Angiotensin converting enzyme inhibitors (ACEIs) for anthracycline-induced cardiotoxicity: a systematic review and meta-analysis of randomized controlled trials

Section 7: Heart Failure in Patients With Left Ventricular Systolic Dysfunction

Prevention of Heart Failure With Chlorthalidone in ALLHAT: Placing the Results Into Perspective

Background. Patients with chronic heart failure (chronic HF) are at high risk of cardiovascular death and recurrent hospital admissions. The authors aimed to find out whether the use of an angiotensin receptor blocker could reduce mortality and morbidity. Methods. In parallel, randomized, double-blind, controlled clinical trials, candesartan was compared with placebo in three distinct populations. The authors studied patients with left-ventricular ejection fraction (LVEF) ≤40% who were not receiving angiotensin-converting enzyme (ACE) inhibitors because of previous intolerance or who were currently receiving ACE inhibitors, and patients with LVEF >40%. Overall, 7601 patients (7599 with data) were randomly assigned candesartan (n=3803, titrated to 32 mg q.d.) or matching placebo (n=3796) and followed-up for at least 2 years. The primary outcome of the overall program was all-cause mortality, and the primary outcome for all the component trials was cardiovascular death or hospital admission for chronic HF. Analysis was by intention to treat. Findings. Median follow-up was 37.7 months. Eight hundred eighty-six (23%) patients in the candesartan group and 945 (25%) in the placebo group died (unadjusted hazard ratio [HR], 0.91; 95% confidence interval [CI], 0.83–1.00; p=0.055; covariate adjusted HR, 0.90; 95% CI, 0.82–0.99; p=0.032), with fewer cardiovascular deaths (691 [18%] vs. 769 [20%], unadjusted HR, 0.88; 95% CI, 0.79– 0.97; p=0.012; covariate adjusted HR, 0.87; 95% CI, 0.78–0.96; p=0.006) and hospital admissions for chronic HF (757 [20%] vs. 918 [24%]; p<0.0001) in the candesartan group. There was no significant heterogeneity for candesartan results across the component trials. More patients discontinued candesartan than placebo because of concerns about renal function, hypotension, and hyperkalemia. Interpretation. Candesartan was generally well tolerated and significantly reduced cardiovascular deaths and hospital admissions for HF. Ejection fraction or treatment at baseline did not alter these effects.—Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet. 2003;362:759–766. Comment. The Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity (CHARMOverall) program is the largest trial program ever undertaken in chronic HF patients. The 7601-patient trial evaluated candesartan in addition to optimal treatment for HF and was made up of three smaller studies in separate populations: patients with left ventricular (LV) dysfunction intolerant to ACE inhibitors (the CHARM-Alternative trial),1 patients with LV dysfunction already taking ACE inhibitors (the CHARM-Added trial),2 and patients with preserved LV function (the CHARM-Preserved trial).3 These three different populations of patients with HF were studied individually and concurrently as a group. For this study design to be successful, each trial had to be similar in terms of inclusion and exclusion criteria, drug therapy utilized, and dose of drug used. This was necessary for data to be combined into the CHARM-Overall program to determine total mortality. In addition, each individual trial had adequate statistical power for analysis in each separate chronic HF population. For the CHARM-Alternative trial, investigators enrolled 2028 patients with symptomatic HF and LVEF ≤40% who were not receiving ACE inhibitors because of previous intolerance. Patients were randomly assigned candesartan (target dose 32 mg q.d.) or matching placebo. The primary outcome of the study was the composite of cardiovascular death or hospital admission for HF. Analysis was by intention to treat. The most common manifestation of ACE-inhibitor intolerance was cough (72%), followed by symptomatic hypotension (13%) and renal dysfunction (12%). During a median follow-up of 33.7 months, 334 (33%) of 1013 patients in the candesartan group and 406 (40%) of 1015 in the placebo group had cardiovascular death or hospital admission for chronic HF (unadjusted HR, 0.77; 95% CI, 0.67–0.89; p=0.0004; covariate adjusted HR, 0.70; 95% CI,0.60–0.81; p<0.0001). Each component of the primary outcome was reduced, as was the total number of hospital admissions for chronic HF. No statistical difference in overall drug discontinuations (21% candesartan vs. 19% placebo) was found, but there were significant increases in discontinuations due to hypotension (3.7% vs. 0.9%), increased creatinine levels (6.1% vs. 2.7%), and increased potassium levels (1.9% vs. 0.3%) in the candesartan group. Despite intolerance to ACE inhibitors, patients can tolerate candesartan and show a reduction in morbidity/mortality, but we still need to monitor hypotension, creatinine, and potassium. Candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic HF and intolerance to ACE inhibitors. Over the duration of the trial, 33% of candesartan compared with 40% of placebo patients had cardiovascular death or first admission to hospital for chronic HF. This absolute reduction of seven major events per 100 patients treated corresponds to the need to treat 14 patients with candesartan to prevent one patient from having cardiovascular death or hospital admission for HF. In addition, multiple chronic HF hospital admissions were reduced. Adequate attempts should be made to place patients with chronic HF and reduced LVEF on ACE inhibitors and β blockers; however, irrespective of the tolerance of an ACE inhibitor, the addition of candesartan improves outcome. In conclusion, candesartan was generally well tolerated and reduced cardiovascular mortality and morbidity in patients with symptomatic chronic HF who were not receiving ACE inhibitors because