The efficacy of valsartan in essential hypertension and its effects on left ventricular hypertrophy

Recent studies demonstrate that, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin-II receptor blockers may decrease left ventricular hypertrophy (LVH) in hypertensive patients. We wanted to assess the efficacy of valsartan on echocardiographic variables of LVH in 30 mild to moderate hypertensive patients. Valsartan was found effective in controlling hypertension, also echocardiographic indices of LVH such as interventricular septum and posterior wall thickness were reduced and left ventricular mass decreased significantly. Thus valsartan favorably influences cardiac structure in hypertensive patients.     

Angiotensin-converting enzyme inhibitors in congestive heart failure

Angiotensin-converting enzyme inhibitors have had a significant impact on the treatment of congestive heart failure (CHF). Hemodynamic and clinical improvements in patients with severe CHF fostered the use of angiotensin-converting enzyme inhibitors in mild to moderate CHF. Angiotensin-converting enzyme inhibitors produce acute and sustained improvements in ventricular hemodynamics and quality of life. Captopril plus diuretic therapy is an effective alternative to digoxin in patients with mild to moderate CHF. Enalapril maleate and lisinopril have been shown to be effective in moderate to severe CHF when combined with digoxin and diuretics. Captopril and enalapril also improve survival in selected patients; captopril attenuates left ventricular dilatation after myocardial infarction. Although all angiotensin-converting enzyme inhibitors are similar in mechanism of action, pharmacokinetic differences impact their clinical use. Prolonged symptomatic hypotension compromising systemic perfusion and organ function has been reported with longer-acting agents; hypotension is usually short-lived and rarely compromises organ function with shorter-acting agents.     

Baseline demographics of the Valsartan Heart Failure Trial. Val-HeFT Investigators

BACKGROUND: The Valsartan Heart Failure Trial (Val-HeFT) is the first large-scale randomized, multinational clinical study to assess the efficacy and safety of valsartan, an angiotensin II receptor blocker, added to conventional therapy, including angiotensin-converting enzyme inhibitors, in heart failure patients. A total of 5010 patients with an ejection fraction <40% have been randomized to either valsartan titrated to 160 mg b.i.d. or to placebo. AIMS: Baseline characteristics of patients in Val-HeFT are presented and compared with other major clinical trials in heart failure. METHODS: Baseline data were collected and summary statistics calculated. RESULTS: The study population has a mean age of 62.7 years and is 80% male, 90.3% white, 6.9% black, and 2.8% Asian. Antecedent coronary heart disease is reported in 57.2% of patients. Angiotensin-converting enzyme inhibitors are prescribed for 92.7% of patients, diuretics for 85.8%, digoxin for 67.3%, and beta-blockers for 35.6%. Subgroup comparisons by age, sex, race and ejection fraction quartile show small differences in baseline characteristics. CONCLUSION: Overall the Val-HeFT population is generally representative of the population of patients with mild to moderate heart failure in industrialized countries.     

Effect of valsartan on quality of life when added to usual therapy for heart failure: results from the Valsartan Heart Failure Trial

BACKGROUND: The effect on quality of life (QOL) of valsartan administered in addition to prescribed background heart failure therapy was assessed as a secondary endpoint in the Valsartan Heart Failure Trial (Val-HeFT). METHODS AND RESULTS: QOL was assessed in 3010 patients receiving either valsartan (160 mg twice daily) or placebo in addition to prescribed background therapy (beta-blockers or angiotensin-converting enzyme inhibitors), using the Minnesota Living with Heart Failure (MLWHF) questionnaire. Treatment differences were compared at intervals to 36 months after randomization and at endpoint (last observation) using analysis of covariance and repeated measures mixed-effects, and at endpoint using a Mantel-Haenszel chi-squared test. Scores lower than baseline were indicative of improved QOL. Valsartan had a significant beneficial effect on the least-square mean change in overall MLWHF score from baseline to study endpoint (+/- standard error) (average followup 23.0 months) compared with placebo (0.19 +/- 0.47 versus 1.94 +/- 0.48; P = .005 respectively). The placebo group was characterized by a deterioration in QOL as the trial progressed. More patients on valsartan reported a clinically meaningful improvement in MLWHF score (a decrease of > or =5 points) than on placebo (34.0% versus 30.2%). CONCLUSION: Valsartan compared to placebo added to prescribed therapy slows progressive worsening of QOL in patients with heart failure.     

