In the British Hypertension Society(BHS)/NICE guidelines for the manage-ment of uncomplicated essential hyper-tension, ie where there is no compellingindication or contraindication for a partic-ular therapy, an ACE inhibitor or angio -tensin-II receptor blocker (ARB) isrecommended as first-line treatment inindividuals aged less than 55 years, anda calcium-channel blocker (CCB) in those55 years or older and in people of Afro-Caribbean heredity. Thus, age and race are used as sur-

rogates for renin-angiotensin system(RAS) activity. The blood pressure-lower-ing effect of RAS-blockers in younger,white people, who tend to have renin-dependent hypertension, is greater thanthat of a CCB; in contrast, older and blackpeople, who tend towards low-renin hyper-tension, respond preferentially to CCBs.1

Underpinning this approach to initia-tion of drug treatment for hypertension isevidence that the benefit of antihyperten-sive therapy is proportional to blood pres-sure lowering.2,3 Reduction of bloodpressure therefore takes priority whilemechanism of action of antihypertensivedrugs is relatively unimportant. As generic ACE inhibitors were much

less expensive than patented ARBs, theBHS/NICE guidelines express a preferencefor ACE inhibition with an ARB reserved forthose unable to tolerate an ACE inhibitor.Since the publication of these guide-

lines, several ARBs have come off patent

(candesartan, irbesartan, losartan andvalsartan) and now have costs on a parwith generic ACE inhibitors. As unit costis no longer an issue, is there now a casefor starting treatment with a generic ARBin preference to an ACE inhibitor?

Extra benefits with ACEinhibitors?At first sight, the answer to this questionappears straightforward. ARBs haveblood pressure-lowering efficacy equiva-lent to that of ACE inhibitors but are bettertolerated.4 Both drug classes are associ-ated with few adverse events but, whileabout 15 per cent of people treated withACE inhibitors develop a dry, irritatingcough,5 ARBs have a side-effect profileindistinguishable from that of placebo.4

However, there are those who arguethat the rationale for the BHS/NICE guide-lines is unsound since ACE inhibitors,

CURRENT ISSUES n

Prescriber 5 September 2013 z 51prescriber.co.uk

Are ARBs now first-line therapy for hypertension?Gordon McInnes BSc, MD, FRCP, FFPM, FBPharmacolS

Now that generic ARBs areavailable and ACE inhibitorshave consequently lost theircost advantage, ProfessorMcInnes makes the case forstarting antihypertensivetreatment with an ARB.

Endorsements

Number of days’ treatmentN.B. Ensure dose is stated

Age

D.o.B

Title, Forename, Surname & Address

Please don’t stamp over age box

Pharmacy Stamp

S

NHS Number:

Losartan Tablets

50 mg 28 tablet

TAKE ONCE DAILY

- - - - - - - - - - - - -

One prescription on form

Figure 1. The availability of generic ARBs has removed the cost differential with ACE inhibitors

despite similar blood pressure reduction,have benefits not shared by ARBs.6,7

There has been much speculation thatACE inhibitors have specific outcomeadvantages.7 Based on the results of trialssuch as HOPE (Heart Outcomes PreventionEvaluation)8 and EUROPA (European Trialon Reduction of Cardiac Events withPerindopril in Stable Coronary ArteryDisease),9 it is suggested that these drugsreduce cardiovascular risk independent ofblood pressure changes. Furthermore, it isproposed that ARBs lack this benefit andmay even increase the risk of MI.10,11

Although meta-regression analysisdoes not support an effect different fromthat expected from blood pressure reduc-tion with either class of RAS-blocker,3

reports continue to appear proposing a

disparate effect on outcomes of ACEinhibitors and ARBs. The most recent suggests that ACE

inhibition is associated with a 10 per centreduction in all-cause mortality while nosuch effect is seen with an ARB.12

The findings from this study have beenhugely influential and therefore the conclu-sions require careful scrutiny. The methodused was a pooled, or network, meta-analy-sis that depends on indirect comparisonsof trials with different drugs, differentdesigns and in different patient popula-tions. An unintended consequence of suchanalyses is the potential for introduction ofbias. There was, for example, markedimbalance between the ACE inhibitor andARB trials with regard to absence of activecomparators (ACE inhibitor trials 43 percent vs ARB trials 15 per cent). Thus, ACEinhibitor trials might be expected to beassociated with better outcomes. Furthermore, while an ARB was first-

line therapy in all ARB trials included, inalmost 50 per cent of ACE inhibitor trialsother drugs were first line making theinfluence of ACE inhibition uncertain. Despite these biases, reduction in car-

diovascular mortality, where there is aplausible role for RAS-blockade, did not dif-fer between ACE inhibitor and ARB trials.

Head-to-head trialsSuch cross-trial comparisons are com-mon but hazardous because of the poten-tial biases. The best method to comparedrugs is direct (head-to-head) randomisedtrials in large populations. Although not included in the above

analysis, there have been no less than sixsuch large-scale comparisons of ACEinhibitors and ARBs. A meta-analysis ofthese trials shows no difference betweenthe drug classes for all-cause mortality,cardiovascular mortality, MI or stroke.13

Thus, ARBs are not inferior to ACEinhibitors in the prevention of cardiovas-

cular events or death and, in all the trials,ARBs are better tolerated.

ConclusionBased on the best evidence, it appearsthat ARBs and ACE inhibitors are inter-changeable in terms of blood pressurelowering and reduction in cardiovascularoutcomes but ARBs have an advantagein tolerability. Now that there is no costdifferential, ARBs should replace ACEinhibitors for initiation of antihypertensivetherapy in appropriate individuals.

References1. Brown MJ, et al. J Hum Hypertens 2003;17:81–6.2. Blood Pressure Lowering Treatment TrialistCollaboration. Lancet 2003;362:1527–35.3. Law MR, et al. BMJ 2009;338:1245–53. 4. Law MR, et al. BMJ 2003;327:1427–35.5. Yeo WW, et al. J Hum Hypertens 1990;4:517–20.6. Blood Pressure Lowering Treatment Trialists’Collaboration. J Hypertens 2007;25:951–8.7. Ruschitzka F, et al. Eur Heart J 2012;33:1996–8.8. HOPE (Heart Outcomes PreventionEvaluation) Study Investigators. N Engl J Med2000;342:145–53.9. EUROPA Investigators. Lancet 2003;362:782–8.10. Strauss MH, et al. Circulation 2006;114:838–54.11. Verma S, et al. BMJ 2004;329:1248–9.12. van Vark LC, et al. Eur Heart J 2012;33:2088–97.13. Reboldi G. J Hypertens 2008;26: 1282–9.

Declaration of interestsProfessor McInnes has received hono-raria from Bayer, Boehringer Ingelheim,Novartis, Servier and Takeda, and hasreceived research grants from Bayer,Boehringer Ingelheim and Pfizer.

Gordon McInnes is professor emeritus,Institute of Cardiovascular and MedicalSciences, Gardiner Institute, WesternInfirmary, Glasgow

n CURRENT ISSUES l ARBs first line?

52 z Prescriber 5 September 2013 prescriber.co.uk

Figure 2. The BHS/NICE guidelines recommend an ACEinhibitor or ARB in younger white patients; is there nownot a case for initiating treatment with an ARB?

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