Meta-Analysis of the Effect of Diabetes on Restenosis Rates Among Patients Receiving Coronary Angioplasty Stenting

Transcription

1 Reviews/Commentaries/Position Statements R E V I E W A R T I C L E / M E T A - A N A L Y S I S Meta-Analysis of the Effect of Diabetes on Restenosis Rates Among Patients Receiving Coronary Angioplasty Stenting JEREMY GILBERT, MD 1 JANET RABOUD, PHD 2,3 BERNARD ZINMAN, MDCM, FRCPC, FACP 1,3,4 OBJECTIVE Coronary artery disease is a significant source of morbidity and mortality in patients with diabetes. Angioplasty has been associated with higher rates of restenosis in patients with diabetes. Numerous studies have been performed to determine whether coronary artery stenting would be useful in decreasing rates of restenosis of coronary vessels in patients with diabetes. This meta-analysis was conducted to determine the effect of diabetes on angiographic restenosis in patients undergoing coronary stenting. RESEARCH DESIGN AND METHODS Six studies were included comprising 6,236 individuals 1,166 with diabetes and 5,070 without. The relationships between restenosis rates and age, the percentage of the study population that was male, and the percentage of the study population receiving insulin therapy were examined. RESULTS The average restenosis rates among patients with and without diabetes were 36.7 and 25.9%, respectively. Restenosis rates were higher among older populations and populations in which a greater percentage of patients with diabetes were treated with insulin, but they did not vary according to the percentage of men in the studies. The odds ratio of coronary artery restenosis associated with diabetes was 1.61 (95% CI , P 0.004) in univariate logistic regression models, but decreased to 1.30 ( , P 0.055) after controlling for age in multivariate models, suggesting that the higher restenosis rates found in patients with diabetes can in good part be explained by the older ages of patients with diabetes in these studies. CONCLUSIONS Although diabetes is a risk factor for restenosis after coronary angioplasty stenting, the apparent effect of diabetes on restenosis rates in the published literature is overstated and was reduced in this meta-analysis by approximately half after adjusting for differences in age. Diabetes is a source of significant morbidity and mortality resulting from long-term micro- and macrovascular complications (1). In addition, the global increase in diabetes has had a substantial burden on health care costs (2 4). Diabetes Care 27: , 2004 Coronary angioplasty has been established as a useful modality for treating coronary artery disease in patients without diabetes. The restenosis rate in patients receiving coronary angioplasty is 25 50% (5). However, in patients with diabetes, reported restenosis rates range From the 1 Department of Medicine, University of Toronto, Toronto, Ontario, Canada; the 2 Division of Infectious Disease, University Health Network, and Department of Public Health Sciences, University of Toronto, Toronto, Ontario, Canada; the 3 Prosserman Center for Health Research, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada; and the 4 Leadership Sinai Centre for Diabetes, Mount Sinai Hospital, Toronto, Ontario, Canada. Address correspondence and reprint requests to Dr. Bernard Zinman, Director, Leadership Sinai Center for Diabetes, Mount Sinai Hospital, 600 University Ave., Room L5 024, Toronto, Ontario M5G 1X5, Canada. zinman@mshri.on.ca. Received for publication 28 October 2003 and accepted in revised form 26 December A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances by the American Diabetes Association. from 47 to 71% (6 8), making angioplasty a less desirable therapeutic option. Stenting has been shown to be especially useful in decreasing the rates of restenosis in coronary vessels in patients without diabetes. A significant reduction in restenosis by 10 12% with coronary artery stents versus angioplasty alone has been documented (9,10). Not surprisingly, a number of studies have been undertaken to determine whether coronary stenting would also be advantageous in patients with diabetes. Unfortunately, the results to date have been uncertain as to whether patients with diabetes and coronary artery disease received the same benefit from this procedure as patients without diabetes. This meta-analysis was conducted to combine data from multiple studies to estimate the overall effect of diabetes on