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Central Blood Pressure: Current Evidence and ClinicalImportance in Hypertensive Disorders during Pregnancy
  JOHTN
PHYSIOLOGY OF BLOOD PRESSURE REGULATION
Central Blood Pressure: Current Evidence and Clinical
Importance in Hypertensive Disorders during Pregnancy
1Nibedita Priyadarsini, 2Sajal C Singh, 3Manish Goyal, 4Sushil C Mahapatra
1Assistant Professor, 2Senior Demonstrator, 3AssociateProfessor, 4Professor and Head
1-4Department of Physiology, All India Institute of MedicalSciences, Bhubaneswar, Odisha, India
Corresponding Author: Manish Goyal, Associate ProfessorDepartment of Physiology, All India Institute of Medical SciencesBhubaneswar, Odisha, India,
e-mail: drmanishgoyal@rediffmail.
 
ABSTRACT
Hypertensive disorders complicate 5 to 10% of all pregnanciesand hypertension is a major pregnancy complication associatedwith both fetal and maternal morbidity and mortality.Measurement of brachial blood pressure (BP) is a routine clinicalassessment tool for management of various hypertensivedisorders. Systolic pressure varies throughout the vasculature;aortic systolic pressure [or central blood pressure (CBP)] isactually lower than that of systolic BP in brachial artery. Centralto peripheral pressure difference is highly variable amongindividuals. In various studies, it has been reported that CBPis a better predictor of cardiovascular events as compared withperipheral BP. Hypertensive disorders in pregnancy are associatedwith increased arterial stiffness indices, both during andafter pregnancy leading to differences in central and peripheralpressures. In this article, the issues related to importance ofCBP measurement for management of hypertensive disordersin pregnancy have been discussed.
Keywords: Central blood pressure, Eclampsia, Hypertension,Preeclampsia, Pregnancy-induced hypertension.
How to cite this article: Priyadarsini N, Singh SC, Goyal M,Mahapatra SC. Central Blood Pressure: Current Evidence andClinical Importance in Hypertensive Disorders during Pregnancy.Hypertens J 2017;3(4):173-177.
Source of support: Nil
Conflict of interest: None
 
 

INTRODUCTION

Hypertensive disorders complicate 5 to 10% of all pregnancies,and hypertension is a major pregnancy complicationassociated with both fetal and maternal morbidityand mortality.1 Pathophysiology of hypertensive disordersin pregnancy is multifactorial and may be contributedin part by hypoxia which leads to release of stressfactors into maternal circulation, resulting in alterationsin systemic vasculature.2 Hemodynamics in pregnancy isdifferent from those of general population. The changes associated with healthy pregnancy are increase in heartrate, cardiac output, and intravascular volume as well asdecrease in peripheral vascular resistance and arterialBP.3,4 These adaptive hemodynamic changes may be dueto the influence of estrogen and increased activity of thelocal metabolites.5,6 In gestational hypertension, oppositeevents are observed like increase in peripheral vascularresistance, vasoconstriction, a decrease in intravascularvolume, and increased reactivity of the maternal vascularbed to pressure factors, with subsequent increase inarterial stiffness, tone, and BP.7,8 Arterial BP in clinicsis traditionally measured with the brachial cuff sphygmomanometer,due to its ease of measurement. Severalrandomized controlled studies have demonstrated thatdecreasing BP in hypertensive individuals with treatmentor lifestyle modification leads to significant reduction inrisk of adverse cardiovascular events.9
 
After the work of Scipione Riva-Rocci on sphygmomanometerin the late 19th century, physicians focused onlyon the pressure waveform peak (systole) and trough(diastole) and ignored the rest of the arterial pressurewaveform. However, brachial BP has been a modality ofchoice for diagnosing and managing various hypertensivedisorders due to its ease of measurement; however,it is a poor surrogate for aortic pressure or CBP, whichis invariably lower than corresponding brachial values.9Kroeker and Wood10 demonstrated that pressure wavein peripheries responds to central changes induced byValsalva maneuver. Peripheral pulse pressure is higherthan at the aortic level. This amplification results due tothe reflection of the pressure wave from the peripheralvasculature.11 The CBP is a better marker than brachialpressure in predicting future cardiovascular events.12,13Moreover, antihypertensive drugs may have differentialeffect on CBP and peripheral BP.14 In the Conduit ArteryFunction Evaluation (CAFE) study, it has been foundthat CBP was associated with clinical outcomes morestrongly than brachial BP.14 Thus, CBP could provide abetter framework for understanding the hemodynamicchanges associated with various diseased states. TheCBP can now reliably be determined by noninvasivetechniques in clinics and it is gaining greater acceptanceas a better prognostic marker than brachial pressure inhypertensive patients.9 These observations regardingutility of CBP in general population and hypertensive individuals have been extrapolated for diagnosing andmanaging hypertensive disorders in pregnancy in severalstudies.15-20

