THRIVE: Culturally Tailored Food‑Is‑Medicine Lowers BP in Black and Hispanic Adults

 A culturally tailored “food‑is‑medicine” intervention significantly lowered systolic blood pressure (SBP) in Black and Hispanic adults with hypertension, compared with individuals who received an equivalent amount of fresh produce without added support, according to the THRIVE trial presented during a Late‑Breaking Clinical Trial session at ACC.26 in New Orleans.

The pilot study randomized 80 adults with hypertension from Maryland communities where access to fresh produce is limited, half to a community‑co‑designed, multipronged intervention that included culturally aligned dietitian coaching, artificial intelligence optimized feedback and encouragement, and flexible produce selection from a mobile farm stand. 

The other half received a weekly bag of fresh produce of equivalent value along with basic nutrition messages. The cohort had a mean age of 55 years, with about two‑thirds Black and one‑third Hispanic participants.

At 24 weeks, participants in the intervention group saw a 6.8 mm Hg reduction in SBP, while the control group saw a reduction of only 0.3 mm Hg. 

Among those who adhered most closely to a DASH‑style diet—rich in fruits, vegetables, nuts, whole grains, and lean proteins, and low in sodium, added sugars, and saturated fat—SBP dropped by 13.3 mm Hg, a decrease that exceeds improvements seen with some hypertensive medications in comparable settings.

The study’s lead author emphasized that nutrition advice alone is not enough; THRIVE demonstrates that embedding food‑is‑medicine supports within clinic workflows and community structures can make heart‑healthy eating more attainable. As a small, geographically limited pilot, the trial is underpowered to define long‑term durability or broad scalability, but the findings support larger trials to explore the cost‑effectiveness, duration, and applicability of such programs across diverse populations. The investigators also caution that food‑based interventions should be used as complements to, not replacements for, guideline‑directed antihypertensive therapy when clinically indicated.

ALERT: Electronic Notifications Improve Management of AS, MR

The ALERT trial shows that automated electronic clinician notification alerts in the electronic health record (EHR) can meaningfully speed up the evaluation and treatment of patients with severe aortic stenosis (AS) or severe mitral regurgitation (MR). 

Conducted across 35 U.S. hospitals and published in JACC, the cluster‑randomized study found that clinicians who received EHR‑based alerts for significant AS or MR were more likely to schedule multidisciplinary heart‑team evaluation and valve intervention within 90 days than those receiving usual care.

Using a hierarchical win‑ratio analysis, the alert group had a win ratio of 1.27 (p = 0.007), with higher rates of valve intervention (13% vs. 10%) and multidisciplinary evaluation (23% vs. 18%), and shorter times to both endpoints. 

The benefit was similar for both AS and MR and across patient subgroups. The authors conclude that EHR‑integrated alerts are a practical, scalable way to reduce undertreatment of valvular heart disease and improve timely access to specialized valve‑disease care in routine clinical practice.

T-TEER Cuts Heart Failure Hospitalizations by 40%

The ALERT trial, presented at ACC.26 and published in JACC, shows that automated electronic clinician notification alerts in the electronic health record (EHR) can meaningfully speed up the evaluation and treatment of patients with severe aortic stenosis (AS) or severe mitral regurgitation (MR). 

In this cluster‑randomized study across 35 U.S. hospitals, 765 clinicians and 2,016 echocardiograms were randomized to an Alert or No Alert group.

Using a hierarchical win‑ratio analysis, the alert group showed superior outcomes (win ratio 1.27; p = 0.007), with higher rates of valve intervention (13% vs. 10%) and multidisciplinary heart‑team evaluation (23% vs. 18%), and shorter times to both endpoints. 

The effect was consistent for AS and MR and across subgroups. 

The authors conclude that EHR‑integrated alerts are a practical, scalable way to reduce undertreatment of valvular heart disease and improve timely access to specialized valve‑disease care in routine clinical practice.

PRO‑TAVI: Should High‑Risk Patients Undergo PCI Before TAVI?

The PRO‑TAVI trial, presented at ACC.26 and published in The Lancet, shows that in high‑risk older adults with severe aortic stenosis and significant coronary artery disease (CAD), performing PCI before TAVI yields similar 1‑year outcomes to a strategy of TAVI first, with PCI deferred if needed afterward. 

