Efficacy and Tolerability in BP Reduction
As expected, combination therapy with an ACEI and a CCB leads to a greater reduction in BP level and greater response rates than does monotherapy with either agent alone. The combination does not significantly increase the incidence of adverse events compared with either agent alone.14,15 In fact, the edema commonly observed with dihydropyridine CCBs is significantly reduced when these agents are used in combination with an ACEI.16
In the Study of Hypertension and the Efficacy of Lotrel in Diabetes (SHIELD) trial,17 hypertensive type 2 diabetics treated with a combination of the CCB amlodipine and the ACEI benazepril (5/10–20 mg) plus other drugs reached BP goals more quickly than those treated with enalapril 10 to 20 mg plus other medications. While add-on therapy with hydrochlorothiazide was permitted in both groups, at 3 months the BP goal of <130/80 mm Hg was reached in patients treated with the fixed-dose combination more often than in those treated with enalapril (63% vs 37%; P= .0002), with no significant differences in rates of adverse events. Attaining better BP control in rates of the first 3 to 6 months of treatment may improve cardiovascular outcomes.18
The Safety of Lotrel vs Amlodipine in a Comparative Efficacy (SOLACE) trial19 compared fixed-dose combination amlodipine/benazepril (5–10/20 mg) with amlodipine monotherapy (5–10 mg) in the initial treatment of stage 2 hypertension. As anticipated, in significantly more patients treated with combination therapy, a ≥25-mm Hg reduction from baseline in systolic BP (74.2% vs 53.9%; P < .0001) and a goal systolic BP of <140 mm Hg were achieved (Figure).
Improved Cardiovascular Outcomes
The Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA) indicated that amlodipine with or without the ACEI perindopril was more effective in lowering BP than the β-blocker atenolol plus the diuretic bendroflumethiazide.20 In ASCOT-BPLA, hypertensive patients (mean age, 63 years) at high risk for cardiac events were randomized to either amlodipine 5 mg or atenolol 50 mg once daily. For patients in whom the BP goal was not achieved, a titration scheme was implemented whereby dosages were increased to either amlodipine 10 mg once daily or atenolol 100 mg once daily, after which perindopril 2 to 4 mg once daily was added to amlodipine and bendroflumethiazide 1.25 to 2.5 rag once daily with potassium was added to atenolol. Throughout the study, especially in the first few months, BP values were lower in patients receiving amlodipine-based than in patients on atenolol-based therapy; this may have contributed to differences in secondary outcomes.
After a median follow-up of 5.5 years, there was a nonsignificant 10% reduction (P= .10) in the primary outcome of nonfatal myocardial infarction (MI), which included silent MI, and fatal coronary heart disease incidence with amlodipine-based compared with atenolol-based therapy. Significant reductions were observed with amlodipine-based therapy in secondary end points, including nonfatal MI (excluding silent MI) and fatal coronary heart disease (–13%; P= .046), cardiovascular mortality (–24%; P= .001), and all-cause mortality (–11%; P= .025). Amlodipine-based therapy was associated with a lower incidence of diabetes.20
Both ASCOT-BPLA and the International Verapamil-Trandolapril Study (INVEST)21 compared a CCB-based strategy plus an ACEI to an atenolol-based treatment plus a thiazide diuretic. The study results differed in several key respects. ASCOT-BPLA used the dihydropyridine CCB amlodipine, whereas INVEST used the nondihydropyridine verapamil. As with ASCOT-BPLA, the calcium antagonist arm of INVEST began with the CCB verapamil-sustained release (verapamil-SR) 240 mg/d and the added trandolapril in step 2 before going to verapamil-SR 180 mg twice daily and trandolapril 2 mg twice daily in step 3. In the non–calcium antagonist arm of the 2 trials, ASCOT-BPLA titrated atenolol to 100 mg once daily before adding a diuretic, whereas INVEST added 25 mg hydrochlorothiazide before advancing atenolol from 50 mg once daily to 50 mg twice daily. ASCOT-BPLA titrated bendroflumethiazide to 2.5 mg once daily, while INVEST titrated hydrochlorothiazide to 25 mg twice daily.20,21
After a mean follow-up of 2.7 years, a BP level of <140/90 mm Hg was achieved in similar proportions of patients in each treatment group of INVEST (verapamil-based group, 71.7%; atenolol-based group, 70.7%). There were no significant differences between groups in reduction of death, first nonfatal MI, or nonfatal stroke. In ASCOT-BPLA, the differences in titration regimens may have accounted for better BP control with amlodipine-based compared with atenolol-based therapy. During the first year of ASCOT-BPLA, systolic BP was ∼5 mm Hg lower in the amlodipine-based than in the atenolol-based group, with a mean difference of 2.7 mm Hg throughout the entire trial.20 In contrast, BP control was virtually identical in the 2 arms of INVEST throughout the trial, possibly because of twice daily administration of atenolol.21 Atenolol administered once daily, as in ASCOT-BPLA, may not have produced consistent 24-hour β-blockade.22 Thus, the BP differences and not the medications used may have accounted for differences in outcome.
The fact that several secondary outcomes were more favorable in ASCOT-BPLA while primary and secondary outcomes, except for new-onset diabetes mellitus, were comparable in the 2 arms of INVEST may have other explanations, however. These include the untested possibility that amlodipine is more effective than verapamil in lowering peripheral and/or central aortic BP.
The cardiovascular protection afforded by atenolol administered once daily compared with twice daily has not been tested directly. Nevertheless, it is conceivable that ineffective β-blockade in the latter portion of the dosing interval may limit the cardioprotective as well as the BP-lowering effects and thereby affect outcome.
Potential Mechanisms for Beneficial Effects of ACEIs and CCBs
The vasodilator effects of nitric oxide in the cardiovascular system are counteracted by local production of superoxide anion. Oxidative stress can negatively affect endothelial function. Amlodipine and other CCBs exert antioxidant effects, possibly by increasing nitric oxide and reducing the production of superoxide anion.23 Use of CCBs may also slow the progression of atherosclerotic lesions, reduce the oxidation of low-density lipoprotein cholesterol (LDL-C), and inhibit the entry of LDL-C particles into the vessel wall, Amlodipine has demonstrated in vitro anti-inflammatory effects, such as modulating the adhesion of monocytes to the endothelium, which may translate into antiatherogenic effects.24 Some evidence suggests that the antiatherogenic properties of CCBs may be independent of their BP-lowering effects. There is also some evidence that β-blockers have a beneficial effect on the atherosclerotic process.
Inhibitors of the renin-angiotensin-aldosterone system (RAAS) also modify oxidative stress and increase the availability of nitric oxide, improve endothelial function, and decrease inflammatory responses (Table II).25 ACEIs and ARBs have demonstrated several vasculoprotective effects, such as decreasing smooth muscle cell growth, delaying atherosclerotic plaque progression, stabilizing plaques, lowering the risk of thrombosis following lesion rupture, and reducing inflammation.25,26 These effects may be unrelated to BP lowering. In addition, ACEIs and ARBs decrease insulin resistance, possibly by modulating insulin signaling pathways.27 This effect is not shared by β-blockers without vasodilating effects.
ACEIs and CCBs interfere with different regulatory mechanisms controlling endothelial function; their actions may be complementary.28 ACEIs promote nitric oxide activity by increasing bradykinin and by reducing superoxide anion formation in the vessel wall; CCBs facilitate the effects of endothelium-derived relaxing factors and inhibit the activities of local vasoconstrictors.23 Preclinical data suggest that amlodipine potentiates formation of nitric oxide during angiotensin-converting enzyme inhibition.29