ACE inhibitors versus ARBs: comparison of practice guidelines and treatment selection considerations

Abstract

Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) play a role in the treatment of hypertension (HTN) and heart failure (HF). The literature shows that in patients with HTN with comorbidities, such as HF, myocardial infarction (MI), diabetes mellitus, chronic kidney disease, and stroke, ACE inhibitors and ARBs appear to provide added benefit beyond solely lowering blood pressure. In addition, clinical trials have also demonstrated that ACE inhibitors and ARBs may be beneficial in the prevention of diabetes, atrial fibrillation (AF), and recurrent stroke. This review evaluates the practice guidelines and current literature to assess the implications for the use of ACE inhibitors or ARBs in HTN and HF. (Formulary. 2006;41:274–284.)

REVIEW OF GUIDELINES

In addition to HTN, both ACE inhibitors and ARBs play a central role in the management of MI and HF. In 2004, the American Heart Association/American College of Cardiology (AHA/ACC) updated the guidelines for management of MI to include recommendations for either an ACE inhibitor (class IA recommendation for all patients) or ARB (valsartan or candesartan) (class IB recommendation for patients intolerant of ACE inhibitors with signs of HF or low ejection fraction) for all patients post-infarction.⁴ The updated ACC/AHA Heart Failure guidelines were published in September 2005. These guidelines recommend that ACE inhibitors should be prescribed to all patients with left ventricular systolic dysfunction HF (class IA recommendation). They recommend ARBs as a "reasonable alternative" first-line therapy (class IIA recommendation).⁵

CLINICAL TRIAL DATA

Since the publication of the guidelines listed in Table 1, four noteworthy trials have been published. The results of these trials may influence subsequent HTN and HF guidelines.

Recent clinical trials. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study was a double-blind, randomized trial of 9,193 patients aged 55 to 80 years with essential HTN and left ventricular hypertrophy (LVH). Patients received losartan-based or atenolol-based antihypertensive therapy for 4.8 years of follow-up. Patients were started on either losartan 50 mg or atenolol 50 mg and titrated upward based on blood pressure (doses increased if diastolic blood pressure was ≥90 mm Hg or systolic blood pressure was ≥140 mm Hg). Titration was executed in the following manner: addition of 12.5 mg hydrochlorothiazide (HCTZ), followed by increasing the atenolol or losartan dose to 100 mg, followed by either increasing HCTZ to 25 mg or adding on other antihypertensives. The addition of an ACE inhibitor, ARB or beta blocker was not allowed. Systolic blood pressure was reduced by 30.2 mm Hg in the losartan group and 29.1 mm Hg in the atenolol group (P=.017), and diastolic blood pressure was reduced by 16.6 mm Hg in the losartan group and 16.8 mm Hg in the atenolol group (P=.37). At the end of the study, 48% of patients in the losartan arm and 42% in the atenolol arm were on >1 antihypertensive. Losartan was better than atenolol in reducing the primary composite end point of cardiovascular mortality, stroke, and MI (unadjusted HR 0.85; 95% CI, 0.76-0.96; P=.009). This difference was primarily due to a 26% relative risk reduction (RRR) in stroke with losartan (unadjusted HR 0.74; 95% CI, 0.63–0.88; P=.0006). There was not, however, a statistically significant difference between the groups with regard to cardiovascular mortality (unadjusted HR 0.87; 95% CI, 0.72–1.05; P=.136) and MI (unadjusted HR 1.05; 95% CI, 0.86–1.28; P=.628). Secondary outcomes demonstrated a 25% lower incidence of new-onset diabetes in losartan-treated patients (unadjusted HR 0.75; 95% CI, 0.63–0.88; P=.001).⁶

The Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) study was a double-blind, randomized trial of 15,245 patients aged 50 years and older with treated or untreated HTN and a high risk of cardiac events. Patients were randomized to receive either valsartan-based or amlodipine-based antihypertensive therapy and were followed for a mean of 4.2 years. Patients were started on either valsartan 80 mg or amlodipine 5 mg and titrated upward based on blood pressure (target blood pressure was less than 140/90 mm Hg). Titration was done in the following manner: increasing valsartan to 160 mg or amlodipine to 10 mg, followed by the addition of 12.5 mg HCTZ, followed by increasing HCTZ to 25 mg, followed by the addition of other antihypertensives. The addition of ARBs was not allowed and ACE inhibitors or calcium antagonists were only allowed if they were indicated for a condition other than HTN. Blood pressure was reduced by 15.2/8.2 mm Hg in the valsartan group and 17.3/9.9 mm Hg in the amlodipine group (P<.0001). At the end of the study, 47.6% of patients in the valsartan arm and 40.6% in the amlodipine arm were on more than 1 antihypertensive. There was not a statistically significant difference between the groups in the primary composite outcome of cardiac mortality and morbidity (HR 1.04; 95% CI, 0.94–1.15; P=.49). Secondary outcomes showed there was a 19% RRR of MI in the amlodipine group (HR 1.19; 95% CI, 1.02–1.38; P=.02), and a 23% lower incidence of new-onset diabetes in the valsartan group (HR 0.77; 95% CI, 0.69–0.86; P<.0001).⁷

