Buflomedil / Buflomedil

CONTEXTO: El buflomedil comenzó a comercializarse en el año 1974, para el tratamiento sintomático de la claudicación intermitente causada por la obstrucción de las arterias de los miembros inferiores. En 2006, el Ministerio de Salud francés tomó una serie de medidas, basadas en las investigaciones realizadas por las áreas de farmacovigilancia, que revelaron casos graves asociados al uso de buflomedil, tales como trastornos neurológicos (mioclonía, convulsiones y estado epiléptico) y cardiovasculares (hipotensión, trastornos del ritmo y paro cardíaco), uso inapropiado (incumplimiento de la indicación y/o contraindicaciones, inadecuada dosificación, uso en pacientes con insuficiencia renal) y casos de intoxicación voluntaria, principalmente en adultos jóvenes. TECNOLOGÍA: IFA: BUFLOMEDIL Código ATC: C04AX20 Categoría Terapéutica: vasodilatador periférico. El buflomedil es un vasodilatador que aumenta el flujo sanguíneo en el cerebro y otras partes del organismo. Está indicado en el tratamiento de: -Los síntomas de la arteriopatía oclusiva periférica (AOP en estadio II) que genera claudicación intermitente; -Fenómeno de Raynaud, que es una afección causada por espasmos vasculares desencadenados por bajas temperaturas o emociones fuertes que bloquean el flujo sanguíneo a las extremidades, orejas y nariz; -Accidente Cerebro Vascular Isquémico (ACVI). OBJETIVO: Evaluar la seguridad y eficacia del buflomedil para el tratamiento del accidente cerebrovascular isquémico, la claudicación intermitente y el fenómeno de Raynaud. BÚSQUEDA Y ANÁLISIS DE LA EVIDENCIA CIENTÍFICA: Se realizó una búsqueda en MEDLINE, NICE, INHATHA, Portal salud Madrid, BIREME, Universidad York, PROSPERO, EPISTEMONIKOS, Brisa, LILACS, Trip, Base de datos ensayos clínicos OMS, Clinical trials.gov, DOAJ, RedETSA, IACS, Embase, Instituto Carlos III, Osteba, Revista Nature, búsqueda manual y en las Agencias Regulatorias de Japón, Australia, EE.UU., Canadá, Uruguay, Brasil y Chile. La estrategia de búsqueda fue buflomedil, en humanos, lenguaje restringido a inglés y español, teniendo en cuenta los estudios publicados desde 1998 hasta el 10 abril 2018. Para la realización de este informe se incluyeron 3 metaanálisis (MA), una serie de casos y un informe de EMA. RESULTADOS: Eficacia: Fenómeno de Raynaud (FR): El MA de Stewart5 et al (2012) incluyó numerosos estudios para el tratamiento de este fenómeno, pero sólo una ICCA (Investigación Clínica Controlada Aleatorizada) para buflomedil (Le Quintrec6 , 1991) que incorporó 31 participantes con FR primario, aleatorizados en dos ramas a recibir buflomedil 300 mg dos veces por día o placebo, con un seguimiento de seis meses. Se midió frecuencia y severidad de FR. Los participantes presentaron una frecuencia basal para este fenómeno de 24 ataques por semana en ambos grupos. Luego de la intervención, la diferencia en la frecuencia de ataques semanales entre ambos grupos favoreció a buflomedil con una diferencia de medias (DM) -8,82 IC95% -17,55 a -0,09, el intervalo de confianza fue amplio y cerca de la línea de no discriminación. La DM, en el score de severidad del fenómeno de Raynaud, también resultó a favor de buflomedil, pero no fue estadísticamente significativa (DM -0,41 IC95% -0,84 a 0,02). Consideramos que la calidad de evidencia de este estudio resultó baja según el sistema Grade, por imprecisión debido al bajo tamaño muestral y a los amplios intervalos de confianza. Claudicación Intermitente (CI): El MA de deBacker7 et al (2013) incluyó dos ICCAs para el tratamiento de la CI, con 127 participantes que recibieron buflomedil oral comparado con placebo. Los puntos finales evaluados fueron la distancia de caminata libre de dolor (DCLD) y la distancia máxima de caminata (DMC), las que se analizaron mediante una prueba de ejercicio estandarizada. Los autores determinaron que la evidencia para evaluar la eficacia de buflomedil fue escasa. Las 2 ICCAs incluidas mostraron resultados moderadamente positivos a favor del buflomedil; esto se ve menoscabado por el sesgo de publicación (los autores refirieron que al menos 4 estudios no fueron publicados). El estudio de Trübesteinet8 et al (1984) (N=113; 20 abandonaron el tratamiento) fue bien diseñado, con una duración del seguimiento de 12 semanas. La Diferencia Ponderada de Medias (DPM) para la distancia de caminata libre de dolor fue de 75,1 m IC95% 20,6 a 129,6 y para la distancia máxima de caminata la DPM 80,7 m IC95% 9,4 a 152. El estudio de Diamantopulus9 et al (2001), que incluyó participantes diabéticos (N=40; 6 abandonaron) con