The Take Home: ACC Scientific Session
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The American College of Cardiology Scientific Session was held March 4 to 6 in New Orleans. Healio | Cardiology Today was on-site for the latest news in cardiology and experts’ reactions to it.
Among those who offered their insights were American Heart Association President Michelle A. Albert, MD, MPH, FAHA, from the University of California, San Francisco; Megan Coylewright, MD, MPH, FACC, FSCAI, from Erlanger Health System; Robert A. Harrington, MD, FAHA, from Stanford University; Alice H. Lichtenstein, DSc, from Tufts University; Sumeet S. Mitter, MD, from Icahn School of Medicine at Mount Sinai; and Howard Weintraub, MD, from NYU Langone Health.
Editor’s Note: All coverage from the ACC Scientific Session can be found here .
CLEAR Outcomes
Weintraub: This study is relevant and important because it demonstrates the efficacy and safety of bempedoic acid (Nexletol, Esperion Therapeutics), a relatively new nonstatin drug that effectively lowers LDL, and it is well tolerated by patients who are “statin intolerant.” Further, it shows that when this drug is used in these patients, it was able to reduce the frequency of major adverse CV events such as the need for cardiac surgery, fatal heart attacks, CV death and nonfatal stroke.
The study included 13,970 adults from 1,250 sites across 32 countries who were unable or unwilling to take statins owing to unacceptable adverse effects and had or were at high risk for CVD. At a median of 40.6 months, the primary endpoint of CV death, nonfatal MI, nonfatal stroke or coronary revascularization was lower with bempedoic acid than with placebo (11.7% vs. 13.3%; HR = 0.87; 95% CI, 0.79-0.96; P = .004). Similarly, incidence of CV death, nonfatal MI and nonfatal stroke was lower with bempedoic acid vs. placebo (HR = 0.85; 95% CI, 0.76-0.96; P = .006), as was fatal or nonfatal MI (HR = 0.77; 95% CI, 0.66-0.91; P = .002) and coronary revascularization (HR = 0.81; 95% CI, 0.72-0.92; P = .001).
These findings are significant because they demonstrated that there is a drug that is useful and safe in a population of patients that frequently go untreated. It also demonstrated that even a modest amount of LDL reduction over a 3.5-year period was able to have a very meaningful impact on CV risk. Finally, and very importantly, it was one of the few studies to include a large proportion of women. Women comprised 48% of the participants in this trial, and 46% of the patients had diabetes.
This could be practice changing because many patients are reluctant to use any of the cholesterol-lowering medications due to adverse symptoms with the use of statins. Two important differences were the low incidence of muscle aches and the low incidence of the development of type 2 diabetes. Muscle aches are the most common adverse events from statins, but the development of type 2 diabetes is also reported. There were slightly more patients with elevated liver enzymes, and elevations in uric acid were much more frequent.
In this trial, researchers studied patients who have had prior CV events as well as those at increased risk for an event. Both groups saw a meaningful reduction in the combined endpoint. The population of patients who are statin intolerant or perceived as statin intolerant is not a small number of patients. It would be good to have a drug that has been proved in this population but has been shown to reduce events.
There is also the possibility to combine ezetimibe with bempedoic acid. This is available as a single pill and has been shown in clinical trials to lower LDL by as much as 35% to 38%.
TRILUMINATE
Coylewright: It is really challenging to take care of people with severe tricuspid regurgitation. They suffer, and we have limited medical therapies to offer. Most of these patients are elderly and frail and it is very difficult for them to take high-dose diuretics. We don’t typically offer surgery for isolated functional tricuspid regurgitation. This is a huge unmet need.
Cardiologists and physicians are very hopeful that we can make people feel better. In the methods, the authors describe that an improvement in quality of life was 15 points on the Kansas City Cardiomyopathy Questionnaire (KCCQ). We usually define a change of 10 points as a moderate improvement. John Spertus, MD, Suzanne Arnold, MD, and others wrote a JACC State of the Art review in 2020 that walks us through this patient-reported measure, including its use in trials. They note that mean differences can be difficult to interpret, as opposed to the proportion of patients who experienced a benefit, for example.
