The issue of the equivalence of the various classes of antihypertensive agents, and of various agents within a given class, has been a long debated one, heralded in the 1970s by the incautious suspicion of a role played by reserpine in breast cancer , and continuing in the 1990s with the campaign against calcium antagonists as responsible for coronary events, bleeding, and cancer [138,139]. After the acquittal of calcium antagonists, even by their prosecutors, attention has been recently focused by different groups of investigators on a possible inferiority of β-blockers and diuretics as well as on the possible inferiority of ACE inhibitors for stroke prevention and of angiotensin receptor antagonists for coronary disease prevention. Obviously, paying careful attention to possible adverse effects or limitations of both new and old drugs is an obligation of physicians and clinical epidemiologists and must be taken seriously by members of guidelines committees. On the contrary, unfounded suspicion should not be used to deprive patients of the benefits of drugs.
The evidence upon which β-blockers have been questioned as first choice antihypertensive drugs  and actually downgraded in the British recommendations  was discussed in the 2007 European guidelines. New arguments on the place of β-blockers in antihypertensive therapy have been added since then [142–144]. In a meta-analysis of nine of 22 randomized controlled trials of β-blockers , a significant inverse correlation has been reported between the heart rate achieved by β-blocker therapy and cardiovascular outcomes (i.e., the lower the achieved heart rate, the higher the incidence of outcomes), including myocardial infarction and heart failure, known to be favorably influenced by β-blockade [146,147]. On the contrary, a recent meta-analysis of 147 randomized trials (the largest meta-analysis so far available) reports only a slight inferiority of β-blockers in preventing stroke (17% reduction rather than 29% reduction with other agents), but a similar effect as other agents on preventing coronary events and heart failure, and a higher efficacy than other drugs in patients with a recent coronary event . Furthermore, the recent publication of a 20-year follow-up of the UKPDS trial  comparing atenolol and captopril in diabetes has found the incidence of cardiovascular outcomes to be similar in patients on the β-blocker or the ACE inhibitor, with a reduction in all-cause mortality favoring the β-blocker. This is consistent with retrospective observational data of large numbers of patients on different antihypertensive treatment regimens for longer periods than in randomized trials, showing that the incidence of cardiovascular outcomes was not higher on atenolol-based treatment than on other antihypertensive agents .
Finally, no systematic analysis has been made of the possible role of a smaller BP reduction by β-blocker-based treatment in those trials in which β-blockers appeared to have a smaller effect on stroke. For instance, interpolation of ASCOT data on stroke in the meta-regression analysis of the Blood Pressure Lowering Treatment Trialists' Collaboration  makes it clear that the odd ratio falls very close to the place expected because of the 2.7 mmHg difference in SBP between β-blocker/diuretic and calcium antagonist/ACE inhibitor treatments . On the whole, however, β-blockers do not appear to be systematically inferior to other antihypertensive agents in their ability to reduce BP. A recent pooling analysis from more than 40 000 hypertensive patients under different monotherapies has shown no inferiority (and, possibly, a numerical superiority) of β-blocker monotherapy  in lowering brachial BP. However, studies like CAFÉ  suggest that, for the same brachial SBP, central SBP may be higher with β-blockers than with other antihypertensive agents because of a greater wave reflection due to bradycardia and/or peripheral vasoconstriction. This interesting observation deserves to be confirmed, although its real impact on antihypertensive management may be small because the difference between peripheral and central BPs is known to become attenuated at an older age [155,156], when hypertension and antihypertensive treatment are most common.
There is no doubt that β-blockers as well as diuretics (especially when combined together) have adverse metabolic effects and facilitate new-onset diabetes [157,158] in predisposed patients such as those with the metabolic syndrome or impaired glucose tolerance [55,159,160]. The importance of this phenomenon, however, may have been exaggerated by the way results of most prospective studies and trials have been analyzed; that is, by limiting analyses of changes in plasma glucose or in antidiabetic prescriptions to patients initially free of diabetes or with a blood glucose below 7.0 mmol/l (126 mg/dl). Indeed, a recent analysis of data from the 3.8-year long ELSA trial has shown that new diagnoses of diabetes at the end of this study in patients without diabetes at baseline are accompanied by a number of cases in which diagnosis of diabetes at baseline was no longer confirmed at the end of the study. However, the overall balance remains positive for new-onset diabetes . Furthermore, it is still unclear whether drug-induced diabetes carries the same negative prognosis as naturally occurring diabetes, with some authors emphasizing studies showing that trial patients with new-onset diabetes do not have a higher incidence of cardiovascular outcomes during the trial and several years thereafter [133,161], whereas others underline the opposite conclusions in other studies [143,162–164].
