blood pressure control and prevention of stroke

Review

10.1586/14737175.6.2.203 2006 Future Drugs Ltd ISSN 1473-7175 203www.future-drugs.com

Blood pressure control and prevention of strokeV J Karthikeyan and Gregory YH Lip

Author for correspondenceUniversity Department of Medicine, City Hospital, Dudley Road, Birmingham B18 7QH, UKTel.: +44 121 507 5080Fax: +44 121 554 [email protected]

KEYWORDS: -blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, -blockers, calcium channel blockers, cardiovascular disease, cerebrovascular disease, diuretics, stroke

Hypertension is an important risk factor for stroke. The latter results in disability and premature death and represents a major public health problem. Various studies have established a strong relationship between increasing blood pressure and stroke risk, as well as clear evidence of a reduction in the incidence of strokes in response to even relatively small decreases in blood pressures. In this review, the pharmacological treatment of hypertension and the benefit on stroke prevention is outlined.

Expert Rev. Neurotherapeutics 6(2), 203212 (2006)

Currently, hypertension is identified as one ofmost important causes of premature death indeveloped countries [1]. Hypertension is also acause of severe disability, with stroke being oneof its most devastating consequences.

Approximately 40% of strokes in the UK areattributable to systolic blood pressures (SBPs)of 140 mmHg and above; the risk of stroke isdirectly proportional to the systolic BP (previ-ously above 140 mmHg [2], but now noted in alarge study to be 115 mmHg) [1] with a similarrelationship to the diastolic pressures. Con-versely, an average reduction in BP of just9/5 mmHg results in a 34% reduction in theincidence of stroke and a reduction of19/10 mmHg results in a 56% lower incidenceof stroke [2].

This is illustrated by data from the Fram-ingham heart study [3], where the associationbetween BP category at baseline and the inci-dence of cardiovascular disease (CVD) onfollow-up among 6859 participants (includ-ing those from the Offspring Study) whowere initially free of hypertension and CVDwas investigateda stepwise increase in cardi-ovascular event rates in people with higherbaseline BP categories was found (risk factor-adjusted hazard ratio for CVD of 2.5 [95%confidence interval [CI]: 1.64.1] in womenand 1.6 [95% CI: 1.12.2] in men).

The presence of hypertension in the elderlyalso makes them more prone to all forms ofstroke and causes multiple small asymptomaticcerebral infarcts, leading to progressive loss of

intellectual function and dementia; conversely,treatment of isolated systolic hypertension(ISH) prevents dementia [4]. Hypertension isalso associated with an increased risk of atrialfibrillation, and a previous history of hyperten-sion increases the risk of stroke by nearlyfourfold, despite aspirin therapy [5].

This article reviews the pharmacologicaltreatment of hypertension, with a specialemphasis on available evidence on the efficacyand role of these drugs in the optimal controlof BP towards the primary and secondaryprevention of strokes.

DiureticsDiuretics are well established drugs for thetreatment of hypertension and have demon-strated a reduction in the incidence of strokes.Numerous historical studies such as the Systo-lic Hypertension in the Elderly Program(SHEP) [6] and the Antihypertensive andLipid-Lowering treatment to prevent HeartAttack Trial (ALLHAT) [7] have demonstratedthat low-dose thiazide diuretic-based (chlo-rthalidone) treatment was effective in pre-venting major CVD, both cerebral and car-diac, in both noninsulin-treated diabetic andnondiabetic older patients with ISH. Simi-larly, the Medical Research Council trial oftreatment of hypertension in older adults(MRC trial) [8], that compared the reductionin cardiovascular events in patients treatedwith a diuretic (hydrochlorothiazide) with thoseon a blocker (atenolol) or placebo found a

CONTENTS

Diuretics

Angiotensin-converting enzyme inhibitors & angiotensin II receptor blockers

Calcium-channel blockers

-blockers

Other drugs

Summary

Expert commentary

Five-year view

Key issues

ReferencesAffiliations

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Karthikeyan & Lip

204 Expert Rev. Neurotherapeutics 6(2), (2006)

reduction in BP in both the active treatment groups, with a25% reduction in stroke (95% CI: p = 0.04); this reduction instroke increased to 31% (p = 0.04) in the diuretic group com-pared with placebo (particularly in non-smokers), with no sig-nificant reduction in end points in the -blocker group. Inaddition, more patients randomized to -blocker treatmentrequired supplementation with other antihypertensive agentsthan those randomized to diuretics.

Thiazides are often used in combination with many otherantihypertensive drugs. For example, the Losartan InterventionFor End point reduction in hypertension (LIFE) study [9] com-pared the stroke outcomes in patients on an angiotensin recep-tor blocker (losartan) and those on conventional therapy with a-blocker (atenolol) and reported that losartan was superior toatenolol in the prevention of stroke in hypertensive patientswith left ventricular hypertrophy. However, hydrochlorothi-azide was used along with these two drugs and was suspected tobe contributory to the lower incidence of stroke in the losartanstudy carried out by Kato and Eto [10], a suspicion refuted bythe LIFE investigators [11]. Similarly, combination therapy withperindopril and indapamide in the secondary prevention ofstroke prevented recurrence of the disorder more effectivelythan monotherapy with perindopril in the Perindopril Protec-tion against Recurrent Stroke Study (PROGRESS) [12]. Thus,these studies essentially confirm the importance and the roleplayed by thiazide diuretics in combination with other classesof antihypertensive agents in controlling BP effectively andhence preventing cardiovascular events.

