Intra‐aortic balloon pump counterpulsation (IABP) for myocardial infarction complicated by cardiogenic shock
Abstract
This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:
The primary aim of this review is to evaluate, in terms of efficacy and safety, the effect of intra‐aortic balloon pump counterpulsation (IABP) on mortality and morbidity in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock.
Background
Description of the condition
Worldwide, cardiovascular disease is estimated to be the leading cause of death and loss of disability‐adjusted life years (Murray 1996). Each year approximately 920,000 people in the United States experience acute myocardial infarction (AMI), and about 150,000 of them die. 5.1% of all males and 2.5% of females experienced AMI. The estimated direct and indirect 2008 cost of coronary hart disease (ICD/10 codes I20‐I25) was $156.4 billion (AHA 2008). In the United Kingdom about 227,000 heart attacks (myocardial infarctions) occur annually. It is estimated that about 1 million people over 35 years old, living in the United Kingdom, have had a myocardial infarction (BHF 2007). Data from the INTERHEART study showed that rates of cardiovascular disease have risen greatly in low‐income and middle‐income countries with about 80% of the global burden of cardiovascular disease occurring in these countries (Yusuf 2004).
Acute myocardial infarction is complicated by cardiogenic shock in 7‐10% of cases (Hochman 1999; Goldberg 1999). Cardiogenic shock after AMI is a complex syndrome that involves a cascade of acute left ventricular dysfunction, decreased cardiac output, hypotension, and tissue hypoperfusion (Hochman 2007). Subsequently, complicating multi‐organ dysfunction might occur due to ischemia/reperfusion and the following inflammatory response. Clinically defined, cardiogenic shock is decreased cardiac output and evidence of tissue hypoxia in the presence of adequate intravascular volume. Hemodynamic criteria include sustained hypotension (systolic blood pressure < 90 mmHg for at least 30 minutes) and a reduced cardiac index (< 2.2 L/min/m2) in the presence of elevated pulmonary capillary occlusion pressure (> 15 mmHg) (Forrester 1976a; Forrester 1976b). Patients with sustained hypotension, suspected cardiogenic shock or suspected acute heart failure at the time of acute myocardial infarction are at increased risk for mortality, approaching 30 to 70 % mortality within 30 days (Ohman 2005) and fewer than 50% patients with CS survive up to 1 year (Hochman 2007).
The poor outcome associated with medical management of cardiogenic shock has spurred more aggressive interventional approaches, including thrombolysis, intra‐aortic balloon support and early diagnostic angiography with percutaneous coronary revascularisaton (PCI) (Ohman 2005). Early mechanical revascularisation, using either percutaneous coronary intervention or coronary artery bypass graft (CABG) surgery, along with supportive care, improves short‐term survival in these patients when compared with initial medical stabilisation (Hochman 2001).
Description of the intervention
Aortic counterpulsation (intra‐aortic balloon pump (IABP)) was introduced in 1968 into clinical practice (Kantrowitz 1968) as a means for supporting patients undergoing surgical revascularisation. Initial experience documented that this device had important physiologic effects including an improvement of cardiac function and diastolic blood pressure and a reduction in systemic acidosis. More recently, several investigators have also shown enhanced coronary, cerebral and renal perfusion (even microperfusion) with IABP, particularly among patients having percutaneous transluminal coronary angioplasty during cardiogenic shock. However, this impressive physiological profile has not been followed by equally important randomised clinical trial data (Ohman 2001).
Although the incidence of complications is difficult to determine because of differing definitions, they are most likely decreasing as techniques, equipment, and experience improves. Studies reporting complication rates are diverse in terms of the indications for aortic counterpulsation, the technique used for insertion (surgical or percutaneous), the duration of use, and the specific definition of a complication. The presence of peripheral arterial disease (including a history of claudication, femoral bruit, or absent pulses) has been the most consistent and reproducible predictor of complications (Santa‐Cruz 2006). Arafa 1999 reported major vascular complications (limb ischemia, aortic dissection, abdominal aorta perforation, bilateral limb ischemia) in 8 %, minor vascular complications (hematoma requiring operative revision, hemorrhage treated by IABP‐removal, limb ischemia relieved by IABP‐removal, local infection and ischemic skin loss) in 3 % and late vascular complications in 2 % (foot drop, pseudoaneurysm, limb ischemia) of patients.
