Journal of Human Hypertension (2006) 20, 829–832 & 2006 Nature Publishing Group All rights reserved 0950-9240/06 $30.00 www.nature.com/jhh COMMENTARY Does eplerenone have a future in the management of hypertension in Europe?

P Gosse1 and RJ Macfadyen2 1Cardiologie/Hypertension Arte´rielle, Hypertension Unit Hoˆpital Saint Andre´, Bordeaux University, 1 rue Jean Burguet, CHU Bordeaux, Bordeaux, France and 2University Department of Medicine, City Hospital, Birmingham, UK

Journal of Human Hypertension (2006) 20, 829–832. doi:10.1038/sj.jhh.1002070; published online 10 August 2006

Introduction A view from France: Philippe Gosse Eplerenone is now available in Europe, but in Eplerenone (Inspra, Pfizer, New York, USA), a 9,11- contrast to the USA, approval was only obtained epoxy derivative of spironolactone, is the second for the restrictive indication of post-infarction aldosterone antagonist commercially available for cardiac failure following the results of the epler- the present time. In the USA, it received Food and enone post-acute myocardial infarction heart failure Drug Administration approval in September 2002 efficacy and survival study (EPHESUS).8 It is also for the treatment of hypertension, and in July 2003 costed at a high price, 70 euros for 28 tablets (in for post-myocardial infarction congestive heart France) for the two 25 and 50 mg dosages, which are failure. the only ones available. This is around ninefold the The medical profession has been looking forward price of spironolactone 25 mg. A price difference to this new inhibitor of aldosterone receptors as of this magnitude between a new drug and the it appears to present significantly fewer adverse reference in its class is unusual, in the absence of effects than does spironolactone, owing to a more 1 any proven greater efficacy to that of spironolactone. selective binding to the mineralocorticoid receptor. Moreover, the doses required in hypertension are These effects, gynaecomastia and impotence, stem higher than those recommended for heart failure. from a dose-dependent antiandrogen action owing The few comparative trials published in essential to a nonspecific binding to various steroid recep- hypertension are summarized in Table 1.9 tors,2 which limits the utilization of spironolactone Interestingly, Weinberger et al.9 concluded that in men. With spironolactone 100 mg daily, the eplerenone 100 mg is around 25% less efficient on incidence of gynaecomastia in men is 11.5% at 10 BP reduction than equivalent dosages of spirono- months, 15% at 20 months and 29% at 25 months;3 lactone and showed a dose–response effect of up to however, this side effect increases to 52% with 400 mg daily with greater efficiency on systolic 150 mg daily or higher.4 blood pressure than on diastolic blood pressure, In cases of primary hyperaldosteronism, the and with a similar incidence of adverse effect to antihypertensive action of an aldosterone antagonist placebo. The efficient dosage to produce a similar is unequalled. High doses of spironolactone, up to reduction in BP as a reference treatment is between 400 mg daily, are sometimes required to normalize 100 and 200 mg, which represents a daily cost of blood pressure (BP) in patients with primary 5–10 euros. Long-term efficacy and tolerance hyperaldosteronism, especially in cases of idio- of eplerenone has been reported13 in a population pathic hyperaldosteronism.5 Spironolactone and of 586 hypertensives followed up for 14 months, eplerenone are also useful in some forms of resistant with 74% of the patients achieving BP control at the hypertension,6 especially in cases of low-renin end of the study with eplerenone alone in 44% and hypertension.7 in association with other antihypertensive drugs in 34%. Eplerenone also reduces left ventricular hyper- trophy in hypertensive patients.14 The adverse effects of eplerenone are directly related to its Correspondence: Dr P Gosse, Cardiologie/Hypertension Arte´r- aldosterone receptor antagonism, with a dose- ielle, Hypertension Unit Hopital Saint Andre´, Bordeaux Uni- dependent increase in potassium concentrations versity, 1 rue Jean Burguet, CHU Bordeaux, Bordeaux 33075, France. and an incidence of hyperkalaemia similar to that E-mail: [email protected] observed with spironolactone. Renal failure and Published online 10 August 2006 a creatinine clearance below 50 ml/min are Management of hypertension in Europe P Gosse and RJ Macfadyen 830 contraindications to the use of aldosterone antago- nists. Concomitant administration with angiotensin- converting enzyme inhibitors, angiotensin receptor antagonists and non-steroidal anti-inflammatory drugs may increase the risk of hyperkalaemia. Am: 70 Ep: 64 No differences No differences Although there is not enough evidence to promote this drug as a first-line therapy in hypertension, this generally well-tolerated aldosterone antagonist is 15

