Protecting hypertensive patients with stable coronary artery disease: new lessons from the evidence




Kim FOX, MD, FRCP, FESC
Professor of Clinical Cardiology
Department of Cardiology Royal Brompton Hospital
London, UK

Protecting hypertensive patients with stable coronary artery disease: new lessons from the evidence
by K. Fox, United Kingdom

In patients with arterial hypertension and coronary artery disease (CAD), mortality remains high despite the positive decreasing trend observed over the last few decades. This article will examine options to further improve the pharmacological management of hypertension in contemporary, optimally treated patients with stable CAD, taking into consideration lessons from recent clinical trials and analyses. Specific therapy for hypertension in the presence of CAD is chosen based on pathophysiological mechanisms common to both, such as overactivation of the renin-angiotensin-aldosterone system (RAAS) and early vascular aging, which mediate damage to target organs, including coronary vessels and the myocardium. One should also note that our traditional beliefs about blood pressure (BP) goals, as well as about the accuracy of “usual” BP in predicting the risk of cardiovascular (CV) events, have been challenged. In addition to brachial BP reduction, the reduction of other key BP parameters—BP variability, 24-hour BP, and central BP—has been shown to be important if we are to improve the quality of antihypertensive therapy to improve outcomes in populations at high CV risk. Inhibitors of the RAAS, especially angiotensin-converting enzyme (ACE) inhibitors, with a proven efficacy to improve prognosis and with proven dosages, should be considered as first-line treatment for hypertension, particularly in the presence of CAD. The results of some recent large trials have supported the rationale for combining ACE inhibitors and calcium channel blockers (CCBs) in hypertensive patients, including those with stable CAD.

Medicographia. 2012;34:39-47 (see French abstract on page 47)

The coexistence of hypertension and coronary artery disease (CAD) has a substantial negative impact on a patient’s clinical profile and prognosis. Arterial hypertension is one of the most common and important factors responsible for the development and manifestation of CAD. Hypertension is present in 47% of CAD patients1 and responsible for up to 54% of cardiovascular (CV) deaths.2 Evidence of this fact is that more effective reductions in blood pressure (BP) and total cholesterol levels, as well as reduction in the prevalence of current smokers, account for the large decline in mortality rate from CAD in the United States from 1980 to 2000.3 However, epidemiological data reported in 2011 still indicate the existence of a large gap between the rates of all-cause and CV mortality in the hypertensive and nonhypertensive CAD populations. The age-adjusted rate of mortality in CAD is almost double in hypertensive patients compared with those without hypertension (3.6 and 1.9 per 1000 person-years, respectively).4

This coexistence of hypertension and CAD also determines specific treatment objectives and approaches, because both hypertension and CAD are vascular diseases with common pathophysiological mechanisms. These mechanisms lead to the development of the diffuse arteriosclerosis seen in hypertension, the more patchy atherosclerotic lesions of epicardial CAD, and the remodeling of conduit and resistant arteries, as well as medium and small coronary arteries. Prevention and reversal of these processes are major goals of therapy in hypertension and CAD.

Common pathophysiological relationships between mechanisms in hypertension and CAD

_ Blood pressure and blood flow are the most important physical forces influencing cardiac and vascular structure and function. Increased myocardial oxygen demand and diminished coronary blood flow or, at least, diminished coronary flow reserve, are common features of hypertension and CAD.
– When systolic blood pressure (SBP) is elevated, there is an increase in both left ventricular (LV) output impedance and intramyocardial wall tension, which increases myocardial oxygen demand.
– Diminished coronary flow reserve is a complex function of plaque-related occlusive CAD, remodeling of medium and small coronary arteries, and, if diastolic pressure is low enough, a decrease in coronary perfusion pressure.

_ Early vascular aging is commonly seen in patients with hypertension. Vascular aging, an inescapable fact of life, is drastically accelerated by elevated BP.5
– Hypertension prompts degenerative vascular changes and endothelial dysfunction, leading to increased arterial rigidity. Systolic hypertension with enhanced pulse pressure is one of the clinical manifestation of early vascular aging.6

– As a consequence of arterial stiffening, and resultant increases in pulse wave velocity and pulse wave reflection, SBP is not constant within the arterial tree and varies substantially between peripheral and central arteries, as described by both invasive and noninvasive studies.7 Increased central SBP greatly increases the LV pressure load, cardiac work, afterload, and pressure-related cardiac pathology, including CAD (angina pectoris) and LV hypertrophy. At the same time, decreased diastolic blood pressure (DBP) has the potential to compromise coronary perfusion pressure.
– Structural and functional variations in arterial properties are also thought to be responsible for increased BP variability, which may contribute to acceleration of structural changes of the heart and perturbation of coronary perfusion, especially in the presence of CAD.8

