Author + information
- Received July 31, 2009
- Revision received October 13, 2009
- Accepted October 15, 2009
- Published online December 1, 2009.
- Eric L. Eisenstein, DBA⁎,⁎ (, )
- Martin B. Leon, MD†,
- David E. Kandzari, MD‡,
- Laura Mauri, MD, MSc§,
- Rex Edwards, BA⁎,
- David F. Kong, MD⁎,
- Patricia A. Cowper, PhD⁎,
- Kevin J. Anstrom, PhD⁎,
- ENDEAVOR III Investigators
- ↵⁎Reprint requests and correspondence:
Eric L. Eisenstein, Assistant Professor in Medicine, Duke Clinical Research Institute, 2400 Pratt Street, Terrace Level 0311, Durham, North Carolina 27705
Objectives The aim of this study was to evaluate clinical and economic outcomes for subjects receiving zotarolimus-eluting (ZES) (n = 323) versus sirolimus-eluting stents (SES) (n = 113) in the ENDEAVOR III (Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) clinical trial.
Background Although previous clinical trials have evaluated long-term clinical outcome for drug-eluting stents, none considered their economic implications.
Methods We analyzed case report form information with quality-of-life adjustment and Medicare cost weights applied from secondary sources; compared differences in clinical outcomes, quality-adjusted survival, medical resource use, and medical costs; and evaluated cost-effectiveness through 3-year follow-up.
Results The use of ZES versus SES reduced the 3-year rates/100 subjects of death or myocardial infarction (3.9 vs. 10.8; difference, −6.9; 95% confidence interval [CI]: −13.0 to 0.8; p = 0.028), with no difference in target vessel revascularization rates (17.9 vs. 12.2; difference, 5.7; 95% CI: −3.7 to 15.1; p = 0.23) but greater use of coronary artery bypass graft (CABG) surgery (3.5 vs. 0.0; difference 3.5; 95% CI: 1.3 to 5.7; p = 0.002). After discounting at 3% per annum, total medical costs for ZES versus SES were similar ($23,353 vs. $21,657; difference, $1,696; 95% CI: −$1,089 to $4,482, p = 0.23), and the 3-year cost-effectiveness ratio was $57,002/quality-adjusted life year.
Conclusions Despite a reduction in death or myocardial infarction and no difference in total revascularizations, medical costs were not decreased due to increased CABG repeat revascularization procedures for subjects receiving ZES versus SES. If future trials observe similar differences, improved safety with no difference in medical costs, the use of ZES versus SES will be a clinically and economically attractive treatment strategy. (The Medtronic Endeavor III Drug Eluting Coronary Stent System Clinical Trial [ENDEAVOR III]; NCT00217256)
Since their introduction, questions have been raised regarding the relative clinical and economic attractiveness of drug-eluting stents (DES) versus other treatment strategies (1). Economic analyses were conducted for each of the major DES (Cypher [Cordis Corporation, Bridgewater, New Jersey], Taxus [Boston Scientific, Natick, Massachusetts], and Endeavor [Medtronic, Minneapolis, Minnesota]) in their primary DES versus bare-metal stent (BMS) clinical trials, and each of these analyses demonstrated that DES are able to recoup most of their higher initial costs through reductions in repeat target vessel revascularization (TVR) procedures during the first follow-up year (2–4). Although a number of studies have compared DES versus DES clinical outcomes, none have evaluated both long-term clinical and economic outcomes (5–8).
The ENDEAVOR III (Randomized Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Cypher Sirolimus-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) clinical trial compared the Endeavor zotarolimus-eluting stent (ZES) with the Cypher sirolimus-eluting stent (SES) (9). Because the ENDEAVOR II (Randomized Controlled Trial to Evaluate the Safety and Efficacy of the Medtronic AVE ABT-578 Eluting Driver Coronary Stent in De Novo Native Coronary Artery Lesions) economic analysis demonstrated that the benefits of ZES versus BMS in reducing repeat TVR procedures might continue well beyond the first follow-up year, we decided to evaluate the clinical and economic attractiveness of ZES versus SES with 3-year follow-up information from the ENDEAVOR III clinical trial. Our objectives were to compare treatment-related differences for subjects receiving ZES versus SES with regard to clinical outcomes, economic outcomes, and comprehensive cost-effectiveness (incremental medical costs/quality-adjusted life year [QALY] saved).
