Mary Branch, MD, MS – The Early Career Voice

Solutions to Cardiology D&I Connection

December 9, 2021December 8, 2021 Mary Branch, MD, MS

Now that we know the harmful myths, importance & benefits of inclusion, as well as steps towards inclusion of BIPOC in cardiology. I hope we are aware too that this is not a zero sum game and we all can benefit by practicing together in this field.

So, what is the answer? Well, from someone who has integrated many spaces growing up, I know. You find connection, you learn from one another, and you grow.

The same principles can apply for all. Here are some final thoughts about how we can achieve cardiology workplace equity.

Communication

We all have one thing in common. We’re human. Finding commonality with trainees can help bridge any gaps and change biases. Socializing in the beginning to get to know people can be one way to start. This fosters good relationships and we all start on equal ground and build trust. It can be helpful also to check-in. These conversations can be open and honest in a safe space to share experiences (without judgement and non punitive).

Benefit of the Doubt

This is an important principle. With bias and hierarchy this can manifest into lack of benefit of the doubt. Many trainees who graduate medical school are smart. After a certain IQ, there is a marginal difference (discussed in Outliers by Malcolm Gladwell). If a mistake is made, assume the person is smart and discuss better strategies moving forward. It helps to give each other grace. Being clear about your own biases may address this issue. Negative actions stemming from bias and hierarchy can play out during frustration or stress. This can make an uncomfortable environment for the trainees. Consider addressing issues in your own life and this may be a remedy to this issue. We all have bias and personal issues, building awareness is a starting point.

Sponsorship

Once a trainee makes it through medical school and residency, they are smart and have endurance. Those who have drive and passion can likely be molded into successful researchers, teachers, and bedside clinicians. One way to help build community and help it grow in training is sponsorship. This can include recommendations for research projects or offering to bring them along to a talk or presentations (hopefully will be in-person soon). It can be fun to be a part of someone’s journey.

For BIPOC medical students and trainees

The above principles apply to us too. In any situation, it helps to look at the man/woman in the mirror and take accountability. We can recognize our own bias and ego. We also can work strategically towards excellence. Remember that at the end of the day; game recognize game. Further, we can determine how we may be holding ourselves back with imposter syndrome. You belong on that wall too! Some of us carry generational weight and feel the need to represent an entire community. You don’t have to hold that weight and can let go. Consistently remember to keep your eye on the prize and rise above the mellow drama. Just hold on. This too shall pass. There is a reckoning in this country; and this is the time to step out into the light. You are worthy.

This essay does not include every principle. Recommendations for how to connect can also be program specific. Many may grumble about these efforts and worry there will be a reversal of inequity. It’s important we swing the pendulum back to the center first. This takes intentionality. We all will benefit from this work to make a more peaceful environment. This can translate to improved patient outcomes and address health disparities, if we start from within.

“The views, opinions and positions expressed within this blog are those of the author(s) alone and do not represent those of the American Heart Association. The accuracy, completeness and validity of any statements made within this article are not guaranteed. We accept no liability for any errors, omissions or representations. The copyright of this content belongs to the author and any liability with regards to infringement of intellectual property rights remains with them. The Early Career Voice blog is not intended to provide medical advice or treatment. Only your healthcare provider can provide that. The American Heart Association recommends that you consult your healthcare provider regarding your personal health matters. If you think you are having a heart attack, stroke or another emergency, please call 911 immediately.”

The Medical Program Inclusivity List

May 26, 2021May 20, 2021 Mary Branch, MD, MS

In medicine, there is no widespread list of medical programs that are considered inclusive. During this time, the cardiology community has both publicized the need for addressing racial bias in medicine and advocating for inclusivity. Dr. Quinn Capers IV, who is an interventional cardiologist and appointed the Chair of the ACC’s Diversity and Inclusion Committee in 2020, has made great strides in this effort. Dr. Capers has traveled the country describing the experience of BIPOC (Black Indigenous People of Color) patients and physicians. He is presenting to different institutions to tackle racial bias in medicine. Drs. Laxmi Mehta, Sharonne Hayes, Toniya Singh, and additional exceptional colleagues have identified concerning data regarding discrimination, harassment, and a hostile work environment (HWE) in cardiology. They found higher rates of HWE in women (68%, over three-fold higher than men) and African Americans (53% with 46% increased odds compared to Whites). These issues require real solutions and likely have deep roots for BIPOC (‘Equity & Inclusion in Medicine Part II’). The importance of including more BIPOC in medicine is to increase community representation. The less community representation we have, the more progressive community chronic disease and inequity we will see.

