Treatment of stable angina pectoris by ivabradine in every day practice: The REDUCTION Study

doi:10.1016/j.ahj.2009.06.008

American Heart Journal

Volume 158, Issue 4, October 2009, Pages e51-e57

https://doi.org/10.1016/j.ahj.2009.06.008 Get rights and content

Background

The antianginal efficacy of ivabradine was studied in controlled clinical trials. Strict patient selection criteria may cause a discrepancy between the results of highly controlled clinical trials and everyday routine practice. The objective of this study was to evaluate the efficacy and safety of ivabradine in everyday routine practice.

Methods

In this multicenter study, 4,954 patients with stable angina pectoris received ivabradine in everyday routine practice and underwent follow-up for 4 months. The heart rate (HR), angina pectoris attacks, nitrate consumption, overall efficacy, and tolerance were evaluated.

Results

Within 4 months of treatment with ivabradine, HR was reduced by 12.4 ± 12.2 beat/min from 82.9 ± 15.3 to 70.4 ± 9.2 beat/min (P < .0001). Angina pectoris attacks were reduced from 2.4 ± 3.1 to 0.4 ± 1.5 per week (P < .0001). Consumption of short-acting nitrates was reduced from 3.3 ± 4.4 to 0.6 ± 1.6 U/wk (P < .0001). Seventy-eight cases of adverse drug reactions were reported. The most common adverse drug reactions were nausea (n = 11, 0.22%) and dizziness (n = 9, 0.18%). Efficacy and tolerance were graded by physicians as being “excellent/very good” for 97% and 98% of the patients treated.

Conclusion

Ivabradine reduces the HR and is highly effective and well tolerated in the treatment of patients with symptomatic coronary artery disease. The results confirm the findings of controlled clinical trials in a broad patient population in everyday routine practice.

Section snippets

Design

This trial was performed as a multicenter, prospective, open-label, noninterventional study. A total of 4,954 patients treated with ivabradine were included and prospectively followed by 1,503 general practitioners, internal medicine physicians, and cardiologists in private practice in Germany. All participating physicians filled out standardized questionnaires during the patient's course of treatment.

The study complies with the Declaration of Helsinki. It was conducted in accordance with the

Study population

Of the 4,954 patients, 59% were men and 41% were women. Mean age was 65.1 ± 10.4 years. A total of 3,964 (80%) patients had arterial hypertension; 3,806 (77%) had hypercholesterolemia; 2,170 (44%) were overweight; 1,422 (29%) were smokers or exsmokers; and 1,421 (29%) had diabetes mellitus.

The mean duration of coronary artery disease in the group was 5.2 ± 4.9 years. The duration of the history of angina pectoris was 3.6 ± 3.9 years. In 19% of the patients, the duration of angina pectoris was<6

Discussion

Because of strict patient selection criteria, there may be a discrepancy between the results of highly controlled clinical trials and everyday clinical practice.²² Observational databases can be useful adjuncts to randomized, controlled trials to see whether efficacy under controlled conditions in specialist clinics translates into effective treatment in routine practice. Therefore, in this study, the efficacy, safety, and tolerance of ivabradine were evaluated deliberately under everyday

Conclusions

Ivabradine reduces heart rate in everyday practice in a broad population of patients. It is highly effective in the treatment of stable angina pectoris and reduces the attacks and nitrate consumption in combination with a standard medical therapy.

Ivabradine was well tolerated by most patients and has a lower rate of reported ADR in everyday practice compared with available reports from controlled trials.

The results confirm the findings from randomized controlled trials for the routine use of

Disclosures

T.M.'s and R.K.'s participation at scientific congresses has been supported by Servier Deutschland. T.M. is member of the advisory board. J.K. has no conflict of interest.