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PHYSIOLOGICAL CONCEPT OF CBP

Though there is continuous variation of BP throughoutthe cardiac cycle, in clinical practice, only systolic anddiastolic pressures are measured. Traditionally, thesepressures are usually determined by brachial cuff sphygmomanometerin clinical practice.

Blood pressure thus determined peripherally is notthe same as that at aortic level because as the pulse wavepropagates from aorta to periphery, its characteristicschange due to progressive increase in arterial stiffnessand decrease in arterial diameter. As the pressure wavetravels from the highly elastic central arteries to stifferperipheral arteries, the upper portion of the waveformbecomes narrower, the systolic peak becomes moreprominent, and systolic pressure increases (Fig. 1).9

This pulse waveform is the result of a forward wavegenerated by left ventricle and a reflected backwardwave from various points of obstruction in peripheralvasculature.21,22 The magnitude of pressure amplificationmay be influenced by several demographic variablesincluding age, gender, and height,23 as well as clinicaland physiological factors, such as hypercholesterolemia,24recreational stimulants,25 vasoactive medications,26 meanarterial pressure,23 heart rate,27 exercise,28 and posture.29

MEASUREMENT OF CBP

Direct measurement of CBP at aortic level is possiblethrough cardiac catheterization, which was first demonstratedby Dr Werner Forssmann and was later used fordiagnostic purposes by Cournand and Ranges.30 Procedurefor cardiac catheterization provided a way to directlyasses the cardiopulmonary system, but for routine clinicaluse, this technique is highly invasive and may notbe recommended. Fortunately, with recent advances innoninvasive assessment of BP, pressure waveform andadvanced algorithms to predict CBP from it have rekindledthe interest exploring the clinical utility of CBP. Mostof the available noninvasive CBP measurement devicesinvolve recording of pressure waveforms in vessels distal to the aorta like carotid using applanation tonometryalong with cuff BP measurement. Carotid artery tonometry,owing to its proximity to the aorta, is expected tobe the most representative of the aortic pressure, butsometimes, it is difficult to record accurate waveformsparticularly in obese individuals. Alternatively, pulsewaves may be recorded from a peripheral artery likeradial and brachial arteries by either tonometry or cuffBP and may be used to derive the central artery waveformfor identification and analysis of late systolic shoulderand pressures using various algorithms or a generalizedtransfer function.31

Central Blood Pressure: Current Evidence and ClinicalImportance in Hypertensive Disorders during Pregnancy
Fig. 1: Amplification of the pressure waveform moving from theaorta to the radial artery
 
The peripheral pulse pressure does not alwaysprovide a reliable measure of central pulse pressure.Though there is a considerable increase in pulse pressurefrom the aorta to the brachial artery, its degree isnot constant, as it is influenced by age, posture, exercise,as well as heart rate, and BP value itself.29 In addition,the estimate of CBP depends on late systolic shoulder inpulse waveform and may not be a true reflection of aorticBP in people with low BP.32

Differences between central and peripheral BP may beclinically important because aortic pressure determinesthe left ventricular workload, rather than brachial pressure.Moreover, studies show that CBP is significantlyrelated to cardiovascular events, and in addition, the effectof antihypertensive agents on BP seems to be differentin brachial and aortic circulation.19 Provided the clinicalutility of CBP, the increasing availability of CBP measuringdevices and relative ease in using them, despite itslimitations, are gaining acceptance in clinical practice.

IMPORTANCE OF CBP IN PREGNANCY

Heart disease is the leading cause of morbidity andmortality in women throughout the world.33 Gestationalhypertension is associated with increased arterial stiffnessindices, both during and after pregnancy, contributingto the increased future cardiovascular risks.15Cardiovascular events are more closely related to centralthan peripheral pressure because heart, kidney, and brainare exposed to aortic than brachial pressure. Moreover, ithas been found that CBP is more closely correlated withwidely accepted surrogate measures of cardiovascularrisk, such as carotid intima media thickness34-36 and leftventricular mass,36-38 than brachial pressure in crosssectionalstudies.

