ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use

ACE inhibitors in heart failure due to systolic dysfunction: Therapeutic use

INTRODUCTION — The medical therapy of heart failure (HF) with systolic dysfunction, as recommended in the 2005 ACC/AHA guidelines on chronic heart failure can be summarized as following (show table 1) [1]. (See "Overview of the therapy of heart failure due to systolic dysfunction").
The following therapies are appropriate for all patients, unless a contraindication is present:

• An angiotensin converting enzyme (ACE) inhibitor to slow progression of the HF and improve survival.

• A beta blocker, also to slow progression of the HF and improve survival; the benefits of ACE inhibitors and beta blockers are additive.

• A loop diuretic and dietary salt restriction to correct fluid overload.

In addition, drugs that can adversely affect patients with heart failure due to systolic dysfunction should be avoided or withdrawn. These include nonsteroidal antiinflammatory drugs, most antiarrhythmic drugs, and the non-dihydropyridine calcium channel blockers (ie, diltiazem and verapamil). (See "Calcium channel blockers in heart failure due to systolic dysfunction").
The following should be given to selected patients in the absence of a contraindication:

• The addition of the combination of hydralazine and a nitrate for patients (particularly blacks) with a reduced LVEF who have persistent symptoms despite therapy with an ACE inhibitor and beta blocker.

• The addition of an aldosterone antagonist (spironolactone or, if not tolerated, eplerenone) to improve survival in patients with NYHA class III/IV symptoms (show table 2) and a reduced left ventricular ejection fraction who can be monitored for preserved renal function and a normal plasma potassium concentration. Aldosterone antagonists also may be used to assist in the management of diuretic-induced hypokalemia (plasma potassium ≤3.8 meq/L) in patients with mild-to-moderate HF.

• Angiotensin II receptor blockers (ARBs) as an alternative to ACE inhibitors in patients who cannot tolerate these drugs; the addition of an ARB to an ACE inhibitor may be considered in patients who are persistently symptomatic and have a reduced left ventricular ejection fraction despite being treated with conventional therapy.

• Digoxin to reduce hospitalization for HF or for rate control in patients with concomitant atrial fibrillation.

In addition to these pharmacologic therapies, two types of devices are recommended in selected patients with HF (show table 1):

• An implantable cardioverter-defibrillator (ICD) for secondary prevention of sudden cardiac death (SCD) and for primary prevention in selected patients. The criteria for ICD implantation are discussed separately. (See "Role of implantable cardioverter-defibrillators for the primary prevention of sudden cardiac death after myocardial infarction" and see "Ventricular arrhythmias in heart failure and cardiomyopathy").

• Cardiac resynchronization therapy (CRT) with biventricular pacing can improve symptoms and survival in patients who are in sinus rhythm and have an LVEF ≤35 percent, cardiac dyssynchrony, which is currently defined as a prolonged QRS duration (≥120 msec), and moderate to severe symptoms (NYHA class III or IV HF) despite optimal medical therapy. Most patients who satisfy these criteria are also candidates for an ICD and receive a combined device. (See "Cardiac resynchronization therapy (biventricular pacing) in heart failure").

The clinical data supporting the use of ACE inhibitors in patients with HF will be reviewed here. The mechanisms of action of these agents in HF, their role in patients with diastolic dysfunction, and the efficacy of angiotensin II receptor blockers are discussed separately. (See "Angiotensin converting enzyme inhibitors and receptor blockers in heart failure: Mechanisms of action" and see "Treatment and prognosis of diastolic heart failure" and see "Angiotensin II receptor blockers in heart failure due to systolic dysfunction: Therapeutic use").
BENEFIT OF ACE INHIBITORS
General efficacy — ACE inhibitors are a standard therapy for HF because multiple, large, prospective, randomized trials have consistently demonstrated a significant reduction in mortality [2-6]. The benefit ACE inhibitors has been demonstrated in all severities of symptomatic HF and in patients with asymptomatic left ventricular (LV) dysfunction; a benefit has also been demonstrated after myocardial infarction (MI).
A meta-analysis evaluated five trials (three post-MI) involving 12,763 patients; ACE inhibition had the following benefits [7]:

• A lower total mortality (23 versus 27 percent for placebo, odds ratio 0.80, 95% CI 0.74-0.87) (show figure 1). Most of the mortality benefit was due to fewer deaths from progressive HF. This benefit of treatment was apparent soon after the start of treatment and continued to increase after more than four years.

