27th february 2023, Dr Chee L Khoo
We have covered many aspects of the diagnosis, definition and management of heart failure quite extensively over the last 18 months on GPVoice. If you have been following the conversation, you will realise that the diagnosis previously very subjective. We depended much on symptoms according to the New York Heart Association (NYHA) classification to guide diagnosis, investigations and most importantly, management. We saw how the universal definition of heart failure now require objective confirmation of heart failure. So, how well does the NYHA classification fare with long term prognosis? How useful is the NYHA classification in directing management?
Just a reminder how heart failure is classified under the NYHA:
| I | Presence of cardiac disease. No limitation of physical activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea (shortness of breath). |
| II | Slight limitation of physical activity. Comfortable at rest. Ordinary physical activity results in fatigue, palpitation, dyspnea. |
| III | Marked limitation of physical activity. Comfortable at rest. Less than ordinary activity causes fatigue, palpitation, or dyspnea. |
| IV | Unable to carry on any physical activity without discomfort. Symptoms of heart failure at rest. If any physical activity is undertaken, discomfort increases. |
First conceived in 1921, NYHA classification evolved from a simple assessment of symptoms during activity to become a benchmark inclusion criterion in contemporary heart failure (HF) clinical trials. The classification is also an important basis in treatment decision making in management guidelines. For example, NYHA class I is not eligible for current HF therapies. Not only is the classification based on pretty subjective measures, there is much overlap between Class I and Class II. Concordance between cardiologists is also limited, and the final classification correlates poorly with cardiopulmonary exercise tests (1-3).
The cardinal purpose of any classification system is to individualise risk, predict outcomes and to predict therapeutic response. Baseline NYHA class has been shown to be a marker of hospitalisation, disease progression, and mortality in a wide spectrum of ambulatory patients with chronic HF (4). The hazard ratios for patients in NYHA classes III and IV, compared with those for those in NYHA classes I and II, for other outcomes were 1.29 for cardiovascular mortality (95% CI 1.12 to 1.48, p <0.0001), 1.49 for HF mortality (95% CI 1.20 to 1.84, p <0.0001), 1.18 for cardiovascular hospitalization (95% CI 1.06 to 1.32, p = 0.002), and 1.17 for HF hospitalization (95% CI 1.03 to 1.34, p = 0.017).
In a recent secondary analysis of the PARADIGM-HF trial, the association between NYHA classes and long term prognosis was explored (5). The PARADIGM-HF trial was a multicentre, double-blind, randomised clinical trial comparing sacubitril-valsartan vs enalapril. The trial enrolled adults with chronic HF, left ventricular ejection fraction (LVEF) of 40% or less, and elevated levels of plasma B-type natriuretic peptide (BNP) or N-terminal pro–B-type natriuretic peptide (NT-proBNP). At screening, patients were classified as NYHA II through to NYHA IV.
Association between NYHA class and cardiovascular outcomes was not consistent. While higher NYHA classification (III and IV) was associated with worse prognosis, NYHA class I patients with high natriuretic peptides presented higher event rates than patients with low natriuretic peptides from any NYHA class.
Similarly, Caraballo C et al performed secondary analyses of 4 multi-centre National Institutes of Health–funded HF clinical trials that included patients classified as NYHA class II or III: TOPCAT, DIG, HF_ACTION and GUIDE-IT (6). NT‐proBNP (N‐terminal pro–B‐type natriuretic peptide), Kansas City Cardiomyopathy Questionnaire (KCCQ) scores, 6‐minute walk distances, left ventricular ejection fraction, and cardiopulmonary test parameters were used for the comparisons.
Mortality at 20 months for NYHA class II ranged from 7% for patients in HF‐ACTION to 15% in GUIDE‐IT, whereas mortality for NYHA class III ranged from 12% in TOPCAT to 26% in GUIDE‐IT. There was substantial percentage overlap in values for NT‐proBNP levels (79% and 69%), KCCQ scores (63% and 54%), 6‐minute walk distances (63% and 54%), and left ventricular ejection fraction (88% and 83%). The authors concluded that the NYHA system poorly discriminates HF patients across the spectrum of functional impairment.
In summary, these findings challenge the use of NYHA class as the leading criteria to enrol patients in HF trials and to select therapeutic strategies in clinical guidelines. This is particularly true in patients with “mild” HF. Using NT-ProBNP levels, there can be significant overlap between Class I and Class II. Patients with “Class I” function may be at higher risk of mortality that we think. It is thought that perhaps, chronic HF might lead to a compensatory increase in lymphatic flow that allows patients to remain asymptomatic at high filling pressures (6)
References:
1. Raphael C, Briscoe C, Davies J, et al. Limitations of the New York Heart Association functional classification system and self-reported walking distances in chronic heart failure. Heart. 2007;93 (4):476-482. doi:10.1136/hrt.2006.089656
2. Goldman L, Hashimoto B, Cook EF, Loscalzo A. Comparative reproducibility and validity of systems for assessing cardiovascular functional class: advantages of a new specific activity scale. Circulation. 1981;64(6):1227-1234. doi:10.1161/01.CIR.64.6.1227
3. Zimerman A, Cardoso De Souza G, Engster P, et al. Reassessing the NYHA classification for heart failure: a comparison between classes I and II using cardiopulmonary exercise testing. Eur Heart J.2021;42(suppl 1).
4. Ahmed A. A propensity matched study of New York Heart Association class and natural history end points in heart failure. Am J Cardiol. 2007;99(4): 549-553. doi:10.1016/j.amjcard.2006.08.065
5. Rohde LE, Zimerman A, Vaduganathan M, Claggett BL, Packer M, Desai AS, Zile M, Rouleau J, Swedberg K, Lefkowitz M, Shi V, McMurray JJV, Solomon SD. Associations Between New York Heart Association Classification, Objective Measures, and Long-term Prognosis in Mild Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial. JAMA Cardiol. 2023 Feb 1;8(2):150-158. doi: 10.1001/jamacardio.2022.4427. PMID: 36477809; PMCID: PMC9857149.
Caraballo C, Desai NR, Mulder H, Alhanti B, Wilson FP, Fiuzat M, Felker GM, Piña IL, O’Connor CM, Lindenfeld J, Januzzi JL, Cohen LS, Ahmad T. Clinical Implications of the New York Heart Association Classification. J Am Heart Assoc. 2019 Dec 3;8(23):e014240. doi: 10.1161/JAHA.119.014240. Epub 2019 Nov 27.
6. Houston BA, Tedford RJ, Baxley RL, et al. Relation of lymphangiogenic factor vascular endothelial growth factor-D to elevated pulmonary artery wedge pressure. Am J Cardiol. 2019;124(5):756-762. doi:10.1016/j.amjcard.2019.05.056