Underutilization of guideline-recommended therapy in patients 80 years and older with peripheral artery diseases

Introduction

Ageing is neither modifiable nor escapable and the share of older patients is expected to increase further. A model by the United Nations predicts this share will double in the next 30 years [1].

The mechanisms by which ageing promotes cardiovascular diseases are diverse. In addition to a higher prevalence of comorbidities in the older population, ageing itself leads to specific changes that increase the risk of developing atherosclerotic diseases like peripheral artery disease (PAD). Those include alterations on the genomic level culminating in mitochondrial dysfunction and impaired vascular elasticity [2, 3, 4]. This explains why, despite overall decreasing mortality rates of cardiovascular diseases, the share of patients dying from cardiovascular causes is still high in the octogenarian and older population [5].

PAD is a major manifestation of atherosclerotic cardiovascular diseases (ACVD) and the prevalence increases worldwide, especially in the older population. Atherosclerotic lesions are the hallmarks of PAD, leading to impaired blood flow and decreased peripheral perfusion. Subsequently, intermittent claudication (IC) is defined by a reduced pain-free walking distance and results in disabling conditions with a reduced quality of life [6]. Especially in an older population, a reduced pain-free mobility has various implications since it limits the patient’s capacity to participate in active lifestyle which in turn is a risk factor for obesity, cardiovascular events, cognitive decline like dementia, orthopaedic diseases and an increased frailty [7]. The severest stage of PAD is critical limb-threatening ischemia (CLTI), which requires even more attention. According to current guidelines, CLTI is defined as chronic ischemic rest pain, ulceration or gangrene due to PAD [8]. CLTI is associated with increased mortality, risk of major amputation and impaired quality of life [2, 9, 10]. Frequent complications include limb related outcomes like infections, gangrene as well as major amputations. CLTI has a particularly high ten-year mortality rate in the older population of up to 75% [11]. Taken together, there is an urgent need to treat every stage of PAD according to current guidelines.

To ensure optimal treatment, lipid lowering and antiplatelet therapy have been identified as the most important tools and are consistently recommended by all major societies in ACVD patients [12, 13, 14]. Despite guideline recommendations regarding medical treatment, implementation of those guideline recommendations is inadequate and depends on social status, race and gender amongst other factors [15, 16, 17]. Although increasing age is associated with an increased prevalence of cardiovascular disease, others have shown that pharmacotherapy is often insufficient in this population due to fear and ignorance of drug interactions and age-related side-effects, like bleeding complications [18]. Current literature, however, has proven noteworthy benefits from guideline-recommended pharmacotherapy, including a large reduction in all-cause mortality, especially in octogenarians [19].

Given the significance of ageing on cardiovascular morbidity, it is essential to identify insufficiencies in current treatment structures and adherence to guideline recommended medical therapy to improve outpatient care in this high-risk population. To this aim, this study investigated age-related differences in PAD prevalence, outpatient care and treatment from 2009 to 2018 in a nationwide cohort.

Patients and methods

Our analysis is based on ambulatory claims data for all statutorily insured patients in Germany, comprising 70.1 million patients per year and 87% of the German population. Privately insured patients, which represent 13% of the German population were not included in the study due to lack of availability of data. Within the study frame from 2009 to 2018 prevalence was stratified by age. Special focus was put on guideline adherence to medical treatment with lipid-lowering agents and antiplatelet drugs as well as outpatient treatment patterns by vascular specialists.

The study is based on the ambulatory claims data of the panel doctors’ services according to § 295 SGB V and drug prescription data (2009–2016) according to § 300 SGB V. Diagnosis of PAD was defined according to medical diagnosis of PAD ICD I70.2-9. Analysis of overall PAD prevalence and outpatient care distribution was based on all patients aged ≥40 years with one of the ICD diagnosis codes consistent with PAD (I70.2, I70.8, I70.9). Analysis of pharmacotherapy was based on all ambulatory patients regardless of age, if one of the following ICD diagnoses codes consistent with PAD was documented: I70.20, I70.21, I70.22, I70.23, I70.24, I70.25, I70.29. In the case of repetitive ICD diagnoses per patient and year, the most severe diagnosis was included.

In addition, identification of current age distribution of patients to ambulatory care by the doctors’ specialities (internal medicine, cardiologists, angiologists, vascular surgeons) was based on “lifelong physician codes” (LANR). Potential duplicate counts were not excluded, thus the present data present actual outpatient contacts for each specialty.

