Volume 96, Issue 11 , Pages 1469-1475, 1 December 2005
Does Diabetes Mellitus Abolish the Beneficial Effect of Primary Coronary Angioplasty on Long-term Risk of Reinfarction After Acute ST-Segment Elevation Myocardial Infarction Compared With Fibrinolysis? (A DANAMI-2 Substudy)
Article Outline
Little is known about the effect of diabetes mellitus on long-term clinical outcome after primary percutaneous coronary intervention (pPCI) compared with fibrinolysis in patients who have acute ST-elevation myocardial infarction. We analyzed 3-year clinical outcome in diabetic patients and nondiabetic patients who had been randomized to fibrinolysis or pPCI in the DANAMI-2 trial to compare long-term clinical outcome. The primary end point was a composite of death, clinical reinfarction, or disabling stroke. Median follow-up was 3.8 years. Among 1,572 consecutive patients who had ST-elevation myocardial infarction and were randomized to pPCI or fibrinolysis, 173 (11.0%) had diabetes mellitus; 60 of these patients received metformin treatment and were excluded. After 3 years no difference was found between diabetic patients who underwent pPCI versus fibrinolysis (combined event p = 0.37, reinfarction p = 0.06 in favor of fibrinolysis), whereas pPCI was superior to fibrinolysis in nondiabetic patients (combined event p = 0.002, clinical reinfarction p <0.001). Three-year incidence of clinical reinfarction analyzed with Cox’s regression showed that pPCI compared with fibrinolysis increased the relative risk of clinical reinfarction in diabetic patients (relative risk 2.57, 95% confidence interval 1.48 to 4.46, p <0.001) but decreased the risk in nondiabetic patients (relative risk 0.52, 95% confidence interval 0.36 to 0.74, p <0.001). In conclusion, from the DANAMI-2 trial we hypothesize that diabetes may abolish the beneficial effect of pPCI on long-term risk of clinical reinfarction.
Diabetes mellitus is a strong and independent predictor of morbidity and mortality after acute ST-segment elevation myocardial infarction (STEMI).1, 2, 3, 4 Although the overall incidence of cardiovascular mortality has decreased worldwide, the mortality that is attributable to diabetes has increased. Primary percutaneous coronary intervention (pPCI) has been shown to be superior to fibrinolysis in decreasing major adverse cardiovascular events.5 This effect has been documented in patients who were admitted directly to hospitals with interventional capabilities and those who were transferred from centers without such capabilities.6 Therefore, pPCI has become the treatment of choice for patients who have acute STEMI.
In a meta-analysis of 11 randomized trials from 1989 to 1996, the PCAT Collaborators concluded that pPCI was more effective than thrombolytic therapy in decreasing death or nonfatal reinfarction after 30 days in 367 diabetic patients and 2,151 nondiabetic patients.7 In the Global Use of Strategies to Open Occluded Arteries in Acute Coronary Syndromes IIb (GUSTO-IIb) substudy, pPCI was compared with tissue plasminogen activator for treatment of STEMI. After 30 days of follow-up, the same relative decrease in the composite end point of death, reinfarction, and stroke in favor of pPCI was found in 961 nondiabetic patients (significant) and in 177 diabetic patients (nonsignificant).8
To our knowledge no data have been published on long-term clinical outcome in patients who have diabetes and STEMI and undergo pPCI (with stent implantation) compared with fibrinolysis. In the present study, we report a 3-year clinical outcome after pPCI versus fibrinolysis (accelerated alteplase) for acute STEMI in patients who had diabetes and patients who did not in the Second Danish Trial in Acute Myocardial Infarction (DANAMI-2).
Methods
The DANAMI-2 multicenter study design has been described in detail.9 In brief, from December 1997 to September 2001, 4,278 consecutive patients were screened for enrollment in the DANAMI-2 study. A total of 1,572 patients who had STEMI was randomly assigned to undergo fibrinolysis (accelerated alteplase) or pPCI, and 1,129 of these patients were enrolled at local referral hospitals. Transfer to the nearest angioplasty center had to be completed within 3 hours. Inclusion criteria included presence of symptoms for <12 hours and cumulative ST-segment elevation ≥4 mm in ≥2 contiguous leads.
