This is the largest and longest evaluation of the risk of death among those with diabetes and LEA. Individuals in the U.K. treated by a health care provider who participates in THIN with diabetes who have had an LEA are three times more likely to die at any point in time than their counterparts who have not had an LEA. In any given year, >5% of those with diabetes and an LEA will die. The goal of this study was to determine whether complications of diabetes well-known to be associated with death in those with diabetes, like cardiovascular disease and renal failure, explained the higher rate of death among those who have undergone an LEA. It is important to understand whether these factors increase the risk of death in those who have had an LEA. LEA is a procedure, and many receiving this procedure will also have these medical conditions. Many of these conditions are also associated with the reason for the LEA such as severe PVD and therefore are associated with both the procedure and, potentially, death. The surgical procedure by itself is unlikely to contribute to a patient's risk of dying. We were not able to demonstrate that the increased risk of death in those with diabetes and an LEA was primarily explained by MI, CKD, CVA, CHF, PVD, or a previously validated mortality index, the Charlson index. Furthermore, we were able to show that to fully explain the association between death and LEA, we would need to hypothesize a risk factor that is very highly associated with death and very common—a risk factor that one might imagine should already be known.
The indication for an LEA is as variable as is the procedure itself (e.g., the part of the lower extremity removed). Recently, it was reported that the annual incidence of LEA is between 4 to 5 per 1,000 person-years in 5 million beneficiaries with diabetes in the U.S. Medicare population between 2006 and 2008. There was also a three- to fivefold geographic variation in amputation incidence. Similarly, a study in 2012 by Holman et al. demonstrated an incidence of LEA in those with diabetes of ~2.5 per 1,000 person-years and also noted an eightfold geographic variation in LEA rates among the Primary Care Trusts in England.
Death from anesthesia during the performance of an LEA is very uncommon, and it is similar to the risk of death from anesthesia for a person of similar medical health. Previous studies on why LEA is associated with high mortality found associations similar to ours. A study from Zambia from 2003 showed that 55% of those with LEA and PVD died within 5 years of their LEA. A study of 390 individuals form Scotland in 2006 of individuals with nontraumatic LEA showed that those with diabetes and CHF were the most likely to die within a year of surgery. A study of 38 subjects with diabetes and amputation from Germany demonstrated that older age, renal insufficiency, and PVD were all associated with an increased risk of death. A study in 2012 from the U.S. Veterans Administration system showed that those with CVA and those who had intensive care unit stays during their admission for LEA had an increased risk of death. A small study of 93 individuals who had a nontraumatic amputation from Denmark in 2012 showed that individuals with diabetes, vascular disease, and more severe systemic illnesses were more likely to die within the first year postamputation. A study from the Netherlands in 2013 of 299 patients with diabetes and LEA revealed that renal disease and cerebrovascular disease were associated with an increased risk of death. Our study is larger, includes longer follow-up, evaluates those with LEA to those without over time, and was from a database that is thought to be highly representative of the U.K.
LEA is often performed because of an end-stage disease process like chronic nonhealing foot ulcer. By the time a patient has a foot ulcer and an LEA is offered, they are likely suffering from the end-stage consequence of diabetes. A recent study indicated that the 30-day mortality rate after LEA was 7.1%. This number included all individuals receiving an LEA and was not specific to patients with diabetes. The majority of the cases who died had sepsis, again demonstrating that this procedure is reserved for individuals who are critically ill. Because we were interested in long-term mortality and not that associated with the immediate surgical intervention, we excluded from our analyses those who died within the first 2 weeks after their LEA. However, a possible explanation for our findings and the previous findings of regional variation is that the selection of whom to offer an LEA is biased to those who are significantly ill and have marked increased risk of mortality compared with others with diabetes. This unmeasured bias is significant, not represented in the Charlson index, and likely clinically obvious to those making the treatment selection.
As with all epidemiologic studies, our study has several potential limitations. We used the THIN database. It is possible that we missed patients with diabetes who had an LEA. This is unlikely in that our rates of diabetes are similar to those of other U.K. studies. It is important to remember that the GPs who recorded clinical information in THIN were unlikely to have performed the LEA. As a result, it is possible that patients could have died, which would have been recorded in THIN, just after their LEA in hospital without receiving care by their GP postsurgery, thereby resulting in the failure to record the LEA in THIN. These individuals would have contributed to deaths in our individuals with diabetes who did not have an LEA, thereby biasing our results toward the null. Immortal time bias can occur in longitudinal studies of treatment interventions. However, to control for this form of bias, we allowed LEA to be a time-varying covariate. With respect to other forms of bias like information bias, others have demonstrated the accuracy of THIN in the past. In large studies like this one, most information bias tends to be nondifferential. There is no reason to suspect that among individuals with diabetes, important factors like cardiovascular illness or renal failure would be more accurately reported depending on whether an LEA was going to happen in the future. It is also important to realize that we focused on all-cause mortality and while we focused on risk factors that are consistent with cardiovascular complications of diabetes and thus associated with cardiovascular-associated death, we did not evaluate modifiable risk factors like lipids and blood pressure. For ~65% of our population, we did have data on total cholesterol, HDL, LDL, and blood pressure. We did conduct a secondary analysis on these subjects, which was not formally reported, but it did not have an effect on the multivariate HR reported in Table 2 for LEA and all-cause death. It is also important to realize that in this study we focused on all-cause death and not the cause of death. Cause of death is difficult to properly determine in THIN. Finally, generalizability is always a concern. THIN is thought to represent the U.K. population. The LEA rate is somewhat lower than in the U.S., but as long as the effect ratios of those with and without LEA are consistent across populations our results should generalize outside of the U.K.
In summary, individuals with diabetes and an LEA are more likely to die at any given point in time than those who have diabetes but no LEA. While some of this variation can be explained by other known complications of diabetes, the amount that can be explained is small. Based on the results of this study, including a sensitivity analysis, it is highly unlikely that a "new" major risk factor for death exists. It is possible that the risk of death is related to those being selected for LEA, which is a procedure commonly viewed as a last effort to treat a patient's foot ulcer. However, it is likely that the major causes of death in those with diabetes and LEA is similar to the causes in those who have not had an LEA (e.g., MI, CVA, CHF, CKD, etc.). If this were true, then based on our results GPs could be failing to evaluate those with an LEA for these medical conditions or, as others have opined, the diagnosis of these conditions in those with LEA might be different as well as the pathophysiology of cardiovascular disease and its relationship with all-cause death. We would therefore suggest that patients who have had an LEA require even more vigilant follow-up and evaluation to assure that their medical care is optimized. It is also important that GPs communicate to their patients about the risk of death to assure that patients have proper expectations about the severity of their disease.
Diabetes Care. 2015;38(10):1852-1857. © 2015 American Diabetes Association, Inc.