Angiotensin-converting enzyme inhibitors & angiotensin II receptor blockersAs indicated earlier, angiotensin-converting enzyme (ACE)inhibitors and angiotensin II receptor blockers (ARBs) are cur-rently amongst the most studied modern antihypertensive drugclasses. Most trials in recent years have involved the use of bothof these classes of drugs, either alone or in combination with diu-retics, and compared them head to head with other drug classes,such as calcium channel blockers and -blockers. Certainly, thereis strong evidence from trials in the last 5 years that these drugsnot only lower BP, but also prevent cardiovascular events [13].

ACE inhibitorsThe BP-Lowering Treatment Trialists Collaborative(BPLTTC) [14], in their meta-analysis in 2003 based on datafrom 29 randomized, controlled trials involving 162,341patients with a mean duration of follow-up ranging from 2 to8 years and over 700,000 patient-years of follow-up, noted riskreduction of stroke by 28% compared with placebo.

Interestingly, ACE inhibitor-based therapy was found to bemarginally less effective than conventional therapy inpreventing strokes, both fatal and nonfatal. Similar conclusionswere noted in another meta-analysis conducted for theNational Institute of Clinical Excellence (NICE), UK [101]. Incontrast, the nonhypertension treatment trial Heart OutcomesPrevention Evaluation (HOPE) [15], which compared ACE

inhibitor-based treatment with placebo, reported greater strokeprevention with the former, suggesting drug-specific benefitsbeyond mere BP lowering.

In the HOPE study [15], a total of 9297 high-risk patients(55 years of age or older) with evidence of vascular disease ordiabetes plus one other cardiovascular risk factor and whowere not known to have a low ejection fraction or heart fail-ure, were randomly assigned to receive ramipril (10 mg/dayorally) or matching placebo for a mean of 5 years, the primaryoutcome being a composite of myocardial infarction, strokeor death from cardiovascular causes. Ramipril was found tosignificantly reduce the rates of death, myocardial infarctionand stroke in a broad range of high-risk patients (14.0 vs17.8% in the placebo group; relative risk: 0.78; 95% CI:0.700.86; p < 0.001). The incidence of stroke was 3.4% inthe ramipril group versus 4.9% in the placebo group (relativerisk: 0.68; p < 0.001).

PROGRESS was a randomized, controlled trial of an ACEinhibitor (perindopril) in patients with a previous neurologicalevent [12]. Active antihypertensive treatment with perindoprilwas initially associated with a 5/3 mmHg reduction in BP, withno significant reduction in stroke risk. However, addition of adiuretic (indapamide) resulted in a BP drop of 12/5 mmHgand a 43% reduction in stroke. The average reduction in BPwas 9/4 mmHg, with a 28% reduction in stroke and a 26%reduction in cardiovascular events.

Of the hypertension treatment trials, the second AustralianNational BP (ANBP2) study, comparing the outcomes in elderlypatients with hypertension treated with ACE inhibitors withthose on diuretics, noted a similar drop in BPs in bothgroups [16]. However, the difference in cardiovascular events ordeaths from any cause was not statistically significant (hazardratio for a cardiovascular event or death with ACE inhibitortreatment was 0.89 [95% CI: 0.831.21; p = 0.98]). The rates ofnonfatal cardiovascular events and myocardial infarctions werelower with ACE inhibitor treatment, whereas stroke incidencewas similar in both groups (although there were more fatalstrokes in the ACE inhibitor group, for reasons that are unclear).

The other studies that compared ACE inhibitor therapy andconventional treatment for hypertension include the SwedishTrial in Old Patients with Hypertension (STOP-Hypertension-2) [17], Captopril Prevention Project (CAPPP) [18,19], the UKProspective Diabetes Study (UKPDS) [20] and the Noninsulin-dependent Diabetes, Hypertension Microalbuminuria or pro-teniuria, Cardiovascular events, and Ramipril (DIABHYCAR)study [21] and are listed in TABLE 1.

Angiotensin II receptor blockers ARBs and ACE inhibitors have both been demonstratedexperimentally to decrease angiogenesis and cellularproliferation and favor cellular differentiation. Furthermore,experimental studies in mammals have suggested roles forangiotensin II in early reperfusion following acute ischemia byrecruitment of pre-existing collateral vascularization vianonangiotensin (AT)-1 receptor stimulation (possibly AT2).

Blood pressure control and prevention of stroke

www.future-drugs.com 205

Table 1. Summary of trials and drugs studied for control of blood pressure and stroke prevention .

Drug Trial Patients (n)/(follow-up in years)

Average baseline BP (mmHg)

Drop in BP (mmHg)

Results (stroke outcomes) Ref.