Acknowledgements

We thank Dieter Schremmer from the ‘Gesellschaft für Therapieforschung’ and all investigators for their contributions to the study. The investigators who participated were J. Taggeselle, L. Feβ, R. Aubele, N. Hassler, K. Hofmann, V. Adelberger, T. Arnold, B. Holz, M. Hwaidi, H.-D. Kombächer, R. Meysing, S. Appel, J. Bazowski, R. Bernauer, H. Böneke, M. Braun, E. Daelmann, M. Deiβner, S. Duddy, M.-A. Eisenbarth, H. Fissan, C. Freese, G. Gölz, M. Gutting, K. Hallbaum, M. Hilgedieck, J.-A. Hintze,

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Cited by (52)

Ivabradine and metoprolol in fixed dose combination: When, why and how to use it
2019, Pharmacological Research
Citation Excerpt :
The REDUCTION was a multicenter, prospective, open-label, non-interventional study which evaluated the efficacy, safety and tolerability of ivabradine in 4,954 patients with CAD and stable angina. The follow up was performed by physicians in private practice, with the intend to reproduce «real life» conditions rather than the controlled environment of a randomized clinical trial [43]. Of note, only 344 (6.9%) patients received ivabradine on top of beta-blocker, and the rest 2350 (54.4%) who were treated with a beta-blocker at the beginning of the study discontinued.
Heart rate is an important factor in coronary artery disease and its manifestations, and as such has been considered as a possible target for therapy. Although in epidemiological, and in less degree, in clinical studies derived indications of a possible pathogenetic role of heart rate in major cardiac diseases, clinical trials did not provided any strong evidence. However, even as a simple risk marker, remains important in the treatment of coronary artery disease and heart failure. Beta-blockers are the drugs most frequently used for heart rate control. However, recent studies constantly find insufficient effectiveness of beta-blockers in heart rate control and go further to question their efficacy on outcomes, making clear the need for an additional therapy. Ivabradine, a pure heart rate inhibitor, added to classic beta-blocker treatment represent the new therapeutic option in stable coronary disease and heart failure.
The Medical Treatment of Stable Angina
2018, Chronic Coronary Artery Disease: A Companion to Braunwald's Heart Disease
The Medical Treatment of Stable Angina
2017, Chronic Coronary Artery Disease: A Companion to Braunwald's Heart Disease
Ivabradine in combination with beta-blocker reduces symptoms and improves quality of life in elderly patients with stable angina pectoris: Age-related results from the ADDITIONS study
2014, Experimental Gerontology
Citation Excerpt :
Overall, these findings suggest a good tolerance of the drug under everyday conditions in elderly patients. The results for the combination of ivabradine and beta-blocker are in good agreement with controlled studies with predominantly younger patients (Fox et al., 2008a; Swedberg et al., 2010; Tardif et al., 2009) and two open-label studies (Köster et al., 2009; Werdan et al., 2012). Most notably, the encouraging safety data mirror the results from the octogenarian subset of patients in the REDUCTION trial (Köster et al., 2010).
Clinical trials have proven the anti-anginal and anti-ischemic efficacy of the pacemaker current inhibitor ivabradine in combination with beta-blockers in patients with stable angina pectoris (AP). This retrospective subgroup analysis of the ADDITIONS study evaluated the effectiveness and tolerability of ivabradine combined with beta-blockers, and its effects on angina symptoms and quality of life in elderly patients ≥ 75 years in everyday practice.
In the non-interventional, multicenter, prospective, open-label ADDITIONS study 2330 patients with stable AP of different age groups were treated with a flexible dose of ivabradine twice daily in addition to beta-blockers for 4 months. Heart rate (HR), number of angina attacks, nitrate consumption, tolerance, and quality of life (QoL) were evaluated. A subgroup analysis was performed, focusing on 479 patients (21%) ≥ 75 years.
