Multivessel vs. culprit vessel-only percutaneous coronary intervention in ST-segment elevation myocardial infarction with and without cardiogenic shock

Background Early revascularization of the culprit vessel is the most effective treatment for reducing the risk of mortality from acute STEMI with and without cardiogenic shock. However, the most recent trends and impact of multivessel percutaneous coronary intervention (PCI) during the index hospitalization on in-hospital outcomes are unknown. Methods The National Inpatient Sample was queried from October 2015 to 2019 for hospitalizations with STEMI. The impact of multivessel PCI on in-hospital outcomes of patients with and without cardiogenic shock was evaluated. Results Of 624,605 STEMI hospitalizations treated with PCI, 12.5% were complicated by cardiogenic shock. Among hospitalizations without cardiogenic shock, 15.7% were treated by multivessel PCI, which declined from 20.8% in 2015 to 13.9% in 2019 (Ptrend < 0.001). Multivessel and culprit-only PCI had similar rates of In-hospital mortality (2.4 vs. 2.3%, p = 0.027) and major adverse cardiac and cerebrovascular events (MACCE; 7.4 vs. 7.2%, p = 0.072). Among hospitalizations with cardiogenic shock, 22.1% were treated by multivessel PCI, which declined from 29.2% in 2015 to 19.4% in 2019 (Ptrend < 0.001). Multivessel PCI was associated with higher rates of in-hospital mortality (30.9 vs. 28.4%, p < 0.001) and MACCE (39.9 vs. 36.5%, p < 0.001) than culprit-only PCI. Conclusion The frequency of multivessel PCI for STEMI with and without cardiogenic shock is declining. Multivessel PCI is associated with worse in-hospital outcomes for STEMI with cardiogenic shock but not for STEMI without cardiogenic shock.


Introduction
In patients presenting with ST-segment elevation myocardial infarction (STEMI) with or without cardiogenic shock, early revascularization-mainly percutaneous coronary intervention (PCI) on the culprit vessel-is the most effective therapeutic strategy to reduce both short-and long-term mortality (1)(2)(3). However, over half of patients with hemodynamically stable STEMI have at least 1 other obstructive lesion in non-culprit vessels (4); in STEMI with cardiogenic shock, up to 80% of patients present with multivessel coronary artery disease (5). Optimal strategies for the treatment of nonculprit lesions have been widely studied (6). Several randomized controlled trials including the COMPLETE trials comparing multivessel vs. culprit-only PCI have reported improved clinical outcomes including decreased cardiac mortality, myocardial reinfarction, and revascularization (7)(8)(9)(10)(11)(12); however, the optimal time to treat non-culprit lesions is not known. Additionally, data supporting multivessel PCI have been derived from hemodynamically stable myocardial infarction (MI) patients as cardiogenic shock patients were excluded from these studies. The results of the CULPRIT-SHOCK trial enrolling patients with acute MI complicated by cardiogenic shock suggested that immediate treatment of non-culprit lesions during primary PCI was harmful (13). Real-world data regarding impact of multivessel PCI for STEMI with and without cardiogenic shock on in-hospital outcomes are limited and inconsistent (14)(15)(16). The most recent practice trends of multiple PCI are unknown, To address these issues, in this study we analyzed data for patients hospitalized for STEMI with and without cardiogenic shock using the latest United States (US) National Inpatient Sample (NIS) database.

Data source
The data were obtained from the NIS database developed for the Healthcare Cost and Utilization Project (HCUP) (17). It is the largest inpatient care database in the US and includes over 7 million unweighted hospital stays annually with more than 100 clinical and non-clinical data elements. It is accessible at https://www.ahrq.gov. In accordance with NIS recommendations, proper weighting was applied using the individual weight variable provided by the HCUP to establish national estimate statistics. Comorbidities were identified using Elixhauser Comorbidity Software Refined for International Classification of Disease, 10th Revision, Clinical Modification (ICD-10-CM), which assigns data elements provided by HCUP. The use of the NIS database to describe outcomes and trends in cardiovascular disease in different patient populations has been previously validated (18,19). As data from the NIS are publicly available and de-identified, the study was exempt from Institutional Review Board approval. The authors vouch for the accuracy and completeness of the data. the date of last database interrogation was on 10 July 2022.

Study population and outcome measures
Starting from 1 October 2015, all hospitals in the US transitioned from ICD-9-CM (i.e., the 9th revision) to ICD-10-CM coding of diagnoses and procedures. Significant disruption of statistics has been reported, and it was suggested that analyses rely on a single coding system (20,21). In the present study, we queried the NIS database from inception of the ICD-10-CM coding system to the latest available time (from October 2015 through 2019). STEMI hospitalizations were identified using the ICD-10-CM diagnosis codes I21.0x, I21.1x, I21.2x, and I21.3 (Supplementary Table 1), which have been previously validated (22, 23). We excluded records of patients who did not undergo PCI; with missing information on the number of treated vessels in procedure codes; with age at admission <18 years; and with missing data on in-hospital mortality (Supplementary Figure 1). The primary outcome was in-hospital all-cause mortality, and the secondary outcome was major adverse cardiac or cerebrovascular events (MACCE) including a composite of all-cause mortality, cardiac complications (hemopericardium and cardiac tamponade necessitating pericardiocentesis), and stroke. Hospital cost was obtained by merging the cost-to-charge ratio files with total charge.

