Early (≤ 30Days), Late (31–360Days) and Very Late (> 360Days) Stent Thrombosis in Patients with Insulin-Treated versus Non-Insulin-Treated Type 2 Diabetes Mellitus: A Meta-Analysis

Early (≤ 30Days), Late (31–360Days) and Very Late (> 360Days) Stent Thrombosis in... Diabetes Ther (2018) 9:1113–1124 https://doi.org/10.1007/s13300-018-0425-1 ORIGINAL RESEARCH Early (£ 30 Days), Late (31–360 Days) and Very Late (> 360 Days) Stent Thrombosis in Patients with Insulin-Treated versus Non-Insulin-Treated Type 2 Diabetes Mellitus: A Meta-Analysis . . Wei Chen Yubin Wu Yubao Hu Received: March 23, 2018 / Published online: April 11, 2018 The Author(s) 2018 ITDM and NITDM and stent thrombosis fol- ABSTRACT lowing PCI using specific terms. Early stent thrombosis, late stent thrombosis and very late Introduction: At this time in 2018, with type 2 stent thrombosis were the clinical outcomes. diabetes mellitus (T2DM) and coronary artery The main analysis was carried out using the disease (CAD) still on the rise, the post-percu- latest version of the RevMan software (version taneous coronary interventional (PCI) out- 5.3) whereby odds ratios (OR), and 95% confi- comes observed in patients with diabetes dence intervals (CI) were generated. mellitus who are on insulin therapy (ITDM) and Results: A total of 8524 participants with those who do not require insulin (NITDM) are T2DM (2273 participants were on insulin ther- still controversial and require further investiga- apy and 6251 participants were not) were tion. Considering this idea to be of particular included. Results of this analysis showed early interest to the readers, as well as being an stent thrombosis to be significantly higher in important issue in interventional cardiology, patients with ITDM (OR 1.81, 95% CI 1.04–3.15; we aimed to systematically assess early P = 0.04), whereas late and very late stent (B 30 days), late (31–360 days) and very late thromboses were not significantly different fol- ([ 360 days) stent thrombosis in patients with lowing PCI with DES in diabetic patients with ITDM and NITDM following drug-eluting stent versus without insulin therapy (OR 1.44, 95% (DES) implantation. CI 0.73–2.84, P = 0.30 and OR 0.80, 95% CI Methods: Well-known online databases (the 0.33–1.92, P = 0.62, respectively). Late stent Cochrane, EMBASE and MEDLINE databases thromboses associated exclusively with ever- and http://www.ClinicalTrials.gov) were sear- olimus-eluting stents (EES) and paclitaxel-elut- ched for relevant English publications based on ing stents (PES) were not significantly different in patients with ITDM and NITDM. Conclusion: Following PCI with DES, early stent thrombosis was significantly higher in Enhanced Digital Features To view enhanced digital patients with ITDM. However, late and very late features for this article, go to https://doi.org/10.6084/ m9.figshare.6086210. stent thromboses were not significantly differ- ent in patients with type 2 diabetes mellitus W. Chen  Y. Wu (&)  Y. Hu who were treated with or without insulin. Department of Cardiology, Guilin People’s Hospital, Comparison with individual DES was not suffi- No. 12, Wenming Road, Guilin 541002, Guangxi, ciently powerful to reach a conclusion. China e-mail: wyb201819@163.com 1114 Diabetes Ther (2018) 9:1113–1124 Keywords: Coronary artery disease; Drug- NITDM and stent thrombosis following PCI eluting stents; Early stent thrombosis; Insulin- using the terms: treated type 2 diabetes mellitus; Late stent 1. Diabetes mellitus and percutaneous coro- thrombosis; Percutaneous coronary intervention nary intervention/PCI; 2. Diabetes mellitus and coronary angioplasty; Abbreviations 3. Drug-eluting stents and diabetes mellitus; DAPT Dual antiplatelet therapy 4. Diabetes mellitus and stent thrombosis; DES Drug-eluting stents 5. Insulin-treated diabetes mellitus and percu- PCI Percutaneous coronary intervention taneous coronary intervention. ST Stent thrombosis T2DM Type 2 diabetes mellitus These searched terms were applied to each of the electronic databases, and the searched out- comes were carefully assessed for relevant pub- lications that would be suitable for this current INTRODUCTION research topic and would be expected to con- tain data to possibly be used for this analysis. At this time in 2018, with type 2 diabetes mel- litus (T2DM) and coronary artery disease (CAD) still on the rise [1], the post-percutaneous Inclusion and Exclusion Criteria coronary interventional (PCI) outcomes observed in patients with diabetes mellitus who The two major inclusion criteria were: are on insulin therapy (ITDM) and those who 1. Research papers comparing patients with do not require insulin (NITDM) are still con- ITDM and NITDM following PCI; troversial and require further investigation. 2. With reference to the above criterion (1), In October 2015, Bundhun et al. published early, late and/or very late stent thrombosis an interesting meta-analysis based on the com- should be reported among the endpoints. parison of outcomes observed in patients with Exclusion criteria were: ITDM and NITDM following PCI [2]. Recently, 1. Research paper dealing with patients with we came up with a new idea based on stent T2DM without further dividing the patients thrombosis in patients with ITDM versus into ITDM and NITDM; NITDM who were treated with drug-eluting 2. Early, late or very late stent thromboses stents (DES). were not reported; instead, definite and/or Considering this idea to be of particular probable stent thromboses were reported; interest to the readers, as well as being an 3. Research that involved patients with type 1 important issue in interventional cardiology, diabetes mellitus; we aimed to systematically assess early 4. Duplicated studies; (B 30 days), late (31–360 days) and very late 5. Review articles, meta-analyses and letters to ([ 360 days) stent thrombosis in patients with editors. ITDM and NITDM following DES implantation. Definitions of Specific Terms METHODS ITDM was defined as patients with T2DM who required insulin as treatment. Searched Materials (Searched Databases NITDM was defined as patients with T2DM and Terms) who did not require insulin as treatment, but instead were dependent on oral hypoglycemic Well-known online databases (the Cochrane, agents. EMBASE and MEDLINE databases and http:// Early stent thrombosis [3] was defined as www.ClinicalTrials.gov) were searched for rele- acute and sub-acute stent thrombosis observed vant English publications based on ITDM and at B 30 days following PCI. Diabetes Ther (2018) 9:1113–1124 1115 Late stent thrombosis [3] was defined as stent Data Extraction, Quality Assessment