Provider and Caregiver Connection Live: Aligning Oncology and Cardiology Care to Identify and Manage ICI-Related Myocarditis

ACC ICI-Associated Myocarditis Archived Webcast 

An expert-led podcast with a focus on clinical trials hosted by Muthiah Vaduganathan, MD, and Stephen Greene, MD

Don't Miss a Beat

The approval of mavacamten (Camzyos), cardiac myosin inhibitor from Bristol Myers Squibb, from the US FDA for treatment of symptomatic obstructive hypertrophic cardiomyopathy (HCM) in April 2022 was met with applause from the cardiology community.

Based on the results of the EXPLORER-HCM trial, the FDA approved mavacamten for of adults with symptomatic New York Heart Association (NYHA) class II-III obstructive hypertrophic cardiomyopathy (obstructive HCM) to improve functional capacity and symptoms. To date, it is the only FDA-approved allosteric and reversible inhibitor selective cardiac myosin inhibitor targeting the underlying pathophysiology of obstructive HCM, but that could be changing in the near future.

Now, the next-generation cardiac myosin inhibitor, aficamten, is riding that same aforementioned wave of excitement as the community awaits the results of the phase 3 SEQUIOA-HCM trial, with additional excitement brought forth by the results of the phase 2 REDWOOD-HCM. At the 

Heart Failure Society of America (HFSA) 2022 annual scientific meeting,

 a pair of presentations focused on data related to quality of life and symptom burden from the REDWOOD-HCM OLE trial as well as data related to the design of the SEQUOIA-HCM trial.

With an interest in learning more about aficamten and the landscape of HCM management, 

 sat down with Martin Maron, MD, director of the Hypertrophic Cardiomyopathy Center at Lahey Health Medical Center, at HFSA 2022. A transcript of that conversation can be found below.

As a next-generation cardiac myosin inhibitor, what do we know about the differences between aficamten and the previous generation cardiac myosin inhibitor, mavacamten?

Aficamten is the next generation myosin inhibitor to follow from the first generation mavacamten. Aficamten is in currently phase 3 study for treatment of symptomatic obstructive HCM. I think, as a next generation myosin inhibitor, aficamten works in a similar way as mavacamten. It decreases the number of myosin head and actin filament interactions, which decreases the force of contractility, and, through that mechanism, can lower outflow tract gradients. By doing that, we can improve how patients feel.

One of the differences between aficamten and mavacamten relates to the pharmacodynamic profile or the pharmacologic profile of the drug. There are some distinctions related to its shorter half-life and a difference in the dose response curves of the drug. So, those are the distinguishing features right now. There's a different pharmacodynamic profile compared to mavacamten and one of the questions that's being investigated is whether that difference in the pharmacology of aficamten will translate into differences in efficacy and potentially decreases in issues related to safety of the drug. We don't know the answer to that yet. Of course, that's going to be part of what will be looked at and that is the SEQUIOA-HCM study.

Coming back to the phase 2 REDWOOD-HCM study, REDWOOD demonstrated that aficamten, over several weeks of treatment, can substantially lower both resting and provokable outflow tract gradients in patients that have symptomatic obstructive HCM and can improve significantly the symptom burden in those patients as well. The study showed aficamten was also very well tolerated in terms of safety.

Now, of course, we are going to get a much better idea about how efficacious aficamten with a larger, broader, more expansive clinical trial with the SEQUIOA initiative. So, I think there's a lot more we're going to be learning about this drug soon and, as that experience with aficamten expands, I think we'll be more able to make some sense of how aficamten may compare to mavacamten, but I think it's just way too early to try to do that at this point. We just don't have the information to really kind of provide any kind of reliable comparisons between the two at this point. We are just too early in the experience.

Practical Cardiology: How did what we learned from the EXPLORER-HCM in mavacamten and phase 2 REDWOOD-HCM trial with aficamten influence the design of SEQUIOA-HCM?

Well, I think the overall study design of SEQUIOA-HCM is pretty similar, not identical, but similar to EXPLORER-HCM. I think what we, perhaps, learned from the mavacamten and EXPLORER experience is avenues for how we will ultimately address the important issue of dosage adjustments: As patients get started on the drug, what they will require in terms of longitudinal echo studies to assess systolic function, which, again, is one of the most important potential safety issues with these drugs. I think it was approximately 7% of patients in the EXPLORER-HCM trial had systolic dysfunction that was very relevant and led the US FDA warning of systolic dysfunction and heart failure for these drugs.

So, I think what we're hoping to learn more in SEQUIOA with aficamten, which, again, has a different pharmacodynamic profile than mavacamten, is whether or not the issue of systolic dysfunction is as present. We are also hoping to learn how we can best address that issue in terms of longitudinal echo follow ups for patients that go aficamten, will they need that less than what we know from the EXPLORER-HCM trial, will it be fewer and far between? I think a lot of the interest is for safety; part of the focus in the SEQUIOA trial is really to try to understand that aspect of this drug better than we know currently from the phase 2 effort.

Practical Cardiology: Where is the most pressing gap in knowledge related to hypertrophic cardiomyopathy?

 I would say that the biggest or most relevant treatment gap or unmet need in the disease right now is in the treatment of symptomatic nonobstructive HCM—1-in-3 patients with this disease have nonobstructive HCM. Among these patients, a small, but important, subgroup develop end-stage heart failure. Right now, we have no therapy currently to help mitigate or prevent that progression to heart failure and we have very few treatment options when patients develop end-stage heart failure with nonobstructive HCM other than heart transplant.

So, there is no question that I think that it would be very fair to say that, as we go forward here, I hope the focus shifts in a way to exploring new therapies for the nonobstructive group of patients. Since those, again, are the patients that perhaps have the most to gain from new therapies at this point the greatest unmet need for the disease.

Editor’s Note: This transcript has been edited for length and clarity.

Articles

Martin Maron, MD, sits down to discuss aficamten, the SEQUOIA-HCM trial, and the most pressing unmet needs in the management of hypertrophic cardiomyopathy. 

Understanding Aficamten and the SEQUOIA-HCM Design, with Martin Maron, MD

A recent analysis of data from the Get With The Guidelines-Heart Failure (GWTG-HF) Registry is providing clinicians with new insight into the potential benefit of dapagliflozin in Medicare beneficiaries with 

 with preserved ejection fraction (HFpEF).

Using the eligibility criteria from the landmark DELIVER trial, results of the analysis, which were presented at the 

Heart Failure Society of America (HFSA) 2022 annual scientific meeting

, indicate 76% of beneficiaries hospitalized for heart failure with an ejection fraction greater than 40% would have been eligible for the trial based on inclusion criteria, with investigators pointing out a potential label expansion could expand eligibility to up to 81% of beneficiaries included in the study.

“The main conclusions are that 3 out of 4 Medicare beneficiaries hospitalized for heart failure with mildly reduced or preserved ejection fraction in the US would be eligible for dapagliflozin even when applying the stringent DELIVER clinical trial“ said Muthiah Vaduganathan, MD, MPH, cardiologist and codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital, during his presentation at HFSA 2022.

