Adherence and Persistence to Antiplatelet Therapy in Lower Extremity Peripheral Arterial Disease: A Danish Population Based Cohort Study.

OBJECTIVE: Adherence to antiplatelet therapy is recommended but unexplored in patients with symptomatic lower extremity peripheral arterial disease (PAD). Therefore, this study aimed to determine adherence and persistence to antiplatelet therapy in patients with PAD, defined as intermittent claudication and chronic limb threatening ischaemia. DESIGN: Population based nationwide cohort study. METHODS: This study included all Danish citizens aged ≥ 40 years with a first inpatient or outpatient diagnosis of symptomatic PAD between 2010 - 2017, and who had at least one prescription claim for aspirin and/or clopidogrel within 90 days after diagnosis. Adherence was determined by the proportion of days covered (PDC) during the first year after diagnosis. Persistence was defined as no treatment gap ≥ 30 days between prescription renewals over three year follow up. RESULTS: A total of 39 687 patients were eligible for inclusion, of whom 23 279 (58.7%) claimed a prescription for aspirin and/or clopidogrel within 90 days of diagnosis. Among these, 12 898 (55.4%) were prevalent users, while the remainder comprised new users who initiated the therapy after the index PAD diagnosis. The mean PDC was 74.5% (SD 35.0%) for prevalent users and 60.5% (SD 30.5%) for new users. Adherence increased with age and number of concomitant drugs. The overall one year cumulative incidence treatment discontinuation was 13.0% (95% CI 12.5 - 13.4%) overall, 17.2% (CI 16.6 - 17.9%) for prevalent users, and 7.9% (CI 7.4 - 8.4%) for new users. At three year follow up, the cumulative incidence of discontinuation was 31.5% (CI 30.9 - 32.2%) overall, 44.6% (CI 43.7 - 45.4%) for prevalent users, and 14.6% (CI 13.9 - 15.3) for new users. CONCLUSION: Less than 60% of patients with newly diagnosed symptomatic PAD claimed a prescription for antiplatelet therapy within 90 days of diagnosis, and both adherence and persistence were moderate during the first year after diagnosis. These findings underscore the importance of efforts to improve the initiation and continuation of antiplatelet therapy in patients with PAD.

Characterizing patient-reported claudication treatment goals to support patient-centered treatment selection and measurement strategies.

OBJECTIVE: Patient-reported outcomes (PRO) have been increasingly emphasized for peripheral artery disease (PAD). Patient-defined treatment goals and expectations, however, are poorly understood and might not be achievable or aligned with guidelines or clinical outcomes. We evaluated the patient-reported treatment goals among patients with claudication and the associations between patient characteristics, goals, and PAD-specific PRO scores. METHODS: Patients with a diagnosis of claudication were prospectively recruited. Patient-defined treatment goals and outcomes related to walking distance, duration, and speed were quantified using multiple-choice survey items. Free-text items were used to identify activities other than walking distance, duration, or speed associated with symptoms and treatment goals. The peripheral artery disease quality of life and walking impairment questionnaire instruments were included as PRO. The treatment goal categories were compared with the PRO percentile scores using 95% confidence intervals (CIs), categorical tests, and logistic regression models. Associations between the patient characteristics and PRO were evaluated using linear and ordinal logistic regression models. RESULTS: A total of 150 patients meeting the inclusion criteria were included in the present study. Of these 150 patients, 144 (96%) viewed the entire survey. Their mean age was 70.0 ± 11.3 years, and 32.9% were women. Most of the respondents had self-reported their race as White (n = 135), followed by Black (n = 3), Asian (n = 2), Native American (n = 2), and other/unknown (n = 2). Two participants self-reported Hispanic ethnicity. The primary treatment goals were an increased walking distance or duration without stopping (62.0%), the ability to perform a specific activity or task (23.0%), an increased walking speed (8.0%), or other/none of the above (7.0%). The specific activities associated with symptoms or goals included outdoor recreation (38.5%), labor-related tasks (30.7%), sports (26.9%), climbing stairs (23.1%), uphill walking (19.2%), and shopping (6%). Among the patients choosing an increased walking distance and duration as the primary goals, 64% had indicated that a distance of ≥0.5 mile (2640 ft) and 59% had indicated a duration of ≥30 minutes would be a minimum increase consistent with meaningful improvement. Increasing age was associated with lower odds of a distance improvement goal of ≥0.5 mile (odds ratio [OR], 0.68 per 5 years; 95% CI, 0.51-0.92; P = .012) or duration improvement goal of ≥30 minutes (OR, 0.76 per 5 years; 95% CI, 0.58-0.99; P = .047). Patient characteristics associated with PAD Quality of Life percentile scores included age, ankle brachial index, and gender. Ankle brachial index was the only patient characteristic associated with the walking impairment questionnaire percentile scores. CONCLUSIONS: Patients define treatment goals according to their desired activities and expectations, which may influence their goals and perceived outcomes. Patients' expectations of minimum increases in walking distance and duration consistent with meaningful improvement exceeded reported minimum important difference criteria for many patients and would not be captured using common clinic-based walking tests. Patient age was associated with both treatment goals and PRO scores, and the related floor and ceiling effects could influence sensitivity to PRO changes for younger and older patients, respectively. Heterogeneity in treatment goals supports consideration of tailored decision-making and outcomes informed by patient characteristics and perspectives.

