Trial emulation to assess the effect of surgery on survival when there are competing risks, with application to patients with thoracic aortic aneurysms

Abstract

Objectives

This study extends methods to estimate average causal effect of aneurysm repair surgery on (i) overall survival and (ii) aneurysm-related mortality, accounting for competing risks using data from the Effective Treatment for Thoracic Aortic Aneurysm (ETTAA) cohort.

Study Design and Setting

ETTAA, a prospective cohort study, recruited 886 patients between 2014 and 2018. Patients were linked to UK national hospital and mortality databases by National Health Service digital and followed-up for later surgeries and deaths. We compared a strategy of open or endovascular surgery (whichever appropriate) within 12 months of enrollment to ETTAA with no surgery within 12 months using the trial emulation framework and cloning-censoring-weighting (CCW) analysis. Key confounders at baseline were controlled for using inverse probability weighting methods.

Results

In complete case analysis, if everyone received surgery within a 12-month grace period, an estimated 7-year survival probability was 57.4% (95% CI: 47.3%, 67.4%) vs 49.9% (44.0%, 55.0%) if no one received surgery. This benefit was primarily attributable to reduction in aneurysm-related deaths (difference −8.7%, 95% CI: −14.0%, −3.9%), with no significant effect on deaths from other causes. The findings were consistent under sensitivity analyses, including multiple imputation of missing confounders. Our CCW approach addressed selection-for-treatment, allowed for surgery to be received within a grace period, and used appropriate methods to separate aneurysm-related mortality from competing risks.

Conclusion

The study demonstrates the utility of trial emulation and counterfactual methods in estimation of causal effects on competing risks using observational data. The findings suggest a benefit for aneurysm-related survival up to 7 years after enrollment.

Plain Language Summary

This study shows how to estimate effects of surgery on different causes of death, when we cannot do a clinical trial, and illustrates this using an example from heart surgery. The aorta is the main artery that carries oxygen-rich blood from the heart to the body. In some people, a part of the vessel wall becomes weak and loses its elastic properties, so it doesn’t return to its normal shape after the blood has passed through. This can lead to swelling or bulging in the aorta, called an aneurysm. A thoracic aortic aneurysm, or TAA for short, is an aneurysm in the section of the aorta in the chest (https://www.bhf.org.uk/informationsupport/conditions/thoracic-aortic-aneurysm).

We have used data from the Effective Treatment for Thoracic Aortic Aneurysm (ETTAA) study, which investigated aneurysm growth rates, patient outcomes, quality of life, and costs, in 886 patients diagnosed with TAA. ETTAA compared two surgical treatments, Open Heart Surgery, where the section of the aorta that contains the aneurysm is removed and replaced by a new aorta made from a synthetic material, and Stent Grafting, where tubes are inserted into arteries to allow blood to flow freely using less invasive “keyhole” surgery. ETTAA reviewed existing research evidence but data comparing the effectiveness of these two approaches to each other and to outcomes without surgery were of sparse or limited quality and outdated. The results of ETTAA up to 2020 have been published in a monograph. (https://pubmed.ncbi.nlm.nih.gov/35094747/).

Two findings from ETTAA motivated this study. First, there were no clinical trials comparing surgery with no surgery and no studies that mimic clinical trials. Second, we had not considered whether surgery overall prevents deaths due to aneurysm or deaths from other causes. We call these two types of death, competing risks.

It is unlikely that a clinical trial comparing surgery with no surgery will ever be completed because the number of people who are diagnosed with TAA is small. Also, TAA can become a serious problem if left untreated. On the other hand, surgery for TAA is difficult and can result in serious complications, including death. Therefore, it is important to know how much surgery improves survival related to the aneurysm and whether it improves survival overall.

Recent developments in statistics provided methods for investigating survival in a way which increases confidence in the cause-effect relationship between surgery and outcomes. In this study, we show how these statistical methods can be used to estimate the proportion of patients who die from the competing risks, if all patients had surgery within 12 months compared with if no patients had surgery within 12 months. We take into account the different times between diagnosis of TAA and surgery and adjust for the main differences between surgery and no surgery patients. Using these methods, we estimate that surgery reduces deaths due to aneurysms at 7 years by 8.7%, with no effect on deaths from other causes. The benefit of surgery was significant by 3 years after diagnosis. We also provide discussion about using routine medical records to repeat this type of study.