• A lower rate of readmission for HF (14 versus 19 percent, odds ratio 0.67, 95% CI 0.61-0.74).

• A lower incidence of MI (9 versus 11 percent, odds ratio 0.79, 95% CI 0.70-0.89), but no difference in stroke.

Overall, there was a significant reduction in death, MI, and hospital admission for HF (odds ratio 0.72, 95% CI 67-78 percent). This translates into 7 patients with at least one event prevented for every 100 patients treated.
Severity of HF — The individual trials assessed patients with a defined severity of HF, using the New York Heart Association classification (show table 2). ACE inhibitors were compared to placebo and, in one trial, to the combination of hydralazine and isosorbide dinitrate:

• The CONSENSUS study group evaluated 253 patients with advanced NYHA III or IV HF who were being treated with diuretics, digitalis, and vasodilating agents, primarily nitrates [2]. The administration of enalapril significantly reduced the six month mortality by 40 percent when compared to placebo (26 versus 44 percent) and the 12 month mortality by 31 percent (36 versus 52 percent) (show figure 2). This benefit was sustained for at least four years and the risk reduction averaged over the 10 year duration of the trial was 30 percent (show figure 3) [8].

• The SOLVD treatment trial evaluated 2569 patients with symptomatic NYHA class II to III HF [3]. When compared to placebo, enalapril resulted in a significant in all-cause mortality (35 versus 40 percent, risk reduction 16 percent, 95 percent confidence interval [CI] 5 to 26 percent) (show figure 4).

A subsequent analysis, called XSOLVD, followed the patients in the SOLVD treatment trial out to a median of 12 years; the outcome was determined in virtually all of the original participants [9]. The reduction in all-cause mortality in the enalapril group narrowed over time and was no longer significant at 12 years at which time 80 percent of patients in both groups had died (hazard ratio 0.93, 95% CI 0.85 - 1.01). Overall, enalapril significantly increased median life expectancy by 8.6 months.

• The efficacy of ACE inhibitors compared to hydralazine and isosorbide dinitrate in patients with NYHA class II and III HF was evaluated in the V-HeFT II trial of 806 men [4]. After two years, the mortality rate was lower with enalapril (18 versus 25 percent with isosorbide/hydralazine, p = 0.016) (show figure 5). However, the mortality benefit with enalapril was only seen in white patients with hypertension and higher plasma renin activity [10]. (See "Influence of race" below).

After MI — ACE inhibitors improve the outcome in patients with asymptomatic LV dysfunction or overt HF occurring after an acute MI. The trials confirming these benefits are described in detail elsewhere. (See "Angiotensin converting enzyme inhibitors and receptor blockers in acute myocardial infarction: Clinical trials"). The range of findings can be illustrated by results from the SAVE and AIRE trials:

• In the SAVE trial, 2231 asymptomatic patients with an LVEF ≤40 percent were randomly assigned to treatment with either captopril (12.5 mg TID increasing to a final target dose of 50 mg TID) or placebo starting 3 to 16 days after MI [6]. At a mean follow-up of 42 months, captopril therapy was associated with a 19 percent (95% CI 3 to 32 percent) decrease in mortality (20 versus 25 percent for placebo) (show figure 7), a 37 percent reduction in the incidence of severe HF, a 22 percent reduction in hospitalization for HF, and a 25 percent reduction in the incidence of recurrent MI.

• The efficacy of ACE inhibition in patients who develop overt HF post-MI was evaluated in the AIRE trial, which randomly assigned 2006 patients with clinical evidence of HF to ramipril or placebo between day 3 and 10 post-MI [11]. After an average of 15 months follow-up, ramipril was associated with a 27 percent (95% CI 11 to 40 percent) decrease in mortality (17 percent versus 23 percent with placebo). Other benefits included a 23 percent reduction in the incidence of severe, resistant HF by 23 percent (14 versus 18 percent for placebo) and a 30 percent reduction in sudden death [12]. The survival benefit was maintained over the long-term (show figure 8) [13].