In this Netherlands‑based, open‑label trial, 466 patients (median age 81, 36% women) were randomized 1:1 to PCI‑first (n=233) or deferred‑PCI (n=233), with many carrying substantial CAD burden.

At one year, the composite of death, MI, stroke, or moderate‑to‑severe bleeding occurred in 24% of the deferral group versus 26% of the PCI‑first group (HR 0.89), meeting the prespecified noninferiority threshold with no evidence of superiority for either approach. 

The key difference was in major bleeding, which occurred in 15% of the PCI‑first arm versus 6% of the deferred‑PCI arm, largely because of dual‑antiplatelet therapy after PCI. 

The editorialists note that, in this elderly population, reducing hemorrhagic events is clinically meaningful, but emphasize that PRO‑TAVI should not be read as proof that PCI is unnecessary in all TAVI candidates. 

Instead, the trial supports a more selective, TAVI‑first, PCI‑deferred strategy in intermediate‑ to high‑risk older patients, while reserving upfront PCI for truly high‑risk coronary lesions.

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Checklists for the practicing cardiologist

• For intermediate‑ to high‑risk TAVI patients ≥80 years with hemodynamically significant CAD, a TAVI‑first, PCI‑deferred strategy is noninferior and reduces early bleeding risk; reserve upfront PCI for truly high‑risk lesions or unprotected left‑main disease.

• Use stress testing or invasive FFR/IMR when feasible to triage which obstructive lesions actually need PCI before or after TAVI, rather than treating anatomy alone.

• For patients randomized to PCI‑first, plan PCI before TAVI in a single‑stage fashion if possible, balance ischemic risk against bleed risk, and minimize dual antiplatelet duration when appropriate.

• For defer‑then‑PCI patients, monitor for recurring or worsening angina post‑TAVI and reserve PCI for symptomatic, high‑risk lesions; maintain single antiplatelet therapy in most.

• For younger, low‑risk TAVI patients, recognize that PRO‑TAVI does not apply, and let individual‑level anatomy, ischemia burden, and multidisciplinary discussion guide the timing of PCI versus TAVI rather than a one‑size‑fits‑all algorithm.

PROTECT H2H: Emboliner vs. Sentinel Embolic Protection Devices in TAVR

The PROTECT H2H trial, presented at ACC.26, is the first head‑to‑head comparison of two embolic‑protection systems used during transcatheter aortic valve replacement (TAVR). 

In this multicenter, open‑label trial across 20 sites in Brazil, Germany, and the U.S., 522 patients with severe aortic stenosis were randomized to the investigational Emboliner full‑body filter catheter or the U.S. FDA‑approved Sentinel cerebral‑protection system. 

At 30 days, the composite of all‑cause death, stroke, and acute kidney failure occurred in 4.9% of the Emboliner group versus 5.0% of the Sentinel group, with stroke rates of 2% vs. 2.1%—among the lowest reported in any TAVR‑protection trial.

The Emboliner captured three times as many particles larger than 150 microns and nearly twice as many total debris as Sentinel, with successful placement in 96% of cases versus 87% for Sentinel.

Rates of bleeding, thrombosis, and other procedural adverse events were similar between systems. The authors highlight that the Emboliner’s broader full‑body debris capture raises the hypothesis that blocking embolic material to organs beyond the brain—such as the kidneys, gut, and lower extremities—could further improve TAVR outcomes, as long as the platform remains safe and easy to use. 

Given the short 30‑day follow‑up and limited sample size, the trial was underpowered to detect differences in kidney‑failure risk or very rare events, so longer‑term registries will be key to defining the incremental benefit of more extensive embolic‑protection strategies.

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Checklists for the practicing cardiologist

• Consider embolic‑protection devices (Sentinel or Emboliner‑like platforms) in high‑risk TAVR patients, especially those with prior stroke, atrial fibrillation, or extensive aortic‑calcification, pending full regulatory and guideline adoption.

• For Emboliner‑type systems, weigh the potential benefit of full‑body debris capture against added catheter‑manipulation complexity, procedural time, and cost, particularly in patients with multiple comorbidities.

• For Sentinel‑type systems, continue using them as a cerebral‑centric standard of care when available, ensuring proper positioning in the common carotid and subclavian arteries and confirming wire‑safe snare technique.