The analysis from HFSA 2022 was designed with the specific intent of assessing eligibility for dapagliflozin, post-discharge clinical risk, and projected benefits of optimal implementation among Medicare beneficiaries hospitalized with heart failure with an ejection fraction greater than 40% in the US. From the 146,616 individuals with data included within the GWTG-HF Registry, investigates identified 52,964 adults with 12 months follow-up or greater hospitalized with heart failure from January 2014-December 2018 who were aged 65 years or older and with an LVEF of 40% or less.

For the purpose of analysis, the potential expanded level exclusions for dapagliflozin were defined as an eGFR closest to discharge less than 25 mL/min/1.73m2, type 1 diabetes, in-hospital dialysis, or a history of chronic dialysis. The specific trial exclusions included a discharge systolic blood press less than 95 or exceeding 180 mmHg, having nonelevated natriuretic peptide levels, undergoing an in-hospital cardiac procedure, having a BMI exceeding 50 kg/m2, and ischemia or acute coronary syndrome precipitating heart failure event.

From the target population of 52,964, investigators determined 81% (n=45,147) could be considered candidates for initiation of Dapagliflozin under the potential label expansion used in the analysis. When using the DELIVER inclusion criteria, results indicated 76% of the target population from the GWTG-HF registry would have been considered candidates for inclusion. Further analysis suggested there would be a projected absolute risk reduction of 9% (4-13%) for heart failure readmission or death in the year proceeding hospitalization if effect sizes from DELIVER were translated to clinical practice. Vaduganathan also pointed out the number needed to treat to prevent 1 of these events was 11 (7-23).

 sat down with study investigator Stephen Greene, MD, assistant professor of medicine at Duke University School of Medicine, to learn more about the study and its implications for use of dapagliflozin.

This study, “Translating the Findings of the DELIVER Trial to Medicare Beneficiaries Hospitalized for HF in the United States,” was presented at HFSA 2022.

An analysis applying data from the DELIVER trial to the Get With The Guidelines-Heart Failure Registry suggests 81% of hospitalized Medicare beneficiaries with HFpEF could be considered candidates for dapagliflozin use under a potential FDA label expansion.

8-in-10 Medicare Beneficiares Hospitalized with HFpEF Could be Considered Candidates for Dapagliflozin

Data from an analysis of the DELIVER trial suggest the benefits of dapagliflozin in 

heart failure with preserved ejection fraction (HFpEF)

 were statistically significant for the trial’s primary endpoint in less than 2 weeks.

A prespecified secondary analysis of the trial, results indicate the time to first nominal statistical significance for the primary endpoint was 13 days and this significance was sustained from day 15 and beyond in the trial.

“These data from the DELIVER trial underscore the rapid clinical benefits observed with the SGLT-2 inhibitor dapagliflozin and highlight key opportunities for the early identification and prompt management of this patient population without delay,” wrote investigators.

originally presented at ESC Congress 2022

, randomized 6263 patients from 350 centers in 20 countries to dapagliflozin 10 mg or placebo therapy. This cohort had a mean age of 71.7 (SD, 9.6) years, 43.9% were women, and the median follow-up time was 2.3 (IQR, 1.7-2.8) years. Results of the trial suggested use of dapagliflozin was associated with an 18% (HR, 0.82 [95% CI, 0.73-0.92]; 

 <.001) relative risk reaction for the primary composite endpoint of cardiovascular death or worsening heart failure, with this effect consistent in those with an ejection fraction greater than 60% compared to the overall study population (HR, 0.83 [95% CI, 0.73-0.95]; 

The current analysis, which was presented at the 

 by Muthiah Vaduganathan, MD, MPH, cardiologist and codirector of the Center for Cardiometabolic Implementation Science at Brigham and Women’s Hospital, was designed with the specific intent of assessing time to first and sustained statistical significance of dapagliflozin for the trial’s primary composite end point and worsening heart failure alone.

In the analysis, results suggested the time to first nominal statistical significance for the primary composite end point was 13 days (HR, 0.45 [95% CI, 0.20-0.99]; 

=.046) and this observed significance was sustained from day 15 onwards. Further analysis suggested first and sustained statical significance for worsening heart failure events was achieved by day 16 (HR, 0.45 [95% CI, 0.21-0.96]; 

=.04). Additionally, investigators pointed out the benefits for both the primary endpoint (HR, 0.82 [95% CI, 0.73-0.92]) and for worsening heart failure events (HR, 0.79 [95% CI, 0.69-0.91]) were sustained at 30 days, 90 days, 6 months, 1 year, 2 years, and the final follow-up.

“This timeline of clinical benefit was highly consistent with similar observations from the EMPEROR-Preserved trial in which the nominal significance was first reached at day 18 after randomization and in trials of SGLT-2 inhibitors in patients with HF with reduced ejection fraction (12 to 28 days),” investigators added. “Furthermore, these data align with rapid improvements in symptoms, physical limitations, and quality of life seen with SGLT-2 inhibition as early as 2 to 4 weeks.”

Time to Clinical Benefit of Dapagliflozin in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction

,” was presented at HFSA 2022 and published in 

A prespecified analysis of the DELIVER trial presented at HFSA 2022 indicates dapagliflozin provides early benefit in patients with heart failure with preserved ejection fraction, with the effect on the trial's primary end point evident in just 13 days.

Dapagliflozin's Benefit in HFpEF Reaches Significance Within 2 Weeks, Study Finds

Use of sacubitril/valsartan in patients with heart failure with reduced ejection fraction was associated with a reduction in mitral regurgitation, according to a new analysis of the PROVE-HF trial.

An analysis of 724 people from within the trial with interpretable mitral regurgitation data, results of the analysis suggest use of sacubitril/valsartan was associated with a 45% relative reduction in prevalence of grade 3-4+ mitral regurgitation at 6 months and this was sustained out to 12 months, with an observed relative reduction of 44.7%.

An exploratory open-label study designed with the intent of examining potential cardiac remodeling associated with use of sacubitril/valsartan among patients with heart failure with reduced ejection fraction, the original results of the PROVE-HF trial provided evidence suggesting the reductions in NT-proBNP observed with the agent were significantly correlated with improvements in markers of cardiac volume and function at 12 months. Presented at ESC Congress 2019 and simultaneously published in JAMA, the prospective, single-group trial enrolled 794 patients.

After exclusion of those without interpretable mitral regurgitation data and those with prior mitral valve procedures, 724 individuals were included in the current analysis, which was presented at the 

 by Michael Felker, MD, professor of medicine at Duke University School of Medicine. The cohort of patients included in the HFSA 2022 data had a mean age of 65.0±12.4 years, 1.5% were men, and 72.9% were White. Investigators noted 76.4% of patients were using an ACE or ARB at baseline and 46.1% had nonischemic heart failure.

