Abstract
Background In current international guidelines the recommendation for intra-aortic balloon pump (IABP) use has been downgraded in cardiogenic shock complicating acute myocardial infarction on the basis of registry data. In the largest randomised trial (IABP-SHOCK II), IABP support did not reduce 30 day mortality compared with control. However, previous trials in cardiogenic shock showed a mortality benefi t only at extended follow-up. The present analysis therefore reports 6 and 12 month results. Methods The IABP-SHOCK II trial was a randomised, open-label, multicentre trial. Patients with cardiogenic shock complicating acute myocardial infarction who were undergoing early revascularisation and optimum medical therapy were randomly assigned (1:1) to IABP versus control via a central web-based system. The primary effi cacy endpoint was 30 day all-cause mortality, but 6 and 12 month follow-up was done in addition to quality-of-life assessment for all survivors with the Euroqol-5D questionnaire. A masked central committee adjudicated clinical outcomes. Patients and investigators were not masked to treatment allocation. Analysis was by intention to treat. This trial is registered at ClinicalTrials.gov, NCT00491036. Findings Between June 16, 2009, and March 3, 2012, 600 patients were assigned to IABP (n=301) or control (n=299). Of 595 patients completing 12 month follow-up, 155 (52%) of 299 patients in the IABP group and 152 (51%) of 296 patients in the control group had died (relative risk [RR] 1·01, 95% CI 0·86-1·18, p=0·91). There were no signifi cant diff erences in reinfarction (RR 2·60, 95% CI 0·95-7·10, p=0·05), recurrent revascularisation (0·91, 0·58- 1·41, p=0·77), or stroke (1·50, 0·25-8·84, p=1·00). For survivors, quality-of-life measures including mobility, self-care, usual activities, pain or discomfort, and anxiety or depression did not diff er signifi cantly between study groups. Interpretation In patients undergoing early revas cularisation for myocardial infarction complicated by cardiogenic shock, IABP did not reduce 12 month all-cause mortality. Funding German Research Foundation; German Heart Research Foundation; German Cardiac Society; Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte; University of Leipzig-Heart Centre; Maquet Cardiopulmonary; Teleflex Medical.
| Original language | English |
|---|---|
| Journal | The Lancet |
| Volume | 382 |
| Issue number | 9905 |
| Pages (from-to) | 1638-1645 |
| Number of pages | 8 |
| ISSN | 0140-6736 |
| DOIs | |
| Publication status | Published - 01.01.2013 |
Funding
In this prospective, randomised trial of patients with cardiogenic shock complicating acute myocardial infarction, IABP support did not increase 6 and 12 month survival compared with control, supporting the short-term 30 day follow-up data ( ). Despite early revascularisation and optimum medical therapy in both groups, mortality was still slightly higher than 50% at 1 year follow-up. Nevertheless, for survivors, the self-reported quality of life was moderate to good. panel There are several possible explanations for the absence of benefit. Although experimental and clinical studies have shown haemodynamic improvements with IABP, its effect on cardiac output is only modest with an absolute increase in cardiac output of 0·5 L/min. 6 Furthermore, most trials investigating haemodynamic IABP effects had no control group. 6 In the IABP-SHOCK I randomised pilot trial, no significant differences between IABP and control were observed in cardiac power output, left ventricular stroke work index, and systemic vascular resistance. 20 Interestingly, there was a significant increase in cardiac power output, a haemodynamic measure correlating well with mortality, 21 in both groups indicating that initial haemodynamic improvements might be more affected by revascularisation as well as fluid and inotropic optimisation than by IABP effects. Notably, however, there is currently no evidence that the use of catecholamines, levosimendan, fluids, or assist devices leads to improved survival. In IABP-SHOCK II, no detailed haemodynamic monitoring data were available. However, there were no effects on markers of systemic inflammation or serum lactate as a measure of tissue hypoxia, thereby providing pathophysiological explanations for the lack of mortality benefit. 11 The results were fairly consistent for all subgroups studied except for patients without a history of hypertension. However, data for any subgroup, in particular in a negative trial, are only hypothesis-generating. Furthermore, the results of the current trial with its long-term follow-up are in line with previous registry data in the PCI era and two small randomised trials in the fibrinolytic and PCI era, which were all negative for surrogate and combined clinical endpoints. 7,19,22 We cannot entirely rule out the possibility that a potential beneficial effect of IABP on clinical endpoints is confined to patients in whom the support was started before revascularisation. 23 Mortality did not differ significantly between patients in whom IABP was started before and after revascularisation. However, pre-PCI IABP was done in less than 15% of patients and therefore no definitive conclusions can be drawn. Currently, data from observational studies are conflicting with one small retrospective registry trial in 48 patients with cardiogenic shock showing a benefit of pre-PCI implantation, 23 whereas in a more recent trial in 173 patients, IABP insertion before PCI led to increased creatine kinase concentrations and had no effect on mortality. 24 A negative trial usually raises a question of power. Although we cannot definitively rule out a type II error, the absolute difference of only 0·4% in mortality rates between the groups together with the lack of benefit for any of the other outcome variables and a trend towards more recurrent infarctions in the IABP group compared with control make any clinically meaningful positive effect of IABP unlikely. The event rate in the control group was lower than the value initially used in the sample size calculation (41·3% vs 56·0%), which might have further affected statistical power. In the current trial there was an additional absolute 10% mortality increase at 12 months by comparison with the 30 day results. This difference is slightly higher by comparison with the only other large randomised cardiogenic shock trial that reported long-term follow-up (SHOCK trial), which had mortality rates of 46·7% at 30 days and 53·3% at 12 months in the early revascularisation group. 