Clinical advantage of heart rate lowering with Procoralan in the managementof cardiovascular patients






Irina ELYUBAEVA, MD, PhD
Servier International – Division of Medical Information
Suresnes, FRANCE

Clinical advantage of heart rate lowering with Procoralan in the management of cardiovascular patients


by I . Elyubaeva, France



Procoralan (ivabradine) is the first selective and specific If inhibitor, and provides pure heart rate (HR) reduction without alteration to myocardial contractility, the cardiac conduction system, or coronary vascular resistance. Experimental data have demonstrated the specific nature of the HR-lowering action of Procoralan, and suggest that the mechanism by which slowing of HR is achieved may affect the extent of its benefit. Selective HR slowing with Procoralan offers additional benefits not found with other HR slowing agents, and enables the full benefits of HR reduction to be realized for improved coronary perfusion and pump efficiency. Dual cardiac and vascular protection through prevention of endothelial dysfunction and development of atherosclerosis may contribute to the reduction in cardiac events seen in the clinical setting with Procoralan. The ability of Procoralan to positively affect angina symptoms and myocardial ischemia and to improve clinical outcomes makes it an important agent in the management of patients with CAD. Following the breakthrough results of SHIFT (Systolic Heart failure treatment with If inhibitor ivabradine Trial), Procoralan was approved for use in heart failure (HF) patients with left ventricular systolic dysfunction, representing a major step forward in the management of these patients. This approval brings the promise of a better prognosis and improved quality of life for millions of patients with chronic HF.

Medicographia. 2012;34:440-448 (see French abstract on page 448)


Pure heart rate reduction with Procoralan: anti-ischemic effect and dual cardiac and vascular protection in CAD and HF

Procoralan (ivabradine) is a specific heart rate (HR)–lowering agent, and the first agent of its type to be approved for therapeutic use.1 In contrast with other HR-lowering agents such as β-blockers, Procoralan acts uniquely on the pacemaker activity of the sinoatrial node of the heart, which results in important differences between Procoralan and other HR-reducing agents. Procoralan inhibits If, an ionic current that modulates pacemaker activity, and it thus lowers HR without directly affecting cardiac conduction or contractility.2 Myocardial perfusion, particularly in the subendocardium, takes place almost entirely during diastole. Normal physiological changes in HR mainly involve adjustments to the duration of diastole, and a lower HR leads to prolonged diastole, both in absolute terms and as a fraction of the cardiac cycle, facilitating myocardial perfusion.3 Procoralan, in common with physiological HR reduction, lowers HR essentially by prolonging diastole.4 By contrast, β-blockers, because of their negative effect on myocardial contractility, tend to also prolong systole, which reduces their beneficial effect on diastolic time fraction. β-Blockers also affect vasomotion in the coronary circulation by unmasking α-adrenergic vasoconstriction, resulting in constriction of large and small coronary arteries during exercise.3 By contrast, Procoralan maintains the vasodilation that occurs during exercise. All of the experimental data suggest that pharmacological HR reduction with Procoralan more closely resembles physiological changes in HR than does HR reduction with β-blockade, so that physiological changes in diastolic time fraction, left ventricular (LV) relaxation and synchrony, and coronary vasomotion are not compromised.5 As a consequence, the full benefit of HR reduction in improving coronary perfusion and pump efficiency can be realized.

By reducing HR, Procoralan decreases myocardial oxygen consumption and increases myocardial perfusion, both of which explain its ability to preserve cardiac energy metabolism, something that is profoundly impaired during heart failure (HF). Sustained HR reduction with Procoralan has been shown to improve cardiac function by significantly decreasing LV end-systolic diameter and stroke volume.6 Procoralan preserves cardiac output through its ability to increase stroke volume, reduces LV collagen density, and increases LV capillary density. Similar cardiac effects were observed in rats when Procoralan was given either immediately before or after myocardial infarction (MI), highlighting both the preventive and curative benefits of Procoralan in HF.7 These experimental data show that long-term HR reduction with Procoralan optimizes energy consumption, reverses remodeling, and prevents disease progression in HF.





