1. Section VIII: Heart failure:
The RAS as the key to prevention and treatment
Relative risks for heart failure: Framingham Study
Content points:
• This slide summarizes the risks of heart failure determined in 5143 Framingham Heart Study participants in a 14-year follow-up.1 Hypertension, MI, angina pectoris, diabetes, left ventricular hypertrophy, and valvular heart disease were identified as independent risk factors for heart failure.
• Hypertension is the most frequently encountered risk for heart failure, found in 91% of cases. Men with hypertension were more than twice as likely to develop heart failure and women with hypertension were more than three times as likely to develop heart failure than people without hypertension.
• Women with diabetes had a nearly four-fold increase for heart failure than those without diabetes, which was much greater than in men with diabetes.

2. Progression of hypertension to LVH and heart failure
Content points:
• The two principal factors contributing to heart failure are hypertension and coronary artery disease. Of the two, hypertension is more common.
• Hypertension is frequently the initial step in the pathophysiologic progression to heart failure, which is a complex syndrome that involves a variety of linked hemodynamic and metabolic changes.2
• Left ventricular hypertrophy and associated left ventricular dysfunction are among the most common cardiac sequelae of hypertension.
• Left ventricular hypertrophy leads to congestive heart failure (CHF) through a variety of mechanisms. At first, mild left ventricular hypertrophy allows the heart to compensate for increases in vascular resistance. In time, however, the increase in left ventricular wall thickness and left ventricular remodeling lead to diastolic dysfunction and subsequently to systolic dysfunction.
• In addition to pressure-related mechanical strain, pathologic changes that are a direct result of stimulation of the RAS contribute to left ventricular hypertrophy.
• Clinically overt heart failure develops when the hypertrophied left ventricle can no longer maintain its output. The downward spiral of ventricular dilation and symptomatic disease begins.
• The structural and functional changes associated with hypertension and the development of left ventricular hypertrophy occur over decades and are preventable with effective treatment.

3. Mechanisms of disease progression in heart failure
Content points:
• Chronic heart failure is a complex syndrome involving activation of multiple cellular, metabolic, and neurohumoral pathways.3
• The benefits of blocking activated neurohumoral vasoconstrictor systems in CHF are now well recognized. This has been supported by the success of treatment strategies involving blockade of the renin-angiotensin system (RAS), specifically with ACE inhibitors, and the sympathetic nervous system, specifically with b-blockers.
• Recently, further understanding of other key systems involved in pathophysiologic responses to myocardial injury related to the progression of CHF have led to promising new avenues of pharmacologic intervention. Other than the RAS, the most advanced new strategy is inhibition of the endothelin system, which is intimately involved in CHD disease progression.
• Activation of a number of key proinflammatory cytokines that contribute to progression of CHF. The best characterized are tumor necrosis factor alpha (TNF-a) and endothelin (ET).
• In the future, blockade of multiple pathways may be involved to maximize the therapeutic benefit of intervention. New drug strategies in addition to ACE inhibition and b-blockade are currently in various stages of development.

4. Aims of heart failure management and therapeutic approaches
Content points:
• In the past 15 years, several large-scale, randomized controlled trials have revolutionized the management of patients with heart failure. Although some drugs clearly improve symptoms, others offer both symptomatic and prognostic benefits. Today, the management of heart failure should be aimed at improving both quality of life and survival.4,5
• Diuretics and ACE inhibitors remain the basis of treatment in patients with CHF.
• Diuretics provide symptomatic relief and remain first-line treatment, particularly in the presence of edema. Nevertheless, there is no evidence that loop and thiazide diuretics improve prognosis in patients with CHF.
• ACE inhibitors have been shown to decrease morbidity and mortality in virtually all types of heart failure in large-scale, prospective clinical trials. ACE inhibitors are indicated in all stages of symptomatic heart failure resulting from impaired systolic dysfunction.
• Digoxin improves symptoms and exercise capacity, and results in fewer hospital admissions.
• b-Blockers (carvedilol, metoprolol, and bisoprolol) improve symptoms and survival in stable patients who are already receiving ACE inhibitors.
• Nitrates and hyralazine improve survival in symptomatic patients intolerant of ACE inhibitors (or angiotensin receptor antagonists).
• The potential benefit of spironolactone in reducing mortality is now increasingly recognized.
• These treatments are discussed in greater detail on the upcoming slides.

