Late clinical events of drug eluting versus bare metal stenting; OPCES’ ancillary study

Objective: To compare one year clinical outcomes of patients with chronic stable angina who underwent implantation of bare metal stent (BMS) or drug eluting stent (DES). Methodology: Four hundred forty two (442) participants of OPCES study (Osvix versus Plavix in Cardiovascular Events after Stenting) were included in this sub-study. After evaluation of exclusion criteria (combined DES and BMS stenting (n=31) and incomplete data (n=48) patients were divided in two groups according to selected stent(DES or BMS). Follow-up was conducted by a structured telephone interview after 6 and 12 months. The patients’ documents were reviewed by the Study Event Committee in the Isfahan Cardiovascular Research Center to evaluate the occurrence of study endpoints which consisted of clinical success rate and major adverse cardiac events (Major Adverse Cardiac Events (MACE), cardiac death, nonfatal MI, target vessel revascularization and stroke) in hospital, after 6 and 12 months. Results: One hundred sixty six (45.7%) patients were in the DES and 197(54.3%) were in the BMS group. Procedural complications were seen more frequently in the DES group (1.0% vs. 4.8%, P=0.027), the prevalence of the in-hospital MACE, angiographic and clinical success rate were the same between both the groups. There was no significant difference regarding 6 and 12 months MACE rate in patients treated by BMS or DES (6 months: 1.1% vs. 0.6%, p>0.999 12 month: 3.4% vs 2.6%, P = 0.755). Conclusion: Considering the same clinical outcome and the economical parameters, use of the BMS after proper patient selection are recommended. KEY WORD: Coronary artery disease, Angioplasty, Drug eluting stents, Bare metal stents, Major adverse cardiac events. doi: http://dx.doi.org/10.12669/pjms.291(Suppl).3512 How to cite this: Khosravi AR, Raoufi A, Pourmoghadas M, Paydari N, Gharipour M, Namdari M, et al. Late clinical events of drug eluting versus bare metal stenting; OPCES’ ancillary study. Pak J Med Sci 2013;29(1)Suppl:258-263. doi: http://dx.doi.org/10.12669/pjms.291(Suppl).3512 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

][9][10] Recent studies suggest a 0.5% increased long-term thrombosis risk with DES; however, the clinical significance of these events remains under debate 11 and in a real-world setting, use of DES in all patients is less cost effective than in studies with selected patients. 12n Iran, long-term clinical outcome of stenting by DES versus BMS were compared in a few studies but all of them were based on single center registries or trials.In present study we aimed at comparing the 1-year clinical outcomes of the patients who underwent BMS or DES placement in the Iranian patients' subsets participating in the multicentric study.

METHODOLOGY
The present study was a case-cohort ancillary study included in the Osvix versus Plavix in Cardiovascular Events after Stenting (OPCES) study. 13Briefly, OPCES is a randomized, double blind, multi-centric clinical trial which compared the early and late cardiovascular events as well as side effects of Osvix versus Plavix, two generic form of Clopidogrel, regimens in patients with chronic stable angina who underwent Drug eluting or bare metal stenting.The study was approved by the ethical committee of the Isfahan Cardiovascular Research Center, a WHO collaborating center, and all patients provided written informed consents for participation.OPCES study was registered in Iranian Randomized Clinical Trial with register No: IRCT138712111723N1.Study protocol and procedural details were mentioned before. 13In brief, stent placement procedures were performed according to standard methods and the selection of stent Type, the size of any devices and the pressure used during dilation were dependent on the operator's discretion.
Furthermore, Choice of stent was partly influenced by the participant's financial situation.DES is more expensive than BMS in the market.Lesion types were noted according to the American College of Cardiology/American Heart Association (ACC/AHA) lesion characteristics classification 14 and Thrombolysis in Myocardial Infarction (TIMI) flow grade, were determined by visual estimation using the guiding catheter as a reference object for calibration.
After successful percutaneous coronary intervention (PCI) each participant was considered as eligible for follow-up which was conducted by a structured telephone interview with the patients or one of his(er) immediate relatives up to one year.In the presence of any events the patient was evaluated by his(er) cardiologist at first and all patient's documents were reviewed by the Study Event Committee in the Isfahan cardiovascular research center for evaluation of his(er) event`s documents to decide about the occurrence of study endpoints.Patients: From March 2007 to November 2009, 442 patients were included in the OPCES study.In our study exclusion criteria were combined DES and BMS stenting (n=31), and incomplete data (n=48).Two hundred seventy four (75.5%) and 23(6.3%) of the patients were enrolled in Isfahan centers (University and Private Hospitals, respectively).Other patients were enrolled in Shiraz (28(7.7%)),Tabriz (14(3.9%)),Mashhad 6(1.7%)) and Khoram Abad (18(5.0%)centers.Definition: Myocardial infarction (MI) was defined by Ischemic symptoms accompany by at least one of the following criteria: positive cardiac enzymes, electrocardiographic changes (pathologic Q wave or new ST changes) and new cardiac motion abnormality on echocardiographic or radionuclide imaging.Non-Qwave MI was defined as a 5-fold increase in MB fraction of creatinine kinase without the development of new Q waves.Angiographic success was defined as residual stenosis <20% plus normal TIMI flow grade three in the target vessel.Clinical success was defined as angiographic success in all target lesions without any in-hospital major adverse cardiac events (In-hospital MACE: death, MI, emergency bypass surgery or PCI) during hospitalization.Early and late MACE were defined as the presence of cardiac death, non-fatal MI, or target vessel revascularization (TVR) or stroke during the 6 and 12 months of follow-up period, respectively.TVR was defined as ischemia-driven repeat percutaneous intervention or bypass surgery of the target vessel.Target lesion revascularization was defined as ischemia-driven repeat percutaneous intervention of the target lesion or bypass surgery of the target vessel.Endpoints: The primary endpoint of this study was in-hospital MACE and clinical success rate.The secondary endpoints were consisted of early and late MACE.Statistical analysis: Continuous variables are expressed as mean ± SD, and dichotomous variables as frequencies.Categorical variables were compared using the chi-square test (or Fisher's exact test if required) and continuous variables by using student t test or Mann-Whitney U test and p values < 0.05 were considered as statistically significant.Univariate and multivariate analyses of hazard ratios, including 95% confidence intervals, were calculated using the Cox proportional hazard method.Factors with p values <0.15 in the univariate analysis were entered into the multivariate model.All the statistical analyses were performed using SPSS version 15.0 (SPSS Inc., Chicago, IL, USA) for windows.

