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Primary stroke prevention and hypertension treatment: which is the first-line strategy?
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PMID:  22053259     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Hypertension (HT) is considered the main classic vascular risk factor for stroke and the importance of lowering blood pressure (BP) is well established. However, not all the benefit of antihypertensive treatment is due to BP reduction per se, as the effect of reducing the risk of stroke differs among classes of antihypertensive agents. Extensive evidences support that angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), dihydropyridine calcium channel blockers (CCB) and thiazide diuretics each reduced risk of stroke compared with placebo or no treatment. Therefore, when combination therapy is required, a combination of these antihypertensive classes represents a logical approach. Despite the efficacy of antihypertensive therapy a large proportion of the population, still has undiagnosed or inadequately treated HT, and remain at high risk of stroke. In primary stroke prevention current guidelines recommend a systolic/diastolic BP goal of <140/<90 mmHg in the general population and <130/80 mmHg in diabetics and in subjects with high cardiovascular risk and renal disease. The recent release in the market of the fixed-dose combination (FDC) of ACEI or ARB and CCB should provide a better control of BP. However to confirm the efficacy of the FDC in primary stroke prevention, clinical intervention trials are needed.
Roberta Ravenni; Joe F Jabre; Edoardo Casiglia; Alberto Mazza
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Type:  Journal Article     Date:  2011-09-29
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Title:  Neurology international     Volume:  3     ISSN:  2035-8377     ISO Abbreviation:  Neurol Int     Publication Date:  2011 Jul 
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Created Date:  2011-11-04     Completed Date:  2011-11-10     Revised Date:  2013-05-29    
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Nlm Unique ID:  101551564     Medline TA:  Neurol Int     Country:  Italy    
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Languages:  eng     Pagination:  e12     Citation Subset:  -    
Department of Neuroscience, Santa Maria della Misericordia Hospital, Rovigo, Italy;
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Journal ID (nlm-ta): Neurol Int
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ISSN: 2035-8385
ISSN: 2035-8377
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©Copyright R. Ravenni et al., 2011
Received Day: 30 Month: 6 Year: 2011
Revision Received Day: 10 Month: 8 Year: 2011
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collection publication date: Day: 05 Month: 7 Year: 2011
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PubMed Id: 22053259
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DOI: 10.4081/ni.2011.e12

Primary stroke prevention and hypertension treatment: which is the first-line strategy?
Roberta Ravenni1
Joe F. Jabre2
Edoardo Casiglia3
Alberto Mazza4
1Department of Neuroscience, Santa Maria della Misericordia Hospital, Rovigo, Italy;
2Department of Neurology, Boston University School of Medicine, Massachusetts, USA;
3Department of Clinical and Experimental Medicine, University of Padova;
4Department of Internal Medicine, Santa Maria della Misericordia Hospital, Rovigo, Italy
Correspondence: Correspondence: Alberto Mazza, Department of Internal Medicine, Santa Maria della Misericordia Hospital, viale Tre Martiri 140, 45100 Rovigo, Italy. Tel: +39.0425.394567 - Fax: +39.0425.394157. E-mail:


Stroke is a leading cause of death and disability worldwide, exacting an enormous financial toll.1 The total incidence of stroke is expected to increase considerably over the next two decades particularly in European Union where the estimated number of stroke events will increase to 1,500,000 by 2025.2 Among the risk factors for stroke, epidemiological studies carried out in the past decades have definitely established that arterial hypertension (HT) is the main risk factor for stroke,3,4 and that its disabling complications are directly associated to the severity of blood pressure (BP) increase.5

However, other evidences have been outlined that the risk of stroke associated with high BP values is not irreversible, as the risk of stroke incidence could be strongly reduced if BP values were controlled by and optimal antihypertensive treatment.6 The latter is fundamental for stroke prevention as the early discontinuation of the anti-hypertensive treatment is associated with a 30% increase in risk of stroke.7 In this respect all anti-hypertensive drugs classes may be useful in preventing stroke, but some of these may exert a cerebrovascular protection independently to their BP reduction.6

This paper reviews the role of HT as a risk factor for stroke, provides an update on which is the antihypertensive treatment recommended in primary stroke prevention and explores the potential efficacy of fixed-dose combination therapy in preventing stroke.