As programs grow to understand how to boost the numbers of underrepresented minorities in general, it is also important for trainees to know which programs are considered supportive currently. Therefore, I decided to identify which specific programs were considered inclusive. Further, the goal of this inquiry was to share the names of these programs to the cardiology community interested in boosting diversity and inclusion (D&I).

In October of 2020, I sent out a Facebook posting to a group of African American physicians and dentists. I polled the group to ask which medicine programs were inclusive. All members were included to answer with no one excluded. A tally was created each time a member mentioned a program with the addition of ‘likes’.

After a follow-up time of approximately a week, there were 97 mentions and 329 tallies with the addition of ‘likes’. A total of 15 (4.5%) was the highest tally. The top three programs and specialties on the list were Emory – Emergency Medicine, Johns Hopkins-Internal Medicine, University of Chicago- Emergency Medicine (15,14,13 tallies respectively). The programs with the most frequent mentions were Baylor, Emory, and Mayo Clinic (mostly Minnesota) (5 mentions each). The most frequent specialties mentioned were family medicine (15), emergency medicine (11), internal medicine (11), and OB-GYN (11). In terms of cardiology, the top-rated programs in this specialty were Duke, Mayo Clinic, and Marshall with one tally each. I did a separate poll from a group of BIPOC/African cardiology fellows and the top program mentioned as being diverse and inclusive more than once was Duke. Other programs mentioned were Yale, Vanderbilt, SUNY Downstate, Mayo Clinic Arizona and Florida, UPENN, Rush, and the University of Kentucky Lexington. What constituted inclusive for the cardiology group came down mostly to pure numbers.

*EM-emergency medicine, *IM-internal medicine, *Anesth-anesthesia, *Neurosx-neurosurgery, *Peds-pediatrics, *FM-family medicine

This list is a helpful initial guide based on physician feedback regarding program diversity and inclusivity. This is a relatively novel approach to receiving feedback regarding D&I with crowdsourcing from social media/WhatsApp. Certainly, not all programs were represented, so one cannot extrapolate negative inclusivity from the lack of mention. As well, there may be a selection bias towards a program or specialty related to the group composition. Further, for both groups, this poll was on social media/WhatsApp and they may not have been alerted to it with busy training schedules.

Cardiology is a specialty that is encouraging diverse recruitment and aiming to create an environment of appreciation for fostering inclusivity (see ‘Equity & Inclusion in Medicine Part III’). The top programs have clearly invested time and resources into recruitment and retention. Cardiology program directors may benefit from their strategies. The goal of improving the number of underrepresented trainees in cardiology could boost curriculum innovation, incorporate a broader reach to a diverse patient population, and improve mentorship for URIM medical students and residents.

Equity & Inclusion in Medicine – Part III: How to Create a Diverse Cardiology Workforce

March 30, 2021March 29, 2021 Mary Branch, MD, MS

In Part I, I discussed experiences of BIPOC in medicine as well as those underrepresented in cardiology as a framework to build understanding. In Part II, I made a good case for why diversity will help cultivate innovation and improve health disparities. In the final part of this blog series, I will review how cardiology programs can improve diversity.

We are in an era of great reflection and growth as we endure the extreme pressures of the COVID19 pandemic. This horrendous experience has fostered some positivity which is the strong motivation towards racial harmony and equity. This is a special time of modernity and we can capitalize on this momentum by amplifying initiatives towards increasing diversity in cardiology.