of intolerance. For the CHARM-Added trial, the investigators enrolled 2548 patients with New York Heart Association functional class II-IV, chronic HF, LVEF ≤40%, and who were being treated with ACE inhibitors. They randomly assigned patients to candesartan (n=1276, target dose 32 mg q.d.) or placebo (n=1272). At baseline, 55% of patients were also treated with β blockers and 17% were treated with spironolactone. The primary outcome of the study was the composite of cardiovascular death or hospital admission for chronic HF. Analysis was done by intention to treat. The median follow-up was 41 months. Four hundred eighty-three (38%) patients in the candesartan group and 538 (42%) in the placebo group experienced the primary outcome (unadjusted HR, 0.85; 95% CI, 0.75–0.96; p=0.011; covariate adjusted p=0.010. Candesartan reduced each of the components of the primary outcome significantly, as well as the total number of hospital admissions for chronic HF. The benefits of candesartan were similar in all predefined subgroups, including patients receiving baseline β-blocker treatment. Overall, the addition of candesartan to ACE inhibitor and other treatment leads to a further clinically important reduction in relevant cardiovascular events in patients with chronic HF and reduced LVEF. The results of the CHARM-Added trial differ in some ways from those of the Valsartan Heart Failure Trial (Val-HeFT). Like the CHARM-Added trial, Val-HeFT studied the effect of an angiotensin receptor blocker in HF patients, 93% of whom also received treatment with an ACE inhibitor. While Val-HeFT did show a reduction in the combined end point of morbidity and mortality in valsartan patients compared with placebo, it did not show a significant decrease in total or cardiovascular mortality. Also, it demonstrated an increase in mortality in a subgroup of patients who were receiving a β blocker in addition to an ACE inhibitor and valsartan. It was postulated that extensive blockade of multiple neurohormonal systems in patients with chronic HF may be detrimental. In contrast, patients in the CHARM-Added trial who received the triple therapy combination of ACE inhibitor, β blocker, and angiotensin receptor blocker, the benefit was explained by the different angiotensin receptor blockers utilized or the dose of these agents employed. Another possible explanation is that subgroup analyses (like the one used in Val-HeFT) are often underpowered, and the results may have occurred due to chance. Candesartan had a similar rate of mortality compared with patients not treated with a β blocker. The CHARM-Preserved trial investigators randomly assigned 3023 patients to candesartan (n=1514, target dose 32 mg q.d.) or matching placebo (n=1509). Patients had New York Heart Association functional class II-IV, chronic HF, and LVEF >40%. The primary outcome was cardiovascular death or admission to a hospital for chronic HF. Analysis was done by intention to treat. Median follow-up was 36.6 months. Three hundred thirty-three (22%) patients in the candesartan and 366 (24%) in the placebo group experienced the primary outcome (unadjusted HR, 0.89; 95% CI, 0.77–1.03; p=0.118; covariate adjusted HR, 0.86; 95% CI, 0.74–1.0; p=0.051). Cardiovascular death did not differ between groups (170 vs. 170), but fewer patients in the candesartan group than in the placebo group were admitted to a hospital for chronic HF once (230 vs. 279; p=0.017) or multiple times. Composite outcomes that included nonfatal myocardial infarction and nonfatal stroke showed results similar to the primary composite (388 vs. 429; unadjusted HR, 0.88; 95% CI, 0.77–1.01; p=0.078; covariate adjusted HR, 0.86; 95% CI, 0.75–0.99; p=0.037). Candesartan has a moderate impact in preventing admissions for chronic HF among patients who have HF and LVEF >40%. The management of patients with preserved LVEF and HF is based on sparse data. This trial provides direct information on this large group of patients with HF. Among patients with preserved LVEF who have no contraindications, candesartan reduces the number of hospital admissions for chronic HF. It is not absolutely conclusive, but it is highly persuasive. We need more data on this group. This should be the beginning of many studies in this population, and the results of the Irbesartan in chronic HF Patients With Preserved LV Function (I-PRESERVE) trial are anxiously awaited. All patients were considered in the CHARM-Overall trial, with a primary end point of all-cause mortality. This was reduced by 9%, which was borderline significant in the unadjusted analysis (p=0.055); the p value dropped to 0.032 after adjustment for baseline variables. Cardiovascular death was also significantly reduced by 12%, and cardiovascular death and HF hospitalization, the primary end point of the component trials, was reduced by a highly statistically significant 16%, wagain mostly driven by a reduction in hospitalization. There was no effect of candesartan on myocardial infarction, stroke, or revascularization procedures, but a significant reduction in the development of new diabetes was seen with the angiotensin II blocker (7.6% placebo vs. 6.0% candesartan; HR, 0.78; p=0.02). In terms of side effects in the CHARMOverall program, as in the individual trials, candesartan was associated with significant increases in hypotension (3.5% vs. 1.7%), serum creatinine levels (6.2% vs. 3.0%), and hyperkalemia (2.2% vs. 0.6%). CHARM-Overall suggests that 23 patients need to be treated with candesartan for 3 years to prevent one cardiovascular death or chronic HF hospitalization. In an editorial in The Lancet, Dr. Harvey White of Green Lane Hospital, Auckland, New Zealand, calculates that over 3 years the treatment effect seen in CHARM equates to one death prevented per 63 patients treated, one first hospitalization with HF prevented per 23 patients treated, and one new case of diabetes prevented per 71 patients treated.