• Monitor stroke, acute kidney injury, and major bleeding within 30 days after TAVR, and link these outcomes to registry data to help clarify whether broader embolic‑protection translates into meaningful reductions in non‑cerebral organ injury over time.

• In multidisciplinary TAVR meetings, balance anatomical risk factors (calcified aortic arch, porcelain aorta, peripheral‑vessel disease) and patient‑specific factors (frailty, anticoagulation status, prior embolic events) when deciding which, if any, embolic‑protection strategy to deploy, and remain vigilant for future outcomes‑driven guidance from extended follow‑up and real‑world registries.

CADENCE: Sotatercept Significantly Benefits Patients With CpcPH, HFpEF

The CADENCE study, presented at ACC.26 and simultaneously published in Circulation, shows that sotatercept, an activin signaling inhibitor, meaningfully improves pulmonary vascular and cardiac hemodynamics in patients with heart failure with preserved ejection fraction (HFpEF) and severe combined post‑ and precapillary pulmonary hypertension (CpcPH). 

In this phase 2, randomized trial, 164 patients (mean age 75, 70% women) on guideline‑directed HFpEF therapy were assigned to sotatercept 0.3 mg/kg, 0.7 mg/kg, or placebo every 3 weeks for 24 weeks.

At 24 weeks, the primary endpoint, pulmonary vascular resistance (PVR), dropped significantly with sotatercept versus placebo, with median changes of −0.67 and −0.33 Wood units in the lower‑ and higher‑dose groups versus +0.26 in placebo. 

Both sotatercept doses also reduced mean pulmonary artery pressure (mPAP) by about 9 mm Hg, pulmonary arterial wedge pressure (PAWP) by 2.5–3.0 mm Hg, and improved six‑minute walking distance, with a marked reduction in time to clinical worsening at the 0.3 mg/kg dose. 

Adverse events were modest, led mainly by increased hemoglobin and diarrhea, and were generally consistent with prior sotatercept trials.

The authors interpret the results as proof of concept that targeting activin signaling can improve both right‑ and left‑sided heart failure parameters—including left atrial pressure and volume—beyond modest PVR reductions. 

An editorial highlights that CADENCE shifts the focus from purely hemodynamic improvement to reversing fibrosis and cellular hypertrophy, marking an early step toward mechanism‑driven therapy for HFpEF‑associated pulmonary vascular disease. 

These findings support further development of sotatercept and similar ligand‑trap strategies in CpcPH and advanced HFpEF.

ALL‑RISE: AI‑Supported Coronary Flow Assessment Performs Similarly to Gold‑Standard Wire‑Based Testing

The ALL‑RISE trial, presented at ACC.26 and simultaneously published in the New England Journal of Medicine, shows that FFRangio, an AI‑supported, angiography‑derived method for fractional flow reserve (FFR), performs similarly to traditional wire‑based invasive FFR in patients with coronary artery disease (CAD) referred for PCI. 

Investigators randomly assigned patients undergoing coronary angiography who were found to have at least one intermediate coronary stenosis to physiological assessment with measurements derived from angiographic images (FFRangio) or with pressure-wire–based measurements.

In this large, international noninferiority study, 1,930 patients were randomized 1:1 to FFRangio or conventional pressure‑wire‑based FFR, with a mean age of 68, 25% women, and high rates of prior MI, PCI, hypertension, hyperlipidemia, and diabetes.

At one year, the composite primary endpoint of death, MI, or unplanned clinically indicated revascularization occurred in 6.9% of the FFRangio group versus 7.1% of the wire‑based group (HR 0.98), meeting the prespecified criterion for noninferiority. 

There were no differences in bleeding, acute kidney injury, or procedure‑related adverse events. The FFRangio approach was also faster (39 vs. 42 minutes per case), required less fluoroscopy, less contrast, and avoided additional coronary manipulation beyond standard angiography.

The senior investigator notes that FFRangio provides similar clinical outcomes at one year to the current gold‑standard wire‑based assessment, while being less invasive. 

In an accompanying editorial, an expert stresses that the broader implication is a shift away from angiographic anatomy alone toward routine, integrated physiologic assessment; AI‑derived FFR may become a practical, first‑line tool during diagnostic coronary angiography to guide revascularization decisions. 

Limitations include the trial’s open‑label design and exclusion of patients with prior CABG, but the data support wider adoption of physiology‑guided PCI using software‑based tools like FFRangio.