The Duke cardiology group published a data-driven manual on how cardiology fellowships can improve diversity, especially for those who are underrepresented. In this article, Rymer et al.¹ designed a quality improvement study from 2017-2019 with the aim of increasing the numbers of underrepresented cardiology fellows in their training program. This initiative included reorganizing the fellowship recruitment committee, changing the applicant process and interview day, as well as making changes to the applicant ranking process. Finally, there was a postmatch intervention. This involved developing a diversity and inclusion task force to spearhead these initiatives. Comparing applicants 10 years before and during the intervention period, there was a significant increase in women and underrepresented applicants. Women increased from a 5-year mean of 27% to 54.2% after the intervention and underrepresented fellows increased from 5.6% to 33.3%. After the intervention, the fellowship population was 2/3rds either women or members from an underrepresented ethnic group!

Williams et al. further pushed toward cultivating an antiracist cardiology culture in their article entitled: How to Build an Antiracist Cardiovascular Culture, Community, and Profession ². The authors took a deep dive into several ways to build a diverse team. They state that to purposely create a culture of diversity, especially for those that lack diversity; programs should aim to share their objectives in creating a less biased training program for applicants. This strategy also includes having a diversity and inclusion committee to evaluate promotional materials to ensure they do not include racially biased language. Once trainees are there, they recommend continuing this initiative by having structured teaching sessions that include implicit bias training. They further recommend allowing for space for underrepresented trainees to share microaggressions. One example of a microaggression expressed by underrepresented physicians is constant questioning regarding country of origin or ability to speak English with a condescending tone. These stories can be shared on a personal level to help each other understand and appreciate different experiences.

There are professional ways to support trainees and create an inclusive environment. The authors suggest encouraging respect by introducing fellows as “Dr.” and leaders of the team. They emphasize intentional mentorship for underrepresented trainees shared amongst faculty. They further warn against perpetuating the “minority tax”, which puts the entire onus of diversity and inclusion on faculty of color with often a lack of compensation. In addition, the authors encourage all faculty to help introduce trainees into a network and provide a platform for successful promotion by nominating under-represented minority members to appropriate positions. Certainly, this can extend beyond fellowship. It goes without saying, that nomination and promotion is suggested for those who earn it; however, not uncommonly underrepresented fellows meet this criterion and may be overlooked.

The future of this country is one in which there may not be a majority. It is important that we understand one another and work together to move forward. Diversifying cardiology will bring about innovation and growth in the field. The patient experience can improve as well with more physicians who share their personal experiences. This can build communication and preventative measures. I hope that we continue this momentum and cultivate a better experience for all.

References:

Rymer et al. Evaluation of Women and Underrepresented Racial and Ehnic Group Representation in a General Cardiology Fellowship After a Systematic Recruitment Initiative. JAMA Netw Open. 2021; 4(1)
Williams et al. How to Build an Antiracist Cardiovascular Culture, Community, and Profession. JACC 2021 77 (9)

Equity & Inclusion in Medicine – Part II: Inclusion in Cardiology

February 17, 2021February 16, 2021 Mary Branch, MD, MS

In Part 1, I shared common experiences between myself and other BIPOC physicians in medicine and cardiology. In this piece, I will dive into the importance of why increasing diversity and inclusion in cardiology is so urgent. Cardiology is a coveted specialty and can incentivize a power dynamic that does not often include BIPOC. I would argue that for a progressive program, creating an inclusive workforce will help programs progress, be innovative, and positively impact patient care in the community. This change will be a win-win for all.

When reflecting on this topic, I am reminded of an African American woman who was crying on the cath table the other day, with a look of fear and helplessness. This was not long after a report of a physician of color, who was infected with COVID19, reported that her symptoms were dismissed, and later died. If a physician feels unheard, how can a woman of color who is not a physician feel safe? The cath team did a great job of comforting her, but it was hurtful to see her in such fear.

African Americans are significantly affected by heart disease risk factors; in fact, together these conditions contributed to >2.0 million years of life lost in the African American population between 1999 and 2010¹, with heart disease being the leading cause of mortality in African Americans. Unfortunately, there is a lack of African Americans in the physician workforce considering African Americans make up ~ 13% of the U.S population, but only 4% of U.S. doctors². According to the Harvard Business Review, increasing the numbers may improve health outcomes. They described a study in Oakland that assigned African American male patients recruited from barbershops to African American and Non-African American physicians. What they found was that African American patients were more inclined to agree to more invasive and preventative services than those with non-African American doctors. This is not an argument for a segregated system, but certainly increasing the numbers and learning from colleagues can help BIPOC patient outcomes.

