SEARCH

SEARCH BY CITATION

Abstract

  1. Top of page
  2. Abstract
  3. RATIONALE FOR COMBINATION THERAPY
  4. COMBINATION THERAPY WITH ACEIs AND CCBs
  5. FUTURE DIRECTIONS
  6. CONCLUSIONS
  7. References

More than 1 medication is required in many hypertensive patients to reach blood pressure (BP) goals, and initial treatment with 2 agents has been recommended for patients whose BP level is >20/10 mm Hg above target. Diuretics reduce BP levels and the incidence of target organ complications and together with angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers, which are recommended in patients with comorbid cardiovascular disease, nephropathy, or diabetes, are effective antihypertensive combinations. Calcium channel blockers (CCBs) are also effective antihypertensive agents, and evidence suggests that a CCB/ACEI combination is well tolerated and also decreases the risk of cardiovascular and renal disease. Some evidence suggests that this combination may improve endothelial function more than either agent alone, and its use could potentially lead to better cardiovascular outcomes than a diuretic/ACEI or diuretic/ARB combination. The ongoing Avoiding Cardiovascular Events Through Combination Therapy in Patients Living With Systolic Hypertension (ACCOMPLISH) trial compares these 2 effective combinations (ie, an ACEI/diuretic and ACEI/CCB) as initial treatment for reducing cardiovascular morbidity and mortality in older high-risk hypertensive patients. The results of this trial, when reported, should help to clarify the relative benefits of these different therapies.

Approximately 65 million US adults, or nearly one-third of the adult population, had an elevated blood pressure (BP) level in 1999 to 2000; this represents an increase of ∼30% from 1988 to 1994.1 A change in definition may, however, account for some of the apparent increase. Despite the availability of various antihypertensive agents that are effective as monotherapy and combination therapy, as well as recent improvements in controlling BP in treated hypertensives,2 control of BP level to < 140/90 mm Hg in the general population remains low, at <37%.3 The comparatively low hypertension control rates in the population are of concern, given the increasing numbers of patients at high risk for clinical cardiovascular and renal complications who would benefit from better control; these include the elderly, ethnic/racial minorities, and persons with disorders of glucose and lipid metabolism.4

Hypertension imposes a major health and economic burden in the United States. While age-adjusted rates changed little between 1992 and 2002, deaths primarily due to or associated with high BP increased by 57% and accounted for more than 2.4 million fatalities in 2002.5 Estimated direct (eg, hospitalization, physician visits) and indirect (eg, lost productivity) costs of hypertension in 2002 totaled nearly $60 billion in the United States. There is, however, good evidence that treatment of hypertension significantly reduces heart failure, stroke, coronary heart disease, and overall mortality and that individuals are living longer as a result of better treatment. Despite these facts, there is an ongoing need to continue to focus efforts on better control of hypertension.6

If the Healthy People 2010 goal of controlling BP levels to <140/90 mm Hg in 50% of all hypertensive patients is to be attained, it is important to raise control rates to ∼70% of treated patients.4 Progress toward the national objective for hypertension control requires an increase in the proportion of patients who are adherent to necessary lifestyle changes and antihypertensive medication regimens7 and a reduction of therapeutic inertia by clinicians.8 In fact, recent evidence indicates these important changes are occurring and appear to be contributing to a substantial increase in the proportion of treated patients with hypertension and in the percentage of all hypertensive patients in whom a BP level of <140/<90 mm Hg is attained.2,3 Combination regimens represent a potentially useful tool to improve hypertension management and may help overcome adherence barriers and inertia and permit the attainment of greater benefits from antihypertensive therapy.9

RATIONALE FOR COMBINATION THERAPY

  1. Top of page
  2. Abstract
  3. RATIONALE FOR COMBINATION THERAPY
  4. COMBINATION THERAPY WITH ACEIs AND CCBs
  5. FUTURE DIRECTIONS
  6. CONCLUSIONS
  7. References