As part of the trial protocol for PROVE-HF echocardiograms were performed at baseline, 6 months, and 12 months. These were interpreted in a blinded fashion and categorized on a scale of 0 (none), 1+ (trace), 2+ mild, 3+ (moderate) and 4+ (severe).

Results of the investigators’ analyses indicated improvement in mitral regurgitation was observed from baseline through 12 months. Specifically, the prevalence of 3-4+ mitral regurgitation decreased from 14.9% to 8.2% at 6 months, which represents a 45.0% relative reduction in prevalence. At 12 months, the prevalence of 3-4+ was 8.4%, which reprints a 44.7% relative reduction.

Further analysis suggested those who experienced a decrease in 3-4+ mitral regurgitations experienced greater reductions in NT-proBNP from baseline to 12 months (912 vs 1512 pg/mL; 

=.01), exhibited greater improvement in left ventricular remodeling (11.0% vs. 7.6%; 

=.05), and had significantly improved KCCQ-23 scores (82.3 vs. 72.9; 

Association Between Sacubitril/Valsartan Initiation and Mitral Regurgitation Severity in Heart Failure With Reduced Ejection Fraction: The PROVE-HF Study,

” was presented at HFSA 2022 and simultaneously published in 

An analysis of data from the PROVE-HF trial suggests use of sacubitril/valsartan was associated with a reduction in prevalence of mitral regurgitation among patients with heart failure with reduced ejection fraction.

Sacubitril/Valsartan Use Could Reduce Mitral Regurgitation in HFrEF

Interim results from the REDWOOD-HCM OLE trial are providing clinicians with insight into the impact of aficamten on symptom improvement and quality of life in patients with obstructive hypertrophic cardiomyopathy.

, data from the analysis suggest use of aficamten was associated with significant and sustained reduction in left ventricular outflow gradient (LVOT-G) as well as improvements in heart failure symptoms and reductions in NT-proBNP and hs-cTnL.

Discovered from the optimization of indoline compound 1, excitement for surrounding the next-generation cardiac myosin inhibitor, aficamten, has reached a fever pitch with the approval of mavacamten for obstructive hypertrophic cardiomyopathy in April 2022. At HFSA, aficamten drew attention with the current study an additional poster outlining the design of the phase 3 SEQUOIA-HCM trial, which launched in February 2022.

A phase 2 dose-finding trial, the interim analysis of REDWOOD-HCM OLE, which was presented by Ahmad Masri, MD, director of the Oregon Health and Science University Hypertrophic Cardiomyopathy Center, provides the latest insights into the effects of aficamten. The outcomes of interest for the interim analysis were changes in LVOT-G, NYHA function class, and cardiac biomarkers among the 38 individuals receiving aficamten in the trial. During his presentation, Masri pointed out more than 50% of patients who had reached 24 weeks of treatment with aficamten were using aficamten 15 mg by week 24 of the trial, with more than 75% using a dosage of 10 mg or greater.

Upon analysis, results indicated 61% of patients receiving aficamten had a 1 class improvement in NYHA class at 24 weeks, with 17% experiencing an improvement of 2 classes. Of note, 22% of patients experienced no change in NYHA class from baseline to week 24, but no patient experienced a worsening of NYHA class from baseline to week 24. Masri also pointed out there were no events of a left ventricular ejection fraction (LVEF) dropping below 50% were observed during the open-label extension trial. When assessing cardiac biomarkers, results indicated mean levels of NT-proBNP were reduced by 70% (

 <.0001) occurred from baseline to week 12 and a reduction of 20% (

=.002) was observed for mean hs-cTnL during the same time period.

In a late-breaking oral presentation at HFSA 2022, a new analysis of REDWOOD-HCM OLE evaluates patients’ self-reported health status using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and comparing baseline values to those collected at Week 12 and Week 24.

In qaa release from Cytokinetics, the company noted that, at weeks 12 and 24 of the trial, the mean change in KCCQ-OSS from baseline was 16.5 (SD, 16.7; 

=.0015). Further, the release pointed out an improvement of 5 points or more on the KCCQ-OSS was observed among 72.7% at week 12 and 72.0% at week 24. When assessing improvements of 20 points or more, results indicated this level of improvement was observed among 36.4% at week 12 and 40.0% at week 24, according to the release.

“These new data suggest that improvements in cardiac function associated with treatment with aficamten translate to patients reporting an overall improvement in their symptoms – particularly in their quality of life – which is of critical importance to patients with HCM who face a substantial symptom burden that impacts their daily lives.” said Fady I. Malik, MD, PhD, executive vice president of Research & Development at Cytokinetic, in a 

. “As REDWOOD-HCM OLE continues, aficamten is also under study in SEQUOIA-HCM, the phase 3 registrational clinical trial in patients with obstructive HCM.”

This study, “Efficacy And Safety Of 'Aficamten' In Patients With Symptomatic Obstructive Hypertrophic Cardiomyopathy: Interim Results From The Randomized Evaluation Of Dosing With Ck-3773274 In Hypertrophic Cardiomyopathy Open Label Extension Study,” was presented at HFSA 2022.

Data presented at HFSA 2022 examining aficamten provides insight into the effects of the agent on LVOT-G, NYHA class, and KCCQ-OSS among patients with hypertrophic cardiomyopathy from the open-label extension trial. 

Aficamten Could Improve Quality of Life, Symptom Burden in Hypertrophic Cardiomyopathy

Although the ever-flowing tap of revelations surrounding the benefits of SGLT2 inhibitor therapy that has appeared in the last half-decade continues to flow, a much more prominent emphasis has been placed on implementation science at the 

The recognition of these benefits with SGLT2 inhibitors achieved a new milestone with inclusion in the European Society of Cardiology 2021 heart failure guidelines and, later, the ACC/AHA/HFSA 2022 heart failure guidelines. To kick off the second day of HFSA 2022, Practical Cardiology Advisory Board member Stephen Greene, MD, assistant professor of medicine at Duke University School of Medicine, participated in a presentation titled “The Trajectory of Worsening Heart Failure and Considerations for Outcomes and Cost of Care”. With the latest iterations of international guidelines, a new emphasis has been placed on optimization of guideline guideline-directed medical therapy (GDMT) for patients with heart failure.

This is because, despite inclusion in guidelines, the fear among clinicians is that the lack of optimized uptake and delayed initiation of these therapies, which has been linked to risk of adverse outcomes, will continue. With an interest in learning more about the current evidence base surrounding in-hospital initiation of GDMT in patients with heart failure, 

 caught up with Greene after his presentation for a deep dive into the subject.

Optimizing Initiation of GDMT in Heart Failure, with Stephen Greene, MD

y: In the last 3 years, how much progress or lack of have you observed regarding optimal initiation of GDMT for heart failure?

