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Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease logoLink to Journal of the American Heart Association: Cardiovascular and Cerebrovascular Disease
. 2015 Aug 17;4(8):e002204. doi: 10.1161/JAHA.115.002204

Outcome Reporting in Cardiac Surgery Trials: Systematic Review and Critical Appraisal

Michael Goldfarb 1, Laura Drudi 3, Mohammad Almohammadi 5, Yves Langlois 2, Nicolas Noiseux 7, Louis Perrault 8, Nicolo Piazza 6, Jonathan Afilalo 1,4
PMCID: PMC4599473  PMID: 26282561

Abstract

Background

There is currently no accepted standard for reporting outcomes following cardiac surgery. The objective of this paper was to systematically review the literature to evaluate the current use and definition of perioperative outcomes reported in cardiac surgery trials.

Methods and Results

We reviewed 5 prominent medical and surgical journals on Medline from January 1, 2010, to June 30, 2014, for randomized controlled trials involving coronary artery bypass grafting and/or valve surgery. We identified 34 trials meeting inclusion criteria. Sample sizes ranged from 57 to 4752 participants (median 351). Composite end points were used as a primary outcome in 56% (n=19) of the randomized controlled trials and as a secondary outcome in 12% (n=4). There were 14 different composite end points. Mortality at any time (all-cause and/or cardiovascular) was reported as an individual end point or as part of a combined end point in 82% (n=28), myocardial infarction was reported in 68% (n=23), and bleeding was reported in 24% (n=8). Patient-centered outcomes, such as quality of life and functional classification, were reported in 29% (n=10). Definition of clinical events such as myocardial infarction, stroke, renal failure, and bleeding varied considerably among trials, particularly for postoperative myocardial infarction and bleeding, for which 8 different definitions were used for each.

Conclusions

Outcome reporting in the cardiac surgery literature is heterogeneous, and efforts should be made to standardize the outcomes reported and the definitions used to ascertain them. The development of standardizing outcome reporting is an essential step toward strengthening the process of evidence-based care in cardiac surgery.

Keywords: cardiac surgery, outcomes, systematic review

Outcome measures vary between trials, particularly in the field of cardiac surgery, for which there is currently no widely accepted standard for reporting postoperative adverse events. The lack of uniformity has hindered the ability to compare and synthesize findings across different trials. Efforts to perform meta-analyses in cardiac surgery have often been impeded by the heterogeneity of pooled outcomes. Furthermore, generic composite outcomes traditionally used in cardiology such as major adverse cardiac events (MACE; death, myocardial infarction [MI] with or without revascularization) and major adverse cardiovascular and cerebrovascular events, or MACCE (death, MI, stroke), are neither designed nor adapted for cardiac surgery because they do not reflect other important postsurgical complications. The Society of Thoracic Surgeons (STS) has provided definitions of postsurgical complications and a surgery-specific composite outcome consisting of in-hospital death, stroke, prolonged ventilation, acute kidney injury, deep sternal wound infection, or reoperation1; however, the extent to which this composite outcome has been adopted for use in clinical trials is unknown. The appropriateness of combining adverse events with differing clinical impacts (eg, stroke and wound infection) has also been questioned.2

There is a pressing need to improve and homogenize outcome reporting in cardiac surgery, similar to what was successfully achieved in other fields such as the RIFLE classification3, the Bleeding Academic Research Consortium4 and the Transcatheter Valve Academic Research Consortium (VARC).5 The objective of this paper was to review the selection and definition of individual and composite outcomes reported in the recent body of randomized controlled trials in cardiac surgery. With this knowledge, stakeholders would be better equipped to develop recommendations for standardized outcome reporting adapted to cardiac surgery.

Methods

Search Strategy

The PubMed search string “Cardiac Surgical Procedures” (MeSH) AND “Randomized Controlled Trial” (Publication Type) was used to identify cardiac surgery randomized controlled trials published between January 1, 2010, and June 30, 2014. Our search was limited to 5 high-impact journals in general medicine, cardiovascular medicine, and cardiothoracic surgery6: New England Journal of Medicine, Circulation, Journal of the American College of Cardiology, Annals of Thoracic Surgery, and The Journal of Thoracic and Cardiovascular Surgery. Reference lists from retrieved manuscripts were hand searched to supplement the PubMed search.

