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Surgical thrombectomy in horses with aortoiliac thrombosis: 17 cases
Equine Veterinary Journal
Abstract
Reasons for performing study:
Aortoiliac thrombosis (AIT) is a progressive vascular disease characterised by an exercise-induced hindlimb lameness. After developing a surgical technique, a follow-up study was required.
Objectives:
To assess the surgical results of a surgical thrombectomy in horses with AIT, a chronic arterial occlusive disease of the aorta and its caudal arteries.
Methods:
Seventeen cases showed the typical signs of AIT and diagnosis was confirmed by Doppler-ultrasonography. Average age of the horses was 12 years. Seven stallions, 6 mares and 4 geldings were included.
Results:
The thrombus was located in the left hindlimb (5 cases), the right hindlimb (9 cases) or in both hindlimbs (3 cases). Two cases were operated on both limbs with a few days between surgeries. Nine (53%) horses regained their athletic performance and 2 horses were able to work for at least 30 min without complaint, instead of the initial 5 min prior to surgery. During surgery one horse had to be subjected to euthanasia because the thrombus was too tightly attached to the arterial wall and could not be removed. Two horses were subjected to euthanasia post operatively due to severe myopathy and one due to a femoral fracture during recovery. Two reocclusions of the treated artery occurred 4 months after surgical intervention: one horse was reoperated and, due to the extent of the thrombus and quality of the arterial wall, the horse was subjected to euthanasia; the other horse was subjected to euthanasia without a second surgery. A severe complication was the appearance of AIT in the contralateral limb after surgery as result of occlusion caused by an embolus loosened by the procedure. Post anaesthetic myopathy was seen in 4 (24%) of the cases and could be so severe that euthanasia had to be considered.
Conclusion and potential relevance:
Surgical intervention by means of a thrombectomy in horses with AIT should be considered; 65% of the horses regained athletic activity and 53% of the operated horses in this study performed at their previous level. Adequate padding, correct positioning, prevention of intraoperative hypotension and keeping surgery time as short as possible, are important parameters to prevent post operative myopathy.
... 23 Current treatment includes the administration of sodium gluconate with or without fibrinolytic enzymes, anticoagulant therapy, and continued exercise to maintain collateral circulation; 23 more recently, ultrasoundguided balloon and surgical thrombectomy have achieved limited success. 16,27 In NHP, paresis and paralysis due to aortic thromboembolism is uncommon and has been reported in 3 owl monkeys and in a mustached tamarin. 11,18 In addition, acute death due to aortic thrombi has been reported in capuchin monkeys infected with herpes simplex 2 virus. ...
... We thank Dr Robert Purcell and Dr Sue Emerson for kindly letting us use tamarin tissue samples from their previous studies and Cindy Clark, NIH Library Writing Center, for manuscript editing assistance. This case report was presented as an abstract at the 44 th Association of Primate Veterinarians Annual Workshop, Charlotte, NC, October [26][27][28][29] 2016. ...
A wild-caught, research-naïve, adult male mustached tamarin (Saguinus mystax) experienced sudden onset of bilateral hindlimb paresis. Physical examination established the presence of paralysis and the lack of femoral pulses and deep pain in both legs. There were no signs of external trauma and, due to a poor prognosis, euthanasia was elected. Necropsy findings included pleural effusion, partial pulmonary atelectasis and congestion, dilatatory cardiomyopathy, a renal hemorrhagic infarct, and a thromboembolus located at the trifurcation of the distal abdominal aorta. The clinical and histologic findings were indicative of an aortic-iliac thrombosis.
... In patients with peripheral arterial disease, pentoxifylline has been reported to improve abnormal erythrocyte deformability, reduce blood viscosity, and decrease platelet reactivity and plasma hypercoagulability (Weitz et al. 1996;Kabbesh et al. 2012). The beneficial effect of aspirin is most likely due to prevention or retardation of platelet thrombogenesis on the surface of the thrombus and maybe cilostazol might be an option (Rijkenhuizen et al. 2009). ...
... In horses, cases have been known to improve on medication, but rarely in horses with intermittent lameness with partial or total occlusion of the femoral artery, surgery is indicated in such cases (Brama et al. 1996;Rijkenhuizen et al. 2009). In human patients, robot-assisted laparoscopically assisted aortofemoral bypasses have been performed with satisfactory results. ...
... Vascular and soft tissue phase scintigraphy performed respectively in the first seconds or minutes after injection of the radiopharmaceutical [2,10,26], in comparison with bone scintigraphy typically obtained 2 to 3 h post injection, have had a few specific indications that now have greatly been replaced by other modalities. Vascular scintigraphy allowed diagnosis of aortoiliac thromboembolism [27] but ultrasound has now been developed as a robust and convenient alternative [28][29][30]. Soft tissue phase scintigraphy has been reported for suspensory ligament [2] and deep digital flexor tendon [31] imaging but this has now been by far replaced by ultrasound and/or MRI. A comparative study with MRI regarding identification of deep digital flexor tendon injury in the pastern demonstrated a limited sensitivity (40%) but a high specificity as no false positive cases were identified [31]. ...
