Daily Cardiology Research Analysis
Three impactful cardiology studies stood out today: a randomized trial (HELIOS-B) showing that the RNAi therapy vutrisiran reduces mortality and cardiovascular events in transthyretin amyloid cardiomyopathy; a SEQUOIA-HCM analysis indicating aficamten benefits even mildly symptomatic obstructive HCM; and a large cohort analysis linking long-term wearable-measured physical activity with lower incident atrial fibrillation risk.
Summary
Three impactful cardiology studies stood out today: a randomized trial (HELIOS-B) showing that the RNAi therapy vutrisiran reduces mortality and cardiovascular events in transthyretin amyloid cardiomyopathy; a SEQUOIA-HCM analysis indicating aficamten benefits even mildly symptomatic obstructive HCM; and a large cohort analysis linking long-term wearable-measured physical activity with lower incident atrial fibrillation risk.
Research Themes
- RNA interference therapy improves outcomes in ATTR cardiomyopathy
- Myosin inhibition benefits across symptom severity in obstructive HCM
- Wearable-derived physical activity and atrial fibrillation prevention
Selected Articles
1. Vutrisiran Improves Survival and Reduces Cardiovascular Events in ATTR Amyloid Cardiomyopathy: HELIOS-B.
In HELIOS-B (n=655), subcutaneous vutrisiran significantly reduced all-cause mortality, cardiovascular mortality, and heart failure-related events over up to 39–42 months of follow-up, with consistent benefits irrespective of baseline tafamidis use. These findings reinforce and extend prior efficacy signals, demonstrating durable survival and morbidity benefits in ATTR-CM.
Impact: This is a large randomized trial showing mortality reduction with an RNAi therapy in ATTR-CM, addressing a high-need population and potentially reshaping standard care.
Clinical Implications: Vutrisiran can be considered to reduce mortality and heart failure events in ATTR-CM, including in patients already on tafamidis; integration into guideline-directed therapy should be discussed.
Key Findings
- Reduced all-cause mortality vs placebo (HR 0.64; 95% CI 0.46–0.88).
- Reduced cardiovascular mortality vs placebo (HR 0.67; 95% CI 0.47–0.96).
- Lowered composite of CV mortality and CV events (HR 0.72; 95% CI 0.55–0.94).
- Decreased CV hospitalizations (RR 0.75), HF hospitalizations (RR 0.67), and urgent HF visits (RR 0.54).
- Benefits were consistent regardless of baseline tafamidis use.
Methodological Strengths
- Randomized, double-blind trial with large sample (n=655) and prespecified analyses.
- Long follow-up (DB 33–36 months plus up to 6 months OLE) with comprehensive CV endpoints.
Limitations
- Mortality analyses included up to 6 months of open-label extension, introducing potential bias.
- Generalizability may be limited to trial-eligible ATTR-CM populations.
Future Directions: Head-to-head or combination strategies with tafamidis, long-term safety surveillance, and evaluation across genotype and cardiac staging subgroups.
BACKGROUND: Patients with transthyretin amyloidosis with cardiomyopathy (ATTR-CM) have high mortality and morbidity. Vutrisiran, a subcutaneous RNA interference therapeutic, reduced the composite of all-cause mortality (ACM) and cardiovascular (CV) events (CV hospitalizations and urgent heart failure [HF] visits) in HELIOS-B (A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy) in patients with ATTR-CM. OBJECTIVES: Here we present data from HELIOS-B evaluating the impact of vutrisiran on ACM and CV mortality with additional patient follow-up through 42 months, and CV events such as CV hospitalizations, HF hospitalizations, and urgent HF visits. METHODS: The HELIOS-B trial randomized 655 patients to vutrisiran 25 mg or placebo once every 3 months for up to 33 to 36 months in the double-blind (DB) period, followed by an open-label extension. Prespecified mortality and CV mortality analyses used data through 39 to 42 months of follow-up (DB period and up to 6 months of the open-label extension). CV hospitalizations and HF events were evaluated over the DB period of 33 to 36 months. Differences between vutrisiran and placebo were evaluated in the overall population, and in those stratified by baseline tafamidis use. RESULTS: In the overall population, vutrisiran reduced the risk of ACM (HR: 0.64; 95% CI: 0.46-0.88) and CV mortality (HR: 0.67; 95% CI: 0.47-0.96) vs placebo. Vutrisiran also reduced the risk of a composite of CV mortality and CV events (HR: 0.72; 95% CI: 0.55-0.94), and lowered rates of CV hospitalizations (rate ratio [RR]: 0.75; 95% CI: 0.62-0.91), urgent HF visits (RR: 0.54; 95% CI: 0.30-0.98), and HF hospitalizations (RR: 0.67; 95% CI: 0.52-0.86) vs placebo. Consistent trends were seen regardless of baseline tafamidis use. CONCLUSIONS: Consistent with the primary trial results, vutrisiran reliably reduced the risk of ACM, CV mortality, CV hospitalizations, HF hospitalizations, and urgent HF visits vs placebo in patients with ATTR-CM. (HELIOS-B: A Study to Evaluate Vutrisiran in Patients With Transthyretin Amyloidosis With Cardiomyopathy; NCT04153149).
2. Efficacy of Aficamten in Patients with Obstructive Hypertrophic Cardiomyopathy and Mild Symptoms: Results from the SEQUIOA-HCM Trial.