The Diabetics Exposed to Telmisartan and Enalapril (DETAIL) study was a double-blind, randomized, non-inferiority, controlled trial of 250 patients aged 35 to 80 years with type 2 diabetes and HTN taking an ACE inhibitor. Patients were randomized to receive telmisartan or enalapril and were followed for 5 years. Systolic blood pressure was reduced 6.9 mm Hg in the telmisartan group and 2.9 mm Hg in the enalapril group (95% CI, –8.5 to 0.5). At the end of the study, at least 52% of patients were on more than 1 antihypertensive. There was not a statistically significant difference between the groups in the primary end point of change in glomerular filtration rate, determined by measuring the plasma clearance of iohexol (95% CI, –9.2 to 3.4). Both groups experienced a decrease in glomerular filtration rate, but it was found that telmisartan was not inferior to enalapril in preventing the progression of renal disease.⁸

The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) was a blinded, randomized control trial of 19,257 patients aged 40 to 79 years with HTN and at least 3 other cardiovascular risk factors. Patients were randomized to either an amlodipine-based regimen (amlodipine adding perindopril as required to reach blood pressure goals) or atenolol-based regimen (atenolol adding bendroflumethiazide and potassium as required to reach blood pressure goals) and were followed for a median of 5.5 years. At the end of the trial, 78% of patients were taking at least 2 antihypertensive medications. Blood pressure was reduced an average of 26.6/16.6 mm Hg in both treatment groups combined. There was not a statistically significant difference between the groups in the primary combined end point of non-fatal MI (including silent) and fatal coronary heart disease (CHD) (unadjusted HR 0.90; 95% CI, 0.79–1.02; P=.1052). The amlodipine adding perindopril group showed a statistically significant difference in reducing the secondary end points of combined non-fatal MI (excluding silent) and fatal CHD (unadjusted HR 0.87; 95% CI, 0.76–1.00; P=.0458), total coronary end points (unadjusted HR 0.87; 95% CI 0.79–0.96; P=.0070), total cardiovascular events and procedures (unadjusted HR 0.84; 95% CI 0.78–0.90; P<.0001), cardiovascular mortality (unadjusted HR 0.76; 95% CI, 0.65–0.90; P=.0010), and fatal and non-fatal stroke (unadjusted HR 0.77; 95% CI, 0.66–0.89; P=.0003). Tertiary outcomes showed a 30% lower incidence of the development of diabetes in the amlodipine plus perindopril-based treatment group (unadjusted HR 0.70; 95% CI, 0.63–0.78; P<.0001).⁹

Overall, these new data demonstrate that a treatment regimen containing an ACE inhibitor or ARB is no different or better than other antihypertensive therapies in decreasing cardiovascular morbidity and mortality. However, it is important to note that in all of these studies, patients were treated with multiple antihypertensive medications and the trials actually compared strategies of initiating therapies. In patients with HTN, it appears that ACE inhibitors offer similar benefits with regard to the prevention of HF when compared to other classes of antihypertensives.¹⁰ In addition, some have questioned the appropriateness of using atenolol as representative of beta-blocker therapy for the treatment of HTN, as it has never been proven to reduce cardiovascular outcomes.¹¹

Prevention of comorbidities in patients with hypertension or heart failure. ACE inhibitors and ARBs may be beneficial in the prevention of some comorbidities such as nephropathy, new onset diabetes, atrial fibrillation, stroke, and the progression of prehypertension to HTN. Table 3 lists areas in which new evidence exists for the benefits of both ACE inhibitors and ARBs in managing patients with these disorders.

Prevention of progression of nephropathy in renal insufficiency. ACE inhibitors and ARBs have proven to be beneficial in the prevention of diabetic nephropathy. However, there is more limited information with regard to their benefits in prevention of progression of renal insufficiency in patients with non-diabetic renal disease and HTN. In the Ramipril Efficacy in Nephropathy (REIN) trial, patients with non-diabetic nephropathies and HTN were randomized to receive treatment with ramipril or placebo plus other antihypertensives in order to reach a diastolic blood pressure of <90 mm Hg. The investigators concluded that ramipril decreased proteinuria (P=.002) and the decline of the glomerular filtration rate (GFR) (P=.03).¹² However, in the REIN-2 study, patients with non-diabetic nephropathies already receiving treatment with an ACE inhibitor were randomized to either conventional blood pressure control (diastolic <90 mm Hg) or intensified blood pressure control (systolic/diastolic <130/80 mm Hg) with the addition of a calcium channel blocker. They concluded that there was no additional benefit from further blood pressure reduction by the calcium channel blocker (HR 1.00; 95% CI, 0.61–1.64; P=.99).¹³ In the Combination Treatment of Angiotensin-II Receptor Blocker and Angiotensin-Converting-Enzyme Inhibitor in Non-Diabetic Renal Disease (COOPERATE) study, treatment with a combination of an ACE inhibitor (trandolapril) and ARB (losartan) in patients with non-diabetic renal disease and HTN decreased progression of renal disease more than monotherapy with trandolapril (HR 0.38; 95% CI, 0.18–0.63; P=.018) or losartan (HR 0.40; 95% CI, 0.17–0.69; P=.016).¹⁴ However, as stated previously, additional research in the area of combined inhibition of the RAS is needed. Currently, the National Kidney Foundation (NKF) recommends patients with non-diabetic kidney disease, with or without HTN, should be treated with either an ACE inhibitor or ARB, giving preference to neither class.¹⁵