Why it is important to do this review
IABP is currently the most commonly used mechanical assist device for patients with cardiogenic shock. Its use is encouraged by a class I recommendation in the American Heart Association (AHA)/American College of Cardiology (ACC) guidelines for the management of AMI patients with cardiogenic shock (Ryan 1999). The Level B evidence behind this recommendation can largely be attributed to pathophysiological considerations and benefits observed in registries that predominantly enrolled patients treated with thrombolytic therapy in the pre‐PCI era. There are still the controversial differences in therapeutic behaviour in the US and European countries with far greater use of IABP in the US than in Europe. In the US with the highest rate of IABP use, the mortality rate was significant lower than in European countries like the UK (Hudson 1999).
In the early 1980s two smaller randomised trials failed to show any benefit of IABP compared with control therapy on infarct size or left ventricular function in patients with cardiogenic shock (Flaherty 1985; O'Rourke 1981). Previous randomised trials of IABP in high‐risk patients without cardiogenic shock have suggested a lower morbidity, particularly among the patients with several high‐risk features (Ohman 1994; Stone 1997). These studies were too small to be able to address mortality, but directionally they favoured a better outcome with IABP treatment. Randomised trials of IABP in cardiogenic shock are clearly needed, and several have been attempted but have not been completed because of physician bias and difficulties in obtaining consent among critically ill patients (Ohman 2001).
Non‐randomised clinical studies have nearly uniformly shown a benefit associated with IABP for patients with cardiogenic shock. But patients receiving IABP are in general younger, have fewer comorbid illnesses, and are more aggressively treated with cardiac catheterisation and revascularisation compared with patients not treated with IABP which might be explained as selection bias (Hudson 1999; Sanborn 2000). However, data from other large, prospective registries suggest little benefit of IABP placement in cardiogenic shock patients treated with primary PCI (Barron 2001). One trial has even reported higher mortality rates associated with IABP use in this group of patients (Rogers 2000).
Based on recent publications it seems probable that not all patients in cardiogenic shock benefit from IABP therapy. Judith Hochman (Hochman 2003) introduced the component of inflammation and established a relationship to SIRS (systemic inflammatory response syndrome) and septic organ failure ‐ this leads to the question whether IABP may be beneficial in inflammatory conditions and whether IABP may accelerate systemic inflammation by continuous blood cell surface activation.
The systematic review by Field 2007 suggests that preoperative IABP use may be beneficial on mortality and morbidity in specific high risk patients groups undergoing coronary artery bypass surgery.
This review will assess whether IABP leads to a systematic reduction of mortality over all patients in cardiogenic shock. IABP‐insertion in critically ill patients is correlated with some risk complications and these potential risks can only be justified by an acceptable (evidence‐based) opportunity of measurable beneficial clinical effects in IABP‐treated patients. This could have implications for clinical practice by excluding patients from IABP‐therapy or alternatively by extending the indications for IABP treatment to include patients with huge myocardial infarction, and with an increased risk for the development of hemodynamic instability leading to cardiogenic shock.
Objectives
The primary aim of this review is to evaluate, in terms of efficacy and safety, the effect of intra‐aortic balloon pump counterpulsation (IABP) on mortality and morbidity in patients with acute myocardial infarction (AMI) complicated by cardiogenic shock.
Methods
Criteria for considering studies for this review
Types of studies
Randomised and quasi‐randomised (Green 2005) controlled trials with or without blinding and any report of mortality that examined the effectiveness of IABP versus standard therapy will be included. Possible randomised designs are parallel group trials and factorial trials. Abstracts or unpublished data will be included only if sufficient information is available and are to be confirmed by contact with the first author. We will accept cross‐over studies.
Observational trials will be excluded.
Types of participants
Adult patients (from the age of 18) with a clinical diagnosis of myocardial infarction complicated by cardiogenic shock undergoing percutaneous coronary intervention, artery bypass graft surgery or thrombolysis.
Types of interventions
IABP versus non‐IABP or other assisting devices guideline compliant standard therapy. The term standard therapy describes guideline‐compliant therapies (percutaneous coronary intervention, coronary artery bypass graft surgery or thrombolysis, pharmacological haemodynamic and, as required ventilatory support). Three types of revascularisation will be distinguished:
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percutaneous coronary intervention;
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thrombolytic therapy; and
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coronary artery bypass graft surgery.
