Results
A total of 5861 patients with established PAD were included, of which 2492 (42.5%) had a history of or current intermittent claudication only (ABI value < 0.9 without prior revascularization), 3085 (52.6%) had undergone prior lower extremity arterial revascularization (angioplasty/stenting/bypass graft), and 800 (13.6%) had undergone prior leg amputation at any level. Among these patients, 48.6% had concomitant coronary artery disease (CAD), 22.4% had cerebrovascular disease, 58.7% had polyvascular disease, and 12.3% had established disease in all three territories. Overall statin use in this patient population was 62.2% (74.5% in patients with concomitant CAD and in 64.0% patients with concomitant cerebrovascular disease) (Figure 2). Approximately two-thirds of these patients (65.0%) were enrolled by primary care or family practice physicians, 15.0% by vascular surgeons, 7.0% by cardiologists, 5.3% by angiologists, and 7.8% by others (Figure 3). Baseline characteristics of the study population based on statin use are demonstrated in Table 1. Patients who were not on statins at the time of enrolment were more likely to be older, male, and have experienced a PAD event (symptom/procedure) within the preceding year. Conversely, patients who were on statins were more likely to have multiple comorbidities including diabetes, hypercholesterolaemia, obesity, heart failure, CAD, and polyvascular disease; they were also more likely to be current smokers.
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Figure 2.
Proportion of patients on statins at enrolment.
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Figure 3.
Proportion of patients on statins at enrolment based on enrolling investigator's subspecialty. Also reported are proportions based on the presence of concomitant CAD or not. CAD indicates coronary artery disease.
Statin Use and Adverse Limb Outcomes
A total of 1207 new adverse limb events occurred over 4 years (incidence = 23.6%), including 999 new revascularization procedures and 222 new ischaemic amputations. On multivariate analysis, the composite adverse limb outcome was lower in patients who were on statins at study enrolment when compared with those who were not on statins (22.0 vs. 26.2%; HR, 0.82; 95% CI, 0.72–0.92; P = 0.0013). The individual components of the primary endpoint, including worsening claudication or new critical limb ischaemia (14.7 vs. 18.2%; HR, 0.82; 95% CI, 0.70–0.95; P = 0.0087), new lower extremity percutaneous/surgical revascularization (18.2 vs. 21.7%; HR, 0.83; 95% CI, 0.72–0.95; P = 0.0079), and new ischaemic amputation (3.8 vs. 5.6%; HR, 0.64; 95% CI, 0.48–0.86; P = 0.0027) were all higher in patients who were not on statins. Time-varying analysis and the propensity analysis demonstrated similar results ( Table 2 ). A separate analysis was performed in all patients with PAD in the REACH registry, not just in those with available 4-year data (7994 patients with available baseline and statin use information). Results were quantitatively similar (HR, 0.85, 95% CI 0.75–0.98; P = 0.023). On competing risk analysis, the cumulative incidence of the adverse limb outcome remained significantly lower in patients who were on statins at study enrolment (21.1 vs. 25.1%; P = 0.0007).
On subgroup analysis, overall results were similar in those with stable claudication only at baseline vs. those with lower extremity revascularization procedures or amputations. None of interaction terms tested attained statistical significance (Figure 4).
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Figure 4.
Subgroup analysis of the effect of statin use on the composite adverse limb outcome at 4 years. CI, confidence intervals; HR, hazard ratio.
Statin Use and Systemic Events
Over a follow-up period of 4 years, patients who were on statins demonstrated a 17% lower risk of the primary systemic endpoint of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke on multivariate analysis (19.6 vs. 20.3%; HR, 0.83; 95% CI, 0.73–0.96; P = 0.01). Other endpoints including all-cause mortality (17.3 vs. 19.7%; HR, 0.83; 95% CI, 0.72–0.96, P = 0.014), cardiovascular mortality (11.4 vs. 12.4%; HR, 0.84; 95% CI, 0.70–1.00; P = 0.05), and non-fatal stroke (6.0% vs. 6.8%; HR, 0.74, 95% CI 0.57–0.95; P = 0.016) were all similarly higher in patients who were not on statins at study enrolment. No difference was noted in the rates of non-fatal myocardial infarction (HR, 0.85; 95% CI, 0.63–1.14; P = 0.28) or non-cardiovascular mortality (HR, 0.83; 95% CI, 0.65–1.06; P = 0.13). Time-varying Cox models and the propensity analysis noted similar results ( Table 2 ). Cumulative incidence curves for the primary adverse limb outcome and for the composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke are demonstrated in Supplementary material online, Figures S1 and S2.