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J Am Coll Cardiol, 2000; 35:1502-1512 © 2000 by the American College of Cardiology Foundation |
a Rabin Medical Center, Petah Tikva, Israel
* Duke Clinical Research Institute, Durham, North Carolina, USA
Mayo Clinic, Rochester, Minnesota, USA
Cleveland Clinic Foundation, Cleveland, Ohio, USA
Manuscript received March 6, 1999; revised manuscript received November 9, 1999, accepted January 13, 2000.
Reprint requests and correspondence: Dr. David R. Holmes, Jr., Division of Internal Medicine and Cardiovascular Diseases, Mayo Clinic, 200 First St. Southwest, Rochester, Minnesota 55905
holmes.david{at}mayo.edu
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Abstract |
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We sought to compare the efficacy of primary angioplasty in diabetics versus nondiabetics and to evaluate the relative benefits of angioplasty over thrombolytic therapy among diabetics.
BACKGROUND
Primary angioplasty for myocardial infarction is at least as effective as thrombolytic therapy in the general population. However, the influence of diabetic status on outcome after primary angioplasty versus thrombolysis remains unknown.
METHODS
Patients in the Global Use of Strategies To Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) Angioplasty Substudy were randomized to receive either primary angioplasty or accelerated alteplase. The interaction of diabetic status (diabetics n = 177, nondiabetics n = 961) and treatment strategy with the occurrence of the primary end point (death, nonfatal reinfarction or nonfatal, disabling stroke at 30 days) was analyzed (power to detect a 40% relative reduction in the primary end point with alpha = 0.05 and beta = 0.20). Among patients who were randomized to and underwent primary angioplasty, procedural success (defined as residual stenosis <50% and TIMI grade 3 flow) was assessed based on diabetic status.
RESULTS
Compared with nondiabetics, diabetics had worse baseline clinical and angiographic profiles. Despite more severe stenosis and poorer flow in the culprit artery, procedural success with angioplasty was similar for diabetics (n = 81; 70.4%) and nondiabetics (n = 391; 72.4%). Outcome at 30 days was better for nondiabetics randomized to angioplasty versus alteplase (adjusted odds ratio, 0.62; 95% confidence interval, 0.41–0.96) with a similar trend for diabetics (0.70, [0.29–1.72]). We noted no interaction between diabetic status and treatment strategy on outcome (p = 0.88).
CONCLUSIONS
Primary angioplasty was similarly successful in diabetics and nondiabetics and appeared to be more effective than thrombolytic therapy among diabetics with acute infarction.
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ventricular systolic function, yet their adjusted 30-day mortality was significantly higher (8). However, vital information that could explain the worse outcome for diabetics is lacking. For example, there are few data on angiographic status before reperfusion therapy among diabetic and nondiabetic patients.
Primary angioplasty is an alternative strategy to achieve reperfusion in AMI (17), but the effect of diabetic status on angiographic and clinical outcomes of this strategy have not been well documented. Primary angioplasty may be less successful among diabetics owing to the more extensive atherosclerosis, impaired microvascular autoregulation and prothrombotic and vasospastic effects of diabetes (2,4).
The Global Use of Strategies To Open Occluded Arteries in Acute Coronary Syndromes (GUSTO-IIb) Angioplasty Substudy is the largest randomized trial to compare primary angioplasty with accelerated thrombolysis using alteplase (18). In this substudy, short-term outcomes were improved with primary angioplasty, and at six months the two strategies were comparable. The present analysis of the GUSTO-IIb Angioplasty Substudy cohort aimed to examine the impact of diabetic status on 1) the clinical and angiographic characteristics of patients before and after primary angioplasty and 2) the relative benefits of primary angioplasty versus thrombolysis for AMI.
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Methods |
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20 min with ST segment elevation 2 mm in at least two contiguous leads or left bundle branch block) were eligible. Criteria for exclusion were previous stroke, active bleeding, contraindication to heparin, serum creatinine > 177 µmol/L (>2.0 mg/dL), blood pressure > 200 mm Hg systolic or > 110 mm Hg diastolic, warfarin use at enrollment, ineligibility for angioplasty due to lack of arterial access site, childbearing potential and prior enrollment in GUSTO-II. Eligible patients were randomized in a 2 x 2 factorial design to either intravenous heparin (5,000-U bolus followed by a three- to five-day infusion at 1,000 U/h) or intravenous hirudin (0.1-mg/kg bolus followed by infusion at 0.1 mg/kg/h for three to five days) and either primary angioplasty or accelerated alteplase (15 mg intravenous bolus followed by an infusion of 0.75 mg/kg over 30 min, not to exceed 50 mg, then 0.50 mg/kg over the next hour, not to exceed 35 mg). Heparin and hirudin infusions were titrated to maintain an activated partial thromboplastin time (aPTT) of 60 to 85 s. All patients received aspirin (160 mg to be chewed at enrollment, followed by a daily dose of 80 to 325 mg); all other medications were given at the discretion of the attending physician.
