Results Of Comparative Clinical Trials Research Articles

Role of disarticulation and guillotine amputation of the shin in the lower limb ischemic gangrene surgical treatment strategy

Ischemic foot gangrene is one of the most common reasons of nontraumatic low limb amputations all over the world. Objective: to analyze the clinical effectiveness of an individual treatment strategy application for patients with absolute indications for high limb amputation, aimed to reduce amputation level, the number of postoperative complications and mortality. Materials and methods. This article presents the results of comparative clinical trial executing a lower-extremity amputation in 992 patients with ischemic gangrene. Applied in this study strategy of surgical treatment included usual below-knee, above-knee amputations and guillotine amputations in the lower third of the shin also the shin exarticulation without wound plastic. Guillotine amputations was used as an intermediate stage of treatment in cases where due to the severe general condition of patients to perform a classic myoplastic amputation with stump formation was impossible, since it is accompanied by a very high risk of postoperative complications and mortality. Results. Using guillotine amputations and shin exarticulation as the first stage of complex surgical strategy aimed to rapid elimination of the purulent focus with minimal risks and the speedy stabilization of the patients general condition, emaciated and weakened by developing gangrene, led to reduce general lethality by 17.1 % and increased the quantity of below-knee amputations by 23.0 % compared with the comparison group. Conclusion. Patients with ischemic gangrene require the development of an individual strategy for surgical treatment (taking into account the severity of the patients general condition, the prevalence of the purulent-necrotic process in the lower limb, the nature and degree of peripheral macroangiopathy), which can reliably and significantly reduce the number of amputations at the hip level (by 46.2%), as well as reduce mortality after high amputations of the lower extremities (by 17.1%) in an emergency city hospital. We consider it extremely important to reduce the number of primary amputations at the hip level!

Efficiency of an implant: new criterion of objective assessment of implants for osteosynthesis of femoral neck fracture.

In line with several designs for osteosynthesis of femoral neck fracture (FNF), their effectiveness is still estimated by the results of biomechanical and clinical trials, finite element method (FE). But surgeons require the criteria which would define their properties in advance and allow improve the results of treatment. When new implant (NI) is being designed, we developed such criterion - index efficiency of an implant (IEI) - and performed mathematical comparative researches of properties of NI with the known designs. We analyzed the results of comparative clinical trials on treatment of FNF with various implants considering their IEI. Analysis showed that results of comparative clinical trials with the use of various implants for osteosynthesis FNF completely correlated to their IEI; IEI of the NI two to three times exceeds IEI of all known designs, and the destruction percentage of a bone tissue is two to three times less when it is applied. The offered IEI can be used for designing new implants and allows improving the results of treatment of patients with FNF by optimizing the choice of implant for osteosynthesis.

Assessment of the Feasibility of Therapeutic Equivalence Studies

The introduction of the «therapeutic equivalence» concept into the Russian legislation is critical for evaluation of medicines interchangeability and for recognising them as generics. It is stipulated by the legislation that therapeutic equivalence has to be evaluated using a special instrument — «therapeutic equivalence study». The aim of this work was to analyse the validity of considering a therapeutic equivalence study as the only study that allows for confirmation of therapeutic equivalence of medicines. The term «therapeutic equivalence» has been adopted by the leading world regulators, but there is no clear concept of what is a therapeutic equivalence clinical study. The key distinctive features of the foreign approach, as compared to the Russian one, are comparison of medicines with one active pharmaceutical ingredient, and additional conditions for the establishment of therapeutic equivalence. The clinical trial methodology, which is based on the use of statistical analysis methods, also imposes constraints on evaluation of «similarity» of properties, efficacy and safety of medicines in a single study. Hence, there are several reasons why the results of comparative clinical trials can not be used as a sole basis for the establishment of therapeutic equivalence. These results have to be substantiated by confirmation of comparable composition and pharmacokinetic parameters of medicines in order for them to be considered therapeutically equivalent. This does not contradict the existing regulatory framework and is consistent with the current scientific methodology for conducting clinical trials.

Urinary Versus Recombinant Gonadotropins for Ovarian Stimulation in Women Undergoing Treatment with Assisted Reproductive Technology.

