Introduction
Coronary heart failure (HF) is a troublesome analysis to make: signs are non-specific,1 scientific indicators are troublesome to elicit,2 natriuretic peptide testing is insensitive3 and echocardiography is susceptible to errors in measurement.4 5 Maybe as a consequence, the true incidence and prevalence of HF should not clear.
Epidemiological research report the prevalence as being between 1% and seven% of the overall inhabitants.6–10 The prevalence will increase with age and impacts greater than 1 in 10 sufferers aged over 80 years.11 Nevertheless, within the UK, the prevalence of HF recorded in major care HF registers is 0.9%.12
Loop diuretics are among the many mostly prescribed drugs in major care however they’ve few indications aside from the therapy of venous congestion as a result of HF.13 An audit of scientific follow discovered that the prevalence HF based on the register was a lot the identical because the prevalence of loop diuretic prescription amongst sufferers who didn’t have a analysis of HF. Sufferers prescribed a loop diuretic and not using a analysis of HF had a charge of HF hospitalisation or all-cause loss of life of 25% after 2 years.14 It’s potential a proportion of sufferers prescribed loop diuretics in the neighborhood have underlying HF.
We used knowledge from the Medical Apply Analysis Datalink (CPRD), Hospital Episode Statistics (HES) admitted affected person care (APC) data and Workplace of Nationwide Statistics (ONS) loss of life data to evaluate the frequency of HF-related occasions in sufferers prescribed a loop diuretic and not using a analysis of HF in contrast with sufferers with a analysis of HF. Loop diuretics can also be prescribed for different situations related to an elevated threat of HF corresponding to hypertension or continual kidney illness (CKD). Thus, in a second evaluation, we additionally assessed the frequency of HF-related occasions in a management group of sufferers prone to creating HF to match consequence profiles.
Strategies
Knowledge sources
The CPRD database incorporates anonymised longitudinal affected person knowledge on demographics, life-style, diagnoses, drugs, investigations together with blood assessments and referrals collected from major care throughout the UK.15
Major care digital data had been linked to the HES APC data and the ONS loss of life data. HES APC and ONS loss of life data are databases of all hospital admissions and deaths, respectively, within the UK. The reason for every is ascribed an Worldwide Classification of Ailments 10 (ICD-10) code.
Research populations
All sufferers aged over 18 years of age contributing knowledge to the CPRD between 1 January 2010 and 31 December 2015, who had been registered with their follow for no less than 1 12 months, with data deemed acceptable by CPRD high quality management, and authorized for linkage to the HES APC and ONS loss of life file datasets had been eligible for inclusion. The time-frame was chosen to incorporate the time when the Nationwide Institute for Well being and Care Excellence launched a tenet for the diagnostic course of for HF (2010),16 and to permit nearly all of sufferers to have no less than 5 years of follow-up previous to the peaks of the coronavirus pandemic in 2020–2021.
Sufferers had been cut up into three teams: (1) sufferers prescribed a loop diuretic however who didn’t have a recorded analysis of HF (loop diuretic group); (2) sufferers with a brand new recorded analysis of HF (HF group); and (3) sufferers with a brand new analysis of HF threat elements—ischaemic coronary heart illness (IHD) or a analysis of diabetes with a pre-existing analysis of hypertension, or vice versa (at-risk group).
Case identification
Learn and ICD-10 code lists had been generated from medical dictionary key phrase searches, beforehand revealed literature6 and on-line scientific code repositories (on-line supplemental file appendix).17 The index dates had been the date of the primary remedy code for a loop diuretic, the date of the primary Learn or ICD-10 code for HF for the HF group, and the date of the primary Learn code for IHD or the primary Learn code for diabetes in a affected person with pre-existing hypertension (or vice versa) for the loop diuretic, HF and at-risk teams, respectively.18
Numerous exclusion standards had been utilized to the three teams (determine 1). Sufferers with an present Learn or ICD-10 code for HF predating 1 January 2010 (exclusion standards 1–2), or a Learn code particularly excluding HF earlier than the index date (exclusion criterion 3), or whose date of loss of life was previous to the index date (exclusion criterion 8) had been excluded from all three teams.