IntroductionAnthracyclines treat a myriad of malignancies; however, they are known to lead to cancer therapy-related cardiomyopathy (CTRC). Randomized controlled trials (RCTs) evaluating the role of angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) in primary prevention of CTRC have yielded mixed results.MethodsA systematic search of MEDLINE, Cochrane, and Scopus databases was performed to identify RCTs that evaluated outcomes in patients receiving anthracyclines and ACEi or ARBs versus control. The primary outcome was occurrence of CTRC. All data were pooled using a random-effects model.ResultsThe final analysis included 10 RCTs, with 1049 patients assessed. The weighted follow-up period was 16.8 months. The average age was 43.2 years and 90% were female. Breast cancer (80%) and lymphomas (13%) were the most common malignancies. There was no statistically significant difference between the groups with regards to occurrence of CTRC (16% vs 24%; risk ratio (RR) 0.67, 95% confidence interval (CI) [0.31, 1.45]). Compared with control, ACEi/ARBs were associated with favorable absolute changes in left ventricular ejection fraction (LVEF) (standardized mean difference (SMD) + 1.20%, 95% CI [0.40, 2.00]), left ventricular end-diastolic volume (SMD − 0.36 mL, 95% CI [− 0.66, − 0.06]), and left ventricular end-systolic volume (SMD − 1.04 mL, 95% CI [− 1.79, − 0.29]). There was also a lower risk of arrhythmias in the ACEi/ARBs group compared to control (1.6% vs 8.0%; RR 0.30, 95% CI [0.10, 0.94]), but no difference in all-cause mortality (2.8% vs 3.2%; RR 0.82, 95% CI [0.26, 2.61]), or heart failure (1.2% vs 7.1%; RR 0.40, 95% CI [0.03, 4.54]).ConclusionsACEi/ARBs therapy was not associated with a reduction in CTRC among patients with cancer receiving anthracyclines. However, there were favorable changes in LVEF and left ventricular remodeling with ACEi/ARBs therapy. Further large-scale studies are needed to better understand the potential role of ACEi/ARBs in preventing long-term cardiotoxicity.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40119-025-00401-z.

