Lessons from BEAUTIFUL: new frontiers in heart rate control



by Å. Hjalmar son, Sweden

Åke HJALMARSON, MD, PhD
Professor of Cardiology Wallenberg Laboratory Sahlgrenska Academy at University of Gothenburg – Gothenburg, SWEDEN

Elevated heart rate is an independent risk predictor among patients with coronary artery disease (CAD). Studies on the use of β-blockers in patients after myocardial infarction (MI) or with chronic heart failure have previously reported improved outcome and reduced mortality and morbidity, especially among patients with elevated heart rate at baseline. BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) was designed to test whether ivabradine, a specific inhibitor of the If current in the sinoatrial node with pure heart rate–lowering ability, could reduce mortality and morbidity in patients with CAD and left ventricular ejection fraction <40%. 10 917 patients were randomized in a double-blind, parallel-group trial to receive ivabradine (n=5479) titrated to an average dose of 6.2 mg twice daily, or placebo (n=5438). Patients were receiving optimal cardioprotective medication including β-blockers (87%) and angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers (90%). At 6 months, compared with placebo, ivabradine reduced heart rate by 7.2 beats per minute (bpm), and by 9 bpm in the subgroup with baseline heart rate of ≥70 bpm. There was no significant effect on the primary composite end point—cardiovascular death, admission to hospital for acute MI or for new onset or worsening heart failure—nor on mortality, heart failure, and coronary end points. In a prespecified subgroup with a baseline heart rate of ≥70 bpm (n=5492), there was a significant effect on coronary end points including admission to hospital for MI or unstable angina or the need for revascularization. Treatment was well tolerated. Ivabradine can be safely used in conjunction with β-blockers and may also improve coronary outcome in patients with baseline heart rates of ≥70 bpm.

Medicographia. 2009;31:377-383 (see French abstract on page 383)


Heart rate is an independent risk predictor for the onset of acute coronary events, including all-cause mortality, cardiovascular mortality, sudden cardiac death, and acute coronary syndromes.1-3 This has been demonstrated in healthy subjects, patients with risk factors such as hypertension, hyperlipidemia, and diabetes, as well as in patients with established coronary artery disease with angina pectoris, myocardial infarction, arrhythmias, and chronic heart failure.4-9

Elevated heart rate has also been found to play a role in the development and progression of atherosclerosis and coronary artery disease resulting in myocardial infarction, sudden death, and chronic heart failure.10,11

Heart rate reduction

β-Blockers were the first class of drugs for which there was a clear demonstration of their ability to reduce mortality and the number of hospitalizations in patients with acute myocardial infarction; this was shown in patients treated with timolol, metoprolol, and propranolol.12 Upon pooling data from major placebo-controlled β-blocker trials in patients with acute myocardial infarction, Kjekshus proposed that there was a significant relationship between reduction in resting heart rate and a decrease in all-cause mortality. The β-blockers that reduced heart rate by about 12-15 beats per minute (bpm) reduced mortality by more than 30%, while those that produced a smaller or no reduction in heart rate had no significant effect on mortality. A review of studies on chronic heart failure showed a similar relationship between changes in heart rate and all-cause mortality with the use of â-blockers (Figure 1).13 In the two large trials in patients with chronic heart failure, MEtoprolol CR/XL Randomized Intervention Trial in congestive Heart Failure (MERIT-HF) and Cardiac Insufficiency Bisoprolol Study–II (CIBIS-II),8,9 patients with the highest heart rates at baseline had the highest mortality, and among these patients, there was a more marked effect with the β-blockers bisoprolol and metoprolol CR/XL. A metaregression analysis of randomized controlled clinical trials confirmed that the beneficial effect of β-blockers and calcium channel blockers on mortality in post–myocardial infarction patients was related to reduction in resting heart rate.14 Because of the beneficial effects of β-blockers, it has been generally accepted and also stated in international guidelines that β-blockers should be used in patients suffering from acute myocardial infarction or chronic heart failure in order to reduce mortality and morbidity.15 Since more marked effects have been seen in subgroups of patients with elevated heart rate, it has been assumed that heart rate reduction per se is of major importance in the effect of β-blockers on outcome. However, β-blockers do not only reduce heart rate, but have, in addition, a number of potential beneficial effects resulting from their blocking action, for example, their effects on sympathetic activation. It is well known that sympathetic activation and catecholamines increase the risk of serious ventricular arrhythmias and ventricular fibrillation in animal experimental models of acute myocardial ischemia.16 In large placebo-controlled clinical trials, both in patients with myocardial infarction and in patients with chronic heart failure, β-blockers have been found to have a very marked effect on the incidence of sudden cardiac death.16 In fact, the effects on sudden cardiac death are in general more marked than the overall effects on total mortality or on other modes of death.17 This may be due to a specific antifibrillatory effect of β-blockers.16