Prevention of new-onset diabetes. ACE inhibitors and ARBs may be considered as potential therapy to help prevent the new onset of diabetes in patients with HTN or HF. Several large clinical trials (Captopril Prevention Project [CAPPP], Heart Outcomes Prevention Evaluation [HOPE], Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial [ALLHAT], Studies of Left Ventricular Dysfunction [SOLVD]) have shown a statistically significant decrease in the frequency of new onset diabetes in patients taking ACE inhibitors when compared with placebo or other agents such as thiazide diuretics, beta blockers, and calcium channel blockers.^16–19 The RRR of new onset diabetes in patients receiving ACE inhibitors ranged from 14% to 78%. Similar results have been observed in ARB trials. Several clinical trials (LIFE, Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation [ALPINE], VALUE, Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity [CHARM]) have shown a statistically significant decrease in the new onset of diabetes in patients taking ARBs compared with placebo, beta blockers, or calcium channel blockers.^{6–7,20–21} The RRR of new onset diabetes in patients on ACE inhibitors ranged from 23% to 75%. This data suggests that inhibition of RAS activity may help in the prevention of new-onset diabetes.

Prevention of the development of atrial fibrillation. Newer data suggest that ACE inhibitors and ARBs may reduce the risk of developing atrial fibrillation (AF). Angiotensin converting enzyme expression is increased in atrial tissue of patients with AF. Stimulation of the RAS causes myocyte stretch and cardiac remodeling and promotes arrhythmogenesis. The antiarrhythmic effects of inhibition of the RAS include reduction in stretch receptor activation and reduction in protein kinase signal transduction decreasing fibrosis and intracellular calcium.²² The LIFE study demonstrated that new-onset AF was significantly reduced by losartan compared with atenolol (HR 0.67; 95% CI, 0.55–0.83; P<.001) in patients with HTN.²³ In addition, cardiovascular morbidity and mortality in hypertensive patients with a history of AF was reduced in patients treated with losartan compared with atenolol (unadjusted HR 0.58; 95% CI, 0.39–0.87; P=.009).²⁴ A retrospective, longitudinal cohort study in patients with HTN demonstrated that treatment with ACE inhibitors was associated with a reduced incidence of AF when compared to a long-acting calcium channel blocker (adjusted HR 0.85; 95% CI, 0.74–0.97; P=.0183).²⁵ A recent meta-analysis concluded that ACE inhibitors and ARBs both appear to be effective in the prevention of AF (RRR 28%; 95% CI, 15–40; P=.0002); however, this effect appears to be more beneficial for patients with HF (RRR 44%; 95%, CI 15–63; P=.007).²⁶ These studies suggest that patients with either HTN or HF who are treated with an ACE inhibitor or ARB may have a lower incidence of AF. While these retrospective analyses suggest a potential benefit of ACE inhibitors or ARBs in the prevention of AF, it is still necessary to look at this indication prospectively.

Reduction in the risk of stroke. Studies have also evaluated the effects of ACE inhibitors and ARBs in stroke prevention in patients with hypertension or who have CAD or other risk factors for cardiovascular events. Several prospective, randomized trials have shown that ACE inhibitors reduce the incidence of stroke in patients with HTN by between 5% and 32% (Perindopril Protection Against Recurrent Stroke Study [PROGRESS], Post-stroke Antihypertensive Treatment Study [PATS], HOPE). Conversely, the CAPPP study demonstrated a 25% increase in the incidence of stroke with captopril, the ALLHAT study demonstrated a 15% increase with lisinopril, and the Australian National Blood Pressure (ANBP) (enalapril) and Effects of Low Dose Ramipril on Cardiovascular and Renal Outcomes in Patients with Type 2 Diabetes and Raised Excretion of Urinary Albumin (DIABHYCAR) (ramipril) studies demonstrated that there was no difference between ACE inhibitor treatment and the comparator group. When looking at the effects of ARBs on the frequency of stroke, several studies demonstrated a decrease of 25% to 42% (LIFE, LIFE-ISH, Study of Cognition and Prognosis in the Elderly [SCOPE], SCOPE-ISH, Morbidity and Mortality After Stroke-Eprosartan Compared with Nitrendipine for Secondary Prevention Study [MOSES]). However, the Acute Candesartan Cilexetil Therapy in Stroke Survivors (ACCESS) study demonstrated no difference between the ARB therapy (candesartan) and placebo, while the VALUE study demonstrated a trend towards an increase in stroke incidence in the ARB group (valsartan) compared with a calcium channel blocker.²⁷ While there are some conflicting data, evidence leans towards ACE inhibitors and ARBs being beneficial in the prevention of stroke.

Prevention of hypertension. The use of an ARB for the prevention of progression of pre-HTN to HTN was studied in the recently published Trial of Preventing Hypertension (TROPHY). Patients with pre-HTN, defined as a systolic blood pressure of 130 to 139 mm Hg and diastolic blood pressure of 85 to 89 mm Hg, were randomly assigned to receive candesartan or placebo for a period of 2 years, followed by a 2-year period of placebo in both arms. The primary objective was to see if following 2 years of treatment with candesartan prevented the advancement to clinical HTN. The results demonstrated that there was a reduction in the progression to hypertension in the candesartan group 2 years after discontinuing treatment (RR 0.84; 95% CI, 0.75–0.95; P=.007). Further studies are necessary to determine if early treatment of pre-HTN with ARBs prevents the occurrence of clinical events such as stroke or MI or whether the effects of other antihypertensives may be equally as effective in prevention of HTN.²⁸