Hypertension and risk of stroke

Approximately 54% of strokes can be attributed worldwide to high BP values in both gender and in all ages.4 As a consequence, hypertensive subjects are 3 to 4 times more likely to have a stroke than the normotensives.8 In particular, it was established that a 2 mmHg rise in systolic BP in middle life is associated with 10% increase in risk of stroke.9 In addition the relationship between BP and risk of first stroke is direct, continuous and independent, with the risk increasing continuously above a BP of 115/75 mmHg.5

Among BP components, many researchers have established a different role of systolic and diastolic on cerebrovascular risk, especially when diastolic is associated with high systolic levels. This association determines an increase of the pulsatile component of BP (pulse pressure, PP). The increase of PP is an age-related phenomenon10 and it is commonly believed that PP is an indicator of large artery stiffness.11 High PP is associated with higher incidence of carotid stenosis12,13 and reduction in cerebral flow,14,15 and is recognized as an independent predictors of stroke mortality16,17 particularly in elderly people from general population.18 In particular, 10 mmHg PP increases is associated with 11% increase in stroke.19 Increase in systolic and decrease in diastolic BP results in high prevalence of isolated systolic hypertension (ISH), defined as systolic ≥140 with diastolic <90 mmHg. ISH is the most common form of HT in the elderly, and a major risk factor for stroke and cardiovascular disease.20 Large-scale placebo-controlled clinical trials have demonstrated the efficacy on stroke prevention of treating elderly with ISH.21,22 However the studies of Langer et al.23 and of Benetos et al.24 showed higher stroke mortality in treated hypertensives having a prevalent decrease in diastolic. Low diastolic levels have been associated with increased coronary events, a phenomenon known as the J-curve effect.25 Interestingly, this relationship was not observed for stroke and was not present among patients who had undergone coronary revascularization.26 In contrast to the heart, the brain is very infrequently subjected to J-curve effect as the brain’s blood flow autoregulation depends mostly on systolic BP.27 This was confirmed by the results of the Ongoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study (ONTARGET), where no J-curve pattern did appear for stroke.28 For the latter the assumption the lower the systolic BP, the lower the risk was correct, and it was confirmed in a meta-analysis by Staessen et al.29 who found in treated and untreated elderly patients with ISH low systolic levels be associated with a strong benefit for stroke prevention.

Blood pressure targets to achieve in primary stroke prevention

Despite the overwhelming evidence that HT represents the first risk factor for stroke and that the cerebrovascular benefits the most from BP lowering, no randomized clinical trials provided a BP target for effective primary prevention of stroke.30 Current international guidelines recommend a systolic/diastolic goal of <140/<90 mmHg in the general population and <130/<80 mmHg in diabetic subjects and in those with renal disease.31,32 Whether a lower target has further benefits in primary stroke prevention is uncertain. Although in a meta-analysis comparing trials with more-intensive than those with less-intensive targets of BP found a 23% reduced risk of stroke in the former than in the latter, the target <140/<90 mmHg was not achieved.33 In the HOT study there was no difference in rates of stroke among groups of hypertensive patients who achieved mean diastolic values of 85.2, 83.2 or 81.1 mmHg.34 For ISH, no trial has been performed. Finally, the investigators of the HYVET trial35 provided evidence that antihypertensive treatment is beneficial also in the elderly and in very-elderly subjects (>80 years of age); the latter a group excluded from most other trials of antihypertensive therapy. The primary end point of HYVET was fatal or nonfatal stroke. At two years of follow-up, active treatment was associated with a 30% reduction in the rate of all strokes and a 39% reduction in the rate of death from fatal stroke. The greater reduction of risk was observed for a BP target of <150/<80 mmHg in treated patients over age 80, but the efficacy of further reductions in BP needs to be established.

What are the available evidences with renin angiotensin system blockade?

