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Journal of Human (2003) 17, 505–511 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh VIEWPOINT Why not prescribe the best for hypertension now?

SYS Wong1, GT McInnes2 and TM MacDonald1 1Department of Clinical , Hypertension Research Centre, Ninewells Hospital and Medical School, Dundee, UK; 2University Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, UK

As Westernised societies have become more affluent, new ’. -converting enzyme (ACE) inhi- the attitudes of the population have become more risk- bitors and angiotensin II receptor antagonists are as aware. People are now intolerant of small risks as well safe and as efficacious as other antihypertensive as the physical or mental discomforts from drug side and better tolerated. Large trials (HOT, effects. Safety and tolerability are now major forces HOPE, UKPDS and PROGRESS) point to the need for driving the development of new medicines for the rigorous control of pressure particularly in high- treatment of chronic illnesses and the prevention of risk individuals. Antihypertensive drugs that act on the increasingly rare events. For example, over the past –angiotensin system will probably impact signifi- decades, lower and lower treatment thresholds have cantly on achieving optimal levels. been recommended in hypertension. Public perception Should it not now be accepted that high-risk patients of risk strongly influences the acceptability of lifetime should have ACE inhibitors and angiotensin II receptor treatment, especially for mild hypertension. This era antagonists prescribed as first-line agents? We review has also witnessed great advances in the development the evidence for the use of ACE inhibitors and of antihypertensive drugs that combine efficacy with angiotensin II receptor antagonists as antihypertensive unsurpassed tolerability. However, the philosophy of agents. Scottish teachers of Materia medica still appears to be Journal of Human Hypertension (2003) 17, 505–511. followedF‘never be the first or the last to prescribe a doi:10.1038/sj.jhh.1001576

Keywords: renin–angiotensin system; ACE inhibitors; angiotensin II receptor antagonists

Introduction individuals. Since high-risk patients gain greater absolute benefit, the emphasis of treatment has Hypertension is one of the most important cardio- shifted from individuals categorised on the basis of vascular risk factors amenable to prevention and blood pressure to individuals with high cardiovas- treatment. Over 50% of the population aged 60 years cular risk. Hypertension is a largely asymptomatic of age or more has hypertension.1 The wave of condition and its management has much in common cardiovascular now sweeping across the with selling life insurance. Each involves long-term developing world is due in part to the epidemic of hypertension preceding it.2 The Global Burden of investment (drug treatment or premiums) to guard Disease Study found that hypertension was the third against an event far in the future. Thus, antihyper- most preventable cause of death world-wide and tensive treatment must be not only effective but also the second most common condition in Westernised well tolerated. societies.3 Many studies have demonstrated the Although public awareness of the diagnosis of value of treating hypertension in preventing stroke, hypertension has increased, improvement in cardio- vascular disease rates have not followed in paral- , failure, cardiovascular 6 6–10 events and all cause mortality.4,5 lel. Despite many guidelines, which emphasise The benefits of antihypertensive therapy are the importance of achieving optimal blood pressure proportionately the same in low-risk and high-risk particularly in high-risk patient such as those with , only about 29% of hypertensive patients have blood pressure controlled to a target of 140/ 11 Correspondence: Professor TM MacDonald, Hypertension Re- 90 mmHg. The physician has a wide choice of search Centre, Ninewells Hospital and Medical School, Dundee antihypertensive drugs. Outcome benefits have been DD1 9SY, UK. demonstrated for , beta-blockers,4 E-mail: [email protected] 5 Received 26 July 2002; revised 10 January 2003; accepted 19 long-acting calcium antagonists, and angiotensin February 2003 converting enzyme ACE inhibitors.5 Best drugs for hypertension SYS Wong et al