Patient population and treatment protocol
The ENDEAVOR III clinical trial randomly assigned 436 subjects to receive either the ZES (n = 323) or the SES (n = 113) (9). Subjects undergoing elective percutaneous coronary intervention (PCI) were included if their lesion length was 14 to 27 mm, the reference vessel diameter was 2.5 to 3.5 mm, and they underwent intracoronary stenting in a single, untreated, native coronary artery. The primary study end point, as assessed by quantitative coronary angiography, was in-segment late lumen loss at 8-month follow-up.
Although the ENDEAVOR III clinical trial showed no difference in target vessel failure for subjects receiving ZES versus SES, it did reveal a difference in nonfatal myocardial infarction (MI). Due to the uncertain economic implications of these results, a plan was submitted to this study's publications committee on March 24, 2008, for the evaluation of clinical and economic outcomes of subjects receiving ZES versus SES with 3-year follow-up results from the ENDEAVOR III trial. The study protocol for the ENDEAVOR III trial was approved by the institutional review board at each study site and all study subjects consented to participate before treatment. The Duke University Medical Center's institutional review board approved the long-term clinical and economic analysis protocol.
Study data identification
Clinical events used in the economic study were identified from ENDEAVOR III case report form and major adverse cardiac event (MACE) information. Serious adverse event records were used to identify non-MACE hospital stays, and Medical Dictionary for Regulatory Activities preferred terms from adverse events were used to group hospital stays for medical cost assignments. All study subjects were assigned an index procedure episode of care. Study events were used to define follow-up period episodes of care. We defined inpatient stays by the occurrence of a MACE or serious adverse event hospital stay. Deaths not associated with a hospital stay were the only outpatient episodes.
We used the logic of the Centers for Medicare and Medicaid Services Medicare Severity Diagnosis Related Grouper to assign diagnosis-related groups (DRGs) to episodes of care (10). These assignments were then audited by a trained medical record professional. Medical costs and lengths of stay for cardiovascular episodes of care were estimated with Medicare's 2008 national average payment amounts (calculated with an average hospital Medicare base rate of $4,893) and arithmetic mean lengths of stay by DRG (11,12). For noncardiovascular episodes, these values were assigned with Medicare's national average relative weight and arithmetic mean length of stay. We estimated DRG-specific costs for physician services with published sources and adjusted them to 2008 values with the consumer price index medical care component (13). Because Medicare's payment amounts for DES DRGs do not include the costs for specific stent types, we included these by adding the estimated 2008 unit costs ($2,100) for the Endeavor and Cypher stents to balloon angioplasty procedure reimbursement amounts (data on file, Medtronic Cardiovascular, Santa Rosa, California). The type of repeat PCI procedure was not identified in the ENDEAVOR III case report form, so we used results for repeat PCI procedures at Duke University Medical Center during the ENDEAVOR III study period to define a distribution of 13% balloon angioplasty, 19% BMS, and 68% DES (14).
Previously defined methods were used to assign quality-of-life weights to specific clinical events throughout the 3-year study period (15). First, a 0.79 QALY adjustment representing a revascularization procedure was assigned to all subjects for their index procedure year. Next, a 0.85 QALY adjustment, representing subjects having coronary artery disease, was assigned to all years without a revascularization procedure. During the year that subjects underwent repeat revascularization procedures, this QALY estimate was decreased to 0.79. When subjects experienced a nonfatal MI, they received a permanent 0.88 relative utility weight adjustment. Lastly, a quality-adjusted life day decrement (.0028 QALY) was issued for each day of estimated length of stay during a hospital stay (16).
Study outcomes: clinical outcomes
All study outcomes were assessed at 3-year follow-up. The individual study outcomes included death, stroke, nonfatal MI, TVR (PCI, CABG, and total), non-TVR (PCI, CABG, and total), total revascularizations (PCI, CABG, and total), hospital stays (revascularization, other cardiac, and noncardiac), survival and quality-adjusted survival (both with and without discounting at 3% per annum), and total follow-up period length of stay. Composite study outcomes included death or MI and death or MI or TVR.
