Clinical Impact of Second-Generation Everolimus-Eluting Stents Compared With First-Generation Drug-Eluting Stents in Diabetic Patients Undergoing Multivessel Percutaneous Coronary Intervention

Abstract: Objectives. This study aimed to evaluate the safety and efficacy of everolimus-eluting stent (EES) use compared with first-generation drug-eluting stent (DES) use in diabetic patients undergoing multivessel percutaneous coronary intervention (PCI). Background. Although the benefits of EES over first-generation DES were demonstrated for the general population, there is a paucity of data in diabetic patients with multivessel disease. Methods. The retrospective study cohort included 429 consecutive diabetic patients who underwent native multivessel PCI, defined as ≥2 same-generation DESs in ≥2 different native vessel territories during the index procedure. The primary safety endpoint was the combined incidence of death, non-fatal Q-wave myocardial infarction, and definite stent thrombosis (ST) at 1 year. Results. At 1 year, the primary safety endpoint was reached in 2.9% of the patients in the EES group, which was significantly lower than the 9.3% noted with first-generation DES (P=.03). The occurrence of definite or probable ST was lower in the EES group (0% vs 3.7%; P=.04). Similarly, there was a trend toward lower all-cause mortality (2.9% vs 8.5%; P=.05) and cardiac death (1% vs 4.9%; P=.08) in the EES group. However, there were no significant differences in the rates of target lesion revascularization (12.6% vs 9.3%; P=.33) between groups. In a multivariate model, EES was independently associated with a lower risk of composite primary endpoint compared with first-generation DES (hazard ratio, 0.28; 95% confidence interval, 0.09-0.94). Conclusion. In diabetic patients undergoing native multivessel PCI, the use of EES was associated with superior 1-year safety as compared with use of first-generation DES.  

J INVASIVE CARDIOL 2015;27(6):263-268

Key words: drug-eluting stents, diabetes mellitus, multivessel PCI

______________________________

Coronary artery disease is a major cause of morbidity and mortality in patients with diabetes mellitus.¹ Coronary artery bypass graft (CABG) surgery and percutaneous coronary intervention (PCI) have been established as cornerstone therapies for patients with coronary artery disease and are generally considered complementary treatment options for patients with multivessel disease.² Clinical results from the Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease (FREEDOM) trial showed that for patients with diabetes mellitus and multivessel disease, CABG was associated with lower rates of both death and myocardial infarction (MI) compared to PCI with drug-eluting stent (DES) implantation; however, stroke remained more frequent in the surgical group.³ A proportion of diabetic patients still undergo multivessel PCI due to both patient- and non-patient related factors. Patients with diabetes mellitus represent a particularly difficult subset for both CABG and PCI and are shown to have poorer outcomes as well as a higher risk of repeat revascularization procedures.^4-6

Although CABG has traditionally been the revascularization choice in patients with diabetes mellitus and multivessel disease, the improved safety and efficacy of contemporary second-generation everolimus-eluting stent (EES) implantation, compared with first-generation DES use, may have led to a higher rate of multivessel-disease patients being treated with the catheter-based approach in an all-comer population.^7-9 In the present study, we retrospectively compared long-term PCI outcomes of diabetic patients who underwent multivessel PCI with the use of DES implantation to evaluate the safety and efficacy of EES use as compared with first-generation DES use.

Methods

Utilizing our institutional PCI database, demographic, angiographic and clinical data were collected on 429 consecutive diabetic patients who underwent native multivessel PCI with DES implantation from May 2003 to March 2012. The characteristics and outcomes of patients who underwent PCI with first-generation DES (sirolimus-eluting stent [Cordis Corporation] or paclitaxel-eluting stent [Boston Scientific Corporation]) were compared with patients undergoing PCI with EES (Xience V [Abbott Vascular] or Promus [Boston Scientific Corporation]). Multivessel PCI was defined as ≥2 same-generation DESs in ≥2 different native vessel territories (left anterior descending, left circumflex, and right coronary artery) during the same index procedure. Patients with left main coronary disease or a prior bypass surgery were excluded. Patients who received a combinations of first-generation DES and EES were excluded. Patients were followed by qualified personnel at 1, 6, and 12 months by either clinic visit or telephone call. Clinical events were adjudicated via source documentation by independent physicians not involved in the procedures. Written informed consent was obtained from all patients. The analysis was conducted in accordance with the local institutional review board regulations. 

