ACOs in these NSTEMI cohorts generate a benefit for the early intervention groups?”

There is a moderately-sized body of literature which has been mistakenly used to claim that there is no difference in outcomes between immediate vs. urgent invasive treatment for NSTEMI, explained in detail below. Even if this were an accurate representation of the literature, it would not disprove the theory that the subgroup of NSTEMI patients with ACO benefit from emergent invasive management. If the percentage of patients with ACO is low in the study population of NSTEMIs, even a large mortality benefit (for those with ACO) will not be observable in a small RCT. If you randomize five patients with ACO as well as 300 without ACO, you may not detect a difference in outcomes even if all five ACO patients were saved by emergent intervention. If you use expert ECG interpretation to successfully select out those few patients with ACO, however, the benefit will be obvious (because acute occlusion is who benefits). There has never been any prospective interventional study using expert ECG interpretation to examine the effects of immediate vs. non-immediate cardiac catheterization. We hope to change this in the future.

Nevertheless, we must inoculate ourselves with the literature concerning immediate vs. urgent invasive treatment for NSTEMI because it is frequently used as an objection to the idea that any subgroup of NSTEMI patients might need emergent intervention. The misconceptions in the following studies generally stem from the fact that “early” intervention was not actually performed emergently, and that NSTEMI patients with ischemia refractory to maximal medical therapy were excluded from the trials (as they already have an indication for emergent [less than 2 hours] angiography according to both the European Society of Cardiology guidelines and the ACC/AHA guidelines (24,25).

Mehta et al. Early versus delayed invasive intervention in acute coronary syndromes. The TIMACS (Timing of Intervention in ACS) Trial. NEJM 2009

3031 NSTEMI patients were randomized to “early” intervention (less than 24 hours) vs. delayed (36 hours or later) intervention. The median time from presentation to coronary angiography was 14 vs. 50 hours in the “early” vs. delayed groups, respectively. Because the “early” intervention was not actually early, the study cannot be used to inform the decision to pursue emergent (generally considered less than 2hrs) invasive intervention on NSTEMI patients, let alone on ACO patients without obvious STE. Unsurprisingly, there was no difference in the rates of death, MI, or stroke in these two groups. Although not stated in the methods, personal communication between the lead author and Dr. Smith revealed that patients with refractory ischemia were (appropriately) excluded from the trial altogether. When effects of early intervention were stratified by GRACE risk score, a significant reduction in the primary outcome (composite of death, MI, or stroke) was found in the group with GRACE score more than 140 (13.9% vs. 21.0%, P=0.006).

Hoedemaker et al. Early Invasive Versus Selective Strategy for Non-ST-Segment Elevation Acute Coronary Syndrome: The ICTUS Trial. JACC 2017
The ICTUS trial randomized 1,200 NSTEMI patients with elevated troponin T to “early invasive” (“within 24 to 48 hours after randomization”) vs. “selectively invasive” groups. There was no difference in 1-year mortality (2.5% in both groups) or spontaneous MI, but there was a 5% absolute increase (15 vs. 10%) in myocardial infarction in the early invasive group which was ascribed to procedure-related MI. At 10-year follow up there was again no statistical difference in death or spontaneous MI (34 vs 29%). Notably, patients were excluded for “an indication for reperfusion therapy, hemodynamic instability or overt congestive heart failure,” which by the current guidelines includes refractory ischemia. Prevalence of angiographic occlusion and detailed ECG analysis are not reported. Although this study has no bearing on any question regarding emergent reperfusion therapy, the 5% absolute increase in peri-procedural MI (NNH=20) does reinforce the significant harms of emergent catheterization for those without benefit (those without ACO).

van't Hof et al. A comparison of two invasive strategies in patients with non-ST elevation acute coronary syndromes: results of the Early or Late Intervention in unStable Angina (ELISA) pilot study. European Heart Journal 2003
220 patients with non-ST elevation ACS were randomized to “early” vs. “late” (median time to angiography 6 vs. 50 hours). There was no difference in clinical outcomes at 30 days follow up. Refractory ischemia was excluded. Although 6 hours is certainly sooner than 24-48, it is still not soon enough to qualify as emergent reperfusion therapy. No detailed ECG analysis performed, and no angiographic occlusion data reported. Remember this important fact: refractory chest pain was excluded. Patients with OMI with persistent occlusion generally have refractory pain; thus, such patients would have been excluded.

Neumann et al. Evaluation of prolonged antithrombotic pretreatment (“cooling-off” strategy) before intervention in patients with unstable coronary syndromes: a randomized controlled trial. The ISAR-COOL Study. JAMA 2003
410 patients with Non-STE ACS but with either ST depression or elevated troponin T levels were randomized to antithrombotic pretreatment for 3-5 days or to early intervention with less than 6hrs of pretreatment. The two groups received catheterization with a median time of 2.4 vs. 86 hours from presentation. All patients received aspirin, clopidogrel, heparin, and tirofiban. There was significantly higher rate of death or “large” MI in the delayed strategy group compared to the early invasive group (11.6% vs. 5.9%, P=0.04). This difference was driven by an excess of 3 deaths and 10 large MIs in the delayed strategy group which all occurred before delayed angiography. Incredibly, the authors' conclusion is spun as the following: “In patients with unstable coronary syndromes, deferral of intervention for prolonged antithrombotic pretreatment does not improve the outcome compared with immediate intervention accompanied by intense antiplatelet treatment.” Stated more appropriately to their opening metaphor, it appears the supposed “cooling-off” period was more of a smoldering burn period, during which the patients’ myocardium was sizzling on the back-burner. No angiographic occlusion data or detailed ECG analysis was reported.