The potential value of CBP measurement has beenfurther supported by several longitudinal studies. In theResearch into Elderly Patient Anaesthesia and SurgeryOutcome Numbers (REASON) Study, and in a substudyof The Anglo-Scandinavian Cardiac Outcomes Trial(ASCOT), the CBP turned out to be a better predictor for adverse cardiovascular events as compared with brachialBP. Left ventricular mass also had stronger associationwith CBP compared with brachial BP.39,40
 
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CBP in Hypertensive Disorders During Pregnancy

The role and significance of CBP in diagnosing andmanaging hypertensive disorders in pregnancy areincreasingly being realized. In the postpartum periodin healthy women, while their brachial systolic BP wassimilar to those of nonpregnant controls, they have higherwith smaller pulse pressure amplification. Physiologically,this is probably because of an increase in arterialstiffness and/or vasoconstriction resulting from thelack of influence of estrogens on the arterial wall in thefirst months after delivery.3-5,41-47 In recent studies, CBP,augmentation index, and pulse wave velocity have beenreported to be higher in preeclampsia and gestationalhypertension compared with normotensive pregnancies48-50 and it has been suggested that these parameterscould be used to predict preeclampsia even as early asthe 11th to 13th week of gestation.51 According to availabledata, CBP assessment showed significantly bettersensitivity than the assessment of brachial BP parametersin pregnancy.16-20 Szczepaniak-Chichel et al20 reportedthat, in hypertensive pregnancies, the difference betweenaortic and peripheral BP was significantly smaller in thesecond and third trimester than in healthy pregnancy.

An important issue in preferring CBP over peripheralpressure in diagnosing and managing hypertensive disordersin pregnancy is defining cut-off values for CBPin such patients. It has been observed that reduced brachialsystolic BP to aortic systolic pressure difference inhypertensive pregnancies may signify a narrower safetymargin for complications20 and can be taken into considerationin the management of pregnancy hypertension.

If CBP is effectively proved to be a better indicatorfor prediction and prognosis of hypertensive disordersin pregnancy, another issue will lie in effective and safemanagement of such cases. Several antihypertensivedrugs usually prescribed currently may not effectivelylower CBP as well as brachial cuff pressures. For example,beta-blockers have differential effect on aortic and brachialpressures. While they reduce peripheral BP, they arequite ineffective in reducing the CBP as well as adversecardiovascular events.52-54 The only class of drugs foundto be highly effective in reducing CBP are the vasodilatorslike nitrates. However, antihypertensive drugs which canbe prescribed during pregnancy are limited and mustbe carefully studied for their effectiveness for loweringCBP as well.

CONCLUSION

The CBP appears to be a better predictor for hypertensivedisorders in pregnancy apart from other adverse cardiovascular events in general population. It would beinteresting to witness the evolution of better techniquesfor determining CBP.

 
Before CBP can be prescribed as a standard clinicalevaluation tool for management of hypertensive disordersin pregnancy, more data need to be generated andimprovement in technique for determining CBP may bewatched for. Pharmacological management of increasedCBP needs to be further studied so that effective regimencan be developed for patients in general population aswell as in pregnant women.

