Arterial hypertension and stroke prevention: an update

High blood pressure (BP) is the most important modifiable risk factor for stroke and other vascular diseases. Evidence from randomized controlled trials supports the use of antihypertensive drugs to lower blood pressure for stroke prevention. There is some evidence that specific classes of antihypertensive drugs have different effects and/or their pharmacological actions differ in patient subgroups. This review evaluates the development of antihypertensive therapies and the latest studies of arterial hypertension and stroke prevention: HOPE trial (ramipril versus placebo), ALLHAT trial (CCB or/ and Angiotensin-Conventing enzyme Inhibitors (ACE-Is) versus diuretic), LIFE trial (losartan versus atenolol), and PROGRESS trial (perindopril or/and indapamide versus placebo). Despite the results of these relevant clinical trails, some aspects still remain unresolved. Future clinical trials on hypertension and stroke prevention should answer the following questions: Does lowering BP reduce stroke risk due to specific drug effect or class effect? Are angiotensin II receptor blockers (ARBs) better than ACE-Is? Should ACE-Is and ARBs be considered routinely for either high-risk stroke patients or patients with history of stroke or transient ischemic attack, irrespective of blood pressure? What is the role of lifestyle in BP control?     

Antihypertensive,antiproteinuric therapy and myocardial infarction and stroke prevention

Proteinuria is a graded marker for kidney damage, as well as the risk for future cardiovascular events. Angiotensinconverting enzyme inhibitors (ACEIs) and angiotensinreceptor blockers (ARBs) reduce urinary protein excretion and slow progression of renal impairment, independent of blood pressure lowering. Both the Irbesartan Diabetic Nephropathy Trial (IDNT) and the Reduction in Endpoints in NIDDM with the Angiotensin Antagonist Losartan (RENAAL) study were large, randomized, prospective studies in type 2 diabetic patients with proteinuria. There was no reduction in the incidence of myocardial infarction or stroke with the ARBs compared to placebo in either trial. A broader overview of clinical trials comparing ACEIs and ARBs with other antihypertensive drugs fails to show any substantive blood pressure-independent effects on stroke or myocardial infarction with these classes of drugs. Therefore, for cardiovascular end points (as opposed to renal end points), it may be more important that the blood pressure is reduced, rather than how the process is started.     

Lowering blood pressure to prevent stroke recurrence: a systematic review of long-term randomized trials

Albeit hypertension is a leading risk factor for an initial stroke, the role of blood pressure (BP) lowering to prevent a subsequent stroke is controversial. The present systematic review searched randomized trials published from January 1990 to January 2014 with the aim to assess antihypertensive treatment effects on recurrent stroke prevention. Seven randomized placebo-controlled trials enrolling 49,518 patients, two randomized trials not placebo controlled comparing antihypertensive drugs, and one randomized trial that compared the effects of intensive systolic BP lowering with a more conservative systolic BP management, were identified. The placebo-controlled trials had substantial methodological differences, explaining the difficulties to compare their results. An important obstacle arises from the large dispersion in the window's time between the qualifying stroke and randomization. Another barrier is the variation among studies in the recruited patient's stroke subtypes. Differences between trials could not be attributed to disparity in lowering BP or to different degrees of no adherence. The American Heart Association/American Stroke Association stated that although an absolute target of BP level has not been clearly defined, a reduction in recurrent stroke has been associated with an average lowering of 10/5 mm Hg. It should be taken into account that it is not advisable to reduce BP levels to <120/80 mm Hg. It should carry out an individualized selection, based on demographic characteristics and comorbidities (cardiovascular disease, diabetes mellitus, and chronic disease) among diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor blockers, or calcium channel blockers.     