In the hypertensives, the renin angiotensin system (RAS) has been linked to the risk of stroke.36,37 Therefore, it has been suggested that RAS blockade would provide a neuroprotective effect. In the literature studies with ACEI have produced different results in primary stroke prevention. In the Heart Outcomes Prevention Evaluation (HOPE) study, ramipril reduced all stroke by 32% and fatal stroke by 61% compared with placebo.38 On the contrary, in the Captopril Prevention Project, fatal and nonfatal strokes were found to be more frequent in patients randomized to captopril than to conventional therapy.39 In the ALLHAT, lisinopril was less effective in preventing stroke than diuretic therapy.40 As a consequence, the common belief in that in clinical practice ACEI in primary stroke prevention it has yet to be fully confirmed. On the other hand, it has been well established that the inhibition of the negative effects of angiotensin in the cerebral circulation by ARB, determines a neuroprotective effect through the over activation of the AT2 receptors (see below). This observation comes from large clinical trials. In the LIFE study, that enrolled hypertensive patients with left ventricular hypertrophy, losartan significantly reduced the rate of fatal and nonfatal stroke by 25%.41 In the SCOPE, candesartan-based treatment reduced non-fatal stroke by 30% and all stroke by 24% compared with placebo in elderly subjects.42 In the JIKEI Heart study, the HTs receiving valsartan had a significant reduction of stroke risk when compared with those not taking ARB.43 Valsartan and other ARB appear to reduce the risk of stroke more than placebo in primary stroke prevention. This result was also confirmed in a meta-analysis of about 50,000 patients, where treatment with ARB were associated with a significant reduction of stroke risk (∼8%) compared with ACEI.44

In conclusion the cerebrovascular benefits of ARB seem to be class-related rather than drug-related and in general all ARB might be used in primary stroke prevention.

Are there evidences with CCB?

Different studies have compared the effects of CCB vs. placebo or an active treatment for preventing stroke events.4547 In particular, nitrendipine-based treatment reduced the incidence of fatal and nonfatal stroke by 38%.48 In the ACTION study, nifedipine GITS reduced the risk of any stroke or TIA by 30% compared with placebo in hypertensive patients whit high cardiovascular risk.49 CCB have also been shown to provide better protection against fatal and nonfatal stroke than older drugs, such as β-blockers, diuretics and ACEI.50,51 This has particularly been observed in a meta-analysis involving 4 trials, where CCB have been shown to provide benefit compared to ACEI.52 In the ASCOT study, amlodipine reduced fatal and nonfatal stroke better than atenolol (+23%).53,54 Moreover, the risk of stroke with amlodipine was statistically less when compared with non-ARB antihypertensive drugs and with ARB therapies separately.

What are the available evidences with diuretics?

In the literature, it is well known that diuretic therapy, particularly thiazide diuretics, reduced the risk of stroke compared to placebo or to no antihypertensive treatment.55 This has particularly been observed in the elderly with ISH. In the Systolic Hypertension in the Elderly Program (SHEP) chlorthalidone caused a 36% reduction in the incidence of stroke.56 The SHEP documented that the benefit of BP lowering therapy is maintained also in very elderly hypertensives aged ≥80 years.57 Another meta-analysis found that diuretic therapy was superior to ACEI therapy,58 particularly in blacks.40 However, because of their lower tolerance and efficacy on regression of target organ damage compared with ARB, ACEI and CCB, in clinical practice diuretics are rarely used alone as first-line treatment for primary stroke prevention.

What is the mechanism of modulation of the pathophysiology of stroke by renin angiotensin system blockade and CCB?