Thiele et al. Optimal timing of invasive angiography in stable non-ST-elevation myocardial infarction: the Leipzig Immediate versus early and late PercutaneouS coronary Intervention triAl in NSTEMI (LIPSIA-NSTEMI Trial). European Heart Journal 2012
201 patients with NSTEMI were randomized to receive immediate (less than 2 hours, median 1.1 hour) catheterization, while 200 patients were randomized to an receive 10-48 hour (median 18.6 hours) catheterization. There was no difference in death or MI within 6 months. Exclusion criteria appropriately featured refractory ischemia. No detailed ECG analysis available, and no angiographic occlusion outcomes available. With a truly short time to catheterization in the immediate group, the most likely explanation for lack of benefit is that the patients with subtle occlusion (who were more likely to have refractory ischemic symptoms) were correctly excluded in the first place.

Montalescot et al. Immediate vs delayed intervention for acute coronary syndromes: a randomized clinical trial. JAMA 2009
352 patients with non-STE ACS, TIMI score 3 or greater, but without refractory ischemia were randomized to receive immediate or next working day intervention (between 8 and 60 hours). Actual average time from randomization to sheath insertion was 70 minutes vs. 21 hours between the two groups. Median peak troponin I values did not differ between the two groups (2.1 vs. 1.7 ng/mL). There was no difference in the secondary endpoint composite of death, MI, or revascularization at 1 month follow up (13.7 vs 10.2%). Prevalence of angiographic occlusion is not available, nor is detailed expert ECG analysis. Again, lack of benefit likely confirms that patients with subtle occlusion were correctly excluded from the study based on refractory symptoms.

Reuter et al. Early invasive strategy in high-risk acute coronary syndrome without ST-segment elevation. The Sisca randomized trial. International Journal of Cardiology 2015
170 patients were enrolled primarily in the pre-hospital setting based on NSTE-ACS and at least one of three ECG findings in at least two contiguous leads: “(1) T-wave inversion of more than 3 mm, (2) a ST segment depression of at least 0.5 mm and/or (3) a transient ST-segment elevation of at least 1 mm.” These patients were randomized to either an early invasive strategy (angiography within 6 hours) or a delayed invasive strategy (angiography within 6 hours not advised but per physician discretion). Notably, because these patients were enrolled pre-hospital, “refractory angina” could not be excluded as the patients had not yet received maximal medical management. The median time from randomization to sheath insertion was 2.8 hours in the early invasive strategy group compared to 20.9 hours in the delayed invasive strategy group.

The primary endpoint (composite outcome including death, MI, or urgent revascularizations at 30 days) was significantly lower for early invasive strategy group (2% vs. 24%, p value less than 0.01). However, closer inspection reveals that this difference was largely driven by 14 patients in the delayed strategy group who received urgent revascularization before the sixth hour after randomization. Twenty one (24%) patients in the delayed invasive strategy group had their randomized strategy overridden by treating physicians due to development of STEMI (n=2), persistent chest pain (n=13), recurrent pain (n=3), arrhythmia (n=2), and undocumented (n=1); 14 of those patients received PCI, which was then counted in the composite 30-day outcome as an urgent revascularization. There was a trend toward reduction in index visit MIs in the early invasive group (1 vs 10 MIs, 1% vs. 12%) which did not reach statistical significance given the very small sample size. Long term mortality was 16% in both groups after 4.1 years median follow up. There was no detailed ECG analysis available, and no angiographic occlusion data is provided.

Milosevic et al. Immediate versus delayed invasive intervention for non-STEMI patients: the RIDDLE-NSTEMI Study. JACC Cardiovascular Intervention. 2016
323 patients without STEMI but with elevated cardiac troponin I and “new ST-segment depression at least 1mV and/or T-wave inversion in at least 2 contiguous leads” were randomized to immediate intervention (less than 2 hours) and delayed intervention groups (2 to 72 hours). Refractory angina was excluded, as well as “posterior MI” (no criteria stated). Median time from randomization to angiography was 1.4 vs. 61.0 hours. The primary endpoint (occurrence of death or new MI at 30-day follow up) was less frequent in the immediate intervention group compared to the delayed intervention group (4.3% vs. 13%, P=0.008). This difference was almost entirely accounted for by an excess of adverse outcomes occurring in the delayed intervention group prior to catheterization (0 deaths and 0 MIs in the immediate intervention group vs. 1 death and 10 MIs in the delayed intervention group before catheterization). At 1 year, all cause death was nonsignificantly lower in the immediate intervention group (4.9 vs. 5.6%), but the significant reduction in MI persisted (3.1% vs. 13.8%, P=0.002), as well as the significant reduction in the composite outcome of death or MI (6.8% vs. 18.8%, P=0.002). No detailed ECG analysis was performed, and the incidence of angiographic occlusion is not reported.

1 comment:

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