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

Article Outline

• Abstract
• Methods
  • Design
  • Inclusion and exclusion criteria
  • Clinical examinations
  • Statistical analysis
• Results
  • Study population
  • Concomitant diseases, medication, and procedures
  • Heart rate and ECG parameters
  • Angina pectoris and nitrate consumption
  • Adverse events/ADR
• Discussion
  • Study limitations
• Conclusions
• Disclosures
• Acknowledgements
• References
• Copyright

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.

In patients with coronary artery disease, a high heart rate can induce myocardial ischemia with angina pectoris.¹, ², ³ Therefore, current guidelines recommend a heart rate reduction to 55 to 60 beat/min for the treatment of stable angina pectoris.⁴, ⁵, ⁶ Epidemiological studies have demonstrated that a low resting heart rate is associated with low total mortality and low cardiovascular mortality.⁷, ⁸, ⁹, ¹⁰, ¹¹, ¹² A recent study confirmed the impact of resting heart rate on cardiovascular events in a prospective setting.¹³

Ivabradine reduces heart rate by acting specifically on the sinoatrial node.¹⁴ It selectively inhibits the I_f current of cardiac pacemaker cells, which leads to an exclusive heart rate reduction.¹⁵ The antianginal and anti-ischemic efficacy of ivabradine in patients with angina pectoris was demonstrated in controlled clinical trials.¹⁶, ¹⁷, ¹⁸, ¹⁹, ²⁰

Although efficacy of treatment with ivabradine in coronary artery disease has been demonstrated within the setting of controlled trials, there is a need to evaluate whether these favorable results can be repeated outside of clinical studies in large-scale patient populations in everyday routine practice.¹⁶, ¹⁷ In controlled clinical studies, patients do not represent everyday populations because they are subject to a detailed selection process and are more frequently followed up.²¹ Mostly, in this type of study, patients who have a better compliance than those patients treated under everyday conditions are included. Multimorbid patients, patients with polytherapy, and geriatric patients are often excluded from controlled trials. In addition, study populations are often relatively small and less common, or rare side effects may not develop within any of the study groups.²²

Therefore, the objective of this open-label, multicenter study was to evaluate the efficacy, safety, and tolerance of ivabradine in a broad range of patients with stable angina in everyday routine practice.

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Methods 

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 ethical guidelines of the European Independent Ethics Committee.

Inclusion and exclusion criteria 

The inclusion criterion was the need for symptomatic treatment of chronic stable angina pectoris in patients with sinus rhythm, in which β-blockers were contraindicated or where β-blocker intolerance was evident.

The patients had the following indications for ivabradine treatment:

Therapy was started with ivabradine 5 mg, twice daily. Increase of dosage was possible after 2 to 4 weeks up to a maximum target dose of 7.5 mg, twice daily.

A reduced dose of 2.5 mg, twice daily, was recommended in patients with the following features: age, ≥75 years; renal insufficiency with a creatinine clearance, <15 mL/min; heart rate continuously, <50 beat/minute during treatment; and symptomatic bradycardia.

Clinical examinations 

Three visits were conducted: at baseline and after approximately 1 and 4 months of ivabradine treatment. At the initial visit, general and the cardiac history were recorded. Risk factors, concomitant disease, and concomitant therapy were evaluated. Blood pressure and heart rate were measured. The number of angina pectoris attacks within the last week and the consumption of short-acting nitrates (nitrate hubs and capsules) were registered. The participating cardiologists could carry out an additional electrocardiogram (ECG) at each visit.

The first control examination took place after 2 to 4 weeks. At this time, heart rate, blood pressure, number of angina pectoris attacks within the last week, and the consumption of short-acting nitrates were documented. The dose of ivabradine was adjusted when necessary, and suspected adverse drug reactions (ADR) were documented. Overall efficacy and tolerance were assessed according to the physician's judgment. The second control followed after approximately 4 months. At this time, the same controls as after 1 month were repeated. In addition, the change of concomitant therapy was documented, and a final assessment of the efficacy and tolerance of ivabradine was compiled according to the physician's judgment using a scale including excellent, very good, moderate, or poor.

Statistical analysis 

A descriptive statistical analysis was performed using SAS® software, version 9.1. All patients that had valid data from all 3 visits were considered. Changes to heart rate and blood pressure were evaluated using the 1-sample t test. Differences in the occurrence of angina pectoris attacks and in the need for the use antianginal drugs were evaluated using the Wilcoxon signed rank test. A P value <.05 was considered to be significant.