It is also true that, when compared with other agents in trials using subclinical organ damage as an endpoint, β-blockers have been shown to be less powerful than ACE inhibitors, angiotensin receptor antagonists, and calcium antagonists in reducing an increased left ventricular mass , carotid IMT thickening , aortic stiffness , and increased small artery wall-to-lumen ratio [167–169], and this may be supposed to result in less cardiovascular protection in the long run. When discussing β-blockers, however, it should not be ignored that they are not a homogeneous class, and that vasodilating β-blockers, such as celiprolol, carvedilol, and nebivolol, appear not to share some of the negative properties described for other compounds. For instance, celiprolol lowers aortic stiffness and central pulse pressure , whereas atenolol does not . Nebivolol, at doses producing the same BP reduction, lowers heart rate significantly less than atenolol , and because of the lesser bradycardia combined with peripheral vasodilatation, it has better effects on central BP than atenolol . In the GEMINI study , carvedilol had less adverse effects on glycosylated hemoglobin, total cholesterol, and triglycerides than metoprolol; and nebivolol, at variance from metoprolol, has been found to improve insulin sensitivity  and to have the same metabolic effects as an ACE inhibitor . Both carvedilol and nebivolol have been used in outcome trials in chronic heart failure (admittedly not in hypertension) and found capable of reducing the primary endpoint of mortality and hospitalization : in COMET, carvedilol treatment was accompanied by less new-onset diabetes than metoprolol , and in the SENIORS trial, new-onset diabetes had the same incidence on nebivolol or placebo . When compared with metoprolol, carvedilol resulted in significantly less cases of microalbuminuria and progression to proteinuria in hypertensive diabetic patients , and nebivolol has recently been shown to improve coronary flow reserve and left ventricular filling pressure in the hypertensive heart . Whether the protective cardiovascular action shown by carvedilol and nebivolol in patients with heart failure is also displayed in hypertension remains to be determined in a controlled trial.
A prominent role for thiazide-like diuretics in antihypertensive therapy, such as that given to these compounds in the JNC-7 report , is an object of continuing debate [143,161]. The evidence that a BP lowering induced by diuretics can reduce all types of cardiovascular events is robust , but it cannot be denied that most of the trials, the meta-analysis of which has been the basis for raising doubts on β-blockers, have also used thiazides. This makes it difficult to distinguish the separate role of these two drug classes. Likewise, the diabetogenic role of β-blockers and diuretics is difficult to discriminate, and when it has been dissociated diuretics appear worse than β-blockers . Diuretics have rarely been studied in depth for their capacity to regress organ damage, and when tested have often been found inferior to calcium antagonists or ACE inhibitors [165,180,181]. Furthermore, all large studies that have explored the tolerability of various classes of antihypertensive agents on persistence to therapy have found diuretics to be, together with β-blockers, the least tolerated compounds  or those accompanied by the least persistence on treatment [182,183]. Finally, a recent meta-analysis has reported outcome benefit for low-dose but not for high-dose diuretics . In addition, the results of the ACCOMPLISH trial (to be discussed in the preferred drug combinations section) have raised doubts as to whether thiazides are always the best protective component of combination therapy .
The concept that ACE inhibitors may be somewhat inferior to other antihypertensive agents in preventing stroke has repeatedly been raised on the basis of some meta-analyses [148,186] and meta-regression analyses . A pathophysiological hypothesis to support the claim that ACE inhibitors may be inferior to angiotensin receptor antagonists in preventing stroke has also been elaborated . On the contrary, it has been suggested that angiotensin receptor antagonists would be inferior to ACE inhibitors in preventing myocardial infarction [189,190].
All these concepts, as well as their pathophysiological interpretations, have been undermined by the results of the very large ONTARGET, directly comparing cardiovascular outcomes under treatment with an ACE inhibitor (ramipril) or an angiotensin receptor antagonist (telmisartan) . ONTARGET has shown telmisartan not to be statistically inferior to ramipril as far as the incidence of a composite endpoint including major cardiac outcomes are concerned. A similar incidence of strokes was also observed on both treatments. Recent meta-analyses including older and more recent trials confirm the conclusion that ACE inhibitors and angiotensin receptor antagonists have the same preventive effect on myocardial infarction [192,193].
