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Importance: Patients with lower extremity peripheral artery disease (PAD) have reduced lower extremity perfusion, impaired lower extremity skeletal muscle function, and poor walking performance. Telmisartan (an angiotensin receptor blocker) has properties that reverse these abnormalities., Objective: To determine whether telmisartan improves 6-minute walk distance, compared with placebo, in patients with lower extremity PAD at 6-month follow-up., Design, Setting, and Participants: Double-blind, randomized clinical trial conducted at 2 US sites and involving 114 participants. Enrollment occurred between December 28, 2015, and November 9, 2021. Final follow-up occurred on May 6, 2022., Interventions: The trial randomized patients using a 2 × 2 factorial design to compare the effects of telmisartan plus supervised exercise vs telmisartan alone and supervised exercise alone and to compare telmisartan alone vs placebo. Participants with PAD were randomized to 1 of 4 groups: telmisartan plus exercise (n = 30), telmisartan plus attention control (n = 29), placebo plus exercise (n = 28), or placebo plus attention control (n = 27) for 6 months. The originally planned sample size was 240 participants. Due to slower than anticipated enrollment, the primary comparison was changed to the 2 combined telmisartan groups vs the 2 combined placebo groups and the target sample size was changed to 112 participants., Main Outcomes and Measures: The primary outcome was the 6-month change in 6-minute walk distance (minimum clinically important difference, 8-20 m). The secondary outcomes were maximal treadmill walking distance; Walking Impairment Questionnaire scores for distance, speed, and stair climbing; and the 36-Item Short-Form Health Survey physical functioning score. The results were adjusted for study site, baseline 6-minute walk distance, randomization to exercise vs attention control, sex, and history of heart failure at baseline., Results: Of the 114 randomized patients (mean age, 67.3 [SD, 9.9] years; 46 were women [40.4%]; and 81 were Black individuals [71.1%]), 105 (92%) completed 6-month follow-up. At 6-month follow-up, telmisartan did not significantly improve 6-minute walk distance (from a mean of 341.6 m to 343.0 m; within-group change: 1.32 m) compared with placebo (from a mean of 352.3 m to 364.8 m; within-group change: 12.5 m) and the adjusted between-group difference was -16.8 m (95% CI, -35.9 m to 2.2 m; P = .08). Compared with placebo, telmisartan did not significantly improve any of the 5 secondary outcomes. The most common serious adverse event was hospitalization for PAD (ie, lower extremity revascularization, amputation, or gangrene). Three participants (5.1%) in the telmisartan group and 2 participants (3.6%) in the placebo group were hospitalized for PAD., Conclusions and Relevance: Among patients with PAD, telmisartan did not improve 6-minute walk distance at 6-month follow-up compared with placebo. These results do not support telmisartan for improving walking performance in patients with PAD., Trial Registration: ClinicalTrials.gov Identifier: NCT02593110.

Importance: Lower extremity peripheral artery disease (PAD) affects approximately 8.5 million people in the US and approximately 230 million worldwide., Observations: Peripheral artery disease is uncommon before aged 50 years but affects up to 20% of people aged 80 years and older. It can be noninvasively diagnosed with the ankle-brachial index (ABI), a ratio of Doppler-recorded pressures in the dorsalis pedis and/or posterior tibial artery in each leg to brachial artery pressures. An ABI value less than 0.90 is 57% to 79% sensitive and 83% to 99% specific for arterial stenosis of at least 50%. Intermittent claudication, consisting of exertional calf pain that does not begin at rest and that resolves within 10 minutes of rest, is considered the classic symptom of PAD. However, 70% to 90% of people with an ABI value less than 0.90 either report no exertional leg symptoms (ie, asymptomatic) or report leg symptoms with walking that are not consistent with classic claudication. Over time, people with PAD restrict walking activity or slow walking speed to avoid leg symptoms. Thus, although approximately 75% of people with PAD report no change in leg symptoms over time, those with PAD have significantly greater annual declines in 6-minute walk performance compared with those without it. Approximately 11% of people with PAD develop chronic limb-threatening ischemia, the most severe form of PAD. Compared with people without PAD, those with the disease have approximately twice the rate of all-cause mortality, cardiovascular mortality, and major coronary events at 10-year follow-up. High-dose statins and antiplatelet therapy with or without antithrombotic therapy reduced rates of coronary events and stroke in people with PAD. Supervised treadmill exercise improved 6-minute walk distance by 30 to 35 m, consistent with a clinically meaningful change, whereas effective home-based walking exercise interventions improved 6-minute walk by 42 to 53 m. Effective home-based exercise programs require behavioral methods, including monitoring by a coach., Conclusions and Relevance: Peripheral artery disease affects approximately 230 million people worldwide and is associated with increased rates of cardiovascular events, lower extremity events, and functional decline compared with that of people without PAD. People with PAD should be treated with the highest dose of statin tolerated, antithrombotic and/or antiplatelet therapy, and exercise.