Diuretics

Chlorthalidone SHEP 4736 (4.5) 170/77 27/9 36% total stroke reduction, 5-year absolute benefit of stroke 30 events and major cardiovascular events 55 events per 1000 participants

[6]

ALLHAT 33,357 (4.9) 146/84 in all groups (SD/~15/10) (chlorthalidone, amlodipine and lisinopril)

~12/9 vs12/9 vs 10/9

Lower stroke incidence in the chlorthalidone arm

[7]

Hydrochlorothiazide vs atenolol vs placebo

MRC 4396 (5.8) 183/92 vs 183/91 vs 183/91 (men)186/90 vs 186/91 vs 18/90 (women)

~34/14 in both the active groups

25% lower strokes in the active treatment arms; 30% lower in the diuretic arm

[8]

Angiotensin converting enzyme inhibitorsRamipril HOPE 9297 (4.0) 139/79 in both

groups3/3 vs 0/2 Relative risk of stroke 0.68;

p < 0.001[15]

Perindopril + indapamide

PROGRESS 6105 (4.0) 147/86 in both groups

9/4 (perindopril alone) compared with placebo; 12/5 (combination) compared with placebo

43% relative risk reduction in secondary stroke

[12]

Enalapril vs hydrochlorothiazide

ANBP 2 6084 (4.1) 167/91 vs 168/91 (hydrochlorothiazide)

26/12 in both groups

Higher incidence of fatal stroke in the enalapril group (HR 1.91, p = 0.04); nonfatal stroke HR 0.93, p = 0.65)

[16]

Enalapril/lisinopril or felodipine/isradipine vs conventional therapy (diuretics +/-blockers)

STOP-Hypertension 2

6614 (4.0) 194/98 in all groups

35/17 (ACE-I) vs 35/18 (CCBs) vs 36/17 (-blockers + diuretics)

Relative risk of stroke 0.80 (p = 0.13) with newer drugs vs conventional drugs

[17]

ACE-I: Angiotensin-converting enzyme inhibitors; ADVANCE: Action in Diabetes and Vascular Disease; ALLHAT: Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial; ANBP: Australian National Blood Pressure; ASCOT-BPLA: Anglo-Scandinavian Cardiac Outcomes Trial; BP: Blood pressure; CAPPP: The Captopril Prevention Project; CCB: Calcium channel blockers; CI: Confidence interval; CONVINCE: Controlled Onset Verapamil Investigation of Cardiovascular End Points; DIABHYCAR: Diabetes, Hypertension microalbuminuria or proteniuria, Cardiovascular events, And Ramipril; HOPE: Heart Outcomes Prevention Evaluation; HR: Hazard ratio; INVEST: International Verapamil-Trandolapril Study; LIFE: Losartan Intervention For End point reduction in hypertension; MOSES: Morbidity and Mortality after Stroke- Eprosartan compared with nitrendepine for Secondary prevention: MRC: Medical Research Council; ONTARGET: Ongoing Telmisartan Alone and in combination with Ramipril Global End point Trial; PRoFESS: Prevention Regimen For Effectively avoiding Second Strokes; PROGRESS: Perindopril Protection against Recurrent Stroke Study; SCOPE: Study on Cognition and Prognosis in the Elderly; SD: Standard deviation; SHEP: Systolic Hypertension in the Elderly Program; STOP-hypertention: Swedish Trial in Old Patients with hypertension; Syst-Eur: Prevention of dementia in randomized double-blind placebo-controlled systolic hypertension in Europe; TRANSCEND: Telmisartan Randomized assessment Study in ACE-I Intolerant subjects with cardiovascular Disease; UKPDS: UK Prospective Diabetes Study; VALUE: Valsartan Antihypertensive Long-term Use Evaluation.

Karthikeyan & Lip


Captopril CAPPP 10,985 (6.1) ~162/100 vs 160/98 (conventional therapy)

11/8 vs~10/7 Fatal and nonfatal stroke commoner in captopril group (RR 1.25, p = 0.044); related to lower baseline BP in the conventional group

[18]

UKPDS 1148 (8.4) 159/94 vs 159/93 (atenolol)

14/8 vs 14/7 Tight BP control reduced the risk of death and complications due to Type 2 diabetes (44% reduction in risk of stroke, fatal and nonfatal)

[20]

Ramipril (low dose, 1.25 mg)

DIABHYCAR 4912 (4.0) ~146/82 vs 145/82 (placebo)

~4/2 vs ~2/2 No significant difference in stroke risk compared with placebo, suggesting low-dose ACE-I ineffective in preventing cardiovascular events

[21]

Angiotensin II receptor blockers

Losartan vs atenolol LIFE 9193 (4.8) ~174/98 vs~175/98 (atenolol)

~30/17 vs~30/17

24.9% total stroke reduction with losartan compared with atenolol

[9]

Candesartan SCOPE 4964 (3.7) 169/82 in both groups

22/6 vs 20/5 27.8% nonfatal stroke reduction with candesartan

[24]

Eprosartan vs nitrendipine

MOSES 1405 (2.5) ~140/82 in both groups

13/3 in both groups

21% risk reduction (total mortality and cardiovascular and cerebrovascular events p = 0.014); 25% risk reduction (total cerebrovascular events p = 0.02) with eprosartan

[25]

Valsartan vs amlodipine

VALUE 15,245 (4.2) ~155/87 in both groups

15/8 (valsartan) vs 17/10 (amlodipine)

Stroke incidence lower in the amlodipine arm, with a particular excess in the valsartan arm in the first year (attributed to the large BP difference)

[26]

Telmisartan + ramipril

ONTARGET Ongoing trials [28]

Telmisartan TRANSCEND [28]

PRoFESS

Perindopril ADVANCE [30]

Table 1. Summary of trials and drugs studied for control of blood pressure and stroke prevention (cont.).



Drop in BP (mmHg)





Pretreatment with an ACE inhibitor has been demonstrated toworsen stroke in experimental studies in mammals. In contrast,a significant reduction in ischemic brain damage and mortalityby pretreatment with losartan has been demonstrated, with aloss of this preventive effect by coadministration ofenalapril [22,23].