Lowering BP is per se the most important determinant of stroke risk reduction.59 This has particularly been observed with CCB.35 However this benefit appears in part independent of BP lowering.54,60 The same result were been found with ARB, suggesting that these agents also have some BP-independent benefits. In experimental animal models, pre-treatment with an ARB at a sub-antihypertensive dose was more effective than an ACEI for reducing infarct size and neurological deficits following transient focal ischemia.61

The mechanisms by which CCB and ARB prevent stroke beyond BP reductions is unknown, although it is common belief that these antihypertensive drugs promote their protective action on stroke by reducing the progression towards the vascular and cardiac organ damage associated with hypertension.62

The increase of carotid intima-media thickness (IMT) is an independent risk factor of stroke63 and it is well established that - despite comparable reductions in BP - CCB reduce IMT more than ACEI do.64 This has particularly been observed in the INSIGHT study, where the hypertensives receiving nifedipine gastrointestinal-transport-system (GITS) had greater regression of IMT than those taking diuretic.65

In the same manner, ARB reduce IMT more than atenolol despite a similar effect on BP, an effect that seems to be mediated by improvements in nitric oxide production and decreases in oxidative stress.66,67 Changes in central aortic pressure but not in peripheral BP could explain some differences between CCB and other antihypertensive drugs. In the CAFE study, despite comparable brachial pressures, amlodipine-based treatment reduced central systolic BP more than atenolol.68 It has been suggested that heart rate is a major determinant of the difference between central and brachial BP, and might account for the less effective lowering of central BP with atenolol. As a consequence, in the CAFE study the effect on central BP and heart rate could explain some of the differences in stroke incidence between atenolol and amlodipine.

The increase of left ventricular mass is an independent risk factor for stroke.6 In a meta-analysis, CCB and ARB were reported to reduce left ventricular mass index by 11% and 13%, respectively.69

There is evidence that antihypertensive treatment with ARB and ACEI prevents new-onset of non-valvular atrial fibrillation, a condition that is common in the hypertensives and associated with 5-fold increased risk of embolic stroke.70 RAS blockade appears to reduce the incidence of stroke by 51% in patients with new-onset atrial fibrillation.71 Although results obtained from the few clinical studies were mostly post-hoc analysis, the benefits in terms of stroke prevention seem to be superior in subjects with cardiac damage secondary to HT and with heart failure.7175

Potential benefit of fixed-dose combination therapy

Despite the availability of a wide range of antihypertensive agents, almost two-thirds of the hypertensives fail to achieve the BP goals recommended by current ESH/ESC hypertension guidelines and have poorly controlled BP.62 As a consequence, they remain at a high risk of morbid and fatal stroke and require effective treatment options. Sub-optimal BP control is often due to poor patient compliance and results in a significant health and economic burden. Numerous clinical trials have shown that most patients require at least two antihypertensive agents to achieve adequate BP control and associated significant reductions in stroke morbidity and mortality. Combination therapy using two drugs with different mechanisms of action achieves better efficacy and tolerability outcomes than treatment with either component drug alone. Furthermore, when this combination is administered as a fixed-dose combination, other benefits are achieved, such as an improved compliance and potentially lower costs of treatment. The good efficacy and tolerability of the fixed-dose of a CCB with an ACEI or an ARB is well established, and this combination is recommended in the reappraisal of the ESH/ESC guidelines as a first choice in high-risk hypertensive patients.31 In clinical trials the fixed-dose combination improves BP to a greater extent than either drug as monotherapy and, when compared with antihypertensive mono-therapies, it may also offer equivalent or better efficacy and the same or improved tolerability. Therefore, fixed-dose combination has the potential to reduce both the risk of stroke and the non-drug healthcare costs associated with HT.

Direct neuroprotective benefit of the antihypertensive agents

As mentioned above, RAS blockade seems to determine a direct neuroprotective effect. This is particularly true for ARB, as it has been observed that angiotensin II induces cerebrovascular hypertrophy and remodelling, inhibits endothelium-dependent relaxation and disrupts the blood-brain barrier.36 Two types of angiotensin II receptors have been implicated to explain this benefit.76,77 Type 1 receptors, expressed in different tissues, induce vasoconstriction, sodium and water retention, smooth-muscle proliferation, and vascular endothelial damage, while type 2 receptors, expressed in fetal tissues and up-regulated in ischemic brain tissue, modulate the type 1 receptor activity reducing inflammation and neuronal apoptosis and inducing vasodilation, thereby mediating neuroprotective effect.

