Despite celiprolol therapy, patients with vascular Ehlers-Danlos syndrome remain at risk of vascular events: A 12-year experience in an Italian referral center.

BACKGROUND: Vascular Ehlers-Danlos syndrome (vEDS) is an inherited connective tissue disorder characterized by arterial fragility. Celiprolol has been suggested to significantly reduce rates of vascular events in this setting, though real-world evidence is limited. The aim of this study was to report our experience with celiprolol therapy in vEDS management. METHODS: Patients with a genetically confirmed diagnosis of vEDS who were referred for outpatient consultation at the Brescia University Hospital between January 2011 and July 2023 were included. At each visit, patients' medical history, results of vascular imaging, and office blood pressure measurements were recorded. Celiprolol therapy was progressively titrated to the maximum tolerated dose of up to 400 mg daily, according to the patients' tolerance. RESULTS: Overall, 26 patients were included. Female sex was prevalent (62%). Mean (SD) age was 37 (16) years. Follow-up duration was 72 (41) months. At the last follow-up visit, all patients were on celiprolol therapy, 80% of whom were taking the maximum recommended dose. The yearly risk of symptomatic vascular events was 8.8%, the majority of which occurred after reaching the maximum recommended dose of celiprolol. No significant predictor of symptomatic vascular events was identified among patients' clinical characteristics. CONCLUSION: In our cohort, rates of celiprolol use were high and the drug was well tolerated overall. Nonetheless, the risk of symptomatic vascular events remained nonnegligible. Future studies should identify reliable predictors of major adverse events and explore additional therapeutic strategies that could further lower the risk of life-threatening events in this population.

Do beta-adrenergic blocking agents increase asthma exacerbation? A network meta-analysis of randomized controlled trials.

Beta-adrenergic blocking agents (abbreviated as beta-blockers) have been used for treating various cardiovascular diseases. However, the potential for asthma exacerbation is one of the major adverse effects of beta-blockers. This study aimed to compare the level of risk for an asthma attack in patients receiving various beta-blockers. We searched for randomized controlled trials (RCTs) of either placebo-controlled or active-controlled design. The current network meta-analysis (NMA) was conducted under a frequentist model. The primary outcome was the incidence of asthmatic attack. A total of 24 RCTs were included. Overall NMA revealed that only oral timolol [risk ratio (RR) = 3.35 (95% confidence interval (CI) 1.04-10.85)] and infusion of propranolol [RR = 10.19 (95% CI 1.29-80.41)] were associated with significantly higher incidences of asthma attack than the placebo, whereas oral celiprolol [RR = 0.39 (95% CI 0.04-4.11)], oral celiprolol and propranolol [RR = 0.46 (95% CI 0.02-11.65)], oral bisoprolol [RR = 0.46 (95% CI 0.02-11.65)], oral atenolol [RR = 0.51 (95% CI 0.20-1.28)], infusion of practolol [RR = 0.80 (95% CI 0.03-25.14)], and infusion of sotalol [RR = 0.91 (95% CI 0.08-10.65)] were associated with relatively lower incidences of asthma attack than the placebo. In participants with a baseline asthma history, in addition to oral timolol and infusion of propranolol, oral labetalol, oxprenolol, propranolol, and metoprolol exhibited significantly higher incidences of asthma attack than did the placebo. In conclusion, oral timolol and infusion of propranolol were associated with a significantly higher risk of developing an asthma attack in patients, especially in those with a baseline asthma history, and should be avoided in patients who present a risk of asthma.Trial registration: PROSPERO CRD42020190540.

Effects of Celiprolol and Bisoprolol on Blood Pressure, Vascular Stiffness, and Baroreflex Sensitivity.

