Correspondence
See Correspondence page 659
662
(χ²=1·87, I²=0, p=0·87). With treatment given within 3 h, the effect of rt-PA is equivalent to 90 more patients alive and independent for every 1000 patients treated, net of the early risk of intracranial haemorrhage and death. Thus, the earlier the treatment the bigger the benefit. This highly statistically and clinically significant benefit is true for younger and older people, most severities of stroke, and other subgroups. How is it that a drug can have overall benefit despite causing early hazard? For surgical operations, the early hazard versus later benefit is well understood. Stroke is a very nasty disease if untreated, with a high death rate from complications in the brain (eg, swelling) or of impaired swallowing and immobility (chest infection or pulmonary embolism). These hazards of not treating with alteplase have received less attention, but reflect the substantial mortality and morbidity of untreated stroke. Hence, by 3–6 months after stroke, the total deaths in the control group and in alteplase-treated patients have balanced out: for patients treated within 6 h of stroke, by 3–6 months after stroke 679 (19·6%) of 3458 given alteplase and 640 (18·5%) of 3464 allocated to control had died, OR 1·06 (95% CI 0·94–1·20, p=0·33), with no heterogeneity (p=0·09); for patients treated up to 3 h after stroke, 224 (24·6%) of 910 receiving alteplase and 233 (26%) of 896 allocated to control had died, OR 0·91 (95% CI 0·73–1·13, p=0·39), with no heterogeneity (p=0·22). Roger Shinton is concerned about inconsistencies between trials. The results for treatment within 3 h are highly consistent between trials, including IST-3, confirming the NINDS trial result.6 A thorough independent review removed concerns about the NINDS trial 10 years ago.7 The licence restricts use to within 3 h in the USA, or 4·5 h in Europe,
thus primarily to the time for which there is complete consistency. We still do not understand why some patients have early bleeding, and further trials are ongoing. All patients considered for rt-PA treatment need to be fully informed of the risks when weighing up the benefits. Consistent effects observed across trials, continents, and patients should provide confidence in this highly effective, very valuable, licensed treatment that can mitigate the otherwise devastating effects of stroke, especially if given as soon as possible after symptom onset. We received academic funding to do trials of rt-PA including IST-3 (full details in reference 5).
*Joanna M Wardlaw, Veronica Murray, Eivind Berge, Gregory J Del Zoppo [email protected] University of Edinburgh, Edinburgh, EH4 2XU, UK (JMW); Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden (VM); Oslo University Hospital, Oslo, Norway (EB); and University of Washington, Seattle, WA, USA (GJDZ) 1
2
3
4
5
6
7
Wardlaw JM, Murray V, Berge E, Del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2009; 4: CD000213. The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomised controlled trial. Lancet 2012; 379: 2352–63. Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 2012; 379: 2364–72. Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014; published online Aug 6. DOI:10.1016/S01406736(14)60584-5. Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2014; 7: CD000213. The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischaemic stroke. N Engl J Med 1995; 333: 1581–87. Ingall TJ, O’Fallon WM, Asplund K, et al. Findings from the reanalysis of the NINDS tissue plasminogen activator for acute ischemic stroke treatment trial. Stroke 2004; 35: 2418–24.
In his Correspondence Roger Shinton expresses his concerns regarding the balance of benefits and risks of alteplase in the treatment of acute ischaemic stroke and calls for a review by regulators. Data in support of the indication for alteplase in treating acute ischaemic stroke have been extensively discussed and analysed by the European regulators with input from the Medicines and Healthcare Products Regulatory Agency (MHRA), both when concluding at the time of its initial approval in 2002 that the benefit–risk balance is favourable and again in 2012 when the time window for treatment was increased from 3 h to 4·5 h after symptom onset. In line with MHRA’s role, any new information or concerns about the data that underpin the present marketing authorisation are thoroughly investigated. In this respect, we have recently critically appraised the results of the International Stroke Trial-3 (IST-3),1,2 the reanalysis of the National Institute of Neurological Disorders and Stroke (NINDS) trial data,3 a recently published meta-analysis,4 and specific concerns arising from these datasets that have been brought to our attention. This evidence was considered in the context of the data used to support the original 3 h indication and its subsequent extension. Independent expert advice from the Commission on Human Medicines (CHM, the UK’s main independent committee that provides expert advice on the efficacy, safety, and quality of drugs) on the evidence and analyses presented was that the data did not change the favourable balance of benefits and risks for alteplase in the treatment of acute ischaemic stroke. However, to be assured that all relevant sources of evidence have been taken into consideration the CHM has advised that an expert working group should be set up. This group will review information from a range of sources and consider potential implications for the favourable balance of benefits www.thelancet.com Vol 384 August 23, 2014
Correspondence
Medicines and Healthcare Products Regulatory Agency (MHRA), London SW1W 9SZ, UK 1
2
3
4
The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomised controlled trial. Lancet 2012; 379: 2352–63. The IST-3 collaborative group. Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18–month follow-up of a randomised controlled trial. Lancet Neurol 2013; 12: 768–76. O’Fallon M, Asplund K, Goldfrank LR, et al. Report of the t-PA Review Committee. 2004. http://stroke.nih.gov/ resources/t-pa-review-committee.htm (accessed July 31, 2014). Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014; published online Aug 6. DOI:10.1016/S01406736(14)60584-5.
