In NSTE-ACS patients, the survival benefit of an initial invasive strategy seen at 5 years fades over the longer-term and is absent after a decade, according to follow-up from the RITA 3 trial published in the August 4, 2015, issue of the Journal of the American College of Cardiology.

The findings were first reported at the 2014 European Society of Cardiology Congress in Barcelona, Spain.

“Future trials should prospectively seek to identify and validate specific clinical risk factors that predict benefit from an initially invasive treatment strategy for patients presenting with NSTE-ACS,” say study coauthor Robert A. Henderson, DM, of Nottingham University Hospitals (Nottingham, England), and colleagues.

Between 1997 and 2001, researchers randomized 1,810 patients with NSTE-ACS to 1 of 2 strategies:

• Routine invasive: angiography within 72 hours of an ischemic episode followed by medical therapy or revascularization as indicated
• Selective invasive: medical management and, in those with signs of ischemia, angiography with revascularization if needed.

Baseline characteristics and use of guideline-recommended medications were well matched between the groups. Overall, electrocardiographic evidence of myocardial ischemia was seen in 92%, and 41% showed at least minimal ST-segment deviation. One-quarter had elevated creatine kinase or troponin, 28% had a history of MI, and 13% had diabetes.

During the index hospitalization, 96% of patients in the routine invasive group underwent angiography and 55% received revascularization, while 16% of those in the selective invasive group had angiography and 10% underwent revascularization.

At 5 years, the routine invasive strategy was associated with an estimated 26% reduction in the risk of cardiovascular death and MI and a 24% reduction in all-cause death.

Mortality Difference Dissipates After 5 Years

By 10 years, 1 in 4 had died, with about half of those deaths occurring at least 5 years after randomization. Rates of all-cause and cardiovascular death were similar between the routine and selective invasive groups (table 1).

However, there was an interaction between treatment and time. All-cause mortality was lower for the routine compared with the selective invasive strategy during the first 5 years but higher during the second 5 years. A similar pattern was seen for cardiovascular death (table 2).

On multivariate analysis, baseline characteristics associated with mortality at both 5 and 10 years were younger age, lower heart rate, smoking, diabetes, previous MI, ST-segment depression, and heart failure. Additionally, risk of all-cause mortality at 10 years was increased by the occurrence of a new MI during the first 5 years but was not associated with revascularization.

When patients were stratified using a modified postdischarge Global Registry of Acute Coronary Events (GRACE) score into low-, medium-, or high-risk categories, 10-year mortality ranged from 13.4% in the low-risk group to 58.0% in the high-risk group. All-cause mortality did not differ by strategy for the low- and intermediate-risk groups. A trend favoring the routine invasive strategy in those with high risk at 5 years was attenuated in later follow-up due to a low mortality rate in patients who received the selective invasive strategy.

At 10 years, there was no evidence of interaction between GRACE risk score and treatment effect. 

Second Thoughts About the 5-Year Benefit  

Differences in revascularization rates between the groups during the index admission and over 5 years do not appear to translate into a survival disparity at 10 years, the authors say. “It is therefore unclear whether the mortality difference at 5 years… is due to a direct treatment effect that attenuates over time, perhaps due to treatment crossovers, or due to the play of chance,” they write.

Although the study found a potentially clinically important increase in survival of 1.09 years in high-risk patients who received a routine rather than selective invasive strategy, the difference was observed in an underpowered subgroup analysis, and there was no evidence of an interaction between GRACE score and treatment, Dr. Henderson and colleagues caution. “Further investigation of the effect of underlying risk on the impact of a routine invasive strategy on outcome is warranted, and an updated individual patient data meta-analysis of the FRISC-II, ICTUS, and RITA 3 trials is planned,” they add.

Stressing that the RITA 3 results should not be generalized to the overall NSTE-ACS population, the investigators report that patients at highest risk have been consistently excluded in prior studies. Thus, they note, “the optimal treatment strategy for these patients has not been defined.”

Even in the absence of a survival benefit, there may be advantages to routine invasive treatment with regard to ischemia and MI among patients eligible for either strategy, the authors comment. Nonetheless, they conclude, “for many patients at lower levels of baseline risk, a conservative treatment strategy remains a reasonable treatment option.”

Trial Feedback Likely Swayed Long-term Outcomes

In an accompanying editorial, Manesh R. Patel, MD, and E. Magnus Ohman, MD, of the Duke Clinical Research Institute (Durham, NC), note that an early invasive strategy has become standard of care for ACS patients in most countries and is supported by a class 1B recommendation in the American College of Cardiology/American Heart Association guidelines and a level 1A recommendation from the European Society of Cardiology.

Referring to the RITA 3 investigators’ call for further trials using contemporary interventional strategies and addressing baseline risk, Drs. Patel and Ohman predict that the updated findings “will likely give clinicians and guideline committees pause as they consider the current recommended strategies.”

Amid the various possible explanations for why routine invasive care eventually lost its potency, the editorialists say, one stands out—RITA 3 itself.

“[T]he significant treatment effect from the initial study, the widespread clinical presentation of the trial findings, and the guideline recommendations caused clinical practice to shift toward more routine care,” they explain.

“[W]e should be heartened by the fact that physicians may be using the latest clinical trial data to improve the care for their patients with ACS, and, therefore, our ability to interpret late outcomes may be heavily affected by the improving physicians’ performance around guidelines and the optimal care for patients with ACS,” they conclude. “This is a very positive message indeed if you are a patient, but it makes it much harder if you are a researcher or guidelines writer in the field of cardiology.”

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Sources: 
1. Henderson RA, Jarvis C, Clayton T, et al. 10-year mortality outcome of a routine invasive strategy versus 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.
2. Patel MR, Ohman EM. The early invasive strategy in acute coronary syndromes: should the guideline recommendations be revisited [editorial]? J Am Coll Cardiol. 2015;66:521-523.

Related Stories:

• RITA-3: Advantage of Routine Invasive Strategy for NSTE-ACS Gone by 10 Years
• Meta-analysis: Routine Invasive Strategy Holds Long-Term Advantage for ACS
• Revascularization, Not Early Invasive Strategy, Key in NSTE-ACS Patients