Implicor: a new therapeutic solution for patients with angina

by K. Werdan, Germany

Department of Medicine III
University Hospital Halle (Saale)
Martin Luther University Halle-
Wittenberg, Germany

Since drug approval 10 years ago, the role of ivabradine in the treatment of stable coronary artery disease (SCAD) has changed from a rare alternative to β-blockers—in the case of contraindications or intolerance— to a partner drug. β-Blockers, the symptomatic first-line medication in SCAD, lower heart rate and thereby improve diastolic coronary perfusion and reduce myocardial oxygen demand. However, because of contraindications and intolerance, recommended target doses of β-blockers often cannot be given to the patient and therefore heart rate reduction is often lower than recommended, with more than half of β-blocker−treated SCAD patients having a resting heart rate ≥70 beats per minute (bpm). In these patients, if in sinus rhythm, adding ivabradine to concomitant β-blocker therapy can reduce resting heart rate by a further 6 to 20 bpm, and this additional heart rate reduction results in further symptomatic improvement, as shown by a reduction in angina pectoris attacks and in the use of short-acting nitrates, as well as by an improvement in health-related quality of life. Patient adherence is good with this effective combination of β-blocker and ivabradine, which is safe —the only rare, reversible side effects being bradycardia and visual disturbances (phosphenes). And if a SCAD patient in sinus rhythm ≥70-75 bpm suffers from systolic heart failure, then ivabradine will support the β-blocker as a proven heart failure agent; no alternative second-line antianginal agent can do the same. Metoprolol is one of the most often used β-blockers in the symptomatic treatment of SCAD patients. The combination of metoprolol and ivabradine in daily practice has been analyzed in more than 1300 patients from prospective observational studies, and the results were comparable to those described above for the combination of ivabradine and β-blockers as a group. Implicor, the fixeddose combination of ivabradine and the β-blocker metoprolol (ivabradine 5 mg/ 7.5 mg + metoprolol tartrate 25 mg/50 mg) can therefore help those SCAD patients already taking metoprolol and ivabradine separately to simplify their medication regimen.

Unmet needs in the treatment of angina

Treatment goals: reduction in mortality is not everything!
The annual rates of cardiac death and nonfatal myocardial infarction (MI) in stable coronary artery disease (SCAD) are low (0.6%-1.4% and 0.6%-2.7%, respectively)1; so while reduction in mortality as a treatment goal is important, it is only a poor reflection of how SCAD patients experience their situation and what impact treatment may have on a patient’s day-to-day life.2 Health-related quality of life (HRQoL)—as reflected by symptoms and the impact of disease on social, emotional, and occupational function—may be even more important than longevity. Many SCAD patients report moderate or severe problems with respect to pain/discomfort (78.5%), anxiety/depression (42.4%), mobility (35.6%), and usual activities (22.5%).3 Treatment goals in patients with SCAD are therefore not only to reduce the rates of cardiovascular death, nonfatal MI, and heart failure, but also to attenuate angina symptoms effectively and thereby decisively improve HRQoL!

Angina treatment with β-blockers and calcium channel blockers – many patients remain symptomatic
For relief of angina and myocardial ischemia, the ESC guidelines on the management of SCAD1 recommend β-blockers and/or calcium channel blockers as first-line treatment to control heart rate and symptoms. But even with this first-line medical treatment, 25% of patients with SCAD report monthly angina, and 8% report daily or weekly angina, with an inverse correlation of angina symptoms and HRQoL.4 One-fifth of patients who have had an acute MI have symptoms of angina one year later,5 and even after revascularization two-fifths of SCAD patients remain symptomatic.6 These data clearly indicate an unmet need for treatment options to relieve angina and improve HRQoL in patients with SCAD, beyond first-line medications, which are associated with low adherence7 and also have little power to improve HRQoL.8,9

Synergy between β-blocker and ivabradine in the treatment of patients with stable coronary artery disease

