Article Text
Abstract
Objectives The aim of the present study was to assess the outcome of patients with acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) receiving drug-eluting stents (DES) compared with bare-metal stents (BMS). Data comparing these two stent technologies in AMI with CS were limited.
Methods A total of 783 patients with AMI and CS undergoing early revascularisation were included in the randomised Intra-aortic Balloon Pump in Cardiogenic Shock II trial (n=600) and the associated registry (n=183). Patients receiving no stent or both, DES and BMS, were excluded. Primary end point was the composite of 1-year mortality or re-AMI.
Results Of the total cohort, 652 (83%) patients received either solely DES or BMS and were included in the present analysis. Of these, 276 (42%) patients received DES and 376 (58%) received BMS. After adjustment for baseline characteristics, there was no significant difference between DES and BMS regarding the primary end point (HR 0.83 (CI 0.64 to 1.06); p=0.14). There was an independent association of BMS use with older age, atrial fibrillation and coronary single-vessel disease. DES use was associated with prior known dyslipidaemia, baseline haemoglobin level, anterior AMI and treatment at frequently enrolling centres.
Conclusions Despite the frequent use of DES nowadays, a substantial number of patients were treated by BMS in AMI complicated by CS. After adjustment for risk factors, the 1-year outcome of patients treated by DES compared with BMS was similar.
Trial registrationnumber www.clinicaltrials.gov: NCT00491036.
- Percutaneous coronary intervention
- Acute myocardial infarction
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Introduction
The pivotal Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock (SHOCK) trial demonstrated that an early invasive strategy with revascularisation should be the standard treatment of acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) as percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) improved the long-term survival when compared with early conservative therapy only.1 Mainly based on the long-term data of the Comparison of Biolimus Eluted From an Erodible Stent Coating With Bare Metal Stents in Acute ST-Elevation Myocardial Infarction (COMFORTABLE AMI)2 and Everolimus-Eluting Stents Versus Bare-Metal Stents in ST-Segment Elevation Myocardial Infarction (EXAMINATION) trials,3 current European guidelines recommend the use of drug-eluting stents (DES) over bare-metal stents (BMS) in AMI regardless of presentation with ST-elevation or non-ST-elevation infarction.4 In contrast, current US guidelines do not recommend a preference for DES in AMI.5 6
Patients with CS are largely under-represented in these trials. The superiority of DES is predominantly based on a reduction in long-term target vessel reinfarction and target vessel revascularisation.2 3 Due to the lack of data and to the very high hospital mortality rate of approximately 40% in AMI complicated by CS,7 rather related to severity of CS and comorbidities than to stent type, there is uncertainty regarding the benefit of DES in this setting.8 Therefore, BMS use is not uncommon in patients with AMI and CS. Unfortunately, with only two small single-centre non-randomised analyses available in the literature comparing both stent types, the evidence in this field is very limited.9 10
The aim of this work is to assess the rates of patients either receiving DES or BMS and the outcome of the two treatment strategies in the particular setting of AMI with CS. This analysis will also determine independent predictors for BMS use.
Materials and methods
Study design and population
The present study is a retrospective analysis of the open-label multicentre randomised Intra-aortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II; clinicaltrials.gov identifier: NCT00491036) trial, which randomised 600 patients with CS complicating AMI undergoing early revascularisation in 1:1 ratio to therapy with or without IABP and its accompanying registry. The design, inclusion and exclusion criteria, and outcome of the trial have been published previously.11–13 CS was defined by a systolic blood pressure <90 mm Hg for >30 min or inotropes requirement to maintain a systolic blood pressure >90 mm Hg in the absence of hypovolaemia, signs of pulmonary congestion and signs of impaired organ perfusion with at least one of the following: (1)altered mental status, (2)cold, clammy skin, (3) urine output <30 mL/h or (4) serum lactate >2 mmol/L. All patients were planned to undergo early revascularisation using primary PCI or CABG and to receive optimal medical treatment according to current guidelines.
Patients with AMI complicated by CS who met any exclusion criterion of the randomised IABP-SHOCK II trial were enrolled into an associated registry (183 patients). Therefore, a total of 783 patients out of the original intention-to-treat trial and its associated registry treated from 2009 until 2012 were available for the current analysis. Exclusion criteria of the present analysis were primary conservative treatment, primary CABG, balloon angioplasty only and the use of both BMS and DES in one patient. Primary PCI was performed immediately after hospital admission with all issues beside IABP insertion left at the discretion of the interventionalist including type of stents used.
Clinical follow-up was performed at 1, 6 and 12 months following the procedure.
Written informed consent was obtained from all patients or their legally authorised representatives. The trial was approved by the ethics committee and it complied with the Declaration of Helsinki.