Blood Pressure Control and Primary Prevention of Stroke: Summary of the Recent Clinical Trial Data and Meta-Analyses

Stroke is the second most common cause of death worldwide and of adult disability, but in the near future the global burden of cerebrovascular diseases will rise due to ageing and adverse lifestyle changes in populations worldwide. The risk of stroke increases at blood pressure levels above 115/75 mm Hg and high blood pressure (BP) is the most important modifiable risk factor for stroke, associated with 54 % episodes of stroke worldwide. There is strong evidence from clinical trials that antihypertensive therapy reduces substantially the risk of any type of stroke, as well as stroke-related death and disability. The risk attributed to BP is associated not only with absolute values but also with certain parameters describing BP diurnal pattern as well as short-term and long-term variability. Many studies reported that certain features of BP like nocturnal hypertension, morning surge or increased variability predict an increased stroke risk. However, there is no accepted effective modality for correction of these disturbances (chronotherapy, certain classes of antihypertensive drugs). In the elderly, who are mostly affected by stroke, the primary prevention guidelines recommend treatment with diuretics and calcium channel blockers to lower blood pressure to the standard level.     

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 II

BACKGROUND: Stroke prevention by antihypertensive therapy is believed to be related to the fall in blood pressure (BP). Experimental data have documented that activation of non-AT1 receptors of angiotensin II may exert anti-ischaemic mechanisms in the brain. The present meta-analysis of various randomized clinical trials attempts to relate stroke risk to angiotensin II formation during antihypertensive therapy. METHODS: Primary and secondary stroke prevention was examined in 26 prospective, randomized clinical trials including 206,632 patients without heart failure, in whom a total of 7,108 strokes occurred. The trials were selected because a difference in angiotensin II generation was expected between the two treatment arms on the basis of the drugs' pharmacodynamic effects, and allowed 36 evaluations of the relative risk of stroke. FINDINGS: In placebo-controlled trials, stroke risk was significantly higher with angiotensin II-decreasing than increasing drugs, but systolic BP decreased less in the former. Compared with an active therapy having a neutral effect on angiotensin II formation, stroke risk was also higher with angiotensin-decreasing drugs than with angiotensin-increasing drugs, whereas BP decrease was comparable with both drug classes. When angiotensin II-decreasing drugs were directly compared with angiotensin II-increasing drugs in the same trials, stroke risk was significantly increased. On-treatment systolic BP was minimally and significantly higher with angiotensin II-decreasing drugs, but not large enough to explain the excess in stroke risk. CONCLUSION: Within the limitations of the methodology, our meta-analysis supports the hypothesis that angiotensin II-decreasing drugs are less stroke protective than angiotensin II-increasing drugs, although this difference is not entirely explained by their smaller BP-lowering effect.     

Prevention of stroke and myocardial infarction by amlodipine and Angiotensin receptor blockers: a quantitative overview

In the present quantitative overview of outcome trials, we investigated the efficacy of amlodipine or angiotensin receptor blockers in the prevention of stroke and myocardial infarction in patients with hypertension, coronary artery disease, or diabetic nephropathy. The analysis included 12 trials of 94 338 patients. The analysis of trials involving an amlodipine group showed that amlodipine provided more protection against stroke and myocardial infarction than other antihypertensive drugs, including angiotensin receptor blockers (-19%, P<0.0001 and -7%, P=0.03) and placebo (-37%, P=0.06 and -29%, P=0.04). The analysis of trials involving an angiotensin receptor blocker group showed contrasting results between trials versus amlodipine and trials versus other antihypertensive drugs for stroke (+19% versus -25%; P<0.0001) and myocardial infarction (+21% versus +1%; P=0.03). The results of 3 trials comparing an angiotensin receptor blocker with placebo were neutral (P> or =0.14). The within-trial between-group difference in achieved systolic pressure ranged from -1.1 to +4.7 mm Hg for trials involving an amlodipine group and from -2.8 to +4.0 mm Hg for trials involving an angiotensin receptor blocker group. The metaregression analysis correlating odds ratios with blood pressure differences showed a negative relationship (regression coefficients: -3% to -8%), which reached statistical significance (regression coefficient: -6%; P=0.01) for stroke in trials involving an amlodipine group. In conclusion, blood pressure differences largely accounted for cardiovascular outcome.     