REFERENCES
  1. Cunningham FG, Leveno KJ, Bloom SL, Hauth JC, GilstrapIII LC, Wenstrom KD. Chapter 34: Hypertensive disordersin pregnancy. William's obstetrics. 22nd ed. New York (NY):McGraw-Hill; 2005. p. 761.
  2. Redman CW, Sargent IL. Placental stress and pre-eclampsia:a revised view. Placenta 2009 Mar;30 (Suppl A):S38-S42.
  3. Abbas AE, Lester SJ, Connolly H. Pregnancy and the cardiovascularsystem. Int J Cardiol 2005 Feb 15;98(2):179-189.
  4. Valensise H, Novelli GP, Vasapollo B, Borzi M, Arduini D,Galante A, Romanini C. Maternal cardiac systolic and diastolicfunction: relationship with uteroplacental resistances.A Doppler and echocardiographic longitudinal study. UltrasoundObstet Gynecol 2000 Jun;15(6):487-497.
  5. Tihtonen K, Koobi T, Huhtala H, Uotila J. Hemodynamicadaptation during pregnancy in chronic hypertension.Hypertens Pregnancy 2007;26(3):315-328.
  6. Hunter S, Robson SC. Adaptation of the maternal heart inpregnancy. Br Heart J 1992 Dec;68(6):540-543.
  7. Hays PM, Cruikshank DP, Dunn LJ. Plasma volume determinationin normal and preeclamptic pregnancies. Am J ObstetGynecol 1985 Apr;151(7):958-966.
  8. Visser W, Wallenburg HC. Central hemodynamic observationsin untreated preeclamptic patients. Hypertension 1991Jun;17(6 Pt 2):1072-1077.
  9. McEniery CM, Cockcroft JR, Roman MJ, Franklin SS,Wilkinson IB. Central blood pressure: current evidence andclinical importance. Eur Heart J 2014 Jun;35(26):1719-1725.
  10. Kroeker EJ, Wood EH. Beat-to-beat alterations in relationshipof simultaneously recorded central and peripheral arterialpressure pulses during Valsalva maneuver and prolongedexpiration in man. J Appl Physiol 1956;8(5):483-494.
  11. Roman MJ, Devereux RB, Kizer JR, Lee ET, Galloway JM, Ali T,Umans JG, Howard BV. Central pressure more stronglyrelates to vascular disease and outcome than does brachialpressure: the Strong Heart Study. Hypertension 2007Jul;50(1):197-203.
  12. Pini R, Cavallini MC, Palmieri V, Marchionni N, DiBari M,Devereux RB, Masotti G, Roman MJ. Central but not brachialblood pressure predicts cardio vascular events in anunselected geriatric population: the ICARe Dicomano Study.J Am Coll Cardiol 2008 Jun;51(25):2432-2439.
  13. Williams B, Lacy PS, Thom SM, Cruickshank K, Stanton A,Collier D, Hughes AD, Thurston H, O'Rourke M. Differentialimpact of blood pressure-lowering drugs on central aorticpressure and clinical outcomes: principal results of theConduit Artery Function Evaluation (CAFE) study. Circulation2006 Mar;113(9):1213-1225.

Hypertension Journal, October-December, Vol 3, 2017 175

Nibedita Priyadarsini et al

  1. Asmar RG, London GM, O'Rourke ME, Safar ME. Improvementin blood pressure, arterial stiffness and wave re?ectionswith a very-low-dose perindopril/indapamide combinationin hypertensive patient: a comparison with atenolol. Hypertension2001 Oct;38(4):922-926.
  2. Carty DM, Neisius U, Rooney LK, Dominiczak AF, Delles C.Pulse wave analysis for the prediction of preeclampsia.J Hum Hypertens 2014 Feb;28(2):98-104.
  3. Khalil AA, Cooper DJ, Harrington KF. Pulse wave analysis:a preliminary study of a novel technique for the predictionof pre-eclampsia. BJOG 2009 Jan;116(2):268-276.
  4. Khalil A, Cowans NJ, Spencer K, Goichman S, Meiri H,Harrington K. First trimester markers for the prediction ofpre-eclampsia in women with a-priori high risk. UltrasoundObstet Gynecol 2010 Jun;35(6):671-679.
  5. Fujime M, Tomimatsu T, Okaue Y, Koyama S, Kanagawa T,Taniguchi T, Kimura T. Central aortic blood pressure andaugmentation index during normal pregnancy. HypertensRes 2012 Jun;35(6):633-638.
  6. Avolio AP, Van Bortel LM, Boutouyrie P, Cockcroft JR,McEniery CM, Protogerou AD, Roman MJ, Safar ME, Segers P,Smulyan H. Role of pulse pressure amplification in arterialhypertension: experts' opinion and review of the data.Hypertension 2009 Aug;54(2):375-383.
  7. Szczepaniak-Chichel L, Markwitz W, Tykarski A. Differencebetween central and peripheral blood pressure in healthy andhypertension-complicated pregnancy. Blood Press Monit 2016Apr;21(2):103-110.
  8. Nichols WW, O'Rourke MF, Vlachopoulos C. McDonald'sblood flow in arteries: theoretical, experimental and clinicalprinciples. 6th ed. London: Edward Arnold; 2011. p. 210.
  9. Westerhof N, Sipkema P, vanden Bos GC, Elzinga G. Forwardand backward waves in the arterial system. Cardiovasc Res1972 Nov;6(6):648-656.
  10. McEniery CM, Yasmin, Hall IR, Qasem A, Wilkinson IB,Cockcroft JR. Normal vascular aging: differential effects onwave reflection and aortic pulse wave velocity: the Anglo-Cardiff Collaborative Trial (ACCT). J Am Coll Cardiol 2005Nov;46(9):1753-1760.
  11. Wilkinson IB, Prasad K, Hall IR, Thomas A, MacCallumH, Webb DJ, Frenneaux MP, Cockcroft JR. Increasedcentral pulse pressure and augmentation index in subjectswith hypercholesterolemia. J Am Coll Cardiol 2002 Mar;39(6):1005-1011.
  12. Vlachopoulos C, Kosmopoulou F, Panagiotakos D,Ioakeimidis N, Alexopoulos N, Pitsavos C, Stefanadis C.Smoking and caffeine have a synergistic detrimental effecton aortic stiffness and wave reflections. J Am Coll Cardiol2004 Nov;44(9):1911-1917.
  13. Wilkinson IB, MacCallum H, Hupperetz PC, van Thoor CJ,Cockcroft JR, Webb DJ. Changes in the derived central pressurewaveform and pulse pressure in response to angiotensin IIand noradrenaline in man. J Physiol 2001 Feb;530(Pt 3):541-550.
  14. Wilkinson IB, Mohammad NH, Tyrrell S, Hall IR, Webb DJ,Paul VE, Levy T, Cockcroft JR. Heart rate dependency of pulsepressure amplification and arterial stiffness. Am J Hypertens2002 Jan;15(1 Pt 1):24-30.
  15. Sharman JE, McEniery CM, Campbell R, Coombes JS, WilkinsonIB, Cockcroft JR. The effect of exercise on large arteryhemodynamics in healthy young men. Eur J Clin Invest 2005Dec;35(12):738-744.

