Journal of the American Society of Hypertension
Volume 2, Issue 4, Supplement , Pages S3-S9, July 2008

The broadening landscape for hypertension management

Based on material presented at a Boehringer Ingelheim-Sponsored Meeting held in Madrid, Spain, May 4–5, 2007.

  • Giuseppe Mancia, MD

      Affiliations

    • Corresponding Author InformationCorresponding author: Giuseppe Mancia, MD, Clinica Medica, Dipartmento di Medicina Clinica e Prevenzione, Università Milano-Bicocca, Ospedale San Gerardo, Monza, Milan, Italy. Tel: +39 039 233 3357; fax: +39 039 322274.

Clinica Medica, Dipartmento di Medicina Clinica e Prevenzione, Università Milano-Bicocca, Ospedale San Gerardo, Monza, Milan, Italy

Article Outline

Abstract 

Several lines of evidence show that office blood pressure (BP) reduction can substantially decrease the risk of major cardiovascular events in hypertensive patients. It is also increasingly recognized that home and 24-hour ambulatory BPs provide additional prognostic information, and there is evidence to suggest that BP lowering over the 24-hour period is crucial for optimal risk reduction. However, BP is often difficult to control, even under the near-optimal conditions of clinical trials. Ideally, antihypertensive therapy should aim to control both office and out-of-office (i.e., 24-hour) BPs, and multiple risk factors in order to provide optimal cardiovascular risk reduction. This approach usually necessitates the use of polypharmacy with an attendant increase in costs and the risk of adverse events. For these reasons, increasing attention is being devoted to drugs that exert beneficial, BP-independent effects on target-organ damage or reduce the incidence of conditions (such as diabetes and metabolic syndrome) that are associated with high cardiovascular risk. Several studies have consistently shown that the incidence of new-onset diabetes is lower with angiotensin receptor blockers, angiotensin-converting enzyme inhibitors, and calcium antagonists than “older” drugs such as diuretics and beta-blockers. However, long-term studies examining target-organ protection may more fully illustrate the BP-independent benefits of specific antihypertensive agents.

Keywords: Antihypertensive therapy, blood pressure, cardiovascular risk, target-organ damage

 

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Introduction 

The importance of hypertension as a cardiovascular risk factor has been amply demonstrated in epidemiological studies. Furthermore, hypertension has been the first cardiovascular risk factor to have been studied in randomized trials based on ‘hard’ endpoints such as cardiovascular morbid and fatal events.1 Such studies have shown that blood pressure (BP) reduction is associated with a 20% to 25% decrease in myocardial infarction and a 35% to 40% decrease in stroke.2 It is widely accepted that a substantial proportion of these benefits is attributable to BP reduction. However, antihypertensive therapy may offer additional benefits, including the reduction of target-organ damage, that are independent of BP.

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Importance of BP Reduction in Decreasing Cardiovascular Risk 

Several lines of evidence show that BP reduction per se can substantially decrease the risk of major cardiovascular events. For example, in the Blood Pressure Lowering Treatment Trialists' Collaboration,3 which incorporated data from 29 randomized trials based on different treatments involving a total of 162,341 patients, there were linear relationships between the relative risk of stroke or coronary heart disease (CHD) and the decrease in systolic blood pressure (SBP) achieved. That is, despite the different treatment types, the greater was the treatment-induced BP reduction, and the greater was the size of the benefit.

Also, an analysis from the Valsartan Antihypertensive Long-term Use Evaluation (VALUE) Study compared the reductions in cardiovascular risk achieved with the angiotensin receptor blocker (ARB) valsartan and the dihydropyridine calcium antagonist amlodipine.4 Among patients in whom BP control was achieved, i.e., in whom SBP was reduced by treatment to <140 mm Hg, the odds ratio (OR) for the risk of fatal or nonfatal cardiovascular events was 0.76 (95% confidence interval [CI], 0.66 to 0.88) with valsartan compared with 0.73 (95% CI, 0.63 to 0.85) for amlodipine. Thus, in this study both treatments were equally capable of reducing cardiovascular events, an effect which originated from the BP reduction, regardless of how it was achieved. Similar findings were obtained in the INternational VErapamil Sr-Trandolapril (INVEST) Study5 in which the incidence of cardiovascular events was less in patients achieving an SBP <140 mm Hg compared with those in whom no BP control was obtained, regardless of the type of treatment used (calcium antagonist plus angiotensin-converting enzyme [ACE] inhibitor or beta-blocker plus diuretic) and the patients' clinical condition.

