AIM OF TREATMENT FOR HYPERTENSION
The aim of antihypertensive treatment is to reduce the cardiovascular morbidity and mortality associated with high blood pressure (BP) levels by measures aimed at reducing BP levels and minimizing the impact of possible associated risk factors or co-morbidities [1-5]. This therapeutic goal requires previous cardiovascular risk stratification to assess the global risk of hypertensive patients, followed by the determination of BP values at the start of treatment (threshold blood pressure) and the BP values to be achieved by antihypertensive treatment (BP target). Bothaspects are closely related to the total cardiovascular risk of the patient, which may be calculated by using various risk stratification tables.
The continuous relationship between the level of BP and cardiovascular risk makes any numerical definition and classification of hypertension arbitrary. The operational definition offered by Geoffrey Rose more than 30 years ago - Hypertension should be defined in terms of a blood pressure level above which investigation and treatment domore good than harm - also indicates that any numerical definition must be a flexible one resulting from evidence of risk and availability of effective and well tolerated treatment. Because of these considerations, it would perhaps be more correct to use a classification of bloodpressure levels without the term “hypertension”. The European Society of Hypertension/European Society of Cardiology (ESH/ESC) 2007 Guidelines  use a combined approach to this concern, defining five categories for the classification of BP: normal and highnormal BP, and mild (grade 1), moderate (grade 2) or severe (grade 3) hypertension.
From this perspective the ESH/ESC 2007 Guidelines  include a table to calculate the total absolute risk in subjects with normal and high-normal BP values and in patients with mild, moderate or severe hypertension. This approach classifies the added risk in terms of low, moderate, high and very high added risk, indicating an absolute 10-year risk of cardiovascular disease of <15%, 15-20%, 20-30% and >30%, respectively, according to the Framingham criteria, coinciding with an absolute 10-year risk of cardiovascular mortality of <4%, 4-5%, 5-8% and >8%, respectively, according to the SCORE criteria (Figure 1).
||Figure 1. Cardiovascular risk stratification to quantify prognosis.
(Adapted with permission from the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2007 guidelines for the management of arterial hypertension. J Hypertens 2007;25:1105-1187)
The primary goal of treatment of the patient with high blood pressure is to achieve maximum reduction in the long term total risk of cardiovascular morbidity and mortality. This requires treatment of all reversible risk factors identified, including smoking, dyslipidemia, or diabetes and the appropriate management of established cardiovascular or renal disease, as well as treatment of the elevated blood pressure per se.
Regarding BP reduction, it seems logical that the aim of antihypertensive treatment should be to reduce BP to the lowest values tolerated by the patient, given that the relationship between BP levels and cardiovascular risk is continuous. The VII Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure , and the ESH/ESC 2007 Guidelines  both agree that the therapeutic target in the general population of essential hypertensive patients over 18 years of age is a sustained BP reduction to levels lower than 140 mmHg systolic (SBP) and 90 mmHg diastolic (DBP) blood pressure. But all guidelines [1-5] also agree that in high risk patients, such as those with type 2 diabetes, BP should be reduced to lower values than those of the general population of hypertensives (<130/80 mmHg). The goal to be achieved, as well as the achievable goal, may depend on the pre-existing blood pressure level,particularly systolic values; and systolic values below 140 mmHg may be difficult to achieve, particularly in the elderly. Therefore, in order to make the correct therapeutic decisions it is imperative to consider previous stratification of the global cardiovascular risk.
CARDIOVASCULAR RISK STRATIFICATION TO DEFINE THERAPEUTIC ATTITUDES
Contribution of blood pressure “per se” to the global absolute risk of patients
Figure 1 shows the risk stratification proposed by the ESH/ESC 2007 guidelines and clearly demonstrates that although blood pressure levels contribute notably to the increased risk, they are not the only variables to consider . The first horizontal line in figure 1 shows the association between BP and risk in subjects without other cardiovascular risk factors. Reading from left to right shows the progressive increase in cardiovascular risk from normal (SBP between 120-129 and DBP between 80-84 mmHg) and high-normal levels (SBP between 130-139 and DBP between 85-89 mmHg) to grade 3 hypertension (SBP ≥ 180 or 110 ≥ DBP mmHg). For people without other associated cardiovascular risk factors, normal or high-normal BP levels mean they have the reference risk of the general population and their BP levels should be maintained but not reduced. Starting at a BP level of 140/90mmHg, the absolute cardiovascular risk increases slightly (the probability of suffering cardiovascular complications at 10 years is below 15%) and the added risk is low. Grade 2 hypertension (160/100 mmHg onwards) is defined as conferring a moderate added risk (the probability of suffering cardiovascular complications at 10 years is 15-20%) and in grade 3 hypertension, the BP levels themselves confer a high added risk (probability of suffering cardiovascular complications at 10 years is 20-30%).
Contribution of blood pressure in association with other cardiovascular risk factors to the global absolute risk of patients
In a patient with BP of 168/96 mmHg and an additional risk factor, for example abdominal obesity, the reduction of BP to 138/86 mmHg (below the objective of 140/90 mmHg) would reduce the risk from moderate to low, meaning that even though BP is controlled, the probability of suffering cardiovascular complications at 10 years would remain lower than 15% (Figure 2, white arrow), but not at the comparable level of the general population. Only when weight and waist circumference are reduced simultaneously would the probability of cardiovascular events be reduced to levels similar to those of the healthy reference population (Figure 2, black arrow).
||Figure 2. Goals of treatment in low-to-moderate risk patients: blood pressure lowering and total cardiovascular risk reduction.