The absolute benefit induced by the relatively small BP reduction produced by either treatment is more difficult to calculate, because ONTARGET was deliberately conducted in high-risk patients and for obvious ethical reasons could not include a placebo comparison arm. Therefore, it is difficult to decide whether the benefit has to be gauged from historical comparison with the placebo arm of the HOPE trial , carried out several years earlier, or with the placebo arm of the simultaneously run TRANSCEND, on patients intolerant to ACE inhibitors . The patients of TRANSCEND treated with placebo had a slightly lower incidence of cardiovascular events than placebo-treated patients in HOPE, either because higher prevalence of concomitant therapies than in HOPE (but similar to that in ONTARGET) or because of a higher proportion of women.
Calcium antagonists have been cleared from the suspicion of causing a relative excess of coronary events by the same authors who had raised the suspicion . On the contrary, some recent meta-analyses [148,186,187,196] suggest that these agents may have some additional advantage in preventing stroke, although it is not clear whether this can be ascribed to a specific protective effect or to a slightly better BP control, often achieved in the calcium-antagonist-treated patients. It is still unclear whether calcium antagonists are less effective in protecting against new-onset heart failure, as is apparent in several studies and large meta-analyses [148,186]. The recent meta-analysis by Law et al. , however, shows that trials in which a BP difference was sought between an antihypertensive agent and control, the efficacy of calcium antagonists in preventing heart failure was only slightly lower than that of other antihypertensive agents (19 versus 24%). The question revolves around how much of this apparent inferiority of calcium antagonists is a real limitation in their cardiovascular protection, the result of a difficulty in diagnosing a clinically relevant but soft outcome such as an incipient heart failure, or a consequence of trial designs preventing the use of diuretics and ACE inhibitors (agents essential in heart failure therapy) in patients randomized to calcium antagonists. It is relevant that in trials in which a calcium antagonist was always or commonly administered in combination with a diuretic (FEVER ) or an ACE inhibitor (ASCOT ), there was no statistically significant excess of heart failure in the calcium antagonist arm. Incipient heart failure has also been found to be markedly reduced (−39%) in hypertensive patients on calcium antagonist treatment compared with those on placebo in the ACTION trial [96,198–200].
The new drug that has substantially increased its database in the last 2 years is aliskiren, a direct inhibitor of renin at the site of its activation, which is now available for treating patients both in United States and Europe. The new data on aliskiren can be summarized as follows. First, although the specific advantages of interfering with the activation of renin are not yet clear [201,202], aliskiren has been shown to be effective in lowering SBP and DBP in hypertensive patients when given in monotherapy at a single daily dose. Second, the drug is effective also in combination with a thiazide diuretic, a calcium antagonist and an ACE inhibitor or an angiotensin receptor antagonist [203–205]. Third, data have recently emerged on the ability of aliskiren to protect against subclinical organ damage when combined with an angiotensin receptor antagonist. In one study in diabetic hypertensive patients with proteinuria, this drug combination led to a greater reduction in urinary protein excretion than the administration of an angiotensin receptor antagonist alone , but in another study on hypertensive patients with LVH, the combination did not cause a LVM reduction significantly greater than that obtained by administration of an angiotensin receptor antagonist alone . In a third study in heart failure patients, this combination was significantly superior to angiotensin receptor antagonist administration in causing a reduction in the plasma concentration of brain natriuretic peptide , a recognized prognostic marker for heart failure . It remains to be seen whether greater effects on organ damage may also be obtained by increasing the dose of traditional blockers of the renin–angiotensin system. The completion of ongoing hard endpoints trials with aliskiren in mono and combination therapies is expected with interest. Meanwhile the available evidence justifies its use in hypertension, particularly in combination with other agents. This is also supported by the favorable tolerance profile of aliskiren. The main side-effect appears to be an increased incidence of diarrhea, but only at doses higher than the recommended dose .