_ Oxidative stress is another critical feature in both hypertension and atherogenesis. Excess generation of reactive oxygen species provokes a low-grade, self-perpetuating vascular inflammatory process, damages endothelial and muscle cells, helps perpetuate the ongoing atherosclerotic process, and leads to acute and chronic changes in CV structure and function.9,10

_ Renin-angiotensin-aldosterone system (RAAS) hyperactivity is among the mechanisms responsible for the initiation and maintenance of hypertension and CAD. Angiotensin II elevates BP and promotes target-organ damage, including atherosclerosis, by a large variety of mechanisms. Angiotensin II has a direct effect on vasoconstriction, aldosterone synthesis and release, enhancement of sympathetic stimulation from the brain, and facilitation of catecholamine release from the adrenal glands and peripheral sympathetic nerve terminals.11,12 Angiotensin II promotes cardiac and vascular smooth muscle cell hypertrophy directly via activation of the angiotensin II type 1 receptor, and indirectly by stimulating the expression of a number of growth factors and cytokines. Finally, there is a link between RAAS activation and fibrinolysis,13 as well as evidence of a link between the RAAS and dyslipidemia, in which the RAAS stimulates the accumulation of lowdensity lipoprotein cholesterol in the arterial wall.14 Therefore, antihypertensive drugs may exert at least some of their beneficial effects on the vasculature by actions that are independent of BP lowering alone. In addition, RAAS inhibitors have been shown to block the activation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase, thus limiting the degree of oxidative processes in the vasculature. This finding further supports the concept that RAAS blockers may have vasoprotective effects beyond BP lowering alone.15

_ Calcium is also one of the crucial elements in the pathogenesis of hypertension and CAD. Calcium ions are major intracellular mediators of vascular smooth muscle cell contraction, as well as of inotropic and chronotropic functions of the heart. In addition to these acute regulatory functions, increased in- tracellular calcium has atherosclerosis-promoting effects.16 Absence of coronary artery calcification has been associated with a favorable prognosis.17 The presence of coronary artery calcification increases the risk of cardiac events and all-cause mortality in CAD patients and in hypertensive patients at high CV risk who are still free of CAD, as does the extent of coronary artery calcification.18 Calcium channel blockers (CCBs), particularly dihydropyridine CCBs, are widely used in the treatment of high blood pressure and CAD (angina), because they are highly selective for arterial/arteriolar tissue, including the coronary arteries, where they cause vasodilation.

_ Elevated heart rate has been proposed as an emergent CV risk factor by the latest hypertension guidelines.19 Heart rate is one of the major determinants of myocardial oxygen consumption, and, consequently, heart rate reduction is one of the cornerstones of angina prevention and treatment. Despite this, evidence for the benefit of reducing heart rate in patients with stable CAD was not available until recently, with the publication of the BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) trial results. In the placebo armof BEAUTIFUL,20 we found that in CAD patients with heart rates ≥70 beats/minute (bpm), there were significant increases in CV death (8%), admission to hospital for heart failure (HF) (16%), and coronary revascularization (8%) for every 5 bpm increase in heart rate. Further analyses from the LIFE (Losartan Intervention For Endpoint reduction in hypertension) trial21 and ONTARGET/TRANSCEND (ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease) trial populations also identified a systematic increase in CV events among patients with a baseline heart rate >70 bpm vs those with a baseline heart rate ≤70 bpm.22 Thus, findings on the prognostic importance of heart rate are consistent and should be considered in the management of stable CAD patients, including those with hypertension.

