Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction.

BACKGROUND: Most trials that have shown a benefit of beta-blocker treatment after myocardial infarction included patients with large myocardial infarctions and were conducted in an era before modern biomarker-based diagnosis of myocardial infarction and treatment with percutaneous coronary intervention, antithrombotic agents, high-intensity statins, and renin-angiotensin-aldosterone system antagonists. METHODS: In a parallel-group, open-label trial performed at 45 centers in Sweden, Estonia, and New Zealand, we randomly assigned patients with an acute myocardial infarction who had undergone coronary angiography and had a left ventricular ejection fraction of at least 50% to receive either long-term treatment with a beta-blocker (metoprolol or bisoprolol) or no beta-blocker treatment. The primary end point was a composite of death from any cause or new myocardial infarction. RESULTS: From September 2017 through May 2023, a total of 5020 patients were enrolled (95.4% of whom were from Sweden). The median follow-up was 3.5 years (interquartile range, 2.2 to 4.7). A primary end-point event occurred in 199 of 2508 patients (7.9%) in the beta-blocker group and in 208 of 2512 patients (8.3%) in the no-beta-blocker group (hazard ratio, 0.96; 95% confidence interval, 0.79 to 1.16; P = 0.64). Beta-blocker treatment did not appear to lead to a lower cumulative incidence of the secondary end points (death from any cause, 3.9% in the beta-blocker group and 4.1% in the no-beta-blocker group; death from cardiovascular causes, 1.5% and 1.3%, respectively; myocardial infarction, 4.5% and 4.7%; hospitalization for atrial fibrillation, 1.1% and 1.4%; and hospitalization for heart failure, 0.8% and 0.9%). With regard to safety end points, hospitalization for bradycardia, second- or third-degree atrioventricular block, hypotension, syncope, or implantation of a pacemaker occurred in 3.4% of the patients in the beta-blocker group and in 3.2% of those in the no-beta-blocker group; hospitalization for asthma or chronic obstructive pulmonary disease in 0.6% and 0.6%, respectively; and hospitalization for stroke in 1.4% and 1.8%. CONCLUSIONS: Among patients with acute myocardial infarction who underwent early coronary angiography and had a preserved left ventricular ejection fraction (≥50%), long-term beta-blocker treatment did not lead to a lower risk of the composite primary end point of death from any cause or new myocardial infarction than no beta-blocker use. (Funded by the Swedish Research Council and others; REDUCE-AMI ClinicalTrials.gov number, NCT03278509.).

A Retrospective Observational Real-Word Analysis of the Adherence, Healthcare Resource Consumption and Costs in Patients Treated with Bisoprolol/Perindopril as Single-Pill or Free Combination.

INTRODUCTION: The present real-world analysis aims to compare the drug utilization, hospitalizations and direct healthcare costs related to the use of single-pill combination (SPC) or free-equivalent combination (FEC) of perindopril and bisoprolol (PER/BIS) in a large Italian population. METHODS: This observational retrospective analysis was based on administrative databases covering approximately 7 million subjects across Italy. All adult subjects receiving PER/BIS as SPC or FEC between January 2017-June 2020 were included. Subjects were followed for 1 year after the first prescription of PER/BIS as FEC (± 1 month) or SPC. Before comparing the SPC and FEC cohorts, propensity score matching (PSM) was applied to balance the baseline characteristics. Drug utilization was investigated as adherence (defined by the proportion of days covered, PDC) and persistence (evaluated by Kaplan-Meier curves). Hospitalizations and mean annual direct healthcare costs (due to drug prescriptions, hospitalizations and use of outpatient services) were analyzed during follow-up. RESULTS: The original cohort included 11,440 and 6521 patients taking the SPC and FEC PER/BIS combination, respectively. After PSM, two balanced SPC and FEC cohorts of 4688 patients were obtained (mean age 70 years, approximately 50% male, 24% in secondary prevention). The proportion of adherent patients (PDC ≥ 80%) was higher for those on SPC (45.5%) than those on FEC (38.6%), p < 0.001. The PER/BIS combination was discontinued by 35.8% of patients in the SPC cohort and 41.7% in the FEC cohort (p < 0.001). The SPC cohort had fewer cardiovascular (CV) hospitalizations (5.3%) than the free-combination cohort (7.4%), p < 0.001. Mean annual total healthcare costs were lower in the SPC (1999€) than in the FEC (2359€) cohort (p < 0.001). CONCLUSION: In a real-world setting, patients treated with PER/BIS SPC showed higher adherence, lower risk of drug discontinuation, reduced risk of CV hospitalization, and lower healthcare costs than those on FEC of the same drugs.

