Long-Term Angiographic Follow-Up of Coronary Balloon Angioplasty in Patients With Diabetes Mellitus

A Clue to the Explanation of the Results of the BARI Study

1.1 Patients and Angiographic Procedure

Between September 1989 and August 1991 (within the time period of enrollment of patients in BARI) 2,587 coronary angiography and 1,385 percutaneous transluminal coronary angioplasty procedures were performed at the Hadassah University Hospital. In 572 cases, a previous angiogram obtained at least 1 month earlier in our laboratory was available for comparison. Our study comprised 353 pairs of coronary angiograms from 248 patients (1.4 ± 0.6 [mean ± SD] repeat diagnostic angiograms/patient) who underwent balloon angioplasty at the initial procedure. Patients who underwent dilation of a bypass graft were excluded. Referral for angiography was made by the patient’s attending physician according to common clinical practice: stable or unstable angina or a myocardial infarction in 326 patients and planned angioplasty in 27 patients who initially underwent only partial revascularization, with further angioplasty postponed >1 month (none of these patients participated in a research protocol that required angiographic follow-up after angioplasty). The time interval between the first and second catheterization was 250 ± 305 days (25, 50 and 75 percentiles: 94, 172 and 333 days, respectively).

Coronary angiography was undertaken using 4.5-in. image intensifier mode with an overframing lens to achieve maximal optical magnification of the arteries. Multiple oblique views were taken to define the details of each coronary narrowing. Coronary balloon angioplasty was performed using standard technique (in no patient was an alternative device, such as a stent, atherectomy catheter or rotablator used).

1.2 Data Analysis

Coronary angiograms were reviewed in pairs by an experienced angiographer (Y.R.) who had no knowledge of the patient’s clinical information (specifically, whether the patient was diabetic or nondiabetic). The severity of the stenosis was measured on a single end-diastolic frame in the projection with the most severe stenosis by means of a high magnification projector and mechanical calipers. A special attempt was made to choose the same projection in the pair of angiograms when analyzing each of the narrowings for 1) the presence and severity of restenosis in the dilated narrowings, and 2) progression/regression of narrowings not dilated during the angioplasty procedure. Diameters were measured twice (>6 months apart) in 54 narrowings by the same observer (Y.R.), to assess the intraobserver variability. The second measurement was performed in blinded manner with regard to the specific frame or projection in which the initial measurements had been made. The standard deviation of the difference between the two measurements was 0.41 mm, 0.28 mm and 8.6% for normal arterial diameter, lumen narrowing diameter and percent stenosis, respectively. A more detailed description of the method of measurement appears elsewhere [13].

1.3 Definitions

Successful angioplastywas defined as <50% residual diameter stenosis without major complications (death, emergency coronary artery bypass or Q wave myocardial infarction). Restenosiswas defined as >50% diameter stenosis at follow-up angiography after successful angioplasty (in any location that was subjected to balloon inflation during the angioplastic procedure).

Progression/regressionwas defined as an increase/decrease in diameter stenosis >20%. New narrowingwas defined as >20% diameter stenosis, present only on the second angiogram. Progression/regression and new narrowing were defined only for coronary artery sites that were not subjected to previous balloon inflation (nondilated narrowing). We used the 20% cutoff (2.5 times the standard deviation of the difference between repeated measurements) to ensure that the difference in the measured stenosis severity did not reflect an inaccuracy in the method of measurement. This value has been used previously by us [14]and others [15]to define a definite change in diameter stenosis of a coronary narrowing.

The angioplasty arterywas defined as one of the three major coronary arteries (including major branches) in which at least one narrowing was dilated by angioplasty. Nondilated narrowingswere classified according to their relation to the angioplasty artery [14].

1.4 Statistical Analysis

Data were analyzed using SAS software. Chi-square and ttests were used for between-group comparisons. The rate of appearance of new narrowings over time was compared among groups by means of life-table analysis. In the life table, each new narrowing was counted at the time of its detection (the second catheterization). The Kaplan-Meier method was used to construct life tables, and the log-rank test was used for comparisons among groups. Treated diabetes mellituswas defined as diabetes involving the use of insulin or oral hypoglycemic agents; p < 0.05 was considered statistically significant.

2.1 Baseline Angiography

Table 1describes the clinical and angiographic baseline characteristics of the study patients (55 with and 193 without diabetes mellitus). There was no difference in the number of narrowings/angiogram (an index of diffuse disease) between groups (2.5 in diabetic, 2.6 in nondiabetic patients). The lumen diameter of the normal artery was slightly smaller, the minimal lumen diameter of the narrowings significantly smaller and percent diameter stenosis slightly higher in diabetic than nondiabetic patients. Initial revascularization tended to be more complete in diabetic patients: 60% of all narrowings and 1.27 ± 0.48 arteries/patient were dilated after the initial angiogram (vs. 53% of narrowings and 1.17 ± 0.45 arteries/patient in nondiabetic patients: p = 0.11 for narrowings, p = 0.09 for arteries/patient). However, although the normal artery and minimal lumen narrowing diameters of dilated narrowings were similar in diabetic and nondiabetic patients, they were significantly smaller in the nondilated narrowings of diabetic patients.