Figure 1
Figure 1. Relationship between reduction in resting heart rate and reduction in mortality from β-blocker trials. Bpm, beats per minute

After reference 13: Kjekshus J, Gullestad L. Eur Heart J. 1999;1(suppl H):H64-H69. Copyright © 1999, European Society of Cardiology.

Ivabradine is a novel specific heart rate–lowering agent that acts in sinoatrial node cells by selectively and specifically inhibiting the If pacemaker current in a dose-dependent manner.18 As a result, it is a pure heart rate–lowering agent in patients with sinus rhythm. Ivabradine does not affect blood pressure, myocardial contractility, intraventricular conduction, or ventricular repolarization.19,20 It has antianginal effects comparable to those of β-blockers, and is used in patients with angina pectoris with an approved clinical indication.21 Treatment with ivabradine therefore provides an opportunity to assess the effects of lowering heart rate, without directly altering other aspects of cardiac function.

BEAUTIFUL design and results

BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with coronary disease and left ventric- ULar dysfunction) was designed to test whether the addition of ivabradine to standard treatment to lower heart rate can reduce cardiovascular deaths and morbidity in patients with stable coronary artery disease and left ventricular systolic dysfunction.22 This randomized double-blind placebocontrolled trial was performed at 781 centers in 33 countries. A total of 10 917 patients with coronary artery disease and a left ventricular ejection fraction of <40% were randomized: 5479 of these patients received 5 mg of ivabradine with the intention of increasing the dose to the target of 7.5 mg twice a day, and 5438 received matching placebo in addition to optimal cardiovascular medication. The primary end point was a composite of cardiovascular death, admission to hospital for acute myocardial infarction, and admission to hospital for new onset or worsening of heart failure. Patients eligible for inclusion were males and females aged 55 years or older (or 18 years or older if diabetic) with coronary artery disease, a left ventricular ejection fraction of <40%, and an end-diastolic internal dimension of greater than 56 mm on echocardiography. Patients had to be in sinus rhythm with a resting heart rate of ≥60 bpm.

During the course of the study, publication of other studies indicated that heart rate was only important as a predictor of outcome when it was elevated above 70-75 bpm. It was therefore prespecified in the protocol that one should analyze the effect of ivabradine in a subgroup of patients with a heart rate of ≥70 bpm. The Table shows the baseline characteristics of the ivabradine and placebo groups. It can be seen that 88% of the patients had a history of myocardial infarction, 52% had previous revascularization, 37% a history of diabetes, and left ventricular ejection fraction was on average about 32% in both groups. It can also be seen that 84% of the patients were in New York Heart Association (NYHA) class II-III, indicating that this is a study not only in patients with systolic dysfunction, but also in a majority with symptomatic heart failure. Furthermore, it can be seen that 87% of the patients were on â-blocker treatment, and 90% were on an angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker. The subgroup of patients with a prespecified heart rate of ≥70 bpm included 5392 patients, and among these patients, the baseline characteristics did not differ between the ivabradine and the placebo groups.

Table
Table. Baseline characteristics of the BEAUTIFUL (morBidity-mortality EvAl-
UaTion of the If inhibitor ivabradine in patients with coronary disease and left ventricULar dysfunction) study population.

Data are number (%) or mean (SD). NYHA, New York Heart Association.
After reference 22: Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators. Lancet. 2008; 372:807-816. Copyright © 2008, Elsevier Ltd.

Figure 2
Figure 2. Kaplan–Meier time-to-event plot, by treatment group for composite primary end point in the total study population.

After reference 22: Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators.
Lancet. 2008;372:807-816. Copyright © 2008, Elsevier Ltd.

Figure 3
Figure 3. Kaplan–Meier time-to-event plots, by treatment group in the prespecified subgroup with heart rate of 70 beats per minute or greater, for the secondary end points of (A) admission to hospital for acute myocardial infarction and (B) admission to hospital for acute myocardial infarction or unstable angina.

