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The New England Journal of Medicine Sep 2014We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies,... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
We compared the angiotensin receptor-neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients.
METHODS
In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 (at a dose of 200 mg twice daily) or enalapril (at a dose of 10 mg twice daily), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes.
RESULTS
The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P<0.001). A total of 711 patients (17.0%) receiving LCZ696 and 835 patients (19.8%) receiving enalapril died (hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P<0.001); of these patients, 558 (13.3%) and 693 (16.5%), respectively, died from cardiovascular causes (hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% (P<0.001) and decreased the symptoms and physical limitations of heart failure (P=0.001). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group.
CONCLUSIONS
LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. (Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255.).
Topics: Aged; Aminobutyrates; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Double-Blind Method; Drug Combinations; Enalapril; Female; Heart Failure; Hospitalization; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Neprilysin; Stroke Volume; Tetrazoles; Valsartan
PubMed: 25176015
DOI: 10.1056/NEJMoa1409077 -
The Lancet. Diabetes & Endocrinology May 2017Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Diabetes is an independent risk factor for heart failure progression. Sacubitril/valsartan, a combination angiotensin receptor-neprilysin inhibitor, improves morbidity and mortality in patients with heart failure with reduced ejection fraction (HFrEF), compared with the angiotensin-converting enzyme inhibitor enalapril, and improves peripheral insulin sensitivity in obese hypertensive patients. We aimed to investigate the effect of sacubitril/valsartan versus enalapril on HbA and time to first-time initiation of insulin or oral antihyperglycaemic drugs in patients with diabetes and HFrEF.
METHODS
In a post-hoc analysis of the PARADIGM-HF trial, we included 3778 patients with known diabetes or an HbA ≥6·5% at screening out of 8399 patients with HFrEF who were randomly assigned to treatment with sacubitril/valsartan or enalapril. Of these patients, most (98%) had type 2 diabetes. We assessed changes in HbA, triglycerides, HDL cholesterol and BMI in a mixed effects longitudinal analysis model. Time to initiation of oral antihyperglycaemic drugs or insulin in subjects previously not treated with these agents were compared between treatment groups.
FINDINGS
There were no significant differences in HbA concentrations between randomised groups at screening. During the first year of follow-up, HbA concentrations decreased by 0·16% (SD 1·40) in the enalapril group and 0·26% (SD 1·25) in the sacubitril/valsartan group (between-group reduction 0·13%, 95% CI 0·05-0·22, p=0·0023). HbA concentrations were persistently lower in the sacubitril/valsartan group than in the enalapril group over the 3-year follow-up (between-group reduction 0·14%, 95% CI 0·06-0·23, p=0·0055). New use of insulin was 29% lower in patients receiving sacubitril/valsartan (114 [7%] patients) compared with patients receiving enalapril (153 [10%]; hazard ratio 0·71, 95% CI 0·56-0·90, p=0·0052). Similarly, fewer patients were started on oral antihyperglycaemic therapy (0·77, 0·58-1·02, p=0·073) in the sacubitril/valsartan group.
INTERPRETATION
Patients with diabetes and HFrEF enrolled in PARADIGM-HF who received sacubitril/valsartan had a greater long-term reduction in HbA than those receiving enalapril. These data suggest that sacubitril/valsartan might enhance glycaemic control in patients with diabetes and HFrEF.
FUNDING
Novartis.
Topics: Aged; Aminobutyrates; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Biphenyl Compounds; Blood Glucose; Diabetes Mellitus, Type 2; Drug Combinations; Enalapril; Female; Heart Failure; Humans; Male; Middle Aged; Tetrazoles; Valsartan
PubMed: 28330649
DOI: 10.1016/S2213-8587(17)30087-6 -
BMC Medicine Oct 2022For hypertensive patients without a history of stroke or myocardial infarction (MI), the China Stroke Primary Prevention Trial (CSPPT) demonstrated that treatment with... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
For hypertensive patients without a history of stroke or myocardial infarction (MI), the China Stroke Primary Prevention Trial (CSPPT) demonstrated that treatment with enalapril-folic acid reduced the risk of primary stroke compared with enalapril alone. Whether folic acid therapy is an affordable and beneficial treatment strategy for the primary prevention of stroke in hypertensive patients from the Chinese healthcare sector perspective has not been thoroughly explored.