BACKGROUND: We tested the hypothesis that celiprolol and bisoprolol have differential effects on blood pressure (BP), flow-mediated dilation (FMD), and vascular stiffness. METHODS: We analyzed 102 hypertensives (mean age: 59±14 years) who were being treated other than beta-blockers. They were randomized to receive add-on treatment with either celiprolol 100-200mg (C group) or bisoprolol 2.5-5mg (B group), and followed up for 3 months. In addition to clinic, home, and ambulatory BP monitoring, the FMD, radial augmentation index (AI), brachial-ankle pulse wave velocity (baPWV), urine albumin-to-creatinine ratio, and baroreflex sensitivity (BRS) were measured at baseline and at the end of the study. RESULTS: Compared to the baseline values, home and 24-hour BP were significantly lowered in the third month in both groups (all Ps < 0.05). Pulse rate (PR) and baPWV were reduced (P < 0.001), and BRS was increased significantly only in the B group (P = 0.02). Radial AI was unchanged in the C group but was significantly increased in the B group (P < 0.001). Central BP was significantly reduced in the C group (P = 0.003) but was unchanged in the B group. FMD was significantly increased in both groups (both P < 0.01). CONCLUSION: Bisoprolol achieved the greater reduction of PR and improved BRS and vascular stiffness, whereas, celiprolol reduced the central BP level. In treated hypertensive patients, add-on use of celiprolol may be favorable in uncomplicated stage of hypertension. On the other hand, bisoprolol may be useful in hypertensives with cardiac or vascular diseases who have advanced atherosclerotic changes and sympathetic nervous system activation.

Celiprolol-induced lupus-like syndrome.

Systemic lupus erythematosus can be idiopathic or drug-induced. Although a number of beta-blockers have been reported to induce a lupus-like syndrome, to the best of our knowledge, no such case has been described following celiprolol therapy. We diagnosed a lupus-like syndrome in a 67-year-old female patient who developed febrile polyarthritis, percarditis, antinuclear and anti-histone antibodies after taking celiprolol for 2 years. Despite drug withdrawal, prolonged corticotherapy was needed to obtain clinical and biological remission.

Detrimental effects of beta-blockers in COPD: a concern for nonselective beta-blockers.

INTRODUCTION: beta-Blockers are known to worsen FEV(1) and airway hyperresponsiveness (AHR) in patients with asthma. Both characteristics determine the outcome of COPD, a disease with frequent cardiac comorbidity requiring beta-blocker treatment. OBJECTIVE: To determine the effects of beta-blockers on AHR (provocative concentration of methacholine causing a 20% fall in FEV(1) [PC(20)]), FEV(1), and response to formoterol in patients with COPD. DESIGN: A double-blind, placebo-controlled, randomized, cross-over study. SETTING: An ambulatory, hospital outpatient clinic of pulmonary diseases. PATIENTS: Patients with mild-to-moderate irreversible COPD and AHR. INTERVENTION: Fifteen patients received propranolol (80 mg), metoprolol (100 mg), celiprolol (200 mg), or placebo for 4 days, followed by a washout period >/= 3 days. On day 4 of treatment, FEV(1) and PC(20) were assessed. Immediately hereafter, formoterol (12 microg) was administered and FEV(1) was measured for up to 30 min. RESULTS: PC(20) was significantly lower (p < 0.01) with propranolol and metoprolol treatment (geometric means, 2.06 mg/mL and 2.02 mg/mL, respectively) than with placebo (3.16 mg/mL) or celiprolol (3.41 mg/mL). FEV(1) deteriorated only after propranolol treatment (2.08 +/- 0.31 L) [mean +/- SD] compared with placebo (2.24 +/- 0.37 L). The fast bronchodilating effect of formoterol was hampered by propranolol (mean increase in FEV(1) at 3 min, 6.7 +/- 8.9%) but was unaffected by the other beta-blockers (16.9 +/- 9.8%, 22 +/- 11.6%, and 16.9 +/- 9.0% for placebo, metoprolol, and celiprolol, respectively). CONCLUSIONS: Pulmonary effects did not occur by celiprolol. Only propranolol reduced FEV(1) and the bronchodilating effect of formoterol. Both metoprolol and propranolol increased AHR. Thus, different classes of beta-blockers have different pulmonary effects. The anticipated beneficial cardiovascular effects of a beta-blocker must be weighted against the putative detrimental pulmonary effects, ie, effect on FEV(1), AHR, and response to additional beta(2)-agonists.