Importance: Supervised high-intensity walking exercise that induces ischemic leg symptoms is the first-line therapy for people with lower-extremity peripheral artery disease (PAD), but adherence is poor., Objective: To determine whether low-intensity home-based walking exercise at a comfortable pace significantly improves walking ability in people with PAD vs high-intensity home-based walking exercise that induces ischemic leg symptoms and vs a nonexercise control., Design, Setting, and Participants: Multicenter randomized clinical trial conducted at 4 US centers and including 305 participants. Enrollment occurred between September 25, 2015, and December 11, 2019; final follow-up was October 7, 2020., Interventions: Participants with PAD were randomized to low-intensity walking exercise (n = 116), high-intensity walking exercise (n = 124), or nonexercise control (n = 65) for 12 months. Both exercise groups were asked to walk for exercise in an unsupervised setting 5 times per week for up to 50 minutes per session wearing an accelerometer to document exercise intensity and time. The low-intensity group walked at a pace without ischemic leg symptoms. The high-intensity group walked at a pace eliciting moderate to severe ischemic leg symptoms. Accelerometer data were viewable to a coach who telephoned participants weekly for 12 months and helped them adhere to their prescribed exercise. The nonexercise control group received weekly educational telephone calls for 12 months., Main Outcomes and Measures: The primary outcome was mean change in 6-minute walk distance at 12 months (minimum clinically important difference, 8-20 m)., Results: Among 305 randomized patients (mean age, 69.3 [SD, 9.5] years, 146 [47.9%] women, 181 [59.3%] Black patients), 250 (82%) completed 12-month follow-up. The 6-minute walk distance changed from 332.1 m at baseline to 327.5 m at 12-month follow-up in the low-intensity exercise group (within-group mean change, -6.4 m [95% CI, -21.5 to 8.8 m]; P = .34) and from 338.1 m to 371.2 m in the high-intensity exercise group (within-group mean change, 34.5 m [95% CI, 20.1 to 48.9 m]; P < .001) and the mean change for the between-group comparison was -40.9 m (97.5% CI, -61.7 to -20.0 m; P < .001). The 6-minute walk distance changed from 328.1 m at baseline to 317.5 m at 12-month follow-up in the nonexercise control group (within-group mean change, -15.1 m [95% CI, -35.8 to 5.7 m]; P = .10), which was not significantly different from the change in the low-intensity exercise group (between-group mean change, 8.7 m [97.5% CI, -17.0 to 34.4 m]; P = .44). Of 184 serious adverse events, the event rate per participant was 0.64 in the low-intensity group, 0.65 in the high-intensity group, and 0.46 in the nonexercise control group. One serious adverse event in each exercise group was related to study participation., Conclusions and Relevance: Among patients with PAD, low-intensity home-based exercise was significantly less effective than high-intensity home-based exercise and was not significantly different from the nonexercise control for improving 6-minute walk distance. These results do not support the use of low-intensity home-based walking exercise for improving objectively measured walking performance in patients with PAD., Trial Registration: ClinicalTrials.gov Identifier: NCT02538900.