A meta-analysis of ARB studies revealed a marked benefit instroke prevention [14]. For example, candesartan was used inelderly patients with isolated systolic hypertension, in the Studyon Cognition and Prognosis in the Elderly (SCOPE) [24]. In theMorbidity and Mortality after Stroke-Eprosartan comparedwith nitrendepine for Secondary prevention (MOSES) [25],

-blockers:Hydrochlorothiazide vs atenolol vs placebo

MRC 4396 (5.8) 183/92 vs 183/91 vs 183/91 (men)186/90 vs 186/91 vs 18/90 (women)

~34/14 in both the active groups

25% lower strokes in the active treatment arms; 30% lower in the diuretic arm

[8]

Losartan vs atenolol LIFE 9193 (4.8) ~174/98 vs ~175/98 (atenolol)

~30/17 vs ~30/17

24.9% total stroke reduction with losartan compared with atenolol

[9]

Enalapril/lisinopril or felodipine/isradipine vs conventional therapy (diuretics +/-blockers)

STOP-Hypertension-2

6614 (4.0) 194/98 in all groups

35/17 (ACE-I) vs 35/18 (CCBs) vs 36/17 (- blockers + diuretics)

Relative risk of stroke 0.80 (p = 0.13) with newer drugs vs conventional drugs

[17]

Amlodipine + perindopril vs atenolol + bendroflumethiazide

ASCOT-BPLA 19,257 (5.5) 164/95 ~26/15 23% reduction in fatal and nonfatal stroke incidence in the amlodipine-based arm compared with the atenolol-based arm

[38]

Calcium channel blockers

Nitrendipine Syst-Eur 4695 (2.0) 174/86 ~22/6 42% stroke reduction in the nitrendipine group

[4]

Amlodipine + perindopril vs atenolol + bendroflumethiazide

ASCOT-BPLA 19,257 (5.5) 164/95 ~28/18 23% reduction in fatal and nonfatal stroke incidence in the amlodipine based arm

[38]

Verapamil CONVINCE 16,602 (3.0) 150/87 ~14/8 HR for fatal and nonfatal stroke in the verapamil group 1.15 (95% CI: 0.901.48) compared with diuretic/-blocker group

[33]

INVEST 22,576 (2.7) 150/86 ~19/10 Relative risk of stroke, fatal and nonfatal 0.88, (95% CI)

[34]

Table 1. Summary of trials and drugs studied for control of blood pressure and stroke prevention (cont.).



Drop in BP (mmHg)



Karthikeyan & Lip


LIFE [9] and Valsartan Antihypertensive Long-term UseEvaluation (VALUE) [26] studies, eprosartan, losartan andvalsartan were used, respectively.

In the SCOPE study, candesartan-based antihypertensivetreatment in elderly patients with isolated hypertension wasfound to significantly reduce the incidence of strokes (42% rel-ative risk reduction) compared with other antihypertensivetherapy despite little difference in BP reduction(2.0/1.2 mmHg) [24]. This relatively small difference in BP washypothesized to be partly responsible for the observed clinicalbenefit on stroke.

MOSES was a trial that aimed at secondary prevention ofstroke and involved patients with a previous history of cerebralischemia or hemorrhage (within 24 months prior to studyenrolment) [25]. It was a prospective, randomized, open,blinded end point study, with the primary end point beingmortality and total number of cardiovascular and cerebrovascu-lar events. Secondary end points defined included change inmental capacity and functional status (Barthel index andRankin scale) or individual elements of the combined primaryend point. The drugs chosen for the trial were eprosartan andnitrendipine, as the former had been demonstrated to effec-tively lower systolic BP, reduce sympathetic nervous systemactivity and reduced secondary stroke in experimental models,whilst the latter was used in, and found to reduce the risk of afirst stroke in the Prevention of Dementia in RandomizedDouble-blind Placebo-controlled Systolic Hypertension inEurope (Syst-Eur) trial [4]. Eprosartan was found to reduce theincidence of primary end point (mortality and cerebrovascularand cardiovascular events by 21%, with a reduction incerebrovascular events alone by 25%).

The LIFE study, as discussed earlier, noted a 24.9% reduc-tion in the incidence of stroke with losartan in patients withhypertension [9]. The VALUE trial was a double-blind, rand-omized, controlled trial that compared the long-term effectson cardiac morbidity and mortality, of valsartan oramlodipine in hypertensive patients with high cardiovascu-lar risk [26]. No significant difference was noted between thetwo groups for the primary end point of cardiac morbidityand mortality and all-cause mortality. However, the mostconsistent and statistically significant difference between thegroups was in BP control, with the amlodipine-based ther-apy being more efficacious, particularly in the early stages oftreatment. In contrast to the findings in the above studies,the stroke incidence in the VALUE trial was 15% lower (butonly p < 0.08) in the amlodipine-based group than thevalsartan group.

