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Validation of cause of death classification after heart transplantation and cause‐specific life expectancy compared to the general population

Abstract Background Post heart‐transplant survival has increased, but information is lacking on specific causes of death and life expectancy. We aimed to assess cause‐specific loss of life‐years compared to the general population, evaluate classification for cause of death after heart transplantation, and assess validity of cause of death data from the International Society of Heart and Lung Transplant (ISHLT) registry. Methods In this single center study, we included 239 heart recipients transplanted between 1988 and 2019 in Lund, Sweden (n = 239, 50% of the transplanted population where the cause of death was available). Two cardiologists retrospectively assigned causes of death according to a published classification (CLASS) in the 91 recipients who died during follow‐up. Life expectancy was compared to data from the general population. Results Compared to the average Swedish population, life expectancy for heart transplant recipients was 20 years shorter (IQR 12.9–27.2). The largest number of life‐years lost were for deaths due to acute (49 years) and chronic rejection (27 years). Primary graft dysfunction (24 years) accounted for 24% of deaths, followed by malignancy (20 years) and infection (17 years), each accounting for ∼20% of deaths. Use of CLASS revealed moderate inter‐rater agreement (56%) and moderate agreement with the ISHLT registry (62%). Conclusions Survival after heart transplantation was 20 years lower than in the general population. In the young, more life‐years were lost due to acute graft rejection, whereas chronic graft rejection and primary graft failure were more important causes of death in older patients. Agreement was moderate between CLASS and the ISHLT registry classifications.


INTRODUCTION
Survival of heart transplant recipients has increased steadily over the last decades, paralleling improvements in surgical technique, organ preservation, immunosuppression, transplantation logistics, infection control, and long-term graft surveillance. 1 According to the International Society for Heart and Lung Transplantation (ISHLT) registry, the largest register in the world of heart and lung transplant recipients, which also includes information on time and cause of death from follow-up, median survival has been reported to be 12.5 years. 2 Data on Scandinavian heart transplant recipients are entered into a common register (Scandiatransplant registry), from which data are exported to the ISHLT registry. This includes information on cause of death as coded according to the ISHLT. In Scandinavian heart transplant recipients, median survival was 13.2 years in 2009 3  Classification of cause of death is notoriously complicated and often displays substantial inter-rater variability, with low validity in registries representing diagnoses from routine clinical practice. [5][6][7] For transplant recipients, it may be particularly difficult to identify a single cause of death. To our knowledge, no study has validated death causes in the ISHLT or Scandiatransplant registries.
Recently, a new method, the Classification of death causes after transplantation (CLASS) was developed in a broad transplantation context, and shown to display high reliability by Wareham et al. 8 Substantial discordance was observed between the CLASS classification and death causes reported from clinical routine in the Danish National Death Cause Registry. 8 The importance of individual causes of death can be described with several metrics. One highly relevant measure is life expectancy and lifeyears lost, calculated from comparison with a normal population.
In this retrospective single center study from the heart transplant center at Skane University Hospital in Lund, Sweden, we aimed to validate the death causes reported in the ISHLT registry by application of the CLASS classification to heart transplant recipients, and additionally to evaluate the inter-rater agreement for the CLASS system in this context. Further, we compared the transplant recipients to a matched non-transplanted general population sample to determine cause-specific life years lost in a transplanted population.

Study sample
In this single center study, patients that had undergone heart transplantation in the period 1998-2019 and were followed at Skåne University Hospital, Lund Sweden, were included ( Figure 1).

Cause of death classification
Two independent reviewers separately investigated the hospital records of deceased patients. The death cause was determined according to the CLASS death cause classification. 8

Analysis of life-years lost
The

Statistical analysis
Continuous variables were presented as medians with first to third

Deceased patients and clinical characteristics
Between 1988 and 2019, 472 patients underwent heart transplantation at Skåne University Hospital Lund. Two hundred and forty-six patients received their follow-up locally. Of these patients, 148 patients were still alive on December 31, 2019, while 98 patients were deceased. In the case of seven patients, we were unable to locate their old paper journal records. They were excluded from further analysis.
The electronic journals of the remaining 91 patients were reviewed for cause of death analysis ( Figure 1). Analyses were based on a sample size (n = 239. Fifty percent of whole population).
The baseline characteristics of the cohort are reported in Table 1.
In brief, the major etiologies of heart failure prior to transplantation were idiopathic dilated cardiomyopathy (in 46%) and coronary artery disease (21%

