Methods applied in cost-effectiveness models for treatment strategies in type 2 diabetes mellitus and their use in Health Technology Assessments: a systematic review of the literature from 2008 to 2013.

OBJECTIVE: To identify and compare health-economic models that were developed to evaluate the cost-effectiveness of treatments for type 2 diabetes mellitus (T2DM), and their use within Health Technology Assessments (HTAs). METHODS: In total, six commonly used databases were searched for articles published between October 2008 and January 2013, using a protocolized search strategy and inclusion criteria. The websites of HTA organizations in nine countries, and proceedings from five relevant conferences, were also reviewed. The identified new health-economic models were qualitatively assessed using six criteria that were developed based on technical components, and characteristics related to the disease or the treatments being assessed. Finally, the number of times the models were applied within HTA reports, published literature, and/or major conferences was determined. RESULTS: Thirteen new models were identified and reviewed in depth. Most of these were based on identical key data sources, and applied a similar model structure, either using Markov modeling or microsimulation techniques. The UKPDS equations and panel regressions were frequently used to estimate the occurrence of diabetes-related complications and the probability of developing risk factors in the long term. The qualitative assessment demonstrated that the CARDIFF, Sheffield T2DM and ECHO T2DM models seem technically equipped to appropriately assess the long-term health-economic consequences of chronic treatments for patients with T2DM. It was observed that the CORE model is the most widely described in literature and conferences, and the most often applied model within HTA submissions, followed by the CARDIFF and UKPDS models. CONCLUSION: This research provides an overview of T2DM models that were developed between 2008 and January 2013. The outcomes of the qualitative assessments, combined with frequent use in local reimbursement decisions, prove the applicability of the CORE, CARDIFF and UKPDS models to address decision problems related to the long-term clinical and economic consequences of new and existing T2DM treatments.

Cost-effectiveness of dapagliflozin versus DPP-4 inhibitors as an add-on to Metformin in the Treatment of Type 2 Diabetes Mellitus from a UK Healthcare System Perspective.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is a chronic, progressive condition where the primary treatment goal is to maintain control of glycated haemoglobin (HbA1c). In order for healthcare decision makers to ensure patients receive the highest standard of care within the available budget, the clinical benefits of each treatment option must be balanced against the economic consequences. The aim of this study was to assess the cost-effectiveness of dapagliflozin, the first-in-class sodium-glucose co-transporter 2 (SGLT2) inhibitor, compared with a dipeptidyl peptidase-4 inhibitor (DPP-4i), when added to metformin for the treatment of patients with T2DM inadequately controlled on metformin alone. METHODS: The previously published and validated Cardiff diabetes model was used as the basis for this economic evaluation, with treatment effect parameters sourced from a systematic review and network meta-analysis. Costs, derived from a UK healthcare system perspective, and quality-adjusted life years (QALYs), were used to present the final outcome as an incremental cost-effectiveness ratio (ICER) over a lifetime horizon. Univariate and probabilistic sensitivity analyses (PSA) were carried out to assess uncertainty in the model results. RESULTS: Compared with DPP-4i, dapagliflozin was associated with a mean incremental benefit of 0.032 QALYs (95% confidence interval [CI]: -0.022, 0.140) and with an incremental cost of £216 (95% CI: £-258, £795). This resulted in an ICER point estimate of £6,761 per QALY gained. Sensitivity analysis determined incremental costs to be insensitive to variation in most parameters, with only the treatment effect on weight having a notable impact on the incremental QALYs; however, there were no scenarios which raised the ICER above £15,000 per QALY. The PSA estimated that dapagliflozin had an 85% probability of being cost-effective at a willingness-to-pay threshold of £20,000 per QALY gained. CONCLUSIONS: Dapagliflozin in combination with metformin was shown to be a cost-effective treatment option from a UK healthcare system perspective for patients with T2DM who are inadequately controlled on metformin alone.

The cost-effectiveness of dapagliflozin versus sulfonylurea as an add-on to metformin in the treatment of Type 2 diabetes mellitus.

