Abstract
Aim
Several clinical trials have demonstrated the antianginal and anti-ischemic efficacy of ivabradine in combination with beta-blocker in patients with stable angina pectoris. The ADDITIONS (PrActical Daily efficacy anD safety of Procoralan® In combinaTION with betablockerS) study evaluated the efficacy, safety, and tolerability of ivabradine added to beta-blocker, and its effect on angina symptoms and quality of life in routine clinical practice.
Methods
This non-interventional, multicenter, prospective study included 2,330 patients with stable angina pectoris treated with a flexible dose of ivabradine twice daily in addition to beta-blocker for 4 months. The parameters recorded included heart rate, number of angina attacks, nitrate consumption, tolerance, and quality of life.
Results
After 4 months ivabradine (mean dose 12.37 ± 2.95 mg/day) reduced heart rate by 19.4 ± 11.4 to 65.6 ± 8.2 bpm (p < 0.0001). The number of angina attacks was reduced by 1.4 ± 1.9 per week (p < 0.0001), and nitrate consumption by 1.9 ± 2.9 U per week (p < 0.0001). At baseline (i.e., on beta-blocker), half of the patients (51%) were classified as Canadian Cardiovascular Society (CCS) grade II; 29% were CCS grade I. After 4 months’ treatment with ivabradine, most of the patients were CCS grade I (68%). The EQ-5D index improved by 0.17 ± 0.23 (p < 0.0001). The overall efficacy of ivabradine was considered by the physicians as “very good” (61%) or “good” (36%) in most patients. Suspected adverse drug reactions were documented in 14 patients; none were severe.
Conclusion
In daily clinical practice, combining ivabradine with beta-blocker not only reduces heart rate, number of angina attacks, and nitrate consumption, but also improves the quality of life in patients with stable angina pectoris.
Similar content being viewed by others
References
Heusch G (2008) Heart rate in the pathophysiology of coronary blood flow and myocardial ischaemia: benefit from selective bradycardic agents. Br J Pharmacol 153(8):1589–1601
Andrews TC, Fenton T, Toyosaki N, Glasser SP, Young PM, MacCallum G, Gibson RS, Shook TL, Stone PH (1993) 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 88(1):92–100
Fox K, Borer JS, Camm AJ, Danching N, Ferrari R, Lopez-Sendon J, Steg PG, Tardif JC, Tavazzi L, Tendera M (2007) Resting heart rate in cardiovascular disease. J Am Coll Cardiol 50(9):823–830
Diaz A, Bourassa MG, Guertin MC, Tardif JC (2005) Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J 26(10):967–974
Graham I, Atar D, Borch-Johnson K, Boysen G, Burell G, Praha R, Dalloneville J, Herrmann-Lingen C, Hoes A (2007) European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur Heart J 28(19):2375–2414
Reil JC, Custodis F, Swedberg K, Komajda M, Borer JS, Ford I, Tavazzi L, Laufs U, Bohm M (2010) Heart rate reduction in cardiovascular disease and therapy. Clin Res Cardiol 100(1):11–19
Cooney MT, Vartiainen E, Laatikainen T, Joulevi A, Dudina A, Graham I (2010) Simplifying cardiovascular risk estimation using resting heart rate. Eur Heart J 31(17):2141–2147
Tardif JC (2009) Heart rate as a treatable cardiovascular risk factor. Br Med Bull 90:71–84
Böhm M, Swedberg K, Komajda M, Borer JS, Ford I, Dubost-Brama A, Lerebours GLT (2010) Heart rate as a risk factor in chronic heart failure (SHIFT): the association between heart rate and outcomes in a randomised placebo-controlled trial. Lancet 376:886–894
Nationale Versorgungsleitlinie chronische KHK (2006). http:\\www.versorgungsleitlinie.de
Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS, Ferguson TB, Jr, Fihn SD, Fraker TD, Jr, Gardin JM, O’Rourke RA, Pasternak RC, Williams SV (2002) ACC/AHA 2002 Guideline update for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to update the 1999 Guidelines for the Management of Patients With Chronic Stable Angina). J Am Coll Cardiol:1–125
Fox K, Ferrari R, Tendera M, Steg PG, Ford I (2006) Rationale and design of a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease and left ventricular systolic dysfunction: the morBidity-mortality EvAlUaTion of the I(f) inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction (BEAUTIFUL) study. Am Heart J 152(5):860–866
Fox K, Ford I, Steg PG, Tendera M, Ferrari R (2008) Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet 372(9641):807–816
Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R (2008) Heart rate as a prognostic risk factor in patients with coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a subgroup analysis of a randomised controlled trial. Lancet 372(9641):817–821
Fox K, Ford I, Steg PG, Tendera M, Robertson M, Ferrari R (2009) Relationship between ivabradine treatment and cardiovascular outcomes in patients with stable coronary artery disease and left ventricular systolic dysfunction with limiting angina: a subgroup analysis of the randomized, controlled BEAUTIFUL trial. Eur Heart J 30(19):2337–2345
Di Francesco D (1986) Characterization of single pacemaker channels in cardiac sino-atrial node cells. Nature 324(6096):470–473
Di Francesco D, Camm AJ (2004) Heart rate lowering by specific and selective I(f) current inhibition with ivabradine: a new therapeutic perspective in cardiovascular disease. Drugs 64(16):1757–1765
Di Francesco D (2005) Cardiac pacemaker I(f) current and its inhibition by heart rate-reducing agents. Curr Med Res Opin 21(7):1115–1122
Tardif JC, Ponikowski P, Kahan T, ASSOCIATE I (2009) Efficacy of the If current inhibitor ivabradine in patients with chronic stable angina receiving beta-blocker therapy: a 4 month, randomized, placebo-controlled trial. Eur Heart J 30:540–548
Köster R, Kaehler J, Meinertz T (2009) Treatment of stable angina pectoris by ivabradine in every day practice: the REDUCTION study. AHJ 158:e51–e57
Koester R, Kaehler J, Ebelt H, Soeffker G, Werdan K, Meinertz T (2010) Ivabradine in combination with beta-blocker therapy for the treatment of stable angina pectoris in every day clinical practice. Clin Res Cardiol 99(10):665–672
Koester R, Kaehler J, Meinertz T (2011) Ivabradine for the treatment of stable angina pectoris in octogenarians. Clin Res Cardiol 100(2):121–128
Burstrom K, Johannesson M, Diderichsen F (2001) Swedish population health-related quality of life results using the EQ-5D. Qual Life Res 10(7):621–635
Goldsmith KA, Dyer MT, Schofield PM, Buxton MJ, Sharples LD (2009) Relationship between the EQ-5D index and measures of clinical outcomes in selected studies of cardiovascular interventions. Health Qual Life Outcomes 7:96
Shu DF, Dong BR, Lin XF, Wu TX, Liu GJ (2011) Long-term beta blockers for stable angina: systematic review and meta-analysis. Eur J Cardiovasc Prev Rehabil [Epub ahead of print]
Gandjour A, Lauterbach KW (1999) Review of quality-of-life evaluations in patients with angina pectoris. Pharmacoeconomics 16(2):141–152
Kardas P (2007) Compliance, clinical outcome, and quality of life of patients with stable angina pectoris receiving once-daily betaxolol versus twice daily metoprolol: a randomized controlled trial. Vasc Health Risk Manag 3(2):235–242
Rehnqvist N, Hjemdahl P, Billing E, Bjorkander I, Eriksson SV, Forslund L, Held C, Nasman P, Wallen NH (1996) Effects of metoprolol vs verapamil in patients with stable angina pectoris. The Angina Prognosis Study in Stockholm (APSIS). Eur Heart J 17(1):76–81
Palatini P, Benetos A, Julius S (2006) Impact of increased heart rate on clinical outcomes in hypertension: implications for antihypertensive drug therapy. Drugs 66(2):133–144
Dolan P (1997) Modeling valuations for EuroQol health states. Med Care 35:1095–1108
Tardif JC, Ponikowski P, Kahan T (2009) 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. Eur Heart J 30(5):540–548
Pocock SJ, Elbourne DR (2000) Randomized trials or observational tribulations? N Engl J Med 342(25):1907–1909
Savelieva I, Borer JS, Camm AJ (2007) Low incidence of significant bradycardia during therapy with an I(f) current inhibitor ivabradine: heart rate reduction depends on baseline heart rate. J Am Coll Cardiol 49(9 Suppl A):1007
Swedberg K, Komajda M, Böhm M, Borer JS, Dubost-Brama A, Lerebours GLT (2010) Ivabradine and outcomes in chronic heart failure (SHIFT): a randomised placebo-controlled study. Lancet 376:875–885
Maggioni AP, Dahlström U, Filippatos G, Chioncel O, Leiro MC, Drozdz J, Fruhwald F (2010) EURObservational Research Programme: the Heart Failure Pilot Survey (ESC-HF Pilot). Eur J Heart Fail 12:1076–1084
Gislason GH, Rasmussen V (2006) Long-term compliance with beta-blockers, angiotensin-converting enzyme inhibitors, and statins after acute myocardial infarction. Eur Heart J 27:1153–1158
Daly CA, Clemens F, Sendon JL, Tavazzi L, Boersma E, Danchin N, Delahaye F, Gitt A, Julian D, Mulcahy D, Ruzyllo W, Thygesen K, Verheugt F, Fox KM (2010) Inadequate control of heart rate in patients with stable angina: results from the European heart survey. Postgrad Med J 86(1014):212–217