There is some evidence that ARB may provide greater reduction in the risk of stroke than diuretics, long-acting dihydropyridine CCB, ACEI and β-blockers despite similar reduction in BP.78 This evidence has particularly been demonstrated with losartan vs. atenolol,41 candesartan vs. hydroclothiazide [42] and eprosartan vs. nitrendipine79 in clinical studies where the risk of stroke was low. However, the ONTARGET study was unable to show a significant reduction in stroke with telmisartan than ramipril.28 In addition, CCB and ARB seem to have BP-independent effects on stroke in animal models, probably via a reduction of inflammation in cerebral microvessels,80 protection of cerebral circulation (improving of cerebral blood flow auto-regulation) and reduction of superoxide production .81,82 However, these data should be cautiously translated to humans, where these mechanisms have not been readily observed.


Hypertension remains the most important established and modifiable classic vascular risk factor for stroke, and antihypertensive treatment the most effective strategy for preventing stroke as well as other BP-related target organ damage. Reduction in BP is generally more important than the choice of specific agents, but some classes of antihypertensives offer direct neuroprotective benefit: those acting on RAS blockade, CCB and thiazide diuretics represent the three classes with the strongest effect in primary stroke prevention. The use of fixed-dose combination of these drugs may increase patient compliance and persistence to antihypertensive treatment. However further studies are required to evaluate the neuroprotective effect of FDC therapy in primary stroke prevention.83