Endothelial dysfunction is a common feature of many cardiac diseases, including coronary artery disease (CAD) and congestive HF. HR lowering with Procoralan may improve endothelial function and inhibit development of atherosclerotic plaque. In dyslipidemic mice expressing human apolipoprotein B 100, 3 months of treatment with Procoralan completely prevented deterioration of endothelium-dependent vasodilation in the renal and cerebral arteries.8 Despite similar HR reduction, the protective effect of Procoralan was not fully reproduced by metoprolol, possibly due to inhibition of β- adrenoceptor–mediated activation of endothelial nitric oxide synthase. In another model involving severe hypercholesterolemia in apolipoprotein E–deficient mice, Procoralan treatment improved endothelial function and reduced the atherosclerotic plaque area in the aortic root (by over 40%) and ascending aorta (by over 70%).9

These experimental data emphasize the specific nature of the HR–lowering action of Procoralan, and suggest not only that HR slowing is associated with cardiovascular benefits, but also that the mechanism by which HR slowing is achieved may affect the extent of the benefit. Selective HR slowing with Procoralan offers additional advantages that enable the full benefit of HR reduction to be realized for improved coronary perfusion and pump efficiency, and whichmay produce greater improvements in exercise capacity than β-blockade for a given reduction in HR. Dual cardiac and vascular protection through prevention of endothelial dysfunction and development of atherosclerosis may contribute to the reduction in cardiac events seen in the clinical setting.

Clinical benefits of pure heart rate reduction with Procoralan

The results of clinical trials have underlined the importance of HR in the pathophysiology of CAD and HF, and they support the value of pure HR reduction for the management of patients with stable CAD and HF.

_ Clinical benefits of heart rate reduction with Procoralan in stable coronary artery disease
_ Heart rate
Procoralan significantly reduces HR at rest and during exercise. In the large randomized, double-blind, controlled multicenter INITIATIVE trial (INternatIonal TrIAl on the Treatment of angina with IVabradinE versus atenolol) involving 939 patients with stable angina, Procoralan significantly reduced HR after 1 and 4 months of treatment, both at rest and at peak exer- cise.10 At rest, HR was reduced by 14.3 beats perminute (bpm) in the Procoralan 7.5 mg twice-daily group and by 15.6 bpm in the atenolol 100 mg once-daily group.

A further characteristic of the HR–lowering action of Procoralan is that its effect is largest in those patients with the highest HR before treatment.11 This important property is related to the use-dependence of the HR-lowering mechanism of Procoralan: the magnitude of If inhibition is directly related to the frequency with which channels are open. Inverse linear correlations between pretreatment HR and changes in HR during treatment have been observed for all dosages of Procoralan (Figure 1). This property has important clinical implications, as it results in greater efficacy in patients with higher HR at baseline and protects against excessive bradycardia.


Figure 1
Figure 1. Change in heart rate with Procoralan treatment according
to heart rate at baseline. Data are from a pooled analysis of
patients treated with Procoralan 7.5 mg twice daily (bid; n=940).

Abbreviations: bid, twice daily; bpm, beat per minute.
After reference 11: Borer JS, Le Heuzey JY. Am J Ther. 2008;15:461-473.
© 2008, Lippincott Williams & Wilkins, Inc.



A randomized double-blind trial involving 386 patients with stable angina treated with Procoralan twice daily for 1 year (either 5 mg or 7.5 mg) showed that HR reduction with Procoralan in patients with stable angina is maintained during long-term treatment.12 Both doses of Procoralan were associated with a substantial reduction in resting HR: 10 bpm with Procoralan 5 mg twice daily (from 71 to 62 bpm) and 12 bpm with Procoralan 7.5 mg twice daily (71 to 59 bpm). This reduction is consistent in magnitude with that found in earlier studies, and confirms that patients can be optimally treated with Procoralan over the long term.

_ Antianginal efficacy
HR reduction with Procoralan is associated with a substantial decrease in angina symptoms and short-acting nitrate consumption, both with short-term and long-term treatment. In a randomized double-blind study, Procoralan substantially reduced the frequency of angina attacks compared with placebo from 4.14 attacks to 0.95 attacks per week (P<0.001). Procoralan also reduced the consumption of short-acting nitrates compared with placebo, which decreased from 2.28 units per week to 0.50 units per week (P<0.001).13 The antianginal efficacy of Procoralan was also confirmed in INITIATIVE: at 4 months, the number of angina attacks decreased by 1.6 with Procoralan 7.5 mg twice daily and by 1.2 with atenolol 100 mg once daily.10

The aforementioned long-term study with Procoralan 5 mg and 7.5 mg twice daily in patients with stable angina demonstrated the maintenance of substantial antianginal efficacy over 1 year of treatment. The mean number of angina attacks per week decreased significantly by more than 50% with both dosages of Procoralan after 12 months of treatment (P<0.001).12

In a study comparing the efficacy of the combination of Procoralan 7.5 mg twice daily plus bisoprolol 5 mg once daily versus full-dose bisoprolol (10 mg once daily) in patients with stable angina and LV systolic dysfunction, 2 months of treatment with Procoralan substantially reduced the mean weekly number of angina attacks compared with bisoprolol alone (from 3.3 to 1.7 compared with 3.2 to 2.5; P=0.041).14 As a result, there were more patients with Canadian Cardiovascular Society (CCS) Class I stable angina in the Procoralan group than in the group receiving bisoprolol alone (82% versus 67%, respectively; P=0.037).