(Adapted with permission from the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2007 guidelines for the management of arterial hypertension. J Hypertens 2007;25:1105-1187)
Contribution of blood pressure in association with multiple cardiovascular risk factors, metabolic syndrome, or subclinical organ damage to the global absolute risk of patients
When patients with multiple (3 or more) associated c a rdiovascular (CV) risk factors (Table 1), metabolic syndrome, subclinical organ damage (OD) or diabetes, shown in the third row of figure 2, are analyzed, the situation is totally different. Their absolute risk is defined as moderate even when their BP levels are in the range considered as normal, while for those with high-normal pressure the added risk is high. Therefore, the measures aimed at BP reduction and the goal to attain will be different from those for subjects without additional risk factors and will need to be included in the other measures for global risk prevention. As shown in Figure 3, if in a high risk patient with BP levels of 168/96 mmHg, the BP is only reduced to 138/88 mmHg, the risk continues to be high (white arrow). To reduce it, levels below 130/80 should be reached (grey arrow). However, if this further reduction in BP was the only measure taken, the risk would be maintained as moderate. Only when the other associated CV risk factors are controlled simultaneously or the regression of OD is achieved (black arrow) will the risk be reduced to that of the general reference population.
TABLE 1. Factors influencing prognosis
(Reproduced with permission from the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2007 guidelines for the management of arterial hypertension. J Hypertens 2007;25:1105-1187)
||Figure 3. Goals of treatment in high-risk patients: blood pressure lowering and total cardiovascular risk reduction.
(Adapted with permission from the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). 2007 guidelines for the management of arterial hypertension. J Hypertens 2007;25:1105-1187)
In summary, it is necessary to analyze the BP targets to be attained based on the global risk of the hypertensive patients and their clinical situation, which is fundamentally determined by the coexistence of multiple cardiovascular risk factors, the presence of metabolic syndrome, subclinical organ damage, type 2 diabetes mellitus, or established CV or renal disease.
ANTIHYPERTENSIVE STRATEGIES TO ACHIEVE TARGET BLOOD PRESSURE DEPENDING ON GLOBAL RISK
Blood pressure targets in patients at high or very high risk: hypertension in type 2 diabetics
From a practical perspective, all patients with type 2 diabetes or established CV or renal disease are hypertensives, because the levels that define hypertension in these subjects are lower (130/80 mmHg) than those applicable to the non-diabetic population (140/90 mmHg). As commented above, all guidelines agree that the target blood pressure to be achieved and maintained should be lower than that of the general hypertensive population (<130/80 mmHg). It is well established that the lower the BP, the lower the progression of diabetic nephropathy [6-8] (Figure 4). In patients with non-diabetic renal disease, data on the effects of a greater or smaller BP reduction on the appearance of cardiovascular episodes are scarce. In the HOT study, no significant reduction in cardiovascular events in the subgroup of patients with plasma creatinine >115 μmol/L (>1.3 mg/dL) was found in relation to a greater or smaller BP reduction . In a post-hoc analysis  no differences were found in morbidity or mortality with respect to a greater or smaller reduction in blood pressure (139/82 versus 143/85 mmHg) between patients with clinical renal injury and plasma creatinine >133 μmol/L (>1.5 mg/dL). However, none of these studies suggests an increase in cardiovascular risk with a greater reduction in BP.
||Figure 4. Blood pressure control and progression of type 2 diabetic nephropathy expressed as the decline in glomerular filtration rate (GFR) in ml/minute/year.
(Adapted with permission from Bakris GL, Williams M, Dworkin L, et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. National Kidney Foundation Hypertension and Diabetes executive committees working group. Am J Kidney Dis 2000;36:646-661)
A further consideration is that in diabetic patients or those with clinical vascular disease, BP control is more difficult to achieve, not only because the levels to attain are lower [1-5], but also because the structural vascular damage of patients with type 2 diabetes or hypertension with subclinical organ damage or clinical disease is much greater. This includes greater endothelial dysfunction, greater arterial remodeling, increased rigidity and less distensibility. Consequently, there is greater difficulty in attaining the BP reduction itself, particularly in SBP. The therapeutic strategy of any high risk patient will therefore require more antihypertensive drugs to achieve the same reduction in BP as that of subjects with a lower risk . For this reason, the ESH/ESC 2007 Guidelines state that for patients with marked BP elevation, or those at high or very high risk for whom lower BP targets must be achieved, such as hypertensive patients with type 2 diabetes, it appears reasonable to initiate therapy with a strategy based on the use of a low-dose combination of two agents. One of the advantages of initiating treatment with two drugs with different mechanisms of action is that it is more likely to control blood pressure and its complications. In addition, using low doses of both compounds reduces the risk of side effects. Fixed low-dose combinations are available in Europe and some other parts of the world, allowing the administration of two agents with a single tablet, thus optimizing patient compliance with treatment .