AIMS: To assess the cost-effectiveness of dapagliflozin, a sodium-glucose co-transporter-2 (SGLT-2) inhibitor, compared with a sulfonylurea, when added to metformin for treatment of UK people with Type 2 diabetes mellitus inadequately controlled on metformin alone. METHODS: Clinical inputs sourced from a head-to-head randomized controlled trial (RCT) informed the Cardiff diabetes decision model. Risk equations developed from the United Kingdom Prospective Diabetes Study (UKPDS) were used in conjunction with the clinical inputs to predict disease progression and the incidence of micro- and macrovascular complications over a lifetime horizon. Cost and utility data were generated to present the incremental cost-effectiveness ratio (ICER) for both treatment arms, and sensitivity and scenario analyses were conducted to assess the impact of uncertainty on the final model results. RESULTS: The dapagliflozin treatment arm was associated with a mean incremental benefit of 0.467 quality-adjusted life years (QALYs) [95% confidence interval (CI): 0.420; 0.665], with an incremental cost of £1246 (95% CI: £613; £1637). This resulted in an ICER point estimate of £2671 per QALY gained. Incremental costs were shown to be insensitive to parameter variation, with only treatment-related weight change having a significant impact on the incremental QALYs. Probabilistic sensitivity analysis determined that dapagliflozin had a 100% probability of being cost-effective at a willingness-to-pay threshold of £20,000 per QALY. CONCLUSIONS: Dapagliflozin in combination with metformin was shown to be a cost-effective treatment option compared with sulfonylurea from a UK healthcare perspective for people with Type 2 diabetes mellitus who are inadequately controlled on metformin monotherapy.

Dapagliflozin compared with other oral anti-diabetes treatments when added to metformin monotherapy: a systematic review and network meta-analysis.

AIMS: Indirect evidence from randomized controlled trials (RCTs) was used to estimate the effect of dapagliflozin, a new agent with a novel mechanism of action (SGLT-2 inhibition), relative to other anti-diabetes therapies after 1 year of treatment. METHODS: A systematic literature review and Bayesian network meta-analysis (NMA) of RCTs involving anti-diabetes treatments added to metformin were conducted. RCTs enrolling subjects with type 2 diabetes inadequately controlled on metformin monotherapy were included. Comparators included dipeptidyl peptidase-4 (DPP-4) inhibitors, thiazolidinediones (TZDs), sulphonylureas, glucagon-like peptide-1 (GLP-1) analogues and dapagliflozin. Outcomes of interest were mean change from baseline HbA1c, weight and systolic blood pressure, and incidence of hypoglycaemia. RESULTS: From 4270 abstracts, six RCTs were included in the primary analysis; no RCTs involving GLP-1 analogues met primary inclusion criteria. All RCTs were actively controlled with sulphonylureas. The mean change in HbA1c from baseline was similar across comparators. The treatment effect (95% credible interval) of dapagliflozin on HbA1c was -0.08% (-0.25, 0.10) relative to DPP-4 inhibitors, -0.02% (-0.24, 0.21) relative to TZDs and 0.00% (-0.16, 0.16) relative to sulphonylureas. Non-sulphonylureas showed significantly lower risk of hypoglycaemia relative to sulphonylureas. Dapagliflozin had a significant effect on weight change: the relative difference was -2.74 kg (-5.35, -0.10) compared with DPP-4 inhibitors, and -4.67 kg (-7.03, -2.35) compared with sulphonylureas. Systolic blood pressure was not meta-analysed due to infrequent reporting. CONCLUSION: Compared with DPP-4 inhibitors, TZDs and sulphonylureas, dapagliflozin offers similar HbA1c control after 1 year, with similar or reduced risk of hypoglycaemia and the additional benefit of weight loss, when added to metformin.

Quantitative and qualitative control of cytotoxic preparations by HPLC-UV in a centralized parenteral preparations unit.