Sacubitril/Valsartan: The Newest Addition to the Toolbox for Guideline-Directed Medical Therapy of Heart Failure

Sacubitril/valsartan combines a neprilysin inhibitor with an angiotensin receptor blocker. As an inhibitor of neprilysin, an enzyme that degrades biologically active natriuretic peptides, this first-in-class therapy increases levels of circulating natriuretic peptides, resulting in natriuretic, diuretic, and vasodilatory effects. In patients with chronic New York Heart Association class II-IV heart failure with reduced ejection fraction, the PARADIGM-HF trial demonstrated that sacubitril/valsartan significantly reduced the primary endpoint of cardiovascular mortality and heart failure hospitalization, compared with enalapril. The rate of all-cause mortality was also significantly reduced. Subsequently, the American College of Cardiology/American Heart Association/Heart Failure Society of America recently updated guideline recommendations for Stage C patients with heart failure with reduced ejection fraction to recommend angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or sacubitril/valsartan in conjunction with other evidence-based therapies to reduce morbidity and mortality. Several analyses have suggested the cost-effectiveness of this new therapy. To ensure tolerability, initiating the lower dosage form of sacubitril/valsartan is warranted in patients with severe renal impairment, moderate hepatic impairment, and low blood pressure, and close monitoring is warranted in such patients. A 36-hour washout period is recommended when switching patients from an angiotensin-converting enzyme inhibitor to sacubitril/valsartan. Similarly, sacubitril/valsartan is contraindicated in patients receiving concomitant angiotensin-converting enzyme inhibitor or angiotensin receptor blocker and those with a history of angioedema.     

Effect of valsartan added to background ACE inhibitor therapy in patients with heart failure: results from Val-HeFT

AIMS: To investigate the effect of valsartan in the Valsartan-Heart Failure Trial (Val-HeFT) when added to angiotensin-converting enzyme inhibitor (ACEi) alone in patients with heart failure (HF). METHODS: Subjects in Val-HeFT receiving ACEi but not beta-blocker at baseline were analysed; 1532 were assigned to valsartan and 1502 assigned to placebo. Primary outcome events (all-cause mortality, hospitalisation for adjudicated heart failure, sudden death with resuscitation and need for >4 h of parenteral therapy for worsening heart failure) were monitored. RESULTS: Mortality was not affected by valsartan but morbidity endpoints were significantly reduced (36.3% in placebo, 31.0% in valsartan, p=0.002) in patients receiving an ACEi but no beta-blocker. Quality of life (QOL) was significantly improved, ejection fraction (EF) significantly increased, left ventricular (LV) diameter significantly reduced and plasma B-type natriuretic peptide, norepinephrine and aldosterone levels significantly reduced with valsartan compared to placebo. The morbidity benefit was significant in patients on ACEi doses below the median (22% reduction, p=0.003) and not statistically significant in those receiving ACEi doses above the median (14% reduction, p=0.143). CONCLUSION: Valsartan reduces heart failure hospitalisations and slows LV remodelling in patients treated with an ACEi in the absence of beta-blockade, particularly in those on lower doses of ACEi.     

