John E.A. Blair, MD

Study Overview

Objective. To compare the effectiveness and safety profiles of various second-generation drug-eluting stents (DES) for left main coronary intervention.

Design. Retrospective study using 3 multicenter prospective registries (IRIS-DES, IRIS-MAIN, PRECOMBAT).

Setting and participants. Among the 4470 patients enrolled in the 3 registries treated between July 2007 and July 2015, the authors identified 2692 patients with significant left main coronary artery disease who received second-generation DES for inclusion in the study. The centers for IRIS-DES and PRECOMBAT are academic and community hospitals in South Korea, with IRIS-MAIN involving academic and community hospitals in South Korea, China, India, Indonesia, Japan, Malaysia, Taiwan, and Thailand. Of the patients in these registries, 1254 received cobalt-chromium everolimus-eluting stents (CoCr-EES), 232 biodegradable polymer biolimus-eluting stents (BP-BES), 616 platinum-chromium EES (PtCr-EES) and 590 Resolute zotarolimus-eluting stents (Re-ZES).

Main outcome measure. Target-vessel failure.

Main results. At 3 years, rates of target-vessel failure were not significantly different for the different types of stents (16.7% for the CoCr-EES, 13.2% for the BP-BES, 18.7% for the PtCr-EES, and 14.7% for the Re-ZES; P = 0.15). The adjusted hazard ratios (HRs) for target-vessel failure were similar in between-group comparisons of the different stents, except for the PtCr-EES versus the BP-BES (HR 1.60, 95% confidence interval 1.01 to 2.54; P = 0.046). There were no significant differences in risk of composite of all-cause death, any myocardial infarction, or any revascularization and its individual components according to the different types of stents.

Conclusion. There was no significant between-group differences in 3-year risk of target-vessel failure, except for a higher risk of primary outcome with PtCr-EES compared to BP-BES.

Commentary

Left main coronary artery disease is identified in 5% to 7% of the population and is one of the more perplexing lesions to treat given the poorer outcome compared to non–left main lesion and the importance of the vessels the left main supplies [1]. Historically, coronary artery bypass grafting (CABG) has been the standard of care on the basis of the survival benefit observed in early trials compared with medical therapy. Left main percutaneous coronary intervention (PCI) has evolved as an alternative to CABG over the past few decades. Early studies using balloon angioplasty or bare metal stents were limited primarily due to high restenosis rate [1]. In the DES era, results have been overall comparable to CABG. Unprotected left main PCI using first-generation DES was non-inferior compared to CABG in the pre-specified sub-study of SYNTAX trial and in PRECOMBAT trial using paclitaxel-eluting stents and sirolimus-eluting stents, respectively [2,3]. Largely based on these trials, the 2014 ACC/AHA guidelines give class IIa recommendation for patients with low-risk anatomy (Syntax score 0–22) and class IIb recommendation for patients with intermediate-risk anatomy (Syntax score 23–32) for left main PCI [4]. Moreover, European guidelines give class Ib recommendation for patients with low-risk anatomy, and class IIa recommendation for intermediate-risk anatomy for left main PCI [5]. However, the SYNTAX trial and PRECOMBAT trial were limited by not meeting non-inferiority (SYNTAX) and wide non-inferiority (PRECOMBAT) and selection bias due to large exclusion criteria. In addition, first-generation DES were used in these trials (tacrolimis-eluting stent for SYNTAX and sirolimus-eluting stent for PRECOMBAT). The standard of care has now shifted to wide use of second-generation DES [1].

Subsequently, 2 larger-scale clinical trials using second-generation DES were designed and results have been reported recently [6,7]. The EXCEL trial enrolled 1905 patients with significant left main coronary disease and compared CoCr-EES to CABG. At 3 years, the primary endpoint of a composite of death from any cause, stroke, or myocardial infarction occurred in 15.4% of the PCI patients and in 14.7% of the CABG patients (P = 0.02 for non-inferiority; P = 0.98 for superiority). Similarly, the NOBLE trial enrolled 1201 patients with significant left main coronary disease and compared PCI to CABG. In this trial, the biolimus-eluting second-generation stent became their preferred stent during the study period. At 5 years, the primary endpoint of a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary intervention, and stroke was higher in PCI compared to CABG patients (28% vs 18%, HR 1.51, 95% CI 1.13–2.00), exceeding the limit of non-inferiority, and CABG was significantly better compared to PCI (P = 0.004). The difference in the results is likely due to trial design. The primary endpoint was different in the 2 studies—EXCEL did not include repeat coronary intervention in the composite endpoint. The NOBLE study had a longer enrollment period and earlier-generation stents (sirolimus-eluting) were used in the earlier stages of the trial. In addition, the NOBLE study did not assess for peri-procedural myocardial infarction as an endpoint, which is known to be associated with adverse outcome. In both trials, cardiovascular mortality and all-cause mortality were similar at the end of follow-up.

In this context, the Lee et al study compared 4 types of currently available second-generation stents by pooling data from 3 large registries in Asia [8]. The main finding from this study was that target-vessel failure, defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization at 3 years follow-up was not different among the types of second-generation drug eluting stents (P = 0.15).