SPECIAL PATIENT POPULATION CONSIDERATIONS

Treatment of hypertension in patients with diabetes. As noted in the clinical guidelines (Table 1), diabetes is often a compelling comorbidity dictating the use of an ACE inhibitor or ARB in the treatment of HTN. The United Kingdom Prospective Diabetes Study (UKPDS) provided strong evidence that blood pressure control can reduce the risk of developing nephropathy in patients with type 2 diabetes.²⁹ It has also been shown that achieving optimal glucose control is fundamental in reducing the risk of nephropathy in patients with diabetes. This has been demonstrated in both the UKPDS and Diabetes Control and Complications Trial (DCCT). The UKPDS was a study of 1,148 patients with hypertension and type 2 diabetes looking at the effects of tight blood pressure control on macrovascular and microvascular complications. The DCCT trial, on the other hand, looked at 1,441 patients with type 1 diabetes and the effects of intensive versus conventional insulin therapies on long-term complications. These 2 large, prospective, randomized trials demonstrated that intensive diabetes management achieving near normal glucose levels (HbA_1c <7%) delays the onset of microalbuminuria and the progression of micro- to macroalbuminuria in patients with type 1 and type 2 diabetes.^29–30 More specifically, ACE inhibitors have been shown to delay the progression of nephropathy in patients with type 1 diabetes and to delay the progression of micro- to macroalbuminuria in patients with type 2 diabetes.^31–33 ARBs have been shown to delay the progression of macroalbuminuria to nephropathy in patients with type 2 diabetes.^34–37 ARBs have not been compared to ACE inhibitors in patients with type 2 diabetes and macroalbuminuria. A recent article reviewed the literature regarding the dual blockade of the RAS by both ACE inhibitors and ARBs in diabetic nephropathy. The article concluded that the combination therapy did result in statistically significant reductions in albuminuria (95% CI, 15–34; P<.001), systolic blood pressure (P=.002), and diastolic blood pressure (P=.003). However, more studies are needed to better assess whether the combination results in a decreased progression to proteinuria or end-stage renal disease.³⁸

A systemic review and meta-analysis was conducted looking at randomized, double-blind controlled trials of ARBs versus placebo or standard treatment for hypertension. Three studies that met the inclusion criteria were identified. These studies, using losartan and irbesartan, concluded total mortality (OR 0.99; 95% CI, 0.81–1.20) and cardiovascular morbidity and mortality were not significantly reduced in patients with type 1 or type 2 diabetes (OR 0.91; 95% CI, 0.77–1.08).³⁹ The HOPE study, which included patients with a history of CAD, stroke, peripheral vascular disease, or diabetes and at least 1 other cardiovascular risk factor (eg, HTN, elevated total cholesterol, low high-density lipoprotein [HDL], cigarette smoking, or microalbuminuria), demonstrated that patients receiving ACE inhibitor therapy (ramipril) had lower risks of death (RR 0.84; 95% CI, 0.75–0.95, P=.005), MI (RR 0.80; 95% CI, 0.70–0.90; P<.001), stroke (RR 0.68; 95% CI, 0.56-0.84; P<.001), coronary revascularization (RR 0.85; 95% CI, 0.77–0.94; P=.002), HF (RR 0.77; 95% CI, 0.67–0.87; P<.001), and other complications related to diabetes (RR 0.84; 95% CI, 0.72–0.98; P=.03).¹⁶ In addition, a study conducted by Eurich and colleagues demonstrated that patients treated with an ACE inhibitor who had type 2 diabetes and no cardiovascular disease had a significant reduction in all-cause mortality (unadjusted HR 0.43; 95% CI, 0.35–0.52; P<.001) and cardiovascular mortality (unadjusted HR 0.54; 95% CI, 0.39–0.76; P<.001).⁴⁰ The current recommendation for patients with diabetes is treatment with an ACE inhibitor or ARB to reduce the risk of cardiovascular morbidity and mortality and nephropathy.^15,41,42 It should also be noted that ACE inhibitors and ARBs reduced the progression of albuminuria in patients with diabetes regardless of hypertensive or normotensive status.⁴³ Additionally, dual blockade of RAS activity with a combination of an ACE inhibitor and an ARB may potentially reduce the progression of diabetic nephropathy more than either agent alone.^43–44 More trials are needed in this area.

More recently, ARBs have been investigated for their benefits in the treatment of systolic HF. In the Losartan Heart Failure Survival Study II (ELITE II), 3,152 elderly ACE inhibitor-naïve patients with symptomatic HF and ejection fraction <40% were randomized to either losartan 50 mg once daily or captopril 50 mg 3 times daily. There was no significant difference in all-cause mortality (HR 1.13; 95.7% CI, 0.95–1.35; P=.16) or hospitalizations (HR 1.04; 95% CI, 0.94–1.16; P=.45).⁴⁸ In the Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan (OPTIMAAL) of 5,477 patients with symptomatic HF and systolic dysfunction following MI, there was a non-significant trend towards lower mortality in patients treated with captopril 50 mg 3 times a day compared with losartan 50 mg once daily (16% vs 18%; P=.07).⁴⁹ In both ELITE II and OPTIMAAL, fewer patients discontinued ARB therapy secondary to side effects.