Primary angioplasty was performed according to local standards, with the intent of reestablishing blood flow in the infarct artery as soon as possible. Heparin or hirudin was given after securing arterial access, but before angioplasty, at a dose titrated to reach an activated clotting time (ACT) 350 s. In general, the culprit artery was the only target. After intervention, the study drug was stopped temporarily to allow for sheath removal.
The Angiographic Core Laboratory analyzed cineangiograms with a validated edge-detection method (Artrek, version 1.69, Quinton Imaging Systems, Bothell, Washington) (20). The following variables were recorded: pre- and post-treatment Thrombolysis In Myocardial Infarction (TIMI) flow grade, minimum luminal and reference diameter dimensions and percent diameter stenosis within the treated segment. Procedural success was defined as <50% residual diameter stenosis of the treated segment with TIMI grade 3 flow. (Antegrade flow into the coronary bed distal to the obstruction occurs as promptly as into the bed proximal to the obstruction, and clearance of the contrast material occurs as promptly as clearance of material from an uninvolved bed in the same vessel or opposite artery.) Extent of coronary artery disease before angioplasty was determined by the number of major epicardial arteries with 70% stenosis; multivessel disease was defined as 70% stenosis in at least two major epicardial arteries or 50% stenosis of the left main coronary artery.
Diabetes status. Diabetes mellitus was considered present if a patient had been informed of this diagnosis and was on prescribed treatment (diet, tablets or insulin). In the study case report form, patients with diabetes mellitus were further categorized based on insulin/noninsulin treatment. Among the patients not receiving insulin, we did not record whether the treatment was diet alone or diet and tablets.
End points. The primary end point of the GUSTO-IIb Angioplasty Substudy (18) and of our analysis was a composite of overall death, nonfatal reinfarction or nonfatal, disabling stroke at 30 days, as confirmed by the clinical events committee. Reinfarction was confirmed by follow-up electrocardiogram and recurrent elevation of creatine kinase and creatine kinase-myocardial band levels. Computerized axial tomography or magnetic resonance imaging of the brain was recommended for all patients with suspected stroke. Ancillary end points included clinical event rates during hospitalization and at six and 12 months. The incidences of stroke and AMI were assessed only within the first 30 days and 180 days, respectively. Procedural success, defined above, also was assessed among patients who were randomized to and underwent angioplasty. This substudy analysis was designed to detect a 40% relative reduction in the primary end point (30-day death, nonfatal reinfarction or nonfatal disabling stroke) with alpha = 0.05 and beta = 0.20 (or power = 0.80).
Data analysis.
All analyses were performed using SAS software (SAS Institute, Cary, North Carolina). Continuous variables were summarized as medians with 25th and 75th percentiles, and categorical variables as frequencies and percentages. Prespecified baseline variables were compared with the outcome variables of interest using chi-square tests for categorical variables (likelihood ratio chi-square or Fisher exact test and Cochran-Mantel-Haenszel test for stratified tables). Analysis of variance was used to compare the means of continuous variables, while the nonparametric Wilcoxon rank-sum test was used to compare the distributions of ranked outcomes. For both diabetic and nondiabetic groups, odds ratios with 95% confidence intervals were used to compare treatments with regard to the primary end point, under the intention-to-treat principle. Logistic regression modeling was used to assess the relationships of treatment assignment (angioplasty or alteplase) and diabetic status and their interaction (if any) with the primary end point. The baseline characteristics of interest are listed in Table 1. Kaplan-Meier curves were also formulated to predict event-free survival at six months (death or reinfarction) and at 12 months (death) for diabetic and nondiabetic patients, and the curves were compared using the log-rank statistic. All tests of significance were two-tailed. Differences between groups were considered significant at p 
0.05.
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Results |
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Baseline demographic and clinical variables based on diabetic status. The diabetic patients were older, were more often women, weighed more and had a greater frequency of hypertension and peripheral vascular disease than nondiabetic patients (Table 1). Baseline systolic blood pressure and heart rate were higher in diabetics. Current smoking was more common among nondiabetics. The times from symptom onset to hospital arrival, randomization and treatment (angioplasty or alteplase) were significantly longer for diabetics. In contrast, the time from arrival to treatment was similar for both groups, although diabetics had a slightly longer time to administration of alteplase after randomization than nondiabetics. The proportions of diabetic and nondiabetic patients randomized to heparin or hirudin were similar. The use of cardiac medications before and after randomization was similar between groups, except for a greater use before enrollment of beta-adrenergic blocking agents and angiotensin-converting enzyme inhibitors in diabetics (Table 2).