Patients with cardiovascular conditions often need to take many pills. This may result in patients not taking their pills as prescribed (i.e., low adherence) and compromise the potential benefits derived from prescription of cardiovascular protective drugs. Simplifying treatment by combining drugs into a single pill can improve adherence and, consequently, patient outcomes. In this analysis using data from real clinical practice, we explored whether using a single pill of perindopril and bisoprolol is associated with higher levels of adherence, lower proportion of patients with hospitalizations and lower economic costs than using the same drugs prescribed as free-equivalent combination in a large sample of the Italian population of approximately 7 million people. We identified two groups of patients taking single pill or free-equivalent combination of perindopril and bisoprolol (4688 patients in each cohort). Over 1-year follow-up, patients taking single pill were more likely to be adherent and were less likely to stop taking their treatment. They also had fewer cardiovascular hospitalizations with shorter hospital admission and had lower healthcare direct costs. In conclusion, simplifying treatment by combining perindopril and bisoprolol in a single pill instead of two may have a positive effect on adherence, outcomes and healthcare costs already after 1 year.

Genetic polymorphisms in ADRB1, ADRB2 and CYP2D6 genes and response to beta-blockers in patients with acute coronary syndrome.

Betablockers (BBs) are prescribed for ischaemia in patients with acute coronary syndrome (ACS). In Spain, bisoprolol and carvedilol are the most prescribed BBs, but patients often had to discontinue them due to adverse effects. Single nucleotide polymorphisms (SNPs) in ADRB1, ADRB2 and CYP2D6 genes have strong evidence of pharmacogenetic association with BBs in heart failure or hypertension, but the evidence in ACS is limited. Therefore, our study focuses on investigating how these genes influence the response to BBs in ACS patients. We analysed the association between SNPs in ADRB1 Gly389Arg (rs1801253) and Ser49Gly (rs1801252), ADRB2 Gly16Arg (rs1042713) and Glu27Gln (rs1042714), and CYP2D* 6 (*2- rs1080985, *4- rs3892097, *10 - rs1065852) and the occurrence of bradycardia/hypotension events during one year of follow-up. We performed an observational study and included 285 ACS-PCI-stent patients. A first analysis including patients treated with bisoprolol and a second analysis including patients treated with other BBs were performed. We found that the presence of the G allele (Glu) of the ADRB2 gene (rs1042714; Glu27Gln) conferred a protective effect against hypotension-induced by BBs; OR (CI 95%) = 0,14 (0,03-0,60), p < 0.01. The ADRB2 (rs1042713; Gly16Arg) GG genotype could also prevent hypotensive events; OR (CI 95%) = 0.49 (0.28-0.88), p = 0015. SNPs in ADRB1 and CYP2D6 * 2, CYP2D6 * 4 weren´t associated with primary events. The effect of CYP2D6 * 10 does not seem to be relevant for the response to BBs. According to our findings, SNPs in ADRB2 (rs1042713, rs1042714) could potentially affect the response and tolerance to BBs in ACS-patients. Further studies are necessary to clarify the impact of ADRB2 polymorphisms.

Unilateral adrenalectomy for a drug-resistant bilateral primary aldosteronism with heart failure: pathophysiology and surgical indication.

BACKGROUND: Patients with bilateral primary aldosteronism (PA) generally are treated with antihypertensive drugs, but optimal treatment for patients with complications due to refractory hypertension has not been established. In this report, we present a case with bilateral PA who presented with persistent hypertension, despite treatment with 6 drugs, and left-dominant heart failure, which was improved after unilateral adrenalectomy. CASE PRESENTATION: A 61-year-old man was admitted to our hospital because of severe left-dominant heart failure. His heart rhythm was atrial fibrillation and the left ventricle was diffusely hypertrophic and hypokinetic. Coronary arteries were normal on coronary arteriogram. Primary aldosteronism was suspected based on severe hypokalemia (2.5 mEq/L) and plasma aldosterone concentration (PAC; 1,410 pg/mL). Although computed tomography (CT) showed a single left cortical nodule, adrenal vein sampling (AVS) indicated bilateral PA. Early in the case, heart failure and hyperkalemia in this patient were improved by treatment with a combination of 6 antihypertensive drugs (spironolactone 25 mg/day, eplerenone 100 mg/day, azosemide 60 mg/day, tolvaptan 7.5 mg/day, enalapril 5 mg/day, and bisoprolol fumarate 10 mg/day); however, heart failure relapsed after four months of treatment. We hypothesized that hypertension caused by excess aldosterone was inducing the patient's heart failure. In order to reduce aldosterone secretory tissue, a laparoscopic adrenalectomy was performed for the left adrenal gland, given the higher level of aldosterone from the left gland compared to the right. Following surgery, the patient's heart failure was successfully controlled despite the persistence of high PAC. Treatment with anti-hypertensive medications was reduced to two drugs (eplerenone 100 mg/day and bisoprolol fumarate 10 mg/day). In order to elucidate the mechanism of drug resistance, immunohistochemistry (IHC) and real time-polymerase chain reaction (RT-PCR) assays were performed to assess the expression of steroidogenic factor 1 (SF-1), a regulator of steroid synthesis in adrenal tissue. IHC and RT-PCR demonstrated that the expression of SF-1 in this patient (at both the protein and mRNA levels) was higher than that observed in unilateral PA cases that showed good responsivity to drug treatment. CONCLUSIONS: Unilateral adrenalectomy to reduce aldosterone secretory tissue may be useful for patients with drug-refractory, bilateral PA. Elevated expression of SF-1 may be involved in drug resistance in PA.