Use in the elderly — All of the major randomized trials included many elderly patients. It is possible, however, that some elderly patients with comorbidities would have been excluded from these trials. Despite this concern, community-based observational studies support a benefit from ACE inhibitors in elderly patients with HF that is similar in magnitude to that seen in younger patients [14,15]. Long-term benefit is seen even in those who have a perceived contraindication to ACE inhibitors (systolic pressure ≤90 mmHg, serum creatinine ≥2.5 mg/dL [221 µmol/L], serum potassium ≥5.5 meq/L, and severe aortic stenosis) [16,17]. Although lower doses are associated with improved outcomes, the benefit is greater if the dose is titrated up to that used in the clinical trials [14,18]. (See "Effect of dose" below).
Influence of gender — A meta-analysis of ACE inhibitor trials suggested that the benefit from these drugs may not apply to women [19]. A total of 3492 men and 1079 women from three trials were included. The relative mortality risk with ACE inhibitor therapy was significantly reduced in men at 0.80 (95% CI 0.68-0.93) but showed only a trend toward significance in women at 0.90 (95% CI 0.78-1.05) for women. However, until more definitive data are provided, ACE inhibitors should continue to be used in women with HF.
Influence of race — The V-HeFT trial and a matched cohort study from the SOLVD trial suggested that there were important differences between blacks and whites in the response to ACE inhibitors [10,20,21]. Two major findings were noted:

• Blacks had higher rates of both progressive HF and overall mortality. In the SOLVD analysis, the respective values were 13 versus 8 per 100 patient-years in whites for hospitalization for HF and 12 versus 10 per 100 patient-years for overall mortality [21].

• Blacks had a lesser response than whites to ACE inhibition with enalapril despite receiving similar doses. In the SOLVD matched cohort study, enalapril therapy in whites was associated with a significant 44 percent reduction in hospitalization for HF compared to placebo; in contrast there was no significant reduction among blacks (show figure 9) [21].

The apparent lack of response in blacks has some biologic plausibility since similar findings have been noted in patients with hypertension. Blacks respond less well to ACE inhibitors than to most other antihypertensive drugs (show figure 10) [22]. In the matched cohort study from SOLVD, there were significant reductions in systolic and diastolic pressure with enalapril in whites (5/3.6) but not blacks [21]. (See "Treatment of hypertension in blacks").
In contrast to these findings, another analysis of the SOLVD trials using mortality as the end point found that the relative risk (RR) of death was reduced to the same degree in both blacks and whites (RR for blacks 0.89, 95% CI 0.74-1.06; RR for whites 0.89, 95% CI 0.82-0.97) [19]. The risk reduction was significant in whites but not blacks, an observation that is likely to be explained by the smaller number of blacks in the trials (800 versus 5718).
In an analysis limited to the SOLVD prevention trial, enalapril was largely as effective in blacks as whites in preventing progression from asymptomatic LV dysfunction to symptomatic HF [23]. As in the matched-cohort study, a significant reduction in first hospitalization for HF was seen only in whites (relative risk 0.64 versus 0.85 in blacks). However, this end point was much less frequent than progression to symptomatic HF and it is therefore uncertain if the difference in response was real. (See "Evaluation and management of asymptomatic left ventricular systolic dysfunction").
A separate issue is the relative effect of other vasodilating agents on survival in blacks and whites. The V-HeFT I trial found that blacks, but not whites, had a significant reduction in mortality with hydralazine plus isosorbide dinitrate compared to placebo [10]. However, it is not certain if this combination is more effective than an ACE inhibitor in blacks.
Influence of diabetes — The above meta-analysis of ACE inhibitor trials found that the beneficial effect of ACE inhibitors in HF was the same for patients with and without diabetes [19]. (See "Heart failure in diabetes mellitus").
Effect of dose — It has been suggested that the benefit of ACE inhibitors is greater with higher doses. Support for the use of high doses comes from the observation that, in patients on chronic ACE inhibitor therapy, gradual reactivation of vascular tissue formation of angiotensin II occurs over time [24,25], This is seen in those with progressive heart failure as well as those who are clinically stable. Conversion can be suppressed by increasing the dose of the ACE inhibitor.
However, it is uncertain if high doses are more effective than standard doses, both of which may be associated with similar plasma angiotensin II and aldosterone concentrations [26]. One analysis evaluated 16,539 patients with a first HF hospitalization [27]. During one year of follow-up, 4186 (25 percent) died. Compared to patients on a low dose ACE inhibitor, those on a high dose had a significant reduction in mortality (hazard ratio 0.76).
Three controlled trials have addressed the issue of optimal dosing (low compared to standard or high doses) and clinical outcome, with conflicting results:

• One trial randomly assigned 1532 patients with HF to three different doses of enalapril (2.5, 5, and 10 mg twice per day) for six months; the incidence of the primary end point of death, HF related hospitalization, or worsening of HF was similar in the three groups (12, 13, and 15 percent, respectively) (show figure 11) [28].