Blood pressure targets in elderly hypertensive patients
Age is another factor that should be considered when making therapeutic decisions and establishing BP objectives to achieve. There is little doubt from randomized controlled trials that older patients benefit from antihypertensive treatment in terms of reduced cardiovascular morbidity and mortality, irrespective of whether they have systolic-diastolic hypertension or isolated systolic hypertension. However, there has always been a concern about the effects of an excessive reduction in DBP in elderly patients, inexorably linked with the SBP reduction, since the possibility of reductions in the perfusion of essential organs such as the heart or brain, if the DBP reduction was excessive has been suggested. Historically, some investigators had supported the J curve theory to explain the relationship between DBP and morbidity and mortality (increase in cardiovascular morbidity and mortality due both to the increase and the excessive reduction of DBP). However, the data from the SHEP study do not support this hypothesis ; at five years of active treatment the DBP reached was 68 mmHg and this was associated with a reduction of 27% in the incidence of myocardial infarction. Similar conclusions were reached in the SYST- EUR  and SYST-CHINA  studies which, together with the results of the HOT  study, definitively reject the concept of a J curve until levels of 65 DBP of mmHg. In addition, the post-hoc analysis of the SHEP study data carried out by Somes et al  concluded that DBP can safely be reduced to 65-70 mmHg in elderly hypertensives (Figure 5).
||Figure 5. Risk of cardiovascular events in relation to diastolic blood pressure achieved by treatment among patients with isolated systolic hypertension in the Systolic Hypertension in the Elderly Program (SHEP) study.
(Data taken from )
Based on the evidence of these studies, a well-tolerated reduction below 140/90 mmHg can be recommended in the elderly. Successful achievement of the final objective will depend on the baseline BP levels, with SBP levels of below 140 mmHg being difficult to achieve in a large number of elderly hypertensives, particularly if their initial levels exceed 180/110 mmHg. Finally, in view of the possible prognostic importance of pulse pressure, it would be of interest to know whether drugs that decrease systolic pressure more than diastolic pressure in comparison with other drugs would bemore beneficial for the prevention of cardiovascular complications in the elderly. Initiation of antihypertensive treatment in elderly patients should follow the general guidelines: “start low and go slow”. Many patients will have other risk factors, subclinical organ damage and established cardiovascular or renal disease, to which the choice of the first drug should be tailored.
Blood pressure targets in hypertensive patients with concomitant cerebrovascular disease
In patients with a history of stroke or transient cerebral ischemia, the PROGRESS study  showed benefits in the incidence of recurrent stroke when DBP was reduced to 79 mmHg in the active treatment group in comparison with the 83 mmHg of the placebo group. However, the reduction inmorbidity and mortality in the PROGRESS study was only significant in patients randomized to combination therapy, where the mean reduction in SBP/DBP was 12.3/5.0 mmHg compared with a mean reduction of 4.9/2.8 mmHg in the monotherapy group (Figure 6). This strengthens the fact that greater BP reduction is also beneficial in secondary prevention of stroke in very high risk patients even when the usual blood pressure is in the range of high-normal BP. The other issue, whether elevated blood pressure during an acute stroke should be lowered at all, or to what an extent, and how, is still a disputed one for which there are more questions than answers. However, trials on this topic are currently in progress.
||Figure 6. Secondary prevention of stroke by antihypertensive treatment in the PROGRESS study. Only patients treated with combined therapy achieved a substantial reduction of blood pressure and a significant reduction in recurrent stroke events.
(Data taken from )
Blood pressure targets in hypertensive patients with concomitant coronary heart disease or heart failure
In the 22,576 hypertensives with ischemic heart disease included in the INVEST study, the lowest incidence of stroke (0.88%) during the 2.7 years of hypertensive treatment was produced in the patients with a mean SBP of between 120 and 130 mmHg throughout the study (Figure 7), whereas in patients with a mean SBP of ≥130 mmHg, a progressive increase in the incidence from 1.3% in patients with SBP of 130-140 mmHg to 5.6% for those with a mean SBP of >180 mmHg  was observed. In the very high-risk patients with coronary heart disease included in the HOPE study  the slight difference in final SBP between the active treated group and the placebo group (about 2 to 3 mmHg) was interpreted as being irrelevant in justifying the significant differences in the prevention of morbidity and mortality observed between groups. However, the results of the VALUE study [19,20] in very high risk hypertensives with characteristics very similar to those of the patients included in the HOPE study puts this interpretation in doubt. Differences in SBP of between 2 and 4 mmHg during a follow-up of 4.2 years had a substantial impact on the prevention of cardiac and cerebrovascular events . In summary, there is absolute evidence supporting that first priority in hypertension treatment is blood pressure reduction per se.
||Figure 7. Stroke incidence in relation to average systolic blood pressure (SBP) values during follow-up among hypertensive patients with coronary artery disease included in the INVEST study.
(Data taken from )
PREVENTION OF ORGAN DAMAGE IN ESSENTIAL HYPERTENSION
As mentioned earlier, the association of arterial hypertension and silent or clinical organ damage at cardiac, vascular, renal, or cerebral levels identifies a state where the risk for future cardiovascular events is high. The concept that overall cardiovascular risk rather than blood pressure level alone should serve as a guide for devising therapeutic strategies and identifying treatment goals is widely accepted. Therefore, noninvasive assessment of OD has become a key issue in the evaluation process of each hypertensive patient, since it may significantly modify the individual risk profile and physician attitude (Table 1).