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In addition, 9 (9.1%) diabetic and 24 (5.2%) nondiabetic patients randomized to angioplasty received thrombolytic therapy. Ten of these patients underwent coronary angiography and received thrombolytic therapy, and 23 received thrombolytic therapy alone and did not undergo coronary angiography.
Of the patients randomized to alteplase, 74 (95%) diabetics and 477 (96%) nondiabetics received this or another thrombolytic agent. Angiography was later performed in 53 (68%) diabetics and 305 (62%) nondiabetics, and 20 (26%) diabetics and 110 (22%) nondiabetics underwent intervention. Angiography was performed within 6 h of enrollment in 7 (14%) diabetics and 44 (16%) nondiabetics randomized to alteplase.
Among the patients randomized to angioplasty who underwent angiography, multivessel disease was more prevalent in diabetics than it was in nondiabetics (p = 0.06, Table 3). Left ventricular ejection fraction also was significantly lower in diabetics (p = 0.003). The minimum luminal diameter was smaller in diabetics (p = 0.07), as was the reference-segment diameter (p = 0.08), resulting in a greater percent diameter stenosis among diabetics (p = 0.054). Although the distribution of initial TIMI flow grades did not differ significantly between diabetics and nondiabetics, 80.7% of diabetics had TIMI grade 0 or 1 flow compared with 71.8% of nondiabetics (p = 0.10). There was no difference in culprit-artery distribution between groups.
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Discussion |
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Diabetes and factors before reperfusion therapy. Our study highlights two important pretreatment factors that may partly explain the worse outcomes of diabetics reported in prior studies. The first, the significant delay from symptom onset to hospital arrival, results in a significant delay in the administration of reperfusion treatment. This has been reported in other trials (7,8,20–22) and may partially reflect the difficulty in interpreting the electrocardiograms of diabetic patients, who frequently have complex coronary artery disease. In addition, the presenting symptoms of diabetic patients may be more difficult to relate to active ischemic heart disease.
The second factor is the significantly worse angiographic features of the culprit artery before reperfusion therapy. Current knowledge about the effect of diabetes on the angiographic characteristics of patients with AMI is based primarily on data derived from trials in which angiography was performed after thrombolysis. Our data are unique in that angiography was performed before reperfusion therapy in a large proportion of patients. Our findings show that before reperfusion treatment, diabetics have a higher incidence of TIMI grade 0 or 1 flow and more severe stenosis of the culprit artery than do nondiabetics.
Several possible mechanisms may explain the relatively greater stenosis of the culprit artery and worse flow among diabetics before reperfusion therapy. First, as mentioned above, there are significant delays until hospital arrival and treatment among diabetics. Thus, by the time reperfusion therapy is contemplated for diabetics, the occluding thrombus may be in advanced stages of organization. In addition, diabetics have increased platelet aggregatory and procoagulant activity, leading to an inherently greater incidence and rate of thrombus formation (2,11). The dynamic balance between thrombosis and endogenous fibrinolysis probably is shifted toward accelerated thrombosis in diabetics (4,11), possibly due to 1) the enhanced activation, adhesion and aggregation of platelets, 2) elevated levels of circulating procoagulant factors (such as fibrinogen, von Willebrand factor, Factor VII) and 3) impaired endogenous fibrinolysis secondary to elevation in plasminogen activator inhibitor-1 levels (2,4,11,23). Last, the severity of atherosclerosis at the site of occlusion may be greater among diabetics.
Diabetes and primary angioplasty. Due to the more extensive atherosclerosis, impaired microvascular autoregulation and prothrombotic and vasospastic effects of diabetes (2,4), angioplasty might be expected to be less effective in achieving adequate reperfusion in diabetics. Moreover, diabetics more often have complex lesions underlying the site of plaque rupture (24). However, we saw no difference in the proportions of diabetics and nondiabetics achieving a successful primary angioplasty result (TIMI grade 3 flow and <50% residual stenosis in 70.4% of diabetics and 72.4% of nondiabetics). However, moderate/severe bleeding complications were more prevalent among diabetics. Thus, primary angioplasty appears to be an effective method to achieve reperfusion among diabetics at the cost of increased bleeding complications.
