Risk Stratification in Patients With Inferior Acute Myocardial Infarction Treated by Percutaneous Coronary Interventions
The Role of Admission Troponin T
Background—Cardiac troponin T (cTnT) elevations on admission indicate a high-risk subgroup of patients with ST-segment elevation acute myocardial infarction (AMI). This finding has been attributed to less effective reperfusion after thrombolytic therapy. The aim of this study was to determine the role of admission cTnT on the efficacy of percutaneous coronary interventions (PCIs) in inferior AMI.
Methods and Results—One hundred fifty-nine consecutive patients with inferior ST-segment AMI were enrolled and followed up for a mean of 448 days. Patients were stratified by cTnT on admission. A cTnT ≥0.1 μg/L was found in 58% of patients. These patients had longer time intervals from onset of symptoms to therapy (P<0.001) and higher 30-day (10.8% versus 1.5%, P=0.027) and long-term (17.2% versus 4.5%, P=0.023) cardiac mortalities. Rates of the combined end point of death, nonfatal reinfarction, and need for repeated target vessel revascularization procedures were not different in cTnT groups (log rank, 0.69; P=0.41). PCI was attempted in 93.3% of cTnT-positive and 98.5% cTnT-negative patients (P=0.24) but was less frequently successful in patients with cTnT ≥0.1 μg/L (77.9% versus 96.9%, P<0.001). Coronary stenting reduced 30-day and long-term cardiac mortality, particularly among cTnT-positive patients. In a multivariate analysis, cTnT indicated an ≈5-fold-higher risk (adjusted OR, 4.6; 95% CI, 0.79 to 27.11; P=0.089) and was a strong albeit not independent risk predictor.
Conclusions—In inferior AMI, a positive admission cTnT is associated with lower success rates of direct PCI and higher rates of cardiac events over the short and long term. These patients benefit from coronary stenting.
The prognosis of inferior acute myocardial infarction (AMI) is generally considered to be better than that of anterior AMI.1 However, patients with inferior AMI represent a heterogeneous risk group that includes cardiogenic shock, older age, concomitant left precordial ST-segment depression, third-degree AV block, and right ventricular infarction.2 3 4 5
Cardiac troponins (cTnTs) have improved AMI detection and allow risk stratification in acute coronary syndromes.6 7 8 9 10 Recently, large-scaled clinical studies revealed an important prognostic role of the admission cTnT value in patients with ST-elevation AMI.10 11 12 In the Global Utilization of Streptokinase and TPA for Occluded Arteries (GUSTO)-IIa study, 30-day mortality was 13.0% among patients with ST-segment elevation and a positive admission cTnT compared with 4.7% among those with a negative test result.10 Concordantly, the GUSTO-III troponin T substudy, which enrolled 12 806 patients, and a single-center study of 240 patients found that positive admission cTnT values were associated with worse early and long-term prognosis.11 12 In the GUSTO substudy, excess mortality did not relate to the duration of symptoms and was independent of the thrombolytic agent used.11 Interestingly, the Fragmin During Instability in Coronary Artery Disease (FRISC) study group and others have attributed this excess mortality to lower rates of complete reperfusion (TIMI grade 3 flow) after thrombolysis in patients with a positive cTnT.13 14
The present study focused on the clinical significance of admission cTnT and its impact on efficacy of percutaneous coronary interventions (PCI) in a well-defined subset of patients with inferior AMI.
Between May 1996 and February 1999, 159 consecutive patients with a confirmed diagnosis of inferior or true posterior AMI who were admitted within 24 hours of onset of symptoms were enrolled in this single-center study. Diagnosis of AMI was based on chest pain history, enzyme measurements, and ECG according to World Health Organization criteria.15 Only AMI with characteristic ascending limbs of creatine kinase (CK) and CK-MB activities as disclosed by serial measurements was defined as an acute event. Data on chest pain history just before the episode leading to admission were not collected. Standard 12-lead and right precordial ECGs were obtained immediately after admission. Inferior AMI was defined by the presence of ST-segment elevation of ≥0.1 mV in ≥2 of the leads II, III, and aVF. Diagnosis of true posterior AMI was based on the presence of an R/S ratio of >1 in lead V1 or V2 with R waves of >40 ms. Right ventricular involvement was defined as ST-segment elevation of >0.1 mV in lead V4R.