Simple Summary
Nuclear medicine imaging techniques consist of acquiring images after intravenous administration of a small dose of radioactive molecules. Different nuclear medicine techniques are available in the horse. Scintigraphy provides two-dimensional images and has been used for the detection of bone injuries in horses since the late 1970s. This was at the time the only alternative to radiographs to detect bone issues in horses. As other imaging techniques such as computed tomography (CT) and magnetic resonance imaging (MRI) have developed, the role of scintigraphy in horses has reduced. Scintigraphy remains, however, commonly used in racehorses to detect stress injuries and is also used in other horses to image larger body areas or even the whole body of a horse. In the last 10 years, positron emission tomography (PET) has become available in horses and provides higher resolution three-dimensional images. PET shows promising applications by either replacing the use of scintigraphy for the smaller areas of the limbs or by adding useful information to other imaging techniques. PET allows detection of some injuries prior to their identification with CT or MRI and also helps decide if an injury is active or represents an old scar.
Abstract
Scintigraphy and Positron Emission Tomography (PET) are both nuclear medicine imaging techniques, providing functional information of the imaged areas. Scintigraphy is a two-dimensional projected imaging technique that was introduced in equine imaging in the late 1970s. Scintigraphy allows imaging of large body parts and can cover multiple areas, remaining the only technique commonly used in horses for whole body imaging. PET is a cross-sectional imaging technique, first used in horses in 2015, allowing higher resolution three-dimensional functional imaging of the equine distal limb. This manuscript will cover current use and values of these two modalities in equine lameness diagnosis.
... Zur Behandlung der Aortenthrombose beim Kalb fi nden sich keine zuverlässigen Angaben in der Literatur. Eine medikamentelle Therapie mit gerinnungshemmenden und fi brinolytischen Medikamenten wie bei der Katze (Smith und Tobias, 2004) oder gar eine chirurgische Intervention wie beim Pferd (Rijkenhuizen et al., 2009), kam beim Rind, insbesondere aus fi nanziellen Gründen bisher nur selten zum Einsatz. Es fi ndet sich demzufolge lediglich ein Bericht über zwei Fälle einer erfolgreichen Behandlung der Aortenthrombose beim Kalb (Buczinski et al., 2007). ...
A two month-old female Simmental calf was presented with sensomotoric dysfunction and recumbency. Neurologic examination revealed dysfunction of the cerebral cortex and paralysis of both hind limbs. Examination of the skeletal system revealed a marked reduction of the skin temperature of both hind limbs and the absence of femoral pulse. Examination of cerebrospinal fluid yielded physiological parameters. The radiographic examination of the vertebral column, hip and femur on both sides revealed no evidence of alteration of the bone structures. Thiamine pyrophosphate test indicated thiamine deficiency. Based on these findings a tentative diagnosis of cerebrocortical necrosis and aortic thrombosis were made and the animal was euthanised. Post mortem examination yielded thrombosis of the abdominal aorta cranial to the branching of the iliac arteries and consecutive necrosis of the skeletal muscle of the hind limbs. Possible causes of pathogenesis are discussed.
La chirurgie minimalement invasive correspond aux techniques chirurgicales qui permettent de limiter ou d’éliminer les incisions cutanées, diminuant ainsi le traumatisme tissulaire, la douleur et la morbidité postopératoires associées, tout en permettant une convalescence plus rapide. L’arthroscopie est devenue la technique gold standard pour la quasi-totalité des chirurgies articulaires, alors que la laparoscopie est la technique de choix pour explorer l’abdomen dorsal. L’instrumentation et la technique sont des prérequis essentiels pour réaliser ces procédures avec succès chez le patient tranquillisé ou sous anesthésie générale. Alors que les indications pour la laparoscopie chez le cheval se sont multipliées, de nouveaux concepts ont été développés pour diminuer encore le traumatisme tissulaire chez le cheval et améliorer le diagnostic, comme la chirurgie par endoscopie transvaginale ou par aiguille endoscopique. L’ostéosynthèse minimalement invasive a également gagné en intérêt, car il a été démontré qu’elle permettait de diminuer les risques d’infection du site chirurgical. Le guidage par imagerie bi- ou tridimensionnelle s’est développé pour améliorer la précision, dans les cas de réparation de fractures complexes par chirurgie minimalement invasive. Cet article décrit les principes de base et les indications de la chirurgie minimalement invasive utilisant des endoscopes rigides et flexibles, les procédures cardiovasculaires minimalement invasives et l’ostéosynthèse minimalement invasive.
