Discussion
This study was the first to analyze age-standardized mortality rates due to PAD at the national and regional levels, as well as their trends from 2011 to 2020. Since 2018, mortality has increased in all NUTS-2 regions in Croatia, with significant regional differences in average mortality rates by sex.
Among the 16 799 deaths due to PAD, the highest proportional mortality was for the diagnoses I70.9 (43.2%) and I70.2 (14.3%), followed by diagnoses associated with diabetes, which can be explained by the high atherogenic potential of this disease (Figure 2). The effects of diabetes on morbidity and mortality in the population are undoubtably underestimated both in official statistics and in clinical practice. (21, 22) Of all NUTS-2 regions, the greatest percentage change in mortality in 2020 in comparison with 2011 for both men and women was found in the City of Zagreb; 60.71% and 38.13%, respectively. For men, the City of Zagreb was followed by Adriatic and Pannonian Croatia with regard to percentage change, with similar percentages, and ultimately also by Northern Croatia. The ranking was the same for women, but the percentage increases were lower. The increase in standardized mortality rates can be observed starting from 2018 (Figure 2, Figure 3).
This trend of increasing mortality has also been observed in other EU member states. Namely, between 1990 and 2017, all EU15+ countries have had an increase in mortality in women, and an increase in mortality in men was observed in as many as 16 out of 19 of the countries. A negative trend was reported in Italy (-25.1%), Portugal (-1.9%), and Sweden (-0.6%). (4, 23) The etiology of the mortality increase is multifactorial, and can certainly be largely ascribed to the dynamics of the disease in the population. Improved registration of causes of death may have also contributed to the positive trend, since inadequate identification of this disease in the general population and reduced awareness represents a global problem. Studies in other countries have indicated inadequate knowledge on PAD in both the general population and in medical professionals, but no such studies have been conducted in the Republic of Croatia. (5, 24)
The results of our study indicate a wide spectrum of mortality rates by sex and by region. For 2020, the ratio of the highest and lowest mortality rate in the City of Zagreb in comparison with the Adriatic region indicates a 40% higher mortality in men and a 70% higher rate in women. Northern Croatia has the highest average mortality rate for both sexes. Men, except in the City of Zagreb, have higher average mortality rates in all the other regions (Table 2). Mortality was significantly higher in men in Pannonian and Adriatic Croatia in comparison with the City of Zagreb and Northern Croatia, where men and women had similar rates (Figure 4).
Sex is a significant factor in diagnosis and therapy selection. (25) In women, the clinical symptoms of PAD are often not present, resulting in failure to diagnose and treat the disease according to recommendations. (26) These systemic errors can influence study outcomes and must be considered when interpreting epidemiological indicators. Furthermore, significant regional differences in mortality were observed within the same sex. For example, men in Northern Croatia had significantly higher mortality than men in Adriatic Croatia, whereas mortality rates were similar among other regions. These results are to be expected due to lower prevalence of risk factors and the protective cardiovascular effect of the Mediterranean lifestyle in Adriatic Croatia. Mortality rates in women were similar in the City of Zagreb and in Northern Croatia, but the City of Zagreb had significantly higher mortality rates in comparison with Adriatic and Pannonian Croatia. When examining other regions, we can conclude that Northern Croatia has significantly higher mortality rates than Adriatic and Pannonian Croatia, and the Pannonian region has higher rates than Adriatic Croatia (Figure 4). These differences can be primarily ascribed to risk factors and the lack of effective prevention, although the influence of better identification of the disease itself cannot be excluded. Namely, the national program for the prevention of CVD from 2001 was not applied in clinical practice, and it was also subsequently determined that there were clinical and public health practices that did not match recommendations applied in other countries. Some regions, such as Adriatic Croatia, have implemented preventive programs for CVD that may have reduced morbidity and mortality. (27) It should be emphasized that the Croatian healthcare systems lacks strategies for the prevention of leading causes of poor health such as smoking, high arterial pressure, and poor diet, which would be implemented at all levels of healthcare. (28)
