Skip to main content
NCBI home page
The AAPS Journal logoLink to The AAPS Journal
. 2006 Mar 10;8(1):E146–E152. doi: 10.1208/aapsj080117

Blood pressure as an example of a biomarker that functions as a surrogate

Mehul Desai 1,✉, Norman Stockbridge 1, Robert Temple 1
PMCID: PMC2751433  PMID: 16584122

Abstract

There are many important uses of biomarkers in drug development. An area of particular interest is the use of biomarkers as surrogate end points. Only a small minority of biomarkers are established surrogate end points. Blood pressure is an example of a surrogate end point accepted by both clinicians and regulators. It was a plausible surrogate because of the large epidemiologic databases demonstrating a correlation between elevated blood pressures and adverse cardiovascular outcomes. That plausibility has been supported, however, by the numerous placebo-controlled outcome studies evaluating several pharmacologically distinct agents that showed an effect on stroke and coronary heart disease outcomes from lowering blood pressure.

Keywords: biomarker, surrogate endpoint, blood pressure

Full Text

The Full Text of this article is available as a PDF (171.7 KB).

References

  • 1.Biomarkers Definitions Working Group Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89–95. doi: 10.1067/mcp.2001.113989. [DOI] [PubMed] [Google Scholar]
  • 2.Temple R. Are surrogate markers adequate to assess cardiovascular disease drugs? JAMA. 1999;282:790–795. doi: 10.1001/jama.282.8.790. [DOI] [PubMed] [Google Scholar]
  • 3.Echt D, Liebson P, Mitchell L, et al. CAST Investigators. Mortality and morbidity in patients receiving encainide, flecainide, or placebo: the Cardiac Arrhythmia Suppression Trial. N Engl J Med. 1991;324:781–788. doi: 10.1056/NEJM199103213241201. [DOI] [PubMed] [Google Scholar]
  • 4.Packer M, Carver J, Rodehoffer R, et al. Effect of oral milrinone on mortality in severe chronic heart failure. The PROMISE Study Research Group. N Engl J Med. 1991;325:1468–1475. doi: 10.1056/NEJM199111213252103. [DOI] [PubMed] [Google Scholar]
  • 5.White PD. Heart Disease. New York, NY: MacMillan Company; 1931. [Google Scholar]
  • 6.Goldring W. Hypertension: seven decades of treatment. Bull NY Acad Med. 1969;45:902–909. [PMC free article] [PubMed] [Google Scholar]
  • 7.Fry J. Natural history of hypertension. Lancet. 1974;2:431–433. doi: 10.1016/S0140-6736(74)91816-9. [DOI] [PubMed] [Google Scholar]
  • 8.Prentice R. Surrogate endpoints in clinical trials: definition and operational criteria. Stat Med. 1989;8:431–440. doi: 10.1002/sim.4780080407. [DOI] [PubMed] [Google Scholar]
  • 9.Fleming TR, DeMets DL. Surrogate endpoints in clinical trials: are we being misled? Ann Intern Med. 1996;125:605–613. doi: 10.7326/0003-4819-125-7-199610010-00011. [DOI] [PubMed] [Google Scholar]
  • 10.MacMahon S, Peto R, Cutler J, et al. 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. doi: 10.1016/0140-6736(90)90878-9. [DOI] [PubMed] [Google Scholar]
  • 11.Kannel WB. Blood pressure as a cardiovascular risk factor: prevention and treatment. JAMA. 1996;275:1571–1576. doi: 10.1001/jama.1996.03530440051036. [DOI] [PubMed] [Google Scholar]
  • 12.Neaton J, Wentworth D, Sherwin R, et al. Comparison of 10-year Coronary and Cerebrovascular Disease Mortality Rates by Hypertensive Status for Black and Non-Black Men Screened in the Multiple Risk Factor Intervention Trial (MRFIT) [abstract]Circulation 1989;80(4): Abstract 1195.
  • 13.Davey Smith G, Neaton JD, Wentworth D, Stamler R, Stamler J. Mortality differences between black and white men in the USA: contribution of income and other risk factors among men screened for the MRFIT. Lancet. 1998;351:934–939. doi: 10.1016/s0140-6736(00)80010-0. [DOI] [PubMed] [Google Scholar]
  • 14.Van Den Hoogen P, Feskens E, Nagelkerke N, et al. The relation between blood pressure and mortality due to coronary heart disease among men in different parts of the world. N Engl J Med. 2000;342:1–8. doi: 10.1056/NEJM200001063420101. [DOI] [PubMed] [Google Scholar]
  • 15.Neaton J, Wentworth D. Serum cholesterol, blood pressure, cigarette smoking, and death from coronary heart disease: overall findings and differences by age for 316,099 white men. Arch Intern Med. 1992;152:56–64. doi: 10.1001/archinte.1992.00400130082009. [DOI] [PubMed] [Google Scholar]