Another important finding from this study was that the stent thrombosis rate at follow-up was very low (< 1%). This is consistent with the EXCEL study, which reported a definite stent thrombosis rate of 0.7% and was lower than in the NOBLE study, which reported a rate of 3%. One of the possible explanations for this difference could be stent selection. In contrast to the EXCEL study, which exclusively used Co-Cr EES by study protocol, NOBLE
study included first-generation sirolimus-drug eluting stent (11%) and BP-BES (89%). However, there are multiple factors that contribute to stent thrombosis other than stent selection, such as lesion characteristics, adequate stent expansion, and use of dual antiplatelet therapy [9].

The observed finding of small increase in target-vessel failure in PtCr-EES versus the BP-BES needs to be interpreted with caution. First, this was an observational study, and the treatment strategy or choice of stent was determined by a local interventional cardiologist, which could lead to selection bias. Although the authors performed propensity analysis, residual cofounding is likely. Second, since there was no difference in the primary analysis, the subgroup analysis becomes less important. In addition, authors did not perform statistical correction for multiple comparisons.

Despite the above limitations, this large-scale observational study gives us important insights to the performance of each second-generation DES. All currently available second-generation DES appear to be an option for use for left main coronary intervention.

Applications for Clinical Practice

In patients presenting with significant left main disease, left main PCI using a contemporary second-generation stent is safe and effective and likely has equivalent outcomes to CABG. However, PCI may be associated with higher rate of repeat revascularization. The rate of target-vessel failure was similar between different types of second-generation DES.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To compare the effectiveness and safety profiles of various second-generation drug-eluting stents (DES) for left main coronary intervention.

Design. Retrospective study using 3 multicenter prospective registries (IRIS-DES, IRIS-MAIN, PRECOMBAT).

Setting and participants. Among the 4470 patients enrolled in the 3 registries treated between July 2007 and July 2015, the authors identified 2692 patients with significant left main coronary artery disease who received second-generation DES for inclusion in the study. The centers for IRIS-DES and PRECOMBAT are academic and community hospitals in South Korea, with IRIS-MAIN involving academic and community hospitals in South Korea, China, India, Indonesia, Japan, Malaysia, Taiwan, and Thailand. Of the patients in these registries, 1254 received cobalt-chromium everolimus-eluting stents (CoCr-EES), 232 biodegradable polymer biolimus-eluting stents (BP-BES), 616 platinum-chromium EES (PtCr-EES) and 590 Resolute zotarolimus-eluting stents (Re-ZES).

Main outcome measure. Target-vessel failure.

Main results. At 3 years, rates of target-vessel failure were not significantly different for the different types of stents (16.7% for the CoCr-EES, 13.2% for the BP-BES, 18.7% for the PtCr-EES, and 14.7% for the Re-ZES; P = 0.15). The adjusted hazard ratios (HRs) for target-vessel failure were similar in between-group comparisons of the different stents, except for the PtCr-EES versus the BP-BES (HR 1.60, 95% confidence interval 1.01 to 2.54; P = 0.046). There were no significant differences in risk of composite of all-cause death, any myocardial infarction, or any revascularization and its individual components according to the different types of stents.

Conclusion. There was no significant between-group differences in 3-year risk of target-vessel failure, except for a higher risk of primary outcome with PtCr-EES compared to BP-BES.

Commentary

Left main coronary artery disease is identified in 5% to 7% of the population and is one of the more perplexing lesions to treat given the poorer outcome compared to non–left main lesion and the importance of the vessels the left main supplies [1]. Historically, coronary artery bypass grafting (CABG) has been the standard of care on the basis of the survival benefit observed in early trials compared with medical therapy. Left main percutaneous coronary intervention (PCI) has evolved as an alternative to CABG over the past few decades. Early studies using balloon angioplasty or bare metal stents were limited primarily due to high restenosis rate [1]. In the DES era, results have been overall comparable to CABG. Unprotected left main PCI using first-generation DES was non-inferior compared to CABG in the pre-specified sub-study of SYNTAX trial and in PRECOMBAT trial using paclitaxel-eluting stents and sirolimus-eluting stents, respectively [2,3]. Largely based on these trials, the 2014 ACC/AHA guidelines give class IIa recommendation for patients with low-risk anatomy (Syntax score 0–22) and class IIb recommendation for patients with intermediate-risk anatomy (Syntax score 23–32) for left main PCI [4]. Moreover, European guidelines give class Ib recommendation for patients with low-risk anatomy, and class IIa recommendation for intermediate-risk anatomy for left main PCI [5]. However, the SYNTAX trial and PRECOMBAT trial were limited by not meeting non-inferiority (SYNTAX) and wide non-inferiority (PRECOMBAT) and selection bias due to large exclusion criteria. In addition, first-generation DES were used in these trials (tacrolimis-eluting stent for SYNTAX and sirolimus-eluting stent for PRECOMBAT). The standard of care has now shifted to wide use of second-generation DES [1].