The constantly growing incidence of cancer and long-term treatment are leading to an increasing number of cytotoxic preparations in hospital pharmacies. Security and quality standards of cytotoxic preparations are essential to assure treatment efficiency and limit iatrogenic toxicity. In order to secure the process of cytotoxic preparations; we decided to install a quantitative and qualitative High Performance Liquid Chromatography (HPLC) control of cytotoxic preparations carried inside our pharmacotechnic unit. A 100 microl sample of each preparation was assayed by HPLC with ultraviolet/visible-diode array detection, which enabled the identification of all cytotoxic agents thanks to their characteristic UV spectra. We developed rapid and specific HPLC assays that determined qualitatively and quantitatively the presence of 21 different cytotoxic agents in less than 3.5 min. A fifteen per cent tolerance from the theoretical concentration was chosen in agreement with preparation and dosage bias, and a first period control of more than 4400 preparations revealed that around 7.7% preparations did not conform. The main objective of these controls was to avoid the administration of defective chemotherapies to patients and finally to use their results to identify error factors; as a result we will take corrective measures in order to reduce error frequency.

[Thrombosis of valvular prostheses: the role of medical treatment]. / Thrombose de prothèses valvulaires: place du traitement médical.

Thromboses of valvular prostheses represent a rare but serious complication for mechanical valves, and are sometimes fatal. Obstructive thromboses present an immediate threat to life, while the more common, more insidious, non-obstructive thromboses are essentially manifested by thrombo-embolic events. These thromboses often occur at times of insufficient anticoagulation, especially during the first post-operative year and during treatment breaks for non-cardiac surgery, an increasingly common situation. The therapeutic management of an 'obstructive' thrombosis is above all surgical. However, fibrinolysis represents an effective alternative, although it does present a not insignificant risk of systemic embolism (in the order of 10 to 15%). The main indications for fibrinolysis are thromboses of right heart valves, and for left heart prostheses, patients in a very unstable haemodynamic state, remoteness from a cardiac surgery centre, any surgical contraindications, and cases where a large thrombus has been excluded by trans-oesophageal ultrasound. In cases of contraindications to both surgery and fibrinolysis, treatment with heparin might be proposed, but without any great hopes of completely unblocking the prosthesis. Treatment of a 'non-obstructive' thrombosis is primarily medical: optimising anticoagulation with intravenous heparin, or even the addition of aspirin. When the thrombus is large and mobile, surgery should be envisaged if medical treatment fails.

Effect of metformin on fibrinolytic parameters in insulin-treated, type 2 diabetic patients.

OBJECTIVE: In the present study, we measured fibrinolytic parameters, including PAI-1 antigen and activity in a group of type 2 diabetic patients in secondary oral anti-diabetic failure treated with insulin alone or with insulin plus metformin. RESEARCH DESIGN AND METHODS: 12 type 2 diabetic patients in secondary oral anti-diabetic failure were randomly allocated into two groups receiving insulin alone or insulin plus metformin 1000 mg twice a day; six weeks later, the treatments were swapped over. At the end of each treatment period, blood samples were withdrawn for metabolic and fibrinolytic analysis. RESULTS: There were no significant differences in fasting blood glucose, fructosamine or fibrinogen; LDL cholesterol, PAI-1 antigen and activity, insulin needs were reduced by the inulin plus metformin regimen (LDL cholesterol: 1.59 +/- 0.62 versus 1.28 +/- 0.5 mmol/l, PAI-1 antigen: 28.3 +/- 17.4 versus 23.9 +/- 18 ng/ml, PAI-1 activity: 23.8 +/- 9.6 versus 21.9 +/- 10 IU/ml, insulin needs: 64 +/- 18 versus 52 +/- 15 U/day (p<0.05). CONCLUSION: In type 2 diabetic patients with secondary oral treatment failure, insulin alone controlled blood glucose but had no effect on the levels of PAI-1; addition of metformin improved the fibrinolytic parameters.

[Fibrinolysis and thrombosis of mechanical valvular prosthesis: risk stratification by transesophageal echocardiography]. / Fibrinolyse et thrombose de prothèse valvulaire mécanique: stratification du risque par échocardiographie transoesophagienne.