1. Tu JV. Reducing the global burden of stroke: INTERSTROKELancetYear: 201037674520561674
2. Truelsen T,Piechowski-Jó wiak B,Bonita R,et al. Stroke incidence and prevalence in Europe: a review of available dataEur J NeurolYear: 2006135819816796582
3. D’Agostino RB,Wolf PA,Belanger AJ,Kannel WB. Stroke risk profile: adjustment for antihypertensive medication. The Framingham StudyStrokeYear: 1994254038266381
4. Lawes CM,Vander Hoorn S,Rodgers A. International Society of Hypertension. Global burden of blood-pressure-related disease, 2001LancetYear: 20083711513818456100
5. Lewington S,Clarke R,Qizilbash N,et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Prospective Studies CollaborationLancetYear: 200236019031312493255
6. Grassi G,Quarti-Trevano F,Dell’oro R,Mancia G. Antihypertensive treatment and stroke prevention: from recent meta-analyses to the PRoFESS trialCurr Hypertens RepYear: 2009112657019602327
7. Breekveldt-Postma NS,Penning-van Beest FJ,Siiskonen SJ,et al. The effect of discontinuation of antihypertensives on the risk of acute myocardial infarction and strokeCurr Med Res OpinYear: 200824121718031596
8. Gorelick PB. New horizons for stroke prevention: PROGRESS and HOPELancet NeurolYear: 200211495612849483
9. Lewington S,Clarke R,Qizilbash N,et al. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studiesLancetYear: 20021436019031312493255
10. Safar ME. Pulse pressure in essential hypertension: a haemodynamic studyJ HypertensYear: 19875213183611771
11. Benetos A,Laurent S,Asmar RG,Lacolley P. Large artery stiffness in hypertensionJ HypertensYear: 199715S8997
12. Sutton-Tyrrell K,Alcorn HG,Wolfson SK,et al. Predictors of carotid stenosis in older adults with and without isolated systolic hypertensionStrokeYear: 199324355618446969
13. Suurkula M,Agewall S,Fagerberg B,et al. Ultrasound evaluation of atherosclerotic manifestations in the carotid artery in high-risk hypertensive patients. Risk Intervention Study (RIS) GroupArterioscler ThrombYear: 19941412973048049191
14. Millar JA,Lever AF,Burke V. Pulse pressure as a risk factor for cardiovascular events in the MRC Mild Hypertension trialJ HypertensYear: 19991710657210466460
15. Lee ML,Rosner BA,Weiss ST. Relationship of blood pressure to cardiovascular death: the effects of pulse pressure in the elderlyAnn EpidemiolYear: 19999101710037553
16. Voko Z,Bots ML,Hofman A,et al. J-shaped relation between blood pressure and stroke in treated hypertensivesHypertensionYear: 1999341181510601115
17. Selmer R. Blood pressure and twenty-year mortality in the city of Bergen, NorwayAm J EpidemiolYear: 1992136428401415163
18. Mazza A,Pessina AC,Gianluca P,et al. Pulse pressure: an independent predictor of coronary and stroke mortality in elderly females from the general populationBlood PressYear: 2001102051111800058
19. Domanski MJ,Davis BR,Pfeffer MA,et al. Isolated systolic hypertension: prognostic information provided by pulse pressureHypertensionYear: 1999343758010489379
20. SHEP Cooperative Research GroupPrevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP)JAMAYear: 19912653255642046107
21. Staessen JA,Fagard R,Thijs L,et al. Randomised double-blind comparison of placebo and active treatment in older patients with isolated systolic hypertensionLancetYear: 1997350757649297994
22. Dahlof B,Lindholm LH,Hansson L,et al. Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension)LancetYear: 1991338128151682683
23. Langer RD,Ganiats TG,Barrett-Connor E. Paradoxical survival of elderly men with high blood pressureBr Med JYear: 1989298135672502252
24. Benetos A,Zureik M,Morcet J,et al. Decrease in diastolic blood pressure combined with an increase in systolic blood pressure is associated with a higher cardiovascular mortality in menJ Am Coll CardiolYear: 2000356738010716470
25. Stewart IM. Relation of reduction in pressure to first myocardial infarction in patients receiving treatment for severe hypertensionLancetYear: 19791861586103
26. Bangalore S,Messerli FH,Wun CC,et al. J-curve revisited: An analysis of blood pressure and cardiovascular events in the Treating to New Targets (TNT) TrialEur Heart JYear: 201031289790820846991
27. Chrysant SG. Current status of aggressive blood pressure controlWorld J CardiolYear: 20113657121499494
28. ONTARGET InvestigatorsYusuf S,Teo KK,et al. Telmisartan, ramipril, or both in patients at high risk for vascular eventsN Engl J MedYear: 200835815475918378520
29. Staessen JA,Gasowski J,Wang JG,et al. Risks of untreated and treated isolated systolic hypertension in the elderly: meta-analysis of outcome trialsLancetYear: 20003558657210752701
30. Gorelick PB. Challenges of designing trials for the primary prevention of strokeStrokeYear: 200940Suppl 3S82419064811
31. Mancia G,Laurent S,Agabiti-Rosei E,et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force documentJ HypertensYear: 20092721215819838131