and Statistical Analysis thrombosis that occurred after 30 days (31–- 360 days) following PCI. Very late stent thrombosis [3] was defined as Three reviewers, Wei Chen, Yubin Wu and stent thrombosis that occurred after 360 days Yubao Hu, independently extracted the follow- following PCI. ing data: 1. The study type (randomized controlled tri- als, cohort studies, retrospective studies); Outcomes, Types of Participants, Types of DES and Follow-Up Periods 2. The types of participants involved; 3. The total number of participants who were on insulin treatment or were on oral hypo- The three endpoints of this analysis were early, glycemic drugs; late and very late stent thrombosis as shown in 4. The baseline characteristics of the Table 1. participants; The follow-up time period varied from 1 to 5. The endpoints (early, late and very late 3 years. stent thrombosis); All participants were candidates for 6. The total number of events in each T2DM ? CAD who underwent revasculariza- category; tion by PCI. 7. The year internal period of patient The types of DES varied: everolimus-eluting enrollment; stents (EES), paclitaxel-eluting stents (PES), sir- 8. The types of DES reported; olimus-eluting stents (SES) and zotarolimus- 9. The methodologic quality of the trials for eluting stents (ZES) were used as shown in assessment. Table 1. Table 1 Outcomes, follow-up periods and types of participants Studies Outcomes reported Follow-up time period Types of participants Types of (years) DES Banning et al. Early (acute and sub-acute) and 1 Left main and triple vessel PES [6] late ST disease Jain et al. [7] Early (acute and sub-acute) and 1 CAD ZES late ST Jiang et al. [8] Early, late and very late ST 2 CAD DES Kereiakes et al. Early (acute and sub-acute) and 1 CAD EES, PES [9] late ST Nakamura et al. Early, late and very late ST 3 CAD ? hemodialysis SES [10] Silber et al. [11] Early, late and very late 2 CAD ZES Simek et al. [12] Early, late and very late 3 CAD EES, SES, PES Early stent thrombosis: 0–30 days Late stent thrombosis: 31–360 days Very late stent thrombosis: [ 360 days ST stent thrombosis, DES drug-eluting stents, CAD coronary artery disease, PES paclitaxel-eluting stents, EES everolimus- eluting stents, SES sirolimus-eluting stents, ZES zotarolimus-eluting stents 1116 Diabetes Ther (2018) 9:1113–1124 Any disagreement that followed was solved by Since this analysis involved a small volume consensus. of studies, publication bias was better assessed The methodologic quality of the trials was by funnel plots, which could be generated using assessed based on the criteria recommended by the RevMan software. the Cochrane collaboration [4] whereby grades were given in accordance with whether a low, Compliance with Ethics Guidelines moderate or high risk of bias was reported. The main analysis was carried out using the This meta-analysis, based on previously con- latest version of RevMan software (version 5.3) ducted studies, does not contain any studies whereby odds ratios (ORs) and 95% confidence with human participants or animals performed intervals (CIs) were generated. by any of the authors. Hence, ethical approval In this analysis, ORs were used to compare was not required. the relative odds of the occurrence of stent thrombosis (early, late and very late), given exposure to insulin treatment. These ORs were RESULTS also used to determine whether exposure to insulin therapy was a risk factor for stent Searched Outcomes and the General thrombosis in these patients with T2DM who Properties of the Included Studies had previously been implanted with DES. However, the presence of a positive OR in The PRISMA guideline was followed [5]. A this case did not necessarily indicate that this thorough search of online databases resulted in association was statistically significant. We also 6187 publications. Figure 1 shows the flow dia- had to consider the CIs and P values to deter- gram for the study selection. mine significance. Seven publications [6–12] were selected for The 95% CI is used to estimate the precision this analysis, as shown in Fig. 1. of the OR obtained. A large CI indicates a low Table 2 lists the studies selected for this level of precision of the OR, whereas a small CI analysis. indicates higher precision. The CI indicates the After a careful assessment of the method- level of uncertainty around the measure of ologic quality of the trials, a low-to-moderate effect, which is expressed as an OR in this risk of bias was observed and graded from A to C analysis. Similar to other studies, we have also whereby ‘A’ signified low risk of bias, ‘B’ signi- reported the 95% CIs in this analysis. fied moderate risk of bias, and ‘C’ signified a Heterogeneity is a common feature in meta- high risk of bias. analyses. Heterogeneity was assessed by the A total of 8524 participants with T2DM following: (2273 participants were on insulin therapy and 6251 were not) were included in this analysis. 1. The Q statistic test whereby P C 0.05 was The period of patient enrollment varied from considered statistically significant; 2004 to 2012. All the patients received dual 2 2 2. The I statistic test whereby an increasing I antiplatelet therapy (DAPT) following stent value signified increasing heterogeneity and implantation. However, the duration of DAPT a low I value signified low heterogeneity. was not stated. In addition, the statistical model used was based on this heterogeneity value whereby a fixed Participants’ Baseline Features effects model was used if I was B 50% and a random effects model was used if the I value The participants’ baseline features are listed in was [ 50%. Table 3. Sensitivity analysis was carried out by an Mean age of 63.3–67.2 years was reported expulsion method for comparison with the with a predominance of male patients. Features main results. such as hypertension, dyslipidemia and current Diabetes Ther (2018) 9:1113–1124 1117 Fig. 1 Flow diagram showing the selection of studies smoking were also reported in patients with was also not significantly different (OR 0.80, ITDM and NITDM, as shown in Table 3. Overall, 95% CI 0.33–1.92; P = 0.62), as shown in Fig. 2. there was no significant difference in baseline Late stent thromboses associated with dif- features between the diabetic patients with and ferent individual DES subgroups were also ana- without insulin therapy. lyzed separately. Late stent thromboses associated with PES and EES were also not sig- nificantly different between patients with ITDM Main Analysis Results and NITDM (OR 0.63, 95% CI 0.18–2.20, P = 0.47 and OR 0.66, 95% CI 0.11–3.89, Results of this analysis showed early stent P = 0.65, respectively), as shown in Fig. 3. Even thrombosis to be significantly higher in patients if late stent thrombosis associated with ZES was with ITDM (OR 1.81, 95% CI 1.04–3.15; significantly higher in patients with ITDM (OR P = 0.04), but late stent thrombosis was not 3.14, 95% CI 1.20–8.20; P = 0.02), only two significantly different following PCI with DES in studies with an insufficient number of patients diabetic patients with versus without insulin comprised this particular subgroup, which was therapy (OR 1.44, 95% CI 0.73–2.84; P = 0.30), insufficient for reaching conclusions. as shown in Fig. 2. Very late stent thrombosis Sensitivity analysis was consistent through- out the analysis. 