REDUCTION (Reduction of ischemic Events by reDUCtion of hearT rate In the treatment Of stable aNgina with ivabradine) confirmed the antianginal efficacy of Procoralan in routine clinical practice in 4954 patients with stable angina.15,16 After 4 months of treatment with Procoralan, angina attacks were reduced from 2.4 to 0.4 per week (P<0.0001). Consumption of short-acting nitrates was reduced from 3.3 to 0.6 units per week (P<0.0001). In the recent non-interventional, multicenter, prospective trial ADDITIONS (prActical Daily efficacy anD safety of Procoralan In combinaTIONwith betablockerS),which involved the treatment of 2330 patients with stable angina in routine clinical practice with Procoralan added to β-blockers, the addition of Procoralan resulted in a significant reduction in angina attacks and short-acting nitrate consumption (from 1.7 to 0.3 and from 2.3 to 0.4 units per week, respectively).17

_ Anti-ischemic efficacy and improvement of exercise capacity
HR is a major determinant of myocardial oxygen consumption and thus resting myocardial blood flow and coronary flow reserve (CFR). Auto-regulation of coronary vessels maintains a marginal balance of oxygen supply and demand under physiological conditions. The coronary circulation is particularly sensitive to increased HR, particularly if endothelial dysfunction, atherosclerosis, or hypertensive wall thickening impair auto- regulation. The effect of Procoralan on coronary blood flow velocity and CFR was assessed in a study involving 21 patients with stable CAD, in whom coronary blood flow was assessed invasively using intracoronary Doppler measurements.18 After 2 weeks of treatment with Procoralan, HR was found to be significantly lower (reduced by 13 bpm; P<0.001). Treatment with Procoralan significantly improves hyperemic coronary flow velocity and CFR in patients with stable CAD (Figure 2). These data have important clinical implications, not only regarding the anti-ischemic effect of Procoralan, but also regarding the impact of Procoralan on ischemic events, as CFR predicts adverse cardiovascular long-term outcomes.19 Procoralan showed significant anti-ischemic efficacy compared with placebo in a randomized double-blind study.13 The time to 1-mm ST-segment depression improved by more than 1 minute compared with placebo (P<0.001). The anti-ischemic effect of Procoralan was also demonstrated using the treadmill stress test in INITIATIVE, where it produced an increase of approximately 1.5 minutes.10 The group receiving Procoralan 7.5 mg twice daily also showed an increase in total exercise duration of 86.8 seconds at trough of drug activity; this was compared with 78.8 seconds in the atenolol 100 mg once-daily group. Noninferiority with atenolol was demonstrated for all exercise tolerance test parameters (P<0.001). The addition of Procoralan to bisoprolol in the treatment of patients with stable angina and LV systolic dysfunction resulted in an improvement in exercise capacity: workload increased from 5.9 ±1.6 to 7.0 ±1.4 metabolic equivalents (P=0.004) compared with bisoprolol alone (from 5.7 ±1.4 to 6.2 ±1.4 metabolic equivalents, P=0.141).14

_ Improvement of quality of life
Poor quality of life (QOL) is a major issue for angina patients. Improvement of QOL is therefore an important goal and measure of therapeutic success in the management of angina. Few studies, however, have reported the effects of antianginal therapy on QOL, and those results that have been reported have been inconsistent. In ADDITIONS, the effect of Procoralan on QOL was assessed using the EQ-5D questionnaire.17 After 4 months of therapy with Procoralan, the proportion of patients at CCS Class I had more than doubled, and Procoralan significantly improved QOL (EQ-5D index as well as Visual Analogue Scale score). This improvement in QOL was consistent with the substantial reduction in the number of angina attacks and consumption of short-acting nitrates. Procoralan is thus an important treatment option for patients with stable angina for improvement of both symptoms and QOL.