End points
Primary end point for this analysis was defined as composite of mortality and re-AMI within 12 months after randomisation. Secondary end point was all-cause mortality after 12 months. In patients surviving the first 3 days after a randomisation landmark analysis with respect to the primary end point was performed. As further secondary outcomes, in-hospital adverse events such as stroke, implantation of an active assistant device, sepsis, need for dialysis, vascular complications and bleeding complications according to the Global Use of Strategies to Open Occluded Arteries definition were prospectively assessed.
Statistical analysis
The population was divided into two groups according to the implantation of either DES or BMS. Categorical variables were expressed as numbers and percentages. Continuous variables were expressed as median with IQRs. For comparison between both stent groups Χ2 and Mann-Whitney U test were performed for categorical and continuous variables, respectively.
For assessment of 1-year outcome, time-to-death or AMI analysis by Kaplan–Meier method with log-rank testing was used. If entities of the combined end point occurred in one patient, the first was counted. To identify independent predictors for the primary end point, a Cox regression model was built including the following variables: age, gender, prior stroke, known peripheral artery disease, diabetes mellitus, arterial hypertension, dyslipidaemia, prior use of vitamin-K antagonists, mechanical ventilation at admission, need for cardiopulmonary resuscitation, mean arterial blood pressure at admission, body temperature at admission, arterial serum lactate at admission, serum creatine at admission, serum creatine kinase at admission, haemoglobin at admission, atrial fibrillation on admission ECG, anterior AMI on admission ECG, culprit lesion in left anterior descending or left main coronary artery, single-vessel disease and thrombolysis in myocardial infarction (TIMI) flow III after PCI. The expected survival curves were adjusted for the significant covariates from the Cox proportional hazard model and presented for a standard patient (70 years old, serum lactate 5 mmol/L, serum creatine 100 µmol/L, multivessel coronary artery disease, no history of stroke and successful PCI). The reported Χ² in the Cox regression model is based on a likelihood ratio test. Furthermore, a logistic regression analysis was performed using the same variables except for TIMI flow to point out predictors for the use of DES. In this analysis, it was also tested whether the status of a high volume centre (defined as the four leading sites with regards to the number of enrolled patients) had an influence on stent selection. For selection of the final model in Cox and logistic regression analyses, stepwise parameter selections were used. The level for entry and elimination of variables was 0.05.
All p values were calculated by two-tailed tests and statistical significance was defined at p<0.05. Statistical analysis was performed by an independent statistician at the Institut für Herzinfarktforschung, Ludwigshafen, Germany using SAS version 9.3 (Cary, North Carolina, USA).
Results
Baseline characteristics
Of 783 patients with AMI and CS enrolled in the IABP-SHOCK II trial and the associated registry, 652 (83%) patients received either solely DES or BMS and were included in the present analysis. Of these, 276 (42%) patients received DES and 376 (58%) received BMS. The study flow is illustrated in figure 1.
Patients in whom a DES was implanted were younger, more often male, and suffered more frequently from dyslipidaemia (table 1). Furthermore, they presented more often with anterior AMI and showed less often atrial fibrillation on admission ECG. With respect to the severity of CS, patients with a DES implanted had a higher mean arterial pressure prior to PCI and tended to have a lower serum lactate (table 1).
Procedural data
In accordance with the admission ECG, the culprit lesion was localised more often in the left main coronary artery among patients in the DES group. In contrast, the right coronary artery was more often identified as culprit lesion in patients undergoing BMS implantation (table 2). There was a higher rate of thrombus aspiration use and administration of glycoprotein IIb/IIIa inhibitors in patients with DES. Furthermore, multivessel PCI was more often preformed in the DES group. Restoration of TIMI flow III after PCI was achieved more often in the DES group (table 2). No significant difference regarding IABP use was detected between both groups (table 2).
Patients treated by DES received more often prasugrel/ticagrelor instead of clopidogrel comparedwith patients treated by BMS (table 2).
Hospital outcome
Hospital complications (defined as complications occurring within 30 days following hospital admission) are displayed in figure 2. Patients with implanted DES had a higher rate of ventricular assist device implantation and a lower stent thrombosis rate. There was no significant difference in both severe and moderate bleeding.
Mortality and myocardial infarction
The unadjusted rate of the primary end point (composite of 1-year mortality and re-AMI) was higher in the BMS group compared with the DES group (figure 3A). Similarly, unadjusted all-cause mortality at 1 year was higher in patients treated with BMS (figure 3B). A landmark analysis assessing the primary end point from day 3 continued to show an increased rate of the composite of 1-year mortality or re-AMI in the BMS group (figure 3C). After adjustment for baseline risk factors, there was no significant difference between both groups regarding the primary end point (figure 3D).