Study outcomes: medical costs
Medical costs were reported at annual increments (first year, second year, and third year) and cumulatively for the 3-year follow-up period (with and without discounting at 3% per annum).
Intention to treat analyses: index procedure
Baseline clinical characteristics and index procedure resource use information are presented as percentages for discrete variables and as medians with interquartile ranges for continuous variables. The chi-square statistic is used to assess differences between dichotomous variables, and the Kruskal-Wallis test is used to assess differences between continuous variables.
Intention to treat analyses: follow-up period
Follow-up period clinical outcomes, number of hospital stays, survival, quality-adjusted survival, and medical costs are reported as 3-year cumulative values by treatment (ZES or SES) with differences, 95% confidence intervals, and p values. Additionally, medical costs are presented by annual time periods. Analyses of follow-up period results were performed on partitioned data with generalized linear models with empirical standard errors and an adjustment for censoring (17,18). Statistical analyses were performed with SAS software (version 8.2 or higher, SAS Institute, Cary, North Carolina). Figures are used to supplement model results by depicting changes in clinical event rates and medical costs during the follow-up period.
We performed a comprehensive cost-effectiveness analysis to estimate the incremental total medical costs (Costs)/QALY saved with the use of ZES versus SES during the 3-year follow-up period: This cost-effectiveness ratio was calculated with estimates of the quantities shown in the preceding text. The variability of the cost-effectiveness ratios was assessed with a nonparametric bootstrap procedure. Results are shown as mean values for the ratio with the percent of bootstrap samples for which the ZES versus SES treatment strategy cost <$50,000/QALY saved (19,20). We calculated incremental values for total medical costs, quality-adjusted survival, and the comprehensive cost-effectiveness ratio with a 3% annual discount rate adjustment.
Subjects receiving ZES versus SES were well-matched with regard to age and race; however, more women received ZES than received SES (Table 1). Although subjects receiving either stent type typically had 1 or more cardiac risk factors, less than one-third of patients had either a history of MI or a prior revascularization procedure. Most subjects underwent revascularization because of angina or MI, and approximately 40% had multivessel coronary artery disease. During the index DES procedure, most subjects received pretreatment with balloon angioplasty, and 86.9% received a single intracoronary stent. There were no instances of emergency bypass surgery, and post-procedural length of stay was similar in both study arms.
Over a 3-year follow-up period, the use of ZES versus SES led to a significant reduction in MI and death or MI but a higher rate of CABG procedures (target vessel, nontarget vessel, and total) (Table 2,Fig. 1). Of 18 study deaths, 8 occurred in SES subjects (2 cardiac and 6 noncardiac), whereas 10 occurred in ZES subjects (1 cardiac and 9 noncardiac). The MIs for subjects receiving either stent type largely were non–Q-wave, and they occurred primarily during the index hospital stay. In contrast, a disproportionate number of TVR procedures occurred at approximately the time of protocol-mandated follow-up angiography (months 7 to 9). Overall, there were only 5 stent thrombotic events in this study (2 SES and 3 ZES) that were associated with 3 deaths, 1 nonfatal MI, and 1 PCI TVR procedure. There were no treatment-related differences in the resource use outcomes of hospital stays and total length of stay, all at 3-year follow-up (Table 3).
3-year quality-adjusted survival and medical costs
At 3-year follow-up, subjects receiving ZES versus SES had similar survival and quality-adjusted survival (undiscounted and discounted) (Table 4,Fig. 2). The use of the ZES versus SES was associated with a nonsignificant difference in total medical costs (undiscounted and discounted) (Table 4, Fig. 3).
In 500 bootstrap samples, the comprehensive cost-effectiveness ratio averaged $57,002/QALY saved after discounting. However, these point estimates were highly variable (Fig. 4). At the end of 3 years of follow-up, the comprehensive cost-effectiveness ratio for a ZES versus a SES treatment strategy cost ≤$50,000/QALY in 41.0% of bootstrap samples.
