Reactions 830 - 2 Dec 2000

on the contrary, the consistency of the subgroupIntracranial haemorrhage withanalyses used underscores the robustness of theirbolus thrombolytics: meta-analysis findings. They point out that their analysis included the

criticised totality of evidence from properly randomised phase IIItrials and did not just look at a post hoc data-derivedAn increased frequency of intracranial haemorrhage subset of the studies. In addition, they say that thewith bolus, compared with infusion, thrombolytic populations included in their analysis were similar andtherapy has previously been reported by Dr Shamir that they used a clear and irreversible event for theirMehta and colleagues from Canada.* However, other primary outcome.researchers are critical of the results of their meta- Dr Mehta and colleagues further add that whenanalysis which included 7 studies involving several thrombolytics are administered as a bolus, they producedifferent thrombolytic agents. peak blood concentrations that are several-fold higher

Findings misleading than those produced by thrombolytics administered asan infusion. As there is a clear association between dose-According to Dr D Collen from Belgium and Dr Bintensity and risk of intracranial haemorrhage withSobel from the US, the meta-analysis is ‘fundamentallythrombolytics, they say that the increased rate of thisflawed and misleading to current clinical practice’.1 Theycomplication seen with bolus administration should notsay that such pooling of diverse agents into 1 analysis isbe surprising.not clinically meaningful. In view of their findings, Dr

Mehta and colleagues concluded that there is little * see Reactions 814: 4, 12 Aug 2000; 800839096justification for bolus thrombolytic therapy in routine

1. Collen D, et al. Intracranial haemorrhage with bolus thrombolytic agents. Lancetpractice in hospital. However, Drs Collen and Sobel say 356: 1848, 25 Nov 2000.2. Menown IBA, et al. Intracranial haemorrhage with bolus thrombolytic agents.that Dr Mehta and colleagues have inappropriately

Lancet 356: 1848-1849, 25 Nov 2000.drawn guidelines for clinical practice from trials3. Armstrong PW, et al. Intracranial haemorrhage with bolus thrombolytic agents.

undertaken with discontinued regimens or agents. Drs Lancet 356: 1849, 25 Nov 2000.4. Mehta SR, et al. Intracranial haemorrhage with bolus thrombolytic agents.Collen and Sobel point out that approximately 3 lives are

Reply. Lancet 356: 1850, 25 Nov 2000.saved per 100 patients treated with thrombolytic800840269

therapy for myocardial infarction, and say that if bolusadministration was not an option, the outcome ofmyocardial infarction would be fatal for approximately 3out of every 100 patients who wouldn’t have beentreated by infusion. They further add that they ‘believethat a single bolus regimen with highly clot-selectivefibrinolytic agents is desirable’ for the treatment ofmyocardial infarction.

Bolus therapy may have benefitsThe opinion that there are relevant benefits of bolus

thrombolytic therapy is also held by Drs Ian Menownand Jennifer Adgey from the UK.2 They believe that bolusadministration allows for the more rapid administrationof thrombolytics and that this could be of clinicalimportance. Drs Menown and Adgey point out that only2 of the 7 studies included in the meta-analysis of DrsMehta and colleagues compared infusion with bolusadministration of the same drug. They are also critical ofthe fact that Drs Mehta and colleagues did not comparethe rate of intracranial haemorrhage in patients aged >75 years with those aged ≤ 75 years, and say that ‘thisage threshold is important’. They add that further studiescomparing the rate of intracranial haemorrhage withbolus and infusion of the same drug are necessarybefore conclusions can be drawn.

Further criticismCriticism of the findings of the meta-analysis has also

come from Dr Paul Armstrong and colleagues fromCanada.3 They say that they ‘do not believe that clinicallyreliable information can be derived from groupingdifferent fibrinolytic regimens according to whether theirmode of administration is bolus or intravenous infusion’.They add that they ‘believe that reteplase andtenectoplase are safe and effective new bolus fibrinolyticagents’.

Authors’ replyIn response to the criticism of their meta-analysis, Dr

Mehta and colleagues say that the opinion that thepooling of diverse thrombolytic agents into 1 analysis isnot valid, is not supported by their data.4 They say that

1

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