Thiazide diuretics, β-blockers, calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin II type 1 receptor blockers (ARBs) all lower BP level and hypertension-related morbidity and mortality;6 however, many patients, particularly those with stage 2 hypertension, require the use of more than 1 antihypertensive medication to reach their BP goal.9 According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7), a second drug from a different class should be added when results from use of a single agent are inadequate. Moreover, consideration should be given to starting therapy with 2 agents when BP level is >20/10 mm Hg above goal (ie, initial BP level >160/100 mm Hg for patients without diabetes or chronic kidney disease and >150/95 mm Hg for patients with these comorbid conditions).9 Combination therapy often results in greater BP reduction at lower doses of the component agents, leading to fewer adverse effects. Moreover, fixed-dose combinations may offer convenience, simplicity, and cost savings compared with the individual components.

Rationale for Combination

Therapy Including a Diuretic

Addition of a thiazide diuretic enhances the BP-lowering efficacy of other types of antihypertensive agents,9 and combinations that include a diuretic have been widely available for many years. Diuretics are commonly combined with ACEIs, β-blockers, or ARBs and are recommended by JNC 7 for high-risk patients with cardiovascular, metabolic, or renal comorbid conditions (Table I). Thiazide diuretic-based regimens have proved comparable in reducing cardiovascular outcomes to regimens based on CCBs or ACEIs,6 despite concerns about possible adverse effects on potassium, glucose, and lipid levels.

Some evidence suggests that thiazide diuretics have benefits beyond BP control,10 a feature sometimes attributed to other drug classes including ACEIs and ARBs. Among the possible benefits, thiazide diuretics reduce urinary calcium loss and appear effective in maintaining bone density and reducing fracture risk.11 Other studies have identified an inverse relationship between bone mineral density and aortic calcification.12 These data suggest potentially beneficial effects of diuretics on arterial remodeling through effects on calcium metabolism. Moreover, diuretics, especially in combination with ACEIs, may raise levels of angiotensin 1–7, a peptide that has BP-lowering actions and beneficial effects on cardiovascular and renal target organs.13 Thus, diuretic/ACEI combinations may have benefits beyond BP reduction.

COMBINATION THERAPY WITH ACEIs AND CCBs

  1. Top of page
  2. Abstract
  3. RATIONALE FOR COMBINATION THERAPY
  4. COMBINATION THERAPY WITH ACEIs AND CCBs
  5. FUTURE DIRECTIONS
  6. CONCLUSIONS
  7. References

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

FUTURE DIRECTIONS

  1. Top of page
  2. Abstract
  3. RATIONALE FOR COMBINATION THERAPY
  4. COMBINATION THERAPY WITH ACEIs AND CCBs
  5. FUTURE DIRECTIONS
  6. CONCLUSIONS
  7. References

Therapy with more than one antihypertensive medication is required to control BP in many hypertensive patients.9 Combination therapy is associated with more rapid BP control, which may contribute to better outcomes.18 One recent study suggests that therapy with a dihydropyridine CCB/ACEI affords greater protection from cardiovascular events than alternative combination treatment strategies;20 however, multiple confounders, most notably unequal BP control, significantly limit the certainty of this conclusion. And, as noted earlier, diuretic/ACEI or diuretic/β-blocker combinations have also been shown to reduce BP level and cardiovascular events. Thus, studies comparing the benefits of 2 different and widely used combination regimens could prove useful in guiding combination therapy choices.30

The ongoing Avoiding Cardiovascular Events Through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial compares the effects of 2 fixed-dose combinations as initial therapy on cardiovascular mortality and morbidity in high-risk hypertensive patients.31 A benazepril/hydrochlorothiazide combination (force-titrated to 40/12.5 mg) or amlodipine/benazepril (force-titrated to 5/40 mg), with further up-titration allowed to 40/25 mg or 10/40 mg, is being compared in >11,000 patients.

