In this large, nationally representative cohort study of individuals with incident AF, 18% patients were prescribed loop-diuretic agents with no recorded diagnosis of HF and subsequently experienced a high risk of HF hospitalisation and death. Isolated loop-diuretic use was more common with increasing age and more common in women than men in every age-category. Importantly, one third of patients with a new diagnosis of HF (after AF onset) had an earlier record of ‘isolated’ loop-diuretic use, often for several months or years before HF or AF diagnosis. Taken together, these findings imply that the true prevalence of HF is substantially underestimated amongst patients with AF, particularly in women, and isolated loop-diuretic therapy may be a useful marker in primary care of unrecognised or impending HF, as well as a poor prognostic sign.
Isolated loop-diuretic use in AF
Fluid retention and congestion are recognised hallmarks of HF syndromes, and loop-diuretics are frequently needed to achieve diuresis and symptom relief in this setting. Although a number of non-HF indications for loop-diuretics exist, and some degree of overlap with other chronic conditions invariably occurs, the observed similarities in baseline characteristics, including comorbidity burden, between patients with isolated loop-diuretic use and diagnosed HF, their increased risk of future HF hospitalisation, and comparable mortality risk to diagnosed HF, support at least a reasonable likelihood of unrecognised HF in a significant proportion of these individuals.
Under-recognition of HF in AF has been reported in older people [
5], in hospitalised cohorts [
17], and in clinical trials [
18]. Furthermore, many individuals labelled as having ‘lone’ AF exhibit cardiac structural and functional abnormalities [
19,
20], which are compatible with early or mild (stage B) HF. While existing AF guidelines recommend comprehensive evaluation of patients with a new presentation of AF, HF may also develop several months or years after initial AF diagnosis. In this scenario, repeat prescriptions of loop-diuretic agents may highlight individuals in primary care who should be reassessed, clinically, by cardiac imaging or measurement of natriuretic peptides.
The disproportionate number of women, high rates of hypertension, obesity, and lower rates of ischaemic heart disease seen in patients with isolated loop-diuretic use, resemble patient characteristics associated with HF and preserved (HFpEF) or mildly reduced EF (HFmrEF), more closely than HF with reduced EF (HFrEF), in population-based studies, and may suggest a predominance of these HF phenotypes in this AF subgroup. There is often a greater level of diagnostic uncertainty associated with HFpEF and HFmrEF, for which specialist evaluation may be required (e.g., exercise testing or invasive cardiac catheterisation). Further research is needed to identify whether targeted evaluation and enhanced clinical surveillance of patients with AF and isolated loop-diuretic use may lead to earlier and more comprehensive identification of these HF classifications. In addition, a subset of these patients had HF diagnosed during an emergency hospitalisation for acute decompensated HF. It is plausible that some of these admissions could be avoided with earlier HF diagnosis and initiation of treatment in primary or secondary outpatient care.
We cannot exclude the possibility that loop-diuretic agents themselves may have a detrimental effect, via potential electrolyte disturbances or neuro-endocrine activation, that may precipitate HF progression or adverse outcomes. Loop-diuretic therapy has additionally been associated with an increase in mortality in a Swedish cohort study of patients with AF and hypertension (n = 5602) [
21]. In the current study, patients with isolated loop-diuretic use were, on average, less likely to receive prognostically beneficial treatments (ACEIs, ARBs, and MRAs) than patients with known HF [
4], even though such therapies are also recommended for the treatment of hypertension (without HF) in AF [
21,
22], which was equally prevalent. Thus, despite inexact specificity, repeat prescriptions of loop-diuretic agents in patients with AF represent a valuable opportunity to initiate or optimise prognostically beneficial therapy both for HF and HF-precursor conditions, or to stop potentially unnecessary prolonged diuretic use, wherever possible.
Unexpectedly, baseline prescription of loop-diuretics, in the presence or absence of a diagnosis of HF was associated with a lower risk of stroke in our analysis. This association was attenuated when isolated loop-diuretic use at any time during follow-up was examined, suggesting an element of immortal time bias. However, the apparent protective effect of HF with diuretic use persisted. This contrasts with previous studies where a convincing positive association [
23] has been demonstrated between HF and stroke, even in the absence of AF [
24]. Although we comprehensively adjusted for baseline medication use between groups, residual confounding may explain this result if, for example, loop-diuretic use was associated with greater compliance or lower discontinuation of cardioprotective medications such as statins or a lower time out of therapeutic range for anticoagulation, due to more frequent blood tests and assessment by healthcare professionals. That said, patients with HF who were not prescribed loop-diuretics use would also likely be under close surveillance but did not display a reduced risk of stroke. Patients treated with loop-diuretics also did not have a lower blood pressure that might have explained a difference in stroke rates. Thus, our finding of an apparent protective effect of loop-diuretic use on the risk of stroke requires further examination.
Gender differences in AF outcomes
The ESC guidelines for AF stipulate a need for the ‘identification and resolution of sex-specific barriers to implementation of guideline-recommended treatments for AF’ [
22]. Previous reports suggest that women with AF experience, on average, more symptoms, greater functional impairment, and poorer quality of life, than men [
25‐
27], though data regarding sex differences in prognosis are conflicting [
25,
27,
28]. In our large population cohort, women with AF had a worse prognosis than men, in particular women with AF and HF without congestion. Women in our cohort were older than men at the time of AF diagnosis and more commonly hypertensive. However, women were also less likely to have ischaemic heart disease or cancer. Fewer women were smokers, and on average, women had a lower BMI. Additionally, prescription rates of several medicines were either greater (beta-blockers, digoxin) for women, or similar (ACEI or ARB) between men and women, except anticoagulants which were less commonly prescribed to women. Thus, differences in characteristics do not provide a clear explanation for poorer outcomes for women with AF.