Subsequently, 2 larger-scale clinical trials using second-generation DES were designed and results have been reported recently [6,7]. The EXCEL trial enrolled 1905 patients with significant left main coronary disease and compared CoCr-EES to CABG. At 3 years, the primary endpoint of a composite of death from any cause, stroke, or myocardial infarction occurred in 15.4% of the PCI patients and in 14.7% of the CABG patients (P = 0.02 for non-inferiority; P = 0.98 for superiority). Similarly, the NOBLE trial enrolled 1201 patients with significant left main coronary disease and compared PCI to CABG. In this trial, the biolimus-eluting second-generation stent became their preferred stent during the study period. At 5 years, the primary endpoint of a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary intervention, and stroke was higher in PCI compared to CABG patients (28% vs 18%, HR 1.51, 95% CI 1.13–2.00), exceeding the limit of non-inferiority, and CABG was significantly better compared to PCI (P = 0.004). The difference in the results is likely due to trial design. The primary endpoint was different in the 2 studies—EXCEL did not include repeat coronary intervention in the composite endpoint. The NOBLE study had a longer enrollment period and earlier-generation stents (sirolimus-eluting) were used in the earlier stages of the trial. In addition, the NOBLE study did not assess for peri-procedural myocardial infarction as an endpoint, which is known to be associated with adverse outcome. In both trials, cardiovascular mortality and all-cause mortality were similar at the end of follow-up.

In this context, the Lee et al study compared 4 types of currently available second-generation stents by pooling data from 3 large registries in Asia [8]. The main finding from this study was that target-vessel failure, defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization at 3 years follow-up was not different among the types of second-generation drug eluting stents (P = 0.15).

Another important finding from this study was that the stent thrombosis rate at follow-up was very low (< 1%). This is consistent with the EXCEL study, which reported a definite stent thrombosis rate of 0.7% and was lower than in the NOBLE study, which reported a rate of 3%. One of the possible explanations for this difference could be stent selection. In contrast to the EXCEL study, which exclusively used Co-Cr EES by study protocol, NOBLE
study included first-generation sirolimus-drug eluting stent (11%) and BP-BES (89%). However, there are multiple factors that contribute to stent thrombosis other than stent selection, such as lesion characteristics, adequate stent expansion, and use of dual antiplatelet therapy [9].

The observed finding of small increase in target-vessel failure in PtCr-EES versus the BP-BES needs to be interpreted with caution. First, this was an observational study, and the treatment strategy or choice of stent was determined by a local interventional cardiologist, which could lead to selection bias. Although the authors performed propensity analysis, residual cofounding is likely. Second, since there was no difference in the primary analysis, the subgroup analysis becomes less important. In addition, authors did not perform statistical correction for multiple comparisons.

Despite the above limitations, this large-scale observational study gives us important insights to the performance of each second-generation DES. All currently available second-generation DES appear to be an option for use for left main coronary intervention.

Applications for Clinical Practice

In patients presenting with significant left main disease, left main PCI using a contemporary second-generation stent is safe and effective and likely has equivalent outcomes to CABG. However, PCI may be associated with higher rate of repeat revascularization. The rate of target-vessel failure was similar between different types of second-generation DES.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To compare the effectiveness and safety profiles of various second-generation drug-eluting stents (DES) for left main coronary intervention.

Design. Retrospective study using 3 multicenter prospective registries (IRIS-DES, IRIS-MAIN, PRECOMBAT).

Setting and participants. Among the 4470 patients enrolled in the 3 registries treated between July 2007 and July 2015, the authors identified 2692 patients with significant left main coronary artery disease who received second-generation DES for inclusion in the study. The centers for IRIS-DES and PRECOMBAT are academic and community hospitals in South Korea, with IRIS-MAIN involving academic and community hospitals in South Korea, China, India, Indonesia, Japan, Malaysia, Taiwan, and Thailand. Of the patients in these registries, 1254 received cobalt-chromium everolimus-eluting stents (CoCr-EES), 232 biodegradable polymer biolimus-eluting stents (BP-BES), 616 platinum-chromium EES (PtCr-EES) and 590 Resolute zotarolimus-eluting stents (Re-ZES).

Main outcome measure. Target-vessel failure.

Main results. At 3 years, rates of target-vessel failure were not significantly different for the different types of stents (16.7% for the CoCr-EES, 13.2% for the BP-BES, 18.7% for the PtCr-EES, and 14.7% for the Re-ZES; P = 0.15). The adjusted hazard ratios (HRs) for target-vessel failure were similar in between-group comparisons of the different stents, except for the PtCr-EES versus the BP-BES (HR 1.60, 95% confidence interval 1.01 to 2.54; P = 0.046). There were no significant differences in risk of composite of all-cause death, any myocardial infarction, or any revascularization and its individual components according to the different types of stents.

Conclusion. There was no significant between-group differences in 3-year risk of target-vessel failure, except for a higher risk of primary outcome with PtCr-EES compared to BP-BES.

