Abstract: In patients with peripheral artery disease (PAD), statins may improve the symptoms of claudication. The Intermittent Claudication Proof of Principle (ICPOP) study tested the hypothesis that the combination of extended release niacin plus lovastatin would improve exercise performance in patients with PAD and claudication compared with a diet intervention. A phase 3 double-blind, parallel-group, multi-center, 28-week multi-national study evaluated subjects with a history of claudication who had an ankle—brachial index (ABI) ≤ 0.90, a reproducible peak treadmill walking time (PWT) of 1—20 minutes, and a low-density lipoprotein (LDL)-cholesterol level 〈 160 mg/dl ( 〈 4.1 mmol/l). Subjects were randomly assigned to low-dose niacin 1000 mg plus lovastatin 40 mg (low niacin—statin), high-dose niacin 2000 mg plus lovastatin 40 mg (high niacin—statin), or diet intervention (diet). The co-primary efficacy endpoint of percent change in PWT and claudication onset time (COT) at 28 weeks was assessed using a graded treadmill protocol. At completion, 385 subjects were analyzed for safety and 370 subjects were analyzed for efficacy. The primary efficacy analysis showed no statistical significance for overall treatment effect at week 28 for the co-primary endpoint of PWT and COT. The PWT component of the primary endpoint increased 26.5% on diet, 37.8% on high niacin—statin ( p = 0.137) and 38.6% on low niacin—statin ( p = 0.096). Flushing as the most common event leading to discontinuation and treatment was associated with increases in liver enzymes, fasting blood glucose concentration and a decrease in platelet count.

Abstract: Pharmacologic therapy for intermittent claudication in patients with peripheral artery disease (PAD) is limited. We aimed to determine the durability of cilostazol treatment response over time, treatment effects in various subpopulations, and long-term safety. This analysis pooled original data from nine randomized, controlled trials evaluating cilostazol in intermittent claudication, including 1258 subjects treated with cilostazol 100 mg bid. Analysis of covariance was used to compare differences in walking distance, and a pooled random-effects weighted mean difference in maximal walking distance (MWD) was determined. Temporal effects were analyzed by compiling data at 4-week intervals in studies of 24 weeks in duration. Cilostazol was associated with a 50.7% improvement from baseline in MWD compared with placebo (24.3%), with an absolute improvement of 42.1 meters greater than the improvement with placebo ( p 〈 0.001) over a mean follow-up period of 20.4 weeks. Continued increases were demonstrated over the 24-week treatment period. These benefits were seen in all subgroups, after stratifying by age, sex, smoking status, duration of PAD, diabetes, hypertension, prior myocardial infarction, or beta-blocker use. Cilostazol did not increase the risk of all-cause mortality (RR 0.95 [0.68—1.35]). In conclusion, treatment with cilostazol achieves benefits in walking distance that are sustained at 24 weeks and observed irrespective of baseline clinical characteristics. Cilostazol demonstrated no increased risk of all-cause mortality.

Abstract: Study objective: The objective of ASTRAL was to determine whether percutaneous revascularization combined with medical therapy compared to medical therapy alone improves renal function and other outcomes, such as blood pressure, time to first renal event, time to first major cardiovascular event, and mortality. Study population: ASTRAL enrolled 806 patients with atherosclerotic renovascular disease from 57 centers. Patients were screened if treating clinicians felt they had clinical features suggestive of underlying atherosclerotic renovascular disease (i.e. hypertension refractory to medical therapy, or renal impairment as suggested by laboratory measurements). All patients had to have an imaging modality (i.e. computed tomographic angiography (CTA), magnetic resonance angiography (MRA) or renal artery ultrasound). This imaging had to convey that the patient had ‘substantial’ anatomical atherosclerotic stenosis in at least one renal artery that was suitable for endovascular therapy. Also, the treating clinician had to be ‘uncertain’ that the patient would benefit from revascularization. Fifty-nine percent of patients were reported to have renal artery stenosis of 〉 70%, and 60% had a serum creatinine of ≥ 150 mmol per liter. Design and methods: ASTRAL was a randomized, unblinded study of patients with atherosclerotic renal artery disease who were assigned to percutaneous revascularization plus best medical therapy or best medical therapy alone. The primary outcome of the ASTRAL trial was the change of renal function over time, as determined by the mean slope of the reciprocal of serum creatinine. Secondary outcomes included blood pressure, time to first renal event (defined as: new onset of kidney injury, dialysis, renal transplantation, nephrectomy, or death from renal failure), time to first major cardiovascular event (defined as: myocardial infarction, stroke, death from cardiovascular cause, hospitalization for angina, fluid overload or congestive heart failure, coronary artery revascularization, or another peripheral arterial procedure), and all-cause mortality. Randomization was 1:1 via computer algorithm and was stratified by serum creatinine, glomerular filtration rate (GFR), severity of renal artery stenosis, kidney length on ultrasound, and rate of progression of renal impairment. Patients who were assigned to the revascularization plus medical therapy arm underwent percutaneous revascularization within 4 weeks. The procedure type (angioplasty alone or with stenting), was left to the discretion of the local operator. Distal protection devices were not used. Medical therapy in both arms consisted of antihypertensive drugs, statins, and antiplatelet agents. The trial was powered to detect a 20% reduction in the mean slope of the reciprocal of serum creatinine. Based on low crossover rates, it was determined that at least 750 patients would have to be enrolled. Analysis was by intention to treat. Continuous variables were subject to repeated measures analysis. Time-to-event data were expressed via Kaplan Meier curves and compared via log-rank testing. Prespecified subgroup analyses included baseline serum creatinine, GFR, severity of renal artery stenosis, kidney length, and progression of renal disease. Results: Of the 806 patients included, 403 were randomized to the revascularization arm and 403 to medical therapy only. The median follow-up was 34 months. Only 337 (83%) patients randomized to revascularization underwent the procedure, whereas 24 patients (6%) randomized to the medical therapy arm underwent revascularization. The number of antihypertensive medications used was greater in the medical therapy group than in the revascularization group at the 12-month follow-up: 2.97 versus 2.77 ( p = 0.03). The mean slope of the reciprocal of the serum creatinine concentration was —0.07 × 10 — 3 liters per micromole per year in the revascularization group versus —0.13 × 10 —3 liters per micromole per year in the medical-therapy group (difference of 0.06 × 10 —3 liters per micromole per year) (95% confidence interval [CI], —0.002 to 0.13, p = 0.06) with a trend favoring revascularization. After 5 years of fol low-up, there was a trend toward lower mean systolic blood pressure (1.6 mmHg lower, p = 0.06) in the revascularization group. However, the mean diastolic blood pressure was significantly lower in the medical therapy group at long-term follow-up (divergence of slope of mean diastolic blood pressure: 0.61 mmHg per year, p = 0.03). There was no significant difference between renal events, time to first renal event, acute kidney injury, or development of end-stage renal disease in either group. Further, there was no difference in major cardiovascular events or overall survival in either group. The periprocedural complication rate within the revascularization group was 9% (31/359 patients). Fifty-five out of 280 patients (20%) had an adverse event by 1 month post procedure. Overall, there were 31 serious complications of revascularization in 23 patients. Per protocol analysis of patients suggested that there was no significant difference in outcomes between patients who received revascularization versus medical therapy. No differences between treatment groups were identified in any of the pre-specified subgroup analyses. Conclusions: Renal artery stenting combined with medical therapy did not improve renal function compared to medical therapy alone in patients with atherosclerotic renal artery disease.