New insights: expanding our knowledge of the relationship between BP and CV risk

Effective BP control is indispensable to successful antihypertensive therapy.19 However, new clinical trial results and the latest analyses of older trials, which appeared in 2010, have challenged two traditional beliefs in hypertension management. The findings have raised major questions about the appropriateness of aggressive BP lowering in high-risk patients (systolic BP <120 mm Hg)—which has been thought to be beneficial in high-risk patients for the past several decades— as well as about our exclusive reliance on “usual” BP (based on brachial tonometry readings) to guide clinical decisions and assess prognosis. The debate over the benefits of a “the lower, the better” approach to BP management in patients with established CAD or those at risk of CAD, and the BP J-curve, has been going on since 1979, when Stewart demonstrated that among patients with severe arterial hypertension, the relative risk of myocardial infarction (MI) was over 5-fold higher in individuals whose DBP had fallen below 90 mm Hg than in those with a BP in the 100-109 mm Hg range.23 We still cannot definitively answer all the questions relating to this effect, although today,24 hypertension specialists agree that there is a lowest BP value (the so-called “nadir”) below which the maintenance of life would be impossible. This constitutes the basis for the J-curve phenomenon and might reflect the physiological range of arterial BP. The absence of significant benefit in CV disease outcomes other than stroke in the ACCORD (Action to Control CardiOvascular Risk in Diabetes) trial25 is consistent with post hoc analyses of other outcome trials published in 2009 and 2010. An observational subgroup analysis of the 6400 participants in INVEST (INternational Verapamil SR/trandolapril STudy)26 who had both diabetes and CAD showed little difference in CV disease outcomes between those who maintained tight BP control and those with usual control. Moreover, patients with SBP <110 mm Hg had increased risk of all-cause mortality. Similarly, a retrospective analysis of outcomes in 25 588 high-risk participants in ONTARGET revealed no relationship between in-trial SBP reduction and risk of MI, HF, and CV mortality. In addition, the analysis defined a Jshaped curve with a nadir ≈130mmHg for the relationship between achieved SBP and risk for all outcomes, except stroke.27

Figure 1
Figure 1. Results of the Anglo-Scandinavian Cardiac Outcomes Trial blood pressure
variability substudy.

Results show the greater extent of reduction in blood pressure variability with amlodipine/perindopril vs
β-blocker and thiazide.
Abbreviations: ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering
Arm; CV, coefficient of variation; SBP, systolic blood pressure.
Adapted from reference 36: Rothwell et al. Lancet Neurol. 2010;9:469-480. Copyright © 2010, Elsevier Ltd

There is also the opinion that in an era when BP management is not particularly effective, drawing attention to the J-curve issue might have a negative impact, by disposing physicians to aim for less strict control of BP.28,29

At this point, it is worth noting yet another important aspect associated with the J-curve and pulse pressure (PP). As SBP and DBP lowering are closely linked, a problem may arise in patients with high PP, in whom SBP is high and DBP is low. The current position of the majority of experts is that SBP should be lowered, irrespective of DBP, as it is high SBP that is most predictive of the occurrence of CV events.28-31 Clearly, SBP is the main focus of hypertension treatment, yet caution is advisable to avoid excessive lowering of both SBP (to <110- 120 mm Hg) and DBP (to <70 mm Hg) in patients with CAD.32

The question about the accuracy of mean BP in predicting the risk of CV events also has a long history. Evidence collected during the last decade suggests that standard brachial blood pressure measurements are not adequate, and may even be misleading for the evaluation of CV risk.32,33 Data and analyses from the Stroke Prevention Research Unit at Oxford in the UK have shown a particularly striking relationship between within-individual variability in SBP and the risk of stroke and coronary events, independent of mean SBP.34,35

These data are important because variability in home and ambulatory BP readings, and transient fluctuations in BP in response to specific stimuli (such as stress, pain, or postural changes), are not generally thought to predict future CV events, and treatment is normally the same as that for elevation in usual BP. However, patients with arterial hypertension have greater arterial stiffness, which leads to decreased arterial elasticity, loss of arterial buffering capacity, and, ultimately, greater BP variability.

An important analysis of data from major trials of antihypertensive treatments—including the ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm), MRC (Medical Research Council), and UK-TIA (United Kingdom Transient Ischemic Attack) trials—supports the hypothesis that treatments effecting the greatest reductions in BP variability are associated with the greatest reductions in risk of stroke, coronary events, and mortality, independent of mean SBP reduction (Figure1).32,35,36

Indeed, in the latest megatrials investigating additional benefits of antihypertensive therapy, a systematic link between the magnitude of BP reduction and reduction in CV outcomes and mortality was not always observed. For example, in the TRANSCEND trial (in high-risk patients, 76% of whom were hypertensive), a 4 mm Hg greater reduction in mean SBP with an angiotensin receptor blocker (ARB) vs placebo did not translate into greater reduction in CV outcomes andmortality.37 Similar observations have been made in other trials, such as SCOPE (Study on COgnition and Prognosis in the Elderly)38 and PRoFESS (Prevention Regimen For Effectively avoiding Second Strokes),39 which compared the effect of an ARB vs placebo in hypertensive patients.Astatistical adjustment analysis of the ASCOT-BPLA study showed that the difference in brachial BP (mean &Lamdba; SBP, 2.7 mm Hg) would only partially account for the superiority of amlodipine±perindopril vs atenolol± bendroflumethiazide in reducing CV events and mortality in ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial). There was still a significant residual difference in events, which was totally accounted for after the results were further adjusted for the reduction in BP variability.40