Selection Criteria

Studies were included if the study design was randomized and the study population was undergoing coronary artery bypass grafting and/or heart valve repair or replacement surgery. Studies were excluded if the primary outcome was not a clinical event (eg, the primary outcome was a biomarker) or if the study population was pediatric or focused on congenital heart disease. Case reports, case series, editorials, reviews, and post hoc analyses of randomized controlled trial data were also excluded.

Data Extraction

For each article meeting inclusion criteria, the following variables were extracted: first author, journal, year of publication, trial name and registration, sample size, study population, intervention, control, primary outcomes, secondary outcomes, and duration of follow-up. In addition, the operational definitions used to ascertain MI, stroke, prolonged ventilation, acute renal injury, and bleeding were extracted. Patient-centered outcomes included postoperative pain, quality of life, mood, neurocognitive function, and New York Heart Association functional class. Health care resource utilization included hospital and intensive care unit length of stay and cost analyses.

Analysis

Studies were reviewed, and data were extracted in duplicate by 2 independent observers (M.G., L.D.); disagreements were resolved by consensus. The primary and secondary outcomes were represented in tabular format and summarized according to the number and proportion of randomized controlled trials reporting each outcome measure. The Stata 13 software package (StataCorp) was used to organize the extracted data and to prepare summary statistics.

Results

Of 190 potentially relevant trials, 34 met the selection criteria and were included in our systematic review (Figure 1). Included trials were evenly distributed among the journals searched (Table 1). Sample sizes ranged from 57 to 4752 participants (median 351; quartiles 1 to 3: 198 to 699). Overall, 26 trials involved coronary artery bypass grafting only, 5 involved valve repair or replacement only, and 3 involved a combination. The maximum duration of follow-up for outcome surveillance ranged from 5 to 14 days (median 7.5 days) in 6 trials, from 30 days to 1 year (median 365 days) in 19 trials, and was >1 year (median 1825 days) in 9 trials.

Figure 1.

Figure 1

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Flow diagram for search strategy. CABG indicates coronary artery bypass grafting.

Table 1.

