Guidelines should be based on confirmatory data

Current guidelines for treating patients with non-ST elevation MI with an early invasive strategy cannot be justified in light of the new data.

Patients with non-ST elevation acute coronary syndrome can be risk stratified into low- and high-risk groups at initial presentation. Identification of patients in the high-risk group is considered essential in the current ACC/AHA and ESC guidelines in order to institute measures to improve the prognosis. A history of accelerating tempo of ischemic symptoms in the proceeding 48 hours, prolonged ongoing (>20 minute) rest pain, pulmonary edema, older age (>65 years), transient ST-segment changes and elevated cardiac biomarkers, especially troponin T or I, characterize high-risk patients.

Non-ST elevation acute coronary syndrome (NSTE-ACS) patients with elevated cardiac troponin T or I are considered to be at the highest risk as they already have sustained myocardial injury or MI, and these NSTEMI patients are at increased risk of cardiac death, reinfarction and recurrent ACS episodes. Current AHA/ACC and ESC guidelines recommend an early invasive approach in these patients with routine coronary angiography followed by percutaneous coronary intervention if feasible.

Udho Thadani

This recommendation, however, is derived from retrospective subgroup analysis of the data of reported trials, rather than from prospective, randomized clinical trials in patients with NSTEMI with elevated troponin levels. Furthermore, this retrospective data have been compiled from different studies utilizing different biomarker criteria for diagnosing MI, antiplatelet and antithrombotic agents, and variable time intervals of invasive procedures from the initial presentation.

Conservative or invasive strategies

Earlier studies were carried out before the availability of GPIIb/IIIa inhibitors, low molecular weight heparin and clopidogrel. In these studies a conservative strategy was either similar (TIMI IIIB trial) or superior (VANQWISH trial) to an invasive strategy. The latter trial is of special interest in that it was performed in patients with NSTEMI (elevated cardio biomarker, CKMB rather than elevated troponin levels). The number of patients with either fatal or recurrent nonfatal MI was higher in the invasive strategy group at hospital discharge with a strong trend benefiting patients in the conservative group at two years (hazard ratio 0.72; 95% CI, 0.51 to 1.01).

In the FRISC II study, 3,048 ACS patients were treated with LMWH, dalteparin, for five to seven days. Of these, 2,457 were randomized to continue either dalteparin or placebo and were assigned to either invasive or noninvasive strategy. At six months, there were no differences between continued dalteparin therapy compared with placebo. However, death or recurrent MI occurred in 9.4% of patients assigned to invasive therapy and 12.1% assigned to noninvasive strategy (P<.031). At one year the mortality rate in the invasive strategy group was 2.2% compared to 3.9% in the noninvasive strategy group (P=.016). In this trial GPIIb/IIIa inhibitors were not used.

In the TACTICS-TIMI-18 trial, 2, 220 patients with UA or NSTEMI were treated with ASA, heparin and GPIIb/IIIa inhibitor tirofiban. They were randomized to an early invasive strategy with routine coronary angiography within 48 hours followed by revascularization if the coronary anatomy was deemed suitable, or a more conservative strategy.

Death, MI or rehospitalization for ACS at six months occurred in 15.9% of patients assigned to invasive strategy vs. 19.4% assigned to more conservative strategy, P=.025. At 30 days, mortality in the invasive group was 2.2% compared to 1.6% in the conservative group; at six months mortality was similar (3.3% vs. 3.5%) in the two groups. MI was reduced at six months: 4.8% vs. 6.9% (P<.05) in the invasive strategy group. The beneficial effect on the outcome was primarily observed in medium- and high-risk patients as defined by an elevated troponin T >.01 ng/mL, the presence of ST segment elevation or TIMI score greater than three.

The RITA 3 trial results, with 1,810 patients with ACS who were treated with ASA plus enoxaparin but not a GPIIb/IIIa inhibitor, showed a reduction in composite end point of death, recurrent MI or refractory angina at four months in the early intervention group compared to conservative treatment group (9.6% vs. 14.5% P<.001). However, death or MI at one year, 7.6% vs. 8.3% (P=.58), was similar in the two groups. The incidence of refractory angina (P<.001) was lower in the invasive treatment group.