Sixty of 173 screened diabetic patients were excluded because of treatment with metformin due to a suspected risk of lactate acidosis in these patients who underwent contrast angiography at the time of planning the trial.10, 11 Information about diabetes was missing for 4 patients and these patients died within the first 24 hours after randomization. Of the 113 included patients who had confirmed diabetes mellitus, 13 (11.5%) had type 1 diabetes mellitus and received insulin. Of the 100 patients who had type 2 diabetes mellitus, 34 received insulin, 49 received sulfonylurea, and 30 received only dietary treatment. At the time of discharge after the index infarction, 7 of the patients who reported not having diabetes mellitus had been diagnosed as having the condition and had insulin (n=2) or oral antidiabetics (n=5) prescribed.
Treatment
A detailed description of the revascularizing treatment has been published.9 Patients who were assigned to undergo fibrinolysis received aspirin, β blocker, accelerated tissue plasminogen activator (alteplase, which was given as a 15-mg bolus, followed by an infusion of 0.75 mg per kilogram of body weight administered over 30 minutes, and then followed by an infusion of 0.5 mg per kilogram for 60 minutes), and intravenous unfractionated heparin.
Patients who were assigned to undergo angioplasty received aspirin, β blocker, and unfractionated heparin. Platelet glycoprotein IIb/IIIa receptor blockers were administered at the discretion of the treating physician. Stenting of the culprit lesion was attempted in all patients unless the vessel had a diameter <2.0 mm. All stents were made of bare metal. Ticlopidine or clopidogrel was given daily for 1 month after stenting. Angiograms obtained before and after angioplasty were evaluated by an independent core laboratory (Cardialysis, Rotterdam, The Netherlands).
Diabetes mellitus status
Patients were considered as having diabetes mellitus if they had been informed of this diagnosis before randomization and received antidiabetic treatment (diet, sulfonylurea, or insulin). All medical records and laboratory data of patients who were reported as having diabetes were analyzed to confirm this diagnosis (according to criteria of the American Diabetes Association12) and treatment.
End point
The primary end point was a composite of death from any cause, clinical reinfarction, or disabling stroke. All patients were followed for ≥2 years, with a median of 3.8 years (1,380 days, interquartile range 1,092 to 1,716). No patients were lost to follow-up.
The primary end point of this substudy was clinical reinfarction, which was diagnosed when creatine kinase-MB levels exceeded the reference limit in patients who had normalized levels after the index infarction or when an increase of ≥50% from the final non-normalized measurement was noted. Detailed definition of the end points is available elsewhere.9
Statistical analysis
Details of the study design and statistical analyses are described elsewhere.6, 9 Results were analyzed according to the intention-to-treat principle. For comparison of categorical variables, Pearson’s chi-square test was used. Values for continuous variables are reported as means ± SD or medians with interquartile ranges. Groups were compared with the Mann-Whitney rank-sum test. Kaplan-Meier curves were used to illustrate cumulative event rates in patients who had diabetes versus those who did not and between invasive and noninvasive strategies, and curves were compared using the log-rank test. To evaluate the presence and effect of an interaction between diabetic status and treatment modality on clinical outcome, Cox’s regression analysis was used.
Results
Baseline characteristics
Baseline characteristics of patients who had diabetes and those who did not in the 2 treatment groups are shown in Table 1. Those who had diabetes had a greater body mass index and higher frequencies of hypertension and index anterior myocardial infarction and received more cardioprotective medications compared with patients who did not have diabetes.
