Regulatory science (RS) is a field dedicated to developing and applying scientific methods, tools, standards, and evidence-based frameworks to improve regulatory policies and decision-making related to medical and device products. The acceleration of cardiovascular innovations over the past two decades has underscored the need for efficient evidence generation and streamlined regulatory pathways for new drugs and devices.RS seeks to address these challenges by strengthening the evidence base that informs policy and guidance, enhancing transparency, expediting approval processes, and enabling more agile responses to emerging public health needs. By evaluating innovative trial designs and employing advanced statistical methods, RS can reduce resource demands of clinical trials while preserving scientific integrity. RS also facilitates the standardization of biomarker evaluations and surrogate endpoints, supporting advancements in precision medicine. In addition to clinical evaluation, RS can enhance post-marketing surveillance by utilizing real-world evidence and advanced analytics to promptly identify safety signals, ensuring patient safety and continuous product monitoring. RS also supports global regulatory harmonization efforts, reducing redundancies and accelerating access to therapies across regions.RS aims to guide the development of regulatory policies, refine communication strategies to optimize the use of medical products, and maintain efficient, transparent, and scientifically rigorous regulatory frameworks. Continued investment in RS is essential for improving patient outcomes in cardiovascular medicine by safeguarding safety while accelerating innovation and access to therapies.

BACKGROUND:Hypertriglyceridemia is associated with increased atherosclerotic cardiovascular disease and pancreatitis risk, yet durable triglyceride reduction remains challenging. Olezarsen, an antisense oligonucleotide targeting APOC3, substantially reduced triglycerides in phase 3 trials. Fibrates lower triglycerides through complementary lipoprotein lipase and apolipoprotein C-III (APOC3) pathways. Whether fibrate therapy modifies olezarsen's effects is unknown. OBJECTIVE:To evaluate the effects of olezarsen on triglycerides and other lipid parameters according to baseline fibrate use. METHODS:This prespecified secondary analysis included 3 phase 3, randomized, double-blind, placebo-controlled trials. Adults with severe hypertriglyceridemia (triglycerides ≥500 mg/dL; CORE-TIMI 72a/CORE2-TIMI 72b, pooled) or moderate hypertriglyceridemia with elevated cardiovascular risk (triglycerides 150-499 mg/dL; Essence-TIMI 73b) were randomized to monthly olezarsen (50 or 80 mg) or placebo. Placebo-adjusted triglyceride changes at 6 and 12 months were estimated using adjusted analysis-of-covariance models with treatment-by-fibrate interaction terms. Secondary endpoints included levels of APOC3 and lipid parameters, with subgroup analyses by diabetes. RESULTS:Among 1061 patients with severe and 1349 patients with moderate hypertriglyceridemia, 64% and 23% used fibrates at baseline. Olezarsen reduced triglycerides across all groups, with greater effects in fibrate users. In severe hypertriglyceridemia, placebo-adjusted triglyceride changes for fibrate users vs nonusers were -68.0% (95% CI: -75.2, -60.8) vs -53.2% (-62.9, -43.5) at 6 months (interaction P [Pint] = .02) and -66.3% (-73.4, -59.1) vs -48.4% (-58.2, -38.7) at 12 months (Pint = .004). In moderate hypertriglyceridemia, changes were -71.1% (-84.1, -58.1) vs -57.4% (-64.9, -49.9) at 6 months (Pint = .07) and -76.0% (-95.8, -56.2) vs -49.5% (-61.3, -37.8) at 12 months (Pint = .02). Similar patterns were observed for APOC3 and select atherogenic lipoproteins. Interactions were more consistently observed among patients with diabetes. Safety was similar across groups. CONCLUSION:Olezarsen reduced triglycerides across the hypertriglyceridemia spectrum, with greater effects in patients on background fibrates, particularly with diabetes. Findings support potential complementary mechanisms and further investigation of concomitant triglyceride-reducing therapy.