Cause of death classification and comparison with ISHLT
Using the CLASS methodology, there was initial agreement between the two reviewers in 51 cases (56%) and disagreement in 40 cases (44%) leading to a moderate inter-reviewer agreement with a Cohen's Kappa Coefficient of 0.51. For these latter patients the specialist board determined the validated death cause. However, using the "grouped death causes" the inter-reviewer agreement was substantial at 67% with a Cohen's Kappa coefficient of 0.63.
Cumulative incidence of the "grouped death causes" are presented in Figure 2. A summary of registered and grouped ISHLT death cause versus validated grouped CLASS death cause are presented in Table S3 (Supplements).
The validated CLASS death cause was compared with the registered ISHLT death cause and led to moderate agreement at 62%, with a Cohen's Kappa coefficient of 0.57.
Next, the "grouped death causes" in CLASS and validated CLASS codes were compared for each reviewer separately, and led to a substantial to almost perfect agreement rate of 79% and 85% with Cohen's Kappa coefficients of 0.76 and 0.83, respectively. However, agreement with the validated grouped CLASS codes and the ISHLT codes remained moderate with inter-agreement of 62% and Cohen's Kappa of 0.57.

3.3
Life expectancy compared to the matched general population

DISCUSSION
To our knowledge this is the first study to systematically assess the validity of ISHLT data on cause of death. We found that specific causes of death in heart transplant recipients are difficult to determine, leading to moderate agreement between the heart specialists and com- The validity of cause of death is notoriously poor in the general population. 12,13 In our study, we found a moderate validity on the cause of death registered in the Scandiatransplant/ISHLT registries, comparable to that found in previous studies in non-transplanted populations. 5,14 Most clinicians are likely to have experienced that defining an individual underlying cause of death for patients with complex disease can be demanding. For example, patients who die with sepsis may also have been diagnosed with cancer, and kidney function may very well also be affected. It can be difficult to determine if these patients die from sepsis, cancer, electrolyte disturbances due to kidney failure or multi organ failure. Further, one could argue that in some cases it may be the combination of these conditions rather than one specific cause that leads to death in this vulnerable patient population.
The complexity is reflected in the present study by the relatively high number of cases that required validation by a specialist board due to reviewers' initial disagreement on the cause of death.
Further, the validated death causes differed significantly from the registered ISHLT death causes. This difference may be due to issues specific to our transplant center. However, more likely this is due to the complex nature of the courses leading to death in this patient population making it difficult to determine on a specific cause of death.
The CLASS as well as the ISHLT death Grouping death causes into a larger and hence, less meticulous classification system would decrease the specificity of information, but potentially increase validity. In the present study, using the grouped death causes, the two reviewers had an almost perfect agreement with the validated CLASS methodology. However, agreement with the ISHLT causes of death remained only moderate even when using the larger pathophysiological relevant death codes.
In the second part of the study, we analyzed the grouped death causes according to the age at transplantation, survival and life years lost in comparison to a matched cohort. As shown in Figure 3, death as a result of acute graft rejection is most common in patients with a younger age at the time of transplantation. As previously known acute graft rejections often occur shortly after the transplant, and more often affect younger patients who have a more active immune system, 15 resulting in a high number of years lost. Although acute rejection is becoming less frequent with modern immunosuppressive therapy, 16,17 our findings underscore that it remains an important issue. In comparison, death causes such as myocardial ischemia, infection, malignancy, cerebrovascular events and bleeding affect more, but relatively older patients and following several years of immunosuppression, resulting in a lower, although still high number of years lost compared to the non-transplanted population. Multi-organ failure affects patients of all ages, demonstrating that it often is the final consequence of other disease rather than an entity in itself, as well as a demonstration of the complexity of disease in transplanted patients.
In our material, the group major bleeding contains some patients with cardio-or cerebrovascular bleeding and some patients with other forms of bleeding (e.g., gastrointestinal or traumatic). One could argue the need to separate this groups, which we have chosen not to do in this material due to the small numbers.
The main limitation of the statistical analysis regarding death cause, is that the data are derived from a single center with a limited number of patients and small number in each stratification group. On the other hand, data was reviewed in detail. As approximately half of the patients transplanted at our center receive their follow-up on other sites, and patient journals and hence death cause information on these patients were unavailable for this study, there is a risk of selection bias.
The study demonstrates the problems with deciding on a single death cause for complex patients and defining the death cause even from such detailed data.

CONCLUSION
In this single center study, we have shown that the registered death causes in the Scandiatransplant registry according to the ISHLT death cause classification displayed moderate concordance with the validated death causes achieved by using the CLASS methodology.
After introducing a simplified version of the cause of death classification system, agreement between the two methods was markedly improved although at the cost of lower detail.
Survival after heart transplantation remains 20 years lower than in the general population, with the largest number of life-years lost due to acute graft rejection, chronic graft rejection and primary graft failure.
Although modern immunosuppressive treatment has improved during the last decades, rejection remains a considerable issue and remains an important factor.