The ACCOMPLISH Trial and Renal Outcomes

The renoprotective actions of ACEIs and ARBs (usually with a diuretic) in hypertensive persons with diabetic kidney disease and proteinuria are generally recognized.32 On the other hand, the effects of dihydropyridine CCBs on renal outcomes are less consistent. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the prespecified secondary end point of development of end-stage renal disease (ESRD) was not significantly different among groups treated with lisinopril-, chlorthalidone-, or amlodipine-based regimens. A recent post hoc analysis of renal outcomes in ALLHAT reported that in hypertensive patients with reduced glomerular filtration rate, neither amlodipine nor lisinopril was more effective than chlorthalidone in reducing the rate of development of ESRD or a ≥50% decrement in glomerular filtration rate.33

ALLHAT did not specifically study patients with diabetic nephropathy and/or proteinuria, a population in which RAAS blockade has shown benefit34 and where concerns have been raised about dihydropyridine CCBs. In the Irbesartan Diabetic Nephropathy Trial (IDNT), which studied type 2 diabetics with frank proteinuria, the ARB irbesartan was associated with a lower incidence of primary outcomes (doubling of serum creatinine, progression to ESRD or death) than amlodipine.35 In addition, in the African American Study of Kidney Disease and Hypertension (AASK),36 non-diabetic patients with proteinuric renal disease experienced a slower decline in glomerular filtration rate with an ACEI (ramipril)-based than an amlodipine-based treatment regimen. When proteinuria was absent, ramipril and amlodipine appeared equally effective. Despite concerns about the effects of CCBs and specifically dihydropyridines on renal outcomes, both dihydropyridine and nondihydropyridine CCB therapy in combination with angiotensin-converting enzyme inhibition appears to slow progression of renal disease in patients with or without diabetes.32,37–40 The ACCOMPLISH trial, which compares outcomes with a combination ACEI/diuretic vs a combination ACEI/dihydropyridine CCB in high-risk older hypertensive patients, may also provide information on renal outcomes. Results of this trial are expected to be reported in early 2009.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. RATIONALE FOR COMBINATION THERAPY
  4. COMBINATION THERAPY WITH ACEIs AND CCBs
  5. FUTURE DIRECTIONS
  6. CONCLUSIONS
  7. References

The prevalence of hypertension in US adults is high; control rates remain low among all hypertensives but are improving among the subset of patients with treated hypertension. Better BP control is especially important for the growing numbers of high-risk patients. Most high-risk hypertensive patients require therapy with more than 1 medication for BP control. The JNC 7 report recommends a diuretic as initial therapy or as a part of combination therapy for most patients, and evidence suggests that a combination of an ACEI/diuretic, an ARB/diuretic, or a CCB/ACEI is effective in lowering BP and decreasing cardiovascular events. The ACCOMPLISH trial will compare the effects of 2 effective combinations (ie, a dihydropyridine CCB/ACEI combination compared with a diuretic/ACEI combination) on major cardiovascular outcomes in high-risk older hypertensive patients.

Acknowledgments and disclosure: Raquel Da Rosa, Senior Editor, Landmark Programs, provided expert editorial assistance in the preparation of this manuscript. Dr Egan is an investigator and consultant on the ACCOMPLISH study and lectures at medical programs supported by Novartis Pharmaceuticals Corporation.