  • 16.Blaufox MD, Frishman WH, Miller G, et al. 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. doi: 10.1001/jama.1991.03460240051027. [DOI] [PubMed] [Google Scholar]
  • 17.Staessen J, Fagard R, Thijs L, et al. Randomized double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350:757–764. doi: 10.1016/S0140-6736(97)05381-6. [DOI] [PubMed] [Google Scholar]
  • 18.VA Cooperative Study Group on Antihypertensive Agents Effects of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA. 1967;202:1028–1034. doi: 10.1001/jama.1967.03130240070013. [DOI] [PubMed] [Google Scholar]
  • 19.VA Cooperative Study Group on Antihypertensive Agents Effects of treatment on morbidity in hypertension, II: results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA. 1970;213:1143–1152. doi: 10.1001/jama.1970.03170330025003. [DOI] [PubMed] [Google Scholar]
  • 20.Hypertension Detection and Follow-Up Program Cooperative Research Group Five-year findings of the Hypertension Detection and Follow-up Program: reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA. 1979;242:2562–2571. doi: 10.1001/jama.1979.03300230018021. [DOI] [PubMed] [Google Scholar]
  • 21.Management Committee The Australian Therapeutic Trial in Mild Hypertension. Lancet. 1980;1:1261–1267. [PubMed] [Google Scholar]
  • 22.MRC Working Party MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party. BMJ. 1985;291:97–104. doi: 10.1136/bmj.291.6488.97. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Amery A, Birkenhager W, Brixko P, et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly trial. Lancet. 1985;1:1349–1354. doi: 10.1016/S0140-6736(85)91783-0. [DOI] [PubMed] [Google Scholar]
  • 24.Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. BMJ. 1986;293:1145–1151. doi: 10.1136/bmj.293.6555.1145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Dahlof B, Lindholm LH, Hansson L, et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) Lancet. 1991;338:1281–1285. doi: 10.1016/0140-6736(91)92589-T. [DOI] [PubMed] [Google Scholar]
  • 26.MRC Working Party Medical Research Council trial of treatment of hypertension in older adults: principal results. MRC Working Party. BMJ. 1992;304:405–412. doi: 10.1136/bmj.304.6824.405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.UK Prospective Diabetes Study Group Tight blood pressure and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703–713. doi: 10.1136/bmj.317.7160.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.HOPE Investigators Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–153. doi: 10.1056/NEJM200001203420301. [DOI] [PubMed] [Google Scholar]
  • 29.Dahlof B, Devereux R, Kjeldsen S, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension Study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995–1003. doi: 10.1016/S0140-6736(02)08089-3. [DOI] [PubMed] [Google Scholar]
  • 30.Officers ALLHAT Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone. JAMA. 2000;283:1967–1975. doi: 10.1001/jama.283.15.1967. [DOI] [PubMed] [Google Scholar]
  • 31.Lewis E, Hunsicker L, Clarke W, et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–860. doi: 10.1056/NEJMoa011303. [DOI] [PubMed] [Google Scholar]
  • 32.Officers ALLHAT Major cardiovascular events in hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic. JAMA. 2002;288:2981–2997. doi: 10.1001/jama.288.23.2981. [DOI] [PubMed] [Google Scholar]
  • 33.Wing L, Reid C, Ryan P, et al. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003;348:583–592. doi: 10.1056/NEJMoa021716. [DOI] [PubMed] [Google Scholar]
  • 34.Dahlof B, Sever P, Poulter N, et al. 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 randomized controlled trial. Lancet. 2005;366:895–906. doi: 10.1016/S0140-6736(05)67185-1. [DOI] [PubMed] [Google Scholar]
  • 35.New Drug, Antibiotic, and Biological Drug Product Regulations, Accelerated Approval. Final rule. 57Federal Register 58942 (1992). [PubMed]

Articles from The AAPS Journal are provided here courtesy of American Association of Pharmaceutical Scientists

RESOURCES