All patients were scheduled for immediate (within 30 minutes) coronary angiography and direct PCI unless adequate hemodynamic stabilization for transportation to the catheterization laboratory could be achieved. Treatment decisions were left to the discretion of the interventionalists who were unaware of the cTnT result during the procedure. On admission, all patients received a parenteral loading dose of 500 mg acetylsalicylic acid and 5000 IU unfractionated heparin. Other standard medications, including nitrates and β-adrenoreceptor blockers, were given at the discretion of the physician on duty. Therapy with glycoprotein (GP) IIb/IIIa antagonists was based on the presence of large intraluminal filling defects on coronary angiography or incomplete reperfusion, ie, less than TIMI grade 3 flow after recanalization despite coronary stenting. When coronary stenting was required, patients received an oral loading of 500 mg ticlopidin followed by 250 mg twice daily for another 4 weeks. After removal of the arterial sheath, patients received a subcutaneous dose of low-molecular-weight heparin (7500 U dalteparin) daily for ≥48 hours. An oral dose of 100 mg acetylsalicylic acid was continued indefinitely.
The study protocol was approved by the local ethics committee of the University of Luebeck.
Clinical variables were recorded on admission. Occurrence of complete AV block, sustained ventricular tachyarrhythmias, and cardiogenic shock and the need for atropine or temporary pacing were registered prospectively.
Blood for measurement of cTnT was collected immediately on admission and was determined by either qualitative test (Trop T, Roche Diagnostics) or quantitative immunoassay (Elecsys Troponin T, Roche Diagnostics). A cutoff level of 0.1 μg/L was used to discriminate cTnT results. Total CK and CK-MB activities were measured with commercially available kits. The upper limit of normal CK was 80 IU/L for men and 70 IU/L for women.
Data were collected on the infarct-related artery, site of infarction (proximal or distal to the origin of the first marginal branch of the right coronary), extent of coronary artery disease, left ventricular performance, TIMI flow before and after coronary intervention, and rate of distal thrombus dislocation during PCI. Coronary angiograms underwent offline quantitative analysis (Medis Medical, QCA-CMS). Procedural success was defined as residual stenosis of <50% and TIMI grade 3 flow after PCI. Target vessel reintervention (TVR) was defined as repeated PCI of the target vessel or CABG involving the target vessel.
Patients with bundle-branch block, paced rhythm, or an uninterpretable ECG were excluded. Quantitative measurements were made in all 12 leads and lead V4R of the admission ECG on a digitizer board (Sigma Scan, Summasketch). Anterior ST-segment depression was defined as ST-segment depression of ≥0.5 mV in ≥2 precordial leads.
Follow-up was ≥6 months. Data on vital status and follow-up events, including cardiac and noncardiac death, nonfatal reinfarction, and need for TVR (PTCA, CABG), were obtained from hospital records, death certificates, and general practitioner questionnaire.
Means and SDs were calculated for continuous variables, and absolute and relative frequencies were measured for discrete variables. Differences between groups were tested by the χ2 test or Fisher’s exact test in the case of discrete variables and by a 2-sample t test in the case of continuous variables. Multiple logistic regression was used to test the independent contribution of univariate risk predictors. Cumulative hazard function plots were generated with the Kaplan-Meier method. Differences were examined by the log-rank statistical test. For subgroup analysis, patients were split into cTnT-positive and cTnT-negative groups. The end points studied were 30-day mortality, long-term all-cause mortality, long-term cardiac mortality, and the combined end point of death, nonfatal reinfarction, and TVR (PTCA, CABG). For all statistical evaluations, a 2-sided P<0.05 was considered statistically significant. For all statistical analyses, a commercially available statistical package (SPSS system 8.0) was used.
