Efficacy of the I(f) current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4-month, randomized, placebo-controlled trial.
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ABSTRACT: Aims
To evaluate the anti-anginal and anti-ischaemic efficacy of the selective I(f) current inhibitor ivabradine in patients with chronic stable angina pectoris receiving beta-blocker therapy.Methods and results
In this double-blinded trial, 889 patients with stable angina receiving atenolol 50 mg/day were randomized to receive ivabradine 5 mg b.i.d. for 2 months, increased to 7.5 mg b.i.d. for a further 2 months, or placebo. Patients underwent treadmill exercise tests at the trough of drug activity using the standard Bruce protocol for randomization and at 2 and 4 months. Total exercise duration at 4 months increased by 24.3 +/- 65.3 s in the ivabradine group, compared with 7.7 +/- 63.8 s with placebo (P < 0.001). Ivabradine was superior to placebo for all exercise test criteria at 4 months (P < 0.001 for all) and 2 months (P-values between <0.001 and 0.018). Ivabradine in combination with atenolol was well tolerated. Only 1.1% of patients withdrew owing to sinus bradycardia in the ivabradine group.Conclusion
The combination of ivabradine 7.5 mg b.i.d. and atenolol at the commonly used dosage in clinical practice in patients with chronic stable angina pectoris produced additional efficacy with no untoward effect on safety or tolerability.
SUBMITTER: Tardif JC
PROVIDER: S-EPMC2649284 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:IntroductionIn the prospective, open-label, non-interventional, multicenter RESPONSIfVE study, the effectiveness, response rates and tolerability of ivabradine with or without beta blocker (BB) were evaluated in patients with chronic stable angina pectoris (AP) in daily clinical practice.MethodsIn patients with AP, ivabradine was given twice daily in flexible doses for 4 months. Resting heart rate (HR), number of angina attacks, short-acting nitrate use, severity of symptoms [by Canadian Cardiovascular Society (CCS) score] and tolerability with or without existing BB therapy were documented and analyzed using descriptive statistical methods.ResultsIn total, 1250 patients with AP (mean age 66.0 ± 10.9 years, 59.6% male, 31.9% previous myocardial infarction) and an indication for ivabradine were included. Sixty-five percent of all patients received BB. Further concomitant standard medication included aspirin (74.2%), statins (69.3%), angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (84.2%), diuretics (40.0%), long-acting nitrates (15.7%), and calcium antagonists (21.4%). After 4 months of ivabradine treatment (mean daily dose 11.0 ± 2.7 mg), mean HR was reduced from 82.4 ± 11.8 beats per minute (bpm) to 67.1 ± 8.4 bpm. The average number of angina attacks/week decreased from 1.2 ± 1.9 to 0.1 ± 0.6 and the average use of short-acting nitrates/week from 1.5 ± 2.8 units to 0.2 ± 1.0 units. CCS classification of patients improved from 76% classified in CCS grades II or III and 24% in CCS grade I to 66% classified in CCS grade I and only 35% remaining in CCS grades II or III at study end. Response rate to ivabradine (defined as HR <70 bpm or HR reduction ≥10 bpm) reached 87%. HR reduction, symptomatic improvement and response rates were comparable in patients with or without BB. Adverse drug reactions were reported for 2.2% of patients.ConclusionIn this prospective study over a four-month period in clinical practice, ivabradine effectively reduced HR, angina attacks, and nitrate consumption in patients with AP with or without concomitant BB therapy. Ivabradine improved CCS scores and achieved a high treatment response rate with good general tolerability.FundingServier.Trial registrationControlled-trials.com identifier, ISRCTN73861224.
| S-EPMC5020130 | biostudies-literature
Project description:Aims: β-blockers are underused in Chinese patients with coronary heart disease. The prescribed dose is often low. The aim of this study was to investigate the effect of metoprolol succinate doses of 95 mg and 190 mg on heart rate (HR) control, as well as drug tolerance, in Chinese patients with stable angina, low-dose β-blocker use and unsatisfactory HR control. Methods: This was a multicenter, randomized, open-label, parallel-group trial in 15 clinical sites. Patients with stable angina, taking low-dose β-blockers (equivalent to metoprolol succinate 23.75-47.5 mg/day), and having a resting HR of ≥ 65 bpm were enrolled and randomized to either the metoprolol 95-mg group or the 190-mg group. The change in 24-h average HR from baseline recorded by Holter monitoring and the percentages of patients with resting HR controlled to ≤ 60 bpm were compared between the two groups. Results: Two hundred thirty-one patients entered the intent-to-treat population for the main analysis. The change in 24-h average HR from baseline was -0.62 ± 0.66 bpm in the 95 mg group and -2.99 ± 0.62 bpm in the 190 mg group (p = 0.0077) after 8 weeks of treatment. The percentages of patients with resting HR controlled to ≤ 60 bpm were 24.1% (95% CI: 16.35%, 31.93%) and 40.0% (95% CI: 31.05%, 48.95%), respectively (p = 0.0019). Only 4 and 2 of the patients, respectively, discontinued the study drugs because of hypotension or bradycardia. Conclusions: The metoprolol succinate dose of 190 mg is superior to the 95 mg dose in terms of HR control, in Chinese patients with stable angina, low-dose β-blocker use and unsatisfactory HR control. Both doses were well tolerated.