Ep a potentially useful tool in resistant hypertension En on 4 and hyperaldosteronism. The restrictive indication 4 Lo Lo: 72 Ep: 63 that accompanies the commercial marketing of this 4

Am for SBP drug in Europe and the high cost will tend to Lo in white; Lo in blacks for DBP En. Ep ¼ ¼ 4 albuminuria deprive patients who may need it most, for example, BP reduction Side effects (%) ¼ and PP; Am Ep Ep men with various forms of hyperaldosteronism

d pressure. who do not support the sometimes high doses of spironolactone required for good control of their BP. Furthermore, there is no proof that the benefits of eplerenone in patients with post-infarction heart failure are superior to spironolactone 25 mg (as (mg) demonstrated in the randomized aldactone evalua- 16 average: 155 tion study (RALES) ), as the EPHESUS trial was

Eplerenone dosage performed against placebo. European specialists in hypertension and their patients who have been looking forward to this drug owing to its enhanced tolerance have perhaps been a little let down by the unexpected side effect of cost and restrictive indication. (mg)

Comparative drug A view from the United Kingdom: Robert MacFadyen As suggested above, the re-emergence of spirono-

24 Am 2.5–10 50–200; lactone in recent years has been nothing short of (weeks) astounding and has in turn revitalized the apprecia- tion of aldosterone and mineralocorticoid biology as a major independent mediator in cardiovascular disease. All too often, many physicians regard spironolactone as a useful adjuvant diuretic, a property it shares with potassium canrenoate, its

140 mm Hg marketed active metabolite and the prototypical o inhibitors of epithelial sodium flux amiloride and

Randomized 16 Lo 50–100triamterene, 50–200 Ep all available for decades and with

to SBP trivial cost issues. Notably, neither amiloride nor triamterene share the side-effect profile of spirono- lactone use in hyperaldosteronism. Of course, whether amiloride use could mimic the renaissance 269 Randomized, titration 168 Randomized 16of spironolactone Lo 50–100 in 100–200 resistant hypertension Ep care is ¼ ¼ 203 348; n n ¼

¼ untested. Of note, we have little information on 499 Randomized 24 En Ep n n

¼ eplerenone’s diuretic efficacy in any setting, but it

n should be emphasized that the aldosterone antago- white: 50 years, Black: nists (spironolactone and eplerenone) have rela- Low renin, 4 tively limited diuretic effects if plasma aldosterone or cortisol are low. Their effects are clearly different from amiloride, which is a true diuretic. 7 . 12 . et al 10 . 11 . et al Comparative trials with Ep in essential hypertension Eplerenone in hypertension – practicality et al et al The advantages of the side-effect profile of epler- enone seem clear when compared to spironolactone White Author Population Trial Duration Table 1 Abbreviations: Am, amlodipine; BP, blood pressure; DBP, diastolic blood pressure; En, enalapril; Ep, eplerenone; Lo, losartan; SBP, systolic bloo Flack Weinberger Williams and it would be wrong to suggest that anything other

