By Jeffrey Zimmet, MD, PhD
Associate Professor of Medicine, University of California, San Francisco; Director, Cardiac Catheterization Laboratory, San Francisco VA Medical Center
Dr. Zimmet reports no financial relationships relevant to this field of study.
SOURCE: Henderson RA, et al. Ten-year mortality outcome of a routine invasive strategy vs a selective invasive strategy in non-ST-segment elevation acute coronary syndrome: The British Heart Foundation RITA-3 randomized trial. J Am Coll Cardiol 2015;66:511-520.
Current U.S. and European guidelines assign a class I indication to a routine early invasive strategy for evaluation and treatment of non-ST elevation acute coronary syndromes (NSTEACS). This is based on the outcomes of a bevy of randomized clinical trials comparing routine invasive with selective invasive strategies. One of these trials, RITA-3, enrolled 1810 moderate-risk NSTEACS patients and randomized them to a planned invasive strategy, usually with coronary angiography within 72 hours, or to a conservative strategy where cardiac cath was reserved for patients with ongoing or recurrent ischemia. The publication of the 1-year results in The Lancet in 2002 assigned a significant advantage to the planned invasive strategy in terms of the composite endpoint, driven primarily by a nearly 50% reduction in refractory angina. Death and myocardial infarction (MI) were similar between the two groups at 1 year. However, the mortality curves separated over time, such that by the planned 5-year follow up, not only were revascularization, MI, and angina lower in the invasive group, but there was also a 24% relative reduction in all-cause mortality. Because all surviving patients were prospectively entered into a national registry in the United Kingdom, national mortality data are now available for this cohort at the 10-year mark.
What the authors report appears surprising. At 10 years, the mortality advantage earlier assigned to the routine invasive strategy had dissipated, with the death of approximately 25% of patients in each group. The usual suspects emerged as independent predictors of death in a multivariate analysis: age, previous MI, heart failure, smoking status, diabetes, heart rate, and ST-segment depression. Patients were further stratified into low-risk, medium-risk, and high-risk groups based on a post-discharge Global Registry of Acute Coronary Events (GRACE) score. And while mortality at 10 years was markedly different between the low-risk (14.4%) and high-risk (56.2%) groups, there was no difference in within-group mortality based on the treatment strategy.
The authors conclude that the mortality benefit of the routine early invasive strategy seen at 5 years is attenuated at later follow-up, and suggest that further trials of more contemporary treatment strategies in NSTEACS are needed.
NSTEACS patients are a heterogeneous group, and treatment must be individualized without trying to heed absolutes (e.g., all patients must go to cath within 72 hours). Certain groups of high-risk patients should nearly always take an early-invasive approach (e.g., the patient with positive biomarkers and ongoing ischemia despite maximal medical therapy). Such high-risk patients for whom there is a lack of clinical equipoise were excluded from trials such as RITA. Other patients are decidedly low-risk, and the same trials have consistently failed to demonstrate benefit of the early-invasive strategy for this group, even in terms of softer outcomes, such as recurrent ischemia.
Several points are worth noting about the trial itself. Because the data from this study are derived from a national registry rather than from the follow-up mechanisms of the trial, there are no data beyond 5 years for other important endpoints, including recurrent angina, revascularization, and MI. The trial included a relatively modest-risk population, and the revascularization rate during the initial hospitalization in the early invasive group (~55%) was significantly lower than in other contemporary NSTEACS trials such as ACUITY and ICTUS. It is certainly worth asking whether the previously reported 5-year mortality benefit was a plausible result in this trial.
How important is the purported intermediate-term mortality benefit in the current guideline recommendations for routine early intervention? The various trials in this space (TACTICS TIMI 18, FRISC II, ISAR-COOL, etc.) have been relatively consistent in terms of reduction in recurrent MI, recurrent ischemia, and revascularization in the short and intermediate terms. The RITA-3 trial did not examine these outcomes past 5 years, and therefore, the longer-term effects of this strategy remain unknown. However, the known positive effects are important to both patients and clinicians, and clearly support early intervention.
The RITA-3 10-year results should certainly prompt a re-evaluation of the mortality data associated with the early interventional strategy in NSTEACS. A more contemporary trial, as suggested by the study authors, would certainly be welcome. Significant changes have occurred in ACS management since these trials were performed — DES, radial access, newer antiplatelet agents, etc. Until then, however, I do not expect my own practice to change very much. Medium- and high-risk patients who are good candidates for cardiac cath will continue to go early to planned coronary angiography. And for low-risk patients, both conservative and planned invasive strategies remain viable alternatives.