Is blood pressure reduction a valid surrogate endpoint for stroke prevention? an analysis incorporating a systematic review of randomised controlled trials, a by-trial weighted errors-in-variables regression, the surrogate threshold effect (STE) and the biomarker-surrogacy (BioSurrogate) evaluation schema (BSES)

BMC Medical Research Methodology

David Rees²  Michal Schiff¹  Kent R Johnson¹  Marissa N Lassere³ 

[1] St. George Clinical School, Faculty of Medicine, University of New South Wales, Sydney 2217, NSW, Australia;Department of Cardiology, St. George Hospital, Sydney 2217, NSW, Australia;Department of Rheumatology, St George Hospital, Sydney, NSW 2217, Australia

关键词: Biomarker;    Surrogate Endpoint;    Stroke;    Blood pressure;   

Others  :  1136798
DOI  :  10.1186/1471-2288-12-27

 received in 2011-10-28, accepted in 2012-03-12,  发布年份 2012

【 摘 要 】

Background

Blood pressure is considered to be a leading example of a valid surrogate endpoint. The aims of this study were to (i) formally evaluate systolic and diastolic blood pressure reduction as a surrogate endpoint for stroke prevention and (ii) determine what blood pressure reduction would predict a stroke benefit.

Methods

We identified randomised trials of at least six months duration comparing any pharmacologic anti-hypertensive treatment to placebo or no treatment, and reporting baseline blood pressure, on-trial blood pressure, and fatal and non-fatal stroke. Trials with fewer than five strokes in at least one arm were excluded. Errors-in-variables weighted least squares regression modelled the reduction in stroke as a function of systolic blood pressure reduction and diastolic blood pressure reduction respectively. The lower 95% prediction band was used to determine the minimum systolic blood pressure and diastolic blood pressure difference, the surrogate threshold effect (STE), below which there would be no predicted stroke benefit. The STE was used to generate the surrogate threshold effect proportion (STEP), a surrogacy metric, which with the R-squared trial-level association was used to evaluate blood pressure as a surrogate endpoint for stroke using the Biomarker-Surrogacy Evaluation Schema (BSES3).

Results

In 18 qualifying trials representing all pharmacologic drug classes of antihypertensives, assuming a reliability coefficient of 0.9, the surrogate threshold effect for a stroke benefit was 7.1 mmHg for systolic blood pressure and 2.4 mmHg for diastolic blood pressure. The trial-level association was 0.41 and 0.64 and the STEP was 66% and 78% for systolic and diastolic blood pressure respectively. The STE and STEP were more robust to measurement error in the independent variable than R-squared trial-level associations. Using the BSES3, assuming a reliability coefficient of 0.9, systolic blood pressure was a B + grade and diastolic blood pressure was an A grade surrogate endpoint for stroke prevention. In comparison, using the same stroke data sets, no STEs could be estimated for cardiovascular (CV) mortality or all-cause mortality reduction, although the STE for CV mortality approached 25 mmHg for systolic blood pressure.

Conclusions

In this report we provide the first surrogate threshold effect (STE) values for systolic and diastolic blood pressure. We suggest the STEs have face and content validity, evidenced by the inclusivity of trial populations, subject populations and pharmacologic intervention populations in their calculation. We propose that the STE and STEP metrics offer another method of evaluating the evidence supporting surrogate endpoints. We demonstrate how surrogacy evaluations are strengthened if formally evaluated within specific-context evaluation frameworks using the Biomarker- Surrogate Evaluation Schema (BSES3), and we discuss the implications of our evaluation of blood pressure on other biomarkers and patient-reported instruments in relation to surrogacy metrics and trial design.