This paper describes the clinical and histopathological features of a 16‐year‐old Cob mare who sustained a haemorrhagic cerebrovascular accident or stroke. The mare presented with an acute onset of neurological signs, with a neuroanatomical localisation to the midbrain and thalamus regions. The mare was reported to have suffered from ataxia on all four limbs which started 7 days prior to referral and was also showing several signs of left‐sided cranial nerve deficits. On initial examination, the mare presented with quadrilateral ataxia, left‐sided facial paralysis, weak tongue tone and a left‐sided nose tilt as well as a hemineglect syndrome characterised by an inability to eat food presented on the right side of her mouth. Complete blood count and biochemistry analyses did not reveal any abnormalities, and a standing head CT revealed the presence of a hyperdense lesion localised in the left ventral cortex and thalamus region, which could be consistent with a vascular lesion, cholesterol granuloma or a mass. The mare was monitored, and as her condition slightly improved, was discharged from the hospital. Four weeks later, the clinical signs recurred and as the ataxia presented a danger for the mare and anyone handling her, the decision was made to euthanise the mare. A post‐mortem CT scan of the head revealed an enlargement of the previous lesion, and the histopathological examination confirmed the presence of a haemorrhage within the brain, associated with neoplastic emboli. Haemorrhagic stroke has not previously been well described in horses therefore presents a challenge in diagnosis. Treatment in small animals is mainly conservative.
As in other chapters in Part III the diseases discussed herein are ordered to follow the anatomic groupings: diffuse brain, forebrain, brainstem, cerebellum, spinal cord, peripheral nerves, neuromuscular junction, muscle. If one accepts the adage that most diseases have an input from the patient's genotype, even if there are environmental inputs to the phenotype, then likely many diseases here, such as stiff horse syndrome and some forms of exertional rhabdomyolysis, will ultimately be reclassified as genetic. Likewise, post anesthetic myoneuropathy could be classified as having a metabolic basis, nervous coccidiosis as a toxic basis, kangaroo‐gait as a traumatic basis and equine cervical vertebral malformation as a nutritional basis. We feel that until the pathophysiology of all these disorders becomes clearer it is prudent to include them here as being multifactorial and idiopathic disorders.
This case report describes the clinical appearance, diagnosis and surgical management of thrombosis of the median artery and its branches in a gelding. The 4‐year‐old Danish Warmblood presented with acute severe progressive right front leg lameness, not responding to painkillers. Initial clinical examination including radiographs revealed no significant findings, and a scintigraphic examination showed decreased radiopharmaceutical uptake in the right front toe in comparison to the left limb. The following day, the temperature of the right front leg was significantly decreased, especially in the area distal to the carpus. No pulsation of the digital arteries could be detected. Ultrasonography showed partial thrombosis of the medial digital artery (A. digitalis palmaris medialis). Occlusion of this artery is a sporadic event with impressive clinical signs and might not be directly diagnosed due to it being a rare occurrence. Ultrasound is an excellent technique for diagnosing the presence of thrombosis and can also help delineate the extent. Our case did not respond to the initial treatment with phenylbutazone and acetylsalicylic acid. The ischaemia became even worse, requiring surgical intervention. A similar approach as for the aorta‐iliac thrombosis in the hindlimb was undertaken in the front limb, which has not been described previously. The gelding recovered initially. Unfortunately, restenosis occurred and due to a poor prognosis for a second surgery, the gelding was euthanised.
This case report describes the clinical progression of a 5‐day‐old Oldenburg colt presented for acute severe right hindlimb lameness. The foal had diarrhoea at presentation, and over the next 24 h became tachycardic and febrile with cold extremities in the hindlimbs and began to bear weight on the dorsum of both hind fetlocks. Diagnostic work‐up included physical examination, radiography, ultrasonography and clinicopathological testing. Treatment consisted of antibiotics, anti‐inflammatories, gastroprotectants, oral di‐tri‐octahedral smectite, hyperimmune plasma and isotonic crystalloid fluids for diarrhoea. Bandages and splints were applied to the hindlimbs to assist ambulation and prevent weightbearing on the dorsum of the fetlocks. The foal developed oedema of both hindlimbs, and ultrasonographic evaluation revealed gas pockets within the subcutaneous tissues. An ultrasound‐guided aspirate of the right hindlimb oedema was submitted for cytology, which revealed presumed Clostridial spores, and culture, which yielded heavy growth of Escherichia coli. Surgical fenestration of the hindlimbs was performed due to suspected Clostridial myositis. The foal continued to decline clinically and was humanely subjected to euthanasia. Post‐mortem evaluation revealed septicaemia and thromboembolism of the terminal abdominal aorta resulting in partial obstruction of blood flow to the pelvic limbs with resultant bacterial myositis (Clostridium [suspected] and Escherichia coli [confirmed]). In summary, thrombosis is a potential sequela to coagulopathy seen in septicaemia and should be considered a differential diagnosis in neonatal foals presenting for lameness.