A review of olmesartan medoxomil monotherapy: antihypertensive efficacy similar to that of other angiotensin II receptor blocker/hydrochlorothiazide combinations?

Angiotensin II receptor blockers (ARBs) have been available in the United States since 1995. These agents have demonstrated antihypertensive efficacy at least similar to that of agents from other antihypertensive classes. Recent large-scale, randomized, controlled clinical trials have demonstrated that ARBs offer cardiovascular and renal protective benefits independent of their effects on systemic blood pressure (BP), which make them valuable as first-line antihypertensive agents, especially in high-risk patients. However, as is the case with other antihypertensive classes, monotherapy with the first-available ARBs (losartan potassium, valsartan, and irbesartan) may not provide sufficient BP reduction to achieve currently recommended BP goals in many patients. The diuretic hydrochlorothiazide is frequently added to enhance the ability of ARBs to lower BP. Several head-to-head comparison studies have shown differences in antihypertensive efficacy among the available ARBs. The newest ARB, olmesartan medoxomil, was recently compared with losartan potassium, irbesartan, and valsartan in a prospective, head-to-head, randomized trial. In this study, olmesartan medoxomil demonstrated a significantly greater reduction in diastolic BP, the primary end point, compared with the other three ARBs. Further, a review of the absolute reductions in diastolic BP achieved with olmesartan medoxomil monotherapy appears comparable to that of previously available ARBs when they are used in combination with hydrochlorothiazide. These comparisons may have important clinical implications regarding the optimal choice of first-line antihypertensive therapy.     

Prevention of dementia and cerebroprotection with antihypertensive drugs

High blood pressure is a major risk factor for stroke and is also closely correlated with cognitive decline and dementia. Indeed, most longitudinal studies showed that cognitive functioning is often inversely proportional to blood pressure values measured 15 or 20 years previously. Because of the aging of the population, the frequency of stroke and dementia will dramatically increase in the coming years. Therefore, the prevention of cerebrovascular and cognitive disorders represents a major challenge. Antihypertensive drugs have shown clinical benefits in both primary and secondary prevention of strokes. Consensus is generally that blood-pressure lowering represents the major determinant of the benefit conferred by the antihypertensive treatment for stroke prevention; however, recent studies have suggested some differences between classes of antihypertensive drugs. The results of therapeutic trials (Systolic Hypertension in Europe [Syst-Eur], Perindopril Protection Against Recurrent Stroke Study [PROGRESS]) open the way to the prevention of dementia (vascular or Alzheimer’s type) by antihypertensive treatments. These two studies suggest different mechanisms for the prevention of cognitive decline using antihypertensive drugs. In this context, reduced incidence of dementia should be the primary outcome of future trials comparing different classes of antihypertensive drugs.     

Angiotensin-converting enzyme inhibitors and calcium channel blockers for coronary heart disease and stroke prevention

We investigated whether protection from coronary heart disease (CHD) and stroke conferred by angiotensin-converting enzyme inhibitors (ACEIs) and calcium channel blockers (CCBs) in hypertensive or high-risk patients may be explained by the specific drug regimen. We extracted summary statistics regarding CHD and stroke from 28 outcome trials that compared either ACEIs or CCBs with diuretics, beta-blockers, or placebo for a total of 179,122 patients, 9509 incident cases of CHD, and 5971 cases of stroke. CHD included myocardial infarction and coronary death. In placebo-controlled trials, ACEIs decreased the risk of CHD (P<0.001), and CCBs reduced stroke incidence (P<0.001). There were no significant differences in CHD risk between regimens based on diuretics/beta-blockers and regimens based on ACEIs (P=0.46) or CCBs (P=0.52). The risk of stroke was reduced by CCBs (P=0.041) but not by ACEIs (P=0.15) compared with diuretics/beta-blockers. Because heterogeneity between trials was significant, we investigated potential sources of heterogeneity by metaregression. Examined covariates were the reduction in systolic blood pressure (BP), drug treatment (ACEIs versus CCBs), their interaction term, sex, age at randomization, year of publication, and duration of treatment. Prevention of CHD was explained by systolic BP reduction (P<0.001) and use of ACEIs (P=0.028), whereas prevention of stroke was explained by systolic BP reduction (P=0.001) and use of CCBs (P=0.042). These findings confirm that BP lowering is fundamental for prevention of CHD and stroke. However, over and beyond BP reduction, ACEIs appear superior to CCBs for prevention of CHD, whereas CCBs appear superior to ACEIs for prevention of stroke.     