METHODS
We performed a cost-effectiveness analysis alongside the CSPPT, which randomized 20,702 hypertensive patients. A patient-level microsimulation model based on the 4.5-year period of in-trial data was used to estimate costs, life years, quality-adjusted life years (QALYs), and incremental cost-effectiveness ratios (ICERs) for enalapril-folic acid vs. enalapril over a lifetime horizon from the payer perspective.
RESULTS
During the in-trial follow-up period, patients receiving enalapril-folic acid gained an average of 0.016 QALYs related primarily to reductions in stroke, and the incremental cost was $706.03 (4553.92 RMB). Over a lifetime horizon, enalapril-folic acid treatment was projected to increase quality-adjusted life years by 0.06 QALYs or 0.03 life-year relative to enalapril alone at an incremental cost of $1633.84 (10,538.27 RMB), resulting in an ICER for enalapril-folic acid compared with enalapril alone of $26,066.13 (168,126.54 RMB) per QALY gained and $61,770.73 (398,421.21 RMB) per life-year gained, respectively. A probabilistic sensitivity analysis demonstrated that enalapril-folic acid compared with enalapril would be economically attractive in 74.5% of simulations at a threshold of $37,663 (242,9281 RMB) per QALY (3x current Chinese per capita GDP). Several high-risk subgroups had highly favorable ICERs < $12,554 (80,976 RMB) per QALY (1x GDP).
CONCLUSIONS
For both in-trial and over a lifetime, it appears that enalapril-folic acid is a clinically and economically attractive medication compared with enalapril alone. Adding folic acid to enalapril may be a cost-effective strategy for the prevention of primary stroke in hypertensive patients from the Chinese health system perspective.
Topics: Humans; Cost-Benefit Analysis; Enalapril; Folic Acid; Hypertension; Primary Prevention; Quality-Adjusted Life Years; Stroke
PubMed: 36280851
DOI: 10.1186/s12916-022-02601-z -
The New England Journal of Medicine Aug 1991Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently. We studied the effect of an angiotensin-converting-enzyme... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
BACKGROUND
Patients with congestive heart failure have a high mortality rate and are also hospitalized frequently. We studied the effect of an angiotensin-converting-enzyme inhibitor, enalapril, on mortality and hospitalization in patients with chronic heart failure and ejection fractions less than or equal to 0.35.
METHODS
Patients receiving conventional treatment for heart failure were randomly assigned to receive either placebo (n = 1284) or enalapril (n = 1285) at doses of 2.5 to 20 mg per day in a double-bind trial. Approximately 90 percent of the patients were in New York Heart Association functional classes II and III. The follow-up averaged 41.4 months.
RESULTS
There were 510 deaths in the placebo group (39.7 percent), as compared with 452 in the enalapril group (35.2 percent) (reduction in risk, 16 percent; 95 percent confidence interval, 5 to 26 percent; P = 0.0036). Although reductions in mortality were observed in several categories of cardiac deaths, the largest reduction occurred among the deaths attributed to progressive heart failure (251 in the placebo group vs. 209 in the enalapril group; reduction in risk, 22 percent; 95 percent confidence interval, 6 to 35 percent). There was little apparent effect of treatment on deaths classified as due to arrhythmia without pump failure. Fewer patients died or were hospitalized for worsening heart failure (736 in the placebo group and 613 in the enalapril group; risk reduction, 26 percent; 95 percent confidence interval, 18 to 34 percent; P less than 0.0001).
CONCLUSIONS
The addition of enalapril to conventional therapy significantly reduced mortality and hospitalizations for heart failure in patients with chronic congestive heart failure and reduced ejection fractions.
