Journal of Human Hypertension (2000) 14, 79–81 2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh COMMENTARY When will the ACE-inhibitors be declared obsolete? WJ Elliott Department of Preventive Medicine, RUSH Medical College of RUSH University at RUSH-Presbyterian-St. Luke’s Medical Center, Chicago, IL, USA Keywords: ACE inhibitors; angiotensin II receptor blockers Although there are currently many effective classes There are essentially two scenarios in which it of antihypertensive medications from which to might be possible to consider the ACE-inhibitors choose a specific agent to treat elevated blood press- obsolete medications, having been ‘put out to pas- ure, the angiotensin-converting enzyme (ACE) ture’ by the angiotensin II receptor blockers. One inhibitors occupy a special place. Besides the fact scenario is based on the current penchant for ‘evi- that these agents were developed in a rather more dence-based medicine’, and the other is primarily ‘rational’ way1 than many other drugs which were based on a more fundamental issue: economics. derived from natural products or synthetic chemi- One of the most pervasive trends in medicine in cals, there are few antihypertensive agents that have the last 20 years has been the growth and wide been as widely studied and whose benefits have acceptance of ‘evidence-based medicine’: the theory now been proven in clinical trials in a broad variety that medicine should adopt those practices and pro- of concomitant medical conditions. ACE-inhibitors cedures which have been shown by clinical trials to have been shown, in trials against placebo, to result in improved outcomes for individuals with improve prognosis in heart failure,2 post-myocardial the disease in question.19 This trend satisfies both infarction,3–7 renal impairment,8–10 Type I diabetic the medical scientists (whose work in clinical trials nephropathy,11 and many other conditions (eg, largely forms the basis for widespread recom- scleroderma12). mendations) and traditional (ie, ‘conservative’) The ACE-inhibitors are now being challenged physicians. Because clinical trials of a new treat- worldwide by another effective way of interfering ment typically require many years for completion, with the vasoconstriction and other untoward phar- ‘older treatments’ usually have a several-year advan- macological properties of angiotensin II: direct tage over ‘newer treatments’, based on the precepts 13 blockade of the AT1 receptor. The angiotensin II of ‘evidence-based medicine’. This situation is very receptor blockers (ARBs) have apparently nearly the well illustrated in the comparison of ACE-inhibitors same efficacy in lowering blood pressure (at least in and ARBs: the ACE-inhibitors have a 10–15 year meta-analysis) as the ACE-inhibitors,14 and very lead in clinical trial data, with many studies show- much lower rates of adverse effects (especially ing (for instance) a major significant survival benefit cough15–18 and angioneurotic oedema). Many phar- among heart failure patients, such that a prominent maceutical companies have begun large marketing editorial about one such trial anointed ACE-inhibi- efforts to persuade physicians and patients to use tors the ‘cornerstone of heart failure therapy’.20 the newer agents first, which has sometimes resulted Although there have been some recent refinements in the following conversation in consulting rooms: to ‘optimal’ therapy for heart failure (which now Healthcare provider: ‘I am going to prescribe these often includes digoxin, a low-dose beta-blocker,21,22 tablets for your high blood pressure. If they cause and spironolactone23), most current research in side-effects, don’t worry; I will give you a somewhat heart failure is being done with the blinded study similar medication that typically doesn’t cause these medication being added to standard-of-care therapy side-effects.’ (which nearly always includes an ACE-inhibitor). In Healthcare consumer: ‘Well, then, why don’t you fact, for many of the ongoing and currently-planned just give me the second medication now, and avoid studies of ARBs in heart failure, it was considered the side-effects all together!’ unethical to ‘deprive’ patients of ACE-inhibitors, and instead give them the newer ARBs; as a result, several of the clinical trials are being conducted Correspondence: Dr William J Elliott, Department of Preventive Medicine, RUSH Medical College of RUSH University at RUSH- with all heart failure patients on an ACE-inhibitor, Presbyterian-St. Luke’s Medical Center, 1700 West Van Buren to which is added either placebo or an ARB. This Street, Suite 470 Chicago, IL 60612, USA situation essentially makes it impossible to obtain ACE-inhibitors replaced by ARBs? WJ Elliott 80 data supporting the use of an ARB alone as an effec- tive treatment for heart failure (or any of the other disease states for which ACE-inhibitors are now so useful). When (and if) current and future research proves that ARBs