TAVR was first approved by the US Food and Drug Administration (FDA) in 2011 for use in patients with severe aortic stenosis who are ineligible for surgery, and approvals for additional patient groups followed.¹ In 2019, TAVR received FDA approval for use in patients with severe aortic stenosis who are at low risk for death or complications associated with open-heart surgery.²
 
In randomized clinical trials, TAVR was noninferior or superior to SAVR in patients at various levels of surgical risk.³ Ongoing advances in technological design and operator experience have led to continued improvements in TAVR’s safety and complication rates.⁴
 
Sammy Elmariah, MD, MPH, is an associate professor of medicine and chief of Interventional Cardiology at the University of California San Francisco (UCSF), medical director of the UCSF Cardiac Catheterization Laboratory, and codirector of the UCSF Heart Valve Program. Dr Elmariah leads clinical trials evaluating new transcatheter devices for the treatment of heart valve disease, and he is also involved in research exploring ways to expand access to heart valve disease treatments and in studies investigating the potential role of blood biomarkers to guide the timing of heart valve procedures. In this article, Dr Elmariah describes the current state of progress and ongoing developments in TAVR.

With more patients with severe aortic stenosis opting for TAVR, how does the latest generation of transcatheter heart valves improve procedural outcomes and QOL in these patients, especially those considered at high risk or ineligible for traditional surgical intervention?

The TAVR devices have undergone numerous iterations that have made the procedure much safer and much more reliable, and I think the entire community has established more streamlined ways of doing these procedures. Very frequently, efficiency goes hand in hand with safety, so patients are now undergoing this procedure under monitored anesthesia, not general anesthesia. It is being done without intubating patients and without transesophageal echocardiogram guidance, and most patients are going home within 1 hospital day, despite the fact that these are elderly patients with multiple comorbid conditions.
 
Over the years, the devices have become smaller and smaller in profile, which has allowed us to insert these valves using smaller and smaller catheters, so that has certainly made rates of vascular complications lower. Device iterations have also made rates of paravalvular leak — which was initially kind of the Achilles’ heel of TAVR — lower across the board, whether in bicuspid or tricuspid aortic valve disease. Because of the improved safety of this technology and the improved outcomes with the procedure, TAVR has been serially approved for healthier populations and younger patients.
 
Robust QOL improvement is seen with TAVR, and a major advantage of TAVR over SAVR is that patients reap that QOL benefit much more rapidly because they do not have to go through the recovery period and healing process of an open-heart surgery procedure. Generally, with open-heart surgery, the improvement in QOL does not happen until 3 to 6 months after surgery, whereas with TAVR, there is robust improvement in QOL by the patient’s 1-month follow-up visit.⁵

Which patient-level and clinical factors are associated with more favorable outcomes after TAVR, and which patient groups are generally better candidates for SAVR?

I think TAVR works quite well in the majority of patients. The problem that we are having now is that more patients want TAVR than we feel comfortable offering it to, and the biggest variable there is age. We started studying TAVR in the absolute sickest of patients, so in those very early studies, the TAVR outlasted the patients; we never got a good understanding of valve durability in studies done 15 to 20 years ago.
 
In more recent studies, we are studying TAVR in a healthier, younger population of patients over the age of 65. We have a 3- to 4-year follow-up in that patient population, and that was a randomized study (ClinicalTrials.gov identifier: NCT02701283) compared against surgery.⁶ At this moment in time, it seems that valve durability is comparable to surgical valves that are implanted using open-heart surgery. But we do not know what is going to happen down the line, so we are conservatively telling patients that these valves will last about 10 years, whereas with a surgical valve, we tell patients that it will last around 15 years.
 
To be honest, we really do not have great data on either technology, and the current ongoing studies will follow patients for 10 years and will continue to compare the valve performance out to the 10-year follow-up point.⁶ That is really the piece of data that we need to determine whether we can expand TAVR to patients who are younger than 65. Currently, many patients come to us who are in their 50s, or even 40s, and want TAVR; we are forced to say, “It is not approved or appropriate for you, and you need something that is going to last you for 40, 50, or 60 years, not our estimated 10 to 15 years.”

Which advancements in transcatheter heart valve design and delivery systems have contributed to enhanced valve stability and reduced instances of paravalvular leak, ultimately leading to improved patient safety and long-term durability?