Valsartan has also been studied in patients with symptomatic HF and systolic dysfunction following MI. In the Valsartan in Acute Myocardial Infarction Trial (VALIANT) of 14,808 patients with recent MI and either symptoms of HF, ejection fraction of <40%, or both, mortality was similar between patients treated with either valsartan 160 mg twice daily, captopril 50 mg 3 times daily, or the combination of valsartan 80 mg twice daily and captopril 50 mg 3 times daily (HR 1.00 for valsartan versus captopril; 95% CI, 0.90–1.11; P=.98; P value for non-inferiority=.004; HR 0.98 for valsartan plus captopril versus captopril alone; 95% CI, 0.89–1.09; P=.73). The combination of valsartan and captopril did not impact mortality and resulted in a higher incidence of adverse effects leading to study discontinuation, namely hypotension and renal insufficiency, compared with captopril alone.⁵⁰ In the Valsartan in Heart Failure Trial (VAL-HeFT), mortality was also similar to control when valsartan 160 mg twice daily was added to standard therapy, including ACE inhibitors and beta blockers, in patients with symptomatic systolic HF (RR 1.02; 95% CI, 0.88–1.18; P=.80).⁵¹

Candesartan has been studied in HF in the CHARM program consisting of 3 separate trials in patients with symptomatic HF: CHARM-Alternative (N=2,028 patients with systolic HF and an ejection fraction <40% who were intolerant to an ACE inhibitor), CHARM-Added (N=2,548 patients with systolic HF and an ejection fraction <40% who were already taking an ACE inhibitor), and CHARM-Preserved (N=3,023 patients with HF and preserved left ventricular systolic function with an ejection fraction >40%) comparing candesartan 32 mg once daily versus placebo. As an alternative to an ACE inhibitor in patients with systolic HF, candesartan significantly reduced the primary end point of cardiovascular death or admission for HF by 23% (unadjusted HR 0.85; 95% CI, 0.67–0.89; P=.0004) and hospitalization for HR by 32% (unadjusted HR 0.68; 95%, CI 0.57–0.81; P<.0001).⁵² When added to an ACE inhibitor in patients with systolic HF, candesartan significantly reduced cardiovascular death or admission for HF by 15% (unadjusted HR 0.85; 95% CI, 0.75–0.96; P=.011), cardiovascular death by 16% (unadjusted HR 0.84; 95% CI, 0.72–0.98; P<.029), and hospitalization for HF by 17% (unadjusted HR 0.83; 95% CI, 0.71–0.96; P<.014).⁵³ In patients with preserved ventricular function, candesartan did not reduce the primary end point (unadjusted HR 0.89; 95% CI, 0.77–1.03; P=.118), cardiovascular mortality (unadjusted HR 0.99; 95% CI, 0.80–1.22; P=.918), or hospitalization for HF (unadjusted HR 0.85; 95% CI, 0.72–1.01; P=.072).⁵⁴ Overall, adverse events, including hypotension, increase in serum creatinine, and hyperkalemia, were more frequent in candesartan-treated patients.²¹

Based upon the results of VALIANT, CHARM-Alternative (50% of patients with a history of MI), CHARM-Preserved (45% of patients with a history of MI), HOPE (patients with stable CAD or at high risk for MI), European Trial On Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease (EUROPA) (patients with stable CAD without evidence of HF treated with perindopril or placebo), and Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) trial, the 2004 ACC/AHA MI guidelines recommend either an ACE inhibitor or an ARB (valsartan or candesartan) for all patients following MI regardless of left ventricular function.^{4,50,52,54–56} In 2004, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO) revised its core measures of quality care for MI to include the prescribing of either an ACE inhibitor or an ARB to patients with systolic dysfunction following MI as well as for patients with HF.^57,58 A recent meta-analysis of >24 trials involving >38,000 patients also support this revision, as ARBs were associated with a significant 17% reduction on mortality (OR 0.83; 95% CI, 0.69–1.00) and a 36% reduction in HF hospitalizations compared with placebo (OR 0.64; 95% CI, 0.53–0.78). Also, compared with ACE inhibitors, ARBs had similar mortality (OR 1.06; 95% CI, 0.90–1.26), and HF hospitalization rates (OR 0.95; 95% CI, 0.80–1.13). The combination of an ACE inhibitor and an ARB did not improve survival (OR 0.97; 95% CI, 0.87–1.08) but did reduce HF hospitalizations by 23% (OR 0.77; 95% CI, 0.69–0.87).⁵⁹ More recently, the ACC/AHA heart failure guidelines published in 2005 suggest that ARBs may be considered a "reasonable" alternative to an ACE inhibitor for the management of symptomatic systolic HF. Based upon the data presented here, the guidelines recommend either candesartan, losartan, or valsartan.⁵

ADDITIONAL CONSIDERATIONS

Compliance and persistence with antihypertensive medications continues to be a barrier to increasing the overall blood pressure control rates in hypertensive individuals. Some potential causes of this patient compliance and persistence challenge include the demonstration of medication tolerability issues related to the commonly utilized and guideline-recommended antihypertensive medications.³ Some of these common adverse events include headache, general fatigue, swelling of extremities, and persistent cough.^3,60 The latter adverse event is most frequently associated with the ACE inhibitor class of medications, and the use of ARBs to target the RAS pathway provides an alternative with a lower potential for causing this specific adverse event. In clinical trials, as well as in "real-world" observational data, ARBs have been shown to be well-tolerated agents, with specifically lower incidences of cough than ACE inhibitors and calcium channel blockers.^61,62 Additional data demonstrate that the use of ARBs in hypertensive individuals is associated with improved long-term persistence compared with ACE inhibitors, calcium channel blockers, diuretics, and beta blockers.⁶³

Numerous cost-effectiveness analyses of both ACE inhibitors and ARBs for the treatment of HTN, HF, and diabetes have been published.^64–70 While a detailed review is beyond the scope of this article, it is noteworthy that most of these cost-effectiveness reports are not comparisons between ACE inhibitors and ARBs. One cost-effectiveness analysis of VALIANT, which was described previously, reported $1,065 higher costs over 2 years for valsartan compared with captopril for patients with reduced left ventricular function following MI.⁶⁴ In patients with systolic HF who were not receiving an ACE inhibitor, the use of valsartan compared to no RAS-blocking agent was cost-saving, while the agent's use in patients receiving both an ACE inhibitor and a beta blocker increased costs by $1,246 over 23 months.^65,66 One analysis of ACE inhibitors in elderly patients with diabetes mellitus demonstrated the potential to reduce Medicare program costs and increase quality-adjusted life years when co-pays for ACE inhibitor prescriptions were $0.⁶⁷ This study has the potential to have a significant impact on healthcare.

