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Abstract
Objectives To describe the population of patients diagnosed with hypertrophic cardiomyopathy (HCM) in Denmark and determine temporal trends in incidence and patient characteristics over time.
Design Nationwide retrospective cohort study.
Setting Danish nationwide administrative and clinical registers and databases.
Participants All patients aged ≥16 years diagnosed with HCM from 2005 to 2018.
Outcomes measures Time trends in HCM diagnosis, patient characteristics, comorbidities and pharmacotherapy were identified and tested for significance using the Cochran-Armitage trend test.
Results 3856 HCM patients were included (median age 68 years (IQR 56–78)). Although there were more males (53%), females were older (72 years vs 63 years) and more likely to have their type of HCM classified as obstructive (54% vs 38%). A consistent rise in HCM cases per year was detected and there was a significant decline in prevalence of heart failure (2005: 20% to 2018: 12%, p<0.001) and ischaemic heart disease (2005: 31% to 2019: 16%, p≤0.001). Prevalence of atrial fibrillation and stroke remained notable and unchanged. Lastly, the rate of hospitalisations decreased over time (2005: 64% to 2016: 46%, p<0.001), while the rate of outpatient follow-up increased (2005: 81% to 2016: 87%, p 0.003).
Conclusion There was a consistent rise in HCM cases with decreasing morbidity burden. Females were older at diagnosis and more likely to have their type of HCM classified as obstructive. The rate of outpatient follow-up is increasing.
- Cardiac Epidemiology
- Cardiomyopathy
- Adult cardiology
Data availability statement
No data are available. Data for this study are derived from and accessed through Statistics Denmark. By law, these data are not allowed to be shared. For this reason, data cannot not be made available to other researchers.
This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
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STRENGTHS AND LIMITATIONS OF THIS STUDY
Large nationwide cohort study design capturing all Danish adults diagnosed with hypertrophic cardiomyopathy (HCM) over a 14-year period.
Utilisation of comprehensive national registries for data collection, ensuring minimal missing data and a complete follow-up.
Lack of specific data on echocardiographic features, genetic testing and implementation rate of genetic counselling.
Reliance on International Classification of Diseases, the 10th revision coding for HCM diagnosis and classification, which may vary between healthcare institutions.
Absence of long-term outcome analysis, limiting assessment of the impact of HCM on morbidity and mortality beyond the 2-year follow-up period.
Introduction
Hypertrophic cardiomyopathy (HCM) is a hereditary heart disease caused by a multitude of mutations integral to the structure and function of the cardiac muscle tissue, and it is one of the most common genetic cardiovascular diseases worldwide.1 2 It is a condition that affects patients irrespective of age, ethnicity and sex, but the penetrance of the disease can vary by age.2 3 However, the absolute number of patients diagnosed and registered with HCM suggests that the condition is highly underdiagnosed.1 Furthermore, several epidemiological studies have shown this is especially prevalent in females, where HCM detection rates are significantly lower than in males.4–9
The presence of functional obstruction of the left ventricular outflow tract referred to as hypertrophic obstructive cardiomyopathy, increases the probability of developing symptoms compared with non-obstructive HCM.1 10
Patients with HCM have an increased risk of cardiovascular complications, such as atrial fibrillation (AF), stroke, heart failure (HF) and sudden cardiac death.11–13 Especially AF in HCM patients can be challenging since symptoms, and haemodynamic changes, are often poorly tolerated. Moreover, HCM patients with AF have an elevated risk of thromboembolic events compared with AF patients without HCM.12–15
Given the relative rarity of the condition, few large-scale epidemiological studies pertaining to the demographics and morbidity burden of the HCM population exist so far. Hence, in this study, we sought to describe the population of patients diagnosed with HCM in Denmark and determine temporal trends in incidence and patient characteristics over time.
Methods
Study design
This study was designed as a nationwide retrospective cohort study aiming to identify all Danish adults diagnosed for the first time with HCM between 1 January 2005 and 31 December 2018, describe their characteristics, comorbidities and pharmacotherapy, and identify changes and trends within these parameters over time.
