Geographic variation and risk factors for systemic and limb ischemic events in patients with symptomatic peripheral artery disease: Insights from the REACH Registry

Background Patients with symptomatic peripheral artery disease (PAD) are at high risk of ischemic events. However, data about predictors of this risk are limited. Hypothesis We analyzed baseline characteristics and 4‐year follow‐up of patients enrolled in the international REduction of Atherothrombosis for Continued Health (REACH) Registry with symptomatic PAD and no history of stroke/transient ischemic attack to describe annual rates of recurrent ischemic events globally and geographically. Methods The primary outcome was systemic ischemic events (composite of cardiovascular death, myocardial infarction, or stroke) at 4 years. The secondary outcome was limb ischemic events (composite of lower limb amputation, peripheral bypass graft, and percutaneous intervention for PAD) at 2 years. Multivariate analysis identified risk factors associated with recurrent ischemic events. Results The primary endpoint rate reached 4.7% during the first year and increased continuously (by 4%–5% each year) to 17.6% by year 4, driven mainly by cardiovascular mortality (11.1% at year 4). Japan experienced lower adjusted ischemic rates (P < 0.01) vs North America. Renal impairment (P < 0.01), congestive heart failure (P < 0.01), history of diabetes (P < 0.01), history of myocardial infarction (P = 0.01), vascular disease (single or poly, P < 0.01), and older age (P < 0.01) were associated with increased risk of systemic ischemic events, whereas statin use was associated with lower risk (P = 0.03). The limb ischemic event rate was 5.7% at 2 years. Conclusions Four‐year systemic ischemic risk in patients with PAD and no history of stroke or transient ischemic attack remains high, and was mainly driven by cardiovascular mortality.


| INTRODUCTION
Over 202 million people worldwide were estimated to be living with peripheral artery disease (PAD) in 2010, with estimated prevalence rates of 9% in North America and 11% in Europe. 1 The spectrum of PAD includes acute and chronic limb ischemia, asymptomatic PAD, claudication, and critical limb ischemia. 2,3 PAD is a strong predictor of myocardial infarction (MI), stroke, and death from vascular causes, 4,5 with an annual incidence of approximately 5% for the composite endpoint of stroke, MI, and death in patients with PAD over 1 year. 6 Understanding the current trends in PAD prevalence and risk factors is critical in guiding preventive strategies to reduce the burden of PAD. However, contemporary, real-world data regarding patient profiles, treatment patterns, and cardiovascular (CV) risks for PAD patients beyond 1 year are insufficient, and are often limited to a single geographic region.
To address gaps in evidence for characterization of longer-term ischemic risk in PAD patients, we analyzed 4-year data from the REduction of Atherothrombosis for Continued Health (REACH) Registry, an international registry of atherothrombosis [7][8][9] in patients with symptomatic PAD with no history of stroke or transient ischemic attack (TIA), focusing on both systemic (MI, stroke, and CV death) and limb ischemic complications (lower limb amputation, peripheral bypass graft, and percutaneous intervention for PAD). Patients with prior stoke or TIA were excluded, because the risk and benefit balance of antithrombotic agents in this population is specific and has been previously published as a separate analysis. 10 The objectives of the present study were to (1) describe annual rates of systemic ischemic events (MI, stroke, and CV death) over 4 years globally and by geographic region, and to identify associated risk factors; and (2) to describe limb ischemic event rates (a composite of lower limb amputation, peripheral bypass graft, and percutaneous intervention for PAD) over 2 years.

| Population
The design, methods, and main results of the REACH Registry, an international, prospective, observational study, have been previously described. 7,11 Briefly, from December 2003 to June 2004, consecutive outpatients ages 45 years or older with established coronary artery disease (CAD), cerebrovascular disease, or PAD, or with at least 3 atherothrombotic risk factors were enrolled. Documented PAD was defined as 1 or more of the following: current intermittent claudication with ankle-brachial index of less than 0.9 or a history of intermittent claudication together with a previous and related intervention such as angioplasty, stenting, atherectomy, peripheral arterial bypass graft, or other vascular intervention including amputation. Documented CAD was defined as 1 or more of the following: stable angina with documented CAD, history of unstable angina with documented CAD, history of percutaneous coronary intervention, history of coronary artery bypass graft surgery, or previous MI. Data were collated centrally using standardized case report forms. The initial follow-up period was 2 years, but centers were invited to participate in a 2-year extension. Only patients with PAD and no history of stroke or TIA were included in the present analysis.
Signed informed consent was obtained from all patients, and the institutional review board in each country approved the protocol.