The 1-year rate for non-fatal AMI showed no significant difference between both groups (5.1% in DES vs 7.0% in BMS; p=0.48). This remained unchanged after including fatal AMI (total rate of AMI 7.0% in DES vs 8.9% in BMS; p=0.53).
Cox regression analysis revealed age, prior stroke, baseline serum lactate and baseline creatine as independent predictors for the primary end point. Single-vessel coronary artery disease and TIMI flow III after PCI were inversely associated with the primary end point (table 3).
Factors influencing stent type use
Increasing age, atrial fibrillation on admission ECG and coronary single-vessel disease were independently associated with BMS use. Dyslipidaemia, increasing baseline haemoglobin level, treatment at frequently enrolling centres and anterior AMI were found to be significant predictors for DES use (figure 4).
Discussion
The present predefined substudy of the IABP SHOCK II trial represents the largest and first multicentre analysis comparing BMS versus DES in the setting of AMI complicated by CS. The main finding was that a large percentage of patients received BMS implantation (58%) and that BMS provided similar results compared with DES with regards to the primary end point of 1-year mortality or re-AMI after adjustment for baseline risk factors. Another important finding is that DES are safe in patients with CS with no increase in acute or subacute stent thrombosis.
Proportion of BMS and DES use
Since data revealed an increased risk for very late stent thrombosis with first-generation DES beyond 1-year following implantation,14–16 BMS continued to serve as an established revascularisation strategy in AMI. A large observational US trial showed an increase in BMS use from 21% to 39% and a decline in DES use from 65% to 46% in the setting of AMI complicated by CS during a period from 2005 to 2013.8 This is presumably based on delayed vessel healing and increased endothelial inflammation caused by the first-generation DES polymer.17 Particularly in the setting of ST-elevation myocardial infarction (STEMI), which is characterised by high thrombogenicity and inflammation, these DES characteristics may promote stent thrombosis. Therefore, the high proportion of patients with BMS implantation in the present analysis (enrollment from 2009 to 2012) is not surprising. In recent years, technical progress in second-generation DES contributed to a slightly lower risk for stent thrombosis compared with BMS in the setting of AMI.18 Improvements in platform technology (bioabsorbable polymer or polymer-free stents, lower profile of stent struts) and development of new antiproliferative agents (everolimus, zotarolimus, biolimus) helped to reduce the risk for stent thrombosis. However, despite mainly used, results of randomised second-generation DES trials in the setting of AMI were not available at the time of patient enrollment in the present trial.
Stent type dependent outcome
In the unadjusted analysis of the present report, the BMS group had a higher rate for the primary end point. To prove if the difference in 1-year mortality and re-AMI between both groups mainly originated in the very early phase of the index event, a landmark analysis assessing the outcome after day 3 was performed. The Kaplan-Meier curves still continued to diverge after the first 3 days. The difference was indeed attenuated but it remained significant during the further follow-up period. This clearly demonstrated that potential benefits of DES may come evident beyond the acute phase of CS.
It must be assumed that older age and higher comorbidity in the BMS group partly led to the impaired outcome at 1 year. Furthermore, a less frequent use of prasugrel or ticagrelor instead of clopidogrel in the BMS group might also contribute to the poor prognosis of those patients. A major influence of stent type on the 1-year result appears to be unlikely as the difference in outcome predominantly accrued during the first 30 days. In this period, superiority of DES over BMS is implausible as the beneficial effect of DES is mainly based on a reduction in long-term target vessel reinfarction and repeat target vessel revascularisation. However, these advantages did not translate into improved mortality at 1 year.19 20 Similarly, the recently published Norwegian Coronary Stent Trial showed a comparable rate of mortality or re-AMI in patients treated with BMS versus DES in the overall and STEMI population.21 Importantly, the rate for re-AMI was similar for the two stent types in the present analysis. Congruent with that, the Cox regression model showed no association of DES use and the primary end point. However, the upper margin of the CI was just above 1. Therefore, statistical significance might be reached with a larger study population.
Age, prior stroke, baseline serum creatine and baseline serum lactate were independent predictors for the composite of mortality and re-AMI, and single-coronary vessel disease as well as TIMI flow III after PCI was inversely associated with poor outcome. These results further highlight comorbidity, severity of CS and restoration of myocardial perfusion—independent from stent type—to be the main influencing factors for outcome after AMI complicated by CS. In light of the present results, the beneficial effect of DES with respect to target vessel failure observed in AMI without CS seems to play a minor part when AMI is complicated by CS, which is also in line with a recent study by Champion et al.10 However, Jaguszewski et al 9 reported a poorer outcome of BMS compared with DES. In their analysis, the main difference again arose within the first 30 days so that comorbidity and CS severity rather than stent selection might have driven their findings. Yet, we cannot rule out a possible difference at longer follow-up beyond 1 year and with a larger population tested.
