The prescribing of cardioprotective medications and the impact on survival for patients with peripheral artery disease that undergo intervention

Cardiovascular disease guidelines recommend that patients with established peripheral artery disease (PAD) are prescribed antihypertensive, lipid‐lowering, and antiplatelet medication to reduce cardiovascular ischaemic events. However, the prescribing of these medications for patients with PAD within New Zealand (NZ) remains undefined.


Introduction
Lower limb peripheral arterial disease (PAD) conveys a large health burden in Aotearoa New Zealand (NZ). 1 PAD is a marker of generalized atherosclerotic disease, and thus patients are at higher risk of major adverse cardiovascular events (MACE) and increased risk of early mortality. 2,3Prompt and aggressive secondary prevention with medical therapy may improve cardiovascular related outcomes for patients with PAD. 4,5Despite strong evidence of their use, the prescription of cardioprotective medications for patients with PAD remains largely unknown with the NZ population.
In NZ, current cardiovascular disease (CVD) guidelines recommend that all patients with established PAD are prescribed lipid-lowering medication unless contraindicated, an antihypertensive medication in the presence of hypertension, and an antiplatelet medication if age is <70 years. 6This mirrors international guidelines, which establish that combination cardioprotective medication is the predominant therapeutic aim to prevent the progression of the atherosclerotic disease and cardiovascular ischaemic events. 7,8nticoagulant medication should not be used to reduce cardiovascular ischaemic events, however, there will be a subset of patients on dual antithrombotic or isolated anticoagulation due to comorbidities, such as atrial fibrillation or mechanical value prosthesis.
For patients with symptomatic PAD, there is a clear relationship between cardioprotective medication use and survival, with statins possibly providing the greatest reduction in MACE and all-cause mortality. 9,10However, patients with PAD are often found to be under prescribed these medications, 11 particularly when compared to other manifestations of CVD, such as ischaemic heart disease (IHD), and for women with PAD. 12 These reports raise concerns that there may be an unmet need for cardioprotective medication for PAD patients within NZ.
The aim of this study was to report the use of cardioprotective medication for patients with PAD after their first percutaneous or surgical intervention within the Midland region of NZ over a 12-year period, and determine the impact of cardioprotective medications on survival.

Study design
Reporting of this observational study has followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. 13The methodology, criteria for inclusion and exclusion, and comorbidity definitions has previously been defined. 1 In brief, this was a retrospective observational study of patients in the Midland region of NZ that underwent percutaneous and surgical intervention for lower limb PAD at a tertiary referral centre (Waikato Hospital, NZ) between 1st of January 2010 and 31st of December 2021.
Ethics approval was granted by New Zealand Central Health and Disability Ethics Committee (20/CEN/122) and the Waikato Hospital Research Department (RDO020044).

Study protocol and data collection
The primary outcome was the number of patients with PAD within the Midland region that were treated with cardioprotective medications.The secondary outcome was overall survival.
Patients were identified from hospital-based operation reports, Picture Archiving and Communication System (PACS) software, and the Australasian Vascular Audit.Manual review of patient electronic medical records was conducted to ensure Midland region residency and gather demographic and surgical information.The National Health Index was utilized to ensure each patient was entered into the database once at their incident presentation.M aori patients were defined as those that self-identified as a member of the indigenous people of NZ (NZ M aori) on hospital records.Non-M aori patients were defined as all other ethnicities.The use of antihypertensive, lipid-lowering, and antithrombotic medication prior to and up to 1 year after the limb procedure was gathered.Best medical therapy (BMT) was defined as prescription of antihypertensive, lipid-lowering and antiplatelet medication.The outcome of date of death was recorded.

Statistical analysis
Analyses were conducted overall, and then separately for men and women.Continuous data are summarized as median and interquartile range (IQR) and categorical data as percentages.Pearson Chi-Square and Fisher Exact Tests were used to compare categorical variables where appropriate, and P-value <0.05 was considered significant.Univariate survival analysis was conducted using Kaplan-Meier survival analysis.Cox proportional hazards regression was performed adjusting for age, sex, dialysis and presence of chronic limb-threatening ischaemia (CLTI) to determine the hazard ratio (HR) with 95% confidence interval (CI).Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) version 28 (IBM Corp., Armonk, NY, USA).