Valsartan in acute myocardial infarction trial (VALIANT): rationale and design

BACKGROUND: Survivors of acute myocardial infarction (MI) complicated by heart failure and/or resulting in left ventricular dysfunction are at heightened risk for subsequent death and major nonfatal cardiovascular events. Inhibition of the renin-angiotensin system with an angiotensin-converting enzyme inhibitor has consistently been demonstrated to result in reductions in these risks by approximately 20%. The development of angiotensin II receptor blockers offers a new, more specific, and theoretically more complete pharmacologic mode to inhibit the adverse influence of angiotensin II. METHODS: Valsartan in Acute Myocardial Infarction (VALIANT) is a multicenter, double-blind, randomized, active controlled parallel group study comparing the efficacy and safety of long-term treatment with valsartan, captopril, and their combination in high-risk patients after MI. The trial is designed with 3 arms, giving equal statistical consideration to survival comparisons of captopril versus the angiotensin II receptor blocker valsartan, as well as the combination of captopril plus valsartan, compared with a proven effective dose of captopril. This 14,500-patient trial is designed with an 86% power to detect a 15% reduction in mortality rate with either use of valsartan compared with captopril. The trial encourages optimal individualization of other proven therapies in acute and chronic infarction, and the international patient body ensures good representation of multiple practice patterns. CONCLUSION: VALIANT is a large international investigative effort that will evaluate the role of valsartan in the management of patients with MI associated with heart failure and/or left ventricular dysfunction. 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 angiotensin II receptor blocker can make an additional improvement in clinical outcomes beyond angiotensin-converting enzyme inhibitors.     

Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors

OBJECTIVES: A subgroup analysis of the Valsartan Heart Failure Trial (Val-HeFT) was performed to evaluate the effects of the angiotensin II receptor blocker, valsartan, in the patients with chronic heart failure (HF) not receiving angiotensin-converting enzyme (ACE) inhibitors. BACKGROUND: The ACE inhibitors reduce mortality and morbidity in patients with HF. Nonetheless, nearly 20% of potentially eligible patients may not be prescribed ACE inhibitors. RESULTS: Val-HeFT was an international, randomized, double-blinded trial that compared valsartan with placebo when added to the prescribed treatment of patients with HF. The two primary end points of the study were all-cause mortality and the composite of all-cause mortality and morbidity (sudden death with resuscitation, hospital admission for HF, or administration of intravenous inotropic or vasodilator drugs for >or=4 h without hospital admission). Of the 5,010 patients enrolled in the trial, 366 (7.3%) were not treated with ACE inhibitors at baseline. The effects of valsartan on the primary and secondary end points of the study were assessed in this subgroup of patients. RESULTS: Both all-cause mortality and combined mortality and morbidity for patients not treated with ACE inhibitors were significantly reduced in the valsartan treatment group compared with the placebo group (17.3% vs. 27.1%, p = 0.017 and 24.9% vs. 42.5%, p < 0.001, respectively). Consistent with the data on clinical events, patients randomized to valsartan showed improvements in physiologic variables, such as ejection fraction, left ventricular internal diameter in diastole, and plasma neurohormone levels. Permanent discontinuation of study treatment because of adverse experiences was comparable between the two groups. CONCLUSIONS: Val-HeFT has provided the first placebo-controlled outcome data demonstrating a favorable effect of an angiotensin receptor blocker on mortality and morbidity in patients with HF not treated with ACE inhibitors. Based on these results, valsartan appears to be an effective therapy in ACE inhibitor-intolerant patients.     

The impact of race on response to RAAS inhibition

Retrospective analyses of the Studies of Left Ventricular Dysfunction (SOLVD) and Vasodilator Heart Failure Trials (V-HeFT) have addressed the question of whether angiotensin-converting enzyme (ACE) inhibitors are equally efficacious in black patients and white patients with heart failure. In SOLVD, there was no ethnic difference in the efficacy of enalapril for reducing mortality and preventing the development of heart failure, but enalapril was more effective in whites in reducing hospitalizations. In V-HeFT II, enalapril was more efficacious than the combination of isosorbide dinitrate and hydralazine in whites in reducing mortality, but not in blacks. However, the combination of isosorbide dinitrate and hydralazine may be particularly advantageous in black patients as suggested by V-HeFT I and the recent African American Heart Failure Trial. In aggregate, the available data suggest that ACE inhibitors should remain a cornerstone of therapy for heart failure with a reduced ejection fraction in white patients and black patients.     