Commentary

Left main coronary artery disease is identified in 5% to 7% of the population and is one of the more perplexing lesions to treat given the poorer outcome compared to non–left main lesion and the importance of the vessels the left main supplies [1]. Historically, coronary artery bypass grafting (CABG) has been the standard of care on the basis of the survival benefit observed in early trials compared with medical therapy. Left main percutaneous coronary intervention (PCI) has evolved as an alternative to CABG over the past few decades. Early studies using balloon angioplasty or bare metal stents were limited primarily due to high restenosis rate [1]. In the DES era, results have been overall comparable to CABG. Unprotected left main PCI using first-generation DES was non-inferior compared to CABG in the pre-specified sub-study of SYNTAX trial and in PRECOMBAT trial using paclitaxel-eluting stents and sirolimus-eluting stents, respectively [2,3]. Largely based on these trials, the 2014 ACC/AHA guidelines give class IIa recommendation for patients with low-risk anatomy (Syntax score 0–22) and class IIb recommendation for patients with intermediate-risk anatomy (Syntax score 23–32) for left main PCI [4]. Moreover, European guidelines give class Ib recommendation for patients with low-risk anatomy, and class IIa recommendation for intermediate-risk anatomy for left main PCI [5]. However, the SYNTAX trial and PRECOMBAT trial were limited by not meeting non-inferiority (SYNTAX) and wide non-inferiority (PRECOMBAT) and selection bias due to large exclusion criteria. In addition, first-generation DES were used in these trials (tacrolimis-eluting stent for SYNTAX and sirolimus-eluting stent for PRECOMBAT). The standard of care has now shifted to wide use of second-generation DES [1].

Subsequently, 2 larger-scale clinical trials using second-generation DES were designed and results have been reported recently [6,7]. The EXCEL trial enrolled 1905 patients with significant left main coronary disease and compared CoCr-EES to CABG. At 3 years, the primary endpoint of a composite of death from any cause, stroke, or myocardial infarction occurred in 15.4% of the PCI patients and in 14.7% of the CABG patients (P = 0.02 for non-inferiority; P = 0.98 for superiority). Similarly, the NOBLE trial enrolled 1201 patients with significant left main coronary disease and compared PCI to CABG. In this trial, the biolimus-eluting second-generation stent became their preferred stent during the study period. At 5 years, the primary endpoint of a composite of all-cause mortality, non-procedural myocardial infarction, any repeat coronary intervention, and stroke was higher in PCI compared to CABG patients (28% vs 18%, HR 1.51, 95% CI 1.13–2.00), exceeding the limit of non-inferiority, and CABG was significantly better compared to PCI (P = 0.004). The difference in the results is likely due to trial design. The primary endpoint was different in the 2 studies—EXCEL did not include repeat coronary intervention in the composite endpoint. The NOBLE study had a longer enrollment period and earlier-generation stents (sirolimus-eluting) were used in the earlier stages of the trial. In addition, the NOBLE study did not assess for peri-procedural myocardial infarction as an endpoint, which is known to be associated with adverse outcome. In both trials, cardiovascular mortality and all-cause mortality were similar at the end of follow-up.

In this context, the Lee et al study compared 4 types of currently available second-generation stents by pooling data from 3 large registries in Asia [8]. The main finding from this study was that target-vessel failure, defined as the composite of cardiac death, target-vessel myocardial infarction, or target-vessel revascularization at 3 years follow-up was not different among the types of second-generation drug eluting stents (P = 0.15).

Another important finding from this study was that the stent thrombosis rate at follow-up was very low (< 1%). This is consistent with the EXCEL study, which reported a definite stent thrombosis rate of 0.7% and was lower than in the NOBLE study, which reported a rate of 3%. One of the possible explanations for this difference could be stent selection. In contrast to the EXCEL study, which exclusively used Co-Cr EES by study protocol, NOBLE
study included first-generation sirolimus-drug eluting stent (11%) and BP-BES (89%). However, there are multiple factors that contribute to stent thrombosis other than stent selection, such as lesion characteristics, adequate stent expansion, and use of dual antiplatelet therapy [9].

The observed finding of small increase in target-vessel failure in PtCr-EES versus the BP-BES needs to be interpreted with caution. First, this was an observational study, and the treatment strategy or choice of stent was determined by a local interventional cardiologist, which could lead to selection bias. Although the authors performed propensity analysis, residual cofounding is likely. Second, since there was no difference in the primary analysis, the subgroup analysis becomes less important. In addition, authors did not perform statistical correction for multiple comparisons.

Despite the above limitations, this large-scale observational study gives us important insights to the performance of each second-generation DES. All currently available second-generation DES appear to be an option for use for left main coronary intervention.

Applications for Clinical Practice

In patients presenting with significant left main disease, left main PCI using a contemporary second-generation stent is safe and effective and likely has equivalent outcomes to CABG. However, PCI may be associated with higher rate of repeat revascularization. The rate of target-vessel failure was similar between different types of second-generation DES.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To determine the prognostic impact of multivessel percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) multivessel disease presenting with cardiogenic shock.

Design. Retrospective study using the nationwide, multicenter, prospective KAMIR-NIH (Korea Acute Myocardial Infarction-National Institutes of Health) registry.

Setting and participants. Among the 13,104 patients enrolled in the KAMIR-NIH registry, 659 patients with STEMI with multivessel disease presenting with cardiogenic shock who underwent primary PCI were selected.

