Arun Jose, MD, on Outcomes of Anticoagulating Patients With PAH

In this podcast, Arun Jose, MD, discusses his team's research on the outcomes of anticoagulation therapy with vitamin K antagonists among patients with pulmonary arterial hypertension.

Additional Resources:

• Jose A, Eckman MH, Elwing JM. Anticoagulation in pulmonary arterial hypertension: a decision analysis. Pulm Circ. 2019;9(4):2045894019895451. https://doi.org/10.1177/2045894019895451. 
• Olsson KM, Delcroix M, Ghofrani HA, et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation. 2014;129(1):57-65. https://doi.org/10.1161/circulationaha.113.004526. 
• Preston IR, Roberts KE, Miller DP, et al. Effect of warfarin treatment on survival of patients with pulmonary arterial hypertension (PAH) in the Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL). Circulation. 2015;132(25):2403-2411. https://doi.org/10.1161/circulationaha.115.018435. 
• Galiè N, McLaughlin VV, Rubin LJ, Simonneau G. An overview of the 6th World Symposium on Pulmonary Hypertension. Our Respir J. 2019;53(1):1802148. https://doi.org/10.1183/13993003.02148-2018. 

Arun Jose, MD, is an assistant professor in the division of pulmonary, critical care, and sleep medicine at the University of Cincinnati.

TRANSCRIPT:

Amanda Balbi: Hello, everyone, and welcome to another installment of Podcasts360—your go-to resource for medical news and clinical updates. I'm your moderator, Amanda Balbi, with Consultant360 Specialty Network.

My guest today is Dr Arun Jose, who is an assistant professor in the Department of Pulmonary, Critical Care and Sleep Medicine at the University of Cincinnati.

Dr Jose and his colleagues recently conducted a study in which they developed a 31-state Markov Decision model to explore the outcomes of anticoagulation therapy with vitamin K agonists among patients with pulmonary arterial hypertension or PAH.

Dr Jose joins us today to discuss the findings of his team's study as well as discusses other research in this area.

Thank you so much for joining us today, Dr Jose. To start, can you tell us more about your study and its findings?

Arun Jose: You're welcome. Sure. There have been two relatively large registry studies trying to assess what is the benefit or harm of performing systemic anticoagulation on patients with pulmonary arterial hypertension. Those are the compare and reveal registries.

The tricky thing is they found disparate conclusions that compare a study noted that there was a significant benefit in anticoagulating idiopathic pulmonary arterial hypertension patients, and there didn't appear to be any harm in connective-tissue-disease-associated pulmonary arterial hypertension.

The REVEAL study found that there was no significant benefit to idiopathic PAH patients. They did find a significant harm in connective-tissue-disease-associated PAH.

With that in mind, it wasn't really clear whether or not we should be an anticoagulating pulmonary arterial hypertension patients and which kinds of pulmonary arterial hypertension would benefit from anticoagulation.

The most recent guidelines on treatment of pulmonary arterial hypertension suggest that they should avoid systemic anticoagulation in connective-tissue-disease-associated PAH. It can be considered in selective idiopathic PAH patients as it may offer some benefit, but it didn't specify who and what kind of benefits that would be.

With that confusion around the decision to anticoagulate, we decided to study it from a decision-analytic perspective using a Markov model. Markov models are a tool that you can use to assess what the impact of a certain decision would be.

Essentially what they do in simplified manner is you take a hypothetical cohort of patients. You follow them over the course of their hypothetical life. As they go through this course, they experience different states of disease or wellness.

Those are associated with adjustments in their quality of life. If they start out all well and they have a good quality of life as they progress through their lifetime and experience complications like a pulmonary embolism or developing atrial fibrillation or being hospitalized, they will experience decrements to their quality of life.

Some of these states are transient. For example, you can have a hospitalization, and your quality of life will decrease while you're hospitalized. But after the hospitalization, you're back home. Presumably, your quality of life will return to close to what it was before you were hospitalized.

Other states are a little bit more permanent. For example, if you get hospitalized and you require an invasive procedure, let's say, to put in a pacemaker, then that's somewhat of a permanent change in your quality of life.

Eventually, these hypothetical patients all eventually progressed to the end of their lifespan. Once they reach the end of their lifespan and are deceased, their quality of life is zero.