Table 1. Baseline characteristics
| Variable | Diabetes Mellitus | |||
|---|---|---|---|---|
| Yes (n = 113) | No (n = 1,455) | |||
| Angioplasty (n = 57) | Fibrinolysis (n = 56) | Angioplasty (n = 731) | Fibrinolysis (n = 724) | |
| Age (yrs) | 64.0 ±12.0 | 63.2±14.0 | 62.6±12.4 | 63.5±12.7 |
| Men | 44(0.77) | 37(0.66) | 536(0.73) | 536(0.74) |
| Current smoker (n = 1,534)‡ | 28(0.53) | 23(0.43) | 420(0.59) | 424(0.60) |
| Body mass index (kg/m2) | 27.8±4.8 | 28.2±6.1 | 26.2±4.0 | 26.3±4.2 |
| Previous coronary angioplasty (n = 1,564)‡ | 2(0.04) | 2(0.04) | 32(0.04) | 18(0.03) |
| Previous acute myocardial infarction (n = 1,564)‡ | 11(0.20) | 5(0.09) | 75(0.10) | 86(0.12) |
| Hypertension (n = 1,562)‡ | 20(0.36) | 24(0.43) | 137(0.19) | 136(0.19) |
| Index anterior acute myocardial infarction⁎ | 34(0.60) | 38(0.68) | 384(0.53) | 372(0.51) |
| Medical treatment (n = 1,562)‡ | ||||
| Sulfonylurea | 23(0.42) | 26(0.46) | ||
| Insulin | 15(0.27) | 19(0.34) | ||
| Aspirin | 22(0.40) | 15(0.27) | 142(0.20) | 163(0.23) |
| β Blockers | 7(0.12) | 13(0.23) | 92(0.13) | 89(0.12) |
| Angiotensin-converting enzyme inhibitors | 11(0.19) | 15(0.27) | 55(0.08) | 55(0.08) |
| Calcium antagonists | 8(0.14) | 11(0.20) | 70(0.10) | 79(0.11) |
| Nitrate | 5(0.09) | 7(0.13) | 41(0.06) | 43(0.06) |
| Diuretics | 18(0.33) | 16(0.29) | 97(0.13) | 102(0.14) |
| Lipid-lowering drugs | 6(0.11) | 4(0.07) | 42(0.06) | 40(0.06) |
| Heart rate (beats/min) | 77±22 | 82±21 | 75±19 | 74±19 |
| Systolic blood pressure (mm Hg) | 138±27 | 138±28 | 136±27 | 134±27 |
| Peak creatinine kinase-MB (U/L) (n = 988)†, ‡ | 96(48–236) | 138(54–299) | 130(59–221) | 125(56–232) |
| Peak lactate dehydrogenase (U/L) (n = 1,068)‡ | 1,212(616–2,173) | 1,426(756–2,100) | 1,172(648–1,895) | 1,116(603–1,794) |
⁎ Index anterior infarction defined as electrocardiographic changes in leads I, aVL, and/or V1 to V6. |
† Values of 580 patients in whom creatinine kinase-MB levels are presented as mass concentration are omitted. |
‡ Numbers of patients whose information about individual features are available. Missing data are equally distributed across 4 groups. |
Treatment delay was defined as the time from onset of symptoms to arrival in the catheterization laboratory or start of fibrinolysis. Treatment delay was longer in patients who had been randomized to undergo pPCI than in patients who had been randomized to undergo fibrinolysis in the diabetic and nondiabetic groups (259 ± 139 vs 231 ± 162 minutes, p = 0.05; 243 ± 153 vs 207 ± 136 minutes, p <0.001, respectively), but no difference was found between patients who had diabetes and those who did not (p = 0.11).
Angiographic data for patients who had diabetes and those who did not and underwent pPCI are listed in Table 2. Patients who had diabetes showed a trend toward a more widespread coronary artery disease compared with patients who did not have diabetes.