angiographic restenosis rates among patients undergoing coronary stenting. RESEARCH DESIGN AND METHODS Identification and selection of studies We conducted a search of the medical literature for studies evaluating restenosis rates after coronary angioplasty in patients with and without diabetes. We searched the English language literature in Medline between 1990 and 2002, using the search phrases stent, coronary artery angioplasty, and diabetes. Ten articles containing primary reports were identified (7,11 19). Two authors of this meta-analysis independently reviewed each article (J.G. and J.R.). Studies were selected for analysis if they had angiographic follow-up at a minimum of 6 months; if the sex and ages of their population were included; and for patients with diabetes if the mode of therapy, namely diet, oral agents, or insulin, was documented. Trials were included in the meta-analysis if patients both with and without diabetes were studied and if rates of restenosis were calculated for each group. Studies were excluded if fewer 990 DIABETES CARE, VOLUME 27, NUMBER 4, APRIL 2004

2 Gilbert, Raboud, and Zinman Table 1 Restenosis rates in patients with and without diabetes Diabetes n Mean Restenosis rate 95% CI Mean age Percent male Percent treated with insulin Study Carozza et al. (14) Yes No Difference Suselbeck et al. (17) Yes No Difference Elezi et al. (13) Yes No 2, Difference Mattos et al. (16) Yes No Difference Van Belle et al. (12) Yes No Difference Schofer et al. (15) Yes No 1, Difference All Yes 1, No 5, Total 6,236 than 150 people participated. Six articles met the inclusion criteria for the metaanalysis (7,12 17). The studies by Silva et al. (11) and Mehilli et al. (18) were excluded because of the small sample size, and Mehilli et al. only studied patients with diabetes. The studies by Abizaid et al. (7) and Huynh et al. (19) were excluded because they only assessed clinical outcome, without analyzing angiographic restenosis rates. This analysis incorporates one substudy (16) and five primary studies, including one case series (14), one prospective study (13), one study based on a prospective registry (17), and two retrospective studies (12,15). All studies used native coronary vessels, and one study also included saphenous vein graft stenting (14). Restenosis was defined in the studies as a 50% decrease in target vessel diameter at angiographic follow-up. Most of the patients in the studies had type 2 diabetes, and the proportion of patients treated with diet, oral agents, or insulin was similar among the studies. In particular, most patients were being treated with oral agents, and insulin was the therapy used in about one-quarter of the patients with diabetes. Statistical analysis Restenosis rates for patients with and without diabetes used in our analysis were obtained from the published reports for each of the six trials. In one instance (17), the restenosis rates were calculated from published data presented as numerators and denominators. In another instance (15), the restenosis rates among patients with diabetes were based on the weighted average among patients with diabetes receiving insulin versus oral therapy. The homogeneity of the effect of diabetes on restenosis rates was tested using methods described by DerSimonian and Laird (20). Restenosis rates after coronary stenting among patients with diabetes and without diabetes from each study were plotted against average age, percentage of the study population that was male, and the percentage of the population with diabetes receiving insulin therapy. Logistic random effects models were used to estimate the effect of diabetes on restenosis rates after controlling for the percentage of men and the average age of each study population. The outcome for each study was the percentage of patients developing restenosis in patients with and without diabetes after coronary angioplasty with stent placement. The effect of diabetes on restenosis rates was estimated with a random effect, whereas the effects of age and sex were estimated with fixed effects using restricted maximum likelihood estimates. RESULTS The restenosis results from six studies were available for 6,236 individuals 1,166 with diabetes and 5,070 without. After weighting studies by the number of participants, the average age was 64.8 years among patients with diabetes and 61.3 years among patients without diabetes. The percentage of patients with diabetes who were male was 71.7%, and among patients without diabetes, 78.6% were male. The average restenosis rate among patients with diabetes was 36.7% (range 25 55%) and 25.9% ( %) among patients without diabetes. After weighting studies by the number of participants, the average difference in restenosis rates between patients with and without diabetes within a study was 10.8% (2 35%). Restenosis rates and 95% CIs are shown for patients with and without diabetes for each study in Table 1. The effect of diabetes on restenosis rates was not homoge- DIABETES CARE, VOLUME 27, NUMBER 4, APRIL