The primary endpoint of TRILUMINATE — a composite of mortality or tricuspid valve surgery, hospitalization for HF and quality of life improvement of at least 15 points using the KCCQ, evaluated at 1 year in a hierarchical fashion — was met, demonstrating superiority of transcatheter edge-to-edge repair (TEER) over medical therapy alone (win ratio = 1.48; 95% CI, 1.06-2.13; P = .02).
Results did not show a difference, at 1 year at least, in the outcomes of mortality or need for surgery (TEER group, 90.6%; medical therapy group, 89.4%; P = .75) or HF hospitalization (85.1% vs. 87.9%, respectively; P = .41). We are not seeing a large change in quality of life either. I would say that’s counter to some of our own experiences in the clinic after performing this procedure; we really see that patients are feeling a lot better. There is a chance our own experience of people feeling better, and the trial results may be limited by not having a sham control.
One thing we’re all very curious about is what success looks like for interventional HF trials. We’re learning as we go along about how to define success when it comes to quality of life. In interventional cardiology, we have recruited tens of thousands of people and measured mortality or measured receiving another stent. We’re now partnering with our HF colleagues to understand a little bit more of this space that is driven by quality of life. When we hear the results from TRILUMINATE, we’re wondering, is an increase in a KCCQ quality of life score of 12 points meaningful enough to lead to a device approval and therefore a change in our clinical practice? People are excited that it is safe, but we also need to be helpful. If we’re going to sit a patient down and go through a shared decision-making discussion where we discuss the pros and the cons and listen to what’s most important to them, if we cannot communicate that they’re going to feel better, then there won’t be an indication to go forward with the therapy.
I don’t think this trial means that tricuspid repair is unhelpful. It’s 1-year follow-up. We have to look closely at the patients that were included, but we also have to think about whether the ways that we’re measuring quality of life are adequate. Is the KCCQ quality of life score enough to reflect some of the outcomes of my patients who underwent tricuspid repair, like the ability to reduce diuretic dosing, or the ability to bend over and tie their shoes, or the ability to get out of the car without two grandkids lifting them out? These are life-changing for the patients.
NUDGE-FLU
Harrington: NUDGE-FLU is a very interesting study. The researchers looked at whether behavioral nudging would be a viable strategy to boost vaccination update on a population level. More than 964,000 individuals aged 65 years and older (mean age, 74 years; 51% women) in Denmark were randomly assigned to one of nine electronic letters or usual care, which was standard annual correspondence about influenza vaccination from the Danish Health Authority. Communications were delivered before the 2022-2023 influenza season via the country’s governmental electronic letter system.
Subsequent influenza vaccine uptake was higher in two groups: those who received the electronic letter highlighting the potential CV benefits (81% vs. 80.12%; P < .0001) and those who received a reminder letter 2 weeks after the first (80.85% vs. 80.12%; P = .0006).
We did something in our health system a few years ago that was very similar to try to nudge people with different types of contact. That was a localized health system, but this is a much bigger effort. You can’t do a countrywide effort everywhere, but in certain health systems, you can. The sheer scope was impressive.
Also impressive was the different types of behavioral nudges, and that the researchers actually got a result that showed that something might be effective. Perhaps not surprisingly, giving people insight into flu vaccine lowering direct risk for CVD was one of the winners. For cardiologists, that felt good. I thought the social-good option might win, given the perception of Scandinavian countries placing a priority on doing things for the social good.
Not surprising from a human behavior perspective is that if you do something repeatedly, you increase the yield.
This is actionable. In the U.S., it may be hard to get this at the national level, but we can get it at the county level. It would be nice to see something like this rolled out in counties across the U.S. I could also see individual health systems doing this. I get texts from my county about road closures; why couldn’t I also get one reminding me to get my flu shot?
The one caution is that Danes are more ethnically homogenous in terms of racial backgrounds, experiences, socioeconomics, etc, than we are in the U.S. It would be nice to see more data across difference racial and socioeconomic subgroups, because of the hypothesis that different behavioral nudges may work in different groups.
Oral PCSK9 inhibitor
Albert: A number of patients from diverse clinical backgrounds still do not get to optimal LDL levels on statins alone. Adding a PCSK9 inhibitor on top of statins allows them to get closer to optimal levels. It is an important alternative for people who cannot get to optimal levels on statins and for people who are intolerant to higher doses of statins. Adding something on top of statins can be very effective.