32. Chobanian AV,Bakris GL,Black HR,et al. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 reportJAMAYear: 200328925607212748199
33. Turnbull F. Effects of different blood-pressure-lowering regimens on major cardiovascular events: results of prospectively-designed overviews of randomised trialsLancetYear: 200336215273514615107
34. Hansson L,Zanchetti A,Carruthers SG,et al. 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 GroupLancetYear: 19983511755629635947
35. Beckett NS,Peters R,Fletcher AE,et al. Treatment of hypertension in patients 80 years of age or olderN Engl J MedYear: 200835818879818378519
36. Iadecola C,Gorelick PB. Hypertension, angiotensin, and stroke: beyond blood pressureStrokeYear: 2004353485014757875
37. Schrader J,Kulschewski A,Dendorfer A. Inhibition of the renin-angiotensin system and the prevention of strokeAm J Cardiovasc DrugsYear: 20077253717355164
38. Bosch J,Yusuf S,Pogue J,et al. Heart outcomes prevention evaluation. Use of ramipril in preventing stroke: double blind randomised trialBMJYear: 200232469970211909785
39. 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 trialLancetYear: 1999353611610030325
40. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research GroupMajor 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)JAMAYear: 200228829819712479763
41. Dahlöf B,Devereux RB,Kjeldsen SE,et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenololLancetYear: 2002359995100311937178
42. Lithell H,Hansson L,Skoog I,et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): Principal results of a randomized double-blind intervention trialJ HypertensYear: 2003218758612714861
43. Mochizuki S,Dahlöf B,Shimizu M,et al. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality studyLancetYear: 20073691431917467513
44. Reboldi G,Angeli F,Cavallini C,et al. Comparison between angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on the risk of myocardial infarction, stroke and death: a meta-analysisJ HypertensYear: 2008261282918550998
45. Pitt B,Byington RP,Furberg CD,et al. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT InvestigatorsCirculationYear: 200010215031011004140
46. Staessen JA,Fagard R,Thijs L,et al. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. The Systolic Hypertension in Europe (Syst-Eur) Trial InvestigatorsLancetYear: 1997350757649297994
47. Staessen JA,Thijs L,Fagard RH,et al. Calcium channel blockade and cardiovascular prognosis in the European trial on isolated systolic hypertensionHypertensionYear: 19983241069740604
48. Wang JG,Staessen JA,Gong L,Liu L. Chinese trial on isolated systolic hypertension in the elderly. Systolic Hypertension in China (Syst-China) Collaborative GroupArch Intern MedYear: 20001602112010647760
49. Lubsen J,Wagener G,Kirwan BA,et al. Effect of long-acting nifedipine on mortality and cardiovascular morbidity in patients with symptomatic stable angina and hypertension: the ACTION trialJ HypertensYear: 200523641815716708
50. Bangalore S,Messerli FH. A review of stroke in patients with hypertension and coronary artery disease: Focus on calcium channel blockersInt J Clin PractYear: 2006601281616942591
51. Staessen JA,Li Y,Thijs L,Wang JG. Blood pressure reduction and cardiovascular prevention: an update including the 2003–2004 secondary prevention trialsHypertens ResYear: 20052838540716156503
52. Lawes CM,Bennett DA,Feigin VL,Rodgers A. Blood pressure and stroke: an overview of published reviewsStrokeYear: 20043510243315053002
53. Dahlöf B,Sever PS,Poulter NR,et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required vs atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trialLancetYear: 200536689590616154016
54. Wang JG,Li Y,Franklin SS,Safar M. Prevention of stroke and myocardial infarction by amlodipine and angiotensin receptor blockers. A quantitative overviewHypertensionYear: 200750181817502490
55. Wright JM,Musini VM. First-line drugs for hypertensionCochrane Database Syst RevYear: 2009CD001841.
56. 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)SHEP Cooperative Research GroupJAMAYear: 19912653255642046107
57. Beckett NS,Peters R,Fletcher AE,et al. Treatment of hypertension in patients 80 years of age or olderN Engl J MedYear: 200835818879818378519
58. Psaty BM,Lumley T,Furberg CD,et al. Health outcomes associated with various antihypertensive therapies used as first-line agents: a network meta-analysisJAMAYear: 200328925344412759325
59. Verdecchia P,Reboldi G,Angeli F,et al. Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke preventionHypertensionYear: 2005463869216009786
60. Poulter NR,Wedel H,Dahlöf B,et al. Role of blood pressure and other variables in the differential cardiovascular event rates noted in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA)LancetYear: 20053669071316154017