Comorbidities
Over the 12-year period, 2550 patients underwent percutaneous or surgical intervention for PAD.Three patients were excluded due to partial or no medication history.Hence 2547 patients were included and 37.8% were female.Patients were followed until June 2022 and median follow up was 6.6 years (range 0.5-12.5 years).Overall, 62% were prescribed an antihypertensive, lipid-lowering and antithrombotic medication.
Overall, 80.7% of the cohort were prescribed an antihypertensive medication (Table 1).Concomitant IHD, CHF, end-stage renal failure (ESRF), and diabetes improved prescribing of hypertensive medication.There were no differences in the prescribing of antihypertensives between sex (Supplemental Table 1).
Antithrombotic prescription (either antiplatelet and/or anticoagulant) occurred in 89.9% of patients.Concomitant IHD increased the use of both antiplatelet and anticoagulant.CHF decreased the use of antiplatelets, however increased anticoagulant prescription.There were no differences between sex.

Trend over time
The prescribing of medications remained stable over the 12-years (Fig. 1).Consistently, around 10% were not prescribed an antithrombotic and around 20% were not prescribed lipid-lowering medication each year (Supplemental Table 2).

Age
The prescription of each medication increased with age, before decreasing in older age (Supplemental Fig. 1).Lipid-lowering medication prescribing was poorer for younger patients.

Survival
The overall 30-day mortality was 3.65% and after removal of this group there were 2454 patients remaining.Overall, 1279 (52.1%) deaths occurred during follow up and the median survival was 5.6 years (95% CI 5.3-6 years).In univariate analysis, lipidlowering and antiplatelet medication showed survival advantage, while antihypertensive and anticoagulation did not (P < 0.001, Supplemental Table 4).After adjustment, prescription of BMT was associated with improved survival (Table 2).

Discussion
The NZ CVD guidelines recommend thorough assessment and risk management for patients with pre-existing CVD, 6 despite this, within this population of patients with diagnosed PAD there appears to be a deficit in prescribing of cardioprotective medications.This study is novel in reporting the use of these medications in a large PAD cohort in NZ.A recent ANZ study suggested that 460/688 (66.9%) patients that underwent infrainguinal bypass were prescribed an antihypertensive, lipid-lowering and antithrombotic medication. 14This was similar to our study (62%) and highlights the under-prescribing of cardioprotective medications.

Antihypertensive medication
CVD guidelines recommend patients commence hypertensive medication when systolic blood pressure (SBP) ≥130 mmHg or diastolic ≥80 mmHg, and target SBP should be <130 mmHg. 6Hence the prescribing of antihypertensive therapy may reflect the experience of hypertension within our cohort, in that some patients developed PAD in the absence of hypertension.Furthermore, antihypertensive therapy was associated with increased age, cardiac and renal comorbidities, which may reflect the rising incidence of hypertension with age and the role of hypertension in the development of these comorbidities.
In contrast to studies that suggest hypertensive medication is linked with improved survival in PAD, 15,16 in this study, antihypertensives were not associated with better survival.Studies suggest a dose related therapeutic response for the survival benefit of antihypertensives in PAD, with high-dose medication associated with less mortality, whereas low-dose medication was not. 17In line with aggressive hypertensive management, there appears to be linear association of the achieved BP and risk of mortality, with lowest risk for patients that achieved SBP 120-124 mmHg. 18Future PAD research could review antihypertensive medication dosing and achieved BP, which may shed light to the survival outcome observed.

Lipid-lowering medication
All patients with established PAD are recommended to commence lipid-lowering medication, with treatment aim for low-density lipoprotein <1.8 mmol/L. 6The decision to start lipid-lowering medication is based on individual CVD risk, not cholesterol levels. 19espite this, lipid-lowering medications was the most omitted medication, similar to other studies. 14Furthermore, younger patients experienced a larger gap, with only 70% of the PAD population aged 40-49 years covered.Younger patients in NZ have similarly been found to receive appropriate lipid-lowering medication despite adjustment for CVD risk. 20The poor prescribing of lipid-lowering medication, particularly for younger patients, is concerning given the survival advantage of lipid-lowering medication. 10,21Hence improvement in prescription may increase survival for PAD patients.Lower prescribing may have occurred for a few reasons.Possibly, earlier discontinuation of a statin medication due to believed intolerance. 22However, statin adverse effects are uncommon, 22 and in the setting of patients reporting 'statin-associated symptoms' there is a recommended management approach including monitoring creatine kinase levels, reduced dosing, or medication switching. 19Secondly, the decision to start therapy is not made on isolated cholesterol levels.There may exist a large cohort of patients with high absolute risk of CVD that have "normal" serum cholesterol levels. 23A review of these factors and effective patient communication by prescribing clinicians may create opportunity for improved lipid-lowering prescribing.