Apart from BP variability, other key BP parameters, such as central BP and 24-hour BP, have also been demonstrated to be superior to peripheral BP as indicators of CV disease prognosis.41,42 The European Society of Hypertension has acknowledged this phenomenon in the latest guidelines.19

Treatment strategy to further improve prognosis

The treatment objectives in stable CAD and hypertension are to prevent CV complications and death, as well as minimize or abolish symptoms. Lifestyle changes and drug treatment play a vital role in halting the progression, or inducing the regression, of coronary atherosclerosis. Reducing all key blood pressure parameters, as well as inflammatory vascular abnormalities, endothelial dysfunction, and prothrombotic disorders, is critical tominimize CV complications. In certain circumstances, such as in patients with severe lesions in coronary arteries that supply a large area of jeopardized myocardium, revascularization may improve prognosis by improving existing perfusion or by providing alternative routes of perfusion.19,43,44

Today, through the united efforts of the medical establishment, programs for secondary prevention measures in CV disease have been implemented. The rationale and benefits of lipidlowering and antiplatelet therapy, as well as of reperfusion measures, have been discussed elsewhere.43,44 In light of new evidence-based lessons in hypertension management, the potential of RAAS inhibitors to further improve prognosis in hypertensive patients with CAD will be reviewed here. The results of some recent large trials support the benefits of combining ACE inhibitors and CCBs in patients with high CV risk, whether stable coronary patients or hypertensive patients.

The four trials that tested the use of ACE inhibitors in secondary prevention in CAD patients are, in order of appearance in the literature, QUIET (QUinapril Ischemic Event Trial), HOPE (Heart Outcomes Prevention Evaluation), EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease), and PEACE (Prevention of Events with Angiotensin-Converting Enzyme inhibition) (Figure 2).45-48 Although all the trials tested a similar hypothesis, they came to quite different conclusions. While QUIET did not show a prognostic benefit for ACE inhibition with quinapril 20 mg/day,45 HOPE showed a significant prognostic benefit with ramipril 10 mg/day in high-risk patients, including those with CAD.46 Next, EUROPA extended the use of ACE inhibitors to all-risk populations, showing a prognostic benefit with perindopril tert-butylamine at a target dose of 8 mg/day (corresponding to perindopril arginine 10 mg) in a population with stable CAD.47 Finally, and very surprisingly, PEACE did not find a prognostic benefit for trandolapril 4 mg/day in a population that was very similar to that in EUROPA.48

Figure 2
Figure 2. Primary outcomes of the four major ACE inhibitor trials (QUIET, HOPE, EUROPA, PEACE) in stable coronary artery disease.

Abbreviations: CI, confidence interval; CV, cardiovascular; EUROPA, EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease;
HOPE, Heart Outcomes Prevention Evaluation;MI, myocardial infarction; PEACE, Prevention of Events with Angiotensin-Converting Enzyme inhibition; QUIET,
QUinapril Ischemic Event Trial;RR, relative risk; y, years.
Adapted from references 45-48: A. Pitt et al. Am J Cardiol. 2001;87:1058-1063. Copyright © 2001, Elsevier. B. Fox. Lancet. 2003;362:782-788. Copyright © 2003, Elsevier. C. Yusuf et al. N Engl J Med. 2000;342:145-153. Copyright © 2000, Massachusetts Medical Society. D. Braunwald et al. N Engl J Med. 2004;351:2058-2068. Copyright © 2004, Massachusetts Medical Society.

A meta-analysis of HOPE, EUROPA, and PEACE that included data from nearly 30 000 patients found that ACE inhibition was systematically better than placebo and significantly reduced the risk of total and CV mortality, fatal and nonfatal MI, HF, revascularization, and stroke in patients with atherosclerosis without existing evidence of HF or LV dysfunction.49 The results of this meta-analysis left no doubt that CAD patients should receive ACE inhibitors.

Although one mechanism of action is BP reduction, this may not be the only one. The degree of BP reduction was very similar in the four trials. In fact, BP reduction alone could not be the sole explanation for the results of EUROPA: the effect of perindopril was independent of BP at entry and was even recorded in patients inwhomtherewas no reduction in brachial BP. It might also be due to a greater reduction in other important BP parameters that are more closely related to coronary events than BP measured in the brachial artery, and to the effects of perindopril on central BP and BP variability, which have been demonstrated clinically.28,29