Table 2. Angiographic data in the angioplasty group
| Variable | Diabetes Mellitus | p Value | |
|---|---|---|---|
| Yes (n = 57) | No (n = 731) | ||
| Preangioplasty data | |||
| No. of diseased vessels (n = 7,46)† | 0.06 | ||
| 0 | 1(0.02) | 29(0.04) | |
| 1 | 8(0.16) | 219(0.32) | |
| 2 | 19(0.37) | 230(0.33) | |
| 3 | 23(0.45) | 217(0.31) | |
| Culprit coronary artery (n = 722)† | 0.5 | ||
| Left anterior descending | 19(0.37) | 255(0.38) | |
| Left circumflex | 29(0.57) | 328(0.49) | |
| Right | 3(0.06) | 83(0.12) | |
| Left main | 0 | 5(0.01) | |
| Angioplasty data | |||
| Stent (n = 685)† | 44(0.94) | 594(0.93) | 0.9 |
| Glycoprotein IIb/IIIa inhibitors (n = 776)† | 23(0.42) | 287(0.40) | 0.8 |
| Postangioplasty data | |||
| TIMI grade 3 flow in culprit artery (n = 669)† | 39(0.85) | 510(0.82) | 0.6 |
| Percent diameter stenosis in culprit artery (n = 663)† | 22±20 | 20±14 | 0.9 |
| Successful angioplasty (n = 661)⁎, † | 38(0.83) | 503(0.82) | 0.9 |
⁎ Culprit artery with <50% diameter stenosis and TIMI grade 3 flow after angioplasty. |
† Number of patients having information about individual angiographic features. Missing data are equally distributed across 4 groups. |
Of the 1,572 randomized patients, 110 patients died before discharge. Table 3 presents parameters at discharge for the 1,462 survivors. Fewer patients who did not have diabetes and underwent pPCI were in a CCS class >0 compared with patients who did not have diabetes and underwent fibrinolysis. No such difference was found among patients who had diabetes.
Table 3. Parameters at discharge for survivors
| Variable | Diabetes Mellitus | p Value for Diabetes Versus No Diabetes | |||||
|---|---|---|---|---|---|---|---|
| Yes (n = 101) | No (n = 1,361) | ||||||
| Angioplasty | Fibrinolysis | Angioplasty | Fibrinolysis | ||||
| (n = 52) | (n = 49) | p Value | (n = 688) | (n = 673) | p Value | ||
| Angina pectoris class >0 (n = 1,457)⁎ | 6(0.12) | 4(0.08) | 0.6 | 33(0.05) | 69(0.10) | <0.001 | 0.4 |
| Heart failure class >1 (n = 1,449)⁎ | 18(0.35) | 15(0.31) | 0.6 | 112(0.16) | 128(0.19) | 0.2 | <0.001 |
| Ejection fraction (%) (n = 1,356)⁎ | 46±8 | 45±11 | 0.5 | 51±11 | 50±11 | 0.2 | <0.001 |
| Medical treatment | |||||||
| Oral antidiabetics (sulfonylurea) | 18(0.35) | 14(0.29) | 0.5 | 2(0.003) | 2(0.003) | 1.0 | <0.001 |
| Insulin | 20(0.39) | 23(0.47) | 0.4 | 2(0.003) | 0 | 0.2 | <0.001 |
| Aspirin | 51(0.98) | 47(0.96) | 0.5 | 660(0.96) | 645(0.96) | 0.9 | 0.6 |
| β Blockers | 47(0.90) | 37(0.76) | 0.046 | 604(0.88) | 577(0.86) | 0.3 | 0.3 |
| ACE inhibitors | 27(0.52) | 31(0.63) | 0.2 | 224(0.33) | 242(0.36) | 0.2 | <0.001 |
| Calcium antagonists | 5(0.10) | 8(0.16) | 0.3 | 43(0.06) | 47(0.07) | 0.6 | 0.02 |
| Nitrate | 9(0.17) | 9(0.18) | 0.9 | 70(0.10) | 91(0.14) | 0.1 | 0.07 |
| Diuretics | 22(0.42) | 27(0.55) | 0.2 | 170(0.25) | 185(0.28) | 0.2 | <0.001 |
| Lipid-lowering drugs | 28(0.54) | 19(0.39) | 0.1 | 347(0.50) | 353(0.53) | 0.5 | 0.34 |
⁎ Numbers of patients whose information about individual features were available. Missing data are equally distributed across 4 groups. |
In-hospital events
No difference was found in in-hospital events between patients who had diabetes and underwent angioplasty and those who underwent fibrinolysis (combined event 13.3% vs 14.3%, reinfarction 3.5% vs 3.6%, reintervention: 14.0% vs 10.7%, p values NS). Patients who did not have diabetes and underwent pPCI had fewer in-hospital events than did those who underwent fibrinolysis (combined event 7.0% vs 11.3%, p = 0.004; reinfarction 1.2% vs 4.7%, p <0.001) or reintervention (PCI and/or coronary artery bypass grafting, 7.1% vs 18.6%, p<0.001).
