Early Aggressive Strategy in Elderly NSTE ACS Patients Not Harmful, Advantage Still Elusive

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New randomized trial data again have failed to definitively settle the issue of whether early aggressive treatment is worth the risk for elderly patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS). But the study, which lacked sufficient statistical power to detect differences in clinical outcome within the overall cohort, does demonstrate significant gains among the subset of patients with elevated baseline troponin levels.

Findings were published online September 17, 2012, ahead of print in JACC: Cardiovascular Interventions, and first presented at the 2011 European Society of Cardiology Congress in Paris, France.

For the Italian Elderly ACS study, researchers led by Stefano Savonitto, MD, of Azienda Ospedaliera Santa Maria Nuova, IRCCS (Reggio Emilia, Italy), randomized 313 NSTE ACS patients aged at least 75 years to 1 of 2 treatment strategies:

• Early aggressive (n = 154): coronary angiography and, when necessary, revascularization performed within 72 hours
• Initially conservative (n = 159): angiography and revascularization only performed if ischemia recurred

Mean patient age in both groups was 82 years, with similar baseline characteristics in both study arms. A higher proportion of those treated conservatively had severe recurrent ischemia occur while hospitalized (9.4% vs. 0.6% with early aggressive strategy; P = 0.0004).

Similar Outcomes at 1 Year

During the index hospital stay, 136 patients (88.3%) in the early aggressive group underwent catheterization at a median of 24 hours after randomization, with 85 patients (55%) undergoing revascularization, which included 76 PCI and 9 CABG procedures. Catheterization was indicated in 46 patients (28.9%) belonging to the initially conservative group at a median of 67 hours after randomization, with 37 patients (23.3%) undergoing revascularization, including 36 PCI cases and 1 CABG surgery.

Within 1 year, the cumulative rate of the primary endpoint (composite of death, MI, disabling stroke, and repeat hospitalization for cardiovascular causes or severe bleeding) numerically favored early aggressive treatment but did not reach significance. The same pattern was seen for each of its components (table 1).

Table 1. Cumulative Event Rates Within 1 Year of Randomization

Analyzing results according to baseline troponin levels, however, teased out differential effects. Patients with normal troponin did not derive benefit from more intensive treatment, but those assigned to the early aggressive strategy showed a significant reduction in the likelihood of experiencing the primary endpoint (HR 0.43; 95% CI 0.23-0.80; P for interaction = 0.0375). Additional subgroup analyses showed trends toward greater benefit in men, older patients, and those with ischemic ECG changes.

During the index hospitalization and subsequent follow-up, TIMI major bleeding was observed only 4 times (twice in each of the study arms). According to the paper, the rarity of bleeding likely arose from low use of glycoprotein IIb/IIIa inhibitors (less than 20%) and high use of radial access (more than 70%).

Study Not Conclusive

Due to being powered to detect a 40% difference in the primary endpoint, “the present study does not allow a definite conclusion about the benefit of an [early aggressive] approach when applied systematically among elderly patients with NSTE ACS,” the investigators conclude. “The finding of a significant interaction for the treatment effect according to troponin status at baseline, with benefit confined in troponin-positive patients, should be confirmed in a larger trial.”

In an editorial accompanying the paper, Freek W.A. Verheugt, MD, of Onze Lieve Vrouwe Gasthuis (Amsterdam, The Netherlands), describes the trial as “highly interesting.”

“The appealing feature of this Italian study is that it is the first and only trial available performed specifically in very elderly patients with this syndrome. But the weakness is that the trial did not reach its aim with regard to the number of recruited patients,” he writes, pointing out that Italian Elderly ACS had originally planned to randomize 504 patients, a goal that was tapered down after slow enrollment. Even with this limitation, “[i]t clearly shows that in very elderly patients a routine invasive strategy can be helpful without clear excess harm.”

Messages for Practice

Dr. Verheugt advises that the advantage of early aggressive treatment should be confirmed in a larger trial enrolling only troponin-positive patients.

In an e-mail communication with TCTMD, Dr. Savonitto said that such a trial, though justified to confirm “striking” subgroup results from the “neutral” Italian Elderly ACS study, would not be forthcoming. However, he commented, “risk stratification, including troponin measurement, is now standard of care as recommended by practice guidelines. I would suggest not proceeding to angiography in elderly patients who are hemodynamically stable and have negative troponin values during initial observation.”

Dr. Savonitto encouraged using the radial approach as much as possible when treating elderly patients and questioned whether the higher bleeding and rehospitalization rates reported in earlier studies were unrealistic, given the favorable outcomes achieved here. Overall, he said, “doing randomized controlled trials in elderly patients is hard but feasible. Enthusiasm is needed.”

Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), told TCTMD in a telephone interview that the “major finding is that there didn’t appear to be much harm related to going early [in appropriately selected elderly patients]. It’s nice to have data on a population of patients this old.

“There are actually several studies that have demonstrated that there is a paradoxical under treatment of the most vulnerable or high-risk patients,” such as the elderly, he continued. “In some respects, those are the patients who have the most to gain.”

 

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Sources:
1. Savonitto S, Cavallini C, Petronio AS, et al. Early aggressive versus initially conservative treatment in elderly patients with non-ST-segment elevation acute coronary syndrome: A randomized controlled trial. J Am Coll Cardiol Intv. 2012;5:906-916.

2. Verheugt FWA. Don’t forget the intervention in very elderly persons with acute coronary syndromes. J Am Coll Cardiol Intv. 2012;5:917-918.

 

 

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