3 Restenosis rates after coronary angioplasty Figure 1 Restenosis rate versus mean age. The solid line indicates with diabetes; the dotted line indicates without diabetes. neous across studies (P 0.001). When restenosis rates in patients with and without diabetes were plotted against mean age by study and diabetes status (Fig. 1), restenosis rates were shown to increase with age. Restenosis rates also increased with the percentage of the diabetic population treated with insulin (Fig. 2) but were not affected by the percentage of the population that was male (graph not shown). In a univariate random effects logistic regression model, the odds ratio of restenosis associated with diabetes was 1.61 (95% CI , P 0.004) (Fig. 3). From this model, the estimated probabilities of restenosis were 0.36 among patients with diabetes and 0.26 among patients without diabetes. After controlling for age in a multivariate logistic regression model, the odds ratio of restenosis was 1.30 ( , P 0.055). The odds ratio of restenosis associated with a 10-year increase in age was 2.01 (P 0.016). From the multivariate model adjusting for age, the estimated probabilities of restenosis were among patients with diabetes and among patients without diabetes. CONCLUSIONS While the rates of restenosis varied among the studies, all but one study included in this review found diabetes to be a risk factor for restenosis after coronary stent placement. However, patients with diabetes were older on average than patients without diabetes in every study. This is important because diabetes and older age are known Figure 2 Restenosis rates versus percentage of patients with diabetes treated with insulin. risk factors for restenosis (21). Adjusting for the difference in the ages of patients with and without diabetes in a multivariate model reduced the apparent effect of diabetes on restenosis rates by approximately half. There is much debate in the literature about the affect of sex on restenosis rates after coronary stent placement. Initially, reports suggested that women have a less favorable outcome after angioplasty than men, possibly because of the greater age to which women live, the greater prevalence of other coronary risk factors among women, and the smaller vessel size in women (22). Watanabe et al. (23) showed that women receiving angioplasty have a twofold higher mortality than men with or without stent placement. They concluded that female sex is an independent predictor of mortality even after adjustment for age and a poorer cardiovascular profile among women. More recent data suggest this correlation may not be true. Jacobs et al. (24) concluded, based on the National Heart, Lung and Blood Institute Dynamic Registry, that despite the high cardiovascular risk factors found in women, outcomes in women have improved and sex differences in patients undergoing coronary angioplasty have decreased. In all but one study included in our meta-analysis, there were more women among the population with diabetes than among the population without diabetes. However, adjusting for sex in multivariate models did not significantly change the effect of diabetes on restenosis rates. Among the diabetic populations of the studies included in our meta-analysis, rates of restenosis after coronary stenting were higher among populations with higher proportions of patients treated with insulin. Because most patients with diabetes had type 2 diabetes, insulin therapy may be a marker for disease duration and severity (25,26). Because follow-up angiograms necessary to assess restenosis may not be available for patients experiencing clinical outcomes such as fatal myocardial infarction or sudden death, our results may be biased if patients with diabetes are more likely to have clinical outcomes after coronary angioplasty. We compared death rates between patients with and without diabetes in the studies included in the meta-analysis and found no significant 992 DIABETES CARE, VOLUME 27, NUMBER 4, APRIL 2004