Venezuela’s failure in malaria control In their recent Correspondence (June 7, p 1967),1 José Félix Oletta and colleagues noted that in the past 15 years the Venezuelan Government has been incapable of implementing a coherent plan to address the health needs of its people, and importantly, failed in the control of vector-borne diseases such as malaria and dengue. Malaria control in Venezuela contrasts with the progress made globally and by neighbouring countries that have substantially decreased the morbidity, mortality, and economic burden associated with malaria. For example, Brazil and Colombia have decreased disease burden due to Plasmodium falciparum and P vivax by more than 50%: the burden in Brazil www.thelancet.com Vol 384 August 23, 2014
80
For the minutes of the Commission on Human Medicines see http://www.mhra. gov.uk/Committees/ Medicinesadvisorybodies/ CommissiononHumanMedicines/ Minutes/index.htm
76 621
70
r2=0·67 p
See Correspondence page 659
662
(χ²=1·87, I²=0, p=0·87). With treatment given within 3 h, the effect of rt-PA is equivalent to 90 more patients alive and independent for every 1000 patients treated, net of the early risk of intracranial haemorrhage and death. Thus, the earlier the treatment the bigger the benefit. This highly statistically and clinically significant benefit is true for younger and older people, most severities of stroke, and other subgroups. How is it that a drug can have overall benefit despite causing early hazard? For surgical operations, the early hazard versus later benefit is well understood. Stroke is a very nasty disease if untreated, with a high death rate from complications in the brain (eg, swelling) or of impaired swallowing and immobility (chest infection or pulmonary embolism). These hazards of not treating with alteplase have received less attention, but reflect the substantial mortality and morbidity of untreated stroke. Hence, by 3–6 months after stroke, the total deaths in the control group and in alteplase-treated patients have balanced out: for patients treated within 6 h of stroke, by 3–6 months after stroke 679 (19·6%) of 3458 given alteplase and 640 (18·5%) of 3464 allocated to control had died, OR 1·06 (95% CI 0·94–1·20, p=0·33), with no heterogeneity (p=0·09); for patients treated up to 3 h after stroke, 224 (24·6%) of 910 receiving alteplase and 233 (26%) of 896 allocated to control had died, OR 0·91 (95% CI 0·73–1·13, p=0·39), with no heterogeneity (p=0·22). Roger Shinton is concerned about inconsistencies between trials. The results for treatment within 3 h are highly consistent between trials, including IST-3, confirming the NINDS trial result.6 A thorough independent review removed concerns about the NINDS trial 10 years ago.7 The licence restricts use to within 3 h in the USA, or 4·5 h in Europe,
thus primarily to the time for which there is complete consistency. We still do not understand why some patients have early bleeding, and further trials are ongoing. All patients considered for rt-PA treatment need to be fully informed of the risks when weighing up the benefits. Consistent effects observed across trials, continents, and patients should provide confidence in this highly effective, very valuable, licensed treatment that can mitigate the otherwise devastating effects of stroke, especially if given as soon as possible after symptom onset. We received academic funding to do trials of rt-PA including IST-3 (full details in reference 5).
