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Circulation. 1996;93:2097-2105

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(Circulation. 1996;93:2097-2105.)
© 1996 American Heart Association, Inc.

Articles

Diabetics With Coronary Disease Have a Prevalence of Asymptomatic Ischemia During Exercise Treadmill Testing and Ambulatory Ischemia Monitoring Similar to That of Nondiabetic Patients

An ACIP Database Study

Presented in part at the 43rd Scientific Session of the American College of Cardiology, Atlanta, Ga, March 14-18, 1993, and published in abstract form (J Am Coll Cardiol. 1994;23:318A).

Eugene A. Caracciolo, MD; Bernard R. Chaitman, MD; Sandra A. Forman, MA; Peter H. Stone, MD; Martial G. Bourassa, MD; George Sopko, MD; Nancy L. Geller, PhD; C. Richard Conti, MD; for the ACIP Investigators1

From the St Louis (Mo) University Health Sciences Center (E.A.C., B.R.C.); the Maryland Medical Research Institute (S.A.F.), Baltimore; Brigham & Women's Hospital (P.H.S.), Boston, Mass; the Montreal (Quebec) Heart Institute (M.G.B.); the National Heart, Lung, and Blood Institute (G.S., N.L.G.), Bethesda, Md; and the University of Florida (C.R.C.), Gainesville.

Correspondence to Eugene A. Caracciolo, MD, Cardiac Catheterization Laboratory, St Louis University Health Sciences Center, 3635 Vista Ave and Grand Blvd, St Louis, MO 63110.


*    Abstract
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 *Abstract
down arrowIntroduction
 down arrowMethods
 down arrowResults
 down arrowDiscussion
 down arrowReferences
 
Background There are conflicting data as to whether diabetics have a higher prevalence of asymptomatic ST-segment depression during exercise treadmill testing (ETT) and ambulatory ECG (AECG) monitoring. This study was conducted to determine whether diabetic patients with coronary disease enrolled in the Asymptomatic Cardiac Ischemia Pilot (ACIP) have more episodes of asymptomatic ischemia during ETT and 48-hour AECG monitoring than nondiabetic patients and to compare differences in angiographic variables and the magnitude of ischemia as measured by standard ETT and AECG criteria.

Methods and Results Angiographic variables and the prevalence and magnitude of ischemia during the qualifying ETT and 48-hour AECG were compared by the presence and absence of diabetes mellitus in 558 randomized ACIP patients. Seventy-seven patients had a history of diabetes and were taking oral hypoglycemics or insulin (diabetic group); 481 patients did not meet these criteria (nondiabetic group). Multivessel disease (87% versus 74%, P=.01) was more frequent in the diabetic group. The percentages of patients without angina during the ETT were similar in the diabetic and nondiabetic groups (36% and 39%, respectively). Time to onset of >=1-mm ST-segment depression and time to onset of angina were similar in both groups. The percentages of patients with only asymptomatic ST-segment depression during the 48-hour AECG were similar in the diabetic and nondiabetic groups (94% versus 88%, respectively). However, total ischemic time per 24 hours (15.0±21.4 versus 23.6±31.1 minutes, P=.02), ischemic time per episode (6.3±4.6 versus 9.0±8.7 minutes, P<.01), and the maximum depth of ST-segment depression tended to be less in the diabetic group.

Conclusions Patients enrolled in ACIP were selected on the basis of an abnormal ETT and 48-hour AECG and ability to undergo coronary revascularization. When patients with diabetes mellitus were compared with those without diabetes, there was a similar prevalence of asymptomatic ischemia during ETT and 48-hour AECG monitoring. Despite more extensive and diffuse coronary disease, diabetic ACIP patients tended to have less measurable ischemia during the 48-hour AECG.


Key Words: diabetes mellitus • coronary disease • ischemia • exercise


*    Introduction
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 up arrowAbstract
 *Introduction
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 down arrowResults
 down arrowDiscussion
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Patients with diabetes mellitus are at significantly increased risk for the development of coronary atherosclerosis1 2 3 4 5 and may experience "silent" myocardial infarction in the absence of chest pain.6 7 8 9 10 11 However, there are conflicting data as to whether diabetic patients with coronary disease have a higher prevalence of asymptomatic ischemia during ETT and AECG monitoring compared with nondiabetic patients. Although some have reported a higher prevalence of asymptomatic ischemia in diabetic patients during ETT12 13 14 15 and AECG monitoring,15 others have shown a similar prevalence of asymptomatic ischemia in diabetic and nondiabetic patients during ETT.16 17 Development of an autonomic neuropathy that can be histologically characterized18 and physiologically demonstrated12 19 20 21 22 23 is postulated as a mechanism responsible for the defective anginal warning system attributed to diabetic patients.