One historical change in medicine that impacts care in the African American community is likely rooted in the Abraham Flexner Report³. An African American medical student applying to medical school in 1900 had 10 choices which declined to approximately a quarter of that by 1920. The Flexner Report, which was meant to trim the medical workforce to only those with the greatest quality of training, decided that only two medical schools that trained African Americans (Howard University and Meharry Medical College) were worthy of staying open. His devastating comments terminated the rest⁴. My cousin, Dr. Hubert Eaton, wrote about this dilemma in his book Every Man Should Try⁵. He graduated from the University of Michigan School Medical School in 1942 and his father went to Leonard Medical School (see Table 1⁴). He found his father’s exam scores and noted they matched his own. He was perplexed that Leonard was shut down and he wondered: Who validated the Flexner report? Why was one individual able to create this modernity in medicine without any scrutiny?

By building diversity and increasing contact between those who have shared experiences, the field of cardiology could improve BIPOC patient trust and compliance as well as reduce cardiovascular disease outcomes. This change could lead to lower hospital admissions and increase prevention efforts. Many BIPOC is inspired by giving back to the community and being involved in community engagement. This community service is via BIPOC oriented organizations (e.g., The Divine 9 fraternity and sororities, the Boule, The Links, Incorporated, etc.) as well as the Black Churches. As BIPOC cardiologists, we have the ability to teach important primary prevention to thousands of people and the message is stronger if that provider looks like the community they represent.

Cardiology is a prestigious field and as such should aim to set an example for leadership across the country. We know that inequities exist in all aspects of cardiovascular disease and one way to combat this issue is to build a diverse workforce. When we lost community physicians after the Flexner report, we lost the community itself; the field of cardiology has the resources to restore this relationship and improve heart disease outcomes.

References:

Carnethon et al. Cardiovascular Health in African Americans: A Scientific Statement From the American Heart Association. Circulation 2017: 136(21)
Research: Having a Black Doctor Led Black Men to Receive More-Effective Care by Nicole Torres. Harvard Business Review 2018
Flexner A. Medical Education in the United States and Canada. Washington, DC: Science and Health Publications, Inc.; 1910.
Savitt. Abraham Flexner and the Black Medical Schools. Journal of the National Medical Association. 2006: 98 (9)
Every Man Should Try by Dr. Hubert Eaton

Equity & Inclusion in Medicine – Part 1: my experience as a BIPOC in medical training

January 18, 2021January 15, 2021 Mary Branch, MD, MS

As someone who integrated her elementary school in Ohio (a Yeshiva), enrolled in an exclusive prep school in New England and became the first AA female in her cardiology program, I’ve spent my life analyzing how to adapt to environments in which I was different. When I enter an environment, I learn the lay of the land, identify key players, and observe interactions. I am a fourth-generation African American physician and was raised learning about my relatives’ experiences as minorities in medicine. If I, as early as age 9, could learn how to thrive in diverse environments others can too. I would like to share these experiences and make a case for diversity in cardiology. With this blog, I will help kick off the New Year with part 1 of a multiple part series that aims to define bias in medical training; openly make a case for and provide solutions towards inclusion in cardiology.

In this blog, I will review specific features that demonstrate bias, which can lead to less diversity in training programs. These are topics related to experiences in medicine that are shared by myself as well as my BIPOC and women colleagues.

Affirmative Action, The myth

There’s this assumption that BIPOC has a leg up unfairly given by Affirmative Action, and therefore are enrolled in academic programs without earning it and being unqualified. Truthfully, nepotism and ease of identifying mentors provide more opportunities than any small % quota which does not seem to translate to faculty positions. In research, at times I have had to become my own mentor to continue to propel myself forward. Without visible faculty mentors, it is difficult to envision a role in academic medicine which makes this career aspiration less likely for many BIPOC. The educational system’s balance as a whole has been skewed related to the American Caste system (consider reading Caste by Isabel Wilkerson). This affects testing metrics and exposure to certain educational experiences. However, with the right inclusion, training, and belief in someone; talented students will become great physicians and cardiologists. In fact, this idea that BIPOC is all unqualified is ironic; many of us feel we have to work twice as hard with a cool and steady temperament all the way through (think of President Obama) to get half as far. Despite strong backgrounds; I often hear colleagues make comments like: “ They are not as clinical.” I already know the race before hearing the full story. We can’t all be inept; not possible.