Heart rate reduction – a general treatment goal in SCAD patients
Elevated heart rate is independently associated with cardiovascular and all-cause mortality and morbidity in patients with established cardiovascular disease.10,11 In SCAD patients, several large series show an association of higher resting heart rate with higher all-cause mortality, cardiovascular (CV) mortality, CV morbidity, and CV rehospitalizations, as well as with the risk of developing myocardial ischemia.12-16 SCAD patients with reduced ejection fraction (<40%) and a resting sinus rhythm ≥70 bpm showed—in comparison with those with a sinus rhythm <70 bpm—a 34% higher risk for CV death, a 46% higher risk for MI, a 38% higher risk for coronary revascularization, and a 53% higher risk for hospital admission because of heart failure, with each 5 bpm increment in resting heart rate (RHR) being associated with approximate increases of 8% in CV death, 7% in MI, 8% in coronary revascularization, and 16% in admission with heart failure.17

Also, SCAD patients in sinus rhythm without heart failure in the SIGNIFY trial (Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease)18—with 83% being treated with a β-blocker— have yielded important information: RHR was reduced by ivabradine from 77.1±6.9 bpm initially to 60.7±9.0 bpm at 3 months, while in the placebo group heart rates were 77.2±7.1 bpm initially and 70.6±10.1 bpm after 3 months. This 10 bpm lower heart rate in the ivabradine group coincided in 2084 patients with CCS≥2 angina, with a significant reduction in angina frequency and a better disease perception, angina stability, treatment satisfaction, and health status than in the 2103 patients in the placebo group.19 The latter findings seem to be of special practical importance, as more than half of SCAD patients have an RHR of ≥70 bpm.20 Therefore, lowering heart rates from ≥70 bpm to <70 bpm is a therapeutic target in SCAD patients for symptomatic relief and improvement in HRQoL.

Heart rate reduction by β-blockers improves prognosis only during the first years after myocardial infarction, but attenuates symptoms also thereafter
β-Blockers produce their therapeutic effects mainly by heart rate reduction, which results in improved diastolic coronary perfusion and reduced myocardial oxygen consumption, thereby bringing relief in myocardial ischemia, rhythm disturbances, and anginal symptoms.21 Heart rate reduction is responsible for the prognostic benefit of β-blockers in MI patients within the first one to three years after MI, but no longer.22-25 In MI patients more than three years after the event and in patients with SCAD without a history of MI, no prognostic benefit with respect to reduction in mortality is seen despite heart rate reduction.24,26

However, independently of the prognostic effects, heart rate reduction by β-blockers in SCAD patients is an effective way to reduce angina pectoris symptoms and consumption of short-acting nitrates, and to improve exercise tolerance.27

Table I. Treatment of patients with stable coronary artery disease with b-blockers – mean daily doses as percentage of target doses.

Side effects and contraindications limit achievable -blocker dose in daily practice to 40%-70% of recommended target doses
What should be done with SCAD patients remaining symptomatic when first-line treatment with a β-blocker—albeit accepted by the patientc—is not enough? It is known from randomized controlled trials (RCTs) as well as from daily outpatient practice that achievement of β-blocker treatment at the recommended doses28—atenolol 100 mg/day, bisoprolol 10 mg/day, carvedilol 50 mg/day, metoprolol 200 mg/day—is not easy, because of side effects like dizziness, fatigue, bradycardia, and hypotension, or because of physicians’ reservations based on existing comorbidities of their patients, like obstructive pulmonary disease and/or peripheral artery disease.29 As a consequence, suboptimal β-blocker doses are used in SCAD patients, as seen in RCTs, multicenter surveys, and registries, but also in non-interventional observational studies reflecting daily practice, with mean doses of only 40% to 70% of the recommended target doses, or even less (Table I).

Ivabradine – the partner drug of β-blockers in heart rate reduction
In this situation it makes sense to combine the tolerated β-blocker dose with another drug with heart rate−reducing and antianginal effects, but lacking the β-blocker−specific side effects. Therefore, combination of a β-blocker with the pacemaker channel inhibitor ivabradine is a valuable option in those patients who do not tolerate recommended doses of β-blockers or those with insufficient reduction of heart rate or persisting angina symptoms despite the tolerated β-blocker medication in use. Ivabradine given twice daily in a daily dose of 10 to 15 mg in combination with a β-blocker, or without in the case of β-blocker contraindications or intolerance, reduced mean resting sinus rhythm by 6 bpm30 and 10 bpm18 in RCTs, and by 19.4 bpm,31 12.4 bpm,32 and 15.4 bpm33 in prospective observational studies.