1118 Diabetes Ther (2018) 9:1113–1124 Table 2 General characteristics of the included studies Studies Patients with Patients with Type of Year of patients’ Antiplatelets ITDM (n) NITDM (n) study enrollment used Banning et al. [6] 89 142 RCT 2005– 012 DAPT Jain et al. [7] 644 1919 Cohort 2005–2007 DAPT Jiang et al. [8] 68 132 Retrospective 2010–2013 DAPT Kereiakes et al. [9] 209 ? 119 577 ? 280 RCT 2006–2009 DAPT Nakamura et al. 200 647 Cohort 2004–2005 DAPT [10] Silber et al. [11] 455 1080 RCT – DAPT Simek et al. [12] 231 ? 147 ? 111 573 ? 465 ? 436 Cohort 2002–2009 DAPT Total no. of 2273 6251 patients (n) ITDM insulin-treated diabetes mellitus, NITDM non-insulin-treated diabetes mellitus, RCT randomized-controlled trials, DAPT dual antiplatelet agents (aspirin and clopidogrel) Table 3 Participants’ baseline features Studies Age (years) Males (%) HTN (%) DS (%) CS (%) ITDM/NITDM ITDM/NITDM ITDM/NITDM ITDM/NITDM ITDM/NITDM Banning et al. [6] 65.4/65.4 71.0/71.0 69.9/69.9 81.5/81.5 15.8/15.8 Jain et al. [7] 66.6/64.9 62.2/71.8 82.1/77.5 67.9/67.7 13.9/18.0 Jiang et al. [8] 65.1/66.8 72.1/74.2 75.0/76.1 79.4/78.0 25.0/22.8 Kereiakes et al. [9] 63.3/63.3 63.3/63.3 87.0/87.0 82.5/82.5 18.3/18.3 Nakamura et al. [10] 66.2/67.2 66.2/75.4 68.1/72.0 58.0/60.4 12.1/19.5 Silber et al. [11] 64.6/65.5 56.4/70.4 91.6/86.0 86.8/86.0 17.2/18.6 Simek et al. [12] 65.1/65.1 69.2/69.2 70.6/70.6 65.5/65.5 32.1/32.1 ITDM insulin-treated diabetes mellitus, NITDM non-insulin-treated diabetes mellitus, HTN hypertension, DS dyslipi- demia, CS current smoker Evidence of publication bias was minimal Nevertheless, even though the authors across the studies that were involved in assess- assessed stent thrombosis in their previous ing early and late stent thrombosis in the work, this particular outcome was not assessed patients with ITDM and NITDM, as shown in in detail. We therefore came up with the new Figs. 4 and 5. idea of systematically comparing early, late and very late stent thrombosis post-PCI in patients with ITDM and NITDM. DISCUSSION In the previous analysis, stent thrombosis was shown to be significantly higher in patients Previous meta-analyses based on ITDM patients with ITDM compared with NITDM (OR 1.66, with cardiac problems were well appreciated 95% CI 1.16–2.38, P = 0.005 for short-term ST; [2, 13]. Diabetes Ther (2018) 9:1113–1124 1119 Fig. 2 Early, late and very late stent thrombosis in patients with type 2 diabetes mellitus who were treated with versus without insulin following percutaneous coronary intervention with drug-eluting stents OR 1.59, 95% CI 1.21–2.10; P = 0.001 for long- P = 0.62) were not significantly different in term ST) [2]. patients with ITDM and NITDM. When data were closely assessed, it could be Several reasons have been suggested for the seen that stent thrombosis was definitely signif- high level of stent thrombosis in patients with icantly higher in patients with ITDM compared ITDM: Patients on insulin therapy have more with NITDM. This result was obtained when advanced disease, and their risk of complica- definite and probable or possible stent throm- tions after PCI is higher according to their high boses were analyzed all together. However, in the risk profile. Also, iatrogenic hyperinsulinemia current analysis, when stent thrombosis was might promote proinflammatory macrophage assessed based on the time period following PCI, responses and stimulate hormonal hyperactiv- early stent thrombosis was significantly higher in ity, which might in return disturb the balanced patients with insulin therapy (OR 1.81, 95% CI synthesis and release of endothelial mediators. 1.04–3.15; P = 0.04). However, late (OR 1.44, Insulin therapy might also cause platelet 95% CI 0.73–2.84; P = 0.30) and very late stent hyperactivity, which can then increase the thromboses (OR 0.80, 95% CI 0.33–1.92; chance of stent thrombosis after PCI with DES. 1120 Diabetes Ther (2018) 9:1113–1124 Fig. 3 Late stent thrombosis in patients with insulin-treated versus non-insulin-treated type 2 diabetes mellitus with individual drug-eluting stents (EES, PES, ZES) Reasons that have been considered for a example, in the E-five registry [7], 14 patients similar rate of late and very late stent throm- out of a total of 644 (2.17%) patients with ITDM bosis in this analysis could be that: experienced stent thrombosis as defined by the Academic Research Consortium (ARC), whereas 1. The total number of studies reporting these 25 out of 1919 (1.30%) patients with NITDM outcomes were few and not sufficient to experienced stent thrombosis as defined by the reach a robust result in terms of very late ARC. However, when stent thrombosis was stent thromboses, which were only reported further divided into early and late stent in four studies; thrombosis, 1.6% of patients with ITDM expe- 2. This issue is controversial, and the number rienced early stent thrombosis and 1.0% of the of studies favoring ITDM was similar to the patients with NITDM experienced early stent number of studies favoring NITDM, result- thrombosis, whereas 0.8% and 0.3% of the ing in an insignificant result for favoring patients with ITDM and NITDM, respectively, either ITDM or NITDM in case of late and experienced late ST. Even if the percentage of very late stent thrombosis; patients with ITDM experienced more throm- 3. The total number of early stent thromboses bosis, the percentage was reduced when stent in patients with ITDM was indeed higher thrombosis was further divided, especially in compared with late and very late stent the case of late stent thrombosis. thrombosis. The results of the SPIRIT IV Trial were dif- ferent from those of the E-five registry [9]. The In other studies where early and late stent early stent thrombosis rate was 0.48% with EES thromboses were reported following PCI in in ITDM and 0.85% with PES in ITDM, and patients with and without insulin therapy, for Diabetes Ther (2018) 9:1113–1124 