New antihypertensive agents that are currently under investigation include nitric oxide donors, vasopressin antagonists, neutral endopeptidase inhibitors, AT2 angiotensin receptor agonists, and antagonists of endothelin receptors. Although their mechanisms of action hold promise of BP-lowering effectiveness and possibly of specific organ protection, their investigational phase is still far away from use in the clinical setting, and thus assessment of their pros and cons compared with current drug options is impossible. An exception is represented by endothelin receptor antagonists, because a compound of this class that selectively blocks ETA receptors, darusentan, has been recently tested in patients defined as resistant, because of lack of BP control on treatment with at least three drugs, including a diuretic. Administration of darusentan on the top of the existing treatment significantly reduced office and 24 h mean BP over a 14-week period, with a doubling of the percentage of patients achieving BP control and only a moderate increase in the rate of side-effects (mainly edema and sodium retention) compared with placebo . These results are potentially important because resistant hypertension is not a phenomenon of marginal proportion, the number of patients unable to achieve BP control despite multiple drug treatment being around 15–20% .
However, once it is agreed that (1) the major mechanism of the benefits of antihypertensive therapy is BP lowering per se, (2) the effects on cause-specific outcomes of the various agents are similar or differ by a minor degree, (3) the type of outcome to occur in a given patient is unpredictable, and (4) all classes of antihypertensive agents have their pros and cons (well summarized in Tables 7 and 8 of the 2007 ESH/ESC guidelines), it is obvious that any all-purpose ranking of drugs for general antihypertensive usage is unnecessary and probably deceiving . It is on the basis of this striving for ranking that at different times investigators have been warning the media that millions of people may be dying every year because of the use of calcium antagonists, the use of β-blockers, or the use of angiotensin receptor antagonists. These campaigns cause lay people to wonder whether antihypertensive therapy is beneficial or dangerous. This behavior should be discouraged. Even reasons based on costs, often used to justify ranking, have recently been weakened by the advent of generic compounds within every class of antihypertensive agents.
Some of the large-scale trials published in the last 2 years importantly expanded information on the advantages and disadvantages of several two-drug combinations in hypertension. The new evidence available and its implications for guidelines recommendations are discussed below.
The combination of an ACE inhibitor, perindopril, and the diuretic indapamide had already been shown in the PROGRESS study to have a greater BP-lowering effect than the ACE inhibitor alone and, in parallel, a much greater preventive effect on recurrent stroke . In ADVANCE , the same combination of indapamide and perindopril given to patients with type 2 diabetes (on top of continuation of preexisting therapy) for more than 4 years was followed by a significantly greater antihypertensive effect than administration of placebo (SBP and DBP difference −5.6 and −2.2 mmHg, respectively). This was associated with a reduced incidence (−9%) of diabetes-related complications (composite endpoint of macrovascular and microvascular outcomes). In addition, the perindopril–indapamide combination was well tolerated with an overall rate of adverse effects only slightly greater than that observed in the placebo group, and a high number of patients (>80%) remaining on active drug treatment throughout the trial. Similarly, in the large majority of the very elderly patient of HYVET , the administration of the indapamide–perindopril combination resulted in a greater BP reduction as well as a lower rate of cardiovascular outcomes and serious side-effects compared with placebo.
A combination of an ACE inhibitor and a dihydropyridine calcium antagonist was the most widely used combination therapy in Syst-Eur and Syst-China [81,82], as well as in the HOT study  in order to achieve lower BP goals. INVEST used the combination of a nondihydropyridine calcium antagonist, verapamil, and the ACE inhibitor trandolapril with comparable beneficial effects as the combination of a β-blocker and a diuretic . The combination amlodipine–perindopril was widely used in the ASCOT study, being more effective in lowering BP and cardiovascular events than the combination of a β-blocker with a thiazide .
An angiotensin receptor antagonist has been frequently combined with a diuretic in a number of trials, such as LIFE  and SCOPE [83,220], which have documented the protective effects of this treatment strategy. Until now, no outcome study has been conducted using the combination of an angiotensin receptor antagonist with a calcium antagonist. An exception is the RENAAL trial, in which the benefit of losartan (versus placebo) in delaying progression to end-stage renal disease was seen on the top of preexisting antihypertensive therapy frequently including calcium antagonists . Furthermore, a large body of evidence exists that combining an angiotensin receptor antagonist with a calcium antagonist or a diuretic provides an effective reduction of BP and a high rate of BP control in a variety of hypertension categories, has a tolerability profile even more favorable than that seen when an ACE inhibitor is used instead (because cough and angioedema are much less frequently seen) and protects against subclinical organ damage [221–223]. Evidence has grown in particular on the combination of an angiotensin receptor antagonist with a calcium antagonist (usually amlodipine), which has been proved capable of most effectively reducing even severe hypertension [223,224].