The biggest development that has reduced rates of paravalvular leak with TAVR is the addition of a skirt or wrap of some sort around the bottom edge of these prostheses.⁷ Think about a TAVR valve compared with a surgical valve: when a surgeon does a SAVR, they cut out the valve and clean out all the calcium. They essentially have this nice, round, clean annulus in which to sew a brand-new valve. Because they are sewing it in place, they can also make sure that it nicely seals all the way around.
 
However, when we do a TAVR, we go in, open up the valve, and just push the old valve aside, so there are all these nooks and crannies between elements of the valve and the bulky calcium on the valve leaflets where there is potential for a leak of blood around the valve back into the left ventricle. With the addition of these fabric wraps on the bottom of the valve, that softer material can help to fill some of those nooks and crannies, which substantially reduces the amount of paravalvular leak we are seeing.
 
Valve stability has really never been an issue, to my knowledge. These valves are pretty reliable from that perspective. Regarding the future iterations of these valves, what people are starting to think about now is how these valves are going to act when we put more than 1 valve in a patient. Let’s say their first TAVR valve fails 10 to 15 years down the line, and they need a second valve. How is that geometrically going to fit in the patient? Are we still going to re-access the coronaries? Are we still going to have superior hemodynamics for these valves?
 
All of those design elements are starting to be considered now as we think about expanding TAVR to younger and healthier populations. The biggest development that I see in the future is a change in design that maintains access to the coronary arteries, even with repeat procedures. I think that is something that will tremendously help our ability to roll this out to a broader population.

What are some of the more common complications after TAVR, and what strategies do clinicians rely on to help minimize these issues or address them when they arise?

With current-day TAVR, the in-hospital mortality rate is about 1%.⁸ The stroke rate is about 2%.⁹ Major vascular complications have dropped to the single digits as well — about 4% or 5%.¹⁰ So the procedure has become quite safe, which is why it makes sense to expand it to healthier populations. The fact that we are now doing it in low-risk patient populations is dependent on that evolution and improvement in patient safety.
 
It is a bit tough to answer the question of what we do to reduce complications. We are not treating this as a surgical procedure; it is more akin to what is happening in a catheterization laboratory — by removing things such as intubation, transesophageal echocardiogram, placement of an arterial line, and placement of a Foley catheter, we can help reduce complication rates. This is because the more you do to a patient in a healthcare setting, the more opportunities there are for complications. By streamlining these procedures and getting people in and out of the hospital quickly, I think we can reduce some of the complications that were previously attributed to the procedure.

A 2021 paper noted that improvements in TAVR have allowed expansion of the procedure to younger, lower-risk patients with longer life expectancies.³ What are the unique issues and clinical considerations associated with TAVR in this patient population?

When we started doing TAVR, focusing on patients who were very elderly and very sick, it was all about the procedure itself. How do we do the procedure better? How do we do the procedure more safely? How do we perform the procedure more efficiently?
 
Now that we are talking about healthier patients, the added consideration is, how can we provide lifelong management to this patient? If we are seeing a 65-year-old patient and our intent is for that patient to live to 100, then we need to be confident that we can manage that patient’s aortic stenosis for at least 35 years. Technically, on the basis of the current guidelines, TAVR is approved if somebody has a life expectancy of less than 20 years, because the idea is that you can do 1 TAVR that will last around 10 years.¹¹ At that point, you put a second valve in place that will hopefully give the patient another 10 years.
 
Again, I think 10 years is a little conservative, based on the current literature. Hopefully, the valve will last 15 years or maybe even longer, but what we have to think about is what happens when we do a valve-in-valve or a TAV-in-TAV. When you put a valve inside a valve, the second valve pins open the leaflets of the first valve. If the coronary arteries are right behind the open stent frame of a TAVR valve and all of a sudden you pin open the solid-tissue leaflets, you could occlude or obstruct the coronary arteries.
 
That is a major limitation that will become more relevant as we treat younger patients. We have to develop techniques either for removing leaflet tissue or cutting leaflet tissue so that we can ensure there is flow into the coronary arteries when we do a second procedure. Some of the new device iterations are providing larger cells and valve shape differences that may help maintain blood flow into the coronary arteries even with a TAV-in-TAV procedure. Another thing is that when you put a valve in a valve, and maybe another valve in 2 valves, you are going to have a smaller valve each time. Trying to think about what the hemodynamic consequences of that are and how we can mitigate that risk is going to become more important as we move forward.
 