The place of fibrinolysis in the treatment of mechanical valvular prostheses is still much discussed. The aim of this work is to define the role of transoesophageal echocardiography in risk stratification. This monocentric study draws on 49 cases of thrombolysis preceded by transoesophageal echocardiography (average age 62.1 years, 37 mitral, 11 aortic, 1 tricuspid, 1 mitro-tricuspid). There were 41 obstructive thromboses (OT) and 8 non-obstructive thromboses (NOT). Clinical events and the effectiveness of fibrinolysis were studied as a function of the obstructive or non-obstructive character of the thrombosis and the size of the thrombus < 10 mm (n = 33) or > or = 10 mm (n = 16). Complete success was observed in 34 patients (69.4%). Follow up revealed 2 early cerebral haemorrhages (4.1%) of which one was in the NOT group, and six systemic emboli (12.2%) of which one was in the NOT group. There was a relationship between the size of the thrombus and embolus at the limit of significance in favour of an increased risk of embolus for a voluminous thrombus. Furthermore, the mobility of the thrombi went in hand with an increased rate of systemic emboli (p < 0.01). The rate of failure of fibrinolysis and/or complications correlated with the size of thrombus (complete success in 88% of the < 10 mm thrombus group, versus 35% in the > or = 10 mm; p < 0.01). This work underlines the significance of trans-oesophageal echocardiography in the therapeutic choice for valvular prosthesis thrombosis and suggests that the existence of a voluminous thrombus especially if mobile is a contra-indication for fibrinolysis.

[Anticoagulation in mechanical valve prostheses. A difficult situation]. / Anticoagulation des prothèses valvulaires mécaniques. Les situations difficiles.

Although long-term anticoagulant therapy in patients with mechanical valve prostheses is well codified, a number of difficult situations persists because of the high thromboembolic risk. The protocols of anticoagulation suggested in these situations are controversial as there are no large scale prospective therapeutic trials. However, modern protocols take more and more into account the thromboembolic risk in each individual case. The authors review the most common situations: the early postoperative period for which no precise consensus exists in the literature; anticoagulation in extra-cardiac surgery, a common situation for which the protocols remain very debatable; anticoagulation in pregnancy, a special situation because of the risk of embryopathy with oral anticoagulant therapy and the risk of thromboembolism with heparin; anticoagulation in cases of thromboembolic complications; anticoagulation during infectious endocarditis; anticoagulation during serious haemorrhage.

Multicenter study of an erythro-aggregometer: quality control and standardization.

There is a need for quality assurance procedures in hemorheology, especially for clinical and pharmacological studies, which require reliable and well-calibrated instruments to be interpretable and comparable. Preliminary investigations allowed preparation of standardized SM (normal NS and hyperaggregable HS), and checking of storage conditions (in accordance with the guidelines of the SSC of ISTH) of RBC in nutritive SAG mannitol for at least 2 or 3 weeks with subsequent washings and resuspension in SM. In our study, we compared erythro-aggregometers of the same brand in 6 laboratories, using the same red blood cells (RBC) and suspending media (SM) for each series of tests. EA was measured by laser backscattering with determination of aggregation time (AT), partial dissociation threshold (PDT) and aggregation index (AI). Prior to the study, devices were set up on the same day with the same standardized blood, and calibration data were then analyzed. Within-assay precision (WAP) was assessed on 3 days for the 2 types of SM (n = 18 x 2). Between-assay precision (BAP) was assessed on 6 occasions, once every month (n = 6 x 2 x 6). Accuracy was studied with 3 series of RBC resuspended in 10 SM of "unknown" aggregability. Good agreement was observed between 5/6 centers for the 3 parameters of EA. WEP was good: CV of AT ranging from 1.4 to 2.5% for the NS and from 1.4 to 2.4% for the HS. In each center, BAP was slightly lower than WEP (CV: 8-11.8% for the NS and 3.8-4.7% for the HS over the 6-month study), with no drift, except for one center. Precision was always better with the HS than with the NS which seemed a better tool to assess it. As to accuracy, non-significant differences were generally found between centers, with similar data to the reference values. This work also stressed the importance of the RBC parameter itself in rheological data. For the first time, a protocol for standardization of EA has been developed and evaluated, permitting the Quality Control of this technique.

[Antithrombotic therapy in patients with mechanical valve prostheses]. / Traitement antithrombotique chez le porteur de prothèse valvulaire mécanique.