Importance: Clinical practice guidelines support home-based exercise for patients with peripheral artery disease (PAD), but no randomized trials have tested whether an exercise intervention without periodic medical center visits improves walking performance., Objective: To determine whether a home-based exercise intervention consisting of a wearable activity monitor and telephone coaching improves walking ability over 9 months in patients with PAD., Design, Setting, and Participants: Randomized clinical trial conducted at 3 US medical centers. Patients with PAD were randomized between June 18, 2015, and April 4, 2017, to home-based exercise vs usual care for 9 months. Final follow-up was on December 5, 2017., Interventions: The exercise intervention group (n = 99) received 4 weekly medical center visits during the first month followed by 8 months of a wearable activity monitor and telephone coaching. The usual care group (n = 101) received no onsite sessions, active exercise, or coaching intervention., Main Outcomes and Measures: The primary outcome was change in 6-minute walk distance at 9-month follow-up (minimal clinically important difference [MCID], 20 m). Secondary outcomes included 9-month change in subcomponents of the Walking Impairment Questionnaire (WIQ) (0-100 score; 100, best), SF-36 physical functioning score, Patient-Reported Outcomes Measurement Information System (PROMIS) mobility questionnaire (higher = better; MCID, 2 points), PROMIS satisfaction with social roles questionnaire, PROMIS pain interference questionnaire (lower = better; MCID range, 3.5-4.5 points), and objectively measured physical activity., Results: Among 200 randomized participants (mean [SD] age, 70.2 [10.4] years; 105 [52.5%] women), 182 (91%) completed 9-month follow-up. The mean change from baseline to 9-month follow-up in the 6-minute walk distance was 5.5 m in the intervention group vs 14.4 m in the usual care group (difference, -8.9 m; 95% CI, -26.0 to 8.2 m; P = .31). The exercise intervention worsened the PROMIS pain interference score, mean change from baseline to 9 months was 0.7 in the intervention group vs -2.8 in the usual care group (difference, 3.5; 95% CI, 1.3 to 5.8; P = .002). There were no significant between-group differences in the WIQ score, the SF-36 physical functioning score, or the PROMIS mobility or satisfaction with social roles scores., Conclusions and Relevance: Among patients with PAD, a home-based exercise intervention consisting of a wearable activity monitor and telephone coaching, compared with usual care, did not improve walking performance at 9-month follow-up. These results do not support home-based exercise interventions of wearable devices and telephone counseling without periodic onsite visits to improve walking performance in patients with PAD., Trial Registration: clinicaltrials.gov Identifier: NCT02462824.

Importance: Benefits of granulocyte-macrophage colony-stimulating factor (GM-CSF) for improving walking ability in people with lower extremity peripheral artery disease (PAD) are unclear. Walking exercise may augment the effects of GM-CSF in PAD, since exercise-induced ischemia enhances progenitor cell release and may promote progenitor cell homing to ischemic calf muscle., Objectives: To determine whether GM-CSF combined with supervised treadmill exercise improves 6-minute walk distance, compared with exercise alone and compared with GM-CSF alone; to determine whether GM-CSF alone improves 6-minute walk more than placebo and whether exercise improves 6-minute walk more than an attention control intervention., Design, Setting, and Participants: Randomized clinical trial with 2 × 2 factorial design. Participants were identified from the Chicago metropolitan area and randomized between January 6, 2012, and December 22, 2016, to 1 of 4 groups: supervised exercise + GM-CSF (exercise + GM-CSF) (n = 53), supervised exercise + placebo (exercise alone) (n = 53), attention control  + GM-CSF (GM-CSF alone) (n = 53), attention control + placebo (n = 51). The final follow-up visit was on August 15, 2017., Interventions: Supervised exercise consisted of treadmill exercise 3 times weekly for 6 months. The attention control consisted of weekly educational lectures by clinicians for 6 months. GM-CSF (250 μg/m2/d) or placebo were administered subcutaneously (double-blinded) 3 times/wk for the first 2 weeks of the intervention., Main Outcomes and Measures: The primary outcome was change in 6-minute walk distance at 12-week follow-up (minimum clinically important difference, 20 m). P values were adjusted based on the Hochberg step-up method., Results: Of 827 persons evaluated, 210 participants with PAD were randomized (mean age, 67.0 [SD, 8.6] years; 141 [67%] black, 82 [39%] women). One hundred ninety-five (93%) completed 12-week follow-up. At 12-week follow-up, exercise + GM-CSF did not significantly improve 6-minute walk distance more than exercise alone (mean difference, -6.3 m [95% CI, -30.2 to +17.6]; P = .61) or more than GM-CSF alone (mean difference, +28.7 m [95% CI, +5.1 to +52.3]; Hochberg-adjusted P = .052). GM-CSF alone did not improve 6-minute walk more than attention control + placebo (mean difference, -1.4 m [95% CI, -25.2 to +22.4]; P = .91). Exercise alone improved 6-minute walk compared with attention control + placebo (mean difference, +33.6 m [95% CI, +9.4 to +57.7]; Hochberg-adjusted P = .02)., Conclusions and Relevance: Among patients with PAD, supervised treadmill exercise significantly improved 6-minute walk distance compared with attention control + placebo, whereas GM-CSF did not significantly improve walking performance, either when used alone or when combined with supervised treadmill exercise. These results confirm the benefits of exercise but do not support using GM-CSF to treat walking impairment in patients with PAD., Trial Registration: clinicaltrials.gov Identifier: NCT01408901.

