choice of initial treatment which included a thiazide type diuretic (chlorthalidone), ACEI (lisinopril) and a CCB (amlodipine) the results indicated that thiazide type diuretics should be considered first for pharmacologic therapy in patients with hypertension. For patients who cannot take a diuretic, first-step therapy with CCBs and ACEI could be considered. The ALLHAT was instrumental in shaping the Joint National Committee (JNC) 7 guidelines to endorse the role of thiazide type diuretic as an initial therapy. Beta-blockers which were once a corner stone in the management of hypertension fell out of favor as in comparison with other antihypertensive drugs. The effect of BBs (atenolol) was found to be less than optimal with an increased risk of stroke when compared to losartan in the Losartan Intervention for Endpoint (LIFE) Study.7 Guidelines suggested that in the absence of established CAD or heart failure BBs should not be used as initial therapy.2

Joint National Committee 7 has provided guidelines for selection of initial drug choices in doing so, patients with “compelling indications” are defined.8 These represent comorbidities such as CAD, diabetes mellitus, heart failure, postmyocardial infarction, chronic kidney disease and recurrent stroke prevention, where particular drug classes have been proven as beneficial based on outcomes studies/evidenced-based conclusions from studies or existing clinical guidelines (Figure 1). Without compelling indications and for stage 1 hypertension (systolic BP 140–159 mm Hg, diastolic BP 90–99 mm Hg), thiazide-type diuretics are considered as adequate therapy for most individuals. Similarly, for stage 2 hypertension (systolic BP 160 mm Hg, diastolic BP 100 mm Hg) two drugs in combination should be prescribed for most individuals (a thiazide-type diuretic and ACEI), or angiotensin receptor blocker (ARB), or BB, or CCB. The European Society of Hypertension/European Society of Cardiology (ESH/ESC) hypertension guidelines published back in 2007 stated all classes of antihypertensive drugs should be potentially considered as first choice.1 However, JNC7 guidelines indicate that ACEIs have more compelling indications as compared with ARBs, indirectly supporting a greater beneficial effect of one drug class as compared with the other.8 It is worth noting that the only indication specific for ARBs is the cough caused by the ACEIs.

THE STORY OF RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM BLOCKERSThe blood pressure lowering treatment trialists’ collabo ration (BPLTTC) assessed the blood pressure-dependent and independent effects of ACEIs and ARBs on major cardiovascular events in patients with hypertension, diabetes, a history of coronary heart disease, or cerebrovascular disease in a meta-analysis which included 26

Does Your First Line Antihypertensive Reduce Death?—The Untold Story of the Renin-Angiotensin-Aldosterone System Blockers

JS Bhuvaneswaran

Chapter 18

INTRODUCTIONEver since the Framingham study established hypertension as a risk factor of coronary artery disease (CAD), the purpose of treating hypertension is to reduce mortality and prolong survival. Worldwide, annually 7.5 million deaths (13% of all deaths) are attributable to high blood pressure (BP): related diseases, particularly cardiovascular diseases (CVDs).1 For that reason, the guidelines of hypertension and cardiology societies emphasize that hypertension treatment should aim at reducing the long-term risk of (cardiovascular) morbidity and mortality.2,3

BLOOD PRESSURE LEVELS VERSUS CHOICE OF TREATMENTThe benefits of antihypertensive treatment on cardiovascular morbidity are thought to be mainly due to the BP-lowering effects, independent of the class of drug employed, as has been demonstrated with beta-blockers (BBs), diuretics, calcium channel blockers (CCBs) and recently with the renin-angiotensin-aldosterone system (RAAS) inhibitors.2 But, present clinical evidence in our disposal does not conclusively provide answers to whether it is BP levels or the drug class which is important while selecting a specific treatment strategy. The second Australian National Blood Pressure (ANBP2)4 study which compared an angiotensin-converting enzyme inhibitor (ACEI) with hydrochlorothiazide concluded that initiation of antihypertensive treatment involving ACEI in older subjects lead to better outcomes than treatment with diuretic agents, despite similar reductions of BP. On the other hand, the hypertension optimal trial (HOT) stated that the lowering of BP per se was associated with a lower risk of cardiovascular events.5

OPTIMAL TREATMENT STRATEGIES FOR HYPERTENSIONThe definitions relating to hypertension have changed significantly over the years, as have opinions concerning optimal BP targets, especially as they relate to patients with comorbidities. Initial recommendations for therapy to achieve this goal very likely will continue to involve lifestyle modifications as are recommended by various guidelines. If these fail or are inadequate, then pharmacologic therapy will be necessary. Review of literature suggests that despite the known benefits of various drug classes, there has been no clear consensus on the choice of the drug therapy. Antihypertensive and Lipid-Lowering Tr eatment to Prevent Heart Attack Trial (ALLHAT)6 study published in the Journal of the American Medical Association (JAMA) in the year 2002 for the first time compared three drug classes for the