Recognition of subclinical organ damage induced by hypertension in a given patient, such as left ventricular hypertrophy (LVH), microalbuminuria (MAB), increased intima media thickness (IMT), reduced ankle/brachial index, slight increase in plasma creatinine, or low estimated glomerular filtration rate (GFR), is imperative due to the need to start antihypertensive therapy in these patients. In the vast majority of hypertensive patients, major events are the result of long-term exposure to multiple risk factors, and are usually preceded by asymptomatic abnormalities at the vascular and cardiac levels . This so-called subclinical organ damage phase rep resents an intermediate end-point and in turn, is a strong independent predictor of unfavorable outcomes.
Non-invasive assessment of OD by ultrasound techniques is a reliable way to assess the cardiac and peripheral arterial structures, and has proven to be useful in the evaluation of the overall cardiovascular risk profile. While this procedure may have a significant impact on the evaluation of absolute risk, it is not routinely recommended by international guidelines, and is only performed on a small number of hypertensive patients. The ESH/ESC 2007 guidelines indicate several approaches for the evaluation of global cardiovascular risk, depending on resource availability and local know-how. In fact, it has been shown that the more extensive the diagnostic work-up, the higher the percentage of correctly identified patients at risk. The ESH/ESC Guidelines recommend obtaining blood samples for a simple biochemical study and performing an electrocardiogram in all hypertensive patients. Unfortunately, because of potential medical and financial impact on clinical practice, other specific examinations can only be considered as recommended tests, particularly in patients in whom OD is not discovered by routine investigations despite having a high CV risk profile (i.e., several associated CV risk factors or family history of CV disease).
HOW TO PROTECT THE KIDNEY IN HYPERTENSION
Microalbuminuria is an integrated marker of OD and of increased cardiovascular morbidity and mortality in non diabetic hypertensive patients and in patients with diabetes. It has proven to be highly specific in identifying patients with LVH and carotid atherosclerosis. Thanks to its low cost and easy applicability it has been proposed for the assessment of overall cardiovascular risk. However, the measurement of urinary albumin excretion is still neglected too often in clinical practice and in the medical guidelines.
Implications of microalbuminuria in hypertensive patients
The presence of MAB (elevated urinary albumin excretion below the proteinuric level, i.e., MAB: 30-300 mg/24h or urinary albumin/creatinine ratio ≥2.5 mg/mmol in men, and ≥3.5 mg/mmol in women) has long been recognized as a marker of kidney disease and increased CV risk in bothtypes of diabetes mellitus. Subsequent clinical evidence documented an association between MAB and other CV risk factors, subclinical organ damage and the risk of CV disease in the general population and in specific clinical contexts including essential hypertension. There appears to be a linear relationship between the degree of MAB and CV risk. Evaluation of MAB is one of the recommended laboratory tests proposed by the European Society of Hypertension Guidelines to assess OD in hypertensive subjects, in whom the reported prevalence of MAB ranges from 4% to 46% in various studies . These differences may be explained by the huge intraindividual variability in MAB, age and ethnicity, discrepancies in the measurement techniques and different definitions of MAB. Increased MAB has been associated with subclinical hypertensive organ damage. In fact, a higher prevalence of concentric LVH and subclinical impairment of LV performance, in addition to carotid atherosclerosis, have been reported in patients with MAB . These associations might justify a greater incidence of CV events per se in hypertensive patients with MAB. In a 10-year prospective study of more than 2000 patients with hypertension, a urinary albumin/creatinine ratio >1.07 mg/mmol strongly and independently predicted ischemic heart disease, more than doubling the risk .
Measurement of MAB is a widely available inexpensive test that could represent an alternative approach to risk stratification and the identification of patients at high CV risk, and is suitable for use in clinical practice.
Antihypertensive therapy and microalbuminuria
Any antihypertensive treatment or strategy should reduce MAB since treatments that lower MAB are associated with CV protection. In this sense, tight BP control has been shown to slow progression of the disease compared to less tight BP control [25,26]. Angiotensin receptor blockers (ARBs) are considered the first line treatment in patients with type 2 diabetes and nephropathy at various clinical stages. Studies in hypertensive patients with diabetes mellitus and MAB have shown that treatment with irbesartan 300 mg daily significantly decreased the rate of progression to overt nephropathy with clinical proteinuria . Similar results were found with valsartan as compared to amlodipine .
Although there is no doubt of the usefulness of ARBs in the prevention and treatment of type 2 diabetic nephropathy, one major criticism of clinical trials is that the use of Angiotensin-Converting Enzyme (ACE) inhibitors was not allowed in enrolled patients and there was no direct comparison between ARBs and ACE inhibitors. The recently published DETAIL study compared telmisartan vs. enalapril in 250 subjects with microalbuminuria (80%) or proteinuria (20%) and normal serum creatinine . The primary endpoint was the change in the glomerular filtration rate. At the end of the 5-year observation period, there were no differences between the two treatment regimens.
