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 minimising 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 to start treatment (threshold BP) and BP values to be achieved by antihypertensive treatment (BP target). Both aspects are closely related to the total cardiovascular risk of the patient, which may be calculated by using different risk stratification tables.
The 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 BP level above which investigation and treatment do more good than harm – also indicates that any numerical definition must be flexible, resulting from evidence of risk and the availability of effective and well-tolerated treatment. Due to these considerations, it would perhaps be more correct to use a classification of BP levels without the term hypertension. The European Society of Hypertension/European Society of Cardiology (ESH/ESC) guidelines1 use a combined approach to this concern, defining five categories for the classification of BP: normal/ high to normal BP hypertension, mild (grade 1), moderate (grade 2) hypertension or severe (grade 3) hypertension.
From this perspective, the ESH/ESC guidelines1 include a table to calculate the total absolute risk in subjects with normal and high to 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 score criteria (FSC), coinciding with an absolute 10-year risk of cardiovascular mortality of <4, 4–5, 5–8 and >8%, respectively, according to the FSC (see Table 1).
The primary goal of treatment of patients with high BP is to achieve the maximum reduction in long-term total risk of cardiovascular morbidity and mortality. This requires treatment of all of the reversible risk factors identified, including smoking, dyslipidaemia or diabetes, and the appropriate management of associated clinical conditions, as well as treatment of the raised BP.
In terms of 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. Both the seventh Report of the Joint National Committee on the Prevention, Detection, Evaluation and Treatment of High Blood Pressure2 and the 2007 ESH/ESC guidelines1 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 140mmHg of systolic BP (SBP) and 90mmHg of diastolic BP (DBP). However, all guidelines1–5 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 (<130/80mmHg). The goal to be achieved, as well as the achievable goal, may depend on the pre-existing BP level, particularly systolic values. Systolic values below 140mmHg may be difficult to achieve, particularly in the elderly. Therefore, in order to make the correct therapeutic decisions it is imperative that a stratification of the global cardiovascular risk be defined.
Cardiovascular Risk Stratification to Define Therapeutic Attitudes
Contribution of Blood Pressure to the Global Absolute Risk of Patients
Table 1 shows the risk stratification proposed by the ESH/ESC in 2007 and clearly demonstrates that although BP levels contribute notably to the increased risk, they are not the only variables to consider.1 The first horizontal line of 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 and 129 and DBP between 80 and 84mmHg) and high to normal levels (SBP between 130 and 139 and DBP between 85 and 89mmHg) to grade 3 hypertension (SBP ≥180 or DBP ≥110mmHg). For people without other associated cardiovascular risk factors, normal or high to normal BP levels mean they have the reference risk of the general population and their BP levels should be maintained but not reduced. From a BP level of 140/90mmHg, the absolute cardiovascular risk increases slightly (the probability of suffering cardiovascular complications at 10 years is <15%) and the added risk is low. Grade 2 hypertension (160/100mmHg upwards) 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 of 20–30%).
Contribution of Blood Pressure in Association with Other Cardiovascular Risk Factors to the Global Absolute Risk of Patients
In a patient with a BP of 168/96mmHg and an additional risk factor, for example abdominal obesity, the reduction of BP to 138/86mmHg (below the objective of 140/90mmHg) 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% (see Figure 2, blue arrow), but not at the similar 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 (see Figure 2, grey arrow).
Contribution of Blood Pressure in Association with Multiple Cardiovascular Risk Factors or Target Organ Damage to the Global Absolute Risk of Patients
When patients with multiple (three or more) associated risk factors (see Table 1), patients with type 2 diabetes or hypertensives with target organ damage (TOD), shown in the third row of Figure 1, are analysed, the situation is totally different. Their absolute risk is defined as moderate even when their BP levels are in the range considered normal, while for those with high to normal pressure the added risk is high. Therefore, the measures aimed at BP reduction and the objective to reach will be different from those for subjects without additional risk factors and will necessarily be included in the other measures of global risk prevention. As shown in Figure 3, if in a high-risk patient with BP levels of 168/96mmHg the BP is reduced to only 138/88mmHg, the risk continues to be high (grey arrow). To reduce it, levels below 130/80 should be reached (yellow 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 risk factors are controlled simultaneously or the regression or TOD is achieved (blue arrow) will the risk be reduced to that of the general reference population. In summary, it is necessary to analyse the BP targets to be reached based on the global risk of the hypertensive patients and their clinical situation, which is fundamentally determined by the co-existence of multiple cardiovascular risk factors, type 2 diabetes, TOD or associated clinical conditions.