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Chapter 18 Does Your First Line Antihypertensive Reduce Death?...Section 3

trials involving either drug class.9 The authors reported similar BP dependent effects of ACEIs and ARBs for the risk of stroke, coronary heart disease and heart failure. In terms of blood pressure-independent effects, however, only ACEIs was associated with a significant additional relative risk reduction for major coronary disease events of 9%. A 2011 meta-analysis included all randomized clinical trials comparing ARBs with controls (placebo or active treatment),10 with a total of 37 randomized trials and 147,000 patients. When compared with controls, ARBs were not found to be associated with a reduction in risk of myocardial infarction (MI) [relative risk (RR) 0.99; 95% confidence interval (CI) 0.92–1.07]. There was also no detectable beneficial effect for the outcome of MI in trials comparing ARBs versus placebo (RR 0.93; 95% CI 0.81–1.07), as well as for the outcome of all-cause or cardiovascular death, despite lower BP with ARBs. When compared with active treatment, the relative risk of MI with ARBs was 1.04 (95% CI 0.98–1.11), while all-cause and cardiovascular death were also not reduced.5 While these meta-analyses point out of significant differences between and ARBs, despite being in clinical use, there has been no head-to-head comparison between ACEIs and ARBs in a randomized controlled trial set-up for assessing mortality outcome in hypertension. The Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) Study11 did compare the two, but it was not a hypertension drug trial. The population it studied was high-risk CAD patients, rather than that hypertension (large proportions were normotensive). Now if one looks at studies independently, five outcome trials in hypertension have compared ACEI with other agents. In ALLHAT6 (lisinopril vs diuretic or CCB); ANBP24 (enalapril vs diuretic); Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)12 (perindopril and CCB vs BB and diuretic); Hypertension in the Very Elderly Trial (HYVET)13 (perindopril and indapamide vs placebo) and Avoiding

Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH)14 (benazepril vs diuretic or CCB). Angiotensin receptor blocker have been compared with other agents in LIFE7 (losartan vs atenolol) and Valsartan Antihypertensive Long-term Use Evaluation (VALUE)15 (valsartan and diuretic vs diuretic and calcium antagonist). This distribution of trial evidence suggests a greater quantum of evidence backing ACEI than ARB in the treatment of hypertension. The evidence on mortality from these hypertension trials broadly covers three groups of patients: (1) those at low-risk of CAD; (2) those at high-risk of CAD and (3) those in special situations. Among patients at relatively low-risk of CAD, the only evidence of a beneficial impact on mortality is with lisinopril (ALLHAT).6 Among patients at high-risk CAD, who are in a majority, the combination of perindopril and CCB (ASCOT)12 was significantly more effective in reducing mortality than the combination of valsartan and diuretic (VALUE),15 or the combination of benazepril and CCB (ACCOMPLISH).14 Among patients in special situations, the combination of perindopril and indapamide (HYVET)13 and enalapril (ANBP)4 had a significant impact on mortality in the elderly, whereas, losartan had no impact in patients with left ventricular hypertrophy (LIFE).7

DIFFERENT MECHANISMS OF ACTION BETWEEN ACEI AND ARBS: COULD BE THE REASON?The ACEIs act by inhibiting the ACE enzyme and thereby preventing the formation of angiotensin II from angiotensin I and degradation of bradykinin. The inhibition of bradykinin degradation exerted by ACEIs is only considered an “adjunctive” mechanism with a limited clinical significance. But, if we consider the potential beneficial effect of bradykinin on the cardiovascular system, it is plausible that this pathway could possibly be responsible for many effects

Figure 1: Recommendation-drug selection in practice

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Hypertension Section 3

Figure 2: Angiotensin-converting enzyme inhibitors: a complete mode of action on RAAS and kallikrein-kinin system Courtesy: Dominyak, unger (Eds) in Arg 11-AT1-Receptor Antagonists, steinkopff; 1997

Figure 3: Angiotensin receptor blockers might cause plaques rupture

of ACEIs usually attributed to RAAS blockade. In hypertensive patients, bradykinin can act on the endothelium by a nitric oxide (NO)-independent pathway, conceivably by the activation of endothelium-derived hyperpolarizing factors.15 Through this compensatory mechanism, bradykinin can induce endothelium-dependent relaxation or tissue plasminogen activator release, even in the presence of impaired NO availability, an effect not shared by other endothelial agonists, including acetylcholine.15 Therefore, the results of the comparative studies discussed earlier in patients with

hypertension or CAD, ACEIs, but not ARBs can improve endothelial function in large arteries.16,17

When ARBs were first introduced into clinical practice they were expected to lead to at least similar, if not greater, blood pressure lowering effects than ACEIs. Angiotensin receptor blockers act via a selective blockade of the angiotensin II type 1 receptor (AT-I), leaving the other angiotensin receptors (such as AT-II) relatively unchallenged. Importantly, as a consequence of the AT1 receptor blockade by ARBs (Figures 2 and 3), angiotensin II levels increase