Nonspecific performance and rideability issues are more likely a manifestation of pain in the ridden horse rather than a true behavioural problem. A systematic and thorough investigation focusing on the potential presence of pain‐related conditions is thus crucial in horses with such complaints. It can, however, be challenging to determine whether the complaint is indeed related to pain, where the pain is located, and what the underlying cause is. This review describes the challenges of pain recognition in ridden horses and summarises the recently developed ridden horse ethograms that might enable pain to be assessed in an objective, valid and reliable way. Furthermore, the differential diagnosis and diagnostic approach to horses presenting potentially pain‐related performance and rideability issues are discussed.
A 4-year-old Thoroughbred gelding with severe left hindlimb lameness and colic-like signs lasting 30–60 min post-exercise was diagnosed with unilateral internal aorto-iliac thrombosis. The thrombus was identified using transrectal ultrasonography in the terminal aorta and was initially thought to extend into the left external iliac artery. However, attempted thrombectomy via a left femoral arteriotomy performed under general anaesthesia using thrombectomy and angioplasty catheters was unsuccessful, as the thrombus was located in the left internal iliac artery. Transrectal ultrasound evaluation was repeated monthly for 12 months post-operatively during which time the gelding remained asymptomatic at rest. As removal of thrombi in the external but not internal iliac artery may be possible, correct diagnosis of the location of the thrombus is critical in preventing unnecessary attempts at surgical correction. The aetiology remains unknown, but altered haemodynamics within the abdominal aorta with mechanical stresses during intense exercise are proposed as a cause of thrombus formation. The sequential monitoring of this case also conflicts the assumption that thrombi in this location propagate over time as partial regression was observed 6 months after referral and 9 months after onset of clinical signs.
This unique, comprehensive approach to lameness describes the diagnosis and management of conditions that can cause gait abnormalities in horses, exploring both traditional treatments and alternative therapies. Broader in scope than any other book of its kind, it offers detailed descriptions of equine sporting activities and specific lameness conditions in major sport horse types. Up-to-date information on all imaging modalities encompasses radiography, ultrasonography, nuclear scintigraphy, thermography, computed tomography, magnetic resonance imaging, arthroscopy, tenoscopy and bursoscopy. Particular emphasis is placed on clinical examination and diagnostic analgesia. A companion CD-ROM features nearly 60 minutes of video segments that demonstrate common forelimb and hindlimb lameness and gait abnormalities.
Although primary coagulopathies are rare in horses, changes in coagulation and fibrinolysis are commonly associated with inflammatory diseases. A clear understanding of the pathophysiology of normal and abnormal hemostasis is required to be able to choose and interpret diagnostic tests evaluating coagulation and fibrinolysis. After diagnosis, treatment of the underlying disease must occur regardless of whether clinical manifestations (excessive bleeding or thrombosis) of the coagulopathy are present or not. Specific treatment may be initiated if there are clinical signs of coagulopathy.
The pathology of aortic-iliac thrombosis(AIT) in two adult Thoroughbred horses from the same breeding farm is reported. No. 1 showed sudden falls with moaning and profuse sweating at mating and during hard exercise repeatedly for more than two years. The symptoms subsided within several tens of minutes. No. 2 showed intermittent lameness of the left hind leg progressively for more than three years. In both horses, thromboembolism was observed in the abdominal aorta, terminal quadrifurcation, and branchial arteries bilaterally. Arterial intima without adherent thrombi had formed intimal plaques frequently. Other noticeable changes were parasitic aneurysm and Hemomelasma ilei. From these findings of the two cases it is suggested that AIT is one of the pathological conditions caused by Strongylus vulgaris infection.
Vascular obstruction of the hindlimbs was diagnosed clinically in 15 horses, and was characterized at necropsy in eight of those horses. The condition was identified as an incidental post mortem finding in two additional horses. The principal clinical signs in affected horses were progressive exercise intolerance and hind-leg lameness. At post mortem the oldest lesions were located at the aortic quadrifurcation and in the distal portions of the femoral and internal iliac arteries, and consisted of partially or completely occlusive masses of well-organized and well-vascularized fibrous tissue, occasionally containing hemorrhagic or degenerate areas. Proximal to these organized masses, large unorganized thrombi were often present. In the region of the occlusive masses, the tunica intima was obliterated, except for the internal elastic lamina which usually remained intact. The tunica media was largely unaffected, except for ischemic necrosis of the media in greatly distended arteries or under thick plaques. The pathogenesis of the lesions is unresolved. The lesions may result from organization of strongyle-related thromboemboli or the inciting cause may be progressive enlargement and organization of spontaneously developing fibrous intimal plaques. Hypercoagulability of the blood may have contributed to thrombosis in one mare with the nephrotic syndrome. Routine examination of the aortic quadrifurcation and its major branches is recommended in order that subclinical changes may be detected and the natural history of the lesion elucidated.