Finally, we need to work in partnership with our surgeons because 1 approach that has been discussed in the literature is whether we could do a TAVR in a younger patient. When that first valve degenerates, maybe we could put a second valve in, and then when that valve degenerates, we would remove it surgically, put in a surgical valve, and then do 2 valve-in-valve TAVRs after that.¹² That would be a whole string of procedures, but the order in which you perform these procedures may allow TAVR to be done at earlier life stages.
 
Our surgical colleagues need to become more proficient in removing these valves, and we may require some device iterations that make it easier to remove these valves surgically because current literature suggests that when these valves need to come out, that can sometimes be a more complex surgery.¹³

An observational study by Elbadawi et al found racial and ethnic disparities in rates of TAVR uptake in the US. While Black and Hispanic individuals constitute roughly 13% and 17.1% of the US population, respectively, these groups represented only 3.9% and 3.7% of TAVR procedures, respectively.¹⁴ What are some of the possible factors driving these disparities?

The disparities are quite stark, and the fundamental reasons are difficult to pin down. It seems that patients who are members of ethnic or racial minority groups frequently are less linked into the healthcare system, and they have less access to specialty care.¹⁵ Either aortic stenosis is identified in a patient and falls through the cracks or a patient is not recognized as having this and not treated until very late in their disease stage.
 
To give you an example and a summary of a recent study we published, we took patients who had already undergone an echocardiogram, so they already had the diagnostic test to diagnose severe aortic stenosis. We looked at the proportion of patients who received a billing code for aortic stenosis, essentially indicating that someone in the healthcare community recognized the aortic stenosis and acknowledged it, added it to the problem list, and was managing it. That very simple step did demonstrate racial and ethnic disparities, with patients of Black and Hispanic backgrounds being much less likely to get the diagnosis code.¹⁵ We looked at the reason, and it seems that people for whom the echocardiogram was done in the inpatient setting were less likely to get the diagnosis code because, of course, providers in the inpatient setting are focused on whatever medical problem the patient is admitted for.
 
If a patient is admitted for kidney trouble or gout or knee pain, for example, and they happen to get an echocardiogram because somebody heard a murmur and aortic stenosis was appropriately identified, once that patient leaves the hospital, who follows up on it if that patient does not have a cardiologist or if their primary care doctor never gets the results of the echocardiogram? Unfortunately, that scenario is more likely to happen in minority groups and people who have a lower socioeconomic background because they do not have as much access to the healthcare system.

What should be the focus of ongoing research in this area to further improve outcomes in patients undergoing TAVR? What are some of the most notable emerging developments in this regard?

The field has done a fantastic job of improving the procedural outcomes, and now we need to shift beyond that and look at how we can improve the delivery of this lifesaving technology to all the patients who need it. We have touched on that issue with the racial and ethnic disparities, but to give you another sense of things, severe symptomatic aortic stenosis that goes untreated results in death in about 50% of patients at 2 years.¹⁵
 
We can treat it with SAVR or TAVR, and those are lifesaving therapies that essentially cure the disease, yet we treat only about one-half of patients in the US who have symptomatic severe aortic stenosis.¹⁶ That means that about one-half of patients likely have a 50% chance of dying within 2 years — that is a tremendous healthcare issue. We can do so much better in caring for our patients with valvular heart disease simply by improving their access to this lifesaving technology.
 
Importantly, these patients need to universally be sent to heart valve teams — teams that are multidisciplinary or that are experts in managing valvular heart disease — so they can determine whether the patient is ready for the therapy and what the appropriate approach is for that patient, whether surgical or transcatheter. A lot of patients are not getting to those specialists, so they do not get the treatment they need. Increasing attention is being given to leveraging technology in the electronic health record — leveraging artificial intelligence or machine learning — to essentially flash a bright light to warn providers that their patients have severe aortic stenosis so the patients can be referred to the appropriate specialists who can manage the disease.
 
This Q&A was edited for clarity and length.

Disclosures

Sammy Elmariah, MD, MPH, reported affiliations with Edwards Lifesciences Corporation and Medtronic.