Importance: Epidemiological evidence suggests that physical activity benefits cognition, but results from randomized trials are limited and mixed., Objective: To determine whether a 24-month physical activity program results in better cognitive function, lower risk of mild cognitive impairment (MCI) or dementia, or both, compared with a health education program., Design, Setting, and Participants: A randomized clinical trial, the Lifestyle Interventions and Independence for Elders (LIFE) study, enrolled 1635 community-living participants at 8 US centers from February 2010 until December 2011. Participants were sedentary adults aged 70 to 89 years who were at risk for mobility disability but able to walk 400 m., Interventions: A structured, moderate-intensity physical activity program (n = 818) that included walking, resistance training, and flexibility exercises or a health education program (n = 817) of educational workshops and upper-extremity stretching., Main Outcomes and Measures: Prespecified secondary outcomes of the LIFE study included cognitive function measured by the Digit Symbol Coding (DSC) task subtest of the Wechsler Adult Intelligence Scale (score range: 0-133; higher scores indicate better function) and the revised Hopkins Verbal Learning Test (HVLT-R; 12-item word list recall task) assessed in 1476 participants (90.3%). Tertiary outcomes included global and executive cognitive function and incident MCI or dementia at 24 months., Results: At 24 months, DSC task and HVLT-R scores (adjusted for clinic site, sex, and baseline values) were not different between groups. The mean DSC task scores were 46.26 points for the physical activity group vs 46.28 for the health education group (mean difference, -0.01 points [95% CI, -0.80 to 0.77 points], P = .97). The mean HVLT-R delayed recall scores were 7.22 for the physical activity group vs 7.25 for the health education group (mean difference, -0.03 words [95% CI, -0.29 to 0.24 words], P = .84). No differences for any other cognitive or composite measures were observed. Participants in the physical activity group who were 80 years or older (n = 307) and those with poorer baseline physical performance (n = 328) had better changes in executive function composite scores compared with the health education group (P = .01 for interaction for both comparisons). Incident MCI or dementia occurred in 98 participants (13.2%) in the physical activity group and 91 participants (12.1%) in the health education group (odds ratio, 1.08 [95% CI, 0.80 to 1.46])., Conclusions and Relevance: Among sedentary older adults, a 24-month moderate-intensity physical activity program compared with a health education program did not result in improvements in global or domain-specific cognitive function., Trial Registration: clinicaltrials.gov Identifier: NCT01072500.

Importance: In older adults reduced mobility is common and is an independent risk factor for morbidity, hospitalization, disability, and mortality. Limited evidence suggests that physical activity may help prevent mobility disability; however, there are no definitive clinical trials examining whether physical activity prevents or delays mobility disability., Objective: To test the hypothesis that a long-term structured physical activity program is more effective than a health education program (also referred to as a successful aging program) in reducing the risk of major mobility disability., Design, Setting, and Participants: The Lifestyle Interventions and Independence for Elders (LIFE) study was a multicenter, randomized trial that enrolled participants between February 2010 and December 2011, who participated for an average of 2.6 years. Follow-up ended in December 2013. Outcome assessors were blinded to the intervention assignment. Participants were recruited from urban, suburban, and rural communities at 8 centers throughout the United States. We randomized a volunteer sample of 1635 sedentary men and women aged 70 to 89 years who had physical limitations, defined as a score on the Short Physical Performance Battery of 9 or below, but were able to walk 400 m., Interventions: Participants were randomized to a structured, moderate-intensity physical activity program (n = 818) conducted in a center (twice/wk) and at home (3-4 times/wk) that included aerobic, resistance, and flexibility training activities or to a health education program (n = 817) consisting of workshops on topics relevant to older adults and upper extremity stretching exercises., Main Outcomes and Measures: The primary outcome was major mobility disability objectively defined by loss of ability to walk 400 m., Results: Incident major mobility disability occurred in 30.1% (246 participants) of the physical activity group and 35.5% (290 participants) of the health education group (hazard ratio [HR], 0.82 [95% CI, 0.69-0.98], P = .03).Persistent mobility disability was experienced by 120 participants (14.7%) in the physical activity group and 162 participants (19.8%) in the health education group (HR, 0.72 [95% CI, 0.57-0.91]; P = .006). Serious adverse events were reported by 404 participants (49.4%) in the physical activity group and 373 participants (45.7%) in the health education group (risk ratio, 1.08 [95% CI, 0.98-1.20])., Conclusions and Relevance: A structured, moderate-intensity physical activity program compared with a health education program reduced major mobility disability over 2.6 years among older adults at risk for disability. These findings suggest mobility benefit from such a program in vulnerable older adults., Trial Registration: clinicaltrials.gov Identifier: NCT01072500.