Summary of Trials Meeting Inclusion Criteria

First Author Trial Name or Identifier Journal and Year N Intervention Control Primary Outcomes
Adams et al 201411 NCT01240902 NEJM 2014 795 TAVR SAVR Mortality (1 year)
Morice et al 201312 SYNTAX Circ 2014 1800 CABG PCI Composite: mortality, MI, CVA, revasc. (5 years)
Chocron et al 201313 MOTIV CABG ATS 2013 361 Escitalopram after CABG Placebo after CABG Composite: mortality, MI, low CO syndrome, ventilation >24 hours, reintubation, brain injury, delirium, AKI, pneumonia, sepsis, DSWI, heart failure, hospitalization, reoperation (1 year)
Diegeler et al 201314 GOPCABE NEJM 2013 2539 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA, AKI requiring dialysis, revasc. (30 days, 1 year)
Kamalesh et al 201315 VA CARDS JACC 2013 198 PCI CABG Composite: mortality, MI (2 years)
Karkouti et al 201316 NCT00914589 JTCS 2013 409 Recombinant factor XIII after cardiac surgery Placebo after cardiac surgery Blood transfusions (7 days)
Lamy et al 201317 CORONARY NEJM 2013 4752 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA, AKI requiring dialysis (30 days); Composite with revasc. (5 years)
Sezai et al 201318 UMIN000004537 ATS 2013 367 Carperitide during CABG Placebo during CABG Composite: mortality, MI, CVA, revasc., heart failure, hospitalization (1 year)
Shi et al 201319 NCT01596738 ATS 2013 120 Tranexamic acid during CABG Placebo during CABG Blood transfusions (perioperative)
Bokesch et al 201220 CONSERV-2 JTCS 2012 218 Tranexamic acid during CABG Ecallantide during CABG Composite: MI, blood transfusions, chest tube drainage, creatinine change (30 days)
Deja et al 201221 — JTCS 2012 390 Aspirin before CABG Placebo before CABG Blood loss and chest tube drainage (12 hours)
Desai et al 201222 — JTCS 2012 189 Strict glucose control after CABG Liberal glucose control after CABG Composite: mortality, AKI, DSWI, ventilation >24 hours, pneumonia, length of stay, AF; time to target glucose range (30 days)
Farkouh et al 201223 FREEDOM NEJM 2012 1900 PCI CABG Composite: mortality, MI, CVA (30 days, 1 year)
Houlind et al 201224 DOORS Circ 2012 900 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA (30 days)
Kang et al 201225 EASE NEJM 2012 57 Early surgery for endocarditis (<48 hours) Usual care for endocarditis Composite: mortality, clinical embolic event (6 weeks)
Lemma et al 201226 On-Off JTCS 2012 411 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA, AKI, ARDS, reoperation for bleeding (30 days)
Mannacio et al 201227 — ATS 2012 230 IABP for 12 hours before CABG IABP for 2 hours before CABG Mortality (in hospital)
Sezai et al 201228 UMIN000002489 JTCS 2012 105 Landiolol IV with or without oral bisoprolol after CABG No beta blocker after CABG AF (1 week)
Torina et al 201229 — JTCS 2012 60 Modified ultrafiltration after CABG Usual care after CABG Blood transfusions, chest tube drainage, hospital and critical care length of stay (48 hours)
Bonow et al 201130 STITCH NEJM 2011 601 CABG Medical therapy Mortality (1 year)
Feldman et al 201131 EVEREST II NEJM 2011 279 Percutaneous MV repair Surgical MV repair or replacement Composite: mortality, MI, CVA, AKI, DSWI, ventilation >48 hours, reoperation GI complication, AF, sepsis, transfusion ≥2 units (30 days) Composite: mortality, reoperation, severe MR (30 days)
Kourliouros et al 201132 ISRCTN41309956 JTCS 2011 104 Atorvastatin high dose after CABG or SAVR Atorvastatin low-dose after CABG or SAVR AF (in hospital)
Mehta et al 201133 PREVENT-IV Circ 2011 1034 Edifoligide before treatment to venous grafts Placebo before treatment to venous grafts Composite: mortality, MI, revasc. (5 years) Venous graft failure (1 year)
Sezai et al 201134 NU-HIT for CRF JACC 2011 303 Carperitide during CABG Placebo during CABG AKI (1 year)
Smith et al 201135 PARTNER NEJM 2011 699 TAVR SAVR Mortality (1 year)
Wimmer-Greinecker et al 201136 NCT00985634 ATS 2011 110 CABG with thermosensitive polymer CABG with conventional vessel loops Composite: mortality, MI, graft occlusion, low CO syndrome (30 days)
Grossi et al 201037 RESTOR-MV JACC 2010 165 CABG with ventricular reshaping CABG with or without MV repair Composite: mortality, MI, CVA, reoperation, device failure (2 years)
Hueb et al 201038 MASSII Circ 2010 611 CABG or PCI Medical therapy Composite: mortality, MI, revasc. (10 years); individual end points
Hueb et al 201039 MASSIII Circ 2010 308 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA, revasc. (5 years)
Kapur et al 201040 CARDia JACC 2010 510 PCI CABG Composite: mortality, MI, CVA (1 year)
Moller et al 201041 Best Bypass Surgery Circ 2010 341 Off-pump CABG On-pump CABG Composite: mortality, MI, CVA, cardiac arrest, low CO syndrome, revasc. (30 days)
Omran et al 201042 — JTCS 2010 220 CABG with ventral cardiac denervation CABG AF (in hospital)
Veeger et al 201043 CABADAS ATS 2010 726 Aspirin/dipyridamole or warfarin after CABG Aspirin after CABG Composite: mortality CV, MI, revasc. (14 years)
Weltert et al 201044 — JTCS 2010 320 Erythropoietin before CABG Usual care Blood transfusions (in hospital)
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AF indicates atrial fibrillation; AKI, acute kidney injury; ARDS, acute respiratory distress syndrome; ATS, Annals of Thoracic Surgery; CABG, coronary artery bypass grafting; Circ, Circulation; CO, cardiac output; CVA, cerebrovascular accident; DSWI, deep sternal wound infection; GI, gastrointestinal; IABP, intra-aortic balloon pump; IV, intravenous; JACC, Journal of American College of Cardiology; JTCS, Journal of Thoracic and Cardiovascular Surgery; MI, myocardial infarction; MR, mitral regurgitation; MV, mitral valve; NEJM, New England Journal of Medicine; PCI, percutaneous coronary intervention; revasc., repeat revascularization; SAVR, surgical aortic valve replacement; TAVR, transcutaneous aortic valve replacement.