【 授权许可】

   
2012 Lassere et al; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

【 参考文献 】

• [1]Lassere MN: The biomarker-surrogacy evaluation schema: a review of the biomarker-surrogate literature and a proposal for a criterion-based, quantitative, multidimensional hierarchical levels of evidence schema for evaluating the status of biomarkers as surrogate endpoints. Stat Methods Med Res 2008, 17:303-340.
• [2]Committee on Qualification of Biomarkers and Surrogate Endpoints: Evaluation of biomarkers and surrogate endpoints in chronic disease. Appendix A. Washington: The National Academies Press; 2010. IOM (Institute of Medicine) DC; 2010
• [3]Boissel JP, Collet JP, Moleur P, Haugh M: Surrogate endpoints: a basis for a rational approach. Eur J Clin Pharmacol 1992, 43:235-244.
• [4]Lassere MN, Johnson KR, Boers M, Tugwell P, Brooks P, Simon L, Strand V, Conaghan PG, Ostergaard M, Maksymowych WP, Landewe R, Bresnihan B, Tak PP, Wakefield R, Mease P, Bingham CO, Hughes M, Altman D, Buyse M, Galbraith S, Wells G: Definitions and validation criteria for biomarkers and surrogate endpoints: development and testing of a quantitative hierarchical levels of evidence schema. J Rheumatol 2007, 34:607-615.
• [5]Lassere MN: The Innovative Evaluation Schema of Validating Putative Surrogate Endpoints. [http:/ / www.amstat.org/ meetings/ jsm/ 2010/ onlineprogram/ AbstractDetails.cfm?abstractid=3069 21] webciteJoint Statistical Meetings Vancouver, Canada;
• [6]Buyse M, Molenberghs G, Burzykowski T, Renard D, Geys H: The validation of surrogate endpoints in meta-analyses of randomized experiments. Biostat 2000, 1:49-67.
• [7]Burzykowski T, Molenberghs G, Buyse M (Eds): The evaluation of surrogate endpoints In Springer Science+Business Media Inc 2005.
• [8]Daniels MJ, Hughes MD: Meta-analysis for the evaluation of potential surrogate markers. Stat Med 1997, 16:1965-1982.
• [9]Burzykowski T, Buyse M: Surrogate threshold effect: An alternative measure for meta-analytic surrogate endpoint validation. Pharmaceut Statist 2006, 5:173-186.
• [10]Johnson K, Ringland C, Stokes B: Response rate or time to progression as predictors of survival in trials of metastatic colorectal cancer or non-small-cell lung cancer: a meta-analysis. Lancet Oncology 2006, 7:741-746.
• [11]Johnson KR, Freemantle N, Anthony DM, Lassere MN: LDL-cholesterol differences predicted survival benefit in statin trials by the surrogate threshold effect (STE). J Clin Epidemiol 2009, 62:328-336.
• [12]Temple R: Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA 1999, 282:790-795.
• [13]Lesko LJ, Atkinson AJ Jr: Use of biomarkers and surrogate endpoints in drug development and regulatory decision making: criteria, validation, strategies. Annual Review of Pharmacology & Toxicology 2001, 41:347-366.
• [14]Desai M, Stockbridge N, Temple R: Blood pressure as an example of a biomarker that functions as a surrogate. AAPS Journal 2006, 8:E146-152.
• [15]Turnbull F, Kengne AP, MacMahon S: Blood pressure and cardiovascular disease: tracing the steps from Framingham. Prog Cardiovasc Dis 2010, 53:39-44.
• [16]Staessen JA, Wang JG, Thijs L: Cardiovascular protection and blood pressure reduction: a meta-analysis. Lancet 2001, 358:1305-1315.
• [17]Blood Pressure Lowering Treatment Trialists' Collaboration, Turnbull F, Neal B, Ninomiya T, Algert C, Arima H, Barzi F, Bulpitt C, Chalmers J, Fagard R, Gleason A, Heritier S, Li N, Perkovic V, Woodward M, MacMahon S: Effects of different regimens to lower blood pressure on major cardiovascular events in older and younger adults: meta-analysis of randomised trials. BMJ 2008, 336:1121-1123.
• [18]Law MR, Morris JK, Wald NJ: Use of blood pressure lowering drugs in the prevention of cardiovascular disease: meta-analysis of 147 randomised trials in the context of expectations from prospective epidemiological studies. BMJ 2009, 338:b1665.
• [19]Willett W: An overview of issues related to the correction of non-differential exposure measurement error in epidemiologic studies. Statistics in Medicine 1989, 8:1031-1040.
• [20]Gillard J, Iles T: Methods of fitting straight lines where both variables are subject to measurement error. Current Clinical Pharmacology 2009, 4:164-171.
• [21]Tobin J: Estimation of relationships for limited dependent variables. Econometrica 1958, 26:24-36.
• [22]Roystan P, Altman DG: Regression using fractional polynomials of continuous variables: Parsimonious parametric modelling. Applied Statistics 1994, 43:429-467.
• [23]Altman DG: Practical statistics for medical research. London: Chapman and Hall; 1991.