BACKGROUND:Whether lowering triglyceride-rich lipoproteins and remnant cholesterol favorably modifies coronary atherosclerosis is unclear. Olezarsen, an antisense oligonucleotide that targets apolipoprotein C-III, reduces triglycerides by ~60% and remnant cholesterol by ~70%, has a neutral effect on LDL (low-density lipoprotein) cholesterol (LDL-C), and reduces apoB (apolipoprotein B) by ~15% in moderate hypertriglyceridemia. We investigated the effect of olezarsen on coronary plaque in adults with largely moderate hypertriglyceridemia. METHODS:We conducted a coronary computed tomography angiography study within Essence-TIMI 73b, a randomized, placebo-controlled trial of olezarsen versus placebo that enrolled patients between November 2022 and February 2024. Inclusion criteria were triglycerides ≥150 mg/dL (2.26 mmol/L), presence of or high risk for cardiovascular disease, and, for this imaging study, noncalcified plaque on baseline coronary computed tomography angiography. The primary end point was percent change from baseline to 12 months in noncalcified plaque volume. RESULTS:Of 468 participants (349 olezarsen, 119 placebo), the median age was 63 years (interquartile range, 56-70); 31% were women, and 97% received lipid-lowering therapy. Median baseline triglycerides were 249 mg/dL (interquartile range, 197-331), and remnant cholesterol was 53 mg/dL (interquartile range, 38-76). Median baseline noncalcified plaque volume was 125.3 mm³ (interquartile range, 63.2-213.3). At 6 months, olezarsen reduced triglycerides by 63.9%, remnant cholesterol by 71.9%, and apoB by 16.0% over placebo, with no difference in LDL-C. The percent change in noncalcified plaque volume from baseline to month 12 did not differ between olezarsen and placebo (placebo-adjusted least-squares mean difference, 2.98% [95% CI, -3.4 to 9.3]; p=0.36). No significant differences between olezarsen and placebo were observed for changes in low-attenuation, calcified, or total plaque volumes at 12 months. CONCLUSIONS:Despite substantial triglyceride and remnant cholesterol lowering, treatment with olezarsen for 12 months on top of standard-of-care lipid-lowering therapy in patients with largely moderate hypertriglyceridemia did not affect noncalcified coronary plaque volume. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05610280.

BACKGROUND:The clinical benefit of intensive LDL cholesterol (LDL-C) lowering with evolocumab in patients with prior percutaneous coronary intervention (PCI) but without a prior myocardial infarction (MI) is not established. METHODS:VESALIUS-CV (The Effect of Evolocumabin Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke) randomized patients with atherosclerosis or high-risk diabetes but without prior MI or stroke and with LDL-C ≥90 mg/dL to evolocumab versus placebo. The median follow-up was 4.6 years. The dual primary end points were coronary heart disease death, MI, or ischemic stroke (3-point major adverse cardiovascular event [MACE]) and the same composite plus ischemia-driven revascularization (4-point MACE). For this prespecified subgroup analysis, patients were categorized by whether they had undergone PCI at any time before trial enrollment. RESULTS:Among 12 257 randomized patients, 3627 (29.6%) had undergone prior PCI with a median time between PCI and enrollment of 4 years. Their median age was 66 years, and 30.7% were women. The median LDL-C in a lipid substudy at 48 weeks was 41.5 (26.0-67.0) mg/dL versus 107.0 (84.0-135.0) mg/dL in the evolocumab versus placebo arms (P<0.0001). Evolocumab reduced the relative rate of 3-point MACE by 30% (5-year Kaplan-Meier rates 7.0% versus 9.5%; hazard ratio [HR], 0.70 [95% CI, 0.56-0.89]; P=0.004) and 4-point MACE by 18% (17.9% versus 21.7%; HR, 0.82 [95% CI, 0.71-0.96]; P=0.012) as well as both MI by 50% (3.0% versus 6.1%; HR, 0.50 [95% CI, 0.36-0.70]; P<0.001), with the effect apparent as soon as 6 months after randomization, and urgent coronary revascularization by 39% (HR, 0.61 [95% CI, 0.46-0.80]; P<0.001). There were nominally lower rates of cardiovascular death (2.6% versus 3.7%; HR, 0.66 [95% CI, 0.45-0.96]; P=0.030) and all-cause death (8.2% versus 10.2%; HR, 0.76 [95% CI, 0.60-0.95]; P=0.016) with evolocumab. CONCLUSIONS:Evolocumab reduced the risk of major cardiovascular events in stable patients with prior PCI but no MI. These findings support intensive LDL-C lowering in patients who have undergone PCI even in the absence of prior MI. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT03872401.