CI, tuvo un seguimiento de 6 meses. La DPM para la distancia de caminata libre de dolor fue 80,6 m IC95% 3 a 158,2 y para la distancia máxima de caminata la DPM fue 171,4 m IC95% 51,3 a 291,5. Ambas ICCAs mostraron significación estadística en pacientes que utilizaron buflomedil, tanto para DCLD como para DMC; sin embargo, mostraron amplios intervalos de confianza. Consideramos que estos dos estudios poseen muy baja calidad, tal como se aprecia en la siguiente tabla. Cabe destacar que los autores excluyeron gran número de estudios por su mala calidad. Accidente cerebrovascular isquémico (ACVI): El MA de Wu10 et al (2015) evaluó 26 ICCAs (N=2756) realizados en China. Los estudios incluyeron pacientes hospitalizados durante los primeros días luego de la presentación clínica del ACVI. La media de edad fue de 58 a 75 años. La mayoría de los ICCAs administraron buflomedil intravenoso, con una dosis diaria de 200 mg durante 14 días. El punto final primario fue mortalidad o discapacidad a largo plazo (3 meses). Además, los autores reportaron mortalidad y discapacidad a corto plazo (al finalizar el tratamiento con buflomedil). Los puntos finales secundarios fueron: mejoría del déficit neurológico y seguridad. Para el punto final primario se incluyó el estudio de Cui et al (2005) (N=200), por ser el único que reportó muerte y discapacidad a largo plazo (3 meses). Los sobrevivientes de ACVI tratados con buflomedil presentaron menor riesgo de sufrir el resultado combinado muerte o discapacidad a largo plazo que aquellos en el grupo control (N=200; RR 0,71, IC95% 0,53 a 0,94). La mortalidad en el grupo con buflomedil a los 3 meses de seguimiento, fue 14% versus 15% en el grupo control (RR 0,93 IC95% 0,48 a 1,83). El grupo buflomedil presentó una incidencia de discapacidad a los 3 meses de 27% versus 43% en el grupo control (RR 0,63 IC95% 0,42 a 0,93), siendo ésta una diferencia estadísticamente significativa. También se incluyeron 8 estudios (Bu 2010; Chen 2002a; Dong 2004; Lu 2003; Niu 2008, Pan 2007; Qian 2006; Yang 2012) con 1.056 participantes que reportaron mortalidad a corto plazo y un estudio (Li, 2008) con 85 participantes que reportó discapacidad a corto plazo. La mortalidad a corto plazo fue evaluada en ocho estudios, de los cuales los autores tomaron sólo cuatro (Pan, 2007; Chen 2002a; Qian 2006; Lu 2003) para realizar la revisión del MA, que no demostró diferencia en el riesgo de muerte entre ambos tratamientos (buflomedil N=369 vs control N=362; RR 0,45 IC95% 0,14 a 1,46; I2= 0%). La discapacidad a corto plazo fue evaluada en un estudio (Li, 2008) que comparó buflomedil N=44 vs control N=41, mediante el índice de Barthel. Informaron una DM 15 IC95% 5,83 a 24,17 en el grupo buflomedil que sugiere mejor resultado. Respecto al punto final secundario, se incluyeron 26 estudios con 2.756 participantes que reportaron déficit neurológico. No se encontró evidencia robusta para ninguno de los resultados analizados. Dado que no se pudo acceder a los estudios primarios, el análisis de calidad de evidencia no pudo ser realizado por este Programa. Sin embargo, los investigadores del MA determinaron que la calidad de evidencia fue baja, de acuerdo a los principios de Grade por presencia de sesgos, falta de cegamiento y enmascaramiento, sesgo de publicación e imprecisión por bajo tamaño muestral y amplios intervalos de confianza. DISCUSIÓN: De acuerdo a la evidencia presentada anteriormente, los investigadores encontraron resultados moderadamente positivos a favor del buflomedil en el tratamiento del fenómeno de Raynaud, la claudicación intermitente y el accidente cerebrovascular isquémico. Sin embargo, la baja o muy baja calidad metodológica, el pequeño tamaño muestral, los amplios intervalos de confianza y el sesgo de publicación debilitan la estimación del efecto para los puntos finales analizados. Por otra parte, el uso de buflomedil se asocia a EA cardiológicos (principalmente taquicardia, hipotensión, trastornos del ritmo ventricular y paro cardíaco) y neurológicos (principalmente convulsiones, mioclonía y estado epiléptico) que ocurren bajo condiciones terapéuticas, especialmente en pacientes de edad avanzada que son la principal población para la cual se encuentra indicado. Estos riesgos se ven agravados por el hecho de que buflomedil es un fármaco con un índice terapéutico estrecho, lo cual requiere adaptación/ajuste de la dosis para la función renal. Este tópico es de particular importancia en la práctica asistencial, pues de lo contrario se podría generar una toxicidad que pondría en riesgo la vida del paciente.

Cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for the treatment of intermittent claudication in people with peripheral arterial disease.

We assessed the cost-effectiveness of cilostazol, naftidrofuryl oxalate, and pentoxifylline for intermittent claudication due to peripheral arterial disease (PAD) in adults whose symptoms continue despite a period of conventional management. A Markov decision model was developed to assess the lifetime costs and benefits of each vasoactive drug compared to no vasoactive drug and with each other. Regression analysis was undertaken to model the relationship between maximum walking distance and utility. Resource use data were sourced from the literature and sensitivity analyses were undertaken. Naftidrofuryl oxalate is more effective and less costly than cilostazol and pentoxifylline and has an estimated cost per quality-adjusted life year gained of around £6070 compared to no vasoactive drug. The analysis uses effectiveness evidence from a network meta-analysis. In contrast to previous guidelines recommending cilostazol, the analysis suggests that naftidrofuryl oxalate is the only vasoactive drug for PAD which is likely to be cost-effective.

A study on the efficacy and safety assessment of propionyl-L-carnitine tablets in treatment of intermittent claudication.

OBJECTIVE: This study investigated the efficacy, safety and tolerability of propionyl-L-carnitine (PLC) in patients with intermittent claudication in the Chinese population. METHODS: In this randomized, multicentre, phase III, double-blind, parallel-group study, 239 patients were randomized to receive PLC 2g / day orally or placebo for 4 months (120 vs.119). The primary efficacy endpoint was the improvement of peak walking time (PWT) after treatment over baseline, and the secondary endpoints were the improvement of claudication onset time (CT) and ankle/brachial index (ABI). RESULTS: In the Per Protocol Set (PPS), PWT of the intervention group increased 1.6±1.6 minutes after treatment (p<0.05). With PLC treatment, CT was significantly decreased in the treatment group. ABI was increased in both treatment and control groups. However, no statistical significance was found. In the Safety Analysis Set (SS), there were 110 adverse events during the course of the study (67 in PLC group vs. 43 in control group). There were two serious adverse events in the PLC group and four in the placebo group. All of the SAEs were assessed as unrelated to the study drug which indicated that PLC was well-tolerated in PAD patients. CONCLUSION: The study showed PLC significantly prolonged the maximum walking time and walking distance of Chinese patients with peripheral arterial disease with well-tolerated performance.

[Severe intermittent claudication: PGE1 treatment. A 40-week registry, efficacy and costs]. / Claudicatio intermittens severa: trattamento con PGE1. Registry, follow up (40 settimane), efficacia e costi.

AIM: Intermittent claudication (IC) in peripheral vascular disease is characterized by lower limb pain appearing on effort. Treatment with PGE1 has been successfully used to manage IC patients. This registry has evaluated safety and costs of PGE1 in the management of IC. METHODS: In this study a long-term treatment protocol (LTP), a short-term protocol (STP) and an outpatient (OP), "on-demand" treatment have been compared. A treadmill effort test has been used to evaluate walking distance. The follow up for these three protocols was 40 weeks. PGE1 treatment was associated to a risk reduction plan and to an exercise program. RESULTS: The final analysis has included 252 LTP patients, 223 STP patients and 284 OP patients (total 659 valid cases). A group of 171 comparable patients not treated with PGE1 was used for a parallel comparison. Cardiovascular mortality and morbidity has been evaluated in 731 PGE1 patients completing 24 months of follow up. All protocols have been well tolerated. No side effects were observed. The lower cost has been observed for OP patients. In the long term, mortality and morbidity were lower in patients treated with PGE1 in comparison with patients not treated with PGE1. CONCLUSION: Considering costs and results (increase in walking distance) and improvement in Karnofsky scale the STP plan appears to be better than LTP for IC patients. The OP, "on-demand" treatment offers further improvements. This last treatment plan is simpler; the plan allows better timing for exercise. The treatment can be used even in non-specialized centers.