5. ACE inhibitors in post-MI patients with LV dysfunction or heart failure
Content points:
• A growing body of data confirms the relationship between ischemia and heart failure and the benefits of ACE inhibitor treatment in a broad range of high-risk patients. The use of ACE inhibitors for both secondary prevention and treatment of heart failure has been clearly established.6,7
• When added to diuretics, ACE inhibitors improve symptoms, exercise tolerance, and survival and reduce hospital admission rates in CHF. ACE inhibitors reduce afterload, preload, and systolic wall stress, making them favorable in patients with systolic dysfunction; cardiac output increases without an increase in heart rate.
• Large scale, randomized controlled trials of ACE inhibitors, including the Acute Infarction Ramipril Efficacy (AIRE) study, the Survival and Ventricular Enlargement (SAVE) study with enalapril, and the trial of Trandolapril Cardiac Evaluation (TRACE) have shown lower mortality in patients with impaired systolic dysfunction after MI. 8-10
• In SAVE, AIRE, and TRACE, mortality was reduced significantly by 19%, 27%, and 18%, respectively.
• In AIRE, ramipril 10 mg reduced the risk of sudden death by 30% (P = 0.011). The mortality reduction was apparent at 30 days and consistent across all subgroups. In TRACE, the mortality curve diverged early and continued to diverge throughout the trial.8

6. ACEI benefits post-AMI patients with heart failure: AIRE, TRACE, SAVE
Content points:
• A prospective overview of data from three trials that enrolled patients within a week after acute MI, including AIRE, TRACE, and SAVE, showed that patients who took ACE inhibitors had a lower mortality than patients who took placebo. In the three trials, there were 702 deaths among 2995 patients taking ACE inhibitors (23.4%) vs 866 among 2971 patients taking placebo (29.1%), representing a risk reduction of 26% (P < ).
• Among patients taking ACE inhibitors 355 patients (11.9%) were readmitted to the hospital with heart failure vs 460 patients (15.5%) taking placebo, representing a 27% reduction in risk (P < ).
• In the ACE inhibitor group, reinfarction occurred in 324 patients (10.8%) compared with 391 patients (13.2%) of patients taking placebo, representing a reduction of 20% (P < ).
• The benefits were observed early after the start of therapy and persisted long term. The benefits were independent of other variables, such as age, sex, and baseline use of diuretics, aspirin, and b-blockers.
• The data suggest that even among patients with relatively preserved ejection fractions there is a clinically important benefit of ACE inhibition.6
• ACE inhibitors are thought to exert their beneficial effects after MI by favorably modifying functional and structural changes in the myocardium that occur in response to myocardial damage and necrosis (remodeling). There may be other important benefits from long-term ACE inhibition on the arterial vessel wall, as indicated by prevention of MI that appears to be independent of ejection fraction.6

7. AIREX: ACEI benefits long-term survival in patients with post-AMI
heart failure
Content points:
• Three years after the AIRE study was completed, the AIREX study assessed the long-term magnitude, duration, and reliability of the survival benefits observed in AIRE after treatment with ramipril (target dose 5 mg twice a day) for 15 months.11
• AIREX investigated the mortality status of all 603 patients in the AIRE Study. Through government records they confirmed the death or survival of all 603 patients exactly 3 years after the close of the AIRE Study. Follow-up was for a minimum of 42 months and a mean of 59 months. The average duration of treatment was 13.4 months for placebo and 12.4 months for ramipril.
• On long-term follow up, death from all causes occurred in 117 (38.9%) of 301 placebo patients and 83 (27.5%) of 302 ramipril patients, representing a relative risk reduction of 36% (95% CI 15-52%; P = 0.002) and an absolute reduction in mortality of 11.4% (114 additional 5-year survivors per 1000 patients treated for an average of 12.4 months).
• Clinical summary:
The findings of AIREX provide strong evidence that administration of
ramipril to patients with heart failure after AMI results in a survival
benefit that is large in magnitude and sustained over many years.