Aims In the Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Patients with Elevated Risk (FOURIER) trial, the PCSK9 inhibitor evolocumab (Evo) significantly reduced the rate of major adverse cardiovascular events and coronary revascularization. The aim was to investigate the effect of initial randomization to Evo on the incidence of complex coronary revascularization during long-term follow-up. Methods and results In FOURIER, patients with atherosclerotic cardiovascular disease with low-density lipoprotein cholesterol (LDL-C) >= 70 mg/dL despite optimized statin therapy were randomized to Evo or placebo. At the end of the trial, patients had the option to be treated with Evo in the open-label extension (OLE) at participating sites. All cases of coronary revascularization were centrally reviewed, and complex revascularization was defined as coronary artery bypass graft surgery (CABG) or complex percutaneous coronary intervention (PCI) using the GLOBAL LEADERS definition. Event rates through 8 years were compared between patients randomized in the parent trial to Evo or placebo. Of 27 564 patients in FOURIER, 6635 patients (median achieved LDL-C 30 mg/dL) continued in OLE (total median follow-up 7.2 years). Patients initially randomized to Evo were treated on average 2.2 years earlier than patients starting treatment during OLE. In patients receiving Evo earlier, the rate for complex coronary revascularization through 8 years was reduced by 24% (HR 0.76 [0.67, 0.87], P < 0.001). This effect was consistent for both CABG (HR 0.77 [0.63, 0.94], P = 0.01) and complex PCI (HR 0.78 [0.65, 0.93], P = 0.006) individually. Early vs. delayed Evo therapy resulted in lower total stent length implanted (22 521 mm vs. 28 946 mm, P < 0.001). Conclusion Compared with delayed treatment initiation, early and sustained treatment with Evo significantly reduced the likelihood of complex revascularization during long-term follow-up. Lay summary Lowering circulating LDL-cholesterol reduces its accumulation in the blood vessels of the heart, legs, and other parts of the body, known as atherosclerosis. Evolocumab is a drug that lowers LDL-cholesterol by similar to 60%. In this study, patients with known atherosclerosis were randomly assigned to receive evolocumab earlier or later. Patients who started evolocumab earlier less frequently needed complex invasive procedures to restore the blood flow to the heart. These results show that early, aggressive lowering of LDL-cholesterol results in fewer coronary bypass surgeries and complex stenting procedures. Trial Registration clinicaltrials.gov, unique identifiers NCT01764633, NCT02867813, and NCT03080935.

BACKGROUND:In FOURIER, the PCSK9 inhibitor evolocumab (Evo) significantly reduced the rate of major adverse cardiovascular events and coronary revascularization. AIMS:To investigate the effect of evolocumab on the incidence of complex coronary revascularization during long-term follow-up. METHODS:In FOURIER, patients with atherosclerotic cardiovascular disease with LDL-C ≥70mg/dL despite optimized statin therapy were randomized to evolocumab or placebo. At the end of the trial, patients had the option to be treated with evolocumab in the open label extension (OLE) at participating sites. All cases of coronary revascularization were centrally reviewed, and complex revascularization was defined as coronary artery bypass graft surgery (CABG) or complex percutaneous coronary intervention (PCI) using the GLOBAL LEADERS definition. Event rates through 8 years were compared between patients randomized in the parent trial to evolocumab or placebo. RESULTS:Of 27,564 patients in FOURIER, 6,635 patients (median achieved LDL-C 30 mg/dL) continued in OLE (total median follow-up 7.2 years). Patients initially randomized to evolocumab were treated on average 2.2 years earlier than patients starting treatment during OLE. In patients receiving evolocumab earlier, the rate for complex coronary revascularization through 8 years was reduced by 24% (HR 0.76 [0.67, 0.87], p<0.001). This effect was consistent for both CABG (HR 0.77 [0.66, 0.94], p=0.01) and complex PCI (HR 0.78 [0.65, 0.93], p=0.006) individually. Early versus delayed evolocumab therapy resulted in lower total stent length implanted (22,521 mm vs 28,946 mm, p<0.001). CONCLUSION:Compared with delayed treatment initiation, early and sustained treatment with evolocumab significantly reduced the likelihood of complex revascularization during long-term follow-up.

PURPOSE:Drug-eluting stents fail in up to 20% of patients. In failed cases, intravascular brachytherapy (IVBT) is administered with β-emitting 90Sr90Y through a guidewire. Current clinical dosimetry is water-based, neglecting attenuation from patient-specific materials such as plaques, stents, and the off-centered guidewire, leading to a discrepancy between prescribed and delivered dose. This study retrospectively performed patient-specific IVBT dose calculations using Optical Coherence Tomography (OCT) to quantify uncertainties in clinical dosimetry. METHODS AND MATERIALS:Dose calculations on OCT images from ten patients were performed using RapidBrachyIVBT, a Monte Carlo-based dose calculation software. Heterogeneities, including guidewire(s), stents, and fibrotic and calcified plaques, were contoured and assigned material properties; surrounding tissue was modeled as smooth muscle. Absorbed dose to water and medium were calculated. The prescribed dose to water was 18.4 or 23 Gy at 2 mm from the source, depending on lumen diameter. The dose homogeneity index was defined as the ratio of the maximum to the minimum dose in the target volume. RESULTS:When heterogeneities were included, median maximum dose attenuation was 76.7% (75.0-77.1) in the artery segment and 56.2% (52.2-65.1) in the target volume. The median dose homogeneity index increased from 1.29 in water to 2.93 (2.44-3.33) with patient-specific materials. The guidewire produced asymmetric dose distributions in all patients, with the greatest attenuation where it opposed thick calcified plaques. CONCLUSIONS:Standard water-based IVBT dosimetry is inaccurate due to dose-attenuating materials present during treatment. Personalized, image-guided IVBT planning that accounts for patient-specific heterogeneities may improve treatment accuracy and clinical outcomes.