Another point of interest is the possible additive effect of ARBs and ACE inhibitors on renal protection. The COOPERATE study, comparing the combination of losartan and trandolapril against monotherapy with either drug in patients with non-diabetic nephropathy, showed that the combination had a greater effect on a composite endpoint of doubling serum creatinine and endstage renal disease , suggesting the possibility of using combined renin-angiotensin system (RAS) blockade in the protection of hypertensive patients with renal disease.
In the BENEDICT study , 1204 hypertensive patients with type 2 diabetes and normoalbuminuria were treated with the fixed combination of trandolapril/verapamil (sustained release) in comparison with any drug in monotherapy and placebo. The fixed combination prolonged the time to onset of persistent microalbuminuria compared with placebo. Monotherapy with trandolapril obtained similar results but was not the case for the use of verapamil in monotherapy. Although the renoprotective effects of ACE inhibitors and ARBs cannot be entirely dissociated from reductions in BP, these agents can achieve greater urinary protein effects than other antihypertensive drugs at equivalent BP reductions.
HOW TO PROTECT THE HEART IN HYPERTENSION
Several structural and functional alterations of the heart, such as increased left ventricular mass (LVM), abnormal left ventricular geometry, left atrial and aortic root enlargement, left ventricular dysfunction and impairment of the coronary reserve have been reported in patients with arterial hypertension. Most attention has been focused on LVH because of the high prevalence of this phenotype and its association with an increased risk of cardiovascular morbidity and mortality. Left ventricular hypertrophy can be detected by a variety of diagnostic methods with varying sensitivity and specificity, such as electrocardiographic examination (ECG), ultrasound or magnetic resonance imaging. The ECG is the simplest technique for detecting LVH in patients with hypertension; unfortunately its sensitivity is lower than that of echocardiography, especially in mild-to-moderate hypertensive individuals or among newly diagnosed hypertensive patients. Recent reports assessing the prevalence of LVH determined by echocardiography and its effect on cardiovascular risk stratification in hypertensive patients previously defined to be at relatively low or medium risk on the basis of routine evaluation, showed that a significant fraction of hypertensive patients are reclassified as being at high risk after the detection of LVH. Although echocardiography is more sensitive and specific than ECG in identifying LVH, its systematic use in the assessment of cardiovascular risk is not recommended in uncomplicated hypertensive individuals because of its relatively high cost.
Implications of left ventricular hypertrophy in hypertensive patients
In 1969, the Framingham study demonstrated that once LVH is clinically recognized by electrocardiography it is a strong predictor of CV disease. Later, a number of studies reported that LVH determined by electrocardiogram or echocardiogram is an independent risk factor for cardiovascular morbidity and mortality in essential hypertensive patients [32,33]. Cardiovascular event rates are 2 to 4 fold higher in the presence of LVH. In hypertension, LVH is initially a useful compensatory process to abnormal loading conditions but is also the first step towards the development of overt clinical disease such as congestive heart failure, ischemic heart disease, cardiac dysrhythmias, and stroke. It has also been proposed that left ventricular geometric patterns add prognostic information to both the development of cardiovascular disease  and the presence of extracardiac subclinical organ damage in essential hypertension. Indeed, hypertensive patients with concentric LVH have more advanced subclinical organ damage, including renal [34,35], retinal  and silent cerebrovascular involvement , than those with other patterns of left ventricular geometry.
Antihypertensive therapy and left ventricular hypertrophy
LVH and its regression with antihypertensive treatment clearly have an affect on the risk of future cardiovascular events . Several meta-analyses have examined the effect of the main antihypertensive drug classes on LVH regression, the most recent of which included studies with ARBs and concluded that LVH regression with ARBs was similar to that observed with ACE inhibitors or calcium channel blockers. These three classes of drugs were more potent LVH regressors than classic treatment with diuretics and/or betablockers . The comparison of losartan versus atenolol in the LIFE trial also showed that losartan produced greater LVH regression than atenolol . This was demonstrated by measuring ECG indexes of LVH (the Sokolow-Lyon and Cornell products) in all patients. Moreover, in a recent report on a subgroup including patients with left ventricular mass index determined by echocardiography, the LIFE investigators confirmed that losartan was more effective than atenolol on LVH regression .
HOW TO PROTECT LARGE ARTERIES IN HYPERTENSION
Carotid IMT measurements have increasingly been used in observational and intervention studies. Carotid IMT has been used as a surrogate outcome in studies focused on analyzing the determinants of atherosclerosis, and it has been employed as an exposure variable in studies on the prognostic value of carotid IMT in the prediction of coronary artery disease and stroke. In this sense, carotid IMT is increasingly used as a surrogate marker for atherosclerosis. Its use relies on its ability to predict future clinical cardiovascular endpoints. In a recent systematic review and meta-analysis of 8 studies, Lorenz et al  showed that carotid IMT is a strong predictor of future vascular events, and that the relative risk per IMT difference is slightly higher for the end point stroke than for myocardial infarction.
However, criticism of the value of these measurements can also be heard throughout the scientific community. Part of that comes from the observation that IMT is a combined measure of the intimal and medial layer of the arterial wall whereas the atherosclerotic process is restricted to the intimal layer only, in particular in its early phase. Furthermore, the virtual absence of data showing that progression of carotid IMT predicts coronary artery disease and stroke further supports criticism of the research utility of IMT measurements. Several studies are currently in progress to address these questions.