References

  1. Top of page
  2. Abstract
  3. RATIONALE FOR COMBINATION THERAPY
  4. COMBINATION THERAPY WITH ACEIs AND CCBs
  5. FUTURE DIRECTIONS
  6. CONCLUSIONS
  7. References
  • 1
    Fields LE, Burt VL, Cutler JA, et al. The burden of adult hypertension in the United States 1999 to 2000: a rising tide. Hypertension. 2004;44:398404.
  • 2
    Moser M, Franklin SS. Hypertension management: results of a new national survey for the Hypertension Education Foundation: Harris Interactive. J Clin Hypertens. 2007;9:316323.
  • 3
    Ong KL, Cheun BMY, Man YB, et al. Prevalence, awareness, treatment and control of hypertension among United States adults 1999–2004. Hypertension. 2007;49:6975.
  • 4
    Egan BM, Basile JN. Controlling blood pressure in 50% of all hypertensive patients: an achievable goal in the healthy people 2010 report? J Investig Med. 2003;51(6):373385.
  • 5
    American Heart Association. Heart Disease and Stroke Statistics-2005 Update. Dallas , TX : American Heart Association; 2005.
  • 6
    Blood Pressure Lowering Treatment Trialists' Collaboration. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus. Arch Intern Med. 2005;165:14101419.
  • 7
    Weir MR, Maibach EW, Bakris GL, et al. Implications of a healthy lifestyle and medication analysis for improving hypertension control. Arch Intern Med. 2000;160:481490.
  • 8
    Okonofua EC, Simpson KN, Jesri A. Therapeutic inertia is an impediment to achieving the Healthy People 2010 blood pressure control goals, Hypertension. 2006;47:345351.
  • 9
    Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:12061252.
  • 10
    Messerli FH, Grossman E, Lever AF. Do thiazide diuretics confer specific protection against strokes? Arch Intern Med. 2003;163:25572560.
  • 11
    Aubin R, Menard P, Lajeunesse D. Selective effect of thiazides on the human osteoblast-like cell line MG-63. Kidney Int. 1996;50:14761482.
  • 12
    Hak AE, Pols HA, van Hemert AM, et al. Progression of aortic calcification is associated with metacarpal bone loss during menopause: a population-based longitudinal study. Arterioscler Thromb Vasc Biol. 2000;20:19261931.
  • 13
    Ferrario CM. Angiotensin-converting enzyme 2 and angiotensin-(1–7): an evolving story in cardiovascular regulation. Hypertension. 2006;47:515521.
  • 14
    Fogari R, Corea L, Cardoni O, et al. Combined therapy with benazepril and amlodipine in the treatment of hypertension inadequately controlled by an ACE inhibitor alone. J Cardiovasc Pharmacol. 1997;30:497503.
  • 15
    Pittrow DB, Antlsperger A, Welzel D, et al. Evaluation of the efficacy and tolerability of a low-dose combination of isradipine and spirapril in the first-line treatment of mild-to-moderate essential hypertension. Cardiovasc Drugs Ther. 1997;11:619627.
  • 16
    Sica DA. Calcium channel blocker-related peripheral edema: can it be resolved? J Clin Hypertens (Greenwich). 2003;5:291294, 297.
  • 17
    Bakris GL, Weir MR, on behalf of the Study of Hypertension and the Efficacy of Lotrel in Diabetes (SHIELD) Investigators. Achieving goal blood pressure in patients with type 2 diabetes: conventional versus fixed-dose combination approaches. J Clin Hypertens (Greenwich). 2003;5:202209.
  • 18
    Julius S, Kjeldsen SE, Weber M, et al, for the VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363:20222031.
  • 19
    Jamerson KA, Nwose O, Jean-Louis L, et al. Initial angiotensin-converting enzyme inhibitor/calcium channel blocker combination therapy achieves superior blood pressure control compared with calcium channel blocker monotherapy in patients with stage 2 hypertension. Am J Hypertens. 2004;17:495501.
  • 20
    Dahlöf B, Sever PS, Poulter NR, et al, for the ASCOT investigators. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomized controlled trial. Lancet. 2005;366:895906.
  • 21
    Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al, for the INVEST Investigators. A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): a randomized controlled trial. JAMA. 2003;290:28052816.
