CRITICAL LIMB ISCHEMIA UNITED STATES EPIDEMIOLOGY TABLE OF CONTENTS

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1 CRITICAL LIMB ISCHEMIA UNITED STATES EPIDEMIOLOGY TABLE OF CONTENTS CRITICAL LIMB ISCHEMIA... 1 CONCLUSION... 9 U.S. CRITICAL LIMB ISCHEMIA PREVALENCE... 9 MARKET OPPORTUNITY ENDOVASCULAR... 9 MARKET OPPORTUNITY PHARMACEUTICAL... 9 MARKET OPPORTUNITY MECHANICAL THROMBECTOMY MARKET FOR PATIENTS UNSUITABLE FOR REVASCULARIZATION DIAGNOSTIC MARKET NEW MARKET FOR ADJUNCT THERAPY IN REVASCULARIZED PATIENTS Restenosis Prevention Market OPTIMUM METHODS TO ESTIMATE CLI INTRODUCTION PURPOSE REVISED CRITICAL LIMB ISCHEMIA ESTIMATES METHODS PERIPHERAL ARTERIAL DISEASE (PAD) INTERMITTENT CLAUDICATION AN UNCOMMON SYMPTOM LIMB ISCHEMIA ACUTE LIMB ISCHEMIA (ALI) LEG ATTACK Location Occlusion Classification System CRITICAL LIMB ISCHEMIA (CLI) SYMPTOMS RISK FACTORS A Bilateral Disease Multilevel Disease CLI CLINICAL CLASSIFICATION FONTAINE DISEASE CLASSIFICATION SYSTEM RUTHERFORD CLASSIFICATION SYSTEM CHRONIC ISCHEMIA VESSEL ALTERATIONS, TISSUE DAMAGE AND SYSTEMIC EFFECTS ENDOTHELIAL DYSFUNCTION COLLATERAL VESSEL GROWTH SUPPRESSED Factors Inhibiting Growth MICROCIRCULATION DAMAGED BY INADEQUATE BLOOD FLOW AND PRESSURE MALFUNCTION RESULTS IN STATE OF CONSTANT VASODILATION Flooded Capillaries EDEMA SHORT-TERM CONSEQUENCES DEATH AND LIMB LOSS SIX MONTHS 20% MORTALITY AND 40% AMPUTATION... 19

2 PATIENTS UNSUITABLE FOR REVASCULARIZATION HIGH ONE-YEAR AMPUTATION RATE ABI INVERSELY ASSOCIATED WITH AMPUTATION OUTCOMES IN REVASCULARIZED PATIENTS DAY MORTALITY AND AMPUTATION The Swedish Vascular Registry (Swedvasc) Bypass versus Angioplasty in Severe Ischemia of the Leg (BASIL) Trial Project or Ex-Vivo Vein Graft Engineering via Transfection Study III (PREVENT III) THREE-MONTH OUTCOMES ONE-YEAR OUTCOME END-STAGE DISEASE 30% FIVE-YEAR SURVIVAL FIVE-YEAR MORTALITY EXCEEDS MOST OTHER DEADLY DISEASES DISEASE SEVERITY REDUCES SURVIVAL FOUR-YEAR EVENT-FREE SURVIVAL DECLINES WITH DISEASE SEVERITY LONG-TERM MORTALITY INCREASES WITH DISEASE SEVERITY CAUSE OF DEATH SERIOUS COMORBIDITIES DIABETES DIABETES DEFINED A Note on Diabetes Terminology PREDIABETES DEFINED RISK FACTORS MORTALITY DIABETES AND PREDIABETES AN EPIDEMIC DIABETES AND PREDIABETES 42% OF THE U.S. ADULT POPULATION DIABETES AND RACE/ETHNICITY DIABETES PREVALENCE INCREASES WITH AGE DIABETES AND PAD PAD PREVALENT IN DIABETICS DIABETIC ABNORMALITIES PROMOTE ATHEROSCLEROSIS AND THROMBOSIS Structural and Functional Vessel Abnormalities Endothelial Dysfunction Hypercoagulable State GREATER RISK OF DEVELOPING PAD FACTORS THAT INCREASE RISK OF PAD IN DIABETICS EXCESS CARDIOVASCULAR MORBIDITY AND MORTALITY DISEASE LOCATED BELOW THE KNEE THE NEUROISCHEMIC FOOT NEUROPATHY IS COMMON CAUSED BY MICROCIRCULATORY DYSFUNCTION AND METABOLIC ABNORMALITIES A BIOLOGICALLY COMPROMISED FOOT VULNERABLE TO ISCHEMIA PROPENSITY TO DEVELOP ULCERS, INFECTION AND GANGRENE Eurodiale High Prevalence of PAD in Patients with Foot Ulcers FOOT ULCERS PRECEDE AMPUTATIONS DIABETES AND CRITICAL LIMB ISCHEMIA HIGHER RISK OF CLI AND MORE SEVERE DISEASE... 34

