signify trial

Ivabradine in Stable Coronary Artery Disease without

Clinical Heart Failure

Kim Fox et al,NEJM,Aug 31,2014

ORIGINAL ARTICLE

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

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.

• Ivabradine is known to improve outcomes in patients with systolic

heart failure.

• 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.

SHIFT trial,Lancet 2010;376:875-85.

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.

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

19 102 patients, 51 countries, 1139 centersFox 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.

The SIGNIFY study

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.

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.

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.

Study end points

Cardiovascular death or nonfatal myocardial infarction

Primary composite end point

Secondary end pointsAll-cause deathCardiovascular deathCoronary deathNonfatal myocardial infarctionCoronary revascularizationElective coronary revascularizationNew-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.

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.

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).

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%).

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.

Baseline characteristics Whole population (N = 19 102)

Demographic characteristicsAge (y)<70≥70≥75

Body mass index (kg/m2)Heart rate (beats/min)MaleEthnic originWhiteAsianOther

Systolic blood pressure (mm Hg)Diastolic blood pressure (mm Hg)CAD duration (y) 

 65.0 ± 7.213 669 (72)5433 (28)2227 (12)28.8 ± 4.677.2 ± 7.013 840 (72) 15 532 (81)2547 (13)1022 (5)130.5 ± 13.678.2 ± 8.26.2 ± 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.

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.

Baseline characteristics

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 REVASCULARIZATION

61.1% 79.3%

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.

• 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.

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).

• Ivabradine use was associated with an in the incidence of the 1end 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).

• 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).

Fig 2

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).

• 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).

Table 3

Ivabradine

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.

• 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 )

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.

• 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

?).

• 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.

• 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.

• 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.

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.

• 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.

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 –beneficialBlack –not beneficial

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