Unfortunately, you know, there hasn't been major progress in cracking this clinical inertia problem and getting GDMT to our patients. I think part of it relates to the culture we've had in heart failure. We have lots of different drugs, but we, generally, do this serial and selective approach where it's one medication at a time and that leads us down a long circuitous pathway where we have to take up to a year before you actually get to maximally tolerated target doses. In the meantime, the patient is exposed to excess risks of death and worsening heart failure. However, there is also the very simple fact that you're probably never going to get there in a lot of cases just because of clinical inertia getting in the way. There are missed clinic visits, hospitalizations, etc.

What myself and others have proposed is that we need to treat heart failure with the sense of urgency that it deserves and that includes rapid sequence initiation. If a patient is hospitalized, starting quad therapy at low doses is the best evidence-based approach based on the totality of evidence for implementation to maximally improve outcomes, but also to give the people the chance to benefit from each of these 4 drugs. I've been talking about this for a long time, but I think this is a major key if we really want to move the needle and give our patients the best chance of benefiting from quad therapy.

: Although cost and coverage remain barriers, what else is inhibiting optimal initiation of these agents?

There are the barriers and, as you identified for our branded medications for select patients, certainly cost and access are major barriers for these patients, but I think we need to actually just look at the totality of evidence and recognize it's not just that. Even our generic medications that we have had for some time, there are enormous gaps in use of these for people that are eligible for them. We see patients that have blood pressures of 120 mmHg and GFR is 50-60. Yet, we still have 2 of 3 eligible people are not getting a generic spironolactone, 1 of 3 to 1 of 4 not getting a beta blocker or an ACE/ARB/ARNI, not just ARNI but even ACE/ARB/ARNI.

So, it's not just about the cost and access, in my opinion, for this the widespread problem. We really need to have address clinical inertiatoday. We can't rest, we need to recognize that heart failure is an extreme risk condition, and we need to take every opportunity every time we see a patient to ask ourselves, "Are they really on the maximally tolerated medication regimen that they can tolerate? Do we really do everything we can to give them all for the mortality reducing drugs?". I think the answer is likely no.

: What are some things a clinician could do to address clinical inertia within their own practice or institution?

The first thing to do is be able to have your own data and reflect on it. There are national initiatives on this, for example the Get With The Guidelines initiative from American Heart Association. At a hospital level, you can see how your hospitals performing for key quality measures like discharge medication use, but also even within the institution. At Duke, for example, we've instituted what you could call clinician report cards.This actually shows the patients that I'm taking care of what GDMT are they eligible for and how many opportunities are being met when I am the provider. I can compare that to the average provider in my section and see how I stack up.

So, again, I think that's the first step to understand what you're doing and what your data look like. Then you can try to move the needle and improve things. Again, it's surprising to me that we have these gaps, but a lot of them are floating under the radar even at an institutional level.

After a presentation on cost considerations and outcomes at HFSA 2022, Stephen Greene, MD, provides perspective on the current state of optimization for GDMT in heart failure. 

Optimizing Initiation of GDMT for Heart Failure, with Stephen Greene, MD

About 8 months away from the agent’s PDUFA date, data from a post-hoc analysis of SOLOIST-WHF is providing insight into the effects of sotagliflozin on first and subsequent heart failure-related events among people admitted for worsening heart failure.

A dual SGLT1/2 inhibitor, results of the study, which were presented at the Heart Failure Society of America (HFSA) 2022 annual scientific meeting, suggest use of sotagliflozin could reduce the relative risk of the study’s primary composite endpoint by a third compared to placebo therapy.

“In conclusion, in patients hospitalized for an episode of worsening heart failure, sotagliflozin was relatively well-tolerated and significantly reduced the primary endpoint of cardiovascular death, hospitalization for heart failures and urgent visits for heart failure by 33%,” said Bertram Pitt, MD, professor of medicine emeritus at the University of Michigan School of Medicine, during his presentation at HFSA 2022. “Patients treated with sotagliflozin experienced fewer single as well as multiple heart failure events. Thus, we conclude that sotagliflozin alters the trajectory of patients hospitalized for worsening heart failure.”

The revelations of the cardiometabolic benefits of SLGT2 inhibitors had major impact on the outlook for sotagliflozin. Once examined for the treatment of type 1 diabetes, renewed optimism surrounded the agent and the phase 3 program in heart failure added to the growing optimism. Originally presented at ESC Congress 2021, SOLOIST-WHF and SCORED provided evidence in support of sotagliflozin’s effect on reducing adverse heart failure outcomes. More recently, a multitude of analyses have further detailed the apparent benefits on cardiometabolic health, including renal endpoints. The current post-hoc analysis was designed with the intent of exploring the impact of sotagliflozin on outcomes among patients experiencing a single or multiple heart failure-related events during the trial.

Initial analyses indicated, of the 608 patients randomized to sotagliflozin in the trial, 14.5% experienced 1 primary endpoint event, 4.9% experienced 2 primary endpoint events, and 3.9% experienced 3 or more primary endpoint events. Of the 614 included in the placebo arm, 17.9% experienced 1 primary endpoint event, 8.0% experienced 2 primary endpoint events, and 5.7% experienced 3 or more primary endpoint events. Based on these results investigators determined the odds ratio for experiencing an eventwith sotagliflozin compared to placebo was 0.66 (95% CI, 0.51-0.84; 

With an interest in learning more about the totality of sotagliflozin data and how it might inform sotagliflozin’s role in care, if approved by the US Food and Drug Administration, 

reached out to Deepak Bhatt, MD, MPH, executive director of interventional cardiovascular programs at Brigham and Women’s Hospital, who served as the principal investigator of both the SOLOIST-WHF and SCORED trials. That conversation can be found in the video below.

This study, “Sotagliflozin, A Dual SGLT1 And SGLT2 Inhibitor, Reduces First And Subsequent Heart Failure-related Events In Patients Admitted For Worsening Heart Failure,” was presented at HFSA 2022.

New sotagliflozin data at HFSA 2022 provides insight into the apparent reduction in recurrent heart failure events achieved in the SOLOIST-WHF trial. Deepak Bhatt, MD, MPH, provides perspective on the potential role of the dual SGLT1/2 inhibitor, based on trial data, if approved by the US Food and Drug Administration.

Sotagliflozin Reduces Risk of Recurrent Heart Failure Events

A new study is providing insight into the impact of advances in care on risk of mortality from sudden cardiac death among patients with hypertrophic cardiomyopathy.

Regarded as the largest single cause of premature death among this patient population, results of the study, which leveraged more than 470,000 patient-years of data from nearly 100 studies, suggest the risk of mortality from SCD in patients with hypertrophic cardiomyopathy, with results pointing to a reduction in risk of death more than 70% among those in North America for the 2015-present time period compared to 2000 or earlier.

Led by Martin Maron, MD, director of the Hypertrophic Cardiomyopathy Center at Lahey Hospital, the study was launched with the intent of exploring how changes in management over the last several decades may have influenced risk of SCD among patients with hypertrophic cardiomyopathy. With this in mind, Maron and a team of colleagues designed the current study to assess contemporary trends in risk of morality from a meta-analysis of study data on the subject.