506 is a heterogeneous condi- population were Afro-Americans who do not re- tion, so not surprisingly there is variable blood spond well to ACE inhibitors and the diagnosis of pressure lowering response to each drug group. was not well validated. Most hypertensive patients require an average of The recently published Second Australian Na- two to three drugs to achieve optimal target levels.12 tional Blood Pressure Study (ANBPS-2) reported Therefore compliance is an important issue, contradictory findings.20 In the ANBPS-2, 6083 although nonadherence with therapy does not people aged 65–84 years were randomised to explain failure to attain target blood pressure.13,14 therapy based on or A more significant factor in poor control may be and followed up for an average of 4.1 years. professional noncompliance, that is, failure of the Enalapril treatment was associated with fewer clinician to prescribe appropriate therapy.15 deaths, heart attacks, strokes and other cardiovas- One of the questions currently facing clinicians is cular problems. Thus, ACE inhibitors appear to be a when to accept that a new class of drugs or new better first choice in older subjects. treatment strategy should be put into practice. For In hypertensive patients with high cardiovascular example, is there sufficient evidence to consider risk, the focus of current recommendations for antihypertensive medicines that act on the renin– intervention and control of blood pressure, ACE angiotensin– system (RAS) more readily inhibitors exhibit consistent advantages. Diabetic as first choice in the management of patients in CAPPP gained significantly more protec- hypertension? Is the physician who does this tion from ACE inhibition than from conventional justified for doing so while waiting for the results therapy, despite less good control of blood pres- of long-term mortality trials? sure.17 In the Appropriate Blood Pressure Control (ABCD) trial,21 hypertensive diabetics had a signifi- cantly lower incidence of myocardial infarction ACE inhibitors in hypertension while taking enalapril treatment compared with the group on nisoldipine, despite higher baseline ACE inhibitors lower blood pressure as effectively risk of cardiovascular event in the enalapril group as older antihypertensive medications. In uncom- and equivalent control of blood pressure. Similar plicated hypertension, ACE inhibitor-based therapy advantages of over in diabetic provided outcome benefits equivalent to those with hypertensives were seen in the Fosinopril vs treatment based on diuretics or beta-blockers,16,17 Amlodipine Cardiovascular Event Trial (FACET).22 and had statistically significant advantages over The combined results of the ABCD, CAPPP and calcium channel blockers in prevention of myocar- FACET showed a significant reduction in all cause dial infarction and heart failure.16 However, these mortality (62%, P ¼ 0.01) with ACE inhibition trials had major shortcomings. In the Scandinavian compared with other therapies in diabetic patients Trial of Old Patients with Hypertension-2 with hypertension.23 It is generally accepted that in (STOP-2),16 about one-third of patients did not patients with nephropathy due to type I diabetes remain on randomised therapy at the conclusion, mellitus, the use of ACE inhibitors, independent of while in the Prevention Project (CAPPP),17 blood pressure control, slows the progression of the blood pressure was significantly higher in ACE renal disease.24 This advantage of ACE inhibition inhibitor-treated patients at randomisation and now appears to extend to the prevention of cardio- throughout the trial. Thus, the benefits of ACE vascular complications, the major cause of morbi- inhibition may have been underestimated. dity and mortality in type II diabetes. The publication of the Antihypertensive and Two recent large trials provide evidence for a Lipid Lowering treatment to prevent Heart Attack protective effect of ACE inhibitors in patients with Trial (ALLHAT) should have settled the issue.18,19 high cardiovascular risk whether or not they have ALLHAT was the largest ever randomised trial of hypertension or diabetes mellitus. The Heart Out- antihypertensive therapy with over 40000 high-risk comes Prevention Evaluation (HOPE) study25 exam- individuals randomised to treatment based on the ined the influence of in patients with high thiazide-like (chlorthalidone), or the ACE risk of cardiovascular events but who did not have inhibitor (), the left ventricular dysfunction or failure. Despite little (amlodipine) or the alpha-blocker (). No effect on blood pressure, ACE inhibition signifi- differences between the groups were observed for cantly reduced the rates of death, myocardial the primary outcome (coronary heart disease infarction or stroke. The Protection events). However, diuretic-based treatment was against Recurrent Stroke (PROGRESS) study26 came associated with fewer strokes and less congestive to similar conclusions for ACE inhibitor-based heart failure. treatment in patients with prior evidence of cere- ALLHAT had adequate statistical power but the brovascular disease. In PROGRESS, the ACE inhi- conduct of the trial led to uncertainties. Only a little bitor, perindopril, was used alone or in combination more than 50% in each group remained on rando- with the diuretic, , at the discretion of mised therapy, diuretic-treated participants had the investigator (ie nonrandomised). Therefore, it is better blood pressure control, 35% of the study difficult to determine whether one component was