Clinical Characteristics on Admission
Of the 159 patients included, 93 patients (58%) were cTnT-positive. Admission characteristics are displayed in Table 1⇓. Both groups compared favorably with respect to most clinical, hemodynamic, and ECG variables.
CTnT-positive patients had significantly longer time intervals from symptom onset to therapy than cTnT-negative patients (7.26 versus 4.11 hours, P<0.001), developed higher peak levels of C-reactive protein (77.4 versus 42.8 mg/L, P<0.001), and tended to stay longer (56.6 versus 39.1 hours, P=0.082) in the intensive care unit.
Angiographic Characteristics and Procedural Success After Direct PCI
CTnT groups were comparable for baseline angiographic characteristics, as listed in Table 2⇓. In 2 patients (1.3%), severe hemodynamic compromise prohibited transportation to the catheterization laboratory.
Although the rates of patients who received early angiography (98.9% versus 98.5%, P=1.0) and attempted direct PCI (93.3% versus 98.5%, P=0.241) were comparable between cTnT-positive and cTnT-negative patients, significantly more patients with a positive cTnT on admission (22.1% versus 3.1%, P<0.001) had unsuccessful direct PCI.
In the entire group, the rate of coronary stenting was 55.3%; 22% received GP IIb/IIIa antagonists (abciximab). An intra-aortic balloon pump was inserted in 4.4% for cardiogenic shock. There was a tendency for more frequent use of abciximab (26.9% versus 15.1%, P=0.085) and more frequent embolization of thrombi (8.6% versus 1.5%, P=0.082) during angioplasty among cTnT-positive versus cTnT-negative patients.
ECG Analyses According to Admission cTnT
ECG recordings useful for quantitative analysis of ST-segment deviations were available in 149 of the 159 patients. Detailed results are displayed in Table 1⇑.
Short-Term and Long-Term Outcome of Patients According to Admission cTnT
cTnT-positive patients had higher in-hospital cardiac mortality rates (10.8% versus 1.5%, P=0.027) and tended to have higher rates of reinfarction (4 of 93 versus 0 of 66, P=0.088). The rates of other major prehospital and in-hospital complications, including ventricular fibrillation, complete AV block, development of cardiogenic shock during follow-up, and the need for catecholamines, atropine, or temporary pacemaker therapy, were comparable in both groups (Table 3⇓).
Long-term all-cause mortality (18.3% versus 6.1%, P=0.032) and cardiac mortality (17.2% versus 4.5%, P=0.023) were significantly higher in patients with elevated cTnT (Figure 1⇓, top). In contrast, rates of the combined end point were not different (Figure 1⇓, bottom) because of a high rate of CABG procedures in the cTnT-negative patients (Table 4⇓).
The final multivariate regression model testing the contribution of univariate risk predictors is displayed in Table 5⇓. After adjustment, only cardiogenic shock and older age remained independent predictors of long-term prognosis, whereas cTnT was a strong albeit not independent predictor indicating an ≈5-fold-higher mortality risk (P=0.089).
Impact of Coronary Stenting
The rate of coronary stenting was significantly lower among cTnT-positive versus cTnT-negative patients (48.4% versus 65.2%, P=0.043). In the former, stenting reduced cardiac mortality rates at 30 days (17.2% versus 2.2%, P=0.03). This effect tended to persist until the end of follow-up (23.4% versus 8.9%, P=0.089; Figure 2⇓, top). In contrast, survival rates in the cTnT-negative patients were not affected by stenting (0% versus 4.3%, P=0.35, at 30 days; 2.3% versus 8.7%, P=0.28, at the end of follow-up).
Stenting also reduced the rates of the combined end point in both the cTnT-positive (4.4% versus 36.2%, P<0.001, at 30 days; 6.9% versus 26.1%, P=0.055, at end of follow-up) and cTnT-negative patients (11.1% versus 46.8%, P<0.0005, at 30 days; 16.3% versus 39.1%, P=0.08, at the end of follow-up). The effect of stenting was driven by lower rates of TVR. However, even for the combined end point, benefits of stenting tended to be more prominent in the cTnT-positive patients (Figure 2⇑, bottom).