Cilostazol: a Review of Basic Mechanisms and Clinical Uses.

Primarily used in the treatment of intermittent claudication, cilostazol is a 2-oxyquinolone derivative that works through the inhibition of phosphodiesterase III and related increases in cyclic adenosine monophosphate (cAMP) levels. However, cilostazol has been implicated in a number of other basic pathways including the inhibition of adenosine reuptake, the inhibition of multidrug resistance protein 4, among others. It has been observed to exhibit antiplatelet, antiproliferative, vasodilatory, and ischemic-reperfusion protective properties. As such, cilostazol has been investigated for clinical use in a variety of settings including intermittent claudication, as an adjunctive for reduction of restenosis after coronary and peripheral endovascular interventions, and in the prevention of secondary stroke, although its widespread implementation for indications other than intermittent claudication has been limited by relatively modest effect sizes and lack of studies in western populations. In this review, we highlight the pleiotropic effects of cilostazol and the evidence for its clinical use.

How To Assess a Claudication and When To Intervene.

PURPOSE OF THE REVIEW: Peripheral artery disease (PAD) affects close to 200 million people worldwide. Claudication is the most common presenting symptom for patients with PAD. This review summarizes the current diagnostic and treatment options for patients with claudication. Comprehensive history and physical examination in order to differentiate between claudication secondary to vascular disease vs. neurogenic causes is paramount for initial diagnosis. Ankle-brachial index is the most commonly used test for screening and diagnostic purposes. Treatment consists of four different approaches, which are best utilized in combination: non-pharmacological treatment for claudication improvement, pharmacological treatment for claudication improvement, pharmacological treatment for secondary risk reduction, and interventional treatment for claudication improvement. RECENT FINDINGS: Cilostazol is the only Food and Drug Administration (FDA)-approved agent for symptomatic treatment of claudication. Supervised exercise programs provide the maximum benefit for claudication improvement, but home-based exercise programs are an alternative. High-intensity statins and an antiplatelet agent should be prescribed to all patients with PAD. Angiotensin-converting-enzyme inhibitors can provide additional risk reduction, especially in patients with diabetes or hypertension. Rivaroxaban of low dosage (2.5 mg twice daily) in combination with aspirin further decreases cardiovascular risk, but this reduction comes at the cost of higher bleeding risk. Peripheral artery disease (PAD) is a form of atherosclerotic disease that affects hundreds of millions of people worldwide-one of its most common manifestations is intermittent claudication (IC), which results from insufficient blood flow to meet the metabolic demands of an affected extremity. This paper reviews the current literature regarding the workup, diagnosis, diagnostic modalities, treatment options, and management of intermittent claudication.

Pharmacological treatment of intermittent claudication does not have a significant effect on gait impairments during claudication pain.