References

1. Mahmaljy H, Tawney A, Young M. Transcatheter aortic valve replacement. In: StatPearls. StatPearls Publishing; 2023. Accessed August 25, 2023. https://www.ncbi.nlm.nih.gov/books/NBK431075/
 
2. FDA expands indication for several transcatheter heart valves to patients at low risk for death or major complications associated with open-heart surgery. News release. US Food and Drug Administration. August 16, 2019. Accessed August 25, 2023. https://www.fda.gov/news-events/press-announcements/fda-expands-indication-several-transcatheter-heart-valves-patients-low-risk-death-or-major
 
3. Avvedimento M, Tang GHL. Transcatheter aortic valve replacement (TAVR): recent updates. Prog Cardiovasc Dis. 2021;69:73-83. doi:10.1016/j.pcad.2021.11.003
 
4. Rouleau SG, Brady WJ, Koyfman A, Long B. Transcatheter aortic valve replacement complications: a narrative review for emergency clinicians. Am J Emerg Med. 2022;56:77-86. doi:10.1016/j.ajem.2022.03.042
 
5. Lauck SB, Arnold SV, Borregaard B, et al; 3M TAVR Investigators. Very early changes in quality of life after transcatheter aortic valve replacement: results from the 3M TAVR trial. Cardiovasc Revasc Med. 2020;21(12):1573-1578. doi:10.1016/j.carrev.2020.05.044
 
6. Forrest JK, Deeb GM, Yakubov SJ, et al; Low Risk Trial Investigators. 3-year outcomes after transcatheter or surgical aortic valve replacement in low-risk patients with aortic stenosis. J Am Coll Cardiol. 2023;81(17):1663-1674. doi:10.1016/j.jacc.2023.02.017
 
7. Chiarito M, Spirito A, Nicolas J, et al. Evolving devices and material in transcatheter aortic valve replacement: what to use and for whom. J Clin Med. 2022;11(15):4445. doi:10.3390/jcm11154445
 
8. Murthi M, Velagapudi S, Sharma B, et al. Comparison of in-hospital mortality and clinical outcomes between patients aged more than and less than 80 years undergoing transcatheter aortic valve replacement. Cureus. 2022;14(4):e24534. doi:10.7759/cureus.24534
 
9. Huded CP, Tuzcu EM, Krishnaswamy A, et al. Association between transcatheter aortic valve replacement and early postprocedural stroke. JAMA. 2019;321(23):2306-2315. doi:10.1001/jama.2019.7525
 
10. Sardar MR, Goldsweig AM, Abbott JD, et al. Vascular complications associated with transcatheter aortic valve replacement. Vasc Med. 2017;22(3):234-244. doi:10.1177/1358863X17697832
 
11. Otto CM, Nishimura RA, Bonow RO, et al. 2020 ACC/AHA guideline for the management of patients with valvular heart disease: executive summary: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. 2021;143(5):e35-e71. doi:10.1161/CIR.0000000000000932
 
12. Virgili G, Romano SM, Valenti R, et al. Transcatheter aortic valve implantation in younger patients: a new challenge. Medicina. 2021;57(9):883. doi:10.3390/medicina57090883
 
13. Bapat VN, Zaid S, Fukuhara S, et al; EXPLANT-TAVR Investigators. Surgical explantation after TAVR failure: mid-term outcomes from the EXPLANT-TAVR International Registry. JACC Cardiovasc Interv. 2021;14(18):1978-1991. doi:10.1016/j.jcin.2021.07.015
 
14. Elbadawi A, Naqvi SY, Elgendy IY, et al. Ethnic and gender disparities in the uptake of transcatheter aortic valve replacement in the United States. Cardiol Ther. 2019;8(2):151-155. doi:10.1007/s40119-019-0138-1
 
15. Crousillat DR, Amponsah DK, Camacho A, et al. Racial and ethnic differences in the clinical diagnosis of aortic stenosis. J Am Heart Assoc. 2022;11(24):e025692. doi:10.1161/JAHA.122.025692
 
16. Li SX, Patel NK, Flannery LD, et al. Trends in utilization of aortic valve replacement for severe aortic stenosis. J Am Coll Cardiol. 2022;79(9):864-877. doi:10.1016/j.jacc.2021.11.060
 
Posted by Haymarket’s Clinical Content Hub. The editorial staff of Cardiology Advisor had no role in this content’s preparation.

Marat Fudim, MD, MHS, is an assistant professor of medicine and a member of the Duke Clinical Research Institute at Duke University School of Medicine in Durham, North Carolina. His research and clinical efforts focus on HF, including advanced therapies such as mechanical assist devices and heart transplantation. He also performs cardiac catheterizations to better understand a patient’s disease state.