Cardiovascular News

Background: Almost all Duchenne muscular dystrophy (DMD) patients that reach their 30s present cardiomyopathy. As a result, this population remains under-treated. There is no sufficient proof of the efficacy of anti-remodeling cardiac therapy for DMD cardiomyopathy (DMDCM). We aim to assess the efficacy of anti-remodeling cardiac therapy for DMDCM by using meta-analysis.Methods: PubMed (MEDLINE), Embase, and Cochrane library were searched through January 2021. Randomized control trials, case-control studies, and observational studies that reported assessments of cardiovascular outcomes and death of participants using angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta-blockers, mineralocorticoid-receptor antagonists and Ivabradine, were included. The primary outcome was total mortality. Secondary outcomes included changes in left ventricular ejection fraction (LVEF), serum natriuretic peptide levels (BNP), and heart rate (HR). Data were extracted for eligibility by two independent reviewers. Random-effects meta-analysis was used to pool results.Results: Twelve studies with 439 patients were included in our meta-analysis. Treated patients have lower HR, mean difference of −17 beats per minute (CI [−25]–[−9], p < 0.01). The LVEF was improved in treated patients, with a mean difference of LVEF of 3.77% (CI 0.44–7.12, p < 0.03). Although mortality rates did not reach statistical significance there was a trend for total mortality reduction (hazard ratio 0.36, CI (0.1–1.25), p = 0.107) and for BNP reduction (SSMD: 0.141, CI ([−0.19]–[0.47]), p = 0.3).Conclusion: Pharmacologic treatment for DMDCM patients is associated with decreased HR and improved LVEF. Therefore, DMDCM patients may benefit from implementing guideline therapy for HF.

FDA Approves First-in-Class Combo Drug for Heart Failure

Since the initial description of angiotensin II–mediated hypertension >40 years ago, basic and clinical investigations of the renin-angiotensin system (RAS) have resulted in a broader understanding of cardiovascular pathophysiology and significant advances in therapy. Angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists are now widely prescribed for the treatment of hypertension and left ventricular (LV) dysfunction; more recently, the aldosterone receptor antagonist, spironolactone, has proven beneficial in severe heart failure. This article will focus on our current understanding of the RAS and how pharmacological manipulation of this system can improve clinical outcomes in patients with cardiovascular disease. ### Pathophysiological Rationale for RAS Manipulation Renin is released by juxtuloglomerular cells in the kidney in response to renal hypoperfusion, decreased sodium delivery, and sympathetic activation (Figure 1). Angiotensinogen produced by the liver is cleaved by renin to yield the inactive decapeptide angiotensin I. Circulating angiotensin I is, in turn, converted to angiotensin II in the lungs by the action of ACE. ACE, or kininase II, also plays a key role in the kallikrein-kinin system by cleaving bradykinin to inactive peptides. In addition to the hormonal effects of circulating angiotensin II, all of the necessary components of the RAS exist in several organs and tissues, including the heart, kidneys, and vasculature. Figure 1. Pathophysiology of the RAS. SMC indicates smooth muscle cell. Angiotensin II exerts its actions in target organs and tissues by binding to both angiotensin II type 1 and 2 (AT1 and AT2) receptors, although adverse effects in humans seem to be mediated primarily by the AT1 receptor (Figure 1). In the kidney, angiotensin II causes sodium and water retention and efferent arteriolar vasoconstriction. Constriction of the systemic vasculature by angiotensin II causes hypertension, whereas coronary vasoconstriction may cause myocardial ischemia and arrhythmias. Angiotensin II–stimulated secretion of aldosterone by the adrenal cortex and arginine …