After reference 22: Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators. Lancet. 2008;372:807-816. Copyright © 2008, Elsevier Ltd.

One month after randomization, the mean dose of ivabradine was 6.2 mg twice daily, and at 6 months after randomization, the difference in heart rate between the two groups was 7.2 bpm. In the subgroup of patients in whom heart rate was ≥70 bpm at baseline, the difference in heart rate between the two groups was 9 bpm at 6 months.

Figure 2 shows that there was no treatment effect on the composite primary end point in the total study population. There was a nonsignificant favorable trend with ivabradine regarding hospital admission for myocardial infarction and coronary revascularization. The treatment was well tolerated with a similar number of serious adverse events in the two groups. Interestingly, visual symptoms were unexpectedly rare (0.5%). In the ivabradine group, 28% discontinued the study medication, compared with 16% in the placebo group. This difference in discontinuation was mainly explained by the fact that 13% of the patients in the ivabradine group had bradycardia, compared with 2% in the placebo group.

In the prespecified subgroup with a heart rate of ≥70 bpm, ivabradine tended to reduce the primary composite end point (9%; nonsignificant). However, as can be seen from Figure 3, in the group of patients with a heart rate of ≥70 bpm, ivabradine significantly reduced admission to hospital for myocardial infarction (P<0.001) and admission to hospital for myocardial infarction or unstable angina (P=0.02). As can be seen in Figure 4, there was also a reduction in the proportion of patients who underwent coronary revascularization (P=0.016).

Figure 4
Figure 4. Kaplan–Meier time-to-event plot, by treatment group in the prespecified subgroup with heart rate of 70 beats per minute or greater, for the secondary end point of coronary revascularization.

After reference 22: Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators. Lancet. 2008;372:807-816. Copyright © 2008, Elsevier Ltd.

Subanalysis was carried out on the placebo group to test the hypothesis that elevated resting heart rate at baseline is a marker for subsequent cardiovascular death and morbidity.23 In Figure 5 it can be seen that a heart rate of ≥70 bpm was a highly significant and independent predictor of cardiovascular death, admission to hospital for heart failure, admission to hospital for myocardial infarction, and the use of coronary revascularization.

Figure 5
Figure 5. Kaplan–Meier time-to-event plots split by heart rate for (A) cardiovascular death, (B) admission to hospital for heart failure, (C) admission to hospital for myocardial infarction, and (D) coronary revascularization. Bpm, beats per minute.

After reference 23: Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators. Lancet. 2008;372:817-821. Copyright © 2008, Elsevier Ltd.

Discussion of BEAUTIFUL results

It was clearly demonstrated in BEAUTIFUL, this large trial in patients with coronary artery disease and left ventricular dysfunction, that ivabradine at an average dose of 6.2 mg twice daily had no effect at all on mortality or morbidity in patients with a heart rate of between 60 and 70 bpm. However, in patients with a basal heart rate of ≥70 bpm, there was a marked reduction in admission to hospital for myocardial infarction (36%; P<0.001), and additionally significant effects on admission to hospital for myocardial infarction or unstable angina, or coronary revascularization (22%-30% reduction). One major question is whether the heart rate reduction with ivabradine was too small to be effective on outcomes. In BEAUTIFUL, ivabradine reduced heart rate by 6 bpm at 12 months and 5 bpm at 24 months. The major β-blocker trials in myocardial infarction with timolol, metoprolol, and propranolol reduced heart rate by 12-15 bpm.12 In two of the major â-blocker trials in heart failure (MERIT-HF and CIBIS-II),8,9 heart rate was reduced by about 11 bpm. It should be noted that 87% of the patients in BEAUTIFUL were on a β-blocker (84% among patients with baseline heart rate of β70 bpm). Even if the â-blocker dose had been doubled, it is most likely that further heart rate reduction would not have exceeded 5%-6% (ie, comparable to the effect of ivabradine).

