J Wight

The epidemiology of inhibitors in haemophilia A: a systematic review

Summary.  This paper emphasizes the importance of distinguishing between the prevalence, incidence and cumulative incidence of inhibitors in haemophilia A. Incidence and cumulative incidence data will include patients with transient inhibitors or whose inhibitors have been eliminated by treatment. As these will not be included in prevalence data, prevalence studies will tend to give rise to lower figures than incidence studies. As a result, the most accurate estimates of the true risk of inhibitor development comes from prospective studies of newly diagnosed haemophiliacs who are tested regularly for the presence of inhibitors. This paper reports a systematic review of the best available evidence relating to the epidemiology of inhibitors in haemophilia A. Cohort studies, registry data reporting incidence or prevalence of inhibitors in patients with haemophilia A, and prospective studies of factor VIII (FVIII) in the treatment of previously untreated patients which reported the development of inhibitors as an outcome, were included in the review. The overall prevalence of inhibitors in unselected haemophiliac populations was found to be 5–7%. The cumulative risk of inhibitor development varied (0–39%). Incidence and prevalence were substantially higher in patients with severe haemophilia. Studies of patients using a single plasma‐derived FVIII (pdFVIII) preparation reported lower inhibitor incidence than those using multiple pdFVIII preparations or single recombinant FVIII preparations. Incidence data should be used to estimate the likely demand for treatments aimed at eliminating inhibitors, whereas the best estimates of the overall burden to the National Health Service (NHS) of treating bleeding episodes in patients with continuing inhibitors will come from prevalence studies.

Pulsatile machine perfusion vs. cold storage of kidneys for transplantation: a rapid and systematic review

Abstract: Objective: To identify and prioritize key areas for further research in kidney preservation systems.

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.

Control of bleeding in patients with haemophilia A with inhibitors: a systematic review

This paper reports a systematic review of the best available evidence of clinical effectiveness in the treatment of acute bleeding in haemophilia A patients with inhibitors. Because of the lack of randomized controlled trials (RCTs) on this topic, broad inclusion criteria with regard to study design were applied in order to assess the best available evidence for each intervention. Because of the clinical and methodological heterogeneity of the evidence, it was not appropriate to pool data across studies; instead, data were synthesized using tabulation and qualitative narrative assessment. No evidence was found to support the use of high‐dose factor VIII (FVIII) in bleeding episodes. However in surgery it was found to be highly successful (100%) for low‐titre, low‐responding inhibitors although not reliable for high‐responding inhibitors. Porcine FVIII (pFVIII) was effective in the control of severe bleeding episodes with high‐titre or high‐responding inhibitors (100%) and in 60–90% of surgical procedures. Activated prothrombin complex concentrates (APCCs) appear to be more effective than prothrombin complex concentrates (PCCs) in the control of mild to severe bleeding episodes. There was no good evidence for the use of PCCs in surgery. APCCs controlled bleeding in approximately 90% of surgical episodes. Recombinant factor VIIa (rFVIIa) controlled 70–100% of mild to severe bleeding episodes with high‐responding inhibitors, and achieved better results when used early. It was effective in 60–100% of surgical episodes. Doses varied from study to study, and side‐effects from mild to infrequent but serious adverse events were reported. The quality of the evidence is variable. Limited evidence relating to other treatment options is also included in the review.

Clinical effectiveness of oral treatments for spasticity in multiple sclerosis: a systematic review

Spasticity is a common disabling feature of multiple sclerosis. A variety of drugs are in regular use as oral treatment, including baclofen, dantrolene, tizanidine, and diazepam. Published evidence of effectiveness is limited. Most trials are of small size, of short duration, and have not reported on functional outcomes. Studies have been published which suggest that baclofen, tizanidine, and diazepam are all effective in reducing clinical measures of spasticity, but there is little evidence that they lead to an improvement in patient function. There is no evidence to suggest any difference in effectiveness between them. The evidence that dantrolene has any effect on spasticity is of poor quality. Diazepam and dantrolene are associated with more side effects than baclofen and tizanidine. There is evidence for the effectiveness of gabapentin in reducing spasticity and improving function in the short term, though longer-term studies are needed to establish its true value. One randomized controlled trial of threonine does not support its effectiveness.

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.

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.