| S-EPMC5441040 | biostudies-literature
Project description:In chronic stable angina, elevated heart rate contributes to the development of symptoms and signs of myocardial ischaemia by increasing myocardial oxygen demand and reducing diastolic perfusion time. Accordingly, heart rate reduction is a well-known strategy for improving both symptoms of myocardial ischaemia and quality of life (QOL). The heart rate-reducing agent ivabradine, a direct and selective inhibitor of the If current, decreases myocardial oxygen consumption while increasing diastolic time, without affecting myocardial contractility or coronary vasomotor tone. Ivabradine is indicated for treatment of stable angina and chronic heart failure (HF). This review examines available evidence regarding the efficacy and safety of ivabradine in stable angina, when used as monotherapy or in combination with beta-blockers, in particular angina subgroups and in patients with stable angina with left ventricular systolic dysfunction (LVSD) or HF. Trials involving more than 45 000 patients receiving treatment with ivabradine have shown that this agent has antianginal and anti-ischaemic effects, regardless of age, sex, severity of angina, revascularisation status or comorbidities. This heart rate-lowering agent might also improve prognosis, reduce hospitalisation rates and improve QOL in angina patients with chronic HF and LVSD.
| S-EPMC5888443 | biostudies-literature
Project description:Background and objectivesCoronary artery disease (CAD) is the number one cause of death worldwide. The If channel inhibitor ivabradine serves as second line medication for the CAD leading symptom angina pectoris. This systematic review and meta-analysis assess the existing evidence of ivabradine in angina pectoris.MethodsWe systematically searched MEDLINE, Embase, CENTRAL, and Web of Science (September 2019) for randomized controlled trials (RCTs) that compared ivabradine versus placebo, standard therapy (ST) or other anti-anginal drugs. Two review authors independently assessed trials for inclusion and performed data extraction. We completed a 'risk of bias' assessment for all studies and assessed quality of the trial evidence using the Grading of Recommendations Assessment, Development and Evaluation methodology. We meta-analysed data were applicable and calculated mean differences (MDs) and risk ratios using a random-effects model.ResultsA total of 11 RCTs (n=16,039) were included. Compared to placebo/ST, we found significant effects on the frequency of hospitalisation in a small cohort (n=90; hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.04, -0.92; p=0.04), but no effects on cardiovascular mortality (n=19,102; HR, 1.10; 95% CI, 0.94, 1.28; p=0.25) or the frequency of angina pectoris episodes (n=167; weighted MD, -1.06; 95% CI, -2.74, -0.61; p=0.21).ConclusionsThe present work makes an important contribution to optimal patient care in angina pectoris by complementing the current European Society of Cardiology guideline-recommending class IIa with evidence level B-decisively with 8 further studies.
| S-EPMC7440996 | biostudies-literature
Project description:IntroductionBeta-blockers are recommended by the European Society of Cardiology as first-line antianginal therapy for reducing heart rate (HR) and symptoms in patients with chronic coronary syndrome, despite a lack of data showing superiority to other antianginal agents. Most patients with angina pectoris require combination therapy to manage symptoms, with a second-line agent chosen to manage the predominant cardiovascular problem. Ivabradine, a selective sinus node If channel inhibitor shown to reduce HR and protect against anginal symptoms, has previously demonstrated noninferior anti-ischaemic and antianginal efficacy to beta-blockers.MethodsThis systematic review and meta-analysis assessed the efficacy and safety of ivabradine in patients with stable angina pectoris who remained symptomatic despite receiving beta-blockers. Keyword searches of PubMed, The Cochrane Central Library Register, ClinicalTrials.gov, The World Health Organization International Clinical Trials Registry Platform (ICTRP) and Google Scholar identified studies comparing ivabradine plus beta-blockers with placebo or other first- or second-line antianginal agents in patients with stable angina pectoris. No date limits or language restrictions were applied. Outcomes were evaluated after 1 and 4 months of treatment, including changes in HR, angina attacks, use of short-acting nitrates, quality of life and safety. Risk of bias was evaluated on the basis of recommendations of the Cochrane Handbook for Systematic Reviews of Interventions.ResultsSeven relevant studies were identified (N = 6821). Ivabradine plus a beta-blocker consistently reduced HR, anginal symptoms and short-acting nitrate consumption within 1 month of initiating therapy, with continued reductions for up to 4 months. Furthermore, ivabradine plus beta-blocker therapy was well tolerated, with bradycardia rarely reported (0.1% of patients overall). This study is limited by the inclusion of only two randomised studies, which may lead to result interpretation bias.ConclusionsIvabradine may be valuable for tailoring early antianginal treatment when used in combination with beta-blockers for chronic stable angina inadequately controlled by beta-blockers.