[Safety and efficacy of celiprolol in hypertensive patients with chronic obstructive lung disease]. / Seguridad y eficacia de celiprolol en hipertensos con enfermedad pulmonar obstructiva crónica.

BACKGROUND: Third generation beta blockers have an intrinsic simpatico-mimetic activity and are cardioselective. Therefore, they should not have adverse bronchial effects and could even have a slight bronchodilator activity. AIM: To test the efficacy and safety of celiprolol in hypertensive patients with chronic obstructive lung disease. PATIENTS AND METHODS: Uncomplicated hypertensive patients with chronic obstructive lung disease received celiprolol during 12 weeks. They were subjected to monthly clinical assessment and ventilatory function was measured on the basal period and at the end of the trial. RESULTS: During the study period, blood pressure fell significantly from 179 +/- 6/112 +/- 8 to 161 +/- 4.7/98 +/- 1.6 mmHg. No changes were observed in forced expiratory volume in 1 s or in forced expiratory flow between 25 and 75% of the vital capacity. No subjective changes in respiratory function were reported during the trial. CONCLUSIONS: No changes in ventilatory function were observed in these patients with chronic obstructive lung disease, treated with celiprolol during 12 weeks.

Treatment of heart failure with celiprolol, a cardioselective beta blocker with beta-2 agonist vasodilatory properties. The CELICARD Group.

Treatment with beta blockers results in improvement in functional status, and reduces mortality in patients with heart failure. A number of differences in the results noted could be due to additional properties of the specific beta blockers studied: absence of cardioselectivity, and existence of a vasodilator effect and of an associated antioxidant effect. We studied the effects of celiprolol, a cardioselective beta blocker with a stimulant effect on beta2 receptors. One hundred thirty-two patients presenting with chronic heart failure of various etiologies, with an ejection fraction of <40% and New York Heart Association cardiac functional status grades II and III were included in a randomized, double-blind, placebo-controlled study. The maximum dose of celiprolol (100 mg) was attained after 1 month. The study lasted 1 year. The primary evaluation criterion was functional class as evaluated using the Goldman questionnaire. There was no difference in efficacy between the 2 treatment groups in terms of functional class (p = 0.56). With regard to the secondary evaluation criteria, an improvement in DiBianco functional score was seen with celiprolol (p = 0.03), as well as a significant reduction in heart rate (p = 0.01). Ejection fraction increased in both groups (p = 0.15). There was no difference regarding improvement in left ventricular volume as determined at echocardiography or in exercise capacity. The safety profile of celiprolol was excellent. There was no difference in terms of cardiovascular mortality (2 receiving celiprolol vs 4 placebo), onset of arrhythmias (2 receiving celiprolol vs 3 placebo), worsening of heart failure (26 receiving celiprolol vs 23 placebo), or noncardiovascular adverse events (9 receiving celiprolol vs 14 placebo). The absence of a significant efficacy of celiprolol, a beta blocker with vasodilator properties, but exerting stimulation of beta2 receptors, suggests an unfavorable role of this latter property in heart failure. However, the safety profile of celiprolol was excellent. This beta blocker may consequently be used for its other indications, hypertension and angina, in patients presenting with altered cardiac function.

Hypotension in patients with coronary disease: can profound hypotensive events cause myocardial ischaemic events?