Another explanation is that ACE inhibitors have BP-independent effects, such as endothelial protection that arrests or impairs the process of atherosclerosis, as seen in the EUROPA trial. In CAD patients participating in the EUROPA trial, we measured markers of endothelial function, including endothelial nitric oxide synthase (eNOS), the rate of apoptosis, and the level of von Willebrand factor (vWF), and we have clinical results showing that perindopril normalizes the angiotensin II/ bradykinin balance, reduces inflammation, and prevents endothelial apoptosis (Table I).50 It also appears that perindopril may be able to reverse new atherosclerotic plaque formation if it occurs. A higher rate of apoptosis vs regeneration disrupts endothelial continuity, which in turn leads to pathological sequelae, such as the onset of atherosclerosis, and plaque erosion and rupture. A post hoc analysis of the PERSPECTIVE (PERindopril’s proSPective Effect on Coronary aTherosclerosis by IntraVascular ultrasound Evaluation)51 substudy of EUROPA found that perindopril was able to reduce the size of noncalcified plaques compared with placebo. Moreover, there is accumulating preclinical evidence for the absence of a class effect for ACE inhibitors, including evidence that they have differences in their effects on eNOS52 and on the rate of endothelial apoptosis.53 These differences appear to be related to tissue affinity, penetration of atherosclerotic plaque, and affinity for the target enzyme.

Table I
Table I. Effects of perindopril on markers of endothelial function in patients with stable
coronary artery disease, assessed as part of the PERTINENT substudy of EUROPA.

Data are expressed as mean ± standard deviation. *P<0.05 for change associated with perindopril vs placebo. Abbreviations: arb.units, arbitrary units; eNOS, endothelial nitric oxide synthase; EUROPA, EUropean
trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease; PERTINENT,
PERindopril-Thrombosis InflammatioN, Endothelial dysfunction and Neurohormonal activation Trial;
TNF-alpha, tumor necrosis factor–alpha.
Adapted from reference 50: Ceconi et al. Cardiovas Res. 2007;73:237-246. Copyright © 2006, European
Society of Cardiology. Published by Elsevier B.V. All rights reserved.

In this context, current European guidelines for stable angina recommend prescription of ACE inhibitors at doses with proven efficacy.44 ACE inhibitors are recommended for CV event prevention in hypertension. ARBs are also recommended, despite this being a matter of controversy after the publication of results from the latest large-scale trials, ONTARGET54 and TRANSCEND.37 These two trials were conducted with the same inclusion criteria: populations with stable vascular disease and hypertension (around 2/3 of patients). In ONTARGET, the ARB telmisartan showed no benefit in preventing CV events ormortality vs the ACE inhibitor ramipril; in TRANSCEND, the same ARB failed to demonstrate superiority vs placebo. Evidence-based medicine currently considers RAAS inhibitors and CCBs to be among the best components of an antihypertensive combination. The reappraisal of the hypertension guidelines55 highlights ACE inhibitor/ CCB combinations as being supported by the strongest evidence, fromACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension)56 and, particularly, ASCOT.57 ASCOT was considered a breakthrough in hypertension management due to the reduction in all-cause mortality seen in hypertensive patients treated with a combination of amlodipine and perindopril— a first for a modern antihypertensive treatment. Moreover, recent trials, such as ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation)58 and HYVET (HYpertension in the Very Elderly Trial), 59 have confirmed the ASCOT finding that antihypertensive treatment that includes perindopril reduces all-cause mortality.

Figure 3
Figure 3. Kaplan-Meier curves for (A) primary end
point (a composite of cardiovascular mortality,
nonfatal myocardial infarction, and resuscitated
cardiac arrest) and (B) total mortality in patients
receiving perindopril/CCB vs placebo/CCB.

Abbreviations: CCB, calcium channel blocker; CI, confidence
interval; HR, hazard ratio.
Reproduced from reference 60: Bertrand et al. Am Heart J.
2010;159:795-802. Copyright © 2010, Elsevier.

Table II
Table II. Modes of action of angiotensin-converting enzyme (ACE) inhibition with
perindopril and calcium channel blockade (CCB) with amlodipine.

Abbreviations: BP, blood pressure; eNOS, endothelial nitric oxide synthase; NO, nitric oxide; PAI-1,
plasminogen activator inhibitor 1; SMC, smooth muscle cell; t-PA, tissue plasminogen activator.
Adapted from reference 61: Ferrari R. Current Med Res Opin. 2008;24:3543-3557. Copyright © 2008,
Informa UK Ltd.

