Effect of Statin Treatment on Coronary Collateral Development in Patients With Diabetes Mellitus
Article Outline
Coronary collateral development is an important compensatory mechanism in advanced coronary artery disease, and patients with diabetes mellitus have impaired coronary collateral development. This study tested the hypothesis that statin treatment may increase coronary collateral development in patients with diabetes mellitus. The study population consisted of 149 consecutive diabetic patients who underwent clinically indicated coronary angiography and had >95% stenosis of ≥1 major coronary artery. Clinical information, including age, gender, history of hypertension, smoking, myocardial infarction, clinical presentation, and medications, was recorded before coronary angiography. Coronary collaterals were graded according to the Cohen-Rentrop method. Collateral grading was classified as poor when the collateral grade was 0 to 1 and good when it was 2 to 3. Among 149 patients (85 men; mean age 62 ± 10 years), 74 (56%) were receiving statin treatment. In multivariate analysis, among demographic, clinical, and angiographic parameters, only statin therapy (odds ratio 3, 95% confidence interval 1.5 to 6.03, p = 0.002) and stable angina pectoris (odds ratio 3.24, 95% confidence interval 1.42 to 7.41, p = 0.005) were found to be independent predictors of better collateral formation. In conclusion, stable angina pectoris and statin treatment are associated with better coronary collateral development in patients with diabetes mellitus.
The presence and extent of coronary collateral circulation have been shown to affect the prognosis of patients with coronary artery disease (CAD).1, 2, 3 However, there is great variability in the extent and adequacy of coronary collateral formation among patients, and diabetes mellitus has been shown to have a negative effect on coronary collateral development.4, 5, 6, 7 In the present study we tested the hypothesis that statin treatment increases coronary collateral development in diabetic patients with advanced CAD.
The study population consisted of 149 consecutive diabetic patients who underwent clinically indicated coronary angiography in the Cardiology Department Coronary Angiography Laboratory of the Ankara University Medical Faculty (Ankara, Turkey) from December 2003 to February 2005 and had >95% stenosis of ≥1 major coronary artery. The study was approved by the local ethics committee, and patients gave written informed consent to participate.
Clinical information, including age, gender, history of hypertension, smoking, myocardial infarction, clinical presentation, and medications (including aspirin, β blocker, calcium channel blocker, angiotensin-converting enzyme inhibitor, nitrates, insulin or oral antidiabetic agents, and statins, including doses and duration of treatment), were recorded before coronary angiography. Fasting blood chemistry including lipid profile was obtained on the day of coronary angiography.
Diabetes mellitus was defined as previous treatment with insulin or oral antidiabetic medications.
Statin doses were converted to atorvastatin equivalents based on estimates of their potential to decrease low-density lipoprotein (LDL) levels to evaluate the effect of these doses on coronary collateral development.8 Accordingly, 10 mg of atorvastatin was considered to have the same LDL lowering potential as 20 mg of simvastatin, 40 mg of pravastatin, and 80 mg of fluvastatin. Patients with high LDL levels were categorized into 3 groups according to statin dose: a high dose was defined as an atorvastatin-equivalent dose ≥40 mg, a medium dose as an atorvastatin-equivalent dose of 10 to 20 mg, and a low dose as an atorvastatin-equivalent dose <10 mg. Duration of statin treatment was also divided into 3 groups, i.e., 0 to 3, 3 to 12, and >12 months.
Selective coronary angiography was performed according to Judkins’ technique. Coronary angiograms were reviewed by 2 experienced interventional cardiologists who were blinded to the clinical information of the patients.
Coronary collaterals were graded according to the Cohen-Rentrop9 method as grade 0 (no filling of any collateral vessel), grade 1 (filling of side branches of the artery to be perfused by collateral vessels without visualization of epicardial segments), grade 2 (partial filling of an epicardial artery by collateral vessels), or grade 3 (complete filling of an epicardial artery by a collateral vessel). Collateral grading was classified as poor collateral development when the collateral grade was 0 to 1 and as good collateral development when the grade was 2 to 3.
Statistical analysis was performed with SPSS 11.5 (SPSS, Inc., Chicago, Illinois). Data were expressed as mean ± SD for continues variables and number of subjects (percentage) for categorical variables. Univariate analysis was done with possible confounding variables for collateral development. Multivariate logistic regression analysis was used to evaluate the effect of significant correlates in univariate analysis with collateral development and expressed as odds ratio (95% confidence interval). Clinical presentation, statin use, and doses and duration of statin treatment were included as variables in multivariate analysis. All significance tests were 2-tailed. The criterion for statistical significance was a p value <0.05.
The study population consisted of 149 patients (85 men; mean age 62 ± 10 years). Of the 149 patients, 74 (56%) were using statins. Patients were categorized as having poor or good collateral development. Seventy of 149 patients (52%) had poor collateral development and 79 (48%) had good collateral development. There were no relations between collateral development and age, gender, history of hypertension, myocardial infarction or smoking, concomitant medications, ejection fraction, and extent of CAD. There were no significant differences in collateral development between subjects with a total cholesterol level >160 mg/dl and those with a level <160 mg/dl. Similarly, there were no significant differences in collateral development between subjects with a LDL cholesterol level >100 mg/dl and those with a level <100 mg/dl. Only patients with stable angina pectoris as a clinical presentation (p = 0.001) and patients who used statin therapy (p = 0.001) had good collateral development (Table 1). Duration of statin therapy was divided into 3 periods, i.e., 0 to 3, 3 to 12, and >12 months. Statin therapy for <3 months had no affect on collateral development (p = 0.88); in contrast, patients who used statin therapy for 3 to 12 months and >12 months had significantly better collateral development (p = 0.001 and 0.02, respectively). There was also a correlation between doses of statin therapy and collateral development. Statin therapy had no effect on coronary collateral development in patients who received an atorvastatin-equivalent dose of <10 mg (p = 0.771); in contrast, patients who used a medium dose (atorvastatin-equivalent dose 10 to 20 mg) had better collateral development (p <0.001). In the study population, we had only 4 patients who were taking an atorvastatin-equivalent dose ≥40 mg. Among these, 3 patients had good collateral development, but this did not reach statistical significance (p = 0.08). However, these data should be interpreted with caution due to the small number of patients who received low and high atorvastatin-equivalent doses.