Mechanical valvular prostheses have the advantage of longevity but carry a risk of thrombosis which is itself dependent on many haemodynamic, haemostatic and parietal factors. Antithrombotic therapy in patients with mechanical valvular prostheses is based on vitamin-K antagonists, the optimal dosage of which should reflect the type and location of the prosthesis and the underlying pathology. The patient with a mechanical valvular prosthesis treated by oral anticoagulation must be fully informed and regularly followed up. Special situations: extracardiac surgery, dental extraction, gastrointestinal endoscopy, require specific, well established management.

Fibrinolysis and hemorheology in chronic venous insufficiency: a double blind study of troxerutin efficiency.

Abnormal increase of erythrocyte aggregation and reduction of profibrinolytic activity are the two most frequent biological perturbations found in chronic venous insufficiency (CVI). A randomised, controlled, double blind trial was undertaken on 85 patients suffering from grade 1 and 2 CVI, to compare troxerutin with placebo. Two types of biological parameters were measured after 15 days of treatment. Erythrocyte aggregation as evaluated with a Myrenne erythroaggregometer by the indices M (stasis) and M1 (3s-1) progressed favorably in the troxerutin group. The values of M1 at D15 (p < 0.05), and the progression of M (p < 0.001) and M1 (p < 0.01) from D0 to D15, are significantly better in the troxerutin group. Progression of fibrinolytic activity at rest was not significantly different between the 2 groups. Conversely, the progression from D0 to D15 of the values after occlusion of euglobulin lysis time (p < 0.01), tPA (p < 0.01), and PAI activity (p < 0.05) are significantly better in the troxerutin group. The fibrinolysis capacity estimated by euglobulin lysis time (p < 0.01) and tPA (p < 0.05) also progressed favorably in the troxerutin group. These results confirm the anti-erythrocyte aggregation effect of troxerutin, and suggest a favorable effect on blood fibrinolytic activity. They could explain the positive action of this drug on stasis, capillary perfusion and trophic complications of CVL.

Mechanical cardiac valve thrombosis. Is fibrinolysis justified?

BACKGROUND: Thrombosis is a serious complication of heart valve replacement, and management is often difficult. In recent years, thrombolytic therapy has been used as the primary technique by some investigators. METHODS AND RESULTS: Sixty-four consecutive patients presenting with 75 instances of prosthetic heart valve thrombosis (41 mitral, 33 aortic, one tricuspid) were treated with fibrinolytic agents. Obstructed prosthetic valves comprised 39 tilting disc and 36 bileaflet valves. The time interval between valve replacement and obstruction ranged from 15 days to 192 months (mean, 38 months). Fibrinolytic agents used were streptokinase (42 patients), urokinase (27 patients), or recombinant tissue-type plasminogen activator (six patients). Immediate results of fibrinolytic treatment were 1) full success after one or several consecutive fibrinolytic regimens in 55 cases (73%), 2) incomplete improvement in two cases, and 3) failure in 18 cases, leading to an emergency surgery in nine cases. Nine patients died (four strokes, four cardiac arrests, one hemorrhage). Only one severe hemorrhagic complication was observed, but 11 cases of embolism occurred during fibrinolytic treatment (14.6%) (four major cerebral embolisms with death). The immediate efficacy was better for thrombosed aortic prosthesis than with the mitral prosthesis (85% versus 63%). CONCLUSIONS: Fibrinolytic treatment appears to be an attractive nonsurgical alternative for prosthetic heart valve thrombosis, but because of the risk of cerebral embolism, its use should be reserved for tricuspid valve thrombosis or critically ill patients with mitral or aortic valve thrombosis. The use of a fibrinolytic agent in cases of small, nonobstructive paravalvular thrombosis demonstrated with transesophageal echocardiography needs further studies.

[Prevalence of asthma and respiratory diseases in schools in Bouake (Ivory Coast): preliminary results]. / Prévalence de l'asthme et des maladies respiratoires en milieu scolaire à Bouake (Côte d'Ivoire): résultats préliminaires.

Using an auto-administered questionnaire, a cluster sample survey was carried out in January 1990 among 2433 secondary schoolchildren in Bouake (Cote d'Ivoire). The prevalence rate of asthma was fairly high (10.8%), as well as that of wheezing (19.8%), dyspnea (42.8%), broncho-pulmonary diseases (25.8%) and smoking habit (14.5%). The results are discussed with regard to the published data.