Topics: Blood Pressure; Cause of Death; Chronic Disease; Double-Blind Method; Electrolytes; Enalapril; Female; Follow-Up Studies; Heart Failure; Hospitalization; Humans; Kidney; Male; Middle Aged; Patient Compliance; Stroke Volume; Survival Rate
PubMed: 2057034
DOI: 10.1056/NEJM199108013250501 -
The New England Journal of Medicine Apr 2016Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such... (Comparative Study)
Comparative Study Randomized Controlled Trial
BACKGROUND
Among patients with chronic heart failure, angiotensin-converting-enzyme (ACE) inhibitors reduce mortality and hospitalization, but the role of a renin inhibitor in such patients is unknown. We compared the ACE inhibitor enalapril with the renin inhibitor aliskiren (to test superiority or at least noninferiority) and with the combination of the two treatments (to test superiority) in patients with heart failure and a reduced ejection fraction.
METHODS
After a single-blind run-in period, we assigned patients, in a double-blind fashion, to one of three groups: 2336 patients were assigned to receive enalapril at a dose of 5 or 10 mg twice daily, 2340 to receive aliskiren at a dose of 300 mg once daily, and 2340 to receive both treatments (combination therapy). The primary composite outcome was death from cardiovascular causes or hospitalization for heart failure.
RESULTS
After a median follow-up of 36.6 months, the primary outcome occurred in 770 patients (32.9%) in the combination-therapy group and in 808 (34.6%) in the enalapril group (hazard ratio, 0.93; 95% confidence interval [CI], 0.85 to 1.03). The primary outcome occurred in 791 patients (33.8%) in the aliskiren group (hazard ratio vs. enalapril, 0.99; 95% CI, 0.90 to 1.10); the prespecified test for noninferiority was not met. There was a higher risk of hypotensive symptoms in the combination-therapy group than in the enalapril group (13.8% vs. 11.0%, P=0.005), as well as higher risks of an elevated serum creatinine level (4.1% vs. 2.7%, P=0.009) and an elevated potassium level (17.1% vs. 12.5%, P<0.001).
CONCLUSIONS
In patients with chronic heart failure, the addition of aliskiren to enalapril led to more adverse events without an increase in benefit. Noninferiority was not shown for aliskiren as compared with enalapril. (Funded by Novartis; ATMOSPHERE ClinicalTrials.gov number, NCT00853658.).
Topics: Aged; Amides; Angiotensin-Converting Enzyme Inhibitors; Chronic Disease; Diabetes Mellitus, Type 2; Double-Blind Method; Drug Therapy, Combination; Enalapril; Female; Follow-Up Studies; Fumarates; Heart Failure; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Renin; Stroke Volume; Treatment Failure
PubMed: 27043774
DOI: 10.1056/NEJMoa1514859 -
Archives of Pathology & Laboratory... Nov 2003Angiotensin-converting enzyme inhibitors are prescribed for many cardiovascular and renal diseases. Adverse hepatic events, especially cholestasis, have rarely been... (Comparative Study)
Comparative Study
CONTEXT
Angiotensin-converting enzyme inhibitors are prescribed for many cardiovascular and renal diseases. Adverse hepatic events, especially cholestasis, have rarely been reported with captopril, enalapril, lisinopril, and fosinopril. To date, hepatic injury associated with ramipril has not been reported.
OBJECTIVE
To describe 3 patients who developed hepatitis, with or without jaundice, after receiving ramipril.
DESIGN
Medical records and liver biopsies of the 3 patients were reviewed. Clinical, laboratory, and histologic findings were compared with findings in other cases of angiotensin-converting enzyme inhibitor-induced liver injury reported in the literature.
RESULTS
The 3 patients were middle-aged men. In 2 patients, jaundice appeared 4 and 8 weeks after starting ramipril. Bilirubin levels peaked at 15.5 and 5 mg/dL, and alkaline phosphatase values peaked at 957 and 507 U/L. Aminotransferase levels were mildly elevated. Endoscopic retrograde cholangiopancreatography and ultrasonography showed no bile duct obstruction. Liver biopsies from the jaundiced patients were similar, with cholestasis, duct necrosis, and extravasation of bile, ductular proliferation, and portal inflammation. Cholestasis improved in 1 patient 6 weeks after stopping ramipril and was prolonged for 14 months in the other, in whom biliary cirrhosis was present on biopsy. The third patient developed hepatitis without jaundice 3 weeks after starting ramipril; symptoms resolved after stopping the drug. Ramipril-associated liver injury is similar to that seen with other angiotensin-converting enzyme inhibitors, but liver biopsy findings of duct necrosis and extravasation of bile have not been reported previously.