缬沙坦治疗慢性心力衰竭的临床疗效

目的观察缬沙坦治疗慢性心力衰竭的临床疗效。方法心力衰竭患者58例,随机分为两组:即缬沙坦治疗组30例服用缬沙坦80 mg/d;常规治疗组28例未服用缬沙坦及其他血管紧张素Ⅱ-1型受体拮抗剂。缬沙坦组和常规治疗组均于治疗前,治疗后半年分别行心脏彩色多普勒检查。结果两组在治疗前及治疗后对比,缬沙坦组比常规治疗组左心室舒张末期容积(LVEDV)[(102.6±25.6)mlvs.(117.2±28.5)ml,P<0.05]及左心室收缩末期容积(LVESV)[(53.1±20.6)mlvs.(66.4±28.7)ml,P<0.05]明显减小,而左室射血分数(LVEF)明显提高[(56.1±9.6)%vs.(47.4±13.2)%,P<0.01]。随访1年,结果缬沙坦组(24.0%)比常规治疗组(46.7%)心力衰竭再发生率降低有统计学意义(P<0.05)。结论应用缬沙坦治疗心力衰竭,患者心功能有明显的改善。     

Lessons from recent randomized controlled trials for the management of congestive heart failure

In 1987 the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) was published, which was a milestone for the treatment of patients with heart failure. The study showed a highly significant reduction in mortality in patients with severe heart failure treated with enalapril in comparison to placebo in combination with conventional treatment for heart failure, including the use of other vasodilators. The improvement in survival was exclusively due to a reduction of progression of pump failure. The incidence of sudden cardiac death was not affected. In 1991 2 studies were published in which patients with mild and moderate heart failure were included. The Second Vasodilator-Heart Failure Trial (V-HeFT II) compared the efficacy of enalapril with the effects of a vasodilator therapy consisting of the combination of hydralazine and isosorbide dinitrate. The study showed a highly significant reduction in mortality in the group of patients on the angiotensin-converting enzyme (ACE) inhibitor. In contrast to CONSENSUS, the benefit on survival was due to a reduction of sudden cardiac death. The second study was the Studies of Left Ventricular Dysfunction (SOLVD) treatment arm trial, which compared enalapril and placebo in combination with standard therapy in symptomatic patients with mild-to-moderate heart failure. The SOLVD treatment trial showed a highly significant improvement in survival on enalapril in comparison with placebo. ACE inhibition resulted in a borderline significant reduction of fatal myocardial infarctions, suggesting an impact of ACE inhibition on the pathogenesis of coronary artery disease. The data available show a clear indication for the treatment of symptomatic patients with mild and moderate-to-severe heart failure with ACE inhibitors as a first-line therapy.     

The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: an analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT).

OBJECTIVES: We attempted to compare the effect of an angiotensin-converting enzyme (ACE) inhibitor and angiotensin receptor blocker (ARB) on atherosclerotic events. BACKGROUND: Angiotensin-converting enzyme inhibitors and ARBs interrupt the renin-angiotensin system by distinct mechanisms. It is not clear whether ARBs reduce atherosclerotic events such as myocardial infarction (MI) like ACE inhibitors. This evidence gap may reflect the nature of the studies conducted, to date. Placebo-controlled studies enrolled cohorts at low risk of atherosclerotic events (e.g., patients with chronic heart failure, most treated with an ACE inhibitor). One of the main active controlled trials was confounded by a blood pressure difference between treatments. METHODS: We compared the effects of captopril, valsartan, and their combination on atherosclerotic events in 14,703 patients randomized in the Valsartan in Acute Myocardial Infarction Trial (VALIANT). RESULTS: The number of individuals adjudicated as having a fatal or non-fatal MI in the captopril group was 559 (total investigator reported events 798), 587 (796) in the valsartan group, and 554 (756) in the combination group; valsartan versus captopril, p = 0.651 (0.965); combination versus captopril, p = 0.187 (0.350). Overall, all atherosclerotic events examined occurred at a similar frequency in the captopril and valsartan groups. CONCLUSIONS: Angiotensin receptor blockers appear to be as effective as ACE inhibitors in reducing atherosclerotic events, even when used in addition to other secondary preventive treatments. These data, although not conclusive, also support the hypothesis that adding an ARB to an ACE inhibitor may have a small additional anti-infarction effect, a possibility that needs to be prospectively tested.     