CHIP‑BCIS3: LV Unloading Not Beneficial During PCI in Patients With Severe LV Dysfunction

The CHIP‑BCIS3 trial, presented at ACC.26 and simultaneously published in the New England Journal of Medicine, shows that elective LV unloading with a microaxial flow pump did not improve outcomes—and may have increased harm—among patients with severe left ventricular (LV) dysfunction undergoing complex PCI. 

In this UK‑based, open‑label study, 300 patients with LVEF ≤ 35% and extensive coronary disease were randomized to elective unloading versus standard‑care PCI, and 299 actually underwent the procedure.

At a median follow‑up of 22 months, the primary hierarchical endpoint—a composite of all‑cause death, disabling stroke, spontaneous MI, cardiovascular hospitalization, and periprocedural myocardial injury—was no better with LV unloading, with a win ratio of 0.85 (p = 0.30) favoring the control group in pairwise comparisons. 

The microaxial flow pump arm had a higher rate of all‑cause death (32.6% vs 23.4%) and cardiovascular death (26.7% vs 14.5%), and more periprocedural myocardial injury than the standard‑care group, without a reduction in bleeding or vascular complications.

The investigators describe the results as “surprising,” since the theoretical rationale for LV unloading is to protect the heart during high‑risk PCI; instead, patients assigned to unloading appeared to sustain more LV damage.

The accompanying editorial stresses that CHIP‑BCIS3 underscores the need for a more selective, indication‑driven use of mechanical circulatory support in high‑risk PCI, especially in patients without clear hemodynamic instability. 

For practicing interventionalists, these data argue against routine prophylactic LV unloading in complex PCI for severe LV dysfunction and reinforce that physiological benefit does not automatically translate into clinical benefit in this population.

ORBITA‑CTO: Angioplasty Reduces Chest Pain, Boosts QoL in Chronic Total Occlusion

The ORBITA‑CTO trial, presented at ACC.26 and simultaneously published in JACC, shows that percutaneous coronary intervention (PCI) for chronic total occlusion (CTO) meaningfully reduces angina and improves quality of life (QoL) in carefully selected patients. 

In this small, randomized, blinded study, 50 adults with single‑vessel CTO and stable, refractory chest pain were randomly assigned to CTO PCI plus medical therapy or a placebo procedure plus the same medical regimen, with antianginal drugs temporarily stopped and later re‑introduced only as needed.

During a 24‑week follow‑up, patients who underwent CTO PCI had a greater drop in angina symptom scores compared with the placebo group, largely driven by fewer angina episodes. 

On average, treated patients enjoyed about 31 more angina‑free days over 168 days than those in the placebo arm. The CTO‑PCI group also reported better QoL scores and clinicians rated their angina severity as lower, with no deaths, myocardial infarctions, or withdrawals due to worsening symptoms.

The investigators emphasize that in this controlled, blinded design, coronary angioplasty and stenting for CTO clearly improved both symptoms and patient‑reported well‑being over a 6‑month period. 

A related editorial notes that ORBITA‑CTO confirms the benefit of CTO PCI is not just a placebo effect, while underscoring that the magnitude of benefit depends on the individual patient. 

The trial’s small size, highly selected population, and exclusion of the most complex CTOs mean clinicians should use these data as a signal rather than a broad mandate, and future work will need to define precisely which CTO patients gain the most from revascularization.

SCOUT‑HCM: Mavacamten Benefits Adolescents With HCM

The SCOUT‑HCM trial, presented at ACC.26 and simultaneously published in the New England Journal of Medicine, shows that mavacamten, a first‑in‑class cardiac myosin inhibitor, significantly improves left ventricular outflow tract (LVOT) gradient in adolescents with obstructive hypertrophic cardiomyopathy (oHCM). 

In this first mavacamten trial in pediatric patients, 43 symptomatic adolescents (ages 12–17, NYHA II–III, peak LVOT gradient >50 mm Hg, LVEF >60%) were randomized to 28 weeks of daily mavacamten or placebo.

At week 28, the mavacamten group had an average drop in Valsalva LVOT gradient of 48.5 mm Hg versus only 0.5 mm Hg with placebo (p < 0.001). 

The treatment arm also showed larger reductions in resting LVOT gradient and maximal LV wall thickness, along with improved peak oxygen consumption and fewer symptoms such as fatigue and shortness of breath. 