Finally, there is evidence that in high-risk individuals such as those with renal disease, coronary disease, or cerebrovascular disease and diabetes, a greater degree of protection can be obtained via more aggressive BP reductions and BP targets not just lower than 140/90 mm Hg but lower than 130/80 mm Hg (Figure 1). For example, in the Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) trial in 6,105 patients with a history of cerebrovascular events, treatment with perindopril (alone or in combination with indapamide) produced a progressively greater reduction in the risk of recurrent ischemic or hemorrhagic stroke in subgroups of patients with achieved SBPs from above 160 mm Hg to 140 to 159 mm Hg, 120 to 139 mm Hg, and less than 120 mm Hg.6 Moreover, there were significant associations between the incidence of both ischemic (P =.0005) and hemorrhagic (P < .0001) stroke and achieved SBP over the range, 112 to 168 mm Hg.

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  • Figure 1. 

    Overview of the studies that have provided evidence that in patients at high-risk (i.e., renal disease, diabetes, coronary artery disease, or cerebrovascular disease) cardiovascular protection is greater if: 1) BP is more aggressively reduced and target values are set at less than 130/80 mm Hg; and 2) antihypertensive drug treatment is started at BP values below 140/90 mm Hg. ABCD, Alternans Before Cardioverter Defibrillator Trial; ADVANCE, Action in Diabetes and Vascular Disease Trial; BP, blood pressure; CAD, coronary artery disease; CAMELOT, Comparison of Amlodipine vs. Enalapril to Limit Occurrences of Thrombosis Trial; EUROPA, European Trial on Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease; HOPE, Heart Outcomes Prevention Evaluation trial; HOT, Hypertension Optimal Treatment Study; IDNT, Irbesartan Diabetic Nephropathy Trial; INVEST, International Verapamil-Trandolapril Study; PROGRESS, Perindopril Protection against Recurrent Stroke Study; TIA, transient ischemic attack; UKPDS, United Kingdom Prospective Diabetes Study.

In the PROGRESS Study the reductions in BP achieved in hypertensive patients were similar to those in nonhypertensive patients (mean decreases 9.5/3.9 mm Hg and 8.8/4.2 mm Hg, respectively), and the standardized reductions in the risk of stroke or cardiovascular events were also similar in the two cohorts (Figure 2).7 These findings as well as those obtained in other studies (Figure 1) create a strong case for initiating treatment in high-risk patients irrespective of BP, a conclusion recently supported also by the results of the Effects of a Fixed Combination of Perindopril and Indapamide on Macrovascular and Microvascular Outcomes in Patients With Type 2 Diabetes Mellitus (ADVANCE) Study on normotensive and hypertensive diabetic patients.8

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  • Figure 2. 

    Reductions in relative risk of stroke of major cardiovascular events achieved with antihypertensive therapy in hypertensive and nonhypertensive patients in the PROGRESS Trial. CI, confidence interval; PROGRESS, Perindopril Protection against Recurrent Stroke Study Trial. Reprinted with permission from PROGRESS Collaborative Group. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6,105 individuals with previous stroke or transient ischemic attack. Lancet 2001;358:1033–41.7

Out-of-Office BP and Cardiovascular Risk 

Much of the evidence for the benefits of antihypertensive therapy in decreasing the risk of cardiovascular events has been based on measurements of office BP. However, there is increasing evidence that BPs measured out-of-office (ambulatory or home BPs) are also important determinants of cardiovascular risk. Important insights into this issue have come from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) Study, in which office, home, and 24-hour ambulatory BPs were monitored for a mean of 131 months in 2,051 subjects recruited from the general population in Monza (Milan, Italy). This study showed that the relationship between BP and cardiovascular mortality was exponential.9 The steepest relationship was seen with 24-hour BP, followed by home BP and then office BP. Furthermore, the risk of cardiovascular death showed a progressive increase from one, two, and three BP elevations (regardless of whether the elevation involved clinic, home, or ambulatory values) above their respective normality values (Figure 3).9, 10 These trends remained significant after adjustment for age, gender, and other cardiovascular risk factors. Thus, out-of-office BP measurements provide complementary prognostic information to office BP. This implies that, while control of office BP is clearly important for decreasing cardiovascular risk, treatment should ideally aim to control out-of-office (i.e., 24-hour) BP as well.11

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  • Figure 3. 