Antihypertensive Strategies to Achieve Target Blood Pressure Depending on Global Risk
Blood Pressure Targets in High- or Very-high-risk Patients – Hypertension in Patients with Type 2 Diabetes
From a practical perspective, all patients with type 2 diabetes or associated cardiovascular clinical conditions are hypertensives because the levels that define hypertension in these subjects are lower (130/80mmHg) than those applicable to the population without diabetes (140/90mmHg). As noted above, all guidelines agree that the target BP to be achieved and maintained should be lower than that of the general hypertensive population (<130/80mmHg). It is well established that the lower the BP, the lower the progression of diabetic nephropathy.6–8 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 Hypertension Optimal Treatment (HOT) study, no significant reduction in cardiovascular events in the subgroup of patients with plasma creatinine >115μmol/l (>1.3mg/dl) was found in relation to a greater or smaller BP reduction.9 In a post hoc analysis10 no differences were found in morbidity or mortality in terms of a greater or smaller reduction in BP (139/82 versus 143/85mmHg) between patients with clinical renal injury and plasma creatinine >133μmol/l (>1.5mg/dl). However, none of these studies suggests an increase in cardiovascular risk with a greater reduction in BP.
A further consideration is that in patients with diabetes or those with clinical vascular disease, BP control is more difficult to achieve, not only because the levels to reach are lower,1–5 but also because the structural vascular damage of patients with type 2 diabetes or hypertension with silent organ damage or clinical disease is much greater, with greater endothelial dysfunction, greater arterial remodelling, greater rigidity and less distensibility. Consequently, there is greater difficulty in achieving the BP reduction itself, particularly in SBP, and thus the therapeutic strategy for any high-risk patient will need more antihypertensive drugs to achieve the same reduction in BP as that of subjects with a lower risk.11 For this reason, the initial 2003 ESH/ESC guidelines and the subsequent 2007 ESH/ESC guidelines state that, depending on the baseline BP and the presence or absence of cardiovascular complications, it appears reasonable to initiate therapy with a strategy based on the use of a low-dose combination of two agents in hypertensive patients with diabetes.
One of the advantages of initiating treatment with two drugs with different mechanisms of action is that this strategy is more likely to control BP 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 optimising patient compliance with treatment.1
Blood Pressure Targets in Elderly Hypertensive Patients
Age is another factor that should be considered when making therapeutic decisions and setting out BP objectives. There is little doubt from randomised controlled trials that older patients benefit from antihypertensive treatment in terms of reduced cardiovascular morbidity and mortality, irrespective of whether they have systolic or diastolic hypertension or isolated systolic hypertension. However, there has always been concern about the effects of an excessive reduction in DBP in elderly patients – inexorably linked with the SBP reduction – as the possibility of reductions in the perfusion of essential organs, such as the heart or brain has been suggested, if the DBP reduction is excessive. 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 to both the increase and the excessive reduction of DBP). However, the data from the Systolic Hypertension in the Elderly Program (SHEP) study do not support this hypothesis:12 at five years of active treatment the DBP reached was 68mmHg, which was associated with a reduction of 27% in the incidence of myocardial infarction. Similar conclusions were reached in the Systolic Hypertension in Europe (SYST-EUR)13 and Systolic Hypertension in China (SYST-CHINA)14 studies, which, together with the results of the HOT9 study, definitively reject the concept of a J-curve until DBP levels of 65mmHg. In addition, the post hoc analysis of the SHEP study data carried out by Somes et al.15 concluded that DBP can safely be reduced to 65–70mmHg in elderly hypertensives.