BACKGROUND:Patients with severe hypertriglyceridemia have an increased risk of acute pancreatitis. The efficacy and safety of olezarsen, an antisense oligonucleotide targeting apolipoprotein C-III messenger RNA, have not been established in this population. METHODS:We conducted two double-blind, randomized, placebo-controlled trials (CORE-TIMI 72a and CORE2-TIMI 72b). Patients with severe hypertriglyceridemia were assigned in a 1:1:1 ratio to receive olezarsen at a dose of 50 mg, olezarsen at a dose of 80 mg, or placebo monthly for 12 months. The primary outcome was the percent change in the triglyceride level at 6 months, reported as the difference between each olezarsen dose group and the placebo group (placebo-adjusted change). Secondary lipid outcomes included the percent change in the triglyceride level at 12 months and in apolipoprotein C-III, remnant cholesterol, and non-high-density lipoprotein (non-HDL) cholesterol at 6 months and 12 months. Acute pancreatitis events were assessed across both trials. RESULTS:A total of 1061 patients were included in the primary analysis (617 in the CORE-TIMI 72a trial and 444 in the CORE2-TIMI 72b trial). At 6 months, the placebo-adjusted least-squares mean change from baseline in the triglyceride level was -62.9 percentage points in the olezarsen 50-mg group and -72.2 percentage points in the olezarsen 80-mg group in the CORE-TIMI 72a trial and was -49.2 percentage points in the olezarsen 50-mg group and -54.5 percentage points in the olezarsen 80-mg group in the CORE2-TIMI 72b trial (P<0.001 for all comparisons of olezarsen with placebo). Decreases in the levels of triglycerides, apolipoprotein C-III, remnant cholesterol, and non-HDL cholesterol were greater with olezarsen than with placebo (P<0.001 for all comparisons). The incidence of acute pancreatitis was lower with olezarsen than with placebo (mean rate ratio, 0.15; 95% confidence interval, 0.05 to 0.40; P<0.001). The incidence of any adverse events appeared to be similar across trial groups. Elevations in liver-enzyme levels and thrombocytopenia (platelet count, <100,000 per microliter) were more common with the 80-mg dose of olezarsen, and a dose-dependent increase in the hepatic fat fraction was noted. CONCLUSIONS:Among patients with severe hypertriglyceridemia, treatment with olezarsen led to a significantly greater reduction in the triglyceride level at 6 months and in the incidence of acute pancreatitis than placebo. (Funded by Ionis Pharmaceuticals; CORE-TIMI 72a and CORE2-TIMI 72b ClinicalTrials.gov numbers, NCT05079919 and NCT05552326.).

BACKGROUND:Coronary microvascular dysfunction (CMD) and vasospastic angina (VSA) are common, yet underdiagnosed. Existing studies of invasive CMD/VSA assessment have specified patient selection and procedural technique, with little known about testing use in real-world practice. OBJECTIVES:The purpose of the study was to observe procedural and therapeutic decision-making for patients undergoing invasive CMD/VSA assessment. METHODS:FlowLab was a multicenter, prospective study of patients with possible CMD in whom the treating physician used the CoroFlow bolus thermodilution system to measure coronary flow reserve and index of microcirculatory resistance (IMR). As the purpose was to observe how testing is performed in current practice, procedural technique, including whether to perform vasospasm testing, was at operator discretion. Procedural data were collected in real-time. RESULTS:A total of 253 procedures were performed at 14 U.S. sites. The most common presenting symptoms were chest pain (222/253; 88%) and dyspnea (93/253; 37%). The median CoroFlow duration was 10 (IQR: 7-14) minutes and provocative vasospasm testing was performed in 50% (124/246). Forty-three percent (110/253) of patients had abnormal coronary flow reserve (<2.5) and 28% (72/253) had abnormal IMR (≥25). CMD/VSA was identified in 53% (135/253) of patients, with a final diagnosis of CMD in 59% (19/32) of these and VSA in 28% (9/32). Anginal therapy addition was more common in those with elevated IMR (61% [44/72] vs 29% [53/181]; P < 0.0001). CONCLUSIONS:In a prospective assessment of invasive testing for CMD/VSA, we observed varied procedural and technical approaches. Testing was rapid, and a final diagnosis of CMD or VSA was common with immediate implications for patient management. Further integration of CMD/VSA evaluation may help address current gaps in diagnosis and treatment.