Impact of bisoprolol and amlodipine on cardiopulmonary responses and symptoms during exercise in patients with chronic obstructive pulmonary disease.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) often have exercise intolerance. The prevalence of hypertension in COPD patients ranges from 39-51%, and ß-blockers and amlodipine are commonly used drugs for these patients. OBJECTIVES: We aimed to study the impact of ß-blockers and amlodipine on cardiopulmonary responses during exercise. METHODS: A total 81 patients with COPD were included and the patients underwent spirometry, cardiopulmonary exercise tests, and symptoms questionnaires. RESULTS: There were 14 patients who took bisoprolol and 67 patients who did not. Patients with COPD taking ß-blockers had lower blood oxygen concentration (SpO2) and more leg fatigue at peak exercise but similar exercise capacity as compared with patients not taking bisoprolol. There were 18 patients treated with amlodipine and 63 patients without amlodipine. Patients taking amlodipine had higher body weight, lower blood pressure at rest, and lower respiratory rates during peak exercise than those not taking amlodipine. Other cardiopulmonary parameters, such as workload, oxygen consumption at peak exercise, tidal volume at rest or exercise, cardiac index at rest or exercise were not significantly different between patients with or without bisoprolol or amlodipine. Smoking status did not differ between patients with or without bisoprolol or amlodipine. CONCLUSIONS: COPD is often accompanied by hypertension, and ß-blockers and amlodipine are commonly used antihypertensive drugs for these patients. Patients with COPD taking bisoprolol had lower SpO2 and more leg fatigue during peak exercise. Patients taking amlodipine had lower respiratory rates during exercise than those not taking amlodipine. Exercise capacity, tidal volume, and cardiac index during exercise were similar between patients with and without bisoprolol or amlodipine.

Managing postoperative atrial fibrillation after open-heart surgery using transdermal ß1 blockers.

BACKGROUND: Postoperative atrial fibrillation (POAF) after open-heart surgery is a non-negligible complication. We aimed to describe the efficacy of a transdermal patch of bisoprolol for managing POAF and flutter in thoracic surgical procedures. METHODS: We analyzed the data of 384 patients who underwent open-heart surgery at our hospital and received oral bisoprolol to prevent POAF. Among them, 65 patients (16.9%) also received a 4-mg transdermal patch of bisoprolol to control the heart rate due to POAF. We applied the bisoprolol transdermal patch when the heart rate was > 80 bpm and removed it at ≤ 60 bpm; an additional patch was applied when the heart rate was > 140 bpm. Heparin calcium injections were administered twice daily for anticoagulation between 2 and 6 days postoperatively. RESULTS: The average number of prescriptions for transdermal patches of bisoprolol during hospitalization was 1.8 ± 1.1 (1-5). The median first prescription date was on postoperative day 2 (range: days 0-37). Sinus rhythm recovered within 24 h in 18 patients (27.7%). Eight patients (12.3%) were switched to continuous landiolol infusion because of persistent tachycardia. In three patients, the transdermal patch was removed owing to severe bradycardia. Fifteen patients experienced persistent atrial fibrillation and were treated with electrical cardioversion during hospitalization. We did not observe any serious complications that could be directly attributed to bisoprolol transdermal patch use. CONCLUSIONS: Single-use bisoprolol transdermal patch may help control the heart rate during the initial treatment of POAF after open-heart surgery.

Efficacy of Antihypertensive Drugs of Different Classes After Renal Denervation in Spontaneously Hypertensive Rats.