SUMMARY

There have been numerous clinical trials looking at the use of ACE inhibitors and ARBs in HTN, HF, and other special populations. Overall, it has been noted that ACE inhibitors and ARBs appear to have an additional benefit beyond just the blood pressure-lowering effect when used in certain populations. When compared to each other in head-to-head trials, ACE inhibitors and ARBs generally appear to demonstrate no difference in primary outcomes. With regard to side effect profiles, ARBs do tend to be better tolerated than ACE inhibitors. While ACE inhibitors and ARBs may increase initial medical costs, over time they may prove to be very cost-effective. Generally, either ACE inhibitors or ARBs may be selected in the treatment of HTN or HF, and the deciding factor may be largely patient-specific.

Dr Miller is an assistant professor of clinical pharmacy, Department of Pharmacy Practice and Pharmacy Administration, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia. She can be reached at a.miller@usip.edu
. Dr Cziraky is executive vice president, HealthCore, Inc, Newark, Del. Dr Spinler is a professor of clinical pharmacy, Department of Pharmacy Practice and Pharmacy Administration, Philadelphia College of Pharmacy, University of the Sciences in Philadelphia, and an adjunct professor of pharmacy in medicine, Department of Medicine, Cardiovascular Division, University of Pennsylvania, Philadelphia.

Disclosure Information: Drs Miller and Cziraky have no financial disclosures to report as related to products discussed in this article. Dr Spinler is on the speaker's bureau for Bristol-Myers Squibb.

REFERENCES

1. American Heart Association. Heart Disease and Stroke Statistics-2005 Update. Dallas, Texas: American Heart Association; 2005. Available at: http:// http://www.americanheart.org/downloadable/heart/1105390918119hdsstats2005Update.pdf . Accessed May 22, 2006.

2. Williams B. Recent hypertension trials: implications and controversies. J Am Coll Cardiol. 2005;45:813–827.

3. Chobanian AV, Bakris GL, Black HR, et al; Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure; National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program Coordinating Committee. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206–1252.

4. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction-executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44:671–719.

5. Hunt SA, Abraham WT, Chin MH, et al. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult-summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). J Am Coll Cardiol. 2005;46:1116–1143.

6. Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359:995–1003.

7. Julius S, Kjeldsen SE, Weber M, et al; 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;363:2022–2031.

8. Barnett AH, Bain SC, Bouter P, et al; Diabetics Exposed to Telmisartan and Enalapril Study Group. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med. 2004;351: 1952–1961.

9. Dahlö B, Sever PS, Poulter NR, et al. 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 randomised controlled trial. Lancet. 2005;366: 895–906.

10. Angeli F, Verdecchia P, Reboldi GP, et al. Meta-analysis of effectiveness or lack thereof of angiotensin-converting enzyme inhibitors for prevention of heart failure in patients with systemic hypertension. Am J Cardiol. 2004;93:240–243.

11. Carlberg B, Samuelsson O, Lindholm LH. Atenolol in hypertension: is it a wise choice? Lancet. 2004;364:1684–1689.

12. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet. 1997;349:1857–1863.

13. Ruggenenti P, Perna A, Loriga G, et al, for the REIN-2 Study Group. Blood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet. 2005;365: 939–946.

14. Nakao N, Yoshimura A, Morita H, Takada M, Kayano T, Ideura T. Combination treatment of angiotensin-II receptor blocker and angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet. 2003;361:117–124.

15. National Kidney Foundation. K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis. 2004;43(Suppl 1):S1–S290.

16. Yusuf S, Sleight P, Pogue J, Bosch J, Davies R, Dagenais G. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. The Heart Outcomes Prevention Evaluation Study Investigators. N Engl J Med. 2000;342:145–153.

17. Hansson L, Lindholm LH, Niskanen L, et al. Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: the Captopril Prevention Project (CAPPP) randomised trial. Lancet. 1999;353:611–616.

18. 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;288:2981–2997.

19. Vermes E, Ducharme A, Bourassa MG, Lessard M, White M, Tardif J-C. Enalapril reduces the incidence of diabetes in patients with chronic heart failure. Insight from the Studies Of Left Ventricular Dysfunction (SOLVD). Circulation. 2003;107:1291–1296.

20. Lindholm LH, Persson M, Alaupovic P, Carlberg B, Svensson A, Samuelsson O. Metabolic outcome during 1 year in newly detected hypertensives: results of the Antihypertensive Treatment and Lipid Profile in a North of Sweden Efficacy Evaluation (ALPINE Study). J Hypertens. 2003;21:1563–1574.

21. Pfeffer MA, Swedberg K, Granger CB, et al; CHARM Investigators and Committees. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759–766.