Table 1. Patient characteristics according to collateral grade
| Variable | Coronary Collaterals | ||
|---|---|---|---|
| Poor (n = 79) | Good (n = 70) | Univariate (p Value) | |
| Age (yrs) | 63 ±9.2 | 62±10 | 0.81 |
| Men | 48(50%) | 48(50%) | 0.32 |
| Previous MI | 44(56%) | 34(44%) | 0.38 |
| Hypertension | 55(52%) | 51(48%) | 0.66 |
| Smoker | 26(51%) | 21(49%) | 0.72 |
| No. of coronary arteries with ≥95% stenosis | |||
| 1 | 51(58%) | 36(42%) | 0.19 |
| 2 | 20(49%) | 21(51%) | |
| 3 | 8(38%) | 13(62%) | |
| Clinical presentation | |||
| Stable angina pectoris | 11(29%) | 26(71%) | 0.001 |
| Unstable angina pectoris, non–ST-elevation MI, ST-elevation MI | 67(60%) | 44(40%) | |
| Medications | |||
| Aspirin | 59(52%) | 54(48%) | 0.72 |
| β Blocker | 32(51%) | 30(49%) | 0.77 |
| Calcium antagonists | 19(59%) | 13(41%) | 0.41 |
| Angiotensin-converting enzyme inhibitors | 36(49%) | 37(51%) | 0.37 |
| Nitrates | 23(51%) | 22(49%) | 0.81 |
| Statin treatment | 31(39%) | 47(61%) | 0.001 |
| Total cholesterol ≥160 mg/dl | 52(49%) | 53(51%) | 0.18 |
| LDL cholesterol ≥100 mg/dl | 41(49%) | 43(51%) | 0.2 |
| Ejection fraction (%) | 51±11 | 49±15 | 0.3 |
In multivariate analysis, statin therapy (odds ratio 3, 95% confidence interval 1.5 to 6.03, p = 0.002) and stable angina pectoris (odds ratio 3.24, 95% confidence interval 1.42 to 7.41, p = 0.005) were found to be independent predictors of better collateral formation (Figure 1).
Figure 1.
In multivariate analysis, only statin treatment and history of stable angina pectoris (SAP) were associated with good (light gray bars) versus poor (dark gray bars) collateral development. OR = odds ratio; 95% = 95% confidence interval.
There are few clinical studies concerning the influence of statins on human coronary collateral formation, with discordant results. In 2 studies, statin treatment was associated with better collateral development.10, 11 However, 1 recent trial demonstrated no effect of statins on coronary collateral formation.12 Effect of statin treatment on collateral formation in diabetic patients has not been investigated previously. Our results have demonstrated that, in diabetic patients, stable angina pectoris and statin treatment are associated with better coronary collateral development. There was also a relation of duration and dosage of statin therapy to collateral development. However, there were only a few patients in the low and high atorvastatin-equivalent dose groups. Nonetheless, our findings support the hypothesis that statin treatment increases collateral development in diabetic patients.
Our study was a nonrandomized, retrospective, observational study. Although the doses and duration of statin treatment were obtained from patients, due to the retrospective nature of our study, these data should be interpreted with caution. A large randomized, controlled trial of statins in patients with diabetes mellitus and CAD is warranted to evaluate potential effects of these agents, including doses and duration, on coronary collateral development.
References
- . Physiologically assessed coronary collateral flow and adverse cardiac ischemic events (a follow up study in 403 patients with coronary artery disease) . J Am Coll Cardiol . 2002;40:1545–1550
- . Coronary collateral circulation (clinical significance and influence on survival in patients with coronary artery occlusion) . Am Heart J . 1989;117:290–295
- . Influence of coronary collateral vessels on myocardial infarct size in humans (results of phase I Thrombolysis in Myocardial infarction (TIMI) trial) . Circulation . 1991;83:739–746
- . Frequency distribution of collateral flow and factors influencing collateral channel development . J Am Coll Cardiol . 2001;38:1872–1878
- . Coronary collateralisation (determinants of adequate distal vessel filling after arterial occlusion) . Coron Artery Dis . 2002;13:155–159
- . Effects of diabetes mellitus on formation of coronary collateral vessels . Circulation . 1999;99:2239–2242
- . Diabetes, hypertension, and cardiovascular disease (an update) . Hypertension . 2001;37:1053–1059
- . Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (The Curves Study) . Am J Cardiol . 1998;81:582–587
- . Changes in collateral channel filling immediately after controlled coronary artery occlusion by an angioplasty balloon in human subjects . J Am Coll Cardiol . 1985;5:587–592
- . Pravastatin promotes coronary collateral circulation in patients with coronary artery disease . Coron Artery Dis . 2002;13:377–381
- . Statin use is associated with enhanced collateralization of severely diseased coronary arteries . Am Heart J . 2003;146:876–881
- . Effect of statin treatment on coronary collateral flow in patients with coronary artery disease . Heart . 2004;90:448–449
PII: S0002-9149(05)02060-6
doi:10.1016/j.amjcard.2005.09.124
© 2006 Elsevier Inc. All rights reserved.