2.2 Follow-Up Angiography

Table 2describes the findings at follow-up angiography. The rate of restenosis was slightly higher (although not statistically significant) in diabetic patients, but the severity of the narrowings with restenosis was similar in the two groups. The rates of progression and regression of narrowings were similar in diabetic and nondiabetic patients; however, narrowings with progression reached a higher percent stenosis in diabetic patients (91% vs. 74%, p = 0.03).

The main difference between diabetics and nondiabetic patients was in the appearance of new narrowings (Table 2). There was a 22% increase in the number of narrowings on the follow-up angiogram in diabetic patients (38 new, 174 preexisting narrowings) compared with 12% (86 new, 734 preexisting narrowings) in nondiabetic patients (p < 0.004). The number of new narrowings was higher in diabetic patients when measured either per patient or per angiographic pair. Even though according to our definition, a new narrowing could have been a mild, nonsignificant lesion (close to 20% diameter stenosis), most of these narrowings were important, with a mean diameter stenosis >60% and similar stenosis severity in diabetic and nondiabetic patients (Table 2).

2.3 Effect of Angioplasty on Appearance of New Narrowings

To examine the effect of angioplasty on the appearance of new narrowings (in diabetic and nondiabetic patients), we compared the appearance rate of these new narrowings in the angioplasty and nonangioplasty arteries. New narrowings were located in 57 (13.6%) of 420 angioplasty arteries and in 54 (8.5%) of 639 nonangioplasty arteries (p = 0.01). As we showed before, new narrowings were more common in diabetic patients (31 [14.8%] of 210 arteries) than in nondiabetic patients (80 [9.4%] of 849 arteries, p = 0.03). Fig. 1describes the proportion of arteries with new narrowings for angioplasty versus nonangioplasty arteries in patients with and without diabetes mellitus. The highest proportion (16.9%) was observed in the angioplasty artery of diabetic patients; an intermediate value was found in the nonangioplasty artery of diabetic patients (13.2%) and in the angioplasty artery of nondiabetic patients (12.7%); and the lowest proportion was found in the nonangioplasty artery of nondiabetic patients (7.3%, p = 0.009). The findings were similar when the rate of detection of new narrowings as a function of the time interval between catheterizations was compared among groups using the life-table method (Fig. 2).

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Fig. 1

Percent of arteries with new narrowings at follow-up angiography after angioplasty. DM(+) = diabetic patients; DM(−) = nondiabetic patients; n = number of arteries in each group; PTCA(+) = angioplasty artery; PTCA(−) = nonangioplasty artery.

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Fig. 2

Rate of appearance of new narrowings in the various groups presented as a function of the time interval between coronary angioplasty and follow-up angiography. Abbreviations as in Fig. 1.

3.1 Baseline Variables

Coronary atherosclerosis is more extensive in diabetic than in nondiabetic patients [16, 17]. Multivessel disease is a common finding at autopsy and was observed in >75% of asymptomatic diabetic patients [17]. However, diabetic patients who are selected for coronary angioplasty form a special subset not representative of all diabetic patients because patients with diffuse disease are not considered suitable candidates for angioplasty. There was no significant difference in our study group between patients with and without diabetes in the number of narrowings/patient (a measure of diffuse disease), and even though diabetic patients tended to have smaller arteries with slightly more severe diameter stenosis, the differences were small and of questionable clinical significance. Other investigators [12]found slightly more diffuse disease in the diabetic patients who underwent angioplasty compared with nondiabetic patients, but only one-third of them had multivessel disease (only 6.6% with three-vessel disease), and there was no difference in left ventricular ejection fraction. Thus, at least according to angiographic criteria, the extent of atherosclerotic involvement is similar in diabetic and nondiabetic patients who are selected for balloon angioplasty. Therefore, even if baseline variables have some contribution to the poor long-term outcome of diabetic patients after angioplasty, they are not the major determinant.

3.2 Procedural Outcome and Restenosis

Procedural outcome and major in-hospital complications are similar in diabetic and nondiabetic patients [12]. This similarity is probably due to better selection of the patients in both groups, so that the success rate of coronary angioplasty is high and complications rare. In our study, the dilated narrowings had similar normal diameters and diameter stenosis in diabetic and nondiabetic patients. Restenosis is probably more common in diabetic patients [12, 18–21]and can explain their higher rate of repeat interventions during the first year after angioplasty [12]. However, other investigators [22, 23]could not find an association between diabetes mellitus and restenosis, suggesting that even if diabetic patients have a higher restenosis rate, this higher rate not sufficient to explain the observed difference in long-term outcome. Moreover, although restenosis can explain differences among groups within the first year after angioplasty, most of the difference in the long-term outcome between diabetic and nondiabetic patients occurred after the first year [12]. Additionally, restenosis is rarely associated with myocardial infarction and death [24], so restenosis does not explain the poor outcome of diabetic patients who underwent angioplasty in BARI.