The prognosis of aortic-iliac thrombosis (TAI) is usually considered to be poor, although affected horses are reported to have recovered following treatment with sodium gluconate. This paper presents some diagnostic techniques to monitor the development of hypoxemia in the diseased limb and to visualise the extension of the thrombosis into the femoral artery. Also, a surgical technique using a Fogarty thrombectomy catheter for partial or total removal of thrombi to restore blood flow, is described. One horse recovered completely, allowing it to resume its former career, the other horse improved. The preliminary results of surgical interference in horses with TAI are promising.
There is no consensus on the efficacy of physical training, smoking cessation, and pharmacological therapy (pentoxifylline or nafronyl oxalate) in the treatment of patients with intermittent claudication at Fontaine stage II of disease.
A MEDLINE and manual search was used to identify relevant publications. Uncontrolled or retrospective studies, double reports, and trials without clinically meaningful outcomes were excluded. Included studies were graded level 1 (randomized and double- or assessor-blind), level 2 (open randomized), or level 3 (nonrandomized). Pain-free and total walking distance were the main outcomes considered; when feasible, end-of-treatment results were combined with appropriate meta-analytical procedures.
In 5 level 2 studies, physical training increased pain-free and total walking distance significantly (139.0 m [95% confidence interval {CI}, 31.0 to 246.9 m] and 179.1 m [95% CI, 60.2 to 298.1 m], respectively). In a level 3 study, smoking cessation resulted in a nonsignificant increase in total walking distance of 46.7 m (95% CI, -19.3 to 112.7 m). In 6 level 1 studies, pentoxifylline increased both pain-free and total walking distance by 21.0 m (95% CI, 0.7 to 41.3 m) and 43.8 m (95% CI, 14.1 to 73.6 m), respectively. In 4 level 1 trials, nafronyl significantly increased pain-free walking distance (58.6 m [95% CI, 30.4 to 86.8 m]) and total walking distance (71.2 m [95% CI, 13.3 to 129.0 m]).
Physical training increased pain-free and total walking distance in level 2 studies. Only level 3 studies support the usefulness of smoking cessation. In level 1 studies, pentoxifylline and nafronyl increased pain-free and total walking distance, but the average effects were relatively small.
In the past ten years, there have been significant advances in the diagnosis and therapy of arterial vascular disease. While long-term morbidity can only be improved by changing the patient's life-style and removing any risk factors that may be present(hypertension, hyperlipidemia,obesity,diabetesmellitus, nicotine abuse), symptomatic relief may be obtained by various procedures. Besides conservative treatment of arterial occlusive disease (physical therapy, medical treatment) and surgical vascular interventions (thromboendarterectomy, bypass procedures), balloon catheters introduced percutaneously under local anesthesia have found increased application in virtually all areas for the dilatation and recanalization of obstructive lesions in the past few years. The technique of balloon dilatation, as introduced by Griintzig as a further development of the percutaneous interventions by Dotter and Judkins, is no longer the decisive issue. The main objective of present clinical research is to de termine the proper indications and patient selection for this procedure, which has found its place between conservative treatment and surgery. The contents of this Symposium should provide some guidelines for the indi cations and postprocedural therapy for the referring physician, the angiologist, and for the radiologist and cardiologist performing the dilatation. We owe our thanks to all the specialists involved, who have provided us with the benefits of their experience. Mrs. H. Beilmann and Dr. M. Wojtowycz con tributed substantially to the preparation of the text. I would like to thank them and the staff of Springer-Verlag for their conscientious work in the interest of composition and publication quality.
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 100mg 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.
Pharmacodynamic Profile
Cilostazol has antiplatelet, antithrombotic and vasodilating properties. In vitro, ex vivo and in vivo studies have shown that cilostazol inhibits both primary and secondary platelet aggregation induced by ADP, collagen, arachidonic acid, epinephrine (adrenaline), thrombin, remnant-like lipoprotein and shear stress without affecting bleeding time. In animal models, cilostazol inhibited thrombus formation induced by various stimuli.
Cilostazol causes vasodilation by inhibiting calcium-induced contractions of smooth muscle cells (SMCs) while having no direct effect on contractile proteins. Cilostazol 100mg twice daily for 6 weeks significantly increased skin temperature, ankle blood flow and skin blood flow in the legs of patients with intermittent claudication (p < 0.05).
The drug also inhibits proliferation of vascular SMCs induced by a variety of growth factors in animal models and human cells in vitro and demonstrates beneficial effects on certain plasma lipids. High density lipoprotein-cholesterol levels increased and levels of triglycerides decreased relative to placebo or baseline after 8–12 weeks’ treatment with cilostazol 100mg twice daily in two randomized, double-blind trials.
The precise mechanism by which cilostazol improves the symptoms of intermittent claudication is not fully known, but is thought to be multifactorial. Cilostazol is a selective inhibitor of phosphodiesterase-III (PDE-III), thereby suppressing cyclic adenosine monophosphate (cAMP) degradation. Cilostazol also inhibits adenosine uptake into cells which augments the cAMP-elevating effect of PDE-III inhibition.