Background/Synopsis Angiopoietin-like 3 (ANGPTL3) inhibition is known to significantly reduce the levels of remnant cholesterol (RC), which is comprised of the cholesterol found on very low-density lipoproteins (VLDL) and non-VLDL-RC from intermediate-density lipoproteins (IDL), chylomicrons, and chylomicron remnants. Whether the effect of ANGPTL3 inhibition is consistent across these RC subtypes is not known. Objective/Purpose To evaluate the effect of ANGPTL3 inhibition on subtypes of RC. Methods TRANSLATE-TIMI 70 was a randomized, double-blind, placebo-controlled trial of vupanorsen in patients with non-HDL-C ≥ 100 mg/dL and triglycerides 150–500 mg/dL. Participants were randomized to one of 8 treatment arms (60 mg, 80 mg, 120 mg or 160 mg of vupanorsen every 2 weeks, 80 mg, 120 mg or 160 mg every 4 weeks, or placebo). The endpoints of interest were percent change in RC (Total Cholesterol – HDL-C – direct LDL-C), VLDL-C (directly measured), and non-VLDL-RC (RC – VLDL-C) from baseline to 24 weeks. Subgroup analyses by sex, race/ethnicity, T2DM, obesity and background statin use were performed. Results A total of 286 patients with a median age of 64 years were included in the study. Baseline lipid values included a mean RC of 44.9 mg/dL, VLDL-C of 34.1mg/dL, and non-VLDL-RC of 10.8 mg/dL, with VLDL-C contributing 74% of total RC. This proportion varied significantly depending on baseline triglyceride levels, spanning from approximately 60% when TGs were 100 mg/dL to 95% as TGs approached 400 mg/dL (p < 0.001, Fig A). With treatment, the magnitude of ANGPTL3 inhibition was positively correlated with the magnitude of RC reduction, which ranged from approximately 25% to 60% (red line, Fig B). This effect was driven by 60-80% reductions in VLDL-C (green line, Fig B), whereas there was no reduction in non-VLDL-RC across the spectrum of ANGTPL3 inhibition (blue line, Fig B). As a result, the pooled on-treatment lipid levels included a RC of 24.7 mg/dL, VLDL-C of 11.7 mg/dL, and non-VLDL-RC of 13.6 mg/dL, with VLDL-C now only contributing 42% of total RC. These findings were consistent across key subgroups including sex, race/ethnicities and other cardiovascular comorbidities such as T2DM and obesity. Conclusions Among patients with mild-to-moderate hypertriglyceridemia, the majority of RC is carried on VLDL-C, and this proportion is most pronounced at higher TG levels. Treatment of these individuals with ANGPTL3 inhibition significantly lowers RC through VLDL-C lowering only, with no effect on non-VLDL-remnant cholesterol levels.

BACKGROUND:A novel optical coherence tomography (OCT)-based physiology assessment technique, virtual flow reserve (VFR), has been demonstrated to perform as a reliable surrogate for invasive physiology. OBJECTIVES:The authors sought to examine the performance of post-percutaneous coronary intervention (PCI) VFR as a predictor of 2-year clinical outcomes independent from the OCT-based minimal stent area (MSA). METHODS:The ILUMIEN IV (Optical Coherence Tomography [OCT] Guided Coronary Stent Implantation Compared With Angiography: A Multicenter Randomized Trial in PCI) trial prospectively recruited 2,487 patients with diabetes or high-risk coronary lesions randomizing to OCT- vs angiography-guided drug-eluting stent implantation. All patients with single-lesion treatment who had a final OCT imaging available underwent retrospective post-PCI VFR analysis offline. Of 2,128 eligible patients, VFR analysis was successfully performed in 2,057 (96.6%). Independent OCT predictors for the primary endpoint of 2-year target vessel failure (TVF), a composite of cardiac death, target-vessel myocardial infarction, and ischemia-driven target vessel revascularization, were evaluated by multivariable analysis. RESULTS:The median post-PCI VFR was 0.90 (Q1-Q3: 0.86-0.92), with a significant difference in VFR observed between the angiography- and OCT-guided groups (0.89 [Q1-Q3: 0.86-0.92] vs 0.90 [Q1-Q3: 0.87-0.92]; P < 0.001). By multivariable analysis, both MSA (per 1 mm2) and VFR (per 0.1 mm Hg/mm Hg) were independent predictors of 2-year TVF. Overall, MSA, proximal edge dissection and VFR independently predicted both TVF and target lesion failure. CONCLUSIONS:Post-PCI OCT-based VFR assessment is predictive of 2-year clinical outcomes independent of MSA. Online VFR analysis can provide operators with an immediate assessment of post-PCI physiology in addition to OCT anatomy, providing incremental value in assessing procedural success and informing on clinical prognosis (ILUMIEN IV [Optical Coherence Tomography (OCT) Guided Coronary Stent Implantation Compared With Angiography: A Multicenter Randomized Trial in PCI]; NCT03507777).