Effect of Valsartan on hospitalization: results from Val-HeFT

BACKGROUND: Although current therapies have improved heart failure (HF) outcome, hospitalizations continue at high rates. The Valsartan Heart Failure Trial (Val-HeFT) showed that valsartan reduced the risk of first worsening HF hospitalization by 27.5% versus placebo (P <.001). This article analyzes all-cause and investigator-assessed HF hospitalization in Val-HeFT overall and in subgroups defined by preexisting HF therapy. METHODS: Val-HeFT was a randomized, double-blind parallel-arm study in which HF patients (New York Heart Association class II-IV) received either valsartan (n = 2511, force-titrated to 160 mg twice daily) or placebo (n = 2499) in addition to prescribed HF therapy. Total and per patient-year investigator-assessed hospitalizations (all-cause or HF) were analyzed according to prescribed therapy at baseline (angiotensin-converting enzyme inhibitors [ACEI] and beta-blockers [BB]). RESULTS: Hospitalization for worsening HF accounted for 35% of all hospitalizations. There were 2856 and 3106 total all-cause hospitalizations in the valsartan and placebo groups, respectively, an 8% reduction (P =.145). Valsartan significantly reduced the overall number of investigator-assessed HF hospitalizations (-22.4%, P =.002) and reduced HF hospitalizations in the combination therapy subgroups (significant for ACEI+/BB- P =.003 and ACEI-/BB- P =.028) except those receiving both ACEI and BB. The benefit of valsartan versus placebo was more pronounced in reducing the number of patients with recurrent HF hospitalization (-20.6%) than single hospitalizations (-8.7%). CONCLUSIONS: Addition of valsartan to prescribed HF therapy demonstrated significant reductions in HF hospitalizations and was particularly beneficial in reducing recurrent HF hospitalization.     

Inhibitory effect of candesartan cilexetil on left ventricular remodeling after myocardial infarction

Although angiotensin-converting enzyme inhibitors (ACEIs) have been shown to reduce left ventricular remodeling after acute myocardial infarction (AMI), the effects of angiotensin receptor blockers have yet to be established. This study was conducted to examine the effects of candesartan on left ventricular remodeling after AMI. Consecutive AMI patients were assigned to a candesartan group or ACEI group after successful coronary intervention. The patients in the candesartan group (n = 77, mean age, 62.8 +/- 1.3) received candesartan and the patients in the ACEI group (n = 80, mean age, 63.3 +/- 1.2) received lisinopril, enalapril, or trandolapril. Four mg was the most frequent dose in the candesartan group at 6 months. Lisinopril, enalapril, and trandolapril were administered to 52%, 27%, and 21% of the patients in the ACEI group, respectively. No significant differences in the incidences of cardiac death, nonfatal MI, or hospitalization for heart failure (P = NS) were found between the groups. The candesartan group exhibited a somewhat higher percent increase in left ventricular ejection fraction and significantly lower percent increases in left ventricular end-diastolic volume index and left ventricular end-systolic volume index compared to the ACEI group (P < 0.05, P < 0.05, respectively). Candesartan is more effective than ACEI in preventing left ventricular remodeling after AMI.     

Angiotensin II receptor antagonists in arterial hypertension

Angiotensin II receptor antagonists (AT-1) represent a new group of orally active antihypertensive agents. Activation on AT-1 receptor leads to vasoconstriction, stimulation of the release of catecholamines and antidiuretic hormone with production of thirst, and promote growth of vascular and cardiac muscle; these effects are blocked by AT-1 antagonist agents. The first chemically useful, orally active AT-1 receptor antagonist was losartan, followed by other agents currently in clinical use, such as: valsartan, eprosartan, irbesartan, telmisartan, candesartan, and many others under investigation. AT-1 receptor antagonists are effective in reducing high blood pressure in hypertensive patients. Monotherapy in mild to moderate hypertension controls blood pressure in 40 to 50% of these patients; when a low dose of a thiazide diuretic is added, 60 to 70% of patients are controlled. The efficacy is similar to angiotensin-converting enzyme inhibitors, diuretics, calcium antagonists and beta-blocking agents. Tolerability has been reported to be very good. AT-1 receptor antagonists would be a drug of choice in otherwise well-controlled hypertensive patients treated with angiotensin-converting enzyme inhibitors who developed cough or angioedema. The final position in the antihypertensive therapy in this special population and other clinical situations, such as left ventricular hypertrophy, heart failure, diabetes mellitus and renal disease, has to be determined in large prospective clinical trials, some of which are now being conducted.     