Pharmacokinetic Profile
In patients with intermittent claudication, steady state was reached within 4 days following multiple doses of cilostazol. The peak plasma concentration (Cmax) at steady state was 1331.5 μg/L with a regimen of 100mg twice daily and occurred 2.7 hours after the final dose. The high apparent volume of distribution of cilostazol (2.76 L/kg) suggests extensive tissue binding. Cilostazol is extensively bound to plasma proteins with a free fraction of 2–5%.
Coadministration of cilostazol with food (a high fat meal) increased the rate and also the extent of cilostazol absorption.
Cilostazol is extensively metabolized (oxidative metabolism) to dehydro-cilostazol (OPC-13015) by cytochrome P450 (CYP) 3A4 and to monohydroxy-cilostazol (OPC-13213) via CYP2C19. A radiolabeled dose of cilostazol in healthy volunteers showed that urine (73.8%) and feces (21.7%) were the major routes of excretion. Cilostazol had an elimination half-life of 10.5 hours in patients with intermittent claudication.
The pharmacokinetic profiles of cilostazol and its two main metabolites (OPC-13015 and OPC-13213) after the administration of cilostazol 100mg twice daily over a 7-day period to healthy middle-aged and elderly men and women (aged 50–80 years) were not significantly affected by age or gender.
Mild to moderate renal impairment did not affect the pharmacokinetics of multiple doses of cilostazol (50mg twice daily for 6 days). However, severe renal impairment alters plasma concentrations and the protein binding of cilostazol and its metabolites, and the drug is contraindicated in these patients in Europe. Mild or moderate hepatic impairment had no appreciable effect on the pharmacokinetic properties of a single dose of cilostazol 100mg or its metabolites, while the effects of severe hepatic impairment on cilostazol pharmacokinetics have not been evaluated.
Coadministration of cilostazol with moderate inhibitors of CYP3A4 led to significantly increased cilostazol Cmax values (by 47% with erythromycin) or exposure (by 53% with diltiazem). Coadministration of cilostazol with an inhibitor of CYP2C19, omeprazole, resulted in a significant increase in the systemic exposure of cilostazol (26%).
Cilostazol does not appear to inhibit CYP3A4, as there were no changes in the pharmacokinetics of a single dose of lovastatin 80mg or its metabolites when coadministered with cilostazol at steady state (lovastatin is primarily metabolised by CYP3A4.
There were no clinically significant interactions after coadministration of cilostazol 100mg twice daily and aspirin 325 mg/day and cilostazol 100mg twice daily and a single dose of warfarin 25mg as measured by the prothrombin time, activated partial thromboplastin time and bleeding time or platelet aggregation.
Therapeutic Efficacy
Results from eight well designed 12- to 24-week clinical trials involving more than 2000 patients with intermittent claudication have shown that treatment with cilostazol 100mg twice daily is generally associated with significant improvements in maximum walking distance (MWD) and pain-free walking distance (PFWD) at study end compared with placebo (p < 0.05). The efficacy of cilostazol was seen as early as 4 weeks after initiation of therapy.
The efficacy of cilostazol 50mg twice daily has been studied in two clinical trials. One trial, found that cilostazol 50mg twice daily resulted in significantly greater improvements in MWD (p < 0.001) and PFWD (p < 0.001) compared with placebo. However, the other trial found no significant difference in the improvements in MWD seen with cilostazol 50mg twice daily and placebo.
Cilostazol 100mg twice daily (n = 205 intent-to-treat [ITT] analysis) was significantly more effective in increasing the MWD (p < 0.0002) and PFWD (p < 0.02) than pentoxifylline 400mg three times daily (n = 212 ITT analysis) after 24 weeks of treatment in a large clinical trial in patients with moderate to severe intermittent claudication. There was no significant difference between pentoxifylline and placebo with regards to changes in walking distance during the trial.
Evidence suggests that patients with intermittent claudication perceive their functional status and quality of life to be significantly improved with cilostazol compared with placebo. Patient perceptions of functional status or quality of life were similar for those receiving cilostazol 100mg twice daily or pentoxifylline 400mg three times daily. However, significantly more patients treated with cilostazol assessed their response to treatment as successful relative to baseline compared with those receiving pentoxifylline.
Treatment with cilostazol 100mg twice daily significantly increased the resting ankle brachial index (ABI) compared with placebo (p < 0.05); however, this was only a moderate improvement in terms of clinical significance. There was no significant difference for the change in ABI between the cilostazol or pentoxifylline treatment groups.
Withdrawal of treatment was studied in a subgroup of patients (n = 45) who participated in the large comparative study with pentoxifylline. The results of this small study suggest that withdrawal of cilostazol resulted in a significant loss of walking distance in patients with intermittent claudication by 2 weeks (p = 0.001). Conversely, the withdrawal of pentoxifylline did not significantly affect walking distances.
