The incidence and prevalence of kidney disease have nearly doubled over the past decade, presently affecting more than 20 million Americans18-20
. Given the increasing magnitude of this disease, the frequency with which these patients are hospitalized, and increased bleeding risk associated with most anticoagulants, a better understanding of the clinical profile, current management, and outcomes of patients with reduced kidney function who are at risk for, and/or develop VTE, is needed.
In our population-based study, patients with decreased eGFR on clinical presentation comprised more than one-third of patients experiencing VTE in this large, central New England community. Approximately 8% of patients with VTE during our study years had severe reductions in eGFR (eGFR < 30 ml/min/1.73m2
) at the time of clinical presentation. The prevalence of reduced kidney function in our study population was approximately two times greater than national estimates of kidney disease prevalence in the United States population18
. Not surprisingly, patients with decreased eGFR were older and more likely to have important underlying co-morbidities present as compared to patients with eGFR ≥ 90 ml/min/1.73m2
at the time of initial VTE presentation.
Approximately 35-45% of patients with reduced eGFR experienced their VTE event during a hospitalization for another condition or had a recent (< 3 month), non-VTE related hospitalization. Accordingly, adequate prophylaxis during hospital encounters may be the most effective way to decrease the risk of VTE in these high-risk patients. Although it was encouraging that prior anticoagulant prophylaxis in these patients did not differ according to the extent of kidney function as measured by eGFR, the overall use of these anticoagulants during these at-risk periods remained woefully suboptimal (40-50%). Even though appropriate dosing of low-molecular weight heparin in patients with kidney disease for VTE prophylaxis remains somewhat controversial, there are data to suggest limited bioaccumulation of low molecular weight heparin in this population at standard doses for finite periods21, 22
. Furthermore, low-dose unfractionated heparin remains an option in patients with severe kidney disease23
Patients with reduced eGFR were significantly less likely to have been started on anticoagulant therapy for acute VTE. Approximately 1 in 6 patients with decreased eGFR had an inferior vena cava filter placed as part of their acute management. More than 20% of subjects with reduced eGFR were discharged without anticoagulation. Among patients with severe declines in kidney function not discharged on anticoagulant therapy, 32% had suffered in-hospital major bleeding episodes compared to 23% of those with eGFR ≥ 90 ml/min/1.73m2. While we cannot adequately explore the rationale for treatment decisions using these retrospective observational data, they most likely reflect a combination of perceived increased bleeding risk and early post-treatment bleeding events in patients with kidney disease.
Prior studies have demonstrated a heightened risk of developing subsequent VTE events in patients who have already experienced a first VTE episode, with the greatest risk of recurrence occurring during the first 6 to 12 months after the index event24-27
. Cumulative incidence rates of recurrent events have ranged from approximately 1-5% within the first month to 15-20% within 3 years following the incident VTE episode25, 27-31
. Our data fall within the range of these previously reported results; between 4-7% of our patients experienced a recurrent episode of VTE during the first 30-days of the index VTE episode and between 13-19% developed a recurrence within 3-years of the initial event. Patients with eGFR > 30 ml/min/1.73m2
were at increased risk for experiencing a recurrent episode of VTE compared to patients with eGFR ≥ 90 ml/min/1.73m2
over our extended follow-up. Although we cannot satisfactorily explore the reasons for this increased risk, which is most likely multi-factorial, an increase in thrombotic risk in patients with kidney disease can be postulated. However, it is also likely that additional co-morbidities resulting in frequent hospitalizations and interruptions of initial VTE therapy due to bleeding related issues (as well as concomitant increased use of inferior vena cava filters) contributed to these findings.