A systematic review and economic evaluation of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate for the treatment of intermittent claudication in people with peripheral arterial disease.

BACKGROUND: Peripheral arterial disease (PAD) is a condition in which there is blockage or narrowing of the arteries that carry blood to the legs and arms. It is estimated to affect around 4.5% of people aged between 55 and 74 years within the UK. The most common symptom of PAD is intermittent claudication (IC), characterised by pain in the legs on walking that is relieved with rest. OBJECTIVE: To assess the effectiveness and cost-effectiveness of cilostazol, naftidrofuryl oxalate, pentoxifylline and inositol nicotinate, compared with no vasoactive drugs, for IC due to PAD in adults whose symptoms continue despite a period of conventional management. DATA SOURCE: Electronic bibliographic databases were searched during April to June 2010 (MEDLINE, MEDLINE In-Process & Other Non-Indexed Citations, EMBASE, The Cochrane Library databases, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Conference Proceedings Citation Index, BIOSIS Previews). REVIEW METHODS: Effectiveness outcomes sought were maximal walking distance (MWD), pain-free walking distance (PFWD), ankle-brachial pressure index, cardiovascular events, mortality, adverse events (AEs) and health-related quality of life (HRQoL). A narrative synthesis was provided for all outcomes and a network meta-analysis was undertaken for the walking distance outcomes. A Markov model was developed to assess the relative cost-effectiveness of the interventions from a NHS perspective over a lifetime. The model has three states: vasoactive drug treatment, no vasoactive drug treatment and death. Each 1-week cycle, patients may continue with the drug, discontinue the drug or die. Regression analysis was undertaken to model the relationship between MWD and utility so that a cost per quality-adjusted life-year (QALY) outcome measure could be presented. Univariate and probabilistic sensitivity analyses were undertaken. All costs and outcomes were discounted at 3.5%. RESULTS: Twenty-six randomised controlled trials were identified that met the inclusion criteria for the clinical effectiveness review. There was evidence that walking distance outcomes were significantly improved by both cilostazol and naftidrofuryl oxalate; the 95% credible intervals for the difference from placebo in the logarithm mean change MWD from baseline were 0.108 to 0.337 and 0.181 to 0.762, respectively. It was not possible to include inositol nicotinate within the meta-analysis of MWD and PFWD owing to the lack of 24-month data; however, the shorter-term data did not suggest a significant effect. AEs were minor for all drugs and included headaches and gastrointestinal difficulties. The incidence of serious adverse events (SAEs), including cardiovascular events and mortality, was not increased by the vasoactive drugs compared with placebo; however, most studies had a relatively short follow-up time to address this outcome. HRQoL data were limited. Two studies of limited quality were identified within the review of cost-effectiveness. The de novo model developed suggests that naftidrofuryl oxalate dominates cilostazol and pentoxifylline and has a cost per QALY gained of around £6070 compared with no vasoactive drug. This result is reasonably robust to changes within the key model assumptions. Inositol nicotinate was not included within the main analysis owing to lack of data. However, it is unlikely to be considered to be cost-effective due to its high acquisition cost (£900 vs £100-500 per year for the other drugs). CONCLUSIONS: Naftidrofuryl oxalate and cilostazol both appear to be effective treatments for this patient population, with minimal SAEs. However, naftidrofuryl oxalate is the only treatment that is likely to be considered cost-effective. The long-term effectiveness is uncertain and hence a trial comparing cilostazol, naftidrofuryl oxalate and placebo beyond 24 weeks would be beneficial. Outcomes associated with naftidrofuryl oxalate could also be compared with those associated with supervised exercise programmes and angioplasty.

Gender differences in the prevalence and management of metabolic syndrome and its components in patients with peripheral artery disease.

We compared the prevalence and management of metabolic syndrome (MetS) and its components in men and women with peripheral artery disease (PAD). A total of 70 men and 70 women with PAD were evaluated for presence of MetS. There was no significant gender difference in presence of MetS (P = .399) and the number of MetS components (P = .411). Among PAD patients with each MetS component, there was no significant gender difference in the use (P = .617) and number (P = .716) of blood pressure medications, the use (P = .593) and number (P = .591) of lipid-lowering medications, and the number (P = .155) of diabetic medications. Significantly more women were treated with diabetic medications compared with men (85 vs 57%, P = .026). The prevalence and management of MetS and its components was similar between men and women with PAD, except that more women were treated for diabetes. Patients with PAD having MetS did not receive optimal medical management.

