Michelle O'Donoghue, MD, is the McGillycuddy-Logue Endowed Chair in Cardiology at Brigham and Women's Hospital and associate professor at Harvard Medical School

Michelle O'Donoghue, MD

Gray Areas and Controversies in the 2025 ACS Guidelines, With Michelle O’Donoghue, MD, MPH

Although the 2025 guidelines for the management of 

 are exhaustive and relatively all-inclusive, recent research has highlighted gray areas, controversies, and potential points of confusion for clinicians.

American College of Cardiology (ACC) Scientific Sessions 2026

 in New Orleans, Louisiana, the editorial team at 

 spoke with Michelle O’Donoghue, MD, MPH, the McGillycuddy-Logue Endowed Chair in Cardiology at Brigham and Women’s Hospital, associate professor at Harvard Medical School, and member of the original guideline authors, to discuss the presentations she chaired regarding the ACS guidelines.

“The body of knowledge that we have to support our recommendations continues to evolve at a pretty dizzying pace, so it’s almost hard for guideline writers to keep up,” O’Donoghue told 

 in an exclusive interview. “Part of what we’d like to discuss during this session is the subsequent evidence that has come to light post-completion of the guidelines and how that might shape our thinking.”

The guidelines were initially drafted following a comprehensive literature search, which was conducted from July 2023 to April 2024. The process included clinical studies, systematic reviews, meta-analyses, and other evidence involving human participants. However, O’Donoghue notes that the constant and rapid evolution of research in both ACS and more broadly in cardiology means that any guidelines will be incomplete after publication.

O’Donoghue also indicated several gray areas within the guidelines in terms of treatment, particularly regarding beta blockers. These decrease myocardial oxygen demand via a reduction in the heart rate, blood pressure, and myocardial contractility. Although beta blockers have a well-established clinical benefit in patients with left ventricular ejection fraction (LVEF) <40% and stabilized heart failure, no adequately powered trials have examined the benefit of beta blockers during hospitalization for patients with non-ST-segment elevation ACS (NSTE-ACS).

“Beta blocker therapy is one of the areas where there continues to be additional clinical trials that have been released since the finalization of the 2025 document,” O’Donoghue said. “I think that’s going to be an interesting discussion – how do we start all patients with an ACS on beta blockers at the beginning, and do we continue it post-discharge? Is it only going to be a select group of patients that we continue beta blocker therapy? Is there any risk from beta blocker discontinuation?”

Ultimately, O’Donoghue suggests that documents such as the ACS guidelines inevitably need to be transformed into a “living document” – in other words, a version that is open to regular updates following the completion of new trials or the release of new suggestions.

“There is a plan to make it more of a living document, and some of that might be in the form of more annual – or at least regular – updates rather than completely redrafting the whole document,” O’Donoghue said. “We need more focused updates, since we certainly went too long with a 10-year gap between the last version of the ACS guidelines and this new release.”

Editors’ Note: O’Donoghue reports disclosures with Amgen, Novartis, Janssen, AstraZeneca, GlaxoSmithKline, Intarcia, and others.

Rao SV, O’Donoghue ML, Ruel M, et al. 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline for the management of patients with acute coronary syndromes: A report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. 

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O’Donoghue addresses the inherent limitations in the ACS guidelines, from the constant influx of further research to the ambiguity of certain treatment recommendations.

Very Low LDL-C Improves Risk of MACE in Patients With ASCVD, With Michelle O’Donoghue, MD

 has shown a monotonic relationship with lower incidence of future major adverse cardiovascular events, including recurrent stroke, in patients with 

atherosclerotic cardiovascular disease (ASCVD)

, according to an analysis of the FOURIER trial. These data also support that an LDL-C of <40 mg/dL may be a reasonable target for cardiovascular outcome improvement.

ASCVD is a well-known contributor to the pathogenesis of first and recurrent ischemic stroke. Although existing guidelines have long endorsed lowering LDL-C for the prevention of major adverse cardiovascular events in patients with ASCVD, limited data exist regarding patients who have already experienced an ischemic stroke. To that end, O’Donoghue and colleagues conducted this analysis.

 spoke with Michelle O’Donoghue, MD, the McGillycuddy-Logue Endowed Chair in Cardiology at Brigham and Women’s Hospital and associate professor at Harvard Medical School, to discuss the impacts these data may have on LDL-C-lowering therapies going forward.