| Outcomes
Following enrollment, detailed baseline characteristics, treatment, and outcomes were collected annually. Endpoints were not adjudicated and were based on physician report at the time of follow-up. We analyzed 3 systemic ischemic outcomes over 4 years: nonfatal MI, nonfatal stroke, and CV death; and 3 limb ischemic outcomes at 2 years: lower limb amputation, peripheral bypass graft, and percutaneous intervention for PAD. Limb ischemic outcomes were not adjudicated, but were tracked on a declarative basis at the end of followup. Consequently, due to missing data at 4 years, this endpoint was analyzed at 2 years.
The primary outcome was the composite of the 3 systemic ischemic events, and the secondary outcome was the composite of the 3 limb ischemic events. Other secondary outcomes of interest included CV death, MI, and stroke analyzed separately, as well as CV hospitalization.
Stroke was verified by a neurologist consultation or hospital records. CV death was defined as any MI or stroke followed by death in the next 28 days regardless of the cause, death from pulmonary embolism, heart failure, death following vascular surgery, death following a visceral or limb infarction, or any sudden death unless proven to be non-CV by autopsy.

| Statistical analysis
Descriptive statistics, including frequencies and percentages for categorical variables, and mean and standard deviation for continuous variables were calculated to describe the patients' baseline characteristics, medical history, and treatment patterns using the overall study population. Kaplan-Meier estimates were used to assess cumulative incidence rates at each year of follow-up. Patients from each region were also investigated as subgroups.
The exact date of each systemic ischemic event was systematically collected, whereas limb events were collected on a yearly basis during follow-up visits, precluding assignment of a precise date.
Therefore, systemic and limb ischemic outcomes were analyzed separately.
The risks of CV events in each geographic region were estimated by Cox proportional hazards models adjusted for the REACH risk score predicting CV events, 12 after exclusion of the geographic items of the score. Multivariate Cox regression models were used to assess the factors associated with CV risk in the study population. Univariate models were first built to assess the impact of each individual variable on CV outcomes. A set of variables was then selected according to their statistical significance in the univariate model (P ≤ 0.10), clinical significance, and nonredundancy with other variables in the model, and was introduced into the multivariate models. In addition, clinically relevant factors with plausible clinical association with ischemic events were forced into the multivariate Cox regression model. Data were processed using the SAS software package (version 9.3; SAS Institute, Cary, NC). Elbez Yedid had access to all of the data in the study and takes responsibility for its integrity and the data analysis.

| Baseline characteristics
In the overall population, the mean age was 70 AE 10 years, and 69.2% were men. At enrollment, 47.3% had diabetes mellitus, 66.2% had hypercholesterolemia, 89.1% had hypertension, 20.9% were current smokers, and 18.7% were overweight/obese. Important differences in baseline characteristics were observed according to geographic region (Table 1).

| Limb ischemic events
The 2-year rate of the composite endpoint of limb ischemic events was 5.7%. Angioplasty and/or stenting for PAD accounted for 3.2% of these events, peripheral bypass graft accounted for 2.1%, and lower limb amputation accounted for 1.3% (patients could experience more than 1 event, explaining why the total was lower than the sum of each event). Overall, the composite outcome of systemic and limb ischemic events was 11.9% at 2 years.  19,20 In the present analysis, use of statin therapy was associated with reduced risk of ischemic events. European and US guidelines recommend low-density lipoprotein (LDL) cholesterol reduction in patients at high CV risk. 21,22 A previous analysis of the REACH Registry showed a reduction of adverse limb outcomes in patients treated with statins for symptomatic PAD as well as overall ischemic events. 23 The addition of more potent treatment regimens and more aggressive reduction of LDL cholesterol could provide even greater Residual ischemic risk was uniformly distributed over the different geographic areas, except for Japan, where patients experienced lower event rates. The explanations for such differences have been described previously. 29 Briefly, differences in disease management and medication use have been reported (in particular, the use of clopidogrel is substantially higher in Japan than in other regions of the world), which may have contributed to some extent in the improved outcomes in Japan, supported by evidence that clopidogrel use may be superior to aspirin in reducing major CV events in PAD Results of the EUCLID (Examining Use of tiCagreLor In paD) trial, which compared monotherapy with ticagrelor or clopidogrel in PAD patients without indication for dual antiplatelet therapy, did not show a reduction in composite ischemic or limb events or in major bleeding, although a reduction in ischemic stroke was observed. 35 Of note, patients who were homozygous for loss of function alleles to clopidogrel were excluded, though this exclusion did not seem to be the  Therefore, all patients included in the EUCLID trial were receiving effective antiplatelet therapy. 35 The use of a dual antiplatelet therapy rather than a single antiplatelet therapy might provide additional benefit for PAD patients.

| DISCUSSION
A subgroup analysis of the PLATO (Study of PLATelet inhibition and patient Outcomes) trial showed that the benefit of ticagrelor over clopidogrel in acute coronary syndrome patients was consistent in the subgroup of PAD patients compared with the global population. 36  well as analyses on geographic differences must be interpreted cautiously. Clinical events were not adjudicated in the REACH Registry, but measures were taken to select high-quality physicians, and diagnoses were provided by hospitals and doctors based on their expertise. Patient adherence to medication was not captured in the registry, and adherence could impact patient outcomes. Finally, although the data were taken from a large cohort, the analysis may have been underpowered for some comparisons.