Double Standards/ Lack of Benefit of the Doubt

Double standards, a topic at this nation’s center as we watched different responses to the siege on Capitol Hill. In cardiology and medicine, it is not uncommon that the same errors in one person may receive a different response from leadership compared to another. One cardiologist stated that he, like many of his colleagues, inadvertently caused a coronary dissection. The response, however, was harsher than what his colleagues experienced for the same incident. One simple misunderstanding with a BIPOC resident or medical student led to unnecessary poor feedback to this resident that could have been remedied with a conversation. She was not given the benefit of the doubt like her peers would have; in fact, I don’t think the incident would have been reported at all considering how trivial it was. At times, we feel closely observed and overly scrutinized. At times by other women and BIPOC as well. Perhaps there is a “crabs in a barrel” mentality when there are so few represented in one place, this can actually create tension. What’s most difficult is, there’s less ability to be human; which is amplified when it seems as if there is not always a trustworthy authority to turn to. It may not be that one BIPOC placed in a leadership position; they may not want to rock the boat.

So we feel that we must work twice as hard; smile (wear the mask long before COVID19), with only marginal to no room for error (there is a great scene in the movie about the Tuskegee Airmen on HBO that highlights this point).

Abstract Feedback

Often we receive feedback that is very vague and abstract and seemingly more personal than constructive. It’s generally a vague comment that has one racking their brain over and over with no real tangible solution provided by the person giving the feedback; this was described in “Research: Vague Feedback Is Holding Women Back.” For example, I was once told, “You’re too confident.” How do I change my confidence? How can I be less confident, but at least somewhat self-assured? Do you see how this happens? Not too uncommonly we receive nonactionable feedback that has one racking their brain and can have an emotional impact. It’s distracting. Actionable feedback is more helpful especially if it is not something very personal and aimed more at patient care. One mentee of mine received an overall vague evaluation and marked her with critical deficiencies without good evidence. I did not want this practice to continue, and I wrote to the associate program director to describe the scenario and shared my concerns. It was determined that this evaluation was a mistake after a larger review. Imagine a situation had it stayed on her record; it could have had negative implications to her career, especially, when she is planning to pursue a selective fellowship.

Assumptions

During a medical school interview, I was asked if they should accept fewer women due to pregnancy. I was never comfortable sharing my pregnancy considering this was my first introduction. He assumed women couldn’t make these decisions, and that, affirmative action should be taken away (this was 2008; not long ago). I have also found that, before really knowing one’s interest, it is assumed a female cardiologist will pursue a career in imaging. I am often asked “ You’re doing imaging, right?” Or I’ve heard, “ she is an imager, typical.” This can impact cath scheduling if there are no fixed schedules for all fellows. In fact, scheduling is where bias can creep in ( I have heard of giving longer hours to BIPOC forcing one group of residents to threaten federal intervention.) This can be avoided with as much equal scheduling as possible (not always perfectly feasible) without assuming anything. Assumptions are not meant to be hurtful; it’s human nature. However, at times it may pigeonhole folks to roles that must end with women’s health, equity, or inclusion (exceptionally relevant roles). These folks can also have leadership roles related to other clinical interests as well.

Certainly, these may not all be unique to BIPOC and women; however, I hear similar stories over and over again, as if they are told by the same person. As we enter into a new era, I hope cardiology joins the future of progress. In parts II and III, I will answer why inclusion is important and some solutions on how to cultivate an inclusive specialty.

For this series, we will be discussing –

Part 1. My experience
Being hypnotized that I am lower in the caste system and limited. The emotion clouded my abilities and held me back from further progress. I have to prove my resume more than my colleagues every time and it’s exhausting. In research, I’ve felt like an outsider constantly having to build my own way and have been directly judged for lack of prolific publications.