The study population was at intermediate to high risk for coronary disease and about 55% had diabetes. Despite so many of these patients having diabetes, only 20% were taking a high-intensity statin in accordance with guidelines. A lot more of these patients should have been on high-intensity statins; it should parallel close to the percentage of those with diabetes.
The researchers randomly assigned 381 participants to placebo or one of four doses of the oral PCSK9 inhibitor: 6 mg, 12 mg, 18 mg or 30 mg, all once daily.
At 8 weeks, the differences in least squares mean percentage change in LDL compared with placebo were as follows:
- –41.2% for the 6 mg group;
- –55.7% for the 12 mg group;
- –59.1% for the 18 mg group; and
- –60.9% for the 30 mg group (P for all < .001).
What was very intriguing is that lipoprotein(a) levels in those who took the oral PCSK9 inhibitor were lowered by about 20%, even though that was not what the researchers were looking to study. That is important for the Black population, who have higher Lp(a) levels than other groups.
There were very few Black people in this study, but it was gratifying to see that each assignment group was 17% to 23% Asian, and there were a few American Indian/Alaska Native participants, who are traditionally not well represented in studies.
STOP-CA
Mitter: The most important take-home message from the STOP-CA trial is that statins potentially could help attenuate the drop in the EF among patients exposed to anthracyclines for lymphoma.
Unfortunately, with anthracyclines, which patients need to treat their malignancy in lymphoma or breast cancer, sometimes there are off-target effects, such as damage to the heart muscle. We’ve been trying to find ways to attenuate the drop in EF and eventual HF events.
Prior to anthracycline treatment, 300 patients were assigned atorvastatin or placebo for 12 months. The primary outcome of the proportion of participants with a decline in LVEF of 10% to less than 55% at 12 months was 9% in the atorvastatin group compared with 22% in the placebo group (P = .002). The likelihood of decline in cardiac dysfunction after anthracyclines was nearly threefold among patients randomly assigned placebo (OR = 2.9; 95% CI, 1.4-6.4).
What it means for patients is that potentially there may be a push to start high-dose statins — such as atorvastatin 40 mg in this trial — to attenuate that drop in EF.
What we don’t know from STOP-CA, and what I think most cardiologists will be wanting from this and looking forward prospectively in further studies, is will this also amount to a reduction in HF events? There is a dichotomy there in what this implies, more so in patients receiving placebo vs. those receiving atorvastatin; we didn’t necessarily measure the actual HF syndrome, event, hospitalization or quality of life, here. That is very different from what we interpret on an echocardiogram. Ultimately, the magnitude of difference in the mean EF between two arms is only 1%, which frankly is not that much in terms of clinical meaning.
The future is bright though. If we continue to conduct well-performed studies looking at agents that could help attenuate the drop in EF, we may one day find also a therapy that stops a drop in EF that may result in reduction of HF events, but ultimately will also be associated with a reduction in HF events and overall improvement in survival and quality of life for our patients afflicted with these malignancies.
CV risk of keto-style diet
Lichtenstein: In a study of 305 participants who followed a keto-style diet and 1,220 who followed a standard diet who were not on lipid-lowering therapy, the overall prevalence of severe hypercholesterolemia (> 5 mmol/L) was higher among individuals who followed a keto-style diet (11.1% vs. 6.2%; P < 001). The risk for incident ASCVD events was more than twofold among patients following a keto-style diet compared with a standard diet (HR = 2.18; 95% CI, 1.39-3.43; P < .001).
The outcome of long-term consumption of a keto-style diet likely depends on the type of foods — hence, the type of fat — that predominates. If animal fat — meat and milk fat — predominates, high in saturated fat, it is not surprising the researchers reported a positive association with elevated CVD risk. Given LDL cholesterol levels were higher, that is likely the case in this study. If a person decides to follow a keto-style diet and gets their fats predominantly from plant sources, high in unsaturated fat such as plant oils — soybean, canola, corn, olive, nuts and seeds — it is very possible the results will be different.
There is a paper that recently came out in Diabetes Care in patients with type 2 diabetes that supports this premise (Hu Y, et al. Diabetes Care. 2023;doi:10.2337/dc22-2310).
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