Tolerability
Cilostazol was generally well tolerated in clinical trials. Pooled tolerability data from placebo-controlled clinical trials indicated headache, diarrhea, abnormal stools, pain, infection, pharyngitis, rhinitis, peripheral edema and nausea were the most common adverse events, occurring in 5% or more of cilostazol recipients (n = 1301). Adverse events were generally mild to moderate in intensity, transient or resolved after symptomatic treatment and rarely required treatment withdrawal.
Adverse events reported more often with cilostazol than with pentoxifylline were headache, diarrhea, abnormal stools and palpitations. However, a similar percentage of patients receiving cilostazol and pentoxifylline withdrew from the large clinical trial because of adverse events (16% vs 19%).
The rate of serious adverse events (myocardial infarction, chest pain or angina pectoris) was low and similar between the three treatment groups (cilostazol, pentoxifylline and placebo).
Pharmacoeconomic Considerations
Data from a single study presented as an abstract and poster suggest that although cilostazol has a higher acquisition cost than both pentoxifylline and placebo the incremental cost per quality-adjusted life-year is reasonable compared with pentoxifylline and placebo. No studies assessing the cost effectiveness of cilostazol have been reported.
Dosage and Administration
Cilostazol is indicated for the reduction of symptoms of intermittent claudication in the US and for the improvement of MWD and PFWD in patients with intermittent claudication in Europe.
The recommended dosage of cilostazol for intermittent claudication is 100mg twice daily administered orally half an hour before, or 2 hours after, meals. No dosage adjustments are recommended for the elderly. In Europe, no dosage adjustments are recommended for patients with mild hepatic impairment or those with mild to moderate renal dysfunction (creatinine clearance [CLCR] of >1.5 L/h [>25 mL/min]).
Cilostazol is contraindicated in patients with congestive heart failure of any severity due to theoretical concerns related to its mechanism of action and classification as a PDE-III inhibitor. Caution is recommended when using cilostazol in patients with coronary heart disease as the long-term effects of cilostazol in these patients are unknown. The effects of cilostazol in patients with moderate or severe hepatic impairment and in nursing or pregnant women have not been extensively studied; however, in Europe cilostazol is contraindicated in these patients. In Europe, cilostazol is also contraindicated in patients with severe renal impairment (CLCR <-1.5 L/h [<-25 mL/min]), patients with any known predisposition to bleeding, those with a history of ventricular tachycardia, ventricular fibrillation or multifocal ventricular ectopics or patients with a prolongation of the corrected QT interval. In the US, caution is recommended when cilostazol is to be coadministered with inhibitors of CYP3A4 or CYP2C19 and a lower dosage of 50mg twice daily should be considered; however, in Europe cilostazol is contraindicated in patients receiving these drugs.
Of 64 complete iliac obstructions, 50 (78%) were recanalized using the Gruntzig balloon catheter. Life-table analysis of the patency rate over a 4-year period gives a cumulative success rate of 78%. Only three of eight obstructions that involved both the common and external iliac arteries were successfully dilated. The only serious complication was distal embolization, which occurred in two cases (3.1%). Although the procedure is difficult, with a relatively low technical success rate, the high cumulative patency rate should make it an option in the treatment of all patients with totally occluded iliac artery segments.
Percutaneous transluminal angioplasty (Dotter technique) was used in 2,942 cases of iliofemoral atheromatous disease. Results varied with the characteristics of the obstructing lesion (length and location) and the clinical stage of ischemia (claudication, rest pain, gangrene). Based on the foregoing, angioplasty is done either as the preferred primary treatment or for the relief of clinically advanced disease in patients unsuitable for high risk surgery. Success is favored by the use of aggregation inhibitors and single-use Teflon or balloon catheters; complications are few.
We performed a randomized, double-blind, placebo-controlled, multicenter trial to evaluate the relative efficacy and safety of cilostazol and pentoxifylline.
We enrolled patients with moderate-to-severe claudication from 54 outpatient vascular clinics, including sites at Air Force, Veterans Affairs, tertiary care, and university medical centers in the United States. Of 922 consenting patients, 698 met the inclusion criteria and were randomly assigned to blinded treatment with either cilostazol (100 mg orally twice a day), pentoxifylline (400 mg orally 3 times a day), or placebo. We measured maximal walking distance with constant-speed, variable-grade treadmill testing at baseline and at 4, 8, 12, 16, 20, and 24 weeks.
Mean maximal walking distance of cilostazol-treated patients (n = 227) was significantly greater at every postbaseline visit compared with patients who received pentoxifylline (n = 232) or placebo (n = 239). After 24 weeks of treatment, mean maximal walking distance increased by a mean of 107 m (a mean percent increase of 54% from baseline) in the cilostazol group, significantly more than the 64-m improvement (a 30% mean percent increase) with pentoxifylline (P <0.001). The improvement with pentoxifylline was similar (P = 0.82) to that in the placebo group (65 m, a 34% mean percent increase). Deaths and serious adverse event rates were similar in each group. Side effects (including headache, palpitations, and diarrhea) were more common in the cilostazol-treated patients, but withdrawal rates were similar in the cilostazol (16%) and pentoxifylline (19%) groups.