Peripheral arterial disease (PAD) is a manifestation of atherosclerosis resulting in intermittent claudication (IC) or leg pain during physical activity. Two drugs (cilostazol and pentoxifylline) are approved for treatment of IC. Our previous work has reported no significant differences in gait biomechanics before and after drug interventions when PAD patients walked without pain. However, it is possible that the drugs are more efficacious during gait with pain. Our aim was to use advanced biomechanical analysis to evaluate the effectiveness of these drugs while walking with pain. Initial and absolute claudication distances, joint kinematics, torques, powers, and gait velocity during the presence of pain were measured from 24 patients before and after 12 weeks of treatment with either cilostazol or pentoxifylline. We found no significant improvements after 12 weeks of treatment with either cilostazol or pentoxifylline on the gait biomechanics of PAD patients during pain. Our findings indicate that the medications cilostazol and pentoxifylline have reduced relevance in the care of gait dysfunction even during pain in patients with PAD.

[Ginkgo biloba--effect, adverse events and drug interaction]. / Ginkgo biloba--effekt, bivirkninger og interaksjoner.

Ginkgo is probably one of the most widely used medicinal herbs in Europe. In Norway products of ginkgo leaf extract have been approved by the Norwegian Medicines Agency for the following indication: traditionally used to improve blood circulation, for example, cold hands and feet. Elsewhere, ginkgo is used for cognitive impairment and dementia, acute ischaemic stroke, intermittent claudication, tinnitus and age-related macular degeneration. Evidence of the efficacy of ginkgo for these indications has previously been studied by the Cochrane Collaboration. In this update we have repeated all the searches in Medline and EMBASE exactly as described in the five Cochrane Systematic Reviews (last search date: 16.02.2011). We identified two new randomised and placebo-controlled studies on cognitive impairment and dementia (3187 patients) and one study on acute ischaemic stroke (3069 patients). The results of these studies gave no reason to change the conclusions of earlier reviews by the Cochrane Collaboration. There is no convincing evidence that ginkgo is effective for cognitive impairment or dementia, acute ischaemic stroke, intermittent claudication or tinnitus. There is still a lack of conclusive evidence for the effect on age-related macular degeneration. Ginkgo leaf extract appears to be safe to use, with no excess side effects compared with placebo. It can cause some minor side effects such as stomach upset, headache, dizziness, constipation, forceful heartbeat, and allergic skin reactions. There is some concern that ginkgo leaf extract might increase the risk of bruising and bleeding, and interactions with anticoagulants/antiplatelet drugs cannot be ruled out. As a general precaution, it is recommended withdrawing ginkgo two weeks before elective surgery.

Bilateral asymmetric popliteal entrapment syndrome treated with successful surgical decompression and adjunctive thrombolysis.

Popliteal artery entrapment syndrome (PAES) is the most common cause of lower leg claudication in patients younger than 50 years. The different types of PAES can result in different rates of arterial damage, leading to aneurysmal degeneration or occlusion. We report a rare case of a young patient presenting with asymmetrical bilateral popliteal artery entrapment. Type III PAES on the right resulted in severe limb ischemia and was treated by division of the accessory tendon and replacement of damaged artery with vein graft. On the left, the medial head of gastrocnemius was resected to release a type I PAES.

Effectiveness of Bilateral Transforaminal Epidural Steroid Injections in Degenerative Lumbar Spinal Stenosis Patients With Neurogenic Claudication: A Case Series.

BACKGROUND: As our population ages, neurogenic claudication (NC) from central canal stenosis of the lumbar spine is becoming an increasingly common condition. Studies have been undertaken to assess the efficacy of caudal, interlaminar, or unilateral transforaminal epidural injections, but bilateral transforaminal epidural injections (BTESIs) have not been evaluated to date. OBJECTIVE: To assess the therapeutic value and long-term effects of fluoroscope-guided BTESIs in patients with NC from degenerative lumbar spinal stenosis (DLSS) of the central spinal canal. DESIGN: Case series. SETTING: Single institution spine clinic. PATIENTS: Twenty-six adults between the ages of 40 and 90 years with a diagnosis of DLSS and a history of subacute or chronic NC. METHODS/INTERVENTIONS: Patients meeting inclusion criteria received fluoroscope-guided BTESI of local anesthetic and steroid at the level immediately below the most stenotic level. Patient self-reported pain level, activity level, and overall satisfaction were recorded by telephone interview at 1, 3, and 6 months after injection by an independent observer. MAIN OUTCOME MEASURES: Pain score and Swiss Spinal Stenosis score at baseline, 1, 3, and 6 months. RESULTS: Of the 22 participants eligible for analysis, 20, 19, and 18 had follow-up data available at 1, 3, and 6 months, respectively. Reduction in numeric pain scale score of at least 50% was noted in 30% of participants at 1 month, 53% at 3 months, and 44% at 6 months. Swiss Spinal Stenosis subscale scores indicated a significant reduction in the proportion of participants reporting the presence of severe pain in the back, buttocks, and legs (particularly the back or buttocks) at 1, 3, and 6 months of follow-up compared with baseline (P < .05). The proportion of participants reporting severe weakness in the legs or feet also decreased after injection and was statistically significant at 3 months of follow-up (P = .04). CONCLUSIONS: Fluoroscope-guided BTESI was moderately effective in reducing pain, improving function, and achieving patient satisfaction in patients with NC from DLSS at the central spinal canal in this clinical case series. LEVEL OF EVIDENCE: IV.