    Kaplan-Meyer curves for cardiovascular mortality over an 11-year follow-up in the subjects of the PAMELA Study in whom office, home, and 24-hour mean BP were all normal or one, two, or three BPs were elevated (regardless of whether the elevation involved clinic, home, or ambulatory values). Values separating office, home, and ambulatory BP normality from elevation were 140/90 mm Hg, 132/83 mm Hg, and 125/79 mm Hg, respectively.10, 11 BP, blood pressure; PAMELA, Pressioni Arteriose Monitorate e Loro Associazioni Study.

There is also evidence to suggest that BP fluctuations within a 24-hour period may be prognostically important (see article by McInnes in this supplement). In particular, nocturnal BP and BP variability are emerging as significant cardiovascular risk factors. For example, a recent analysis from the PAMELA Study,12 which investigated the relationship between SBP and diastolic blood pressure (DBP) variability and the risk of cardiovascular death, showed that day-night and preprandial-postprandial differences accounted for more than 95% of the variability in DBP. The remaining variability, the individual residual variability, was assumed to reflect erratic DBP variations. During the 148-month follow-up period, there was no significant relationship between preprandial-postprandial BP changes and the risk of morbidity. However, the risk showed: 1) a significant inverse relationship with the day-night DBP difference (beta coefficient = −0.040; P < .02); and 2) a significant direct relationship with residual DBP variability (beta coefficient = 0.175; P < .002). Thus, mortality was: 1) lower among participants in whom BP decreased during the night (“dippers”) than in those in whom the decrease was less (“nondippers”); and 2) in participants who had greater erratic BP variations compared with those in whom these variations were less erratic.

Studies such as the PAMELA Study highlight the complex nature of the relationship between BP and cardiovascular risk. It is clear that hypertension should no longer be regarded as merely an elevation of office BP; circadian and other variations in both office and out-of-office BPs can markedly influence the risk of cardiovascular events.

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Difficulties in Controlling BP 

There is general agreement that BP is often difficult to control, even under the near-optimal conditions of clinical trials, where motivated patients are intensively managed and often receive combination therapy to achieve BP targets. A review of 16 randomized controlled trials published during the late 1990s and early 2000s shows that, while DBP is often well controlled, SBP remains uncontrolled in a significant proportion of patients: approximately 90% of patients in these studies achieved DBP below 90 mm Hg, whereas only 50% approximately of patients achieved SBP below 140 mm Hg.13 The situation is even less satisfactory in diabetic patients, in whom BP targets are more stringent because of the higher cardiovascular risk associated with hypertension; the BPs achieved were generally higher than in nondiabetic patients, despite the use of larger numbers of drugs.13

Consistent control of 24-hour ambulatory BP and office BP can also be extremely difficult to achieve. In a meta-analysis of 44 randomized controlled trials, involving approximately 5,800 patients, mean office SBP and DBP decreased during treatment from 161.9 mm Hg to 142.8 mm Hg, and from 100.2 mm Hg to 89.9 mm Hg, respectively. By contrast, mean 24-hour SBP decreased from 151.5 mm Hg to 139.0 mm Hg, and 24-hour DBP decreased from 94.5 mm Hg to 86.2 mm Hg.14 The mean office BP value obtained (142.8/89.9 mm Hg) was only slightly higher than the office BP target (140/90 mm Hg), whereas the mean 24-hour BP (139.0/86.2 mm Hg) was much greater than the 24-hour BP target (125/80 mm Hg), i.e., the value that is believed to represent the upper normality value for 24-hour mean BP.

Achieving effective control of BP in general practice is also an issue. In the Blood Pressure Control and Risk of Stroke in Untreated and Treated Hypertensive Patients Screened From Clinical Practice (FORLIFE) Study, which included 12,792 hypertensive patients (7,512 treated) recruited from primary care practices in Italy, BP below 140/90 mm Hg was achieved in only 18.4% of treated patients, while among diabetic patients the optimal target (recommended by guidelines, i.e., 130/80 mm Hg) was achieved in only 3%.15 Clearly, there remains considerable scope to improve the management of hypertension in routine clinical practice (see article by Williams in this supplement).