Concomitant pharmacotherapy was analysed both prevalent at baseline and during the first 2 years after initial diagnosis, and the changes over time were compared.
To quantify resource utilisation of HCM patients, hospitalisations and outpatient visits up to 2 years following inclusion were analysed, and changes over time were described.
Data sources
All Danish residents are provided with a unique civil registration number, enabling linkage between the individual national Danish registries for research purposes. For this register-based cohort study, three registers were used as follows:
The Civil Registration System holds data on age, gender and vital status, and all deaths are registered within 14 days.
The Danish National Patient Register holds information on every hospitalisation in Denmark since 1978. Primary diagnosis is registered according to the International Classification of Diseases, the 10th revision (ICD-10) since 1994. The database further holds information on operations and procedures performed in Denmark. These procedures have been registered since 1996 and coded according to the Nordic Classification of Surgical Procedures by The Nordic Medico-Statistical Committee.
The Danish National Prescriptions Registry contains data on all prescriptions dispensed by Danish pharmacies since 1994. Pharmaceuticals are registered in accordance with the Anatomical Therapeutic Chemical (ATC) classification system.
Inclusion
All Danish patients of 16 years or more, diagnosed with first-time HCM (ICD-10: DI421, DI422) between 1 January 2005 and 31 December 2018 were included. All patients with incomplete data and those without a history of permanent residence in Denmark during the observation period were excluded from the analysis.
Variables and factors of interest
Patient characteristics more closely analysed were gender, age and type of HCM (obstructive and non-obstructive). For analytical purposes, patients were divided into two groups according to age: those over 60 and those younger.
Comorbidities included AF, HF, ischaemic heart disease (IHD), hypertension, ischaemic stroke, chronic kidney disease and chronic obstructive pulmonary disease (COPD) and were registered 5 years before study inclusion. ICD-10 codes used for these comorbidities are provided in online supplemental table 1.
Supplemental material
Concomitant pharmacotherapy at baseline was defined as any claimed prescription 180 days prior to the date of study inclusion. Additionally, pharmacotherapy was also analysed for a follow-up period of 2 years after the initial HCM diagnosis. In order to ensure complete follow-up, this analysis included only patients diagnosed with HCM in the years 2005–2016. Medications included in the analysis were beta-blockers, calcium channel blockers (CCB), ACE inhibitors, loop diuretics, spironolactone, oral anticoagulant therapy (OAC), digoxin and amiodarone. OAC comprised warfarin, phenprocoumon, dabigatran, rivaroxaban, apixaban and edoxaban. ATC codes used for these pharmaceuticals are provided in online supplemental table 2.
Implantable cardioverter defibrillator (ICD) implantations were analysed at inclusion and separately during a follow-up period of 2 years after the initial HCM diagnosis. Procedural codes used for ICD implantation are provided in online supplemental table 1.
Hospitalisations and outpatient visits were solely analysed for the 2-year follow-up after inclusion at initial HCM diagnosis. Hospitalisations were defined as any admission to a Danish hospital, regardless of diagnosis, within these 2 years. Likewise, outpatient visits were defined as any outpatient visit at a Danish hospital, regardless of diagnosis within the same follow-up period.
Statistical analysis
Descriptive tables were employed to describe the study population by morbidity burden with continuous variables reported as medians and IQRs and categorical variables summarised with counts and corresponding percentages. Statistical differences were calculated using the χ2 test, for categorical variables the Kruskal-Wallis test was employed. Time trends were calculated for gender, age, HCM subtype, comorbidities and concomitant pharmacotherapy. Significant changes in trends over time were tested using the Cochran-Armitage trend test and linear regression. A two-sided p<0.05 was considered significant.
Statistical analysis and programming were conducted using R statistical software (R Core Team (2021). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. URL https://www.R-project.org/).
Patient and public involvement
None.