1121 Fig. 4 Funnel plot showing publication bias (A) there was no late stent thrombosis in ITDM. group, whereas in patients with NITDM, 0.45% However, in patients with NITDM, early stent and 0.62% patients experienced late and very thrombosis was 0.35% with EES and 0.36% with late stent thrombosis, respectively, which partly PES, whereas late stent thrombosis was 0.18% contributed to the results that were obtained. with EES and 0.76% with PES. A conclusion Nevertheless, following the previously pub- could be that there was no late stent thrombosis lished research article [2] based on patients with in patients with ITDM who were implanted ITDM and NITDM post PCI, and upon reader with DES. requests, this analysis has further shown a new In the 2-year results from the Prospectively outcome, whereby early stent thrombosis was Pooled Analysis of the International Global significantly higher in ITDM patients compared RESOLUTE Program [11], 0.9% of patients with with those with NITDM, whereas late and very ITDM and 0.8% of patients with NITDM expe- late stent thromboses were not significantly rienced early stent thrombosis, whereas 0.2% different in patients with ITDM and NITDM. and 0.1% of patients with ITDM and NITDM, This scientific concept should be of significant respectively, experienced late stent thrombosis. clinical importance and definitely find a place The number of patients who experienced late in medical libraries. stent thrombosis events was similar between Finally, while recent analyses have focused the ITDM and NITDM groups, further support- on different types of drug-eluting stents and the ing this analysis. associated stent thrombosis [14, 15], future In contrast, insights from a sub-study of the analysis should compare stent thrombosis in Cypher Stent Japan Post-Marketing Surveillance male versus female patients with diabetes mel- (Cypher J-PMS) Registry [10] showed no early, litus [16], specifically in male and female late or very late stent thrombosis in the ITDM patients with ITDM and NITDM. In addition, 1122 Diabetes Ther (2018) 9:1113–1124 Fig. 5 Funnel plot showing publication bias (B) the SYNTAX score [17, 18] should be included are all DESs; this could also have influenced the results. in future studies with ITDM and NITDM patients, and stent thrombosis should be asses- 3. For those studies that had a follow-up period [ 1 year, it was not known whether DAPT sed in patients with a low versus a high SYNTAX score. was continued or discontinued. This might also have influenced the results. Limitations CONCLUSIONS Limitations were: 1. Although the total number of patients was Following PCI with DES, early stent thrombosis sufficient to reach a conclusion based on was significantly higher in patients with ITDM. patients who were treated with DES as a However, late and very late stent thromboses whole, the number of patients was not were not significantly different in patients with sufficient to reach a conclusion when each type 2 diabetes mellitus who were treated with DES (EES, SES, PES, ZES) was individually or without insulin. Comparison with individual assessed. DESs was not sufficiently powerful to reach a 2. First- and second-generation DESs were conclusion. combined and analyzed assuming that they Diabetes Ther (2018) 9:1113–1124 1123 ACKNOWLEDGEMENTS REFERENCES We thank the participants in the study. 1. Oikonomou E, Mourouzis K, Fountoulakis P, Papa- mikroulis GA, Siasos G, Antonopoulos A, Vogiatzi G, Tsalamadris S, Vavuranakis M, Tousoulis D. Funding. 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Wei Chen, Yubin 4. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring Wu and Yubao Hu were responsible for the inconsistency in meta-analyses. BMJ. conception and design, acquisition of data, 2003;327:557–60. analysis and interpretation of data, drafting the 5. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA initial manuscript and revising it critically for statement for reporting systematic reviews and important intellectual content. Dr. Wei Chen is meta-analyses of studies that evaluate health care the first author and wrote and approved the interventions: explanation and elaboration. BMJ. 2009;339:b2700. final manuscript. 6. Banning AP, Westaby S, Morice MC, Kappetein AP, Disclosures. The authors Wei Chen, Yubin Mohr FW, Berti S, Glauber M, Kellett MA, Kramer Wu and Yubao Hu have nothing to disclose. RS, Leadley K, Dawkins KD, Serruys PW. Diabetic and nondiabetic patients with left main and/or Compliance with Ethics Guidelines. 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Early (≤ 30Days), Late (31–360Days) and Very Late (> 360Days) Stent Thrombosis in Patients with Insulin-Treated versus Non-Insulin-Treated Type 2 Diabetes Mellitus: A Meta-Analysis

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Medicine & Public Health; Internal Medicine; Diabetes; Cardiology; Endocrinology
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Diabetes Ther (2018) 9:1113–1124 https://doi.org/10.1007/s13300-018-0425-1 ORIGINAL RESEARCH Early (£ 30 Days), Late (31–360 Days) and Very Late (> 360 Days) Stent Thrombosis in Patients with Insulin-Treated versus Non-Insulin-Treated Type 2 Diabetes Mellitus: A Meta-Analysis . . Wei Chen Yubin Wu Yubao Hu Received: March 23, 2018 / Published online: April 11, 2018 The Author(s) 2018 ITDM and NITDM and stent thrombosis fol- ABSTRACT lowing PCI using specific terms. Early stent thrombosis, late stent thrombosis and very late Introduction: At this time in 2018, with type 2 stent thrombosis were the clinical outcomes. diabetes mellitus (T2DM) and coronary artery The main analysis was carried out using the disease (CAD) still on the rise, the post-percu- latest version of the RevMan software (version taneous coronary interventional (PCI) out- 5.3) whereby odds ratios (OR), and 95% confi- comes observed in patients with diabetes dence intervals (CI) were generated. mellitus who are on insulin therapy (ITDM) and Results: A total of 8524 participants with those who do not require insulin (NITDM) are T2DM (2273 participants were on insulin ther- still controversial and require further investiga- apy and 6251 participants were not) were tion. Considering this idea to be of particular included. Results of this analysis showed early interest to the readers, as well as being an stent thrombosis to be significantly higher in important issue in interventional cardiology, patients with ITDM (OR 1.81, 95% CI 1.04–3.15; we aimed to systematically assess early P = 0.04), whereas late and very late stent (B 30 days), late (31–360 days) and very late thromboses were not significantly