Journal of Human Hypertension Best drugs for hypertension SYS Wong et al

507 responsible for the benefit. No other drug classes patients treated with ACE inhibitors develop have been studied in large-scale outcome trials of or rarely the more serious , compli- secondary cerebrovascular prevention. Treatment cations that are not seen with angiotensin II receptor based on all the major classes of antihypertensive antagonists. Angiotensin II receptor antagonists are agents, diuretics, beta-blockers, calcium channel unsurpassed for their placebo-like adverse effects blockers and ACE inhibitors have been shown to profile. Angiotensin II receptor antagonists do not have similar benefits in primary prevention of stroke worsen sexual activity in hypertensive men and in uncomplicated hypertension.5 there is a suggestion that they may actually improve These findings from HOPE and PROGRESS sup- sexual function.32,33 Effectiveness combined with a port the notion that blocking the RAS has benefits remarkably clean side effect profile is exactly what beyond blood pressure lowering in high-risk pa- risk-aware Westernised societies have been striving tients. ACE inhibitors already have an established to achieve with new medication. role postmyocardial infarction and in heart failure, Drugs that block the RAS have lesser efficacy in and reduce the risk of sudden death.27,28 Use of these patient populations characterised by low renin drugs now extends to the treatment of heart failure hypertension, for example, African-Americans. without left ventricular systolic dysfunction, stable ACE inhibitors and angiotensin II receptor antago- coronary artery disease and . nists may not be the preferred first-line agents in Recent analysis of the HOPE population also such patients, but since multiple drugs are usually showed that cardiovascular risk was increased with required to achieve blood pressure targets, both any degree of microalbuminuria in both those with classes are important options in management. or without diabetes,29 suggesting that use of these Nonsteroidal anti-inflammatory drugs including agents should perhaps be extended to those subjects isoenzyme 2 (COX 2) inhibitors with any degree of microalbuminuria.30 increase blood pressure and attenuate the effect of ACE inhibitors are well tolerated. However, ACE all antihypertensive agents. The evidence that this is an ubiquitous enzyme with actions outside the interaction is more marked with ACE inhibitors and RAS. Nonspecific effects of ACE inhibitors include angiotensin II receptor blockers is weak and its blockade of . Accumulation of relevance for outcome is unknown. is likely to be responsible for the main Blood pressure is only a surrogate marker for adverse effects of ACE inhibitors, cough and benefit. The emphasis on blood pressure reduction angioedema. In a small proportion of patients, ACE rather than outcome is appealing to the uninformed inhibitors are associated with cough, reversible on prescriber but cannot be justified as evidence of discontinuation. Angioedema is rare but occasional differential effects of treatments accumulates. In fatalities have been reported. Importantly, in long- African-Americans, for equivalent blood pressure term outcome trials, nonfatal and fatal adverse control, ACE inhibitor-based therapy had renal events are no more common with ACE inhibitors protective effects superior to those offered by than with comparator drugs.16,17 The adverse event calcium channel blocker-based treatment, which profile of ACE inhibitors is favourable when has greater antihypertensive efficacy in such compared with other newer drug classes such as patients.34 dihydropyridine calcium channel blockers. Out- The widespread use of angiotensin II receptor come benefits are only likely if therapy is well antagonist is hindered by the lack of long-term tolerated and continued by the patient. The risk– morbidity and mortality data. All this changed with benefit ratio strongly favours ACE inhibitors. publication of the results of the Interven- tion For Endpoint reduction in hypertension (LIFE) study.35,36 This landmark trial demonstrated a clear Angiotensin II receptor antagonists advantage in cardiovascular outcomes for losartan- in hypertension based therapy over conventional treatment based on in hypertensive patients with left ventricu- Blockade of the RAS with these new drugs might be lar therapy for equivalent blood pressure control.35 expected to yield even greater advantages. Angio- Findings in the diabetic subgroup of LIFE partici- tensin II receptor antagonists block the AT1 receptor pants showed even more impressive benefits for subtype, providing complete blockade regardless of losartan.36 The main advantage of the angiotensin II how angiotensin II is generated. The unblocked AT2 receptor antagonist was in prevention of stroke, a receptor mediates a vasodilator action probably via complication known to be effectively reduced by 4 AT2-induced bradykinin and produc- beta-blockers. No significant difference was ob- tion. At doses that are too low to reduce blood served for coronary heart disease events. Although pressure, angiotensin II receptor antagonists im- beta-blockers do not appear to have a particular prove endothelial function probably also as a primary cardioprotective effect in uncomplicated function of AT2 receptor stimulation. hypertension, these drugs are established to be Direct comparisons of ACE inhibitor and angio- cardioprotective in those with cardiovascular com- tensin II receptor antagonists suggest equal efficacy plications.37 The patients in the LIFE study, all had in lowering blood pressure.31 A small proportion of evidence of cardiac damage caused by hypertension.