Journal of Human Hypertension Management of hypertension in Europe P Gosse and RJ Macfadyen 831 than this represents a very useful alternative route added costs. When was a new drug therapy cheaper in blocking aldosterone. In the management of any than the alternatives? In the majority of Europe and chronic disease, polypharmacy is a serious problem the rest of the world, cost might be seen as less and linked to this is adherence/non-compliance, relevant as the patient or their insurance system which is responsible for many hospital admissions chooses whether to accept the drug bill. and apparent treatment failures. Hypertension is the From the industrial point of view, excess financial classic setting where this is evident. cost of course restricts availability and (by defini- In cardiac failure, spironolactone is used at low tion) sales. Eplerenone has been in gestation for dosage (p50 mg o.d.) with few side effects, and many years and was a product of research develop- adverse effects are more easily accepted by elderly ment by Pharmacia and latterly bought over by men severely impaired by heart failure. When used Pfizer.1 Equally commercial manufacturer’s are not in essential hypertension, it is neither unique nor a unaware or unresponsive to patient costs as they first- or even second-line therapy being used mostly need to generate sales in effect to patients who pay in severe resistant hypertension – in this setting, for the treatment. For most global pharmaceutical patients generally appreciate the risks of poor BP suppliers, the retail cost equation for a new therapy control and have accepted the need for both multi- is rarely a simplistic decision to maximize short- ple treatment and generally some degree of drug- term return, but takes into account development related adverse effects. In primary aldosteronism, costs, profile and competition within and between patients are younger without any significant symp- drug class. These factors are all present for epler- toms apart from those caused by hypokalaemia and enone and a decision was made to structure its costs spironolactone; dosages required are much higher accordingly for each market where a license and doses(450 mg o.d.) – in such patients, amiloride is indication was obtained. Whether this was the not always as efficient as spironolactone. correct one for the business will be evident in its sales figures. It is also the duty of a corporate structure to trade Eplerenone in hypertension – the costs of a new sensibly and also within the law provide a reason- therapy able return to its shareholders. For eplerenone – and There is understandable concern over the costs of more specifically in the hypertension market – the using eplerenone in hypertension, yet this is far availability of generic spironolactone, amiloride and from a new issue unique to this drug. After all, we potassium canrenoate are all obvious competitors. In are familiar with many seemingly expensive new the same way, prescribers cannot expect the global therapies in medicine, such as glargine insulin, pharmaceutical industry to operate independent clopidogrel, bisphosphonates or glycoprotein IIb IIIa of logic as a charitable trust for patients and or inhibitors, all of which are drugs that have found prescribers benefit. their place in due course through further trials and Thus, new medical treatments are expensive for understanding of efficacy. It is difficult to imagine fairly clear reasons and one is not simple profit physicians and practicing doctors being well quali- alone. Clearly, development costs of pharmaceuti- fied to assess such a complex area, such as the costs cals evoke huge debate. With increasingly prohibi- of therapy other than by a simplistic bottom line tive costs, many clinical trials relevant to early approach. Indeed, pharmacoeconomics is a complex registration are increasingly conducted in the devel- field and the cost of therapy is not simply the oping economies of Eastern Europe and China. headline financial charge but extend to the broader impact on health-care systems and the place of a new agent in a changing market. Population exposure issues Clearly, in a pan European or global context The use of any new agent involves caution to whether or not drug costs are supported by state establish population efficacy and population safety. funds or the individual patient is a key issue. In Neither can it be achieved nor defined by restricted some private health-care systems, the costs of use. Eplerenone has undoubtedly attracted most therapy borne by the patient are a largely indepen- of its attention not by its use in hypertension but dent transaction. Thus, it is for the patient to decide in post-myocardial infarction, where there are no the value to them of a new medical treatment option comparable data for spironolactone. We should as in discussion with their physician and not for the ever be cautious to extrapolate across between one doctor to decide in isolation. In the hypertensive high-profile trial and its subsequent licensed in- patient, the discussion for eplerenone would then dication and another. In population use, new drugs revolve around its additive efficacy and the value of are rarely used by specialist experts familiar with avoiding antiandrogen side effects. the nuances of clinical pharmacology, responsive- In the United Kingdom, where private health care ness and indications. Indeed, prescribing in hyper- is a minority system of care, the systematic role of tension is (rightly or wrongly) seen as a fairly simple a new drug is decided by regional or national exercise suitable for delegation to non-medical committees who attempt to equate the pharmacolo- practitioners. The impact of this on prescribing gical profile with benefits and against inevitably costs and treatment choices is yet to be tested.