In overviews of randomised trials performed by the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC)16 in 2008 (190,606 individuals included from 31 clinical trials), the results showed that a reduction of BP produces benefits in younger and older adults (<65 and ≥65 years of age, respectively) with no strong evidence that protection against major vascular events afforded by different drug classes varies substantially with age.
In the recent Hypertension in the Very Elderly Trial (HYVET)17 study, hypertensive patients over 80 years of age on active antihypertensive treatment showed a significant 39% reduction in fatal stroke (secondary endpoint) and a 30% reduction of fatal and non-fatal stroke compared with placebo (confidence interval [CI] 95% -1 to 51; p=0.06).17
Based on the evidence of these studies, a well-tolerated reduction below 140/90mmHg can be recommended in the elderly. Successful achievement of the final objective will depend on the baseline BP levels, with SBP levels <140mmHg being difficult to achieve in a large number of elderly hypertensives, particularly if their initial levels exceed 180/110mmHg. Finally, in view of the possible prognostic importance of pulse pressure, it would be interesting to know whether drugs that decrease systolic pressure more than diastolic pressure in comparison with other drugs would be more 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, target organ damage and associated cardiovascular conditions, to which the choice of the first drug should be tailored.
Blood Pressure Targets in Hypertensive Patients with Concomitant Cerebrovascular Disease
The Perindopril Protection Against Recurrent Stroke Study (PROGRESS)18 showed benefits in patients with a history of stroke or transient cerebral ischaemia in incidences of recurrent stroke when DBP was reduced to 79mmHg in the active treatment group in comparison with 83mmHg in the placebo group. However, the reduction in morbidity and mortality in the PROGRESS study was significant only in patients randomised to combination therapy, where the mean reduction in SBP/DBP was 12.3/5mmHg compared with a mean reduction of 4.9/2.8mmHg in the monotherapy group. This strengthens the fact that greater BP reduction is also beneficial in secondary prevention of stroke in very-high-risk patients even when usual BP is in the range of high to normal BP.
Based on current evidence, the American Stroke Association and the European Stroke Organisation19 recommend antihypertensive treatment to prevent stroke recurrences. As this benefit extends to people with and without a history of hypertension, this recommendation should be considered for all ischaemic stroke and transient ischaemic attack patients (class IIa, level of evidence B). Absolute target BP level and reduction are uncertain and should be individualised, but the benefit has been associated with an average reduction of ~10/5mmHg, while normal BP levels have been defined as <120/80mmHg (class IIa, level of evidence B).
Blood Pressure Targets in Hypertensive Patients with Concomitant Coronary Heart Disease or Heart Failure
In the 22,576 hypertensives with ischaemic heart disease included in the International Verapamil SR/Trandolapril Study (INVEST) study, the lowest incidence of stroke (0.88%) during the 2.7 years of hypertensive treatment was observed in patients with a mean SBP of between 120 and 130mmHg throughout the study, whereas in patients with a mean SBP of ≥130mmHg a progressive increase in incidence, from 1.3% in patients with SBP of 130–140mmHg to 5.6% for those with a mean SBP of >180mmHg,20 was observed. In the very-high-risk patients with coronary heart disease (CHD) included in the Heart Outcomes Prevention Evaluation (HOPE) study,21 the mild difference in final SBP between the active treated group and the placebo group (about 2 to 3mmHg) 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 Valsartan Antihypertensive Long-term Use Evaluation (VALUE) study22,23 in very-high-risk hypertensives with characteristics similar to those of the patients included in the HOPE study puts this interpretation in doubt. Differences in SBP of between 2 and 4mmHg during a follow-up of 4.2 years had a substantial impact on the prevention of cardiac and cerebrovascular events.23 In summary, there is absolute evidence supporting that first priority in hypertension treatment is BP reduction.
