“Good order is the foundation of all great things.”—Edmund Burke
In their recently released report, the Institute of Medicine (IOM) states that nearly one of every three adults in the United States has hypertension. In their “A Population-Based Policy and Systems Change Approach to Prevent and Control Hypertension,” the IOM states that one third of heart attacks and almost one half of heart failures in the United States each year are due to untreated or poorly treated hypertension. Hypertension is regarded as simple to diagnose and relatively easy to treat, easy to prevent, and inexpensive to manage; however, it remains the second leading cause of death among Americans. It has been labeled the “neglected disease.”1
While increasing awareness among patients remains important, there is a substantial gap between the number of patients taking treatment and the percentage with controlled hypertension. This suggests that patients are either uniformly noncompliant with their therapy or clinicians are not effectively managing the disease.
The guidelines put forth by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure are quite clear. Two thirds of hypertensive patients are not expected to be controlled on monotherapy and will require combination therapy of ≥2 agents. Since the majority of patients will require combination therapy, the committee additionally recommends that the combination regimen include a second drug from a different pharmacologic class. This is obviously done in an attempt to take advantage of complementary mechanisms of action between the more than 60 individual antihypertensive monotherapy options available. The committee adds specific recommendations that highlight thiazide diuretics as the initial choice and that they should be considered “background” therapy for the addition of either an angiotensin-converting enzyme (ACE) inhibitor, β-blocker, calcium channel blocker, or angiotensin receptor blocker.2
There is little debate that combination therapy offers many advantages in the treatment of hypertension. Advantages associated with combination antihypertensive therapy include using drugs with potentially different pharmacologic mechanisms, using complementary medications that can block compensatory systems stimulated by monotherapy, and the ability to use lower doses to achieve the same clinical effect at a reduced side effect profile. In a meta-analysis of 119 well-controlled studies evaluating all major monotherapy options in hypertension, Law and colleagues3 demonstrated that combination therapy essentially doubled the blood pressure (BP)–lowering effects compared with the components given separately.
Unfortunately, while clinicians have a wealth of data and information documenting the benefits of combination therapy, there has not been a similar level of guidance on the proper approach to using ≥2 drugs to treat hypertension. Since most reasonably selected components of combination therapy will provide an additive effect on BP reduction, it has been accepted that there is no order effect. In other words, it is assumed that administering both drugs together will provide the same clinical benefit compared with administering drug 1 before drug 2 or vice versa. It remains to be seen whether combination therapy via a sequential administration of both components may actually be more effective than providing both agents simultaneously.
We previously reported an order effect in a 4-week, double-blind, placebo-controlled study evaluating the antihypertensive effect of a diuretic (hydrochlorothiazide [HCTZ]) or an ACE inhibitor (enalapril) in a population of elderly men. After a dose-titration period on single-drug therapy, patients who had not met their goal BP were provided the alternative therapy as a combination antihypertensive. This resulted in two cohort populations, one that received diuretic before ACE inhibitor and the other that received ACE inhibitor before diuretic. Only the cohort who received the diuretic before the ACE inhibitor demonstrated additional BP response compared with monotherapy (P<.05). The cohort that received the ACE inhibitor followed by the diuretic did not have significantly different BP reductions compared with the group taking the ACE inhibitor alone.4 However, since this hypothesis was not included in the prospective design and the finding was discovered retrospectively, the data were regarded as causal but not conclusive. We postulated at the time that the reason the combination of the ACE inhibitor and the diuretic was effective based on the order in which they were given was a function of the diuretic “priming” the plasma renin activity allowing for the inhibition of ACE to be maximized. By giving the ACE inhibitor before the diuretic, it was analogous to giving two antihypertensives with similar effects on hemodynamics, and, therefore, no synergism was observed.
The Pharmacogenomic Evaluation of Antihypertensive Responses (PEAR) study is an ongoing hypertension pharmacogenomics trial where the design, inclusion/exclusion criteria, and study aims have been described elsewhere.5 In an interim clinical analysis of PEAR, we tested the hypothesis that the order in which patients received a diuretic plus a β-adrenergic antagonist would influence the eventual response to the combination.6 We theorized that a thiazide diuretic would activate the renin-angiotensin system (RAS) and potentially sensitize patients to a better response to the β-blocker. Since inhibition of the RAS has been an established secondary mechanism of β-blockers, background therapy with a thiazide diuretic would have the potential to provide true synergism to the β-blocker compared with a more modest additive effect.
We also theorized the reverse would not be true, in that background therapy with a β-blocker would not sensitize patients to the thiazide diuretic. In this prospective study, a total of 368 patients received the combination of HCTZ plus atenolol after first receiving either drug alone in a randomized trial design. Patients whose BP was not controlled on monotherapy after dose titration were provided the alternative therapy as part of a combination approach. Combination therapy with HCTZ first followed by atenolol demonstrated greater systolic and diastolic BP reductions (−19.1/14.2 mm Hg vs −15.6/11.3 mm Hg; P<.0001) compared with those patients who received atenolol first, followed by HCTZ. These observed differences were evident in both blacks and whites. We concluded that the order in which the patient receives the antihypertensive does affect total BP lowering. The hypothesis that the thiazide diuretic sensitizes the patient to the β-blocker effect was supported by comparing the plasma renin activity (ng/mL/h) at baseline, following treatment with atenolol or HCTZ monotherapy, and with combination therapy with each drug serving as background therapy. Independent of race, monotherapy with HCTZ resulted in significant increases in plasma renin activity (P<.01).
The potential of an order-effect phenomenon is not restricted to the treatment of patients with hypertension. Sliwa and colleagues7 evaluated the benefit of treating New York Heart Association (NYHA) functional class II and III heart failure patients with carvedilol before or after the addition of the ACE inhibitor perindopril. The authors documented a significantly higher tolerable dose of carvedilol (P=.03), a lower dose of furosemide (P<.05), better improvements in symptoms (NYHA class, P<.002), left ventricular ejection fraction (P<.01 by echo-cardiography), and brain natriuretic peptide concentrations (P<.02) all by administering carvedilol prior to perindopril vs giving the ACE inhibitor first.
So, is initiation order important when treating hypertension with combination therapy? The concept of an order effect requires additional study and clinical replication, but the data suggest that it may be. If proven and validated, the order effect has the potential to change the way clinicians view combination therapy and may redefine fixed-dose combinations from a simultaneous dose to one that is sequential.