Pharmacologic therapy for intermittent claudication.

Peripheral artery disease, defined as atherosclerosis in the lower extremities, affects nearly 8.5 million people in the United States. Due to the frequent asymptomatic manifestation of peripheral artery disease, diagnosis may be delayed and its true incidence underestimated. However, some patients may experience aching pain, numbness, weakness, or fatigue, a condition termed intermittent claudication. Peripheral atherosclerosis is associated with cardiovascular risk and physical impairment; therefore, treatment goals are aimed at decreasing cardiovascular risk, as well as improving quality of life. Little debate exists regarding the management of cardiovascular risk reduction, which consists of both antiplatelet therapy and risk factor modification. Despite recently published guidelines, the treatment of intermittent claudication is less well established and the management remains controversial and uncertain. Exercise remains the first-line therapy for intermittent claudication; however, pharmacologic treatment is often necessary. Although only two prescription drugs have been approved by the U.S. Food and Drug Administration for the treatment of intermittent claudication, several supplements and investigational agents have been evaluated. Therapeutic optimization should balance the anticipated improvements in quality of life with the potential safety risks.

Nurse-led risk assessment/management clinics reduce predicted cardiac morbidity and mortality in claudicants.

Nurse-led assessment/management of risk factors is effective in many chronic medical conditions. We aimed to evaluate whether this finding was true for patients with intermittent claudication and to analyze its impact on patient-reported quality of life and predicted mortality due to coronary heart disease. We prospectively studied a series of 78 patients (51 men; median age, 65 years [IQR: 56-74 years]), diagnosed with intermittent claudication and referred to a nurse-led risk assessment/management clinic (NLC) from a consultant-led vascular surgical clinic. The NLC used clinical care pathways to manage antiplatelet medication, smoking cessation, hyperlipidemia, hypertension, and diabetes and to provide exercise advice. All patients were reassessed at a 3 months. Medication compliance, smoking status, fasting lipid profiles, blood pressure, and HbA1c were recorded. Disease-specific quality of life was assessed using King's College VascuQoL and predicted cardiac morbidity and mortality were calculated using the PROCAM and Framingham risk scores. We found that NLC enrollment produced an antiplatelet and a statin compliance of 100%, a smoking cessation rate of 17% (9 patients) and significant improvements in total cholesterol (median, 5.2-4.5 mmol/l), LDL (median, 3.1-2.5 mmol/l) and triglyceride (median, 1.7-1.4 mmol/l) levels. Significant disease-specific quality of life improvements and significant reduction in both the PROCAM (14% to 10%) and Framingham (14% to 11%) coronary risk scores were observed. Providing care at NLCs for claudicants is effective in assessing and managing risk factors, improves disease-specific quality of life and reduces predicted morbidity and mortality due to coronary heart disease.

[The assessment of TIKLO efficacy in patients with intermittent claudication].

The efficacy of TIKLO was compared with acetylsalicylic acid in treatment of patients with intermittent claudication. Patients were divided into 2 groups (30 and 33 subjects). The first group received TIKLO (250 mg, BID), the second one - Thrombo ASS (100 mg, QD). Outcome measures included platelet aggregation, walking distance and the time of ankle-brachial index (ABI) recovery after treadmill test. TIKLO was shown to reduce platelet aggregation, increase pain-free walking distance and decrease the time of ABI recovery after treadmill test. TIKLO administration was accompanied with minimal adverse events.

Optimal assessment of baseline treadmill walking performance in claudication clinical trials.

Treadmill testing is frequently used to assess the functional capacity of patients with claudication, but the optimal application of treadmill testing in the setting of multicenter clinical trials remains uncertain. The current study used data from a recent clinical trial of the drug NM-702, which employed three baseline assessments of peak walking time (PWT) using a graded treadmill. These data were used to describe the different methods of defining the baseline peak treadmill performance with respect to reproducibility, stability over time and detection of treatment effect. A series of baseline definitions (first test only, last test only, highest PWT of the three tests, arithmetic mean of the three tests, mean of the first two tests, median of the three tests and a reproducibility-based criterion) were used to calculate the population (n = 386) variability in baseline testing, the placebo response over the 24 weeks of treatment, and the effect size of NM-702. Placebo responses and NM-702 effect sizes were not substantively affected by the method used to calculate baseline PWT. Changes in PWT on placebo were less than 25% for all methods of baseline quantitation. No method yielded an NM-702 effect size quantitatively greater than that obtained using only the first baseline test in the analysis for either PWT or claudication onset time. The graded treadmill test quantifies PWT with high reproducibility and stability over time. These characteristics may obviate the need for multiple treadmill tests, potentially saving study costs and improving patient acceptance of trial participation.