OBJECTIVE: To determine whether anginal episodes might be related to extremes of hypotension in patients with ischaemic heart disease taking drugs to treat angina and heart failure. DESIGN AND SETTING: Observational study of patients with ischaemic heart disease attending an urban tertiary referral cardiology centre. INTERVENTIONS AND OUTCOME MEASURES: A selected patient population was enrolled, having: angina on one or more hypotensive cardiovascular medications; hypotension on clinic or ambulatory measurement; and a resting ECG suitable for ambulatory monitoring. Patients had echocardiography, ambulatory blood pressure monitoring, and Holter monitoring. Hypotension induced ischaemic (HII) events were defined as episodes of ST segment ischaemia occurring at least one minute after an ambulatory blood pressure measurement (systolic/diastolic) below 100/65 mm Hg during the day, or 90/50 mm Hg at night. RESULTS: 25 suitable patients were enrolled, and 107 hypotensive events were documented. 40 ST events occurred in 14 patients, of which a quarter were symptomatic. Fourteen HII events occurred in eight patients, with 13 of the 14 preceded by a fall in diastolic pressure (median diastolic pressure 57.5 mm Hg, interquartile range 11, maximum 72 mm Hg, minimum 45 mm Hg), and six preceded by a fall in systolic pressure (chi(2) = 11.9, p < 0.001). ST events were significantly associated with preceding hypotensive events (chi(2) = 40.2, p < 0.0001). Patients with HII events were more frequently taking multiple hypotensive drug regimens (8/8 v 9/17, chi(2) = 5.54, p = 0.022). CONCLUSIONS: In patients with ischaemic heart disease and hypotension, symptomatic and silent ischaemia occurred in a temporally causal relation with hypotension, particularly for diastolic pressures, suggesting that patients with coronary disease may be susceptible to ischaemic events incurred as a result of low blood pressure caused by excessive hypotensive drug treatment.

Quality of life before and during antihypertensive treatment: a comparative study of celiprolol and atenolol.

Hypertensive patients may be adversely affected by complications and other concomitant processes such as anxiety, sedation, and drug side effects. It has been suggested that some recently developed antihypertensive agents do not affect quality of life by causing adverse effects. We compared the effects of two antihypertensive drugs on quality of life: atenolol, a standard cardioselective beta-blocker, and celiprolol, one of a new class of selective beta-blockers with vasodilatory properties. One hundred thirty-two patients with mild-to-moderate hypertension were eligible to enter a 28-week, double-blind, parallel-group study. The study protocol consisted of a 4-week period on placebo and a 24-week period of dosage-adjusted treatment with either atenolol or celiprolol. We assessed both systolic and diastolic blood pressure and quality of life perception by a selected test battery that included the Bulpitt and Fletcher Quality of Life Questionnaire. Supine blood pressure fell from 167/101 (range 120/95 to 200/116) to 150/92 mm Hg (p < 0. 0001) during celiprolol treatment. This antihypertensive effect was at least as good with celiprolol as with atenolol. Quality of life perception was comparable for the two drugs although adverse effects were seen more frequently with atenolol than with celiprolol, particularly after prolonged treatment. Patient compliance was better for celiprolol than for atenolol. Our results show that the selective beta-blocker with vasodilatory property celiprolol is at least as effective as atenolol and that it is more advantageous in terms of some quality of life variables.

Beta-blockers and nitrates in patients with peripheral arterial occlusive disease: long-term findings.

METHODS: The effect of 6 months' administration of celiprolol, atenolol and isosorbide dinitrate on peripheral arterial occlusive disease (PAOD), double-blind and placebo-controlled, was investigated in 56 patients with chronic ischaemic heart disease and stage IIb PAOD, using as criteria the walking distance and the change in resistance index in the femoral artery. The placebo group consisted of 14 patients with chronic ischaemic heart disease and the same stage of PAOD. RESULTS: Patients on 50 mg/day atenolol showed a significant reduction in both pain-free and maximal walking range compared with the controls. In contrast, those taking 200 mg/day celiprolol and those on 80 mg/day isosorbide dinitrate demonstrated significant increases in pain-free and maximal, walking distance compared with the control group. The colour duplex sonographically measured Doppler flow through the femoral artery showed a significant decrease both in the patients taking celiprolol and in those on isosorbide dinitrate, while in those receiving atenolol the resistance index increased significantly. CONCLUSIONS: The study shows that the beta-adrenoceptor blocker celiprolol also possesses a nitrate-like vasodilatory property and can be used in patients with chronic ischaemic heart disease and impaired peripheral arterial blood flow.

Quality of life before and during antihypertensive treatment: a comparative study of celiprolol and atenolol.