Results
Baseline characteristics of HCM patients
A total of 3856 patients were included in the study between 2005 and 2018. The median age was 68 years (IQR 56–78), with a slight majority of males (53%) (table 1). Cardiovascular morbidity and prevalent use of concomitant pharmacotherapy were frequent in the population, with more than 50% having concurrent hypertension. IHD, AF and HF were also frequently observed comorbidities with a prevalence of 22%, 14% and 17%, respectively. Beta-blockers and ACE inhibitors were prescribed to more than one-third of the population, and OAC and loop diuretics were common, being prescribed to 12% and 22% of patients (table 1).
Baseline characteristics of all patients included, 2005–2018
Gender comparison
Forty-seven per cent of patients diagnosed with HCM were female. Female patients were in general older (median age 72 years (IQR 62–81) vs 63 years (52–74)) than their male counterparts and their type of HCM was more likely to be classified as obstructive (54% vs 38%). Regarding concurrent comorbidity, both groups were comparable, although hypertension was more commonly associated with female gender (56% vs 46%) and AF with males (15% vs 19%). At time of diagnosis, female patients received more treatment with beta-blockers (40% vs 34%), CCB (31% vs 23%) and loop diuretics (25% vs 19%) (table 1).
Time trends
Between 2005 and 2018, the number of patients diagnosed with HCM increased steadily from 207 to 256 annually, with a maximum of 361 patients diagnosed in 2012 (figure 1, online supplemental table 3). In the context of the Danish population for each year, these numbers correspond to a rise in incidence of 3.1 per 100 000 people in 2005 to 4.4 newly diagnosed HCM patients per 100 000 in 2018. In 2012, the year with the highest number of newly detected patients, the yearly incidence estimates 6.4/100 000 (online supplemental table 3).
Temporal trends of yearly detection rate, baseline patient characteristics, comorbidities and concomitant pharmacotherapy (2005–2018) (scale: 1771×1181). AF, atrial fibrillation; HCM, hypertrophic cardiomyopathy; HF, heart failure; IHD, ischaemic heart disease.
The number of patients classified as having an obstructive HCM type decreased from 58% in 2005 to 40% in 2018 (p<0.001, figure 1).
Furthermore, there was a decreasing proportion of patients with prevalent IHD (31% in 2005 to 16% in 2018, p<0.001 for time trends), HF (20% in 2005 to 12% in 2018, p<0.001 for time trends) and COPD (9% in 2005 to 7% in 2018, p=0.04 for time trends). Though, prevalent hypertension, AF and stroke remained high and unchanged (online supplemental table 3). Analysing active pharmacotherapy at inclusion, there was a decrease in loop diuretics (26% in 2005 to 16% in 2018, p<0.001) and ACE inhibitors (from 30% in 2005 to 18% in 2018, p<0.001) (online supplemental table 4).
Two-year follow-up of use of concomitant pharmacotherapy and ICD implantations
Up to 2 years following HCM diagnosis, prescription with beta-blockers increased from 36% of patients at baseline to 63% of all HCM patients, while CCB treatment increased from 26% to 35%. Similarly, treatment with ACE inhibitors rose from 26% to 33%, and loop diuretic use increased from 23% to 35%. OACs were prescribed to 20% of patients 2 years after diagnosis, an increase from 11% at baseline. While at the time of inclusion, 2% of patients had received an ICD prior to diagnosis with HCM, and 2 years after diagnosis, 5% of all patients had received an ICD (figure 2, table 2).
Temporal trends of concomitant pharmacotherapy and resource utilisation identified in the follow-up period (2005–2016) (scale: 1771×1181). OAC, oral anticoagulant.
Analysis of concomitant pharmacotherapy and ICD up to 2 years after HCM diagnosis in the years 2005–2016
While there was a noticeable increase in active pharmacotherapy following HCM diagnosis in all years combined, trend analysis for pharmacotherapy in this follow-up period in year-by-year comparison revealed that the use of ACE inhibitors and loop diuretics decreased from 2004 to 2016, while there was an increase in the use of OAC in the same period (figure 2, online supplemental table 5).