The Acute Candesartan Cilexetil therapy in Stroke Survi-vors (ACCESS) study assessed the safety of modest BP reduc-tion by candesartan cilexetil in the early treatment of strokeand estimated the number of cases required to perform alarger Phase III efficacy study [27]. A total of 500 patientswere recruited (of which 342 were randomized and the trialwas stopped prematurely due to an imbalance in end points)in this prospective, double-blind, placebo-controlled randomized

multicenter Phase II study that aimed at a target reduction inBP of 1015% within 2 h of using 416 mg of candesartancilexetil. The primary end point included case fatality anddisability measured as functional status with the use of theBarthel index, 3 months after the end of a placebo-controlled7-day phase. The cumulative 12-month mortality and thenumber of vascular events differed significantly in favor ofthe candesartan cilexetil group. A 7-day course of cande-sartan cilexetil after an acute ischemic stroke significantlyimproved cardiovascular morbidity and mortality (vascularevents: candesartan cilexetil vs placebo 17 [9.8%] vs 31[18.7%]; p = 0.026; mortality: 5 [2.9%] vs 12 [7.2%]; p =0.07). However, it must be pointed out here that ACCESSwas not a study investigating stroke prevention per se, but apilot study aimed at investigating potential cardiovascularprotective effects of candesartan.

Mechanisms of actionAngiotensin II mainly affects vascular tone and structure viatwo different pathways: vasoconstriction, mediated via G-proteins activating phospholipase, which in turn releasesinositol triphosphate; and diacylglycerol, thus inducing cel-lular Ca2+ release and transmembrane Ca2+ influx, respec-tively. Vascular growth and the role of angiotensin II in vas-cular remodelling are known to be mediated via a pathwaystarting with the activation of tyrosine kinases, stimulation ofthe small G-protein Ras, activation of the serine/threoninekinase Raf-1, and subsequently the threonine/tyrosine kinaseand the mitogen-activated protein kinases ERK1/2.

The favorable effects of early angiotensin type 1 (AT1) recep-tor blockade were hypothesized to be mainly due to a lowerincidence of myocardial ischemic events. However, the clinicallink between cerebrovascular remodelling and improved cardio-vascular survival is unclear. However, ACCESS postulated simi-lar beneficial effects of early neurohumoral inhibition in cere-bral and myocardial ischemia. A point of note was thenonoccurrence of cardiovascular or cerebrovascular events as aresult of the hypotension [27].

Ongoing studiesOngoing and future studies are also exploring a possibleincrease in benefit by combining ACE inhibitors and ARBs(dual blockade). The Ongoing Telmisartan Alone and incombination with Ramipril Global End point Trial(ONTARGET) is a large, long-term study (23,400 patients;5.5 years) that compares the efficacy of the ARB telmisartan,the ACE inhibitor ramipril and combination therapy withtelmisartan plus ramipril for reducing cardiovascular andcerebral risk in a study population with established coronaryartery disease, peripheral vascular disease, stroke or diabeteswith end organ damage [28]. The Telmisartan Randomizedassessment Study in ACE-I Intolerant subjects with CVD(TRANSCEND) is a parallel study in patients who areintolerant to an ACE inhibitor and hence comparestelmisartan with placebo treatment [28]. Both ONTARGET



and TRANSCEND trials feature the same primary compositeend point: death caused by CVD, acute myocardial infarction,stroke and hospitalization because of congestive heart failure.The secondary end points will focus on reductions in thedevelopment of Type 2 diabetes mellitus, nephropathy, cognitivedecrease and dementia as well as atrial fibrillation [29].

The Prevention Regimen For Effectively avoiding SecondStrokes (PRoFESS) is another ongoing trial comparing tel-misartan and placebo, as well as the efficacy of well-estab-lished antiplatelet treatments in patients aged over 55 yearsand an ischemic stroke within 90 days before studyentry [30].

Calcium channel blockersCalcium channel blockers (CCBs) are well established drugsin the treatment of hypertension. Although they were ini-tially thought to be associated with an increased risk of car-diovascular events, particularly myocardial infarctions com-pared with diuretics [31], such an association has not beenconfirmed. Trials comparing CCBs versus standard care withdiuretics or -blockers have demonstrated a significantreduction in stroke risk with CCBs. However, the risk ofcoronary heart disease is slightly greater, although not statis-tically significant [32]. The meta-analysis by BPLTTC con-cluded that CCBs were associated with a 39% reduction instroke and a 28% reduction in major cardiovascular eventscompared with placebo [14].

In the ALLHAT study, the incidence of stroke was found tobe lower in the amlodipine group compared to the chlortha-lidone group, although this was statistically insignificant [7].Notably, the differences between treatment groups withrespect to stroke were observed as early as 6 months aftertreatment initiation.

The Controlled Onset Verapamil Investigation of Cardio-vascular End Points (CONVINCE) trial was designed tocompare the effectiveness of controlled onset, extended releaseverapamil with a -blocker (atenolol) or a thiazide (hydro-chlorothiazide) in reducing the risk of CVD [33]. This trial,however, failed to demonstrate the equivalent effectiveness ofcontrolled onset, extended release verapamil with conven-tional antihypertensive therapy based on a diuretic or a-blocker in reducing CVD. Verapamil thus lacks superiorityover conventional therapy based on a thiazide diuretic,-blocker or ACE inhibitor.

Another trial, the International VerapamilTrandolaprilStudy (INVEST), was a randomized, controlled trial thatcompared mortality and morbidity outcomes in patients withhypertension and coronary artery disease who were treatedwith a CCB (verapamil) versus a -blocker (atenolol) [34]. Nosignificant differences between treatment strategies werenoted with respect to the primary outcome. However, someoutcomes in patients without diabetes at baseline were betterin those treated with the CCB, that were, in subsequent anal-yses, found to be a result of the protective effect of add-ontrandolapril to the verapamil group.