22. Lozano HF, Conde CA, Florin T, Lamas GA. Treatment and prevention of atrial fibrillation with nonantiarrhythmic pharmacologic therapy. Heart Rhythm. 2005;2:1000–1007.

23. Wachtell K, Lehto M, Gerdts E, et al. Angiotensin II receptor blockade reduces new-onset atrial fibrillation and subsequent stroke compared to atenolol. J Am Coll Cardiol. 2005;45:712–719.

24. Wachtell K, Hornestam B, Lehto M, et al. Cardiovascular morbidity and mortality in hypertensive patients with a history of atrial fibrillation: the Losartan Intervention For End Point Reduction in Hypertension (LIFE) study. J Am Coll Cardiol. 2005;45:705–711.

25. L'Allier PL, Ducharme A, Keller PF, Yu H, Guertin MC, Tardif JC. Angiotensin-converting enzyme inhibition in hypertensive patients is associated with a reduction in the occurrence of atrial fibrillation. J Am Coll Cardiol. 2004;44: 159–164.

26. Healey JS, Baranchuk A, Crystal E, et al. Prevention of atrial fibrillation with angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: a meta-analysis. J Am Coll Cardiol. 2005;45:1832–1839.

27. Chrysant SG. Possible pathophysiologic mechanisms supporting the superior stroke protection of angiotensin receptor blockers compared to angiotensin-converting enzyme inhibitors: clinical and experimental evidence. J Hum Hypertens. 2005;19:923–931.

28. Julius S, Nesbit SD, Egan BM, et al. Feasibility of treating prehypertension with an angiotensin-receptor blocker. N Engl J Med. 2006;354: 1685–1697.

29. UK Prospective Diabetes Study Group. Tight blood glucose control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317:703–713.

30. The Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int. 1995;47: 1703–1720.

31. American Diabetes Association. Position statement: nephropathy in diabetes. Diabetes Care. 2004;27(suppl 1):S79–83.

32. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. New Engl J Med. 1993;329: 1456–1462.

33. Ahmad J, Siddiqui MA, Ahmad H. Effective postponement of diabetic nephropathy with enalapril in normotensive type 2 diabetic patients with microalbuminuria. Diabetes Care. 1997;20: 1576–1581.

34. Viberti G, Wheeldon NM; MicroAlbuminuria Reduction With VALsartan (MARVAL) Study Investigators. Microalbuminuria reduction with valsartan in patients with type 2 diabetes mellitus: a blood pressure-independent effect. Circulation. 2002;106:672–678.

35. Lewis EJ, Hunsicker LG, Clarke WR, et al; Collaborative Study Group. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. New Engl J Med. 2001;345:851–860.

36. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. New Engl J Med. 2001;345: 861–869.

37. Parving HH, Lehnert H, Bröchner-Mortensen J, Gomis R, Andersen S, Arner P; Irbesartan in Patients with Type 2 Diabetes and Microalbuminuria Study Group. The effect of irbesartan on the development of diabetic nephropathy in patients with type 2 diabetes. New Engl J Med. 2001;345:870–878.

38. Wade VL, Gleason BL. Dual blockade of the renin-angiotensin system in diabetic nephropathy. Ann Pharmacotherapy. 2004;38:1278–1282.

39. Siebenhofer A, Plank J, Horvath A, et al. Angiotensin receptor blockers as anti-hypertensive treatment for patients with diabetes mellitus: meta-analysis of controlled double blind randomized trials. Diabet Med. 2004;21:18–25.

40. Eurich DT, Majumdar SR, Tsuyuki RT, Johnson JA. Reduced mortality associated with the use of ACE inhibitors in patients with type 2 diabetes. Diabetes Care. 2004;27:1330–1334.

41. American Diabetes Association. Standards of medical care in diabetes. Diabetes Care. 2005;28(Suppl 1):S4–36.

42. American Diabetes Association. Position statement: nephropathy in diabetes. Diabetes Care. 2004;27(Suppl 1):S79–83.

43. Fujisawa T, Ikegami H, Ono M, et al. Combination of half doses of angiotensin type 1 receptor antagonist and angiotensin-converting enzyme inhibitor in diabetic nephropathy. Am J Hypertens. 2005;18:13–17.

44. Parving HH, Andersen S, Jacobsen P, et al. Angiotensin receptor blockers in diabetic nephropathy: renal and cardiovascular end points. Semin Nephrol. 2004;24:147–157.

45. Flather MD, Yusuf S, Kober L, et al. Long-term ACE-inhibitor therapy in patients with heart failure or left-ventricular dysfunction: a systematic overview of data from individual patients. ACE-Inhibitor Myocardial Infarction Collaborative Group. Lancet. 2000;355:1575–1581.

46. Garg R, Yusuf S. Overview of randomized trials of angiotensin-converting enzyme inhibitors on mortality and morbidity in patients with heart failure. Collaborative Group on ACE Inhibitor Trials. JAMA. 1995;273:1450–1456.

47. Al-Mallah MH, Tleyjeh IM, Abdel-Latif AA, Weaver WD. Angiotensin-converting enzyme inhibitors in coronary artery disease and preserved left ventricular systolic function: a systematic review and meta-analysis of randomized controlled trials. J Am Coll Cardiol. 2006;47:1576–1583.

48. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial-the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355: 1582–1587.

49. Dickstein K, Kjekshus J; OPTIMAAL Steering Committee of the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Optimal Trial in Myocardial Infarction with Angiotensin II Antagonist Losartan. Lancet. 2002;360:752–760.

