Antihypertensive therapy: from 2003 to 2013 and beyond

Keywords::

• antihypertensive agents
• blood pressure targets
• hypertension guidelines
• resistant hypertension

How research on antihypertensive therapy has moved and progressed since 2003, when Expert Review of Cardiovascular Therapy was inaugurated, to 2013, when it celebrates its 10th anniversary, can clearly be seen by comparing the first edition of the European Society of Hypertension (ESH)–European Society of Cardiology (ESC) guidelines on the management of arterial hypertension [1], published in 2003, with the third edition just published this year [2]. From the pedestal of the 2013 guidelines, we can also easily look forward and scrutinize future progresses if current research needs are going to be fulfilled.

In the second half of the past century, progress in antihypertensive therapy was characterized not only by development of several classes of drugs effectively lowering blood pressure, but also by their careful testing in randomized controlled trials (RCTs) to verify their ability to reduce cardiovascular events. Between 1965 and 1998, RCTs were conducted mostly of active treatment compared with placebo or no treatment, in order to answer the crucial question as to whether drug-induced blood pressure lowering was beneficial or harmful [3]. Indeed, a long-lasting prejudice had considered hypertension as a compensatory reaction that would have been harmful to tamper. The year 2003, when Expert Review of Cardiovascular Therapy initiated its publication, was, so to say, in the middle of a second wave of RCTs, that of trials comparing the effects of different antihypertensive agents, that is, of trials randomizing patients to treatments initiated by agents belonging to different classes. By 2003, 16 of these trials had been completed and their results published, and the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) could publish a meta-analysis of them showing that no significant difference could be found between the effects of angiotensin converting enzyme (ACE) inhibitors, calcium antagonists and diuretics or β-blockers on cardiovascular death, major cardiovascular events and coronary events; calcium antagonists showed a small advantage over ACE inhibitors and diuretics/β-blockers as far as stroke was concerned, but some disadvantage for heart failure [4]. It was on the basis of this meta-analysis that the 2003 ESH–ESC hypertension guidelines [1] could state that the cardiovascular outcome reduction achieved by antihypertensive therapies depends on their blood pressure lowering effects rather than on the specific protective actions of the various agents or class of drugs, and recommend that antihypertensive treatment be initiated by any of the major classes of antihypertensive agents, namely, diuretics, β-blockers, calcium antagonists, ACE inhibitors and angiotensin receptor blockers. Between 2003 and 2008, other important RCTs compared the effects of treatments initiated by different agents. Among these, CONVINCE [5] and INVEST [6] compared the nondihydropyridine calcium antagonist verapamil with conventional therapy with diuretics and β-blockers; the VALUE trial [7], the angiotensin receptor blocker valsartan with the dihydropyridine calcium antagonist amlodipine; ASCOT-BPLA [8] amlodipine with the eventual addition of the ACE inhibitor perindopril to the β-blocker atenolol with the possible addition of a thiazide diuretic; and ONTARGET [9], the ACE inhibitor ramipril with the angiotensin receptor antagonist telmisartan. By 2007, a new meta-analysis by Law et al. [10] could include as many as 46 trials on 230,491 patients comparing regimens based on different antihypertensive agents (although a number of these trials were not on hypertensive patients, but on patients with myocardial infarction or chronic heart failure). On the whole, this extensive meta-analysis fully confirmed the 2003 BPLTTC meta-analysis, showing that no therapeutic regimen initiated by a particular class of drugs is superior to other regimens in reducing incidence of cardiovascular death, major cardiovascular events and coronary events, whereas a regimen initiated by a calcium antagonist is slightly superior to the others, and a regimen initiated with a β-blocker slightly inferior to the others in the prevention of stroke. On the other hand, calcium antagonists appear less effective in preventing heart failure, and β-blockers particularly effective in preventing major cardiovascular events in patients with a recent myocardial infarction. On the basis of this evidence, the second (2007) edition of the ESH–ESC hypertension guidelines [11] could reconfirm the statement that all major classes of antihypertensive agents can 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 in specific conditions.