In the ENDEAVOR III clinical trial, a treatment strategy involving the use of the ZES versus the SES was associated with a significant reduction in death or MI at 3-year follow-up. Although overall TVR did not differ, an excess of CABG-related TVR occurred in subjects receiving ZES. There were no significant differences in other clinical or economic outcomes. These disparate findings were unexpected in a trial of 2 DES and raise several important questions. First, are the clinical results for subjects receiving ZES and SES in the present study consistent with results from other DES versus DES clinical trials involving ZES and SES? Second, is there reason to believe that the MI benefit of ZES versus SES will translate into a future survival benefit? Third, are the economic results from this study consistent with those from previous DES versus BMS economic analyses involving ZES and SES?
Comparison with other DES versus DES trials
Several trials have compared the relative safety and efficacy outcomes after treatment with SES and paclitaxel-eluting stents (PES). In a meta-analysis of 38 randomized trials comparing SES, PES, and BMS (n = 18,023) with follow-up extending to 4 years, similar rates of survival for all 3 stent groups were observed (21). Overall, there were no significant differences in the risk of definite stent thrombosis through 4-year follow-up for either DES relative to BMS, although the risk of definite late stent thrombosis (>30 days to 4 years) was significantly higher with PES compared with the BMS and SES patient groups. Similar differences in the occurrence of stent thrombosis between SES and PES have been reported in a recent meta-analysis of randomized trials (8) in addition to observational registries (22,23). Such differences have not been consistently observed in individual randomized trials comparing SES and PES that might be underpowered to detect these differences (5,24,25).
A pooled analysis of 4 randomized trials of SES versus BMS (n = 1,748) and 5 randomized trials of PES versus BMS (n = 3,513) reported no differences in all-cause mortality, MI, and death or MI between the 2 DES versus BMS. However, the use of both DES was associated with significant reductions in both target lesion revascularization (TLR) and TVR procedures (26). Of note, although this study's 4-year all-cause mortality rate for SES was less than the 3-year mortality rate in the ENDEAVOR III trial, the MI rate was greater.
Other randomized trials have observed differences in safety outcomes among the various types of DES. The ENDEAVOR IV (Randomized, Controlled Trial of the Medtronic Endeavor Drug [ABT-578] Eluting Coronary Stent System Versus the Taxus Paclitaxel-Eluting Coronary Stent System in De Novo Native Coronary Artery Lesions) trial enrolled 1,548 patients with clinical and angiographic characteristics similar to the ENDEAVOR III trial and randomized them to either ZES or PES (27). The rate of MI was significantly lower in the ZES group compared with the PES cohort at 2-year follow-up (2.0% vs. 4.1%, p = 0.02) (27). The SORT-OUT III (Danish Organization on Randomized Trials With Clinical Outcome) randomized trial of ZES versus SES identified significant differences in stent thrombosis, MI, and TLR favoring SES (6). However, the safety and efficacy outcomes observed with SES in the SORT-OUT III trial differ from SES outcomes in other trials of similar design and study population (5,28). More recently, the ZEST (Zotarolimus-Eluting Stent Versus Sirolimus-Eluting Stent and PacliTaxel-Eluting Stent for Coronary Lesions) trial that compared ZES, SES, and PES found no differences in death or in MI at 1-year follow-up, whereas the SPIRIT III (Clinical Evaluation of the Xience V Everolimus Eluting Coronary Stent System in the Treatment of Patients with de novo Native Coronary Artery Lesions) trial reported a borderline significant reduction in death or MI (p = 0.055) for everolimus-eluting stent versus PES at 2 years (7,29).
In the ENDEAVOR III trial, the percentage of SES subjects experiencing an index hospital stay MI was similar to that observed in the SIRIUS (Sirolimus-Eluting Balloon Expandable Stent in the Treatment of Patients With De Novo Native Coronary Artery Lesions) trial (30), whereas the percentage for ZES subjects was less than that reported in the ENDEAVOR II trial. Results from the ENDEAVOR IV trial serve to confirm the ENDEAVOR III MI findings (31). During the ENDEAVOR IV trial, index hospital stay MIs occurred in 0.8% of subjects receiving ZES versus 2.1% of subjects receiving PES (p = 0.051), demonstrating a lower initial MI rate for ZES subjects. The ENDEAVOR IV side branch occlusion study reported associations among use of the ZES stent, the occurrence of fewer side branch occlusions, and lower MI rates (32). Although this also might explain the differences in MI rates for ZES versus SES in the ENDEAVOR III trial, further investigation is needed.