Cilostazol was significantly better than pentoxifylline or placebo for increasing walking distances in patients with intermittent claudication, but was associated with a greater frequency of minor side effects. Pentoxifylline and placebo had similar effects.
We have selected a model of photochemically induced thrombosis in hamsters and mice in which thrombus formation is visualized via transillumination and quantified via image analysis. Applying a gray-compensation method, the images of developing thrombi were presently transformed and a three-dimensional (3D) reconstruction of thrombus evolution performed off line. To this end, a nondimensional Gray-compensated parameter Gc was calculated. The integrated Gc (IGc) correlated linearly (r=0.973) with the amount of light transilluminated and previously quantified as arbitrary light units. Matching Gc for reconstructed occlusive arterial and venous thrombi with the inner diameters of the hamster carotid artery and femoral vein, enabled the further conversion of IGc to real thrombus volumes, up to 0.14 mm3 in the carotid artery. In addition to enabling a graphical three-dimensional reconstruction of experimental thrombosis, via image subtraction, the kinetics of thrombus growth were visualized. Thus, platelet-mediated thrombus growth was found to occur randomly in small thrombi, but in larger thrombi, it occurred preferentially in its tailing vortex in areas of recirculating flow. The present study therefore confirms in vitro findings in an in vivo model. The 3D reconstruction and kinetics of thrombus growth may be helpful in the mechanistic and pharmacological study of experimental thrombosis. © 2003 Biomedical Engineering Society.
PAC2003: 8719Uv, 8750Hj, 8757Gg
Unfractioned heparin (UFH) is widely used for prophylaxis of coagulation disorders, especially in colic-affected horses. However, it is accompanied by certain side effects.
To compare the efficacy and side effects of unfractioned and low molecular weight heparin (LMWH) in horses with colic.
The study was carried out as a randomised, double-blind, controlled clinical trial. Fifty-two horses with colic were treated subcutaneously with either UFH (heparin calcium, 150 iu/kg bwt initially, followed by 125 iu/kg bwt q. 12 h for 3 days and then 100 iu/kg bwt q. 12 h) or LMWH (dalteparin, 50 iu/kg bwt q. 24 h). All horses underwent daily physical examination including assessment of jugular veins, local reaction to heparin injections, haematological evaluation and coagulation profiles over up to 9 days.
The type of heparin used did not affect the general behaviour and condition. There were significantly more jugular vein changes in horses treated with UFH. Packed cell volume decreased significantly within the first few days of UFH treatment, but did not change significantly in horses treated with LMWH. Activated partial thromboplastin time (aPTT) and thrombin time (TT) were prolonged in horses treated with UFH but not in those treated with LMWH.
It was concluded that, in comparison to UFH, LMWH has markedly fewer side effects in horses.
Therefore, LMWH is recommended for prophylaxis of coagulation disorders in colic patients.
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.
We report the primary and mid-term outcome of patients with long chronic iliac artery occlusions after percutaneous excimer-laser-assisted interventional recanalization. Between 2000 and 2001, 43 patients with 46 chronic occlusions of either the common iliac artery (n=27), the external iliac artery ( n=13) or both (n=3) underwent laser-assisted percutaneous transluminal angioplasty and implantation of stents. The average length of the occlusion was 57.1+/-26 mm. After laser-assisted angioplasty and implantation of a total of 60 stents, the patients were followed up for up to 4 years. Patency rates were analyzed by ankle-brachial index (ABI) measurement and duplex ultrasound. The primary technical success rate was 95.3%, with a major complication rate of 6.9%. Clinical improvement as categorized by the Rutherford guidelines could be observed in 97.6% of cases. The ABI of all patients improved from an average of 0.46+/-0.08 before intervention to 0.97+/-0.13 at the end of the follow-up period. The overall primary patency rate was 86.1%. Four reinterventions were successful (secondary patency rate 95.4%). The mid-term results of the percutaneous recanalization of iliac artery occlusions with primary and secondary patency rates of 86.1 and 95.4% are similar to those of the treatment of short stenoses.
Pathology of aortic-iliac thrombosis in two horses) Thrombectomy. Minimally invasive surgical techniques
- Surg
- T Oyamada
- K Saigami
- C H Park
- Y Katayama
- M A Oikawa
Surg. 13, 109-114. Oyamada, T., Saigami, K., Park, C.H., Katayama, Y. and Oikawa, M.A. (2007) Pathology of aortic-iliac thrombosis in two horses. J. equine Sci. 18, 59-65. Rijkenhuizen, A.B.M. (2006) Thrombectomy. Minimally invasive surgical techniques. In: Equine Surgery, 3rd edn., Eds: J.A. Auer and J.A. Stick, W.B