Journal of Human Hypertension Best drugs for hypertension SYS Wong et al

508 Further evidence of the benefits of angiotensin II and microalbuminuria and the combination was antagonism has been provided in studies in patients even more effective at achieving these endpoints.44 with heart failure. In the Losartan Heart Failure The MARVAL trial (Microalbuminuria Reduction Survival Study (ELITE II),38 the angiotensin II with ), valsartan vs amlodipine, showed receptor blocker was not significantly different from similar results in favour of valsartan.45 an ACE inhibitor in modifying outcome in patients So far, randomised placebo-controlled trials of with heart failure and the Valsartan Heart Failure angiotensin II receptor antagonists in hypertension Trial (ValHeFT)39 recently reported that valsartan in and diabetes have demonstrated reduction in pro- addition to standard ACE inhibitor therapy in heart gression to nephropathy, reduction in urinary failure led to a 13% risk reduction in combined albuminuria, regression to normoalbuminuria and morbidity/mortality. Indeed, in patients not given an preservation of glomerular filtration rate indepen- ACE inhibitor, the angiotensin II receptor blocker dent of blood pressure reduction. These favourable was dramatically superior to placebo in preventing results were achieved with drugs that were safe and complications of heart failure. Meanwhile, in hyper- very well tolerated. tension, a comparison of an angiotensin II receptor Further studies with mortality endpoints are blocker and amlodipine, perhaps the most widely currently ongoing. These include Appropriate Blood used antihypertensive agent in the world, the Pressure Control in Diabetes part 2 with Valsartan Valsartan Antihypertensive Long-term Use Evalua- (ABCD-2V)46 with a 5 years follow-up to assess the tion (VALUE) trial,40 is in progress. multisystemic diabetic complication outcomes. Meanwhile, several large-scale outcome trials A secondary outcome in this trial is cardiovascular have demonstrated the advantage of angiotensin II mortality, nonfatal myocardial infarction and receptor antagonists in the treatment of hyper- strokes. There are also trials in postmyocardial tensive patients with coexisting diabetes, proteinur- infarction patients using angiotensin II receptor ia or microalbuminuria. Independent of blood antagonists. In the Optimal Therapy in Myocardial pressure lowering effect, the angiotensin II receptor Infarction with the Angiotensin II Antagonist Lo- antagonists and losartan reduced the sartan (OPTIMAAL) study,47 low-dose losartan was progression from microalbuminuria or not superior to high-dose ACE inhibitor but the to nephropathy by 70% and significantly reduced study was underpowered to test noninferiority. The the risk of progression to endstage renal disease.41–43 valsartan in Acute Myocardial Infarction (VALI- The Reduction of Endpoints in NIDDM with the ANT)48 trial will further investigate whether angio- Angiotensin-II antagonist Losartan (RENAAL)41 tensin II receptor antagonists have additional compared losartan to placebo in patients with type mortality benefits beyond that with ACE inhibitors. II diabetes and established nephropathy in over Angiotensin II receptor antagonists have, in their 1500 patients during 3.4 years of follow-up. Losar- favour, effectiveness in lowering blood pressure in tan significantly reduced the rate of progression of various patient groups with mild to very severe nephropathy to endstage renal failure by 28% and hypertension49 (lowering blood pressure is a very reduced the risk of endstage renal disease or death good surrogate marker for mortality benefits) with by 20%. Losartan was also cardioprotective in placebo-like adverse effects. The combination of reducing the development of heart failure by 32% angiotensin II receptor antagonists and ACE inhi- and reduction of myocardial infarction by 28%. In bitors appears to produce additive blood-pressure- Irbesartan Trial (IDNT) during lowering effects and end-organ protection.44 Their 2.6 years of follow-up, the primary end point combined use in hypertension and other cardiovas- (including death from any cause) was significantly cular conditions needs further evaluation but early improved with irbesartan-based therapy compared findings support the importance of maximising with therapy based on conventional drugs or blockade of the RAS in improving outcome. amlodipine. Patients assigned to receive irbesartan had a rate of congestive heart failure necessitating hospitalisation 23% less than among patients assigned to receive conventional drugs.43 The The philosophy of the new treatment Irbesartan effect on Microalbuminuria in hyperten- sion and (IRMA 2) trial42 showed How many trials have to be favourable before drug that the angiotensin receptor blocker is renoprotec- prescribing habits change? At one extreme, the COX tive independent of its blood pressure-lowering 2 specific inhibitors, celecoxib and were effect in patients with type II diabetes and hyper- licensed and marketed with only surrogate data on tension. The And Lisinopril Micro- these benefits. However, their sales have been albuminuria (CALM) study, compared candesartan astronomic. There are as yet no long-term outcome and lisinopril monotherapy and the combination studies to address their tolerability in patients with effect on blood pressure and urinary albumin active ulcer, with a recent history of ulcer or in in hypertensive patients with type II patients suffering from cardiovascular or renal diabetes and microalbuminuria. Candesartan was . If these were cardiovascular products, as effective as lisinopril in reducing blood pressure would they have been as successful?