Impact of claudication and its treatment on quality of life.

Improvement in quality of life is the ultimate goal of healthcare for the treatment of intermittent claudication. Until recently, the measures of success after therapy were those derived from the vascular laboratory, including ankle-brachial indices and ankle and toe pressures. There are now several validated and reliable survey tools that can assess patient-reported quality of life in a generic or disease-specific manner. Major survey instruments are reviewed. The information gathered through these quality-of-life assessment tools is important to all those involved in the care of patients with peripheral arterial disease. Although claudication is neither life- nor limb-threatening, it has a significant negative impact on quality of life, as measured by these instruments. Patients so afflicted report more bodily pain, worse physical function, and worse perceived health, in addition to limited walking ability. These measures of quality of life do not correlate with standard parameters of ankle-brachial index or ankle pressures. Treatment of the claudicant with exercise therapy and percutaneous or open revascularization also impacts quality of life. Each of these modalities is capable of improving quality of life, but some are associated with decline over time. The major benefits and risks to quality of life of these specific forms of treatment for the claudicant are reviewed. This data demonstrates that patients suffering from symptoms of intermittent claudication are best served by therapies that address their major self-reported impediments to quality of life.

Quality of the assessment of primary and secondary endpoints in claudication and critical leg ischemia trials.

Clinical trials in peripheral arterial disease (PAD) require an accurate definition of the disease for inclusion; they typically use treadmill testing, questionnaires and hemodynamic measures as primary and secondary endpoints. Trials of new pharmacologic therapies for PAD often employ multiple clinical sites with presumed expertise in the diagnosis and management of PAD as well as in clinical trials. However, considerable variability has been observed in the assessment of endpoints used in PAD trials, as well as a marked placebo response with treadmill testing. This variability and placebo response impact adversely on overall trial integrity, necessitate an inflated sample size, and may contribute to the large number of recently negative claudication trials. We hypothesized that site monitoring visits for evaluating testing methods would identify and characterize several critical issues that would contribute to poor testing quality. One hundred sites participating in three claudication trials for which peak walking time on the treadmill was the primary endpoint, and 16 sites participating in a critical leg ischemia study for which transcutaneous oxygen tension (TcPO2) was the primary endpoint were evaluated. Each site was visited one or more times by a clinical monitor trained in conducting a 'site endpoint evaluation visit' focusing on equipment, physical set-up of the room in which testing was to be conducted, and the site staff's ability to conduct each of the specific measurements. Full reports were generated that covered a number of technical issues for each measurement and data were extracted from these reports to summarize the testing problems encountered at each site. Problems with treadmill testing were common. For example, 92% of sites had problems with their treadmill equipment, 58% did not perform proper treadmill familiarization, 24% did not start the treadmill test appropriately, 24% did not conduct the test properly, and 15% did not properly conclude the test to determine the peak walking time of the participant. Similar problems were encountered with the ankle-brachial index test, the administration of questionnaires and measurement of the TcPO2. Major deficiencies were identified at the majority of sites in the assessment of primary and secondary endpoints in PAD trials. These errors and improper testing provide a potential explanation for the wide variability and placebo responses observed in claudication and critical leg ischemia trials. Site interventions need to address these deficiencies in measurement to improve the quality of PAD trials.

Cost effectiveness of cilostazol compared with naftidrofuryl and pentoxifylline in the treatment of intermittent claudication in the UK.