Biomarkers like troponin and natriuretic peptides declined in the mavacamten group but rose in the placebo group.

Adverse events were modest, with syncope and an inappropriate ICD shock in the treatment arm and chest pain and suicidal ideation in the placebo group; no patient developed an LVEF below 50% and there were no deaths. 

The authors suggest that early treatment with mavacamten could remodel the heart and potentially alter the long‑term course of oHCM. 

Limitations include the trial’s small size, short duration, and predominantly White population, with follow‑up planned out to 50 weeks and plans to study the drug in children under 12 and in other HCM subtypes.

SPIRIT‑HF: Spironolactone Falls Short in HFpEF and HFmrEF

The SPIRIT‑HF trial, presented at ACC.26, found that spironolactone, an aldosterone blocker, did not reduce heart failure hospitalizations or cardiovascular death at 24 months in patients with HFpEF or HFmrEF, compared with placebo. 

The double‑blind, European study randomized 730 patients with symptomatic HFpEF or HFmrEF (median age ~78, half women, ~80% HFpEF) across 56 centers from 2018 to 2024.

The primary endpoint—a composite of HF hospitalization and cardiovascular death—showed 10.8 events per 100 patient‑years with placebo versus 12.7 with spironolactone, with no meaningful difference across subgroups by age, sex, ejection fraction, or comorbidities. 

Instead, the spironolactone arm had significantly more total hospitalizations, hypotension, renal events, and elevated potassium, and a trend toward more cardiovascular hospitalizations.

The trial was also limited by a high rate of drug discontinuation during the COVID‑19 pandemic, which reduced its power and makes the efficacy signal “negative or slightly inconclusive.” 

A meta‑analysis combining SPIRIT‑HF with the TOPCAT Americas cohort similarly showed no benefit from spironolactone.

 For clinicians, these data suggest that in routine HFpEF/HFmrEF management, spironolactone should be used cautiously, with close monitoring of renal function and potassium, and that other mechanisms and agents deserve focus in this population.

PCSK9 Inhibitor Very Effective in High‑Risk Patients Without ASCVD: VESALIUS‑CV

A prespecified subgroup analysis from the VESALIUS‑CV trial shows that adding the PCSK9 inhibitor evolocumab (Repatha) to statin therapy markedly reduces major cardiovascular events in high‑risk patients with diabetes but no established atherosclerotic cardiovascular disease (ASCVD). The findings, presented at the American College of Cardiology 2026 Scientific Session and published in JAMA, support using LDL targets typically reserved for secondary prevention—often below 55 mg/dL, and even near 40 mg/dL—for selected high‑risk primary‑prevention patients.

VESALIUS‑CV in high‑risk patients without ASCVD

VESALIUS‑CV enrolled 12,257 patients at high cardiovascular risk, including those with diabetes plus a risk enhancer or established atherosclerosis with elevated LDL‑C ≥ 90 mg/dL. In this subgroup, 3,355 patients had diabetes but no significant atherosclerosis, with a median baseline LDL‑C of about 121 mg/dL.

Over 48 weeks, evolocumab on top of statins cut LDL‑C by roughly half to a median of about 52 mg/dL, and by 96 weeks the LDL‑C in the evolocumab arm dropped to around 44 mg/dL. This produced a mean difference of nearly 60 mg/dL versus placebo‑added statin therapy.

At 5 years, evolocumab reduced three‑point MACE (coronary heart disease death, MI, or ischemic stroke) from 7.1% to 5.0%, an absolute reduction of 2.1%. The four‑point MACE endpoint, which added ischemia‑driven revascularization, fell from 10.5% to 7.6%, an absolute reduction of 2.9%. Both all‑cause and cardiovascular death were significantly lower in the evolocumab group.

How this fits the new dyslipidemia guidelines

The 2026 ACC/AHA dyslipidemia guidelines recommend an LDL‑C target of less than 100 mg/dL for patients with diabetes but no ASCVD and less than 70 mg/dL for those with diabetes plus multiple risk factors; the < 55 mg/dL target is reserved for very high‑risk patients with ASCVD. VESALIUS‑CV was published too late to be incorporated into those guidelines, but the writing committee acknowledged in an accompanying editorial that the trial supports more aggressive LDL‑C lowering in high‑risk individuals with diabetes even before ASCVD appears.