• [24]Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH: Blood pressure, stroke, and coronary heart disease. Part 2, Short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet 1990, 335:827-838.
• [25]Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, Mehlsen J, Nieminen M, O' Brien E, Ostergren J, ASCOT Investigators: Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005, 366:895-906.
• [26]Anonymous: Report by the Management Committee: The Australian therapeutic trial in mild hypertension. Lancet 1980, 1:1261-1267.
• [27]The IPPPSH Collaborative Group: Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: the International Prospective Primary Prevention Study in Hypertension (IPPPSH). J Hypertens 1985, 3:379-392.
• [28]Medical Research Council Working Party: MRC trial of treatment of mild hypertension: principal results. Br Med J (Clin Res Ed) 1985, 291:97-104.
• [29]Coope J, Warrender TS: Randomised trial of treatment of hypertension in elderly patients in primary care. Br Med J (Clin Res Ed) 1986, 293:1145-1151.
• [30]SHEP Cooperative Research Group: Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension. Final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991, 265:3255-3264.
• [31]Dahlof B, Lindholm LH, Hansson L, Schersten B, Ekbom T, Wester PO: Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 1991, 338:1281-1285.
• [32]Medical Research Council Working Party: Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 1992, 304:405-412.
• [33]PATS Collaborating Group: Post-stroke antihypertensive treatment study. a preliminary result. Chin Med J (Engl) 1995, 108:710-717.
• [34]Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, Nachev C, O' Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A: Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. the systolic hypertension in Europe (Syst-Eur) trial investigators. Lancet 1997, 350:757-764.
• [35]Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GB, Miller ME, Riley W: Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators. Circulation 2000, 102:1503-1510.
• [36]PROGRESS Collaborative Group: Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischaemic attack. Lancet 2001, 358:1033-1041.
• [37]Fox KM, EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators: Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet 2003, 362:782-788.
• [38]Lithell H, Hansson L, Skoog I, Elmfeldt D, Hofman A, Olofsson B, Trenkwalder P, Zanchetti A, SCOPE Study Group: The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003, 21:875-886.
• [39]Bulpitt CJ, Beckett NS, Cooke J, Dumitrascu DL, Gil-Extremera B, Nachev C, Nunes M, Peters R, Staessen JA, Thijs L, Hypertension in the Very Elderly Trial Working Group: Results of the pilot study for the Hypertension in the Very Elderly Trial. J Hypertens 2003, 21:2409-2417.
• [40]Braunwald E, Domanski MJ, Fowler SE, Geller NL, Gersh BJ, Hsia J, Pfeffer MA, Rice MM, Rosenberg YD, Rouleau JL, PEACE Trial Investigators: Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med 2004, 351:2058-2068.
• [41]Poole-Wilson PA, Lubsen J, Kirwan BA, van Dalen FJ, Wagener G, Danchin N, Just H, Fox KA, Pocock SJ, Clayton TC, Motro M, Parker JD, Bourassa MG, Dart AM, Hildebrandt P, Hjalmarson A, Kragten JA, Molhoek GP, Otterstad JE, Seabra-Gomes R, Soler-Soler J, Weber S, Coronary disease Trial Investigating Outcome with Nifedipine gastrointestinal therapeutic system investigators: Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with stable angina requiring treatment (ACTION trial): randomised controlled trial. Lancet 2004, 364:849-857.
• [42]Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators, Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P: Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008, 372:1174-1183.
• [43]Beckett NS, Peters R, Fletcher AE, Staessen JA, Liu L, Dumitrascu D, Stoyanovsky V, Antikainen RL, Nikitin Y, Anderson C, Belhani A, Forette F, Rajkumar C, Thijs L, Banya W, Bulpitt CJ, HYVET Study Group: Treatment of hypertension in patients 80 years of age or older. N Engl J Med 2008, 358:1887-1898.
• [44]Rose GA, Holland WW, Crowley EA: A sphygmomanometer for epidemiologists. Lancet 1964, 1:296-300.
• [45]Conway J: Blood pressure and heart rate variability. J Hypertens 1986, 4:261-263.
• [46]Mancia G, Bertinieri G, Grassi G, Parati G, Pomidossi G, Ferrari A, Gregorini L, Zanchetti A: Effects of blood-pressure measurement by the doctor on patient' s blood pressure and heart rate. Lancet 1983, 2:695-698.
• [47]Hebel JR, Apostolides AY, Dischinger P, Entwisle G, Su S: Within-person variability in diastolic blood pressure for a cohort of normotensives. J Chronic Dis 1980, 33:745-750.
