The PROGRESS trial three years later: time for a balanced report of effectiveness
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《英国医生杂志》
1 Department of Medicine, University of Toronto, University Health Network, Toronto, ON, Canada M5T 2S8
Correspondence to: R Wennberg Richard.Wennberg@uhn.on.ca
Has the use of the phrase "perindopril based blood pressure lowering regimen" resulted in an oversimplistic and hence inaccurate interpretation of the results of the PROGRESS trial creeping into the literature and clinical practice?
Introduction
Shortly after the study was published, an editorial (in line with a small number of earlier critical letters and commentaries2-4) in the American Journal of Hypertension stated explicitly the two major problems with PROGRESS. Firstly, it is illogical and misleading to combine two treatment arms that have significantly heterogeneous results—if the findings from two trial arms differ substantially "then the findings need to be presented separately and interpreted separately"; secondly, "the major limitation of the PROGRESS trial was the failure to include a group randomized to indapamide alone."5 These editorialists speculated that indapamide alone may have reduced stroke by as much as 38% (43% for the combined therapy minus 5% for perindopril alone), which would be consistent with the 34% risk reduction seen with low dose diuretics in the primary prevention setting6 and the 29% risk reduction seen with indapamide alone in the post-stroke antihypertensive treatment study (PATS).7 However, from the design of PROGRESS, one cannot know whether the benefit seen with combination therapy is due to indapamide alone or to an additive or synergistic effect of indapamide with perindopril. What is clear is that the benefit is not attributable to perindopril alone.
The same editorial also argues that the blood pressure differences between the two arms (5/3 mm Hg for perindopril alone v 12/5 mm Hg for the combined therapy) are unlikely to explain the large difference in stroke reduction.5 For example, the blood pressure reduction with indapamide alone in the PATS trial was only 5/2 mm Hg, less than the reduction seen with perindopril alone in PROGRESS. Yet indapamide alone in PATS was associated with significant stroke reduction, while perindopril alone in PROGRESS was not. Several other large studies, however, have provided evidence that for most cardiovascular outcomes it is the amount of blood pressure reduction, rather than the particular regimen used, that determines the benefits of treatment.8-10 Although this is acknowledged in the PROGRESS paper, it is not expressed in the conclusion, which says of perindopril and indapamide that "treatment with these two agents should now be considered routinely for patients with a history of stroke or transient ischemic attack."1
Further publications of PROGRESS data
PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with a previous stroke or transient ischaemic attack. Lancet 2001;358: 1033-41.
Staessen JA, Wang J. Blood-pressure lowering for the secondary prevention of stroke . Lancet 2001;358: 1026-7.
Cates C. The lowering of blood pressure after stroke . Lancet 2001;358: 1993.
Tirschwell D. Combined therapy with indapamide and perindopril but not perindopril alone reduced the risk for recurrent stroke. ACP J Club 2002;136: 51.
Psaty BM, Weiss NS, Furberg CD. The PROGRESS trial: questions about the effectiveness of angiotensin converting enzyme inhibitors. Am J Hypertens 2002;15: 472-4.
Psaty BM, Smith NS, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA 1997;277: 739-45.
PATS Collaborating Group. Post-stroke antihypertensive treatment study. A preliminary result. Chin Med J 1995;108: 710-7.
Neal B, MacMahon S, Chapman N. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists and other blood pressure lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000;355: 1955-64.
Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001;358: 1305-15.
Turnbull F. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362: 1527-35.
PROGRESS Collaborative Group. Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease. Eur Heart J 2003;24: 475-84.
PROGRESS Collaborative Group. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003;163: 1069-75.
Fransen M, Anderson C, Chalmers J, Chapman N, Davis S, MacMahon S, et al. Effects of a perindopril-based blood pressure-lowering regimen on disability and dependency in 6105 patients with cerebrovascular disease: a randomized controlled trial. Stroke 2003;34: 2333-8.
Chapman N, Huxley R, Anderson C, Bousser MG, Chalmers J, Colman S, et al. Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS trial. Stroke 2004;35: 116-21.
Tonkin AM. Does lowering blood pressure prevent recurrent stroke? Med J Aust 2002;176: 283-4.
Britov AN, Bystrova MM, Orlov AA. Control of arterial hypertension in stroke prevention. Klin Med (Mosk) 2002;80: 53-7.
Jackson G. Making PROGRESS in stable patients post stroke or transient ischemic attack: implications for general practice. Int J Clin Pract 2003;57: 385-7.(Richard Wennberg, associa)
Correspondence to: R Wennberg Richard.Wennberg@uhn.on.ca
Has the use of the phrase "perindopril based blood pressure lowering regimen" resulted in an oversimplistic and hence inaccurate interpretation of the results of the PROGRESS trial creeping into the literature and clinical practice?