*Joanna M Wardlaw, Veronica Murray, Eivind Berge, Gregory J Del Zoppo [email protected] University of Edinburgh, Edinburgh, EH4 2XU, UK (JMW); Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden (VM); Oslo University Hospital, Oslo, Norway (EB); and University of Washington, Seattle, WA, USA (GJDZ) 1
2
3
4
5
6
7
Wardlaw JM, Murray V, Berge E, Del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2009; 4: CD000213. The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomised controlled trial. Lancet 2012; 379: 2352–63. Wardlaw JM, Murray V, Berge E, et al. Recombinant tissue plasminogen activator for acute ischaemic stroke: an updated systematic review and meta-analysis. Lancet 2012; 379: 2364–72. Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014; published online Aug 6. DOI:10.1016/S01406736(14)60584-5. Wardlaw JM, Murray V, Berge E, del Zoppo GJ. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev 2014; 7: CD000213. The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischaemic stroke. N Engl J Med 1995; 333: 1581–87. Ingall TJ, O’Fallon WM, Asplund K, et al. Findings from the reanalysis of the NINDS tissue plasminogen activator for acute ischemic stroke treatment trial. Stroke 2004; 35: 2418–24.
In his Correspondence Roger Shinton expresses his concerns regarding the balance of benefits and risks of alteplase in the treatment of acute ischaemic stroke and calls for a review by regulators. Data in support of the indication for alteplase in treating acute ischaemic stroke have been extensively discussed and analysed by the European regulators with input from the Medicines and Healthcare Products Regulatory Agency (MHRA), both when concluding at the time of its initial approval in 2002 that the benefit–risk balance is favourable and again in 2012 when the time window for treatment was increased from 3 h to 4·5 h after symptom onset. In line with MHRA’s role, any new information or concerns about the data that underpin the present marketing authorisation are thoroughly investigated. In this respect, we have recently critically appraised the results of the International Stroke Trial-3 (IST-3),1,2 the reanalysis of the National Institute of Neurological Disorders and Stroke (NINDS) trial data,3 a recently published meta-analysis,4 and specific concerns arising from these datasets that have been brought to our attention. This evidence was considered in the context of the data used to support the original 3 h indication and its subsequent extension. Independent expert advice from the Commission on Human Medicines (CHM, the UK’s main independent committee that provides expert advice on the efficacy, safety, and quality of drugs) on the evidence and analyses presented was that the data did not change the favourable balance of benefits and risks for alteplase in the treatment of acute ischaemic stroke. However, to be assured that all relevant sources of evidence have been taken into consideration the CHM has advised that an expert working group should be set up. This group will review information from a range of sources and consider potential implications for the favourable balance of benefits www.thelancet.com Vol 384 August 23, 2014
Correspondence
Medicines and Healthcare Products Regulatory Agency (MHRA), London SW1W 9SZ, UK 1
2
3
4
The IST-3 collaborative group. The benefits and harms of intravenous thrombolysis with recombinant tissue plasminogen activator within 6 h of acute ischaemic stroke (IST-3): a randomised controlled trial. Lancet 2012; 379: 2352–63. The IST-3 collaborative group. Effect of thrombolysis with alteplase within 6 h of acute ischaemic stroke on long-term outcomes (the third International Stroke Trial [IST-3]): 18–month follow-up of a randomised controlled trial. Lancet Neurol 2013; 12: 768–76. O’Fallon M, Asplund K, Goldfrank LR, et al. Report of the t-PA Review Committee. 2004. http://stroke.nih.gov/ resources/t-pa-review-committee.htm (accessed July 31, 2014). Emberson J, Lees KR, Lyden P, et al. Effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials. Lancet 2014; published online Aug 6. DOI:10.1016/S01406736(14)60584-5.
Venezuela’s failure in malaria control In their recent Correspondence (June 7, p 1967),1 José Félix Oletta and colleagues noted that in the past 15 years the Venezuelan Government has been incapable of implementing a coherent plan to address the health needs of its people, and importantly, failed in the control of vector-borne diseases such as malaria and dengue. Malaria control in Venezuela contrasts with the progress made globally and by neighbouring countries that have substantially decreased the morbidity, mortality, and economic burden associated with malaria. For example, Brazil and Colombia have decreased disease burden due to Plasmodium falciparum and P vivax by more than 50%: the burden in Brazil www.thelancet.com Vol 384 August 23, 2014
80
For the minutes of the Commission on Human Medicines see http://www.mhra. gov.uk/Committees/ Medicinesadvisorybodies/ CommissiononHumanMedicines/ Minutes/index.htm
76 621
70
r2=0·67 p