The combination of a β-blocker with ivabradine (IIa/B1) has two advantages in comparison with a combination with another recommended second-line drug, like long-acting nitrates, nicorandil, or ranolazine (IIa/B1). Firstly, since ivabradine is a pacemaker channel inhibitor, it adds to the therapeutically wished-for negative chronotropic effect of β-blockers, thereby further reducing myocardial oxygen demand, increasing oxygen supply to the heart by prolonging diastolic perfusion, improving endothelial function, and enhancing coronary flow reserve as well as coronary collateral flow. Furthermore, ivabradine may reduce left ventricular filling pressure and improve stroke volume in response to exercise.34 Secondly, many patients with SCAD suffer from ischemic heart failure with reduced ejection fraction (HFrEF), as in every second HFrEF patient heart failure is of ischemic origin. In this large subgroup of patients with SCAD, the combination of a β-blocker with ivabradine doubles the benefits to the patient as both β-blockers and ivabradine are effective antianginal drugs and additionally reduce mortality and rehospitalization because of heart failure, in patients with sinus rhythm ≥70-75 bpm in the case of ivabradine.35-37 As mentioned above, no other second-line medication can achieve this double goal like ivabradine.

Figure 1. Pooled analysis of three prospective observational ivabradine studies in 8555 patients with stable coronary heart disease, sinus
rhythm ≥60 bpm, and either concomitant b-blocker therapy (40%) or without b-blocker therapy because of b-blocker contraindications/
A. Antianginal effectiveness of ivabradine in the overall population (n=8555). (a) Angina attacks per week; (b) Short-acting nitrate consumption per week; (c) Canadian
Cardiovascular Society (CCS) angina class. Bars are means ± SD. *P<0.0001 for changes from baseline or CCS class changes.
B. Antianginal effectiveness in the subgroup with concomitant metoprolol treatment (n=1376). (a) Angina attacks per week; (b) Short-acting nitrate consumption per
week; (c) Canadian Cardiovascular Society (CCS) angina class. Bars are means ± SD. *P<0.0001 for changes from baseline or CCS class changes.
Recruitment was from the ADDITIONS study,31 with 2330 patients in 818 centers treated with a mean dose of 12.37 mg/day in addition to b-blocker medication, from
the REDUCTION study,32 with 4954 patients in 1503 centers treated with a mean dose of 10.5 mg/day and with a contraindication or intolerance to b-blockers, and
from the RESPONSIVE study,33 with 1250 patients in 338 centers treated with a mean dose of 11.1 mg/day with or without b-blocker. These ivabradine doses reduced
the mean resting heart rate by 19.4 bpm in the ADDITIONS study, 12.4 bpm in the REDUCTION study, and 15.4 bpm in the RESPONSIVE study.
From reference 38: Werdan K et al. Cardiology. 2016;135:141-150. © 2016, The Author(s). Published by S. Karger AG, Basel.

The “proof of concept” in daily practice
The “proof of concept” of symptomatic angina improvement with the combination of ivabradine—given twice daily—and β-blocker in patients with SCAD comes not only from large randomized controlled trials like BEAUTIFUL30 (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) and SIGNIFY,18 but also from clinical practice represented by a pooled analysis of three prospective, observational studies.38 This pooled analysis in 8555 SCAD patients (age 65.4±10.58 years; 19% ≥75 years; 41% female; CCS I/II/III/IV 27%/53%/20%/ <1%) with sinus rhythm ≥60 bpm, investigated the heart rate− reducing effect of a 4-month treatment with ivabradine with (40%) or without concomitant β-blocker medication (because of contraindication or intolerance) on weekly frequency of angina and consumption of short-acting nitrates, as well as on HRQoL. Ivabradine treatment resulted in a highly significant reduction in angina attacks/week (Figure 1Aa) and in consumption of short-acting nitrates/week (Figure 1Ab) after 1 month and even more after 4 months, as well as an improvement in CCS angina class (Figure 1Ac). Of special interest is the finding that in all subgroups tested (Figure 2) the beneficial antianginal effect (82% to 90%) was demonstrated to a similar degree as in the over all population (87%), with no exception. Similar findings were observed for short-acting nitrate use (82%-90% vs 87%) (Figure 2).