All patients received aspirin 81-325 mg and clopidogrel 600 mg or prasugrel 60 mg before or immediately after the procedure. Anticoagulation regimens were chosen at the operator’s discretion and included unfractionated heparin targeted to achieve an activated clotting time of 250-300 seconds or bivalirudin 0.75 mg/kg followed by an infusion of 1.75 mg/kg/hour for the duration of the procedure. The use of glycoprotein IIb/IIIa antagonists was at the operator’s discretion. After the procedure, aspirin 81-325 mg/day was continued indefinitely and dual-antiplatelet therapy was recommended for ≥12 months in all patients. All patients routinely underwent 12-lead electrocardiography before and after PCI to detect procedure-related ischemic changes and/or the presence of new pathologic Q-waves. 

The primary safety endpoint was the combined incidence of death, non-fatal Q-wave MI, and definite stent thrombosis (ST) at 1 year. The secondary efficacy endpoint was clinically-driven target lesion revascularization at 1 year. Death was defined as mortality from any cause. Q-wave MI was defined as an elevation of creatine kinase isoenzyme-MB ≥2 times the upper normal value in the presence of new pathologic Q-waves (>0.4 seconds) in ≥2 contiguous leads of the electrocardiogram. Non-Q wave MI was defined as typical ischemic chest pain and/or ST-segment and/or T-wave abnormalities with a creatine kinase isoenzyme-MB increase ≥2 times the reference values without any new pathologic Q-waves. Target lesion revascularization (TLR) was defined as clinically-driven revascularization of the index lesion. Target vessel revascularization (TVR) was defined as revascularization occurring in any area along the previously treated vessel. Academic Research Consortium definitions for ST were used. Diabetes mellitus was defined as either a previous diagnosis of diabetes treated with diet, oral agents, peptide analogs, insulin, or a new diagnosis during index hospitalization. 

Statistical analyses were performed using SAS version 9.2 (SAS Institute, Inc). Continuous variables were compared using Student’s t-test and are expressed as mean ± standard deviation. Categorical variables were compared using chi-square or Fisher’s exact test, as appropriate, and are expressed as numbers and percentages. Statistical significance was defined as P<.05. One-year outcomes were compared using the log-rank test and are presented as Kaplan-Meier percentages. A multivariate Cox proportional model was used to determine correlates of the primary safety endpoint at 1 year. Variables were selected on the basis of overall clinical relevance, with particular attention paid to procedural factors that could influence the composite primary endpoint. Covariates for the mutlivariate model included stent generation, number of stents implanted, proximal lesion location, and type-C lesion. The covariates in the model are expressed as hazard ratios with 95% confidence intervals. 

Results 

We analyzed data on 429 consecutive patients with diabetes mellitus who underwent native coronary multivessel PCI, 324 of which underwent first-generation DES implantation (916 lesions; 63% sirolimus-eluting stents and 33% paclitaxel-eluting stents), while 105 patients (265 lesions) underwent EES implantation. Baseline clinical characteristics stratified by DES type are summarized in Table 1. There was a male predominance in both groups. The EES group had more African-Americans (41% vs 29%; P=.02), whereas the first-generation DES group had a greater family history of coronary artery disease (55% vs 40%; P=.01). The rest of the baseline characteristics were similar between groups. Indication for PCI was similar for both groups, with no significant differences in the proportion of patients with acute MI (5% vs 7%; P=.45) at the time of clinical presentation.

Lesion-based angiographic and procedural characteristics are displayed in Table 2. Compared with EES patients, first-generation DES patients had a higher incidence of lesions in the proximal location (46% vs 31%; P<.001), used intravascular ultrasound more (67% vs 52%; P<.001), and had longer stents implanted (20 ± 5 mm vs 19 ± 4 mm; P=.01). The EES group had a higher rate of type-C lesions (47% vs 15%; P<.001). The total number of implanted stents (2.7 ± 0.9 vs 2.7 ± 0.8; P=.84) and stent diameter (2.92 ± 0.3 mm vs 2.97 ± 0.32 mm; P=.18) did not differ between groups. The overall use of glycoprotein IIb/IIIa inhibitors was low (~6%) and was similar in both groups. Bivalirudin was used as the procedural anticoagulation of choice in the majority of patients from both groups, while the EES group used bivalirudin more often (94% vs 79%; P<.001). 