Main outcome measures. The primary outcome was all-cause death at 1 year. Secondary outcomes included patient-oriented composite outcome (composite of all-cause death, any myocardial infarction, and any repeat revascularization) and its individual components.

Main results. A total of 260 patients were treated with multivessel PCI and 399 patients were treated with infarct-related artery (IRA) PCI only. The risk of all-cause death was significantly lower in the multivessel PCI group (21.3% vs 31.7%; hazard ratio [HR] 0.59, 95% CI 0.43–0.82, P = 0.001). Non-IRA repeat revascularization was significantly lower in the multivessel group (6.7% vs 8.2%; HR 0.39, 95% CI 0.17–0.90, P = 0.028). In multivariate model, multivessel PCI was independently associated with reduced risk of 1-year all-cause death and patient-oriented composite outcome.

Conclusion. Among patients with STEMI and multivessel disease with cardiogenic shock, multivessel PCI was associated with significantly lower risk of all-cause death and non-IRA repeat revascularization.

Commentary

Historically, non-culprit vessel revascularization in the setting of acute myocardial infarction (AMI) was not routinely performed. However, recent trials have shown the benefit of non-culprit vessel revascularization in patients with hemodynamically stable AMI [1–3]. The result of these trials have led to upgrade in U.S. guideline recommendations for non-infarct-related artery PCI in hemodynamically stable patients presenting with AMI to Class IIb from Class III [4]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is controversial. Recently, results of a well-designed randomized control trial (CULPRIT-SHOCK) suggested worse outcome with immediate multivessel PCI in this population [5]. The composite endpoint of death and renal replacement therapy at 30 days was higher in the multivessel PCI at the time of primary PCI group compared to initial culprit lesion only group (55.9% vs 45.9%, P = 0.01). The composite endpoint was mainly driven by death (51.6% vs 43.3%, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (16.4% vs 11.6%, P = 0.07).

Lee et al investigated a similar clinical question using the nationwide, multicenter, prospective KAMIR-NIH registry data [6]. In this study, the primary endpoint of all cause death occurred in 53 of the 260 patients (21.3%) in the multivessel PCI group and 126 of the 399 patients (31.7%) in the IRA-only PCI group (relative risk [RR] 0.59, 95% CI 0.43–0.82, P = 0.001). Similarly, the multivessel PCI group had lower non-IRA repeat revascularization (RR 0.39, 95% CI 0.17-0.90, P = 0.028) and lower patient-oriented composite outcome (all-cause death, any myocardial infarction, or any repeat revascularization) (RR 0.58, 95% CI 0.44–0.77, P < 0.001). These results remained similar after multivariate adjustment, propensity matching, and inverse probability weighted analysis.

The discrepancy of the results of the KAMIR study compared to CULPRIT-SHOCK is likely related to the difference in the design of the two studies. First, CUPRIT-SHOCK compared multivessel revascularization during index primary PCI to culprit-only revascularization strategy with staged revascularization if necessary. There were 9.4% randomized to multivessel PCI who crossed over to IRA-only PCI and 17.4% randomized to IRA-only PCI who crossed over to multivessel PCI during the index hospitalization. In contrast, the KAMIR registry compared patients who underwent IRA-only PCI to multivessel PCI, which included those who had immediate revascularization during the primary PCI and those who had staged revascularization during the index hospitalization. Therefore, multivessel PCI is defined very differently in both studies and cannot be considered equivalent.

Second, CULPRIT-SHOCK was a prospective randomized control study and KAMIR was an observational study analyzing data from a prospectively collected large database. Although multiple statistical adjustments were performed, this observational nature of the study is subject to selection bias and other unmeasured biases such as frailty assessment.

Third, the timing of the revascularization was different between two studies. In CULPRIT-SHOCK, immediate revascularization of non-IRA was achieved in 90.6% of patients in the multivessel PCI group. On the other hand, only 60.4% of patients of multivessel PCI group in KAMIR study underwent immediate revascularization of the non-IRA and 39.6 % of patients underwent staged procedure. This leads to significant survival bias, since these 39.6% of patients survived the initial event to be able to undergo the staged procedure. Patients who had planned staged intervention but could not survive were included in the IRA-only PCI group.

Fourth, there may be difference in the severity of the patient population included in the analysis. In the CULPRIT-SHOCK trial, a significant non-IRA was defined as > 70% stenosis, and all chronic total occlusions (CTO) were attempted in the multivessel PCI group according to trial protocol. In CULPRIT-SHOCK, 23% of patient had one or more CTO lesions. In the KAMIR registry, a significant non-IRA was defined as > 50% stenosis of the non-culprit vessel and CTO vessels were not accounted for. Although CTO intervention improves angina and ejection fraction [7,8], whether CTO intervention has mortality benefit needs further investigation. In a recent EXPLORE trial, the feasibility and safety of intervention of chronic total occlusion in non-infarct-related artery in STEMI population was established [8]. However, only hemodynamically stable patients were included in the study and all CTO interventions were performed in staged fashion (5 ± 2 days after index procedure) [8]. There is a possibility of attempting CTO PCI in this acute setting caused more harm than benefit.