Figure 2
Figure 2. Box plots of coronary flow reserve (CFR) at baseline and
after 1 week of treatment with Procoralan 5 mg twice daily.

After reference 18: Skalidis et al. Atherosclerosis. 2011;215 (1):160-165. © 2010,
Elsevier Ireland Ltd.



_ Prevention of coronary events in patients with stable CAD and LV systolic dysfunction with elevated heart rate
Reduction of elevated HR in patients with stable CAD could be a potential approach to lowering the risk of cardiovascular events. Epidemiological studies and retrospective clinical analysis have shown that a high HR is an independent predictor of cardiovascular events in coronary patients.20 BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor Procoralan in patients with coronary disease and left ventricULar dysfunction) was the first randomized controlled trial designed to assess the effect of pure HR reduction with Procoralan on cardiovascular events in patients with documented CAD and associated LV dysfunction. BEAUTIFUL was also the first clinical trial to prospectively determine that patients with elevated HR have a higher risk of cardiovascular events.21 In BEAUTIFUL, Procoralan significantly reduced all coronary end points in patients with an elevated resting HR of ≥70 bpm (n=5392): Procoralan significantly reduced admission to hospital for MI (relative risk reduction [RRR], 36%; P=0.001) (Figure 3, page 444), admission to hospital for MI or unstable angina (RRR, 22%; P=0.023), and coronary revascularization (RRR, 30%; P=0.016).22 These results were achieved in patients already receiving optimal treatment for CAD (87% of patients were taking β-blockers, 90% were taking renin-angiotensin-aldosterone system inhibitors, 94% were taking antithrombotics, and 74% were on statins). In patients whose limiting symptom at baseline was angina (n=1507), Procoralan reduced the composite end point of cardiovascular mortality or hospitalization for fatal and nonfatal MI or HF by 24%(P=0.05).23 Treatment with Procoralan resulted in a 42% reduction in the risk of hospitalization for fatal and nonfatal MI in all patients with limiting angina, and a 73% reduction in those with a resting HR of 70 bpm or higher.23

Another major ongoing trial is evaluating the efficacy of Procoralan in patients with preserved LV function. SIGNIFY (Study assessInG the morbidity–mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease) includes stable CAD patients with an ejection fraction of above 40%, a HR of 70 bpm or higher, and no clinical signs of HF.24After a run-in period of 2 to 4 weeks, patients are randomized to placebo twice daily or Procoralan with a starting dose of 7.5 mg twice daily, which is adjusted at every visit to a target HR of 55 to 60 bpm. Over 19 000 patients have been enrolled in the study, which is expected to end in 2014.


Figure 3
Figure 3. Kaplan-Meier time-to-event plots by treatment group
(Procoralan or placebo) in the BEAUTIFUL trial in patients with
stable coronary artery disease and left ventricular systolic dysfunction
with an elevated resting heart rate (≥70 bpm).

After reference 22: Fox K et al. Lancet. 2008;372:807-816. © 2008, Elsevier.



Figure 4
Figure 4. Kaplan-Meier cumulative event curves for different end
points in the Systolic Heart failure treatment with
If inhibitor ivabradine
Trial (SHIFT) in the Procoralan and placebo arms.

Abbreviations: CI, confidence interval; CV, cardiovascular; HF, heart failure;
HR, hazard ratio.
After reference 26: Swedberg K et al. Lancet. 2010;376:875-885. © 2010,
Elsevier.



_ Clinical benefits of heart rate reduction with Procoralan in heart failure
_ Improvement of major outcomes
Given the prognostic implications of HR in patients with HF, the ability of Procoralan to decrease HR without impairing key cardiovascular or hemodynamic parameters such as myocardial contractility and ventricular relaxation makes it a particularly pertinent treatment in HF.25 The ability of Procoralan to improve prognosis in HF was successfully tested in the SHIFT trial (Systolic Heart failure treatment with If inhibitor ivabradine Trial). This randomized placebo-controlled clinical trial evaluated the effects of Procoralan on morbidity and mortality in 6558 patients with moderate to severe chronic HF and LV systolic dysfunction (LV ejection fraction of ≤35%) and a resting HR of ≥70 bpm. Procoralan was taken on top of guideline recommended therapies, and the median follow-up was 22.9 months.26 After 28 days, Procoralan reduced HR by 15.4 bpm (10.9 bpm, placebo-corrected). The primary composite end point (cardiovascular death or hospital admission for worsening HF) was significantly reduced by 18% (P<0.0001). Procoralan significantly reduced HF death (RRR, 26%; P=0.014) and hospitalization for HF (RRR, 26%; P<0.0001) (Figure 4).