Part 2. Why?
Embracing difference can help a program evolve (% diversity at Harvard ) it’s a win-win; a synergistic relationship in which we grow together. Representation matters, and to diversify the workforce will help the patients’ comfort and compliance.

Part 3. How?
Aim for a standard similar to Goldman Sachs’s 25%¹. Provide resources and assistance to BIPOC. Show up for each other. Engage ABC and uplift ; normalize discussing differences and being different. Check in with your BIPOC trainees’ wellbeings, if there are issues driven by bias speak up with your peers in a collegial way.

Reference

https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2774738?utm_source=twitter&utm_medium=social_jamajno&utm_term=4395647160&utm_campaign=article_alert&linkId=108893385

Cardio-Oncology, Meet Your New Neighbor: Immunology

November 17, 2020November 17, 2020 Mary Branch, MD, MS

In this AHA session, an international group of physician scientists discussed ways to mitigate immune checkpoint inhibitor (ICI) induced myocarditis and future therapies. The session, moderated by Dr. Sakima Smith MD, MPH, FAHA (from THE Ohio State), and Dr. Doug Tiley highlighted studies by Drs. Burkhard Ludewig, DVM, Dr. Han Zhu, MD, Dr. Alcaide, PhD, Dr. Peter Liu, MD and Dr. Joe-Elie Salem, MD, PhD. The talk began with presenting the problem, basic-science T-cell mechanisms including involvement of microbiota, and ended with a possible targeted therapy, Abatacept. This is a hot topic in the cardio-oncology world considering the high mortality in those affected (up to 50%!) ^[1].

Source: Cardio-Oncology, Meet Your New Neighbor: Immunology| American Heart

ICIs (eg. ipilimumab, pembrolizumab) are effective targeted therapies in patients with PDL-1/PD-1 expression on tumor cells. Many cancer phenotypes are FDA approved for treatment which includes melanoma, renal cell carcinoma, non-small-cell lung cancer, Hodgkin lymphoma, and more^[2]. Although these agents have shown to extend cancer survivorship^[3] , they have inadvertent side effects that can lead to myocarditis and cardiomyopathy. ICIs act by “releasing the brake” of T cell immune proliferation. These monoclonal antibodies block PD1/PDL-1 ligands/receptors and allow for T cells to bind to tumor cells leading to reduced tumor burden^[3]. Understanding the mechanism for ICI induced myocarditis is partially based on PDL1 knockout mice^[4]^. Unfortunately, there is cross-reactivity that occurs via binding to cardiac antigens (eg. myosin) leading to the inflammatory response^[4].

Dr. Zhu informed us that the risk of this effect includes dual ICI treatment. In addition, early identification is key, considering 50% mortality. Patients may have a drop in their ejection fraction (EF), but have other signs of cardiac injury including brady and tachyarrhythmias. She highlighted that our current data is from FDA sponsored pharmacovigilance databases collected by Dr. Javid Moslehi, who is a pioneer and leading investigator on this subject. A registry created by Dr. Tom Neilan’s lab at Massachusetts General Hospital demonstrated an increased risk of MI and stroke after treatment with ICI^[5]. Her group at Stanford along with renowned Dr. Ronald Witteles is using biobanking to identify patients with autoimmune myocarditis and controls to conduct downstream high-throughput immune repertoire analysis. Dr. Alcaide supplemented this talk by adding a novel mechanism. She discussed that reactive oxygen species (ROS) play a role in triggering downstream T cell expansion in the heart. Therefore, there may be a role in anti-oxidant therapy to reduce T cell response. Dr. Liu acknowledged our current pandemic and discussed the added risk of inflammation in the setting of concomitant COVID19 viral infection associated with myocarditis.

