Antihypertensive therapy: from 2003 to2013 and beyondExpert Rev. Cardiovasc. Ther. 11(11), 1443–1446 (2013)

Alberto ZanchettiIstituto Auxologico Italiano

Professor Emeritus, University of

Milan, Via L. Ariosto 13,

20145 Milan, Italy

Tel.: +39 02 61911 2237

Fax: +39 02 61911 2901

alberto.zanchetti@unimi.it

“During the last decade, research interest has graduallyshifted from comparing the relative benefits of different

classes of antihypertensive drugs to testing differenttreatment strategies.”

How research on antihypertensive therapyhas moved and progressed since 2003,when Expert Review of CardiovascularTherapy was inaugurated, to 2013, when itcelebrates its 10th anniversary, can clearlybe seen by comparing the first edition ofthe European Society of Hypertension(ESH)–European Society of Cardiology(ESC) guidelines on the management ofarterial hypertension [1], published in2003, with the third edition just publishedthis year [2]. From the pedestal of the2013 guidelines, we can also easily lookforward and scrutinize future progresses ifcurrent research needs are going tobe fulfilled.

In the second half of the past century,progress in antihypertensive therapy wascharacterized not only by developmentof several classes of drugs effectively low-ering blood pressure, but also by theircareful testing in randomized controlledtrials (RCTs) to verify their ability toreduce cardiovascular events. Between1965 and 1998, RCTs were conductedmostly of active treatment comparedwith placebo or no treatment, in orderto answer the crucial question as towhether drug-induced blood pressurelowering was beneficial or harmful [3].Indeed, a long-lasting prejudice had con-sidered hypertension as a compensatoryreaction that would have been harmfulto tamper. The year 2003, when ExpertReview of Cardiovascular Therapy initi-ated its publication, was, so to say, inthe middle of a second wave of RCTs,

that of trials comparing the effects ofdifferent antihypertensive agents, that is,of trials randomizing patients to treat-ments initiated by agents belonging todifferent classes. By 2003, 16 of thesetrials had been completed and theirresults published, and the Blood PressureLowering Treatment Trialists’ Collabora-tion (BPLTTC) could publish a meta-analysis of them showing that no signifi-cant difference could be found betweenthe effects of angiotensin convertingenzyme (ACE) inhibitors, calcium antag-onists and diuretics or b-blockers on car-diovascular death, major cardiovascularevents and coronary events; calciumantagonists showed a small advantageover ACE inhibitors and diuretics/b-blockers as far as stroke was concerned,but some disadvantage for heart failure [4].It was on the basis of this meta-analysisthat the 2003 ESH–ESC hypertensionguidelines [1] could state that the cardio-vascular outcome reduction achieved byantihypertensive therapies depends ontheir blood pressure lowering effectsrather than on the specific protectiveactions of the various agents or class ofdrugs, and recommend that antihyperten-sive treatment be initiated by any of themajor classes of antihypertensive agents,namely, diuretics, b-blockers, calciumantagonists, ACE inhibitors and angioten-sin receptor blockers. Between 2003 and2008, other important RCTs comparedthe effects of treatments initiated by differ-ent agents. Among these, CONVINCE [5]

KEYWORDS: antihypertensive agents • blood pressure targets • hypertension guidelines

• resistant hypertension

THEMED ARTICLE y Hyper- & Hypotension Editorial

www.expert-reviews.com 10.1586/14779072.2013.843451 � 2013 Informa UK Ltd ISSN 1477-9072 1443

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and INVEST [6] compared the nondihydropyridine calciumantagonist verapamil with conventional therapy with diureticsand b-blockers; the VALUE trial [7], the angiotensin receptorblocker valsartan with the dihydropyridine calcium antagonistamlodipine; ASCOT-BPLA [8] amlodipine with the eventualaddition of the ACE inhibitor perindopril to the b-blocker ateno-lol with the possible addition of a thiazide diuretic; andONTARGET [9], the ACE inhibitor ramipril with the angioten-sin receptor antagonist telmisartan. By 2007, a new meta-analysis by Law et al. [10] could include as many as 46 trials on230,491 patients comparing regimens based on different anti-hypertensive agents (although a number of these trials werenot on hypertensive patients, but on patients with myocardialinfarction or chronic heart failure). On the whole, this exten-sive meta-analysis fully confirmed the 2003 BPLTTC meta-analysis, showing that no therapeutic regimen initiated by aparticular class of drugs is superior to other regimens in reduc-ing incidence of cardiovascular death, major cardiovascularevents and coronary events, whereas a regimen initiated by acalcium antagonist is slightly superior to the others, and a reg-imen initiated with a b-blocker slightly inferior to the othersin the prevention of stroke. On the other hand, calcium antag-onists appear less effective in preventing heart failure, andb-blockers particularly effective in preventing major cardiovas-cular events in patients with a recent myocardial infarction.On the basis of this evidence, the second (2007) edition ofthe ESH–ESC hypertension guidelines [11] could reconfirm thestatement that all major classes of antihypertensive agentscan be prescribed, that there is no evidence in favor of any all-purpose ranking of drugs for general antihypertensive usage,but that different agents can be preferentially considered inspecific conditions.

