Antihypertensive Efficacy of Candesartan-Lisinopril in Combination vs. Up-Titration of Lisinopril: The AMAZE Trials

Joseph L. Izzo, Jr., MD; Marc S. Weinberg, MD; James W. Hainer, MD, MPH; Joseph Kerkering, MBA; Conrad K.P. Tou, PhD

Disclosures
In This Article

Discussion

The large AMAZE program sought to determine whether adding the ARB candesartan to lisinopril provided better BP control than up-titration of lisinopril in hypertensive patients inadequately controlled with lisinopril 20 mg daily. Both treatments induced an additional decline in trough BP. In Studies 1 and 2, the combination of candesartan plus lisinopril reduced BP by 11.6/8.3 mm Hg and 9.5/7.4 mm Hg, respectively, compared with lisinopril 40 mg daily, which lowered BP by 6.2/5.9 mm Hg and 8.7/6.2 mm Hg, respectively. When all data from both studies were pooled, post hoc analysis indicated a somewhat greater BP reduction with the candesartan/lisinopril combination (3.1/1.7 mm Hg; 95% CI, -4.8 to -1.5 systolic and -2.8 to -0.7 mm Hg diastolic). A major finding of the AMAZE program was the safety and tolerability of both regimens. The frequency of adverse events was also similar with lisinopril or candesartan, but it is important to emphasize that the study design eliminated patients unable to tolerate lisinopril 20 mg daily. Hyperkalemia, a potential concern for the combination treatment arm, was highly unusual, and probably due to the fact that the study population was essentially free of significant renal impairment.

The greater BP reduction with combination treatment in the AMAZE program is consistent with previous observations with ACE inhibitor/ARB combination therapy in smaller, open-label studies,[7,11,12] but none of these studies has proven definitively that the ACE inhibitor/ARB combination is superior for BP reduction to either drug used alone. Ultimately, proof of the potential superiority of any combination over its individual components is critically dependent on the use of maximal doses of each component. Such studies (often 10-fold above maximum recommended doses) have only been done in animals. Thus, higher doses of lisinopril or candesartan may have achieved a greater degree of RAAS blockade. The maximum approved daily doses of lisinopril and candesartan are 80 mg and 32 mg, respectively. The 40 mg lisinopril dose was based in part on the observation that clinicians do not usually prescribe lisinopril in doses higher than 40 mg daily.

A potential rationale for the combination of ACE inhibitor and ARB is the belief that plasma angiotensin II levels return toward baseline values during long-term ACE inhibitor therapy, yet there is very little evidence of "ACE escape" in the literature. One very small study in hypertension found that plasma angiotensin II levels returned toward baseline several months after initiation of 20 mg enalapril twice daily in nine subjects, five of whom were on diuretic therapy,[19] but used an assay that had significant cross-reactivity with angiotensinogen and angiotensin I (which increase substantially during chronic ACE inhibition). In contrast, a recent small study in heart failure found persistent suppression of plasma angiotensin II during chronic ACE inhibition.[20] With respect to ischemic heart disease, addition of the ARB valsartan to the ACE inhibitor benazepril did not improve postinfarction outcomes.[21] In contrast, AMAZE results are in agreement with those of several recent studies in patients with diabetic and nondiabetic renal disease, where dual RAAS blockade with moderate doses of ACE inhibitors and ARBs provided superior BP control and greater antiproteinuric effects than either agent alone.[13,14,15,22,23,24] Such results should be anticipated in studies using submaximal doses of RAAS blockers, however. Although the presence of non-ACE pathways for angiotensin II production has been established in some tissues,[6,25,26] the clinical significance of these pathways remains unclear. It also remains possible that different racial groups may respond differently to these drugs used alone or in combination due to potential differences in phenotypic expression of various "non-ACE" or "non-AT1" pathways.

Other considerations also deserve mention. All patients had prerandomization experience with lisinopril and demonstrated both tolerance and a degree of resistance to its BP lowering effects; there was no similar pretrial exposure to candesartan. The double-blind lisinopril monotherapy dose of 40 mg was administered for the entire 8 weeks, whereas the full dose of candesartan (32 mg) was administered for only 6 weeks. Another limitation was the lack of a placebo arm, which would have allowed the magnitude of any drug-specific effect to be expressed as a fraction of the total BP decline. Regression to the mean remains a consideration in all such trials, but the magnitude of the observed BP reductions in these studies was similar to the magnitude of BP reductions with ARBs in placebo-controlled trials that were not restricted to patients "resistant" to ACE-inhibitor treatment.[27]

Clinical application of the AMAZE results must be tempered by several caveats. First, as stated in JNC 7, usual clinical practice should include addition of a thiazide diuretic to either agent before consideration of the lisinopril-candesartan combi-nation.[1] Nevertheless, the AMAZE results indicate clearly that when trough BP is not well controlled on lisinopril 20 mg daily, increased RAAS blockade is clinically useful because small reductions in mean BP usually represent a reduction in overall population risk. Vigorous BP reduction is also of particular importance in individuals with BP elevations >20/10 mm Hg above ideal target values (>160/100 mm Hg in uncomplicated hypertension or >150/90 mm Hg in patients with diabetes or chronic kidney disease as per JNC 7 guidelines).[1] In AMAZE, the 84 individuals whose BP values exceeded 160/100 mm Hg achieved a BP decline at 8 weeks of 13.7/-6.1 mm Hg with combination therapy and 13.5/-6.1 mm Hg with lisinopril up-titration. In the diabetic subpopulation, the BP reductions at 8 weeks in the combination therapy group (11.9/8.9 mm Hg) were substantial and tended to be greater than the corresponding reductions in the lisinopril group (6.7/6.4 mm Hg).

In conclusion, for the reduction of BP in hypertensive patients not controlled by lisinopril 20 mg daily, adding candesartan (16 mg daily, up-titrated to 32 mg daily) is an alternative to increasing the lisinopril dose to 40 mg daily. Both antihypertensive regimens are effective and well tolerated, and the combination treatment appears to have no unique adverse safety findings relative to the individual drugs. Whether dual ACE inhibitor/ARB treatment is particularly useful in prevention of target organ damage or in antihypertensive therapy for subpopulations of patients remains to be tested.

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