In these 479 patients ≥ 75 years ivabradine (mean dose 11.61 ± 3.18 mg per day) after 4 months of treatment reduced HR by 19.2 ± 11.6 bpm to 65.4 ± 8.3 bpm. The average number of angina attacks per week was decreased by 1.6 ± 1.8 to 0.4 ± 1.3 and the average consumption of short-acting nitrates per week was reduced by 2.2 ± 3.2 to 0.6 ± 1.8 units (both p < 0.0001). There was a marked shift in Canadian Cardiovascular Society (CCS) grade distribution with most patients (57%) now classified as CCS grade I, and 42% as CCS grades II and III. This was accompanied by an improvement in EQ-5D QoL index to 0.75 ± 0.22 (p < 0.0001). Tolerability of ivabradine treatment was rated by the physicians as “very good/good” for 72%/28% of elderly patients.
In daily clinical practice, addition of ivabradine to beta-blockers was effective in reducing HR, angina attacks and nitrate consumption in elderly patients (≥ 75 years) with stable angina pectoris. In addition, a marked improvement of CCS symptom scores and QoL was demonstrated. Treatment was generally well tolerated.
Angina pectoris in women: Focus on microvascular disease
2013, International Journal of Cardiology
Citation Excerpt :
However, presence of women in these trials was low (10–15%) [100–102], nor was subgroup analysis for gender performed. A large observational study showed effective treatment of stable angina by ivabradine in patients mainly not taking beta-blockers due to contraindications or intolerance [104]; of 4954 patients, 41% were women, and therefore those findings could be translated to a female population; however, because of its open-label design and absence of a placebo-controlled group, those data are not definitive. Very little information is available with respect to the effects of “classical” antianginal drugs on long term outcomes.
Ischemic heart disease (IHD) is the leading cause of death among women in Western countries, and it is associated with higher morbidity and mortality than in men. Nevertheless, IHD in women remains underdiagnosed and undertreated, and the misperception that females are “protected” against cardiovascular disease leads to underestimation of their cardiovascular risk; instead, women with chest pain have a high risk of cardiovascular events. Women suffering from angina pectoris tend to have different characteristics compared to men, with a high prevalence of non-significant coronary artery disease. Angina in women is more commonly microvascular in origin than in men, and therefore standard diagnostic algorithms may be suboptimal for women. This different pathophysiology impacts clinical management of IHD in women. While response to medical therapy may differ in women, they are scarcely represented in clinical trials. Therefore, solid data in terms of gender efficacy of antianginal drugs are lacking, and particularly when angina is microvascular in origin women often continue to be symptomatic despite maximal therapy with classical antianginal drugs. Recently, new molecules have shown promising results in women.
In conclusion, women with angina are a group of patients in whom it seems appropriate to concentrate efforts aimed at reducing morbidity and improving quality of life.
Ivabradine: A new frontier in the treatment of stable coronary artery disease and chronic heart failure
2020, Clinica Terapeutica

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Treatment of stable angina pectoris by ivabradine in every day practice: The REDUCTION Study

Background

Methods

Results

Conclusion

Section snippets

Design

Study population

Discussion

Conclusions

Disclosures

Acknowledgements

Am Heart J

J Am Coll Cardiol

Lancet

Pharmacol Res

Pharmacol Res

Am J Med

Relations between heart rate, ischemia, and drug therapy during daily life in patients with coronary artery disease

Circulation

Subsets of ambulatory myocardial ischemia based on heart rate activity. Circadian distribution and response to anti-ischemic medication. The Angina and Silent Ischemia Study Group (ASIS)

Circulation

The role of heart rate and the benefits of heart rate reduction in acute myocardial ischemia

Eur Heart J

2007 Chronic Angina Focused Update of the ACC/AHA 2002 guidelines for the management of patients with chronic stable angina

Circulation

Guidelines on the management of stable angina pectoris

Eur Heart J

Nationale Versorgungsleitlinie Chronische KHK. Version 2008

Heart rate as a prognostic factor for coronary heart disease and mortality: findings in three Chicago epidemiologic studies

Am J Epidemiol

Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease

Eur Heart J