In SEQUOIA-HCM, patients with mild oHCM symptoms derived significant improvements in pVO2, KCCQ, gradients, and NT-proBNP with aficamten, comparable to those with more advanced symptoms. Serious adverse events were infrequent, supporting consideration of aficamten earlier in the disease course.
Impact: Extends the therapeutic scope of myosin inhibition to less symptomatic oHCM, informing earlier intervention strategies.
Clinical Implications: Clinicians may consider aficamten for symptomatic relief and hemodynamic improvement even in mildly symptomatic oHCM, with monitoring for safety.
Key Findings
- pVO2 improvement at 24 weeks was similar between mild (+1.6 mL/kg/min) and more symptomatic (+1.8 mL/kg/min) groups (p=0.8).
- Secondary endpoints (NYHA class, resting/Valsalva gradient, NT-proBNP) did not differ significantly between groups.
- Both groups improved in KCCQ-CSS; the magnitude was greater in the advanced symptom group (p=0.02 interaction).
- Serious adverse events were infrequent across groups.
Methodological Strengths
- Randomized controlled trial framework with prospectively defined symptom strata.
- Multiple clinically relevant endpoints including exercise capacity, symptoms, hemodynamics, and biomarkers.
Limitations
- Subgroup analysis not powered for between-strata comparisons; risk of multiplicity.
- 24-week follow-up limits assessment of long-term durability and safety.
Future Directions: Longer-term outcomes, head-to-head comparisons with other myosin inhibitors, and evaluation of initiation thresholds in early oHCM.
BACKGROUND AND AIMS: Patients with obstructive hypertrophic cardiomyopathy (oHCM) treated with aficamten in SEQUOIA-HCM (NCT05186818) demonstrated marked improvement in symptoms and functional capacity. This analysis explores whether oHCM and mild symptoms experience similar clinical benefit with aficamten as patients with more advanced limitation. METHODS: Patients in SEQUOIA-HCM (N=282) were grouped at baseline according to symptom severity. Mild symptoms (n=118) were defined as New York Heart Association (NYHA) class II and Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS) ≥80, and moderate to severe symptoms (n=150) as NYHA class II/III/IV and KCCQ-CSS <80. Primary endpoint was change in peak oxygen uptake (pVO2) from baseline to Week 24; secondary endpoints included change in NYHA class, KCCQ-CSS, outflow tract gradients, and N-terminal pro-B-type natriuretic peptide (NT-proBNP). RESULTS: In aficamten-treated patients, change at Week 24 was not different between moderate to severe (1.8 mL/kg/min; n=71) and mild (1.6 mL/kg/min; n=62) symptom groups (p=0.8). Likewise, the change in secondary endpoints (NYHA class, resting or Valsalva gradients, and NT-proBNP) did not differ significantly between the two symptom groups. Both groups experienced statistically significant improvements in KCCQ-CSS, but the extent of improvement was greater in the advanced symptom group (p=0.02 for interaction). Treatment-emergent serious adverse events were infrequent in both groups. CONCLUSIONS: Patients with oHCM and mild symptoms treated with aficamten achieved significant improvement across a range of clinically relevant outcomes, and generally similar to patients with more advanced symptoms. Less severely symptomatic patients could be considered for aficamten treatment.
3. Fitbit-measured physical activity is inversely associated with incident atrial fibrillation among All of Us participants.
Using one year of Fitbit accelerometry from 15,570 All of Us participants and five-year follow-up, higher moderate-to-vigorous physical activity was associated with lower incident atrial fibrillation, independent of clinical and genetic risk factors. This supports leveraging long-term wearable data to refine AF prevention strategies.
Impact: Demonstrates the preventive relevance of objectively measured, long-term free-living physical activity for AF risk—beyond short-term or self-reported assessments.
Clinical Implications: Encourage sustained moderate-to-vigorous activity and consider integrating wearable-derived metrics into AF risk stratification and lifestyle counseling.
Key Findings
- One-year Fitbit-based MVPA was inversely associated with five-year incident AF.
- Association persisted after adjustment for clinical and genetic risk factors.
- Study leverages long-term, free-living accelerometry rather than short-term or self-report.
Methodological Strengths
- Objective, long-term wearable accelerometry in free-living conditions.
- Cox modeling with adjustments including genetic risk, enhancing robustness.
Limitations
- Observational design limits causal inference and is susceptible to residual confounding.
- Cohort demographics and device adherence may limit generalizability.
Future Directions: Interventional trials leveraging wearable-guided activity prescriptions and mechanistic studies linking activity patterns to atrial substrate remodeling.
BACKGROUND: Individuals who report meeting weekly moderate to vigorous physical activity (MVPA) guidelines have lower risk of atrial fibrillation (AF). However existing studies have relied on subjective questionnaires or short-duration (<1 week) objective assessments using accelerometry. The objective of this research was to investigate an association between MVPA levels and the incidence of AF, utilizing long-term, free-living accelerometry data. METHODS: 1-year Fitbit data, in addition to survey and electronic health record (EHR) data, were extracted from the NIH All of Us (AoU) research database. Cox proportional hazards regression was used to model the association of average MVPA and incident AF over a five-year follow-up period. RESULTS: 15570 AoU participants were included (52 ± 16 years, 71% female, 79% White, BMI 28.9 ± 5.0 kg/m CONCLUSIONS: Higher amounts of objectively measured MVPA, measured using free-living, long-term accelerometry data, were inversely associated with risk of incident AF, independent of clinical and genetic risk factors.