BACKGROUND: Renal denervation (RDN) lowers blood pressure (BP) in patients with uncontrolled hypertension. Limited data exist on the effectiveness of different antihypertensive medications following RDN on BP and maladaptive cardiac phenotypes. METHODS: Eighty-nine male spontaneously hypertensive rats with continuous BP recording underwent RDN or sham operation. Ten days postsurgery, spontaneously hypertensive rats were randomized to receive no antihypertensive medication, amlodipine, olmesartan, hydrochlorothiazide, bisoprolol, doxazosin, or moxonidine for 28 days. Cardiac remodeling was determined histologically, and activation of the renin-angiotensin-aldosterone system was explored. RESULTS: Before initiation of antihypertensive drugs, RDN reduced mean arterial pressure (-12.6 mm Hg [95% CI, -14.4 to -10.8]; P<0.001). At study end, mean arterial pressure was lower in RDN compared with sham operation in drug-naïve controls (P=0.006), olmesartan (P=0.002), amlodipine (P=0.0004), hydrochlorothiazide (P=0.006), doxazosin (P=0.001), and bisoprolol (P=0.039) but not in animals receiving moxonidine (P=0.122). Compared with pooled BP change of all other drug classes, mean arterial pressure change was largest for olmesartan (-15.9 mm Hg [95% CI, -18.6 to -13.2]; P<0.001) and amlodipine (-12.0 mm Hg [95% CI, -14.7 to -9.3]; P<0.001). In drug-naïve controls, RDN reduced plasma renin activity (-5.6%¸ P=0.03) and aldosterone concentration (-53.0%; P=0.005). In the presence of antihypertensive medication, plasma renin activity and aldosterone remained unchanged after RDN. Cardiac remodeling was not affected by RDN alone. In animals receiving olmesartan after RDN, cardiac perivascular fibrosis was attenuated. Amlodipine and bisoprolol following RDN reduced cardiomyocyte diameter. CONCLUSIONS: Following RDN, treatment with amlodipine and olmesartan resulted in the largest BP reduction. Antihypertensive medications mediated heterogeneous effects on renin-angiotensin-aldosterone system activity and cardiac remodeling.

Can Pediatric Heart Failure Therapy Be Improved? Yes It Can, But .

Given the heterogenous etiology of pediatric heart failure (pHF), evidence-based studies improving pHF are unlikely. A paradigm shift towards updated medicine-based evidence is therefore necessary. In view of the life expectancy of children, cardiac regeneration strategies are required. Therefore, age- and disease-related differences in myocardial (receptor) physiology require individualized precision medicine. First-line diuretic therapy, adopted from the treatment of adults with HF with no chance for recovery, should be questioned in the treatment of pHF with potential for recovery. Inadequate use of diuretics is a common reason for additional stimulation of the neurohumoral axis. Consecutive intravascular volume depletion led to an inadequate treatment with ß-blocker and renin-angiotensin-aldosterone antagonists. Given the age-related catecholamine-driven cardiovascular (patho-) physiology, highly selective ß1-blockers (bisoprolol) protect against ß1-(noradrenaline)-related myocytic apoptosis and necrosis, but allow ß2-receptor-mediated myocardial regeneration. Based on its high safety-efficacy profile with rarely seen adverse effects but easily monitorable efficacy by the surrogate of heart rate (reduction), bisoprolol is our first-line drug in infancy. Reduced heart rate economizes the heart and full body oxygen consumption and extends the diastolic filling and coronary perfusion time. Based on our many years of institutional experience, physicians should be encouraged to use ß1-selected blockers in infants with dilated cardiomyopathy and hypoplastic left heart syndrome after stage-1 procedure, but also to treat ventricular septal defects with a significant left-to-right shunt. In summary, individualized pHF therapy is the prerequisite for a causal treatment to improve HF symptoms, but above all for the most functional regeneration possible.

The Impact of International Nonproprietary Names Integration on Prescribing Reimbursement Medicines for Arterial Hypertension and Analysis of Medication Errors in Latvia.

The use of international nonproprietary names (INNs) has been mandatory for prescriptions of state-reimbursed drugs in Latvia since 1 April 2020. In a retrospective analysis, we aimed to examine the impact of the new regulation on changes in the prescribing and dispensing practice of antihypertensive agents with an example of bisoprolol or/and perindopril and their combinations. All state-reimbursed bisoprolol and/or perindopril prescriptions for arterial hypertension were evaluated in two time periods: 1 April 2018 to 31 March 2019 and 1 April 2020 to 31 March 2021. The proportion of INN prescriptions increased from 2.1% to 92.3% (p < 0.001, φ = 0.903). The rate of fixed-dose combinations (FDCs) increased from 60.8% to 66.5% (p < 0.001, φ = 0.059). The rate of medication errors was 0.6%. The most common (80.6%) error was that the dispensed medicine dose was larger or smaller than indicated on the prescription. In addition, prescribing an FDC medicine increased the chance of making an error by 2.5 times on average. Regulatory changes dramatically affected the medicine-prescribing habits of INNs. The increase in FDC prescription rates may align with the recommendations of the 2018 ESC/ESH guidelines. The proportion of total errors is estimated as low, but control mechanisms are needed to prevent them.

Hair analysis for beta-blockers and calcium-channel blockers by using liquid chromatography-tandem mass spectrometry as a tool for monitoring adherence to antihypertensive therapy.

