1. Dharam J. Kumbhani, MD, SM, MRCP, Ph. Gabriel Steg, MD, Christopher P. Cannon, MD, Kim A Eagle, MD, Sidney C. Smith, Jr., MD, Shinya Goto, MD, Cannon, MD, Kim A Eagle, MD, Sidney C. Smith, Jr., MD, Shinya Goto, MD, E. Magnus Ohman, MD, Yedid Elbez, MS, Piyamitr Sritara, MD, Iris Baumgartner, MD, Subhash Banerjee, MD, Mark A. Creager, MD, Deepak L. Bhatt, MD, MPH, on Behalf of the REACH Registry Investigators Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: Insights from the REACH registry

2. Disclosures Dr. Kumbhani – Honoraria: American College of Cardiology, Somahlutions, Inc. The REACH Registry was sponsored by Sanofi-Aventis, Bristol-Myers Squibb, and the Waksman Foundation (Tokyo, Japan). The REACH Registry is endorsed by the World Heart Federation.

3. Statin therapy in PAD ► PAD patients have 3- to 5-fold increase in systemic cardiovascular events including mortality. ► Data from Heart Protection Study indicate a 20-25% reduction in the risk of coronary events, stroke or coronary revascularization with simvastatin over placebo. ► Statin therapy carries a class I indication for use in PAD. ► However, PAD patients have a high rate of adverse limb events as well, as high as 25% annual risk of amputation in patients with advanced PAD. ► Statins have been shown to increase pain-free walking distance in patients with PAD; impact on hard limb outcomes unclear. ► We sought to study the impact of statin use on 4-year adverse systemic and limb outcomes in patients with established PAD enrolled in the REACH registry. Bhatt DL, et al. JAMA 2010;304:1350-7. HPS. JVS 2007; 45:645-54. de Lemos JA, Kumbhani DJ. JACC 2013.

4. Methods ► A total of 5,861 patients with established symptomatic PAD and with available 4-year data were included. ► Primary systemic outcome CV death/MI/stroke ► Primary adverse limb outcome Worsening PAD (Worsening claudication/new episode of critical limb ischemia, new lower extremity percutaneous or surgical revascularization, or amputation) ► Multivariate Cox regression analyses with time to systemic events and time to adverse limb events as dependent variable. ► Statin use was independent exposure variable  At baseline (Y/N)  Time-varying covariate  Propensity analysis* * IPTW with normalized weights

5. On statins (N = 3,643) Not on statins (N = 2,218) p-value Mean age (years)68.2 ± 9.570.0 ± 10.0<0.0001 Men71.474.60.0084 Diabetes mellitus44.739.60.0002 Hypercholesterolemia94.315.6<0.0001 Hypertension83.873.7<0.0001 Obesity24.816.7<0.0001 Current smoker53.347.7<0.0001 CAD58.232.7<0.0001 CVD23.121.30.11 Polyvascular disease67.644.2<0.0001 Baseline ABI value0.72 ± 0.180.70 ± 0.190.01 Index PAD diagnosis ABI < 0.9 Prior revascularization Prior amputation 89.4 54.0 13.2 91.5 50.4 14.3 0.0089 0.0076 0.23 Total cholesterol mmol/L5.1 ± 1.55.2 ± 1.20.0042 Baseline characteristics 70.0 ± 10.0 74.6 44.7 94.3 83.8 24.8 53.3 58.2 23.1 67.6

6. Results Multivariate modeling Statin use (Y/N) (N = 5,861) Multivariate modeling Time-varying statin use (N = 5,006) Multivariate modeling Propensity analysis (N = 5,642) Primary systemic outcome (CV death/MI/stroke) 0.83 (0.73 – 0.96) P=0.0094 0.79 (0.67 – 0.93) P=0.0038 0.85 (0.75 – 0.96) P=0.0083 Primary limb outcome (worsening PAD)* 0.82 (0.72-0.92) P=0.0013 0.85 (0.75 – 0.97) P=0.018 0.79 (0.71 – 0.89) P<0.0001 * Worsening claudication/new episode of critical limb ischemia, new lower extremity percutaneous or surgical revascularization, or amputation Hazard ratio (95% CI)

7. Results: Secondary endpoints Multivariate modeling Statin use (Y/N) (N = 5,861) Multivariate modeling Time-varying statin use (N = 5,006) Multivariate modeling Propensity analysis (N = 5,642) All-cause mortality0.82 (0.72 – 0.95) P=0.009 0.79 (0.65 – 0.94) P=0.0098 0.96 (0.84 – 1.09) P=0.51 CV mortality0.83 (0.69 – 0.99) P=0.04 0.78 (0.61 – 0.98) P=0.034 0.90 (0.77 – 1.06) P=0.21 Non-fatal MI0.89 (0.66 – 1.20) P=0.44 0.80 (0.58 – 1.11) P=0.18 0.69 (0.53 – 0.89) P=0.004 Non-fatal stroke0.73 (0.57 – 0.93) P=0.013 0.75 (0.57 – 0.97) P=0.029 0.73 (0.59 – 0.92) P=0.006 Worsening claudication or new CLI 0.82 (0.70 – 0.95) P=0.0087 0.84 (0.72 – 0.99) P=0.037 0.78 (0.68 – 0.90) P=0.0005 New limb revascularization 0.83 (0.72 – 0.95) P=0.0079 0.90 (0.77 – 1.04) P=0.14 0.79 (0.69 – 0.90) P=0.0003 New amputation0.64 (0.48 – 0.86) P=0.0027 0.60 (0.44 – 0.82) P=0.0014 0.57 (0.43 – 0.74) P<0.0001 Non-fatal stroke0.73 (0.57 – 0.93) P=0.013 0.75 (0.57 – 0.97) P=0.029 0.73 (0.59 – 0.92) P=0.006 Worsening claudication or new CLI 0.82 (0.70 – 0.95) P=0.0087 0.84 (0.72 – 0.99) P=0.037 0.78 (0.68 – 0.90) P=0.0005 New limb revascularization 0.83 (0.72 – 0.95) P=0.0079 0.90 (0.77 – 1.04) P=0.14 0.79 (0.69 – 0.90) P=0.0003 New amputation0.64 (0.48 – 0.86) P=0.0027 0.60 (0.44 – 0.82) P=0.0014 0.57 (0.43 – 0.74) P<0.0001

8. Summary ► Despite having a class I indication for use in patients with PAD, data from a large international registry suggest that statin use remains suboptimal (<2/3 rd of eligible patients). ► Statin use is associated with a significant reduction in adverse systemic outcomes (CV death/MI/stroke) and adverse limb outcomes (worsening claudication, new CLI, need for surgical or percutaneous revascularization, need for ischemic amputation) at 4 years. ► Although prior studies have documented improvements in walking distance and coronary revascularization in patients with PAD, this is one of the first and largest studies to demonstrate an impact of adverse limb outcomes. Reduction in need for ischemic amputations with statin use is an especially important finding. ► Future research should focus on identifying barriers to improving patient and physician compliance with statin use across the entire spectrum of patients with PAD.