VALUE: analysis of results
2004; Elsevier BV; Volume: 364; Issue: 9438 Linguagem: Inglês
10.1016/s0140-6736(04)17010-4
ISSN1474-547X
AutoresJan A. Staessen, Lutgarde Thijs, W. H. Birkenhäger,
Tópico(s)Hormonal Regulation and Hypertension
ResumoThe investigators of the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial (June 19, p 2022 and p 2049)1Julius S Kjeldsen SE Weber M et al.Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.Lancet. 2004; 363: 2022-2031Summary Full Text Full Text PDF PubMed Scopus (2384) Google Scholar, 2Weber MA Julius S Kjeldsen SE et al.Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.Lancet. 2004; 363: 2049-2051Summary Full Text Full Text PDF PubMed Scopus (518) Google Scholar sought to prove benefit beyond blood-pressure control. Against projections, the achieved blood pressure was on average 2·2 mm Hg systolic and 1·7 mm Hg diastolic lower on amlodipine than on valsartan. In middle-aged and older patients, systolic pressure is the prevailing blood-pressure component determining the risk of coronary heart disease.3Franklin SS Larson MG Khan SA et al.Does the relation of blood pressure to coronary heart disease change with aging? The Framingham Heart Study.Circulation. 2001; 103: 1245-1249Crossref PubMed Scopus (1115) Google Scholar In a meta-regression analysis,4Staessen JA Wang JG Thijs L Cardiovascular prevention and blood pressure reduction: a meta-analysis.Lancet. 2001; 358: 1305-1315Summary Full Text Full Text PDF PubMed Scopus (839) Google Scholar we noticed that within-trial gradients in achieved systolic pressure almost completely accounted for the differences in cardiovascular outcomes, including stroke and myocardial infarction. For a systolic gradient of 2·2 mm Hg, as observed in VALUE,1Julius S Kjeldsen SE Weber M et al.Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.Lancet. 2004; 363: 2022-2031Summary Full Text Full Text PDF PubMed Scopus (2384) Google Scholar, 2Weber MA Julius S Kjeldsen SE et al.Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.Lancet. 2004; 363: 2049-2051Summary Full Text Full Text PDF PubMed Scopus (518) Google Scholar our model4Staessen JA Wang JG Thijs L Cardiovascular prevention and blood pressure reduction: a meta-analysis.Lancet. 2001; 358: 1305-1315Summary Full Text Full Text PDF PubMed Scopus (839) Google Scholar predicted odds ratios of 1·10 (95% CI 1·04–1·17) for cardiovascular events, 1·15 (1·01–1·30) for fatal and non-fatal stroke, and 0·98 (0·90–1·08) for fatal and non-fatal myocardial infarction. The actually observed risks ratios were 1·06 (0·98–1·16) for cardiovascular events (p value for comparison with predicted value 0·48), 1·15 (0·98–1·36, p>0·99) for stroke, and 1·19 (1·02–1·38, p=0·03) for myocardial infarction. Thus, with respect to myocardial infarction, the results of valsartan-based treatment were worse, or conversely those of amlodipine-based treatment were better, than predicted from the gradient in the achieved systolic blood pressure. Notwithstanding the merits of the VALUE reports,1Julius S Kjeldsen SE Weber M et al.Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.Lancet. 2004; 363: 2022-2031Summary Full Text Full Text PDF PubMed Scopus (2384) Google Scholar, 2Weber MA Julius S Kjeldsen SE et al.Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.Lancet. 2004; 363: 2049-2051Summary Full Text Full Text PDF PubMed Scopus (518) Google Scholar statistical acrobatics diluted the core message that blood-pressure lowering was essential for prevention. First, the VALUE team artificially divided the follow-up period into consecutive intervals characterised by progressively decreasing between-group differences in systolic blood pressure.1Julius S Kjeldsen SE Weber M et al.Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.Lancet. 2004; 363: 2022-2031Summary Full Text Full Text PDF PubMed Scopus (2384) Google Scholar This time-interval specific analysis was biased for all periods except the first (0–3 months), because event rates in each sequential period were conditional on those occurring previously. Indeed, within each period, events and withdrawals were not randomly distributed, but depended on exposure to randomised treatment. Patients who continued to each subsequent period were, therefore, unbalanced with respect to risk and randomisation. Second, in the accompanying report,2Weber MA Julius S Kjeldsen SE et al.Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.Lancet. 2004; 363: 2049-2051Summary Full Text Full Text PDF PubMed Scopus (518) Google Scholar the VALUE group undertook serial median matching with the systolic blood pressure level at 6 months. This matched-pair approach accounted for the attained systolic pressure (within 2 mm Hg), but excluded 5233 patients (34%), whose systolic pressure was too high on valsartan or too low on amlodipine to allow matching. We tested the methods described in VALUE1Julius S Kjeldsen SE Weber M et al.Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.Lancet. 2004; 363: 2022-2031Summary Full Text Full Text PDF PubMed Scopus (2384) Google Scholar to explore the blood-pressure dependent and independent effects of randomised treatment in the Systolic Hypertension in Europe Trial (Syst-Eur).5Staessen JA Fagard R Thijs L et al.Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.Lancet. 1997; 350: 757-764Summary Full Text Full Text PDF PubMed Scopus (2843) Google Scholar We calculated odds ratios for the benefit of active medication over placebo during sequential 6 month intervals. In the initial four intervals, active treatment progressively lowered systolic pressure by more than 10 mm Hg and reduced the incidence of cardiovascular endpoints by 40–50% (figure). However, in subsequent time intervals, despite a sustained net decrease in systolic pressure, the benefit of active treatment over placebo disappeared. These time-interval specific results contradict previous Syst-Eur reports,5Staessen JA Fagard R Thijs L et al.Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension.Lancet. 1997; 350: 757-764Summary Full Text Full Text PDF PubMed Scopus (2843) Google Scholar which showed a cumulative relative benefit of 31% (45–14) at the end of the double-blind trial. As for valsartan,1Julius S Kjeldsen SE Weber M et al.Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.Lancet. 2004; 363: 2022-2031Summary Full Text Full Text PDF PubMed Scopus (2384) Google Scholar, 2Weber MA Julius S Kjeldsen SE et al.Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.Lancet. 2004; 363: 2049-2051Summary Full Text Full Text PDF PubMed Scopus (518) Google Scholar our results (figure) suggest that in the long-term placebo might have benefits beyond blood-pressure lowering. These findings indicate that results of secondary analyses of clinical trials should not be taken at face value. What should be remembered from the VALUE reports1Julius S Kjeldsen SE Weber M et al.Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial.Lancet. 2004; 363: 2022-2031Summary Full Text Full Text PDF PubMed Scopus (2384) Google Scholar, 2Weber MA Julius S Kjeldsen SE et al.Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial.Lancet. 2004; 363: 2049-2051Summary Full Text Full Text PDF PubMed Scopus (518) Google Scholar is the overwhelming contribution of blood-pressure lowering to cardiovascular prevention. VALUE: analysis of resultsAuthors' reply Full-Text PDF
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