8. b-blockers in heart failure: Key clinical trials
Content points:
• Evidence from recent clinical trials supports the use of b-blockers in CHF. These include the US Carvedilol heart failure study, the Metoprolol CR/XL Randomized Intervention Trial in Congestive Heart Failure (MERIT-HF), and the Cardiac Insufficiency Bisoprolol Study II (CIBIS-II). All patients in the trials were receiving the standard therapy of an ACE inhibitor and a diuretic with or without digoxin.12-14
• In the US Carvedilol heart failure study (n = 1094), the average age of patients was 58 years and the mean left ventricular ejection fraction was 22%. Carvedilol recipients had a 65% lower risk of death, mainly manifested as decreases in sudden cardiac death and death from progressive heart failure. Cardiovascular mortality was reduced by 63% and cardiovascular hospitalizations by 27%. The average carvedilol dose was 45 mg/day, while the targeted dose was 25 to 50 mg twice a day.12
• MERIT-HF investigated the used of oral extended-release metoprolol succinate to treat CHF. The trial included patients mainly with NHYA class II-III heart failure (77%) and left ventricular ejection fraction of about 28%. The mean daily metoprolol dose was 159 mg/day, with 64% of patients receiving the targeted dose of 190 mg metoprolol succinate (equivalent to 200 mg metoprolol tartrate). The metoprolol group had a 34% lower risk of death, and reductions of 38% in cardiovascular deaths and 41% in sudden deaths.13
• In CIBIS-II (n = 2647), the population consisted of patients with NYHA class III or IV heart failure. The risk of death in the bisoprolol group was 33% lower than the placebo group. Patients taking bisoprolol also had risk reductions of 29% in cardiovascular deaths, 20% in hospitalizations for all causes, 44% in sudden death. The targeted dose of bisoprolol 10 mg was reached by 57% of recipients.13
• These trials indicate that benefit is probably a class effect of b-blockers. Thus, treatment with carvedilol, bisoprolol, or metoprolol can be recommended.15

9. RALES: Aldosterone receptor blockade improves outcomes in severe heart failure
Content points:
• In the Randomized Aldactone Evaluation Study (RALES) investigators studied the effect of blocking aldosterone in patients with CHF.16 The RALES study enrolled 1663 patients who had severe heart failure and a left ventricular ejection fraction of 35% and who were being treated with an ACE inhibitor, a loop diuretic, and in most cases digoxin. They randomly administered 25 mg or spironolactone daily to 822 patients, while 841 received placebo.
• The trial was discontinued early, after 24 months, because an interim analysis showed that there was a 30% reduction in the risk of death in the spironolactone group compared with the placebo group (P < 0.001). There was 386 deaths in the placebo group (46%) and 284 in the spironolactone group (35%).
• This significant reduction in the risk of death in the spironolactone group was attributed to a lower risk of both death from progressive heart failure and sudden death from cardiac causes.
• The frequency of hospitalization for worsening heart failure was 35% lower in the spironolactone group than in the placebo group (P < 0.001). Patients who received spironolactone had a significant improvement in heart failure symptoms (P < 0.001).
• Gynecomastia, or breast pain, was reported in 10% of men who were treated with spironolactone, as compared with 1% in the placebo group (P < 0.001). The incidence of serious hyperkalemia was minimal in both groups of patients.
• As this study shows, blockade of aldosterone receptors by spironolactone, in addition to standard therapy, substantially reduces the risk of morbidity and death among patients with severe heart failure.

10. ACE inhibition improves vascular flow in heart failure by
increasing NO
Content points:
• Varin et al investigated the effects of long-term ACE inhibition on flow-mediated dilation in a rat model of CHF induced by coronary artery ligation.17 One group of the rats with CHF was treated with perindopril for 10 weeks.
• Flow was measured at basal conditions and in the presence of the NO synthase (NOS) inhibitor L-NA in femoral arteries isolated from treated and untreated CHF rats and controls.
• In arteries isolated from the control rats, flow-mediated dilation was abolished by the NOS inhibitor L-NA. In untreated CHF rats, L-NA had no impact on flow-mediated dilation. In the CHF rats treated with perindopril, flow-mediated vasodilation was abolished by the NOS inhibitor L-NA.
• Thus, the effect of ACE inhibition in heart failure seems to involve a normalization of NO bioavailability that may be partly related to a normalization of NOS expression by the endothelium.
• An improvement of flow-mediated vasodilatation by ACE inhibitors may contribute to their beneficial effects in patients in CHF.