BACKGROUND:Severe hypertriglyceridemia (HTG), defined as a serum triglyceride (TG) concentration ≥500 mg/dl, is present in approximately 1 in every 100 individuals and carries direct clinical consequences, including pancreatitis, which can be life-threatening. Olezarsen is an investigational antisense oligonucleotide targeted to the mRNA for apolipoprotein C-III (apoC-III), a protein known to impair TG clearance by inhibiting lipoprotein lipase and the hepatic uptake of triglyceride-rich remnants. No dedicated trial has tested olezarsen in patients with severe HTG. METHODS:In these 2 pivotal phase 3 trials, CORE-TIMI 72a and CORE2-TIMI 72b, patients with severe HTG were randomized in a 2:1 fashion to either olezarsen (80 mg or 50 mg dose) or matching placebo. Patients will be treated for a total of 12 months and evaluated for the primary endpoint of percent change in TGs from baseline to 6 months compared with placebo. Pooled analyses of CORE and CORE2 will also assess olezarsen's effect on acute pancreatitis events and change in hepatic steatosis. RESULTS:A total of 617 subjects in CORE-TIMI 72a and 446 subjects in CORE2-TIMI 72b were randomized. In these 2 trials, the median age was 54 and 55 years, women made up 24% and 23% of the study population, and the baseline TGs were 836 mg/dl and 749 mg/dl, respectively. A total of 333 subjects, 129 from CORE-TIMI 72a and 204 from CORE2-TIMI 72b, were enrolled in the hepatic MRI substudy. DISCUSSION:Together, CORE-TIMI 72a and CORE2-TIMI 72b are designed to establish the efficacy and safety of olezarsen in patients with severe HTG. TRIAL REGISTRATION:Clinicaltrials.gov: NCT05079919 and NCT05552326.

Coronary stent underexpansion is an important problem and limitation of percutaneous coronary intervention, adversely affecting both short- and long-term patient outcomes. Stent underexpansion occurs when a stent fails to expand adequately compared with the adjacent reference segment, resulting in inadequate luminal gain. Multiple studies suggest that stent underexpansion is associated with increased risks of in-stent restenosis, stent thrombosis, and myocardial infarction, resulting in recurrent symptoms, readmissions, repeat interventions, and increased mortality. Contributing factors for stent underexpansion include severe calcification, inadequate lesion preparation, suboptimal stent deployment, and preexisting in-stent restenosis. Calcific plaques, especially when present behind a previously implanted, underexpanded stent, pose a significant challenge for further stent optimization. These lesions are often resistant to high-pressure balloon dilatation and may require advanced techniques that carry increased risks of complications. Intravascular imaging modalities, such as intravascular ultrasound and optical coherence tomography, have emerged as essential tools in diagnosing and managing stent underexpansion. These techniques provide a more detailed evaluation of the vessel and previously implanted stent, enabling the clinician to understand the exact mechanism of stent failure, and assess plaque burden and morphology, which ultimately helps guide appropriate treatment strategies. Despite the clinical importance of stent underexpansion, there is currently no consensus on its optimal treatment, largely because of the absence of large prospective studies in this area. This comprehensive review aims to summarize the existing evidence, clinical experience, and treatment strategies for coronary stent underexpansion, with the goal of providing practical guidance to clinicians to help optimize percutaneous coronary intervention and patient outcomes.

