What is the clinical evidence from this study?

Study design: Observational. Population: Cardiovascular disease (n=7259). Intervention: NYHA functional class III/IV vs. NYHA functional class I. Primary outcome: All-cause mortality in men (HR 3.64, 95% CI 2.31-5.71, p=<0.001).

August 10, 2022Open Access

Sex Differences in the Relationship between New York Heart Association Functional Classification and Survival in Cardiovascular Disease Patients: A Mediation Analysis of Exercise Capacity with Regular Care Data

Q: What are the key findings of this study?

NYHA functional class III/IV was associated with a higher risk of all-cause mortality in men (HR 3.64) compared to women (HR 1.41), with proportional workload explaining 22.9% and 40.3% of this association, respectively.

Q: What does this research mean for the field?

NYHA functional class III/IV is associated with a higher risk of all-cause mortality in men compared to women, with proportional workload explaining 22.9% and 40.3% of this association, respectively. Novelty: ClaimNovelty.INCREMENTAL. Consensus alignment: ConsensusAlignment.NEUTRAL.

KSKlaske R SiegersmaUniversity Medical Center Utrecht NSNiels A. StensRadboud University Nijmegen FGFloor GroepenhoffNoordwest Ziekenhuisgroep

Key Result

NYHA functional class III/IV was associated with a higher risk of all-cause mortality in men (HR 3.64) compared to women (HR 1.41), with proportional workload explaining 22.9% and 40.3% of this association, respectively.

Study Design

Type

Observational (n=7,259)

Multicenter

Yes

Structured PICO

Does exercise capacity explain the sex differences in the association between NYHA functional class and all-cause mortality in patients with cardiovascular symptoms?

Population

7,259 patients with cardiovascular symptoms (chest pain, dyspnoea, or fatigue), a documented NYHA functional class, and cardiac stress electrocardiogram (ECG), mean age 57.9 years, 52.9% female, based in the Netherlands.

Intervention

NYHA functional classification (Class II and Class III/IV) and exercise capacity assessment (proportional workload and proportional heart rate during stress ECG)

Comparator

NYHA functional class I

Outcome

All-cause mortality at median 5.5 years follow-uphard clinical

NYHA functional class is a stronger predictor of mortality in men than in women, and this association is significantly mediated by objective exercise capacity (proportional workload) in both sexes.

Main Result

Effect estimate: HR 3.64 (95% CI 2.31-5.71)

p-value: p=<0.001

Limitations

Exclusion of older women with NYHA class III/IV who did not undergo an ECG stress test, introducing potential collider bias.
Data regarding subsequent treatment and medication changes during follow-up were not completely captured.
Deviations from the stress ECG protocol by some cardiologists due to patient instability.
Only the first-documented NYHA functional class was used, not accounting for fluctuations over time.
All-cause mortality was the only outcome considered, lacking specific cardiovascular disease endpoints.
Retrospective and observational design.

Abstract

Background: The New York Heart Association (NYHA) functional class has extensively been used for risk stratification in patients suspected of heart failure, although its prognostic value differs between sexes and disease entities. Functional exercise capacity might explain the association between NYHA functional class and survival, and can serve as an objective proxy for the subjective nature of the NYHA classification. Therefore, we assessed whether sex-differences in exercise capacity explain the association between NYHA functional class and survival in patients suspected of cardiovascular disease. Methods: Electronic health record data from 7259 patients with cardiovascular symptoms, a documented NYHA functional class and cardiac stress electrocardiogram (ECG), was analysed. Follow-up for all-cause mortality was obtained through linkage with Statistics Netherlands. A sex-stratified mediation analysis was performed to assess to what extent the proportional heart rate and -workload during ECG stress testing explain the association between NYHA functional class and survival. Results: In men, increments in NYHA functional class were related to higher all-cause mortality in a dose-response manner (NYHA II vs III/IV: hazard ratio HR 1.59 vs 3.64, referenced to NYHA I), whilst in women those classified as NYHA functional class II and III/IV had a similar higher mortality risk (HR 1.49 vs 1.41). Sex-stratified mediation analysis showed that the association between NYHA and survival was mostly explained by proportional workload during stress ECG (men vs women: 22.9%, 95% CI: 18.9%-27.3% vs 40.3%, 95% CI: 28.5%-68.6%) and less so by proportional heart rate (men vs women: 2.5%, 95% CI: 1.3%-4.3% vs 8.0%, 95% CI: 4.1%-18.1%). Post-hoc analysis showed that NYHA classification explained a minor proportion of the association between proportional workload and all-cause mortality (men vs women: 15.1%, 95% CI: 12.0%-18.3% vs 4.4%, 95% CI: 1.5%-7.4%). Conclusions: This study showed a significant mediation in both sexes on the association between NYHA functional class and all-cause mortality by proportional workload, but the effect explained by NYHA classification on the association between survival and proportional workload is small. This implies that NYHA classification is not a sole representation of a patient's functional capacity, but might also incude other aspects of the patient's overall health status.

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