First-Line Anti-Ischaemic Agents Use and Long-Term Clinical Outcomes in Stable Coronary Artery Disease. Insights From The CLARIFY Registry

First-line anti-ischaemic agents use and long-term clinical
outcomes in stable coronary artery disease.
Insights from the CLARIFY registry
E. Sorbets, P.G. Steg, R. Young, N. Danchin, N. Greenlaw, I. Ford, M. Tendera, R. Ferrari, C. Reid,
A. Parkhomenko, B. Merkely, J.C. Tardif, K.M. Fox, for the CLARIFY investigators
Emmanuel SORBETS, MD, PhD
25th August 2018
Emmanuel SORBETS, MD, PhD 25th August 2018
Conflicts of interest:
- During the conduct of the study:
. grants from the French Federation of Cardiology
. personal fees and non-financial support from Servier
- Outside the submitted work:
. personal fees and non-financial support from Novartis
. personal fees and non-financial support from Bayer
. personal fees and non-financial support from Astra-Zeneca
. personal fees and non-financial support from Merck Sharpe & Dohme
Fihn S.D., et al Circulation 2012;126:e354-471
?
Montalescot G., Eur Heart J 2013;34:2949-3003
Available data on the prognostic effect of -blockers and calcium antagonists in stable CAD
§ -blockers: § Calcium Antagonists:
. No RCT (or post-hoc) . “Old” RCT
. Metanalyses of old RCT in acute MI . Metanalyses of old RCT
. Recent observational studies with limitations . No large observational studies
Lack of effects? No prognostic effect

➥ Need for contemporary data
ProspeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease
45 countries § Inclusion criteria for stable coronary artery disease:
. prior myocardial infarction >3 months
2898 physicians
10-15 consecutively enrolled patients &/or . prior revascularisation >3 months
&/or . proven symptomatic myocardial ischaemia
Nov 2009 – Jun 2010
n=32378
&/or . angiographic coronary stenosis >50%
§ Exclusion criteria: conditions interfering with life expectancy
multivariable model
§ Primary outcome: . All-cause death
BB use non CA use § Secondary outcomes: . CV death
mutually
n=22006 exclusive n=22004 . CV death or MI
- Baseline Baseline - § Exploratory analyses: . Non-CV death
- Y1 Y1 - . MI
- Y2 Y2 - . Stroke
- Y3 Y3 -
- Y4 Y4 - § Sensitivity analyses: . BB or CA use over time (from yearly FU)
- Y5 Y5 - . BB doses
Multivariable adjustment model accounted for
CV risk factors, burden of CV disease, treatments, geographical areas and pulmonary comorbidities
§ -blockers cohort - n=22006
§ C. Antagonists cohort - n=22004
. The REACH CV event risk score*
. Sex
. SBP . Age
. DBP . Diabetes . Statin
. BMI <20kg/m2
. Aspirin
. Current smoking
. LVEF
. History of PCI
. History of CABG . Heart failure
. Atrial fibrillation . Geographical zones
. Recent MI (≤1 year)
. COPD . Nb of vascular beds: CVD, PAD, CAD
. Asthma
* Wilson et al. An international model to predict recurrent cardiovascular disease. Am J Med 2012;125:695
BMI: body mass index; CABG: coronary afrtery bypass graft; CAD; coronary artery disease; COPD: chronic obstructive pulmonary disease; CV: cardiovascular; CVD:
cerebrovascular disease; DBP/SBP: systolic/diastolic blood pressure; LVEF: left ventricular ejection fraction; PAD: peripheral artery disease; PCI: percutaneous coronary intervention
§ -blockers study cohort - n=22006 Bisoprolol
35.6%
Full
Asthma/COPD 13.3%
Bradycardia BB
39.6% Fatigue
non-users BB users 27.2% Metoprolol Half to
< Half
intolerance Erectile dysfunction n=4871 n=17135 45.1% < Full
Hypotension
41.6%
No 22.1% 77.9%
intolerance
60.4% 5.9%
12.6%
Others 6.5%
12.3% Carvedilol -blocker
Nebivolol Atenolol doses
§ Calcium Antagonists study cohort – n=22004
79.8% Dihydropyridines
CA
CA users
non users
n=5885
n=16119
26.7% 14.7%
73.3% Diltiazem
4.9%
Verapamil
Calcium No Calcium
-blockers No -blockers
Baseline characteristics Antagonists Antagonists
(n=17135) (n=4871) (n=5885) (n=16119)

CV risk factors Gender Male, % 78.3% 78.0% 74.0% 79.8%
Age (years), mean ±SD 63.3 ±10.5 < 65.5 ±10.7 65.7 ±10.0 > 63.1 ±10.7
Current smoking, % 12.3% 11.9% 10.2% 13.0%
Family history of premature CAD, % 29.1% 28.3% 29.2% 28.8%
Treated Hypertension, % 74.0% 66.1% 87.4% 66.7%
Diabetes, % 30.4% 26.6% 35.8% 27.3%
<
Dyslipidaemia, % 79.0% 78.0% 82.9% 77.3%
>
Past medical history

Myocardial infarction, %
Peripheral artery disease, %
64.8%
10.3%
< 52.5%
13.1%
52.5%
14.1%
> 65.6%
9.8%
Hospitalization for CHF, % 5.9% 4.6% 5.1% 5.8%
Atrial fibrillation/flutter, %
Asthma/COPD
7.8%
5.0%
< 7.5%
5.8%
8.3%
10.0%
> 7.5%
6.4%