Clinical efficacy and safety of cilostazol: a critical review of the literature.

Cilostazol is a unique antiplatelet agent that has been commercially available for over two decades. As a phosphodiesterase III inhibitor, it reversibly inhibits platelet aggregation yet also possesses vasodilatory and antiproliferative properties. It has been widely studied in a variety of disease states, including peripheral arterial disease, cerebrovascular disease, and coronary artery disease with percutaneous coronary intervention. Overall, cilostazol appears to be a promising agent in the management of these disease states with a bleeding profile comparable to placebo; even when combined with other antiplatelet agents, cilostazol does not appear to increase the rate of bleeding. Despite the possible benefit of cilostazol, its use is limited by tolerability as some patients often report drug discontinuation due to headache, diarrhea, dizziness, or increased heart rate. To date, it has been predominantly studied in the Asian population, making it difficult to extrapolate these results to a more diverse patient population. This paper discusses the evolving role of cilostazol in the treatment of vascular diseases.

Measuring treatment effects of cilostazol on clinical trial endpoints in patients with intermittent claudication.

Intermittent claudication (IC) comprises the most common presenting symptoms of peripheral arterial disease (PAD), which itself is a manifestation of systemic atherosclerosis. Typical symptoms of IC are aching pain, numbness, and fatigue in the lower extremities. Symptoms are induced by walking or exercise and usually resolve with rest. The cornerstone of treating IC is risk-factor reduction and a supervised exercise regimen. Pharmacotherapy specifically indicated for the treatment of IC includes a new drug, cilostazol, and the traditional drug, pentoxifylline. Cilostazol also has antiplatelet, antithrombotic, and vasodilatory activity, as well as a positive effect on serum lipids. Eight multicenter clinical trials, seven in the U.S. and one in the U.K., used objective and subjective clinical endpoints to assess the treatment efficacy of cilostazol. Objective endpoints included maximal and pain-free walking distance (MWD and PFWD, respectively), the ankle-brachial index, peripheral hemodynamic measurements, and serum lipid levels. Subjective endpoints, assessed by patient questionnaires, included perceived functional status and health-related quality of life. Cilostazol treatment showed statistically significant increases in MWD and PFWD within 4 weeks, as well as improvements in physical functional status at 24 weeks, compared with placebo and pentoxifylline. Increases in high-density lipoprotein cholesterol and decreases in plasma triglycerides were also noted. Subjective assessments appeared to match objective parameters.

Effects of indobufen and pentoxifylline on walking capacity and hemostasis in patients with intermittent claudication: results of six months of treatment.

Seventy-one patients with peripheral arterial occlusive disease (PAOD) were randomized into two groups of different treatment modalities. The diagnosis of PAOD was established by history of intermittent claudication, clinical examination, and by Doppler pressure assessment or lower extremity arteriography. After a three-month washout period, 35 patients (Group 1) started treatment with indobufen (400 mg per day) and 36 patients (Group 2) with pentoxifylline (600 mg per day). Twenty-nine patients from each group completed six months of treatment. Both of the drugs significantly improved maximal and pain-free walking distances, but the effect of indobufen was more pronounced than that of pentoxifylline. Patients with PAOD exhibited signs of hypercoagulation. Fibrinogen, D-dimer, and b-thromboglobulin concentrations did not change significantly following treatment in both of the groups. The authors observed a decrease of platelet aggregation after treatment with indobufen and a decrease of F1 + 2 fragment and PAI-1 antigen after treatment with pentoxifylline.