Finally, in order to be enrolled in the CULPRIT-SHOCK trial, patients needed to meet stringent criteria for cardiogenic shock. In KAMIR study, this data was retrospectively determined and individual components used to define cardiogenic shock were not available. This difference may have led to inclusion of more stable patients as evidenced by lower mortality rate in KAMIR study compared to CULPRIT-SHOCK (51.6% mortality for multivessel PCI in CULPRIT-SHOCK and 21.3% mortality for multivessel PCI patients in KAMIR study). CULPRIT-SHOCK trial had a high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stays (median 5 days). This information is not reported in the KAMIR study.

Considering above differences in the study design, the evidence level for CULPRIT-SHOCK appears to be stronger compared to the KAMIR study, which should be considered as hypothesis-generating as all other observational studies. However, the KAMIR study is still an important study suggesting possible benefit of multivessel PCI in patients presenting with ST elevation myocardial infarction and cardiogenic shock. This leads us to an answered question whether staged multivessel intervention or less aggressive multivessel intervention (not attempting CTO) is a better option in this population.

Applications for Clinical Practice

In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion-only intervention and staged intervention if necessary, seems to be a better strategy. However, there may be benefit in multivessel intervention in this population, depending on the timing and revascularization strategy. Further studies are needed.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To determine the prognostic impact of multivessel percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) multivessel disease presenting with cardiogenic shock.

Design. Retrospective study using the nationwide, multicenter, prospective KAMIR-NIH (Korea Acute Myocardial Infarction-National Institutes of Health) registry.

Setting and participants. Among the 13,104 patients enrolled in the KAMIR-NIH registry, 659 patients with STEMI with multivessel disease presenting with cardiogenic shock who underwent primary PCI were selected.

Main outcome measures. The primary outcome was all-cause death at 1 year. Secondary outcomes included patient-oriented composite outcome (composite of all-cause death, any myocardial infarction, and any repeat revascularization) and its individual components.

Main results. A total of 260 patients were treated with multivessel PCI and 399 patients were treated with infarct-related artery (IRA) PCI only. The risk of all-cause death was significantly lower in the multivessel PCI group (21.3% vs 31.7%; hazard ratio [HR] 0.59, 95% CI 0.43–0.82, P = 0.001). Non-IRA repeat revascularization was significantly lower in the multivessel group (6.7% vs 8.2%; HR 0.39, 95% CI 0.17–0.90, P = 0.028). In multivariate model, multivessel PCI was independently associated with reduced risk of 1-year all-cause death and patient-oriented composite outcome.

Conclusion. Among patients with STEMI and multivessel disease with cardiogenic shock, multivessel PCI was associated with significantly lower risk of all-cause death and non-IRA repeat revascularization.

Commentary

Historically, non-culprit vessel revascularization in the setting of acute myocardial infarction (AMI) was not routinely performed. However, recent trials have shown the benefit of non-culprit vessel revascularization in patients with hemodynamically stable AMI [1–3]. The result of these trials have led to upgrade in U.S. guideline recommendations for non-infarct-related artery PCI in hemodynamically stable patients presenting with AMI to Class IIb from Class III [4]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is controversial. Recently, results of a well-designed randomized control trial (CULPRIT-SHOCK) suggested worse outcome with immediate multivessel PCI in this population [5]. The composite endpoint of death and renal replacement therapy at 30 days was higher in the multivessel PCI at the time of primary PCI group compared to initial culprit lesion only group (55.9% vs 45.9%, P = 0.01). The composite endpoint was mainly driven by death (51.6% vs 43.3%, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (16.4% vs 11.6%, P = 0.07).

Lee et al investigated a similar clinical question using the nationwide, multicenter, prospective KAMIR-NIH registry data [6]. In this study, the primary endpoint of all cause death occurred in 53 of the 260 patients (21.3%) in the multivessel PCI group and 126 of the 399 patients (31.7%) in the IRA-only PCI group (relative risk [RR] 0.59, 95% CI 0.43–0.82, P = 0.001). Similarly, the multivessel PCI group had lower non-IRA repeat revascularization (RR 0.39, 95% CI 0.17-0.90, P = 0.028) and lower patient-oriented composite outcome (all-cause death, any myocardial infarction, or any repeat revascularization) (RR 0.58, 95% CI 0.44–0.77, P < 0.001). These results remained similar after multivariate adjustment, propensity matching, and inverse probability weighted analysis.

The discrepancy of the results of the KAMIR study compared to CULPRIT-SHOCK is likely related to the difference in the design of the two studies. First, CUPRIT-SHOCK compared multivessel revascularization during index primary PCI to culprit-only revascularization strategy with staged revascularization if necessary. There were 9.4% randomized to multivessel PCI who crossed over to IRA-only PCI and 17.4% randomized to IRA-only PCI who crossed over to multivessel PCI during the index hospitalization. In contrast, the KAMIR registry compared patients who underwent IRA-only PCI to multivessel PCI, which included those who had immediate revascularization during the primary PCI and those who had staged revascularization during the index hospitalization. Therefore, multivessel PCI is defined very differently in both studies and cannot be considered equivalent.