CONCLUSION
Prolonged cholestatic hepatitis and biliary cirrhosis may result from the use of ramipril. Monitoring of liver enzymes is advisable for patients starting on ramipril.
Topics: Angiotensin-Converting Enzyme Inhibitors; Captopril; Chemical and Drug Induced Liver Injury, Chronic; Cholangiopancreatography, Endoscopic Retrograde; Cholestasis, Intrahepatic; Enalapril; Fosinopril; Humans; Jaundice; Liver; Liver Cirrhosis, Biliary; Liver Function Tests; Male; Middle Aged; Ramipril
PubMed: 14567716
DOI: 10.5858/2003-127-1493-RH -
European Review For Medical and... Oct 2022The aim of the study was to review the literature on clinical pharmacology of lercanidipine and experimental and clinical evidence and evaluate its ability to reduce... (Review)
Review
OBJECTIVE
The aim of the study was to review the literature on clinical pharmacology of lercanidipine and experimental and clinical evidence and evaluate its ability to reduce proteinuria and preserve renal function when used as monotherapy or in combination with the angiotensin-converting enzyme (ACE) inhibitor enalapril.
MATERIALS AND METHODS
MEDLINE/PubMed was searched for appropriate keywords.
RESULTS
Lercanidipine, a third-generation calcium channel blocker, has been shown to have a unique pharmacological and clinical profile, which translates into favorable renal hemodynamic changes. The fixed-dose combination lercanidipine/enalapril has been proposed to overcome unmet therapeutic needs, often as the initial treatment in the high-risk patient.
CONCLUSIONS
Lercanidipine may be regarded as an ideal antihypertensive drug for patients at renal risk and possibly the preferred choice among calcium channel blocker drugs.
Topics: Humans; Antihypertensive Agents; Enalapril; Calcium Channel Blockers; Hypertension; Angiotensin-Converting Enzyme Inhibitors; Kidney; Blood Pressure
PubMed: 36314318
DOI: 10.26355/eurrev_202210_30018 -
Cell Death & Disease Jun 20205-Fluorouracil (5-FU) is one of the most effective drugs for the treatment of colorectal cancer (CRC). However, there is an urgent need in reducing its systemic side...
Enalapril overcomes chemoresistance and potentiates antitumor efficacy of 5-FU in colorectal cancer by suppressing proliferation, angiogenesis, and NF-κB/STAT3-regulated proteins.
5-Fluorouracil (5-FU) is one of the most effective drugs for the treatment of colorectal cancer (CRC). However, there is an urgent need in reducing its systemic side effects and chemoresistance to make 5-FU-based chemotherapy more effective and less toxic in the treatment of CRC. Here, enalapril, a clinically widely used antihypertensive and anti-heart failure drug, has been verified as a chemosensitizer that extremely improves the sensitivity of CRC cells to 5-FU. Enalapril greatly augmented the cytotoxicity of 5-FU on the cell growth in both established and primary CRC cells. The combination of enalapril and 5-FU synergistically suppressed the cell migration and invasion in both 5-FU-sensitive and -resistant CRC cells in vitro, and inhibited angiogenesis, tumor growth, and metastasis of 5-FU-resistant CRC cells in vivo without increased systemic toxicity at concentrations that were ineffective as individual agents. Furthermore, combined treatment cooperatively inhibited NF-κB/STAT3 signaling pathway and subsequently reduced the expression levels of NF-κB/STAT3-regulated proteins (c-Myc, Cyclin D1, MMP-9, MMP-2, VEGF, Bcl-2, and XIAP) in vitro and in vivo. This study provides the first evidence that enalapril greatly sensitized CRC cells to 5-FU at clinically achievable concentrations without additional toxicity and the synergistic effect may be mainly by cooperatively suppressing proliferation, angiogenesis, and NF-κB/STAT3-regulated proteins.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Cell Movement; Cell Proliferation; Colorectal Neoplasms; Down-Regulation; Drug Resistance, Neoplasm; Drug Synergism; Enalapril; Epithelial-Mesenchymal Transition; Fluorouracil; Humans; Mice, Nude; NF-kappa B; Neoplasm Invasiveness; Neoplasm Metastasis; Neovascularization, Pathologic; STAT3 Transcription Factor; Signal Transduction
PubMed: 32581212
DOI: 10.1038/s41419-020-2675-x -
Acta Dermatovenerologica Alpina,... Sep 2023Keloids are pathologic conditions characterized by fibroblast hyper-proliferation and excess collagen deposition. Enalapril, one of the angiotensin-converting enzyme...