Statistical analyses
Continuous variables are expressed as mean ± SD or median [interquartile range (IQR)] as appropriate. Categorical variables are expressed as numbers and percentages. Weights for each discharge were used to calculate national estimates as recommended by the HCUP for NIS data. Multivariable logistic regression models were generated to evaluate the association between in-hospital mortality, presented as odds ratios (OR) with 95% confidence interval (CI), and variables included in the model (multivessel PCI, age, sex, race, expected payer, hospital bed size, location and teaching status, atrial fibrillation, smoking status, history of MI, prior PCI, prior coronary artery bypass graft [CABG], family history of coronary artery disease, chronic lung disease, obesity, peripheral artery disease, hypothyroidism, hypertension, and diabetes mellitus). Differences between categorical variables were evaluated with the chi-squared test, and differences between continuous variables were assessed with the Student's t-test or Mann-Whitney U test as appropriate; the corresponding ORs and 95% CIs are presented as forest plots. The Breslow-Day test was used to analyze the interaction between subgroups. Considering the large sample size, a 2-sided P-value <0.01 was considered statistically significant. SAS 9.4 (SAS Institute, Cary, NC, USA) was used for all analyses.

Temporal trends in multivessel percutaneous coronary intervention
The flow chart of patient selection is shown in Supplementary Figure 1. We extracted 912,540 hospitalizations with a diagnosis of STEMI between October 2015 to October 2019 from the NIS database. After excluding age <18 years at admission (n = 440); patients with missing in-hospital mortality data (n = 3,300); hospitalizations did not undergo PCI (283,645); and hospitalizations with missing number of vessel treatments in procedure codes (n = 3,280), the final analysis included 624,605 STEMI hospitalizations, 546,305 (87.5%) without and 78,300 (12.5%) with cardiogenic shock. In the cohort without cardiogenic shock, there were 460,315 (84.3%) hospitalizations where the patient underwent culprit-only PCI and 85,990 (15.7%) where the patient underwent multivessel Trend of multivessel PCI performance during the study period. Percentage of overall STEMI hospitalizations, STEMI hospitalizations with cardiogenic shock, and STEMI hospitalizations without cardiogenic shock in which multivessel PCI was performed.  (Figure 1).