3,12,13 These data confirm that mortality in cardiogenic shock is mainly determined in the early phase, although the risk of death is still substantial after the acute phase. Functional status for survivors is relatively good. Similar to the SHOCK trial, about 90% of survivors were in NYHA class I/II. 13 In the current trial, more detailed quality of life assessment was done with a standardised questionnaire. Health-related quality of life states consisting of five dimensions and a visual analogue scale were similar to a general population survey. 25 The absence of a survival benefit at long-term follow-up in the present study contrasts with the SHOCK trial and is probably explained by the different interventions. Revascularisation might have long-term mortality effects by salvaging myocardium, whereas IABP support does not have an effect on myocardial damage. 26 The fairly low rate of ICD implantations of 10% might be explained by a survivor selection bias and reflects the favourable functional status of survivors. Patients surviving might have left ventricular function at follow-up above established cutoff criteria for ICD implantation. In IABP-SHOCK II, no additional information about left ventricular function and remodelling at follow-up was available. Risk of death varied substantially among patients with cardiogenic shock complicating myocardial infarction. An objective and readily available measure to assess mortality risk for individual patients is crucial to guide treatment. However, no easy score for risk prediction is currently available and used in clinical practice. Several previous analyses revealed different clinical, laboratory, angiographic, and haemodynamic measures as predictors mainly for short-term but also partly for long-term mortality in patients with cardiogenic shock undergoing early revascularisation by PCI. 12,27–30 In the current analysis, outcome predictors were similar to those in previous analyses including age, history of stroke, oliguria, left bundle branch block, and creatinine concentration. Of note, the readily available baseline serum lactate indicating the severity of end-organ hypoxia was one of the strongest predictors of long-term mortality. Previous trials in cardiogenic shock did not measure serum lactate systematically and the measure was therefore not used in multivariable modelling. Baseline serum lactate together with age and oliguria might therefore be integrated in mortality risk assessment in clinical practice. This study has several strengths, including its size, multicentre design, recruitment of a broad risk, real world population managed with current, guideline-supported drugs and interventional techniques, and near complete clinical follow-up. In view of the broad inclusion criteria less than a quarter of initially screened patients were not eligible for the trial, suggesting broad generalisability of the results in interventionally treated patients with cardiogenic shock. Owing to the low number of surgically treated patients the effects of IABP might not be applicable to patients undergoing immediate bypass surgery. Masking of treatment allocation was not possible because of the nature of the intervention. However, several methods to avoid bias were implemented, such as a central randomisation system, a masked clinical event committee, and high standard requirements concerning the experience of centres and investigators. In conclusion, this randomised, multicentre trial showed that IABP support did not reduce 12 month mortality in patients with cardiogenic shock complicating myocardial infarction undergoing early revascularisation. Quality of life was good for survivors of cardiogenic shock at 6 and 12 months. For more on EuroQol see http://www.euroqol.org Contributors HT, UZ, KW, and GS designed the study, analysed and interpreted data, and revised the report. SD, IE, GF, and all other authors contributed to implementation of the study, enrolment and follow-up of patients, and reviewed the report. SS did all statistical analysis. HT wrote the first draft and submitted the final version of the report. All authors have seen the final submitted Article and agree with its contents. Conflicts of interest HT reports receiving consulting fees from Lilly, grant support on behalf of his institution from Lilly and Terumo, and lecture fees from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Lilly, the Medicines Company, and Terumo. JH reports receiving lecture fees from Siemens and Abbott Vascular, and grant support from Siemens. SD reports receiving consulting fees from Osprey Medical and AstraZeneca and lecture fees from Boehringer Ingelheim, Bayer, Maquet, and Terumo. MB reports receiving consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Medtronic, MSD, Novartis, Pfizer, Sanofi-Aventis, and Servier, and lecture fees from AstraZeneca, AWD Dresden, Bayer, Berlin Chemie, Boehringer Ingelheim, Daiichi Sankyo, MSD, Novartis, Pfizer, Sanofi-Aventis, and Servier. GR reports receiving lecture fees from Maquet Cardiovascular. SS reports holding a board membership on the ethics committee of Landesärztekammer Baden-Württemberg, receiving payment for manuscript preparation by Biosense Webster, Grupo Ferrer, and Nycomed, and money received on behalf of his institution's clinical research organisation from Abbott Vascular, AstraZeneca, Bayer Schering, Bayer Vital, Biotronik GmbH, Bristol-Myers Squibb, Boehringer Ingelheim, Cordis, Daiichi Sankyo, Diagenics GmbH, Enverdis, Lilly, GlaxoSmithKline, Guidant, IKKF GmbH, Impulse Dynamics, Medtronic, Merck & Co, MSD, Novartis GmbH, Roche Diagnostics, Sanofi-Aventis, Schering-Plough, Siemens AG, St Jude Medical, Takeda Pharma, Trommsdorff GmbH, and Vifor Pharma. UZ reports holding board membership at Daiichi Sankyo and Lilly, and receiving consulting and lecture fees from Daiichi Sankyo, Lilly, and the Medicines Company. KW reports holding board membership at Biotest and Servier, receiving grant support on behalf of his institution from Biotest and Servier, and lecture fees from Biotest, Brahms, Maquet Cardiovascular, and Servier. We declare no other potential conflicts of interest relevant to this Article. Acknowledgments We thank the patients who agreed to participate in this trial, the study contributors, and the investigators recruiting patients (listed in the appendix ). The trial was supported by the German Research Foundation, the German Heart Research Foundation, the German Cardiac Society, Arbeitsgemeinschaft Leitende Kardiologische Krankenhausärzte, and University of Leipzig—Heart Centre, and also partly funded by unrestricted grants from Maquet Cardiopulmonary, Hirrlingen, Germany, and Teleflex Medical, Everett, MA, USA.
Research Areas and Centers
- Academic Focus: Center for Brain, Behavior and Metabolism (CBBM)