PGE(1) treatment of severe intermittent claudication (short-term versus long-term, associated with exercise)--efficacy and costs in a 20-week, randomized trial.

The efficacy, safety, and cost of prostaglandin E1 (PGE1) in the treatment of severe intermittent claudication was studied comparing a long-term treatment protocol (LTP) with a short-term treatment protocol (STP) in a randomized 20-week study. The study included 980 patients (883 completed the study) with an average total walking distance of 85.5 +/-10 m (range 22-119). Phase 1 was a 2-week run-in phase (no treatment) for both protocols. In LTP, phase 2 was the main treatment phase. In the LTP, treatment was performed with 2-hour infusions (60 microg PGE1, 5 days each week for 4 weeks. In phase 3 (4-week interval period) PGE1 was administered twice a week (same dosage). In phase 4 (monitoring lasting 3 months, from week 9 to 20) no drugs were used. In STP phase 2 treatment was performed in 2 days by a 2-hour infusion (first day: morning 20 microg, afternoon 40 microg; second day morning and afternoon 60 microg). The reduced dosage was used only at the first cycle (week 0) to evaluate tolerability or side effects. Full dosage (60 microg bid) was used for all other cycles. The same cycle was repeated at the beginning of weeks 4, 8, and 12. The observation period was between weeks 12 and 20. A treadmill test was performed at inclusion, at the beginning of each phase, and at the end of 20th week. A similar progressive physical training plan (based on walking) and a reduction in risk factors levels plan was used in both groups. Intention-to-treat analysis indicated an increase in walking distance, which improved at 4 weeks and at 20 weeks in the STP more than in the LTP group. At 4 weeks the variation (increase) in pain-free walking (PFWD) was 167.8% (of the initial value) in the LTP group and 185% in the STP group (p<0.05). At 4 weeks the variation (increase) in total walking distance (TWD) was 227.6% of the initial value in the LTP group and 289% in the STP group (p<0.05). At 20 weeks the increase in PFWD was 496% of the initial value in the LTP group vs 643% in the STP group (147% difference; p<0.02). The increase in TWD was 368% in the LTP group and 529% in the STP group (161% difference; p<0.02). In both groups there was a significant increase in PFWD and TWD at 4 and 20 weeks, but results obtained with STP are better considering both walking distances. No serious drug-related side effects were observed. Local, mild adverse reactions were seen in 6.3% of the treated subjects in the LTP and 3% in the STP. Average cost of LTP was 6,664 Euro; for STP the average costs was approximately 1,820 E. The cost to achieve an improvement in walking distance of 1 m was 45.8 E with the LTP and 8.5 E with the STP (18% of the LTP cost; p<0.02). For an average 100% increase in walking distance the LTP cost was 1,989 E vs. 421 E with STP (p<0.02). Between-group analysis favors STP considering walking distance and costs. Results indicate good efficacy and tolerability of PGE, treatment. With STP less time is spent in infusion and more in the exercise program. STP reduces costs, speeds rehabilitation, and may be easily used in a larger number of nonspecialized units.

Unusual cause of intermittent claudication.

Spontaneous dissection of a peripheral artery is a rare event. We report a case of a spontaneous, non-atherosclerotic and non-aneurysmal dissection limited to the external iliac artery in a 60-year-old woman who was admitted with a left calf claudication. Non-invasive examination documented signs of leg ischemia due to a floating wall dissection of the external iliac artery. After medical treatment over eight weeks the dissection membrane had been adapted to the vessel wall. A similar case of a spontaneous dissection limited to the external iliac artery, followed by a spontaneous healing has not been reported in the literature.

[Thrombosis and antithrombotic agents in peripheral artery disease]. / Thrombose et antithrombotiques dans la pathologie vasculaire des membres inférieurs.