different fol- ([ 360 days) stent thrombosis in patients with lowing PCI with DES in diabetic patients with ITDM and NITDM following drug-eluting stent versus without insulin therapy (OR 1.44, 95% (DES) implantation. CI 0.73–2.84, P = 0.30 and OR 0.80, 95% CI Methods: Well-known online databases (the 0.33–1.92, P = 0.62, respectively). Late stent Cochrane, EMBASE and MEDLINE databases thromboses associated exclusively with ever- and http://www.ClinicalTrials.gov) were sear- olimus-eluting stents (EES) and paclitaxel-elut- ched for relevant English publications based on ing stents (PES) were not significantly different in patients with ITDM and NITDM. Conclusion: Following PCI with DES, early stent thrombosis was significantly higher in Enhanced Digital Features To view enhanced digital patients with ITDM. However, late and very late features for this article, go to https://doi.org/10.6084/ m9.figshare.6086210. stent thromboses were not significantly differ- ent in patients with type 2 diabetes mellitus W. Chen  Y. Wu (&)  Y. Hu who were treated with or without insulin. Department of Cardiology, Guilin People’s Hospital, Comparison with individual DES was not suffi- No. 12, Wenming Road, Guilin 541002, Guangxi, ciently powerful to reach a conclusion. China e-mail: wyb201819@163.com 1114 Diabetes Ther (2018) 9:1113–1124 Keywords: Coronary artery disease; Drug- NITDM and stent thrombosis following PCI eluting stents; Early stent thrombosis; Insulin- using the terms: treated type 2 diabetes mellitus; Late stent 1. Diabetes mellitus and percutaneous coro- thrombosis; Percutaneous coronary intervention nary intervention/PCI; 2. Diabetes mellitus and coronary angioplasty; Abbreviations 3. Drug-eluting stents and diabetes mellitus; DAPT Dual antiplatelet therapy 4. Diabetes mellitus and stent thrombosis; DES Drug-eluting stents 5. Insulin-treated diabetes mellitus and percu- PCI Percutaneous coronary intervention taneous coronary intervention. ST Stent thrombosis T2DM Type 2 diabetes mellitus These searched terms were applied to each of the electronic databases, and the searched out- comes were carefully assessed for relevant pub- lications that would be suitable for this current INTRODUCTION research topic and would be expected to con- tain data to possibly be used for this analysis. At this time in 2018, with type 2 diabetes mel- litus (T2DM) and coronary artery disease (CAD) still on the rise [1], the post-percutaneous Inclusion and Exclusion Criteria coronary interventional (PCI) outcomes observed in patients with diabetes mellitus who The two major inclusion criteria were: are on insulin therapy (ITDM) and those who 1. Research papers comparing patients with do not require insulin (NITDM) are still con- ITDM and NITDM following PCI; troversial and require further investigation. 2. With reference to the above criterion (1), In October 2015, Bundhun et al. published early, late and/or very late stent thrombosis an interesting meta-analysis based on the com- should be reported among the endpoints. parison of outcomes observed in patients with Exclusion criteria were: ITDM and NITDM following PCI [2]. Recently, 1. Research paper dealing with patients with we came up with a new idea based on stent T2DM without further dividing the patients thrombosis in patients with ITDM versus into ITDM and NITDM; NITDM who were treated with drug-eluting 2. Early, late or very late stent thromboses stents (DES). were not reported; instead, definite and/or Considering this idea to be of particular probable stent thromboses were reported; interest to the readers, as well as being an 3. Research that involved patients with type 1 important issue in interventional cardiology, diabetes mellitus; we aimed to systematically assess early 4. Duplicated studies; (B 30 days), late (31–360 days) and very late 5. Review articles, meta-analyses and letters to ([ 360 days) stent thrombosis in patients with editors. ITDM and NITDM following DES implantation. Definitions of Specific Terms METHODS ITDM was defined as patients with T2DM who required insulin as treatment. Searched Materials (Searched Databases NITDM was defined as patients with T2DM and Terms) who did not require insulin as treatment, but instead were dependent on oral hypoglycemic Well-known online databases (the Cochrane, agents. EMBASE and MEDLINE databases and http:// Early stent thrombosis [3] was defined as www.ClinicalTrials.gov) were searched for rele- acute and sub-acute stent thrombosis observed vant English publications based on ITDM and at B 30 days following PCI. Diabetes Ther (2018) 9:1113–1124 1115 Late stent thrombosis [3] was defined as stent Data Extraction, Quality Assessment and Statistical Analysis thrombosis that occurred after 30 days (31–- 360 days) following PCI. Very late stent thrombosis [3] was defined as Three reviewers, Wei Chen, Yubin Wu and stent thrombosis that occurred after 360 days Yubao Hu, independently extracted the follow- following PCI. ing data: 1. The study type (randomized controlled tri- als, cohort studies, retrospective studies); Outcomes, Types of Participants, Types of DES and Follow-Up Periods 2. The types of participants involved; 3. The total number of participants who were on insulin treatment or were on oral hypo- The three endpoints of this analysis were early, glycemic drugs; late and very late stent thrombosis as shown in 4. The baseline characteristics of the Table 1. participants; The follow-up time period varied from 1 to 5. The endpoints (early, late and very late 3 years. stent thrombosis); All participants were candidates for 6. The total number of events in each T2DM ? CAD who underwent revasculariza- category; tion by PCI. 7. The year internal period of patient The types of DES varied: everolimus-eluting enrollment; stents (EES), paclitaxel-eluting stents (PES), sir- 8. The types of DES reported; olimus-eluting stents (SES) and zotarolimus- 9. The methodologic quality of the trials for eluting stents (ZES) were used as shown in assessment. Table 1. Table 1 Outcomes, follow-up periods and types of participants Studies Outcomes reported Follow-up time period Types of participants Types of (years) DES Banning et al. Early (acute and sub-acute) and 1 Left main and triple vessel PES [6] late ST disease Jain et al. [7] Early (acute and sub-acute) and 1 CAD ZES late ST Jiang et al. [8] Early, late and very late ST 2 CAD DES Kereiakes et al. Early (acute and sub-acute) and 1 CAD EES, PES [9] late ST Nakamura et al. Early, late and very late ST 3 CAD ? hemodialysis SES [10] Silber et al. [11] Early, late and very late 2 CAD ZES Simek et al. [12] Early, late and