This is part of a recurring series examining landmark articles in Emergency Medicine, in the style of ALiEM’s 52 Articles.
Discussing: Mehta et al., NEJM 2005. Routine vs. Selective Invasive Strategies in Patients With Acute Coronary Syndromes. A Collaborative Meta-analysis of Randomized Trials PMID: 15956636
- This 2005 meta-analysis was devised to answer one of medicine’s most stubborn (but important) questions: Is an ‘early invasive’ strategy for Unstable Angina (UA) and Non-ST-Elevation Myocardial Ischemia (NSTEMI) associated with improved outcomes compared to medical therapy alone?
- Yes and no! High-risk patients with positive biomarkers and evidence of ongoing ischemia seem to gain long-term benefit from immediate coronary angiography and revascularization. This benefit appears to outweigh the increased hazard associated with a routine invasive strategy.
- Patients with negative biomarkers and lower risk don’t appear to gain long-term benefit from invasive strategy and therefore the increased hazard of a routine invasive strategy is not justified in this group. Patients with negative biomarkers do just as well with medical therapy alone.
Acute Coronary Syndrome (ACS) comprises a spectrum of illness. Presenting signs, symptoms and clinical findings (elevated troponin, EKG changes) are thought to correlate with the degree and the acuity of ischemia. In theory, patients with more severe illness are thought to benefit from more aggressive therapies – i.e. invasive revascularization – while patients with less severe illness have been thought to derive equal benefit medical therapy alone. To an extent, these suppositions have been proven true: There are clear mortality benefits to emergent PCI for patients with STEMI. However, optimal treatment for patients presenting with unstable angina or NSTEMI remains controversial. Importantly, the goal of revascularization in STEMI is different then in NSTEMI/UA. For STEMI, PCI is intended to restore perfusion by eliminating an occlusive thrombus. In NSTEMI, thrombi typically are not occlusive – thus the focus of PCI is to improve long-term outcomes.
The purpose of this study was to determine whether a routine invasive strategy vs. a selective invasive strategy was more effective in the treatment of ACS. The authors devised a meta-analysis of randomized trials to answer this question.
Interpreting this trial can be confusing because the conclusions seem to shift depending on how you slice it. Mortality was increased during the index visit for those undergoing routine PCI, but this trend equalized over the long run so that there was no significant increase or reduction in mortality for one group or the other. The authors did find a small benefit in the routine invasive group when looking at a composite endpoint including death + nonfatal MI. There was no benefit for the so-called low risk group.
Food for Thought:
- High-risk patients with elevated biomarkers benefited the most from PCI.
- There was no benefit to routine invasive strategy among those with negative biomarkers. (7.7% vs. 8.5%, OR 0.90, 95% CI 0.721.14)
- The meta-analysis reported two other important endpoints – persistent angina and hospitalization. These are ‘patient centered’ outcomes and often get ignored: While doctors care about recurrence of nonfatal MI, patients might care about pain (angina) and pain-in-the-ass (recurrent hospital visits).
Mehta and colleagues performed a rigorous meta-analysis of randomized controlled trials comparing benefits and risks of routine early invasive vs. selective invasive strategies for UA/NSTEMI. The defined ‘routine’ invasive strategy as immediate (< 72 hrs) coronary angiography for all patients with UA or NSTEMI. In contrast, a ‘selective’ invasive strategy was defined as coronary angiography only for those patients with persistent signs or symptoms of ischemia despite pharmacological therapy.
The authors only included randomized controlled trials that they identified through MEDLINE and Cochrane databases (1970 through June 2004). They initially identified 84 articles. Exclusion criteria were fairly rigorous: if allotment was not sufficiently opaque to providers (i.e. if allotment was done by day of the week or some way whereby it would be easy for providers to become un-blinded) or if randomization was performed after PCI, then the trial was excluded. Ultimately, 7 articles were included representing 9208 patients (4608 routine invasive and 4604 selective invasive). After the trials were selected for inclusion two separate reviewers extracted data on outcomes. This data was sent back to the PI of the trial in question to be verified for accuracy and to provide additional data if needed!
- Mortality was significantly increased during the initial hospitalization for the routine invasive group (1.8% vs. 1.1%)
- During the follow-up period (avg. 17 months), a routine strategy was associated with significantly decreased mortality rate (5.2% vs. 7.3% [OR] 0.76, 95% CI 0.62-0.94).
- Taken together – i.e. from randomization to the end of follow-up – a routine invasive strategy was associated with a NON-SIGNIFICANT reduction in mortality (6.7% vs. 7.9% [OR] 0.92, 95% CI 0.77-1.09). Yup, you read that right, no difference in mortality. However, routine invasive was associated with a significant reduction in nonfatal MI (7.3% vs. 9.4%, OR 0.75, 95% CI 0.0.65-0.88).
- The authors put this altogether in a so-called composite endpoint (death + MI) and found a significant reduction in the composite end-point for routine strategy (12.2% vs. 14.4%, OR 0.82, 95% CI 0.72-0.93).
Level of Evidence:
This metanalysis meets 1A Level of Evidence.
This meta-analysis is only as good as those therapies it was designed to assess; One would hope that the more widespread use of aggressive antiplatelet therapy along with PCI and the availability of drug-eluting stents since the Mehta’s metanalysis would correlate with improvement for patients in the routine invasive group. This has not yet been born out.
Additionally, a critical limitation to this metanalysis is that patient’s with negative biomarkers (UA) were randomized along with NSTEMI patients. What if only those with positive biomarkers (NSTEMI) were enrolled? Wouldn’t routine invasive strategy be more beneficial? According to the results of the ICTUS trial, which was published in 2005 just after Mehta’s metanalysis, the answer is a disappointing ‘no’. The ICTUS authors randomized 1200 NSTEMI patients to routine invasive vs. selective. 98% of the routine patients vs. 53% of selective group underwent angiography. 76% vs. 40% of these patients were revascularized at 23 hours vs. 11.8 days respectively. In this trial there was no difference in the composite endpoint (death, MI, recurrent angina) at 5 years!
- De Winter RJ, et al. NEJM 2005: Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) Investigators. Early invasive versus selectively invasive management for acute coronary syndromes. PMID: 16162880
- Fox KA, et al. Lancet 2005. 5-year outcome of an interventional strategy in non-ST-elevation acute coronary syndrome: the British Heart Foundation RITA 3 randomized trial. PMID: 16154018
- Lagerqvist B., et al. Lancet 2006. Fast Revascularization during InStability in Coronary artery disease (FRISC II) Investigators: 5-year outcomes in the FRISC II randomized trial of an invasive versus a non-invasive strategy in non-ST-elevation acute coronary syndrome: a follow-up study. PMID: 16980115
- Kerensky RA, et al. J Am Coll Cardiol 2002. Revisiting the culprit lesion in nonQwave myocardial infarction. Results from the VANQWISH trial angiographic core laboratory PMID: 11985907
- Wong GC, et al. Circulation 2002. Elevations in troponin T and I are associated with abnormal tissue level perfusion: a TACTICSTIMI 18 sub-study. Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative StrategyThrombolysis in Myocardial Infarction. PMID: 12105159
Mehta et al., NEJM 2005. Routine vs. Selective Invasive Strategies in Patients With Acute Coronary Syndromes. A Collaborative Meta-analysis of Randomized Trials PMID: 15956636
Dr. Naomi George