OBJECTIVE: To estimate the cost effectiveness of cilostazol (Pletal) compared to naftidrofuryl and pentoxifylline (Trental) in the treatment of intermittent claudication in the UK. DESIGN AND SETTING: This was a modelling study on the management of patients with intermittent claudication who are 40 years of age or above and have at least six months history of symptomatic intermittent claudication, secondary to lower extremity arterial occlusive disease. The study was performed from the perspective of the UK's National Health Service (NHS). METHODS: Clinical outcomes attributable to managing intermittent claudication were obtained from the published literature and resource utilisation estimates were derived from a panel of vascular surgeons. Using decision analytical techniques, a decision model was constructed depicting the management of intermittent claudication with cilostazol, naftidrofuryl and pentoxifylline over 24 weeks in the UK. The model was used to estimate the cost effectiveness (at 2002/2003 prices) of cilostazol relative to the other treatments. MAIN OUTCOME MEASURES AND RESULTS: Starting treatment with cilostazol instead of naftidrofuryl is expected to increase the percentage improvement in maximal walking distance by 32% (from 57% to 75%) for a 12% increase in NHS costs (from 801 pounds sterling to 895 pounds sterling). Treatment with cilostazol instead of pentoxifylline is expected to increase the percentage improvement in maximal walking distance by 67% (from 45% to 75%) and reduce NHS costs by 2% (from 917 pounds sterling to 895 pounds sterling). Treatment with naftidrofuryl instead of pentoxifylline is expected to increase the percentage improvement in maximal walking distance by 27% (from 45% to 57%) and decrease NHS costs by 14% (from 917 pounds sterling to 801 pounds sterling). CONCLUSION: Within the limitations of our model, starting treatment with cilostazol is expected to be a clinically more effective strategy for improving maximal walking distance at 24 weeks than starting treatment with naftidrofuryl or pentoxifylline and potentially the most cost effective strategy. Moreover, the acquisition cost of a drug should not be used as an indication of the cost effectiveness of a given method of care.

Cilostazol: a review of its use in intermittent claudication.

UNLABELLED: Cilostazol (Pletal) is a selective inhibitor of phosphodiesterase-III with antiplatelet, antithrombotic and vasodilating properties. It also exhibits antiproliferative effects on smooth muscle cells and has beneficial effects on high density lipoprotein-cholesterol and triglyceride levels.Randomized, double-blind, placebo-controlled 12- to 24-week trials in >2000 patients with moderate to severe intermittent claudication demonstrated that cilostazol generally significantly increased walking distances and improved quality of life compared with placebo. Additionally, a large comparative 24-week trial showed that cilostazol 100 mg twice daily was significantly more effective than pentoxifylline 400mg three times daily (pentoxifylline was not significantly different from placebo). Cilostazol was generally well tolerated. Adverse events reported significantly more often with cilostazol than with placebo included headache, diarrhea, abnormal stools, infection, rhinitis and peripheral edema and in comparison with pentoxifylline were headache, diarrhea, abnormal stools and palpitations. Adverse events were generally mild to moderate in intensity, transient or resolved after symptomatic treatment and rarely required treatment withdrawal. Significant drug interactions are observed when cilostazol is coadministered with other agents that inhibit cytochrome P450 (CYP) 3A4 (e.g. erythromycin or diltiazem) or CYP2C19 (e.g. omeprazole). As a result, in Europe cilostazol is contraindicated in patients receiving CYP3A4 or CYP2C19 inhibitors and in the US it is recommended that dosage reduction for cilostazol be considered during coadministration of cilostazol and CYP3A4 or CYP2C19 inhibitors. Conversely, cilostazol itself does not appear to inhibit CYP3A4. Coadministration of cilostazol with aspirin or warfarin did not result in any clinically significant changes to coagulation parameters, bleeding time or platelet aggregation. CONCLUSION: In six of eight well designed clinical trials, cilostazol was significantly more effective than placebo in increasing walking distances and improving the quality of life of patients with moderate to severe intermittent claudication. In addition, limited comparative data have shown that cilostazol has superior efficacy compared with pentoxifylline. Cilostazol is also generally well tolerated. Additional comparative trials are required to confirm these results, to determine the place of cilostazol in relation to other agents or exercise therapy and risk factor reduction alone, and to establish the effects of long-term treatment with cilostazol in patients with intermittent claudication. Cilostazol is contraindicated in several subpopulations of patients, particularly those with congestive heart failure and severe hepatic or renal impairment. Nonetheless, current data support the choice of cilostazol as a promising therapy amongst the limited options available for patients with intermittent claudication.

[Treatment of severe intermittent claudication: ORACLE-PGE1 short term study. A randomised 40-week study. Evaluation of efficacy and costs]. / Trattamento della claudicatio intermittens severa: studio ORACLE-PGE1 short term. Registry e studio randomizzato a 40 settimane, valutazione di efficacia e costi.