3.3 Disease Progression

The curves comparing survival, freedom from myocardial infarction and freedom from bypass surgery between diabetic and nondiabetic patients diverge mainly >1 year after angioplasty [12]. A similar finding is observed in the survival curves of diabetic patients after coronary angioplasty or bypass surgery in BARI [1]. Adverse events >1 year after intervention are usually explained by disease progression. Our analysis shows that the main difference between diabetic and nondiabetic patients is in the rate of appearance of new narrowings. New narrowings are more frequently unstable and may be associated with death or unstable angina and myocardial infarction (both of which require frequently revascularization) [25, 26]. In a previous study [15], we showed that new narrowings appear more commonly in the angioplasty than the nonangioplasty artery. This finding was also confirmed in the present study (13.6% vs. 8.5%, angioplasty vs. nonangioplasty arteries with new narrowings—60% increased risk), and we also showed that new narrowings appeared more often in diabetic patients (14.8% vs. 9.4% of arteries with new narrowings in diabetic vs. nondiabetic patients—57% increased risk). The combined effect of angioplasty and diabetes mellitus is additive (16.9% vs. 7.3% of angioplasty arteries of diabetic patients vs. nonangioplasty arteries of nondiabetic patients—132% increased risk); thus, the risk of development of new narrowings in the angioplasty artery of diabetics is especially high.

We suggested that mechanical trauma to the artery during angioplasty could accelerate disease progression and the appearance of new narrowings in angioplasty arteries, whereas normalization of flow rate and pattern, especially in arteries without restenosis, attenuated the rate of atherosclerosis progression in these arteries [15]. New narrowings appeared in that study [15]more commonly in the angioplasty artery both proximal and distal to the site of balloon inflation, but the numbers were too small to conclude whether proximal location is associated with a higher risk. Diabetic patients may exhibit accelerated intimal hyperplasia in response to vascular injury. Such proliferative response has been seen in the mesangium of the kidney in diabetic patients [27]. Insulin induces growth of human vascular smooth muscle cells [28], and the hyperinsulinemia in treated diabetic patients (both insulin-dependent and noninsulin-dependent diabetes mellitus) might be responsible for the higher rate of appearance of new narrowings (in angioplasty and nonangioplasty arteries). We believe that the balance between response to trauma and normalization of flow (by coronary angioplasty) determines the final tendency of the artery to demonstrate disease progression in both diabetic and nondiabetic patients. An accelerated rate of atherosclerosis progression and appearance of new narrowings are seen in angioplasty and nonangioplasty arteries, but since the effect of diabetes mellitus and angioplasty is additive, the risk is especially high in the angioplasty arteries of diabetic patients.

3.4 Comparison Between Coronary Angioplasty and Bypass Surgery in Diabetic Patients

Although this study analyzed only the outcome of coronary angioplasty in diabetic patients, our findings can offer a clue to the better long-term outcome of diabetic patients after bypass surgery than after angioplasty [1]. The prognosis of diabetic patients with coronary artery disease is poor compared with nondiabetic patients regardless of the method of treatment (medical therapy, angioplasty or coronary artery bypass) [8–12, 29]. When various treatment modalities are randomly compared among diabetic patients (e.g., angioplasty and bypass surgery), baseline variables are usually similar because of the randomization process. Variations between the therapeutic strategies should be expected if 1) there is a difference in procedural outcome, or 2) the procedure itself accelerates the progression of atherosclerosis, above the general tendency for accelerated atherosclerosis that is well known in diabetic patients. Because there was no difference in immediate outcome between bypass surgery and angioplasty in diabetic patients [1], the observed difference in BARI can be explained not only by a higher restenosis rate diabetic patients, but also by our finding of the additive effect of diabetes mellitus and angioplasty on new lesion formation. This effect is specific to angioplasty, and a higher risk in patients with at least two coronary arteries instrumented during the angioplastic procedure (most of the BARI population) should be expected.

3.5 Limitations of the Study

This was a retrospective study. Patients had their second catheterization only when clinically indicated. Patients with restenosis or disease progression, or both, are thus overrepresented in our study (both diabetic and nondiabetic patients). To overcome the variations in the time interval between catheterizations, we used the life-table method and analyzed the appearance of each new narrowing according to the time of its detection. The retrospective design of this study introduces two other potential sources of error: 1) No specific attempt was made to control for changes related to variation in coronary tone, although most our patients received pretreatment with a combination of oral nitrates and a calcium channel blocking agent. 2) Although angiograms were reviewed in pairs and a special attempt was made to use similar projections to assess the severity of a specific narrowing on both angiograms, the exact positions of the X-ray gantry in the first angiogram were not reproduced during the later study. Recognizing these sources of inaccuracy, we elected to use a 20% cutoff for the definition of disease progression/regression. We believe that this large value allows for a wide margin of safety and ensures specific determination of progression/regression. However, these limitations preclude sensitive detection of subtle changes in coronary narrowings.

3.6 Conclusions

The combination of diabetes mellitus and an artery that was instrumented during balloon angioplasty is additive and increases the risk of formation of new narrowing in that artery. This finding may explain some of the high adverse event rates observed in diabetic patients in the angioplasty arm of the BARI study, most of whom had at least two arteries/patient treated by angioplasty.