The findings from the above trials are consistent and dem-onstrate unequivocal reduction in the risk of stroke withreduction in systolic BP. CCBs and diuretics may indeed bemore effective in preventing stroke and have particular rele-vance in the Afro-Caribbean population for better BPcontrol [32].

-blockers-blockers have been studied extensively and these drugsalone, or in combination with diuretics, are often used in theprevention of cardiovascular events in the hypertensive popu-lation [35]. However, in a recent meta-analysis [36], althoughthe relative risk for stroke was reduced by 19% with -block-ers compared with placebo or no treatment, it was 16% higherwith -blockers than for other drugs, with no differenceobserved for myocardial infarction. Alhough their effect in thesecondary prevention of coronary heart disease was proven,evidence for their effectiveness in the primary prevention ofstrokes and heart attacks in hypertensives has been lacking.Indeed, the extrapolation from secondary to primary preven-tion has been disproved on more than one occasion [37]. Fur-ther, the Anglo-Scandinavian Cardiac Outcomes Trial(ASCOT) was stopped prematurely as the amlodipineperin-dopril-based regimen was found to prevent more major cardi-ovascular events and induced less diabetes than theatenolobendroflumethiazide-based regimen [38].

Other drugsAmongst other drugs, doxazosin, an -blocker, was used asone of the treatment groups in the ALLHAT trial [7], but thisarm had to be terminated early because of a significantlyincreased CVD risk (particularly heart failure) in the doxa-zosin arm compared with the chlorthalidone arm. In addition,this risk was attenuated, but not eliminated by the addition ofother antihypertensive drugs [39].

Moxonidine has been used in some trials to assess its safetyand efficacy as an add-on agent in the treatment of hyperten-sion in the elderly and in patients with the metabolic syn-drome [4044]. The results from these trials indicated that mox-onidine was a safe and effective add-on drug in the treatmentof arterial hypertension, with possible favorable effects onCVD risk. It was also noted to have a favorable hemodynamicand metabolic profile. One of these studies compared moxo-nidine with metoprolol in 127 patients with essential hyper-tension and Type 2 diabetes mellitus and found similar reduc-tions in BPs in both groups, but a fall in fasting blood glucosein the moxonidine group compared with a rise in the meto-prolol group [44]. However, there are no studies investigatingthe efficacy of moxonidine in reducing the risk of CVD, withclearly defined end points.

Summary

Stroke is a major cause of disability and death

Satisfactory BP control and treatment of high BP is imperativein the prevention of cardiovascular morbidity and mortality

Karthikeyan & Lip


Even a modest reduction in BP is beneficial in preventingand delaying resultant target organ damage andcomplications of hypertension

There are no substantive outcome differences between thevarious drugs used in controlling BP

Thiazide diuretics are inexpensive first-choice drugs withbeneficial effects beyond mere BP control

Blockade of the reninangiotensinaldosterone system(RAAS) by ACE inhibitors and ARBs confers greater protec-tion from vascular events, particularly in the context ofcoexisting diabetes mellitus

CCBs are beneficial in the treatment of hypertension andcontrol of BP, particularly in Afro-Caribbean patients and inthose intolerant to the effects of ACE inhibitors and ARBs

-blockers are more useful in the setting of hypertension inassociation with other heart disease, and may be inappropri-ate as a first-line monotherapy in hypertensive patients,especially if the patient is elderly or Afro-Caribbean

Expert commentaryBlood vessels are subject to high pressures in hypertension, thecomplications of which are, paradoxically, thrombotic morecommonly than hemorrhagic (the so-called thrombotic para-dox of hypertension or Birmingham paradox). Changes inblood flow, vessel wall and blood constituents are the threecomponents of the Virchows triad for thrombogenesis. HighBP, abnormalities in prothrombotic factors, endothelial func-tion, and platelet activation, and abnormalities in the vesselwall, with increased stiffness and cross-sectional area, are allimplicated in the pathogenesis of atherosclerosis [4547].

Satisfactory control of BP is, undoubtedly, essential to pre-vent the progression of atherosclerosis and consequent cardio-vascular events such as stroke. Lifestyle changes, patientsunderstanding and attitudes are very important additionalmeasures, besides optimal drug therapy. Thiazide diuretics,RAAS blockade and CCBs are the drugs of choice inhypertension, with additional neuroprotective effects. Amongst

these, ACE inhibitors and angiotensin receptor blockers shouldbe the drugs of choice in patients with coexisting morbiditiessuch as diabetes mellitus, previous history of stroke or otherrisk factors for stroke.

Five-year viewThe next 5 years will be witness to the results of several pro-spective trials, including PRoFESS, ONTARGET, TRAN-SCEND and ADVANCE, of both mono- and combinationtherapies, which will further increase our knowledge andunderstanding of BP management. Combination therapies,particularly those based on RAAS blockade, are likely to be themainstay of hypertension treatment in the years to come. Thiswould be of particular relevance in patients with diabetes melli-tus, those at risk of, or with, established atherosclerosis andCVD. Indeed, a more holistic approach, with hypertensionmanagement being one part of a larger overall cardiovascularrisk reduction strategy, is likely.

Key issues

Blood pressure (BP) control is a key step towards risk reduction in the prevention of strokes, both primary and secondary.

Even small reductions in BP are known to reduce the risk of strokes.

Treatment and control of BP is beneficial even after a stroke has occurred.