Procedural and in-hospital complication rates were low and similar in both groups. The rate of in-hospital mortality was similar between groups as well (1% vs 1.8%; P>.99). Follow-up outcomes at 1 year are displayed in Table 3. At 1 year, the primary safety endpoint was reached in 2.9% of the patients in the EES group, which was significantly lower than the 9.3% noted with first-generation DES use (P=.03). Similarly, there was a trend for lower all-cause mortality (2.9% vs 8.5%; P=.05) and cardiac death (1% vs 4.9%; P=.08) in the EES group. The occurrence of definite or probable ST was lower in the EES group (3.7% vs 0%; P=.04). There were no differences in the rates of TLR (13% vs 9.3%; P=.33) and TVR (14.6% vs 14.4%; P=.96) between groups. Independent procedural correlates of the primary endpoint at 1 year by multivariate Cox proportional hazard model were use of EES (hazard ratio, 0.26; 95% confidence interval, 0.07-0.89) and number of implanted stents (hazard ratio, 1.40; 95% confidence interval, 1.01-1.94). Kaplan-Meier curves for primary endpoint and all-cause mortality at 1 year are illustrated in Figures 1 and 2.

Discussion

The main findings of the present analysis indicate that EES use in patients with diabetes mellitus and native multivessel PCI was associated with lower rates of the composite safety endpoint of all-cause mortality, non-fatal Q-wave MI, and definite ST compared with patients who received first-generation DES. This benefit was mainly driven by a decreased rate of all-cause mortality and cardiac mortality in the EES group. No significant differences were noted in the rates of TLR and TVR between groups. 

Similar results were observed in a Swedish registry of all-comer diabetic patients undergoing either sirolimus-eluting stent, paclitaxel-eluting stent, or EES therapy. EES use was associated with significantly lower rates of all-cause mortality, but no significant differences in restenosis rates were observed when comparing EES with paclitaxel-eluting and sirolimus-eluting stents at 1 year.¹⁰ These benefits were mainly driven by a lower incidence of ST in the EES group. In the present study, even with multivessel PCI in a diabetic population, there was a clear safety advantage when using EES over first-generation DES. This improved safety endpoint at 1 year in the EES group was driven by lower rates of all-cause mortality and cardiac mortality. The higher rate of cardiac mortality seen with first-generation DES use closely parallels the higher rate of ST seen in that group. Indeed, previous studies have shown that ST is strongly associated with higher rates of mortality and MI.¹¹

Clinical and histopathological studies have implicated impaired arterial healing characterized by incomplete reendothelialization, persistent fibrin deposition, and macrophage infiltration for the increased rate of ST seen with first-generation DES use.¹² Both sirolimus-eluting stent [poly(ethylene co-vinyl acetate) and poly(n-butyl methacrylate)] and paclitaxel-eluting stent polymers [poly(styrene-b-isobutylene-b-styrene)] were shown to be associated with delayed healing, impaired strut endothelization, and hypersensitivity reaction, resulting in granuloma formation and potentially contributing to higher risk of ST.^13,14 The combination of thin struts, a low dose of everolimus, and thrombo-resistant, non-inflammatory proprieties of a more biocompatible fluorinated polymer seen in EES [poly(vinylidene fluoride-hexafluoropropylene)] probably contributes to the improved early endothelialization, lower inflammation, and lower ST rates.^15,16 Joner et al analyzed the endothelial coverage in various polymeric DES using a rabbit iliofemoral artery model. EES and bare-metal stents showed a greater extent of endothelial coverage above struts relative to first-generation DESs.¹⁶ Similarly, other studies have shown that stent-based delivery of everolimus has led to selective removal of macrophages within rabbit atherosclerotic plaques without influencing the viability of smooth muscle cells leading to plaque stabilization.¹⁷ In the present study, there were no reported cases of definite or probable ST up to 1 year in the EES group, whereas 7 cases (2.2%) of definite ST were observed in the first-generation DES group; 5 subacute ST (1.5%) and 2 late ST (0.6%). In SPIRIT V, similar results were described in the diabetic population with regard to ST, with no cases of ST seen with EES versus a 2% ST rate at 1 year with the paclitaxel-eluting stent.¹⁸ These data exemplify the consistent safety of EES in a diabetic population in terms of early and late ST compared with first-generation DES use. 