Discussion
There were five main findings from this large-sample analysis of patients with STEMI with or without cardiogenic shock in the US. (1) The rate of multivessel PCI in the index hospitalization decreased during the study period, corresponding to the declining rates of STEMI with and without cardiogenic shock. (2) In the overall STEMI cohort, in-hospital mortality and rate of MACCE for multivessel PCI were significantly higher than the rate of culprit-only PCI. (3) In STEMI hospitalizations without cardiogenic shock, multivessel PCI was not associated with an elevated risk of in-hospital mortality and MACCE rate. (4) In STEMI hospitalizations with cardiogenic shock, multivessel PCI was associated with a significantly increased risk of in-hospital mortality and MACCE rate. (5) The elevated risk of multivessel PCI in the Values are mean ± SD, n (%), or median (interquartile range). Abbreviations as in Table 1. Forest plot of multivariable regression analysis to predict in-hospital mortality in the STEMI without cardiogenic shock cohort. Abbreviations as in Figure 3.
overall STEMI cohort was driven by the higher portion of cardiogenic shock hospitalizations in which patients underwent multivessel PCI, and higher risk associated with multivessel PCI in cardiogenic shock hospitalizations. Multivessel disease is common in STEMI hospitalizations, and even more prevalent in the setting of cardiogenic shock (5). The presence of multivessel disease is associated with worse clinical outcomes compared with single-vessel disease (24). The optimal strategy for treatment of the non-culprit vessel is unclear, as reflected in the discrepancies in treatment guidelines. The current evidence indicates diverse effects of multivessel PCI on clinical outcomes depending on the presence of cardiogenic shock. Except for the CULPRIT-SHOCK trial, randomized clinical trials have excluded patients with cardiogenic shock and have reported favorable outcomes of multivessel PCI, with earlier trials showing that the benefit was mainly attributable to a reduction in repeated revascularizations (7)(8)(9)(10)(25)(26)(27)(28)(29). The COMPLETE trial (11) showed that the benefit extended beyond repeated revascularizations, also reducing the rates of cardiac death and MI (12). However, the optimal timing of non-culprit vessel revascularization has not been adequately investigated. An analysis of 1,964 patients from 5 clinical trials that included multivessel PCI during the index hospitalization demonstrated a significant reduction in cardiovascular mortality in addition to repeated revascularizations (12). The present analysis of NIS data confirms the safety of non-culprit PCI during the index hospitalization for STEMI without cardiogenic shock.
During the study period, multivessel PCI was performed during the index hospitalization in only 15.7% of STEMI hospitalizations without cardiogenic shock; thus, most patients with multivessel disease admitted with STEMI did not have their non-culprit vessel treated before discharge. Although, the clinical benefit of non-culprit PCI has been established (11), several questions remain unanswered, like what is the optimal timing of non-culprit PCI (30), our data provide support for the treatment of non-culprit vessel coronary disease during the index hospitalization, considering the possible long-term benefit for complete revascularization (31). Thus, for STEMI without cardiogenic shock, multivessel PCI during the index hospitalization appears safe and should be considered, at least in selected hemodynamically stable myocardial infarction patients. However, it is worth noting that in this analysis, 85.7% of multivessel procedures were performed on two vessels. The 2-vessel procedure is safe and does not incur excessive risks Values are mean ± SD, n (%), or median (interquartile range). Abbreviations as in Table 1.
of in-hospital mortality and MACCE compared with culpritonly PCI. Hospitalizations involving a >2-vessel procedure is still associated with a significant increase in in-hospital mortality and MACCE. These results indicate that there is a limit to how many vessels can be safely treated. In cases involving >2 vessels, it is important to consider whether staged PCI to treat the extra vessel(s) is more beneficial or whether CABG is a better option because of the complexity of the coronary artery disease.
The results of the CULPRIT-SHOCK trial showed the detrimental effect of immediate multivessel PCI on cardiogenic shock complicated by MI at 30 days (13). In line with this finding, our analysis showed that in contrast to STEMI hospitalizations without cardiogenic shock, multivessel PCI was associated with increased risk of in-hospital mortality and MACCE in STEMI hospitalizations with cardiogenic shock. An explanation for the differential impact of multivessel PCI in hospitalizations with vs. without cardiogenic shock is that the long procedure time may cause more stress and expose patients to more hemodynamic instability; additionally, injection of a large amount of contrast agent may further impair the function of an underperfused kidney in the setting of cardiogenic shock. To our knowledge, this analysis represents the largest-sample study of the impact of multivessel PCI on STEMI with cardiogenic shock. Our results provide real-world evidence of the harmful effects of immediate multivessel PCI as reported in the CULPRIT-SHOCK trial. The declining trend of multivessel PCI performance in the setting of cardiogenic shock during the study period may reflect the influence of the CULPRIT-SHOCK trial on clinical practice. It has been suggested that immediate multivessel PCI is associated with a higher short-term but lower long-term risk of death than culprit lesion-only PCI; however, this is not supported by the 1-year outcome from the CULPRIT-SHOCK trial that showed no reduction in the multivessel PCI group with a longer follow-up (between 30 days and 1 year) (32). This along with our findings suggest that immediate multivessel PCI should be avoided in STEMI with cardiogenic shock. In the CULPRIT-SHOCK trial, staged PCI of non-culprit lesions within 30 days was only performed on 17.4% patients. Whether performing more stage PCIs can improve outcomes and if so, the optimal time to treat the non-culprit lesion remain to be determined.

Study limitations
The present analysis had certain limitations. Large inpatient cohorts such as the NIS are subject to coding and documentation errors. The administrative database lacked clinical details for individual hospitalization including angiographic and procedural details, biochemistry data, echocardiography, and medications as well as long-term FIGURE 5 Forest plot of multivariable regression analysis to predict in-hospital mortality in the STEMI with cardiogenic shock cohort. Abbreviations as in follow-up data; moreover, the retrospective observational study design made the analysis liable to selection bias. However, the NIS database has been widely validated internally and externally in studies with adequate sampling (33). Our analyses were robust and included subgroup analyses; moreover, they included the most current and largest sample of patients with STEMI with cardiogenic shock and provides insight into the practice patterns and impact of multivessel PCI in the real world, confirming the findings of the CULPRIT-SHOCK trial.

Conclusion
In this national analysis of STEMI hospitalizations with and without cardiogenic shock, we found a significant decrease in the performance of multivessel PCI for STEMI both with and without cardiogenic shock in the US from 2015 to 2019. In STEMI admissions without cardiogenic shock, PCI of no more than 1 non-culprit vessel can be safely performed during the index hospitalization. However, in STEMI with cardiogenic shock, multivessel PCI during the index hospitalization was associated with increased risks of in-hospital mortality and MACCE. Further study is needed to determine whether patients with STEMI with cardiogenic shock benefit from staged multivessel PCI, and the optimal procedure time thereof.

Data availability statement
The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

Ethics statement
Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.