Through a search of electronic databases, 98 studies meeting inclusion criteria were identified by investigators. These studies included data from 70,150 patients with 431,407 patient-years of follow-up data. For the purpose of analysis, a random-effects model was used to pool estimates for overall incidence rates for time-era, geographic region, and age group. Investigators pointed out analyses were planned to assess rates before and after 200, as well as in 5-year intervals following 2000 to assess changes in SCD rates.

Upon analysis, results indicated the overall rate of SCD in hypertrophic cardiomyopathy was 0.43 per year (95% CI, 0.37-0.50%; 

=75%), with a total of 1938 events occurring during the follow-up period. Further analysis suggested patients less than 18 years of age had a more than 2-fold increase in risk for SCD than their counterparts aged 18-60 years of age (IR: 1.09% [95% CI, 0.69-1.73%] vs IR: 0.43% [95% CI, 0.37%-0.50%]; 

In analyses assessing more contemporary trends, results pointed to significantly lower rates of SCD among patients with hypertrophic cardiomyopathy from 2015-present compared to prior to 2000 (IR: 0.32% [95% CI, 0.20-0.52% vs IR: 0.73% [95% CI, 0.53-1.02%], respectively). Investigators also noted the rate of reported SCD from 2015-present was lowest in North America (IR: 0.28% [95% CI, 0.18-0.43%])and greatest in Asia (IR: 0.67% [95% CI, 0.54-0.84%]).

, our editorial team caught up with Maron to discuss data from the conference. After those conversations, Maron provided further insight into the present study and what it is like to specialize in hypertrophic cardiomyopathy during a time where the field is experiencing so many significant advances.

Temporal and Global Trends of the Incidence of Sudden Cardiac Death in Hypertrophic Cardiomyopathy

Martin Maron, MD, provides perspective on a recent study he led examining changes in rate of sudden cardiac death among patients with hypertrophic cardiomyopathy and reflects on the progress made within disease management.

Rates of Sudden Cardiac Death in Hypertrophic Cardiomyopathy Falling in Recent Years

Muthiah Vaduganathan, MD, MPH, is a cardiologist specializing in cardiorenal metabolism at Brigham and Women's Hospital in Boston, MA. Vaduganathan is a member of Practical Cardiology's advisory board and co-host of Don't Miss a Beat, a podcast presented by Inside Cardiology.

Stephen Greene, MD, is an associate professor of medicine at Duke University School of Medicine and cardiologist at the Duke Clinical Research Institute in Durham, NC. Greene is a member of Practical Cardiology's advisory board and co-host of Don't Miss a Beat, a podcast presented by Inside Cardiology.

Few, if any, subspecialties in cardiology have ever seen the explosion in knowledge and therapeutics the heart failure community has bore witness to in the last decade.

In recent years, while heart failure has been thrust into the spotlight and dominated late-breaking sessions at major organizations’ meetings, such as ESC Congress and the ACC annual meeting, the Heart Failure Society of America (HFSA) annual scientific meeting has become the hub for discussions around what many consider the most exciting area in cardiometabolic health at the moment. In years past, the focus of the HFSA meeting and others that have played host to late-breaking trial data and presentations has been on the data from within clinical trials. Now, with the efficacy and safety profiles established, the conversations have shifted to clinical processes and implementation of these therapies.

In this special edition episode of Don’t Miss a Beat, which was filmed on-site at the HFSA 2022 annual scientific meeting, hosts Muthiah Vaduganathan, MD, MPH, codirector of Center for Cardiometabolic Implementation Science at Brigham and Women's Hospital, and Stephen Greene, MD, assistant professor of medicine at Duke University School of Medicine, take the audience on a deep dive into implementation science at the meeting, the potential for a polypill in heart failure, and other highlights from HFSA 2022.

All episodes of Don’t Miss a Beat are available in an audio-only format on 

Don't Miss a Beat: HFSA 2022

New research presented at the Heart Failure Society of America (HFSA) 2022 annual scientific meeting is providing clinicians with insight into the potential risk for acute kidney injury among older adults with heart failure being treated with a newly initiated angiotensin-neprilysin inhibitor (ARNI) compared to a renin-angiotensin system inhibitor (RASi).

An analysis of Medicare fee-for-service claims data from patients with heart failure with reduced ejection fraction (HFrEF), result of the study, which were presented by Ankeet Bhatt, MD, of Kaiser Permanente Northern California, provide evidence suggesting new initiators of ARNI therapy experienced similar hospitalization rates for acute kidney injury as their counterparts receiving RASi.

“Among a large cohort of US Medicare beneficiaries with HFrEF, ARNI treatment was not associated with higher rates of AKI than RASi. These results provide reassurance for providers considering ARNI initiation in older patients who are RASi naïve,” wrote investigators.

Although ARNI has become included in guideline-directed medical therapy for HFrEF, real-world uptake of the class has lagged behind, inhibiting its potential impact on a population level. Many of these concerns are related to cost or effectiveness of the agent but given the early impact on kidney function observed in clinical trials, some have expressed concerns over potential risk of acute kidney injury. With this in mind, Bhatt along with Muthiah Vaduganathan, MD, MPH, and a team of colleagues from Boston-based institutions, including Brigham and Women’s Hospital and Harvard Medical School, launched the current research endeavor with the intent of comparing rate of acute kidney injury among new initiators of ARNI or RASi considered RASi naïve at the time of initiation.

Using Medicare FFS claims from 2014-2017, the study aggregated data from more than 27,166 Medicare Beneficiaries aged 65 years or older with HFrEF and initiating either of the aforementioned therapies. Overall, the cohort had a mean age of 73 (SD, 7.3) years, with 4155 new initiators of ARNI and 23,011 new initiators of RASi.

The primary outcome of tinniest for the analysis was the incidence of hospitalization with acute kidney injury as the primary discharge diagnosis. The secondary outcome of interest was incidence of acute kidney injury as a primary or secondary discharge diagnosis. Investigators noted propensity-score-based fine-stratification weighting was used to account for potential confounding by 81 preexposure characteristics and Vox proportional hazards were used to provide hazard ratios for the study outcomes.

In propensity-score-based analyses, the 180-day cumulative incidence of the study’s primary outcome was 2.7% (2.4-3.1%) among RASi initiators compared to 2.7 (2.2-3.5%) among ARNI initiators. When assessing the secondary outcome, the rate of incidence was 6.5% (6.0-7.1%) for RASi initiators and 6.1% (5.2-7.1%) for ARNI initiators. Further analysis indicated the risk for both the primary outcome (HR, 0.91 [95% CI, 0.72-1.16]) and the secondary outcome (HR, 0.92 [95% CI, 0.79-1.08]) were not increased with ARNI initiation compared to RASi initiation. Investigators noted similar results were observed in intent-to-treat analyses.