The ACIP study is a National Heart, Lung, and Blood Institute–funded international randomized trial designed to compare the efficacy of three treatment strategies—(1) angina-guided therapy, (2) angina-guided plus ambulatory AECG ischemia–guided therapy, and (3) revascularization therapy—to suppress AECG-documented ischemia at 12 weeks of follow-up and to assess the feasibility of conducting a larger clinical trial to evaluate the effects of anti-ischemic therapy on morbidity and mortality.24 The study results show that asymptomatic ischemia is frequent and can be suppressed in {approx}50% of patients with medication or revascularization and that revascularization was the most effective treatment strategy to reduce ischemia. The pilot study demonstrated that a large-scale clinical trial addressing the issue of the effect of anti-ischemic strategy on long-term cardiovascular morbidity and mortality is needed and that a large clinical trial is feasible.25

The objective of this report was to address three clinically important questions among a group of patients selected for the presence of coronary disease, ischemia during an ETT, and asymptomatic ischemia during AECG monitoring: (1) Do diabetics have significantly more episodes of asymptomatic ischemia during ETT and 48-hour AECG monitoring than nondiabetic patients? (2) Are there measurable differences in the magnitude of ischemia evaluated by standard ETT and AECG monitoring in diabetic and nondiabetic patients? and (3) Are there measurable differences in angiographic variables that may explain the differences in ischemia manifestations between the two groups?


*    Methods
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 up arrowAbstract
 up arrowIntroduction
 *Methods
down arrowResults
 down arrowDiscussion
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The design of the ACIP study and baseline characteristics of patients recruited have been reported previously.24 26 Briefly, patients were eligible for inclusion into ACIP if they had objective evidence of stress-related ischemia during an ACIP protocol ETT, had at least one episode of asymptomatic ischemia during 48-hour AECG monitoring, and had one or more stenoses of >=50% reduction in lumen diameter in a major epicardial vessel suitable for revascularization. The patients were ineligible if they had undergone coronary artery bypass graft surgery within the previous 3 months or coronary angioplasty within the previous 6 months; had had a myocardial infarction in the previous 4 weeks; had unstable angina, left ventricular failure (New York Heart Association functional class III or IV), or significant noncardiac illnesses at the time of screening; were taking digitalis; had a contraindication to ß-blocking or calcium channel blocking agents; or had inadequate anginal control on medical therapy. The screening ETT and 48-hour AECG were obtained after all anti-ischemic medications except nitroglycerin had been discontinued for at least 48 hours. Postinfarction patients and patients who required background medication for control of their angina could continue to take either atenolol or diltiazem SR.

Classification of Diabetes Mellitus
The major risk factors for coronary disease by patient self-report were recorded at the time of randomization. Clinical history of diabetes mellitus (yes/no/unknown) and current therapy (oral agent/insulin/both/neither) were recorded. Ninety patients (16%) claimed a clinical history of diabetes mellitus. Of these, 13 patients were taking neither insulin nor oral medication at the time of study entry. The 77 patients (14%) with a clinical history of diabetes mellitus who were receiving insulin or oral agents constitute the diabetic group in this analysis; all other patients, including the 13 with a history of diabetes but on no medication, constitute the nondiabetic group.