Resource utilisation
Finally, the rate of hospitalisations and outpatient follow-up were analysed. In the 2 years following HCM diagnosis, trend analysis revealed a significant fall in hospitalisation from 2005 to 2016 (64% in 2005 to 46% in 2016, p-trend≤0.001). During the same time, outpatient follow-up was significantly increased (81% in 2005 to 87% in 2016, p-trend=0.003) (figure 2, (online supplemental table 5).
Discussion
Overall, this study identified a large cohort of HCM patients with a steady and consistent yearly increase in detected HCM cases and a decreased morbidity burden over time. Gender distribution in this cohort revealed a near equal distribution of males and females; however, females were older and more likely to have their type of HCM classified as obstructive at first diagnosis.
While HCM is often thought of as a disease of the young, most epidemiological studies place the typical age of patients at initial HCM diagnosis well over 60.16–20 This study is no exception, with a median age of 68 years at the time of diagnosis and without major change comparing individual years. While the patients’ age remained stable, there was a significant decrease in the prevalence of comorbidities such as HF, IHD and COPD. Notably, the prevalence of IHD decreased markedly in this study, and this was the case despite the general prevalence of IHD increasing from 1980 to 2009.21
Several factors can be attributed to this rise in detection. For one there have been considerable advances in both availability and capability of imaging modalities such as cardiac MRI and echocardiography. Especially, cardiac MRI has gained a more prominent role in classification of HCM.22 23
Further the importance and availability of genetic testing and counselling has only increased over time. An increasing number of genes have been associated with the development of HCM making it possible to classify patients and their relatives with less severe HCM phenotypes more accurately.24 25 This coupled with the practice of cascade genetic screening can be expected to contribute to the rising number of detected HCM cases.
Lastly advances in the organised management of HCM patients and increased general awareness for rare and genetic diseases cannot be underestimated. The European Society of Cardiology recommended its 2014 guidelines on managing HCM genetic testing patients suspected of HCM.12 In Denmark, this practice is predated by establishing specialised clinics for inherited heart diseases in which clinical and genetic screening are performed based on the first national recommendation for management of inherited heart diseases from 2003. Both factors likely contributed to the rise in detection rate and awareness of HCM in the Danish population.
While the prevalence of cardiovascular comorbidity among the newly diagnosed decreased markedly, this was notably not the case for AF and stroke. There is a well-documented strong association between HCM, AF and stroke,15 16 26–28 and therefore, unsurprising to see a stable prevalence of both conditions, despite a rising detection rate. International guidelines in the treatment of HCM recommend aggressive treatment of AF in the presence of HCM since stroke risk is higher and symptoms of AF can be aggravated in these patients.12–14 The general advances in AF treatment, especially in the context of HCM, were emphasised in the detectable increase of patients in active OAC treatment, both prevalent at baseline and follow-up. In Denmark, a general trend towards increased prescription of OAC in AF patients could previously be detected and attributed to mounting evidence supporting the safety and efficacy of direct oral anticoagulant treatment in this group.29 Looking at the individual temporal trends of warfarin and direct oral anticoagulant treatment in these Danish patients, a clear shift can be detected in which from 2012 onward direct oral anticoagulants increase in usage, while prescriptions of warfarin decline. This was both the case at baseline and follow-up analysis and these data are summarised in online supplemental tables 4 and 5.