are at least as effective (if not more effective) than ACE-inhibitors for the prevention of morbidity and mortality, then the suggestion of the patient in the above vignette may be vindicated. Until then, a reasonable rebuttal to the suggestion would be that, ‘We have clear data showing the benefits of the tablets I’m about to give you, in reducing the complications of high blood pressure. If you can take them without experiencing side- Figure 2 Average wholesale prices for the five ARBs that are com- effects, it is likely that they will improve your prog- mercially marketed in the USA. Costs are annual pharmacy costs nosis as they have improved the lot of patients who for the recommended initial starting dose, as reported in the most recent survey of The Medical Letter on Drugs and Therapeutics.24 were given them in clinical trials. If you can’t toler- ate them, obviously we will be forced to try some- thing else less well-proven.’ about the time that the most popular ACE-inhibitors The second argument which can be marshalled by were at the end of their patent lives, and promoted the health care provider in favour of using an ACE- by companies with large profits to lose when the inhibitor rather than an ARB is based on economics. ACE-inhibitor was no longer protected by patent. If Perhaps because ACE-inhibitors have been seen as (and when) the economics of acquiring an ARB are the most homogeneous of the ‘traditional’ antihyper- competitive with the cost of an ACE-inhibitor, there tensive drugs (as compared, for instance, to will be a greater interest among physicians, pharma- diuretics, beta-blockers, and calcium antagonists), cists, and the organizations that employ them, in many authorities see very little difference between allowing the health care consumer to receive these the agents, except for those related to economics. medications primarily. The ACE-inhibitors are an excellent example of ‘lais- In the USA, it is much more typical for the health sez-faire’ economics: as the therapeutic class became care provider to use the economic argument to rebut more crowded, costs for these agents declined (see the suggestion given by the consumer above. There Figure 1). Furthermore, generic captopril has are currently several methods that enterprising become available at an average wholesale price of medical care systems have put into place to enforce approximately US$0.04 per day to several health the primary choice of ACE-inhibitors in this setting. care plans with aggressive pharmacy benefits man- It is common practice for ARBs to be dispensed only agers, which is competitive with other generic anti- if the pharmacist has a record of a previous dispen- hypertensive agents, and approximately 28 times sing of an ACE-inhibitor, typically within the pre- cheaper than the currently-least expensive ARB.24 vious 90 days. To ensure that only patients with Unfortunately, despite perhaps even greater homo- legitimate previous adverse effects with ACE-inhibi- geneity among the ARBs (even compared to ACE- tors (eg, angioedema or persistent dry cough) receive inhibitors), the ARBs have not shown a similar dec- the more expensive drug, many pharmacy benefits rement in average wholesale prices in the USA (see managers require special forms to be completed Figure 2); the recommended starting dose of each is before an ARB can be dispensed. Typically two priced literally within pennies per day of the physicians’ signatures are required on the request others.24 This situation may improve when the sixth for an ARB; some organizations mandate that the ARB is introduced (see Figure 1). There may be little two physicians must have different Federal Tax ID coincidence that the ARBs were introduced just numbers (so that they cannot be business partners or simply sign each others’ forms without forming an independent assessment). These requirements have been put into place to ensure that the less- expensive ACE-inhibitor, with proven benefits in preventing morbidity and mortality in clinical trials, will not be superceded by the ARBs despite fewer side-effects. References 1 Cushman DW, Ondetti MA. History of the design of captopril and related inhibitors of angiotensin con- verting enzyme. Hypertension 1991; 17: 589–592. 2 The SOLVD Investigators. Effect of enalapril on mor- tality and the development of heart failure in asympto- Figure 1 Average wholesale prices for the nine ACE-inhibitors matic patients with reduced left ventricular ejection that are commercially available in the USA. Costs are the annual fractions. N Engl J Med 1992; 327: 685–691. pharmacy costs for the ‘second-step’ dose, as offered in the largest 3 Pfeffer MA et al. Effect of captopril on mortality and retail pharmacy on the Internet.25 morbidity in patients with left ventricular dysfunction Journal of Human Hypertension ACE-inhibitors replaced by ARBs? WJ Elliott 81 after myocardial infarction. Results of the Survival and 13 Bauer JH, Reams GP.