• A similar lack of dose-dependence was noted in a second study that compared standard doses of enalapril (20 mg/day) to high doses of up to 60 mg/day (mean dose achieved 42 mg/day) [29].

• The ATLAS trial randomly assigned 3164 patients to either low (2.5 to 5 mg) or high dose (32.5 to 35 mg) lisinopril. Compared to the low dose regimens, high dose lisinopril reduced mortality by an insignificant 8 percent, although it significantly lowered the combined end point of mortality and hospitalization for any cause by 12 percent and hospitalizations for HF by 24 percent [18]. These benefits of high dose lisinopril were also seen in high risk patients, including those with diabetes, hypotension, hyponatremia, renal dysfunction, and the elderly [30].

Use with other HF drugs — In addition to angiotensin II inhibition, several other drugs, including beta blockers, spironolactone, and angiotensin II receptor blockers (ARBs) have been shown to improve survival in patients with HF. (See "Overview of the therapy of heart failure due to systolic dysfunction"). Most patients in the major trials evaluating beta blockers were also treated with an ACE inhibitor (as well as diuretics and digoxin as necessary). These studies showed that combination therapy with an ACE inhibitor and beta blocker was more effective than an ACE inhibitor or beta blocker alone in both symptomatic HF and asymptomatic LV dysfunction (show figure 12 and show figure 13) [31]. (See "Use of beta blockers in heart failure due to systolic dysfunction").
It has been recommended that therapy with an ACE inhibitor should be instituted before beta blockade is implemented. However, a small study using carvedilol and perindopril suggested that initiation of the beta blocker before the ACE inhibitor results in higher tolerated doses of beta blocker and better improvements in NYHA class and left ventricular function [32]. We do not recommend a change in practice based upon this report due to the small number of patients and lack of long-term outcome data.
ACE gene polymorphisms may affect the response to combination therapy. The DD genotype of the ACE gene has been associated with increases in ACE activity and mortality and a reduction in transplant-free survival in patients with HF [33]. This difference may be abolished with beta blocker therapy as transplant-free survival is equivalent in patients with the DD, ID, and II genotypes. (See "Actions of angiotensin II on the heart", section on ACE gene polymorphism).
There is also is an additive survival benefit with ACE inhibitors and spironolactone or eplerenone, at least in patients with advanced HF (as demonstrated in the RALES trial) and in patients with HF within two weeks of an acute MI (as demonstrated in the EPHESUS trial) [34,35]. A potential concern is that both drugs tend to raise the plasma potassium concentration, possibly leading to hyperkalemia that may be life-threatening in selected cases. (See "Use of diuretics in heart failure").
The combination of an ACE inhibitor and an angiotensin II receptor blocker (ARB) has been evaluated in several studies. The role of combined therapy with an ACE inhibitor and an ARB is discussed separately. (See "Angiotensin II receptor blockers in heart failure due to systolic dysfunction: Therapeutic use", section on Combined therapy with ACE inhibitors).
Use with aspirin — ACE inhibitors reduce kinin degradation. Increased kinin levels may contribute to the observed benefit seen with these drugs, an effect that may be mediated by enhanced release of vasodilator prostaglandins. Aspirin, which is commonly given to patients with HF due to coronary heart disease, is a prostaglandin synthesis inhibitor and therefore might interfere with the efficacy of ACE inhibitors [36].
Support for such an interaction comes from the following observations:

• Aspirin attenuates the beneficial effect of enalapril on systemic vascular resistance and cardiac output in patients with severe HF [37]. These vascular effects are not seen with enalapril plus ticlopidine, a potent antiplatelet agent that does not interact with kinin synthesis [38], or with the angiotensin II receptor blocker losartan, which also does not affect kinin metabolism [39].

• Aspirin may also offset some of the survival benefit of enalapril [40-42]. The SOLVD trial reviewed data on 6797 patients, 46 percent of whom were taking aspirin [41]. In the entire population (ie, enalapril and placebo groups), the use of aspirin significantly reduced all-cause mortality (hazard ratio 0.82, 95% CI 0.73-0.92) due to reductions in sudden death (not preceded by worsening of HF) and fatal MI (show figure 14). Among the patients receiving enalapril, there was no beneficial effect of aspirin on survival, nor was there a beneficial effect of enalapril on survival among patients receiving aspirin.