11. ACE inhibition reduces QT dispersion in patients with acute MI
and heart failure
Content points:
· Increased QT dispersion following acute MI has been associated with a higher risk of ventricular arrhythmias. In the AIREX study, QT dispersion was an independent predictor of survival in patients with acute MI complicated by heart failure.18
• Spargias et al studied the effects of ramipril on QT dispersion in a cohort of 67 patients from the AIRE study.19
• Ramipril therapy was associated with a significant reduction in QT dispersion over a 2-month period after acute MI.19 Patients allocated to placebo had a slight increase over the same period.
• This reduction of QT dispersion produced by ACE inhibition after acute MI indicates an antiarrhythmic effect and may be an important additional mechanism for the reduced incidence of all-cause mortality and sudden death achieved with ACE inhibition after acute MI.

12. LVH regression: Changes in left ventricular mass index
with 4 drug classes
Content points:
• This study by Schmieder et al was a meta-analysis of 50 double-blind, randomized, controlled clinical trials that evaluated reduction of left ventricular mass with placebo and various antihypertensive agents including diuretics, b-blockers, calcium channel blockers, and ACE inhibitors.20
• Left ventricular mass index was decreased by 12% with ACE-inhibitors (95% confidence interval (CI): 9.0%-14.5%), by 11% with calcium channel blockers (95% CI: 7.8%-13.7%), by 5% with b-blockers (95% CI: 1.2%-7.3%) and by 8% with diuretics (95% CI: 3.9%-11.1%) (overall P < 0.01).
• ACE inhibitors and calcium channel blockers were more effective than b-blockers in reducing left ventricular mass index, with diuretics in the intermediate range. Similar differences between drug classes were found with regard to effect on left ventricular wall thickness (P < 0.05).

13. ATLAS: High-dose ACEI reduces adverse outcomes in patients with
heart failure
Content points:
• The Assessment of Lisinopril And Survival (ATLAS) study was a multicenter, randomized, double-blind trial in which patients with or without previous ACE inhibitor treatment were given medium-dose lisinopril (12.5 or 15.0 mg once a day ) for 2 to 4 weeks and then randomized to high-dose (35.0 or 32.5 mg once daily) or low-dose (5.0 or 2.5 mg once a day) groups. They study included patients with NYHA functional class II to IV CHF and left ventricular ejection fractions of no greater than 30% (N = 3164). They were followed-up for a median of 46 months.21
• The group receiving high-dose ACE inhibitor therapy had a decline of 10% in cardiovascular mortality (P = 0.07), a 12% decrease in death or hospitalization for any reason (P = 0.002), a 16% decline in cardiovascular hospitalizations (P = 0.05), and a 24% decline in hospitalizations for heart failure (P = 0.002).
• There was an 8% difference between the groups in death from all causes, but it was not statistically significant.
• The results support the use of high-dose ACE inhibitor therapy in patients with heart failure. The study also demonstrates that this therapy is safe and well tolerated.

14. ATLAS: High-dose ACEI is well tolerated
Content points:
• Treatment with ACE inhibitors reduces mortality and morbidity in patients with CHF, but many patients are not receiving these agents or are receiving doses lower than those found to be optimal in trials, primarily because of concerns about the safety and tolerability.22
• The ATLAS study examined the safety and tolerability of high-dose compared with low-dose lisinopril in CHF.
• Of 405 patients who had not previously been treated with an ACE inhibitors, 95.8% tolerated the medium dose.
• More than 90% of patients in the high- and low-dose groups were titrated to their target dose, and the mean doses in both groups remained similar throughout the study.
• Withdrawals occurred in 27.1% of the high-dose group and 30.7% of the low-dose group.
• Those patient subgroups that are presumed to be at higher risk for ACE inhibitor intolerance (systolic blood pressure <120 mm Hg, creatinine, 1.5 mg/dL, age 70 years; and patients with diabetes) generally tolerated the high-dose strategy.
• These findings demonstrate that ACE inhibitor therapy in most patients with CHF can be successfully titrated to high doses and maintained at this level over long-term treatment, and that more aggressive use of these agents is warranted to achieve optimal benefits from treatment.