Adherence to therapy is the key to a successful therapeutic intervention, especially in cardiovascular diseases in which a lack of adherence may have serious consequences in terms morbidity and/or mortality. In this context, hair analysis can be an excellent tool to monitor adherence to therapy. Indeed, drugs present in blood are incorporated into the hair matrix, where drugs and metabolites can stay unaltered for a long time protected from metabolism and degradation. In the present study, a simple, specific, and sensitive ultra-high performance liquid-chromatography-tandem mass spectrometry (UHPLC-MS/MS) method set up to determine in human hair seven beta-blockers (viz., metoprolol, sotalol, labetalol, atenolol, nebivolol, bisoprolol, and nadolol) and two calcium-channel blockers (lercanidipine and amlodipine), which are widely prescribed to treat medium-to-severe hypertensive conditions. The optimized method was successfully validated in terms of accuracy, repeatability, reproducibility, matrix effect and extraction recovery. Moreover, the applicability of the method was evaluated by analyzing 34 real samples of hair obtained from patients under long-term therapy with calcium channel blockers and beta-blockers.

Guideline-Directed Medical Therapy in Newly Diagnosed Heart Failure With Reduced Ejection Fraction in the Community.

BACKGROUND: Guideline-directed medical therapy (GDMT) dramatically improves outcomes in heart failure with reduced ejection fraction (HFrEF). Our goal was to examine GDMT use in community patients with newly diagnosed HFrEF. METHODS AND RESULTS: We performed a population-based, retrospective cohort study of all Olmsted County, Minnesota, residents with newly diagnosed HFrEF (EF ≤ 40%) 2007-2017. We excluded patients with contraindications to medication initiation. We examined the use of beta-blockers, HF beta-blockers (metoprolol succinate, carvedilol, bisoprolol), angiotensin converting enzyme inhibitors (ACEis), angiotensin receptor blockers (ARBs), angiotensin receptor neprilysin inhibitors (ARNIS), and mineralocorticoid receptor antagonists (MRAs) in the first year after HFrEF diagnosis. We used Cox models to evaluate the association of being seen in an HF clinic with the initiation of GDMT. From 2007 to 2017, 1160 patients were diagnosed with HFrEF (mean age 69.7 years, 65.6% men). Most eligible patients received beta-blockers (92.6%) and ACEis/ARBs/ARNIs (87.0%) in the first year. However, only 63.8% of patients were treated with an HF beta-blocker, and few received MRAs (17.6%). In models accounting for the role of an HF clinic in initiation of these medications, being seen in an HF clinic was independently associated with initiation of new GDMT across all medication classes, with a hazard ratio (95% CI) of 1.54 (1.15-2.06) for any beta-blocker, 2.49 (1.95-3.20) for HF beta-blockers, 1.97 (1.46-2.65) for ACEis/ARBs/ARNIs, and 2.14 (1.49-3.08) for MRAs. CONCLUSIONS: In this population-based study, most patients with newly diagnosed HFrEF received beta-blockers and ACEis/ARBs/ARNIs. GDMT use was higher in patients seen in an HF clinic, suggesting the potential benefit of referral to an HF clinic for patients with newly diagnosed HFrEF.

To Evaluate the 'Real World' Clinical Performance of Bisoprolol in Post-Myocardial Infarction with Left Ventricular Dysfunction: Tenacity Study.

Beta-blockers are the cornerstone in management of heart failure and are well studied in Acute Coronary Syndromes (ACS). There is paucity of data of Bisoprolol in acute ICU setting in patients admitted with left ventricular systolic dysfunction (LVSD) with recent ACS, especially amongst Asian Indians. We evaluated the impact of Bisoprolol on Heart Rate (HR) and Left Ventricular Ejection Fraction (LVEF) along with metabolic indicators of HbA1C and lipid profile in post-ACS patients with LVSD at 1 year as compared to baseline. MATERIAL: This non-interventional, retrospective, single center, secondary data collection study captured demographics, comorbidities, hemodynamics, concomitant medications and assessed the effectiveness of oral Bisoprolol (1.25, 2.5 mg, 5 mg and 10mg) treatment over a 1-year follow up period, in post-ACS patients with LVSD (i.e., HFmrEF and HFrEF; LVEF <50%). Data-records of 400 patients hospitalized between August 1, 2016 to November 30, 2018 were evaluated for change in LVEF as primary endpoint and change in HR and Lipid profile, HBA1C and ST segment deviation of J point at 1 year as compared to baseline as secondary outcomes. OBSERVATION: The mean age of 400 patients was 55.28±7.9 years of which 29.75% were female. Significant improvement in LVEF (41.45±5.1% vs 48.73±5.5%) with significant reduction in heart rate (85.06±5.64 bpm vs 76.73±4.6 bpm) was observed at the end of 1-year treatment as compared to baseline (p=0.0001 and p=0.0001 respectively) on treatment with Bisoprolol (mean 4.15 + 1.4 mg). NYHA class improved from 1.6 + 0.5 to 1.11 + 0.31 at the end of 1 year. Bisoprolol along with GDMT was neutral for HbA1C (6.2±0.6 % vs 6.1±0.7%; p=0.64), while serum lipids (Total Cholesterol: 199.7 + 7.6 vs 127.6 + 4.85 mg% p=0.001; TG: 196.2 +12.1 vs 111.7 + 6.88 mg%, p=0.001; LDL: 126.9 + 9.1 vs 62.4 + 5.51 p=0.001; HDL: 33.7 + 3 vs 42.8 +1.9 p=0.001) improved at 1 year due to statins. Maximum ST deviation at J point in resting ECG was also lesser at 1 year as compared to baseline (0.29 + 1.5 mm vs 0.05 + 0.22 mm; p=0.0001). CONCLUSION: Bisoprolol administered along with GDMT to patients post-ACS with LVSD significantly improved LVEF with significant reduction in heart rate and ST segment deviation at J point at 1 year without adverse effect on lipid and HBA1C.