In contrast, such an interaction between aspirin and an ACE inhibitor was not noted in the Bezafibrate Infarction Prevention study [43]. Subset analysis of 464 patients in this trial who were taking an ACE inhibitor for HF found that the mortality at five years was significantly lower among those taking aspirin (24 versus 34 percent for no aspirin); this difference persisted after adjustment for confounders (relative risk 0.7, 95% CI 0.49-0.99).
Systematic reviews and a large observational series also have not demonstrated a significant effect of aspirin on the efficacy of ACE inhibitors [7,31,44]. In the meta-analysis of five trials (three post-MI and including SOLVD) involving 12,763 patients with HF or LV dysfunction described above, aspirin did not significantly affect the benefits of ACE inhibitors on mortality or the composite end point of death, heart failure, or myocardial infarction [7].
In summary, although aspirin may attenuate some of the acute hemodynamic effects of ACE inhibitors [37], most of the evidence does not support an inhibitory effect of aspirin on the long-term outcome benefits of ACE inhibitors in HF [36]. In patients with known coronary artery disease, ASA should still be used. However, there is no evidence for using aspirin in patients without coronary artery disease.
An alternative is the use of clopidogrel or ticlopidine rather than aspirin. However, since available data does not suggest that important outcomes are worse with aspirin, we do not recommend this approach because of much higher cost [1,36].
After revascularization — Although the prognosis of patients with coronary artery disease and reduced LV function is improved with revascularization, their outcome is still worse than those who have normal LV function. Since ACE inhibitors improve the outcome of patients with asymptomatic LV dysfunction, they may be of benefit after revascularization (show figure 15). The data supporting this association are presented elsewhere. (See "Long-term outcome after coronary artery bypass graft surgery", section on ACE inhibitors).
Reduced GFR — A reduced glomerular filtration rate (GFR) is associated with a worse prognosis in patients with HF, at least in part because it reflects decreased renal perfusion due to the cardiac disease. It is not known if reduced renal function reduces the beneficial effects of angiotensin converting enzyme inhibitors and other therapies for HF such as beta blockers. (See "Predictors of survival in heart failure due to systolic dysfunction", section on Reduced GFR).
Utilization — Despite the proven benefit of ACE inhibitors for reducing mortality in HF due to systolic dysfunction, many patients are not treated [15,45-49] and treated patients often receive a less than recommended dose [49,50]. This was illustrated in a review of two national surveys of the prescribing practices of office-based physicians [51]. ACE inhibitor use in patients with HF in 1990, 1995, and 2001 increased from 24 to 36 to 39 percent. These percentages may represent an underestimate of appropriate use since systolic and diastolic HF were not distinguished.
Utilization rates have been substantially higher at academic centers [46,48]. In a review of 9580 patients seen at study centers between 1996 and 1997, 80 percent of patients were treated with an ACE inhibitor; perceived intolerance was the main reason for non-use (9 percent) [48].
Cardiologists are more likely to prescribe ACE inhibitors (or angiotensin II receptor blockers) to patients with HF than other physicians. In two studies in different time periods, the respective values 46 versus 22 percent in noncardiologists in 1989 to 1994 [47] and 91 versus 72 percent with new onset HF and an LVEF ≤45 percent in 1996 to 1997 [52].
In addition to underutilization, patients receiving ACE inhibitors are often treated with doses that are less than currently recommended (see "Recommendations" below). In one series of 314 patients with HF who were readmitted to the hospital for HF over a three year period, only 22 percent of those treated with an ACE inhibitor were receiving the recommended dose of enalapril (≥20 mg/day), while the dose was ≤5 mg/day in 41 percent [50]. Renal impairment may be the most important factor responsible for the use of lower than recommended doses, especially in the elderly [49].
Prevention of HF — The efficacy of ACE inhibitors in patients with asymptomatic LV dysfunction was demonstrated in the SOLVD prevention and SAVE trials [5,6]. The SOLVD prevention trial, for example, included 4228 patients with asymptomatic LV dysfunction with an LV ejection fraction (LVEF) <35 percent [5]. The combined incidence of symptomatic HF or cardiovascular death was reduced 29 percent (95% CI 21 to 36 percent) by enalapril (30 versus 39 percent for placebo) at a mean follow-up of just over three years (show figure 16). In the XSOLVD extension of the SOLVD prevention trial, there were significant reductions in all-cause mortality (51 versus 56 percent for placebo) and cardiovascular mortality (37 versus 42 percent for placebo) at 11 years [9]. (See "Evaluation and management of asymptomatic left ventricular systolic dysfunction").