The study was supported by funding from Servier, Germany. The statistical analysis was substantively supported by Dieter Schremmer from the “Gesellschaft für Therapieforschung” in Munich, Germany.

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Results 

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 months. The Canadian Cardiovascular Society (CCS) classification of angina pectoris of the patients is given in Table I.²³

Table I. The CCS classification of angina pectoris grade in the study population

Concomitant diseases, medication, and procedures 

In 2,351 (49%) of the patients, a percutaneous coronary intervention had been performed previously. Seventy hundred eighty-six patients (17%) had been treated with coronary artery bypass surgery. In 2,723 (56%) of the patients, a percutaneous coronary intervention or coronary artery bypass surgery or both had been performed. There were 1,529 patients (32%) who had a previous myocardial infarction; 43 patients (3.1%) were in an early phase (<3 months) after myocardial infarction.

Concomitant diseases are shown in Table II, and comedication during the observation period is shown in Table III, Table IV.

Table II. Concomitant diseases

Table III. Cardiovascular medication before and during the ivabradine therapy

ASS, Acetylsalicyclic acid.

Table IV. Noncardiovascular medication

For 1,575 patients (32%) at the start of ivabradine therapy, this was part of the patient's first antianginal treatment. In 728 patients (15%), ivabradine was added to the existing drug therapy scheme. In 2,638 patients (53%), ivabradine therapy was initiated during a change of preexisting therapy. Change of a preexisting therapy predominantly involved β-blockers (87% of changes in the category).

A total of 2,270 patients had their β-blocker therapy discontinued. In this group, 1,502 patients (66%) had intolerance/side effects, 580 (26%) insufficient clinical effect, and 454 (20%) a contraindication. In 141 patients, calcium-channel blockers were discontinued: 57 (40%) for intolerance/side effects, 93 (66%) for insufficient effect, and 6 (4%) for contraindications. In 167 patients, other therapeutics (including nitrates and molsidomine) were stopped, in 48 patients (29%) due to intolerance/side effects, in 122 patients (73%) due to insufficient effect, and in 6 patients (4%) due to contraindications.

The dosage of ivabradine during follow-up is given in Table V. During follow-up, the administered ivabradine dosage for 1,415 patients (29.6%) was increased and reduced for 46 patients (1.0%).

Table V. Percentage of patients with different dosages of ivabradine during follow-up

BID, Dose applied twice daily.

In 4,646 patients (95.2%), ivabradine therapy continued longer than 4 months, 234 patients (4.8%) had their therapy discontinued. Fifty-three patients in the group in which ivabradine was discontinued showed symptoms of drug intolerance. For 181 patients, ivabradine therapy was discontinued due to other reasons such as incompliance of the patient (n = 49), insufficient effect (n = 20), or due to the fact that the patient was symptom-free and the patient terminated his or her therapy independently (n = 7).

Heart rate and ECG parameters 

Heart rate was significantly reduced by 12.4 ± 12.2 beat/min from 82.9 ± 15.3 to 70.4 ± 9.2 beat/min between the baseline and the third visit after 4 months (P < .0001) (Figure 1).

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• Figure 1. 

  Heart rate reduction by ivabradine over a period of 4 months. Average dosage was 9 mg started at baseline, 10.2 mg at first month, and 10.5 mg after 4 months. The baseline value displayed represents heart rate before start of ivabradine therapy.

No relevant changes were observed in ECG parameters, for example, PQ, QRS, and QTc periods. Marked physiological changes were only observed in R-R interval and in the uncorrected QT associated with reduction of heart rate.

Angina pectoris and nitrate consumption 

Seventy-nine percent of the patients had a minimum of 1 angina pectoris attack per week before the start of therapy with ivabradine. At the follow-up visit after 4 months, the frequency of angina pectoris attacks had been significantly reduced during the modified treatment including ivabradine (2.4 ± 3.1 to 0.4 ± 1.5 attacks per week; P < .0001) (see Figure 2).

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• Figure 2. 

  Number of angina pectoris attacks at baseline and at follow-up. Ivabradine significantly reduced the number of angina pectoris attacks registered in the week before the visit.

The use of nitrates (hubs/capsules) between baseline and the follow-up visit after 4 months was significantly reduced during the treatment with ivabradine (3.3 ± 4.4 to 0.6 ± 1.6; P < .0001) (Figure 3).