Are the patients in BEAUTIFUL comparable to those of the β-blocker trials? In fact, most similar is the CArvedilol Postinfarct suRvIval COntRol in left veNtricular dysfunction (CAPRICORN) trial comparing carvedilol with placebo in patients after myocardial infarction with left ventricular dysfunction.24 In this trial, baseline ejection fraction was 33% (mean patient age 63 years, follow-up 16 months), and all-cause mortality with carvedilol was 12% at 16 months. Corresponding figures for BEAUTIFUL were ejection fraction 32%, age 65 years, and 10% mortality (87% were on β-blockers). In CAPRICORN, all-cause mortality was reduced by 23%. This is similar to that reported in a meta-analysis of 22 long-term randomized controlled trials of the effects of â-blockers after acute myocardial infarction.25 It is important to note, however, that in CAPRICORN as well as in other post-infarct survival studies with β-blockers, the β-blocker was given within 3 to 21 days after myocardial infarction. This particular group of post-myocardial infarction patients was specifically excluded from BEAUTIFUL, which focused on patients with stable coronary artery disease.

Figure 6
Figure 6. Mean heart rate during the study (A) in the total study population and (B) in the subgroup with heart rate of 70 beats per minute (bpm) or greater.

After reference 22: Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators. Lancet. 2008;372:807-816. Copyright © 2008, Elsevier Ltd.

In the β-blocker arms of the two major heart failure trials on β-blockers (MERIT-HF and CIBIS-II), there was a 19-month mortality rate of around 10%, as in BEAUTIFUL, although both β-blocker trials included patients with NYHA Class IV heart failure, who were excluded from BEAUTIFUL. However, in these trials, the β-blockers metoprolol XR/CL and bisoprolol reduced all-cause mortality by 35% and sudden cardiac death by more than 40%.8,9 Also in these trials, the β- blockers reduced heart rate by about 11%. A question is whether further heart rate reduction of 5%-6% (as with ivabradine in BEAUTIFUL) from an increase in the dose of the â-blockers would have caused any further reduction in mortality and morbidity.

During the progress of BEAUTIFUL, the steering committee realized that a higher baseline heart rate meant higher mortality and morbidity in the study patients. Furthermore, the heart rate reduction with ivabradine was more marked. This is clearly seen in Figure 6. The heart rate reduction in the higher heart rate group is similar to that seen in the â-blocker heart failure trials. It should be noted that the average baseline heart rate in MERIT-HF and CIBIS-II was 81-82 bpm and in CAPRICORN it was 77 bpm. The baseline heart rate in BEAUTIFUL was 72 bpm. There is no doubt that the effect of â-blockers on heart rate reduction and on outcome is more marked in patients with a heart rate at baseline of 70-75 bpm or higher. In fact, in the Göteborg metoprolol trial (see reference 12), there was no difference between placebo and metoprolol treatment among patients with a baseline heart rate of <70 bpm at 3 months or 2 years of follow-up. The 5000 patients with a baseline heart rate of <70 bpm in BEAUTIFUL gave a lower statistical power to the study, since these patients are less good responders to heart rate reduction. Another problem is that it is most likely that the best responders to ivabradine among patients with a baseline heart rate of <70 bpm (most of the 705 patients in the ivabradine group) were discontinued due to bradycardia. Both the inclusion and exclusion levels were 60 bpm; the exclusion level should have been lower (ie, 45-50 bpm). The most likely reason for the lack of significant effects with ivabradine on mortality and heart failure end points in BEAUTIFUL is that the optimal use of β-blockers had lowered heart rate and mortality/heart failure events. The data on the 13% of patients in the trial who were not on a β-blocker is of limited value by way of a lack of statistical power due to the low numbers of patients and events.

Conclusion

Ivabradine at an average dose of 6.2 mg twice daily did not improve cardiac outcomes in all patients with stable coronary heart disease and left ventricular systolic dysfunction. However, in the subgroup of patients whose heart rate was ≥70 bpm, there was a favorable trend toward the primary end point with ivabradine (9% reduction), but with no effect on cardiovascular death or admission to hospital for heart failure. There was a marked reduction in the coronary end points, including admission to hospital for myocardial infarction (36%; P<0.001), admission to hospital for myocardial infarction or unstable angina (22%; P=0.02), and coronary revascularization (30%; P=0.016).