Furthermore, no national studies have been conducted that would quantify the effect of risk factors on morbidity, mortality, and treatment costs for CVD, and aggregated data used in the present study limits the precise determination of the possible causes of differences in mortality. However, all epidemiological studies emphasize the very large role played by prevention, estimating that reducing risk factors would prevent as much as 80% of cardiovascular diseases. When examining mortality form CVD alone, it can be said that more than half is ascribable to risk factors, with the rest being determined by medical care. (29-31) Education and awareness of the general population and of medical professionals is a precondition for reducing the high prevalence of traditional risk factors. Education is lacking in Croatia, both among medical students and in the general population, since only a third of the population is aware that CVDs are the leading cause of death. (5, 6, 32, 33) Although no studies have been conducted in the general population on knowledge of the etiology of PAD, we may assume that, as in other populations, knowledge on this disease is worse in comparison with other CVDs, such as IHD. (9, 34) Even clinicians are often unaware that mortality from PAD surpasses mortality from coronary heart disease. (35)
The Republic of Croatia is an EU member state that is severely burdened by CV risk factors. Along with hypertension, environmental risk factors, smoking, and risks associated with diet are the strongest contributors to mortality and morbidity. (9) Smoking and diabetes are especially important in the etiology of PAD. The prevalence of smoking in 2019 was 32.6% in women and 39.1% in men. From 1990 to 2019, the prevalence of smoking was reduced both in women and in men, by -11.7% and -17.6%, respectively, but the negative trend has been significantly worse in comparison with Central European countries. In the same period, Poland reduced smoking by -17.8% in women and by as much as -40.5% in men. (36) Despite the limitations imposed by regional comparisons, the poor success of reduction in the prevalence of smoking in the Republic of Croatia is undoubtably attributable to the lack and inadequate application of demonstrably effective methods such as increasing the prices of tobacco products, advertising smoking cessation in information-providing media, introducing educational materials about hazardous effect of smoking into schools, reducing the capacity of the tobacco industry to market its products, and introducing social norms that make smoking an unacceptable behavior. (37) Aside from smoking, the Republic of Croatia is the EU member state with the highest ratio of women and men with unregulated hypertension, 38% and 36%, respectively. (8, 38) The burden of hypertension is unequally distributed by region, with a higher burden in continental regions and in persons with lower socioeconomic status. (8, 39) In addition to the extremely high prevalence of diagnosed hypertension, it is estimated that as many as one sixth of patients have undiagnosed hypertension, which firmly identifies this disease as an urgent public health issue. Regional differences are present as well, with the ratio of patients with undiagnosed hypertension being higher in Adriatic Croatia. (40) In Europe, patients with PAD usually have a combination of multiple risk factors that include hypertension, dyslipidemia, and increased waist circumference. (41)
Risks associated with diet are, along with smoking, the most common causes of mortality and morbidity. (42) The dietary patterns of the Croatian population increasingly resemble Western diet due to the loss of Mediterranean heritage in transitional processes. The term “the Croatian paradox” was coined to emphasize the discrepancy between having CVD mortality rates similar to those in countries of Eastern and Central Europe despite belonging to the group of Mediterranean countries. (43, 44) In addition to unhealthy diet, it is important to emphasize the role of physical inactivity, which is associated with obesity and increased waist circumference. The prevalence of physical inactivity differs by sex, age, and region. A trend change was observed two decades ago, and almost 36% of the population was physically inactive at the start of the 2000s. Regional differences were also pronounced at the time, with 85.6% of men being physically inactive in the City of Zagreb, as opposed to 15% in Southern Croatia. The distribution by age was unfavorable, and prevalence was highest in the 18-34 age group, which is the period in life where exercise and physical activity habits are predominantly acquired, whereas prevalence was lowest in middle age in both sexes. (45) One decade later, 80% of the adult population was physically active, more so men than women, which represented a positive change. However, the ratio of adolescents who achieved the recommended level of physical activity according the World Health Organization remained low at 25%. (46) Despite the recommendations for physical activity, sedentary behavior, and sleep from 2019, this ratio in adolescents remained the same in 2021, when it was also determined that only the healthcare and social welfare systems follow and monitor the level of physical activity in the population. (47, 48) The evidence on the benefits of physical activity for the reduction of the incidence of numerous chronic non-infectious diseases, including CVDs, is beyond doubt. (49) The present study highlights the noticeable correlation between the level of physical inactivity and the mortality rate due to PAD in Continental Croatia and the City of Zagreb in comparison with Adriatic Croatia, although methodological differences limit the assessment of the causal relationship between the two. Cohort studies would allow precise quantification of the protective role of physical activity for PAD-related morbidity and mortality.