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Hypertension Management in Relation to Other Cardiovascular Risk Factors 

There is evidence to indicate that cardiovascular risk may remain high even when BP is controlled. In one study, the incidence of cardiovascular mortality was compared in 686 treated hypertensive men, aged 47 to 55 years at screening, and 6,810 nonhypertensive men over 22 to 23 years.16 BP control in the hypertensive men remained good throughout the study, with mean BPs comparable with those in the nonhypertensive men. However, the risk of cardiovascular mortality remained elevated despite this effective antihypertensive treatment. Overall mortality among treated hypertensive men was 37.4%, compared with 29.2% in nonhypertensive men (OR, 1.6; 95% CI, 1.4 to 2.1); this was largely attributable to an increased risk of cardiovascular disease (27.6% vs. 14.2%, respectively), particularly CHD (20.1% vs. 10.3%; OR, 1.9; 95% CI, 1.6 to 2.3).

These findings highlight the importance of multiple risk factors as determinants of total (or global) cardiovascular risk. It is now recognized that hypertension seldom occurs alone. For example, in a series of 3,812 consecutive patients with essential hypertension treated by cardiovascular specialists in Italy, only 13.7% had hypertension alone: 39.8% had one additional risk factor, such as diabetes, dyslipidemia, or obesity; 32.4% had two additional risk factors; and 14.1% had three or more additional risk factors.17 There are also significant associations between BP and metabolic variables. In the PAMELA Study, office, home, and 24-hour BP each showed significant (P < .05) associations with total and high-density lipoprotein cholesterol, serum glucose, and body mass index.18 These associations persisted after adjustment for age, gender, and antihypertensive therapy.

Evidence that controlling multiple risk factors in addition to BP results in a reduction in total cardiovascular risk comes from the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), which involved 19,342 hypertensive patients with at least three other cardiovascular risk factors. In the lipid-lowering arm of this trial,19 the addition of a statin to antihypertensive therapy reduced the incidence of fatal CHD or nonfatal myocardial infarction by 36% (hazard ratio [HR], 0.64; 95% CI, 0.50 to 0.83; P = .0005), compared with placebo, and there were also significant reductions in all cardiovascular events (HR, 0.79; 95% CI, 0.69 to 0.90; P = .0005) and all CHD events (HR, 0.71; 95% CI, 0.59 to 0.86; P = .0005).

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Importance of BP-Independent Benefits and Target-Organ Protection 

Although studies such as the ASCOT Trial19 have clearly demonstrated the benefits of treating the multiple cardiovascular risk factors that frequently present in hypertensive subjects, such an approach necessitates the use of several drugs, thereby increasing costs and the potential for adverse effects. For this reason, improving antihypertensive therapy by the use of drugs that exert specific and BP-independent protective effects against target-organ damage is an attractive option. However, most major randomized trials in high-risk patients have demonstrated no unequivocal differences in efficacy, in terms of reductions in cardiovascular events, between classes of antihypertensive agents.20, 21 The few exceptions (4 out of 19 trials) all involve a reduced incidence of events in the group treated with a blocker of the renin-angiotensin system (RAS) (Figure 4).20

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  • Figure 4. 

    Effects on cardiovascular morbid or fatal events of trials comparing different antihypertensive drugs. ACE-I, angiotensin-converting enzyme inhibitor; ALLHAT, Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial; ANBP2, Australian National Blood Pressure Study Group; ARB, angiotensin receptor blocker; ASCOT, Anglo-Scandinavian Cardiac Outcomes Trial; BB, beta-blockers; CA, calcium antagonists; CAPPP, Captopril Prevention Project; CCB, calcium-channel blocker; CHD, coronary heart disease; CI, confidence interval; CONV, conventional treatment; CVD, cardiovascular disease; D, diuretic treatment; HAPPHY, Heart Attack Primary Prevention in Hypertension Trial; IPPPSH, International Prospective Primary Prevention Study in Hypertension; INSIGHT, International Nifedipine GITS Study: Intervention as a Goal in Hypertension Treatment; INVEST, International Verapamil-Trandolapril Study; LIFE, Losartan Intervention For Endpoint reduction in hypertension Study; MOSES, MOrbidity and mortality after Stroke, Eprosartan compared with nitrendipine for Secondary prevention; NORDIL, Nordic Diltiazem Study; SCOPE, Study on COgnition and Prognosis in the Elderly; STOP2, Stent vs. Thrombolysis for Occluded Coronary Arteries in Patients With Acute Myocardial Infarction 2 Study; VALUE, Valsartan Antihypertensive Long-Term Use Evaluation Study. Reproduced with permission from Mancia G. Role of outcome trials in providing information on antihypertensive treatment: importance and limitations. Am J Hypertens 2006;19:1–7.20