High-risk Hypertensive Patients and Combination Therapy
In most trials, a combination of two or more drugs has been the most widely used treatment regimen to reduce BP effectively and reach the pre-determined goal. Use of combination therapy has been found to be even more frequently needed in diabetic, renal and high-risk patients and, in general, whenever lower BP targets are pursued.1 In high-risk hypertensives goal BP should be achieved more promptly, which favours initial combination therapy and quicker adjustment of doses.1 Initial treatment can make use of monotherapy or a combination of two drugs at low doses with a subsequent increase in drug doses or number, if needed. A combination of two drugs at low doses should be preferred as first-step treatment when initial BP is in the grade 2 or 3 range or total cardiovascular risk is high or very high.1
The ACEI + Amlodipine vs ACEI + Hydrochlorothiazide in High Risk Hypertensives (ACCOMPLISH) trial was the first trial to compare the cardiovascular outcomes of initial fixed-dose combination angiotensin-converting enzyme inhibitor (ACEI)/calcium channel blocker (CCB) versus ACEI/diuretic therapy in patients with hypertension and a high risk of cardiovascular events. The results indicate that initial combination therapy is beneficial in this population, with ACEI/CCB therapy providing the greater benefit (reduced cardiovascular morbidity and mortality relative to initial ACEI/diuretic combination therapy).24 The findings of ACCOMPLISH add to a growing body of evidence supporting early use of fixed-dose combination therapy. The results of multiple clinical trials have demonstrated that the renin–angiotensin–aldosterone system (RAAS) inhibitor/CCB combinations are well tolerated and efficacious. It may be that the cardiovascular benefits of combination RAAS inhibitor/CCB therapy are attributable to factors other than just BP lowering. RAAS inhibitors and CCB have individual and combined (potentially synergistic) vasoprotective properties and beneficial actions on endothelial function that likely contribute to this finding. Benefits may include structural and functional changes in resistance arteries, effects on atherosclerosis progression, atherosclerotic plaque stabilisation and fibrinolysis. Further studies are necessary.
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 five 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 >55 years of age, the only way of identifying a significant number of events in short periods. Young hypertensives with low or moderate risk were not represented in these studies. Thus, 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 analyse the prevention of events and not the prevention of the disease that causes such events.25
In contrast, most studies in experimental animals have analysed 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.26–29
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 RAAS or calcium channels in comparison with traditional diuretics and beta-blockers. Recent studies in hypertensives have also examined surrogate end-points, such as structure in resistance arteries,30 intima-media thickness in large arteries,31,32 left ventricular mass and structure,26,33 new-onset atrial fibrillation,34–36 inflammatory markers,37 microalbuminuria38–40 and new-onset diabetes,11,21,22,25,33,41,42 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 favourable effects of angiotensin receptor blockers (ARBs), ACEIs and CCBS on these surrogate parameters beyond that attributable to BP lowering alone.
It seems logical that if some antihypertensive drugs or strategies act more favourably than others on these surrogate markers, the consequence will be less progression of long-term disease and, therefore, less morbidity and mortality. This is particularly important in young patients, in 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 improved survival. In all of these aspects, as mentioned above, RAAS blockers and CCBs 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: first, 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 second, it is not sufficient to reduce BP. We must tackle the global risk of the subject, for which control of obesity, dyslipidaemia, pro-thrombotic state, smoking, etc. is necessary.
In the great majority of high-risk patients, particularly those >55 years of age, 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. 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 >145mmHg, the relative risk of stroke was increased by 42% in comparison with placebo.43 Therefore, before starting antiaggregation for primary prevention in high-risk hypertensive patients, strict BP control is needed.
On the other hand, the data from the Heart Protection Study44 and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)45 are significant in terms of the global control of cardiovascular risk. Both studies have shown that, irrespective of baseline cholesterol or BP levels, statin therapy reduces the risk of stroke and 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 CHD and stroke. The results of the Steno-2 study were pioneering in clearly showing that the strategy of intensive global systematic intervention in patients with type 2 diabetes (objectives were BP <130/80mmHg, glycated haemoglobin [HbA1c] <6.5%, total cholesterol <175mg/dl, triglycerides <150mg/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.8 This is the most effective way to go beyond BP reduction. In summary, the therapeutic strategy going forwards in patients at high cardiovascular risk is not the control of each isolated component of cardiovascular risk, but approaching global cardiovascular risk by using a systematic multifactorial intervention.