With respect to major bleeding episodes, patients with reduced kidney function often suffer from platelet dysfunction and impaired platelet-vessel wall interaction leading to an increased tendency for bleeding32-34
. However, bleeding is also a common complication of VTE, primarily resulting from anticoagulant use for therapeutic management35-37
. Our results show that the risk of major bleeding events is substantially increased in VTE patients with eGFR < 30 ml/min/1.73m2
as compared to patients with eGFR ≥ 90 ml/min/1.73m2
. During the first 30-days after the initial VTE event, almost 15% of patients with severe reductions in eGFR experienced a major bleeding episode as compared to only 6% of patients with eGFR ≥ 90 ml/min/1.73m2
. Within 3-years of the initial VTE episode, bleeding risk more than doubled for patients with severe reductions in eGFR as compared to patients with normal eGFR ranges. These findings are consistent with several studies that have evaluated the risk of bleeding in patients with chronic kidney disease (CKD), and other disease states requiring anticoagulation38-40
. For example, in a nationally representative sample of patients hospitalized with myocardial infarction, higher rates of bleeding were observed in patients with severe CKD as compared to patients with mild/moderate or no CKD38
. Similarly, data from the Global Registry of Acute Coronary Events (GRACE)40
as well as from the OASIS 5 trials39
found that, among patients with acute coronary syndromes, bleeding rates increased with greater severity of CKD in comparison to acute coronary syndrome patients without evidence of CKD.
Long-term mortality was very high in patients with reduced eGFR and VTE in our study, mirroring rates generally seen in patients with heart failure in the community41, 42
. Between 40-50% of patients with eGFR of 30-59 or 60-89 ml/min/1.73m2
, and 70% of patients with eGFR < 30 ml/min/1.73m2
, died over our 3-year follow-up. In agreement with previously published results, significant differences in mortality were observed in VTE patients with decreased eGFR in comparison to patients with normal kidney function9, 13
. Accelerated rates of cardiovascular disease in patients with kidney disease have been shown to increase their risk of dying as compared to patients without kidney disease42
. However, whether or not complications of VTE, such as recurrent pulmonary embolism, contribute to the observed mortality rates in this high-risk population warrants further study beyond the scope of this present investigation.
The strengths of the present study include the generalizability of our population-based design that represents all patients with independently validated VTE from a well-defined, large central New England metropolitan area and our independent review and validation of patients’ medical records.
Similar to the design and conduct of any observational study, the present study has several limitations that must be kept in mind when interpreting the study results. Although a broad screening was conducted for identifying all possible VTE cases that occurred in the greater Worcester population, complete ascertainment of index VTE events, VTE recurrences, or major bleeding episodes may not have been obtained, especially for residents who sought care outside of our catchment area following initial presentation for VTE. Failure to capture these patients likely underestimated the magnitude of these endpoints in our study sample, potentially diluting our study results. Deaths due to VTE recurrences or bleeding episodes were unable to be estimated in this study because of the low autopsy rates. Because patients with moderate/severe kidney disease are more likely to receive transfusions because of their lower baseline hemoglobins, the occurrence of major bleeding episodes in these patients may be overestimated. We cannot comment on the use of non-pharmacological approaches to prophylaxis, including the use of sequential compression devices, or the influence of patients with nephrotic syndrome, proteinuria, or an elevated serum urea nitrogen on study outcomes since these data were not collected; hence, the utilization of prophylactic procedures in our population may not be generalizable to additional patient populations. In addition, we cannot differentiate between patients with acute or CKD since our methods of stratification were based on initial creatinine values. Finally, we cannot comment on the impact of drug dosage, timing, type of anticoagulant therapy during VTE-related adverse events, and issues related to medication adherence on the subsequent risks of death, VTE recurrence, or bleeding. Further study of the influence of long-term treatment strategies on selected patient outcomes remains of crucial importance in decreasing the overall risks of adverse complications associated with VTE.
The results of our population-based study demonstrate significant differences in the clinical characteristics, management approaches, and occurrence of short and long-term outcomes in VTE patients with reduced eGFR on presentation as compared to patients with normal eGFR ranges. Given the increased prevalence, clinical impact, and economic burden of kidney disease, our results may be used to inform efforts designed to improve the monitoring and treatment of VTE complications by health practitioners in these high risk patients. Future studies evaluating novel anticoagulants for the prophylaxis and treatment of deep vein thrombosis should include these high-risk patients given current limitations in available treatments.