Combination of ACE inhibitors and CCBs would also fulfill important therapeutic objectives in CAD. Further reductions in cardiac outcomes and mortality were found in the recent EUROPA analysis in stable CAD patients when perindopril was added to long-term CCB treatment.60 Among study participants who received CCB at every visit in the perindopril arm vs placebo arm of EUROPA (perindopril/CCB, n=1022; placebo/ CCB, n=1100), the total mortality was reduced by 46%(P<0.01 vs placebo) and the primary end point (a composite of CV mortality, nonfatal MI, and resuscitated cardiac arrest) was reduced by 35% (P<0.05 vs placebo) with perindopril/CCB (Figure 3).60 This finding suggests clinical synergy between an ACE inhibitor and a CCB leads to both antihypertensive and cardioprotective effects (Table II).61 Indeed, in hypertensive patients from the ASCOT study, this combination effectively reduced brachial BP and had favorable effects on BP variability, central BP, and nighttime/24-hour BP; new research indicates that these are key BP parameters for determining the impact of treatment on CV risk and mortality.

Additionally, a preliminary report of a metaanalysis of clinical trials in hypertension62 indicates that strategies including perindopril (combined with amlodipine or indapamide) further reduce mortality. This meta-analysis looked at 19 randomized controlled RAAS inhibitor trials conducted during the last decade. Trials in HF, acute MI, stroke, post cardiac surgery, or trials with less than 66% of hypertensive patients were excluded. Only 3 trials—ASCOT, ADVANCE, and HYVET— including 34 242 patients, demonstrated significant reduction in all-cause mortality (13% when pooled; 95% confidence interval [CI], 0.81 to 0.93; P<0.0001). When these three trials were excluded, the treatment effect of other RAAS inhibitors in the remaining 16 trials was neutral (hazard ratio, 0.99; 95% CI, 0.95 to 1.01; P=0.21).

