The SIGNIFY trial investigated the effects of ivabradine in 19,102 patients with stable coronary artery disease without heart failure. It found that ivabradine reduced heart rate but did not improve cardiovascular outcomes and increased adverse events compared to placebo. However, ivabradine was found to improve angina symptoms in patients who had angina at baseline. The results contrast with previous studies and suggest that reducing heart rate may not benefit stable coronary artery disease as it does heart failure.

1. Ivabradine in
ORIGINAL ARTICLE
Stable Coronary Artery Disease without
Clinical Heart Failure
Kim Fox et al,NEJM,Aug 31,2014

2. Does it Signify the benefit of Ivabradine
or Ignify the existing controversies??

3. Background
• An elevated heart rate (HR) is established as a marker of
cardiovascular risk in the general population and among patients
with cardiovascular disease.
• Ivabradine inhibits the If (pacemaker) current in the sinoatrial
node and reduces the heart rate without affecting BP or LV
systolic function.
• It has been shown to lessen symptoms and reduce ischemia in
patients with stable angina pectoris.
Efficacy of Ivabradine,compared with atenolol in pts with CSA,Eur Heart J 2005;26:2529-36.

4. • Ivabradine is known to improve outcomes in patients with systolic
heart failure.
SHIFT trial,Lancet 2010;376:875-85.
• A trial of Ivabradine involving patients with coronary artery disease
and left ventricular systolic dysfunction did not show clinical
benefit. Post hoc analyses suggested that Ivabradine improved
outcomes in patients who had a heart rate of ≥70 bpm , particularly in
those with angina.
BEAUTIFUL ,Lancet 2008;372:807-16.

5. To confirm these findings,
the Study AssessInG the Morbidity–Mortality BeNefits of the If
Inhibitor Ivabradine in Patients with CoronarY Artery Disease
(SIGNIFY), a large, randomized, controlled trial of ivabradine
involving patients who had stable coronary artery disease without
clinical heart failure was conducted.

6. TRIAL DESIGN AND OVERSIGHT
• Randomized, double-blind, parallel-group, placebo-controlled,
event-driven study at 1139 centers in 51 countries.
• The study was designed to determine the effect of the addition of
Ivabradine to standard therapy in patients with stable CAD.
• Approved by the ethics committee at each participating institution.
• The trial was sponsored by Servier

7. The SIGNIFY study
19 102 patients, 51 countries, 1139 centers
Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in
patients with coronarY artery disease (SIGNIFY trial): A randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart
failure. Am Heart J. 2013;166:654-661.

8. Study design
Mean follow-up
of 2.75
years
Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality
beNefits of the If inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY trial): A randomized, double-blind, placebo-controlled
trial of ivabradine in patients with stable coronary artery disease without clinical heart failure. Am Heart J. 2013;166:654-661.

10. Study population
• Proven stable CAD
• Age >55 years
• Without LVSD (EF >40%, no clinical signs of HF)
• In sinus rhythm, with a resting heart rate >70 bpm
• Receiving appropriate stable conventional cardiovascular
medication.
• One major adverse prognostic factor (CCS >II,evidence of
myocardial ischemia within previous year,hospital discharge
after a major coronary event within previous year).
Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality
beNefits of the If inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY trial): A randomized, double-blind, placebo-controlled trial of
ivabradine in patients with stable coronary artery disease without clinical heart failure. Am Heart J. 2013;166:654-661.

11. 2 minor adverse prognostic factors
• (HDL <40mg/l,LDL >160 mg/dl,despite lipid lowering
treatment)
• PAD
• Current smoking
• Age >70 yrs.
Exclusion – Pts with LVD,unstable CV condition are excluded.

12. Study end points
Primary composite end point
Cardiovascular death or nonfatal myocardial infarction
Secondary end points
All-cause death
Cardiovascular death
Coronary death
Nonfatal myocardial infarction
Coronary revascularization
Elective coronary revascularization
New-onset or worsening heart failure
Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in
patients with coronarY artery disease (SIGNIFY trial): A randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart
failure. Am Heart J. 2013;166:654-661.

13. STATISTICAL ANALYSIS
• We estimated that we would need to enroll 16,850 patients for the study to
have 90% power to detect an 18% reduction in the RR of the primary
composite end point with Ivabradine, assuming a 2.7% annual incidence
with placebo and a mean follow-up period of 2.75 years, at a significance
level of 5%.
• During the trial, the data monitoring committee performed two planned
interim analyses — after 35% and 60% of the anticipated number of primary
end points had occurred.
• A P value < 0.001 was required for early termination due to benefit.