There is in contrast much more evidence that although BP reduction remains important, direct protective effects of some antihypertensive drugs may play important roles during earlier stages of the “cardiovascular continuum”.1 Antihypertensive therapy has been shown to have beneficial effects on markers of subclinical organ damage that are associated with a poor prognosis, such as endothelial dysfunction, arterial thickening or plaques, cardiac and vascular remodeling, and increased urinary protein excretion or other markers of renal damage.22 Furthermore, there is evidence that antihypertensive therapy can reduce the incidence of conditions associated with a high cardiovascular risk, such as atrial fibrillation and diabetes. For example, in a meta-analysis of 11 randomized trials involving over 56,300 patients,23 blockade of the RAS with ACE inhibitors or ARBs was found to reduce the incidence of atrial fibrillation by 28% (95% CI, 15% to 40%; P = .0002); the two classes of drugs were comparable in efficacy (ACE inhibitors: 28% reduction; P = .01; ARBs: 29% reduction; P = .00002). Similarly, studies have consistently shown that the incidence of new-onset diabetes during antihypertensive therapy is lower with drugs such as ARBs, ACE inhibitors, and calcium antagonists than during treatment with “older” drugs such as diuretics and beta-blockers (Figure 5).24 There is also evidence that ACE inhibitors and ARBs may be significantly more effective than placebo in reducing the risk of new-onset diabetes, although these data should be interpreted with caution since ACE inhibitors or ARBs were given in addition to multiple background therapies in which diuretics and beta-blockers predominated (Figure 5).24

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  • Figure 5. 

    Comparison of “new” and “old” antihypertensive agents for the outcome of new-onset diabetes. ACEI, angiotensin-converting enzyme inhibitor; ALPINE, Antihypertensive treatment and Lipid Profile In a North Sweden Efficacy evaluation; other abbreviations as in Figure 4. Reproduced with permission from Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens 2006;24:3–10.24

The recent guidelines on hypertension of the European Society of Hypertension and the European Society of Cardiology25 emphasize the importance of adopting early cardiovascular protective strategies as well as to consider treatment goals not only for the prevention of events but also improvements of target-organ damage, metabolic risk factors, and delay in the appearance of high cardiovascular risk diseases.

In the Hypertension Detection and Follow-up Program, in which patients were given either stepped care or referred care (control group), antihypertensive treatment reduced mortality to a greater extent in high- than in low-risk individuals.26 In treated high-risk individuals, however, the residual risk remained almost four times higher than in treated low-risk ones, indicating that late interventions cannot completely reverse a high-risk condition, and thus, measures taken at earlier stages are needed.

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Conclusion 

The landscape of hypertension is changing. Increasingly, the aims of management are shifting away from a focus on controlling office BP to encompass the 24-hour BP profile and its attendant variability. In addition, there is accumulating evidence from large randomized intervention studies that some antihypertensive agents, such as the ARBs and ACE inhibitors, also exert tissue-protective effects to reduce the risk of end-organ damage, in addition to their antihypertensive action. The relative benefits of these BP-dependent and -independent actions will vary according to circumstances; long-term studies examining target-organ protection may more fully illustrate the BP-independent benefits of specific antihypertensive agents.

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References 

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  23. Healey JS, Baranchuk A, Crystal E, Morillo CA, Garfinkle M, Yusuf S, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (A meta-analysis). J Am Coll Cardiol. 2005;45:1832–1839
  24. Mancia G, Grassi G, Zanchetti A. New-onset diabetes and antihypertensive drugs. J Hypertens. 2006;24:3–10
  25. Mancia G, De Backer G, Dominiczak A, Cifkova R, Fagard R, Germano G, et al. 2007 ESH-ESC guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Blood Press. 2007;16:135–232
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 Conflict of interest: none.

PII: S1933-1711(08)00039-9

doi:10.1016/j.jash.2008.03.003

Journal of the American Society of Hypertension
Volume 2, Issue 4, Supplement , Pages S3-S9, July 2008

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