Despite the fact that small pharmacologic studies have raised doubts on the synergistic effects of adding a diuretic to a calcium antagonist, this combination was included in the recent meta-analysis by Wald et al.  without detracting from the demonstration of a greater BP-lowering effect of combining calcium antagonists with other drugs compared with doubling the calcium antagonist dose in monotherapy. Even more importantly, the association of a calcium antagonist with a diuretic has been used in the FEVER, ELSA, and VALUE trials [75,166,225] with greater benefits. No outcome trial has explored the combination of a calcium antagonist with a β-blocker, but this has been the second used association in the HOT study .
Nonetheless, the results of ONTARGET do not support large-scale use of this combination of drugs in hypertension and suggest that its use in proteinuric renal patients should be studied further and more critically. A recent meta-analysis of 49 studies, albeit small and mostly short term, has confirmed that the combination of the two blockers of the renin–angiotensin system has significantly greater antiproteinuric effect than either component . However, although reduction of proteinuria is often considered to lead to and/or reflect renoprotection (i.e., delayed occurrence of end-stage renal disease) , proteinuria reduction, particularly in short-term studies, should not be taken as necessarily equivalent to renal function preservation and prevention of cardiovascular outcomes. An example of this are some findings of the ONTARGET study  already discussed.
In this context, it should be remembered that the results of the only study (the COOPERATE study) that reported a superior protective effect of double blockade of the renin–angiotensin system on renal outcomes  have been questioned [230,231]. Also, the widely quoted favorable results of concomitant ACE inhibitor and angiotensin receptor antagonist administration reported in trials on patients with left ventricular dysfunction or heart failure should be considered cautiously, as the benefits were not seen in all trials (absent in VALIANT ), or they were small (Val-HeFT ) or evident only if hospitalization was added to mortality (CHARM ). Finally, in all these trials, the combination markedly increased the incidence of side-effects such as hyperkalemia and an elevation in serum creatinine.
New and old evidence strongly supports combination treatment as the most effective strategy to control BP, and therefore recommends treatment strategies largely based on the addition of a drug from another class to the initially prescribed agent, whenever BP control is not achieved, unless the starting drug needs to be changed because of side-effects or the absence of any BP reduction. It suggests that the combination of two antihypertensive drugs may offer advantages also as first step treatment, particularly in patients at high cardiovascular risk, in whom early BP control may be desirable. It favors, whenever possible, the use of fixed dose combinations of two drugs in a single tablet because of the advantage brought about by simplification of the treatment regimen. Finally, it warns against the use of a combination of an ACE inhibitor and an angiotensin receptor antagonist at least in very high cardiovascular risk patients such as those in ONTARGET. It remains to be established whether the latter combination may have a beneficial role in patients with chronic renal disease and proteinuria, or even in some lower risk hypertensives.
Finally, it is important to remember that no less than 15–20% of the patients need more than two antihypertensive drugs to achieve an effective BP reduction. The combination of a blocker of the renin–angiotensin system, a calcium antagonist and a thiazide diuretic may be a rational three-drug combination, although other drugs, such as a β-blocker or an α-blocker, may be included in a multiple approach, depending on the clinical circumstances.
Now this gap in the evidence has been filled with the much expected publication of the results of the HYVET . In HYVET, 3845 patients aged 80 years or more in whom entry SBP was 160 mmHg or more (average 173 mmHg) were randomized to receive either placebo or active treatment, consisting of indapamide (1.5 mg daily) and the eventual addition of the ACE inhibitor perindopril (2 and 4 mg daily) with the target to attain a SBP value below 150 mmHg. Drug administration (with the indapamide–perindopril combination given in about three-quarters of the patients) reduced BP to a value much lower than placebo, that is, 144/78 versus 161/84 mmHg. This was accompanied by clear-cut beneficial effects, and, according to advice from the safety board, the trial was stopped after an average treatment duration of less than 2 years. The beneficial effects consisted of a 30% reduction in stroke (just short of statistical significance) and statistically significant reductions in congestive heart failure (64%), major cardiovascular events, and all-cause death (21%). These results indicate that even in the very elderly stratum of the population, antihypertensive treatment does not only prevent cardiovascular morbid events but also translates into prolongation of life.