BACKGROUND: The well-being of hypertensive patients may be adversely affected by the disease itself, its complications, and other concomitant processes such as anxiety, sedation, and side effects of the prescribed drugs. Some recently developed antihypertensive agents have been suggested to be devoid of these deleterious effects on well-being expressed as quality of life. OBJECT: We compared the effect on quality of life of a standard cardioselective beta-blocker atenolol to the effect of celiprolol as a representative of a new class of selective beta-blockers with vasodilatory properties. One-hundred-thirty-two patients with mild to moderate hypertension were eligible to enter a 28-week double-blind parallel-group study, consisting of a 4-week run-in period on placebo and a 24-week period on dosage-adjusted treatment with either atenolol or celiprolol. RESULTS: Both systolic and diastolic blood pressure were assessed, as was quality of life perception by a selected test battery including the Quality of Life Questionnaire of Bulpitt and Fletcher [1990]. During celiprolol treatment, supine blood pressure fell from 167/101 (range 120-200/95-116) to 150/92 mm Hg (p < 0.0001). This antihypertensive effect was at least as good with celiprolol as with atenolol. Quality of life perception was comparable for the 2 drugs, although some adverse effects were more frequent during atenolol than during celiprolol, particularly after prolonged treatment. Also patient compliance was better for celiprolol than for atenolol. CONCLUSIONS: Our results show that the selective beta-blocker with vasodilatory property celiprolol is at least as effective as atenolol and that it has additional advantage in terms of enhancement of some quality of life variables.

Association between serum lipids, glucose tolerance, and insulin sensitivity during 12 months of celiprolol treatment.

The study was undertaken to evaluate the development and association of parameters related to the metabolic syndrome during celiprolol treatment. Hyperinsulinemic euglycemic clamp and independent oral glucose tolerance tests (OGTT) were performed on 25 nondiabetic patients with controlled hypertension and dyslipidemia. The tests were carried out during the patients' previous antihypertensive monotherapy (beta- or Ca-blocker, or an ACE inhibitor), and after 6 and 12 months of celiprolol treatment. About one third of patients were randomized to a control group in which treatment was kept unchanged. Insulin sensitivity index (ISI), measured by the euglycemic clamp test, increased 35% in the celiprolol group at 6 months and remained at that level at 12 months, independent of the previous treatment (p = 0.03, compared to the change in the control group). During a 2 hour OGTT, incremental glucose area under the curve (AUC) decreased from 4.5 to 1.9 hr x mmol/l during 6 months of celiprolol treatment, and decreased further to 1.5 hr x mmol/l at 12 months (p < 0.001). Insulin AUC decreased from 113 to 72 hr x mU/l, and decreased further to 68 hr x mU/l (p < 0.01). All insulin parameters in OGTT were highly significant (p < 0.0001) and inversely associated with ISI. Insulin AUC had the best linear correlation with ISI (r = -0.682, p < 0.0001). Glucose parameters in OGTT correlated only weakly and inversely with insulin sensitivity. From the fasting serum lipids, triglycerides showed an inverse (p < 0.001) and HDL a weak (p < 0.05) positive association with ISI. Four out of 20 metabolic, clinical, and demographic parameters proved to be independently significant predictors for ISI in multiple regression analysis. These were insulin AUC, fasting insulin levels, triglyceride values, and age. The coefficient of determination in this four-parameter linear model was 69%. In this preliminary, observer-masked trial with a limited control group, celiprolol improved the impaired insulin sensitivity and glucose tolerance of dyslipidemic hypertensive patients. A fairly predictive model can be formulated to evaluate the peripheral insulin sensitivity of hypertensive patients with suspected metabolic syndrome using OGTT with serum insulin determinations.

Left ventricular and aortic root structure and function changes with beta blocker antihypertensive therapy. A one-year double blind study of celiprolol and metoprolol.

Using echocardiographic and Doppler methodology, we evaluated the effects of celiprolol 200-400 mg/day and metoprolol 100-200 mg/day, given for one year, on haemodynamics, left ventricular structure and function, and aortic root distensibility in 40 hypertensive patients. Total peripheral resistance was unchanged with metoprolol (-1.7%) but decreased with celiprolol (-11.2%), a significant difference between the two treatments (P = 0.01). Left ventricular mass index was reduced by 5.7% in those patients receiving metoprolol and by 11.8% in those receiving celiprolol (P < 0.001). Cardiac index fell significantly with metoprolol and marginally with celiprolol (-13.9% vs. 5.9%, P = 0.003). Left ventricular diastolic function-as shown by the transmitral early to late peak filling velocity ratio-was not altered with metoprolol, but a significant increase (17%, P = 0.2) was seen with celiprolol. Both metoprolol and celiprolol increased aortic root distensibility, with celiprolol having a significantly greater effect (80% vs. 30%, P < 0.01). We conclude that, in comparison to metoprolol, long term antihypertensive therapy with celiprolol improves left ventricular diastolic and aortic root function, whilst reducing total peripheral resistance and left ventricular hypertrophy.

