Activity Transcript

Charles P Vega, MD: Hello and welcome to “PAH and Physical Activity: Expert Insights on New Evidence”. I’m Chuck Vega.

One of the most impactful consequences of PAH from the perspective of patients is reduced capacity for physical activity, There is clear link between a patient’s daily life physical activity, or DLPA. and health-related quality of life, and yet, despite its importance to patients, DLPA has been underappreciated in evaluations of patient health and assessments of PAH-specific drug effectiveness in both clinical settings and clinical trials. This appears to be changing as clinicians are starting to incorporate measurements of DLPA using actigraphy into evaluations of disease severity and effectiveness of treatment.

To get further insights into the relationship between PAH and daily life physical activity and how DLPA can be incorporated into patient evaluations and clinical efficacy trials, I reached out to Dr. Ioana Preston to join us in our discussion. Dr. Preston is Director of the Pulmonary Hypertension Center at Tufts Medical Center in Boston, Massachusetts, and Associate Professor at Tufts University School of Medicine.

Good morning, Ioana. Thank you for joining us today.

Ioana Preston, MD: Happy to participate, Chuck.

Dr Vega: Our focus in this episode is the relationship between PAH and physical activity and the use of daily life physical activity to assess severity of disease, treatment effectiveness, and quality of life. Why don’t we start off with how symptoms of PAH impact daily life physical activity?

Dr Preston: There was a report by the FDA published in 2014, entitled The Voice of the Patient, that brought together groups of patients to discuss the impact of PAH and its treatment on daily life from the patient’s perspective. One of the key topics of discussion was how symptoms of PAH impacted daily life physical activity and what mattered most to patients. The report identified shortness of breath and fatigue as having the most impact on daily life physical activity.

Other impactful symptoms included dizziness, swelling of the legs and ankles, orthostatic intolerance, chest pain, heart palpitations, and cognitive effects.

Dr Vega: What did patients in the study say specifically about the impact of PAH symptoms on their physical activity and daily lives?

Dr Preston: Well, overall patients reported that shortness of breath and persistent fatigue had dramatically impacted their ability to participate in normal activities and tasks, including those that they enjoyed and those required for daily living.

Patients described their lives after PAH as a “new normal,” in which they either couldn’t participate in daily activities or had to carefully monitor activities in terms of effort or duration to avoid shortness of breath or intense fatigue. Often mundane activities, such as walking up a short flight of stairs, walking around the house doing simple chores, cooking, and washing dishes could induce significant shortness of breath and fatigue. Patients also talked about the impact of PAH symptoms on other aspects of their lives, such as their jobs, self-esteem and feelings of independence, and their relationships with family and friends.

Because PAH symptoms can dramatically limit a patient’s ability to work and force patients to either quit their job or reduce their work hours, the impact of PAH on physical activity can include financial insecurity.

Dr Vega: How does the impact of PAH on daily life physical activity influence patient goals for therapy and how do their perspectives differ from those of physicians?

Dr Preston: When patients were asked what they care about most when starting treatment, they responded that the most meaningful parameter was daily physical activity. They want to feel better in ways that allow them to engage in physical activities that are meaningful to them.

There was an enlightening paper by Dr. Luke Howard and colleagues comparing patient and physician goals and expectations for treatment of PAH. Physician treatment goals tend to be focused primarily on improving measurements associated with reduced disease severity, such as six-minute walk distance, cardiopulmonary hemodynamics, functional class, right ventricle size and function, cardiopulmonary exercise testing, and NP-proBNP levels and In contrast, patient priorities tend to be focused primarily on health-related quality of life issues, such as improved physical function; the convenience of treatment; and managing the social, emotional, and financial difficulties brought on by PAH.

Based on these different perspectives, physicians may gauge a treatment as successful if metrics in various parameters have improved. However, if patients don’t feel significantly better and still can’t move around well enough to carry out their desired and necessary daily activities, then they do not view the treatment as successful even if metrics of disease progression have improved.

PAH impacts many elements of a patient’s life, and therefore multiple therapeutic goals should be a part of any management plan. However, discordance between the patient’s and physician’s treatment goals is not conducive to adherence to drug therapy and an optimal outcome.

Dr Vega: Can you speak a bit more on how the side effects and administration convenience of a PAH-specific drug fits into the contrasting perspectives of patients and physicians on treatment goals and measures of success?

