Monday, 30 Jan 2012 15:57
By Jörn Oliver Balzer
Pulmonary embolism continues to be a major cause of morbidity and mortality in the United States. In most clinical situations, anticoagulation is the preferred form of therapy. The efficacy of inferior vena cava filters is still discussed controversially since several factors for effective pulmonary embolism prevention have to be considered.Inferior vena cava filters are indicated in only a small proportion of patients who have venous thromboembolism. Anticoagulation should be initiated after filter placement as soon as it is safe to do so and the filter should then be removed shortly thereafter. In these situations, retrievable filters are recommended. Inferior vena cava filters are known to be thrombogenic and are associated with an increased risk of recurrent deep venous thrombosis and inferior vena cava thrombosis.According to a study published by Cherry et al (J Trauma. 2008; 65:544 –548), a statistically significant increase in inferior vena cava filter placement over three years without an impact on the overall pulmonary embolism rate among trauma patients was noted in the USA.According to this study the results are similar to other studies published in this field placing the effectiveness of inferior vena cava filters in doubt. The current criteria used for determining which patients will benefit are not sufficient enough to have an effect at reducing the overall rate of pulmonary embolism. In another publication by Ingber et al (Current Opinion in Hematology 2009, 16:402–406) the authors come to the conclusion that despite increasing placement of inferior vena cava filters, particularly in the United States, they believe that the only indication for filter use is in patients with a proximal deep venous thrombosis in whom anticoagulation is contraindicated. According to the recently published guidelines Diagnosis and Management of Acute Pulmonary Embolism (European Heart Journal. 2008; 29:2276–2315) by the European Society of Cardiology, the systematic use of venous filters is not recommended in the general population with venous thromboembolism at present. According to these guidelines, venous filters may be used when there are absolute contraindications to anticoagulation and a high risk of venous thromboembolism recurrence, including, for example, the period immediately after neurosurgery or other major surgery. They may also be considered in pregnant women who develop extensive thrombosis in the weeks before delivery. As soon as it is safe to use anticoagulants, retrievable filters should be removed.So far there is only one randomised publication with a long-term follow-up of up to eight years analysing the risk/benefit of inferior vena cava filters in the prevention of pulmonary embolism (Circulation 2005; 112:416–422). In this study, 400 patients with deep venous thrombosis (with or without pulmonary embolism) were treated either with an anticoagulant (unfractionated vs. low molecular weight heparin plus an oral anticoagulant) alone, or with an anticoagulant combined with the insertion of a vena cava filter.This study shows that a reduced risk of recurrent pulmonary embolism was observed at the cost of an increased risk of recurrent deep venous thrombosis with no overall effect on survival in patients undergoing permanent inferior vena cava filter insertion.In the recent analysis by Young et al (Cochrane Database Syst Rev. 2010 Feb 17;(2)) on inferior vena cava filters for the prevention of pulmonary embolism the authors came to the conclusion that no recommendations can be drawn from the only two randomised studies published so far. One study showed a reduction in pulmonary embolism rates but not in mortality, but was subject to significant biases. The PREPIC study lacked statistical power to detect a reduction in pulmonary embolism over shorter and more clinically significant time periods. However, the PREPIC trial demonstrated that permanent vena cava filters were associated with an increased risk of long-term lower limb deep venous thrombosis.Overall there is a lack of outcome evidence in the use of inferior vena cava filters when used within currently approved indications and a lack of trials on retrievable filters. Further trials are needed to assess vena cava filter safety and effectiveness.
Jörn Oliver Balzer is director, associate professor, Clinic for Radiology and Nuclearmedicine, St Vincenz und Elisabeth Hospital, Mainz, Germany
Monday, 30 Jan 2012 14:50
Regula von Allmen, vascular research fellow, Division of Surgery, Department of Surgery and Cancer, Faculty of Medicine, Imperial College London, UK, attended the VEITHsymposium where a session on chronic cerebrospinal venous insufficiency (CCSVI) was held. She wrote this article for Vascular Newson the controversial subject, based on the discussions from New York.