Background Epistaxis is common with antithrombotic therapy and is often troublesome to patients, yet its frequency, severity, and outcomes are poorly characterized. Methods and Results Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation–Thrombolysis in Myocardial Infarction 48 (ENGAGE AF‐TIMI 48) randomized 21 105 patients with atrial fibrillation and CHADS2 risk score ≥2 to higher‐dose edoxaban regimen (60 mg daily, dose‐reduced to 30 mg), lower‐dose edoxaban regimen (30 mg, dose reduced to 15 mg, daily), or warfarin. Bleeds were adjudicated using International Society on Thrombosis and Haemostasis criteria. Patients with intracranial hemorrhage during follow‐up were excluded; those with >1 bleeding event were categorized according to their most severe event. The safety cohort with interval censoring during drug interruption was analyzed. Proportions were compared using Pearson's chi‐square test and treatment arms were compared using a Cox proportional hazards model. Among 5247 patients with a bleeding event, 1008 (19.2%) had epistaxis and 4239 (80.8%) had nonepistaxis bleeding. Epistaxis events were less severe than nonepistaxis bleeds (International Society on Thrombosis and Haemostasis major: 3.2% versus 20.7%; clinically relevant nonmajor: 64.7% versus 60.1%; minor: 32.1% versus 19.2%; P <0.001). Permanent drug discontinuation was similar following epistaxis versus nonepistaxis bleeding in patients with major (59.4% versus 53.6%; P =0.52) or clinically relevant nonmajor (32.5% versus 33.3%; P =0.70) bleeding but was significantly higher in patients with minor epistaxis versus other minor bleeds (33.3% versus 23.9%; P =0.001). Compared with warfarin, higher‐dose edoxaban regimen had similar risk of epistaxis (hazard ratio [HR], 1.09 [95% CI, 0.95–1.26]), whereas lower‐dose edoxaban regimen conferred reduced risk (HR, 0.73 [95% CI, 0.62–0.86]). Conclusions Epistaxis was frequent, and despite being overall less severe than nonepistaxis bleeding, was associated with similar rates of anticoagulant discontinuation. Compared with warfarin, lower‐dose edoxaban regimen reduced the risk of epistaxis by 27% whereas higher‐dose edoxaban regimen had no effect. Registration URL: https://clinicaltrials.gov ; Unique Identifier: NCT00781391 .

BACKGROUND:There are a lack of randomized controlled trial data comparing outcomes of different catheter-based interventions for intermediate-risk pulmonary embolism. METHODS:PEERLESS is a prospective, multicenter, randomized controlled trial that enrolled 550 patients with intermediate-risk pulmonary embolism with right ventricular dilatation and additional clinical risk factors randomized 1:1 to treatment with large-bore mechanical thrombectomy (LBMT) or catheter-directed thrombolysis (CDT). The primary end point was a hierarchal win ratio composite of the following (assessed at the sooner of hospital discharge or 7 days after the procedure): (1) all-cause mortality, (2) intracranial hemorrhage, (3) major bleeding, (4) clinical deterioration and/or escalation to bailout, and (5) postprocedural intensive care unit admission and length of stay. Assessments at the 24-hour visit included respiratory rate, modified Medical Research Council dyspnea score, New York Heart Association classification, right ventricle/left ventricle ratio reduction, and right ventricular function. End points through 30 days included total hospital stay, all-cause readmission, and all-cause mortality. RESULTS:The primary end point occurred significantly less frequently with LBMT compared with CDT (win ratio, 5.01 [95% CI, 3.68-6.97]; P<0.001). There were significantly fewer episodes of clinical deterioration and/or bailout (1.8% versus 5.4%; P=0.04) with LBMT compared with CDT and less postprocedural intensive care unit use (P<0.001), including admissions (41.6% versus 98.6%) and stays >24 hours (19.3% versus 64.5%). There were no significant differences in mortality, intracranial hemorrhage, or major bleeding between strategies or in a secondary win ratio end point including the first 4 components (win ratio, 1.34 [95% CI, 0.78-2.35]; P=0.30). At the 24-hour visit, respiratory rate was lower for patients treated with LBMT (18.3 +/- 3.3 versus 20.1 +/- 5.1; P<0.001), and fewer had moderate to severe modified Medical Research Council dyspnea scores (13.5% versus 26.4%; P<0.001), New York Heart Association classifications (16.3% versus 27.4%; P=0.002), and right ventricular dysfunction (42.1% versus 57.9%; P=0.004). Right ventricle/left ventricle ratio reduction was similar (0.32 +/- 0.24 versus 0.30 +/- 0.26; P=0.55). Patients treated with LBMT had shorter total hospital stays (4.5 +/- 2.8 overnights versus 5.3 +/- 3.9 overnights; P=0.002) and fewer all-cause readmissions (3.2% versus 7.9%; P=0.03), whereas 30-day mortality was similar (0.4% versus 0.8%; P=0.62). CONCLUSIONS:PEERLESS met its primary end point in favor of LBMT compared with CDT in treatment of intermediate-risk pulmonary embolism. LBMT had lower rates of clinical deterioration and/or bailout and postprocedural intensive care unit use compared with CDT, with no difference in mortality or bleeding. REGISTRATION:URL: https://www.clinicaltrials.gov; Unique identifier: NCT05111613.