Dr Preston: As I mentioned, patients want to feel better, so if the side effects of a drug are not balanced out by significant improvement of symptoms and the capability for increased physical activity, the patient will not consider the treatment successful. As for administration convenience, a classic situation illustrating different patient and physician perspectives is treatment with parenteral prostacyclin drugs. Although infusion with a prostacyclin may satisfy the physician’s goals by improving symptoms and parameters associated with disease severity and progression, the inconvenience of this route of administration may be too much of a burden for some patients and have a significant negative impact on their quality of life.

Lung transplantation represents a similar situation. Yes, it is potentially curative, but it also entails a very complex surgical procedure that not only has its own risks of mortality and morbidity but will also require multiple medications and intensive monitoring for the rest of the patient’s life.

Whether these treatments are viewed as successful by a patient depends on their personal perspectives, lifestyle, and goals for therapy. What may make sense to a physician in terms of survival advantage and may be recommended in treatment algorithms may not align with the patient’s viewpoint and treatment goals.

Dr Vega: As Dr. Preston stated, shortness of breath, fatigue, chest pain, and other symptoms of PAH can severely limit a patient’s ability to engage in daily life physical activity. This creates a vicious circle because physical activity positively impacts physical and mental health, and limiting it can adversely affect the health of patients with PAH.

How does increased physical activity impact the health of patients with PAH?

Dr Preston: We know from studies of other heart and lung diseases that increased physical activity is associated with reduced rates of exacerbation and fewer hospitalizations. There is no reason to think that this relationship does not apply to our PAH patients as well. We also know that increased physical activity is associated with improved mental health and quality of life. So, we always want to encourage our patients to be as active as possible, without overexerting themselves and exacerbating symptoms.

Dr Vega: Are the benefits of physical activity on health and quality of life due to the physical activity itself or the psychological benefits of being more active and engaged in life? Or both?

Dr Preston: That’s a good question, and the answer is multidimensional. Physical movement itself is important for improving health and stamina because it develops the muscles so that they require less oxygen to function. The more efficient the muscles are in using oxygen, the less strain physical activity will put on the cardiopulmonary system. That said, the brain releases endorphins in response to physical activity, especially enjoyable physical activity, and endorphins make us feel better. And if the brain is happier...that is, if we are happier... there’s a beneficial effect on the rest of the body, once again making physical activity easier and life more enjoyable.

Dr Vega: So, it sounds like patients with PAH should ideally engage in physical activities they enjoy so that they reap both the physical and mental health benefits?

Dr Preston: Yes, I think this is important. I did a seminar for the European PAH Forum for patients in 2022. The talk was about exercise, sex, and contraception, which turned out to be the highlight of the meeting because people wanted to understand how to integrate more enjoyable activities into their PAH self-care and get back as much of their normal life as possible.

I recall one patient, who loved swimming, asking me a question about other options for enjoyable exercise because his doctor told him he should no longer swim. Yes, it’s true that light-headedness or episodes of fainting associated with PAH can be problematic when swimming, but this patient was an experienced swimmer and he was stabilized on PAH-specific medications. So, I told him to jump in the water and swim and enjoy himself, maybe not in a rough ocean but certainly in a pool or close to shore in a calm body of water.

The key message here is for patients and healthcare providers to work out an exercise program that matches the patient’s capabilities and preferences and that is focused more on increasing enjoyable physical activity than on just getting exercise for its own sake.

Dr Vega: Have formal exercise training programs been shown to be beneficial in patients with PAH?

Dr Preston: Yes, absolutely. Interestingly, for many years patients with PAH were discouraged from getting exercise because of fears of exacerbating right-heart failure.

More recently, several studies and a meta-analysis have shown that supervised exercise rehabilitation programs in patients with PAH result in significant improvement in symptoms, exercise capacity, and quality of life and may improve hemodynamic parameters as well.

However, it’s important that patients undergoing an exercise training program be in a stable condition with optimized PAH-specific drug therapy and under close supervision in a PAH expert center.

Dr Vega: Six-minute walk distance is a widely used measure of exercise capacity in PAH clinical trials and it is viewed as a surrogate endpoint for disease progression and mortality risk. However, 6MWD has several limitations, including the resources to carry out the test, the need for the patient to be at the test site, and a ceiling effect in patients with mild to moderate disease. Also, 6MWD does not reflect daily life physical activity.

