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Hoenig MR, Aroney CN, Scott IA. Early invasive versus conservative strategies for unstable angina and non-ST elevation myocardial infarction in the stent era. Cochrane Database of Systematic Reviews 2010, Issue 3. Art. No.: CD004815

Efficacy Endpoints

Death, myocardial infarction (heart attack), angina (chest pain)

Harm Endpoints

Bleeding complications, peri-procedural MI (heart attack), death

Narrative

Reperfusion therapy for major heart attacks (i.e. ST-elevation myocardial infarction) is beneficial1. Controversy exists regarding the balance of harms and benefits of revascularization therapy for other types of acute coronary syndromes. This Cochrane review aggregates the best available data from five trials of 7818 subjects randomized to either undergo immediate invasive management with coronary catheterization and stent placement (as necessary) or else be treated with medications and no immediate invasive strategy.

The overall results were mixed. Patients included in the studies were predominantly those with biomarker evidence of ischemia, and most often with electrocardiographic changes indicating ischemia as well (though not ST-elevation). Ultimately, deaths were statistically unaffected, although there appeared to be what the authors refer to as a ‘trend’ toward increased mortality in the group managed with an early invasive strategy (a statistically nonsignificant difference of 0.5% in deaths, or roughly 1 in every 200 subjects). Heart attacks were reduced by 2% over the next year, but increased by 3% in the peri-procedural period. Refractory angina (ongoing chest pain) was present in 22% of those randomized to an invasive strategy and 34% of those treated conservatively, and was thus reduced.

Harms of the procedure were apparent, both in the heart attack rate noted above and also in the rate of bleeding events, although these were typically minor and usually involved the site of arterial puncture for the procedure.

Caveats

The cohort here includes a preponderance of patients suffering overt coronary ischemia including positive serum biomarkers. When the authors analyzed only studies of patients without positive biomarkers there was a statistically significant increase in deaths (RR 1.71, NNT=200). Indeed, the single study in the review designed and powered to test the question of whether benefits are confined to biomarker-positive patients2 found that while death was not reduced overall, MI was slightly reduced (2.1%), However, MIs were reduced only in the subgroup with positive biomarkers. These results suggest that the reduction in heart attacks is likely to be confined to those with a positive biomarker, while there is an increase in deaths among those who are biomarker negative. Furthermore, the Cochrane authors note that when confining their analysis to studies in which 100% of subjects had biomarker elevations they were still unable to detect a mortality benefit to early invasive therapy.

This raises two concerning possibilities: 1) that there may be an increase in death overall, as reflected in the 0.5%, nearly statistically significant difference in the review, and 2) that there is mortal danger to invasive therapy among patients without biomarker elevation.

There are clear limitations to these data. In many of the studies a significant proportion of patients, typically those who fail medical therapy due to ongoing pain or new biomarker elevations, ultimately underwent invasive therapy (typically 20-30%), making it impossible to discern whether having invasive therapy provides benefit over strictly non-invasive therapy. In addition, there is a decrease in rehospitalization among those undergoing early invasive therapy. For a variety of reasons the decision to hospitalize is subjective, and biased in favor of invasive strategies (invasive strategies are a ‘step-up’ therapy, thus the subjects randomized to noninvasive therapy who have ongoing symptoms are far more likely to be readmitted for this). Therefore we have not included this outcome in the final numbers. While we consider it a biased outcome, we offer here the NNT for rehospitalization for those readers who disagree with our assessment of bias (NNT for rehospitalization=10).


Finally, the suggested benefits in refractory angina (i.e. ongoing chest pain) are difficult to interpret. First, there is often a considerable meaning response (i.e. placebo effect) associated with undergoing invasive management, even in the case of sham procedures, and this has classically been apparent for anginal pain associated with coronary ischemia.3 4 Second, while it is clear that most patients prioritize avoiding heart attacks and death, the patient-centered value of pain reduction when it is achieved in just 1 out of 9 patients and entails an invasive procedure with considerable risk and discomfort, is on much shakier ground.

Because of our concerns about a potential increase in mortality, alongside a nominal reduction in nonfatal MI that is equaled or eclipsed by peri-procedural MIs and bleeding events, and despite a reduction in symptoms, we have classified the early invasive strategy for coronary syndromes as ‘Red’. This is largely based on our belief that patients will typically value the avoidance of a 1 in 200 risk of death more than they will value a 1 in 50 chance of preventing a future nonfatal MI, and a 1 in 9 chance of preventing future pain.

Thus we would counsel that, in aggregate, early invasive therapy is not a beneficial intervention. This is clearly true for patients without biomarker elevation. If there is a patient for whom the benefits outweigh the harms it would likely be the high risk patient with biomarker elevations who is judged by the treating physician to be ‘on the ladder’, which is to say showing dynamic changes and evolution that would suggest that STEMI is imminent or active in an early stage.

Additional caveat: for acute coronary syndromes not associated with positive biomarker testing we classify an early invasive strategy as ‘Black’, as current data strongly suggest that this leads to an increase in mortality without a significant decrease in MI.

We note that the Cochrane authors conclude that they believe that an early invasive strategy is superior to a noninvasive strategy. This seems likely to be based on the 2% overall reduction in MI at 6 months. We respectfully disagree that a 1 in 50 chance of an avoided nonfatal MI is adequate justification for this resource-intensive, invasive, risky procedure that appears to be potentially associated with an increase in mortality.

Author

David H. Newman, MD

Published/Updated

February 11, 2013