Mortality (all-cause and/or cardiovascular) was reported as an individual end point or as part of a composite end point in 28 trials (82%), MI was reported in 23 trials (68%), need for repeat revascularization or reoperation was reported in 22 trials (65%), stroke or transient ischemic attack was reported in 18 trials (53%), acute kidney injury was reported in 11 trials (32%), and bleeding complications were reported in 8 trials (24%) (Table 2). Patient-centered outcomes were reported in 10 trials (29%). Health care resource utilization was reported in 12 trials (35%).

Table 2.

Graphical Representation of Primary and Secondary Outcomes in Included Trials With Overview of Commonly Used Combined Endpoints in Cardiovascular Research

graphic file with name jah30004-e002204-tbl2.jpg

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Composite end points were used as the primary outcome measure in 19 trials and as a secondary outcome measure in 4 trials. Overall, 14 different composite end points were used, of which 6 were variants of the MACCE composite, 3 were variants of the MACE composite, and none were based on the STS composite. Eight of 9 trials using the MACE or MACCE composite incorporated repeated revascularization procedures.

The operational definitions of individual end points were equally variable. MI was defined based on World Health Organization criteria in 2 studies, European Society of Cardiology and/or American Heart Association criteria in 4 studies, VARC criteria in 1 study, creatinine kinase elevation greater than the upper limit of normal in 2 studies, creatinine kinase or troponin elevation >3 times the upper limit of normal in 1 study, creatinine kinase or troponin elevation >5 times the upper limit of normal in 4 studies, and creatinine kinase or troponin rise to various levels depending on time after surgery in 3 studies. No diagnostic criteria for MI were provided in 5 trials.

Stroke was defined based on focal neurological deficit with imaging findings in 3 trials and on acute focal neurological deficit lasting ≥24 hours with or without confirmatory imaging in 11 trials; no diagnostic criteria were provided in 6 trials.

Acute kidney injury was defined based on need for renal replacement therapy in 5 trials, need for renal replacement therapy or prespecified elevation in creatinine (each with different thresholds, ranging from 221 mmol/L [2.5 mg/dL] to 309 mmol/L [3.5 mg/dL]) in 3 trials, and prespecified elevation of twice the preoperative creatinine level with or without oliguria in 2 trials; no diagnostic criteria were provided in 2 trials. Prolonged ventilation or intubation was defined as >24 hours in 2 trials and >48 hours in 1 trial. The definition of postoperative bleeding differed in each of the 8 trials in which it was reported.

Discussion

To our knowledge, this review of adult cardiac surgery trials is the first to examine the current state of outcome reporting. We found that mortality and MI were most frequently reported as individual or composite end points and, conversely, that the STS composite was not used as an outcome measure. One of the most striking findings was the heterogeneity of composite end point reporting. This was apparent at 3 different levels. First, the decision to use or not use a composite as the primary outcome measure was evenly split between trials. Second, the choice of events included in composites was highly variable. Third, the operational definitions of events were ill defined, particularly the thresholds used to dichotomize continuous metrics such as troponin rise for MI or ventilation duration. MACE and MACCE also had varied definitions in the trials, similar to prior reports in general cardiology.7

Heterogeneity in cardiac surgery outcome reporting limits the ability to synthesize and meta-analyze results across trials to generate guidelines with the highest level of evidence.8 This is relevant, given the shift toward evidence-based practice derived from randomized controlled trials in cardiac surgery and other surgical subspecialties.9 In addition, nonstandardized outcome measures limit the ability to directly compare the effectiveness of various surgical techniques, perioperative interventions, and providers.10 As new competing techniques and technologies emerge, it is increasingly important that surgical outcome reporting be comparable among trials. Due to the lack of consensus outcome measures in cardiac surgery, investigators often default to using mortality as the end point of choice, despite being grossly underpowered to do so (as was apparent in the many of the trials reviewed and in an even greater proportion of observational studies). Similarly, with the exception of the STS models, most risk scores use mortality as the sole end point, neglecting the importance of other complications and patient-centered outcomes.