The GALACTIC-HF study (ClinicalTrials.gov Identifier: NCT02929329) found that selective cardiac myosin activators, such as omecamtiv mecarbil, result in modest yet statistically significant reductions in initial hospitalizations for HF, especially in the setting of reduced LVEF.¹ Do you believe this class of drug, after further study, may become incorporated into standard of care treatment options for patients with HFrEF?    

I think that following the GALACTIC-HF study, without any need for further studies, the drug has earned itself a place in the treatment algorithm. Once approved, I can imagine that the drug will be, as of now, the sixth-line agent for patients with HFrEF. Given its mechanism of action and the benefit seen in the subgroup of patients with reduced LVEF, this drug will preferentially be used in patients who had been started and up-titrated on 4 or 5 agents and now have borderline low blood pressure, reduced range of ejection fraction, and remain at increased risk for rehospitalization and death. Certainly, more investigation with this drug that solidifies the benefit in certain subgroups will increase its adoption in clinical practice.

The GALACTIC-HF study reported a small increase in troponin I levels when compared with placebo, although it was noted there were no differences in rates of ischemic or ventricular arrhythmic events.¹ How should this finding be interpreted in the context of the study’s findings?

Given the mechanism of action of omecamtiv mecarbil,² increased troponin levels are not a surprise. However, as part of the approval process across a number of studies, the signal of troponin elevation was closely monitored and, as the overall positive results of the trials suggest, the very small elevation in troponin does not appear to be clinically relevant.³

A post-hoc analysis of the GALACTIC-HF trial identified that a subset of patients with more severe HF may have more clinically meaningful outcomes with cardiac myosin activators.⁴ What role could this type of drug class play in these patients who have higher baseline risk and also are more likely to have intolerance to β-blockers, renin-angiotensin-aldosterone system (RAAS) modulators, or mineralocorticoid receptor antagonists due to potential hypotension and renal insufficiency?

I think that is exactly the group of patients most likely to benefit from this drug and likely to be the group in which this drug is first initiated clinically. With time, providers will gain more experience and confidence with the drug and start using it in a broader population.

When might a clinician make the decision not to prescribe a selective cardiac myosin activator?

Good question. The side effect profile of the drug is very good: There is no contraindication in patients with renal dysfunction, it does not lower blood pressure, etc. A key limitation in its uptake will be cost; cost will prevent a broader uptake right from the get-go.

Can you describe your process of risk-benefit determinations when considering an update to HFrEF treatment regimens, especially in patients with severe HFrEF?

My approach to medical management of HFrEF is centered around symptoms and hospitalizations. If patients with HFrEF remain symptomatic with New York Heart Association (NYHA) class II to IV HF symptoms despite guideline-directed medical therapy (GDMT), I discuss with patients their willingness to try something new. This might be a drug that just made it on the market (vericiguat⁵ and soon omecamtiv mecarbil), device therapies, or participation in clinical trials. The biggest mistake we tend to make is to accept ongoing and persistent HF symptoms as the norm and refuse to consider additional therapies instead of presenting additional options to patients. Of course, hospitalizations for HF tend to trigger or accelerate discussion and initiations of therapies given the very apparent deterioration of the clinical course. 

Can you put into context the potential clinical utility of omecamtiv mecarbil as opposed to older inotropic agents, such as dobutamine or milrinone, in the setting of severe HFrEF?

While all the above noted agents have inotropic properties, they achieve the inotropy via different mechanisms. The inotropic properties for agents such as dobutamine and milrinone are more pronounced and are associated with more side effects,⁶ which give the inotropic agents the “bad” reputation. As mentioned earlier, the fear of troponin release and adverse outcomes was not substantiated with omecamtiv mecarbil. In regard to outcomes, it was quite the opposite.

You mentioned GDMT in reference to risk-benefit discussions with patients. Current clinical guidelines recommend that in patients with HFrEF, angiotensin converting enzyme (ACE) inhibitors and β-blockers should be titrated to maximally-tolerated doses. How might newer therapies, including direct myosin activators, be integrated into these guidelines?

Certainly, as it is typical for newer agents, omecamtiv mecarbil will likely be added after the other 4 or 5 drug classes have been started or at least contemplated. I can envision that, for the previously outlined phenotypes of reduced LVEF and low blood pressure, the use of drugs such as omecamtiv mecarbil might move more upstream as providers anticipate (or already have seen patients experience at low doses) side effects with the more established GDMT agents.