| S-EPMC9402524 | biostudies-literature
Project description:The anti-anginal efficacy of ivabradine is well established. We describe a post hoc analysis in the ADDITIONS database to investigate effectiveness and tolerability of ivabradine in combination with beta-blocker in patients with angina who have had a percutaneous coronary intervention (PCI).ADDITIONS was a non-interventional, multicenter prospective study including 2,330 patients with stable angina. In addition to beta-blocker, patients were treated with ivabradine in approved dosages for 4 months. We divided the population according to whether they had previously had a PCI or not, and explored the effect of ivabradine on heart rate, number of weekly angina attacks, frequency of nitrate consumption, as well as quality of life (QoL) and tolerability.Data were available for 2,319 patients, of whom 51.4% had previously had a PCI. There was no difference in the effect of ivabradine on mean heart rate between patients with a previous PCI [64.4 ± 7.6 beats per minute (bpm)] than those without (66.8 ± 8.5 bpm) at 4 months (both P < 0.0001). Similarly, the number of angina attacks decreased from 1.9 ± 2.4 to 0.5 ± 1.5 per week in patients with a previous PCI and 1.5 ± 2.0 to 0.3 ± 1.0 per week in patients without a previous PCI (both P < 0.0001). The frequency of nitrate consumption fell from 2.7 ± 3.7 to 1.0 ± 1.9 per week and 1.8 ± 2.8 to 0.6 ± 1.5 per week (both P < 0.0001) in patients with and without a previous PCI, respectively. There was no difference in the improvements in Canadian Cardiovascular Society class of angina, QoL, and physicians' assessment of effectiveness and tolerability between patients with a previous PCI and those without.Ivabradine is an effective and well-tolerated anti-anginal treatment in patients with stable angina after PCI. Ivabradine reduced the frequency of weekly angina attacks and nitrate consumption, led to an improvement in Canadian Cardiovascular Society class and a substantial improvement in the QoL of stable angina patients.
| S-EPMC4349945 | biostudies-literature
Project description:In coronary artery disease (CAD), medical treatment is the main clinical strategy for controlling ischemia and angina symptoms while restoring a satisfactory level of usual activities and improving quality of life (QOL). This study's purpose was to evaluate in CAD patients the antianginal efficacy of 4-month treatment with ivabradine plus a β-blocker and to record patient compliance and the effect of treatment on QOL.In this noninterventional study, 2403 patients with chronic stable angina were prospectively studied from 245 private cardiology offices. Data were recorded at baseline and at 1 and 4 months after inclusion. Patient quality of life was assessed using the EuroQol 5 dimensions (EQ-5D) questionnaire.From baseline to study completion, mean heart rate decreased from 81.5 ± 9.7 bpm to 63.9 ± 6.0 bpm (P <-0.001), mean number of anginal attacks decreased from 2.0 ± 2.0 times/wk to 0.2 ± 0.6 times/wk (P < 0.001) and nitroglycerin consumption decreased from 1.4 ± 2.0 times/wk to 0.1 ± 0.4 times/wk (P < 0.001). The percentage of patients with Canadian Cardiovascular Society angina class I increased from approximately 38% (baseline) to 84% (study completion; P < 0.001). The reduction in anginal attacks, nitroglycerin consumption, and angina score was correlated with reduction in heart rate (P < 0.001). The mean EQ-5D visual analogue scale index increased by 16.1 points (P < 0.001), and compliance with treatment was high throughout the trial (96%).Ivabradine administration on top of optimal individualized dose of β-blockers is associated with decreased anginal events and with improvement of QOL in CAD patients.