Patients with inferior AMI are considered to have a better prognosis than anterior AMI patients, probably because of smaller infarct size,1 16 although pooled analysis reveals beneficial effects of thrombolytic therapy in inferior AMI. Although its value has been questioned in uncomplicated inferior AMI, the benefits of thrombolytic therapy are established in particular high-risk categories.1 17 Thus, risk assessment in inferior AMI is paramount for the appropriate selection of treatment modalities.
Recently, it was observed that an elevated admission cTnT is associated with a higher risk for cardiac events in patients with ST-segment elevation AMI.10 11 12 First, the GUSTO-IIa study group found that in-hospital event rates were higher in cTnT-positive than in cTnT-negative patients with ST-segment elevation AMI (13.0% versus 4.7%).10 Consistently, Stubbs et al12 reported higher mortality rates at 30 days (11% versus 4%) and at 3 years (28.2% versus 7.5%) in cTnT-positive patients. Those authors speculated that cTnT-positive patients were admitted significantly later after onset of symptoms than cTnT-negative and thus benefited less from thrombolytic treatment. In the GUSTO-III troponin substudy, 12 806 patients were studied prospectively for cardiac events according to their cTnT status on admission.11 Again, cTnT positivity was found to indicate a subgroup with a 3-fold-higher cardiac event rate than cTnT-negative patients. Two aspects were particularly interesting in this trial. First, with respect to cardiac mortality, the admission cTnT value discriminated between high- and low-risk subgroups in both anterior (18.7% versus 8.5%) and inferior (14.5% versus 3.9%) AMI. Second, the duration from onset of symptoms to admission did not correlate with mortality in cTnT-positive patients. Mortality rates for patients presenting between 0 and 2 hours, 2 and 4 hours, 4 and 6 hours, and beyond 6 hours were 14.5%, 15.0%, 17.1%, and 16.7%, respectively. These findings imply that duration of myocardial ischemia before recanalization therapy is not the main cause of excess mortality in cTnT-positive patients. Furthermore, excess mortality was comparable in the patients treated by recombinant tissue plasminogen activator (15.2% versus 6.2%, P=0.0001) or tissue plasminogen activator (16.4% versus 6.1%, P=0.0001). The authors argued that higher rates of reperfusion failures may have accounted for differences in mortality. The FRISC trialists14 and Ramanathan and coworkers14 reported lower rates of TIMI grade 3 flow after thrombolytic therapy in patients with a positive admission cTnT, providing indirect support for the hypothesis of the GUSTO-III investigators. A possible alternative explanation has recently been added by the FRISC trialists, who found that repeated episodes of chest pain shortly before the onset of AMI were more often present among cTnT-positive patients and were independent indicators of long-term mortality.13
In our study, a positive cTnT indicated a significantly higher 30-day (10.8% versus 1.5%, P=0.027) and long-term (17.2% versus 4.5%) cardiac mortality. Even after adjustment, a positive cTnT result was associated with a 5-fold-higher risk of subsequent cardiac death. cTnT was superior to ECG risk predictors, including right ventricular involvement, concomitant anterior ST-segment depressions, or complete AV block, and proved a strong albeit not independent predictor when corrected for older age and cardiogenic shock.
The reason for the observed hazard is unclear but may involve longer time intervals to reperfusion therapy, less effective reperfusion, and previous myocardial damage from repeated episodes of unstable angina before the definite onset of AMI. Although our data do not allow comment on the latter, we found that reperfusion therapy was less effective in cTnT-positive patients. Direct PCI was attempted in a comparable proportion of cTnT-positive and cTnT-negative patients. However, lower rates of successful reperfusion (77.9% versus 96.9%, P<0.001) were achieved in the cTnT-positive patients.