Paolo Zamboni, professor at the University of Ferrara in Italy, launched a great debate in 2009 by claiming to have found the underlying condition for a very dreadful disease, multiple sclerosis. The CCSVI phenomenon was born.Zamboni promoted a venoplasty-based therapy which he called the “liberation procedure”. In fact this approach is very tantalising because it brings multiple sclerosis down to a potentially curable disease and additionally it raises hope for the patients, which is also emphasised by the name of the procedure.Multiple sclerosis is estimated to affect more than 400,000 people in the USA and more than two million people worldwide. It is typically a disease of young adults characterised by either a relapsing or progressive impairment in neurologic function resulting in significant disability. It is an inflammatory neurological disease widely considered to be autoimmune in nature, though its exact origins remain elusive.The CCSVI hypothesis implies that venous congestion, as a result of insufficient venous drainage due to intra-luminal flow obstacles in the jugular veins, increases pericapillary iron deposition causing a subsequent autoimmune response and thus brain damage. This theory found its way immediately into the public consciousness. Moreover, it has also instigated one of the greatest disputes in medicine. There are as many opponents as proponents of it.
At the 38th VEITHsymposium in New York, USA, a whole session was assigned to the CCSVI controversy.Zamboni opened this session with the topic “How can duplex identify large vein stenosis: An enthusiast’s view”. Zamboni explained that the most frequently noted intraluminal defects or abnormalities inside internal jugular veins, such as malformed or fixed valves, septa and webs may be detected in a high resolution B-mode ultrasound. He also emphasised that the assessment of the five criteria for CCSVI should be applied in supine and upright positions due to gravity induced hydrostatic gradient mechanisms.
Moreover, “the localisation of the extracranial venous obstruction is not specific and can occur everywhere” as Michael Dake, chief of Interventional Radiology at Stanford University California, USA, and a clear proponent of CCSVI highlighted later on. Another interventionalist, Claudio Rabbia, chief of the Vascular and Interventional Department at Hospital Molinette of Turin, Italy, raised the question as to whether intravascular ultrasound should become standard to improve accuracy in pre- and postprocedural venous stenosis assessment.The enthusiasts and budding enthusiasts found it interesting to learn that a consensus document regarding 2011 ultrasound-based criteria for screening for CCSVI will be published very soon in International Angiology, Functional Neurology as advertised and recommended by Zamboni: “This is a very important document ensuring more accurate and comparable results around centres”.The core issue in the CCSVI debate is the controversy of how often internal jugular venous stenoses occur in the community. Zamboni reported a prevalence of 70% for CCSVI in multiple sclerosis patients versus 10% in control patients. These findings are combined results from 14 studies. Jean-Baptiste Ricco, professor of Vascular Surgery, University of Poitier, France, and editor-in-chief of the European Journal of Vascular and Endovascular Surgery, an opponent of the theory, stated in his introductory remarks that “there are a lot of negative studies from angiologists and neurologists reporting no difference in the presence of positive CCSVI criteria between multiple sclerosis patients and controls”. He concluded that “CCSVI does not seem to be a disease but a description of an anatomic variation”. He also raised concerns about the rapid worldwide popularity of the treatment, promoted by the help of social networks and by emotional testimonials from treated patients despite the lack of scientific evidence.
