Many patients who receive a diagnosis of heart failure have neither a low left ventricular (LV) ejection fraction nor valve disease. Few substantial randomized controlled trials have been conducted in this population, none has focussed on patients with evidence of diastolic dysfunction and none has shown clear benefit on symptoms, morbidity, or mortality.
This was a randomized double-blind trial, comparing placebo with perindopril, 4 mg/day in patients aged > or =70 years with a diagnosis of heart failure, treated with diuretics and an echocardiogram suggesting diastolic dysfunction and excluding substantial LV systolic dysfunction or valve disease. The primary endpoint was a composite of all-cause mortality and unplanned heart failure related hospitalization with a minimum follow-up of 1 year. A total of 850 patients were randomized. Their mean age was 76 (SD 5) years and 55% were women. Median follow-up was 2.1 (IQR 1.5-2.8) years. Enrollment and event rates were lower than anticipated, reducing the power of the study to show a difference in the primary endpoint to 35%. Many patients withdrew from perindopril (28%) and placebo (26%) after 1 year and started taking open-label ACE-inhibitors. Overall, 107 patients assigned to placebo and 100 assigned to perindopril reached the primary endpoint (HR 0.919: 95% CI 0.700-1.208; P = 0.545). By 1 year, reductions in the primary outcome (HR 0.692: 95% CI 0.474-1.010; P = 0.055) and hospitalization for heart failure (HR 0.628: 95% CI 0.408-0.966; P = 0.033) were observed and functional class (P < 0.030) and 6-min corridor walk distance (P = 0.011) had improved in those assigned to perindopril.
Uncertainty remains about the effects of perindopril on long-term morbidity and mortality in this clinical setting since this study had insufficient power for its primary endpoint. However, improved symptoms and exercise capacity and fewer hospitalizations for heart failure in the first year were observed on perindopril, during which most patients were on assigned therapy, suggesting that it may be of benefit in this patient population.
"when compared with the placebo group. However, it should be noted that, during the one and only study that evaluated an ACE inhibitor in this patient population (i.e. the PEP-CHF [Perindopril in Elderly People with Chronic Heart Failure] trial), only the rate of hospitalization for worsening heart failure showed a substantial decrease compared with placebo [23, 24]. Seven published clinical studies performed with patients with left ventricular dysfunction reported data on total mortality. "
[Show abstract][Hide abstract] ABSTRACT: The renin-angiotensin-aldosterone system plays a major role in the pathophysiology of hypertension and closely related cardio- and cerebrovascular events. Although both angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists (angiotensin receptor blockers; ARBs) are equally important in the treatment of hypertension, according to the results of recent years, there might be substantial differences in their cardiovascular protective effects, and these differences might be explained by our increasing knowledge of their non-overlapping mechanisms of action. The number of studies investigating how ACE inhibitors and ARB agents differ will certainly be increasing in the future. ACE inhibitors are the safe therapeutic opportunity for hypertensive patients at high risk, with a cardiological comorbidity.
American Journal of Cardiovascular Drugs 01/2014; 14(3). DOI:10.1007/s40256-013-0058-8 · 2.42 Impact Factor
"Activation of the renin-angiotensin-aldosterone system (RAAS) has been shown to promote myocardial fibrosis and diastolic dysfunction . However, recent clinical trials of the use of angiotensin converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARBs) have not shown a benefit in HFPEF patients –. One of the potential reasons for the lack of efficacy of ACEI and ARB in clinical trials is that the anti-fibrotic effects of these agents alone or in combination require supra-therapeutic dose ranges . "
[Show abstract][Hide abstract] ABSTRACT: Myocardial fibrosis, a major pathophysiologic substrate of heart failure with preserved ejection fraction (HFPEF), is modulated by multiple pathways including the renin-angiotensin system. Direct renin inhibition is a promising anti-fibrotic therapy since it attenuates the pro-fibrotic effects of renin in addition to that of other effectors of the renin-angiotensin cascade. Here we show that the oral renin inhibitor aliskiren has direct effects on collagen metabolism in cardiac fibroblasts and prevented myocardial collagen deposition in a non-hypertrophic mouse model of myocardial fibrosis. Adult mice were fed hyperhomocysteinemia-inducing diet to induce myocardial fibrosis and treated concomitantly with either vehicle or aliskiren for 12 weeks. Blood pressure and plasma angiotensin II levels were normal in control and hyperhomocysteinemic mice and reduced to levels lower than observed in the control group in the groups treated with aliskiren. Homocysteine-induced myocardial matrix gene expression and fibrosis were also prevented by aliskiren. In vitro studies using adult rat cardiac fibroblasts also showed that aliskiren attenuated the pro-fibrotic pattern of matrix gene and protein expression induced by D,L, homocysteine. Both in vivo and in vitro studies demonstrated that the Akt pathway was activated by homocysteine, and that treatment with aliskiren attenuated Akt activation. In conclusion, aliskiren as mono-therapy has potent and direct effects on myocardial matrix turnover and beneficial effects on diastolic function.
PLoS ONE 12/2013; 8(12):e81612. DOI:10.1371/journal.pone.0081612 · 3.23 Impact Factor
"The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Preserved trial , which showed only moderate reduction in HF hospitalization, when assessing the reduction of mortality and morbidity, showed a 30% reduction in the risk of death at 1 year (P < 0.001) but only a 9% reduction (P > 0.055) over the full-duration followup of 38 months in median. The Perindopril for Elderly People with Chronic Heart Failure (PEP-CHF) study  showed that angiotensin-converting enzyme inhibitors (ACEI) resulted in improved symptoms and exercise capacity and HF hospitalization but no reduction in long-term morbidity and mortality. This may result from insufficient power for lower enrolment and event rates than anticipated. "
[Show abstract][Hide abstract] ABSTRACT: ACCORDING TO THE EJECTION FRACTION, PATIENTS WITH HEART FAILURE MAY BE DIVIDED INTO TWO DIFFERENT GROUPS: heart failure with preserved or reduced ejection fraction. In recent years, accumulating studies showed that increased mortality and morbidity rates of these two groups are nearly equal. More importantly, despite decline in mortality after treatment in regard to current guideline in patients with heart failure with reduced ejection fraction, there are still no trials resulting in improved outcome in patients with heart failure with preserved ejection fraction so far. Thus, novel pathophysiological mechanisms are under development, and other new viewpoints, such as multiple comorbidities resulting in increased non-cardiac deaths in patients with heart failure and preserved ejection fraction, were presented recently. In this review, we will focus on the tested as well as the promising therapeutic options that are currently studied in patients with heart failure with preserved ejection fraction, along with a brief discussion of pathophysiological mechanisms and diagnostic options that are helpful to increase our understanding of novel therapeutic strategies.
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