4 Gilbert, Raboud, and Zinman Figure 3 Odds ratios of restenosis associated with diabetes by study. differences. Limitations of the studies included in this meta-analysis include lack of data on diabetes control, diabetes duration, lipid levels, blood pressure, and inflammatory markers. In general, it must be recognized that a meta-analysis does not allow for a systematic evaluation of important biological confounders that may affect the primary outcome. The advent of drug-eluting stents is a remarkable improvement in preventing restenosis in coronary arteries after coronary angioplasty. The RAVEL study group (27) showed a significant reduction in restenosis with sirolimus-eluting stents compared with standard stents (27 vs. 0%) among 238 patients with coronary artery disease. A subgroup analysis of patients with diabetes showed that among 19 patients who received sirolimuseluting stents, the restenosis rate was 0% compared with 42% among 25 patients who received standard stents. The more recent SIRIUS trial (28) focused on patients with higher risks of restenosis. Among the patients with diabetes, the restenosis rate was 18% in 131 patients who received sirolimus-eluting stents compared with 51% among 148 patients who received standard stents. Thus, it appears that sirolimus-eluting stents further reduce the restenosis rate among patients with diabetes compared with standard stents. Further research addressing the impact of clinical factors, such as age, sex, and treatment with insulin, on restenosis rates after placement of drug-eluting stents in patients with diabetes will help patients and their physicians assess individual risks of restenosis after coronary angioplasty with stenting. In summary, although the published literature suggests that diabetes appears to be a risk factor for higher rates of restenosis in patients receiving coronary angioplasty with stenting, this effect is overstated in that we found that a significant part of this effect appears to be related to the older age of the patients reported in these studies. It seems surprising that the population of patients with diabetes was older, since diabetes is an established risk factor for coronary artery disease and one would expect a younger age of onset of coronary artery disease in these individuals. This emphasizes the importance of recognizing that age is a major contributing factor to the higher restenosis rates found in patients with diabetes. As well, it is unclear if younger patients with diabetes would have increased restenosis rates compared with individuals without diabetes. While not statistically significant in our analyses, sex and treatment with insulin may also be related to the risk of restenosis and could possibly attenuate the perceived risks associated with diabetes even further. Thus, it is important to consider age and other clinical factors when evaluating whether coronary stenting procedures are effective therapeutic options in patients with diabetes. References 1. UK Prospective Diabetes Study Group: Quality of life in type 2 diabetes patients is affected by complications but not by intensive policies to improve blood glucose or blood pressure control. Diabetes Care 22: , King H, Aubert RE, Herman WH: Global burden of diabetes, Diabetes Care 21: , Huse DM, Oster G, Killen AR, Lacey MJ, Colditz GA: The economic costs of noninsulin-dependent diabetes mellitus. JAMA 262: , Brown JB, Pedula KL, Bakst AW: The progressive cost of complications in type 2 diabetes mellitus. Arch Intern Med 159: , Casterella PJ, Teirstein PS: Prevention of coronary restenosis. Cardiol Rev 7: , Quigley PJ, Hlatky MA, Hinohara T, Rendall DS, Perez JA, Phillips HR, Califf RM, Stack RS: Repeat percutaneous transluminal coronary angioplasty and predictors of recurrent restenosis. Am J Cardiol 63: , Abizaid A, Kornowski R, Mintz GS, Hong MK, Abizaid AS, Mehran R, Pichard AD, Kent KM, Satler LF, Hongsheng W, Poopma JJ, Leon MB: The influence of diabetes mellitus on acute and late clinical outcomes following coronary stent implantation. J Am Coll Cardiol 32: , Weintraub WS, Kosinski AS, Brown CL, King SB: Can restenosis after coronary angioplasty be predicted from clinical variables? J Am Coll Cardiol 21:6 14, Serruys PW, de Jaegere P, Kiemeneij F, Macaya C, Rutsch W, Heyndrickx