Another observation from this study is that there was no difference noted in the revascularization rates between groups. Prior studies with large numbers of patients have shown similar results in patients with diabetes mellitus.^19,20 Both SPIRIT IV and the ISAR-TEST-4 trial, comparing EES and first-generation DES in a diabetic population, reported similar revascularization rates.^21,22 Indeed, these findings primarily reflect the severity and complexity of the coronary disease in diabetic patients. Diabetic patients are known to have smaller-sized vessels, longer lesion lengths, greater plaque burden, and possibly a different restenotic cascade as compared with non-diabetic patients, making them more susceptible to restenosis and have a greater need for repeat revascularizations.²³

Determination of the appropriate revascularization strategy for an individual patient is complex. The current guidelines recommend that CABG is preferred to PCI in patients with multivessel disease and diabetes mellitus, particularly if a left internal mammary artery graft can be anastomosed to the left anterior descending coronary artery.²⁴ Large clinical trials, including FREEDOM, have shown that in patients with diabetes mellitus and multivessel disease, CABG had a lower mortality rate compared with PCI.^3,25 Before generalizing the results of the FREEDOM trial to an entire diabetic population, it should be noted that the PCI group comprised a high-risk population: 82% had 3-vessel disease with a mean number of 5.6 ± 2.2 lesions per patient and a significant proportion (34%) required insulin therapy. In addition, 65% of the PCI patients had an intermediate or high SYNTAX score (22% of the cases had bifurcation lesions). The majority of PCIs (94%) were performed with first-generation DES. To extrapolate the findings of the FREEDOM trial for current clinical practice, the incidence of cardiovascular death and MI adjudicated to be due to probable or definite ST is of great interest; PCI with contemporary stents might reduce the incidence of fatal or non-fatal ST and may neutralize at least some the benefits seen in the trial. In the present study, with a patient population similar to that in FREEDOM in terms of native multivessel PCI with ≥2 stents in ≥2 different coronary territories (excluding the left main), we have shown that EES use is associated with superior safety compared with first-generation DES use. 

In addition to diabetes mellitus and multivessel disease, other risk variables should be incorporated to better define a patient’s risk and benefit for CABG versus PCI. In the Bypass Angioplasty Revascularization Investigation (BARI) trial, the mortality benefit for patients with diabetes mellitus was limited to those who received ≥1 mammary artery graft, whereas those who received only vein grafts had mortality similar to angioplasty. In the SYNTAX trial, at 3-year follow-up in patients with the lowest lesion complexity (SYNTAX scores <22), major adverse cardiac and cerebrovascular events were similar between the CABG and paclitaxel-eluting stent groups in both diabetic (30.5% vs 29.8%; P=.98) and non-diabetic patients (20.2% vs 20.3%; P=.99).²⁶ Thus, it is unlikely there is a single answer for all patients with diabetes mellitus who have multivessel disease; physician selection based on overall risk and benefit remains crucial. Furthermore, patients will continue to have unique risk patterns and values. In diabetic patients with multivessel disease and indications for both PCI and CABG, both revascularization strategies should be weighed by a multidisciplinary heart team to assess the risk-benefit ratio of each form of treatment. Patients should be informed about expected long-term results after CABG and about the estimated results after PCI with contemporary stent technology. 