You touched upon issues related to accepting persistent HF symptoms as the norm. Can you expound on what clinical endpoints are used in HF trials and what role alternative patient-centered endpoints may have in HFrEF drug development?

The traditional concept is to focus on HF hospitalization and death as the main clinical endpoints. It has now been increasingly recognized that “softer” clinical endpoints, such as QOL — symptom burden or functional status — might matter to patients just as much if not more. There are broad efforts underway to “promote” patient-centered outcomes, such as using QOL as key endpoints. Now we commonly see QOL metrics as clinical endpoints in HF device and drug trials. While the US Food and Drug Administration (FDA) does not accept QOL improvement as the primary endpoint to approve a therapy at this time, we have made great strides in the last decade to promote QOL as a valid clinical endpoint.

This Q&A was edited for clarity and length.

Disclosure

Marat Fudim, MD, reported affiliations with Edwards Lifesciences Corporation; VisCardia, Inc.; NXT Pharma; Axon Therapies Inc.; Daxor Corporation; Foundry Innovation & Research 1, Ltd. (FIRE1); Bodyport Inc.; ZOLL Medical Corporation; CVRx, Inc.; Boston Scientific Corporation; and Bayer HealthCare Pharmaceuticals Inc.

References

1. Teerlink JR, Diaz R, Felker GM, et al; for the GALACTIC-HF Investigators. Cardiac myosin activation with omecamtiv mecarbil in systolic heart failure. N Engl J Med. 2021;384(2):105-116. doi:10.1056/NEJMoa2025797
 
2. Kaplinsky E, Mallarkey G. Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil. Drugs Context. 2018; 7:212518. doi:10.7573/dic.212518
 
3. Mahajan VS, Jarolim P. How to interpret elevated cardiac troponin levels. Circulation. 2011;124(21):2350-2354. doi:10.1161/CIRCULATIONAHA.111.023697
 
4. Felker MG, Solomon SD, Claggett B, et al. Assessment of omecamtiv mecarbil for the treatment of patients with severe heart failure: a post hoc analysis of data from the GALACTIC-HF randomized clinical trial. JAMA Cardiol. 2022;7(1):26–34. doi:10.1001/jamacardio.2021.4027
 
5. Armstrong PW, Pieske B, Anstrom KJ, et al. Vericiguat in patients with heart failure and reduced ejection faction. N Engl J Med. 2020;382(20):1883-1893. doi:10.1056/NEJMoa1915928
 
6. Dubin A, Lattanzio B, Gatti L. The spectrum of cardiovascular effects of dobutamine – from healthy subjects to septic shock patients. Rev Bras Ter Intensiva. 2017;29(4):490-498. doi:10.5935/0103-507X.20170068

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Cardiology Advisor had no role in this content’s preparation.

Alex Spyropoulos, MD, FACP, FCCP, FRCPC, is a professor of medicine at the Donald and Barbara Zucker School of Medicine at Hofstra/Northwell in Uniondale, New York. He is the Director of Anticoagulation and Clinical Thrombosis Services for the multi-hospital Northwell Health System in New York. He is also a professor at Feinstein Institutes for Medical Research within Northwell’s Institute of Health System Science. His areas of clinical interest include treatment of venous thromboembolic disease, patient self-testing of warfarin, and use of the novel oral anticoagulants, including their use in special patient populations.

Patients with morbid obesity, defined as a body weight of at least 120 kg or BMI of at least 40 kg/m2, were underrepresented in clinical trials of DOACs. Are DOACs considered safe and effective for stroke prevention in patients with comorbid NVAF and obesity? Does the extent of obesity — that is, a BMI of 30 to 35 kg/m2 vs a BMI of 35 to 40 kg/m2 vs BMI greater than 40 kg/m2 — affect the safety and efficacy of DOACs?

Overall, yes. Although patients with morbid obesity were underrepresented in phase 3 clinical trials of DOACs, patients who were obese and morbidly obese were definitely included.^1,2 Subsequently, large observational studies have shown that, at the very least, treatment with DOACs is as safe and effective as dose-adjusted warfarin in the setting of obesity and NVAF.^3-8 Taken together, these findings have led to a change in the guidance documents. Guidance in 2016 from the International Society on Thrombosis and Haemostasis (ISTH) was very conservative and recommended against using DOACs in patients weighing more than 120 kg.⁹ That restriction is no longer applied, and current guidelines and prescriber decisions reflect greater confidence in the use of DOACs for treatment of patients with obesity.^10,11

While the extent of a patient’s obesity does not affect the choice of DOAC therapy in this setting, there are notably fewer data once BMI exceeds 40 kg/m². This is also true of warfarin. However, unlike patients treated with DOACs, patients receiving warfarin can be monitored. In general, data on this specific group of patients with comorbid obesity and NVAF are lacking.