 
  1. Kroeker EJ, Wood EH. Comparison of simultaneouslyrecorded central and peripheral arterial pressure pulsesduring rest, exercise and tilted position in man. Circ Res 1955Nov;3(6):623-632.
  2. Cournand A, Ranges A. Catheterization of the right auriclein man. Proc Soc Exp Biol Med 1941;46:462-466.
  3. Papaioannou TG, Protogerou AD, Stamatelopoulos KS,Vavuranakis M, Stefanadis C. Noninvasive methods andtechniques for central blood pressure estimation: procedures,validation, reproducibility and limitations. Curr Pharm Des2009;15(3):245-253.
  4. Hickson SS, Butlin M, Mir FA, Graggaber J, Cheriyan J, Khan F,Grace AA, Yasmin, Cockcroft JR, Wilkinson IB, et al. Theaccuracy of central SBP determined from the second systolicpeak of the peripheral pressure waveform. J Hypertens 2009Sep;27(9):1784-1788.
  5. Jacobs AK, Eckel RH. Evaluating and managing cardiovasculardisease in women: understanding a woman's heart.Circulation 2005 Feb;111(4):383-384.
  6. Takazawa K, Kobayashi H, Shindo N, Tanaka N, Yamashina A.Relationship between radial and central arterial pulse waveand evaluation of central aortic pressure using the radialarterial pulse wave. Hypertens Res 2007 Mar;30(3):219-228.
  7. Boutouyrie P, Bussy C, Lacolley P, Girerd X, Laloux B, Laurent S.Association between local pulse pressure, mean blood pressure,and large-artery remodelling. Circulation 1999 Sep;100(13):1387-1393.
  8. Wang KL, Cheng HM, Chuang SY, Spurgeon HA, Ting CT,Lakatta EG, Yin FC, Chou P, Chen CH. Central or peripheralsystolic or pulse pressure: which best relates to targetorgans and future mortality? J Hypertens 2009 Mar;27(3):461-467.
  9. Roman MJ, Okin PM, Kizer JR, Lee ET, Howard BV, Devereux RB.Relations of central and brachial blood pressure to left ventricularhypertrophy and geometry: the Strong Heart Study.J Hypertens 2010 Feb;28(2):384-388.
  10. Covic A, Goldsmith DJ, Panaghiu L, Covic M, Sedor J. Analysisof the effect of hemodialysis on peripheral and centralarterial pressure wave forms. Kidney Int 2000 Jun;57(6):2634-2643.
  11. deLuca N, Asmar RG, London GM, O'Rourke MF, Safar ME.Selective reduction of cardiac mass and central blood pressureon low-dose combination perindopril/indapamide inhypertensive subjects. J Hypertens 2004 Aug;22(8):1623-1630.
  12. Manisty CH, Zambanini A, Parker KH, Davies JE, Francis DP,Mayet J, McG Thom SA, Hughes AD. Differences in themagnitudeof wave re?ection account for differential effectsof amlodipine- versus atenolol-based regimens on centralblood pressure: an Anglo-Scandinavian Cardiac OutcomeTrial substudy. Hypertension 2009 Oct;54(4):724-730.
  13. Spaanderman ME, Willekes C, Hoeks AP, Ekhart TH,Peeters LL. The effect of pregnancy on the compliance oflarge arteries and veins in healthy parous control subjectsand women with a history of preeclampsia. Am J ObstetGynecol 2000 Nov;183(5):1278-1286.
  14. Desai DK, Moodley J, Naidoo DP. Echocardiographic assessmentof cardiovascular hemodynamics in normal pregnancy.Obstet Gynecol 2004 Jul;104(1):20-29.
  15. Robson SC, Hunter S, Moore M, Dunlop W. Haemodynamicchanges during the puerperium: a Doppler andM-mode echocardiographic study. Br J Obstet Gynaecol 1987Nov;94(11):1028-1039.