Diuretics are an effective and economical class of antihypertensive drugs that are also beneficial in stroke prevention.-blockers are no longer appropriate as first-line monotherapy in the treatment of hypertension and primary stroke prevention.

Combination therapy would be the way forward in achieving the above goals.

ReferencesPapers of special note have been highlighted as: of interest of considerable interest

1 Ezzati M, Lopez AD, Rodgers A, Vander Hoorn S, Murray CJ. Comparative Risk Assessment Collaborating Group. Selected major risk factors and global and regional burden of disease. Lancet 60(3), 13471360 (2002).

2 Spencer C, Lip GYH. Hypertension: (1) epidemiology and risks. Pharm. J. 7059(263), 280283 (1992).

3 Vasan RS, Larson MG, Leip EP et al. Impact of high-normal blood pressure on the risk of cardiovascular disease. N. Engl. J. Med. 345(18), 12911297 (2001).

4 Forette F, Seux ML, Staessen JA et al. Prevention of dementia in randomized double-blind placebo-controlled systolic hypertension in Europe (Syst-Eur) trial. Lancet 352(9137), 13471351 (1998).

5 Stroke Prevention in Atrial Fibrillation study investigators. Patients at low risk of stroke during treatment with aspirin: Stroke Prevention in Atrial Fibrillation III study. JAMA 279(16), 12731277 (1998).

6 Curb JD, Pressel SL, Cutler JA et al. Effect of diuretic-based antihypertensive treatment on cardiovascular disease risk in older diabetic patients with isolated systolic hypertension. Systolic Hypertension in the Elderly Program Co-operative Research Group. JAMA 276(23), 18861892 (1996).

7 ALLHAT Officers and co-ordinators for the ALLHAT Colloborative Research Group. Major outcomes in high risk hypertensive patients randomized to angiotensin converting enzyme inhibitor or calcium channel blocker vs. diuretic: the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial (ALLHAT). JAMA 288(23), 29812997 (2002).

8 MRC Working Party. Medical Research Council trial of treatment of hypertension in older adults: principal results. BMJ 304(6824), 405412 (1992).

9 Dahlof B, Devereux RB, Kjeldsen SE et al.; LIFE Study Group. Cardiovascular morbidity and mortality in the Losartan



Intervention For End point reduction in hypertension study (LIFE): a randomized trial against atenolol. Lancet 359(9311), 9951003 (2002).

10 Kato J, Eto T. Diuretics in the LIFE study. Lancet 364(9432), 413414 (2004).

11 Dahlof B, Devereux RB, Kjeldsen SE. Authors reply. Lancet 364(9432), 413414 (2004).

12 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 358(9287), 10331041 (2001).

13 Elliott WJ. Cardiovascular events in hypertension trials of angiotensin converting-enzyme inhibitors. J. Clin. Hypertens. 7(8 Suppl. 2), 24 (2005).

14 Blood Pressure Lowering Treatment Trialists Collaborative. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomized trials. Lancet 362(9395), 15271545 (2003).

15 Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N. Engl. J. Med. 342(3), 145153 (2000).

Demonstrates the neuroprotective effects of ramipril.

16 Wing LM, Reid CM, Ryan P et al.; Second Australian National Blood Pressure Study Group. A comparison of outcomes with angiotensin-converting-enzyme inhibitors and diuretics for hypertension in the elderly. N. Engl. J. Med. 348(7), 583592 (2003).

17 Hansson L, Lindholm LH, Ekbom T et al. Randomised trial of old and new antihypertensive drugs in elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension-2 study. Lancet 354(9192), 17511756 (1999).

18 Hansson L, Lindholm LH, Niskanen L et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet 353(9153), 611616 (1999).

19 Hansson L, Hedner T, Lindholm L et al. The Captopril Prevention Project (CAPPP) in hypertension-baseline data and current status. Blood Press. 6(6), 365367 (1997).

20 UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in Type 2 diabetes: UKPDS 39. BMJ 317(7160), 713720 (1998).

21 Chatellier G, Mann JFE, Passa P, Menard J:; DIABHYCAR study investigators. Effects of low dose ramipril on cardiovascular and renal outcomes in patients with Type 2 diabetes and raised excretion of urinary albumin: randomized, double-blind placebo-controlled trial. BMJ 328, 495509 (2004).

22 Fournier A, Achard JM, Mazouz H et al. Could angiotensin II Type I receptor antagonists have a superior beneficial effect than that of angiotensin II converting enzyme inhibitors with respect to the risk of cerebrovascular accident? Arch. Mal. Coeur Vaiss. 92(8), 9971000 (1999).

23 Fournier A, Ghitu A, Darabont R et al. Duality of angiotensin II receptors and risk for stroke and cancer: what is the connection? Presse Med. 28(17), 918922 (1999).

24 Papademetriou V, Farsang C, Elmfeldt D et al.; Study on Cognition and Prognosis in the Elderly study group. Stroke prevention with the angiotensin II Type I-receptor blocker candesartan in elderly patients with isolated systolic hypertension: the Study on Cognition and Prognosis in the Elderly (SCOPE). J. Am. Coll. Cardiol. 44(6), 11751180 (2004).

25 Schrader J, Luders S, Kulschewski A et al.; MOSES Study Group. MOrbidity and mortality after StrokeEprosartan compared with nitrendipine for Secondary Prevention. Stroke 36(6), 12181226 (2005).