14. Results
RANDOMIZATION AND FOLLOW-UP
• Between October 12, 2009, and April 30, 2012, a total of 19,102
patients underwent randomization;9550 were assigned to Ivabradine
and 9552 to placebo
• The median duration of follow-up was 27.8 months (interquartile
range, 21.0 to 35.2).

15. CHARACTERISTICS OF THE PARTICIPANTS
• The two groups were well balanced with respect to baseline characteristics .
• The mean age of the study population was 65 years,
• 72.4%of the patients were men,
• Mean Resting HR(heart rate) was 77.2 bpm.
• 73.3%of the study population had had a previous MI,
• 67.8%had had previous coronary revascularization, and
• 63.1%had activity-limiting angina (CCS class ≥II).
• There was no evidence of left ventricular systolic dysfunction in the overall
study population (mean EF, 56.4%).

16. Baseline characteristics
Whole population
(N = 19 102)
Demographic characteristics
Age (y)
<70
≥70
≥75
Body mass index (kg/m2)
Heart rate (beats/min)
Male
Ethnic origin
White
Asian
Other
Systolic blood pressure (mm Hg)
Diastolic blood pressure (mm Hg)
CAD duration (y)
65.0 ± 7.2
13 669 (72)
5433 (28)
2227 (12)
28.8 ± 4.6
77.2 ± 7.0
13 840 (72)
15 532 (81)
2547 (13)
1022 (5)
130.5 ± 13.6
78.2 ± 8.2
6.2 ± 6.3
Values are means  SD or n (%).
Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in
patients with coronarY artery disease (SIGNIFY trial): A randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart
failure. Am Heart J. 2013;166:654-661.

17. Baseline characteristics
Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in
patients with coronarY artery disease (SIGNIFY trial): A randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart
failure. Am Heart J. 2013;166:654-661.

18. Baseline characteristics
Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in
patients with coronarY artery disease (SIGNIFY trial): A randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart
failure. Am Heart J. 2013;166:654-661.

20. CCS ≥ II CCS I/no Angina
H/O MI 75.3% 69.8%
B BLOCKERS 86.9% 76.7%
NITRATES 49.5% 23.8%
CORONARY
61.1% 79.3%
REVASCULARIZATION

21. STUDY-DRUG USE AND HEART RATE
• The mean study-drug dose throughout the trial was 8.2±1.7 mg bid in
the ivabradine group and 9.5±0.9 mg bid in the placebo group.
• At 3 months, the MHR to 60.7±9.0 bpm with ivabradine and to
70.6±10.1 bpm with placebo .(the difference maintained during the
study).
• The mean proportion of patients who complied with taking the study
drug (as assessed by means of pill counts) was 96.2±9.2% in the
ivabradine group and 96.6±8.3%in the placebo group.

23. • The rates of permanent discontinuation of the study drug were 20.6% in the
ivabradine group (1972 patients) and 14.5% in the placebo group (1384
patients).
• The main reason for study-drug withdrawal in the ivabradine group was
asymptomatic bradycardia (leading to withdrawal in 272 patients, vs. 17 in
the placebo group) and, to a lesser extent, symptomatic bradycardia (194 vs.
33).
• Few patients changed the beta-blocker dose during the study, with 3.2% of
the patients in the ivabradine group increasing the dose, 6.1% decreasing,
and 3.5% stopping, as compared with 5.8%, 3.7%, and 2.3%, respectively,
in the placebo group.

27. SUBGROUP ANALYSES
• There was a significant interaction between the study
treatment and the presence of angina at baseline in the
prespecified subgroup defined according to CCS class (P =
0.02).

28. • Ivabradine use was associated with an  in the incidence of the 1end point
among patients who had angina of CCS ≥class II (7.6%, vs. 6.5% with
placebo; HR,1.18; 95% CI, 1.03-1.35; P = 0.02) but not among patients
without angina or those who had angina of class I (HR, 0.89; 95% CI, 0.74 -
1.08; P = 0.25).
• The effect of ivabradine among patients with angina of CCS class II or
higher appeared to be consistent between the two components of the primary
end point (HR for death from CV causes, 1.16; 95% CI, 0.97-1.40; P = 0.11;
and HR ratio for nonfatal MI, 1.18; 95% CI, 0.97 to 1.42; P = 0.09).

29. • In the subgroup of patients with angina of CCS class II or
higher, 1446 patients in the ivabradine group (24.0%) had an
improvement in the CCS angina class at 3 months, as
compared with 1131 in the placebo group (18.8%) (P = 0.01).

30. Fig 2

31. ADVERSE EVENTS
• Adverse events during the study occurred in 73.3% of the patients in
the ivabradine group and in 66.9% of those in the placebo group
(P<0.001).
• Ivabradine increased the frequency of symptomatic bradycardia
(7.9%, vs. 1.2% with placebo), asymptomatic bradycardia (11.0%
vs.1.3%), AF (5.3% vs. 3.8%), and phosphenes (5.4% vs. 0.5%)
(P<0.001 for all comparisons).

