In this paper we describe the operations of a CEC that had the task of attributing cause of death in patients with COPD and adjudicating whether the deaths were related to COPD in a large multinational clinical trial.
Clinical Endpoint Committees are routinely used in cardiovascular clinical trials, and several reports have concluded that they can provide independent, systematic, standardised adjudication of outcome events.11,12,13,14,15,16
Outcomes of clinical trials may differ substantially when events are independently and systematically adjudicated rather than relying on local site investigators or death certificates.17,18,19,20,21
In contrast to endpoints in coronary artery disease, COPD provides a particular challenge because there are no accepted definitions of when death is caused by or related to COPD. Many patients with COPD die from other causes, particularly cardiovascular disease, pneumonia and lung cancer.22,23,24
This is because patients with COPD suffer from other smoking‐related comorbidities such as coronary artery disease, they are vulnerable to fatal outcomes from other illnesses such as pneumonia, and also because cause of death in COPD may be inaccurately or inconsistently attributed.25,26,27,28
All‐cause mortality is an objective and unbiased outcome measure for clinical trials. Cause‐specific mortality, although limited by reduced power and potential for biased ascertainment, can provide information about subtle beneficial or adverse treatment effects that are not of sufficient magnitude to alter all‐cause death rates. Moreover, the systematic review and attribution of cause of death in well characterised cohorts of patients with COPD participating in a clinical trial can extend our understanding of the health impact, epidemiology and natural history of COPD. Because there are no generally agreed definitions of what constitutes death from COPD or death related to COPD, the CEC had to develop a set of definitions and working principles to guide their deliberations. We emphasise that these definitions were developed in the context of a clinical trial evaluating maintenance treatment of COPD and would not necessarily be appropriate for investigations that were targeting other diseases or treatment approaches.
We also evaluated whether the CEC could provide reproducible adjudications by blindly reviewing a sample of cases on two separate occasions. We found that the reliability of the CEC adjudications were reasonably good with identical adjudications in 85% of cases. We are not aware of similar measures of reproducibility of adjudication by mortality review committees in clinical trials, but our results are comparable to the reproducibility of adjudication of causes of perinatal mortality.29
Two issues were often problematic for the committee. First, it was often difficult to distinguish between pneumonia and COPD exacerbation as the presenting terminal illness. Second, it was difficult to decide when an unattended death should be called sudden death vs unknown cause.
We also evaluated whether the CEC, using an independent review and consensus approach, could provide information that was different from using site investigator specification of cause of death. The CEC ascertained different causes of death from the site investigator's primary or secondary cause of death in about one‐third of cases. Although some of the site investigators also served as treating physicians for trial participants, the attribution of cause of death was probably not as consistently applied as the CEC adjudications. In many cases the site investigators specified the cause of death based on the primary cause listed on the death certificate or from the terminal event, for example, “cardiac arrest or cardiorespiratory arrest”. Many of the cases that the CEC classified as sudden death were attributed to myocardial infarction. Thus, different conclusions regarding cause‐specific mortality and the effect of treatment on cause‐specific mortality would be reached using CEC adjudication versus site investigator adjudication. In general, dependence upon site investigator diagnoses would tend to increase the attribution of death to cardiovascular causes and diminish the attribution to respiratory causes.
The TORCH trial is the first large international clinical trial focusing on COPD mortality. Besides the lack of well established precedence for operation of a CEC for COPD trials, the large number of independent study sites and the multiplicity of countries added challenges to attribution of cause of death to COPD. Linguistic, cultural and legal barriers may have affected the ways that deaths are reported and documented. In several jurisdictions, death certificates were not legally available to investigators or the cause of death was withheld from the public record. The planning for such studies needs to take into account the substantial effort and infrastructure required to obtain, review for completeness, collate, translate and distribute the medical information required for central review.
As expected, the causes of death in this COPD population had a larger proportion attributable to respiratory illness than is found in the general population of industrialised countries where cardiovascular and neoplastic causes of death far exceed respiratory illnesses. Several studies have examined causes of death specifically in COPD and have found a lower proportion of deaths from respiratory conditions. The Lung Health Study mortality review panel adjudicated causes of death in 149 patients with mild to moderate COPD.7
Lung cancer was the most common cause of death, occurring in 33% of patients. Cardiovascular disease, comprising both cerebrovascular accidents and coronary artery disease, occurred in 25% of decedents. Respiratory causes of death were uncommon in this group. In Lung Health Study 2, among 34 deaths adjudicated by a mortality review panel, the most commonly reported cause of death was lung cancer.30
Both Lung Health Studies had patients with milder lung disease than TORCH, so it would be expected that fewer patients would have succumbed to respiratory diseases. Hansell and colleagues examined death certificate causes of mortality in decedents in England and Wales who had COPD or a related condition listed as primary or a contributing condition on their certificate. They found that cardiovascular disease accounted for 25% of deaths, neoplasm 7% of deaths and respiratory conditions accounted for only 4% of deaths.31
They suggested that deaths due to COPD were vastly under‐reported on death certificates. In a study of 215 patients using chronic oxygen, Zielinski et al25
found that 38% died of respiratory failure, 13% of cor pulmonale, 11% of pneumonia, 10% pulmonary embolism, 8% cardiac arrhythmia and 7% died of lung cancer. Thus, in this group of patients with more severe COPD, deaths from respiratory causes were more common than in the TORCH study.
One of the interesting findings of this study was the large proportion of patients who had sudden death (16%) and the low proportion of patients with documented acute myocardial infarction (3%). Sudden deaths are usually classified as cardiovascular deaths and are attributed to arrhythmias in the setting of coronary artery disease. It was therefore surprising that so few patients had documented myocardial infarctions. This finding raises the speculation that many of these deaths might have been attributable to acute respiratory failure as a precipitating cause, a phenomenon that has been well described in asthma but not in COPD.32
It has previously been found that 47% of patients who die after recovering from an episode of acute respiratory failure ultimately die of sudden death, suggesting that this may have accounted for this finding.33
We therefore suggest that future studies of COPD mortality should consider sudden death as a separate entity rather than one necessarily linked to a cardiovascular cause.
One of the most difficult decisions made by the committee, and the cause of several of the disparate classifications on re‐adjudication, was the distinction between COPD exacerbations and pneumonia. Although we had clear definitions to separate the two based on whether an infiltrate was present on the initial presenting chest radiograph, there were some circumstances where the clinical and official reading of the initial chest radiograph was different or where an infiltrate was noted very shortly after the onset of symptoms but not on the initial radiograph. Moreover, in all but one case, deaths from pneumonia were judged to be COPD‐related and the symptoms of cough, sputum and dyspnoea were virtually always present in the setting of pneumonia. Thus, the distinction between death from COPD exacerbation complicated by pneumonia and pneumonia leading to a COPD exacerbation was sometimes unclear. We therefore suggest that future research evaluating COPD mortality should subclassify such events as “COPD exacerbations accompanied by pneumonia” and “COPD exacerbations without pneumonia”.
In conclusion, a CEC can provide systematic and reliable attributions of death in clinical trials of COPD. The key elements of operation of such a committee include preliminary development of principles of operation and working definitions, in‐person meetings for discussion of cases and substantial infrastructure for acquisition of medical information. Based on our experience, we would recommend modifications for future clinical trials of COPD, particularly the classification of COPD exacerbations that occur in the setting of pneumonia, the classification of sudden death as a cardiovascular event, and attention to training of investigators and site personnel about the operational requirements of such a committee and the substantial effort required to obtain, review, translate and collate relevant medical records.