26 Julius S, Kjeldsen SE, Weber M et al.; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomized trial. Lancet 363(9426), 20222031 (2004).

Demonstrates the superiority of amlodipine-based hypertension treatment over valsartan on blood pressure control and cardiovascular protection.

27 Schrader J, Luders S, Kulschewski A et al.; Acute Candesartan Cilexetil Therapy in Stroke Survivors Study Group. The ACCESS Study: evaluation of Acute Candesartan Cilexetil Therapy in Stroke Survivors. Stroke 34(7), 16991703 (2003).

Hypothesis on possible mechanism of angiotensin receptor blockers in stroke prevention.

28 Yusuf S. From the HOPE to the ONTARGET and the TRANSCEND studies: challenges in improving prognosis. Am. J. Cardiol. 89(2A), A18A25 (2002).

29 Zimmermann M, Unger T. Challenges in improving prognosis and therapy: the Ongoing Telmisartan Alone and in combination with Ramipril Global End point Trial programme. Expert Opin Pharmacother. 5(5), 12011208 (2004).

30 Weber MA. Managing the patient at risk for a second stroke. J. Hypertens. 1(Suppl. 23), S41S47 (2005).

31 Psaty BM, Heckbert SR, Koepsell TD et al. The risk of myocardial infarction associated with antihypertensive drug therapies. JAMA 274(8), 620625 (1995).

32 Black HR. Calcium channel blockers in the treatment of hypertension and prevention of cardiovascular disease: results from major clinical trials. Clin. Cornerstone 6(4), 5366 (2004).

33 Black HR, Elliott WJ, Grandits G et al.; CONVINCE Research Group. Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End points (CONVINCE) trial. JAMA 289(16), 20732082 (2003).

34 Pepine CJ, Handberg EM, Cooper-DeHoff RM et al.; INVEST Investigators. A calcium antagonist vs. a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International VerapamilTrandolapril Study (INVEST): a randomized controlled trial. JAMA 290(21), 28052816 (2003).

35 Collins R, Peto R. Antihypertensive drug therapy: effects on stroke and coronary heart disease. In:Textbook of Hypertension. Swales JD (Ed.). Blackwell Scientific Publishing, London, UK, 11561164 (1994).

36 Lindholm LH, Carlberg B, Samuelsson O. Should blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 366(9496), 15451553 (2005).

Good meta-analysis on the role of -blockers in primary hypertension and stroke prevention.

37 Beevers DG. The end of blockers for uncomplicated hypertension? Lancet 366(9496), 15101512 (2005).

38 Dahlof B, Sever PS, Poulter NR et al.; 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

Karthikeyan & Lip


Lowering Arm (ASCOT-BPLA): a multicentre randomized controlled trial. Lancet 366(9489), 895906 (2005).

39 Davis BR, Cutler JA, Furberg CD et al.; ALLHAT Collaborative Research Group. Relationship of antihypertensive treatment regimens and change in blood pressure to risk for heart failure in hypertensive patients randomly assigned to doxazosin or chlorthalidone: further analyses from the Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack Trial. Ann. Intern. Med. 137(5 Pt 1), 313320 (2002).

40 Martin U, Hill C, O Mahony D. Use of moxonidine in elderly patients with resistant hypertension. J. Clin. Pharm. Ther. 30(5), 433437 (2005).

41 Messerli F. Moxonidine: a new and versatile antihypertensive. J. Cardiovasc. Pharmacol. 35(7 Suppl. 4), S53S56 (2005).

42 van Zwieten PA. Centrally acting imidazoline II-receptor agonists: do they have a place in the management of hypertension? Am. J. Cardiovasc. Drugs 1(5), 321326 (2001).

43 Abellan J, Leal M, Hernandez-Menarguez F et al. Efficacy of moxonidine in the treatment of hypertension in obese, noncontrolled hypertensive patients. Kidney Int. 93(Suppl.), S20S24 (2005).

44 Jacob S, Klimm HJ, Rett K, Helsberg K, Haring HU, Godicke J. Effects of moxonidine vs. metoprolol on blood pressure and metabolic control in hypertensive subjects with Type 2 diabetes. Exp. Clin. Endocrinol. Diabetes 112(6), 315322 (2004).

45 Lip GYH. Hypertension and the prothrombotic state. J. Hum. Hypertens. 14, 687690 (2000).

46 Lip GYH, Blann AD, Beevers DG. Prothrombotic factors, endothelial function and left ventricular hypertrophy in isolated systolic hypertension compared with systolic-diastolic hypertension. J. Hypertens. 17, 12031207 (1999).

47 Nadar S, Lip GYH. Hypertension and the prothrombotic state. J. Am. Coll. Cardiol.. 41, 1847 (2003).

Website

101 National Institute of Clinical Excellence (NICE) Clinical Guideline 18. Management of hypertension in adults in primary care 2004. www.nice.org.uk/pdf/CG018NICEguideline.pdf

Affiliations

V J Karthikeyan, MBBS, MRCPResearch Fellow, Cardiology, University Department of Medicine, City Hospital, Dudley Road, Birmingham B18 7QH, UKTel.: +44 121 507 5080Fax: +44 121 554 [email protected]

Gregory YH Lip, MD, FRCPProfessor of Cardiovascular Medicine, University Department of Medicine, City Hospital, Dudley Road, Birmingham B18 7QH, UKTel.: +44 121 507 5080Fax: +44 121 554 [email protected]

blood pressure control and prevention of stroke

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