Our analysis raises another consideration: potential disparity in HF ascertainment between men and women with AF. More women had isolated loop-diuretic use than men, particularly older women. The median time between initiation of diuretics and a diagnosis of HF was also 1.5 years longer for women compared to men for those prescribed a loop-diuretic prior to a diagnosis of HF. This may reflect later detection of HF in women in primary care and may explain why more women than men received their HF diagnosis following an emergency hospitalisation. The reason why women with a diagnosis of HF who were not prescribed loop-diuretics had a higher mortality risk than men is unclear. Interestingly, when we combined isolated loop-diuretic use and diagnosed HF (i.e., ostensibly including all ‘possible’ HF in a single category), the median time between AF detection and ‘first’ HF presentation, as well as survival rates, became similar for men and women, suggesting under-recognition and under-diagnosis of HF in women with AF, rather than sex-specific (i.e., biological) differences in HF susceptibility or prognosis.
Potential sex differences in HF phenotype may be a relevant consideration. Our identification of a lower risk for all-cause mortality amongst the subset of women with isolated loop-diuretic use versus men, after adjusting for the same set of confounders, could suggest a higher proportion of HFpEF in women with AF, which has a somewhat better prognosis than HFrEF. In population-based studies, women reportedly have a higher [
29] or similar [
30] risk of developing HFpEF than men, but a lower risk of developing HFrEF. Interestingly, in the Renal and Vascular Endstage Disease (PREVEND) cohort, AF was identified as a sex-specific risk factor for HF, with AF conferring an increased risk of HFpEF in women but not in men [
29]. Pathophysiological differences such as more concentric (versus eccentric) remodelling [
31], greater aortic stiffness [
32], impaired cardiovascular coupling [
33], or higher heart rates [
34] may be reasons for more clinically manifest HF in women compared to men with AF and preserved LV ejection fraction. However, this may also have been a chance finding and requires validation. Even though evidence-based treatment strategies are currently lacking for HFpEF, improved detection and accurate categorisation of HFpEF in women and men in primary care would encourage close monitoring of volume status, which can lead to symptomatic improvement and possibly avert hospitalisation [
35], as well as minimise the use (and associated side effects) of ineffective therapies, such as those for HFrEF or bronchodilators that may be prescribed for symptoms falsely attributed to lung disease [
36]. It would also identify eligible individuals for recruitment into research studies to test new strategies to improve their care.
Strengths and limitations
Strengths of our study include the large and nationally representative cohort, allowing us to retain power for multiple sensitivity analyses, and comprehensive data regarding prescriptions. Loop-diuretic prescriptions identify the subset of HF patients who have fluid congestion, which will still underestimate the true overall prevalence of HF. Equally, as previously acknowledged, not all patients who receive diuretics do so for HF. Our stipulation of long-term loop-diuretic therapy and exclusion of common non-HF-related reasons improve the specificity of isolated loop-diuretic therapy as a potential surrogate marker of HF.
It is recognised that the quality of coding in primary care can be variable [
37]. However, codes used in this study pertaining to HF and AF that are financially incentivised by schemes, such as the UK’s Quality and Outcomes Framework, are more likely to be complete [
38]. Additional codes for covariates were either validated (e.g., COPD [
39]) or identified and checked by two physician specialists. We did not have information regarding medication adherence, and adequacy of heart rate control or use of rhythm control procedures, which may have been sources of residual confounding of hospitalisation and survival rates. We applied a censoring period of 100 days when ascertaining outcomes to allow time for a diagnosis of HF and repeat prescriptions of loop-diuretics to be recorded (in primary care and between primary and secondary care). When we eliminated this censor period, there was a high mortality soon after AF diagnosis, particularly for patients with diagnosed HF. When we imposed a longer censoring period, this had little impact on the association between possible or diagnosed HF and all-cause mortality, suggesting that HF was not merely a pre-terminal event. For our main analyses, participants were categorised according to their baseline exposure status (i.e., whether they had evidence of HF or isolated loop-diuretic use around or before the time of AF diagnosis). We selected this approach to examine the importance of possible undiagnosed HF at the clinical interaction where AF is first diagnosed. Although this may underestimate the risks associated with exposure over a patient’s lifetime, the overall trends remained similar when exposures were defined using a time-dependent approach.
Amongst patient characteristics, BMI had a relatively high rate of missingness. Sensitivity analyses suggested that missing BMI data had little effect on our estimates, i.e., the results were similar in the cohort of patients with no BMI data available. We considered this approach more appropriate than multiple imputation, because underweight and overweight individuals, may be more likely to have their BMI recorded, thus contradicting the required missing at random assumption [
40]. Other covariates studied had minimal (< 5%) missing data. Finally, although we controlled for patient characteristics and comorbidities, residual confounding due to unmeasured variables remains possible and causal inference cannot be made because of the nature of observational studies.