The use of composite end points in cardiac surgery may be beneficial for several reasons. Composite end points avoid the arbitrary choice of a single outcome when several may be of clinical importance for the cardiac surgery patient45 and allow for estimation of the net clinical benefit of the intervention when risks and benefits are both considered.46 Composite end points encompass postoperative complications, which are important determinants of functional recovery and quality of life.47 Patient recruitment in cardiac surgery trials has historically been difficult48 and continues to be challenging despite the emergence of collaborative research networks.49 Composite end points yield an increased number of events and a smaller required sample size, resulting in improved statistical efficiency and precision.50 This is especially true if event rates are low and efforts to analyze individual outcomes or to perform meta-analyses lead to false-negative and false-positive conclusions.51 Presenting a clear sample size calculation matched to the primary outcome of interest, as was done in most reviewed trials, is critical in this regard.

Choosing the proper events to include in a cardiac surgery–specific composite end point is of vital importance. The breadth of adverse events encountered after cardiac surgery is not captured by generic composite outcome measures traditionally used in cardiology, such as MACE or MACCE. Acute kidney injury and deep sternal wound infections, for example, are postoperative events that are associated with considerable morbidity. MI, the usual driver of MACE-type end points in cardiology trials, has different connotations and prognostic impact in the postoperative setting and concerns pertaining to measurement errors if ascertaining MI soon after surgery. The use of composites may be justified only if each component is of similar importance to the patient,2 whereas it may be questionable if components are empirically different in impact (eg, deep sternal wound infection and stroke).2 Assigning weights to the components may circumvent this caveat and help increase the validity of conclusions.52

Quality of life, physical performance, cognitive function, and dependency for activities of daily living have been broadly categorized as patient-centered outcomes because they reflect domains that are crucial to the patient but are extrinsic to traditional domains of mortality and pathophysiology that are emphasized by physicians and researchers. There is increasing awareness in the cardiovascular community that these data should be collected and reported, particularly when studying elderly populations in which the priority of care may have shifted from longevity to quality of life. Postoperative length of stay, stroke, and readmission have been identified as important indicators of quality of care,53 strengthening the rationale for also reporting these end points.54

For a criterion to be a useful part of a composite end point, it should be clinically important and reliably ascertainable. In the cardiology literature, consensus efforts have been made to standardize adjudication of MI,55,56 renal injury,3 and bleeding.4 These consensus documents are not necessarily portable to the specific context of cardiac surgery, for which the mechanism, magnitude, and clinical implication of certain events are fundamentally different. Consider the difference between medical versus surgical bleeding and ambulatory versus perioperative troponin rise. The STS composite does not include perioperative MI, which is in part due to its low ascertainment reliability.1 Recommended definitions of perioperative MI vary considerably, from a highly restrictive approach requiring evidence of an acute coronary embolus57 to a multifaceted approach incorporating clinical and biomarker criteria.55 Other potentially important cardiac surgery outcomes, such as prolonged postoperative mechanical ventilation, have not been uniformly defined or adopted for use.

VARC is a context-specific consensus document focused on transcatheter aortic valve replacement; it provides standardized end points with clearly defined criteria for reporting.5 A meta-analysis showed that the VARC end points were frequently being implemented to report clinical outcomes.58 Although there has been an initial attempt to develop a similar document focused on pediatric cardiac surgery,59 there has yet to be an attempt in adult cardiac surgery.

Limitations

Because our search was limited to 5 scientific journals (for feasibility purposes), we did not capture trials published in other journals. The selected journals represent the highest ranked impact factors in their respective subspecialties of cardiothoracic surgery, cardiology, and general medicine, and we expect that the heterogeneity of outcome reporting could have been more pronounced if we had included smaller lower ranked studies. Conversely, the selected trials encompassed a wide variety of interventions and comparators (surgery versus surgery, surgery versus transcatheter procedure, surgery plus adjunctive medical therapy versus surgery alone), such that the heterogeneity of outcome reporting could have been less pronounced if we restricted our selection criteria to one of these types of trials. We excluded trials that did not report a clinically driven primary outcome, and this also led to underrepresentation of smaller studies that were underpowered to assess clinical events. We chose to focus on clinical events because these will likely form the basis of future efforts to develop standardized guidelines for reporting outcomes.

Conclusion

Outcome reporting in the cardiac surgery literature is heterogeneous, and efforts should be made to standardize the outcomes reported and the definitions used to ascertain them. Measures of functional status and resource utilization are currently underreported and should be integrated in standardized reporting schema. The development of standardizing outcome reporting is an essential step toward strengthening the process of evidence-based care in cardiac surgery.

Sources of Funding

Dr Afilalo is supported by a Research Scholar award from the FRQ-S.

Disclosures

None.

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