Globally, about 10%–15% couples are affected by infertility, with major role being played by the couple's lifestyle. Several gonadotropin preparations (urinary, purified urinary, recombinant, and biosimilars) are available for use. Purified urinary formulations offer numerous advantages over their predecessor, including lesser injection dose required, ability to be administered subcutaneously, less batch-to-batch variability, better efficacy, ability to individualize protocols as per patient's need, better control of developing follicles, less risk of multiple pregnancies, and hyperstimulation. Published results of Cochrane reviews and meta-analysis show no difference in efficacy or safety between urinary and recombinant gonadotropins. In the absence of any significant difference, cost plays an important role in deciding choice of gonadotropins. In this article, we have reviewed the results of comparative clinical trials, Cochrane analysis, and meta-analysis to derive consensus statements regarding efficacy, safety, and cost implications of urinary versus recombinant gonadotropin preparations.

THE COSTS OF REGIONAL ANESTHESIA WITH THE USE OF LEVOBUPIVACAINE, RACEMIC BUPIVACAINE AND ROPIVACAINE

Background and Objective . Currently in clinical practice are widely used local anesthetics, including racemic bupivacaine, levo isomer of its levobupivacaine and structurally similar to bupivacaine levo isomer ropivacaine. The aim of this work was to assess the cost of anesthesia levobupivacaine, bupivacaine and ropivacaine. Material and methods . In accordance with the results of comparative clinical trials and expert evaluation analysis was conducted in two ways: under the assumption of equal clinical effectiveness of levobupivacaine and bupivacaine and a higher efficiency of levobupivacaine compared with ropivacaine (assumed in various clinical situations with an equal volume of solution used ropivacaine in concentrations of 0.5% may be replaced without reducing clinical efficacy of levobupivacaine in a concentration of 0.5%, ropivacaine in a concentration of 0.75% – levobupivacaine in a concentration of 0.5 and 0.75% (in equal proportions); ropivacaine at a concentration of 1% – levobupivacaine at a concentration of 0.75%. The ropivacaine dose equivalent to 1 mg of levobupivacaine, made when calculating the average of 1.20 mg), and under the assumption of equal clinical effectiveness compare local anesthetics. The analysis was carried out for medicines containing 10 ml of solution per ampoule on the basis of registered prices of bupivacaine and ropivacaine. The cost of levobupivacaine was calculated based on expected rates of registration in the case of inclusion in the Essential Drugs List (0,5% R-R amp. 10 ml №10 – 947,74 RUB; 0.75% of p-p amp. 10 ml №10 – 1421,60 RUB). Results . Subject to the adopted scenario 1 assumptions levobupivacaine allows you to reduce costs 29.6-56.9 per cent compared with bupivacaine and ropivacaine. Taking into account the consumption of local anesthetics in 2016 (according to IMS Health), the replacement of bupivacaine and ropivacaine by levobupivacaine will allow you to reduce costs on average by 38.0%. Projected savings when replacing bupivacaine and ropivacaine in concentrations of 0.5-1.0% in ampoules of 10 ml will be 69,305 million RUB/year, taking into account the accepted assumptions. Under the assumption of equal effectiveness bupivacaine, ropivacaine and levobupivacaine (scenario 2), the replacement of bupivacaine and ropivacaine on levobupivacaine will reduce costs by an average of 29.6%. Given the amount of consumption savings will be 34,012 million RUB/year. Conclusion. Replacement of bupivacaine and ropivacaine in concentrations of 0.5-1.0% in vials of 10 ml levobupivacaine at a concentration of 0.5-0.75% will allow taking into account assumptions significantly reduce budget costs without reducing the effectiveness of treatment. Reducing the burden on the budget could be achieved under the assumption of equal efficacy of drugs and replacement of bupivacaine and ropivacaine by levobupivacaine in the same concentration.

ANALYSIS OF THE INFLUENCE OF THROMBOEMBOLIC COMPLICATIONS PREVENTION WITH ORAL ANTICOAGULANTS ON BUDGET IN PATIENTS WITH NON-VALVULAR ATRIAL FIBRILLATION