15. ACE inhibitors in heart failure: Conclusions
Content points:
• Heart failure treatment has evolved to a combined prevention and symptom management strategy.
• ACE inhibitors are a highly significant part of the recommended treatment management of heart failure. ACE inhibitors are recommended as monotherapy for management of early-stage heart failure due to left ventricular dysfunction. For more severe cases, a regimen consisting of an ACE inhibitor, diuretic, and b-blocker is indicated. Digoxin can be added to therapy in selected patients to improve clinical symptoms and reduce the number of hospitalizations.23
• The ATLAS trial demonstrated that dose optimization is important to achieve the maximum benefit. Patients on high doses of ACE inhibitor achieve better long-term morbidity and mortality outcomes than those on low doses.21 In addition, optimization of ACE inhibitors doses can greatly improve rehospitalization rates and significantly lower cost of care in a heart failure management program.24
• Underutilization of ACE inhibitors due to concerns for adverse events such as hypotenion, hypokalemia, and effects on renal function, and excess cough still exist. Results of the ATLAS study show that most patients tolerate high doses over long-term treatment with no excess in adverse outcomes, even in patients who are frequently considered to be a risk for such effects of ACE inhibition.22

16. Comparative RAS and fibrinolytic effects of ACE inhibition and ARBs
Content points:
• Clinical and basic science research has repeatedly confirmed the importance of the RAS in the pathophysiology of heart failure. Most evidence of the benefit of blocking the RAS has accumulated from studies with ACE inhibitors and blockade of this system has assumed a central role in the treatment of heart failure. Some beneficial effects of ACE inhibitors may be shared by angiotensin II type-1 receptor blockers (ARBs), although there are distinct differences between the two drug classes.25
• In the RAS, ACE inhibitors decrease angiotensin II and have no effect on angiotensin II formed by alternate pathways. Importantly, ACE inhibitors increase levels of bradykinin.
• Among their effects on the RAS, ARBs block the activity of the AT1 receptor and the formation of angiotensin II by alternate pathways. They have no effect on bradykinin levels.
• Experimental evidence demonstrates that PAI-1 is stimulated by angiotensin II, whereas tPA is activated by bradykinin. ACE inhibition decreases PAI-1 and increases tPA levels. In contrast, ARBs have no effect on PAI-1 levels and they decrease tPA.26

17. RESOLVD: ARB vs or plus ACEI in heart failure
Content points:
• The role of ARBs as an alternative to ACE inhibitors or as an additional means of treatment of patients with heart failure has been evaluated in recent trials. The Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) study was a pilot study, lasting 43 weeks, to investigate the effects of the ARB candesartan alone, enalapril alone, or their combination in patients with congestive heart failure.27 RESOLVD studied the effect of increasing levels of neurohormonal blockade. The study compared enalapril (20 mg/day), candesartan (4, 8, or 16 mg/day), or candesartan plus enalapril (4 or 8 mg plus 20 mg/per day) in 768 patients.
• The study participants had NYHA class II to class IV heart failure, ejection fractions of less than 40%, and a 6-minute walk distance of 500 meters or less. At the conclusion of the study, there were no differences among groups with regard to 6-minute walk distance, NYHA-functional class, or quality of life.
• Clinical events including death, hospitalization for heart failure, any hospitalization, and their combinations were not significantly different among the three treatment groups. However, the mortality rate of 3.7% in patients taking enalapril was much lower than that of the two other groups.