Conclusion

Common pathophysiological mechanisms of arterial hypertension and CAD prompt degenerative vascular changes and endothelial dysfunction, leading to acceleration of atherosclerosis and target-organ damage. Lessons from recent clinical trials and analyses have challenged some of the traditional beliefs in hypertension management and seem to be particularly useful to further improve prognosis in hypertensive patients with stable CAD:
_ Clearly, effective reduction in systolic BP remains the objective of hypertension treatment, yet caution is advisable to avoid excessive lowering of both SBP (to <110-120 mm Hg) and DBP (to <70 mm Hg) in patients with CAD. _ In addition to brachial BP reduction, reduction of BP variability, 24-hour BP, and central BP seem to improve quality of antihypertensive therapy and thus, improve prognosis in populations at high CV risk. _ ACE inhibitors with proven efficacy and at proven dosages are indispensible for effective management of contemporary hypertensive patients with stable CAD to further reduce CV events and mortality. _ Combination antihypertensive therapy with ACE-inhibitors, such as perindopril, and CCBs, such as amlodipine, is supported by the results of recent clinical trials in hypertensive patients, including those with stable CAD. _ References
1. Lawes CM, Vander Hoorn S, Rodgers A; International Society of Hypertension. Global burden of blood-pressure-related disease, 2001. Lancet. 2008;371: 1513-1518.
2. Mathers C, Stevens G, Mascarenhas M. Global health risks: mortality and burden of disease attributable to selected major risks. Geneva, Switzerland: World Health Organization; 2009.
3. Ford ES, Ajani UA, Croft JB, et al. Explaining the decrease in US deaths from coronary disease, 1980-2000. N Engl J Med. 2007;356:2388-2398.
4. Ford ES. Trends in mortality from all causes and cardiovascular disease among hypertensive and nonhypertensive adults in the United States. Circulation. 2011;123:1737-1744.
5. Nilsson MP, Lurbe E, Laurent S. The early life origins of vascular ageing and cardiovascular risk: the EVA syndrome. J Hypertens. 2008;26:1049-1054.
6. Franklin SS, Gustin W IV, Wong ND, et al. Hemodynamic patterns of age-related changes in blood pressure. Circulation. 1997;96:308-315.
7. Avolio AP, Van Bortel LM, Boutouyrie P, et al. Role of pulse pressure amplification in arterial hypertension: experts’ opinion and review of the data. Hypertension. 2009;54(2):375-383.
8. Schillaci G, Parati G. Determinants of blood pressure variability in youth: at the roots of hypertension. J Hypertens. 2010;28:660-664.
9. Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. Ann Intern Med. 2003;139:761-776.
10. Stocker R,Keaney JF Jr. Role of oxidative modifications in atherosclerosis. Physiol Rev. 2004;84:1381-1478.
11. Dzau V. The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. J Hypertens Suppl. 2005;23:S9-S17.
12. Schiffrin EL. Effects of aldosterone on the vasculature. Hypertension. 2006;47: 312-318.
13. Oikawa T, Freeman M, Lo W, Vaughan DE, Fogo A. Modulation of plasminogen activator inhibitor-1 in vivo: a new mechanism for the anti-fibrotic effect of renin-angiotensin inhibition. Kidney Int. 1997;51:164-172.
14. Singh BM, Mehta JL. Interactions between the renin-angiotensin system and dyslipidemia: relevance in the therapy of hypertension and coronary heart disease. Arch Intern Med. 2003;163:1296-1304.
15. Yusuf S. Preventing vascular events due to elevated blood pressure. Circulation. 2006;113:2166-2168.
16. Fleckenstein-Grün G, Thimm F, Czirfuzs A, Matyas S, Frey M. Experimental vasoprotection by calcium antagonists against calcium-mediated arteriosclerotic alterations. J Cardiovasc Pharmacol. 1994;24(suppl 2):S75-S84.
17. Blaha M, Budoff MJ, Shaw LJ, et al. Absence of coronary artery calcification and all-cause mortality. JACC Cardiovasc Imaging. 2009;2:692-700.
18. Shemesh J,MotroM,Morag-Koren N, et al. Coronary artery calcification predicts long-term mortality in hypertensive adults. Am J Hypertens. 2011;24(6):681-686.
19. Mancia G, De Backer G, Dominiczak A, et al. 2007 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). Eur Heart J. 2007;28(12):1462-1536.
20. Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R. Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet. 2008;372:817-821.
21. Okin PM, Wachtell K, Kjeldsen SE, et al. Incidence of atrial fibrillation in relation to changing heart rate over time in hypertensive patients: the LIFE study. Circ Arrhythm Electrophysiol. 2008;1:337-343.
22. Rambihar S, Gao P, Teo K, Bohm M, Yusuf S, Lonn E; for the ONTARGET/ TRANSCEND Investigators. Heart rate is associated with increased risk of major cardiovascular events, cardiovascular and all-cause death in patients with stable chronic cardiovascular disease – an analysis of ONTARGET/TRANSCEND. Circulation. 2010;122:A12667.
23. Stewart IM. Relation of reduction in pressure to first myocardial infarction in patients receiving treatment for severe hypertension. Lancet. 1979;1:861-865.
24. Banach M, Michalska M, Kjeldsen SE, Malyszko J, Mikhailidis DP, Rysz J. What should be the optimal levels of blood pressure: does the J-curve phenomenon really exist? Expert Opin Pharmocother. 2011;12(12):1835-1844.
25. ACCORD Study Group; Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. em>N. Engl J Med. 2010;362:1575-1585.
26. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010;304:61-68.
27. Sleight P, Redon J, Verdecchia P, et al; ONTARGET investigators. Prognostic value of blood pressure in patients with high vascular risk in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial study. J Hypertens. 2009;27:1360-1369.
28. Messerli FH, Panjrath GS. The J-curve between blood pressure and coronary artery disease or essential hypertension? Exactly how essential? J Am Coll Cardiol. 2009;54:1827-1834.
29. Williams B. Hypertension and the “J-curve”. J Am Coll Cardiol. 2009;54:1835- 1836.
30. Grassi G, Quarti-Trevano F, Dell’Oro R, Mancia G. The “J Curve” problem revisited: old and new findings. Curr Hypertens Rep. 2010;12:290-295.
31. Verdecchia P, Angeli F, Cavallini C, et al. The optimal blood pressure target for patients with coronary artery disease. Curr Cardiol Rep. 2010;12:302-306.