Implications of intima-media thickness in hypertensive patients
B-mode ultrasound imaging technology has evolved to such an extent that the walls of superficial arteries, such as the carotid or femoral arteries, can be imaged noninvasively in real time and at high resolution. Arterial wall thickness can be measured as a continuous variable from childhood into old age. Large observational studies, such as the Rotterdam  and ARIC  studies and atherosclerosis regression trials of lipid and BP modifying pharmacotherapy have established that the IMT of the carotid and femoral arteries, as measured noninvasively by B-mode ultrasound, is a valid surrogate marker for the progression of atherosclerotic disease . More compelling is evidence showing that carotid atheroma is a predictor of vascular events and is useful for risk stratification. In the ARIC study, a strong, graded relationship was shown between coronary heart disease incidence and carotid IMT. The hazard ratio comparing extreme mean IMT (≥1 mm) to non-extreme (<1 mm) was 5.07 for women and 1.85 for men. The incidence and relative risk for new CV events correlated with measurements of carotid IMT after adjustments for age, gender, and traditional risk factors.
In the latest European Guidelines for the management of hypertension , IMT was introduced as one of the recommended procedures to assess OD in hypertensive subjects, with an IMT ≥0.9 mm being considered as the presence of OD in essential hypertension (Table 2).
||TABLE 2. Primary prevention of stroke by antiplatelet therapy in relation to baseline systolic blood pressure. Sub-analysis of 5,499 men aged 45-69 years from the Medical Research Council (MRC) trial
(Reproduced with permission from Meade TW, Brennan PJ. Determination of who may derive most benefit from aspirin in primary prevention: subgroup results from a randomised controlled trial. Brit Med J 2000;321:13-17)
Antihypertensive therapy and intima-media thickness
Few studies have evaluated the effect of antihypertensive agents on IMT progression. The ELSA study was performed in 2,334 hypertensive patients (aged 45-75 years) randomized to receive lacidipine or atenolol for 4 years to compare the effects on IMT . The results showed a greater efficacy of lacidipine on carotid IMT progression and number of plaques per patient than atenolol.
An ancillary study of the INSIGHT trial compared the effects of nifedipine GITS versus diuretic (hydro- chlorothiazide + amiloride) in 439 hypertensive patients aged 55-80 years and with ≥1 risk factors (smoking, diabetes, hypercholesterolemia, LVH, history of CV disease, proteinuria, family history of myocardial infarction). In this study, 324 hypertensives had ≥1 year of follow-up and 242 of these completed follow-up for 4 years. In the until-end-of-study population, IMT progression rates were different between groups, in favor of nifedipine GITS. In the intent-to-treat population, treatment differences in the IMT rate did not reach statistical significance .
The CAMELOT study  evaluated the effect of antihypertensive agents on CV events in patients with coronary artery disease and normal BP (defined as DBP <100 mmHg with or without treatment). A substudy evaluated the change in percent atheroma volume in 274 patients. Amlodipine, enalapril or placebo were compared. There was a trend toward less progression of atherosclerosis in the amlodipine group versus placebo (p = .12). However, in the subgroup with baseline BP above the mean, a significant reduction in progression was observed in the amlodipine group compared with placebo (p = .02). Compared with baseline, there was progression in the placebo group (p <.001), a trend toward progression in the enalapril group (p = .08), and no progression in the amlodipine group (p = .31). In summary, there is evidence supporting the beneficial effects of calcium channel blockers on IMT progression, although further studies are necessary.
HOW TO PROTECT THE BRAIN IN HYPERTENSION
Hypertension is known to be the most important factor for developing stroke and vascular dementia. Hypertension appears to predispose patients to cognitive impairment, dementia and stroke after a period varying from a few years to several decades. Subtle structural and functional changes such as cerebral white matter lesions (WML) can already be detected by brain-magnetic resonance imaging.
Indeed, high blood pressure may predispose to the development of more subtle cerebral processes based on arteriolar narrowing or pathological microvascular changes. It has been suggested that cerebral microvascular disease contributes to the development of vascular cognitive impairment. The mechanisms underlying hypertension related cognitive changes are complex and are not yet fully understood. Correlations between WML and elevated BP provide indirect evidence that structural and functional changes of the brain over time may lead to lowered cognitive functioning when BP control is poor or lacking. In addition, there is some evidence that antihypertensive drug treatment could play a role in the prevention of cognitive impairment  or vascular dementia  through BP control.
Although the pathogenesis and clinical significance of cerebral WML remain unclear, it is established that age and hypertension are the most important related factors . Silent cerebral WML are an important prognostic factor for the development of stroke [51,52], cognitive impairment , and dementia  and may be considered an early marker of brain damage in essential hypertension.