“There really didn’t seem to be a floor or a basement in terms of lowering LDL further translating into even lower risk,” O’Donoghue told 

. “Perhaps even more importantly, there did not appear to be any safety signals – for patients who achieved very, very low LDL cholesterol concentrations, we did not see an increased risk of hemorrhagic stroke or any other adverse events of concern. I think that provides important reassurances that pushing LDL cholesterol even further down is safe.”

FOURIER was a double-blind, randomized, placebo-controlled, multicenter study investigating the impacts of evolocumab combined with statin therapy in patients with cardiovascular disease. Patients aged ≥40 to ≤85 years with a history of clinically evident cardiovascular disease at high risk for a recurrent event, as well as fasting LDL-C ≥70 mg/dL or non-HDL-C ≥100 mg/dL and fasting triglycerides ≤400 mg/dL were eligible for inclusion. Investigators excluded patients with NYHA class III or IV 

, uncontrolled or recurrent ventricular tachycardia, untreated hyper- or hypothyroidism, homozygous familial hypercholesterolemia, or LDL or plasma apheresis.

A total of 27,564 patients were enrolled in FOURIER and were randomly assigned to either evolocumab 140 mg every 2 weeks or 420 mg once a month, or matching placebo, both of which were administered subcutaneously with a prefilled 1.0 mL pen. The primary endpoint was a composite of time to cardiovascular death, myocardial infarction (MI), hospitalization for unstable angina, stroke, or coronary revascularization.

Ultimately, investigators observed a significant reduction in the primary endpoint with evolocumab compared with placebo (1344 patients [9.8%] vs 1563 patients [11.3%]; HR, 0.85; 95% CI, 0.79-0.92; 

 <.001), with a consistent effectacross all subgroups. Additionally, the least-squares mean percentage reduction in LDL cholesterol levels was 59% with evolocumab, from a median baseline of 92 mg/dL to 30 mg/dL.

Based on these data, O’Donoghue and colleagues selected 5291 patients from the FOURIER study group. The team used modified Poisson regression models to examine the relationship between achieved LDL-C and the incidence of the composite primary endpoint in the original trial.

O’Donoghue and colleagues followed patients for a total of 14,418 patient years, with a maximum follow-up of 8.6 years. Median achieved LDL-C with evolocumab was 31.5 mg/dL (IQR 21.5-47 mg/dL). Additionally, investigators found that patients with lower achieved LDL-C exhibited substantially lower annualized incidence rates of the primary composite endpoint. When modeled categorically, the lowest incidence rates of the primary endpoint were observed in patients with achieved LDL-C <40 mg/dL.

O’Donoghue and colleagues highlighted these results as endorsing the longstanding suggestion to lower LDL-C targets in patients with prior ischemic stroke. Additionally, they suggest that these data indicate the safety of even lower LDL-C goals than are present in current guidelines.

“I think providing further supporting evidence that we should be even more aggressive than we are right now for lowering LDL-C will translate into greater benefits for patients,” O’Donoghue said. “Mainly, I think it would just further increase the absolute benefit, because people are at higher risk when they’re close to the time of their event. And so, we expect that the number needed to treat would probably be even smaller for that very high-risk group.”

Editor's Note: O'Donoghue reports disclosures with Amgen, Novartis, AstraZeneca, Janssen, Novo Nordisk, Verve, and others.

Monguillon V, Kelly P, O’Donoghue ML, et al. Efficacy and safety of very low achieved LDL-cholesterol in patients with prior ischemic stroke. Circulation. Published online November 3, 2025. 

Amgen Pharmaceuticals. Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER). ClinicalTrials.gov Identifier: NCT01764633. Updated May 28, 2024. Accessed November 26, 2025. 

https://clinicaltrials.gov/study/NCT01764633

Sabatine MS, Giugliano RP, Keech AC, et al. EVOLOCUMAB and clinical outcomes in patients with cardiovascular disease. New England Journal of Medicine. 2017;376(18):1713-1722. 