Cohort circulation diagram and exclusion standards. CPRD, Medical Apply Analysis Datalink; DM, diabetes mellitus; HF, coronary heart failure; HTN, hypertension; IHD, ischaemic coronary heart illness.
Sufferers with a Learn code for HF within the 3 months after the index date (exclusion criterion 4), or hospitalisation for HF or loss of life inside 1 month of the index date (exclusion criterion 5) had been presumed to have clinically evident HF on the time of loop diuretic prescription and had been excluded from the loop diuretic group. To make sure a good comparability between the teams, sufferers who met exclusion criterion 5 had been additionally excluded from the HF and at-risk teams.
Sufferers who underwent natriuretic peptide testing, echocardiography or referral to cardiology outpatient departments inside 3 months of the index date had been presumed to have adopted an applicable diagnostic pathway and had been excluded from the loop diuretic group (exclusion criterion 6). Exclusion criterion 6 was additionally utilized to the at-risk group on the idea that some sufferers who underwent investigations might have had HF.
Sufferers with Learn codes for both aortic or mitral valve illness 3 months earlier than or after the index date had been presumed to have HF as a result of valve illness and had been excluded from the loop diuretic group (exclusion criterion 7).
Lastly, sufferers who had been prescribed a loop diuretic earlier than or on the index date had been excluded from the at-risk group (exclusion criterion 9).
We extracted from the first care digital file the next: physique mass index, smoking standing, widespread comorbidities, HF drugs, presentation with HF signs earlier than the index date (peripheral oedema, breathlessness, orthopnoea, paroxysmal nocturnal dyspnoea or fatigue), natriuretic peptide testing, echocardiography referrals or outcomes, and outpatient referrals. Trigger-specific hospitalisation knowledge had been extracted utilizing linkage with HES APC data. Trigger-specific mortality was extracted from ONS loss of life data.
Statistical evaluation
We carried out two separate comparisons: evaluation A—loop diuretic group versus the HF group, and evaluation B—loop diuretic group versus the at-risk group. In evaluation A, sufferers within the loop diuretic group had been matched with sufferers within the HF group utilizing a propensity rating utilizing age as a steady variable, intercourse, and the presence of IHD, diabetes, hypertension and atrial fibrillation (AF). The propensity rating was calculated utilizing a cumulative logit regression mannequin. Matching was on a 1:1 nearest neighbour foundation, with out alternative, with a calliper width of 0.2 of the SD of the logit of the propensity rating.
In evaluation B, sufferers within the examine inhabitants had been matched to sufferers within the at-risk group for age and intercourse. Matching was on a 1:1 nearest neighbour foundation with out alternative with actual matches solely. Standardised imply distinction and distribution plots had been used to examine the adequacy of the matching.
Two sensitivity analyses had been carried out: one for evaluation A during which sufferers had been matched for loop diuretic prescription in addition to age, intercourse, and the presence of IHD, diabetes, hypertension and AF; and one for evaluation B during which sufferers had been matched for the presence of IHD, diabetes, hypertension and AF, in addition to age and intercourse.
Steady knowledge are introduced as medians (first–third quartiles), whereas categorical knowledge are introduced as numbers (%). Variations in baseline traits between unmatched teams and matched teams had been examined utilizing impartial t-tests for steady variables and Χ2 assessments for categorical variables.
Variations in consequence had been assessed utilizing univariable and multivariable Cox regression fashions and Kaplan-Meier curves. The 2-tailed degree of statistical significance was set at <0.05. All statistical analyses had been carried out utilizing SPSS V.28.
End result definitions
The first consequence was time to first HF-related occasion which comprised of presentation to major care with signs of HF, or hospitalisation with HF or all-cause mortality in evaluation A; and presentation to major care with signs of HF, or incident HF (new analysis of HF made in both major or secondary care), or hospitalisation with HF, or all-cause mortality in evaluation B. Secondary endpoints of time to first HF hospitalisation or all-cause mortality, and time to first all-cause hospitalisation or all-cause mortality had been additionally assessed in each analyses. Sufferers had been adopted up till the primary HF occasion occurred or till 5 years.