50. Pfeffer MA, McMurray JJ, Velazquez EJ, et al; Valsartan Heart Failure Trial Investigators. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. New Engl J Med. 2003;349:1893–1906.

51. Cohn JN, Tognoni G; Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. New Engl J Med. 2001;345: 1667–1675.

52. Granger CB, McMurray JJ, Yusuf S, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362:772–776.

53. McMurray JJ, Ostergren J, Swedberg K, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet. 2003;362:767–771.

54. Yusuf S, Pfeffer MA, Swedberg K, et al; CHARM Investigators and Committees. Effects of candesartan in patients with chronic heart failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet. 2003;362:777–781.

55. Fox KM, for the European Trial On Reduction of Cardiac Events with Perindopril in Stable Coronary Artery Disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomized, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362:782–788.

56. Braunwald E, Domanski MJ, Fowler SE, et al; PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. New Engl J Med. 2004;351:2058–2068.

57. Joint Commission on Accreditation of Healthcare Organizations. NQF-endorsed voluntary consensus standards for hospital care: Measure information form (acute myocardial infarction). Available at: http:// http://www.jcaho.org/pms/core+measures/2dami3.pdf. Accessed June 1, 2006.

58. Joint Commission on Accreditation of Healthcare Organizations. NQF-Endorsed voluntary consensus standards for hospital care: Measure information form (heart failure). Available at: http:// http://www.jcaho.org/pms/core+measures/2shf3.pdf. Accessed June 1, 2006.

59. Lee VC, Rhew DC, Dylan M, Badamgarav E, Braunstein GD, Weingarten SR. Meta-analysis: angiotensin-receptor blockers in chronic heart failure and high-risk acute myocardial infarction. Ann Intern Med. 2004;141:693–704.

60. Gregoire JP, Mosian J, Gilbert R, et al. Tolerability of antihypertensive drugs in community-based setting. Clin Ther. 2001;23:715–726.

61. Wogen J, Kreilick CA, Livornese RC, Yokoyama K, Frech F. Patient adherence with amlodipine, lisinopril, or valsartan therapy in a usual-care setting. J Managed Care Pharm. 2003;9:424–429.

62. Dusing P, Lottermoser K, Mengden T, Vetter H. Compliance with antihypertensive therapy, comparison of losartan, amlodipine and metoprolol in an open prospective trial [abstract]. AJH. 14(4):P-205.

63. Conlin PR, Gerth WC, Fox J, Roehm JB, Boccuzzi SJ. Four-year persistence patterns among patients initiating therapy with the angiotensin II receptor antagonist losartan versus other antihypertensive drug classes. Clin Ther. 2001;23:199–201.

64. Reed SD, Radeva JI, Weinfurt KP, et al, for the VALIANT Investigators. Resource use, costs, and quality of life among patients in the multinational Valsartan in Acute Myocardial Infarction Trial (VALIANT). Am Heart J. 2005;150: 323–329.

65. Smith DG, Cerulli A, Frech FH. Use of valsartan for the treatment of heart-failure patients not receiving ACE inhibitors: a budget impact analysis. Clin Ther. 2005;27:951–959.

66. Reed SD, Friedman JY, Velasquez EJ, Gnanasakthy A, Califf RM, Schulman KA. Multinational economic evaluation of valsartan in patients with chronic heart failure: results from Valsartan Heart Failure Trial (Val-HeFT). Am Heart J. 2004;148:122–128.

67. Rosen AB, Hamel MB, Weinstein MC, Cutler DM, Fendrick M, Vijan S. Cost-effectiveness of full Medicare coverage of angiotensin-converting enzyme inhibitors for beneficiaries with diabetes. Ann Intern Med. 143:89–99.

68. Palmer AJ, Annemans L, Roze S, et al. Cost-effectiveness of early irbesartan treatment versus control (standard antihypertensive medications excluding ACE inhibitors, other angiotensin-2 receptor antagonists, and dihydropyridine calcium channel blockers) or late irbesartan treatment in patients with type 2 diabetes, hypertension, and renal disease. Diabetes Care. 2004;27:1897–1903.

69. Herman WH, Shahinfar S, Carides GW, et al. Losartan reduces the costs associated with diabetic end-stage renal disease: the RENAAL study economic evaluation. Diabetes Care. 2003;26: 683–687.

70. Lamy A, Yusuf S, Pogue J, Gafni A; Heart Outcomes Prevention Evaluation Investigators. Cost implications of the use of ramipril in high-risk patients based on the Heart Outcomes Prevention Evaluation (HOPE) study. Circulation. 2003; 107:960–965.

71. Cifkova R, Erdine S, Fagard R, et al; ESH/ESC Hypertension Guidelines Committee. Practice guidelines for primary care physicians: 2003 ESH/ESC hypertension guidelines. J Hypertension. 2003;21:1779–1786.

72. Douglas JG, Bakris GL, Epstein M, et al; Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Management of high blood pressure in African Americans: consensus statement of the Hypertension in African Americans Working Group of the International Society on Hypertension in Blacks. Arch Intern Med. 2003; 163:525–541.

73. Williams B, Poulter NR, Brown MJ, Davis M, McInnes GT, Potter JF, et al. British Hypertension Society Guidelines for Hypertension Management 2004 (BHS-IV) summary. BMJ. 2004;328: 634–640.

74. Facts & Comparisons database. Available at: http:// http://www.factsandcomparisons.com/. Accessed June 1, 2006.