A retrospective cohort study on the provision and outcomes of pharmacological therapy after revascularisation for peripheral arterial occlusive disease: a study protocol

Background

Peripheral arterial occlusive disease (PAOD) is a prevalent circulatory condition caused by reduced blood flow in the lower extremities due to atherosclerosis. It affects over 200 million patients worldwide representing a significant burden to healthcare systems with increasing prevalence.1 2 Patients with PAOD are at risk of worsening limb symptoms resulting in major adverse limb events (MALE), major adverse cardiovascular events (MACE) and a generally impaired survival.3 For preventing such outcomes, a timely detection and adequate treatment of the disease involving all pillars of invasive and non-invasive vascular care are crucial.

Pharmacological therapy as main pillar of secondary prevention after revascularisation represents an integral element of evidence-based revascularisation.4 The rapid progress in the field of endovascular therapy led to an extension of its use in more complex lesions and recently, drug eluting devices have been established in routine care. When compared with the strict regulation of drugs, high risk medical devices in vascular surgery such as drug-eluted or atherectomy devices could be introduced to the market following lower requirements. As a consequence, the lack of randomised and controlled trials led to an increasing utilisation of real-world data to illuminate the benefit, harms and costs of innovative techniques.5 Accordingly, the IDEAL recommendations advise the evaluation of the clinical effectiveness of widely adopted interventions by explicitly using routine data focusing on rates and long-term outcomes.5 6 Yet, for any valid comparison of different revascularisation strategies with respect to amputation risk, re-admission and survival, the assessment of post-discharge pharmacological therapy is crucial.

Valid guidelines highlight the importance of pharmacological control of cardiovascular risk factors, in particular of diabetes, hypertension and dyslipidaemia. Additionally, they also recommend the prescription of lipid-lowering and antiplatelet drugs independently from pathological laboratory testing or comorbidities in all patients with PAOD without contraindications (table 1).4 7 8

Depending on the performed type of revascularisation, the patient’s risk profile and comorbidities, anticoagulation therapy is also indicated in a narrower patient population. Thereby, uncertainty exists regarding the optimal regime of antithrombotic therapy.3 This concerns the indication and optimal duration, particularly the long-term use, of dual-antiplatelet therapy and the combination of single-antiplatelet therapy and anticoagulation (eg, low-dose rivaroxaban and low-dose aspirin).9 10 Guidelines emphasise the importance of evidence on comparative effectiveness of pharmacological therapy along the full spectrum of clinical reality, most importantly distinguished by disease severity (intermittent claudication (IC) vs chronic limb threatening ischaemia (CLTI)), obtained in-hospital procedure (endovascular, open surgery, hybrid cases, minor or major amputation) and concomitant comorbidities (eg, atrial fibrillation, coronary artery disease, prior stroke or myocardial infarction). Besides antithrombotic therapy, gaps exist with respect to time trends in prescription rates of lipid-lowering drugs and the optimal dose of such agents in the CLTI subpopulation.4

Real-world evidence on the extent of adequate provision of pharmacological therapy and related outcomes is scarce. Prior studies either focused on few medical agents only or they included just a small and selective set of patients with PAOD. Other studies did not distinguish important subgroups, that is, disease severity and gender, or were based on meanwhile outdated data.11–14 In general, prior studies reported room for improvement in antiplatelet prescription and low statin prescription rates particularly in women.14–16

This study aims to determine the provision of pharmacological therapy after revascularisation of PAOD in a real-world setting from a longitudinal and patient-based perspective. First, we focus on extent and time trends in provision of pharmacological therapy. Second, we assess the long-term outcomes MACE, MALE and all-cause mortality. For this purpose, German health insurance claims data will be used. All analyses will be performed for all patients and for subgroups, that is, gender and disease severity.

Methods

Discussion

The particular merit of this study is to provide a comprehensive picture of pharmacological therapy after revascularisation in symptomatic PAOD patients and related outcomes, using a large and diverse cohort. Our analysis will be based on a full sample of health claims data, not suffering the selection bias, recall bias, dropout and panel attrition usually found in other study designs. The findings will complement existing evidence on optimal management of evidence-based revascularisation assisting physicians and patients the choice for particular treatment modalities.