Figure 5
Figure 5. Kaplan-Meier cumulative event curves for Procoralan
or placebo for primary cardiovascular death (A) and total death (B)
in patients with baseline heart rates of 57 bpm and above.

After reference 27: Böhm et al. Clin Res Cardiol. 2012 May 11.
Epub ahead of print. © 2012, Springer-Verlag.



Figure 6
Figure 6. Estimate of Procoralan treatment effect on recurrence of hospitalizations for worsening
heart failure.

Abbreviation: CI, confidence interval.
After reference 28: Borer JS et al. Eur Heart J. 2012 Sep 12. Epub ahead of print. © 2012, European Society of
Cardiology.



Results were consistent across all subgroups. On the strength of the absolute risk reduction on the primary end point, 26 patients would need to be treated for 1 year to prevent one cardiovascular death or HF-related hospital admission. Cardiovascular death and all-cause death diminished by 9% and 10%, respectively, and in patients with a HR of ≥75 bpm, there was a statistically significant 17% reduction in all-cause mortality (P=0.0109) and 17% reduction in cardiovascular mortality (P=0.0166) (Figure 5).27 Procoralan reduced the total burden of HF hospitalizations reducing the total number of hospitalizations by 25% (P=0.0002). During the almost 2 years of follow-up, Procoralan reduced the rates for both second and third hospitalizations for worsening heart failure by 34%; (P<0.001) and 29% (P=0.012), respectively.

These results are important for clinical practice as readmissions are not only distressing for patients and their families, but they are also associated with poor prognosis and are the major driver of the economic burden of heart failure (Figure 6).28 The results of SHIFT clearly demonstrate that Procoralan brings major prognostic benefits to patients with HF when taken on top of the best possible recommended therapy.

_ Improvement of symptoms and quality of life
In addition to improvement of outcomes, improvement of symptoms and well-being are also important targets for therapy in HF. In SHIFT, the New York Heart Association (NYHA) class was significantly improved in those patients receiving Procoralan (29.0% versus 24.2% in the placebo group, P<0.0156), as was the patient-reported global assessment score (65.9% versus 61.3% in the placebo group, P<0.0345) in the overall SHIFT population.26 Furthermore, a sub-study of SHIFT in 1944 patients demonstrated that in parallel to the improved outcomes in SHIFT, Procoralan improved health-related QOL in patients with HF, as assessed by the specific Kansas City Cardiomyopathy Questionnaire (KCCQ).29 Treatment with Procoralan significantly improved both the overall summary score and the clinical summary score on the KCCQ. At 12 months, the overall summary score, which includes physical limitations, total symptoms, QOL, and social limitation scores, was improved by 6.7 points with Procoralan compared with 4.3 points with placebo (P<0.001) (Figure 7, page 446). After 12 months, the clinical summary score, which includes physical limitations and the total symptom domain scores, was improved by 5.0 points with Procoralan compared with 3.3 points with placebo (P=0.018). Qualitatively, similar benefits were found with Procoralan compared with placebo at 4 months, and these were maintained throughout the study follow-up period. These data demonstrate that the reduction in HF severity produced by Procoralan, as reflected by reduced hospital admissions and improved NYHA functional class, also translates into a favorable impact on health-related QOL. This makes Procoralan a particularly pertinent treatment for achieving all of the therapeutic targets in HF patients: improvement of symptoms and wellbeing, together with improvement of outcomes. Other treatments that improve prognosis in patients with HF, such as β-blockers or angiotensin-converting enzyme inhibitors, have not demonstrated improvement of QOL in these patients.


Figure 7
Figure 7. Change at 12 months in the Kansas City Cardiomyopathy
Questionnaire overall summary score for the Procoralan and
placebo groups of the SHIFT trial.

Abbreviations: KCCQ, Kansas City Cardiomyopathy Questionnaire; OSS, overall
summary score; SD, standard deviation; SHIFT, Systolic Heart failure treatment
with If inhibitor ivabradine Trial.
Based on data from reference 29: Ekman I et al. Eur Heart J. 2011;32:2395-
2404. © 2011, Oxford University Press.