The statement made by the authors of the BEAUTIFUL publication that ivabradine can be given safely to patients with coronary artery disease and impaired left ventricular dysfunction and in conjunction with β-blockers is certainly justified. In addition, the combination of ivabradine with â-blockade is not only safe, but it also seems to improve a number of coronary end points. _

References

1. Fox K, Borer JS, Camm AJ, et al. Resting heart rate in cardiovascular disease. J Am Coll Cardiol. 2007;50:823-830.
2. Kannel WB, Kannel C, Paffenbarger RS Jr, et al. Heart rate and cardiovascular mortality: the Framingham study. Am Heart J. 1987;113:1489-1494.
3. Jouven X, Empana JP, Schwartz PJ, et al. Heart-rate profile during exercise as a predictor of sudden death. N Engl J Med. 2005;352:1951-1958.
4. Aboyans C, Criqui MH. Can we improve cardiovascular risk prediction beyond risk equations in the physician’s office? J Clin Epidemiol. 2006;59:547-558.
5. Gillum RF. The epidemiology of resting heart rate in a national sample of men and women: associations with hypertension, coronary heart disease, blood pressure, and other cardiovascular risk factors. Am Heart J. 1988;116:163-174.
6. Diaz A, Bourassa MG, Guertin MC, et al. Long-term prognostic value of resting heart rate in patients with suspected or proven coronary artery disease. Eur Heart J. 2005;26:967-974.
7. Hjalmarson Å, Gilpin EA, Kjekshus J, et al. Influence of heart rate on mortality after acute myocardial infarction. Am J Cardiol. 1990;65:547-553.
8. MERIT-HF Study Group. Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet. 1999;253:2001-2007.
9. Lechat P, Hulot JS, Escolano S, et al; CIBIS II Investigators. Heart rate and cardiac rhythm relationships with bisoprolol benefit in chronic heart failure in CIBIS II Trial. Circulation. 2001;103:1428-1433.
10. Kaplan JR, Manuck SB, Adams MR, et al. Inhibition of coronary atherosclerosis by propranolol in behaviourally predisposed monkeys fed an atherogenic diet. Circulation. 1987;76:1364-1372.
11. Heidland UE, Strauer BE. Left ventricular muscle mass and elevated heart rate are associated with coronary plaque disruption. Circulation. 2001;104:1477-1482.
12. Kjekshus J. Importance of heart rate in determining beta-blocker efficacy in acute and long-term myocardial infarction intervention trials. Am J Cardiol. 1986;57:43F-49F.
13. Kjekshus J, Gullestad L. Heart rate as a therapeutic target in heart failure. Eur Heart J. 1999;1(suppl H):H64-H69.
14. Cucherat M. Quantitative relationship between resting heart rate reduction and magnitude of clinical benefits in post-myocardial infarction: a meta-regression of randomized clinical trials. Eur Heart J. 2007;28:3012-3019.
15. Graham I, Atar D, Borch-Johnsen K, et al; Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (Constituted by representatives of nine societies and by invited experts). European guidelines on cardiovascular disease prevention in clinical practice: executive summary. Eur Heart J. 2007;28:2375- 2414.
16. Kendall MJ, Lynch KP, Hjalmarson, et al. Beta-blockers and sudden cardiac death. Ann Intern Med. 1995;123:358-367.
17. Olsson G, Wikstrand J, Warnold I, et al. Metoprolol-induced reduction in postinfarction mortality: pooled results from five double-blind randomized trials. Eur Heart J. 1992;13:28-32.
18. DiFrancesco D, Camm AJ. Heart rate lowering by specific and selective If current inhibition with ivabradine. A new therapeutic perspective in cardiovascular disease. Drugs. 2004;64:1757-1765.
19. Joannides R, Moore N, Iacob M, et al. Comparative effects of ivabradine, a selective heart-lowering agent, and propranolol on systemic and cardiac haemodynamics at rest and during exercise. Br J Clin Pharmacol. 2006;61:127-137.
20. Manz M, Reuter M, Lauck G, et al. A single intravenous dose of ivabradine, a novel I(f) inhibitor, lowers heart rate but does not depress left ventricular function in patients with left ventricular dysfunction. Cardiology. 2003;100:149-155.
21. Borer JS, Fox K, Jaillon P, et al. Antianginal and antiischemic effects of ivabradine, an I(f) inhibitor, in stable angina: a randomized, double-blind, multicentered, placebo-controlled trial. Circulation. 2003;107:817-823.
22. Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators. Ivabradine for patients with stable coronary artery disease and left-ventricular systolic dysfunction (BEAUTIFUL): a randomised, double-blind, placebo-controlled trial. Lancet. 2008;372:807-816.
23. Fox K, Ford I, Steg PG, et al; BEAUTIFUL Investigators. 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. 2008;372:817-821.
24. CAPRICORN Investigators. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet. 2001;357:1385-1390.
25. Yusuf S, Peto R, Lewis J, et al. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis. 1985;27: 335-371.