Myfanwy Lloyd Jones

A systematic review of the clinical effectiveness of pioglitazone in the treatment of type 2 diabetes mellitus

BACKGROUND Pioglitazone is a member of a recently developed class of glucose-lowering agents, the thiazolidinediones, used in the treatment of type 2 diabetes mellitus. In the United States, it is approved for use both as monotherapy and in combination with metformin, a sulfonylurea, or insulin; in Europe, it is approved for use in combination with metformin or a sulfonylurea but not insulin. OBJECTIVE This article presents a systematic review of the published literature on the effectiveness of pioglitazone in the treatment of type 2 diabetes, both as monotherapy and in combination with other antidiabetic agents. METHODS The peer-reviewed English- and foreign-language literature was searched using MEDLINE, PubMED, EMBASE, Science Citation Index, the Cochrane Database of Systematic Reviews, the Cochrane Controlled Trials Register, the UK National Health Service Centre for Reviews and Dissemination databases, and the Office of Health Economics Health Economic Evaluations Database. Searches were not limited to specific publication types, study designs, dates, or languages. The latest search was performed in March 2001. For a trial to be included in the review, at least 1 outcome measure had to involve the effects of pioglitazone on glycemic control or cardiovascular risk factors, or its side effects. Because of the heterogeneity of studies, no formal meta-analysis was performed. RESULTS Eleven studies met the inclusion criteria, 6 involving pioglitazone monotherapy and 5 involving combination therapy. Full reports were available for only 6 of the 11 studies. No studies directly compared pioglitazone with other antidiabetic drugs. Both as monotherapy and in combination therapy, pioglitazone produced decreases in blood glucose levels (up to 95 mg/dL) and glycosylated hemoglobin (up to 2.6%). At doses of > or = 30 mg/d, pioglitazone was associated with reductions in triglyceride levels (-30-70 mg/dL) and increases in high-density lipoprotein cholesterol (HDL-C) levels (-4-5 mg/dL). Pioglitazone treatment was associated with significant weight gain (up to 4 kg over 16 weeks). Adverse effects included mild edema (in up to 11.7% of patients) and a clinically nonsignificant decrease in hemoglobin concentrations. Abnormal results on liver function testing were no more common in treated patients than in control groups. CONCLUSIONS Pioglitazone has been shown to reduce blood glucose levels in patients with type 2 diabetes. Although the observed decreases in triglyceride levels and increases in HDL-C levels could be expected to lead to a reduction in cardiovascular risk, the effects of weight gain may counteract this benefit. The evidence suggests that the preferred role for pioglitazone may be as an adjunct to metformin or a sulfonylurea in patients whose condition is not well controlled with monotherapy and for whom a metformin-sulfonylurea combination is contraindicated. There is a need for large-scale, long-term studies comparing the effectiveness of combination therapy that includes pioglitazone with that of other combinations of antidiabetic drugs.

Percutaneous vertebroplasty and percutaneous balloon kyphoplasty for the treatment of osteoporotic vertebral fractures: a systematic review and cost-effectiveness analysis