There is a strong interrelationship between appearance of cTnT in blood and elapsed time to admission. Although mean time intervals from onset of symptoms to reperfusion were significantly longer in cTnT-positive than in cTnT-negative patients (7.26±5.99 versus 4.11±2.73 hours, P=0.001), time intervals between nonsurvivors and survivors were comparable (5.99±5.17 versus 5.64±5.03 hours, P=0.562). In multivariate analysis, the prognostic role of cTnT did not change after correction for elapsed time risk (OR, 4.4; 95% CI, 0.74 to 25.7; P=0.10), nor did time intervals per se indicate an adverse prognosis (OR,1.03; 95% CI, 0.9 to 1.2; P=0.68).
Coronary stenting has been reported to improve coronary flow reserve and to reduce rates of death, nonfatal AMI, and TVR in ST-segment elevation AMI.18 Consistently, our study disclosed a risk reduction for the composite end point in both cTnT groups that was more prominent in cTnT-positive patients. With respect to cardiac mortality, risk reduction was almost exclusively confined to cTnT-positive patients. Thus, stenting reduced the cardiac mortality rates to the rates observed in cTnT-negative patients. Our findings comply with results observed in patients with refractory unstable angina and non–Q-wave AMI.19 In these trials, beneficial effects of GP IIb/IIIa receptor antagonists were nearly exclusively restricted to the cTnT-positive patients, whereas cTnT-negative patients did not benefit.
It is tempting to speculate that besides differences in the efficiency of restoring coronary blood flow in epicardial arteries, more severe microvascular damage and reduced microvascular reflow may have contributed to the excess mortality rates in cTnT-positive patients.20 21 In addition, larger thrombus burden or higher rates of rethrombosis may have contributed. Because of the small number of patients treated, the effects of GP IIb/IIIa receptor antagonists could not be explored in our study. Although there is some preliminary evidence for a therapeutic benefit of GP IIb/IIIa antagonists in patients treated with direct PCI or in conjunction with thrombolytics22 23 for ST-segment elevation AMI, future randomized trials are mandatory to test whether addition of GP IIb/IIIa antagonists or thrombolytic agents may result in further reduction in the cardiac event rate in cTnT-positive patients treated by stent placement.
Several points must be stressed when our findings are extrapolated. First, results in this study were obtained in patients who underwent PCI and may not relate to patients treated by thrombolytics. Second, although admission cTnT remained a powerful predictor of adverse outcome after adjustment for longer time intervals from onset of symptoms to therapy, it must be acknowledged that the study may have been underpowered to fully exclude a potential relationship between duration of ischemia and cTnT admission status because of small sample size and low event rates. Third, patients in this cohort study were not randomly allocated to coronary stenting or treatment with GP IIb/IIIa antagonists. Therefore, unforeseen bias cannot be ruled out. In addition, although left ventricular ejection fractions and peak CK-MB activities were comparable in both cTnT groups, it cannot be excluded with certainty that cTnT-positive patients may have experienced larger infarcts. Finally, the mechanism by which a positive admission cTnT is linked to a higher cardiac event rate remains speculative. To test for the hypothesis of a higher microcirculatory resistance and poorer reflow in nonstented cTnT-positive patients, further studies with velocity probe measurements are warranted.
Inferior AMI patients with a negative cTnT have very low cardiac event rates and high success rates of mechanical recanalization. In these patients, additional stent implantation does not translate into an improved overall survival rate but reduces only the long-term composite event rate, which is largely driven by TVR. In contrast, patients with a positive cTnT seem to behave differently. These subjects have a higher failure rate of direct PCI and remain a high-risk group even when PCI is deemed successful as determined by visual assessment of TIMI flow. These patients benefit from coronary stenting with respect to cardiac mortality and rates of death, nonfatal AMI, and TVR. Our study using PCI in inferior AMI in aggregate with previous studies leaves little doubt that the cTnT admission value is a valuable risk indicator in ST-segment elevation AMI and may aid in the selection of patients in whom stenting may be beneficial.
Dr Katus developed and patented the troponin T assay in cooperation with Roche Co, Germany.
- Received May 4, 2000.
- Revision received June 6, 2000.
- Accepted June 6, 2000.
- Copyright © 2000 by American Heart Association
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