Prescription of PAD related pharmacotherapy was analysed by the “Anatomical Therapeutic Chemical” (ATC) codes. In this study, PAD related medications included C10AA (statins, HMG CoA reductase inhibitors) and B01AC (platelet aggregation inhibitors, excluding heparin). To count a patient’s consultation to specialised outpatient care or a drug prescription, at least one visit or prescription per year had to be registered in the database per patient. Visits to more than one specialised outpatient care were counted multiple times. The analysis of prevalence and outpatient care distribution was based on 17,633,970 patients from the outpatient claims data. The analysis of PAD and pharmacotherapy was based on 4,515,577 patients, derived from pharmacotherapy claims data. Potential duplicate counts between both claim data pools were not excluded, due to the design of the study.

Statistical analysis was performed with the chi-square test for trend and two-way ANOVA. All analyses were performed with GraphPad Prism 8.0.

Results

This study was based on nationwide ambulatory claims data covering approximately 87% of the German population. 70.1 million statutorily insured patients per year were identified. For the analysis of outpatient-care distribution, 17,633,970 patients with PAD were included between 2009 and 2018, of whom 27.7% were above 80 years old. The analysis of PAD and pharmacotherapy was based on 4,515,577 patients, derived from pharmacotherapy claims data, out of which 26.8% were above 80 years old (Figure 1).

Between 2009 and 2016 PAD prevalence increased continuously, with a particularly steep increase in the older population, while reaching a plateau between 2016 and 2018 (≥80 years: 2009 7.46% to 2018 12.89%, <80 years: 2009 2.71% to 2018 4.39%; Figure 2).

We then analysed the age-related distribution for PAD patients. We observed that most patients with PAD are within the older population, with a shift towards older ages (Figure 3).

We further investigated treatment patterns through outpatient presentations. Age-related outpatient presentation to vascular specialists (angiology, vascular surgery, cardiology) also differed. While mean overall presentation was low throughout the years, older PAD patients were even less likely to present to a vascular specialist than younger patients (angiology 2018: 6.59% vs. 9.17%, vascular surgery 2018: 8.53% vs. 12.01%, cardiology 2018: 29.54% vs. 30.96%; p<.05; Figure 4).

We then not only identified an age-related underutilization of specialized outpatient care structures by PAD patients 80 years of age and older, but also elucidated the age-related underutilization of guideline recommended pharmacotherapy. While the gap in pharmacotherapy underuse between patients older than 80 years and younger patients decreased during the observed time frame, the difference was still statistically significant (p<.05). While overall prescription rates of antiplatelet and lipid lowering treatment are low for PAD, older PAD patients received statins even less frequently (statins 2016: 46.5% vs. 52.4%, p<.05). Prescription rates for antiplatelets were higher in the older population throughout the years antiplatelets (2016 30.6% vs. 29.3%; p<.05; Figure 5).

Discussion

In the present study, we investigated outpatient presentation and guideline-recommended pharmacotherapy prescription patterns stratified by age on a nation-wide basis in a decade.

Despite the rising prevalence of PAD in octogenarians and older patients, we revealed an underutilization of guideline-recommended pharmacotherapy with lipid lowering agents and antiplatelets, as well as insufficient presentation pattern to vascular specialists. While prescription patterns of antiplatelets and lipid lowering agents like statins were low, older patients received the latter even less than younger patients. Interestingly, we did not detect this prescription pattern for antiplatelets, with older patients receiving antiplatelets more frequent than younger patients. In this nation-wide analysis, 28% of all PAD patients were 80 years or older, which indicates a particularly high PAD burden in the older. This emphasizes the importance of optimal outpatient management for this high-risk cohort.

The overall low presentation rates of older patients to outpatient specialists could be in part a result of reduced mobility and fragility in this population [20]. Another aspect that could explain our findings is the lack of awareness in the primary care setting to refer older patients to a specialized outpatient care facility [21]. Our findings are in line with those of others who showed that patients older than 80 years received less inpatient and outpatient care by cardiologists when presenting with myocardial infarction or signs of heart failure [22].