Pharmacological interventions for hypertensive emergencies: a Cochrane systematic review

Hypertensive emergencies occur when high blood pressure is associated with the presence of acute end-organ damage, such as hypertensive encephalopathy. There is controversy as to when and which antihypertensive drugs to use in these situations. Using a comprehensive search strategy in electronic sources, MEDLINE, EMBASE and Cochrane clinical trial register, we conducted a systematic review to look all randomized control trials (RCTs) that compare an antihypertensive drug versus placebo, no treatment or another antihypertensive drug. Fifteen RCTs (representing 869 patients) met the inclusion criteria. Two trials included a placebo arm. All studies (except one) were open-label trials. Seven drug classes were evaluated in those trials: nitrates (nine trials), angiotensin-converting enzyme inhibitors (seven), diuretics (three), calcium channel blockers (six), alpha-1 adrenergic antagonists (four), direct vasodilators (two) and dopamine agonists (one). Mortality event data were reported in seven trials. Due to insufficient data, no meta-analysis was performed for clinical outcomes. Differences in blood pressure changes between antihypertensives were minor. There is no RCT evidence demonstrating that antihypertensive drugs reduce mortality or morbidity in patients with hypertensive emergencies. Furthermore, there is insufficient RCT evidence to determine which drug or drug class is most effective in reducing mortality and morbidity. There were some minor differences in the degree of blood pressure lowering when one class of antihypertensive drug is compared to another. However, the clinical significance is unknown. RCTs are needed to assess different drug classes to determine initial and longer-term mortality and morbidity outcomes.Journal of Human Hypertension (2008) 22, 596-607; doi:10.1038/jhh.2008.25; published online 17 April 2008.     

Benefits of antihypertensive drugs when blood pressure is below 140/90 mmHg

Antihypertensive medications are used to lower blood pressure (BP) but, ultimately, their true value lies in reductions in morbidity and mortality (cardiovascular, cerebrovascular, and renal diseases). Hypertension is defined discreetly (generally 140/90 mmHg) but the actual relationship between BP and adverse cardiac and cerebrovascular outcomes is continuous. Observational studies have demonstrated a powerful log-linear relationship between BP and mortality due to ischemic heart disease (IHD) or stroke over the range of 115/75 to 185/115 mmHg. Clinical trials and meta-analyses have clearly demonstrated benefits of antihypertensive drugs in nonhypertensive individuals: delay or prevention of the onset of hypertension and microalbuminuria and reduced morbidity and mortality from IHD, stroke, and chronic kidney disease. This is not surprising given that various antihypertensive drug classes have multiple potential beneficial effects. A persistent concern is that overtreatment of hypertension may increase risk in individuals with coronary artery disease, but a "J-curve" effect is not consistently found in clinical studies. The use of antihypertensive drugs in at-risk individuals who are below the traditional threshold (140/90 mmHg) is fully justifiable, but the decision requires adequate clinical experience and judgment and a full assessment of risks and benefits.     