3 DIABETIC PATIENTS PRESENT WITH ADVANCED ISCHEMIA CLI DEVELOPS SUDDENLY DIABETES INCREASES THE RISK OF AMPUTATION Risk of Amputation Related to Severity of Diabetes HIGHER MORTALITY...35 ADDITIONAL RISK FACTORS INCREASE SEVERITY Diabetes and Smoking A Deadly Combination CHRONIC KIDNEY DISEASE (CKD) DEFINITIONS DRAMATIC INCREASE IN U.S. ESRD PATIENTS ESRD ASSOCIATED WITH HIGH INCIDENCE OF CARDIOVASCULAR MORBIDITY AND MORTALITY Morbidity and Mortality Increase with Severity of CKD CALCIFICATION Present in 40% to 70% of ESRD Patients Associated with Diabetes PAD AND CHRONIC KIDNEY DISEASE PAD COMMON IN DIALYSIS PATIENTS DIALYSIS OUTCOMES AND PRACTICE PATTERNS STUDY (DOPPS) CKD INCREASES THE RISK FOR DEVELOPING PAD PAD Incidence and Prevalence Higher in More Severe Disease ABI PREDICTS MORTALITY IN ESRD KIDNEY DISEASE, DIABETES AND PAD A LIFE AND LIMB THREATENING COMBINATION HIGH PREVALENCE OF PAD IN PATIENTS WITH BOTH CHRONIC KIDNEY DISEASE AND DIABETES PATIENTS WITH KIDNEY FAILURE CAUSED BY DIABETES PAD PRESENT IN 36% PAD INCIDENCE HIGHEST IN PATIENTS WITH DIABETES AND KIDNEY DISEASE SIGNIFICANTLY INCREASED RISK OF AMPUTATION CRITICAL LIMB ISCHEMIA AND CHRONIC KIDNEY DISEASE CRITICAL LIMB ISCHEMIA IS COMMON IN ESRD PATIENTS CLI SEVERITY RELATED TO SEVERITY OF KIDNEY DYSFUNCTION MORTALITY Critical Limb Ischemia Predicts All-Cause Mortality in Dialysis Patients Renal Dysfunction Predicts Mortality in Critical Limb Ischemia Patients AMPUTATION MORE LIKELY IN DIALYSIS PATIENTS Concurrent with Revascularization Poor Amputation-Free Survival DISEASE LOCATED BELOW THE KNEE CLI A PRIMARY CAUSE OF DEATH IN ESRD? ESTIMATING THE PREVALENCE OF CLI METHODS INCIDENCE AND PREVALENCE DEFINED SUMMARY OF INCIDENCE ESTIMATES INCIDENCE OVERVIEW OF METHODS PROGRESSION FROM IC INCIDENCE ESTIMATE LIMITATIONS NUMBER OF HOSPITALIZATIONS OR REVASCULARIZATION PROCEDURES LIMITATIONS... 49