Coronary Angiography and Left Ventriculography
Patients were eligible for ACIP if they had a >=50% reduction in lumen diameter as measured by electronic calipers in at least one view in one or more major epicardial coronary arteries suitable for revascularization. Major coronary arteries were defined as the left anterior descending, left circumflex, and right coronary arteries. Diagonal, circumflex marginal, and posterolateral branches were considered major vessels if they supplied a large enough area of myocardium suitable for coronary artery bypass graft surgery or percutaneous coronary angioplasty. Angiograms were characterized by single-, double-, and triple-vessel coronary artery disease. Angiographic flow distal to a stenosis was graded by TIMI criteria (TIMI grade 0 to 3).27 Angiographic collateral flow to a vascular territory distal to a stenosis was graded as grade 0 (no angiographic collaterals visualized), grade 1 (minimal collaterals present with minimal to partial filling of the recipient artery), or grade 2 (well-developed collaterals with near-complete to complete filling of the recipient artery). For each patient, the maximal collateral grade in any lesion was defined. Angiograms evaluated for eligibility were obtained within the 3 years preceding screening, provided that the patient did not have a subsequent clinical event. For those patients with three-vessel coronary artery disease, an angiogram performed within the previous 5 years was acceptable, again provided that there was no intercurrent clinical event. Suitable left ventricular systolic function was subsequently confirmed by either echocardiography or radionuclide ventriculography.

ACIP Protocol ETT
The symptom-limited ACIP exercise protocol was used; this protocol produces a more linear increase in oxygen consumption (O2) than the Bruce protocol.28 The walking speed of the ACIP protocol is set at 3 miles/h, with two 1-minute warm-up stages followed by 2-minute stages designed to increase workload by 1.5-MET increments from 2.5 to 15.1 METs. Criteria for ischemia-related ECG changes were defined as (1) ST segment level 80 ms after the J-point (ST 80) depression >=1.0 mm, ST segment horizontal or downsloping <1 mV/s; or (2) ST 80 depression >=1.5 mm and ST segment upsloping >1 mV/s compared with baseline.

48-Hour AECG Monitoring
All AECG monitoring sessions consisted of two consecutive 24-hour recordings on a two-channel AM ambulatory ECG cassette device with automatic calibration. Leads monitored were those that demonstrated the greatest ST-segment deviation during the exercise test. Specific criteria used to ensure interpretable ST-segment activity were normal sinus rhythm; QRS duration <0.1 second (except for right bundle-branch block with isoelectric ST segments in the lateral precordial leads); and no significant Q wave in the monitored leads. The R-wave height was >=15 mm in the lateral precordial leads and >=10 mm in the inferior leads. Patients were excluded if ST-segment deviation of >=1.0 mm occurred during supervised postural maneuvers and hyperventilation.

Ischemic ST-segment depression was defined as >=1 mm horizontal or downsloping below the isoelectric line compared with the baseline ST-segment value. Similarly, ischemic ST-segment elevation was defined as >=1 mm above the isoelectric line compared with the baseline ST segment. An ischemic episode was defined as ST-segment deviation >=1 minute, and the episode duration was defined as the time the ST-segment values deviated >=1 mm. The ST segment had to have returned to the baseline value for at least 5 minutes before new ST-segment deviation was considered to represent a separate ischemic episode.

Statistical Considerations
Differences between groups were analyzed by Student's t test for continuous variables and the {chi}2 test for categorical variables. The percentage of patients with ischemic ST-segment depression during the initial 10 minutes of the exercise test ({approx}9 METs) was estimated by the Kaplan-Meier method29 30 ; patients who did not complete 10 minutes of exercise for reasons other than ST-segment depression were censored without the event at the time the test was stopped. This analytical method was also used to estimate the percentage of patients with angina during the initial 10 minutes of exercise, mean time to angina onset, and mean time to onset of >=1-mm ST-segment depression.

Multivariate analyses of the relationship of AECG variables and ETT variables to the presence of diabetes were performed with adjustment for clinical, hemodynamic, and angiographic variables.

Power to detect differences between our patients with diabetes mellitus versus those without diabetes is limited. As an example, if the outcome is present among 50% of patients with diabetes, it would have to be present in <=30% of patients without diabetes for there to be a probability >=.8 to detect this difference when hypothesis testing is conducted at the .01 significance level.

To take account of the many hypotheses tested in the ACIP study, P=.01 was regarded as showing some evidence against the null hypothesis, and P=.001 was regarded as strong evidence. However, all values of P<=.05 are shown. The closure date for the analysis file was July 8, 1994.