As Dr. Preston explained, from the patient’s perspective, daily life physical activity is a far more meaningful metric of disease severity and treatment effectiveness than exercise capacity. The development of accurate and reliable accelerometers has opened the door to measuring and monitoring a patient’s daily life physical activity objectively and remotely over time and can addresses many of the shortcomings of six-minute walk distance.

How is actigraphy being used to create clinical trial endpoints based on daily life physical activity?

Dr Preston: Given the importance of daily life physical activity to PAH patients and the widespread use and acceptance of accelerometers in the population, there has been a push to make daily life physical activity a clinical endpoint in drug trials.

A study back in 2013 by Sylvia Ulrich and colleagues looked at patients with PAH or CTEPH on either bosentan, sildenafil, or iloprost alone, or on combination therapy. The study demonstrated that the number of hours of physical activity based on actigraphy correlates with transplant-free survival, and that steps per day correlates with health-related quality of life measures, WHO functional class, and six-minute walk distance.

The first trial to evaluate whether changes in physical activity correlate with changes in established markers of disease progression was carried out by Dr. Sameep Sehgal and colleagues. The primary endpoint was the correlation of change in steps per day with change in six-minute walk distance between two consecutive outpatient visits. Exploratory secondary endpoints were correlation of changes in steps per day and time spent doing various activities with changes in other established parameters of disease progression, including WHO functional class, echocardiographic indices, NT-proBNP levels, and health-related quality-of-life measures. The results showed a significant correlation between changes in daily step count and 6MWD over the duration of the study regardless of functional class. As for daily physical activity, changes in time spent engaged in “moderate” and “light” activities also correlated with changes in six-minute walk distance as well as health-related quality of life measures. Although there was no correlation observed between steps per day, level of daily physical activity, or six-minute walk distance with hemodynamic measurements, NT-proBNP levels, or echocardiographic measures of right ventricular function, the small sample size and less-than-rigorous measurement of these variables in this study may have contributed to these results.

The first randomized controlled trial using actigraphy-based daily life physical activity as a primary endpoint in evaluating a drug’s efficacy was the TRACE study.

Dr Vega: Can you tell us about it?

Dr Preston: Yes. It’s an exploratory study evaluating the efficacy of the oral prostacyclin pathway drug selexipag. The primary endpoint was change in DLPA from baseline to week 24, including daily time spent in non-sedentary activities and daily number of steps. Secondary endpoints included change from baseline to week 24 in a health-related quality of life questionnaire and 6MWD. Patients were randomized to receive either selexipag or placebo and used a wrist-worn accelerometer to record DLPA. Most patients were functional class II, at low risk. They were on oral therapy with an ERA alone or in combination with a PDE5 inhibitor or sGC stimulator. The majority were on dual therapy.

Although the study results did not show statistically significant differences in DLPA parameters between selexipag and placebo, these results were not unexpected because the patients were very stable and did not need uptitration of therapy from a disease-progression standpoint. Also, they were not encouraged to increase their activity. However, what the study did provide is a strong baseline reading of the level of daily activity of an average stable PAH patient on one or two PAH-specific medications. In other words, the study provides the foundation for future randomized trials using actigraphy-related parameters as a primary endpoint.

Dr Vega: Ioana, before we finish up the episode, do you have any take-home messages about this topic you would like to share with our audience?

Dr Preston: Daily life physical activity is a critical parameter in patients with PAH. Not only is it a good indicator of disease severity and drug effectiveness, but it is intimately tied with quality of life for patients. As such, measuring daily life physical activity with an accelerometer is gaining traction in both patient evaluations in clinical visits and as endpoints in clinical trials.

Because of the importance of physical activity to a patient’s physical and mental health, I encourage my PAH patients to engage in enjoyable physical activity as much as possible, but to be mindful of not pushing themselves too far and exacerbating symptoms. I tell them that they don’t always have to be an A student. B is a good grade – if they are a B student, it’s fantastic. Every day is different, and it’s important to simply do your best every day and listen to your body and act accordingly.

Dr Vega: Thank you so much for your insights today, Ioana.

Dr Preston: My pleasure, Chuck.

Dr Vega: This brings us to the conclusion. We hope you found it informative and helpful to your practice. To proceed to the online CME test, click on the earn CME credit link on this page. And thank you for watching this program.