Heart failure (HF) represents a major and growing public health problem because of its prevalence, incidence, morbidity, mortality, and economic costs. The prevalence of HF is 2% to 3% of the general population.1 Five million Americans are affected, with >550 000 cases diagnosed each year.2 The mortality rate from severe HF remains >60% within 5 years of diagnosis, and 50% of hospitalized patients with HF require readmission within 6 months of discharge. In the US estimated costs amount to > $35 billion per year.3 Although several therapies (eg, β-blockers, angiotensin-converting enzyme [ACE] inhibitors, and cardiac resynchronization therapy) have been proven effective in improving HF outcomes, many unanswered questions about optimal treatment remain. One area of ongoing uncertainty is the appropriate role for antithrombotic therapy in patients with HF. Observational data suggest that patients with HF have an increased venous thromboembolism (VTE) risk (deep venous thromboembolism [DVT], pulmonary embolism [PE], peripheral arterial thromboembolism, and stroke).4 These epidemiological findings are supported by multiple mechanisms that can contribute to a hypercoagulable state in patients with HF. Despite this increased risk of VTE, the role of antithrombotic therapy remains unclear. In this article, we provide an overview of epidemiology, pathophysiology, clinical trial data, and therapeutic recommendations for prevention of thromboembolism in HF. We searched PubMed for articles published between 1958 and 2010 using the following search terms: epidemiology of heart failure , thromboembolism and heart failure , thrombogenesis and heart failure , anticoagulation in heart failure , antiplatelet agent and heart failure , aspirin and heart failure , bleeding risk and anticoagulation , and aspirin and angiotensin-converting enzyme inhibitors . We also studied abstracts from national and international cardiovascular meetings to identify unpublished studies using the key words anticoagulation and dilated cardiomyopathy . Data from published observational studies and secondary …

Peripartum Cardiomyopathy

ACE inhibitors and AT1 receptor antagonists: Is two better than one?

Analysis of Recent Papers in Hypertension. Jan Basile, MD, Section Editor

Heart failure (HF) remains a major problem in the modern healthcare system, which is a significant cause of hospitalizations, disability and mortality among the population. Left ventricular (LV) ejection fraction (EF) remains one of the main criteria for distribution HF patients into groups and on which the tactics of observation and treatment depend. The European Society of Cardiology distinguishes HF with preserved EF, HF with mid‑range EF, and HF with a reduced EF. Recently, to assess the risks, scientists have divided patients with HF into the following phenotypes according to the left ventricular ejection fraction: stable HF with preserved EF, stable HF with a reduced EF, HF with an increase in EF and HF with a decrease in EF. It has been proven that the lowest mortality rate in the HF group with an increase in EF is 17 %, and the highest mortality rate in the HF group with a decrease in EF is 43 %. From this point of view, special attention is drawn to the HF with mid‑range EF group, since the left ventricular ejection fraction in patients of this group changes more actively than in others (according to studies, after 1 year, the left ventricular ejection fraction increased in 44 % of patients, and decreased in 16 % of cases). To predict changes in the left ventricular ejection fraction, it is promising to determine the levels of biomarkers in the blood. It is known that NT‑proBNP is the most studied and informative cardiac biomarker. Its level in blood plasma correlates with the left ventricular ejection fraction, but focusing only on it is impossible to predict changes in the left ventricular ejection fraction. Moreover, the accuracy of NT‑proBNP determination in the diagnosis and prediction of heart failure is only 75 — 80 %. Other most researched biomarkers, such as galectin‑3, sST‑2, GDF‑15, and high‑sensitivity troponins, separately from each other, were ineffective in predicting changes in left ventricular ejection fraction. Therefore, a multi‑marker forecasting strategy is gaining popularity. The article talks about chronic heart failure (CHF), gives its definition and classification by the left ventricular ejection fraction. A review of modern studies demonstrating the relevance of predicting changes in left ventricular ejection fraction is given, data on the main promising cardiac biomarkers, such as NP, galectin‑3, sST‑2, GDF‑15 and highly sensitive troponins, their advantages and disadvantages in diagnosis and risk stratification in patients with CHF. Including the results of studies of furin, which is a pro‑BNP‑convertase and a promising cardiac biomarker as a component of a multimarker model for predicting the course of heart failure.

Ramipril

Section 5: Management of Asymptomatic Patients with Reduced Left Ventricular Ejection Fraction