Atrial fibrillation (AF) is a risk factor for thromboembolic complications, requiring administration of vitamin K antagonists (warfarin) or the new oral anticoagulants (apixaban, dabigatran and rivaroxaban). Aim. To assess the influence of apixaban use on the budget as an alternative to warfarin, dabigatran or rivaroxaban use in patients with non-valvular AF in the Russian Federation (RF). Material and methods. The analysis was performed with the perspective of the health care budget with 5 year horizon period and by the pharmacoeconomic model developed by Pharmerit International (Rotterdam, Netherlands) and adapted for the RF. The cardiovascular complications rate in the model was in line with the results of comparative clinical trials: ARISTOTLE, AVERROES, RE-LY, ROCKET-AF. The analysis suggested that 100% of patients with atrial fibrillation were transferred on apixaban instead of warfarin, dabigatran or rivaroxaban. The analysis was based on the assumption that patients were fully committed to the therapy over the horizon of the study, ie, refusal of treatment was not considered. The possibility of episodes of ischemic and hemorrhagic strokes, the severity of which corresponded to previously published data for the Russian population, was considered in the study. The present study was performed based on two scenarios. In the first of them the cost of anticoagulation therapy was determined on the basis of the average weighted prices of public procurement for the period from 04.01.2014 to 01.04.2015. The alternative scenario purported to demonstrate potential savings of the budget of the health care system on the inclusion of apixaban in the list of essential drugs. This scenario took into account that the cost of dabigatran and rivaroxaban corresponded to registered maximum selling price including 10% VAT and 10% of the wholesale allowance and the cost of apixaban - presumed maximum selling price which the producer intends to register in case the drug is included in the essential drugs list, subject to 10% VAT and 10% wholesale mark. The cost of complications treatment corresponded to the rate of compulsory health insurance for the city of St. Petersburg for 2015. Results. The estimated number of patients with non-valvular AF who require anticoagulation therapy in the RF is 1,196,600 people according to the epidemiological data. Treatment with apixaban significantly reduces the incidence of cardiovascular events as compared with warfarin and rivaroxaban. The results of the budget impact analysis, taking into account the price obtained at auction from 01.04.14 through 01.04.15, show a decrease in the load on the budget when the apixaban is included in the therapy regimen of non-valvular atrial fibrillation. Potential savings of resources of the health care system reached 10.9 billion rubles as compared with dabigatran and 39.2 billion rubles as compared with rivaroxaban. This advantage can be explained by both the lower cost of apixaban in comparison with reference drugs, and a reduction of the in-hospital expenses on complications treatment. Switching from warfarin to apixaban increases the budget load in 2.81 times. However, previous data demonstrate the economic feasibility of the additional costs of apixaban, that help to achieve significant advantages from a clinical point of view. The results obtained on the basis of prices, intended to include apixaban in the list of essential drugs, showed that in this case the savings of the budget of the health care system will reach 127-129 bln. rubles for 5 years (average 26%) as compared with dabigatran and rivaroxaban. The comparison of apixaban with warfarin showed an increase in total costs of therapy in 2.72 times. Conclusion. The inclusion of apixaban in the therapy regimen of non-valvular atrial fibrillation can significantly reduce the burden on the budget of the health care system as compared with dabigatran and rivaroxaban, as well as reduce the incidence of cardiovascular events compared with warfarin. This allows recommending the inclusion of the drug in the federal and regional programs for the prevention of thromboembolic complications in this group of patients.

Die Rolle der peroralen endoskopischen Myotomie (POEM) bei der ösophagealen Achalasie

Achalasia is a rare motility disorder of the oesophagus. Classic achalasia is characterised by a lack of propulsive peristalsis of the distal oesophagus and incomplete relaxation of the lower oesophageal sphincter (LES). Traditionally achalasia is treated either endoscopically by pneumatic balloon dilatation or laparoscopically by Heller's myotomy. Both therapeutic procedures show a comparable effectiveness. Recently, peroral endoscopic myotomy was introduced as a new definitive treatment option. So far, this minimally invasive therapy was evaluated in a few clinical studies only. In this survey, peroral endoscopic myotomy is presented and compared to the well established surgical treatment. The diagnosis of achalasia is based on the patient's medical history and analysis of symptoms and particularly on oesophageal manometry. In addition, a barium swallow (oesophagram) and upper endoscopy are performed to rule out other reasons causing dysphagia. The patient's complaints should be recorded by use of a symptoms score. The POEM procedure starts with an incision of the mucosa at the level of the mid-oesophagus. Then, a submucosal tunnel is created distally passing approximately 2 cm over the oesophagogastric junction. After this step, myotomy of (at least) the circular muscle bundle of the distal oesophagus is performed and should be extended to a distance of 2 cm over the cardiac. Finally the mucosal entry site at the level of the mid-oesophagus is closed with endoscopic clips. First results of this technique are very promising with significant symptom relief and reduction of the mean LES pressure. In conclusion, POEM is a new, minimally invasive therapeutic option for the treatment of oesophageal achalasia. First results are very promising; long-term results and results of comparative clinical trials with established treatment methods must be awaited.