Bisoprolol for treatment of symptomatic patients with obstructive hypertrophic cardiomyopathy. The BASIC (bisoprolol AS therapy in hypertrophic cardiomyopathy) study.

AIMS: To evaluate the role of bisoprolol to control symptoms and left ventricular outflow tract obstruction (LVOTO) in a consecutive cohort of adults with hypertrophic cardiomyopathy (HCM). METHODS AND RESULTS: In this retrospective study, patients with HCM with an LVOT gradient ≥50 mmHg after Valsalva manoeuvre and New York Heart Association (NYHA) class II-III symptoms were assigned to receive bisoprolol (starting at 1.25 mg daily). The initial dose was increased every two weeks to achieve the target in LVOT gradient <30 mmHg or the maximum tolerated dose. The primary endpoint was the achievement of a LVOT gradient <30 mmHg and ≥ 1 NYHA class improvement. The secondary endpoints were proportion of patients with LVOT gradient <30 mmHg or < 50 mmHg, proportion of patients with ≥1 NYHA class improvement, and change from baseline in LVOT gradient. Between December 2001 and December 2020, 92 patients were enrolled into the study. Sixteen (17%) patients on bisoprolol met the primary endpoint. Bisoprolol reduced the LVOT gradient to less than 30 mmHg in 33 (36%) patients, to less than 50 mmHg in 57 (62%), and improved NYHA class in 30 (33%). The mean reduction of LVOT gradient on bisoprolol was 28 (±14) mmHg and the percentage reduction was 42 (±21) %. In 35 (38%) patients, bisoprolol did not reduce the gradient to less than 50 mmHg requiring disopyramide and/or myectomy to achieve this goal. CONCLUSION: Treatment with bisoprolol was well-tolerated and effective in relieving obstruction and improving symptoms in a significant proportion of patients with symptomatic obstructive HCM.

Pharmacoepigenetics of hypertension: genome-wide methylation analysis of responsiveness to four classes of antihypertensive drugs using a double-blind crossover study design.

Essential hypertension remains the leading risk factor of global disease burden, but its treatment goals are often not met. We investigated whether DNA methylation is associated with antihypertensive responses to a diuretic, a beta-blocker, a calcium channel blocker or an angiotensin receptor antagonist. In addition, since we previously showed an SNP at the transcription start site (TSS) of the catecholamine biosynthesis-related ACY3 gene to associate with blood pressure (BP) response to beta-blockers, we specifically analysed the association of methylation sites close to the ACY3 TSS with BP responses to beta-blockers. We conducted an epigenome-wide association study between leukocyte DNA methylation and BP responses to antihypertensive monotherapies in two hypertensive Finnish cohorts: the GENRES (https://clinicaltrials.gov/ct2/show/NCT03276598; amlodipine 5 mg, bisoprolol 5 mg, hydrochlorothiazide 25 mg, or losartan 50 mg daily) and the LIFE-Fin studies (https://clinicaltrials.gov/ct2/show/NCT00338260; atenolol 50 mg or losartan 50 mg daily). The monotherapy groups consisted of approximately 200 individuals each. We identified 64 methylation sites to suggestively associate (P < 1E-5) with either systolic or diastolic BP responses to a particular study drug in GENRES. These associations did not replicate in LIFE-Fin . Three methylation sites close to the ACY3 TSS were associated with systolic BP responses to bisoprolol in GENRES but not genome-wide significantly (P < 0.05). No robust associations between DNA methylation and BP responses to four different antihypertensive drugs were identified. However, the findings on the methylation sites close to the ACY3 TSS may support the role of ACY3 genetic and epigenetic variation in BP response to bisoprolol.

Effectiveness of bisoprolol versus other ß-blockers and other antihypertensive classes: a cohort study in the Clinical Practice Research Datalink.