Risk Of Acute Kidney Injury Among Older Adults With Heart Failure Treated With Angiotensin-neprilysin Inhibitor Versus Renin-angiotensin System Inhibitor In Routine Clinical Care

,” was presented at HFSA 2022 and simultaneously published in the 

A comparison of data from Medicare Beneficiaries provides insight into the potential for risk of acute kidney injury with use of sacubitril/valsartan among patients who are RASi naive. 

No Excess Risk of Kidney Injury for ARNI Initiation in RASi Naive Patients

Management of transthyretin (ATTR) amyloidosis has undergone a multitude of notable changes in recent decades.

 has reignited discussions about gaps in management of ATTR amyloidosis. Data from the trial, which Alnylam Pharmaceuticals announced will be used in a supplemental new drug application for patisiran, suggested the small interfering RNA reached both its primary and first secondary end points, with the agent providing a statistically significant improvement in 6-minute walk test and a statistically significant improvement in quality of life at 12 months with patisiran compared to placebo.

To learn more about the current state of management for ATTR amyloidosis, particularly, ATTR amyloidosis with cardiomyopathy, 

reached out to Srinivas Murali, MD, professor of medicine and chair of the Department of Cardiovascular Medicine at 

Overview of ATTR Amyloidosis with Cardiomyopathy

Can you discuss the largest current gaps in management of ATTR amyloidosis with cardiomyopathy?

First and foremost, the biggest gap, which has really narrowed substantially, is the gap in diagnosis. Before we talk about treatment gaps we should first talk about the gaps in diagnosis. Roughly 1 out of every 6000 people have ATTR and that gives you a pretty good number of patients who likely have this condition. So, up until a few years ago, the only way to be absolutely certain with the diagnosis of amyloidosis was a biopsy of the organ and biopsy of the heart. This, in particular, is not a slam dunk procedure—it is somewhat risky to go in and get a piece of the heart muscle from somebody. So, heart biopsy was a rate-limiting step in diagnosis because it was not widely available. Then the pathologic examination requires a skilled pathologist who can make the pathologic diagnosis that there is ATTR amyloidosis.

Due to the lack of access to easy diagnostic testing and the special skills necessary to make the diagnosis it was often missed— people would never know they had amyloidosis unless they happen to go see one of those few specialists, but in the past several years there has been a noninvasive diagnostic test that is widely available, which is the cardiac PYP scan and was introduced around 2013-2014. The specificity of this test is pretty high, and the sensitivity is high as well.

So, the gap in diagnosis has significantly narrowed. Now, we are focused on developing a much better understanding of the true prevalence of the disease because more and more patients are getting diagnosed.

Can you provide an overview of treatment options and strategies?

In the treatment of ATTR amyloidosis you want to do several things and there are several places where we can attack this disease. One is we can block the production of this protein in the liver. So, we say 'okay, I'm going to make sure your liver doesn't manufacture this abnormal protein. Let's just shut off the production'. Another treatment strategy is to say 'Okay, we can’t block the production, but let's make sure that when the abnormal protein is misfolded, we stabilize it'. That is another strategy and these drugs are called TTR stabilizers. With the third treatment we are trying to extract that abnormal protein from your heart or other tissues and eliminate it in the body so the organs can recover on their own. So, those are the 3 primary strategies. Obviously, the most drastic treatment for ATTR amyloidosis is to do a liver transplant, but that is a pretty drastic step. So, it is certainly not a practical approach.

Practical Cardiology: When discussing pharmacologic management, how effective are current treatment options?

The TTR stabilizers were the first class approved by the US FDA. What the studies have showed is that, if you take this medication, your heart failure does not deteriorate, you may start to have some stabilization of your symptoms, and you stay out of the hospital. We don't know yet, but we think people could possibly live longer with this strategy as well. They also seem to work in both hereditary ATTR amyloidosis and the wild type.

The second category of drugs are drugs that block the synthesis of block the production of the abnormal protein in the liver. And there are two drugs in the market. One is patisiran and one is called inotersen. Both of these agents are they are called RNA silencers, which means they block the messenger RNA that is giving orders to the liver to produce this protein.

So, these drugs don't get rid of the protein that's already in your tissues, but it prevents production of new proteins. Initially these drugs were evaluated in amyloid neuropathy. More recently, the APOLLO-B data showed that patients with ATTR amyloid cardiomyopathy also seem to have benefits with patisiran. Their heart failure symptoms appeared to stabilize, there is disease progression is diminished, and there was less risk for hospitalization, etc.

Editor’s note: This transcript has bee edited for length and clarity.

Srinivas Murali, MD, of Allegheny Health Network, provides an overview of current management strategies for ATTR amyloidosis with cardiomyopathy as well as offering perspective on the recent APOLLO-B data.

Overview of Management for ATTR Amyloidosis with Cardiomyopathy, with Srinivas Murali, MD

An analysis of nutrition survey data from more than 55,000 US adults paints a grim picture related to food insecurity among individuals with cardiovascular disease or cardiometabolic risk factors.

Results of the analysis, which included data from a 20-year period, suggests the prevalence of food insecurity has increased over time among the overall population, with the frequency among people with cardiovascular disease also increasing.

“Food insecurity is a common problem among people with cardiovascular disease, and we are seeing that issue become even more prevalent in recent years,” said lead investigator Eric J. Brandt, MD, MHS, a cardiologist at the University of Michigan Health (U-M Health) Frankel Cardiovascular Center, 

. “We believe there is a two-way relationship here. Individuals who are food insecure may have increased risk for cardiovascular disease, and vice versa. When one acquires heart disease, it impacts one’s risk for developing socioeconomic problems that could reduce access to adequate and quality food. Food insecurity can often occur with other social determinants of health, such as poor transportation access or access to healthcare, which further compounds this relationship.”

As more research has elucidated the impact of social determinants of health on outcomes, particularly among people with cardiovascular disease, the focus on food insecurity and its impact on health has grown as well. Together with a team of colleagues from U-M Health, Brandt sought to assess how the long-term prevalence of food insecurity has changed among people in the US, with a particular interest in those with cardiovascular disease and cardiometabolic risk factors.

To do so, the team designed a serial cross-sectional study leveraging data from US adults who participated within the National Health and Nutrition Examination Survey during cycles from 1999-2018. Investigators noted food insecurity was assessed using the US department of Agriculture Adult Food Security Survey Module. Investigators also noted prior cardiovascular disease was defined as myocardial infarction, stroke, or heart failure and cardiometabolic risk factors were defined as hypertension, diabetes, obesity, and hyperlipidemia. For the purpose of analysis, investigators planned to estimate the prevalence of food insecurity among those with cardiovascular disease and cardiometabolic risk factors across racial and ethnic groups and prevalence of Supplemental Nutrition Assistance Program (SNAP) participation among those reporting food insecurity.

Overall, an analytic sample of 57,517 US adults, which investigators noted was representative of 312 million, was identified for inclusion in the investigators’ analyses. The sample was s 1.6% Asian, 11.2% Black, 13.8% Hispanic, 68.8% White, and 4.6% other or multiracial. Initial analysis indicated food insecurity was present among 11.8%, but increased throughout the study period. Initial analysis also revealed 7.0% of adults participated in SNAP and any cardiovascular disease was present among 7.9%. When assessing prevalence of cardiometabolic risk factors 49.6% had hypertension, 33.2% had obesity, 11.2% had diabetes, and 30.8% had dyslipidemia.