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• Figure 3. 

  Nitrate consumption at baseline and at follow-up. Total number of nitrate spray and capsule use during the week before evaluation was significantly reduced by ivabradine.

Systolic mean blood pressure was lowered from 139.2 ± 17.2 to 131.3 ± 12.0 mm Hg between baseline and the fourth month of treatment including ivabradine and antihypertensive comedication (−7.9 ± 13.5 mm Hg; P < .0001). Diastolic mean blood pressure was lowered from 83.2 ± 9.8 to 78.8 ± 7.1 mm Hg from baseline to the fourth month of treatment including ivabradine (−4.4 ± 8.8 mm Hg; P < .0001).

Adverse events/ADR 

Seventy-eight suspected ADR were reported in 57 patients (1.2% of 4,954 patients, 0.1% were classified as severe). Most commonly, nausea (11 cases, 0.22%) and dizziness (9 cases, 0.18%) were described. Ten patients complained about ophthalmic events (7 cases of phosphenes [0.14%], 1 with blurred vision, 3 cases of other symptoms). Four patients developed a headache, and 2 had syncopes. Cardiac ADR were reported in 11 patients including atrial fibrillation (4 cases) and bradycardia (3 cases). Others were AV (atrioventricular) block II°, arrhythmia, palpitations, tachycardia, and nonspecific cardiac complaints, in 1 patient each. One patient died from liver dysfunction associated with ethanol-toxic liver cirrhosis during the treatment period, and one other patient, who have chronic obstructive pulmonary disease and heart failure, died of sudden cardiac death. Six patients died from other causes not classified as related to the ivabradine therapy: 1 from recurrent myocardial infarction and 5 from noncardiac causes. Adverse drug reactions were related to ivabradine in 6 patients (mainly visual symptoms), 18 probably related to ivabradine, 22 possibly related, 8 probably unrelated, and 3 were not evaluable. Four ADR including 1 case of atrial fibrillation have not completely recovered.

Physicians graded the efficacy of ivabradine as excellent in 59.4% of the patients, as very good in 37.3%, as moderate in 2.6%, and as poor in 0.7% of the patients. They graded the patient's tolerance of ivabradine as excellent in 66.3% of the patients, as very good in 31.9%, as moderate in 1.3%, and as poor in 0.6%.

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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 routine conditions.

The main findings of this prospective broad-scale study with 4,954 patients were that ivabradine is safe, achieves a significant reduction of heart rate, and is highly efficient to treat angina pectoris. Interestingly, side effects were less frequent than expected from controlled clinical trials.

The patient group included in this study was typical for the broader population with coronary artery disease seen by physicians in day-to-day practice. The high number of patients with concomitant diseases accounting for relative or absolute contraindications to β-blockers demonstrates that there is a broad therapeutic space for ivabradine in everyday practice.

The heart rate reduction of 12 beat/min associated with the addition of an ivabradine therapy was significant and occurred mainly in the first month of treatment. The further reduction of heart rate in this study between the second and third visit after 4 months can be mainly explained by the successive increase of ivabradine dose in the patients. This finding was expected from results of other trials, and the range of heart rate reduction is comparable to that reported in other trials.¹⁶, ²⁴ The absolute reduction of heart rate by ivabradine is likely to be underestimated by this study because at the baseline, the β-blocker therapy was discontinued in 2,270 of the patients. This caused an increase in the heart rate, and this reverse effect may mask the actual ivabradine effect. In addition, only 19% of the patients received the maximum target dose of 7.5 mg twice a day. The reason for this moderate approach may be the common reservation of physicians to increase the dosage of a novel drug to the approved target dose. The heart rate level reached in this group may have allowed for a further increase in dosage in accordance with common guidelines, which suggest a target heart rate of 55 to 60 beat/min for patients with angina pectoris.⁴, ⁵, ⁶

Suspected ADR related to cardiac rhythm involved 1 patient with reversible second-degree AV block, 3 patients with bradycardia, and 4 patients with atrial fibrillation. All of these ADR were very unlikely to be directly related to ivabradine effects. The probability of their onset in this population of 4,954 patients with coronary artery disease and high prevalence of arterial hypertension is within the normal spontaneous onset range.²⁵, ²⁶ However, it cannot completely be ruled out that these are very rare side effects of the drug.