Thrombolysis versus angioplasty for diabetics. Our subgroup analysis highlights several potential advantages of primary angioplasty over thrombolytic therapy for diabetics. As mentioned, primary angioplasty may reduce the time to reperfusion for diabetics compared with thrombolytic therapy. In addition, a strategy of primary angioplasty can promptly identify patients with worse left ventricular function and more extensive disease who benefit most from bypass surgery. Indeed, a larger proportion of diabetics in our cohort was referred to bypass surgery after angiography for precisely these reasons.
More important, primary angioplasty may be particularly effective in reducing recurrent ischemia and reinfarction among diabetics, which can be associated with additional mortality, morbidity and resource use in the long term (25). The benefits of primary angioplasty among diabetics may lessen over longer-term follow-up, however. Diabetes mellitus is associated with increased restenosis after balloon angioplasty and stent implantation (26–31). Because restenosis may occur more than six months after intervention, the difference in the recurrent ischemia rates between the groups in our study may subsequently have diminished.
Of note, up to six months after the acute event, primary angioplasty did not result in a survival benefit for diabetics when compared with thrombolytic therapy. Indeed, the incidence of death was greater among diabetics randomized to angioplasty. Possibly, because of the complexity of the coronary lesions in diabetics, primary angioplasty is associated with an early hazard ratio. However, at 12-month follow-up, both strategies resulted in similar survival among diabetics.
Study limitations. Several issues should be considered in interpreting these findings. In this study, the relationship of diabetic status and outcome after primary angioplasty was evaluated in patients with ST segment elevation or new left bundle branch block who were eligible to receive thrombolytic therapy. For patients presenting with other ST or T segment abnormalities, and for patients ineligible to receive thrombolytic therapy, the effect of diabetes on outcomes of reperfusion strategies may differ. Moreover, because diabetic cardiomyopathy and autonomic imbalance may predispose to arrhythmia, congestive heart failure and cardiogenic shock, diabetics may be more prone to prehospital sudden death than nondiabetics (2). Our data about angiographic characteristics before reperfusion therapy pertain only to patients who survived the initial phases of AMI. Another limitation of this study was the relatively short follow-up. In addition, owing to the advent of interventional cardiology techniques since this study was performed, including the use of intracoronary stents and antiplatelet therapy, the results in the angioplasty arm of our study may be an underestimation of current success rates (novel antiplatelet agents, however, may also improve outcome of thrombolytic therapy). Moreover, in our cohort, 10 patients received thrombolytic therapy after coronary angiography had been performed, presumably because of angiographic evidence of intracoronary thrombi. With the current widespread use of intracoronary stents and platelet glycoprotein IIb/IIIa inhibitors, these lesions would likely be treated percutaneously in current clinical practice. Thrombolysis in Myocardial Infarction 3 flow was achieved in only 83% of patients in our cohort, a significantly lower rate than in most prior studies. While this may reflect variability in core lab definition of TIMI 3 flow, it also raises the possibility that, with better angioplasty results, the relative benefit of angioplasty would be greater. Our analysis was also not a sterile comparison between two therapeutic strategies. A minority of patients randomized to angioplasty did not receive the assigned treatment (i.e., approximately 3% of patients randomized to angioplasty did not even undergo coronary angiography, and 6% of patients randomized to angioplasty received thrombolytic therapy either alone or after coronary angiography had been performed). Likewise, approximately 15% of patients randomized to alteplase underwent coronary angiography within 6 h of enrollment. Although this may slightly confound our results, our analyses were based on the intention-to-treat principle. These findings may be a truer reflection of the "real-world situation," in which coronary angiography or percutaneous coronary interventions are not performed at times, either because of logistic difficulties or because the individual operator considers the culprit lesion either too complex or unsuitable for intervention. In addition, there may be clinical evidence of reperfusion (resolution of pain or regression of ST segment elevation) before thrombolytic therapy or coronary angioplasty are initiated, obviating the need for pharmacological or mechanical reperfusion. These deviations from the study protocol, therefore, should not be viewed as severe flaws in the study, but rather a more accurate portrait of common clinical practice in the years 1994 through 1996. Finally, because patients were not randomized according to diabetic status, this study has limitations applicable to all subgroup analyses of randomized trials. For a more definitive answer concerning the relationship of diabetes and reperfusion strategy, a specifically designed study is needed.
Conclusions. In the GUSTO-IIb Angioplasty Substudy cohort, primary angioplasty was more effective than thrombolytic therapy among diabetics and nondiabetics with AMI. Angiographic success after angioplasty was achieved in similar proportions of diabetics and nondiabetics. Therefore, as with patients without diabetes, primary angioplasty should be contemplated as an alternative reperfusion strategy for diabetics presenting with AMI, if it can be performed promptly by an experienced operator.
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