61. Krikov M,Thone-Reineke C,Müller S,et al. Candesartan but not ramipril pretreatment improves outcome after stroke and stimulates neurotrophin BNDF/TrkB system in ratsJ HypertensYear: 2008265445218300867
62. Mancia G,De Backer G,Dominiczak A,et al. 2007 ESH-ESC Practice Guidelines for the Management of Arterial Hypertension: ESH-ESC Task Force on the Management of Arterial HypertensionJ HypertensYear: 20072517516217762635
63. Lorenz MW,Markus HS,Bots ML,et al. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysisCirculationYear: 20071154596717242284
64. Wang JG,Staessen JA,Li Y,et al. Carotid intima-media thickness and antihypertensive treatment: a meta-analysis of randomized controlled trialsStrokeYear: 20063719334016763185
65. Simon A,Gariépy J,Moyse D,Levenson J. Differential effects of nifedipine and co-amilozide on the progression of early carotid wall changesCirculationYear: 200110329495411413085
66. Mörtsell D,Malmqvist K,Held C,Kahan T. Irbesartan reduces common carotid artery intima-media thickness in hypertensive patients when compared with atenolol: the Swedish Irbesartan Left Ventricular Hypertrophy Investigation vs Atenolol (SILVHIA) studyJ Intern MedYear: 2007261472917444886
67. Olsen MH,Wachtell K,Neland K,et al. Losartan but not atenolol reduce carotid artery hypertrophy in essential hypertension. A LIFE sub-studyBlood PressYear: 2005141778316036498
68. Williams B,Lacy PS,Thom SM,et al. CAFE Steering Committee and Writing CommitteeDifferential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: principal results of the Conduit Artery Function Evaluation (CAFE) studyCirculationYear: 200611312132516476843
69. Lacy PS,Williams B. Impact of heart rate on the differential impact of blood pressure lowering drugs on central and peripheral pressures: Data from the Conduit Artery Function Evaluation (CAFÉ) studyJ HypertensYear: 200826Suppl 1S459S459
70. Klingbeil AU,Schneider M,Martus P,et al. A meta-analysis of the effects of treatment on left ventricular mass in essential hypertensionAm J MedYear: 200311541612867233
71. Independent predictors of stroke in patients with atrial fibrillation: a systematic reviewNeurologyYear: 2007695465417679673
72. Wachtell K,Lehto M,Gerdts E,et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) studyJ Am Coll CardiolYear: 200545712915734615
73. Madrid AH,Bueno MG,Rebollo JM,et al. Use of irbesartan to maintain sinus rhythm in patients with long-lasting persistent atrial fibrillation: a prospective and randomized studyCirculationYear: 20021063313612119249
74. Maggioni AP,Latini R,Carson PE,et al. Val-HeFT Investigators. Valsartan reduces the incidence of atrial fibrillation in patients with heart failure: results from the Valsartan Heart Failure Trial (Val-HeFT)Am Heart JYear: 20051495485715864246
75. Ducharme A,Swedberg K,Pfeffer MA,et al. Prevention of atrial fibrillation in patients with symptomatic chronic heart failure by candesartan in the Candesartan in Heart failure: assessment of Reduction in Mortality and morbidity (CHARM) programAm Heart JYear: 20061519859116644318
76. Fitzmaurice DA,Hobbs FD,Jowett S,et al. Screening versus routine practice in detection of atrial fibrillation in patients aged 65 or over: cluster randomised controlled trialBMJYear: 200733538338317673732
77. Fournier A,Messerli FH,Achard JM,Fernandez L. Cerebroprotection mediated by angiotensin II: A hypothesis supported by recent randomized clinical trialsJ Am Coll CardiolYear: 2004431343715093864
78. Pedelty L,Gorelick PB. Management of hypertension and cerebrovascular disease in the elderlyAm J MedYear: 20081218 supplS23S3118638616
79. Boutitie F,Oprisiu R,Achard JM,et al. Does a change in angiotensin II formation caused by antihypertensive drugs affect the risk of stroke? A meta-analysis of trials according to treatment with potentially different effects on angiotensin IIJ HypertensYear: 20072515435317620946
80. Schrader J,Luders S,Kulschewski A,et al. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: Principal results of a prospective randomized controlled study (MOSES)StrokeYear: 20053612182615879332
81. Ando H,Zhou J,Macova M,et al. Angiotensin II AT1 receptor blockade reverses pathological hypertrophy and inflammation in brain microvessels of spontaneously hypertensive ratsStrokeYear: 20043517263115143297
82. Kumai Y,Ooboshi H,Ago T,et al. Protective effects of angiotensin II type 1 receptor blocker on cerebral circulation independent of blood pressureExp NeurolYear: 2008210441818177860
83. Talbert RL. Role of antihypertensive therapy with angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers in combination with calcium channel blockers for stroke preventionJ Am Pharm AssocYear: 201050e11625

Article Categories:
  • Review

Keywords: Key words: antihypertensive therapy, hypertension, prevention, renin angiotensin system, stroke..

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