Importance: Understanding the major health problems in the United States and how they are changing over time is critical for informing national health policy., Objectives: To measure the burden of diseases, injuries, and leading risk factors in the United States from 1990 to 2010 and to compare these measurements with those of the 34 countries in the Organisation for Economic Co-operation and Development (OECD) countries., Design: We used the systematic analysis of descriptive epidemiology of 291 diseases and injuries, 1160 sequelae of these diseases and injuries, and 67 risk factors or clusters of risk factors from 1990 to 2010 for 187 countries developed for the Global Burden of Disease 2010 Study to describe the health status of the United States and to compare US health outcomes with those of 34 OECD countries. Years of life lost due to premature mortality (YLLs) were computed by multiplying the number of deaths at each age by a reference life expectancy at that age. Years lived with disability (YLDs) were calculated by multiplying prevalence (based on systematic reviews) by the disability weight (based on population-based surveys) for each sequela; disability in this study refers to any short- or long-term loss of health. Disability-adjusted life-years (DALYs) were estimated as the sum of YLDs and YLLs. Deaths and DALYs related to risk factors were based on systematic reviews and meta-analyses of exposure data and relative risks for risk-outcome pairs. Healthy life expectancy (HALE) was used to summarize overall population health, accounting for both length of life and levels of ill health experienced at different ages., Results: US life expectancy for both sexes combined increased from 75.2 years in 1990 to 78.2 years in 2010; during the same period, HALE increased from 65.8 years to 68.1 years. The diseases and injuries with the largest number of YLLs in 2010 were ischemic heart disease, lung cancer, stroke, chronic obstructive pulmonary disease, and road injury. Age-standardized YLL rates increased for Alzheimer disease, drug use disorders, chronic kidney disease, kidney cancer, and falls. The diseases with the largest number of YLDs in 2010 were low back pain, major depressive disorder, other musculoskeletal disorders, neck pain, and anxiety disorders. As the US population has aged, YLDs have comprised a larger share of DALYs than have YLLs. The leading risk factors related to DALYs were dietary risks, tobacco smoking, high body mass index, high blood pressure, high fasting plasma glucose, physical inactivity, and alcohol use. Among 34 OECD countries between 1990 and 2010, the US rank for the age-standardized death rate changed from 18th to 27th, for the age-standardized YLL rate from 23rd to 28th, for the age-standardized YLD rate from 5th to 6th, for life expectancy at birth from 20th to 27th, and for HALE from 14th to 26th., Conclusions and Relevance: From 1990 to 2010, the United States made substantial progress in improving health. Life expectancy at birth and HALE increased, all-cause death rates at all ages decreased, and age-specific rates of years lived with disability remained stable. However, morbidity and chronic disability now account for nearly half of the US health burden, and improvements in population health in the United States have not kept pace with advances in population health in other wealthy nations.