Types of outcome measures
Primary outcomes
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Overall mortality.
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Non‐fatal cardiovascular events (reinfarction, reocclusion, re‐revascularisation, stroke, recurrent ischemia), (hierarchical lower ranked endpoint).
Secondary outcomes
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Haemodynamics (cardiac index, mean arterial pressure, pulmonary capillary wedge).
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Length of hospital and intensive care unit (ICU) stay.
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Quality of life.
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All IABP‐related post‐interventional complications.
Search methods for identification of studies
Searches will be conducted in cooperation with the Cochrane Heart Group to identify published and unpublished randomised controlled trials. Searching for trials will continue throughout the duration of the project and include all information available since 1968 (introduction of IABP into clinical practice, Kantrowitz 1968) to the same (or similar) date. No language restrictions will be included in the search strategy.
Electronic searches
The search strategy for the review will be constructed by using a combination of subject headings and terms relating to the health condition of interest (myocardial infarction and cardiogenic shock), the intervention (intraaortic balloon counterpulsation) and the type of study design (randomized and quasirandomized trial). We will use controlled vocabulary terms and text words and search in the following sources of information:
1. Health‐related electronic bibliographic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library, MEDLINE, EMBASE, LILACS, IndMed and KoreaMed. Search strategies for CENTRAL and MEDLINE are in Appendix 1.
2. Search in registers of ongoing and completed trials:
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http://www.controlled‐trials
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http://www.nrr.nhs.uk
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http://www.centerwatch.com
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Benchmark registry (http://www.datascope.com/ca/pdf/benchmark2_brochure.pdf)
Searching other resources
Hand searching will include the annual conference proceedings of the following societies: American Heart Association (AHA), American College of Cardiology (ACC), European Society of Cardiology (ESC), European Society of Intensive Care (ESICM) and Deutsche Gesellschaft fur Kardiologie.
Members of the Cochrane Heart Group, experts in the field and manufacturers of the device will be contacted.
Data collection and analysis
Selection of studies
Studies identified through the searching strategy described above will be screened by titles. In a second step, two independent authors (one with knowledge in the area under review and one biometrician) will independently screen the abstracts and keywords of the chosen publications. Full articles will be taken into account for further assessment if the information given suggests that the study:
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includes patients with myocardial infarction complicated by cardiogenic shock;
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compares IABP versus non‐IABP guideline compliant standard therapy;
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uses random or quasi‐random allocation to the comparison groups.
After the exclusion of non‐relevant publications and duplicates, the full‐text versions of the remaining papers will be assessed against the inclusion and exclusion criteria and data will be extracted and entered into standardised data extraction forms. The selection process will be recorded in a QUOROM flow chart (Moher 1999).
Data extraction and management
Two authors will independently extract details of study population, interventions and outcomes by using a data extraction form, which will be designed especially for the topic of this review and tested in a pilot study. Differences in data extraction will be resolved by consensus with a third author, referring back to the original article. The data extraction form will include at least the following items:
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General information ‐ title, authors, source, contact address, country, published/unpublished, language and year of publication, sponsoring of trial;
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Trial characteristics ‐ including study design, timing/follow up, quality assessment as specified above;
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Patients ‐ inclusion and exclusion criteria, sample size, baseline characteristics, similarity of groups at baseline, withdrawals and losses to follow‐up;
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Interventions ‐ type of standard therapy and comparison assisting device; and
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Outcomes ‐ time to death (hazard ratios and their 95% confidence intervals), number of deaths and patients per group, mortality at specific time points (in‐hospital, 30 days, 6 months, 1 year and late mortality rates), other clinical event outcomes (reinfarction, reocclusion, re‐revascularisation, stroke, recurrent ischemia), hemodynamics (cardiac index, mean arterial pressure, pulmonary capillary wedge), length of hospital and ICU stay, doses of catecholamines (dobutamine, arterenol, dopamine), quality of life, IABP‐related post‐interventional complications.
As this review is planned as an individual patient‐data (IPD) meta‐analysis, first authors of all eligible trials will be contacted and asked to provide IPD. Analyses based on updated IPD represent both the only reliable and the most powerful method to calculate and compare times to death (Piedbois 2004).
Assessment of risk of bias in included studies
The review will analyse the results of randomised and quasi‐randomised trials. Two authors will independently assess the internal validity of eligible studies according to the risk of bias tool in RevMan 5 (Higgins 2008). Disagreements will be resolved by discussion until consensus is obtained.