Affected person and public involvement
The Contain Hull affected person and public involvement group supplied written suggestions on the examine protocol throughout conception and previous to submission to the CPRD and guided plans for dissemination.
Funding
This examine was funded by the Hull and East Using Cardiac Belief Fund which had no enter within the examine design, knowledge evaluation or drafting of this manuscript.
Outcomes
Of the 180 384 sufferers with both a primary prescription of loop diuretics, or first analysis of both HF, IHD, hypertension or diabetes between 1 January 2010 and 31 December 2015, 78 968 had a brand new loop diuretic prescription, 28 177 had a brand new analysis of HF, 32 701 had a brand new analysis of IHD, and 40 538 had a brand new analysis of diabetes within the context of pre-existing hypertension or vice versa. After utility of exclusion standards, 139 265 had been used within the analyses comprising of 59 694 within the loop diuretic group, 22 352 within the HF group and 57 219 within the at-risk group (determine 1).
Affected person traits
In contrast with sufferers with HF, sufferers taking a loop diuretic and not using a analysis of HF had been youthful, extra more likely to be feminine (38% male vs 52% feminine), and had been much less more likely to have AF (11% vs 24%), CKD (20% vs 30%) and IHD (15% vs 30%) (p<0.001 for all). Furosemide was essentially the most generally prescribed loop diuretic in each teams (desk 1).
Affected person traits: evaluation A
In contrast with sufferers with HF threat elements, sufferers taking a loop diuretic and not using a analysis of HF had been older (74 vs 64 years), extra more likely to be girls (38% male vs 59% feminine), and had been extra more likely to have both AF (11% vs 4%) or CKD (20% vs 12%) (p<0.001 for all) (desk 2).
Affected person traits: evaluation B
Symptom burden
Just one in 5 sufferers within the loop diuretic group and the HF group had a presentation of HF signs to major care within the month earlier than their index date. Of those that had a recorded presentation previous to the index date, sufferers within the loop diuretic group had been extra more likely to current with oedema (80% vs 26%) and fewer more likely to current with breathlessness (16% vs 65%) than these within the HF group (p<0.001 for each) (desk 1).
End result
Evaluation A
Within the propensity-matched cohorts, throughout a median follow-up of 65 (21–92) months, an HF-related occasion occurred in 71.9% of sufferers within the loop diuretic group and 72.1% of sufferers within the HF group. The proportion of sufferers presenting with an HF symptom was better within the loop diuretic group (37.1% vs 27.8%; p<0.001), however each hospitalisation with HF (1.9% vs 4.0%; p<0.001) and all-cause mortality (55.6% vs 61.2%; p<0.001) had been extra frequent within the HF group (desk 3, on-line supplemental determine 1 and on-line supplemental desk 1).
Outcomes in analyses A and B
Sufferers prescribed a loop diuretic and not using a recorded analysis of HF had been solely 6% much less more likely to expertise an HF occasion in contrast with these with HF after adjustment for baseline traits (HR=0.94 (95% CI 0.92 to 0.96; p<0.001) (determine 2 and desk 4).
![Figure 2](https://heart.bmj.com/content/heartjnl/110/12/854/F2.medium.gif)
Danger of HF occasion in sufferers taking a loop diuretic and not using a analysis of HF (loop diuretic group) in contrast with these with an HF analysis (HF group). HF, coronary heart failure.
Univariable and multivariable Cox regression analyses for coronary heart failure (HF) occasions in analyses A and B
The sensitivity evaluation for evaluation A discovered that HF occasions had been considerably extra doubtless in sufferers with a recorded analysis of HF in contrast with these taking a loop diuretic and not using a analysis of HF (on-line supplemental tables 2 and three). Nevertheless, HF occasions had been nonetheless quite common in sufferers prescribed a loop diuretic and not using a recorded analysis of HF (69.3% vs 73.7%; p<0.001).