In this study, there were 344 patients who received an ivabradine therapy in addition to β-blockers. There was no increased incidence of relevant bradycardia in this patient subgroup. This suggests that ivabradine is an effective and safe adjunct to a β-blocker therapy. This has now been confirmed in a large randomized controlled trial.¹³

The reduction of the heart rate was associated with a marked decrease in the clinical symptoms of angina pectoris and with the reduction of consumption of nitrates. This is in accordance with the results from previous controlled trials using ivabradine in patients with angina pectoris.¹⁶, ¹⁷ However, in many of the group's patients, the addition of ivabradine was not the only change of therapy affecting angina pectoris symptoms. In this respect, it has to be taken into account that the number of calcium-channel blockers and ACE (angiotensin converting enzyme) inhibitors slightly increased between baseline and the follow-up visits. These changes might have contributed to the reduction in angina pectoris episodes and in the consumption of nitrates and therefore to the effect of ivabradine. However, because all patients received ivabradine, it can be suggested that ivabradine is one of the primary driving factors for the overall reduction of angina pectoris symptoms in this group.

Systolic blood pressure was lowered between baseline and the follow-up visits. This is apparently not related to ivabradine therapy because ivabradine has previously been shown to have no effect on blood pressure.¹⁷, ²⁴ The decrease of blood pressure can be explained by the additional use of other blood pressure–lowering drugs such as calcium-channel blockers and ACE inhibitors.¹⁷ The reduction of the blood pressure can also contribute to the reduction of angina pectoris symptoms.²⁷ However, in this study, the decrease of 8/4 mm Hg in blood pressure was only moderate and therefore presumably had only a moderate relief effect.

The total rate of ADR in this study was low and comparable to that from controlled trials.¹⁶, ¹⁷ This suggests a high tolerance of the drug under everyday life conditions. Adverse drug reactions occurred in only 1.2% of the patients despite a broad range of concomitant drug therapy and conceivable drug interactions.

Ophthalmic adverse reactions were reported in 0.2% of the patients, including the occurrence of phosphenes, and were less frequent than in the controlled trial, where up to approximately 1% of the patients of the low- and intermediate-dose groups reports such effects.¹⁶ The lower frequency of phosphenes reported in this trial may be explained by the type of questionnaire used in this study. Patients were interviewed in an open mode for side effects and not specifically and suggestively for visual symptoms in the sense of phosphenes. The frequency of phosphenes reported by specifically informed subjects has been 4 times higher than that reported by individuals who were unaware.²⁸ It may be assumed that patients in clinical trials were more informed about phosphenes than those in everyday practice. Therefore, they may have been more aware of these symptoms.²⁹

Cardiac ADR were rare, and the most frequently seen of these events was atrial fibrillation (≤0.1%). This was unlikely to be related to the ivabradine effects. The group with a mean age of 65 years, with 80% of patients having arterial hypertension as a risk factor for atrial fibrillation, has a naturally occurring risk for development of atrial fibrillation, which is in the reported range.²⁵, ²⁶

Considering the low number of ADR in this study group, it is consistent that 98% of physicians regarded the tolerance of ivabradine as good or very good.

Study limitations 

The main limitation of this observational study is the open-label, noninterventional design. This may cause a bias to overestimation of the benefits of ivabradine; however, it closely represents everyday practice conditions. A limitation is the lack of a placebo control group. However, recognizing the results of the controlled trials demonstrating the benefit of ivabradine therapy, it appears unethical to conduct a long-term study using a placebo control group.

Because the mean heart rate reached in this study was still rather high with 70 beat/min after 4 months and that there were only 19% of the patients at the maximum dose of 7.5 mg, twice daily, there was potential to increase the ivabradine dosage. Therefore, the therapeutic potential of ivabradine in this study was not fully utilized, and the benefits may still remain underestimated. On the other hand, this effect may lead to underestimation of the number of possible side effects, which more often occur at high doses.

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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 the drug in symptomatic coronary artery disease patients in clinical practice.

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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.

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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, H. Hohensee, T. Hohenstatt, O. Khan, H.-H. Knäbchen, A. Krämer, K. Krämer, R. Lange, A. Levertov, H. Littwitz, U. Meyer, K. Müller, L. Rokitzki, C. Ruhnau, K. Rybak, R. Schmitt, A. Spingler, H. Stellmach, R. Tietze, W. Türk, R. Vormann, T.-A. Wiegmann, G. Will, E. Wüstenberg, J. Zivojinovic. The list of the further investigators is available from the corresponding author.

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