Further analysis demonstrated food insecurity was more prevalent among Hispanic (24.0%) and non-Hispanic Black (18.2%) individuals than non-Hispanic Asian (8.0%) and non-Hispanic White individuals (8.5%). Food insecurity increased over time and was more frequent among patients with cardiovascular disease, but this was not observed among those with cardiometabolic risk factors. Investigators pointed out non-Hispanic Black individuals with cardiovascular disease experienced a decrease in food insecurity prevalence from 2011-2018 (36.6% [95% CI, 23.9-49.4] vs 25.4% [95% CI, 21.4-29.3]; 

= .04 for trend), but increases were observed for individuals of other races and ethnicities. Investigators also pointed out, for individuals with food insecurity, SNAP participation was greater among those with cardiovascular disease than those without cardiovascular disease (54.2% [95% CI, 46.6-61.8] vs 44.3% [95% CI, 40.5-48.1]; 

“Healthcare providers can impact the health and overall wellbeing of their patients by addressing food insecurity,” said study investigator Tammy Chang, MD, MPH, MS, a family physician at U-M Health and codirector of the National Clinician Scholars Program at the U-M Institute for Healthcare Policy and Innovation, in the aforementioned statement. “More patients than you may think are impacted by food insecurity. A team-based approach including social workers, case managers and social service departments can help patients get connected with local resources. If we are serious about promoting health, healthcare providers need to ensure people have access to healthy foods and don’t go hungry.”

Food Insecurity Among Individuals With Cardiovascular Disease and Cardiometabolic Risk Factors Across Race and Ethnicity in 1999-2018

A University of Michigan-led analysis of NHANES data provides insight into the increases in prevalence of food insecurity among patients with cardiovascular disease in the US across racial and ethnic groups. 

Food Insecurity in the US Increasing, More Prevalent in those with Cardiovascular Disease

Patrick Campbell is the assistant managing editor of Endocrinology Network, as well as its sister publications Practical Cardiology and Rheumatology Network. Prior to joining these brands, he led coverage of cardiology and diabetes with HCPLive. Before joining parent company MJH Life Sciences in 2019, he spent time as a beat reporter with the Pocono Record in Stroudsburg, PA, and Star News Group in Manasquan, NJ. He also touts experience in multimedia, having spent time as a freelance multimedia specialist with NJ Advance Media and multimedia coordinator at the Pocono Record. Follow him on Twitter @RealPatCampbell or reach him via email at PCampbell@mjhlifesciences.com.

Few agents in the landscape of medicine have had as dramatic an impact on disease course as statins for prevention of cardiovascular disease. September 1 marked 35 years since approval of lovastatin in 1987 introduced statins to the general population. To say statins have revolutionized the care of dyslipidemia and prevention of atherosclerotic cardiovascular disease since that approval on September 1, 1987, would be an understatement.

In the past 35 years, mountains of data have emerged outlining the efficacy and safety of these agents as LDL-lowering agents, but also for reducing risk of cardiovascular events. In addition to this, unlike many gamechanging agents that are bogarted by steep prices or limited availability, statins are among the most widely prescribed and inexpensive drugs in the US, with insurance coverage and prescription programs reducing costs to under $100 per month for generics.

Given the availability of statins and growing understanding of LDL-C exposure, some have begun to question whether the role of statins should be expanded to include a wider swath of the population. This question of whether the role of statins in primary prevention should be expanded to be more akin to primordial prevention is the subject of this feature: “Rethinking Statins: Time for Primordial Prevention?”.

 queried a half dozen of the leading experts in cardiometabolic health on the topic. This group of experts includes Erin Michos, MD, of Johns Hopkins School of Medicine, Peter Toth, MD, PhD, of the CGH Medical Center, Deepak Bhatt, MD, MPH, of Brigham and Women’s Hospital, Jorge Plutzky, MD, of Brigham and Women’s Hospital, Alison Bailey, MD, of Centennial Heart, and Robert Busch, MD, of Albany Medical Center.

Rethinking Statins: Time for Primordial Prevention?

Well, it would be great to kind of eradicate atherosclerosis, right? I think this is really important that when we think about LDL years or cholesterol years, we are not only thinking of the magnitude of elevation, but the number of years of exposure. Even with mild to moderately elevated cholesterol for a longer duration of time, these individuals have increased risk for earlier onset of atherosclerotic cardiovascular disease compared to their counterparts that have had lifelong low LDL.

I think we wait too long to treat. The ideal LDL in fetuses and infants is around 30 mg/dL. Compare it to the concept of blood pressure management. So, if you have somebody who is 20-30 years of age that comes in with a systolic blood pressure of 160, you're not going to say, 'Oh, your 10-year risk is low. We're not going to treat your blood pressure'. No, we treat their blood pressure. So, I think that some of the problems of using these 10-year risk scores for cholesterol or for making decisions for initiating statins is that young adults do have a low risk in the next 10 years, but I don't want to just prevent a heart attack in the next 10 years, I want to prevent a heart attack over their lifetime for the next 30 or 40 or 50 years.

So, we wait too long to treat because we focus on these 10-year risk scores and younger adults are never eligible. The whole time their arteries are marinating in these atherogenic lipid particles. The classic example of this is familial hypercholesterolemia. These individuals have genetically very high cholesterol from birth and studies have already shown that if you intervene early and you treat with statins, by adolescence, the offspring don't develop the early onset of ASCVD as their parents. You can change the whole trajectory by starting early. So, that's the classic example with FH.

We should be thinking about this for broader populations and getting LDL lower starting earlier. There is certainly an important role for lifestyle and, particularly, for young adults who are at lower risk. Diet and lifestyle is one of the mainstays of therapy, although the LDL makes that liver makes LDL cholesterol and a lot of cholesterol is genetically determined—up to 3/4ths of this is genetically determined, but 20-30% can still be influenced by diet. So, that does matter, especially in younger adults. If we could be trying to have everybody eating a healthier diet and optimizing lifestyle from utero on through childhood and into young adulthood, that'd be really, really important, but I do think we should have increased consideration for starting statins early.

That's actually a fabulous question. For a long time in primary prevention, an LDL-C of less than 130 was considered to be normal. The average patient who presents to the ER with an MI has an LDL of 128. So, how could that LDL of 128 be normal? It's simply ludicrous. Yet, the older guidelines said less than 130 was normal. In fact, for the low-risk patient, less than 160 was considered to be okay.

I'll tell you right now, for the average patient, if their LDL is above 100, they're experiencing atherogenesis from an early age. We know that in familial hypercholesterolemia, children can have fatty streaks in their coronary tree. We also know, based on autopsy studies from Korea and Vietnam, when looking at young men killed at time of war, more than 50% had anatomical evidence of established plaquing in their coronary arteries. Atherogenesis begins in childhood and it progresses throughout our lifetimes. People, on average, have events in their 5th, 6th, or 7th decades depending upon how much LDL they've been exposed to and what other risk factors they may harbor.