Although the ENDEAVOR III trial provided evidence of a reduction in death or MI with the use of the ZES versus SES, these results did not translate into significant differences in quality-adjusted survival at 3-year follow-up. However, previous researchers have concluded that there is an association between creatine kinase-myocardial band (CK-MB) elevation after PCI procedures and higher risks of death, subsequent cardiac events, and greater medical costs (33). This risk level seems to increase as a continuous function (with no “cutoff” value) and is particularly elevated in patients with side branch occlusions. It has been shown that patients with low CK-MB elevations—such as most subjects with nonfatal MIs in the ENDEAVOR III trial—have elevated intermediate and long-term risks that extend well beyond 3-year follow-up and include patients whose peak CK-MB levels did not exceed 2 times the upper limit of normal (34–36). It remains to be seen whether the 5-year ENDEAVOR III results will provide further evidence regarding relationships between treatment-related differences in nonfatal MIs and other clinical outcomes in this study.
Economic comparisons with DES versus BMS trials
Previous economic analyses have evaluated the Cypher (Cordis Corporation) DES in the SIRIUS trial and the Endeavor (Medtronic) DES in the ENDEAVOR II trial (3,4). The TVR results from these studies are consistent with those from the ENDEAVOR III trial—most TVR procedures occurred during the first follow-up year (31) (The SIRIUS Study: 5-Year Outcomes, unpublished work, 2008).
Although the timing of TVR events in the ENDEAVOR III trial is consistent with the results from the SIRIUS and ENDEAVOR II trials, the frequency of these events differs. The percentage of ENDEAVOR III SES subjects undergoing TLR in the first year is somewhat less than in the SIRIUS trial, whereas the TLR percentage for ZES subjects in the ENDEAVOR III trial is somewhat greater than in the ENDEAVOR II trial. Although these TLR differences are likely not significant, they—and the fact that all CABG procedures occurred in subjects receiving ZES stents—are associated with greater 3-year medical costs for ZES subjects in the ENDEAVOR III trial ($23,727) than was previously reported for the ENDEAVOR II trial ($20,536) (4).
Economic and quality-of-life data were not prospectively collected alongside the ENDEAVOR III clinical trial. This limitation prevented certain cost elements (outpatient and medication costs) from being included in our work. However, this is not a critical factor in the present study, because all subjects were prescribed dual antiplatelet therapy for a minimum of 3 months and aspirin indefinitely, and the only significant treatment-related differences between subjects receiving ZES and SES were in index hospital stay nonfatal MIs and follow-up period CABG procedures. We believe that our methodology ensured that the results accurately reflect the medical cost and quality-adjusted survival implications of all clinical end point differences observed during the ENDEAVOR III trial. A second limitation of the present analysis is that the observed follow-up period ended at 3 years. Although it would have been informative to include longer-term clinical estimates, we do not believe that the trends observed during the first 3 years will be reversed during subsequent follow-up years. Lastly, the ENDEAVOR III trial was underpowered to adequately evaluate differences in clinical and economic results. Whether the results observed in this study can be generalized to the real-world population of patients undergoing PCI procedures with ZES and SES will need to be determined. The outcomes from this study also differ from the disparate results from the SORT-OUT III and ZEST trials. Future researchers will need to determine the extent to which the ENDEAVOR III results are anomalous or representative of results one would expect in other populations.
Use of Endeavor (Medtronic) versus Cypher (Cordis Corporation) led to reductions in death or MI, with no difference in total revascularizations and medical costs. These findings are unexpected in DES comparisons. If future trials observe similar differences, the use of Endeavor (Medtronic) versus Cypher (Cordis Corporation) will be economically attractive by conventional standards.
The authors would like to thank Allyn Meredith, MA, for her expert editorial assistance.
The ENDEAVOR III clinical trial and the 3-year clinical and economic analysis were funded by Medtronic CardioVascular, Santa Rosa, California.