The current guideline framework favors high‑intensity statins, with ezetimibe if needed, and restricts PCSK9 inhibitors mainly to ASCVD patients on maximal oral therapy. In this subgroup, however, baseline LDL‑C was substantially higher than in trials like Ez‑PAVE, so even ezetimibe often would not bring many patients down to < 70 mg/dL, making PCSK9 inhibition a more powerful option.

Clinical takeaways for cardiologists

For the practicing cardiologist, VESALIUS‑CV suggests that high‑risk primary‑prevention patients with diabetes—especially those with long‑standing disease, hypertension, or multiple risk factors—may benefit from LDL‑C targets closer to or below 55 mg/dL, similar to strategies used in secondary prevention. Evolocumab added to statins achieves profound LDL‑C lowering and a robust reduction in first major cardiovascular events, supporting earlier intensification before atherosclerosis becomes clinically evident.

While ezetimibe remains a more cost‑effective first‑step add‑on, in patients with very high baseline LDL‑C who cannot reach < 70 mg/dL on statin plus ezetimibe, PCSK9 inhibitors may be the most practical way to deliver meaningful risk reduction. Community internists, endocrinologists, and cardiologists will need to collaborate closely, and broader payer coverage of PCSK9 inhibitors will likely grow as the data confirm that lower LDL‑C earlier translates into fewer first‑time MACE, even in patients without prior ASCVD.

Barbershop Effort Falls Short for Hypertension Prevention in Black Men

A barbershop‑based community health worker program did not meaningfully lower blood pressure in Black men with elevated BP or stage 1 hypertension, according to a cluster‑randomized trial presented at the American College of Cardiology 2026 Scientific Session. 

Over 1-year, systolic BP changed little in either a facilitator‑supported or self‑directed version of the initiative, although progression to stage 2 hypertension was lower in the facilitated arm at 12 months (2.9% vs 6.9%, P = 0.03), a difference that faded by 18 months.

The Community‑to‑Clinic Linkage Implementation Program (CLIP), delivered through the RESTORE network, used barbershop‑based community health workers to take blood pressure measurements, screen for social determinants of health, provide lifestyle counseling, and link men to primary care and health coaching following the AHA Life’s Essential 8 framework. 

While the trial missed its primary BP‑lowering endpoint, it demonstrated that community health workers can successfully engage young Black men who often avoid clinical care, opening a pathway to earlier diagnosis and treatment.

Going forward, investigators aim to refine which CLIP components drive benefit, test scalability in diverse settings (including rural areas), and work with primary care to align with the latest US hypertension guidelines. 

The trial underscores that although the barbershop model alone may not strongly move blood pressure, it can be a powerful bridge to clinical care and a platform for addressing long‑standing hypertension disparities in Black men.

Very Low LDL Levels Best in Secondary Prevention: Ez‑PAVE

New randomized data from the Ez‑PAVE trial show that targeting low‑density lipoprotein cholesterol (LDL‑C) below 55 mg/dL meaningfully reduces major cardiovascular events in patients with atherosclerotic cardiovascular disease (ASCVD) compared with the more conventional threshold of less than 70 mg/dL. The findings, presented at the American College of Cardiology 2026 Scientific Session and published in the New England Journal of Medicine, provide the first direct evidence that the stricter LDL goal promoted in the updated American dyslipidemia guidelines is superior for secondary prevention.

Key findings from Ez‑PAVE

In Ez‑PAVE, 3,048 patients with established ASCVD were randomized to an LDL‑C target of less than 55 mg/dL or less than 70 mg/dL across 17 South Korean sites. Over a median follow‑up of 3 years, the intensive‑target group achieved a median LDL of 56 mg/dL versus 66 mg/dL in the less‑intensive arm. The primary composite endpoint—cardiovascular death, nonfatal MI, nonfatal stroke, any revascularization, or hospitalization for unstable angina—occurred in 6.6% of the < 55 mg/dL group versus 9.7% of the < 70 mg/dL group, corresponding to a 33% relative‑risk reduction (HR 0.67).

Both nonfatal MI and any revascularization were significantly lower in the lower‑target group, with consistent benefit across age, diabetes status, and baseline risk profile. Although the trial was underpowered for sex‑specific analyses, the editorial in the NEJM notes that the overall pattern aligns with prior lipid‑lowering trials showing similar benefit in men and women. Safety outcomes, including new‑onset diabetes, statin‑associated muscle symptoms, cancer, and liver or kidney‑related events, were similar between groups, with a small but statistically significant reduction in creatinine elevation in the intensive‑target arm.