The recent randomized open blinded end point trial, CARVIVA HF (effect of CARVedilol, IVAbradine or their combination on exercise capacity in patients with Heart Failure), assessed the effect of HR reduction with carvedilol (25 mg twice daily), Procoralan (7.5 mg twice daily), and their combination (12.5/ 7.5 mg twice daily) on exercise capacity and QOL in 121 HF patients receiving the maximal dose of angiotensin-converting enzyme inhibitor.30 After 3 months of therapy, the NYHA class improved significantly more in patients receiving Procoralan or combination therapy than in those allocated to carvedilol alone. Procoralan alone or in combination was also more effective in improving exercise capacity and QOL compared with carvedilol alone.

_ Reversal of ventricular remodeling
Aside from the clinical standpoint, the results of SHIFT have important pathophysiological implications in that they demonstrate that Procoralan is able to reverse remodeling. An echocardiography substudy carried out in 611 patients from SHIFT found that 8 months of therapy with Procoralan produced a 7 mL/m2 reduction in LV end-systolic volume index, as compared with 0.9 mL/m2 in the placebo group (Figure 8).31 LV end-diastolic volume index was also reduced by 7.9 mL/m2 as compared with 1.8 mL/m2 in the placebo group; LV ejection fraction was improved by 2.4%, whereas there was no change in the placebo group at all. Moreover, these results occurred despite treatment with β-blockers and renin-angiotensin- aldosterone system antagonists, each of which was used in more than 90% of patients. Reversal of LV remodeling has important clinical implications in itself, since cardiac remodeling is a central feature of the progression of HF and is an established prognostic factor in patients with HF. The beneficial impact of Procoralan on LV remodeling and function may contribute to the reduction in cardiac morbidity and mortality found with Procoralan in patients with HF.


Figure 8
Figure 8. Change from baseline to 8 months in left ventricular endsystolic
volume index (LVESVI) in the echocardiography substudy
of SHIFT.

Based on data from reference 31: Tardif JC et al. Eur Heart J. 2011;32:2507-
2515. © 2011, Oxford University Press.



_ Good tolerability profile and easy use in practice
Throughout its entire clinical development program, Procoralan has demonstrated a good safety profile consistent with its highly specific and selective mode of action on the If current. Procoralan preserves the main electrophysiological parameters of the heart, including the refractory period of the atrium, the atrioventricular conduction time, and the duration of repolarization.32 The absence of any changes in the corrected QT interval throughout the clinical trial follow-up periods provides strong evidence of a lack of any significant direct effect of Procoralan on the duration of ventricular repolarization, indicating an absence of proarrhythmic action. In some patients, Procoralan can induce visual symptoms, mainly phosphenes; this is related to inhibition of the Ih current in retinal hyperpolarization-activated cyclic nucleotide-gated channels.32 These symptoms are generally mild and well tolerated, resolving spontaneously during or after treatment, and have led to withdrawal in less than 1% of patients, without safety concerns. Bradycardia was reported in 2.2% of angina patients treated with Procoralan 7.5 mg twice daily, compared with 4.4% of angina patients treated with atenolol 100 mg once daily.10 In HF patients receiving Procoralan in SHIFT, bradycardia led to permanent withdrawal from the study in only 1% of patients.26 This low percentage is explained by a clear plateau in the dose-response curve of If current inhibition and by the direct rate-related dynamics of the HR-lowering effect, limiting the risk of excessive bradycardia and ensuring the greatest HR reduction in patients with the highest pretreatment HR.11 Achievement of the target dose of Procoralan is simple, with uptitration from 5 mg (starting dose) through to 7.5 mg twice daily if HR remains above 60 bpm. This simplifies the management of angina or HF patients compared with other treatments. Importantly, the abrupt discontinuation of Procoralan does not result in a rebound phenomenon.11 The absence of rebound tachycardia with Procoralan not only simplifies the management of antianginal treatment, but also reduces the risk of adverse effects following missed doses or unscheduled gaps in medication administration. These characteristics of the HR– lowering action of Procoralan make it suitable and simple to use in most symptomatic patients with CAD or HF.

Conclusion

The pharmacological and clinical properties of Procoralan make it an important agent in the management of patients with stable CAD due to its ability to positively affect angina symptoms and myocardial ischemia and improve clinical outcomes. Following the breakthrough results of SHIFT, Procoralan was approved for use in HF patients, which represents a major step forward in the management of these patients. This approval brings promise of a better prognosis and improved QOL for millions of patients with chronic HF. _

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Keywords: coronary artery disease; heart failure, heart rate reduction; If current; ivabradine; Procoralan; sinus node; stable angina