Predictors for stent selection
Newly developed polymer free DES (Prospective Randomized Comparison of the BioFreedom Biolimus A9 Drug Coated Stent Versus the Gazelle Bare Metal Stent in Patients With High Risk of Bleeding)22 and shortened period of dual antiplatelet therapy in zotarolimus-eluting DES (Zotarolimus-eluting Endeavor sprint stent in Uncertain DES candidates)23 24 may provide better results than BMS also in patients with increased bleeding risk in the setting of stable coronary artery disease, yet no data exist about these new devices in CS. In the logistic regression model atrial fibrillation was found to be associated with BMS use, whereas higher baseline haemoglobin predicted DES use. These factors for increased bleeding risk might promote BMS use due to the potential to shorten dual antiplatelet therapy. In addition, increasing age was associated with BMS use in the present trial which is also seen elsewhere in the literature. The age-dependent selection of stent type is probably reasoned by the results of the COMFORTABLE AMI and EXAMINATION trial which did not show superiority of DES over BMS in patients>65 years19 and >75 years,3 respectively. Single vessel disease predicting BMS use in the present analysis is probably explainable by the higher risk for restenosis with BMS.3 19 This risk is markedly elevated with increasing number of stents implanted per patient. With regards to coronary disease complexity, ESC guidelines for PCI from 2005 did not recommend DES use in several scenarios including AMI.25 With improvements in DES over time, however, high enrolling centres possibly reacted earlier to the technical developments and forced the use of DES in a wider range of indications including AMI. This would explain high enrolling centres being a predictor for DES use in our analysis.
Limitation
Due to the character of a retrospective non-randomised analysis, certain bias with regards to stent selection must be assumed. Although we performed an adjustment for several risk factors, validity of the data still needs to be proven in a prospective randomised trial. As the number of patients enrolled is slightly lower than other large STEMI trials without CS, the size of the population may not provide sufficient statistical power. Based on the HR of 0.83 and a statistical power of 80% at a two-sided alpha level of 5%, a total of 904 patients would be needed. We did not collect information regarding target vessel or target lesion failure. Hence, a possible influence of stent type on this end point could not be evaluated. Since no data regarding specific stent models were recorded, the proportion of first and second-generation DES remained unknown in the present population. As a result, an outcome analysis depending on first compared with second-generation DES was not possible. Nevertheless, it must be assumed that mainly second-generation DES were used based on the period of time when patients were recruited. As follow-up is restricted to only 1 year, a difference in outcome beyond this period is unknown.
Conclusion
Despite the increasing use of DES in stable patients, a substantial number of patients were actually treated by BMS in the particular setting of AMI complicated by CS. After adjustment for risk factors, no significant difference regarding the 1-year outcome of patients treated by DES compared with BMS was evident. It remains questionable if the superiority of DES gained in other settings such as stable coronary artery disease or acute coronary syndrome can be simply transferred to AMI complicated by CS. To ulimately resolve this uncertainty, further prospective randomised trials would be needed. This would help to clarify if DES have the potential to improve the outcome in patients with AMI complicated by CS, at least in survivors of the hospital period.
Key messages
What is already known about this subject?
Very few data regarding the comparison between drug-eluting stents (DES) and bare-metal stents (BMS) in acute myocardial infarction (AMI) complicated by cardiogenic shock (CS) are available and rates of BMS use are still above 50% in this setting.
What does this study add?
The present trial is the largest and only multicentre trial assessing this issue. In univariable analysis, DES use was associated with a better survival and lower rates of reinfarctions. After adjustment, the difference between DES and BMS did not reach significance.
How might this impact on clinical practice?
DES use seems to be safe and at least equal to BMS in AMI complicated by CS. Taken the superiority of DES in other settings (acute coronary syndrome without CS or stable coronary artery disease), more data are required to assess the performance of DES versus BMS in AMI complicated by CS.
References
Footnotes
Contributors JL, GF: manuscript writing, analysis and interpretation of the data, statistical analysis, conception and design of study. SD, GS, IE, KW, UZ, HT: revising the manuscript critically for important intellectual content, analysis and interpretation of the data, conception and design of study. CJ, SW, JP, SS: revising the manuscript critically for important intellectual content, analysis and interpretation of data.
Funding The trial was supported by grants from the German Research Foundation, the German Heart Research Foundation, the German Cardiac Society, Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte, the University of Leipzig Heart Center and by unrestricted grants from Maquet Cardiopulmonary as well as Teleflex Medical.
Competing Interests None declared.
Provenance and peer review Not commissioned; externally peer reviewed.