18. ELITE II: ARB vs ACEI in heart failure
Content points:
• The Evaluation of Losartan in the Elderly II (ELITE II) study) was a follow-up to the ELITE pilot study, enrolling 722 patients, in which losartan was associated with lower mortality than captopril. ELITE II was undertaken to confirm the result of ELITE in a larger and more conclusive trial.28,29
• ELITE II enrolled 3152 patients aged 60 and older with NYHA class II to class IV heart failure and ejection fractions of 40% or less. Subjects received captopril 50 mg three times a day (n = 1574) or losartan 50 mg daily (n = 1578). Follow-up was planned until 510 deaths occurred, expected to be about 2 years.28
• Mortality and sudden cardiac death or resuscitated cardiac arrest did not differ significantly between groups. The rate of all-cause mortality was 11.7% with losartan vs 10.4% with captopril, a 12% reduction (P = 0.16). The rate of sudden death or resuscitated arrests was 9.0 % with captopril vs 7.3%, a 20% reduction (P = 0 .08). The combined end point of total mortality or hospital admission for any reason was 44.9% with captopril vs 47.7% with losartan (P = 0.18).
• Significantly fewer patients in the losartan group discontinued study treatment because of adverse effects (P < 0.001), including cough.
• Losartan did not prove superior to captopril in improving survival in elderly patients with chronic symptomatic heart failure and systolic left-ventricular dysfunction, as suggested by ELITE, although it appeared to be equally as effective.

19. ACE inhibitors vs ARBs in heart failure: RESOLVD, ELITE, ELITE II
Content points:
• An overall analysis of the data from RESOLVD, ELITE, and ELITE II on mortality and hospitalizations showed that while differences were not statistically significant, trends favor ACE inhibition rather than AT type 1 receptor blockade for the treatment of patients with heart failure.27-29
• The combined results of data on mortality and hospitalizations from the two losartan trials, ELITE and ELITE II, similarly favor the use of ACE inhibition in the treatment of patients with heart failure.

20. Val-HeFT: ARB vs usual therapy in heart failure – study overview
Content points:
• The Valsartan Heart Failure Trial (Val-HeFT) was a large-scale, double-blind, placebo-controlled trial examining the effect on morbidity and mortality of the ARB losartan. The study included 5010 patients from 300 centers in the US and Europe.30
• Patients had NYHA functional class II (62%), III (36%), or IV (2%) heart failure, ejection fractions of < 40%, and left ventricular diastolic transverse diameters of >2.9 cm/m2.
• At baseline most patients were taking standard therapy including ACE inhibitors (93%), diuretics (86%), b-blockers (36%), and digoxin (67%).
• Patients were randomly assigned to valsartan titrated from 40 mg twice a day to 160 mg twice a day, or placebo. The drug was well tolerated, with an average dose achieved of 254 mg/day.
• Follow-up was planned until 906 deaths occurred.

21. Val-HeFT: Primary outcomes analysis
Content points:
• The primary outcomes of the Val-HeFT study was all-cause mortality, and combined all-cause mortality plus morbidity, which included hospitalization for heart failure, cardiac arrest with resuscitation, or need for intravenous support for worsening heart failure.30
• After 2 years of follow up, analysis of the data showed no effect of valsartan on all-cause mortality. However, there was a statistically significant risk reduction of 0.87 (95% confidence interval 0.79, 0.96) in the combined outcome of all-cause morbidity and mortality, or a 13% decline (P = 0.009).

22. Val-HeFT: Combined morbidity/mortality in subgroups
Content points:
• A subgroup analysis of the Val-HeFT data provided insights into the effects of valsartan on the combined outcome of all-cause morbidity and mortality in patients taking ACE inhibitors and in patients taking b-blockers.
• In the 7% of patients who were not taking ACE inhibitors, treatment with valsartan was associated with a 45% reduction in the combined outcome of all-cause morbidity and mortality.30
• In contrast, patients on an ACE inhibitor showed only a 13.3% reduction in the combined outcome following added treatment with valsartan.
• The differential effect was even more dramatic in the group taking b-blockers. Those who were not taking a b-blocker exhibited a substantial benefit from valsartan treatment, but among those on b-blockers the trend was toward a negative effect with valsartan.
• Further subgroup analysis showed that the negative outcome seen among those taking a b-blocker was present only in patients who were also taking an ACE inhibitor. However, the analysis may be influenced by the fact that the number of patients was small.

23. Val-HeFT: Summary
Content points:
• Overall, valsartan had a neutral effect on mortality, but significantly reduced combined morbidity and mortality by 13.3%.
• Heart failure hospitalizations were reduced by 27.5% and patients had improved NYHA functional class, ejection fraction, and signs and symptoms of heart failure.30
• Subgroup analysis confirms significant benefits in those patients who were not taking any neurohormonal therapy, or who were taking either an ACE inhibitor or a b-blocker.
• In particular, benefits of valsartan were greatly increased among the 7% of the patients in the study who were not taking an ACE inhibitor.
• A subgroup analysis of the data suggests that the combination of an ACE inhibitor and a b-blocker and valsartan may exert an unfavorable effect. But this requires further clarification, since only small number of patients was involved, which may affect the statistical outcome.