Antihypertensive therapy and cerebral WML
Cross-sectional, population-based MRI studies have shown that treated controlled hypertensive patients have a lower prevalence of WML than both untreated and treated but not controlled hypertensive patients . Van Dijk et al , studying 1805 individuals aged 65-75 years from 10 European cohorts in whom blood pressure measurements were initiated 5 to 20 years before the brain-MRI, found that patients with poorly controlled hypertension had a higher risk of severe WML than those without WML or with controlled or untreated hypertension. Increased systolic and diastolic BP were associated with more severe WML and reduced DBP was associated with more severe periventricular WML. The authors suggest that successful treatment of hypertension may reduce the risk of WML but that reducing DBP may have a potentially negative effect on the occurrence of severe periventricular WML and should be taken into account. However, this lack ofdifference between controlled and untreated hypertensives could be due to the fact that the untreated group had hypertension that was less severe or of shorter duration. Another study performed in 845 subjects showed that hypertension at baseline was significantly associated with an increased risk of severe WML in the brain-MRI at 4 years of follow-up. When both BP levels and antihypertensivedrug intake were taken into account, the risk of severe WML was significantly reduced in subjects with normal BP taking antihypertensive medication compared to those with high blood pressure taking antihypertensive drugs .
An MRI substudy of PROGRESS (Perindopril Protection aGainst REcurrent Stroke Study), a randomized trial of BP lowering using perindopril (in monotherapy or associated with indapamide) versus placebo in normotensive and hypertensive subjects with cerebrovascular disease, has recently found that the mean total volume of new WML was significantly reduced in the active treatment group compared with placebo . A post hoc analysis also indicates that the greatest beneficial effect of antihypertensive therapy on WML progression was observed in patients with severe WML at entry.
Antihypertensive therapy and stroke
The statement on BP lowering and stroke prevention of the International Society of Hypertension  recommends any of the five classes of antihypertensive drugs (diuretics, betablockers, calcium channel blockers, ACE inhibitors, ARBs). However, some trials in hypertensive patients have suggested a protective effect of ARBs in the primary prevention of stroke. As mentioned above, the LIFE  study compared losartan and atenolol in hypertensive patients older than 55 years who had electro-cardiographically detected LVH. Losartan significantly reduced CV endpoints (13%) with minimal differences in BP changes between treatments. The benefit of losartan was mainly due to a decrease in the rate of stroke (25% reduction; p = .001), with no effect on myocardial infarction or total mortality. The SCOPE  study included hypertensive patients aged 70-89, randomly assigned to candesartan or placebo with open-label active antihypertensive treatment added as needed. The primary composite endpoint, a combination of cardiovascular death, stroke and myocardial infarction, was reduced by 10.9%, a difference that did not attain statistical significance. Of all the components of the primary endpoint, only the reduction in non-fatal stroke (27.8%; 95% CI: 1.3-47.2; p = .04) was statistically significant. However, there were marked differences in BP reduction (3.2/1.6 mmHg) between candesartan and placebo treated patients. Recently, a study of another ARB, eprosartan, on secondary stroke prevention  found that the comparison of eprosartan versus nitrendipine in patients with a previous stroke resulted in fewer cerebrovascular and cardiovascular events in eprosartan treated patients, despite a similar BP reduction.
Antihypertensive therapy and cognitive impairment
Cross-sectional and longitudinal data from observational studies have shown some beneficial effects of antihypertensive treatment against cognitive impairment, cognitive decline and dementia in elderly people . There is moderately strong evidence to support the view that hypertension in midlife, especially if not treated effectively, negatively affects cognition and contributes to the development of dementia and even Alzheimer’s disease in later life. High BP in midlife implies a long-term cumulative effect leading to increased severity of atherosclerosis and more vascular comorbidities in later life. There is less evidence that the same negative effect on cognition is present for hypertension that begins in later life. Indeed, some reports on the harmful cognitive effect of low BP seem to suggest that in older adults and particularly those who are very old, an appropriate level of BP may be required to retain cognitive function by maintaining adequate cerebral perfusion. However, the optimum BP remains unknown. Observational results also suggest a protective effect of antihypertensive treatment against cognitive decline and dementia. Confirmation from randomized clinical trials is limited, as it is based mainly on the Syst-Eur trial . Other clinical trials showed no clear treatment effect or only a beneficial effect against post-stroke dementia and cognitive decline. On the other hand, cognitive impairment has been considered a secondary endpoint in all clinical trials until now.
DISEASE PREVENTION VERSUS EVENT PREVENTION: THE RELEVANCE OF INTERMEDIATE DISEASE MARKER ASSESSMENT
Clinical trials have confirmed the relevance of BP reduction in the prevention of cardiovascular events in treatment periods of about 5 years. However, to demonstrate that some strategies are more effective than others in preventing the progression of cardiovascular disease and then, in the reduction of morbidity and mortality, a more prolonged treatment with a greater number of subjects will be necessary. In addition, most clinical trials have been carried out in very high risk hypertensives over 55 years of age, which is the only way of identifying a significant number of events in short periods. Young hypertensives with low or moderate risk have not been represented in these studies. Consequently for this population, we extrapolated the results of trials carried out in elderly people at high risk, meaning that all estimates are speculative. In other words, clinical trials have been designed to analyze the prevention of events and not the prevention of the disease that gives rise to such events .