In conclusion, an evidence-based general recommendation can now be given to prescribe antihypertensive treatment to octogenarians with SBP above 160 mmHg with the target to lower it below 150 mmHg, but because of differences in the general health of very elderly patients, the decision to treat should be taken on an individual basis, and BP lowering should be in any case gradual and carefully monitored by the doctor.
Although diabetic-dependent microvascular complications are all related to BP within a wide range of values , antihypertensive treatment appears to affect them in a different fashion. BP reduction has a pronounced protective effect on renal complications (see Renal disease section). However, it does not appear to substantially affect neuropathy , whereas data on the ability of BP-lowering strategies to protect against eye complications are not consistent. Several years ago, the UKPDS study  reported a reduced incidence of various eye lesions (and of eye interventions) in hypertensive type 2 diabetic patients under tight versus those under standard BP control, strengthening the favorable conclusion drawn from previous smaller or less controlled studies [86,247,248]. However, no significant beneficial effects of BP reduction by an ACE inhibitor–diuretic combination on eye complications has recently been reported in the hypertensive type 2 diabetic patients of ADVANCE [88,249], and substantially negative data have also resulted from the DIRECT trial in normotensive type 1 diabetic patients in whom BP was reduced by an angiotensin receptor antagonist . Interestingly, the inconsistency between older and more recent studies extends to the effect of tight blood glucose control on eye complications, with favorable reports from UKPDS  and negative ones from ADVANCE . Whether a protective effect of BP and glucose control on diabetic retinopathy may only be observed in early phases of the disease and on appearance rather than progression of retinopathy remains to be tested by specific trials.
As mentioned in previous sections, in the last 2 years, further evidence has accumulated in favor of targeting reduction of microalbuminuria and proteinuria, mostly through blockers of the renin–angiotensin system, in order to reduce end-stage renal disease and cardiovascular events. A post hoc analysis of RENAAL data indicates that the incidence of end-stage renal disease showed an independent relationship with SBP and albuminuria reduction, suggesting that improving renal outcomes in patients with diabetic nephropathy may require a dual strategy, targeting both BP and albuminuria . Also, in the type 2 diabetic patients of ADVANCE, urinary protein excretion (both baseline and on-treatment values) has been reported to be closely correlated with the primary outcome of the study (macrovascular and microvascular events) . On the contrary, ONTARGET has recently reported that the combination of full doses of the ACE inhibitor ramipril and the angiotensin receptor antagonist, telmisartan, though reducing BP a few mmHg more than therapy with either ramipril or telmisartan and influencing progress of proteinuria to a slightly but significantly greater extent, was accompanied by a greater incidence of renal outcomes (mostly acute dialysis and doubling of serum creatinine) and by no further reduction of cardiovascular outcomes [53,191]. As mentioned in a previous section, only a minority (about 4%) of ONTARGET patients had overt proteinuria at baseline, whereas worsening of renal outcomes mostly occurred in the patients without baseline microproteinuria or macroproteinuria, in whom changes in urinary protein excretion could only differ to a minor degree . Finally, the changes in urinary protein excretion were small and so the between-treatment differences in renal outcomes were quite infrequent (2.03, 2.21, and 2.49% with ramipril, telmisartan, and the combination, respectively). Therefore, ONTARGET patients can hardly be compared to the more severe nephropathy cohorts in whom the role of urinary protein excretion in predicting end-stage renal disease was mostly investigated. When the effects of telmisartan versus placebo on renal outcomes were studied in the TRANSCEND trial , no significant differences were found as far as rate of GFR decline and end-stage renal disease is concerned . No data on renal outcomes are available from PROFESS , also comparing telmisartan with placebo.