Second, CULPRIT-SHOCK was a prospective randomized control study and KAMIR was an observational study analyzing data from a prospectively collected large database. Although multiple statistical adjustments were performed, this observational nature of the study is subject to selection bias and other unmeasured biases such as frailty assessment.

Third, the timing of the revascularization was different between two studies. In CULPRIT-SHOCK, immediate revascularization of non-IRA was achieved in 90.6% of patients in the multivessel PCI group. On the other hand, only 60.4% of patients of multivessel PCI group in KAMIR study underwent immediate revascularization of the non-IRA and 39.6 % of patients underwent staged procedure. This leads to significant survival bias, since these 39.6% of patients survived the initial event to be able to undergo the staged procedure. Patients who had planned staged intervention but could not survive were included in the IRA-only PCI group.

Fourth, there may be difference in the severity of the patient population included in the analysis. In the CULPRIT-SHOCK trial, a significant non-IRA was defined as > 70% stenosis, and all chronic total occlusions (CTO) were attempted in the multivessel PCI group according to trial protocol. In CULPRIT-SHOCK, 23% of patient had one or more CTO lesions. In the KAMIR registry, a significant non-IRA was defined as > 50% stenosis of the non-culprit vessel and CTO vessels were not accounted for. Although CTO intervention improves angina and ejection fraction [7,8], whether CTO intervention has mortality benefit needs further investigation. In a recent EXPLORE trial, the feasibility and safety of intervention of chronic total occlusion in non-infarct-related artery in STEMI population was established [8]. However, only hemodynamically stable patients were included in the study and all CTO interventions were performed in staged fashion (5 ± 2 days after index procedure) [8]. There is a possibility of attempting CTO PCI in this acute setting caused more harm than benefit.

Finally, in order to be enrolled in the CULPRIT-SHOCK trial, patients needed to meet stringent criteria for cardiogenic shock. In KAMIR study, this data was retrospectively determined and individual components used to define cardiogenic shock were not available. This difference may have led to inclusion of more stable patients as evidenced by lower mortality rate in KAMIR study compared to CULPRIT-SHOCK (51.6% mortality for multivessel PCI in CULPRIT-SHOCK and 21.3% mortality for multivessel PCI patients in KAMIR study). CULPRIT-SHOCK trial had a high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stays (median 5 days). This information is not reported in the KAMIR study.

Considering above differences in the study design, the evidence level for CULPRIT-SHOCK appears to be stronger compared to the KAMIR study, which should be considered as hypothesis-generating as all other observational studies. However, the KAMIR study is still an important study suggesting possible benefit of multivessel PCI in patients presenting with ST elevation myocardial infarction and cardiogenic shock. This leads us to an answered question whether staged multivessel intervention or less aggressive multivessel intervention (not attempting CTO) is a better option in this population.

Applications for Clinical Practice

In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion-only intervention and staged intervention if necessary, seems to be a better strategy. However, there may be benefit in multivessel intervention in this population, depending on the timing and revascularization strategy. Further studies are needed.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL

Study Overview

Objective. To determine the prognostic impact of multivessel percutaneous coronary intervention (PCI) in patients with ST-segment elevation myocardial infarction (STEMI) multivessel disease presenting with cardiogenic shock.

Design. Retrospective study using the nationwide, multicenter, prospective KAMIR-NIH (Korea Acute Myocardial Infarction-National Institutes of Health) registry.

Setting and participants. Among the 13,104 patients enrolled in the KAMIR-NIH registry, 659 patients with STEMI with multivessel disease presenting with cardiogenic shock who underwent primary PCI were selected.

Main outcome measures. The primary outcome was all-cause death at 1 year. Secondary outcomes included patient-oriented composite outcome (composite of all-cause death, any myocardial infarction, and any repeat revascularization) and its individual components.

Main results. A total of 260 patients were treated with multivessel PCI and 399 patients were treated with infarct-related artery (IRA) PCI only. The risk of all-cause death was significantly lower in the multivessel PCI group (21.3% vs 31.7%; hazard ratio [HR] 0.59, 95% CI 0.43–0.82, P = 0.001). Non-IRA repeat revascularization was significantly lower in the multivessel group (6.7% vs 8.2%; HR 0.39, 95% CI 0.17–0.90, P = 0.028). In multivariate model, multivessel PCI was independently associated with reduced risk of 1-year all-cause death and patient-oriented composite outcome.

Conclusion. Among patients with STEMI and multivessel disease with cardiogenic shock, multivessel PCI was associated with significantly lower risk of all-cause death and non-IRA repeat revascularization.

Commentary

Historically, non-culprit vessel revascularization in the setting of acute myocardial infarction (AMI) was not routinely performed. However, recent trials have shown the benefit of non-culprit vessel revascularization in patients with hemodynamically stable AMI [1–3]. The result of these trials have led to upgrade in U.S. guideline recommendations for non-infarct-related artery PCI in hemodynamically stable patients presenting with AMI to Class IIb from Class III [4]. Whether these findings can be extended to hemodynamically unstable (cardiogenic shock) patients is controversial. Recently, results of a well-designed randomized control trial (CULPRIT-SHOCK) suggested worse outcome with immediate multivessel PCI in this population [5]. The composite endpoint of death and renal replacement therapy at 30 days was higher in the multivessel PCI at the time of primary PCI group compared to initial culprit lesion only group (55.9% vs 45.9%, P = 0.01). The composite endpoint was mainly driven by death (51.6% vs 43.3%, P = 0.03), and the rate of renal replacement therapy was numerically higher in the mutivessel PCI group (16.4% vs 11.6%, P = 0.07).