very late 3 CAD EES, SES, PES Early stent thrombosis: 0–30 days Late stent thrombosis: 31–360 days Very late stent thrombosis: [ 360 days ST stent thrombosis, DES drug-eluting stents, CAD coronary artery disease, PES paclitaxel-eluting stents, EES everolimus- eluting stents, SES sirolimus-eluting stents, ZES zotarolimus-eluting stents 1116 Diabetes Ther (2018) 9:1113–1124 Any disagreement that followed was solved by Since this analysis involved a small volume consensus. of studies, publication bias was better assessed The methodologic quality of the trials was by funnel plots, which could be generated using assessed based on the criteria recommended by the RevMan software. the Cochrane collaboration [4] whereby grades were given in accordance with whether a low, Compliance with Ethics Guidelines moderate or high risk of bias was reported. The main analysis was carried out using the This meta-analysis, based on previously con- latest version of RevMan software (version 5.3) ducted studies, does not contain any studies whereby odds ratios (ORs) and 95% confidence with human participants or animals performed intervals (CIs) were generated. by any of the authors. Hence, ethical approval In this analysis, ORs were used to compare was not required. the relative odds of the occurrence of stent thrombosis (early, late and very late), given exposure to insulin treatment. These ORs were RESULTS also used to determine whether exposure to insulin therapy was a risk factor for stent Searched Outcomes and the General thrombosis in these patients with T2DM who Properties of the Included Studies had previously been implanted with DES. However, the presence of a positive OR in The PRISMA guideline was followed [5]. A this case did not necessarily indicate that this thorough search of online databases resulted in association was statistically significant. We also 6187 publications. Figure 1 shows the flow dia- had to consider the CIs and P values to deter- gram for the study selection. mine significance. Seven publications [6–12] were selected for The 95% CI is used to estimate the precision this analysis, as shown in Fig. 1. of the OR obtained. A large CI indicates a low Table 2 lists the studies selected for this level of precision of the OR, whereas a small CI analysis. indicates higher precision. The CI indicates the After a careful assessment of the method- level of uncertainty around the measure of ologic quality of the trials, a low-to-moderate effect, which is expressed as an OR in this risk of bias was observed and graded from A to C analysis. Similar to other studies, we have also whereby ‘A’ signified low risk of bias, ‘B’ signi- reported the 95% CIs in this analysis. fied moderate risk of bias, and ‘C’ signified a Heterogeneity is a common feature in meta- high risk of bias. analyses. Heterogeneity was assessed by the A total of 8524 participants with T2DM following: (2273 participants were on insulin therapy and 6251 were not) were included in this analysis. 1. The Q statistic test whereby P C 0.05 was The period of patient enrollment varied from considered statistically significant; 2004 to 2012. All the patients received dual 2 2 2. The I statistic test whereby an increasing I antiplatelet therapy (DAPT) following stent value signified increasing heterogeneity and implantation. However, the duration of DAPT a low I value signified low heterogeneity. was not stated. In addition, the statistical model used was based on this heterogeneity value whereby a fixed Participants’ Baseline Features effects model was used if I was B 50% and a random effects model was used if the I value The participants’ baseline features are listed in was [ 50%. Table 3. Sensitivity analysis was carried out by an Mean age of 63.3–67.2 years was reported expulsion method for comparison with the with a predominance of male patients. Features main results. such as hypertension, dyslipidemia and current Diabetes Ther (2018) 9:1113–1124 1117 Fig. 1 Flow diagram showing the selection of studies smoking were also reported in patients with was also not significantly different (OR 0.80, ITDM and NITDM, as shown in Table 3. Overall, 95% CI 0.33–1.92; P = 0.62), as shown in Fig. 2. there was no significant difference in baseline Late stent thromboses associated with dif- features between the diabetic patients with and ferent individual DES subgroups were also ana- without insulin therapy. lyzed separately. Late stent thromboses associated with PES and EES were also not sig- nificantly different between patients with ITDM Main Analysis Results and NITDM (OR 0.63, 95% CI 0.18–2.20, P = 0.47 and OR 0.66, 95% CI 0.11–3.89, Results of this analysis showed early stent P = 0.65, respectively), as shown in Fig. 3. Even thrombosis to be significantly higher in patients if late stent thrombosis associated with ZES was with ITDM (OR 1.81, 95% CI 1.04–3.15; significantly higher in patients with ITDM (OR P = 0.04), but late stent thrombosis was not 3.14, 95% CI 1.20–8.20; P = 0.02), only two significantly different following PCI with DES in studies with an insufficient number of patients diabetic patients with versus without insulin comprised this particular subgroup, which was therapy (OR 1.44, 95% CI 0.73–2.84; P = 0.30), insufficient for reaching conclusions. as shown in Fig. 2. Very late stent thrombosis Sensitivity analysis was consistent through- out the analysis. 1118 Diabetes Ther (2018) 9:1113–1124 Table 2 General characteristics of the included studies Studies Patients with Patients with Type of Year of patients’ Antiplatelets ITDM (n) NITDM (n) study enrollment used Banning et al. [6] 89 142 RCT 2005– 012 DAPT Jain et al. [7] 644 1919 Cohort 2005–2007 DAPT Jiang et al. [8] 68 132 Retrospective 2010–2013 DAPT Kereiakes et al. [9] 209 ? 119 577 ? 280 RCT 2006–2009 DAPT Nakamura et al. 200 647 Cohort 2004–2005 DAPT [10] Silber et al. [11] 455 1080 RCT – DAPT Simek et al. [12] 231 ? 147 ? 111 573 ? 465 ? 