J. Antonio Aviña-Zubieta, MD, MSc, PhD, on Venous Thromboembolism in Gout

In this podcast, J. Antonio Aviña-Zubieta, MD, MSc, PhD, from the University of British Columbia, discusses his research on the overall risk and temporal trends of venous thromboembolism, deep vein thrombosis, and pulmonary embolism in patients with gout, as well as how rheumatologists can approach management. 

Additional Resource:

• Li L, McCormick N, Sayre EC, et al. Trends of venous thromboembolism risk before and after diagnosis of gout: a general population-based study [published online September 19, 2019]. Rheumatology. doi:10.1093/rheumatology/kez398

J. Antonio Aviña-Zubieta, MD, MSc, PhD, is an associate professor in the Division of Rheumatology at the University of British Columbia in Vancouver, British Columbia, and a senior scientist of rheumatology at Arthritis Research Canada in Richmond, British Columbia. He is also the Walter and Marilyn Booth Research Scholar at Arthritis Research Canada.

TRANSCRIPT:

Hi, I'm Dr Antonio Aviña-Zubieta. I'm an associate professor at the Department of Medicine at the University British Columbia and also arthritis research Canada scientist here in British Columbia and Vancouver. I'm going to talk about a recent paper that we published on the risk of venous thromboembolism in patients with gout at the population level. The importance of the venous thromboembolism, which includes venous thrombosis and pulmonary embolism is relevant because most of its research in inflammatory arthritis has been focused on the arterial side of the cardiovascular system. In recent years, the risk of thrombotic events on the venous side has been largely ignored. Venous thrombosis, especially pulmonary embolism, is the third-most common cause of cardiovascular death in patients during hospitalizations. Therefore, this is an important cause that can be prevented. The importance of this study also lies on the fact that our findings are based on a population‑based study, meaning that the general usability of the results apply to the average patient that we all see in clinical practice. Most of the previous studies have been done in selected populations, either patients that have been only in the hospital or from tertiary care clinics. Therefore, their results or their findings may not be applied to the general population. Furthermore, the importance of this study is, in rheumatology, as you know, gout is the most prevalent inflammatory arthritis among all rheumatic diseases. Therefore, the impact of complications of venous thromboembolism will have a huge impact in a large number of individuals. The reason why we were interested in answering this question was because previous studies were very limited in numbers and also the general usability as discussed before. We have access to a special population sample in British Columbia, which is one of the provinces in Canada, that includes all individuals who have been diagnosed with gout since 1990 and who received care up until 2015. That will allow us an opportunity to actually answer the question "If patients with gout will have also an increased risk of venous thromboembolism has been previously demonstrated for other type of inflammatory arthritis?" Also, we were interested in exploring for the first time if the risk was also present even before the diagnosis of the disease. This is something that has never been done before. Therefore, this was the key element that brought our attention and our interest to explore this research question. The way we decided to analyze our population was first, we only included individuals with new diagnosis of gout, based on diagnostic codes from the visit to outpatient clinics. Anybody could be general practitioners, could be specialties, internees, etc, or people who have been diagnosed with gout during hospitalizations. In order to define incident cases, we excluded cases who had been diagnosed or had an ICD‑9 code before and during the cohort. Our patients entered the cohort from 1997 and ended up the follow‑up up until 2015. Therefore, people who have the diagnosis before 1997, they were excluded. Also, we excluded individuals who had been diagnosed with either deep venous thrombosis or pulmonary embolism before the gout diagnosis. What we decided to do then was an incident cohort with incident events. Then, when the patient was diagnosed, we followed them up until the end of the study, the occurrence of the event, death, or when the patient left the province, whichever happened first. When the patient developed the event, we stopped the follow‑up for that individual, and continued only following those individuals who never developed the event until they developed the event or other outcomes. We calculated the incident rate per 1000 person‑years. Then, we adjusted for all traditional risk factors for gout, with the intention to define what was the true and solo risk of venous thromboembolism in patients with gout after adjusting for traditional risk factors. Our main findings showed that the risk of venous thromboembolism in the pre‑gout period, which included the first 3 years prior to the diagnosis of gout, was 51% overall, compared to matched individuals with the same age and the same gender from the general population. The risk was 22% during the post‑gout period, which included the first 5 years after the diagnosis of gout. This was a striking finding. We were not expecting to have a higher risk prior to the diagnosis of gout. This is almost double the risk after the diagnosis. This was surprising because gout is a quite acute diagnosis compared to other inflammatory arthritis, where the prediagnosis period could be prolonged and not as an acute as it happens in gout. This study shows that, likely, the high levels of uric acid that are known to happen prior to the acute event of gout could play a role in the development of the thrombotic event. Once you start treatment for gout, the risk starts to decrease, which suggests that the inflammatory process may play a key role here too. There is evidence to suggest that uric acid could have a prothrombotic effect in people with gout. That has been suggested in animal models but also in individuals with gout who have high uric levels, and they correlate with higher risk of myocardial infarction. Therefore, it's not surprising to suggest that the uric acid levels could play a role as a trigger for venous thromboembolism. The fact that the incident risk of venous thromboembolism decreases over time suggests that treatment could also play an important role in the prevention of these complications. This has important