Eric L. Eisenstein has received research or grant support from Medtronic, Inc. and Eli Lilly and Company. Dr. Leon has served as a consultant to Abbott Vascular, Boston Scientific, Cordis, Medtronic, Inc., and the Volcano Corporation. Dr. Kandzari has received research or grant support and consulting honoraria from Medtronic, Inc. and Cordis Corporation. Dr. Mauri has served as a consultant to Abbott Vascular, Boston Scientific, Cordis, and Medtronic, Inc. Rex Edwards has received research support from Medtronic, Inc. Dr. Kong has received research support from Medtronic, Inc. Dr. Anstrom has received research support from AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Co., and Medtronic, Inc., and has served as a consultant for Johnson & Johnson and Pfizer.
- Abbreviations and Acronyms
- bare-metal stent(s)
- coronary artery bypass graft
- creatine kinase-myocardial band
- drug-eluting stent(s)
- diagnosis-related group
- major adverse cardiac events
- myocardial infarction
- percutaneous coronary intervention
- paclitaxel-eluting stent(s)
- quality-adjusted life year
- sirolimus-eluting stent(s)
- target lesion revascularization
- target vessel revascularization
- zotarolimus eluting stent(s)
- Received July 31, 2009.
- Revision received October 13, 2009.
- Accepted October 15, 2009.
- American College of Cardiology Foundation
- Bakhai A.,
- Stone G.W.,
- Mahoney E.,
- et al.
- Cohen D.J.,
- Bakhai A.,
- Shi C.,
- et al.
- ↵Eisenstein EL, Wijns W, Edwards R, et al. Economic Analysis of the Endeavor Drug-Eluting Stent vs. the Driver Bare Metal Stent: Results from the ENDEAVOR II Trial. Presented at: International Society for Pharmacoeconomics and Outcomes Research; 2009; Orlando, FL.
- Lassen J.F.,
- Rasmussen K.,
- Galloe A.,
- et al.
- Parks S.J.
- Schomig A.,
- Dibra A.,
- Windecker S.,
- et al.
- Kandzari D.E.,
- Leon M.B.,
- Popma J.J.,
- et al.
- ↵The Trees. Version 25.0. 2008. INGENIX. CMS MS-DRG Grouper. Available at: http://www.shopingenix.com. Accessed July 29, 2009.
- ↵(2008) DRG Expert: A Comprehensive Guidebook to the DRG Classification System (Ingenix, Salt Lake City, UT), 24th edition.
- (2007) DRG Plus! 2008: A Comprehensive Guide to Medicare Severity Diagnosis Related Groups (Practice Management Information Corporation, Los Angeles, CA).
- Mitchell J.,
- Burge R.,
- Lee A.,
- et al.
- Garg P.,
- Cohen D.J.,
- Gaziano T.,
- Mauri L.
- Tsevat J.,
- Goldman L.,
- Soukup J.R.,
- et al.
- Bang H.,
- Tsiatis A.A.
- Thompson S.G.,
- Barber J.A.
- ↵Daemen J. Incidence of Stent Thrombosis in Bern-Rotterdam Experience: 4-Year Follow-Up. Presented at: European Society of Cardiology Scientific Sessions; 2007; Vienna, Austria.
- Kaltoft A.,
- Jensen L.O.,
- Maeng M.,
- et al.
- Leon M.B.,
- Kandzari D.E.,
- Eisenstein E.L.,
- et al.
- Stone G.W.,
- Midei M.,
- Newman W.,
- et al.
- ↵FDA Executive Summary Memorandum: Endeavor Zotarolimus Drug-Eluting Coronary Stent System & Over-the-Wire (OTW), Rapid Exchange (RX), and Multi-Exchange II (MX2) Stent Delivery Systems. P060033. October 10, 2008. Medtronic, Inc. Prepared for the meeting of the Circulatory System Devices Advisory Panel. Available at: http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4322b1-02-FDA-Executive%20Summary.pdf. Accessed July 29, 2009.
- Califf R.M.,
- Abdelmeguid A.E.,
- Kuntz R.E.,
- et al.
- Abdelmeguid A.E.,
- Whitlow P.L.,
- Sapp S.K.,
- Ellis S.G.,
- Topol E.J.
- Abdelmeguid A.E.,
- Topol E.J.,
- Whitlow P.L.,
- Sapp S.K.,
- Ellis S.G.
- Topol E.J.,
- Ferguson J.J.,
- Weisman H.F.,
- et al.,
- EPIC Investigator Group