436 Cohort 2002–2009 DAPT Total no. of 2273 6251 patients (n) ITDM insulin-treated diabetes mellitus, NITDM non-insulin-treated diabetes mellitus, RCT randomized-controlled trials, DAPT dual antiplatelet agents (aspirin and clopidogrel) Table 3 Participants’ baseline features Studies Age (years) Males (%) HTN (%) DS (%) CS (%) ITDM/NITDM ITDM/NITDM ITDM/NITDM ITDM/NITDM ITDM/NITDM Banning et al. [6] 65.4/65.4 71.0/71.0 69.9/69.9 81.5/81.5 15.8/15.8 Jain et al. [7] 66.6/64.9 62.2/71.8 82.1/77.5 67.9/67.7 13.9/18.0 Jiang et al. [8] 65.1/66.8 72.1/74.2 75.0/76.1 79.4/78.0 25.0/22.8 Kereiakes et al. [9] 63.3/63.3 63.3/63.3 87.0/87.0 82.5/82.5 18.3/18.3 Nakamura et al. [10] 66.2/67.2 66.2/75.4 68.1/72.0 58.0/60.4 12.1/19.5 Silber et al. [11] 64.6/65.5 56.4/70.4 91.6/86.0 86.8/86.0 17.2/18.6 Simek et al. [12] 65.1/65.1 69.2/69.2 70.6/70.6 65.5/65.5 32.1/32.1 ITDM insulin-treated diabetes mellitus, NITDM non-insulin-treated diabetes mellitus, HTN hypertension, DS dyslipi- demia, CS current smoker Evidence of publication bias was minimal Nevertheless, even though the authors across the studies that were involved in assess- assessed stent thrombosis in their previous ing early and late stent thrombosis in the work, this particular outcome was not assessed patients with ITDM and NITDM, as shown in in detail. We therefore came up with the new Figs. 4 and 5. idea of systematically comparing early, late and very late stent thrombosis post-PCI in patients with ITDM and NITDM. DISCUSSION In the previous analysis, stent thrombosis was shown to be significantly higher in patients Previous meta-analyses based on ITDM patients with ITDM compared with NITDM (OR 1.66, with cardiac problems were well appreciated 95% CI 1.16–2.38, P = 0.005 for short-term ST; [2, 13]. Diabetes Ther (2018) 9:1113–1124 1119 Fig. 2 Early, late and very late stent thrombosis in patients with type 2 diabetes mellitus who were treated with versus without insulin following percutaneous coronary intervention with drug-eluting stents OR 1.59, 95% CI 1.21–2.10; P = 0.001 for long- P = 0.62) were not significantly different in term ST) [2]. patients with ITDM and NITDM. When data were closely assessed, it could be Several reasons have been suggested for the seen that stent thrombosis was definitely signif- high level of stent thrombosis in patients with icantly higher in patients with ITDM compared ITDM: Patients on insulin therapy have more with NITDM. This result was obtained when advanced disease, and their risk of complica- definite and probable or possible stent throm- tions after PCI is higher according to their high boses were analyzed all together. However, in the risk profile. Also, iatrogenic hyperinsulinemia current analysis, when stent thrombosis was might promote proinflammatory macrophage assessed based on the time period following PCI, responses and stimulate hormonal hyperactiv- early stent thrombosis was significantly higher in ity, which might in return disturb the balanced patients with insulin therapy (OR 1.81, 95% CI synthesis and release of endothelial mediators. 1.04–3.15; P = 0.04). However, late (OR 1.44, Insulin therapy might also cause platelet 95% CI 0.73–2.84; P = 0.30) and very late stent hyperactivity, which can then increase the thromboses (OR 0.80, 95% CI 0.33–1.92; chance of stent thrombosis after PCI with DES. 1120 Diabetes Ther (2018) 9:1113–1124 Fig. 3 Late stent thrombosis in patients with insulin-treated versus non-insulin-treated type 2 diabetes mellitus with individual drug-eluting stents (EES, PES, ZES) Reasons that have been considered for a example, in the E-five registry [7], 14 patients similar rate of late and very late stent throm- out of a total of 644 (2.17%) patients with ITDM bosis in this analysis could be that: experienced stent thrombosis as defined by the Academic Research Consortium (ARC), whereas 1. The total number of studies reporting these 25 out of 1919 (1.30%) patients with NITDM outcomes were few and not sufficient to experienced stent thrombosis as defined by the reach a robust result in terms of very late ARC. However, when stent thrombosis was stent thromboses, which were only reported further divided into early and late stent in four studies; thrombosis, 1.6% of patients with ITDM expe- 2. This issue is controversial, and the number rienced early stent thrombosis and 1.0% of the of studies favoring ITDM was similar to the patients with NITDM experienced early stent number of studies favoring NITDM, result- thrombosis, whereas 0.8% and 0.3% of the ing in an insignificant result for favoring patients with ITDM and NITDM, respectively, either ITDM or NITDM in case of late and experienced late ST. Even if the percentage of very late stent thrombosis; patients with ITDM experienced more throm- 3. The total number of early stent thromboses bosis, the percentage was reduced when stent in patients with ITDM was indeed higher thrombosis was further divided, especially in compared with late and very late stent the case of late stent thrombosis. thrombosis. The results of the SPIRIT IV Trial were dif- ferent from those of the E-five registry [9]. The In other studies where early and late stent early stent thrombosis rate was 0.48% with EES thromboses were reported following PCI in in ITDM and 0.85% with PES in ITDM, and patients with and without insulin therapy, for Diabetes Ther (2018) 9:1113–1124 1121 Fig. 4 Funnel plot showing publication bias (A) there was no late stent thrombosis in ITDM. group, whereas in patients with NITDM, 0.45% However, in patients with NITDM, early stent and 0.62% patients experienced late and very thrombosis was 0.35% with EES and 0.36% with late stent thrombosis, respectively, which partly PES, whereas late stent thrombosis was 0.18% contributed to the results that were obtained. with EES and 0.76% with PES. A conclusion Nevertheless, following the previously pub- could be that there was no late stent thrombosis lished research article [2] based on patients with in patients with ITDM who were implanted ITDM and NITDM post PCI, and upon reader with DES. requests, this analysis has further shown a new In the 2-year results from the Prospectively outcome, whereby early stent thrombosis was Pooled Analysis of the International Global significantly higher in ITDM patients compared RESOLUTE Program [11], 0.9% of patients with with those with NITDM, whereas late and very ITDM and 0.8% of patients with NITDM expe- late stent thromboses were not significantly rienced early stent thrombosis, whereas 0.2% different in patients with ITDM and NITDM. and 0.1% of patients with ITDM and NITDM, This scientific concept should be of significant respectively, experienced late stent thrombosis. clinical importance and definitely find a place The number of patients who experienced late in medical libraries. stent thrombosis events was similar between Finally, while recent analyses have focused the ITDM and NITDM groups, further support- on different types of drug-eluting stents and the ing this analysis. associated stent thrombosis [14, 15], future In contrast, insights from a sub-study of the analysis should compare stent thrombosis in Cypher Stent Japan Post-Marketing Surveillance male versus female patients with diabetes mel- (Cypher J-PMS) Registry [10] showed no early, litus [16], specifically in male and