The increase in OAC treatment following the years after diagnosis with HCM could be explained by increased awareness of the importance of sufficient anticoagulation within the context of HCM, as highlighted by international guidelines.12 14
Despite a significant gender gap reported in numerous studies,4–9 showing a lower HCM detection rate in females, the distribution between the genders in this cohort of Danish HCM patients was near equal. There was a slight majority of male patients (53%) in this cohort, although this difference was far less pronounced than in comparable studies and did not prove statistically significant.17–20 In terms of temporal changes, although in most years, the detection rate of HCM in females was slightly below that of males, the difference was not significant and did not alter over time. Females, however, were older at the diagnosis and more likely to be classified as obstructive. This is consistent with other large studies examining HCM cohorts.17–20 Whether this difference is due to differences in penetrance or bias in screening/referral remains controversial.4–9
Arguments to support the case for a bias in screening and detection between the genders can be found in this Danish cohort. There was an overweight of AF among males in this HCM cohort. Diagnosis with AF would, in accordance with current guidelines, result in the patient’s referral to follow-up, including procedures such as echocardiography, in which previously unknown HCM would be more likely to be detected. With ever-increasing options for screening and follow-up for AF, this or comparable processes with other cardiovascular comorbidities could explain the difference in age and severity between the genders. However, more research is warranted to explain this disparity between the genders in HCM diagnosis sufficiently.
Strengths and limitations
Given the relative rarity of HCM, large nationwide databases are well suited for research on this topic; however, this method is not without limitations. The Danish National Patient Registry and the general completeness of data in the Danish nationwide registries ensure minimal missing data and a complete follow-up.30 The main limitations are all inherent to the observational study design, and the possibility of residual confounding remains. Most notably, the used registries do not contain data on echocardiography or genetic testing, which limits the ability of detailed cohort description. HCM diagnosis and type classification (obstructive vs non-obstructive) is solely based on ICD-10 coding within the registries and hereby judgement of the treating physician. The specific criteria or definition used for HCM in Denmark during the study period were not explicitly stated or standardised. Therefore, with these data we can solely distinguish between obstructive and non-obstructive HCM as classified at time of inclusion. Since diagnosis of HCM can be challenging and easily mistaken for other conditions presenting with left ventricular hypertrophy, this approach is inherently prone to misdiagnosis and error. This especially applies for patients with hypertension. Prevalence of hypertension in this cohort was high, with 50% opening possibility for misclassification. However, given the low positive predictive value for hypertension within the Danish registries, hypertension was classified as active treatment with two or more antihypertensive pharmaceuticals in this study. This included ACE inhibitors and beta blockers which are often prescribed for HF, AF and other conditions often seen in conjunction with HCM. Therefore, with this method, misclassification of hypertension cannot be excluded in this context and the percentage of patients classified as hypertensive might be inflated.
The positive predictive value for HCM within the Danish National Patient Registry has been shown to be 90% in a study validating a variety of cardiovascular diagnosis within the Danish registries from 2016.31 This study, however, only analysed 20 patients with HCM, possibly necessitating further validation of HCM within the Danish registries. For the purpose of this study, the authors have decided to rely on currently available data.
Conclusion
This large epidemiological study of Danish HCM patients identified a steady increase in detected HCM patients. The previously described gender gap in HCM detection was less pronounced, with near equal distribution between the genders; however, females were older and more likely to have their type of HCM classified as obstructive at first diagnosis.
Data availability statement
No data are available. Data for this study are derived from and accessed through Statistics Denmark. By law, these data are not allowed to be shared. For this reason, data cannot not be made available to other researchers.
Ethics statements
Patient consent for publication
References
Supplementary materials
Supplementary Data
This web only file has been produced by the BMJ Publishing Group from an electronic file supplied by the author(s) and has not been edited for content.
Footnotes
Contributors CRZ: study concept and design, data analysis, drafting manuscript, guarantor. JP: study concept and design, data analysis, critical revision of the manuscript drafts. A-MS: study concept and design, critical revision of the manuscript drafts. MKJ: study concept and design, critical revision of the manuscript drafts. JT: critical revision of the manuscript drafts. LDR-V: critical revision of the manuscript drafts. CM: critical revision of the manuscript drafts. PVR: critical revision of the manuscript drafts. GG: critical revision of the manuscript drafts. MLH: study concept and design, critical revision of the manuscript drafts.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.