Association between routinely reported symptoms and 3 month hospital admission and mortality risk: a landmark analysis investigation in 86,000 individuals with heart failure in the UK

Objectives: In patients with heart failure (HF), investigate the association between symptoms recorded in routine primary care consultations and short-term (3-month) hospitalisation and mortality. Design: Landmark analysis using Royston-Parmar flexible parametric survival models fitted at three different timepoints (landmarks): baseline (diagnosis date), and 6 and 12 month post-diagnosis. Setting: Primary care database analysis using Clinical Practice Research Datalink (CPRD), linked to hospitalisations and mortality (1998 to 2020). Participants: Adults (>40 years) with a first code for HF diagnosis in primary or secondary care records. Exposures: Shortness of breath (SOB), ankle swelling, oedema, fatigue, chest pain, depression and anxiety measured in a 3-month time-window prior to HF diagnosis and in survivors at 6 and 12-months. Main outcome measures: 3-month first all-cause hospitalisation and mortality, separately. Secondary outcomes were hospitalisations for HF and non-cardiovascular disease. Results: There were 86,882 patients with a diagnosis of HF, of whom 62,742 and 54,555 survived 6 and 12 months, respectively. There were differential symptom associations among different landmarks and outcomes. The highest risk associations for symptoms recorded just prior to diagnosis (baseline) were for depression for all-cause hospitalisation (adjusted hazard ratio: 1.26; 95% CI 1.15, 1.39), for non-cardiovascular hospitalisation (1.15; 1.10, 1.21) and death (1.22; 1.09, 1.36) and SOB for HF hospitalisation (1.18; 1.12, 1.26). Patients with HF exhibiting symptoms just prior to 6 and 12 month landmarks had increased risk of hospitalisation and mortality: at 6-months, the highest risk associations were with symptoms of depression for all-cause hospitalisation (1.46; 1.25, 1.70) and non-CVD hospitalisation (1.46; 1.23, 1.74), SOB for HF-specific hospitalisation (1.72; 1.50, 1.98); ankle swelling for mortality (1.49; 1.14, 1.94). At the 12-month landmark, classic HF symptoms had the highest risk associations: ankle swelling for all-cause hospitalisation (1.47; 1.21, 1.79) and non-CVD hospitalisation (1.55; 1.24, 1.93); SOB for HF hospitalisation (1.99; 1.68, 2.35); and fatigue for mortality (1.57; 1.22, 2.03). Conclusions: Symptoms reported by patients with HF were more prominent in patients with HF at 6 and 12-months post-diagnosis than at the point of diagnosis. ### Competing Interest Statement Competing interests All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: Carolyn SP Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from NovoNordisk and Roche Diagnostics; has served as consultant or on the Advisory Board/ Steering Committee/ Executive Committee for Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, CardioRenal, Cytokinetics, Darma Inc., EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research & Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd., Recardio Inc, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics and Us2.ai; and serves as co-founder & non-executive director of Us2.ai. KK has acted as a consultant, speaker or received grants for investigator-initiated studies for Astra Zeneca, Bayer, Novartis, Novo Nordisk, Sanofi-Aventis, Lilly and Merck Sharp & Dohme, Boehringer Ingelheim, Oramed Pharmaceuticals, Roche and Applied Therapeutics. Anna Stromberg has acted as a speaker for Astra Zeneca, Bayer, Novartis, and, Boehringer Ingelheim. ### Funding Statement An NIHR Advanced Fellowship [Reference NIHR300111] funding supported this study. The study sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The views and opinions expressed therein are those of the authors and do not necessarily reflect those of the NIHR. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Approval for this study (protocol 20_000056) was provided by CPRD Research Data Governance Process. This process provides independent scientific and patient advice by an expert review and central advisory committee. National research ethics committee provided ethics approval for use of CPRD data (05/MRE04/87/AM06). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes MRA and CL had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. This study is based in part on data from the Clinical Practice Research Datalink obtained under licence from the UK Medicines and Healthcare products Regulatory Agency. However, the interpretation and conclusions contained in this report are those of the author/s alone. Data access is through permissions from CPRD only.