*    Results
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Data reported here are for 558 patients. All 60 patients from one clinical unit have been excluded as previously reported.31

Baseline Clinical and Hemodynamic Characteristics
Of 558 randomized ACIP patients, 77 (14%) had a clinical history of diabetes mellitus and were taking either insulin or oral hypoglycemic agents (diabetic group). Four hundred eighty-one patients (86%) did not meet these criteria (nondiabetic group) (Table 1Down). Seventy percent of patients in both groups had anginal symptoms at the time of study entry based on history, ETT, or an ischemic episode with angina on the AECG (Table 1Down). A clinical history of hypertension (55% versus 35%, P<.001) was present more frequently in the diabetic group on study enrollment (Table 1Down). ß-Adrenergic blocking agents were used more frequently in nondiabetic than in diabetic patients (46% versus 32%, respectively, P=.02), whereas angiotensin-converting enzyme inhibitors were used more commonly in diabetic than in nondiabetic patients (18% versus 10%, respectively, P=.05) (Table 2Down). Diabetic patients had a significantly higher basal heart rate (72.9±11.1 versus 68.7±11.7 bpm, P=.003) and systolic blood pressure (146.7±18.6 versus 137.6±19.3 mm Hg, P<.001) than did the nondiabetic group (Table 1Down).


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  		Table 1. Baseline Clinical Characteristics of ACIP Patients With and Without Diabetes at the Time of Study Entry


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  		Table 2. Antianginal, Antihypertensive, and Antiplatelet Agents Taken at the Time of Study Entry

Angiographic Data From the Qualifying Catheterization
The time from the qualifying cardiac catheterization to study enrollment was almost twice as long in the diabetic group as in the nondiabetic group (160±313 versus 81±173 days, P<.01). More diabetic group patients had three-vessel disease than nondiabetic group patients (P=.03) (Table 3Down, Fig 1Down). Additionally, diabetic patients had more diffuse coronary disease as quantified by the number of lesions with a >=50% reduction in lumen diameter (Table 3Down, Fig 1Down). Approximately 40% of patients in both groups had at least one occlusion with TIMI grade 0 distal flow. Angiographic collateral grade was similar in both groups.


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  		Table 3. Angiographic Data From the Qualifying Cardiac Catheterization



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  		Figure 1. Qualifying angiography. Diabetic ACIP patients had less single-vessel disease and more three-vessel disease than nondiabetic ACIP patients. Diabetic ACIP patients also had more diffuse coronary disease compared with nondiabetic ACIP patients. Hatched bars indicate diabetic patients; solid bars, nondiabetic patients.

Left ventricular ejection fraction (61.9±10.8% versus 60.7±9.8%) and the maximum percent stenosis (89.4±13.5% versus 88.2±14.4%) were similar for the diabetic and nondiabetic groups, respectively (Table 3Up).

Qualifying ETT Results
During the ETT, the prevalences of patients without angina were similar in the diabetic and nondiabetic groups (36% versus 39%, respectively) (Table 4Down, Fig 2Down). There was no significant difference in the final stage of exercise achieved between the two groups. At peak exercise, the heart rate, systolic blood pressure, and rate-pressure product were similar for the diabetic and nondiabetic groups. At the time to 1-mm ST-segment depression, the heart rates were similar but the systolic blood pressures were higher in the diabetic group than in the nondiabetic group patients (P=.03). The rate-pressure product at the time to >=1-mm ST-segment depression was similarly higher in the diabetic than in the nondiabetic group patients (21.8±4.4 versus 20.5±4.6 mm Hg·bpmx10-3, respectively, P=.02). Both groups had similar times to onset of 1-mm ST-segment depression and times to onset of angina (Table 4Down).


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  		Table 4. Qualifying ETT Results



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  		Figure 2. Percentage of patients who were free of angina during the ETT and had only asymptomatic episodes of ischemia during the 48-hour AECG recording. Diabetic and nondiabetic ACIP patients had a similar prevalence of asymptomatic ischemia during ETT and on the 48-hour AECG recording. Hatched bars indicate diabetic patients; solid bars, nondiabetic patients.

Diabetes was not an important correlate of the ETT variables (time to onset of angina, time to onset of 1-mm ST-segment depression, sum of ST depression) by univariate analysis, and it remained nonsignificant by multivariate analysis when clinical, hemodynamic, and angiographic variables were adjusted for.

Qualifying 48-Hour AECG Test Results
By study design, all patients had at least one episode of asymptomatic ambulatory ischemia during the qualifying 48-hour AECG. The percentages of patients with only asymptomatic episodes were similar in the diabetic and nondiabetic groups (94% versus 88%, respectively, P=NS) (Fig 2Up, Table 5Down). There was no significant difference in the distribution of ischemic episodes between the two groups.