Finding the optimal pharmacotherapy for older patients certainly poses a challenge. Due to age-dependent changes in metabolism and comorbidities such as decreased kidney and liver function, older patients have a higher risk of experiencing adverse effects than younger patients [23]. Moreover, older patients are often multimorbid and frequently experience polypharmacy. This increases the risk of drug interactions and could be a reason for physicians to be more cautious when starting additional pharmacotherapy, even when it is recommended [24]. This requires a continuous system of checks and balances to ensure optimal dosages of pharmacotherapy. In line with our findings, a study in the Netherlands showed that lipid-lowering treatment frequency decreased with increasing age [25]. Accordingly, another study demonstrated that older patients remained on the same antihypertensive regime, despite being hypotensive with a subsequent increased mortality [26]. The beneficial effects on atherosclerotic diseases, progression of PAD or overall mortality have already been shown in the literature, indicating that antiplatelet treatment reduces limb related and general cardiovascular events in all age groups [27]. Similarly, contemporary literature highlights that lipid lowering treatment with statins is associated with an increased overall survival, importantly irrespective of age [28, 29, 30, 31]. Others have demonstrated a relative risk reduction for mortality of 22% over 5 years, as well as a reduction of coronary heart disease mortality, need for revascularization and stroke by statins in an elderly population [32, 33]. The CARE trial and LIPID trial even found a more pronounced effect of statins in elderly patients than in younger patients [34, 35]. This effect was found to be more profound in elderly patients with occlusive cardiovascular disease, like PAD [36]. However, elderly patients may be more prone to side effects by statin treatment, which is why the current guidelines on management of dyslipidemias recommend evaluating statin indication in elderly patients on an individual basis and predominantly in the presence of occlusive cardiovascular diseases [37]. This makes antiplatelet and lipid-lowering treatment the cornerstones of guideline-recommended pharmacotherapy for older patients with PAD.

Limitations

This study has limitations. Claims data enabled the collection of large amounts of information; however, due to the design of the study, only correlations not direct causalities can be drawn. Despite the lack of inpatient data and those from the privately insured, our analysis is based on the large amount of data comprising 70.1 million insured patients per year that allows for a representative examination of age-dependent outpatient treatment structures. Another issue is that outpatient encounters were not traced individually, but were aggregated. With regards to the low frequency of antiplatelet and statin therapy, this study did not account for potential intolerances or contraindications such as bleeding complications. Also, it was not possible to determine actual prescription adherence. This is especially critical in the older population, since impaired cognitive and physical activity in older patients might lead to increased non-adherence to prescribed pharmacotherapy [38].

Another limitation that is due to the design of the study and the available data, is that pharmacotherapy and outpatient presentation rates were analyzed within two different datasets and that stage-dependent pharmacotherapy was not available, but was aggregated for all PAD patients, stratified by age. Moreover, utilizing the ATC code C10AA we only investigated prescription patterns of statins and did not take other lipid lowering pharmaceutical agents or fixed combination drugs into account. With especially increasing ezetimibe monotherapy, our data underestimates to some extent real-world prescription patterns of lipid lowering drugs in the elderly population [39]. Same applies to antiplatelet treatment, which is probably underestimated by our data, since anticoagulative treatment was not considered. In the case of an indicated anticoagulative treatment because of comorbidities, antiplatelet treatment might be discontinued. Furthermore, due to the study of the design our data does not allow to distinguish between symptomatic and asymptomatic patients which might in parts explain the low prescription rates and presentation rates to vascular specialists. Low presentation rates to vascular surgeons in the elderly cohort might be a result of lacking surgical options in those patients.

Interestingly, we identified a plateau of PAD prevalence between 2016 and 2018. Whereas our data cannot fully explain this phenomenon, this could be a result of more frequent implementation of primary prevention measurements and higher awareness levels in physicians and patients alike.

Conclusions

In conclusion, we identified an increased prevalence of PAD in patients 80 years of age and older, which is in line with other studies [40, 41]. We here describe an underutilization of specialized outpatient care and guideline-recommended lipid-lowering therapy with a statin in the older PAD population, which is at a particular high-risk of cardiovascular morbidity and mortality. Despite requiring close monitoring of pharmacotherapy and clinical status due to comorbidities and frailty, older patients seem to face insufficient treatment. Our work sensitizes for the need to further improve the treatment pattern of the older and to evaluate alternative outpatient treatment structures, like specialized home visits or specialized care facilities near geriatric care facilities.