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Chapter 18 Does Your First Line Antihypertensive Reduce Death?...Section 3

several fold through uncoupling of the negative feedback mechanism. The increased levels of angiotensin II leads to unrestricted stimulation of unopposed AT2 receptors. Although there are some mechanisms which has been proposed, stating that the stimulation of AT2 receptors mediates vasodilatation and NO release,18 which would be potentially beneficial, more recent evidence suggest that AT2 stimulation may actually lead to the stimulation of vascular growth, inflammation and fibrosis.19 In an experimental study, overexpression of the AT2 receptor in human cardiac myocytes lead to cardiac hypertrophy,20 whereas AT2 receptor-deficient mice appear to be protected against cardiac hypertrophy.21

To conclude, as recommended by recent international hypertension guidelines, the primary goal of treating hypertension must be aimed at maximum reduction in cardiovascular morbidity and total mortality2 and not just surrogates, such as BP and proteinuria. Special attention should be given to the choice of agent in high-risk hypertensive patients. Presently, the evidence from hypertension trials clearly suggest that there is less risk of death with ACEI than ARB in hypertensive patients at low-risk of CAD (with lisinopril), at high-risk of CAD (with perindopril) and in the elderly (with perindopril). Even among the ACEIs the maximum evidence for reducing hard end points in hypertensive population seems to be in favor of perindopril with ASCOT, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE) and HYVET studies. What is interesting to note is that the most commonly used ACEI (ramipril) in India does not have a study in hypertensive population. In addition to these clear outcome studies, the logical mechanisms which favorably differentiate an ACEI from an ARB have to be considered. Angiotensin-converting enzyme inhibitors should, therefore, be the preferred to ARB in the treatment of hypertension as a first line treatment. As pointed out by guidelines,2 ARBs should be reserved for individuals who do not tolerate an ACEI.

REFERENCES 1. Ezzati M, Lopez AD, Rodgers A, et al. Selected major risk factors and

global and regional burden of disease. Lancet. 2002;360(9343):1347-60. 2. 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):1462-536.

3. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure. Hypertension. 2003;42(6):1206-52.

4. Wing LM, Reid CM, Ryan P, et al. A comparison of outcomes with angiotensin-converting enzyme inhibitors and diuretics for hypertension in the elderly. N Engl J Med. 2003;348(7):583-92.

5. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension:

principal results of the Hypertension Optimal Treatment (HOT) trial. Lancet. 1998;351(9118):1755-62.

6. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288(23):2981-97.

7. Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE):a randomised trial against atenolol. Lancet. 2002;359(9311):995-1003.

8. Chobanian AV, Bakris GL, Black HR, et al. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure: the JNC7 report. JAMA. 2003;289(19):2560-72.

9. Blood Pressure Lowering Treatment, Trialists C, Turnbull F, et al. Blood pressure-dependent and independent effects of agents that inhibit the renin-angiotensin system. J Hypertens. 2007;25(5):951-8.

10. Bangalore S, Kumar S, Wetterslev J, et al. Angiotensin receptor blockers and risk of myocardial infarction: meta-analyses and trial sequential analyses of 147 020 patients from randomised trials. BMJ. 2011;342:d2234.

11. ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high-risk for vascular events. N Engl J Med. 2008;358(15):1547-59.

12. Dahlöf B, Sever PS, Poulter NR, et al. 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(9489):895-906.

13. Beckett NS, Peters R, Fletcher AE, et al. Treatment of hypertension in patients 80 years of age or older. N Engl J Med. 2008;358(18):1887-98.

14. Jamerson K, Weber MA, Bakris GL, et al, ACCOMPLISH Trial Investigators. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med. 2008;359(23):2417-28.

15. Julius S, Kjeldsen SE, Weber M, et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363(9426):2022-31.

16. Giannarelli C, Virdis A, De Negri F, et al. Effect of sulfaphenazole on tissue plasminogen activator release in normotensive subjects and hypertensive patients. Circulation. 2009;119(12):1625-33.

17. Ghiadoni L, Magagna A, Versari D, et al. Different effect of antihypertensive drugs on conduit artery endothelial function. Hypertension. 2003;41(6):1281-6.

18. Anderson TJ, Elstein E, Haber H, et al. Comparative study of ACE-inhibition, angiotensin II antagonism, and calcium channel blockade on flowmediated vasodilation in patients with coronary disease (BANFF study). J Am Coll Cardiol. 2000;35(1):60-6.

19. Lévy BI. Can angiotensin II type 2 receptors have deleterious effects in cardiovascular disease? Implications for therapeutic blockade of the renin-angiotensin system. Circulation. 2004;109(1):8-13.

20. D’Amore A, Black MJ, Thomas WG. The angiotensin II type 2 receptor causes constitutive growth of cardiomyocytes and does not antagonize angiotensin II type 1 receptor-mediated hypertrophy. Hypertension. 2005;46(6):1347-54.

21. Senbonmatsu T, Ichihara S, Price E Jr, et al. Evidence for angiotensin II type 2 receptor-mediated cardiac myocyte enlargement during in vivo pressure overload. J Clin Invest. 2000;106(3):R25-9.