There have been few additional trials comparing different antihypertensive regimens after 2008, mostly because no new class of antihypertensive agents has been developed, with the exception of the renin inhibitor aliskiren. Aliskiren was tested in two trials: in one (ALTITUDE), aliskiren was administered on the top of a renin–angiotensin system (RAS) blocker in diabetic patients [12] and in the other (ASTRONAUT), aliskiren was administered in addition to standard treatment in heart failure [13]. ALTITUDE was prematurely stopped because combination of aliskiren with another RAS blocker was associated with a higher incidence of adverse events, renal complications, hyperkalemia and hypotension [12]. ASTRONAUT was unable to show reduction in mortality and hospitalization in the heart failure patients randomized to aliskiren [13]. Consequently, a third aliskiren trial (APOLLO), in which aliskiren was given to elderly individuals alone or in combination with a thiazide diuretic or a calcium antagonist, was stopped despite no evidence of harm in the aliskiren-treated group. There is no information that other RCTs testing aliskiren are being planned.

The very large, and perhaps too large, number of RCTs devoted to compare antihypertensive treatment regimens initiated by different agents has certainly based on very solid ground the statement, also reiterated by the 2013 ESH–ESC hypertension guidelines [2], that “the main benefits of antihypertensive treatment are due to lowering of blood pressure per se and are largely independent of the drugs employed.” Unfortunately, this huge effort, partly needed to demonstrate equivalent benefits from different classes of antihypertensive agents, but partly motivated by the desire of pharmacological companies to show specific benefits of their own drugs or by stringent requirements of regulatory agencies, has also had the untoward effects of leaving unanswered many questions of practical importance for antihypertensive treatment [14], so that a number of guidelines recommendations had to be based more on experts’ opinion than on trial evidence.

A critical review published in early 2009 [15] made the point that RCT evidence on two major issues was very scanty: when to initiate antihypertensive treatment and the blood pressure target to be achieved by treatment. Until recently, most of the hypertension guidelines recommended to initiate drug treatment in all individuals with a consistent elevation of blood pressure values to ≥140/90 mmHg, and to use lower blood pressure targets in high-risk hypertensive patients, particularly those with diabetes or previous cardiovascular events (<130/80 rather than <140/90 mmHg). The scanty evidence for these recommendations was promptly acknowledged by a reappraisal of the European guidelines published by an ESH Task Force in late 2009 [16], and the point has been fully discussed by the 2013 ESH–ESC guidelines [2], which have consequently modified their previous (2007) recommendations. The 2013 guidelines [2] acknowledge that previous evidence favoring treating “mild hypertension was from trials that used a different grading of hypertension (based on DBP only) or from a substudy of the FEVER trial” [17,18]. Despite these limitations, the 2013 guidelines have considered prudent to suggest initiation of antihypertensive drug treatment in Grade 1 (SBP 140–159 or DBP 90–99 mmHg) hypertensive patients at low-to-moderate risk, when blood pressure remains within this range despite a reasonable period of time with lifestyle measures. The guidelines recognize, however, that a RCT directly supporting this recommendation should be desirable.

As to target blood pressures, the 2013 ESH–ESC guidelines point out that in no condition RCT evidence is available that lowering SBP <130 is more beneficial than lowering it <140 mmHg, and indeed the possibility that excessive blood pressure lowering may be detrimental rather than beneficial (so-called J-curve hypothesis [19]) cannot be ruled out. Therefore, the recommendation is given to use a SBP target <140 mmHg in all hypertensive patients, independently of the level of cardiovascular risk or concomitant disease (diabetes, renal disease, etc.). Of course, lack of evidence does not mean evidence against. Therefore, RCTs investigating different blood pressure targets in different conditions, like the recent ACCORD trial [20], are encouraged and some, such as SPRINT [101] and ESH-ESC SHOT [21], are in progress. It is an easy prediction that results of this type of studies will be of the greatest interest to cardiovascular and hypertension journals in the forthcoming years.

Another problem that it is foreseen will interest the specialized medical press in the near future is that of resistant hypertension, that is those cases in which blood pressure values <140/90 mmHg cannot be achieved despite treatment with multiple 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 research is needed. Indeed, we need a better definition of resistant hypertension, a wider and more systematic use of ambulatory blood pressure monitoring in order to confirm elevated blood pressure values, more refined methods for testing patients’ adherence to therapy and RCTs rigorously assessing the ability of drugs, such as mineralocorticoid receptor antagonists, and new devices, such as those providing carotid sinus stimulation or renal denervation not only in effectively reducing blood pressure but also in reducing cardiovascular outcomes in these difficult and often high-risk patients.

Financial & competing interests disclosure

A Zanchetti has received lecturing fees from Menarini International and Recordati. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.