INTRODUCTION
Keloids are pathologic conditions characterized by fibroblast hyper-proliferation and excess collagen deposition. Enalapril, one of the angiotensin-converting enzyme inhibitors, has recently been highlighted as a new therapeutic modality in treating keloids. This study evaluates the effectiveness of intralesional injection of enalapril versus triamcinolone acetonide (TAA) in keloids.
METHODS
Forty patients with multiple keloids were enrolled in our study. Enalapril and TAA were injected intralesionally in one session per month for three sessions. The clinical outcomes were assessed via the Vancouver Scar Scale (VSS) and the Patient and Observer Scar Assessment Scale (POSAS).
RESULTS
In both groups, according to VSS and POSAS, there was a high statistically significant difference (p-value ≤ 0.01) before treatment, at the end of each session, and 3 months after treatment. There was no significant difference between both groups regarding degree of improvement. Patients treated with TAA developed more significant complications than those in the enalapril group (p-value < 0.05).
CONCLUSIONS
Both enalapril and TAA had the same clinical effect. Enalapril could be a safe alternative to steroids in the treatment of keloid and hypertrophic scars. Further studies on enalapril are needed on a large sample of patients with further focus on the mechanism of this innovative drug.
Topics: Humans; Injections, Intralesional; Keloid; Triamcinolone Acetonide; Enalapril; Cicatrix, Hypertrophic
PubMed: 37749966
DOI: No ID Found -
British Journal of Pharmacology Nov 2021Diabetic nephropathy is a common complications related to high morbidity and mortality in type 2 diabetes. We investigated the action of the dual modulator, PTUPB, a...
BACKGROUND AND PURPOSE
Diabetic nephropathy is a common complications related to high morbidity and mortality in type 2 diabetes. We investigated the action of the dual modulator, PTUPB, a soluble epoxide hydrolase and cyclooxygenase-2 inhibitor against diabetic nephropathy.
EXPERIMENTAL APPROACH
Sixteen-week-old type 2 diabetic and proteinuric obese ZSF1 rats were treated with vehicle, PTUPB or enalapril for 8 weeks. Measurements were made of epoxyeicosatrienoic acids, thromboxane B (TBX ) and prostaglandin E2 (PGE ) in the kidney of these and lean ZSF1 rats along with their blood pressure.
KEY RESULT
Obese ZSF1 rats were diabetic with fivefold higher fasting blood glucose levels and markedly higher HbA1c levels compared with lean ZSF1 rats. PTUPB nor enalapril reduced fasting blood glucose or HbA1c but alleviated the development of diabetic nephropathy. In PTUPB-treated obese ZSF1 rats, glomerular nephrin expression was preserved. Enalapril also alleviated diabetic nephropathy. Diabetic renal injury in obese ZSF1 rats was accompanied by renal inflammation with six to sevenfold higher urinary MCP-1 (CCR2) level and renal infiltration of CD-68 positive cells. PTUPB and enalapril significantly reduced urinary MCP-1 levels and renal mRNA expression of cytokines. Both PTUPB and enalapril lowered blood pressure. PTUPB but not enalapril decreased hyperlipidaemia and liver injury in obese ZSF1 rats.
CONCLUSION AND IMPLICATIONS
Overall, the dual modulator PTUPB does not treat hyperglycaemia but can effectively alleviate hypertension, diabetic nephropathy, hyperlipidaemia and liver injury in type 2 diabetic rats. Our data further demonstrate that the renal actions of PTUPB are comparable with a current standard diabetic nephropathy treatment.
Topics: Animals; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Enalapril; Kidney; Rats
PubMed: 34255857
DOI: 10.1111/bph.15623