RESULTS
Totally, 426 lesions in 363 patients (Lesion/ patient ratio: 1.16±0.39)were treated in this study.One hundred twenty three (33.9%) of the patients were female and their mean age was 59.07 ± 9.41 years old.They were divided in two groups.197(54.3%)and 166(45.7%)patients were in BMS and DES group, respectively.

DISCUSSION
4][5][6] But during the past decade questions about DES safety and long term results are being asked. 3he BASKET-LATE 15 (Basel Stent Kosten-Effekivitats Trial-Late Thrombotic Events) Investigators present the long-term follow-up of a cohort of patients from the BASKET trial, a study of a randomized comparison of BMS with DES among a broad spectrum of unselected patients from a single practice.In the BASKET trial, all patients received the combination of aspirin plus clopidogrel for 6 months; after the cessation of clopidogrel, the investigators prospectively followed patients who had had survived the first 6 months without an ischemic event.Between 7 and 18 months, they observed an increase in the death/ myocardial infarction composite among the DES patients compared with the BMS patients (adjusted hazard ratio 2.2, P=0.03).Their conclusion DES vs. BMS is carefully worded to note that there was an observed continued lesser incidence of target vessel revascularization with the DES and that the late clinical events.But our study could not reveal any significant difference regarding primary endpoints or early and long term MACE between DES and BMS groups.In fact the rate of MACE in our study was more lower than the BASKET and the basket late (7.2% DES and 12.1% BMS in 6 months and 9.3% DES and 7.9% BMS between 6 and 18 months of follow up). 12Also in our study MACE pattern was not the same as BASKET (time dependant) at least in 12 months.
In this regard our results are comparable with the Alidoosti`s study. 16They evaluated long-term clinical outcome of the DES vs. BMS based on their single center registry (1796 patients: 228 DES and 1568 BMS) and they did not find any statistically significant difference between those groups in terms of angiographic and clinical success rates (P=0.72 and P=0.097, respectively).Although, the rate of MACE during follow-up was not significantly different between DES(2.2%) and BMS (4.2%), they reported that the risk of MACE was about one third when DES was compared with BMS (hazard ratio=0.36,95% CI 0.13-0.95)which was not confirmed in our study.
We think that lower rate of MACE in Iranian population comparing to other countries is an important finding which must be investigated in more powerful studies.At first, we have the hypothesis that the same clinical outcome of DES and BMS groups in our study, in regard of some other studies [3][4][5][6] , could be explained by the point that patients of the DES group have higher risk profile than the BMS group.They are more diabetic and they have more diffuse and complex lesions in the smaller vessels.Therefore, longer stents with smaller dimensions were implanted (P<0.001).After more analysis we conclude that although this hypothesis could explain the cause of more procedural complications rate in the DES group but it could not explain the cause of the same results in secondary endpoints, the mentioned factors did not play any role in the development of MACE in the multivariate analysis after adjusting for differences in baseline characteristics.
AS mentioned before, the patients in the DES group were more compliant by the Follow-up protocol.It could be related to different socioeconomical status of the patients.Furthermore, high cost of the DES and higher risk profile of these patients may encourage them to be more compliant with the study follow-up protocols.

Study limitation:
The choice between the two stent types was partly subject to the patients' financial situation, leading to possible selection bias.For the evaluation of effects of drug-eluting stents use during long-term follow up, further studies on larger populations are required.

CONCLUSION
In view of the same clinical outcome and the economical parameters, use of the BMS after proper patient selection are recommended.Of course further studies on large number of patients are needed to confirm our findings.
Table-I reveals the clinical and demographic characteristics of the patients at baseline.As it shows patients in the DES group are more often diabetics (27.4% vs. 38.9%,P=0.013) and less frequently have positive smoking history (48.2% vs. 32.5%,P=0.002).Other baseline characteristics are comparable between the groups.Table-II shows 216 lesion (Lesion/patient ratio: 1.12±0.35)and 176 lesion (Lesion/patient ratio: 1.06±0.27)were treated in the BMS and DES group, respectively.In the DES group, the lesions are more Ali Reza Khosravi et al.The response rate during one year of followup was 95.4% which was significantly different between the groups (92.1% in BMS vs. 99.4% in DES group, p=0.001).There was no significant difference regarding early and late MACE in patients treated by BMS vs. DES (1.1% vs. 0.6%, p>0.999; 3.4% vs. 2.6%, p=0.755, respectively) (Table-IV).The study groups had the same frequency of MI, cardiac death, stroke and TVR (Table-IV).Multivariate analysis reveals that no factor had a predictive role in developing the MACE.
**150 mg/dl and HDL ≤ 40 mg/dl or on treatment of Dyslipidemia ‡Hypertension: Systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg or taking hypertensive drug § smoking: person smoking at least 1 cigarette (or cigar, pipe) in the last month.