Aim: To compare blood pressure (BP) and safety outcomes in patients with hypertension initiating bisoprolol, versus other ß-blockers, angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, calcium channel blockers or diuretics. Materials & methods: New user cohort study. Patients initiating bisoprolol were matched with up to four patients, in each comparator cohort using propensity score. BP outcomes were compared using linear mixed models and safety outcomes using Cox proportional hazards. Results: Differences in average systolic and diastolic BP variation were ≤3 mmHg between bisoprolol versus the compared classes. No difference was observed in risk of diabetes, obesity or erectile dysfunction. An increased dyslipidemia risk was only observed versus diuretics (hazard ratio: 0.76; 98.75% CI: 0.58, 0.99). Conclusion: No differences in BP variation and safety outcomes.

The double anaerobic threshold in heart failure.

BACKGROUND: Cardiopulmonary exercise test (CPET) has an important role in assessing heart failure (HF) patients. Among CPET parameters, a pivotal role is attributed to the anaerobic threshold (AT), normally determined by V-slope, ventilatory equivalent and end-tidal methods. In about 10% of healthy subjects, a lack of concordance between these methods has been reported. This event was named double AT (DT). We hypothesized that DT was due to a delay in chemoreflex response. METHODS: We reanalyzed CPET data of two cross-over studies in which we compared CPET in stable HF patients treated for two months with bisoprolol and carvedilol. In chronic HF, carvedilol has a greater sympathetic inhibition than bisoprolol, as shown by a lower chemoreflex response. RESULTS: In 87 patients, we identified DT in 46% and 66% of cases during bisoprolol and carvedilol treatment, respectively (p < 0.01). Compared with bisoprolol, carvedilol treatment was associated to a lower peak oxygen uptake (from 17.4 ± 4.3 to 16.4 ± 4.1 mL/min/kg) and oxygen pulse (from 11.8 ± 2.9 to 11.1 ± 2.9 mL/min/kg) suggestive of lower peak cardiac output. CONCLUSIONS: DT is frequent in HF and more often with carvedilol than bisoprolol treatment, may be due to a greater inhibition of sympathetic tone and prolonged circulatory time. These findings open an unexplored research field.

Beta-blockers for the treatment of arrhythmias: Bisoprolol - a systematic review.

OBJECTIVES: Beta-blockers have long been successfully used for the treatment of both supraventricular and ventricular arrhythmias. However, differences exist between their chemical structure, pharmacokinetic and pharmacodynamic properties (absorption, bioavailability, metabolism, hydrophilic or lipophilic character, selective or non-selective nature, the presence or absence of intrinsic sympathomimetic activity), which may confer different antiarrhythmic properties to different beta-blockers. The aim of this study was to analyze the current existing evidence for bisoprolol for the treatment of both supraventricular and ventricular arrhythmias. MATERIAL AND METHODS: Using the keywords "bisoprolol" and "arrhythmias" or "atrial fibrillation" or "ventricular tachycardia" or "premature ventricular complexes" or "ventricular fibrillation", the Medline database was searched for articles in English or French until April 2020 assessing the role of bisoprolol in the treatment of arrhythmias. Data was then analyzed according to the type of arrhythmia treated and the quality of evidence using the GRADE approach. RESULTS: A total of 325 studies were identified, of which 28 were considered relevant to the current topic. Among these studies, 19 assessed the role of bisoprolol for the treatment of supraventricular arrhythmias, 8 its role in treating ventricular arrhythmias and 1 its role in supraventricular and ventricular arrhythmias. The quality of evidence varied from low (7 studies) to high (5 studies). CONCLUSION: Current evidence exists supporting the use of bisoprolol for the treatment of supraventricular arrhythmias, especially for rate control during atrial fibrillation. Evidence also exists for its efficacy in the treatment of ventricular arrhythmias, both in primary and in secondary prevention.

An anchored simulated treatment comparison of uptitration of amlodipine compared with a low-dose combination treatment with amlodipine 5 mg/bisoprolol 5 mg for patients with hypertension suboptimally controlled by amlodipine 5 mg monotherapy.