In Figure 1B, the antianginal effects of ivabradine are presented in the subgroup of 1376 SCAD patients of the pooled analysis with concomitant metoprolol, the β-blocker most used (40%) in this series. The mean number of angina attacks progressively decreased from 1.6±2.20 at baseline to 0.5±1.20 and 0.3±0.91 after one and four months, respectively. Use of short-acting nitrates was reduced from 2.2±3.26 at baseline to 0.7±1.43 and 0.3±1.08 after one and four months, respectively. Finally, an improvement in CCS class distribution was noted at the end of the study, with the majority of patients (64%) graded as class I at the last visit (baseline, 26%) and fewer patients as class II (32%; baseline, 51%) and III+IV (4%; baseline, 22%). The effects of ivabradine on angina attacks, nitrate use, and CCS class were comparable with those of other concomitantly used β-blockers (bisoprolol, carvedilol, and nebivolol) in this pooled analysis. Very similar results were found when analyzing the antianginal effects of ivabradine in the metoprolol subgroup (n=877) of the ADDITIONS study, with a mean metoprolol dose of 107.9±50.3 mg/day at baseline and 102.5±49.9 mg/day by month four.39 Even in those patients, in whom metoprolol alone does not achieve heartrate reduction below 70 bpm, addition of ivabradine succeeds in lowering heart rate by more than 20%,39 resulting in a reduction of more than 80% in the number of angina attacks per week (–1.8±1.92) and in weekly nitrate use (–1.8±2.76), similar to the total metoprolol group (Figure 2).

Ivabradine in combination with metoprolol improves health-related quality of life
The symptomatic management of angina is expected to improve HRQoL, primarily by reducing the severity and frequency of angina symptoms.8,40 With respect to improvement of HRQoL by specific antianginal drugs, information is really scarce. For β-blockers, we know at least that they are neutral with respect to HRQoL in patients with peripheral arterial disease and COPD.29 From a methodological point of view, the best information is available for ivabradine and comes from the randomized SIGNIFY trial19: 4187 SCAD patients (2084 in the ivabradine group and 2103 in the placebo group) were evaluated using the Seattle Angina Questionnaire and a generic visual analogue scale (VAS) on health status. Though a significant early positive effect of ivabradine on the physical limitation dimension was seen after 6 months (P=0.048), there was no significant difference in the physical limitation score at 12 months (4.56 points for ivabradine vs 3.40 points for placebo; P=0.085). Notably, ivabradine was associated with a significant maintained improvement in angina frequency and stability, disease perception, treatment satisfaction, and health status. As 83% of the SIGNIFY patients were under treatment with β-blockers,18 these findings can be interpreted as an improvement in important aspects of HRQoL by ivabradine in SCAD patients even on b-blocker treatment.

HRQoL can also be measured in daily practice, as was done in a subgroup of the ADDITIONS study31 with 877 SCAD patients treated for four months with ivabradine (mean dose 12.6 mg/day) in addition to concomitant metoprolol treatment (mean dose 107.9±50.3 mg/day).39 HRQoL measurement with the EQ-5D index score41 significantly (P0.0001) increased from 0.68±0.27 at baseline to 0.76±0.23 at one month, and to 0.84±0.20 after 4 months, and the VAS score rose from 58.1±18.4 to 65.5±16.1 and 72.2±15.5, respectively. It is worth mentioning that the EQ-5D index of patients in this trial on metoprolol alone (0.68±0.27) is similar to the value of patients with stable angina in the Swedish population (0.70±0.018)3as well as in Chinese patients (0.75±0.19)42, while the EQ-5D index after addition of ivabradine to metoprolol (0.84±0.20) in this trial is comparable to that of the general population in Sweden (0.84±0.005)3 and in Chinese patients (0.90±0.20).42 Improvements in HRQoL with ivabradine comparable to those described for the subgroup concomitantly treated with metoprolol were also found for patients concomitantly treated with other β-blockers (bisoprolol, carvedilol, nebivolol) in the pooled analysis.38

