ACE Inhibition Plus Calcium-Channel Blockade: A Logical Choice for Initial Antihypertensive Therapy

There is "real logic" in pairing an angiotensin-converting enzyme (ACE) inhibitor with a calcium-channel blocker (CCB) as initial

therapy in some patients with hypertension, according to Michael A.Weber,MD.

That combination, Dr.Weber said,"should be given consideration as initial therapy for appropriate patients who have blood pressures [BPs] > 160/100 mm Hg."Recent trials, he said,suggest that the 2 drug classes together appear to provide benefits exceeding those of either alone.

Evidence supporting that idea emerged in the recent ALERT (A Lotrel Evaluation of Hypertensive Patients with Arterial Stiffness and Left Ventricular Hypertrophy) trial (Neutel JM, et al.

Am J Hypertens.

2002;15:166A).The study randomized patients to receive amlodipine, benazepril, or the combination of the 2 drugs as initial therapy. In the combination therapy group, the ACE inhibitor and CCB were given at one half the doses used in the 2 monotherapy groups. Yet, Dr. Weber noted, combination therapy as compared with either agent alone was associated with greater BP reductions and improvements in arterial compliance and left ventricular mass (Figure 2). "Even when you cut doses in half but then combine them, you get a powerful additive effect," Dr.Weber said. An ACE inhibitor and a CCB "is a logical and effective combination for BP control."

Other contemporary studies support the use of ACE inhibitors and CCBs as components of initial antihypertensive therapy. For example, the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) compared regimens based on initial monotherapy with chlorthalidone, amlodipine, or lisinopril (ALLHAT Collaborative Research Group.

JAMA.

2002;288:2981-2997). The goal was to compare clinical outcomes among patients who achieve BP control by different drug strategies, Dr. Weber observed. The 3 treatments were associated with essentially equal 5-year cumulative rates of a composite primary end point?a fatal coronary disease event or nonfatal myocardial infarction (MI).

The ALLHAT protocol has been widely criticized, however, for not allowing physicians to use additional drugs to their best advantage in all the treatment groups. Patients who were started on the ACE inhibitor, for example,"could not receive a diuretic or a calcium-channel blocker,which are the logical partners of an ACE inhibitor," Dr. Weber observed. "They were forced, instead, to receive a beta blocker, which is not a logical partner."This may help explain why systolic BP was significantly less well-controlled with the lisinopril-based regimen as compared with the diuretic-based approach, he said.

"Failure of the diuretic to exhibit a benefit over the ACE inhibitor for the primary end point, despite a significant systolic BP advantage," Dr.Weber said,"still leaves open the basic question posed by ALLHAT: For similar BP-lowering effects, would an ACE inhibitor provide superior coronary protection?"

Even in ALLHAT, Dr.Weber noted,"there are reasons why we might think an ACE inhibitor is at least as good for initial antihypertensive therapy as a diuretic for many of our patients."Allcause mortality was the same in the ACE inhibitor and diuretic groups, for example. Had patients treated with the ACE inhibitor been allowed to receive the best additional drugs for optimal BP control, perhaps their mortality would have been even lower.

All-cause mortality was slightly lower among patients in the amlodipine group as compared with those who started on the diuretic."That tells us we can have great confidence that a CCB is an important selection to be considered in initiating treatment of hypertension, and certainly useful as part of any combination,"Dr.Weber said.

"Without diuretics," Dr. Weber acknowledged," it would be very difficult to control BP in many patients. But even so, diuretics come at something of a price." ALLHAT demonstrated a well-recognized disadvantage of diuretics: the 4-year incidence of new-onset diabetes was increased by 18% in the chlorthalidone group as compared with patients following the CCB-based regimen and increased by 43% as compared with the ACE inhibitor group.

"Those are meaningful differences," Dr. Weber said. "They might affect the choice of antihypertensive drug in patients with the metabolic syndrome or some evidence for impaired glucose tolerance, who may not be good candidates for starting with a diuretic."

Therefore, ALLHAT, Dr. Weber said, "in certain ways actually showed potential" for considering a combination of an ACE inhibitor with a CCB as initial antihypertensive therapy.

A trial published shortly after ALLHAT, the Second Australian National Blood Pressure Study (ANBP-2), tested a diuretic-based regimen against therapy centered on ACE inhibitors in more than 6000 patients (Wing LMH, et al.

N Engl J Med.

2003;348:583-592).The 2 regimens achieved the same degree of BP control over 4 years. But ACE inhibition was associated with a

significant reduction (

P

= .05) in the primary composite end point of cardiovascular events or all-cause mortality. The reduction appeared driven by reduced nonfatal cardiovascular events (

P = .03) and, especially, MIs (

P

= .04), Dr.Weber observed.