 
176

CBP in Hypertensive Disorders During Pregnancy

  1. Tihtonen KM, K��bi T, Uotila JT. Arterial stiffness in preeclampticand chronic hypertensive pregnancies. Eur J ObstetGynecol Reprod Biol 2006 Sep-Oct;128(1-2):180-186.
  2. Ronnback M, Lampinen K, Groop PH, Kaaja R. Pulse wavereflection in currently and previously preeclamptic women.Hypertens Pregnancy 2005;24:171-180.
  3. Spasojevic M, Smith SA, Morris JM, Gallery ED. Peripheralarterial pulse wave analysis in women with pre-eclampsia andgestational hypertension. BJOG 2005 Nov;112(11):1475-1478.
  4. Elvan-Taspinar A, Franx A, Bots ML, Bruinse HW, Koomans HA.Central hemodynamics of hypertensive disorders in pregnancy.Am J Hypertens 2004 Oct;17(10):941-946.
  5. Kaihura C, Savvidou MD, Anderson JM, McEniery CM,Nicolaides KH. Maternal arterial stiffness in pregnanciesaffected by preeclampsia. Am J Physiol Heart Circ Physiol2009 Aug;297(2):H759-H764.
  6. Robb AO, Mills NL, Din JN, Smith IB, Paterson F, Newby DE,Denison FC. Influence of the menstrual cycle, pregnancy,and preeclampsia on arterial stiffness. Hypertension 2009Jun;53(6):952-958.
  7. Avni B, Frenkel G, Shahar L, Golik A, Sherman D, Dishy V.Aortic stiffness in normal and hypertensive pregnancy. BloodPress 2010 Feb;19(1):11-15.

 
  1. Khalil A, Akolekar R, Syngelaki A, Elkhouli M, Nicolaides KH.Maternal hemodynamics at 11-13 weeks' gestation andrisk of pre-eclampsia. Ultrasound Obstet Gynecol 2012Jul;40(1):28-34.
  2. Medical Research Council trial of treatment of hypertensionin older adults: principal results. MRC Working Party. BMJ1992 Feb;304(6824):405-412.
  3. Dahlof B, Devereux RB, Kjeldsen SE, Julius S, Beevers G, Faire U,Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O,et al. Cardiovascular morbidity and mortality in the LosartanIntervention For Endpoint reduction in hypertension study(LIFE): a randomised trial against atenolol. Lancet 2002 Mar;359(9311):995-1003.
  4. Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG,Caulfield M, Collins R, Kjeldsen SE, Kristinsson A,McInnes GT, et al. Prevention of cardiovascular events withan antihypertensive regimen of amlodipine adding perindoprilas required versus atenolol adding bendroflumethiazideas required, in the Anglo-Scandinavian Cardiac OutcomesTrials-Blood Pressure Lowering Arm (ASCOT-BPLA): amulticentre randomised controlled trial. Lancet 2005 Sep;366(9489):895-906.

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