Lee et al investigated a similar clinical question using the nationwide, multicenter, prospective KAMIR-NIH registry data [6]. In this study, the primary endpoint of all cause death occurred in 53 of the 260 patients (21.3%) in the multivessel PCI group and 126 of the 399 patients (31.7%) in the IRA-only PCI group (relative risk [RR] 0.59, 95% CI 0.43–0.82, P = 0.001). Similarly, the multivessel PCI group had lower non-IRA repeat revascularization (RR 0.39, 95% CI 0.17-0.90, P = 0.028) and lower patient-oriented composite outcome (all-cause death, any myocardial infarction, or any repeat revascularization) (RR 0.58, 95% CI 0.44–0.77, P < 0.001). These results remained similar after multivariate adjustment, propensity matching, and inverse probability weighted analysis.

The discrepancy of the results of the KAMIR study compared to CULPRIT-SHOCK is likely related to the difference in the design of the two studies. First, CUPRIT-SHOCK compared multivessel revascularization during index primary PCI to culprit-only revascularization strategy with staged revascularization if necessary. There were 9.4% randomized to multivessel PCI who crossed over to IRA-only PCI and 17.4% randomized to IRA-only PCI who crossed over to multivessel PCI during the index hospitalization. In contrast, the KAMIR registry compared patients who underwent IRA-only PCI to multivessel PCI, which included those who had immediate revascularization during the primary PCI and those who had staged revascularization during the index hospitalization. Therefore, multivessel PCI is defined very differently in both studies and cannot be considered equivalent.

Second, CULPRIT-SHOCK was a prospective randomized control study and KAMIR was an observational study analyzing data from a prospectively collected large database. Although multiple statistical adjustments were performed, this observational nature of the study is subject to selection bias and other unmeasured biases such as frailty assessment.

Third, the timing of the revascularization was different between two studies. In CULPRIT-SHOCK, immediate revascularization of non-IRA was achieved in 90.6% of patients in the multivessel PCI group. On the other hand, only 60.4% of patients of multivessel PCI group in KAMIR study underwent immediate revascularization of the non-IRA and 39.6 % of patients underwent staged procedure. This leads to significant survival bias, since these 39.6% of patients survived the initial event to be able to undergo the staged procedure. Patients who had planned staged intervention but could not survive were included in the IRA-only PCI group.

Fourth, there may be difference in the severity of the patient population included in the analysis. In the CULPRIT-SHOCK trial, a significant non-IRA was defined as > 70% stenosis, and all chronic total occlusions (CTO) were attempted in the multivessel PCI group according to trial protocol. In CULPRIT-SHOCK, 23% of patient had one or more CTO lesions. In the KAMIR registry, a significant non-IRA was defined as > 50% stenosis of the non-culprit vessel and CTO vessels were not accounted for. Although CTO intervention improves angina and ejection fraction [7,8], whether CTO intervention has mortality benefit needs further investigation. In a recent EXPLORE trial, the feasibility and safety of intervention of chronic total occlusion in non-infarct-related artery in STEMI population was established [8]. However, only hemodynamically stable patients were included in the study and all CTO interventions were performed in staged fashion (5 ± 2 days after index procedure) [8]. There is a possibility of attempting CTO PCI in this acute setting caused more harm than benefit.

Finally, in order to be enrolled in the CULPRIT-SHOCK trial, patients needed to meet stringent criteria for cardiogenic shock. In KAMIR study, this data was retrospectively determined and individual components used to define cardiogenic shock were not available. This difference may have led to inclusion of more stable patients as evidenced by lower mortality rate in KAMIR study compared to CULPRIT-SHOCK (51.6% mortality for multivessel PCI in CULPRIT-SHOCK and 21.3% mortality for multivessel PCI patients in KAMIR study). CULPRIT-SHOCK trial had a high rate of mechanical ventilation (~80%), requirement of catecholamine support (~90%), and long ICU stays (median 5 days). This information is not reported in the KAMIR study.

Considering above differences in the study design, the evidence level for CULPRIT-SHOCK appears to be stronger compared to the KAMIR study, which should be considered as hypothesis-generating as all other observational studies. However, the KAMIR study is still an important study suggesting possible benefit of multivessel PCI in patients presenting with ST elevation myocardial infarction and cardiogenic shock. This leads us to an answered question whether staged multivessel intervention or less aggressive multivessel intervention (not attempting CTO) is a better option in this population.

Applications for Clinical Practice

In patients presenting with cardiogenic shock and acute myocardial infarction, culprit lesion-only intervention and staged intervention if necessary, seems to be a better strategy. However, there may be benefit in multivessel intervention in this population, depending on the timing and revascularization strategy. Further studies are needed.

—Taishi Hirai, MD, and John E.A. Blair, MD, University of Chicago Medical Center, Chicago, IL