Introduction
Shortly after the study was published, an editorial (in line with a small number of earlier critical letters and commentaries2-4) in the American Journal of Hypertension stated explicitly the two major problems with PROGRESS. Firstly, it is illogical and misleading to combine two treatment arms that have significantly heterogeneous results—if the findings from two trial arms differ substantially "then the findings need to be presented separately and interpreted separately"; secondly, "the major limitation of the PROGRESS trial was the failure to include a group randomized to indapamide alone."5 These editorialists speculated that indapamide alone may have reduced stroke by as much as 38% (43% for the combined therapy minus 5% for perindopril alone), which would be consistent with the 34% risk reduction seen with low dose diuretics in the primary prevention setting6 and the 29% risk reduction seen with indapamide alone in the post-stroke antihypertensive treatment study (PATS).7 However, from the design of PROGRESS, one cannot know whether the benefit seen with combination therapy is due to indapamide alone or to an additive or synergistic effect of indapamide with perindopril. What is clear is that the benefit is not attributable to perindopril alone.
The same editorial also argues that the blood pressure differences between the two arms (5/3 mm Hg for perindopril alone v 12/5 mm Hg for the combined therapy) are unlikely to explain the large difference in stroke reduction.5 For example, the blood pressure reduction with indapamide alone in the PATS trial was only 5/2 mm Hg, less than the reduction seen with perindopril alone in PROGRESS. Yet indapamide alone in PATS was associated with significant stroke reduction, while perindopril alone in PROGRESS was not. Several other large studies, however, have provided evidence that for most cardiovascular outcomes it is the amount of blood pressure reduction, rather than the particular regimen used, that determines the benefits of treatment.8-10 Although this is acknowledged in the PROGRESS paper, it is not expressed in the conclusion, which says of perindopril and indapamide that "treatment with these two agents should now be considered routinely for patients with a history of stroke or transient ischemic attack."1
Further publications of PROGRESS data
PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with a previous stroke or transient ischaemic attack. Lancet 2001;358: 1033-41.
Staessen JA, Wang J. Blood-pressure lowering for the secondary prevention of stroke . Lancet 2001;358: 1026-7.
Cates C. The lowering of blood pressure after stroke . Lancet 2001;358: 1993.
Tirschwell D. Combined therapy with indapamide and perindopril but not perindopril alone reduced the risk for recurrent stroke. ACP J Club 2002;136: 51.
Psaty BM, Weiss NS, Furberg CD. The PROGRESS trial: questions about the effectiveness of angiotensin converting enzyme inhibitors. Am J Hypertens 2002;15: 472-4.
Psaty BM, Smith NS, Siscovick DS, Koepsell TD, Weiss NS, Heckbert SR, et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA 1997;277: 739-45.
PATS Collaborating Group. Post-stroke antihypertensive treatment study. A preliminary result. Chin Med J 1995;108: 710-7.
Neal B, MacMahon S, Chapman N. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of ACE inhibitors, calcium antagonists and other blood pressure lowering drugs: results of prospectively designed overviews of randomised trials. Lancet 2000;355: 1955-64.
Staessen JA, Wang JG, Thijs L. Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001;358: 1305-15.
Turnbull F. Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood-pressure lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trials. Lancet 2003;362: 1527-35.
PROGRESS Collaborative Group. Effects of a perindopril-based blood pressure lowering regimen on cardiac outcomes among patients with cerebrovascular disease. Eur Heart J 2003;24: 475-84.
PROGRESS Collaborative Group. Effects of blood pressure lowering with perindopril and indapamide therapy on dementia and cognitive decline in patients with cerebrovascular disease. Arch Intern Med 2003;163: 1069-75.
Fransen M, Anderson C, Chalmers J, Chapman N, Davis S, MacMahon S, et al. Effects of a perindopril-based blood pressure-lowering regimen on disability and dependency in 6105 patients with cerebrovascular disease: a randomized controlled trial. Stroke 2003;34: 2333-8.
Chapman N, Huxley R, Anderson C, Bousser MG, Chalmers J, Colman S, et al. Effects of a perindopril-based blood pressure-lowering regimen on the risk of recurrent stroke according to stroke subtype and medical history: the PROGRESS trial. Stroke 2004;35: 116-21.
Tonkin AM. Does lowering blood pressure prevent recurrent stroke? Med J Aust 2002;176: 283-4.
Britov AN, Bystrova MM, Orlov AA. Control of arterial hypertension in stroke prevention. Klin Med (Mosk) 2002;80: 53-7.
Jackson G. Making PROGRESS in stable patients post stroke or transient ischemic attack: implications for general practice. Int J Clin Pract 2003;57: 385-7.(Richard Wennberg, associa)