implications for patients and for physicians who provide care for this population. Now, we know, for instance, that the adherence to treatment in patients with gout is very low. Large studies have shown that only around 20% of people will stick to continue taking treatment. Our findings will then encourage individuals to take treatment, not only to treat and prevent gout flares, but also to prevent complications that could be as serious as a pulmonary embolism, which is a preventable cause of mortality. The most surprising findings of the study were the highest risk of gout closer to the diagnosis. For instance, when we explored 3 years prior to the diagnosis of gout, the risk was around 44%, the adjusted risk. That means the independent role of gout on the risk. The risk increased by 61% on the second year, prior to the diagnosis of gout. In the year prior to the diagnosis, the risk was 200% compared to the general population. That means they doubled the risk compared to individuals who would not have gout in the following year. Then the risk after the first year of the diagnosis decreased, compared to the general population was 71%, and then gradually declined. For instance, for the second year, 24%, 21% for the third year, and 18% for the fourth year. Which suggest that (1) the treatment may play a role in decreasing the risk. The treatment decreases the risk of having high uric acid levels, and therefore, this will decrease the risk of developing venous thromboembolism. Unfortunately, we did not have access to lab values, and therefore, we cannot confirm our hypothesis that the uric acid levels correlate with the risk as well. We have now lab data, and we will expand our research to confirm this preliminary hypothesis. We wonder now if this increased risk of venous thromboembolism also happens in other inflammatory arthritis prior to the diagnosis, and we're working on this. As a final point for clinicians, that we need to be aware that uric acid levels could increase the risk of venous thromboembolism in individuals who will develop gout at a later point. Maybe this would prompt to start treatment earlier. This is something that has to be confirmed though, perhaps a clinical trial, before we can actually implement it in clinical practice. After reviewing the findings of our study, I will suggest some key messages for people providing care for individuals with gout. First, we need to be aware that gout on its own increases the risk of developing venous thromboembolism, including DVT or pulmonary embolism. Therefore, we should be looking for those complications in individuals who already have been diagnosed, especially in the first year after the diagnosis. We should tell the patients as well that these complications could occur and seek medical attention if they start to experience symptoms, especially the venous thromboembolism, because if you diagnose early, you could treat early and prevent a subsequent complication, which is the pulmonary embolism, where the fatality is higher. Secondly, we could prevent the development of venous thromboembolism in people who had been diagnosed already with gout, perhaps by using anticoagulation. The only limitation of this is we still do not know who are the individuals at the highest risk. This is something that we're working on now. Number three, we should consider that people who continue increasing the risk of developing gout by increasing levels of uric acid could be alert that the risk of venous thromboembolism also may occur in this patient. They should be aware of that and that also to lead them to seek medical attention earlier. Perhaps we will need to monitor uric acid levels continuously even if the patient has not developed an acute attack of gout. Finally, we should encourage patients who have been diagnosed with gout to stick to treatment. We know it's an epidemic, the low adherence to treatment, and patients tend to only treat the acute phase and not stick to the use of lower urine therapy. By convincing them that adhering to treatment will prevent them to have new flares of gout, they will also avoid serious complications like venous thromboembolism. This should be a good stimuli for people to adhere to treatment. After the findings of this study, our future research will include to identify individuals at the highest risk for developing venous thromboembolism so that we can initiate treatment before the event occurs. As I mentioned before, oral anticoagulation will be the most likely treatment, but only on those individuals who will have a high degree of developing the complication. Number two, we will include likely in the model the potential role of uric acid levels and their ability to predict the risk of developing this complication. If the model shows that uric acid levels are the best predictor, then we could identify a threshold to initiate treatment to decrease uric acid levels to prevent, not just the development of gout, but also the development of venous thromboembolism. A final point is, we have shown in previous research that the number of hospitalizations of patients with gout continues to increase likely to complications. Therefore, by implementing strategies, like the ones I discussed before on prevention, may also decrease the risk of hospitalizations, which is an increased burden for health care systems. We have shown in previous research that, unlike rheumatoid arthritis, people with the disease tend to go less frequently to the hospital, because they received better care and control of the disease as an outpatient, preventing them to being hospitalized. In gout, we have not seen this trend. Therefore, we need to take a more proactive role. This is something that our research is focusing on, if the implementation of the new strategies or translation of findings in research will lead to decrease the number of hospitalizations, and therefore, decrease the burden of gout. Finally, I think we should also be interested in doing strategies to increase adherence to treatment in patients with gout. We're working on what is actually the cost of nonadherence in people with gout, not just on the financial aspect, but also on the risk of complications other than cardiovascular disease. It is very likely that not a human-to-treatment increase the risk of other complications such as, likely, diabetes or hypercholesterolemia, as we have seen in inflammatory arthritis. A lot of things to do and a new opportunity to contribute to the care of this population, where we can impact the quality of life and the survival. I hope you learned something with this podcast. Thank you for listening.