All-cause hospitalisation or loss of life occurred in 67.7% of sufferers within the loop diuretic group and 71.5% of sufferers within the HF group (p<0.001), though all-cause hospitalisation was extra widespread within the loop diuretic group (27.5% vs 23.0%; p<0.001) (on-line supplemental determine 2, desk 3 and on-line supplemental desk 4).
Evaluation B
Within the propensity-matched cohorts, throughout a median follow-up of 89 (66–109) months, an HF-related occasion occurred in 59% of sufferers within the loop diuretic group and 36% of sufferers within the at-risk group (HR 2.04 (95% CI 2.00 to 2.08); p<0.001) (desk 3).
Sufferers within the loop diuretic group had been roughly twice as more likely to expertise an HF occasion in contrast with these within the at-risk group (unadjusted HR=2.04 (95% CI 2.00 to 2.08); p<0.001) (determine 3, desk 4, on-line supplemental determine 3 and on-line supplemental desk 1).
![Figure 3](https://heart.bmj.com/content/heartjnl/110/12/854/F3.medium.gif)
Danger of HF occasion in sufferers taking a loop diuretic and not using a analysis of HF (loop diuretic group) in contrast with sufferers with HF threat elements (at-risk group). HF, coronary heart failure.
The sensitivity evaluation for evaluation B discovered a better prevalence of HF occasions in each teams however equally better threat in sufferers within the loop diuretic group in contrast with the at-risk group (77.0% vs 52.6%; p<0.001) (on-line supplemental tables 2 and three).
All-cause hospitalisation or mortality occurred in 56% of sufferers within the loop diuretic group and 42% of sufferers within the at-risk group (p<0.001) (on-line supplemental desk 4 and on-line supplemental determine 4).
Dialogue
Utilizing a big, consultant pattern of sufferers in major care, we discovered that sufferers who’re prescribed a loop diuretic however who wouldn’t have a recorded analysis of HF have a excessive charge of HF-related occasions—much like that of these with a confirmed analysis of HF, and practically twice that of age-matched and sex-matched sufferers with threat elements for creating HF. Throughout the 5-year index interval of our examine (2010–2015), there have been over twice as many sufferers prescribed a loop diuretic and not using a recorded analysis of HF than got a proper analysis of HF. Contrasting the outcomes of study A and evaluation B, sufferers prescribed a loop diuretic are much more much like sufferers with a recorded analysis of HF by way of symptom burden and consequence than they’re to sufferers with threat elements for HF; undiagnosed or ‘uncoded’ HF might account for lots of the loop diuretic prescriptions.
Sufferers prescribed a loop diuretic and not using a analysis of HF
The demographics of sufferers prescribed a loop diuretic and not using a recorded analysis of HF and people with a recorded HF on this examine are much like these of sufferers with HF and a traditional ejection fraction (HeFNEF): the bulk had been feminine and aged over 70 years with a number of comorbidities (AF, CKD and hypertension had been the commonest, whereas IHD was unusual).19 20
Whereas we can’t infer what quantity of sufferers within the loop diuretic group had underlying HF as a reason for their signs, as a gaggle, they had been extra doubtless than sufferers with HF to current to their common practitioner (GP) with signs, and solely marginally much less more likely to be admitted to hospital or die.