BACKGROUND:Elevated triglycerides are an important risk factor for atherosclerosis. However, the magnitude of triglyceride lowering with currently available therapies is modest and the impact of triglyceride-lowering on atherosclerosis remains undefined. Olezarsen is an antisense oligonucleotide (ASO) targeting mRNA for apolipoprotein C-III (apoC-III), an inhibitor of triglyceride clearance. METHODS:The Essence-TIMI 73b trial (NCT05610280) is a randomized, double-blind, placebo-controlled phase 3 trial of olezarsen 50 mg or 80 mg every 4 weeks compared with placebo. The trial enrolled adults with either moderate hypertriglyceridemia (200-499 mg/dL) plus increased cardiovascular risk, or severe hypertriglyceridemia (≥500 mg/dL). The primary endpoint is the percent change in triglyceride levels from baseline to 6 months, reported as the difference between each olezarsen dose group and pooled placebo. A coronary computed tomography angiography (CTA) substudy will examine changes in noncalcified plaque volume from baseline to 12 months. RESULTS:A total of 1,478 patients were randomized at 160 sites in North America and Europe. The median age is 63 (IQR 56-69) years, 39% are women, and 71% are non-Hispanic White. Overall, 60% of patients have diabetes, and 42% have atherosclerotic cardiovascular disease. At randomization, 97% were receiving lipid-lowering therapies, including 82% on a statin. The median baseline triglyceride level was 249 (195-339) mg/dL and 9% of patients had triglycerides ≥500 mg/dL at enrollment. Approximately 1000 patients completed a baseline CTA, of whom 555 (55%) had measurable noncalcified coronary plaque and continued in the substudy. DISCUSSION:Targeting apoC-III to facilitate clearance of triglyceride-rich lipoproteins is a potential therapeutic strategy for lowering triglyceride levels, regressing atherosclerosis, and reducing cardiovascular risk. The phase 3 Essence-TIMI 73b trial, which has enrolled nearly 1,500 patients, including over 550 in a coronary CTA substudy, should provide key insights into the efficacy and safety of olezarsen in patients with largely moderate hypertriglyceridemia and elevated cardiovascular risk. TRIAL REGISTRATION:Clinicaltrials.gov: NCT05610280.

BACKGROUND:Highly effective therapies to reduce triglyceride levels are lacking. Olezarsen is an N-acetylgalactosamine-conjugated antisense oligonucleotide that targets the messenger RNA of apolipoprotein C-III, which inhibits triglyceride clearance. METHODS:In this phase 3, international, double-blind, randomized, placebo-controlled trial, we enrolled patients with moderate hypertriglyceridemia (triglyceride level, 150 to 499 mg per deciliter) and elevated cardiovascular risk or with severe hypertriglyceridemia (triglyceride level, ≥500 mg per deciliter) and randomly assigned them in a 1:3 ratio to a 50-mg or 80-mg cohort. The patients were then randomly assigned in a 3:1 ratio to receive monthly subcutaneous olezarsen or matching placebo within each cohort. The primary outcome was the least-squares mean percent change in triglyceride level from baseline to 6 months among the patients with moderate hypertriglyceridemia, reported as the difference between each olezarsen dose group and the placebo group (the placebo-adjusted change). RESULTS:A total of 1349 patients (254 in the olezarsen 50-mg group, 766 in the olezarsen 80-mg group, and 329 in the placebo group) were included in the primary efficacy analysis. The median age was 64 years, 40% of the patients were women, and the median triglyceride level at baseline was 238.5 mg per deciliter (interquartile range, 190.5 to 307.5). At 6 months, the placebo-adjusted least-squares mean change in triglyceride level was -58.4 percentage points (95% confidence interval [CI], -65.1 to -51.7; P<0.001) in the olezarsen 50-mg group and -60.6 percentage points (95% CI, -67.1 to -54.0; P<0.001) in the olezarsen 80-mg group. The incidence of serious adverse events appeared to be similar across the trial groups. CONCLUSIONS:Among patients with moderate hypertriglyceridemia and elevated cardiovascular risk, treatment with olezarsen resulted in significantly greater reduction in triglyceride levels at 6 months than placebo. (Funded by Ionis Pharmaceuticals; ESSENCE-TIMI 73b ClinicalTrials.gov number, NCT05610280.).