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  		Table 5. Qualifying 48-Hour AECG Test Results

Hemodynamically, the maximum heart rates recorded during ischemic episodes were similar for diabetic and nondiabetic group patients (116±16.6 versus 119±19.1 bpm, P=NS). Total ischemic time per day (15.9±21.4 versus 23.6±31.1 minutes, P=.02), minutes per episode (6.3±4.6 versus 9.0±8.7 minutes, P=.009), and mean depth of the ST-segment depression (1.7±0.7 versus 2.1±0.9 mm, P=.004) all tended to be less in the diabetic group (Table 5Up). However, diabetes was a nonsignificant correlate of the AECG variables by multivariate analysis when clinical, hemodynamic, and angiographic parameters were adjusted for.

In an attempt to define a surrogate variable of daily life activity, comparison of the maximal heart rate during the AECG as a percentage of the heart rate at ischemia onset during the ETT was performed. In the diabetic group, the maximal heart rate during the AECG as a percentage of the heart rate at ischemia onset during the ETT was lower than in the nondiabetic group (Table 6Down).


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  		Table 6. Comparison of Maximal Heart Rate During AECG Monitoring With Heart Rate at Ischemia Onset During ETT


*    Discussion
up arrowTop
 up arrowAbstract
 up arrowIntroduction
 up arrowMethods
 up arrowResults
 *Discussion
down arrowReferences
 
This study compared the diabetic and nondiabetic patients enrolled in ACIP with respect to angiographic variables and the prevalence and magnitude of ischemia. It is the first published report of a large cohort of patients with complete angiographic, ETT, and AECG data sets available. Diabetic ACIP patients did not have a higher prevalence of asymptomatic ischemia during the qualifying ETT and 48-hour AECG monitoring than nondiabetics. Surprisingly, the diabetic group tended to have less measurable ambulatory ischemia quantified by total ischemic time per day, ischemic time per episode, and maximal depth of ST-segment depression during the 48-hour AECG, even though coronary disease was more extensive and diffuse in the diabetic group, and the times to onset of 1-mm ST-segment depression and angina during the ETT were similar between the diabetic and nondiabetic groups.

Clinical and Angiographic Variables
Hypertension is present more commonly in diabetic than in nondiabetic patients. In one prospective study, hypertension was detected in more than half the diabetic patients >45 years of age.32 Similarly, 55% of diabetic ACIP patients had a history of hypertension, and the resting systolic blood pressure was significantly higher in the diabetic than in the nondiabetic group at study enrollment. Hypercholesterolemia was reported in a similar percentage of diabetic and nondiabetic patients, similar to results in the Framingham study.2

In the literature on patients with known coronary artery disease, the extent of disease is more severe in diabetic than in nondiabetic patients.33 Patients with diabetes have a higher incidence of triple-vessel disease34 35 36 and may also have more diffuse coronary disease than nondiabetic patients,37 although this issue remains unsettled.34 38 These findings are corroborated by ACIP patients, even though the interval between cardiac catheterization and study enrollment was longer in the diabetic group and therefore may have underestimated the extent of disease at the time of study entry. ACIP diabetic and nondiabetic patients had similar ejection fractions, numbers of occluded vessels, and prevalences of myocardial infarction, angina, and surgical and nonsurgical revascularization before enrollment. Although ACIP patients were selected on the basis of specific ETT and AECG criteria and eligibility for coronary revascularization, their baseline clinical and angiographic variables are similar to reported natural history studies of diabetic and nondiabetic patients.

Asymptomatic Ischemia in Diabetic Patients
Since Bradley and Schonfeld11 first reported comparisons of clinical manifestations of acute myocardial infarction in diabetic and nondiabetic patients in 1962, it has been generally accepted that diabetic patients often present with less severe chest pain than nondiabetic patients and that their presenting symptoms of cardiac events are frequently unrelated to chest pain.8 The data from the Framingham study confirmed that truly silent myocardial infarction, as documented by biennial ECGs, occurs in {approx}12% of patients and is more common in diabetic patients.6 9 These clinical findings are supported by autopsy data from patients without a clinical history of myocardial infarction, showing that myocardial scar is more likely to be present in diabetics than nondiabetics.7 10 Histological changes in intracardiac sympathetic and parasympathetic afferent fibers18 are often cited as a potential mechanism for the diminished, altered, or absent sensation of chest pain experienced by diabetic patients with acute myocardial infarction.