复方缬沙坦治疗轻中度原发性高血压患者的疗效观察

目的评价复方缬沙坦（缬沙坦80mg／氢氯噻嗪12．5mg复方制剂）治疗经单用缬沙坦80mg控制不良的轻、中度原发性高血压患者疗效和安全性。方法采用多中心、双盲、双模拟、随机、活性药物对照、平行试验方法。对经2周洗脱期的轻、中度原发性高血压患者[坐位舒张压≥95mmHg（1mmHg=0．133kPa）且〈110mmHg]采用单药缬沙坦80mg／d治疗4周,在单药导入结束后,坐位舒张压仍〉190mmHg的864例患者按1：1随机、双盲分为复方缬沙坦组或缬沙坦80mg／d组,继续治疗8周。在治疗4周和结束时评估药物安全性及有效性。结果在轻、中度原发性高血压患者中复方缬沙坦每日1次比单用缬沙坦80mg／d血压进一步下降、达标率提高。治疗结束时平均坐位收缩压多降低3．5mmHg,平均坐位舒张压多下降2．2mmHg,血压控制〈140／90mmHg的患者在复方缬沙坦组和单用缬沙坦80mg／d组分别为53．9％及40．9％。结论轻、中度原发性高血压患者采用复方缬沙坦治疗组降压有效率及达标率均优于每日1次服用缬沙坦80mg／d组。复方缬沙坦适用于缬沙坦单药控制不良的轻、中度原发性高血压患者。     

Tolerability of enalapril in congestive heart failure

In a double-blind, randomized trial, 253 patients with heart failure (New York Heart Association functional class IV) received either enalapril (n = 127) or placebo (n = 126) in addition to their conventional therapeutic regimens (digitalis, diuretics and vasodilators other than angiotensin-converting enzyme inhibitors). Enalapril was administered in a dose of 2.5 to 40 mg/day. The placebo group was administered placebo tablets in addition to their conventional therapeutic regimen. The study was discontinued prematurely for ethical reasons because of the highly significant (p = 0.003) difference in mortality between the enalapril (n = 50) and placebo groups (n = 68). The important reduction was observed among patients dying from progressive heart failure. Follow-up ranged from 1 day to 20 months (average 188 days). The reduction in mortality was associated with general improvements in symptoms and signs of left and right ventricular heart failure, reduction of heart size, improvements in New York Heart Association classification, reduction of concurrent cardiovascular medication, and reduction in the number of hospital admissions and duration of hospitalization. The overall rate of withdrawal from the study was low and was comparable in the 2 treatment groups (16%). Induced hypotension was an intentional part of the treatment, and symptomatic hypotension was observed in 17% of treated patients vs 0% of the placebo group. Hypotension was the reason for withdrawal in 7 patients. After the initial dose of enalapril was reduced to 2.5 mg in high-risk patients, hypotension was the reason for withdrawal in only 3% of all patients. Hyperkalemia was observed exclusively among patients concurrently using potassium-sparing agents.(ABSTRACT TRUNCATED AT 250 WORDS)     

Reduction of exercise-induced myocardial ischemia during add-on treatment with the angiotensin-converting enzyme inhibitor enalapril in patients with normal left ventricular function and optimal beta blockade