A review of the scientific evidence on the treatment of traumatic brain injuries and strokes with hyperbaric oxygen

Objective: This review sought to determine the strength of the scientific evidence relating to the therapeutic use of hyperbaric oxygen for traumatic brain injury or stroke. In order to reduce the possibility of omitting relevant human clinical trials, parallel searches of the Medline, HealthStar and Embase databases were undertaken, and input was sought from local experts in hyperbaric medicine as well as from a widely noted proponent of this therapy. Papers retrieved were reviewed to ensure that they reported the results of comparative clinical trials and were then reviewed by a panel of scientists. Papers were scrutinized for methodological flaws, and the clinical significance of the results was examined. Outcome: The strongest papers indicated either no effect or harm from hyperbaric oxygen when used to treat traumatic brain injuries or strokes. Conclusion: The scientific literature up to August 2001 does not support the use of hyperbaric oxygen for traumatic brain injuries and strokes.

AT(1)-receptor blockers: differences that matter.

The available angiotensin II type 1 (AT(1))-receptor blockers differ markedly in their pharmacological properties and clinical efficacy. Losartan shifts the dose-response curve for angiotensin II to the right without affecting the maximal response; this antagonism can be overcome by increasing concentrations of angiotensin II and thus losartan acts as a surmountable antagonist. By contrast, other agents suppress the maximal response to angiotensin II to varying extents; this can not be overcome by increasing angiotensin concentrations and hence these agents are insurmountable antagonists. Receptor binding studies have shown that candesartan has the highest affinity for the AT(1)-receptor, followed by irbesartan, valsartan and losartan, and that candesartan dissociates from the receptor more slowly than other antagonists. A meta-analysis using an E(Max) model has shown that differences in receptor binding activity are reflected in differences in maximal antihypertensive effect, and this finding is supported by the results of comparative clinical trials. Moreover, the prolonged binding of candesartan to the receptor is reflected in a longer duration of action, compared with losartan; the antihypertensive effect of candesartan persists for 48 h after dosing, compared with approximately 24 h with losartan. Candesartan thus offers extended therapeutic coverage, an important consideration since a majority of patients miss occasional doses of antihypertensive medication. There is currently no evidence that differences in receptor binding between AT(1)-receptor blockers translate into differences in tolerability. In summary, therefore, pharmacological differences between AT(1)-receptor blockers are reflected in clinically important differences in maximal antihypertensive effect, response rate, and duration of action.

Quinupristin/dalfopristin: A therapeutic review

Background: The proliferation of multidrug-resistant gram-positive bacteria, including methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium (VREF), has created a pressing need for effective alternative antibiotics. Quinupristin/dalfopristin is a new combination streptogramin product with a selective spectrum of antibacterial activity, mainly against gram-positive aerobic bacteria. It has been assessed primarily in emergency-use protocols, in hospitalized patients with skin and skin-structure infections, and in patients with VREF bacteremia. Objectives: The objectives of this review were to summarize important results of in vitro microbiologic studies; to provide information on relevant pharmacokinetic parameters, drug interactions, and Y-site compatibility; and to assess efficacy and safety data from clinical studies of quinupristin/dalfopristin. Methods: Articles included in this review were identified by a MEDLINE ® search of the literature published between 1966 and September 2000 using the terms Synercid ®, quinupristin, and dalfopristin. Additional articles were retrieved from the reference lists of articles identified in the MEDLINE search. Results: In vitro analysis of the spectrum of activity of quinupristin/dalfopristin has confirmed its relatively selective coverage of gram-positive aerobic bacteria. Both quinupristin and dalfopristin undergo hepatic metabolism and are extensively excreted in the feces. Combination quinupristin/dalfopristin inhibits the cytochrome P450 3A4 pathway, and caution is warranted with concomitant use of other medications eliminated via this pathway. In trials in patients with VREF infections, treatment success with quinupristin/dalfopristin varied depending on the site of infection, ranging from 51.9% in bacteremia of unknown origin to 88.9% in urinary tract infections. The results of comparative clinical trials suggest that quinupristin/dalfopristin has similar efficacy to that of commonly used antibiotics, including cefazolin, oxacillin, and vancomycin, in patients with skin and skin-structure infections or nosocomial pneumonia. The most frequently reported adverse effects with administration of quinupristin/dalfopristin were infusion-site inflammation, pain, and edema; other infusion-site reactions; and thrombophlebitis. Arthralgia, myalgia, nausea, diarrhea, vomiting, and rash occurred in 2.5% to 4.6% of patients and were the most frequently reported systemic adverse events. Conclusions: Outcomes data from clinical trials indicate that quinupristin/dalfopristin has the potential to play an important role in the treatment of bacteremia, complicated skin and skin-structure infections, and nosocomial pneumonia caused by VREF. Issues of bacterial resistance to quinupristin/dalfopristin and other appropriate uses of this combination agent remain to be elucidated.