Aspirin remains the most useful antithrombotic agent in peripheral arterial disease. In intermittent claudication, there is no indication for oral anticoagulant except in the presence of emboligen cardiopathy (atrial fibrillation, valvular prosthesis). In critical leg ischemia, there is no proof of benefit for anticoagulation. In the prevention of distal bypass of the legs, the same efficacy is observed for aspirin and oral anticoagulant, but in both treatment occlusion remains frequent, 25% of patients after two years of follow-up.

["Responders and non-responders" to PGE1 and alpha-cyclodextrin]. / "Responders e non-responders" alla PGE1 alpha-ciclodestrina.

BACKGROUND: In this study we evaluated a group of 76 patients (mean age 66 +/- 12) treated with the short-term PGE1 alpha-ciclodestrina protocol (60 micrograms/die for 2 days). Responders to PGE1 alpha-ciclodestrina treatment were considered patients with an increase in flow/perfusion and an associated improvement in signs/symptoms. Moderate responders were considered patients with only flow/perfusion increase or only sign/symptoms improvement. Non-responders were characterised by no increase in flow/perfusion and no clinical improvement. METHODS: Signs/symptoms variations were measured on an analogue scale line. Perfusion measurements (laser Doppler, transcutaneous PO2, arterial inflow with straingauge plethysmography) were recorded after the two days of the short term treatment. RESULTS: In the group of 38 patient with claudication (200-600 m) 54% were considered responders, 12% non responders and 34% moderate responders. In the more severe claudication group (distance < 200 m) including 18 patients, 66% were responders, 8% non responders and 26% were considered moderate responders. In the rest pain group (13 patients) there were 63% responders, 9% non-responders and 28% moderate responders. In the gangrene group (10 patients) 60% were considered responders, 10% non-responders and 3% moderate responders. The overall percentages were 61.25% of responders, 10% of non-responders and 28.75% moderate responders. CONCLUSIONS: The evaluation of the response to PGE1 alpha-ciclodestrina treatment may indicate which group of patients will benefit from the treatment and which group will have no benefits or only limited benefits. This may induce changes in treatment (i.e. increasing doses, more prolonged treatment) or other solutions (revascularisation if possible, arterial infusion or amputation).

[Antiischemic efficacy of trimetazidine in patients with intermittent claudication and effort angina]. / Antiishemicheskaia éffektivnost' trimetazidina u bol'nykh s sochetaniem peremezhaiushcheisia khromoty i stenokardii napriazheniia.

Male patients (n=42) with atherosclerosis obliterans and stage IIA-III ischemia of lower extremities combined with class II-III angina pectoris were divided into 2 groups. Patients of group 1 (n=21) were given simvastatin (10-20 mg/day), clopidogrel (75 mg/day) and trimetazidine (60 mg/day) for 6 months, those of group 2 - simvastatin and clopidogrel also for 6 months. Statistically significant decreases of frequency of attacks of angina, nitroglycerine consumption and increases of walking distance occurred only in group 1.

A review of simple, non-invasive means of assessing peripheral arterial disease and implications for medical management.

Abstract Atherosclerotic peripheral arterial disease (PAD) is highly prevalent in the elderly and subjects with atherosclerotic risk factors such as smoking, diabetes mellitus, hypertension, and hyperlipidemia. Importantly, PAD is rarely an isolated condition, but rather a manifestation of systemic atherosclerosis. Hence, there is often coexisting disease in the coronary and cerebral arteries and, consequently, an increased risk of myocardial infarction and stroke. Intermittent claudication is the classic symptom of PAD, yet up to 50% of patients are asymptomatic. Despite the availability of reliable, non-invasive screening tests, PAD is largely underdiagnosed and undertreated, mostly due to the paucity of symptoms and underutilization of screening tools. The ankle-brachial index (ABI), a simple, rapid, and inexpensive diagnostic tool, holds much prognostic value for PAD diagnosis and is ideal for implementation in the primary care physician's office. The early detection of PAD with ABI screening and subsequent medical management represents a critical opportunity to prevent considerable vascular morbidity and mortality. The management of PAD must address claudication symptoms (with cilostazol or pentoxifylline, or in severe cases endovascular or surgical revascularization) and modifiable atherosclerotic risk factors (with an aggressive global risk-reduction regimen involving lifestyle modifications, exercise, smoking cessation, and antiplatelet, lipid-lowering, and antihypertensive therapy).