G, Emanuelsson H, Marco J, Legrand V, Materne P, Belardi J, Sigwart U, Colombo A, Goy JJ, van den Heuvel P, Delcan J, Morel MA: A comparison of balloon expandable-stent implantation with ballon angioplasty in patients with coronary artery disease. N Engl J Med 331: , Fischman DL, Leon MB, Baim DS, Schatz RA, Savage MP, Penn I, Detre K, Veltri L, Ricci D, Nobuyoshi M, Cleman M, Heuser R, Almond D, Teirstein PS, Fish RD, Colombo A, Brinker J, Moses J, Shaknovich A, Hirshfeld J, Bailey S, Ellis S, Rake R, Goldberg S: A randomized comparison of coronary-stent placement and balloon angioplasty in the treatment of coronary artery disease. N Engl J Med 331: , Silva JA, Ramee SR, Christopher WJ, Collins TJ, Jenkins S, Nunez E, Zhang S, Jain SP: Primary stenting in acute myocardial infarction: influence of diabetes mellitus in angiographic results and clinical outcome. Am Heart J 138: , 1999 DIABETES CARE, VOLUME 27, NUMBER 4, APRIL

5 Restenosis rates after coronary angioplasty 12. Van Belle E, Bauters C, Hubert E, Bodart JC, Abolmaali K, Meurice T, McFadden EP, Lablanche JM, Bertrand ME: Restenosis rates in diabetic patients. Circulation 96: , Elezi S, Katrati A, Pache J, Wehinger A, Hadamitzky M, Dirschinger J, Neumann FJ, Schomig A: Diabetes mellitus and the clinical and angiographic outcome after coronary stent placement. J Am Coll Cardiol 32: , Carozza JP, Kuntz RE, Fishman RF, Baim DS: Restenosis after injury caused by coronary stenting in patients with diabetes mellitus. Ann Intern Med 118: , Schofer J, Schluter M, Rau T, Falk H, Haag N, Mathey DG: Influence of treatment modality on angiographic outcome after coronary stenting in diabetic patients: a controlled study. J Am Coll Cardiol 35: , Mattos LA, Grines CL, De Sousa E, Sousa AG, Stone GW, Cox D, Garcia E, Morice MC, O Neill W, Grines L, Boura J: Oneyear follow-up after primary coronary intervention for acute myocardial infarction in diabetic patients: a substudy of the STENT PAMI trial. Arq Bras Cardiol 77: , Suselbeck T, Latsch A, Siri H, Gonsk B, Poerner T, Pfleger S, Schumacher B, Borggrefe M, Haase KK: Role of vessel size as a predictor for the occurrence of in-stent restenosis in patients with diabetes mellitus. Am J Cardiol 88: , Mehilli J, Kastrati A, Dirschinger J, Dotzer F, Pache J, Hauleiter J, Kramer W, Schulen H, Schomig A: A comparison of stenting with balloon angioplasty for lesions of small coronary vessels in patients with diabetes mellitus. Am J Med 112:13 18, Huynh T, Eisenberg MJ, Deligonul U, Tsang J, Okrainec K, Schechter D, Lefkovits J, Konn-Hou M, Brown DL, Brieger D: Coronary stenting in diabetic patients: results from the ROSETTA registry. Am Heart J 142: , DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 7: , Chauhan MS, Kuntz RE, Kalon HKL, Cohen DJ, Popma JJ, Carrozza JP, Baim DS, Cutlip DE: Coronary artery stenting in the aged. J Am Coll Cardiol 37: , Malenka DJ, O Connor GT, Quinton H, Wennberg D, Robb JF, Shubrooks S, Kellet MA, Hearne MJ, Bradley WA, Ver- Lee P: Differences in outcomes between women and men associated with percutaneous transluminal coronary angioplasty: a regional prospective study of 13, 601 procedures: Northern New England Cardiovascular Disease Study Group. Circulation 94:99 104, Watanabe CT, Maynard C, Ritchie JL: Comparison of short-term outcomes following coronary artery stenting in men versus women. Am J Cardiol 88: , Jacobs AK, Johnston JM, Haviland A, Brooks MM, Kelsey SF, Holmes DR, Faxon DP, Williams DO, Detre KM: Improved outcomes for women undergoing temporary percutaneous coronary intervention: a report from the National Heart, Lung, and Blood Institute Dynamic Registry. J Am Coll Cardiol 39: , UK Prospective Diabetes Study Group: Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet 352: , Turner RC, Cull CA, Frighi V, Homan RR: Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). JAMA 281: , Morice MC, Serruys PW, Sousa JE, Fajadet J, Ban Hayashi E, Perin M, Colombo A, Schuler G, Barragan P, Guagliumi G, Molnar F, Falotico R: A randomized comparison of a sirolimus-eluting stent with a standard stent for coronary revascularization. N Engl J Med 346: , Moses JW, Leon MB, Popma JJ, Fizgerald PJ, Holmes DR, O Shaughnessy C, Caputo RP, Kereiakes DJ, Williams DO, Teirstein PS, Jaeger JL, Kuntz RE: Sirolimus eluting stents versus standard stents in patients with stenosis in native coronary artery. N Engl J Med 349: , DIABETES CARE, VOLUME 27, NUMBER 4, APRIL 2004