  • 22
    Darmansjah I, Wong E, Setiawati A, et al. Pharmacokinetic and pharmacodynamic properties of controlled release (CR/ZOK) metoprolol in healthy Oriental subjects: a comparison with conventional formulations of metoprolol and atenolol. J Clin Pharmacol. 1990;30(suppl 2):S39S45.
  • 23
    Hernandez RH, Armas-Hernandez MJ, Velasco M, et al. Calcium antogonists and atherosclerosis protection in hypertension. Am J Ther. 2003;10:409414.
  • 24
    Yu T, Morita I, Shimokado K, et al. Amlodipine modulates THP-1 cell adhesion to vascular endothelium via inhibition of protein kinase C signal transduction. Hypertension. 2003;42:329334.
  • 25
    Neutel JM. Effect of the renin-angiotensin system on the vessel wall: using ACE inhibition to improve endothelial function. J Hum Hypertens. 2004;18:599606.
  • 26
    Koh KK, Ahn JY, Han SH, et al. Pleiotropic effects of angiotensin II receptor blocker in hypertensive patients. J Am Coll Cardiol 2003;42:905910.
  • 27
    Prasad A, Quyyumi AA. Renin-angiotensin system and angiotensin receptor blockers in the metabolic syndrome. Circulation. 2004;110:15071512.
  • 28
    Ruschitzka FT, Noll G, Lüscher TF. Combination of ACE inhibitors and calcium antagonists: a logical approach. J Cardiovasc Pharmacol 1998;31(suppl 2):S5S16.
  • 29
    Zhang X, Xu X, Nasjletti A, et al. Amlodipine enhances NO production induced by an ACE inhibitor through a kinin-mediated mechanism in canine coronary microvessels. J Cardiovasc Pharmacol. 2000;35:195202.
  • 30
    Jamerson KA. The first hypertension trial comparing the effects of two fixed-dose combination therapy regimens on cardiovascular events: Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH). J Clin Hypertens (Greenwich) 2003;5:2935.
  • 31
    Jamerson KA, Bakris GL, Wun C-C, et al. Rationale and design of the Avoiding Cardiovascular events through COMbination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial: the first randomized controlled trial to compare the clinical outcome effects of first-line combination therapies in hypertension. Am J Hypertens 2004;17:793801.
  • 32
    Karalliedde J, Viberti G. Evidence for renoprotection by blockade of the renin-angiotesin-aldosterone system in hypertension and diabetes. J Hum Hypertens. 2006;20:239253.
  • 33
    Rahman M, Pressel S, Davis BR, et al, for the ALLHAT Collaborative Research Group. Renal outcomes in high-risk hypertensive patients treated with an angiotensin-converting enzyme inhibitor or a calcium-channel blocker vs a diuretic: a report from the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med. 2005;165:936946.
  • 34
    The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002;288:29812997.
  • 35
    Lewis EJ, Hunsicker LG, Clarke WR, et al, for the Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851860.
  • 36
    Wright JT Jr, Bakris G, Greene T, et al, for the African American Study of Kidney Disease and Hypertension Study Group. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA. 2002;288:24212431.
  • 37
    Bakris GL, Weir MR, DeQuattro V, et al. Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int. 1998;54:12831289.
  • 38
    Shigihara T, Sato A, Hayashi K, et al. Effect of combination therapy of angiotensin-converting enzyme inhibitor plus calcium channel blocker on urinary albumin excretion in hypertensive microalbuminuric patients with type II diabetes. Hypertens Res. 2000;23:219226.
  • 39
    Fogari R, Preti P, Zoppi A, et al. Effects of amlodipine fosinopril combination on microalbuminuria in hypertensive type 2 diabetic patients. Am J Hypertens. 2002;15:10421049.
  • 40
    Zuccalà G, Onder G, Pedone C, et al, Use of calcium antagonists and worsening renal function in patients receiving angiotensin-converting-enzyme inhibitors. Eur J Clin Pharmacol. 2003;58:695699.
  • 41
    Schulman IH, Zhou MS, Raij L. Nitric oxide, angiotensin II, and reactive oxygen species in hypertension and atherogenesis. Curr Hypertens Rep. 2005;7:6167.