Yet, diagnoses on PAOD, related comorbidities and treatments extracted from claims data were collected for the purpose of reimbursement and not for research. Within the German DRG system, upcoding from cheaper to more expensive diagnoses might be incentivised in the inpatient setting potentially overstating the actual disease severity of the patients to a certain degree. In the outpatient setting, diagnoses are not necessarily linked to treatment because first they were reported once in each quarter only and second, less possibilities for diagnostics exist in general practices. Consequently, some diseases are likely to remain undiagnosed, under-reported or coded less specific. This is undoubtedly relevant for the case of chronic PAOD often associated with none or atypical symptoms during onset and early progression of the disease. However, the longitudinal perspective of our study following each patient for more than a decade, allows to combine information from a longer sequence of multiple visits in the outpatient and inpatient setting providing a much more comprehensive view on individuals’ disease progression than a single cross-section alone. Despite the potential bias of upcoding, diagnoses from inpatient care are of high value as they are mandatory, directly linked to a specific procedure at a specific date and cross-checked by a special software and about 20% reviewed by special physicians.22

Patients receive prescriptions for medication either in GP’s or specialists’ practice and are required to have their prescription filled at registered pharmacies. Data on filled prescriptions are transferred from the pharmacy to the health insurance and approximately 10% of all prescriptions were never filled.23 Also, pharmacological therapy dispensed during in-hospital stays and over-the-counter medication is not visible in claims data. Hence, the prescription prevalence as will be reported in our study may slightly underestimate the true prevalence. Additionally, the date of prescription, which will be used in our study, and date of dispense could differ so that the true exposure of pharmacological therapy might be overstated. However, validation studies reported that the date of prescription is more reliable than the date of dispense offsetting the small bias due to the delay in time.23 Additionally, validation studies on diagnoses and prescriptions in routine data demonstrated sufficient validity of the data for solid analyses.23

A sound construction of patient biographies using data from a single health insurance fund requires to exclude those that entered during the lookback period or left during follow-up aside from the event death. Yet, the potential bias related to this selection problem is likely to be small as the vast majority of people in Germany enters a specific insurance at younger ages and remains there until death. Particularly at older ages, only few people change their insurance company. A related selection problem associated with the use of a single health insurance fund comprises the characteristics of its members compared with the German population: BARMER members are slightly older, the proportion of insured males much lower, better educated and health-related variables slightly below average.24 However, compared with other large insurance funds, the data are still more representative for the German population and in any case more representative than RCTs or regional registry or survey studies. As this study focuses only on care practices in Germany, its results need to be understood within the properties of the German healthcare system and are not directly transferable to other countries. For this purpose multi-country analyses should be performed.

While providing rich information on diagnoses, treatment and outcomes, routine data do not contain valid information on more specific clinical parameters and health-related lifestyles as smoking, alcohol consumption, nutrition and obesity and only limited information on socioeconomic status. Thus, a certain amount of variance between relevant subgroups, for example, gender, disease severity and age, will be unexplained pointing at potentials for further studies. Yet, recently developed approaches such as the use of instrumental variables in survival models potentially allow to also adjust for such unobserved confounding, which will be assessed in this study.25

Index stay is defined by a first revascularisation for symptomatic PAOD diagnosis using a lookback period of 5 years. Thus, some of the index stays will be artefacts if the patients were diagnosed more than 5 years prior to this date. However, especially chronic and severe diseases were less affected by this issues as demonstrated in validation studies.24 To test the validity of this assumption in more detail, we will use shorter and longer lookback times for a subset of patients as sensitivity analysis. Furthermore, we will take outpatient diagnoses into account to assess whether a validated diagnosis could be stated based on the Q1, Q2 or Q3 criterion (Q=subsequent quarters where the disease was diagnosed).

Finally, we believe that this study will provide valuable insights in PAOD in a real-world setting, generating hypothesis for further research for improving treatment of the disease.