The importance of early antihypertensive efficacy: the role of angiotensin II receptor blocker therapy

Desirable features of antihypertensive agents include efficacy, tolerability, prolonged duration of action and rapid achievement of target blood pressure (BP). Recent studies have examined the relationship between the onset of antihypertensive effect and cardiovascular events. Data from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE), the Study on Cognition and Prognosis in the Elderly (SCOPE), and the Systolic Hypertension in Europe (Syst-Eur) trials support the hypothesis that the time it takes to reach target BP influences cardiovascular outcomes. VALUE, which compared BP-lowering and clinical event rates between patients treated with the angiotensin II receptor blocker (ARB) valsartan or the calcium channel blocker (CCB) amlodipine as well as between those who achieved immediate or delayed BP control, provides the strongest evidence of this to date. Additional data from SCOPE and Syst-Eur suggest that delays of 3 months to 2 years in starting antihypertensive therapy can increase the risk of certain cardiovascular end points, especially stroke. These data suggest that it may be beneficial to examine the efficacy of antihypertensive agents, not only long term, but also at earlier times to assess the onset and impact of early antihypertensive effect. The ARB olmesartan medoxomil (olmesartan) and the CCB amlodipine were compared in a randomized, double-blind, placebo-controlled clinical trial, which demonstrated that the onset of antihypertensive effect of olmesartan is comparable with that of amlodipine. Another study demonstrated that more patients treated with olmesartan achieved target BPs within 2 weeks of treatment compared with the ARBs losartan, valsartan and irbesartan.     

Angiotensin II-receptor antagonist in the treatment of hypertension

Effective treatment of high blood pressure levels represents a crucial point in reducing global cardiovascular risk, and several studies have clearly demonstrated a significant reduction in cardiovascular and renal morbidity and mortality with a more intensive blood pressure-lowering treatment. Other factors beyond blood pressure control may be important in reducing the risk related to hypertension. Pharmacologic agents blocking the renin-angiotensin system, in particular the angiotensin II-receptor blocker (ARB), a novel class of antihypertensive agents, represent an important addition to the therapeutic options for hypertension management, and recent large, international, randomized, trials have demonstrated that ARBs have clinical benefits across the spectrum of disease severity. In this article, we provide some evidence derived from these trials, supporting a role for ARBs in primary and secondary prevention of cardiovascular and renal disease, beyond blood pressure control.     

Blood pressure control in kidney transplantation: therapeutic implications

Post-transplant hypertension remains a significant risk factor for graft loss, but whether or not specific blood pressure (BP) medications affect graft outcome is still unknown. We assessed the interaction between BP control and antihypertensive drugs on graft outcome. We retrospectively examined clinic BP data for 1662 renal transplant (RTx) patients, transplanted between 1994 and 2000 at our centre. The analysis examined all patients who received central alpha-agonists and peripheral alpha-antagonists, beta-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme (ACE) inhibition (ACEI), angiotensin receptor blockers (ARBs). BP recordings during treatment were categorized for each agent. Thus, a particular BP could be categorized for multiple medications. A total of 1462 patients (pts) (88%) were Caucasian and 800 pts (46%) received cadaveric RTx. There were 10.6+/-6.8 BP measurements for each patient post-RTx. CCBs, alone among the classes of antihypertensive drugs evaluated, reduced the risk for graft loss (RR: 0.736; P=0.035) in the overall analysis. Interestingly, stratifying levels of BP control unmasked a beneficial effect on graft survival of ACEI/ARB therapy in individuals with higher levels of systolic (>152 mmHg) and diastolic blood pressure (>98 mmHg) treated with ACEI/ARBs compared to individuals treated with CCBs (P<0.01 for each). Thus, stabilizing BP is important post-RTx. CCBs are associated with improved rates of graft survival. Their role in a compromised RTx, however, deserves further study. ACEI/ARBs have clear benefits, improving graft survival in individuals with elevated systolic blood pressure and proteinuria. CCBs are not as efficacious in this setting.     

Diuretics for cardiovascular prevention in the elderly

High blood pressure (BP) is a major risk factor for cardiovascular and cerebrovascular diseases in elderly subjects. Antihypertensive drugs have shown clinical benefit both in primary and secondary prevention of cardiovascular events. If BP lowering represents the major determinant of the effects conferred by the antihypertensive treatment for prevention, recent studies have suggested some differences between classes of antihypertensive drugs according to age. Based on the available clinical data, the recent medical guidelines have recommended thiazide-type diuretics as the preferred drug for the treatment of elderly hypertensive patients, followed by long-acting calcium antagonists. Indeed, diuretics constitute one of the most valuable classes of antihypertensive drugs, and in the elderly, diuretic-based treatment studies have been clearly shown to prevent major cardiovascular events, including stroke, heart failure and coronary heart disease.     