BACKGROUND Percutaneous vertebroplasty (PVP) is a minimally invasive surgical procedure in which bone cement is injected into a fractured vertebra. Percutaneous balloon kyphoplasty (BKP) is a variation of this approach, in which an inflatable balloon tamp is placed in the collapsed vertebra prior to cement injection. OBJECTIVES To systematically evaluate and appraise the clinical effectiveness and cost-effectiveness of PVP and percutaneous BKP in reducing pain and disability in people with osteoporotic vertebral compression fractures (VCFs) in England and Wales. DATA SOURCES A systematic review was carried out. Ten databases including MEDLINE and CINAHL were searched from inception to November 2011, and supplemented by hand-searching relevant articles and contact with an expert. Studies met the inclusion criteria if they were randomised controlled trials (RCTs) including people with painful osteoporotic VCFs with a group receiving PVP or BKP. In addition, lead authors of identified RCTs were contacted for unpublished data. REVIEW METHODS Primary outcomes were health-related quality of life; back-specific functional status/mobility; pain/analgesic use; vertebral body height and angular deformity; incidence of new vertebral fractures and progression of treated fracture. A manufacturer provided academic-in-confidence observational data indicating that vertebral augmentation may be associated with a beneficial mortality effect, and that, potentially, BKP was more efficacious than PVP. These data were formally critiqued. A mathematical model was constructed to explore the cost-effectiveness of BKP, PVP and operative placebo with local anaesthesia (OPLA) compared with optimal pain management (OPM). Six scenario analyses were conducted that assessed combinations of assumptions on mortality (differential beneficial effects for BKP and PVP; equal beneficial effects for BKP and PVP; and no effect assumed) and derivation of utility data (either mapped from visual analogue scale pain score data produced by a network meta-analysis or using direct European Quality of Life-5 Dimensions data from the trials). Extensive sensitivity analyses were conducted on each of the six scenarios. This report contains reference to confidential information provided as part of the National Institute for Health and Care Excellence appraisal process. This information has been removed from the report and the results, discussions and conclusions of the report do not include the confidential information. These sections are clearly marked in the report. RESULTS A total of nine RCTs were identified and included in the review of clinical effectiveness. This body of literature was of variable quality, with the two double-blind, OPLA-controlled trials being at the least risk of bias. The most significant methodological issue among the remaining trials was lack of blinding for both study participants and outcome assessors. Broadly speaking, the literature suggests that both PVP and BKP provide substantially greater benefits than OPM in open-label trials. However, in double-blinded trials PVP was shown to have no more benefit than local anaesthetic; no trials of BKP compared with local anaesthesia have been conducted. A formal analysis of observational mortality data undertaken within this report concluded that it was not possible to say with certainty if there is a difference in mortality between patients undergoing BKP and PVP compared with OPM. Results from the cost-effectiveness analyses were varied, with all of BKP, PVP and OPLA appearing the most cost-effective treatment dependent on the assumptions made regarding mortality effects, utility, hospitalisation costs and OPLA costs. LIMITATIONS Data on key parameters were uncertain and/or potentially confounded, making definitive conclusions difficult to make. CONCLUSION For people with painful osteoporotic VCFs refractory to analgesic treatment, PVP and BKP perform significantly better in unblinded trials than OPM in terms of improving quality of life and reducing pain and disability. However, there is as yet no convincing evidence that either procedure performs better than OPLA. The uncertainty in the evidence base means that no definitive conclusion on the cost-effectiveness of PVP or BKP can be provided. Further research should focus on establishing whether or not BKP and PVP have a mortality advantage compared with OPLA and on whether or not these provide any utility gain compared with OPLA. STUDY REGISTRATION This study was registered as PROSPERO number CRD42011001822. FUNDING The National Institute for Health Research Health Technology Assessment programme.

A review of the clinical effectiveness of routine antenatal anti-D prophylaxis for rhesus-negative women who are pregnant.

In its mildest form, haemolytic disease of the newborn is detectable only in laboratory tests. However, severe disease causes physical disabilities and often mental retardation; in its most severe form, it causes intrauterine death. Haemolytic disease of the newborn therefore has potentially very serious consequences for human health and happiness. Haemolytic disease of the newborn is caused by the transplacental passage of anti-D antibodies from a RhDnegative mother to a RhD-positive fetus. Any feto-maternal haemorrhage in a RhD-negative mother pregnant with a RhD-positive fetus, whether at or before delivery of that infant, may stimulate the production of anti-D antibodies (a process known as sensitisation). The first RhD-positive infant is not harmed if the mother is sensitised at delivery, but may be affected if the mother is sensitised during pregnancy: one study found that, of 20 infants born to primigravidae who had antibodies before or at delivery, two were moderately affected (requiring exchange transfusion) and 16 were mildly affected. Because the severity of the disease is related to the level of antibodies in the maternal blood and the length of time for which the infant is exposed to them, subsequent RhD-positive infants born to a sensitised mother are likely to be progressively more severely affected. Some women do not have detectable anti-D after the index pregnancy, but nonetheless give a secondary immune response during a later pregnancy; they are described as having been ‘sensibilised’, rather than sensitised, by the index pregnancy. Prophylactic anti-D can suppress primary RhD immunisation. Routine postpartum anti-D immunoprophylaxis was introduced in the United Kingdom in 1969. Prophylaxis was extended in 1976 to include abortions and spontaneous miscarriages, and in 1981 to include a number of other potentially sensitising events. – 4 The guidelines were updated in 1991. Despite this, some women in the United Kingdom continued to become sensitised prior to delivery of the first pregnancy. In some cases, this could be attributed to failure to adhere to existing guidelines through lack of administration of (a) any, (b) enough or (c) timely anti-D in response to potential sensitising events in pregnancy. Audits found that guidelines were followed fully in only 59% to 79% of potentially sensitising events, and in one study only 11 out of 44 RhD-negative women undergoing amniocentesis (25%) received anti-D. A questionnaire survey found that, in the early 1990s, 77% of Accident and Emergency departments in England and Wales did not have a policy for treating with anti-D women who bled in early pregnancy. However, other women, estimated at between 55% and 80% of sensitised women, appeared to be sensitised in the absence of any identifiable risk event such as should have prompted the administration of anti-D (so-called silent sensitisation). As prophylactic anti-D has no effect in women who have already developed anti-D, however weak, it appeared that the most stringent adherence to existing guidelines could not prevent some instances of sensitisation. Attention therefore turned to routine antenatal anti-D prophylaxis as a possible means of reducing sensitisation rates. Owing to the lack of clarity concerning the available evidence for routine antenatal anti-D prophylaxis, and consequent ambiguity of guidance supporting its introduction, in 2001 the UK National Institute for Clinical Excellence (NICE) commissioned a systematic review of the available evidence for the clinical and cost effectiveness of a community programme of routine antenatal anti-D prophylaxis in pregnant RhD-negative women. This article is an abridged version of the systematic review; a more detailed review of the clinical effectiveness and cost effectiveness of such a programme is contained within the monograph.