Data from a post hoc analysis of the HOPE trial suggest that ACE inhibitor therapy may reduce the risk of developing HF in high-risk patients without LV dysfunction [53]. Two prospectively defined end points (HF death and HF hospitalization) were combined with two post hoc end points (HF leading to open label ACE inhibitor use or development of signs and symptoms of HF). Ramipril significantly reduced the event rate compared with placebo (9.0 versus 11.5 percent, RR 0.77). However, it is not clear whether this benefit was a specific effect of ACE inhibition or a consequence of blood pressure reduction. (See "Choice of antihypertensive drug and blood pressure goal in patients at increased risk for a cardiovascular event").
Prevention of AF — ACE inhibitors and angiotensin II receptor blockers (ARBs) may prevent the development of new or recurrent AF in a variety of clinical settings. (See "ACE inhibitors, angiotensin II receptor blockers, and atrial fibrillation").
Such a benefit may occur in patients with left ventricular dysfunction. In an analysis from the TRACE trial of patients with left ventricular dysfunction and sinus rhythm after an acute myocardial infarction, trandolapril significantly reduced the incidence of subsequent AF (2.8 versus 5.3 percent with placebo) [54]. In an analysis of data from SOLVD, enalapril significantly reduced the incidence of subsequent AF among patients with chronic left ventricular dysfunction (5.4 versus 24 percent with placebo) [55].
Use in diastolic dysfunction — ACE inhibitors have not been as widely used in HF due solely to diastolic dysfunction. There have been concerns that peripheral vasodilatation might lead to hypotension, since diastolic filling is impaired and cardiac output possibly reduced. However, some studies have shown that ACE inhibitors may be beneficial in such patients, especially those with hypertensive heart disease or concomitant systolic dysfunction. This subject is discussed elsewhere. (See "Treatment and prognosis of diastolic heart failure", section on ACE inhibitors).
RECOMMENDATIONS — All patients with symptomatic or asymptomatic LV dysfunction (LVEF ≤40 percent), regardless of etiology, should be started on an ACE inhibitor. This approach was given a class I recommendation by a 2005 ACC/AHA task force (show table 1 and show table 3) [1] and by 2004 and 2005 task forces from the European Society of Cardiology [56,57].
It has been recommended that therapy with an ACE inhibitor should be instituted before beta blockade is implemented. However, a small study using carvedilol and perindopril suggested that initiation of the beta blocker before the ACE inhibitor results in higher tolerated doses of beta blocker and better improvements in NYHA class and left ventricular function [32].
We do not recommend a change in practice based upon this report due to the small number of patients and lack of long-term outcome data.
Dose titration — Beginning therapy with low doses (eg, 2.5 mg of enalapril BID or 6.25 mg of captopril TID) will reduce the likelihood of complications such as hypotension and azotemia [58,59]. In the screening phase of the SOLVD trial, for example, a test dose of 2.5 mg of enalapril BID produced symptomatic hypotension in 2.2 percent of almost 7500 patients with NYHA class III or IV HF; cessation of therapy for hypotension was required in only 0.5 percent of patients [58].
If initial therapy is tolerated, the dose is then gradually increased to a maintenance dose of 10 mg BID of enalapril, 50 mg TID of captopril, or up to 40 mg/day of lisinopril or quinapril unless side effects occur [1-4,6]. These relatively high doses reflect those used in the successful trials described above [1].
Although there is uncertainty if these doses are more beneficial than lower doses, maximum dose therapy, if tolerated, is recommended [1,60]. If the target doses cannot be administered or are poorly tolerated, lower doses should be used with the expectation that there are likely to be only small differences in efficacy between low and high doses [1,18]. (See "Effect of dose" above)
Race — There are conflicting data as to whether blacks have (show figure 9) [10,20,21] or do not have a lesser response to ACE inhibition than whites [19,23]. (See "Influence of race" above). Because ACE inhibitors may be beneficial and cause no harm, it is generally recommended that blacks be treated the same as whites. It is not known if higher doses of an ACE inhibitor might be more effective, although such a relationship has been noted in hypertensive patients [61].