It has been pointed out that the results of the PROGRESS trial, though clearly showing the benefits of lowering BP in patients with previous cerebrovascular events , cannot be taken to support a recommendation to initiate BP-lowering treatment in cardiovascular patients with BP in the high normal range, as in this trial the benefits of treatment were seen only in individuals with a baseline SBP of 140 mmHg and above, who often were on antihypertensive drugs already . Nor can the PROGRESS data be taken to support a SBP target below 130 mmHg, as the average SBP achieved on more intense treatment was 132 mmHg. However, the trial did show that an on-treatment SBP of 132 mmHg was better than an on-treatment SBP of 141 mmHg, that is, the average SBP of the placebo patients. In the other trial that first showed the benefits of BP lowering in patients with cerebrovascular disease, the PATS study , SBP values remained too high (143 and 149 mmHg in the active and placebo arms of the trial, respectively) to help clarify when to initiate treatment and to what level should BP be lowered in cerebrovascular patients. The same is the case for ACCESS . Finally, it cannot be denied that the matter has been further confused by the recent publication of the negative results of the PROFESS study . In this very large trial, in patients with previous stroke or transient ischemic attack, bringing SBP to 136 mmHg by adding telmisartan, rather than to 140 mmHg by adding placebo, was not accompanied by any significant reduction in recurrent strokes or major cardiovascular events. Various interpretations have been given for these unexpected negative findings: the small BP difference, in line with the evidence from the PROGRESS that the small BP difference in patients on monotherapy also failed to significantly reduce outcomes, the short duration of the follow-up (only 2.5 years), the frequent use of concomitant therapy (all patients were on antiplatelet agents and half of them were on lipid-lowering agents), the large dropout of patients during treatment, and the initiation of treatment very close to the qualifying cerebrovascular event. The fact remains that PROFESS has not really helped to clarify the remaining issues about antihypertensive treatment of the cerebrovascular patient.
A matter of continuing concern is the optimal BP management during the acute phase of stroke. The results of a small trial, the Controlling Hypertension and Hypotension Immediately Post-Stroke (CHHIPS), suggest a beneficial impact of administering lisinopril or atenolol in patients with acute stroke and a SBP more than 160 mmHg , but many of the current uncertainties remain to be clarified.
It has already been extensively discussed whether the current recommendation to lower SBP below 130 mmHg in patients with concomitant coronary heart disease is well founded. It has been pointed out that some of the analyses of recent trials raising the possibility that low achieved BP values are associated with increased rather than decreased risk of cardiovascular outcomes [113,115] are post hoc with well known limitations. It has also been recognized that a reappraisal of all trials of antihypertensive agents in patients with coronary heart disease has provided contradictory evidence on the presence or absence of benefits of lowering SBP below 130 mmHg . Until firmer evidence is provided by new trials, it appears reasonable to lower SBP down to the 130–139 mmHg range in patients with concomitant coronary heart disease.
The failure to significantly reduce heart failure with preserved systolic function in the I-PRESERVE study  has to be pointed out. Although this type of heart failure is most often related to hypertension, in I-PRESERVE randomization to the angiotensin receptor antagonist, irbesartan, or to placebo, in more than 4000 patients with chronic heart failure and a left ventricular ejection fraction more than 0.45 (88% of whom had a history of hypertension) did not show any difference in the primary endpoint of death from any cause or hospitalization for a cardiovascular cause as well as in the secondary outcome of a composite of heart failure events. This occurred despite a 3.5/2.0 mmHg SBP/DBP difference in favor of irbesartan. The negative results of I-PRESERVE, however, should be seen in the context of the complex design of the trial, in which a background of intense antihypertensive therapy, including 25% of ACE inhibitors (39% during the trial), was maintained, and initial BP was only 136/79 mmHg, thus further strengthening the question as to whether lowering SBP much below 140 mmHg is of any further benefit. It should be noted that 59% of I-PRESERVE patients were on antiplatelet agents, 19% on oral anticoagulant therapy, and 30% on lipid-lowering agents.
The efficacy of angiotensin receptor antagonists in the prevention of heart failure has come under some discussion also as a result of the TRANSCEND  and PROFESS  studies. In both these placebo-controlled trials, randomization to telmisartan did not reduce the incidence of hospitalization for heart failure below that occurring on placebo. In ONTARGET , the number of hospitalizations for heart failure was lower (though not significantly) with ramipril than with telmisartan. However, the risk of heart failure in all these trials was rather low, and definitive conclusions cannot be reached at present.
This aspect deserves a brief comment because of the recent publication of a new meta-analysis from the Blood Pressure Lowering Treatment Trialists' Collaboration, investigating benefit of antihypertensive treatment in men and women : both BP lowering and reduction in outcomes were similar in the two sexes and no sex-related differences in response to various classes of antihypertensive agents could be detected.