24. ACEI + ARB vs ACEI monotherapy in heart failure
Content points:
• Several trials have evaluated the result of combining ACE inhibition with ARBs in patients with heart failure. This combination theoretically provides the most complete and sustained blockade of the angiotensin system, while still affecting the bradykinin system favorably.30
• In small-scale studies, combination therapy consistently showed superior results to ACE inhibitor monotherapy with regard to exercise tolerance,31,32 hemodynamic effects,33 and neurohormonal activation.27,34,35
• In the study by Hamroff et al, more than half the patients receiving combination therapy (9/16) had improvement of at least one NYHA class, compared with only 1 of 17 patients receiving ACE inhibitors alone.32
• Houghton et al found that the combination of losartan and ACE inhibition increased exercise tolerance more than ACE inhibition alone.33
• Baruch et al found that the addition of valsartan reduced plasma aldosterone levels and had favorable hemodynamic effects in patients with heart failure.34
• Guazzi et al found that combination therapy greatly improved oxygen consumption at peak exercise (VO2).35 Reductions in plasma norepinephrine and aldosterone levels were significantly greater with both enalapril and losartan than with either agent alone.
• In the RESOLVD pilot study, McKelvie et al27 observed that although the clinical outcomes data were not statistically significant (see slide 211), combination therapy was superior to monotherapy in preventing left ventricular dilatation and benefiting ejection fraction. However, combination therapy was the only one to have decreased exercise tolerance at 18 and 43 weeks.30

25. ACE inhibitors vs ARBs in heart failure: Clinical summary
Content points:
• The use of ACE inhibitors remains the standard of care in patients with heart failure.31
• In patients intolerant of an ACE inhibitor, ARBs can provide a safe and effective alternative therapy.30,31
• At present, the most promising area in which ARBs may assume a role as first-line therapy as part of a combination with ACE inhibitors.31
• However, for patients who are already taking an ACE inhibitor and a b-blocker, the additional of a third neurohormonal antagonist has no benefit on morbidity and mortality and may be contraindicated.30

26. Ongoing ARB morbidity and mortality trials in patients with HF or LV dysfunction post-MI
Content points:
• A number of studies now under way should further define the role of ARBs, including as combination therapy with ACE inhibitors in patients with heart failure and left ventricular dysfunction:
– Optimal Therapy in Myocardial Infarction with the Angiotensin II Antagonist Losartan trial (OPTIMAAL)36
– Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)37
– Valsartan in Acute Myocardial Infarction Trial (VALIANT)38
• OPTIMAAL will compare losartan vs captopril in 5000 post-MI patients with clinical signs of heart failure and/or a left ventricular ejection of less than 35%, left ventricular interior diameter (LVID) greater than 6.5 cm and/or anterior Q wave infarction or reinfarction.36 The primary end point is all-cause mortality. The study will continue until 937 deaths have been reached.
• CHARM consists of three independent, parallel, placebo-controlled studies in patients with (1) left ventricular ejection fraction less than or equal to 40%, ACE-inhibitor treated, (2) left ventricular ejection fraction less than or equal to 40% and ACE-inhibitor intolerant, and (3) left ventricular ejection fraction greater than 40%, not treated with ACE inhibitors.37 The three studies will be combined to evaluate the effect of candesartan on all-cause mortality in the broad spectrum of symptomatic heart failure. The primary objective in each trial is to evaluate the effects on the combined endpoint of cardiovascular mortality or CHF hospitalization.
• VALIANT will investigate the role of valsartan plus captopril, as well as valsartan and captopril as monotherapy, in the management of patients with MI associated with heart failure and/or left ventricular dysfunction.38 The outcomes of VALIANT include all-cause mortality and morbidity. The use of a proven dose of captopril and the comparator arms with valsartan alone or in combination with captopril provides a unique test of whether the ARB can make an additional improvement in clinical outcomes beyond ACE inhibitors.