NSTEMI and elevated troponin

In a recently published meta-analysis, Mehta and colleagues concluded that a routine invasive strategy exceeded a selective invasive strategy in reducing MI, severe angina and rehospitalization at a mean follow-up of 17 months, but routine early intervention was associated with a higher early mortality hazard and a trend toward a mortality reduction at follow-up. Higher risk patients with elevated cardiac biomarkers at baseline benefited more from routine interventions with no benefit observed in low-risk patients with negative baseline biomarkers. Thus this meta-analysis supported the conclusions of current guidelines that routine early invasive strategy should be used in patients with high-risk ACS.

However, none of the trials analyzed in this meta-analysis had patients with NSTEMI with elevated troponin levels, prospectively randomized to an early invasive vs. a conservative strategy. Furthermore, clopidogrel was not routinely used; this drug reduces mortality, MI and stroke in ACS patients with no early invasive intervention (CURE Trial). In the PURSUIT trial, which utilized eptifibatide, early invasive strategy was not utilized. A subgroup analysis of nonrandomized data did show a greater benefit in patients who underwent a revascularization procedure in both the CURE and PURSUIT trials.

Thus, AHA/ACC and ESC guidelines and published subgroup nonrandomized data from other trials and meta-analysis of these data have perpetuated the utilization of early invasive strategy for managing patients with NSTEMI. Physicians and hospitals who do not follow these guideline recommendations are being closely scrutinized.

Routine early invasive strategy hazardous

This dogma, however, is in serious jeopardy as shown in a recent study from Holland, which compared early invasive strategy to selective strategy in patients with NSTEMI (elevated troponin T levels) and failed to confirm the superiority of routine early invasive strategy.

In this trial deWinter and colleagues randomized 1,200 patients with NSTE ACS patients who had chest pain, an elevated cardiac troponin T level (>.03mg/mL) and either ECG evidence of ischemia at admission or a documented history of CAD to an early invasive strategy or to a more conservative (selective invasive) strategy.

All patients received aspirin daily, enoxaparin for 48 hours, and abciximab at the time of PCI. The use of clopidogrel and intensive lipid-lowering therapy was recommended. The estimated cumulative rate of primary endpoint (death, nonfatal MI, or rehospitalization for anginal symptoms within one year) was 22.7% in the group assigned to early invasive management and 21.2% in the group assigned to selective invasive management (RR 1.07, 95% CI, 0.87 to 1.33, P=.33).

The mortality rate was the same in the two groups (2.5%), MI was significantly more frequent in the group assigned to early invasive management (15.0% vs. 10.0%, P=.055) but hospitalization was less frequent in that group (7.4% vs. 10.9%, P=.04). Revascularization rates, 70% in the invasive group and 40% in the selective invasive strategy group, during initial hospitalization and 79% and 54%, respectively, within one year after randomization were somewhat higher than previously reported in other trials.

Thus, this prospective, randomized trial failed to confirm the benefit of routine early invasive strategy for treating patients with NSTEMI as recommended by the AHAH/ACC and ESC guidelines. As a matter of fact, an early invasive strategy was associated with an increased hazard of MI that was not necessarily prevented by the use of a GPIIb/IIIa agent, abciximab, at the time of PCI.

Whether upfront, early use of a GP IIb/IIIa agent in addition to aspirin, LMWH, clopidogrel would have prevented recurrent MI as shown in TACTIC TIMI 18 study remains speculative. In published ACS trials, including the TACTIC TIMI 18 trial, mortality benefit has not been reported with routine early use of GPIIb/IIIa antagonists.

Therefore, at present, routine invasive strategy for treating patients with NSTE MI with elevated troponin T cannot be recommended, and current AHA/ACC and ESC guidelines need to be revised to reflect this conclusion. Perhaps in the future, guidelines should refrain from making strong treatment recommendations until confirmatory data from randomized, prospectively conducted trials become available.

Udho Thadani, MD, is professor emeritus (active) of medicine, and consultant cardiologist at Oklahoma University Medical Center and VA Medical Center, Oklahoma City, Okla. He is a member of Cardiology Today’s Cardiovascular Pharmacology section.

For more information:

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