Erectile dysfunction is a prevalent condition in hypertensive patients and a predictor of future cardiovascular events. Screening and treatment of erectile dysfunction improves management of cardiovascular risk factors. After initiating therapy with phosphodiesterase (PDE) 5 inhibitors, patients are more likely to take antihypertensive medication and BP control is improved . Older antihypertensive drugs (diuretics, β-blockers, centrally acting drugs) exert negative effects, whereas newer drugs have neutral or beneficial effects (calcium antagonists, ACE inhibitors, angiotensin receptor antagonists, nebivolol) .
A large meta-analysis has just been published of serious cardiovascular outcomes and major bleeds in six primary prevention trials (95 000 individuals at low cardiovascular risk, 660 000 person-years) and 16 secondary prevention trials (17 000 individuals at high cardiovascular risk, 43 000 person-years) that compared long-term aspirin versus control . In the primary prevention trials, aspirin allocation led to a significant 12% reduction in serious cardiovascular events (mostly nonfatal myocardial infarction). However, as a consequence of the overall low risk of the individuals, absolute event reduction amounted to only 0.06 events per 100 patient-years, which was counterbalanced by an absolute increase in major gastrointestinal and extracranial bleeds of 0.03 bleeds per 100 patient-years. In the secondary prevention trials, aspirin allocation yielded a greater absolute reduction in serious cardiovascular events (1.5 event per 100 patient-years). Although only few secondary prevention trials carefully reported bleed incidence, data from trials reporting bleeds suggest an extracranial bleed excess of no more than 0.2 event per 100 patient-years. It can, therefore, be concluded that, although administration of aspirin has a clear benefit/harm ratio in patients with cardiovascular disease, there is only a very tiny excess of benefit over harm in the low-risk patients included in primary prevention trials.
Of course, the division between primary and secondary prevention is artificial and arbitrary, and individuals who have not yet experienced a cardiovascular event can be at very different levels of total risk. Attention has been directed to the possible benefits of aspirin in patients with diabetes but still free of overt cardiovascular disease. In the hypertensive patients with diabetes in the HOT study, cardiovascular outcome reduction by aspirin did not achieve statistical significance [280,281], nor was a clear benefit seen in diabetic patients included in other trials . Furthermore, the recent findings of a large primary prevention study carried out on diabetic patients in Japan could only show that low-dose aspirin was associated with a nonsignificant reduction in cardiovascular outcomes . Therefore, the benefits of antiplatelet therapy in diabetes remain to be established.
The finding that in the HOT study, the greatest benefit of low-dose aspirin and the best benefit/harm ratio occurred in patients with serum creatinine more than 1.3 mg/l  has been further elaborated by estimating GFR and calculating the effects of aspirin versus placebo in three groups with eGFR 60 ml/min per 1.73 m2 or more, 45–59 ml/min per 1.73 m2, and less than 45 ml/min per 1.73 m2. There was a significant trend for increasing reduction in major cardiovascular events and death with progressive decline in eGRF, the reduction being particularly marked in hypertensive patients with eGFR less than 45 ml/min per 1.73 m2. In this group of patients, the risk of bleeding was modest as compared with the cardiovascular benefit .
In the past 10–15 years, several trials of antihypertensive therapy have been completed, but these have mostly centered on comparisons between different agents or focused on high cardiovascular risk patients, and have used so complex designs and so numerous concomitant therapies as to often make interpretation of their results difficult and controversial (Box 9). Although these trials have nevertheless added further useful information, some major issues have not been explored or have been insufficiently clarified. As a consequence, many important decisions on hypertension management are currently taken only on the basis of post hoc analyses of trial data relating cardiovascular events to achieved BP values, which have notorious limitations because of loss of randomized design and potential differences in baseline risk of patients achieving different BP values. Therefore, it appears highly desirable that recommendations on the BP threshold for initiation of drug treatment and on BP targets in different groups of patients are supported by information from prospective randomized trials designed to address persisting gaps in current knowledge.
The following issues appear in urgent need to be approached by simply designed trials:
We are grateful to Fosca Quarti-Trevano, MD, Ms Clara Sincich, Ms Cinzia Tiberi and Ms Donatella Mihalich for their valuable help.
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