Long-term follow-up
Clinical outcome after 3 years of follow-up is presented in Table 4 and illustrated in Figure 1. Overall, diabetic patients had a worse clinical outcome than nondiabetic patients. With respect to the combined event rate of death, stroke, and reinfarction, pPCI was superior to fibrinolysis in nondiabetic patients, whereas no difference was found in diabetic patients. Among diabetic patients there was a trend toward a higher reinfarction rate in the angioplasty group compared with the fibrinolysis group; among nondiabetic patients, a highly significant decrease in reinfarction rate was found in the invasive group compared with the fibrinolysis group. Among diabetic patients, no difference in the mechanical reintervention rate (PCI and/or coronary artery bypass grafting) was found, but the reintervention rate was significantly higher in nondiabetic patients treated with fibrinolysis than in those who underwent pPCI.
Table 4. Clinical outcome after three years of follow-up
| Diabetes Mellitus | p Value for Diabetes Versus No Diabetes | ||||||
|---|---|---|---|---|---|---|---|
| Yes (n = 113) | No (n = 1,455) | ||||||
| Angioplasty | Fibrinolysis | Angioplasty | Fibrinolysis | ||||
| (n = 57) | (n = 56) | p Value | (n = 731) | (n = 724) | p Value | ||
| Combined event rate⁎ | 24(42.1) | 19(33.9) | 0.4 | 127(17.4) | 173(23.9) | 0.002 | <0.001 |
| Reinfarction | 15(26.3) | 7(12.5) | 0.06 | 43(5.9) | 80(11.0) | <0.001 | <0.001 |
| Death | 14(24.6) | 13(23.2) | 0.8 | 92(12.6) | 102(14.1) | 0.4 | 0.002 |
| Mechanical reintervention | 18(31.6) | 19(33.9) | 0.8 | 150(20.5) | 297(41.0) | <0.001 | 0.7 |
⁎ Death, reinfarction, or disabling stroke. |
Figure 1.
Cumulative combined event rate (A) and cumulative reinfarction rate (B) for the 4 groups (diabetic patients treated with angioplasty, diabetic patients treated with fibrinolysis, nondiabetic patients treated with fibrinolysis, and nondiabetic patients treated with angioplasty). The p values apply for comparison across 4 groups.
Cox’s regression analysis showed a significant interaction between diabetes and treatment modality. In diabetic patients, pPCI increased the relative risk of clinical reinfarction compared with fibrinolysis (relative risk 2.57, 95% confidence interval 1.48 to 4.46, p <0.001), whereas pPCI decreased this risk in nondiabetic patients (relative risk 0.52, 95% confidence interval 0.36 to 0.74, p <0.001). No difference in reinfarction rate after pPCI was found among diabetic patients treated with sulfonylurea, insulin, or diet (13.6% in patients who received sulfonylurea vs 33.3% in patients who were treated with insulin or diet, p value NS). Forty of the 60 patients in the pPCI group who had reinfarction (8 of 15 in the diabetic group) underwent repeat angiographic examination during follow-up.
Discussion
In this substudy of the DANAMI-2 trial, the main finding is that diabetes mellitus seems to abolish the beneficial effect of pPCI on the long-term risk of reinfarction compared with fibrinolysis.
In the nondiabetic patients, the cumulative reinfarction rate increased markedly during the first 3 months of follow-up and then leveled off in both treatment groups. In patients who had diabetes, the cumulative reinfarction rate continued to increase during follow-up after both pPCI and fibrinolysis. With Cox’s regression analysis, we found a negative effect of pPCI on long-term incidence of reinfarction in patients who had diabetes. The possible reasons for this finding may be complex.
A prolonged interval between symptom onset and treatment among patients who have STEMI has been associated with poorer clinical outcome.13, 14 In our study, all patients who underwent pPCI had a prolonged interval between symptom onset and treatment compared with those who underwent fibrinolysis due to transfer from the randomizing hospitals to the invasive centers. However, no difference in this interval was found between diabetic and nondiabetic patients.