Defining HF
The advantages of building a analysis of HF for a person are quite a few: within the case of HF with a diminished ejection fraction, there are a number of medical and machine remedies which might enormously cut back the prospect of great morbidity and extend life.21 Within the case of HeFNEF, which can account for about half of all HF diagnoses,22 therapy with sodium glucose co-transporter 2 inhibitors can cut back morbidity associated to HF.23 24 No matter HF phenotype, establishing a analysis supplies readability to the affected person and removes scientific uncertainty for the non-specialist which can forestall delays to therapy.25
The advantages of building a analysis of HF for the broader neighborhood are additionally quite a few: having a correct understanding of the epidemiology of HF is important for planning healthcare companies. Establishing the analysis in the neighborhood is related to decrease healthcare prices and higher scientific outcomes.26 Nevertheless, the proportion of sufferers who obtain their HF analysis in the neighborhood is decreasing26–28; the latest knowledge counsel that as much as 80% of sufferers obtain their analysis solely after hospitalisation with HF.28 This can be as a result of requirement for preliminary investigations previous to specialist referral as a way to make a analysis, resulting in uncertainty earlier than a analysis is confirmed or refuted. Doubtlessly compounding the issue are the varied and sophisticated diagnostic standards, notably for HeFNEF.1
The signs of congestion are sometimes, fairly moderately, handled earlier than a definitive analysis is made. Nevertheless, only a few of the sufferers prescribed a loop diuretic had had applicable investigations throughout 10 years’ follow-up. In distinction, nearly all of sufferers with a analysis of HF have some type of investigation or referral earlier than a analysis is made, whatever the setting during which it’s made.28
Can we depend on coding?
We discovered that just one in 5 sufferers who had been prescribed a loop diuretic or got a analysis of HF had been coded as having an attendance with signs of HF within the month previous to the index date (together with on the index date itself), which appears shocking and will symbolize absent coding. GPs within the UK are financially incentivised through High quality Outcomes Framework to maintain and preserve a register of sufferers inside their follow inhabitants with an HF analysis.12 Whereas absent coding might account for a few of the ‘lacking’ sufferers in our evaluation, this will likely solely have an effect on a minority of sufferers.14
Estimates of the prevalence of HF in neighborhood settings range drastically relying on the strategies of analysis and the populations studied.6–11 Utilizing scientific coding within the common inhabitants, the prevalence of HF within the UK is estimated to be 1.4%.6 If even a small proportion of sufferers prescribed a loop diuretic had underlying HF, no matter whether or not it was clinically recognised by the clinician, utilizing scientific coding to estimate prevalence could be an underestimation. Consequently, planning for and funding of HF companies are unlikely to be satisfactory.
Medical implications
The widespread use of loop diuretics with out additional investigations is an obstacle to a well timed analysis of HF. There are lots of cardiovascular drugs which require blood assessments (renal perform or serum electrolyte concentrations, for instance) to be checked previous to initiation. We imagine that mandating measurement of natriuretic peptide concentrations previous to initiation of loop diuretics is critical, clinically applicable, easy to implement and will enhance care.
Sufferers with HF are being missed at current and, as a consequence, probably not receiving life-prolonging and symptom-relieving remedy. The broader healthcare economic system will not be receiving the advantages of early applicable therapy that reduces the danger of hospitalisation and which might enhance our understanding of HF epidemiology, permitting higher planning and funding of HF companies. A nationwide effort to evaluate all sufferers at present taking loop diuretics and not using a analysis of HF might discover many sufferers with a treatable situation who stand to realize a lot from their analysis.
Limitations
We had incomplete scientific data within the accessible digital well being data. Absent coding might account for almost all of missed diagnoses in sufferers prescribed a loop diuretic and not using a analysis of HF.14 If this discovering is generalisable to the info from the CPRD, our findings are all of the extra necessary. If the absence of a scientific code doesn’t imply the absence of the illness, then epidemiological experiences utilizing digital knowledge are destined to underestimate prevalence. Nevertheless, the optimistic predictive worth of a analysis recorded in CPRD being clinically current is roughly 89%.29
It’s doubtless that some sufferers within the loop diuretic group would have been prescribed a loop diuretic for the therapy of different causes of peripheral oedema corresponding to hypoalbuminaemia, lymphoedema or venous stasis—the sample of signs earlier than the index date had been notably completely different for these within the loop diuretic group in contrast with these within the HF group.
We acknowledge a level of immortal time bias affecting sufferers within the HF group. Though 50% of sufferers had been recorded as being on a loop diuretic on the time of the HF analysis, roughly 25% had been taking a loop diuretic earlier than the analysis was made (25% began a loop diuretic similtaneously the HF analysis).
Though we used propensity matching and multivariable Cox regression analyses, we can’t account for unmeasured scientific variables which will confound the outcomes.