Pharmacokinetic studies have shown that the effect of obesity on DOAC levels in the blood varies based on the specific agent administered. Is there a benefit to using 1 DOAC rather than another in patients with obesity and NVAF?

The clinical significance of pharmacokinetic testing here is unclear. Drug levels in this setting are not meaningful currently because there are insufficient data to establish a therapeutic target value for various DOAC agents.^10,11 We also know that there is tremendous individual variability in the pharmacokinetics of DOACs, independent of obesity as a comorbidity. In that regard, the difference in drug levels does not translate to greater benefit from the use of any single DOAC over another in patients with obesity. There is a slight preference for rivaroxaban, likely due to the much greater amount of observational data on use of rivaroxaban vs other DOACs in patients with obesity.

Results of research comparing DOACs vs warfarin for stroke prevention in comorbid NVAF and obesity have varied. Several studies have demonstrated comparable efficacy and safety whereas others reported improved efficacy and safety with select DOACs, such as rivaroxaban. Can you comment on the available data?

It is important to bear in mind that “efficacy” does not apply to observational studies. The most appropriate outcome to evaluate is “effectiveness.” I am very conservative in the way I interpret observational studies because often the quality of the data is very poor. That said, an advantage is that such studies typically include more patients than could otherwise be evaluated, and therefore include a large amount of data.
 
I believe we can say that treatment with DOACs in patients with obesity is, at the very least, equivalent to warfarin in terms of effectiveness and safety.
 
Although a large recently published study suggested better safety parameters with DOACs,¹² I think that the investigators may be overly optimistic in their conclusions. I would rather be conservative. We all know warfarin is problematic and a target warfarin dose is more difficult to reach in patients who are obese vs nonobese, so that is important to consider as well.

How big of a role does total healthcare cost play in treatment selection for patients with NVAF and obesity? Does patient satisfaction with treatment outcomes or pill burden influence the prescribing of certain medications?

Although patients with obesity treated with warfarin have the same bleeding risk as those who receive DOACs, healthcare resource utilization is much lower with warfarin.⁴ On the other hand, when considering DOACs, much of the decision-making is dictated by insurance coverage. At this time, most private insurers are reasonable regarding use of DOACs rather than warfarin.
 
Of course, patient satisfaction is another key factor in choosing a particular treatment regimen, and it can play a critical role in patients with obesity. The ability to offer patients DOAC therapy can have a notable impact on patient satisfaction and ease of use, because — unlike warfarin — treatment monitoring is not required. In choosing among DOACs, I prefer to use rivaroxaban rather than apixaban because of its once-daily, as opposed to twice-daily, dosing.

What additional monitoring, if any, is recommended for patients with obesity receiving treatment with warfarin or a DOAC for stroke prevention in NVAF?

For warfarin, the target internal normalized ratio and required monitoring remain the same in a patient with obesity. As I mentioned, it can be more difficult to get patients with obesity into the goal range, but the end target is still typically 2 to 3 for NVAF.
 
Regarding DOACs, I am not a big believer in monitoring because there is no evidence that monitoring drug levels or performing DOAC anti-Xa assays leads to better hard clinical outcomes. That said, I may obtain a 1-time DOAC trough level to ensure that the DOAC is at least “on board.” I would also measure a trough in select cases, such as in a patient who requires neurosurgery or is taking prohibitive medications that pose the risk of a drug-drug interaction. Again, the obvious advantage of DOACs is that they do not need to be monitored, since DOAC monitoring was not performed in the pivotal clinical trials.

What role does weight loss play in reducing stroke risk for patients with comorbid NVAF and obesity?

This is an interesting question because of the obesity paradox, which is a U-shaped curve.¹³ Studies have found that obesity actually protects against stroke. Nevertheless, obesity is an independent risk factor for venous thromboembolism, so the relationship between obesity and stroke is paradoxical in some ways.¹⁴
 
Obesity is a chronic, low-grade inflammatory condition. In the setting of stroke and NVAF, the health risks of obesity far outweigh any potential benefits.¹⁵ I always tell my patients that it is a good idea to lose weight since a lower weight is much better from a metabolic and cardiovascular point of view. I am a big advocate of weight loss, and having a patient achieve a BMI of 30 kg/m² or lower would be ideal.