In this light, I think we're now looking at LDL exposure almost like cigarette smoking. What dose of LDL-C you have been exposed to and over how much time can very nicely predict how long it's going to take for that patient to develop significant disease and have an event.

Do I favor lowering LDL cholesterol in everybody? Given the fact that coronary disease is a scourge globally and gives rise to more suffering and more deaths than any other disease? Yes. Do I find it ludicrous that we typically wait till people have their first event and then start a statin? I think it's ludicrous, because certainly we have enough data that this disease starts early, progresses through life, and gives rise to human suffering. Does it make sense to reduce the LDL burden, the burden of atherogenic lipoprotein in serum at a much younger age? You better believe it does.

That's a great question. I never overreact to what's going on in social media, because it's typically an echo chamber of people confirming their own beliefs, but I do think statins could and should have a larger role in primary prevention on the basis of LDL cholesterol. That is, I think there are a lot of people walking around with elevated LDL cholesterol, where starting them on a statin earlier in life would probably reduce a substantial number of atherosclerotic events. We already have positive primary prevention data for statins—the JUPITER trial, for example. So, it's not a data-free zone.

There are certainly patients right now that should be getting statins in the primary prevention universe. So, just how low should the LDL be allowed to be before starting a statin? I think that might be a bit controversial. We should normally have LDL at around 30 if we were newborns again. That's sort of the range of LDL that we have seen historically in more rural parts of the world that hadn't been industrialized and urbanized. That was sort of a"normal LDL".

So, most of us in the US are walking around with an abnormal LDL. You could make a theoretical argument just to treat everyone that's got an LDL above that range, but in the absence of actual data supporting statins for primary prevention in the range I'm talking about, I wouldn't just do it. There is, of course, the occasional real side effect that does occur with statins, then there's the more minor side effects, and then there's the nocebo effects where people are really convinced they're having side effects, but if they were on a placebo they would have the same side effects.

So, it makes life tough. I think advocating too strongly for that, where there isn't data, will just sort of fuel the anti-statin folks and then keep statins from being used where they absolutely should be used, including secondary prevention and high-risk primary prevention. So, for now, I'd say to stick where the data are and not go beyond that, but, if one really thinks that type of primordial prevention is the way to go, perhaps then it's not even a statin, but a PCSK9 inhibitor—where it takes adherence out of the question. I'm not advocating for that, by the way, there would need to be data supporting that. If there were data that ultimately support that approach, there you take adherence out of the question, and you get really large reductions in LDL.

I think we really need more research on what to do. Primary prevention is tough. Secondary prevention, I think is a lot easier because, after someone's had an MI, they ought to be on a statin. The only reason not to be are intolerances, perceived intolerances, or side effects, but otherwise they really ought to do it. But, in primary prevention, it gets trickier because the absolute risk reductions are smaller and adherence is really tough. If somebody's feeling great, and they've never had an ischemic event, it can be tough to take a pill a day the rest of your life. So, I think there are a lot of important interesting questions here, but I suspect future research in lower risk primary prevention populations will help define the right thing to do.

Well, there is considerable evidence that patients are getting undertreated for primary prevention of cardiovascular risk. The idea that you're going to wait for a patient to have an event before you start treating them is really outdated and dangerous, because we know that those events can be very complicated. So, certainly, earlier intervention and use of statins prior to an event is important, but it has to be placed in the context of the risk for that individual. We know that risk is present and we know that risk involves many different factors. So, fully considering that can have you intervening earlier in someone who's considerably younger, who, for example, is smoking, hypertensive, has an elevated number, strong family history, or has an elevated LPa are all things that we actively engaging. At the same time, we want to balance that and not treat people unnecessarily and expose them to all the various issues that can come up with drug therapy.

So, I think it's a question of balance—of recognizing the risk, recognizing we have an intervention, and supporting that. Sometimes in the younger patient, when you're starting to think about risk, that also becomes a great opportunity to implement lifestyle and to really focus on that because you might be seeing a patient who is really years away from when they might have a first event. Using that time to get them off cigarettes, a little bit more active, and eating a little bit better, I think is really important. We should not just be relying on drug therapy.

So, we know that your LDL over your lifespan contributes to your burden of atherosclerosis, not just from heart disease, but also from stroke, kidney disease, and all the other sort of chronic illnesses that we deal with in the United States and increasingly around the world. So, I think low LDL over your lifespan is important. How we get there is also important.

I think the first thing we should focus on is lifestyle for everybody. You know, when I meet people who are overweight, not exercising, and eating poorly, I think they can make pretty substantial changes in their lipid profile by changing their lifestyle. So, I like to have that discussion first. Let's change our lifestyle and then let's reassess.

However, I wouldn't want to walk around with an LDL-C of 130 for the remainder of my life, because I know my risk for cardiovascular disease is going to go up. So, I think statin should be offered to patients earlier, but after a patient-centered discussion about the risks, the benefits, and where the data sits today.

We have lots of tools that we never had before, such as CAC scores. We're learning that using those in younger patients than we ever did before, these lower risk cohorts, may give us additional data. So, I think statins should be expanded after having informed discussions. Obviously, there are groups that are at risk, specifically women who are of childbearing age. To me, that one's the trickiest one. I see a lot of women in my practice and we have very extended discussions about using contraceptive and just knowing what the risks are with statins if they were to get pregnant.

So, the risk with a statin is so minimal and the benefit is so great, I personally feel statins should be in the drinking water, unless your woman is going to get pregnant or are pregnant. The harm of a statin is so minimal and the benefit of statin is so great. Practicing in an era before statins in the 1980s, compared to after that, I'm not seeing the number of strokes and heart attacks that we saw before. That's the game changer.

As an endocrinologist treating someone with diabetes, that's the easiest drug to initiate. It's very well tolerated, it's inexpensive, and we can use it to get to their LDL target goal. That's why the American College of Endocrinology says to everyone with diabetes 'Where is your statin?', based on outcome studies in people with diabetes. But I agree with the notion that we could take it before that. A person with prediabetes is a person with diabetes waiting to happen. Why not treat that patient? What about the obese patient who didn't yet get prediabetes, but they're going to have diabetes in the future?

So, I agree. Statins are imperative for primary prevention and I know a lot of our colleagues calculate a Framingham risk and all that other stuff, and maybe wait for a cardiac calcium score to push the patient, but the fatty streaks are already there. It's unusual to have a zero cardiac calcium score. So, I do think statins are one of the key primary prevention drugs that we have.

Editor's note: These transcripts have been edited for length and clarity. 

Statins and their specific role have been the subject of debate for years. In this feature, 6 leading experts in cardiometabolic health share their perspectives on whether statins should be used in the sense of primordial prevention for ASCVD. 