| S-EPMC4738471 | biostudies-other
Project description:BackgroundPercutaneous coronary intervention (PCI) is frequently performed to reduce the symptoms of stable angina. Whether PCI relieves angina more than a placebo procedure in patients who are not receiving antianginal medication remains unknown.MethodsWe conducted a double-blind, randomized, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all antianginal medications and underwent a 2-week symptom assessment phase before randomization. Patients were then randomly assigned in a 1:1 ratio to undergo PCI or a placebo procedure and were followed for 12 weeks. The primary end point was the angina symptom score, which was calculated daily on the basis of the number of angina episodes that occurred on a given day, the number of antianginal medications prescribed on that day, and clinical events, including the occurrence of unblinding owing to unacceptable angina or acute coronary syndrome or death. Scores range from 0 to 79, with higher scores indicating worse health status with respect to angina.ResultsA total of 301 patients underwent randomization: 151 to the PCI group and 150 to the placebo group. The mean (±SD) age was 64±9 years, and 79% were men. Ischemia was present in one cardiac territory in 242 patients (80%), in two territories in 52 patients (17%), and in three territories in 7 patients (2%). In the target vessels, the median fractional flow reserve was 0.63 (interquartile range, 0.49 to 0.75), and the median instantaneous wave-free ratio was 0.78 (interquartile range, 0.55 to 0.87). At the 12-week follow-up, the mean angina symptom score was 2.9 in the PCI group and 5.6 in the placebo group (odds ratio, 2.21; 95% confidence interval, 1.41 to 3.47; P<0.001). One patient in the placebo group had unacceptable angina leading to unblinding. Acute coronary syndromes occurred in 4 patients in the PCI group and in 6 patients in the placebo group.ConclusionsAmong patients with stable angina who were receiving little or no antianginal medication and had objective evidence of ischemia, PCI resulted in a lower angina symptom score than a placebo procedure, indicating a better health status with respect to angina. (Funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre and others; ORBITA-2 ClinicalTrials.gov number, NCT03742050.).
| S-EPMC7615400 | biostudies-literature
Project description:BackgroundThe organic nitrate pentaerithrityl tetranitrate (PETN) has been shown to have ancillary properties that prevent the development of tolerance and endothelial dysfunction. This randomized, double-blind, placebo-controlled, multicentre study ('CLEOPATRA' study) was designed to investigate the anti-ischaemic efficacy of PETN 80 mg b.i.d. (morning and mid-day) over placebo in patients with chronic stable angina pectoris.Methods and resultsA total of 655 patients were evaluated in the intention-to-treat population, randomized to PETN (80 mg b.i.d., n = 328) or placebo (n = 327) and completed the study. Patients underwent treadmill exercise tests at randomization, after 6 and 12 weeks of treatment. Treatment with PETN over 12 weeks did not modify the primary endpoint total exercise duration (TED, P = 0.423). In a pre-specified sub-analysis of patients with reduced exercise capacity (TED at baseline ≤9 min, n = 257), PETN appeared more effective than placebo treatment (P = 0.054). Superiority of PETN over placebo was evident in patients who were symptomatic at low exercise levels (n = 120; P = 0.017). Pentaerithrityl tetranitrate 80 mg b.i.d. was well tolerated, and the overall safety profile was comparable with placebo.ConclusionAlthough providing no additional benefit in unselected patients with known coronary artery disease, PETN therapy, administered in addition to modern anti-ischaemic therapy, could increase exercise tolerance in symptomatic patients with reduced exercise capacity.
| S-EPMC3977134 | biostudies-literature
Project description:Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels have been focused on as a potential therapeutic target for inflammatory and neuropathic pain in rodent models. However, roles of HCN channels in human pain states have been scarcely investigated. We evaluated analgesic effects of 2-day administration of ivabradine, the only clinically available HCN channel blocker, on a capsaicin pain model in a randomized, double-blinded, placebo-controlled, crossover study. Twenty healthy adult subjects (18 males, 2 females) received ivabradine (5-7.5 mg) or a placebo 3 times in 2 days. Then capsaicin (0.5%) was topically applied on the volar forearm for 30 min. The primary outcome was capsaicin-induced spontaneous pain. The secondary outcomes included heat-pain threshold (HPT), flare size, and areas of secondary punctate mechanical hyperalgesia (PMH) and secondary dynamic mechanical allodynia (DMA). There was no significant difference in spontaneous pain (p = 0.7479), HPT (p = 0.7501), area of PMH (p = 0.1052) or flare size (p = 0.5650) at 30 min after capsaicin application between the groups. In contrast, the area of DMA in the ivabradine group was significantly smaller (p < 0.001) than that in the placebo group. HCN channels may be differentially involved in the various pain signal transmission pathways in humans.
| S-EPMC9568658 | biostudies-literature