How this aligns with the new US guidelines

The 2026 ACC/AHA dyslipidemia guidelines recommend targeting LDL‑C below 70 mg/dL for high‑risk patients and below 55 mg/dL for very high‑risk individuals, typically using statin‑based therapy plus ezetimibe or a PCSK9 inhibitor. Ez‑PAVE strongly supports the 55 mg/dL target in secondary prevention, demonstrating that intensifying lipid‑lowering with high‑intensity statins and ezetimibe, and escalating to PCSK9 inhibitors when necessary, improves outcomes without a clear safety trade‑off.

Experts such as Christopher P. Cannon, MD stress that the event‑reduction curves separate early and remain stable, reinforcing the “lower is better” paradigm and suggesting that 55 mg/dL should become a default goal for most ASCVD patients. Christie Ballantyne, MD has argued that the high‑risk/very‑high‑risk distinction may be unnecessarily complex and that a single, lower LDL‑C target for all secondary‑prevention patients could ease guideline implementation.

Clinical implications for the practicing cardiologist

For a cardiologist managing ASCVD, Ez‑PAVE shifts the practical standard: aiming for LDL‑C below 55 mg/dL, using statin plus ezetimibe as a first‑line intensification and reserving PCSK9 inhibitors for patients who cannot reach goal or cannot tolerate high‑dose statins, appears both safe and effective. The trial also underscores the importance of close lab monitoring, dose titration, and adherence support, since many patients needed multiple adjustments over 3 years to sustain their target LDL.

At the same time, the authors and editorialists caution that Ez‑PAVE was conducted in a South Korean (predominantly Asian) ASCVD population, so direct extrapolation to other ethnic groups—especially in primary‑prevention settings—requires further study. The trial does not define whether all primary‑prevention patients must be targeted below 70 mg/dL, but it does solidify that in secondary prevention, “lower LDL now” is where the strongest outcome signal lies.

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Checklists for the practicing cardiologist

1. Patient selection: who to target below 55 mg/dL

• Confirm established atherosclerotic cardiovascular disease (ASCVD) (prior MI, ischemic stroke, PAD, or coronary revascularization).

• Ensure patient has LDL‑C ≥ 55 mg/dL at baseline on guideline‑directed lipid‑lowering therapy.

• Exclude patients with contraindications to statins, ezetimibe, or PCSK9 inhibitors or those with life‑limiting non‑cardiovascular disease and very short life expectancy.

2. Lipid‑lowering strategy in ASCVD

• Start or intensify high‑intensity statin (e.g., atorvastatin 40–80 mg or rosuvastatin 20–40 mg) unless contraindicated.

• Add ezetimibe 10 mg daily if LDL‑C remains above 55 mg/dL despite maximal tolerated statin dose.

• Consider PCSK9 inhibitor (alirocumab or evolocumab) if LDL‑C remains ≥ 55 mg/dL after statin plus ezetimibe, or if the patient has multiple prior events or very high‑risk features.

3. Monitoring and titration

• Measure fasting LDL‑C 4–8 weeks after any regimen change and at least annually once at target.

• Titrate statin dose or ezetimibe to achieve LDL‑C < 55 mg/dL in ASCVD patients, with individualized targets if CKD or other comorbidities modify risk.

• Document reasons for changes in therapy (e.g., statin‑associated muscle symptoms, liver‑function‑test elevation) and whether the LDL‑C target was achieved before de‑intensifying.

4. Safety and comorbidity optimization

• Monitor for new‑onset diabetes and worsening glycemia in patients with prediabetes or diabetes, but do not withhold statin if LDL‑C benefit outweighs risk.

• Assess for statin‑associated muscle symptoms; consider short‑term dose reduction or intermittent dosing rather than full discontinuation if LDL‑C remains above target.

• Continue standard CV‑risk‑factor optimization (BP control, smoking cessation, weight management, diabetes control) regardless of LDL‑C target.

5. Counseling and documentation

• Educate patients that “lower LDL now” is associated with lower cardiovascular risk, using simple language (e.g., 30% relative risk reduction when LDL‑C is lowered to < 55 mg/dL).