Standard heparin but not LMW heparin induces a concomitant increase of t-PA and PAI-1 without modification of global fibrinolysis: study after 60 days treatment.

The relationship between heparin and fibrinolysis is strongly suggested. We have studied the influence on fibrinolysis of standard heparin (SH), Calciparin and low molecular weight heparin (LMWH), Fraxiparin, given preventively in an elderly population. Patients were randomized into two groups (SH, LMWH). We investigated fibrinolytic parameters (ECLT, t-PA antigen, PAI-1 activity and antigen, t-PA/PAI-1 complexes) before treatment (D0) and at D30 and D60, before and after venous occlusion (VO). Values at D0, D30 and D60 were compared within each group. A significant and marked increase in t-PA and t-PA/PAI-1 complexes at D30 and D60 before and after VO was noted only in the SH group. The mechanism and clinical relevance of this increase remains to be established.

Leucocytic alkaline phosphatase activity in leprosy: a possible guide in the follow-up of leprosy.

In order to investigate a possible involvement of phagocytic cells in the various types of leprosy, we undertook the study of enzymatic activities in circulating leucocytes. The activity of leucocytic alkaline phosphatase was studied by histochemical techniques on blood smears in 31 patients presenting with leprosy and aged between 4 and 73, and in 11 non infected people. The 31 patients suffering from leprosy were distributed as following: 14 lepromatous leprosy of which 6 had not yet been treated and 8 were under treatment, 9 cases of tuberculoid leprosy of which 7 had been treated and 2 had not yet, 3 cases of borderline leprosy which had all been treated, and 5 patients whose form of leprosy was indeterminate (before treatment). The distribution of the different values we obtain shows a very significant difference (p less than 0.001) between patients with and without leprosy (respectively 33.8 +/- 7.3 and 109.8 +/- 12.5). Moreover, the decrease of the alkaline phosphatase activity correlated with the severity of the disease (47.2 +/- 11.4 in tuberculoid leprosy and 20.6 +/- 9.3 in lepromatous leprosy) thus suggesting that the evaluation of leucocytic alkaline phosphatase activity should be advised as a possible prognosis guide in indeterminate leprosy.

[Recurrent thrombosis of an aortic valve prosthesis in a pregnant woman. Treatment with urokinase]. / Thrombose récidivante d'une prothèse valvulaire aortique chez une femme enceinte. Traitement par urokinase.

A 36 year old woman developed two thromboses on aortic valve prosthesis. The first thrombus at the 14th week of pregnancy was treated with urokinase (2,000 U/kg/h) plus heparin (700-1,000 U/h) over 24 hours and normal wing kinetics were obtained. The second thrombus developed at the 36 th week of pregnancy when the patient was receiving calciparin, and only transient improvement was obtained with similar doses of urokinase hourly over 72 hours. Progressive worsening resulted in higher doses (4,000 U/kg/h) being given without heparin and the thrombus then resolved. The use of urokinase for the first time in this indication allowed therefore, on two occasions and without hemorrhagic complications the cure of this recurrent thrombosis on aortic prosthesis, and the birth, by caesarean, of a healthy baby.

Hemorheological changes in elderly subjects--effect of pentosan polysulfate and possible role of leucocyte arachidonic acid metabolism.

The effects of pentosan polysulfate (PPS) on various hemorheological parameters were studied in a group of very elderly subjects in good general health. Alterations in blood viscosity and filterability were detected in these patients, without any concomitant changes in factors which are known to affect these parameters: notably hematocrit, fibrinogen and plasma lipid levels. The hemorheological abnormalities were considerably improved by twice daily treatment with 50 mg of PPS (i.m.). Apart from its anticoagulant activity, PPS has been shown to have an anti-inflammatory action. We were interested to investigate its effects on metabolism of exogenous arachidonic acid (AA) by both platelets and leucocytes. It is becoming increasingly recognized that metabolites of AA via the 5 LO pathway appear to play a role in inflammatory processes. In this study, PPS was found to inhibit leucocyte 5 LO activity. Reduction in the levels of these metabolites may therefore have an effect on whole blood rheology.