Markov modeling is a way that it takes this hypothetical cohort, follow them through their expected lifespan and adjust their life duration for the quality of life and study the decision of whether or not something like anticoagulation would be beneficial, not just from duration of life standpoint, but also from a quality-of-life standpoint.

The modeling approach that we use takes into account that people are anticoagulated. We presume that they remain within the therapeutic range of their vitamin K antagonist anticoagulation therapy.

We did not necessarily directly incorporate if people would have different doses or would exceed or be under anticoagulated. We did incorporate this documented risks of severe and life-threatening bleeding that are known to be associated with vitamin K antagonist therapy and also the protection from above complications.

There's not a specific dose. It's just whatever dose they would need to be therapeutically anticoagulated.

Amanda Balbi: Let's talk a little bit more about your findings. How did anticoagulation therapy affect quality of life scores among patients with PAH?

Arun Jose: What we found was that systemic anticoagulation was detrimental to the quality of life for patients with connective-tissue-disease-associated PAH, which is not surprising given that no study found benefit, and one of the two registries studies found harm.

What we did observe, however, was that systemic anticoagulation was beneficial in the quality-adjusted life for idiopathic PAH patients and could provide an improvement in quality-adjusted life up to half a year.

This is not insubstantial given that the overall three-year survival for idiopathic PAH patients in the modern treatment area is around 70 percent. Then, additional half a year of quality-adjusted life may have significant impact can be quite meaningful to these patients.

Amanda Balbi: Absolutely. You mentioned that you weren't surprised to find that anticoagulants weren't beneficial in some populations with PAH. Did any of your other finding surprise you?

Arun Jose: We were surprised to see that that was such a significant improvement in the quality-adjusted life for idiopathic PAH patients. Mostly, because after the publication of these two registry studies, the field as a whole is shifted away from providing systemic anticoagulation as a disease-modifying therapy in pulmonary arterial hypertension.

In the last couple of years, the most recent registry data suggests that the minority of patients with idiopathic PAH receive systemic anticoagulation therapy as part of their treatment. We were surprised to know that systemic anticoagulation could provide such a benefit to quality-adjusted life-years. Then, that would raise the question of maybe we should be doing it in more people.

Amanda Balbi: Taken all of these findings together, what is the clinical takeaway for practitioners out there?

Arun Jose: I would say that the takeaways are threefold. Number 1, we confirm that systemic anticoagulation in connective-tissue-disease-associated PAH patients is likely to be harmful and probably should be avoided.

Number 2, in certain idiopathic PAH patients, systemic anticoagulation therapy may offer a benefit to quality-adjusted life-years and should be considered as augment to their currently existing therapy.

Number 3, based on the modeling we did and the effect sizes for anticoagulation, we determined that systemic anticoagulation would need to demonstrate a benefit to the hazard ratio for mortality of 0.95 or better in PAH patients to be considered beneficial.

That provides a benchmark to test different anticoagulation strategies, which might have different benefit and harm ratios. For example, in this decision-analytic model, we studied primarily warfarin vitamin K antagonist because those were the medication studied in the reveal and compare registries.

Newer anticoagulation agents such as direct inhibitors have different risks of bleeding and also improved ease-of-use that would change these results regarding the benefit that idiopathic PAH patients could experience in terms of quality of life.

Amanda Balbi: What is your next step in this research?

Arun Jose: The next steps for this research would be primarily to use this information to potentially develop more tailored decision-analytic models to be used at the bedside.

The current model is developed based on a combination of using literature for rates of adverse events such as thromboembolic complications of bleeding that would occur with systemic anticoagulation and as well as estimates from the literature of the impact of quality of life that those events would have.

However, each patient at the bedside is different. They weigh those sorts of complications differently. Some people might consider something like a stroke or a pulmonary embolism to be quite bad and markedly effective quality of life. Other people might think less so.

Those individual assessments of how severe certain complications are to quality of life would directly affect the potential benefit on quality-adjusted life. They might experience with systemic anticoagulation.

Taking this information and generating a tool that can be used at the bedside to provide an individual assessment for a given patient of what kind of benefit they might expect in terms of quality-adjusted life for systemic anticoagulation will be the next logical step.

Amanda Balbi: We'll be on the lookout for that research, definitely. Thank you very much again for speaking with me today.

Arun Jose: My pleasure.