Study limitations. This is a single-center, non-randomized, retrospective observational study. The resulting analysis could have been affected by unknown confounders. We could not analyze target vessel failure, which may be the most suitable variable to evaluate stent efficacy. The reason for choosing multivessel PCI in preference to CABG was not evaluated in the present study. Since this was a longitudinal study, it is possible that the differences can be attributed to the changes and improvements in PCI pharmacology, use of second-generation antiplatelet therapy, and/or a longer duration of antiplatelet therapy in the EES group. The small sample size is also a major limitation. Despite these limitations, this study provides insight into a large series of consecutive diabetic patients treated with native multivessel PCI and their long-term outcomes. 

Conclusion

The present study adds to the growing knowledge concerning the safety of EES use, even in a high-risk patient population like diabetic multivessel CAD. Future trials should directly evaluate new-generation DES implantation versus CABG surgery in patients with diabetic multivessel disease, especially in patients with lower lesion complexity.

References

1. Goraya TY, Leibson CL, Palumbo PJ, et al. Coronary atherosclerosis in diabetes mellitus: a population-based autopsy study. J Am Coll Cardiol. 2002;40:946-953.
2. Qaseem A, Fihn SD, Dallas P, Williams S, Owens DK, Shekelle P. Clinical guidelines committee of the American College of Physicians. Management of stable ischemic heart disease: summary of a clinical practice guideline from the American College of Physicians/American College of Cardiology Foundation/American Heart Association/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society of Thoracic Surgeons. Ann Intern Med. 2012;157:735-743. 
3. Farkouh ME, Domanski M, Sleeper LA, et al. FREEDOM Trial Investigators. Strategies for multivessel revascularization in patients with diabetes. N Engl J Med. 2012;367:2375-2384. 
4. Cohen Y, Raz I, Merin G, Mozes B. Comparison of factors associated with 30-day mortality after coronary artery bypass grafting in patients with versus without diabetes mellitus. Israeli Coronary Artery Bypass (ISCAB) Study Consortium. Am J Cardiol. 1998;81:7-11.
5. Thourani VH, Weintraub WS, Stein B, et al. Influence of diabetes mellitus on early and late outcome after coronary artery bypass grafting. Ann Thorac Surg. 1999;67:1045-1052.
6. Jensen LO, Maeng M, Thayssen P, et al. Long-term outcomes after percutaneous coronary intervention in patients with and without diabetes mellitus in Western Denmark. Am J Cardiol. 2010;105:1513-1519.
7. Kereiakes DJ, Sudhir K, Hermiller JB, et al. Comparison of everolimus-eluting and paclitaxel-eluting coronary stents in patients undergoing multilesion and multivessel intervention: the SPIRIT III (A Clinical Evaluation of the Investigational Device XIENCE V Everolimus Eluting Coronary Stent System [EECSS] in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) and SPIRIT IV (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System in the Treatment of Subjects With De Novo Native Coronary Artery Lesions) randomized trials. JACC Cardiovasc Interv. 2010;3:1229-1239.
8. Stone GW, Rizvi A, Sudhir K, et al. SPIRIT IV Investigators. Randomized comparison of everolimus- and paclitaxel-eluting stents. 2-Year follow-up from the SPIRIT (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System) IV trial. J Am Coll Cardiol. 2011;58:19-25.
9. Park DW, Kim YH, Song HG, et al. Long-term outcome of stents versus bypass surgery in diabetic and nondiabetic patients with multivessel or left main coronary artery disease: a pooled analysis of 5775 individual patient data. J Am Coll Cardiol. 2008;52:1957-1967.
10. Kedhi E, Gomes ME, Lagerqvist B, et al. Clinical impact of second-generation everolimus-eluting stent compared with first-generation drug-eluting stents in diabetes mellitus patients: insights from a nationwide coronary intervention register. JACC Cardiovasc Interv. 2012;5:1141-1149.
11. Mauri L, Hsieh WH, Massaro JM, Ho KK, D’Agostino R, Cutlip DE. Stent thrombosis in randomized clinical trials of drug-eluting stents. N Engl J Med. 2007;356:1020-1029.