Diabetes mellitus is associated with a long-term, increased, low-grade inflammatory state that also affects coronary vessels.15, 16 This in combination with coronary instrumentation has been suggested to lead to an increased risk of formation of new narrowings in the culprit artery in diabetic patients compared with nondiabetic patients.17 Further, platelets from subjects who have diabetes are hyper-reactive and more prone to interact with leukocytes, thus accelerating the cascade of inflammation, injury, and thrombosis that predisposes to negative effects that are caused by arterial injury during angioplastic procedures.18, 19 In our study, we were unable to evaluate the degree of angiographic coincidence between culprit lesions of the index infarction and the reinfarction because only a small number of patients who had diabetes underwent another angiographic examination during follow-up.
Overall, our findings confirmed previous reports of a worse prognosis in diabetic patients with STEMI compared with nondiabetics with STEMI.1, 2, 3, 4
In our study, 44% of diabetic patients received sulfonylureas at baseline. Whether sulfonylureas have any adverse effect on clinical outcome in patients who have diabetes and coronary artery disease is controversial, and previous studies have shown conflicting results.20, 21 In the UGDP study from 1970, a high incidence of cardiovascular mortality was found in patients who were treated with tolbutamide.22 Garratt et al23 found that sulfonylurea drug use was independently associated with an increased risk of in-hospital but not of long-term mortality among patients who had diabetes and underwent coronary angioplasty for acute myocardial infarction. In contrast, Klamann et al24 reported that in-hospital mortality in patients who had diabetes and acute myocardial infarction was higher than that in nondiabetic patients regardless of whether or not they had been treated with sulfonylureas.24 Taking into account that the present study is underpowered to detect any differences in risk of adverse events, no evidence associated sulfonylureas with an increased risk. This is in accordance with recent findings that the newer generations of sulfonylurea are not associated with poorer clinical outcome in patients who have cardiovascular disease.21
Some issues must be considered when interpreting the present data. The DANAMI-2 trial was not designed for post hoc analysis of clinical outcome in subgroups of patients with and without diabetes. Moreover, the study was started before the era of cardiac troponins.
Our study assessed a small number of patients who had diabetes (n = 113), which increases the risk of statistical errors that might lead to incorrect findings. This small sample was caused by exclusion of all patients who received metformin from participation.10, 11 The influence of metformin on clinical outcome in patients who have coronary artery disease is controversial. In a retrospective analysis, metformin with or without adjunctive medical antidiabetic treatment was found to decrease adverse clinical events compared with antidiabetic treatment without metformin.25 However, metformin increases plasma homocysteine levels, which leads to adverse effects on platelets, clotting factors, and endothelium, possibly leading to increased mortality in patients who have coronary artery disease.26 Because patients who used metformin were excluded from the DANAMI-2 trial, caution should be taken if extrapolating the study results to patients who have diabetes and use metformin.
As in most other studies of revascularization of patients who have STEMI, the present study may have been hampered by an inaccuracy in the definition of diabetes mellitus. Categorization of patients as having diabetes was based primarily on the patients having this diagnosis on admission. All hospital records and laboratory data of patients who were reported as having diabetes were carefully analyzed and the diagnosis was confirmed.
From the present data, it can be hypothesized that diabetes eliminates the beneficial effect of pPCI on long-term risk of clinical reinfarction. However, the results of this study should not be applied to clinical practice before they are confirmed by randomized studies that address long-term clinical outcome after pPCI compared with fibrinolysis in large groups of patients who have diabetes.
Appendix
Investigators in the DANAMI-2 study
H.R. Andersen, T.T. Nielsen, K. Rasmussen, L. Thuesen, H. Kelbaek, P. Thayssen, U. Abildgaard, F. Pedersen, J.K. Madsen, P. Grande, A.B. Villadsen, L.R. Krusell, T. Haghfelt, P. Lomholt, S.E. Husted, E. Vigholt, H.K. Kjaergard, and L.S. Mortensen.
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The DANAMI-2 trial was supported by grants from the Danish Heart Foundation, the Danish Medical Research Council, AstraZeneca, Bristol-Myers Squibb, Cordis, Pfizer, Pharmacia-Upjohn, Boehringer Ingelheim, and Guerbet, Denmark.
PII: S0002-9149(05)01430-X
doi:10.1016/j.amjcard.2005.07.053
© 2005 Elsevier Inc. All rights reserved.
Volume 96, Issue 11 , Pages 1469-1475, 1 December 2005