Journal of Human Hypertension Best drugs for hypertension SYS Wong et al

509 Despite 25 randomised trials showing the benefit tions and better tolerated, should it not now be of b-blockers in chronic heart failure, and 39 trials accepted that high-risk patients should have ACE showing the benefit of ACE inhibitors in systolic inhibitors and angiotensin II receptor antagonists heart failure, there has been reluctance to prescribe prescribed as first-line agents? these drugs. Is the other extreme in prescribing In his patriotic mid-19th century collection of being witnessed with ACE inhibitors and angioten- poems ‘The Songs of Ensign Sta˚hl’, the Finnish sin II receptor antagonists use in the treatment of national poet Johan Ludvig Runeberg told the tale hypertension? Clearly, the angiotensin II receptor of the General von Do¨beln, who, mortally ill before antagonists are new and improved (like COX 2 a decisive battle, prays his doctor to administer a inhibitors50). Therefore, why not use these drugs remedy which ‘will make me sevenfold worse now? tomorrow, but lets me fight today’. The doctor There are those who argue against overinterpreta- promptly sweeps all bottles and pills off the table tion of secondary end points51 but this approach and the general rushes off to rejoin the battle. raises the possibility of denying better treatments If angiotensin II receptor antagonists are to be while waiting for perfect data. In the face of used increasingly as first-line treatment for hyper- unequivocal evidence that lowering blood pressure tension, costs will be debated. Why spend large improved morbidity and mortality, does it matter sums on treating asymptomatic people? This atti- how this is achieved as long as the target blood tude can be considered as shortsighted. Why suffer pressure is achieved for the individual patient? economic costs today for benefits 10 years from Antihypertensive drugs that act on the RAS will now? It would be ironic indeed if we were to probably impact significantly on achieving optimal improve management with better drugs, only to have blood pressure levels. Whether there are additional treatments stopped because tax payers and health cardiovascular benefits above and beyond the insurers would rather howl a decade from now than simple blood-pressure-lowering effect need further accept the costs today. After all, Runeberg’s Finland clarification, but in the meantime, why should these lost the war. well-tolerated drugs not be used more widely? Some 6 years after the first angiotensin II receptor antagonists (losartan) was launched for the treat- References ment of hypertension, these agents have been shown to be safe and well tolerated. Blocking the RAS has 1 Colhoun HM, Dong W, Poulter NR. Blood pressure been demonstrated to be beneficial (eg HOPE, screening, management and control in England: results PROGRESS, ValHeFT, RENAAL, IDNT, IRMA 2, from the health survey for England 1994. J Hypertens MARVAL and now LIFE and ANBPS-2). 1998; 16: 747–572. A management decision should ideally be made 2 Horton R. Future of European cardiology: continen- with scientific evidence and outcome data from tally isolated or globally integrated? Lancet 1999; 354: randomised prospective clinical trials when such 791–792. 3 Murray CJ, Lopez AD. Mortality by cause for eight information is available. However, such an approach regions of the world: Global Burden of Disease Study. may be regretted later. How many more lives would Lancet 1997; 349: 1269–1276. have been saved if physicians had used more 4 Collins R, MacMahon S. Blood pressure, antihyper- frequently before the publication of the landmark tensive drug treatment and the risks of stroke and of Scandinavian Survival Study (4S)52 and coronary heart disease. Br Med Bull 1994; 50: 272–298. West of Scotland Coronary Prevention Study (WOS- 5 Blood Pressure Lowering Treatment Trialist’ Collabo- COPS)53 results? In the next decade, when evidence ration. Effects of ACE inhibitors, calcium antagonist, for ACE inhibitors and angiotensin II receptor and other blood-pressure-lowering drugs: results of antagonists use in hypertension is no doubt re- prospectively designed overviews of randomised viewed, will it be regretted that these drugs were not trials. Lancet 2000; 355: 1955–1964. 6 The sixth report of the National Committee on used more widely? With the change in target levels, prevention, detection, evaluation, and treatment the impetus should surely be to lower blood of high blood pressure. 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Journal of Human Hypertension