OBJECTIVE: To compare changes in systolic and diastolic blood pressures (SBP, DBP) from baseline to following 8 weeks of treatment with a low dose combination of amlodipine 5 mg plus bisoprolol 5 mg versus up titration to the maximum daily dose of amlodipine 10 mg, in hypertensive patients uncontrolled by amlodipine 5 mg. METHODS: Individual patient data (IPD) from a randomized clinical trial (RCT) comparing the combination versus amlodipine 5 mg (EudraCT Number: 2019-000751-13) and aggregated data (AgD) from a published RCT comparing amlodipine 10 mg versus amlodipine 5 mg were utilized in an anchored simulated treatment comparison (STC). The RCT with IPD was used to create models assessing how patients might respond to the combination if they were more comparable to those patients in the RCT with AgD. A population-adjusted indirect comparison of the treatment strategies was then conducted, using amlodipine 5 mg as an anchor. RESULTS: In the efficacy analyses, a total of 261 patients were included in the amlodipine 10 mg arm of the RCT with AgD; and a total of 178 patients in the low-dose combination arm of the RCT with IPD. Respectively, in the Amlodipine 10 mg arm and in the low-dose combination arm, the mean age was 54.3 years-old (Standard deviation [SD] 10.6), and 57.1 years-old (13.7); 8.7% and 18.8% of patients were diabetics; and the mean baseline SBP/DBP was 149.3 (12.0)/96.5 (4.7) mmHg, and 148.8 (8.2)/90.2 (7.6) mmHg. The final model for SBP and DBP included the following variables: baseline SBP, baseline DBP, duration of hypertension, age, concomitant diabetes, sex, smoking history (final model for SBP only), and body mass index (final model for DBP only). Mean treatment differences (standard error [SE]) at 8 weeks between the combination and uptitration were -1.6 mmHg (1.9) for SBP; and -3.3 mmHg (1.3) for DBP. CONCLUSION: In this indirect comparison, a more important decrease was observed in DBP with the low-dose combination as compared to the alternative therapeutic approach of up-titration from amlodipine 5 mg to amlodipine 10 mg. No meaningful difference was seen for SBP.

Concomitant Treatment of Hypertensive Patients with Bisoprolol and Perindopril in Routine Clinical Practice: A Post Hoc Analysis of the CONFIDENCE II, PROTECT I, and PROTECT III Observational Studies.

INTRODUCTION: The combination of angiotensin-converting enzyme inhibitors and beta-blockers is recommended in a wide range of patients with hypertension, including those with stable coronary artery disease and/or elevated heart rate. This post hoc analysis of three observational studies provides effectiveness and safety data on treatment with perindopril on top of bisoprolol-based therapy, in routine clinical practice. METHODS: Data were analyzed from three open-label, prospective, multicenter, observational studies of Canadian patients with mild-to-moderate hypertension, which shared the same inclusion and exclusion criteria, treatment duration, and primary outcome. This post hoc analysis focused on the subpopulation of patients treated with perindopril on top of bisoprolol-based therapy. All patients were followed for 16 weeks and underwent baseline, week 4, and week 16 visits. Primary outcomes were mean changes in blood pressure (BP) and proportion of patients achieving BP control (< 140/90 mmHg) in the full analysis set (FAS). RESULTS: A total of 845 patients (mean age 68.3 ± 11.3 years, mean baseline BP 151.5/86.0 mmHg) were analyzed in the FAS. After 16 weeks, mean SBP/DBP decreased by - 20.4/- 9.8 mmHg with statistically significant reductions observed at all visits in all three studies allowing 78% of patients to achieve the BP treatment goal. No statistically significant changes in heart rate were observed and no serious adverse events reported. The most frequent doses of bisoprolol and perindopril were 5 + 4 mg (34.9%), followed by 5 + 8 mg (16.9%), and 2.5 + 4 mg (12.5%). CONCLUSION: The addition of perindopril on top of bisoprolol-based therapy in patients with mild-to-moderate hypertension was associated with significant reductions in BP compared with baseline and with achievement of BP targets in the majority of patients. The results suggest this strategy is safe and effective for use in routine clinical practice.

Effect of bisoprolol on central aortic systolic pressure in Chinese hypertensive patients after the initial dose and long-term treatment.

We conducted a prospective open-label cohort study with the aim of examining the effects of the highly ß1-selective agent bisoprolol on central aortic systolic pressure (CASP) after the first dose and after 6 weeks' treatment and whether the CASP response could be predicted from the early response. Chinese patients with primary hypertension (BP ≥ 140/90 mmHg) on no therapy or background amlodipine were treated with bisoprolol 2.5 mg daily for 6 weeks. Brachial systolic BP (Br-SBP), resting heart rate (HR) and CASP were determined at baseline, 24h after the first dose, and pre-dose after treatment for 6 weeks using the BPro® device. In 42 patients (age 54 ± 9 years) the mean reductions in CASP and Br-SBP after 6 weeks of treatment were not significantly different from each other at -14.5 ± 12.7 and -15.4 ± 12.9 mmHg (both p<0.01), respectively. Changes in CASP and Br-SBP were highly correlated after the first dose (r = 0.964, p<0.01) and after 6 weeks (r = 0.963, p<0.01) and the reductions in CASP after 6 weeks were also associated with the reduction in CASP after the first dose (r = 0.577, p<0.01). Bisoprolol was shown to effectively reduce CASP and this effect was directly proportional to the reduction in Br-SBP and of a similar magnitude. More favourable CASP responses to long term therapy may be predicted by greater reductions in CASP after the first dose.