Meta-analysis of large outcome trials of angiotensin receptor blockers in hypertension

Angiotensin receptor blockers (ARBs), also known as sartans, block the activation of angiotensin type 1 receptors and have a recognised role in the treatment of heart failure and nephropathy. Since 2002, there have been three major outcome trials of ARBs in hypertension. We performed a meta-analysis to evaluate the impact of ARB on major outcomes. Randomised controlled trials of ARBs in hypertensive subjects with an average follow-up of at least 2 years and at least 100 major cardiovascular events were included. For each trial, the ARB used, number and characteristics of subjects, baseline and change in blood pressure, cardiovascular and noncardiovascular outcomes were recorded. Three trials involving 29 375 subjects were included in the meta-analysis. In Losartan Intervention For Endpoint (LIFE) and Study on Cognition and Prognosis in the Elderly (SCOPE) but not in Valsartan Antihypertensive Long-term Use Evaluation trial (VALUE), an ARB reduced the occurrence of the primary end point and stroke compared to control. Compared to other antihypertensive drugs, ARB treatment was associated with no significant change in all-cause mortality (relative risk ratio (RRR) 0.96, 95% CI: 0.88-1.06, P = 0.45). There was an increase in myocardial infarction (RRR, 1.12, 95% CI: 1.01-1.26, P = 0.041), but a decrease in new-onset diabetes mellitus (RRR, 0.80, 95% CI: 0.74-0.86, P < 0.0000001). In conclusion, the reduction in new-onset diabetes partly offsets any increase in the risk of myocardial infarction. Most hypertensive patients require more than one class of drugs. Small differences in treatment outcome should not over-ride the importance of good blood pressure control.     

Left ventricular hypertrophy and clinical outcomes in hypertensive patients

The prevalence of left ventricular hypertrophy (LVH) rises with severity of hypertension (HT), age, and obesity. Its prevalence ranges from 20% in mildly hypertensive patients to almost 100% in those with severe or complicated HT. However, the diagnosis of LVH is not straightforward, and the definitions and criteria used in clinical studies lack consistency. While many factors play a role in the onset and progression of LVH, blood pressure (BP) is recognized as a central factor. Twenty-four-hour BP measurements are more closely related to LVH than conventional BP readings taken in the clinician's office. Increased renin-angiotensin system (RAS) activity also plays an important role in the development of LVH, and various studies show a correlation between plasma renin activity and left ventricular mass (LVM). LVH is a recognized marker of HT-related target organ damage, and a strong and independent risk factor for adverse cardiovascular (CV) outcomes. CV risk increases with increasing LVM, and decreases with regression of LVH in response to antihypertensive treatment. Therefore the detection, prevention, and reversal of LVH are important goals in HT management. Most antihypertensive drugs can attenuate BP and LVH. However, each drug class may induce LVH regression to a different extent and these extents seldom correlate with the degree of BP reduction achieved. Data from the few large comparative studies in this area suggest that certain classes of antihypertensive drugs and/or their combinations are more effective than others. In particular, calcium channel blockers and drugs that target the RAS, such as angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), appear to have a specific effect on LVH, independent of BP reduction. Guidelines, therefore, have recommended these drug classes for the treatment of hypertensive patients with LVH.     