Manish Mehta, a vascular surgeon from the Vascular Group in Albany, USA, reported the Albany experience. They followed 100 multiple sclerosis patients (62% female, mean age 47 years) with CCSVI and venoplasty. The defined endpoints, evaluated preprocedurally and at one, three and every six months thereafter, consisted of a timed 25-foot walk, Multiple Sclerosis Quality of Life-54, and Modified Fatigue Impact Scale. The immediate success rate for the venoplasty procedure, defined as a less than 30% stenosis, was 82%. The results from 79 patients were available for a longer follow-up analysis, at a mean of 4.5 months. Mehta presented a restenosis and occlusion rate of 8% and 2% respectively, with no major complications or deaths. With regard to the endpoints, patients experienced statistically significant improvements in timed 25-foot walk, MSQOL-54, and MFIS, and over two-thirds of the patients reported alleviation in multiple sclerosis symptoms.On the other side, it is evident that any possible treatment for what has been thought of as an incurable disease such as multiple sclerosis immediately gains popularity, as has happened in the past. Kieran Murphy, professor of Neuroradiology in Toronto, Canada, mentioned that even multiple bee stings and hyperbaric oxygen were believed to cure multiple sclerosis in the past and both theories were flawed. Murphy pointed out that the stories of amazing results from the new multiple sclerosis treatment could be more about the “placebo effect”. Placebo is a Latin word for “I shall please” and placebos can have a surprisingly positive effect.In consequence, there is now an urgent need for a double-blinded randomised controlled trial for testing treatment effectiveness and getting level 1 evidence. Nelson Hopkins, professor and chairman of Neurosurgery, professor of Radiology from the University at Buffalo, the State University of New York, USA, presented the status of such a randomised trial launched in 2010, the PREMISE (Prospective Randomized Endovascular therapy in Multiple Sclerosis) trial. In its first phase, 10 multiple sclerosis patients with venous insufficiency underwent minimally invasive venous angioplasty to prove the safety of the procedure. In its second phase, 20 multiple sclerosis patients are randomised to either venous angioplasty or “sham angioplasty” with insertion of a catheter but no inflation of the balloon. So far, 18 patients have been included in this phase. All patients are being followed for six months with an additional fMRI at the end of this stage. The defined endpoints assess safety of the procedure, efficacy of the procedure (restoration of venous outflow, change in relapse rate or disease progression and MRI parameters) and self reported improvement of quality of life.Indeed, in the future a larger number of patients have to be studied in a blinded randomised controlled way to convincingly prove or disprove the association of CCSVI with multiple sclerosis. Is CCSVI an entity and a subset of multiple sclerosis remains? The question remains. This CCSVI session at the 38th VEITHsymposium showed that there are still more questions than answers. We do now need a reliable scientific approach to ensure that a well-intentioned but possibly ineffective treatment is not used to take advantage of a vulnerable group of patients.
Wednesday, 08 Feb 2012 10:58
Timothy Clark, University of Pennsylvania, Philadelphia, USA, stated that triple drug transarterial chemoembolization (TACE) with cisplatin, Adriamycin and mitomycin C has been standard in USA for over 20 years. But recurring drug shortages may be just the prompt needed to re-evaluate drug selection, he said.
Clark, who was speaking at the fourth annual symposium on Clinical Interventional Oncology held in Miami in January, pointed out that drug availability had also become an unexpected problem recently. “However, this is also an opportunity to reassess and optimise drug selection. A methodical, data-driven approach is needed,” he said.“How did triple drug TACE become conventional TACE in the USA?” questioned Clark. He said that cisplatin crosslinks the guanine bases of DNA and prevents mitosis; Adriamycin intercalates DNA and prevents the double helix from re-sealing during replication and mitomycin C also crosslinks DNA.Why were the three drugs combined? Clark told delegates that cisplatin was combined with doxorubicin and mitomycin based on the unpublished pilot experience of Aigner et al who found the treatment to be active and well-tolerated in a few patients.Clark also made the point that drug shortages in the USA increased from 61 in 2005 to 178 in 2010. “In 2010–11, 80% involved sterile injectable drugs for chemotherapy, antibiotics and electrolyte/nutrition. There is now an Executive Order effective from October 2011 for early notification of potential drug shortages,” he said.He noted that Bristol-Myers Squibb stopped manufacturing cisplatin powder in December 2010, which had previously been provided through a restricted access programme free of charge. The company has suggested the use of carboplatin powder as replacement.Similarly, Bedford Laboratories had Adriamycin (doxorubicin) on backorder due to manufacturing delays (as on 2/2/2011). As limited quantities were available, replacement with epirubicin powder was suggested.There were also oil shortages after Guebert LLC acquired Ethiodol, the main supplier of oil, from Nycomed. In the interim, Guerbet was authorised by the FDA to import Lipiodol Ultra-Fluide (same ethyl esters of iodised fatty acids of poppy seed oil). “Interestingly, Ethiodol is 37% iodine weight/weight and Lipiodol Ultra-Fluide is 48% iodine weight/volume,” said Clark.He also suggested that Idamycin (idarubicin) which is more lipophilic than Adriamycin, available as a 20mg lyophilised powder from Pfizer, has a high level of tissue binding and is FDA-approved for leukemia, might be a possible substitute for doxorubicin. A better rationale is needed based on pharmacokinetics, cell culture, pre-clinical and clinical studies to justify the triple therapy TACE with different agents, said Clark.