As an extension of these data, several investigators have reported that diabetics with known coronary disease and in unselected series have a higher prevalence of asymptomatic ischemia during ETT than do nondiabetic patients.12 13 14 15

ETT Data
Nesto et al14 compared 50 diabetic patients with 50 nondiabetic patients, all of whom had evidence of myocardial ischemia by exercise thallium scintigraphy. Although clinical characteristics, total exercise duration, and peak work double product were similar in the two groups, only 28% of the diabetic patients experienced angina during the treadmill test compared with 68% of the nondiabetic patients. However, in 20% of the diabetic and 8% of the nondiabetic patients, the test was terminated when 1 mm of ST-segment depression was reached. Additional patients in both groups might have developed angina if they had exercised longer.

The relationship between the time to 1-mm ST-segment depression and the total exercise time has been compared in diabetic and nondiabetic patients with known coronary artery disease.39 40 Defined as the anginal perceptual threshold, the perception of angina after the onset of ischemic ST-segment depression was significantly delayed in diabetics and was manifested by a significantly shorter time to 1-mm ST-segment depression in the diabetic group, with similar time to angina onset and total exercise time in both groups.39 40 In ACIP, {approx}60% of patients in both the diabetic and nondiabetic groups experienced angina during the exercise test. Because the time to onset of 1-mm ST-segment depression and the time to onset of angina (for those patients who experienced angina) were similar in both groups, the anginal perceptual threshold was not prolonged.

The ACIP ETT data are supported by data from the CASS registry.41 Among 1434 CASS registry patients with documented coronary disease who had symptom-limited exercise testing within 1 month of cardiac catheterization, there were 113 patients with a clinical history of treated diabetes mellitus and 1321 nondiabetic patients. Although the diabetic group had more severe coronary disease, the prevalence of exercise-induced asymptomatic ischemia was similar in the diabetic and nondiabetic groups (40% and 33%, respectively).

In unselected series of patients without known coronary disease, Naka et al13 compared the prevalence of asymptomatic ischemia in 132 diabetic and 140 nondiabetic patients during a symptom-limited ETT. None of the patients in either group experienced chest pain, although {approx}30% of patients in both groups had ischemic ST-segment changes. However, 39% of the diabetic group had angiographic coronary disease, which was significantly greater than the 18% in the nondiabetic group. However, two retrospective studies did not find such differences. Chipkin et al17 reported that the prevalence of asymptomatic ischemia during ETT was not significantly different in diabetic and nondiabetic patients (54% and 47%, respectively). Similarly, Callaham et al16 reported that 62% of diabetic patients with an ischemic ST response during ETT had no chest pain, similar to the 60% of nondiabetic patients.

AECG Data
Many patients with coronary disease and a positive exercise test have episodes of ST-segment depression during ambulatory monitoring, the majority of which are silent.42 43 44 45 46 47 48 49 Surprisingly, ambulatory ischemia monitoring has not been widely applied in the assessment of asymptomatic ischemia in diabetics. Chiariello et al15 compared the incidence of ambulatory ischemia during 24-hour AECG monitoring among 51 patients with diabetes (74% of whom had evidence of coronary disease), 70 nondiabetic patients with coronary disease, and 40 nondiabetic patients without overt coronary disease. They reported that 36% of the diabetic patients had at least one episode of asymptomatic ischemia, significantly higher than the 17% of patients in the nondiabetic group with coronary disease. Additionally, 73% of the total episodes of ST-segment deviation in the diabetic group were asymptomatic, significantly higher than the 60% of episodes in the nondiabetic group. These data cannot be directly compared with ACIP patients, who all had at least one episode of asymptomatic ST-segment deviation by study design. In ACIP, {approx}90% of patients had only asymptomatic ST-segment depression during the qualifying 48-hour AECG recording. There was no difference in the prevalence of asymptomatic ST-segment depression in the diabetic and nondiabetic ACIP groups.