• [48]Gerin W, Rosofsky M, Pieper C, Pickering TG: A test of reproducibility of blood pressure and heart rate variability using a controlled ambulatory procedure. J Hypertens 1993, 11:1127-1131.
• [49]Giaconi S, Palombo C, Genovesi-Ebert A, Marabotti C, Volterrani D, Ghione S: Long-term reproducibility and evaluation of seasonal influences on blood pressure monitoring. J Hypertens Suppl 1988, 6:S64-66.
• [50]Armitage P, Blendis LN, Smyllie HC: The measurement of observer agreement in recoding of signs. J R Statist Soc A 1966, 129:98-109.
• [51]Gardner MJ, Heady JA: Some effects of within-person variability in epidemiological studies. J Chronic Dis 1973, 26:781-795.
• [52]Muntner P, Joyce C, Levian E, Holt E, Shimbo D, Webber LS, Opaaril S, Re R, Krousel-Wood M: Reproducibilitiy of visit-to-visit variability of blood pressure measured as part of routine clinical care. J Hypertens 2011, 29:2332-2338.
• [53]Skirton H, Chamberlain W, Lawson C, Ryan H, Young E: A systematic review of variability and reliability of manual and automated blood pressure readings. J Clin Nurs 2011, 20:602-14.
• [54]Rothwell PM: Limitations of the usual blood-pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet 2010, 375:938-948.
• [55]Clarke R, Shipley M, Lewington S, Youngman L, Collins R, Marmot M, Peto R: Underestimation of risk associations due to regression dilution in long-term follow-up of prospective studies. Am J Epidemiol 1999, 150:341-353.
• [56]MacMahon S, Peto R, Cutler J, Collins R, Sorlie P, Neaton J, Abbott R, Godwin J, Dyer A, Stamler J: Blood pressure, stroke, and coronary heart disease. Part 1, prolonged differences in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990, 335:765-774.
• [57]Li Y, Taylor JM, Elliott MR: A Bayesian approach to surrogacy assessment using principal stratification in clinical trials. Biometrics 2010, 66:523-531.
• [58]Sargent DJ, Wieand HS, Haller DG, Gray R, Benedetti JK, Buyse M, Labianca R, Seitz JF, O' Callaghan CJ, Francini G, Grothey A, O' Connell M, Catalano PJ, Blanke CD, Kerr D, Green E, Wolmark N, Andre T, Goldberg RM, De Gramont A: Disease-free survival versus overall survival as a primary end point for adjuvant colon cancer studies: individual patient data from 20,898 patients on 18 randomized trials. J Clin Oncol 2005, 23:8664-8670.
• [59]Buyse M: Use of meta-analysis for the validation of surrogate endpoints and biomarkers in cancer trials. Cancer Journal 2009, 15:421-425.
• [60]Michiels S, Le Maitre A, Buyse M, Burzykowski T, Maillard E, Bogaerts J, Vermorken JB, Budach W, Pajak TF, Ang KK, Bourhis J, Pignon JP, MARCH and MACH-NC Collaborative Groups: Surrogate endpoints for overall survival in locally advanced head and neck cancer: meta-analyses of individual patient data. Lancet Oncology 2009, 10:341-50.
• [61]Law MR, Wald NJ, Morris JK, Jordan RE: Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ 2003, 326:1427.
• [62]Boissel JP, Gueyffier F, Boutitie F, Pocock S, Fagard R: Apparent effect on blood pressure is only partly responsible for the risk reduction due to antihypertensive treatments. Fundamental & Clinical Pharmacology 2005, 19:579-584.
• [63]Czernichow S, Zanchetti A, Turnbull F, Barzi F, Ninomiya T, Kengne AP, Lambers Heerspink HJ, Perkovic V, Huxley R, Arima H, Patel A, Chalmers J, Woodward M, MacMahon S, Neal B, Blood Pressure Lowering Treatment Trialists' Collaboration: The effects of blood pressure reduction and of different blood pressure-lowering regimens on major cardiovascular events according to baseline blood pressure: meta-analysis of randomized trials. J Hypertens 2011, 29:4-16.
• [64]Boutitie F, Gueyffier F, Pocock SJ, Boissel JP: Assessing treatment-time interaction in clinical trials with time to event data: a meta-analysis of hypertension trials. Stat Med 1998, 17:2883-2903.
• [65]Webb AJ, Fischer U, Mehta Z, Rothwell PM: Effects of antihypertensive-drug class on interindividual variation in blood pressure and risk of stroke: a systematic review and meta-analysis. Lancet 2010, 375:906-915.
• [66]Rothwell PM, Howard SC, Dolan E, O' Brien E, Dobson JE, Dahlof B, Sever PS, Poulter NR: Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension. Lancet 2010, 375:895-905.
• [67]Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S: Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet 1998, 351:1755-1762.
• [68]HOT Study Group: The Hypertension Optimal Treatment Study (the HOT Study). Blood Press 1993, 2:62-68.
• [69]Johnson K: Strengths and weaknesses of renal markers as risk factors and surrogate markers. Kidney Int 2011, 79:1272-1274.