Risk of bias will be described and judged in six specific domains:
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sequence generation;
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allocation concealment;
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blinding of participants, personnel, and outcome assessors;
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incomplete outcome data;
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selective outcome reporting; and
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other sources of bias (such as cross‐over in the trials).
The domains of sequence generation, allocation concealment and selective outcome reporting will be reported by a single entry for each study. For blinding and for incomplete outcomes data more entries will be used beause assessments generally need to be made separately for different (objective and subjective) outcomes. The description will ensure transparency in judgement and be based on the published study report which can be added by mixture of study reports, protocols, published comments on the study and contacts with the investigators. The judgements involve the answers 'yes' (indicates a low risk of bias), 'no' (indicates a high risk of bias) and 'unclear' (if risk of bias is unknown; or if an entry is not relevant to the study) according to table 8.5.c in Cochrane Handbook (Higgins 2008).
Measures of treatment effect
If possible, the meta‐analysis will be performed on the basis of individual patient data. Hazard ratios and their 95% confidence intervals for time to death as primary outcome measures will be calculated. In addition, Kaplan‐Meier curves with median survival, survival rates (in‐hospital mortality, 30‐day mortality; late mortality (6 months, 1 year)) and log rank statistics will be generated.
Dealing with missing data
If data were not available in the trial report or data collection the investigators will be approached to see if the missing data could be provided. Missing hazard ratios and 95% confidence intervals as relevant effect measures can be estimated directly or indirectly from the given data (Machin 1997; Parmar 1998).
Assessment of heterogeneity
Heterogeneity can be classified on statistical and clinical grounds by two independent reviewers. To test for statistical heterogeneity, although of limited power, Cochran´s Q‐test will be performed with the significance threshold of alpha = 0.1. Independently of the presence of statistical heterogeneity, if the differences in outcomes seem clinically important, possible causes will be assessed.
Assessment of reporting biases
Although every effort will be made to identify unpublished studies, publication bias will be assessed using funnel plots. It is acknowledged that asymmetry, of which publication bias is one cause, is difficult to detect with the small numbers of studies (i.e. less than 10) often encountered in systematic reviews.
Data synthesis
The analysis will be based on the intention‐to‐treat principle. The individual patient data should contain data from all randomised patients from all relevant studies. Analyses of individual patient data will be done using SAS software (Whitehead 2002). The meta‐analysis of the finalised individual patient data will be a two‐stage process. First, all trials will be analysed individually and finally a stratified Cox model of all trials with different baseline hazard functions in each single trial will be used to estimate the overall hazard ratio. The fixed‐effect model will be used for meta‐analysis of the relevant studies.
A forest plot will display effect estimates and confidence intervals for both individual studies and meta‐analyses.
IABP‐related post‐interventional complications and all secondary outcome measures will be analysed descriptively.
In case IPD are not provided for some studies, aggregate data and IPD will be combined (Riley 2007). To analyse only aggregate data the latest version of RevMan will be used.
Subgroup analysis and investigation of heterogeneity
Stratified analyses are planned for the prognostic factors age and sex (Menon 2000). In case of significant heterogeneity across studies the random‐effects model will be preferred.
If we are able to re‐evaluate the source data of the published RCTs addressing the issue of IABP treatment in cardiogenic shock, it would be of special interest to differentiate the degree of cardiogenic shock (or hemodynamic instability) according to the four groups of cardiogenic shock as defined below (Menon 2000):
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Group A: no congestion/no hypoperfusion;
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Group B: isolated pulmonary congestion;
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Group C: isolated hypoperfusion; and
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Group D: hypoperfusion with pulmonary congestion.
Because each group is correlated with a different mortality rate, there might be the opportunity to describe shock subgroups, which show different outcomes under IABP support. Is there a subgroup of cardiogenic shock patients that may receive more benefit (or harm) from IABP therapy than other subgroups?
Sensitivity analysis
Sensitivity analyses will be performed to explore the influence of including/excluding certain types of studies and the choice of the primary outcome on the treatment effect size. If there are sufficient data, a sensitivity analysis will investigate possible sources of heterogeneity as:
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standard therapy;
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pharmacological support;
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characteristics of IABP intervention;
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influence of cross‐over; and
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risk of bias in studies.