Wiest FC, Bryson CL, Burman M, McDonell MB, Henikoff JG, Fihn SD (2004) Suboptimal pharmacotherapeutic management of chronic stable angina in the primary care setting. Am J Med 117(4):234–241
Amosova E, Andrejev E, Zaderey I, Rudenko U, Ceconi C, Ferrari R (2011) Efficacy of ivabradine in combination with beta-blocker versus uptitration of beta-blocker in patients with stable angina. Cardiovascular drugs and therapy/sponsored by the International Society of Cardiovascular Pharmacotherapy. doi:10.1007/s10557-011-6327-3
Sy RW, Freedman SB (2011) Beta-blocker dose up-titration or addition of ivabradine in stable angina: more is not necessarily better : editorial to: “Efficacy of ivabradine in Combination with Beta-Blocker Versus Uptitration of Beta-Blocker in Patients with Stable Angina” by E. Amosova et al. Cardiovascular drugs and therapy/sponsored by the International Society of Cardiovascular Pharmacotherapy. doi:10.1007/s10557-011-6340-6
Colin P, Ghaleh B, Monnet X, Hittinger L, Berdeaux A (2004) Effect of graded heart rate reduction with ivabradine on myocardial oxygen consumption and diastolic time in exercising dogs. J Pharmacol Exp Ther 308(1):236–240
Goldsmith KA, Dyer MT, Buxton MJ, Sharples LD (2010) Mapping of the EQ-5D index from clinical outcome measures and demographic variables in patients with coronary heart disease. Health Qual Life Outcomes 8:54
Dyer MT, Goldsmith KA, Sharples LS, Buxton MJ (2010) A review of health utilities using the EQ-5D in studies of cardiovascular disease. Health Qual Life Outcomes 8:13
Dougherty CM, Dewhurst T, Nichol WP, Spertus J (1998) Comparison of three quality of life instruments in stable angina pectoris: Seattle Angina Questionnaire, Short Form Health Survey (SF-36), and Quality of Life Index-Cardiac Version III. J Clin Epidemiol 51(7):569–575
Longworth L, Buxton MJ, Sculpher M, Smith DH (2005) Estimating utility data from clinical indicators for patients with stable angina. Eur J Health Econ 6(4):347–353
Fletcher A, McLoone P, Bulpitt C (1988) Quality of life on angina therapy: a randomised controlled trial of transdermal glyceryl trinitrate against placebo. Lancet 2(8601):4–8 pii: S0140-6736(88)92942-X
Ekman I, Chassany O, Komajda M, Bohm M, Borer JS, Ford I, Tavazzi L, Swedberg K (2011) Heart rate reduction with ivabradine and health related quality of life in patients with chronic heart failure: results from the SHIFT study. Eur Heart J 32(19):2395–2404. doi:10.1093/eurheartj/ehr343
Acknowledgments
The authors thank METRONOMIA Clinical Research GmbH, Munich, for their substantive support of the statistical analysis, and all investigators for their contributions to the study. The investigators participated were M. Abdel- Quader, R. Antar, R. Aubele, S. Bock, P. Borchert, M.C. Brunke, J. Busaker, S. Djatschuk, M. Durak, M. Erdmann, D. Götze, P. Hammerl, S. Jasinski, N. Jung, T. Jung, O. Kahn, F. König, M. Köstering, T. Kornadt, K. Kreye, R. Kubbutat, R. Lange, R. Leischik, H. Littwitz, S. Mittnacht, P.Papachrysanthou, M. Patten, S. Pohl- Wegener, P. Pyriki, G.J. Qagisch, H. Reifenberg, I. Richter, F. Richter, E. Schaubert, O. Scheuermann, T. Scholl, D. Schulz, A. Sobejko, J. Steindorf, R. Stroh, H.J. Stühn- Pfeiffer, S. Vogel, T. Walter, H. G. Weber, A. Wilke, M. Zeydabadinejad. The list of further investigators is available from the corresponding author. The study was supported by funding from Servier Deutschland GmbH, Munich.
Conflict of interest statement
KW, HE, and SN are engaged in RCTs with ivabradine fully or partly supported by Servier (BEAUTIFUL, SHIFT, SIGNIFY, MODIFY and others). KW received honoraria for lectures from Servier, is a member of the German Procoralan advisory board of Servier and receives research grants for experimental and clinical ivabradine research from Servier. GH is an employee of Servier.
Author information
Authors and Affiliations
Corresponding author
Additional information
On behalf of the ADDITIONS Investigators
Rights and permissions
About this article
Cite this article
Werdan, K., Ebelt, H., Nuding, S. et al. Ivabradine in combination with beta-blocker improves symptoms and quality of life in patients with stable angina pectoris: results from the ADDITIONS study. Clin Res Cardiol 101, 365–373 (2012). https://doi.org/10.1007/s00392-011-0402-4
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00392-011-0402-4