In contrast, most studies in experimental animals have analyzed the progression of the disease more than the appearance of events. These models have studied the evolution of structural arterial changes, vascular inflammation, and the development of atheroma and its modification by treatment [44,64-66]. Therefore, experimental studies have been studies of the prevention of the progression of cardiovascular disease rather than studies of the prevention of events and interestingly, are those that have shown some differences in the effects of different antihypertensive drugs, particularly those that block the renin-angiotensin-aldosterone system (RAAS) or calcium channels as opposed to traditional diuretics and beta blockers. Recent studies in hypertensives have also examined surrogate endpoints such as structure in resistance arteries , intima-media thickness in large arteries [45,46], left ventricular mass and structure [39,44],new-onset atrial fibrillation [68-70], inflammatory markers , microalbuminuria [27-29], and new-onset diabetes [11,18,19,39,60,63,72], reflecting the progression of cardiovascular disease in hypertensive patients. These studies have consistently shown similar results to those previously observed in experimental studies concerning the favorable effects of ARBs, ACE inhibitors and calcium channel blockers on these surrogate parameters beyond that attributable to BP lowering alone.
It seems logical that, if some antihypertensive drugs or strategies act more favorably than others on these surrogate markers, the consequence will be less progression to long-term disease and therefore, less morbidity and mortality. This is particularly important in young patients, for whom the possibility of preventing incipient structural damage is much greater and the possibility of avoiding new onset type 2 diabetes or the onset of atrial fibrillation is crucial to better survival. In all these aspects, as mentioned above, RAAS blockers and calcium channel blockers have been shown to be greatly superior to traditional diuretics and beta blockers.
THE MULTIFACTORIAL APPROACH IN HIGH RISK PATIENTS
The current debate is not so much whether one class of antihypertensive drug is better than another, but whether one strategy is better than another. This is due to two main reasons: firstly, monotherapy even at high doses has practically no relevance in the treatment of high risk hypertensives who require a combination of at least three antihypertensive drugs, and secondly, it is not sufficient to reduce BP: we must tackle the global risk of the patient, for which control of obesity, dyslipidemia, prothrombotic state, smoking, etc. is necessary. In the great majority of high risk patients, particularly those over the age of 55, antiaggregation or anticoagulation are necessary. However, the beneficial effect of antiplatelet therapy in the prevention of morbidity and mortality is related to BP levels, particularly SBP. As shown in table 2, in a subanalysis of a group of middle-aged males in the Medical Research Council (MRC) study, the benefits of low-dose aspirin treatment in the primary prevention of stroke were closely related to SBP levels, to such an extent that for levels of SBP >145 mmHg, the relative risk of stroke was increased by 42% in comparison with placebo . Therefore, before starting antiaggregation for primary prevention of high risk hypertensive patients, strict BP control is needed.
On the other hand, the data from the Heart Protection Study  and the ASCOT study  are significant with respect to the global control of cardiovascular risk. Both studies have shown that irrespective of baseline cholesterol or blood pressure levels, statin therapy reduces the risk of stroke and coronary heart disease (CHD) in hypertensives. Therefore, the use of statins should become a routine measure in the treatment of high risk hypertensive patients in the immediate future because they potently complement the primary objective of antihypertensive therapy, which is to reduce the risk of coronary heart disease and stroke. The results of the STENO-2 study (Figure 8) were pioneering by clearly showing that the strategy of intensive global systematic intervention in type 2 diabetic patients (objective of BP <130/80 mmHg; HbA1c <6.5%; total cholesterol <175mg/dL; triglycerides <150 mg/dL, routine aspirin) with RAAS blockade at the maximum dose, and statins and aspirin during 7.8 years of follow-up, reduced the risk of cardiovascular disease by 53% compared with conventional treatment . This is the most effective way to go “beyond blood pressure reduction”. In summary, the current and future therapeutic strategy for patients at highc a rdiovascular risk is not the individual control of each isolated component of cardiovascular risk, but to address global cardiovascular risk by using systematic multifactorial intervention.
||Figure 8. Multifactorial and systematic intensive treatment in type 2 diabetic patients in the Steno-2 study. Comparison of the macro and microvascular complications between the usual care and the intensive care.
(Data taken from )
SUMMARY AND CONCLUSION
On the basis of current evidence provided by various studies, the most recent European, British, Canadian and USA guidelines recommend reducing BP levels to below 140/90 mmHg for all hypertensive patients older than 18 years, including the elderly, when this is clinically tolerated, as a necessary measure to reduce the global cardiovascular risk, the fundamental objective of treatment. This must be accompanied by the additional life style measures and drugs necessary to control other associated cardiovascular risk factors. For high risk hypertensives, such as diabetics and patients with subclinical organ damage or established clinical cardiovascular disease, levels below 130/80 mmHg should be reached and maintained, with still lower levels for patients withestablished renal disease and proteinuria within the nephrotic range. It is obvious that success in reaching the objective set will depend on previous BP levels, particularly SBP levels. If these are very high at the initiation of treatment (>180 mmHg), they may be very difficult to achieve, above all in the elderly and in high risk hypertensives, in whom these reductions to very low levels must be considered in the context of already structurally damaged arteries. Therefore, early drug treatment is imperative in these patients. In addition, blood pressare control in very high risk patients should be achieved as rapidly as possible, using initial strategies that include combinations of antihypertensive drugs. Blood pressure control must be achieved by strategies using the best drugs and combinations with proven capacity to regress silent organ damage and to interrupt the progression of cardiovascular disease. In clinical practice this means that, together with RAAS blockade often associated with calcium channel blockade, statins and antiplatelet drugs should routinely be administered to most patients, particularly those older than 55 years, as they provide the only possibility for global risk prevention leading to greater survival.
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