Disclosures

Dr Spyropoulos has had consulting relationships with Alexion Pharmaceuticals, Inc.; Bayer HealthCare Pharmaceuticals Inc.; Boehringer Ingelheim Pharmaceuticals. Inc.; Bristol-Myers Squibb Company; Daiichi Sankyo Company, Limited.; and Janssen Pharmaceuticals, Inc.

References

1. Weir MR, Chen Y-W, He J, Bookhart B, Campbell A, Ashton V. Effectiveness and safety of rivaroxaban versus warfarin among nonvalvular atrial fibrillation patients with obesity and diabetes. J Diabetes Complications. 2021;35(11):108029. doi:10.1016/j.jdiacomp.2021.108029
 
2. Granger CB, Alexander JH, McMurray JJV, et al; on behalf of the ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981-992. doi:10.1056/NEJMoa1107039
 
3. Patel MR, Mahaffey KW, Garg J, et al; on behalf of the ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883-891. doi:10.1056/NEJMoa1009638
 
4. Peterson ED, Ashton V, Chen Y-W, Wu B, Spyropoulos AC. Comparative effectiveness, safety, and costs of rivaroxaban and warfarin among morbidly obese patients with atrial fibrillation. Am Heart J. 2019;212:113-119. doi:10.1016/j.ahj.2019.02.001
 
5. Navaro-Almenzar B, Cerezo-Manchado JJ, García-Candel F. Real life behaviour of direct oral anticoagulants in patients with nonvalvular atrial fibrillation and morbid obesity. Int J Cardiol Heart Vasc. 2021;37:100913. doi:10.1016/j.ijcha.2021.100913
 
6. O’Kane CP, Avalon JCO, Lacoste JL, et al. Apixaban and rivaroxaban use for atrial fibrillation in patients with obesity and BMI ≥50 kg/m². Pharmacotherapy. 2022;42(2):112-118. doi:10.1002/phar.2651
 
7. Kido K, Shimizu M, Shiga T, Hashiguchi M. Meta-analysis comparing direct oral anticoagulants versus warfarin in morbidly obese patients with atrial fibrillation. Am J Card. 2020;126:P23-P28. doi:10.1016/j.amjcard.2020.03.048
 
8. Deitelzweig S, Keshishian A, Kang A, et al. Effectiveness and safety of oral anticoagulants among NVAF patients with obesity: insights from the ARISTOPHANES study. J Clin Med. 2020;9(6):1633. doi:10.3390/jcm9061633
 
9. Martin K, Beyer-Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost. 2016;14(6):1308-1313. doi:10.1111/jth.13323
 
10. Martin KA, Beyer- Westendorf J, Davidson BL, Huisman MV, Sandset PM, Moll S. Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation. J Thromb Haemost. 2021;19(8): 1874-1882. doi:10.1111/jth.15358
 
11. Mocini D, Di Fusco SA, Mocini E, et al. Direct oral anticoagulants in patients with obesity and atrial fibrillation: position paper of Italian National Association of Hospital Cardiologists (ANMCO). J Clin Med. 2021;10(18):4185. doi:10.3390/jcm10184185
 
12. Boivin-Proulx L-A, Potter BJ, Dorais M, Perreault S. Comparative effectiveness and safety of direct oral anticoagulants vs warfarin among obese patients with atrial fibrillation. CJC Open. 2022;4(4):395-405. doi:10.1016/j.cjco.2022.01.002
 
13. Proietti M, Guiducci E, Cheli P, Lip GYH. Is there an obesity paradox for outcomes in atrial fibrillation? A systematic review and meta-analysis of nonvitamin K antagonist oral anticoagulant trials. Stroke. 2017;48(4):857-866. doi:10.1161/STROKEAHA.116.015984
 
14. Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med. 2005;118(9):P978-P980. doi:10.1016/j.amjmed.2005.03.012
 
15. Stępień M, Stępień A, Wlazeł RN, Paradowski M, Banach M, Rysz J. Obesity indices and inflammatory markers in obese non-diabetic normo- and hypertensive patients: a comparative pilot study. Lipids Health Dis. 2014;13:29. doi:10.1186/1476-511X-13-29

Posted by Haymarket’s Clinical Content Hub. The editorial staff of Cardiology Advisor had no role in this content’s preparation.