Cabazitaxel for the Second-Line Treatment of Metastatic Hormone-Refractory Prostate Cancer: A NICE Single Technology Appraisal

The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of cabazitaxel (Jevtana®, sanofi-aventis, UK) to submit evidence of its clinical and cost effectiveness for the second-line treatment of metastatic hormone-refractory prostate cancer (mHRPC). The School of Health and Related Research Technology Appraisal Group (ScHARR-TAG) at the University of Sheffield was commissioned to act as the independent Evidence Review Group (ERG). The ERG produced a critical review of the evidence for the clinical and cost effectiveness of the technology based upon the manufacturer’s submission to NICE. Clinical evidence was derived from a multinational randomized open-label phase III trial of cabazitaxel plus prednisone or prednisolone in men with mHRPC that had progressed during or following treatment with docetaxel. The comparator was mitoxantrone plus prednisone or prednisolone. Use of cabazitaxel was associated with a statistically significant improvement in overall survival, median progression-free survival and time to tumour progression. However, it was also associated with an increased incidence of adverse events such as neutropenia. Utility data were based on interim results from the early access programme for cabazitaxel. Data were only available for a small number of patients with stable disease, resulting in great uncertainty as to the effect of cabazitaxel on quality of life. For their economic evaluation, the manufacturer estimated that the use of cabazitaxel was associated with an incremental cost of £74,908 per QALY gained. However, the ERG disagreed with the manufacturer over two key methodological points. The first concerned modelling and extrapolating survival; the second point was concerned with the choice of patient population. The ERG altered the manufacturer’s evaluation to take into account these two points of disagreement. The resulting cost per QALY gained was £82,950. The NICE Appraisal Committee believed the analysis presented by the ERG to be more plausible, and likely to be an underestimate of the cost per QALY. They concluded that whilst the clinical effectiveness of cabazitaxel had been proven, it was not likely to represent a cost-effective use of NHS resources and so its use could not be recommended.

The economics of routine antenatal anti-D prophylaxis for pregnant women who are rhesus negative.

Objective  To investigate the economics of routine antenatal anti‐D prophylaxis in the prevention of haemolytic disease of the newborn, in support of the NICE appraisals process.

The Cost Effectiveness of a Randomized Controlled Trial to Establish the Relative Efficacy of Vitamin K1 Compared with Alendronate

Purpose. The authors aimed to evaluate whether vitamin K1 or alendronate (the recommended treatment in England and Wales for postmenopausal women with a previous fracture) appeared to be the more cost-effective treatment for fracture prevention. Furthermore, expected value of sample information (EVSI) analyses were undertaken to estimate whether a head-to-head trial of alendronate and vitamin K1 would be considered cost effective. Method. A published osteoporosis model structure, populated with data from literature reviews, was used to evaluate the costs and quality-adjusted life-years associated with each intervention being provided to women at high risk of fracture, given current information. A lifetime horizon and a national health service and personal social services cost perspective were used. Observed outcomes from head-to-head randomized controlled trials (RCTs) of predetermined sizes were simulated and synthesized with existing data to formulate posterior distributions, which were used to estimate the more cost-effective treatment given these additional data. The EVSI was estimated and the expected net benefit of sampling (ENBS) calculated by subtracting the proposed trial costs. Results. Given current information, vitamin K1 is expected to dominate alendronate. However, this was subject to a considerable degree of uncertainty; dominance was reversed when it was assumed that vitamin K1 had no effect on hip fractures. EVSI analysis indicated that an RCT of 2000 or 5000 women per arm produced high, and comparable, ENBS. These results were maintained in sensitivity analyses. Conclusions. It is concluded that an RCT recruiting between 2000 and 5000 women per arm to evaluate the relative efficacy of alendronate and vitamin K1 appears to be cost effective for informing decision making in England and Wales.