Effect of celiprolol and metoprolol on lipids, fibrinogen and airways function in hyperlipidaemic hypertensives: a randomised double-blind long-term parallel group trial.

The effects of celiprolol 200 mg or 400 mg once daily on blood pressure (BP), serum lipids, plasma fibrinogen and airways function was compared with the effects of metoprolol 100 mg or 200 mg once daily in 171 patients with mild to moderate hypertension and coexistent hyperlipidaemia in a double-blind, multicentre study lasting 1 year. Significant decreases in systolic and diastolic blood pressure and heart rate were observed compared with baseline (DBP: celiprolol -13.3 mm Hg, P < 0.0001; metoprolol -14.3 mm Hg, P < 0.0001; SBP: celiprolol -18.2 mm Hg, P < 0.0001; metoprolol -20.5 mm Hg, P < 0.0001; heart rate celiprolol -4 beats/min, P < 0.003; metoprolol -12 beats/min, P < 0.0001). There was no difference between the effects of the two treatments on BP but celiprolol had less effect on heart rate than metoprolol, (celiprolol-metoprolol 7.3 beats/min, P = 0.0002). When compared with baseline values celiprolol significantly reduced serum low density lipoprotein cholesterol (LDL-C) (-5.8%, P = 0.0401) and produced a slight increase in high density lipoprotein cholesterol (HDL-C) which approached statistical significance (4.1%, P = 0.0659). Metoprolol significantly increased serum triglycerides (32%, P = 0.0001) and the total/HDL-C ratio (7.4%, P = 0.0192). Compared with metoprolol, celiprolol significantly reduced LDL-C (-7.3%, P = 0.0062), total cholesterol (-4.5%, P = 0.0085), apoliproprotein B (-10.1%, P = 0.0001), the apolipoprotein B/A1 ratio (-10.9%, P = 0.0001), the total cholesterol/HDL-C ratio (-10.8%, P = 0.0001) and triglycerides (-24.8%, P = 0.0001), and significantly increased HDL-C (6.0%, P = 0.0043).(ABSTRACT TRUNCATED AT 250 WORDS)

A risk-benefit assessment of celiprolol in the treatment of cardiovascular disease.

Celiprolol is a third-generation beta-adrenoceptor blocker with selective beta 1-antagonist, partial beta 2-agonist and mild alpha 2-antagonist actions. It seems to be as effective as other beta-blockers in the treatment of hypertension and angina pectoris. beta-Blockers have many cardioprotective effects and have been shown to reduce the morbidity and mortality from coronary artery disease in a number of trials. However, there is no good clinical evidence that celiprolol itself has specific cardioprotective properties other than those attributable to this class of drugs. Because of its pharmacological profile, celiprolol is less likely to cause bradycardia, deterioration in cardiac function and other adverse effects mainly caused by beta 2-blockade. Unlike most other beta-blockers, celiprolol has no adverse effects on plasma lipids. It seems to be well tolerated in diabetic patients and patients with renal dysfunction.

Celiprolol pneumonitis.

We report on a patient who developed hypersensitivity pneumonitis during treatment with the beta-blocker, celiprolol. The clinical picture was a severe alveolitis, with compromised gas exchange. Inadvertent subsequent rechallenge with celiprolol led to recurrence of the pneumonitis, 10 weeks after drug readministration. Again, the pneumonitis was fully reversible. Lymphocytes were elevated in bronchoalveolar lavage, and progressively normalized upon discontinuation of the drug. This case is reminiscent of pneumonitis to other beta-blockers, which are reviewed here.