12. Finn AV, Nakazawa G, Joner M, et al. Vascular responses to drug eluting stents: importance of delayed healing. Arterioscler Thromb Vasc Biol. 2007;27:1500-1510. 
13. Virmani R, Liistro F, Stankovic G, et al. Mechanism of late in-stent restenosis after implantation of a paclitaxel derivate-eluting polymer stent system in humans. Circulation. 2002;106:2649-2651.
14. Nakazawa G, Ladich E, Finn AV, Virmani R. Pathophysiology of vascular healing and stent mediated arterial injury. EuroIntervention. 2008;4:C7-C10.
15. Pendyala LK, Yin X, Li J, Chen JP, Chronos N, Hou D. The first-generation drug-eluting stents and coronary endothelial dysfunction. JACC Cardiovasc Interv. 2009;2:1169-1177. 
16. Joner M, Nakazawa G, Finn AV, et al. Endothelial cell recovery between comparator polymer-based drug-eluting stents. J Am Coll Cardiol. 2008;52:333-342.
17. Verheye S, Martinet W, Kockx MM, et al. Selective clearance of macrophages in atherosclerotic plaques by autophagy. J Am Coll Cardiol. 2007;49:706-715. 
18. Grube E, Chevalier B, Guagliumi G, et al. The SPIRIT V diabetic study: a randomized clinical evaluation of the Xience V everolimus-eluting stent vs the Taxus Liberté paclitaxel-eluting stent in diabetic patients with de novo coronary artery lesions. Am Heart J. 2012;163:867-875.
19. Grube E, Chevalier B, Guagliumi G, et al. Differential clinical responsesto everolimus-eluting and paclitaxel-eluting coronary stents in patients with and without diabetes mellitus. Circulation. 2011;124:893-900.
20. Kim WJ, Lee SW, Park SW, et al. ESSENCE-DIABETES Study Investigators. Randomized comparison of everolimus-eluting stent versus sirolimus-eluting stent implantation for de novo coronary artery disease in patients with diabetes mellitus (ESSENCE-DIABETES): results from the ESSENCE-DIABETES trial. Circulation. 2011;124:886-892.
21. Kereiakes DJ, Cutlip DE, Applegate RJ, et al. Outcomes in diabetic and nondiabetic patients treated with everolimus- or paclitaxel-eluting stents: results from the SPIRIT IV clinical trial (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent System). J Am Coll Cardiol. 2010;56:2084-2089.
22. Kufner S, Byrne RA, Mehilli J, et al. Second-versus first-generation “Limus”-eluting stents in diabetic patients with coronary artery disease: a randomized comparison in setting of ISAR-TEST-4 trial. Catheter Cardiovasc Interv. 2013;82:E769-E776. 
23. West NE, Ruygrok PN, Disco CM, et al. Clinical and angiographic predictors of restenosis after stent deployment in diabetic patients. Circulation. 2004;109:867-873.
24. Levine GN, Bates ER, Blankenship JC, et al. American College of Cardiology Foundation, American Heart Association Task Force on Practice G, Society for Cardiovascular Angiography and Interventions. 2011 ACCF/AHA/SCAI Guideline for Percutaneous Coronary Intervention. A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines and the Society for Cardiovascular Angiography and Interventions. J Am Coll Cardiol. 2011;58:e44-e122.
25. Comparison of coronary bypass surgery with angioplasty in patients with multivessel disease. The Bypass Angioplasty Revascularization Investigation (BARI) Investigators. N Engl J Med. 1996;33:217-225.
26. Mack MJ, Banning AP, Serruys PW, et al. Bypass versus drug-eluting stents at three years in SYNTAX patients with diabetes mellitus or metabolic syndrome. Ann Thorac Surg. 2011;92:2140-2146.

___________________________

From the Division of Cardiology, MedStar Washington Hospital Center, Washington, DC.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Satler reports income from the Abbott Vascular speaker’s bureau. Dr Waksman reports personal fees from Biotronik, Abbott Vascular, and Medtronic; grants and personal fees from AstraZeneca and Boston Scientific; grants from The Medicines Company and Edwards Lifesciences. The remaining authors report no conflicts of interest regarding the content herein.

Manuscript submitted June 23, 2014, provisional acceptance given August 1, 2014, final version accepted September 29, 2014.

Address for correspondence: Dr Ron Waksman, MedStar Washington Hospital Center, Division of Cardiology, 110 Irving Street NW, Suite 4B-1, Washington, DC 20010. Email: ron.waksman@medstar.net