BACKGROUND: The efficacy and cost of prostaglandin E1 (PGE1) in severe intermittent claudication was studied comparing a long-term protocol (LTP) with a short-term protocol (STP) in a randomised 40-week study. METHODS: Phase 1 was a 2-week run-in phase (no treatment) for both protocols. In LTP, phase 2 was the main treatment phase. Treatment was performed with 2-hour infusions (60 micro g 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 (40 weeks), no PGE1 were used. In STP, phase 2 treatment was performed in two days by a 2-hour infusion (60 micro g PGE1 twice a day in 2 days). The same cycle was repeated every 4 weeks. A treadmill test was performed at inclusion, at the beginning of each phase and at the end of weeks 12, 16, 20 32 and 40. A progressive training plan (walking) and reduction in risk factors plan was used in both groups. RESULTS: Out of the 1276 included patients 1165 completed the study (606 in LTP group; 559 in the STP). Drop-outs were 111. The two groups were comparable in distribution, risk factors and smoking. Intention-to-treat analysis indicated an increase in pain free walking distance (PFWD). The absolute and percent increase in pain-free walking distance (PFWD) was comparable in both LTP and STP groups with a significative increase in TWD at 4 weeks. At 20 and 40 weeks increase was up to 219% in the LTP and 460% in the STP group (p<0.02). Comparable results concerning PFWD were obtained in the two groups. Both treatments were well tolerated. No side effect was observed. Local effects were observed in 8.5% of the treated subjects in the LTP and 4% in the STP. The average cost of the LTP protocol was 8786 Euro. For STP the costs was 946 (10.8% of LTP). For both protocols the cost of the infusion was 24% of the total for the LTP and 35% in the STP. Therefore 75% of the cost is not drug-related. CONCLUSIONS: In conclusion between-group-analysis favours STP considering walking distance and costs. Results indicate good efficacy and tolerability of PGE1 treatment particularly STP.

Quality-of-life assessment in comparative therapeutic trials and causal structure considerations in peripheral occlusive arterial disease.

When considering the use of quality of life as a primary end-point in phase III to IV comparative trials, the trial designer generally faces some unresolved questions. These include: How does one explain that some dimensions [quality-of-life (QOL) instruments usually have more than 1 dimension] are directly influenced by the studied treatments whereas others are not? How can one interpret conflicting results between conventional clinical measurements and QOL measurements, when the relationships between conventional clinical measurement and quality of life are not known? In this paper, we consider the use of Structural Equation Modelling (SEM) as a methodological alternative to answer these problems. As an example, we analyse the internal causal structure of the Claudication Scale (CLAU-S), a specific QOL 5-dimensional instrument for peripheral occlusive arterial disease. In applying SEM to different studies and different types of calculation, we suggest that CLAU-S is based on a stable, simple and comprehensive QOL model, is compatible with the general International Classification of Impairments, Disabilities and Handicaps (ICIDH) classification, is coherent and complementary with clinical data measurements and, using differences in a prospective study, considerably improves specificity. We suggest that SEM can help in QOL scale validation, in providing a unified scheme of the inter-relationships between internal dimensions and with external variables, in particular, clinical measurements.

Nomograms used to define the short-term treatment with PGE(1) in patients with intermittent claudication and critical ischemia. The ORACL.E (Occlusion Revascularization in the Atherosclerotic Critical Limb) Study Group. The European Study.

Infusional, cyclic PGE1 treatment is effective in patients with intermittent claudication and critical limb ischemia (CLI). One of the problems related to chronic PGE1 treatment in vascular diseases due to atherosclerosis is to evaluate the variations of clinical conditions due to treatment in order to establish the number of cycles per year or per period (in severe vascular disease reevaluation of patients should be more frequent) needed to achieve clinical improvement. In a preliminary pilot study a group of 150 patients (mean age 67+/-12 years) with intermittent claudication (walking range from 0 to 500 m) and a group of 100 patients with CLI (45% with rest pain, and 55% gangrene; mean age 68 +/-11 years) the number of PGE1 cycles according to the short-term protocol (STP) needed to produce significant clinical improvement was preliminarily evaluated. Considering these preliminary observations, the investigators established a research plan useful to produce nomograms indicating the number of cycles of PGE1-STP per year needed to improve the clinical condition (both in intermittent claudication and CLI). A significant clinical improvement was arbitrarily defined as the increase of at least 35% in walking distance (on treadmill) and/or the disappearance of signs and symptoms of critical ischemia in 6 months of treatment in at least 75% of the treated patients. With consideration of the results obtained with the preliminary nomograms a larger validation of the nomograms is now advisable. A cost-effectiveness analysis is also useful to define the efficacy of treatment on the basis of its costs. The publication of this report in two angiological journals (Angeiologie and Angiology) will open the research on nomograms to all centers willing to collaborate to the study. The data are being collected in the ORACL.E database and will be analyzed within 12 months after the publication of this report.

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.