P-24 Milnacipran: A double and well-balanced noradrenaline and serotonin reuptake inhibitor: Results of comparative clinical trials

P-24 Milnacipran: A double and well-balanced noradrenaline and serotonin reuptake inhibitor: Results of comparative clinical trials

Controversies: synthetic or natural surfactant. The case for natural surfactant.

Surfactant replacement therapy for respiratory distress syndrome (RDS) is not new, the first trials having been performed over 30 years ago. These early trials used synthetic protein-free surfactants administered as aerosols and were unsuccessful. Since 1980 a variety of natural and synthetic surfactant preparations have been used to treat or prevent RDS, and both demonstrate clinical effects. I have used evidence derived from 3 areas to demonstrate the superiority of natural surfactants: in vitro physical properties, in vivo physiological effects and the results of comparative clinical trials. using the pulsating bubble surfactometer, the surface tension at maximum and minimum bubble size are significantly lower for natural compared to synthetic surfactants (31 and 0 mN/m versus 53 and 29 mN/m respectively). Physiological effects of surfactants have been compared in immature rabbits and lambs and both models demonstrate the superiority of natural surfactants. For example in immature rabbits lung compliance values after 60 minutes of ventilation are 0.60 ml/cmH2O in natural surfactant treated animals, 0.44 ml/cmH2O in synthetic surfactant treated animals and 0.34 ml/cmH2O in controls (p < 0.01). The technique of meta-analysis was used to analyse the outcome of 6 comparative clinical trials of natural and synthetic surfactants. These 6 studies included 3536 babies and 5 of them compared Survanta (a bovine natural surfactant) and Exosurf (a synthetic protein-free surfactant). One study compared Infasurf (another bovine natural surfactant with Exosurf). Meta-analysis shows a 19% reduction in the odds of neonatal death for natural compared to synthetic surfactant treated babies (OR, 0.81; 95% CI 0.66-0.98). For bronchopulmonary dysplasia there was a non-significant reduction in risk for Survanta-treated babies (OR, 0.93; 95% CO 0.78-1.10). In summary, there is now clear evidence of physiological and clinical superiority of natural compared to synthetic surfactants. Surfactant proteins B and C are needed to facilitate rapid adsorption and spreading of phospholipids. They also account for the more rapid clinical action allowing oxygen and ventilator pressures to be lowered soon after administration. The odds of neonatal mortality are reduced by about 20% if natural surfactants are preferred to their synthetic protein-free counterparts. Long-term follow-up studies of babies treated with both types of surfactant should be a top priority.

THE ROLE OF LEVOCABASTINE IN THE TREATMENT OF ALLERGIC RHINOCONJUNCTIVITIS

SUMMARY Allergic rhinoconjunctivitis is a common atopic condition frequently encountered in clinical practice, with prevalence figures as high as 20% reported. The socioeconomic impact of this condition is considerable — not only in terms of medical costs but lost work and schooldays and quality of life. A wide range of therapeutic approaches is available, including levocabastine, an extremely potent and highly specific H1‐receptor antagonist which has been developed for topical application as eyedrops and nasal spray. The available clinical data demonstrate that this agent is well tolerated, with an adverse effect profile comparable to sodium cromoglycate and placebo. Onset of action is rapid, with maximum therapeutic effects typically being observed within minutes of application. Results of comparative clinical trials suggest that topical levocabastine is as at least as effective as oral antihistamines and sodium cromoglycate for the treatment of allergic rhinoconjunctivitis, and it is suggested as an attractive alternative to oral antihistamines as first‐line therapeutic option.

Third-generation and investigational cephalosporins: II. Microbiologic review and clinical summaries.

In vitro susceptibility of Streptococcus pyogenes, Staphylococcus aureus, Staphylococcus epidermidis, Klebsiella pneumoniae, Pseudomonas aeruginosa, Escherichia coli, Serratia marcescens, Hemophilus influenzae, Bacteroides fragilis, and Neisseria gonorrhea to three new second-generation and eight third-generation cephalosporins is tabulated. In general, the newer cephalosporins have an extended spectrum of activity against gram-negative bacteria, including Serratia marcescens, Pseudomonas aeruginosa, and Neisseria gonorrhea. They also tend to be active against anaerobes, including Bacteroides fragilis. However, they generally have less activity against gram-positive bacteria when compared with the first- and second-generation cephalosporins. Clinical summaries are given for each of the cephalosporins, with emphasis on the results of comparative clinical trials. These cephalosporins may prove especially useful in nosocomial infections with resistant organisms, intraabdominal infections, febrile episodes in the granulocytopenic patient, and meningitis.