4 NUMBER OF AMPUTATIONS INCIDENCE ESTIMATE LIMITATIONS COMBINATION METHODS ITALIAN STUDY INCIDENCE ESTIMATE SURVEY OF VASCULAR SURGEONS IN GREAT BRITAIN AND IRELAND CLI INCIDENCE ESTIMATE STUDY DESCRIPTION...51 UNDERESTIMATES NUMBER WITH CLI OXVASC POPULATION-BASED INCIDENCE BY AGE AND SEX DESCRIPTION INCIDENCE BY AGE AND SEX INCIDENCE ESTIMATE LIMITATIONS PREVALENCE ESTIMATED FROM INCIDENCE SUMMARY OF CLI PREVALENCE ESTIMATES DISEASE PROGRESSION IN IC PATIENTS PREVALENCE ESTIMATE LIMITATIONS ASSOCIATED WITH DISEASE PROGRESSION FROM IC Based on the Minority of PAD Patients Excludes Non-IC Patients SHORTCOMINGS IN OLDER STUDIES THAT MEASURED PROGRESSION AS MANY AS HALF OF CLI PATIENTS DEVELOP CLI WITHOUT PRIOR SYMPTOMS IC MAY PROGRESS TO CLI AT HIGHER RATES PREVALENCE BASED ON POPULATION SURVEYS HUNT STUDY DESCRIPTION RESULTS BY AGE AND SEX PREVALENCE ESTIMATE LIMITATIONS PREVALENCE ADJUSTED FOR POPULATION 70 YEARS AND OLDER Based on 60%-80% CLI Occurring in Population Age 70 and Older Based on 5%-10% of Population Age with CLI NEW SOUTH WALES RURAL COMMUNITY STUDY RESULTS PREVALENCE ESTIMATE CLI PREVALENCE ESTIMATED FROM PAD POPULATION PAD PROJECTIONS METHOD PAD POPULATION BY DISEASE SEVERITY CLI PREVALENCE CLI PREVALENCE ESTIMATED FROM HIGH RISK GROUP DIABETICS A NOTE ON PAD DIAGNOSTIC METHOD Limitations of ABI< Abnormally High ABI May Also Indicate Disease PAD PREVALENCE IN DIABETES... 62

5 CARDIOVASCULAR HEALTH STUDY THE HOORN STUDY SEATTLE STUDY OF DIABETIC AND NONDIABETIC VOLUNTEERS AGE NEWLY DIAGNOSED DIABETICS IN ITALY KRISTIANSTAD POPULATION-BASED STUDY FREMANTLE DIABETES STUDY DIABETICS IN A MICHIGAN HMO SMALL PILOT STUDY IN ENGLISH HOSPITAL CLINIC DIABETICS IN HELSINKI THE MEN BORN IN 1914 STUDY POPULATION IN EAST DORSET, ENGLAND GERMAN EPIDEMIOLOGICAL TRIAL ON ANKLE BRACHIAL INDEX (GETABI) NHANES II PHYSICIANS EXAMINATION NHANES NHANES ELDERLY DIABETICS CLI ESTIMATES BASED ON THE DIABETES METHOD ESTIMATION METHODS AND ASSUMPTIONS POPULATION AGE 65 AND OLDER Glucose Status by Sex PAD Prevalence by Glucose Status Critical Limb Ischemia by Glucose Category POPULATION AGE Glucose Status PAD Prevalence by Glucose Status Critical Limb Ischemia by Glucose Status PAD AND CLI ESTIMATES BASED ON INCREASING PREVALENCE OF DIABETES CLI PROJECTIONS CRITICAL LIMB ISCHEMIA MARKET OPPORTUNITIES ENDOVASCULAR MARKET METHODS AND ASSUMPTIONS CURRENT MARKET METHODS AND ASSUMPTIONS POTENTIAL MARKET Actual CLI Treatment Pathway Often Differs from the Ideal IMPACT OF NEW ENDOVASCULAR TECHNOLOGIES GREATER SHARE OF LIMBS TREATED SIGNIFICANT INCREASE IN MARKET VALUE STENTS CURRENT STENT MARKET IMPACT OF NEW STENT TECHNOLOGY ON MARKET POTENTIAL PHARMACEUTICAL THERAPIES RISK FACTOR MODIFICATION ANTIHYPERTENSIVES ANTILIPIDS ANTIPLATELETS NO REVASCULARIZATION PATIENTS DIAGNOSTIC MARKET... 86

6 ADJUNCT THERAPY IN REVASCULARIZED PATIENTS RESTENOSIS PREVENTION IN BYPASS PATIENTS RESTENOSIS TREATMENTS IN ENDOVASCULAR PATIENTS THROMBOLYTICS MECHANICAL THROMBECTOMY APPENDIX A: COMPARISON OF PAD ESTIMATES WITH PREVIOUS ESTIMATES REFERENCES INDEX OF TABLES INDEX OF FIGURES GLOSSARY DISCLOSURE STATEMENT CONTACT INFORMATION