Abstract: Prospective data regarding risk factors for peripheral artery disease (PAD) are sparse, especially among women; the relative contribution of systolic versus diastolic blood pressure control for incident PAD has not been well studied. We evaluated the association of self-reported blood pressure control with incident symptomatic PAD in middle-aged and older women. We examined the relationship between reported hypertension and incident confirmed symptomatic PAD ( n = 178) in 39,260 female health professionals aged ≥ 45 years without known vascular disease at baseline. Median follow-up was 13.3 years. Women were grouped according to presence of reported isolated diastolic (IDH), isolated systolic (ISH), or combined systolic–diastolic hypertension (SDH) using cut-points of 90 and 140 mmHg for diastolic and systolic blood pressure, respectively. SBP and DBP were modeled as continuous and categorical exposures. Multivariable-adjusted hazard ratios (HRs), including adjustment for cardiovascular risk factors, were derived from Cox proportional hazards models. Adjusted HRs compared to women without reported hypertension were 1.0 (0.4–2.8) for IDH, 2.0 (1.3–3.1) for ISH, and 2.8 (1.8–4.5) for SDH. There was a 43% increased adjusted risk per 10 mmHg of reported SBP (95% CI 27–62%) and a gradient in risk according to SBP category ( 〈 120, 120–139, 140–159, and ≥ 160 mmHg); HRs were 1.0, 2.3, 4.3, and 6.6 ( p-trend 〈 0.001), respectively. Reported DBP, while individually predictive in models excluding SBP, was not predictive after adjustment for SBP. In conclusion, these prospective data suggest a strong prognostic role for uncontrolled blood pressure and, particularly, uncontrolled systolic blood pressure in the development of peripheral atherosclerosis in women.

Abstract: Peripheral arterial diseases (PADs) compromise blood flow to the limbs. Common causes of arterial obstruction include atherosclerosis, thrombus, embolism, vasculitis, arterial entrapment, adventitial cysts, fibromuscular dysplasia, arterial dissection, trauma, and vasospasm. The most frequently encountered cause of PAD is peripheral atherosclerosis. This chapter considers its epidemiology and risk factors, as well as its diagnosis, including clinical presentation and noninvasive diagnostic tests. This chapter also discusses acute arterial occlusion, atheroembolism, popliteal artery entrapment, thromboangiitis obliterans, and acrocyanosis, as well as the etiology, diagnosis, and treatment of Raynaud phenomenon. Tables describe the Fontaine classification and clinical categories of chronic limb ischemia, provide examples of leg segmental pressure measurements in a patient with calf claudication and foot pain, and summarize secondary causes of Raynaud phenomenon. Figures include a photograph of an ischemic foot demonstrating dependent rubor, measurement of the ankle:brachial index, ultrasonography of a stenosis of the right common femoral artery, magnetic resonance angiograms of patients with calf claudication, arteriograms of critical ischemia of the foot and of disabling claudication of the leg, and ischemia of the toes caused by atheroemboli. This review contains 4 highly rendered figures, 7 tables, and 80 references.