32. Oparil S. Hypertension in 2010: new challenges in blood pressure goals and assessment. Nat Rev Cardiol. 2011;8:73-75.
33. Benetos A, Salvi P, Lacolley P. Blood pressure regulations during the aging process: the end of “hypertension era”? J Hypertens. 2011;29:646-652.
34. Rothwell PM. Limitations of the usual blood pressure hypothesis and importance of variability, instability, and episodic hypertension. Lancet. 2010;375:938-948.
35. Rothwell PM, Howard SC, Dolan E, et al. Prognostic significance of visit-tovisit variability, maximum systolic blood pressure, and episodic hypertension. Lancet. 2010;375:895-905.
36. Rothwell PM, Howard SC, Dolan E, et al; ASCOT-BPLA and MRC Trial Investigators. Effects of β-blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke. Lancet Neurol. 2010;9(5): 469-480.
37. Telmisartan Randomised AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease (TRANSCEND) Investigators; Yusuf S, Teo K, Anderson C, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomized controlled trial. Lancet. 2008;372:1174-1183.
38. Lithell H, Hansson L, Skoog I, et al; SCOPE Study Group. The Study on COgnition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens. 2003;21:875-886.
39. Yusuf S, Diener HC, Sacco RL, et al; PRoFESS Study Group. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359: 1225-1237.
40. Dolan E, O’Brien E. Blood pressure variability: clarity for clinical practice. Hypertension. 2010;56:179-181.
41. Protogerou AD, Papaioannou TG, Blacher J, Papamichael CM, Lekakis JP, Safar ME. Central blood pressures: do we need them in the management of cardiovascular disease? Is it a feasible therapeutic target? J Hypertens. 2007; 25(2):265-272.
42. Wang KL, Cheng HM, Chuang SY, et al. Central or peripheral systolic or pulse pressure: which best relates to target organs and future mortality? J Hypertens. 2009;27(3):461-467.
43. Rosendorff C, Black HR, Cannon CP, et al; American Heart Association Council on Epidemiology and Prevention. Treatment of hypertension in the prevention and management of ischemic heart disease. A scientific statement from the American Heart Association Council for High Blood Pressure Research and the Councils on Clinical Cardiology and Epidemiology and Prevention. Circulation. 2007;115(21):2761-2788.
44. Fox K, Garcia MA, Ardissino D, et al. Guidelines on the management of stable angina pectoris: executive summary. The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J. 2006; 27:1341-1381.
45. Pitt B, O’Neill B, Feldman R, et al. The QUinapril Ischemic Event Trial (QUIET): evaluation of chronic ACE inhibitor therapy in patients with ischemic heart disease and preserved left ventricular function. Am J Cardiol. 2001;87:1058-1063.
46. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin- converting-enzyme inhibitor, ramipril, on cardiovascular events in highrisk patients: the Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145-153.
47. Fox KM; EURopean trial On reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782-788.
48. Braunwald E, Domanski MJ, Fowler SE, et al; PEACE Trial Investigators. Angiotensin- converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:2058-2068.
49. Dagenais GR, Pogue J, Fox K, Simoons ML, Yusuf S. Angiotensin-convertingenzyme inhibitors in stable vascular disease without left ventricular systolic dysfunction or heart failure: a combined analysis of three trials. Lancet. 2006;368: 581-588.
50. Ceconi C, Fox KM, RemmeWJ, et al; EUROPA Investigators; PERTINENT Investigators and the Statistical Committee. ACE inhibition with perindopril and endothelial dysfunction. Results of a substudy of the EUROPA study: PERTINENT. Cardiovasc Res. 2007;73:237-246.
51. Bruining N, de Winter S, Roelandt JR, et al; EUROPA/PERSPECTIVE Investigators. Coronary calcium significantly affects quantitative analysis of coronary ultrasound: importance for atherosclerosis progression/regression studies. Coron Artery Dis. 2009;20:409-414.
52. Comini L, Bachetti T, Cargnoni A, et al. Therapeutic modulation of the nitric oxide pathway: are all ACE inhibitors equivalent? Pharmacol Res. 2007;56:42-48.
53. Ceconi C, Francolini G, Bastianon D, et al. Differences in the effect of angiotensinconverting enzyme inhibitors on the rate of endothelial cell apoptosis: in vitro and in vivo studies. Cardiovasc Drugs Ther. 2007;21:423-429.
54. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358:1547-1559.
55. Mancia G, Laurent S, Agabiti-Rosei E, et al; European Society of Hypertension. Reappraisal of European guidelines on hypertension management : a European Society of Hypertension Task Force document. J Hypertens. 2009;27:2121-2158.
56. Weber MA, Bakris GL, Dahlöf B, et al. Baseline characteristics in the Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension (ACCOMPLISH) trial: a hypertensive population at high cardiovascular risk. Blood Press. 2007;16:13-19.
57. Dahlöf B, Sever PS, Poulter NR, et al; ASCOT Investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet. 2005;366: 895-906.
58. Patel A, ADVANCE Collaborative Group, MacMahon S, Chalmers J, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370:829-840.
59. Beckett NS, Peters R, Fletcher AE, et al; HYVETStudyGroup. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358:1887-1898.
60. Bertrand ME, Ferrari R, Remme WJ, Simoons ML, Deckers JW, Fox KM; EUROPA Investigators. Clinical synergy of perindopril and calcium-channel blocker in the prevention of cardiac events and mortality in patients with coronary artery disease. Post hoc analysis of the EUROPA study. Am Heart J. 2010;159: 795-802.
61. Ferrari R. Optimizing the treatment of hypertension and stable coronary artery disease: clinical evidence for fixed-combination perindopril/amlodipine. Curr Med Res Opin. 2008;24(12):3543-3557.
62. Bertrand ME, Fox K, Mourad JJ, Boersma E, Van Vark L. Effect of ACE inhibitors and ARB on all-cause mortality reduction in hypertension trials. Abstract ESH 2011. Accepted.

Keywords: arterial hypertension; calcium channel blockers; cardiovascular outcome; renin-angiotensin system inhibitors; stable coronary artery disease