Importance: Clinical practice guidelines state there is insufficient evidence to support advising patients with peripheral artery disease (PAD) to participate in a home-based walking exercise program., Objective: To determine whether a home-based walking exercise program that uses a group-mediated cognitive behavioral intervention, incorporating both group support and self-regulatory skills, can improve functional performance compared with a health education control group in patients with PAD with and without intermittent claudication., Design, Setting, and Patients: Randomized controlled clinical trial of 194 patients with PAD, including 72.2% without classic symptoms of intermittent claudication, performed in Chicago, Illinois between July 22, 2008, and December 14, 2012., Interventions: Participants were randomized to 1 of 2 parallel groups: a home-based group-mediated cognitive behavioral walking intervention or an attention control condition., Main Outcomes and Measures: The primary outcome was 6-month change in 6-minute walk performance. Secondary outcomes included 6-month change in treadmill walking, physical activity, the Walking Impairment Questionnaire (WIQ), and Physical and Mental Health Composite Scores from the 12-item Short-Form Health Survey., Results: Participants randomized to the intervention group significantly increased their 6-minute walk distance ([reported in meters] 357.4 to 399.8 vs 353.3 to 342.2 for those in the control group; mean difference, 53.5 [95% CI, 33.2 to 73.8]; P < .001), maximal treadmill walking time (intervention, 7.91 to 9.44 minutes vs control, 7.56 to 8.09; mean difference, 1.01 minutes [95% CI, 0.07 to 1.95]; P = .04), accelerometer-measured physical activity over 7 days (intervention, 778.0 to 866.1 vs control, 671.6 to 645.0; mean difference, 114.7 activity units [95% CI, 12.82 to 216.5]; P = .03), WIQ distance score (intervention, 35.3 to 47.4 vs control, 33.3 to 34.4; mean difference, 11.1 [95% CI, 3.9 to 18.1]; P = .003), and WIQ speed score (intervention, 36.1 to 47.7 vs control, 35.3-36.6; mean difference, 10.4 [95% CI, 3.4 to 17.4]; P = .004)., Conclusion and Relevance: A home-based walking exercise program significantly improved walking endurance, physical activity, and patient-perceived walking endurance and speed in PAD participants with and without classic claudication symptoms. These findings have implications for the large number of patients with PAD who are unable or unwilling to participate in supervised exercise programs., Trial Registration: clinicaltrials.gov Identifier: NCT00693940.

Context: Neither supervised treadmill exercise nor strength training for patients with peripheral arterial disease (PAD) without intermittent claudication have been established as beneficial., Objective: To determine whether supervised treadmill exercise or lower extremity resistance training improve functional performance of patients with PAD with or without claudication., Design, Setting, and Participants: Randomized controlled clinical trial performed at an urban academic medical center between April 1, 2004, and August 8, 2008, involving 156 patients with PAD who were randomly assigned to supervised treadmill exercise, to lower extremity resistance training, or to a control group., Main Outcome Measures: Six-minute walk performance and the short physical performance battery. Secondary outcomes were brachial artery flow-mediated dilation, treadmill walking performance, the Walking Impairment Questionnaire, and the 36-Item Short Form Health Survey physical functioning (SF-36 PF) score., Results: For the 6-minute walk, those in the supervised treadmill exercise group increased their distance walked by 35.9 m (95% confidence interval [CI], 15.3-56.5 m; P < .001) compared with the control group, whereas those in the resistance training group increased their distance walked by 12.4 m (95% CI, -8.42 to 33.3 m; P = .24) compared with the control group. Neither exercise group improved its short physical performance battery scores. For brachial artery flow-mediated dilation, those in the treadmill group had a mean improvement of 1.53% (95% CI, 0.35%-2.70%; P = .02) compared with the control group. The treadmill group had greater increases in maximal treadmill walking time (3.44 minutes; 95% CI, 2.05-4.84 minutes; P < .001); walking impairment distance score (10.7; 95% CI, 1.56-19.9; P = .02); and SF-36 PF score (7.5; 95% CI, 0.00-15.0; P = .02) than the control group. The resistance training group had greater increases in maximal treadmill walking time (1.90 minutes; 95% CI, 0.49-3.31 minutes; P = .009); walking impairment scores for distance (6.92; 95% CI, 1.07-12.8; P = .02) and stair climbing (10.4; 95% CI, 0.00-20.8; P = .03); and SF-36 PF score (7.5; 95% CI, 0.0-15.0; P = .04) than the control group., Conclusions: Supervised treadmill training improved 6-minute walk performance, treadmill walking performance, brachial artery flow-mediated dilation, and quality of life but did not improve the short physical performance battery scores of PAD participants with and without intermittent claudication. Lower extremity resistance training improved functional performance measured by treadmill walking, quality of life, and stair climbing ability., Trial Registration: clinicaltrials.gov Identifier: NCT00106327.