Although the distribution of ischemic episodes was similar in the ACIP diabetic and nondiabetic groups, the diabetic group tended to have less measurable ischemia. An explanation for this trend is not readily apparent. Angiographically, more patients in the diabetic group had three-vessel disease and more diffuse coronary disease than in the nondiabetic group. Hemodynamically, the elevated systolic blood pressure recorded in the diabetic group at study enrollment may have been postulated, a priori, to contribute to a greater magnitude of ambulatory ischemia in the diabetic group. Clinically, the diabetic group was initially judged likely to be as active as the nondiabetic group, since both groups had similar exercise capacity, work double product, and maximum heart rate during the ETT. Additionally, there were no differences in the mean heart rate or maximum heart rate during the entire 48-hour monitoring session. However, in the diabetic group, the maximal heart rate during the AECG as a percentage of the heart rate at ischemia onset during the ETT was lower, suggesting that perhaps the diabetic group was, in fact, less active than the nondiabetic group (Table 6Up).

A number of investigations have focused on the possible mechanism of ambulatory ischemia. An increase in heart rate preceding ST-segment depression has been reported by some42 43 50 51 52 53 but not all15 48 54 investigators, suggesting increased myocardial oxygen demand. Similarly, an increase in systolic blood pressure preceding ST-segment depression has also been reported.43 55 Deedwania and Nelson43 showed that although the majority of ambulatory ischemic events were preceded by an increase in both the heart rate and systolic blood pressure, a significant number of events occurred without an increase in the two major measurable determinants of myocardial oxygen demand and thus were assumed to occur from coronary vasomotion. Andrews et al50 extended these findings by showing that the likelihood of developing ischemia was predicted by heart rate variables, including the magnitude and duration of the heart rate increase and the baseline heart rate before the increases in heart rate. Additionally, they showed that the efficacy of ß-adrenergic blocking therapy was in general related to reducing these same heart variables, whereas nifedipine was more effective in reducing the number of ischemic episodes not associated with preceding periods of increased heart rate. The contribution of vasomotor tone to the genesis of ambulatory ischemia is further supported by the observation that the onset of ST-segment depression during AECG monitoring is lower than the heart rate at the onset of ST-segment depression during exercise testing.43 44 45 46 47 48 49

Study Limitations
The ACIP population constitutes a well-defined cohort of patients with documented ischemia during both ETT and ambulatory monitoring and coronary disease amenable to revascularization. During screening for ACIP, {approx}36% of patients with an ischemic response during AECG monitoring were ineligible for ACIP. Since the clinical history of diabetes mellitus was obtained only on randomization, the diabetic state of these additional ACIP-ineligible patients is unknown.

ACIP data may not be comparable to previous studies, since all patients enrolled in ACIP had stable documented coronary disease and asymptomatic cardiac ischemia. The ETT and AECG data were retrospectively analyzed by the presence or absence of diabetes mellitus. A study of ACIP patients is not equivalent to a study comparing unselected patients with and without diabetes mellitus without a previous history of coronary disease or chest pain.

Clinical Implications
ACIP patients with diabetes mellitus have more extensive and diffuse coronary disease, a similar prevalence of asymptomatic ischemia during both ETT and 48-hour AECG monitoring, and less measurable ischemia during AECG monitoring than do nondiabetic ACIP patients. Although these data are not generalizable to diabetic patients without documented coronary disease, our study shows that diabetic ACIP patients become ischemic at a similar rate-pressure product and have a similar exercise capacity but do not have a higher prevalence of asymptomatic ischemia and may be less active throughout the day. In light of their predominantly asymptomatic manifestation of coronary disease, these patients may require closer clinical surveillance to alleviate myocardial ischemia.


*    Selected Abbreviations and Acronyms
 
ACIP = Asymptomatic Cardiac Ischemia Pilot
AECG = ambulatory ECG
ETT = exercise treadmill testing
MET = metabolic equivalent


*    Acknowledgments
 
This study was supported by research contracts HV-90-07, HV-90-08, and HV-91-05 to HV-91-14 from the National Heart, Lung, and Blood Institute, Bethesda, Md.


*    Footnotes
 
Reprint requests to ACIP Clinical Coordinating Center, Maryland Medical Research Institute, 600 Wyndhurst Ave, Baltimore, MD 21210.

1 A list of participating centers and investigators appears in Reference 26.26 Back

Received September 20, 1995; revision received January 24, 1996; accepted January 29, 1996.


*    References
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 *References
 

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