OBJECTIVES: We sought to study the effect of angiotensin-converting enzyme inhibition on exercise-induced myocardial ischemia. BACKGROUND: Although angiotensin-converting enzyme inhibitors have been shown to reduce ischemic events after myocardial infarction, few data are available regarding their direct anti-ischemic effects in patients with coronary artery disease. METHODS: We studied 43 patients (average age 63 +/- 8 years) with exercise-induced myocardial ischemia (> or =0.1 mV ST depression, despite optimal beta blockade) and normal left ventricular function (ejection fraction >0.50). In a double-blind, placebo-controlled parallel design, patients were treated with angiotensin-converting enzyme inhibitor (enalapril 10 mg twice daily) or placebo. Assessments were made after three weeks (short-term) and 12 weeks (long-term). RESULTS: At baseline, the groups were well matched for all clinical characteristics. After three weeks, there was a slight but not significant increase in time to 0.1 mV ST depression in both groups (p = NS); rate pressure product (RPP = heart rate x systolic blood pressure) was also unaffected. After 12 weeks, however, time to 0.1 mV ST depression further increased in the enalapril group (5.6 +/- 1.9 min) but was unchanged in the placebo group (4.4 +/- 1.3 min; p < 0.05 between groups). In contrast, RPP was not affected. Concentrations of both atrial and brain natriuretic peptides at peak exercise tended to be lower by enalapril, if compared to placebo (p = NS). CONCLUSIONS: Angiotensin-converting enzyme inhibition may reduce exercise-induced myocardial ischemia in patients with normal left ventricular function. Further studies are needed to elucidate the mechanisms involved.     

Neurohormonal modulation: The new paradigm of pharmacological treatment of heart failure

The current paradigm of medical therapy for heart failure with reduced ejection fraction (HFrEF) is triple neurohormonal blockade with an angiotensin-converting enzyme inhibitor (ACEI), a beta-blocker (BB) and a mineralocorticoid receptor antagonist (MRA). However, three-year mortality remains over 30%.Stimulation of counter-regulatory systems in addition to neurohormonal blockade constitutes a new paradigm, termed neurohormonal modulation. Sacubitril/valsartan is the first element of this new strategy.PARADIGM-HF was the largest randomized clinical trial conducted in HFrEF. It included 8442 patients and compared the efficacy and safety of sacubitril/valsartan versus enalapril. The primary endpoint was the composite of cardiovascular mortality and hospitalization due to HF, which occurred in 914 (21.8%) patients receiving sacubitril/valsartan and in 1117 (26.5%) patients receiving enalapril (HR 0.8, 95% CI 0.73-0.87, p=0.0000002; NNT 21). Sacubitril/valsartan reduced both primary endpoint components, as well as sudden cardiac death, death due to worsening HF, and death from all causes. Patients on sacubitril/valsartan reported less frequent deterioration of HF and of quality of life, and discontinued study medication less frequently because of an adverse event.PARADIGM-HF demonstrated the superiority of sacubitril/valsartan over enalapril, with a 20% greater impact on cardiovascular mortality compared to ACEIs. Accordingly, in 2016, the European (ESC) and American (ACC/AHA/HFSA) cardiology societies simultaneously issued a class I recommendation for the replacement of ACEIs by sacubitril/valsartan in patients resembling PARADIGM-HF trial participants.     

Rationale and design of the Valsartan Heart Failure Trial: a large multinational trial to assess the effects of valsartan, an angiotensin-receptor blocker, on morbidity and mortality in chronic congestive heart failure.

BACKGROUND: To investigate the role of persistent angiotensin activity despite angiotensin-converting enzyme inhibitor therapy in the progression of heart failure, the Valsartan Heart Failure Trial has been designed to investigate the effect of the angiotensin-receptor blocker, valsartan, on morbidity and mortality. METHODS AND RESULTS: Nearly 5,000 patients with New York Heart Association classes II to IV heart failure, while receiving all standard therapy, are being randomized to treatment with valsartan, 160 mg twice daily, or placebo in a worldwide study. Follow-up will be continued until 906 deaths have been recorded. Additional end points will include the need for hospitalization, other major morbid events, quality--of life measurement, changes in neurohormone levels, and changes in left ventricular size and function. Substudies will explore exercise tolerance, arrhythmias, and magnetic resonance imaging. CONCLUSION: This study should help establish the role of angiotensin-receptor blockade in the treatment of heart failure.