Context: Prediction models to identify healthy individuals at high risk of cardiovascular disease have limited accuracy. A low ankle brachial index (ABI) is an indicator of atherosclerosis and has the potential to improve prediction., Objective: To determine if the ABI provides information on the risk of cardiovascular events and mortality independently of the Framingham risk score (FRS) and can improve risk prediction., Data Sources: Relevant studies were identified. A search of MEDLINE (1950 to February 2008) and EMBASE (1980 to February 2008) was conducted using common text words for the term ankle brachial index combined with text words and Medical Subject Headings to capture prospective cohort designs. Review of reference lists and conference proceedings, and correspondence with experts was conducted to identify additional published and unpublished studies., Study Selection: Studies were included if participants were derived from a general population, ABI was measured at baseline, and individuals were followed up to detect total and cardiovascular mortality., Data Extraction: Prespecified data on individuals in each selected study were extracted into a combined data set and an individual participant data meta-analysis was conducted on individuals who had no previous history of coronary heart disease., Results: Sixteen population cohort studies fulfilling the inclusion criteria were included. During 480,325 person-years of follow-up of 24,955 men and 23,339 women, the risk of death by ABI had a reverse J-shaped distribution with a normal (low risk) ABI of 1.11 to 1.40. The 10-year cardiovascular mortality in men with a low ABI (< or = 0.90) was 18.7% (95% confidence interval [CI], 13.3%-24.1%) and with normal ABI (1.11-1.40) was 4.4% (95% CI, 3.2%-5.7%) (hazard ratio [HR], 4.2; 95% CI, 3.3-5.4). Corresponding mortalities in women were 12.6% (95% CI, 6.2%-19.0%) and 4.1% (95% CI, 2.2%-6.1%) (HR, 3.5; 95% CI, 2.4-5.1). The HRs remained elevated after adjusting for FRS (2.9 [95% CI, 2.3-3.7] for men vs 3.0 [95% CI, 2.0-4.4] for women). A low ABI (< or = 0.90) was associated with approximately twice the 10-year total mortality, cardiovascular mortality, and major coronary event rate compared with the overall rate in each FRS category. Inclusion of the ABI in cardiovascular risk stratification using the FRS would result in reclassification of the risk category and modification of treatment recommendations in approximately 19% of men and 36% of women., Conclusion: Measurement of the ABI may improve the accuracy of cardiovascular risk prediction beyond the FRS.

Context: Among individuals with lower-extremity peripheral arterial disease (PAD), specific leg symptoms and the ankle brachial index (ABI) are cross-sectionally related to the degree of functional impairment. However, relations between these clinical characteristics and objectively measured functional decline are unknown., Objective: To define whether PAD, ABI, and specific leg symptoms predict functional decline at 2-year follow-up., Design, Setting, and Participants: Prospective cohort study among 676 consecutively identified individuals (aged > or =55 years) with and without PAD (n = 417 and n = 259, respectively), with baseline functional assessments occurring between October 1, 1998, and January 31, 2000, and follow-up assessments scheduled 1 and 2 years thereafter. PAD was defined as ABI less than 0.90, and participants with PAD were categorized at baseline into 1 of 5 mutually exclusive symptom groups., Main Outcome Measures: Mean annual changes in 6-minute walk performance and in usual-paced and fast-paced 4-m walking velocity, adjusted for age, sex, race, prior-year functioning, comorbid diseases, body mass index, pack-years of cigarette smoking, and patterns of missing data., Results: Lower baseline ABI values were associated with greater mean (95% confidence interval) annual decline in 6-minute walk performance (-73.0 [-142 to -4.2] ft for ABI <0.50 vs -58.8 [-83.5 to -34.0] ft for ABI 0.50 to <0.90 vs -12.6 [-40.3 to 15.1] ft for ABI 0.90-1.50, P =.02). Compared with participants without PAD, PAD participants with leg pain on exertion and rest at baseline had greater mean annual decline in 6-minute walk performance (-111 [-173 to -50.0] ft vs -8.67 [-36.9 to 19.5] ft, P =.004), usual-pace 4-meter walking velocity (-0.06 [-0.09 to -0.02] m/sec vs -0.01 (-0.03 to 0.003] m/sec, P =.02), and fastest-pace 4-meter walking velocity (-0.07 [-0.11 to -0.03] m/sec vs -0.02 [-0.04 to -0.006] m/sec, P =.046). Compared with participants without PAD, asymptomatic PAD was associated with greater mean annual decline in 6-minute walk performance (-76.8 (-135 to -18.6] ft vs -8.67 (-36.9 to 19.5] ft, P =.04) and an increased odds ratio for becoming unable to walk for 6 minutes continuously (3.63; 95% confidence interval, 1.58-8.36; P =.002)., Conclusions: Baseline ABI and the nature of leg symptoms predict the degree of functional decline at 2-year follow-up. Previously reported lack of worsening in claudication symptoms over time in patients with PAD may be more related to declining functional performance to than lack of disease progression.