A Meta-analysis of antihypertensive effect of telmisartan versus candesartan in patients with essential hypertension

Objective: The comparison of antihypertensive effects between telmisartan and candesartan in patients with essential hypertension has been investigated in several small studies. The results were not consistent. We performed this meta-analysis determining the antihypertensive effect of telmisartan versus candesartan in these patients. Methods: We searched Pubmed, Web of Science, and Cochrane Central for all published studies comparing the antihypertensive effects between telmisartan and candesartan in patients with essential hypertension. Results: The antihypertensive effects were assessed in 302 patients included in 4 trials with a mean follow-up of 10 ± 4 weeks. There were no significant differences between telmisartan and candesartan in reduction of systolic blood pressure (SBP) and diastolic BP (DBP) in patients with essential hypertension (weighted mean differences (WMD) for SBP 1.98 mm Hg (95% confidence interval (CI), ?0.53, 4.49), p > 0.05; WMD for DBP 0.26 mm Hg (95% CI, ?1.65, 2.16), p > 0.05), respectively. In a sub-analysis including 2 randomized studies, there was not a significant difference for the reduction of SBP (WMD 0.90 (95% CI, ?2.88, 4.68) mm Hg, p > 0.05) or DBP (WMD ?0.80 (95% CI, ?3.40, 1.81) mm Hg, p > 0.05) treated with telmisartan or candesartan. Conclusions: This meta-analysis provides the evidence that the antihypertensive effects of telmisartan and candesartan are similar on SBP and DBP reduction in patients with essential hypertension, suggesting that strict designed randomized controlled trial would be helpful to compare antihypertensive effects of angiotensin II receptor blockers (ARBs) and improve the choice of ARBs in antihypertensive therapy.     

Hypertension in women

Essential hypertension presents itself differently in men and women. Before the menopause, there are obvious hormonal differences between the sexes and it is now known that after the menopause, the arterial tree ages differently. At all ages, the shorter stature in women and the obligatory shorter arterial tree induce faster heart rates and earlier reflected arterial pulse waves. These factors operate to influence systolic blood pressure (BP), pulse pressure (PP), PP amplification, diastolic time, and diastolic BP. The circulatory effects of these variables in youth and with aging help to explain the time dependent and aging differences in cardiovascular risk between men and women. The development of left ventricular hypertrophy, isolated systolic hypertension, and the complications after acute myocardial infarction are also explicable in part by these gender-specific hemodynamic factors. Gender differences are also demonstrable in epidemiologic studies. Although an increased systolic BP is a cardiovascular risk in both sexes, a U-shaped curve describes the diastolic BP risk relationship in men but not in women. There is also a difference in the response to antihypertensive therapy, with a lesser benefit for women in heart disease prevention. These findings raise many remaining unanswered questions. Do some antihypertensive agents have gender-specific effects? Are the dose-response curves different for individual drugs or drugs in combination? Should therapeutic targets for systolic BP, diastolic BP, or PP differ between the sexes? Future answers to such questions would reduce the therapeutic trial and error now necessary for the selection of an individual patient's antihypertensive regimen.     

Evaluation of the 24 h effects of the angiotensin II receptor blockers: means to improve cardiovascular outcomes?

Recent research has demonstrated that ambulatory BP is a superior means to predict cardiovascular outcomes in treated patients with hypertension. Ambulatory blood pressure monitoring has been utilized to evaluate the efficacy of all anti-hypertensive drugs including the angiotensin II receptor blockers (ARBs). This paper reviews the relationship of clinic and ambulatory blood pressures to cardiovascular outcomes and the benefits of ARBs to maximize improvement in clinical end-points in patients with hypertension. Clinical trial evidence has demonstrated that ARBs are a preferred class in patients with electrocardiographic evidence of left ventricular hypertrophy, in patients with type 2 diabetes, patients with chronic kidney disease, and in individuals with heart failure who have clinically relevant intolerability to angiotensin converting enzyme inhibitors. In addition, there is increasing evidence from clinical trials that many of the ARBs provide adequate 24 h blood pressure control alone or in combination with other anti-hypertensive agents. We conclude that the combination of event reduction from large-scale clinical trials, adequate 24 h BP reduction, and improved tolerability compared to most other classes of anti-hypertensive agents, make the ARBs a suitable initial treatment for patients with hypertension.