• Document the LDL‑C target set in the EMR (e.g., “LDL‑C < 55 mg/dL in secondary prevention”) and update it after each lipid panel.

• Flag patients who remain above 55 mg/dL despite maximal tolerated oral therapy for discussion of PCSK9 inhibitor use, including cost‑effectiveness and insurance coverage.

6. Special considerations

• For women with ASCVD, aim for the same LDL‑C target as men unless data from future sex‑specific analyses suggest otherwise.

• For non‑South Asian or primary‑prevention populations, adopt the 55 mg/dL target cautiously, weighing trial generalizability and individual patient risk.

• In high‑bleeding‑risk or frail patients, balance LDL‑C goals against overall life expectancy, bleeding risk, and treatment burden.

KARDINAL: Monthly Tonlamarsen May Not Enhance BP Lowering in Resistant Hypertension

In a phase II trial dubbed KARDINAL, monthly injections of the angiotensinogen‑targeted antisense oligonucleotide tonlamarsen (developed by Kardigan) significantly suppressed plasma angiotensinogen (AGT) but did not further improve blood pressure (BP) lowering compared with a single dose in patients with resistant or uncontrolled hypertension already on multiple antihypertensive drugs. The findings, presented at the American College of Cardiology (ACC) 2026 Scientific Session and published in JACC, highlight both the promise and the limitations of targeting hepatic AGT production in the renin‑angiotensin‑aldosterone system (RAAS).

Key KARDINAL results

The KARDINAL trial enrolled adults with an office systolic BP > 135 mm Hg despite being on two to five antihypertensive medications, including ACE inhibitors and angiotensin receptor blockers (ARBs) in over 80% of participants. After a placebo lead‑in and active run‑in with a single subcutaneous 90‑mg injection of tonlamarsen, patients were randomized to either four additional monthly doses or matching placebo over 16 weeks (total 20‑week follow‑up).

The primary endpoints were change from baseline to week 20 in plasma AGT and clinic‑measured systolic BP. While monthly dosing drove a substantially greater decrease in AGT (−67.2% vs −23.0% with a single dose, P < 0.0001), the least‑squares mean reduction in office systolic BP was nearly identical between groups (approximately −6.7 mm Hg), with no statistically significant difference (P = 0.97).

Clinical implications and expert commentary

Lead investigator Luke J. Laffin, MD, emphasized that tonlamarsen suppresses hepatic angiotensinogen production, yet the trial suggests that residual AGT suppression and background RAAS inhibition may blunt any incremental BP benefit from repeated dosing. Daniel W. Jones, MD, a past president of the American Heart Association (AHA) and a key contributor to the 2025 US hypertension guidelines, cautioned that KARDINAL is a phase II trial and that it is too early to define tonlamarsen’s role in routine clinical management of hypertension.businesswire+3

Experts note that nucleic acid–based therapies like tonlamarsen and the small interfering RNA (siRNA) agent zilebesiran (studied in KARDIA‑2) represent a novel approach to RAAS modulation, potentially improving treatment adherence through periodic injection rather than daily oral agents. However, Morris Brown, MD, senior investigator of the BrigHTN trial with the aldosterone synthase inhibitor baxdrostat, stresses that AGT is not the rate‑limiting step for angiotensin II generation in most patients, so near‑complete AGT suppression may be needed to yield meaningful BP reductions beyond conventional RAAS‑directed therapy. 

Next steps and future directions

Despite the lack of incremental BP benefit from monthly dosing, tonlamarsen clearly modulates its intended molecular target, and post‑hoc analyses suggest more pronounced effects in patients with acute severe hypertension (ASH) or higher baseline BP. Sponsor Kardigan plans follow‑on studies, including the KARDINAL‑ASH phase 2b trial, to further explore tonlamarsen as a bridging therapy in high‑risk patients with severe hypertensive burden.finance.yahoo+2

In parallel, a broader pipeline of investigational agents—including lorundrostat and baxdrostat (aldosterone synthase inhibitors), as well as the endothelin receptor antagonist aprocitentan (now FDA‑approved for inadequately controlled hypertension)—continues to reshape the landscape of treatment‑resistant hypertension. The KARDINAL results underscore the need for larger, placebo‑controlled trials and a clearer understanding of factors driving treatment resistance before tonlamarsen can move from an intriguing RAAS‑targeted biologic to a practical tool in everyday hypertension care.