There have been few additional trials comparing differentantihypertensive regimens after 2008, mostly because no newclass of antihypertensive agents has been developed, with theexception of the renin inhibitor aliskiren. Aliskiren was testedin two trials: in one (ALTITUDE), aliskiren was administeredon the top of a renin–angiotensin system (RAS) blocker in dia-betic patients [12] and in the other (ASTRONAUT), aliskirenwas administered in addition to standard treatment in heartfailure [13]. ALTITUDE was prematurely stopped because com-bination of aliskiren with another RAS blocker was associatedwith a higher incidence of adverse events, renal complications,hyperkalemia and hypotension [12]. ASTRONAUT was unableto show reduction in mortality and hospitalization in the heartfailure patients randomized to aliskiren [13]. Consequently, athird aliskiren trial (APOLLO), in which aliskiren was given toelderly individuals alone or in combination with a thiazidediuretic or a calcium antagonist, was stopped despite no evi-dence of harm in the aliskiren-treated group. There is no infor-mation that other RCTs testing aliskiren are being planned.

The very large, and perhaps too large, number of RCTsdevoted to compare antihypertensive treatment regimens initi-ated by different agents has certainly based on very solidground the statement, also reiterated by the 2013 ESH–ESC

hypertension guidelines [2], that “the main benefits of antihy-pertensive treatment are due to lowering of blood pressure perse and are largely independent of the drugs employed.”Unfortunately, this huge effort, partly needed to demonstrateequivalent benefits from different classes of antihypertensiveagents, but partly motivated by the desire of pharmacologicalcompanies to show specific benefits of their own drugs or bystringent requirements of regulatory agencies, has also had theuntoward effects of leaving unanswered many questions ofpractical importance for antihypertensive treatment [14], so thata number of guidelines recommendations had to be basedmore on experts’ opinion than on trial evidence.

“Yet, we do not know whether antihyperten-sive drug treatment should be initiated in all

individuals with a blood pressure$140/90 mmHg, and what is the optimalblood pressure target to be achieved by

treatment.”

A critical review published in early 2009 [15] made thepoint that RCT evidence on two major issues was veryscanty: when to initiate antihypertensive treatment and theblood pressure target to be achieved by treatment. Untilrecently, most of the hypertension guidelines recommendedto initiate drug treatment in all individuals with a consistentelevation of blood pressure values to ‡140/90 mmHg, and touse lower blood pressure targets in high-risk hypertensivepatients, particularly those with diabetes or previous cardio-vascular events (<130/80 rather than <140/90 mmHg). Thescanty evidence for these recommendations was promptlyacknowledged by a reappraisal of the European guidelinespublished by an ESH Task Force in late 2009 [16], and thepoint has been fully discussed by the 2013 ESH–ESC guide-lines [2], which have consequently modified their previous(2007) recommendations. The 2013 guidelines [2] acknowl-edge that previous evidence favoring treating “mild hyperten-sion was from trials that used a different grading ofhypertension (based on DBP only) or from a substudy of theFEVER trial” [17,18]. Despite these limitations, the 2013 guide-lines have considered prudent to suggest initiation of antihy-pertensive drug treatment in Grade 1 (SBP 140–159 or DBP90–99 mmHg) hypertensive patients at low-to-moderaterisk, when blood pressure remains within this range despite areasonable period of time with lifestyle measures. The guide-lines recognize, however, that a RCT directly supporting thisrecommendation should be desirable.

As to target blood pressures, the 2013 ESH–ESC guidelinespoint out that in no condition RCT evidence is available thatlowering SBP <130 is more beneficial than lowering it<140 mmHg, and indeed the possibility that excessive bloodpressure lowering may be detrimental rather than beneficial(so-called J-curve hypothesis [19]) cannot be ruled out. There-fore, the recommendation is given to use a SBP target<140 mmHg in all hypertensive patients, independently of the

Editorial Zanchetti

1444 Expert Rev. Cardiovasc. Ther. 11(11), (2013)

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level of cardiovascular risk or concomitant disease (diabetes,renal disease, etc.). Of course, lack of evidence does not meanevidence against. Therefore, RCTs investigating differentblood pressure targets in different conditions, like the recentACCORD trial [20], are encouraged and some, such asSPRINT [101] and ESH-ESC SHOT [21], are in progress. It isan easy prediction that results of this type of studies will be ofthe greatest interest to cardiovascular and hypertension journalsin the forthcoming years.

“More precise diagnosis and more effectivetreatment of so-called ‘resistant’ hypertensionis a challenge for the forthcoming decade.”

Another problem that it is foreseen will interest the special-ized medical press in the near future is that of resistant hyper-tension, that is those cases in which blood pressure values<140/90 mmHg cannot be achieved despite treatment withmultiple antihypertensive agents (at least three) at full doses.This topic is also extensively discussed in the 2013 ESH–ESC

guidelines [2], which also emphasize that much further researchis needed. Indeed, we need a better definition of resistanthypertension, a wider and more systematic use of ambulatoryblood pressure monitoring in order to confirm elevated bloodpressure values, more refined methods for testing patients’adherence to therapy and RCTs rigorously assessing the abilityof drugs, such as mineralocorticoid receptor antagonists, andnew devices, such as those providing carotid sinus stimulationor renal denervation not only in effectively reducing bloodpressure but also in reducing cardiovascular outcomes in thesedifficult and often high-risk patients.

Financial & competing interests disclosureA Zanchetti has received lecturing fees from Menarini Interna-tional and Recordati. The author has no other relevant affiliationsor financial involvement with any organization or entity with afinancial interest in or financial conflict with the subject matteror materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of thismanuscript.

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