Elsevier

The Lancet Haematology

Volume 3, Issue 10, October 2016, Pages e489-e496
The Lancet Haematology

Articles
High-dose dexamethasone compared with prednisone for previously untreated primary immune thrombocytopenia: a systematic review and meta-analysis

https://doi.org/10.1016/S2352-3026(16)30109-0Get rights and content

Summary

Background

Whether high-dose dexamethasone has long-term efficacy and safety in previously untreated patients with immune thrombocytopenia is unclear. We did a systematic review and a meta-analysis of randomised trials to establish the effect of high-dose dexamethasone compared with prednisone for long-term platelet count response.

Methods

We searched MEDLINE, Embase, Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Library Database for papers published from 1970 to July, 2016, and abstracts from American Society of Hematology annual meetings published from 2004 to 2015 for randomised trials comparing different corticosteroid regimens for patients with previously untreated immune thrombocytopenia who achieved a platelet count response. Trials that compared corticosteroids exclusively with other interventions were excluded. The primary endpoint was overall (platelets >30 × 109/L) and complete (platelets >100 × 109/L) platelet count response at 6 months with high-dose dexamethasone compared with standard-dose prednisone. Children and adults were analysed separately. Estimates of effect were pooled with a random-effects model.

Findings

Nine randomised trials (n=1138) were included. Of those, five (n=533) compared one to three cycles of dexamethasone (40 mg per day for 4 days) with prednisone (1 mg per kg) for 14–28 days followed by dose tapering in adults. We found no difference in overall platelet count response at 6 months (pooled proportions 54% vs 43%, relative risk [RR] 1·16, 95% CI 0·79–1·71; p=0·44). At 14 days, overall platelet count response was higher with dexamethasone (79% vs 59%, RR 1·22, 95% CI 1·00–1·49; p=0·048). The dexamethasone group had fewer reported toxicities. Long-term response rates were similar when the data were analysed by cumulative corticosteroid dose over the course of treatment. No difference in initial platelet count response was observed with different high-dose corticosteroid regimens in children.

Interpretation

In adults with previously untreated immune thrombocytopenia, high-dose dexamethasone did not improve durable platelet count responses compared with standard-dose prednisone. High-dose dexamethasone might be preferred over prednisone for patients with severe immune thrombocytopenia who require a rapid rise in platelet count.

Funding

Canadian Institutes of Health Research, and Canadian Blood Services, and Health Canada.

Introduction

Immune thrombocytopenia is a common autoimmune disease characterised by low platelet counts (<100 cells × 109/L) and an increased risk of bleeding. Guidelines1 and consensus reports2 recommend either high-dose dexamethasone or standard-dose prednisone as first-line therapy; however, there is debate about which dose of corticosteroid to use.3 High-dose dexamethasone is administered as a short pulse, typically 40 mg per day consecutively for 4 days and repeated for one or two additional monthly cycles depending on the response noted by platelet count. This regimen has been reported to produce high, durable platelet count responses in observational studies;4, 5, 6 however, one randomised trial has reported no difference in platelet count response at 6 months compared with prednisone.7 Severe toxic effects were frequently reported with high-dose dexamethasone in some studies8 but not in others.7

Dexamethasone is a corticosteroid that has an anti-inflammatory effect that is more than six times more potent than prednisone (40 mg of dexamethasone is equivalent to 250 mg of prednisone) with a longer biological half-life (36–72 h compared with 12–36 h).9 Hence, any difference in efficacy or toxicity between the two approaches probably reflects differences in dosage rather than intrinsic properties of the drugs. Several studies, including one randomised trial in adults,7 have shown that higher doses of corticosteroids can increase the platelet count more quickly; however, when faced with a new diagnosis of immune thrombocytopenia, clinicians and patients are most interested in treatments that can improve sustained remission.

We aimed to evaluate the long-term efficacy and safety of high-dose corticosteroids as an initial treatment for adults or children with previously untreated immune thrombocytopenia.

Research in context

Evidence before this study

Guidelines recommend either high-dose corticosteroids (eg, dexamethasone 40 mg orally per day for 4 days consecutively in one or more cycles) or standard-dose prednisone (1 mg/kg per day followed by a dose taper) as first-line treatment for adults with primary immune thrombocytopenia. Both regimens were considered equivalent. Observational studies have suggested that high-dose dexamethasone was effective at producing sustained platelet count responses in some patients with immune thrombocytopenia. Small comparative trials have evaluated the efficacy and safety of high-dose dexamethasone compared with prednisone.

Added value of this study

To our knowledge, our study represents the first meta-analysis of randomised trials comparing high-dose dexamethasone versus standard-dose prednisone for patients with newly diagnosed primary immune thrombocytopenia. Our pooled analysis showed no difference in durable platelet count responses in adults, but a higher rate of initial platelet count response without additional toxicity.

Implications of all the available evidence

High-dose dexamethasone might be preferred over prednisone for adults with severe immune thrombocytopenia who require a rapid rise in platelet count.

Section snippets

Search strategy and selection criteria

For this systematic review and a meta-analysis, we searched the electronic databases of MEDLINE, Embase, Cumulative Index of Nursing and Allied Health Literature, and the Cochrane Library Database for papers published in English from 1970 to July, 2016, with the following search terms: “idiopathic thrombocytopenic purpura”, “immune thrombocytopenic purpura”, “ITP”, or “immune thrombocytopenia”; “randomized controlled trial”, “controlled trial”, “random allocation”, “prospective study”, and

Results

We identified 2582 citations in our initial literature search. After excluding 1219 non-relevant titles, we reviewed 1363 abstracts and 306 full text articles in duplicate and independently (figure 1). We identified 12 randomised trials that compared different corticosteroid regimens. Of those, one study was excluded because it compared equivalent corticosteroid doses (prednisone 1 mg per kg per day vs deflazacort 1·4 mg per kg per day)16 and two studies were excluded because they did not

Discussion

Pooling data from randomised trials, we found no difference in platelet count response at 6 months in adults treated with high-dose dexamethasone or standard-dose prednisone; however, responses occurred more rapidly with high-dose dexamethasone without additional toxicities. In children, initial platelet count response rates were similar with various high-dose corticosteroid regimens.

It is hypothesised that pulse high-dose corticosteroids might have a fundamentally different effect on the

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