During this session, we learned about possible therapies to mitigate myocarditis. Dr. Ludewig discussed his teams work with an ICI mouse model. They explored T cell cross-reactivity that led to the lethality of the disease. There was a heart-gut connection! They found elevation of Bacteroides-specific CD4+ T cells in disease models which suggests that mimic peptides from commensal bacteria can promote inflammatory cardiomyopathy in genetically susceptible patients (those with HLA DQB1*03:01 polymorphisms) by showing increased reactivity against myosin 6 (MYH6) (cardiac antigen). His study suggests that the genetic susceptibility along with cross-reactivity antigens in the heart and potentially the intestine put patients at risk for fulminant myocarditis. Therefore, he proposed the use of antibiotics as a cardioprotective agent by blocking the cross-reactivity that leads to ICI induced myocarditis.

Source: Ludewig: ‘Dangerous gut-heart liaison’| When it comes to matters of the heart, don’t always trust your gut/ Cruz et al. Microbiota-derived peptide mimics drive lethal inflammatory cardiomyopathy. Science 2019; 336, 881-886.

Dr. Joe Elie-Salem (making us jealous by Zooming in from Paris; Ca alors!) ended the session with the introduction of abatacept for therapeutic use in ICI induced myocarditis. Corticosteroids are the mainstay of treatment; however steroid therapy is nonspecific and there are unintended off-target side effects. Specifically, there is a high association with concurrent myasthenia gravis-like syndrome with ICI myocarditis that presents a challenge with the use of steroids. Steroids can lead to an exacerbation of myasthenia crisis which can lead to significant respiratory failure^[6]. Based on work with Dr. Moslehi, abatacept (a cytotoxic T-lymphocyte-associated antigen 4 [CTLA-4] agonist, they found that in anti-CTLA4 and Anti—PDL-1 treated disease mouse models, treatment with abatacept reduced myocarditis induced death. This agent will be further explored in a Phase II trial titled: ACHLYS-trial: Phase II trial testing abatacept for ICI-myocarditis.

The take-home points for this session include: 1) ICI used to treat many cancer phenotypes are associated with incident myocarditis with up to 50% mortality 2) Cross-reactivity with cardiac antigens leads to myocyte dysfunction and the clinical sequelae of this includes cardiomyopathy (not always!) and brady/tachyarrhythmias 3) Understanding predisposing immune variants and microbiota (Bacteroides- B. theta) related to immune response associated with this disease is key to identifying all the possible therapies including antibiotics 4) Abatacept is a known T cell immunomodulator and it has a potential role in treating ICI induced myocarditis; especially in those at risk for corticosteroid effects (eg. myasthenia gravis), which will be further explored in a clinical trial.

REFERENCE

Ball, S., et al., Cardiovascular Toxicities of Immune Checkpoint Inhibitors: JACC Review Topic of the Week. J Am Coll Cardiol, 2019. 74(13): p. 1714-1727.
Zhou, Y.W., et al., Immune Checkpoint Inhibitor-Associated Cardiotoxicity: Current Understanding on Its Mechanism, Diagnosis and Management. Front Pharmacol, 2019. 10: p. 1350.
Ferris, R.L., et al., Nivolumab for Recurrent Squamous-Cell Carcinoma of the Head and Neck. N Engl J Med, 2016. 375(19): p. 1856-1867.
Nishimura, H., et al., Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science, 2001. 291(5502): p. 319-22.
Drobni, Z.D., et al., Association Between Immune Checkpoint Inhibitors with Cardiovascular Events and Atherosclerotic Plaque. Circulation, 2020.
Xing, Q., et al., Myositis-myasthenia gravis overlap syndrome complicated with myasthenia crisis and myocarditis associated with anti-programmed cell death-1 (sintilimab) therapy for lung adenocarcinoma. Ann Transl Med, 2020. 8(5): p. 250.

Bending the Curve for CV Disease- Precision or PolyPill?

November 14, 2020November 17, 2020 Mary Branch, MD, MS

Source: https://www.phri.ca/

Drs. Yusuf and Pais from the Population Health Research Institute in Ontario, Canada presented data from the International Polycap Study (TIPS)-3 study[1] as part of the Late-Breaking Science Session: Bending the Curve for CV Disease-Precision or PolyPill? at the AHA20 Scientific Sessions. The aim of this study was to try to simplify primary prevention via a ‘polypill’ (Polycap) for not only cardiovascular disease (CVD) but also conditions with similar risk profiles, such as breast cancer and osteoporosis. The polypill contains 3 blood pressure medications (hydrochlorothiazide (25mg), atenolol (100 mg), ramipril (10mg)) and a statin (simvastatin (40 mg). They are searching for a ‘magic bullet’ if you will, to reduce these chronic diseases with a high burden in the U.S and around the world. Precision medicine can be effective but is costly. The use of a polypill can help to reduce the curve of disease burden or at least shift it towards reducing the number of high cardiovascular risk people worldwide.