female late or very late stent thrombosis in the ITDM patients with ITDM and NITDM. In addition, 1122 Diabetes Ther (2018) 9:1113–1124 Fig. 5 Funnel plot showing publication bias (B) the SYNTAX score [17, 18] should be included are all DESs; this could also have influenced the results. in future studies with ITDM and NITDM patients, and stent thrombosis should be asses- 3. For those studies that had a follow-up period [ 1 year, it was not known whether DAPT sed in patients with a low versus a high SYNTAX score. was continued or discontinued. This might also have influenced the results. Limitations CONCLUSIONS Limitations were: 1. Although the total number of patients was Following PCI with DES, early stent thrombosis sufficient to reach a conclusion based on was significantly higher in patients with ITDM. patients who were treated with DES as a However, late and very late stent thromboses whole, the number of patients was not were not significantly different in patients with sufficient to reach a conclusion when each type 2 diabetes mellitus who were treated with DES (EES, SES, PES, ZES) was individually or without insulin. Comparison with individual assessed. DESs was not sufficiently powerful to reach a 2. First- and second-generation DESs were conclusion. combined and analyzed assuming that they Diabetes Ther (2018) 9:1113–1124 1123 ACKNOWLEDGEMENTS REFERENCES We thank the participants in the study. 1. Oikonomou E, Mourouzis K, Fountoulakis P, Papa- mikroulis GA, Siasos G, Antonopoulos A, Vogiatzi G, Tsalamadris S, Vavuranakis M, Tousoulis D. Funding. No funding or sponsorship was Interrelationship between diabetes mellitus and received for this study or publication of this heart failure: the role of peroxisome proliferator- activated receptors in left ventricle performance. article. The article processing charges were Heart Fail Rev. 2018. https://doi.org/10.1007/ funded by the authors. s10741-018-9682-3. Authorship. All named authors meet the 2. Bundhun PK, Li N, Chen MH. Adverse cardiovas- International Committee of Medical Journal cular outcomes between insulin-treated and non- insulin treated diabetic patients after percutaneous Editors (ICMJE) criteria for authorship for this coronary intervention: a systematic review and article, take responsibility for the integrity of meta-analysis. Cardiovasc Diabetol. 2015;7(14):135. the work as a whole and have given their approval for this version to be published. 3. Modi K, Bhimji SS. Stent thrombosis. Treasure Island: StatPearls Publishing; 2018 (Internet). Author Contributions. Wei Chen, Yubin 4. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring Wu and Yubao Hu were responsible for the inconsistency in meta-analyses. BMJ. conception and design, acquisition of data, 2003;327:557–60. analysis and interpretation of data, drafting the 5. Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA initial manuscript and revising it critically for statement for reporting systematic reviews and important intellectual content. Dr. Wei Chen is meta-analyses of studies that evaluate health care the first author and wrote and approved the interventions: explanation and elaboration. BMJ. 2009;339:b2700. final manuscript. 6. Banning AP, Westaby S, Morice MC, Kappetein AP, Disclosures. The authors Wei Chen, Yubin Mohr FW, Berti S, Glauber M, Kellett MA, Kramer Wu and Yubao Hu have nothing to disclose. RS, Leadley K, Dawkins KD, Serruys PW. Diabetic and nondiabetic patients with left main and/or Compliance with Ethics Guidelines. This 3-vessel coronary artery disease: comparison of outcomes with cardiac surgery and paclitaxel-elut- meta-analysis is based on previously conducted ing stents. J Am Coll Cardiol. 2010;55(11):1067–75. studies and does not contain any studies with human participants or animals performed by 7. Jain AK, Lotan C, Meredith IT, Feres F, Zambahari R, any of the authors. Sinha N, Rothman MT, E-Five Registry Investigators. Twelve-month outcomes in patients with diabetes implanted with a zotarolimus-eluting stent: results Data Availability. All data generated or from the E-Five Registry. Heart. 2010;96(11):848–53. analyzed during this study are included in this published article. 8. Jiang YJ, Han WX, Gao C, Feng J, Chen ZF, Zhang J, Luo CM, Pan JY. Comparison of clinical outcomes after drug-eluting stent implantation in diabetic Open Access. This article is distributed versus nondiabetic patients in China: a retrospec- under the terms of the Creative Commons tive study. Medicine (Baltim). 2017;96(17):e6647. Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/ 9. Kereiakes DJ, Cutlip DE, Applegate RJ, Wang J, YaqubM, SoodP, SuX,SuG, Farhat N, Rizvi A, by-nc/4.0/), which permits any noncommer- Simonton CA, Sudhir K, Stone GW. Outcomes in cial use, distribution, and reproduction in any diabetic and nondiabetic patients treated with ever- medium, provided you give appropriate credit olimus- or paclitaxel-eluting stents: results from the to the original author(s) and the source, provide SPIRIT IV clinical trial (Clinical Evaluation of the XIENCE V Everolimus Eluting Coronary Stent Sys- a link to the Creative Commons license, and tem). J Am Coll Cardiol. 2010;56(25):2084–9. indicate if changes were made. 10. Nakamura M, Yokoi H, Hamazaki Y, Watarai M, Kijima M, Mitsudo K, Cypher J-PMS Investigators. 1124 Diabetes Ther (2018) 9:1113–1124 Impact of insulin-treated diabetes and hemodialysis 14. 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Are Clinical outcome of patients with and without everolimus-eluting stents associated with better diabetes mellitus after percutaneous coronary in- clinical outcomes compared to other drug-eluting tervention with there solute zotarolimus-eluting stents in patients with type 2 diabetes mellitus?: a stent: 2-year results from the prospectively pooled systematic review and meta-analysis. Medicine analysis of the international global RESOLUTE (Baltim). 2016;95(14):e3276. program. JACC Cardiovasc Interv. 16. Bundhun PK, Pursun M, Huang F. Are women with 2013;6(4):357–68. type 2 diabetes mellitus more susceptible to car- ¨ diovascular complications following coronary 12. Simsek C, Raber L, Magro M, Boersma E, Onuma Y, angioplasty?: a meta-analysis. BMC Cardiovasc Stefanini GG, Zanchin T, Kalesan B, Wenaweser P, ¨ Disord. 2017;17(1):207. Juni P, van Geuns RJ, van Domburg RT, Windecker S, Serruys PW. Long-term outcome of the unre- stricted use of everolimus-eluting stents compared 17. 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Journal

Diabetes TherapySpringer Journals

Published: Apr 11, 2018

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