Data from the SIGNIFY trial19 and prospective observational studies38,39 therefore demonstrate an improvement in HRQoL by additional ivabradine treatment concomitant with β-blocker therapy in SCAD patients.

Figure 2. Antianginal effectiveness (reduction in angina attacks/week and in use of short-acting nitrates/week) after 4 months of treatment
with ivabradine, in a pooled analysis (see Figure 1A) in different subpopulations.
Bars are relative changes from baseline (means± SD). Values shown in bars are absolute changes from baseline (means ± SD). P<0.0001 for all changes. See also
legend to Figure 1.
From reference 38: Werdan K et al. Cardiology. 2016;135:141-150. © 2016, The Author(s). Published by S. Karger AG, Basel.

The benefit of a fixed-dose combination like implicor for the treatment of angina

Since drug approval 10 years ago, the role of ivabradine in the treatment of stable angina has changed from a rare alternative to β-blockers in the case of contraindications or intolerance to a partner drug with a proven net increase in therapeutic effects. Therefore a fixed-dose combination of β-blocker with ivabradine can help to optimize antianginal treatment, as fixed-dose combinations in general improve drug adherence.43 Implicor®, the first fixed-dose combination of metoprolol tartrate and ivabradine, which is available in 4 dosages (25 mg/ 5 mg, 50 mg/5 mg, 25 mg/7.5 mg, 50 mg/7.5 mg), will afford more relief of angina and more quality of life improvement for more patients with SCAD than is achievable with β-blocker monotherapy at suboptimal dose or suboptimal effect.

Treating patients with a fixed combination of two heart rate− reducing drugs warrants a thorough review on the occurrence of side effects. The safety profile of Implicor® is assumed to be in the same range as the safety profile of the reported metoprolol-ivabradine−treated subgroup of the ADDITIONS trial39: only 7 out of 989 patients in the safety set (<1%) reported 14 adverse drug reactions, most frequently phosphenes and visual impairment (4 patients) as well as dizziness and headache (3 patients). Bradycardia was reported in only 1 patient. No serious drug reaction occurred. The tolerability of the metoprolol and ivabradine combination was rated as “very good” or “good” by >99% of physicians. Of course, observational studies without a control group may overestimate treatments effects and underestimate adverse effects, as they were spontaneously reported and not specifically sought.

Therefore, we should bear in mind the respective data from the BEAUTIFUL30 and SIGNIFY18 RCTs: in the BEAUTIFUL study with 84% of concomitant β-blocker therapy, reversible visual symptoms (phosphenes, blurred vision, visual disturbance; 0.5% in the ivabradine group and 0.2% in the placebo group) were the only reported adverse events besides bradycardia30; in the SIGNIFY trial, besides bradycardia, again phosphenes and blurred vision occurred more frequently in the ivabradine group (6.6% vs 0.9%); in addition, atrial fibrillation (5.3% vs 3.8%) and QT interval prolongation (1.8% vs 0.7%) were significantly more frequent in the ivabradine group.18


In symptomatic patients with SCAD and sinus rhythm ≥70 bpm, the combination of metoprolol and ivabradine reduces heart rate with a high safety profile, thereby lowering the rate of angina attacks and nitrate use and improving HRQoL in patients with stable angina. Implicor®, the fixed-dose combination of ivabradine and the β-blocker metoprolol, can therefore help those SCAD patients already taking metoprolol and ivabradine separately to simplify their medication regimen. ■

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Keywords: angina pectoris; -blocker; Implicor; health-related quality of life; ivabradine; stable coronary artery disease