32. • A serious adverse event occurred during the study in 3588 patients in
the ivabradine group (37.6%) and in 3375 in the placebo group
(35.4%) (P = 0.001).
• These events were classified as cardiac disorders in 19.0% and 16.7%
of the patients, respectively.
• Adverse events led to study-drug withdrawal in 13.2% of the patients
in the ivabradine group and in 7.4% of those in the placebo group
(P<0.001).

33. Table 3

34. Ivabradine

35. Discussion
• No benefit of Ivabradine in reducing the risk of CV events in CSA pts
without clinical HF,when added to background GDMT.
• Elevated HR is assosciated with an increased risk of CV events in
stable CAD pts (observational studies).
• The result of SIGNIFY contrasts with post hoc analysis of this drug,of
its beneficial effect in stable CAD pts.
• In HF pts,it had a improved outcome in addition to effect of b
blockers.

36. • The incidence of primary end point was relatively low (≈ 2.8%)
compared to high prevalence of risk factors in the people studied in
this trial (background therapy beneficial effect)
• The effect on HR by Ivabradine is clear (10bpm difference).
• The incidences of bradycardia and AF were higher with ivabradine
than with placebo.(more than in previous trial,because of high doses
used )

37. Why conflicting results?
• There are a number of hypotheses to explain the lack of a benefit in
SIGNIFY.
• It is possible that Ivabradine decreased the heart rate too much or
that there may be a J-shaped curve for the relationship between
heart rate and outcome.
• Ivabradine may have unintended effects (e.g., adjustment of the
doses of other heart rate lowering agents) that may have affected
the potential benefits of the lowering of HR with Ivabradine.

38. • However, the use and dosing of beta-blockers after randomization
differed only slightly between patients who received ivabradine and
those who received placebo.
• It is also possible that heart-rate–reducing antianginal agents have no
effect on outcomes in patients with stable coronary artery disease.(B
blockers have mortality benefit post MI,but in stable CAD without HF
?).

39. • In fact, a recent observational analysis has suggested the opposite.
• This contrasts with the results of trials testing the effects of beta-blockers
or ivabradine in patients with systolic heart failure, including
those with heart failure of ischemic origin.

40. • The benefit observed with lowering the HR in pts with HF but not in
those with stable CAD may reflect the fact that an elevated HR is due
to different pathophysiological mechanisms in these two conditions.
• In patients with HF, there is neurohormonal activation, which in
itself leads to ventricular remodeling, further left ventricular
dysfunction, and a vicious cycle of decline.
• In contrast, there is no neurohormonal activation in stable coronary
artery disease without left ventricular dysfunction.

41. • There was a significant interaction between the effect of Ivabradine
and the presence of angina (CCS class ≥II) at baseline.
• In that subgroup, Ivabradine increased the absolute risk of the
primary composite end point of death from cardiovascular causes or
nonfatal myocardial infarction by 1.1 percentage points. The
explanation for this surprising finding is uncertain, although it should
be treated with caution since the results of the primary efficacy
analysis were not significant.

42. Conclusion
• In conclusion, the results of SIGNIFY show that Ivabradine, added to
guideline-recommended medical therapy, did not improve the
outcome in patients who had stable coronary artery disease without
clinical heart failure.
• There is a signal for an increase in the risk of cardiovascular events
among patients with angina of CCS class II or higher.

43. • Given that the primary cardiovascular effect of Ivabradine is to reduce
heart rate, these results suggest that an elevated heart rate is only a
marker of risk — but not a modifiable determinant of outcomes —
in patients who have stable coronary artery disease without clinical
heart failure.

44. Trial evidence on Ivabradine
IVABRADINE
CAD
With LVD
BEAUTIFUL
Without LVD
SIGNIFY
INITIATIVE
(vs Atenolol)
ASSOSCIATE
Added to BB in
CSA
ADDITIONS
study
REDUCTION
SHF
SHIFT
CARVIVA HF 37
(carvedilol)
Red –beneficial
Black –not beneficial

45. Guidelines
ESC guidelines 2012 for HF
• HF in SR,EF<35%,HR>70/min,persisting symptoms(NYHA
II-IV) despite GDMT IIaB
• Who are unable to tolerate BB IIb C
Stable CAD with LVD
• Alternative to BB – IIa A
Only after 4 weeks of ACE,BB,ARBs
C/I – Acute MI,cardiogenic shock,HR <60/min,SSS,pacemaker
dependent,UA,pregnancy,lactation