Journal of Human Hypertension Management of hypertension in Europe P Gosse and RJ Macfadyen 832 Eplerenone in context – not so bad as painted? blocker, in patients with left ventricular dysfunction Many will agree that eplerenone is a valuable new after myocardial infarction. N Engl J Med 2003; 348: drug. Currently, there remain several options for 1309–1321. management in resistant hypertension and hyper- 9 Weinberger MH, Roniker B, Krause SL, Weiss RJ. aldosteronism, and it is possible that further Eplerenone, a selective aldosterone blocker, in mild- comparative trials will show the profile of this drug to-moderate hypertension. Am J Hypertens 2002; 15: 709–716. in a better light. At this stage, more data are clearly 10 White WB, Duprez D, St Hillaire R, Krause S, Roniker needed for eplerenone, even in some fundamental B, Kuse-Hamilton J et al. Effects of the selective effects such as natriuretic and diuretic efficacy. This aldosterone blocker eplerenone versus the calcium will require more investment by the manufacturer’s antagonist amlodipine in systolic hypertension. and more research work by investigators. There is no Hypertension 2003; 41: 1021–1026. doubt that the value of this will show through and 11 Flack JM, Oparil S, Pratt JH, Roniker B, Garthwaite S, eplerenone will take its place in routine care in due Kleiman JH et al. Efficacy and tolerability of course. In the mean time, we could celebrate its eplerenone and losartan in hypertensive black availability and discuss its advantages with our and white patients. J Am Coll Cardiol 2003; 41: patients and/or formulary committees, or the place 1148–1155. of this agent in current cardiovascular risk manage- 12 Williams GH, Burgess E, Kolloch RE, Ruilope LM, 17,18 Niegowska J, Kipnes MS et al. Efficacy of eplerenone ment or hypertension treatment guidelines. versus enalapril as monotherapy in systemic hyperten- sion. Am J Cardiol 2004; 93: 990–996. 13 Burgess ED, Lacourciere Y, Ruilope-Urioste LM, Oparil References S, Kleiman JH, Krause S et al. Long-term safety and 1 Menard J. The 45-year story of the development of an efficacy of the selective aldosterone blocker eplere- anti-aldosterone more specific than spironolactone. none in patients with essential hypertension. Clin Mol Cell Endocrinol 2004; 217: 45–52. Ther 2003; 25: 2388–2404. 2 Corvol P, Michaud A, Menard J, Freifeld M, Mahou- 14 Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips deau J. Antiandrogenic effect of spironolactone: me- RA, Roniker B et al. Effects of eplerenone, enalapril, chanisms of action. Endocrinology 1975; 97: 52–58. and eplerenone/enalapril in patients with essential 3 Froment A, Milon H. Etude en double aveugle de hypertension and left ventricular hypertrophy: the l’adjonction de spironolactone au traitement antihy- 4E-left ventricular hypertrophy study. Circulation pertenseur thiazidique. La fre´quence de la gyne´comas- 2003; 108: 1831–1838. tie aur cours des tratements prolonge´s. In: External 15 Prisant LM, Krum H, Roniker B, Krause SL, Fakouhi K, Activity of Aldosterone and its Antagonists. Excerpta He W. Can renin status predict the antihypertensive Medica: Paris, 1971, pp 64–69. efficacy of eplerenone add-on therapy? J Clin Pharma- 4 Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A, col 2003; 43: 1203–1210. DeVries C, Plouin PF et al. Efficacy and tolerance of 16 Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, spironolactone in essential hypertension. Am J Cardiol Perez A et al. The effect of spironolactone on 1987; 60: 820–825. morbidity and mortality in patients with severe heart 5 Lim PO, Young WF, MacDonald TM. A review of the failure. Randomized Aldactone Evaluation Study medical treatment of primary aldosteronism. J Hyper- Investigators. N Engl J Med 1999; 341: 709–717. tens 2001; 19: 353–361. 17 Jessani S, Watson T, Cappuccio FP, Lip GY. Prevention 6 Nishizaka MK, Zaman MA, Calhoun DA. Efficacy of of cardiovascular disease in clinical practice: The Joint low-dose spironolactone in subjects with resistant British Societies’ (JBS 2) guidelines. J Hum Hypertens hypertension. Am J Hypertens 2003; 16: 925–930. 2006; 20(9): 641–645. 7 Weinberger MH, White WB, Ruilope LM, MacDonald 18 Williams B, Poulter NR, Brown MJ, Davis M, McInnes TM, Davidson RC, Roniker B et al. Effects of epler- GT, Potter JF, et al., British Hypertension Society. enone versus losartan in patients with low-renin Guidelines for management of hypertension: report of hypertension. Am Heart J 2005; 150: 426–433. the fourth working party of the British Hypertension 8 Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Society, 2004-BHS IV. J Hum Hypertens 2004; 18(3): Roniker B et al. Eplerenone, a selective aldosterone 139–185.

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