Interventional vs Conservative Strategy for Non-ST Elevation Acute Coronary Syndrome

Abstract & Commentary

By Michael H. Crawford, MD Dr. Crawford is Professor of Medicine, Chief of Clinical Cardiology, University of California, San Francisco and Editor of Clinical Cardiology Alert. Dr. Crawford is on the speaker's bureau for Pfizer.

Source: Fox KA, et al. 5-Year Outcome of an Interventional Strategy in Non-ST-Elevation Acute Coronary Syndrome: The British Heart Foundation RITA 3 Randomised Trial. Lancet. 2005;366:914-920.

More recent trials, and meta-analyses of all trials, have shown a reduction in death and myocardial infarction (MI) with a routine invasive strategy vs an ischemia or symptom-driven invasive strategy over 6-24 months for patients with non-ST elevation (E) acute coronary syndrome (ACS). However, an increase in death during the initial hospitalization in the routine invasive arm makes long-term outcome data important. Thus, the British Heart Foundation RITA 3 trial 5-year data are of interest. RITA 3 pitted an early (< 72 hours) interventional strategy with revascularization, if appropriate, against a conservative strategy with intervention only for recurrent ischemic symptoms with ECG changes or an ischemic response on stress testing. Both groups received optimal medical management including enoxaparin, thienopyridines, and glycoprotein IIb/IIIa inhibitors. The primary end point for the 5-year follow-up data was death or MI.

Results: RITA 3 enrolled 1810 patients in the United Kingdom between 1997 and 2001. Baseline characteristics were well-matched but, during the early follow-up period, there was more beta-blocker use in the conservative group, which paralleled an increase in reported angina. Overall, 81% were on aspirin, 80% statins, 57% beta-blockers, and 34% ACE inhibitors. In the interventional arm, 97% underwent initial angiography, 38% had angioplasty (88% stents), and 26% had coronary artery bypass graft surgery. In the first month, 45% of the interventional group had revascularization vs 13% of the conservative group. After 1 month, the rates of revascularization were higher in the conservative group. At a median follow-up of 5 years, 543 in the interventional arm (68%) and 345 in the con- servative arm (44%) had had revascularization. There were less deaths or MIs in the intervention group vs the conservative group (142 vs 178, OR = 0.78, 95% CI 0.16-0.99, P = 0.044). Also, there were fewer total deaths in the interventional group (102 vs 132, OR = 0.76, 95% CI 0.58-1.0, P = 0.054). Cardiovascular deaths were lower in the interventional group (7.3% vs 10.6%, 0.68, 0.49-0.95, P = 0.026). MI rates were not significantly different the first year but, thereafter, diverged in favor of the interventional group. At 5 years, the absolute difference was 3.4% (16.6% vs 20.0%). The benefits of an interventional strategy were most marked in high-risk patients, defined clinically (older, diabetics, previous MI, smokers, etc). Fox and colleagues concluded that in patients with non-STE ACS, early invasive strategy results in a long-term reduction in death and recurrent MI, especially in clinically high-risk patients.

Commentary

A recently published meta-analysis of 7 randomized, controlled trials of an invasive vs a conservative strategy in non-STE ACS (Mehta, et al. JAMA. 2005;293: 2908-2917), including TIMI IIIb, VANQWISH, FRISC II, TACTICS, and RITA 3, with follow-up ranging from 6 months to 2 years, showed that an invasive strategy increased in hospital death (OR 1.6, P = .007) and death or MI (OR 1.36, P = .002). This analysis included a RITA 3 report at 1 year of follow-up, in which both endpoints were P = NS (death or MI, 7.6% invasive vs 8.3% conservative). However, RITA 3 at 1 year did show a 50% reduction in refractory angina. Over the next 4 years, despite increasing numbers of crossovers to revascularization in the conservative group, the benefits of revascularization emerged, so that at the 5-year point, death and MI was significantly reduced in the interventional arm (OR 0.82, P = .001). This is the first study to report long-term results and the implications are important. Theoretically, the results could have gone either way. If de novo plague rupture of non-intervened segments was the major factor in recurrent events, then early revascularization would make no difference long-term. Clearly, this was not the case in RITA 3, as the benefits of an early invasive approach increased over time. Since both groups received intensive secondary prevention, including statins in 80%, progression of new plaques may have been halted or markedly reduced. In this situation, fixing the culprit lesions was a highly successful strategy.

One big difference between the newer trials such as TACTICS, RITA 3, and FRISC II is the use of stents, glycoprotein IIb/IIIa agents, and thienopyridine, which was not the case in the older trials such as TIMI IIIb and VANQWISH. Also, the ratio of invasive patients actually revascularized compared to the conservative patients revascularized was lower in the older trials; 1.1-1.3 vs 1.4-2.0 in the newer trials. Thus, proportionally more patients randomized to the invasive arm were revascularized in the newer trials. None of the 7 trials used drug-eluting stents, which should cut down on the incidence of restenosis and the need for repeated invasive procedures.

Risk stratification in RITA 3 and FRISC II showed that higher-risk patients benefited more, but risk stratification was based upon baseline clinical characteristics not more discriminating variables such as troponin levels or BNP. In fact, the new definition of MI agreed upon by the American College of Cardiology and the European Society of Cardiology was not applied in any of these studies. So, even how many were NSTEMI vs unstable angina is not clear. The most predictive characteristics for benefit of intervention in RITA 3 was age, followed by diabetes, previous MI, and smoking. Should we reserve an invasive approach for those > 65 years. . . > 75 years? Do they have to be diabetic smokers with previous MIs to get revascularization? Clearly, this approach leaves a lot to be desired, but the principle is worth considering. Perhaps those known to be at a higher risk from other studies should undergo an interventional approach (eg, those with elevated biomarkers or ischemic ECG changes). In other words, those admitted to the hospital probably should be invasively studied. Low-risk patients are appropriately held in an observation unit or referred for stress testing within 72 hours.