RITA-3: Routine Invasive NSTEMI Care Survival Gain Gone at 10 Years

NOTTINGHAM, UK — The use of a "routine" early invasive strategy for patients with non-ST-segment-elevation ACS (NSTE-ACS) may be no better than a more conservative approach when it comes to improving very long-term clinical outcomes, suggests new research^[1].

Follow-up from the third Randomized Intervention Trial of Unstable Angina (RITA-3), which included 1810 patients from England and Scotland, showed no significant differences in all-cause or CV deaths at 10 years postprocedure between those who were routinely managed with ateriography plus revascularization as indicated and those who underwent a more selective strategy of symptom-driven arteriography and revascularization.

These results differed from those found at the study's 5-year follow-up, where the invasive strategy led to a decrease in death/MI and cardiac deaths.

Still, "I wasn't greatly surprised by these [new] findings," lead author Dr Robert A Henderson (Nottingham University Hospitals, UK) told heartwire from Medscape. "The main message is that there was a modest difference in mortality demonstrated at 5 years that attenuated over 10 years."

Henderson noted that he's "not entirely sure why that is" but speculated that it could be that the difference in mortality reported at 5 years "was simply a chance finding." Or it could be due to the differences in revascularization rates that occurred between the two groups in the years that followed.

Overall, Henderson said the results add to the evidence that routine invasive strategy in everyone with NSTE-ACS "may not be the way to go." The benefits at the 5-year mark appear to have been most evident in patients considered to be high risk. And after extensive subgroup analyses, he concludes that "there is little to be gained from routine invasive treatment in people at the lowest levels of risk."

He added that this emphasizes the importance of risk stratification, such as with Global Registry of Acute Coronary Events (GRACE) scores "and reaffirms that a selective invasive strategy is a perfectly reasonable way" to manage these low- and perhaps even intermediate-risk patients.

The findings were published in the August 4, 2015 issue of the Journal of the American College of Cardiology.

RITA Through the Years

As reported by heartwire , the original RITA-3 results were first presented in Berlin at the European Society of Cardiology (ESC) Congress 2002 and showed that the routine intervention strategy halved subsequent angina in NSTE-ACS patients without increasing death or MI at 1 year. However, the rate of death/MI did not differ between the treatment groups.

The 5-year follow-up results were presented at the 2005 ESC Congress in Stockholm, Sweden and showed a 24% reduction in the odds of all-cause mortality (odds ratio [OR] 0.76, 95% CI 0.58–1.00, P=0.05) in the routine intervention vs conservative strategies.

"The routine invasive strategy involved early coronary arteriography within 72 hours of an index episode . . . and myocardial revascularization as clinically indicated," write the investigators. In this group, 55% underwent PCI (with stents inserted in 88%) and 21% underwent CABG. The selective invasive strategy used continued medication, with coronary arteriography and subsequent revascularization used only for persistent or recurrent ischemia.

At 10 years, 457 patients had died—with 242 of the deaths occurring in the first 5 years postprocedure and the remaining 215 occurring between years 5 and 10.

All-cause death occurred in 25.1% of the routine invasive group vs 25.4% of the selective invasive group by 10 years, and CV deaths occurred in 15.1% vs 16.1%, respectively. "The mortality curves diverged over the first 5 years but then progressively converged," report the researchers.

Predictors of mortality included age, prior MI, heart rate, being a smoker, or having heart failure, diabetes, or ST-segment depression.

Based on GRACE scores, all participants were placed in low-, intermediate-, and high-risk subgroups. At 10 years, all-cause mortality was 58% in the total high-risk group, 37.5% in the intermediate groups, and just 13.4% in the low-risk group. Treatment strategy did not significantly affect these rates.

Challenges Practice

"In the UK, there has been a move toward routine use of an invasive strategy in most patients with a diagnosis of non-ST-segment-elevation [ACS]. And I think this paper challenges that or at least suggests that a selective invasive approach is a reasonable management strategy for many of these patients," said Henderson.

He noted that a limitation of the current analysis is that clinical trials usually select participants from a very narrow risk spectrum compared with the wide spectrum of risk in the population with NSTE-ACS seen in routine clinical practice. "So translating the data from randomized trials to the generality of [these] patients is rather difficult."

Thus, clinicians should thoroughly discuss these issues with each patient "and also consider other benefits that routine invasive strategy may offer." For example, early work from RITA-3 and from the FRISC II and ICTUS trials showed a reduction in recurrent ischemia in the first few months after the index event in those who underwent routine invasive strategy. "There's also some evidence that you reduce the risk of recurrent myocardial infarction. But these benefits do not translate into an overall mortality benefit at 10 years."

Another limitation was that the RITA-3 patients were not managed with contemporary interventional and medical therapies. "But of course, that's to be expected," said Henderson. "When you collect data over a long course of time, therapies change—especially in a rapidly evolving field."

For example, "we now routinely use drug-eluting stents in pretty much everyone, whereas [they] were not available when recruitment into RITA-3 started."

Henderson reported that the investigators aren't planning to follow the RITA patients further. "The 10-year follow-up for this trial is probably going to be it" because of the study design, he said.

Still Points to Benefit?

Overall, the study conclusions "will likely give clinicians and guideline committees pause as they consider the current recommended strategies for management of patients with NSTE-ACS," write Dr Manesh R Patel and Dr Magnus Ohman (both from Duke Clinical Research Institute, Durham, NC) in an accompanying editorial^[2].

To heartwire , Patel noted that the investigators should be congratulated for following the patients for such a long time. "It was interesting that when they followed everybody for mortality, the mortality curves started to come back toward each other at 10 years," he said.

However, "we think there's some optimism here. When you follow people from 5 to 10 years, and there's been a large presentation of the findings, it may be that you're affecting practice and that patients and clinicians are receiving the message sooner. That message was that an early invasive strategy may be beneficial, and these long-term data may in fact show that practice did change," said Patel.

"It's not clear if this loss in mortality reduction is due to the direct treatment effect—that we went to find the high-risk patients with invasive strategy and treated them. Or it could be that there were treatment crossovers over the long-term—so that even those patients managed conservatively eventually got an invasive strategy and benefit."

He also pointed out that changing therapeutics over time could also have had an effect. "Or it could just be chance."

Still, "given that there are several trials that have asked this question, we would say that the majority of the evidence is pointing toward an invasive strategy being beneficial, especially in high-risk patients. But this [new analysis] does make us want longer-term follow-up in all of our studies," said Patel.

RITA-3 was funded by a grant from the British Heart Foundation, which had received a donation from Aventis Pharma. Henderson reports no relevant financial relationships. Disclosures for the coauthors are listed in the article. Ohman has received research grants from Daiichi-Sankyo, Eli Lilly, Gilead Sciences, and Janssen Pharmaceuticals and has served as a consultant for Abiomed, AstraZeneca, Biotie, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Faculty Connection, Gilead Sciences, Janssen Pharmaceuticals, Merck, Stealth Peptides, the Medicines Company, and WebMD. Patel reports no relevant financial relationships.

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