Antithrombotic medications
Antithrombotic medications were the most prescribed.Other PAD studies also suggest that antithrombotic medication is the least omitted CVD therapy. 5,14Antiplatelet therapy was prescribed in 80% of patients and was associated with survival advantage.The reduction in risk of MACE with antiplatelets is well established. 24onversely, anticoagulation was associated with poorer survival.Possibly the indication for anticoagulation contributes to the observed survival outcome.Despite these results, emerging research suggests the combination of aspirin and low-dose rivaroxaban therapy has significant benefits over aspirin monotherapy, particularly for reduction in lower limb amputations in PAD. 3,25

Impact of ethnicity, sex and comorbidities
There is inequity in the supply of funded medicines to M aori patients in NZ, underpinned by systemic barriers. 26,27However, some NZ studies suggest M aori patients receive similar rates of appropriate CVD medications to NZ Europeans. 20In this study, there was a 9.1% decrease in antiplatelet prescription for M aori men.Hence there is need for greater research into medicine dispensing and systemic barriers in PAD, to inform national initiatives aimed at eliminating medication inequity.
International studies have suggested that women with PAD are less often prescribed optimal cardioprotective therapy. 28Women in our cohort were prescribed less lipid-lowering medication.Prescriber concerns during childbearing years should not impact women above this age range, hence research into the specific reasons is required.Correction of this is important, as resultingly women with PAD may experience poorer outcomes and lose their survival advantage (observed as no difference for life-expectancy between sex).
Despite similar risk factors, patients with PAD may be prescribed less cardioprotective medications compared to patients with other CVD manifestations. 4Moreover, patients with PAD and another concurrent CVD diagnosis, such as IHD or stroke, have higher prescription compared to isolated PAD. 2 Our cohort reflects this, as concomitant IHD increased prescription of all medications.Further research could investigate any difference in prescriber attitudes comparing PAD to other CVD conditions, additionally whether shared-care with physicians improves prescribing.

Impact of BMT on survival
Studies show a positive relationship between increasing number of guideline-recommended medications and reduction in long-term mortality risk, with three medications achieving the greatest benefit. 5,9Similarly, improvement in BMT appears important for our NZ cohort, as this was associated with improved survival.

Limitations
This study has some limitations.First, data was collected retrospectively hence there is a potential for documentation errors.To mitigate this, patient level data were collected from multiple hospital and pharmaceutical sources.Second, this study did not assess medication adherence or continuation of medications beyond 1 year post incident procedure.Finally, results do not describe all patients with PAD.Not captured are patients with PAD that were treated nonoperatively, patients with asymptomatic, carotid or mesenteric PAD, patients managed solely by general practitioners, the private sector, small regional hospitals or hospitals outside the Midland region, and patients that did not seek medical help or did not have access to healthcare.Hence future prospective studies could aim to establish the prescription for these cohorts.

Conclusion
The improvement in prescribing of cardioprotective therapy for patients with PAD may result in improved survival.This study has highlighted avenues for further research aimed to elucidate the causes of cardioprotective medication inequity in PAD, particularly for women, M aori, and younger patients, in lipid-lowering prescribing and hypertension management.This knowledge will help inform national health initiatives to improve outcomes for patients with PAD.

Fig. 1 .
Fig.1.The number of patients prescribed each cardioprotective medication either before or within 1 year of percutaneous or surgical intervention for PAD, separated by age.

Table 1
The demographics and prescribing of cardioprotective medications either before or within 1 year of percutaneous or surgical intervention for PAD as separated by comorbidities Abbreviations: CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus; ESRF, end stage renal failure; IHD, ischemic heart disease; IQR, interquartile range; MCI, mild cognitive impairment.