Context: Persons with lower-extremity peripheral arterial disease (PAD) are often asymptomatic or have leg symptoms other than intermittent claudication (IC)., Objective: To identify clinical characteristics and functional limitations associated with a broad range of leg symptoms identified among patients with PAD., Design, Setting, and Participants: Cross-sectional study of 460 men and women with PAD and 130 without PAD, who were identified consecutively, conducted between October 1998 and January 2000 at 3 Chicago-area medical centers., Main Outcome Measures: Ankle-brachial index score of less than 0.90; scores from 6-minute walk, accelerometer-measured physical activity over 7 days, repeated chair raises, standing balance (full tandem stand), 4-m walking velocity, San Diego claudication questionnaire, Geriatric Depression Score Short-Form, and the Walking Impairment Questionnaire., Results: All groups with PAD had poorer functioning than participants without PAD. The following values are for patients without IC vs those with IC. Participants in the group with leg pain on exertion and rest (n = 88) had a higher (poorer) score for neuropathy (5.6 vs 3.5; P<.001), prevalence of diabetes mellitus (48.9% vs 26.7%; P<.001), and spinal stenosis (20.8% vs 7.2%; P =.002). The atypical exertional leg pain/carry on group (exertional leg pain other than IC associated with walking through leg pain [n = 41]) and the atypical exertional leg pain/stop group (exertional leg pain other than IC that causes one to stop walking [n = 90]) had better functioning than the IC group. The group without exertional leg pain/inactive (no exertional leg pain in individual who walks

Context: Peripheral arterial disease (PAD) is a manifestation of systemic atherosclerosis that is common and is associated with an increased risk of death and ischemic events, yet may be underdiagnosed in primary care practice., Objective: To assess the feasibility of detecting PAD in primary care clinics, patient and physician awareness of PAD, and intensity of risk factor treatment and use of antiplatelet therapies in primary care clinics., Design and Setting: The PAD Awareness, Risk, and Treatment: New Resources for Survival (PARTNERS) program, a multicenter, cross-sectional study conducted at 27 sites in 25 cities and 350 primary care practices throughout the United States in June-October 1999., Patients: A total of 6979 patients aged 70 years or older or aged 50 through 69 years with history of cigarette smoking or diabetes were evaluated by history and by measurement of the ankle-brachial index (ABI). PAD was considered present if the ABI was 0.90 or less, if it was documented in the medical record, or if there was a history of limb revascularization. Cardiovascular disease (CVD) was defined as a history of atherosclerotic coronary, cerebral, or abdominal aortic aneurysmal disease., Main Outcome Measures: Frequency of detection of PAD; physician and patient awareness of PAD diagnosis; treatment intensity in PAD patients compared with treatment of other forms of CVD and with patients without clinical evidence of atherosclerosis., Results: PAD was detected in 1865 patients (29%); 825 of these (44%) had PAD only, without evidence of CVD. Overall, 13% had PAD only, 16% had PAD and CVD, 24% had CVD only, and 47% had neither PAD nor CVD (the reference group). There were 457 patients (55%) with newly diagnosed PAD only and 366 (35%) with PAD and CVD who were newly diagnosed during the survey. Eighty-three percent of patients with prior PAD were aware of their diagnosis, but only 49% of physicians were aware of this diagnosis. Among patients with PAD, classic claudication was distinctly uncommon (11%). Patients with PAD had similar atherosclerosis risk factor profiles compared with those who had CVD. Smoking behavior was more frequently treated in patients with new (53%) and prior PAD (51%) only than in those with CVD only (35%; P <.001). Hypertension was treated less frequently in new (84%) and prior PAD (88%) only vs CVD only (95%; P <.001) and hyperlipidemia was treated less frequently in new (44%) and prior PAD (56%) only vs CVD only (73%, P<.001). Antiplatelet medications were prescribed less often in patients with new (33%) and prior PAD (54%) only vs CVD only (71%, P<.001). Treatment intensity for diabetes and use of hormone replacement therapy in women were similar across all groups., Conclusions: Prevalence of PAD in primary care practices is high, yet physician awareness of the PAD diagnosis is relatively low. A simple ABI measurement identified a large number of patients with previously unrecognized PAD. Atherosclerosis risk factors were very prevalent in PAD patients, but these patients received less intensive treatment for lipid disorders and hypertension and were prescribed antiplatelet therapy less frequently than were patients with CVD. These results demonstrate that underdiagnosis of PAD in primary care practice may be a barrier to effective secondary prevention of the high ischemic cardiovascular risk associated with PAD.