O’Donoghue discusses the results of this analysis of the FOURIER trial, highlighting that no limit was found for lowered LDL-C improving MACE risk.

Olpasiran Lowers Lp(a) Irrespective of Apo(a) Isoform Size, With Michelle O’Donoghue, MD

, irrespective of apolipoprotein(a) isoform size, according to results from the OCEAN(a)-DOSE trial.

Lp(a) concentration is predominantly driven by genetics, with a well-documented inverse correlation between it and the number of Kringle IV-2 (KIV-2) repeats on apolipoprotein(a) alleles. However, the relationship between the size of these apo(a) isoforms and the response to Lp(a) lowering via RNA interference via olpasiran has not been studied. To that end, this analysis of the OCEAN(a)-DOSE trial was undertaken.

 spoke with Michelle O’Donoghue, MD, the McGillycuddy-Logue Endowed Chair in Cardiology at Brigham and Women’s Hospital and associate professor at Harvard Medical School, to discuss the implications of this finding, not only for olpasiran, but for apo(a)-targeting ASCVD care at large.

“This is relevant because a lot of studies are looking at participants and individuals who have the highest levels of Lp(a),” O’Donoghue told 

. “We really need to better understand whether all people will have a similar type of response to these therapies, even if we end up pushing down to lower baseline Lp(a) concentrations.”

OCEAN(a)-DOSE was a phase 2, dose-finding randomized clinical trial evaluating 4 active doses of olpasiran – 10 mg every 12 weeks (Q12W), 75 mg Q12W, 225 mg Q12W, and 225 mg Q24W. For inclusion, patients were required to have ASCVD and Lp(a) levels >150 nmol/L. Investigators also measured the number of Kringle IV-2 (KIV-2) repeats, which are inversely correlated to the concentration of Lp(a), in each patient via a gel electrophoresis and immunoblotting system.

A total of 277 patients were enrolled in the trial, with a mean age of 62 years (interquartile range [IQR], 56-69). At baseline, the median Lp(a) concentration was 260.2 (IQR, 197.9-358.5) nmol/L. Lp(a) concentration was generally higher among patients with a lower number of KIV-2 repeats (

 = 0.02). Patients were then randomly assigned to 1 of 4 of the active subcutaneous doses of olpasiran or placebo; the final dose was administered at week 36 for the Q12W arms and at week 24 for the Q24W arm.

By week 36, the placebo-adjusted LSM percent change from baseline in Lp(a) with olpasiran was consistent irrespective of baseline KIV-2 repeat number (

 = .66). Additionally, no significant change was observed over time in the percent expression of the dominant apo(a) isoform with olpasiran versus placebo (mean change from baseline [+/- standard deviation] +1.1 [+/-9.8] % with olpasiran and + 2.1 [+/- 12.8] % with placebo; 

“Most people carry 2 different copies of an apo(a) allele, so they have a variable number of KIV-2 repeats in their blood, reflecting each of those 2 alleles – the dominant isoform is really just determined by what percent expression you have of one or the other,” O’Donoghue said. “We found that olpasiran really seems to target both isoforms equally; it doesn’t seem to matter how many KIV-2 repeats you have. It’s being taken out.”

Monguillon V, Lopez A, Rosenson R, et al. Efficacy of Olpasiran by Apolipoprotein(a) Isoform Size: Insights from the OCEAN(a)-DOSE Trial. Presented at the American Heart Association’s Scientific Sessions 2025. New Orleans, Louisiana. November 8-10, 2025.

Rosenson RS, López JAG, Gaudet D, et al. Olpasiran, Oxidized Phospholipids, and Systemic Inflammatory Biomarkers: Results From the OCEAN(a)-DOSE Trial. JAMA Cardiol. 2025;10(5):482-486. 

O’Donoghue discusses the results of the recent OCEAN(a)-DOSE trial and addresses the implications for Lp(a)-lowering therapies moving forward.

Michelle O'Donoghue, MD

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