Source: Joseph et al. The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct. Am Heart J. 2018 206:72-79

This study enrolled 5,713 middle aged participants from 10 different countries (Including India, Tanzania, and Tunisia). With a 2x2x2 factorial design, randomized controlled trial investigators aimed to assess the effectiveness of PolyCap the ‘Polypill’. Participants were eligible for the study if they did not have prior heart disease or stroke. Participants were excluded if they had any contraindications to the study medications, low and symptomatic hypotension, history of malignancy, and inability to attend follow-up. There were three treatment arms. The participants were randomized to the polypill vs placebo. In addition, participants were also randomized to receive aspirin (75 mg) and vitamin D (60,000 IU monthly) each vs. placebo. The primary outcome was major cardiovascular disease (CVD) (CV death, non-fatal stroke, non-fatal MI), plus heart failure, resuscitated and cardiac arrest, or revascularization with evidence of ischemia in participants taking Polycap versus placebo. For the aspirin arm, the primary outcome was composite CV events ( CV death, MI or stroke) and cancer. For vitamin D arm, the primary outcome was risk of fractures in participants taking Vitamin D. The data presented at AHA2020 Scientific Sessions was for the Polypill with and without aspirin alone vs. placebo. This was an intention to treat analysis. Investigators also conducted a sensitivity analysis for those who were not able to adhere to medications and identified outcomes at 30 days in the active and placebo groups.

Source: Joseph et al. The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct. Am Heart J. 2018 206:72-79

After a follow-up time up to 5 years, the investigators enrolled a cohort of 53% women with intermediate CVD risk based on the IH (INTERHEART) risk score (1.5 % per year risk of CVD). For participants taking the Polypill vs. placebo, there was a significant mean reduction in systolic blood pressure by approximately 5 mm Hg and LDL-C by approximately 19 mg/dL. There was a 21% reduction in the primary outcome; however, overall mortality was not significantly different. The greatest reduction was seen with revascularization with a 60% reduction compared to the placebo. There was a reduction in cancer outcomes as well, but not significantly; this is likely related to low events. The bleeding risk profile was low. With the combination of aspirin and the Polypill, there was a 31 % risk reduction compared to placebo, aspirin alone, and the Polypill alone ( compared to 14% with aspirin vs. placebo alone) in the composite primary outcome but no overall mortality benefit. This was mainly driven by a reduction in stroke. CVD death and cancer were significantly reduced by 30% compared to placebo. There was also a reduction with systolic blood pressure and LDL-C as seen with the Polypill alone. Aspirin alone did not show any difference with major/minor bleeding or GI bleeding likely related to having a run-in period and a lower dose of asa (75 mg). In both cases, the heart failure rate was higher in both groups but this was not significant with a wide confidence interval with low event. It is important to note that lifestyle modification teaching was also instituted and the reduction in outcomes is therefore contributed to both the medication and education. One main issue was adherence to the medications (just two pills) up to 43%! This was in part due to COVID19 by the end of the study. Per the sensitivity analysis, the outcomes of those with some adherence (<30 days) were still significantly lower than the placebo. Taking something for even a short period of time is better than nothing.

The authors highlight the significant limitation of non-adherence which can create a selection bias in the data. However, if only half eligible people adhere to this regimen, 3-5 million CVD events can be avoided each year globally. They note that the challenge of adherence lies in social determinants of health, which have a great impact on CVD outcomes. More needs to be done to understand cost-effective ways to ‘bend the CVD curve’ by identifying effective implementation programs (including telehealth) to distribute this combination of medications.

References:

Joseph et al. The International Polycap Study-3 (TIPS-3): Design, baseline characteristics and challenges in conduct. Am Heart J. 2018 206:72-79