In addition to the dominant role of risk factors in morbidity and mortality, it is also important not to neglect the comparably important influence of medical interventions in more clinically severe forms of PAD. In comparison with the neighboring Hungary, which has the highest amputation rate in Europe, as well as in comparison with Germany and Austria, the Republic of Croatia has noticeably lower age-standardized mortality rates due to PAD, which were similar to the European average for both sexes in the period from 1990 to 2019. (50) However, systematic analyses cannot be performed due to the lack of informational interconnectedness between all levels of healthcare, which prevents routine quantification of the number of interventions per medical institution and monitoring treatment outcomes, cost-benefit analyses, and cost-efficiency analyses. (51, 52) The observed regional differences in mortality are certainly also partially ascribable to the differences in the distribution of human and technological potential in the specialist branches that provide care for patients with PAD, such as radiology, cardiology, and vascular surgery. Previous studies indicate the existence of regional differences in the availability of medical services, such as differences in waiting times for diagnostic examination using computed tomography (CT) and magnetic resonance (MR) imaging, but also differences in mortality from acute and recurrent myocardial infarction. (53-56) Additionally, the mortality from PAD, as with acute coronary syndrome, is ascribable to the natural course of the disease, but can also be caused by medical, endovascular, or surgical interventions, which necessitates differentiating and recording spontaneous unwanted outcomes as opposed to unwanted outcomes associated with medical interventions. (57, 58)
The present study had certain advantages and disadvantages, the latter being the study limitations and the possibility of systemic errors. Its greatest advantage is the fact that this was the first study to quantify the regional differences in PAD-related mortality. According to the WHO, mortality statistics are one of the most reliable sources of scientific data. Mortality data are used for assessing the overall state of health in the population, creating health-related policies, evaluating national healthcare programs, and performing regional and international comparisons. The authors of the Global Burden of Disease (GBD) project analyzed the quality of mortality data in EU member states and evaluated the reliability of annual assessments of causes of death on a scale ranging from 1 to 5, with Croatia being among 14 other countries (Belgium, Bulgaria, the Czech Republic, Denmark, France, Germany, Greece, Luxemburg, the Netherlands, Poland, Portugal, Romania, Slovenia, and Spain) that were marked with a score of 4, indicating that the completeness of mortality data was higher than 65%. (59)
Along with these advantages, the present study had numerous limitations that should be considered when interpreting the data. Firstly, from a methodological perspective, this was an observational study, which means that it can provide only limited demonstration of causal relationships. Furthermore, it is likely that PAD is less often diagnosed as a cause of death than for instance IHD, despite both diseases having atherosclerotic processes as the underlying cause. The causes of death in PAD are rarely the direct result of the disease of the lower extremities, and it is estimated that every other patient with this disease dies from complications related to coronary disease, and every tenth patient dies from complications related to cerebrovascular disease. (60) The comparability of this study is limited, as there is no unified application of ICD diagnoses among different countries. However, despite the lack of comparability at the international level, comparisons between regions are possible, since the existence of systemic errors at the regional level that would lead to differences in outcomes is not anticipated. It is possible that the larger number of medical centers performing treatment on patients with PAD in the City of Zagreb has resulted in improved coding of mortality causes, but there are no studies quantifying such discrepancies between centers. Peripheral artery disease can certainly be included in the group of diseases in which the ICD system does not fully represent the complexity of the clinical picture. (61) Given the clinical course of the disease, it is likely that the more severe forms of the disease are diagnosed, while the majority of the cases remains asymptomatic and are thus diagnosed less often. (62)
In conclusion, despite aggregated data and its limitations, this study has shown significant regional differences in mortality due to PAD, with an increasing trend since 2018. Northern Croatia had the highest mortality for both sexes, while Adriatic Croatia had the lowest mortality. Estimating causal relationships is difficult due to the ecological study design, which was the result of the lack of systematic data collection that includes treatment outcomes. However, epidemiological studies emphasize the role of prevention and early diagnostic in the reduction of mortality, and the effectiveness of this approach is undoubtably also applicable to patients with PAD.