Clinical examination Systolic blood pressure (mmHg), mean ±SD 131.0 ±16.8 131.1 ±15.8 135.3 ±16.7 129.5 ±16.2
Diastolic blood pressure (mmHg), mean ±SD 77.7 ±10.0 77.2 ±9.6 78.4 ±10.2 77.3 ±9.8

Resting heart rate (bpm), mean ±SD
Current angina, %
67.4 ±10.3
25.0%
> 69.7 ±11.3
21.4%
68.4 ±10.6
28.1%
> 67.7 ±10.6
22.8%
Current heart failure symptoms, % 20.1% < 13.0% 18.9% > 18.4%
Left ventricular ejection fraction % value, mean ±SD 55.6 ±11.1 58.0 ±10.4 57.9 ±10.1 55.5 ±11.2
≤ 45%, % 18.7% 12.8% 12.3% 19.3%
Medications
Aspirin, % 89.1% 83.8% 86.7% 88.3%
Statins, % 85.6% 79.8% 84.1% 84.4%
Angiotensin-converting enzyme inhibitors, % 57.2% 42.7% 48.8% 55.9%
Angiotensin II receptor blockers, % 25.5% 31.5% 35.6% 23.6%

-blockers, %
Calcium antagonists, %
NA
24.3% ≈ NA
36.1%
69.6%
NA ≈ 80.9%
NA
REACH cardiovascular event risk score, mean ±SD 11.23.1 11.13.2 11.53.1 11.03.2
Baseline characteristics of patients with all data entered in the multivariable adjustment model
Multivariable adjusted associations according to
-blocker use or Calcium antagonist use at baseline
Use at baseline No Calcium No Calcium

-blockers
-blockers Antagonists Antagonists
(n=17135) (n=4871) HR (95%CI) P-value (n=5885) (n=16119) HR (95%CI) P-value
Primary outcome
All-cause death 7.8% 8.4% 0.94 (0.84-1.06) 0.30 8.4% 7.8% 1.02 (0.91-1.13) 0.76
Secondary outcomes
CV death 5.0% 5.4% 0.91 (0.79-1.05) 0.20 5.3% 5.0% 1.01 (0.88-1.16) 0.87
CV death/MI 7.4% 7.0% 1.03 (0.91-1.16) 0.66 7.8% 7.2% 1.05 (0.94-1.17) 0.39
Exploratory analyses
Non-CV death 2.8% 3.0% 1.00 (0.83-1.21) 0.99 3.1% 2.8% 1.03 (0.86-1.22) 0.77
MI 3.4% 2.9% 1.14 (0.94-1.37) 0.18 3.6% 3.2% 1.12 (0.95-1.32) 0.17
Stroke 2.2% 1.9% 1.13 (0.89-1.42) 0.32 2.5% 2.0% 1.18 (0.96-1.43) 0.11
Survival analysis from Cox proportional hazards models
Multivariable adjustment for SBP, DBP, LVEF, histories of PCI, CABG, PAD, asthma/COPD and the REACH cardiovascular event risk score
Multivariable adjusted associations according to -blocker use at baseline
categorised by time since MI prior to enrollment
Time since MI
Prior MI ≤ 1 year Prior MI 1 to 3 years Prior MI > 3 years
prior to enrollment
(n=3506) (n=2932) (n=7222)
No No No
-blockers -blockers -blockers
-blockers -blockers -blockers
(n=2931) (n=575) HR (95%CI) P-value (n=2426) (n=506) HR (95%CI) P-value (n=5746) (n=1476) HR (95%CI) P-value
Primary outcome
All-cause death 7.0% 10.3% 0.68 (0.50-0.91) 0.01 7.3% 7.9% 1.09 (0.76-1.56) 0.63 9.6% 10.7% 0.91 (0.76-1.10) 0.33
Secondary outcomes
CV death 4.5% 8.5% 0.52 (0.37-0.73) 0.0001 4.6% 5.5% 0.99 (0.64-1.53) 0.96 6.4% 7.0% 0.90 (0.72-1.13) 0.37
CV death/MI 7.2% 10.3% 0.69 (0.52-0.93) 0.01 7.1% 7.3% 1.05 (0.73-1.52) 0.78 8.9% 8.9% 1.00 (0.82-1.21) 0.97
Non-CV death 2.5% 1.7% 1.42 (0.73-2.77) 0.31 2.7% 2.4% 1.32 (0.70-2.51) 0.39 3.2% 3.7% 0.94 (0.69-1.28) 0.69
MI 4.2% 4.7% 0.85 (0.56-1.31) 0.47 3.6% 3.0% 1.25 (0.71-2.18) 0.44 3.9% 3.5% 1.10 (0.81-1.50) 0.54
Stroke 2.0% 1.4% 1.45 (0.69-3.06) 0.33 2.0% 2.2% 1.04 (0.52-2.06) 0.91 2.6% 2.7% 0.98 (0.69-1.40) 0.92
Cumulative hazard of all-cause mortality according to -blocker use at baseline
in patients with previous MI ≤1 year prior to enrollment
MI ≤1 year
prior to enrollment All-cause death
0.15
Cumulative Hazard
No -blockers
0.10
-blockers
0.05
HR: 0.68; 95% CI (0.50-0.91); p=0.01
0.00
0 1 2 3 4 5 6
Follow-up (years)
Multivariable adjusted associations according to Calcium antagonist use at baseline
categorised by time since MI prior to enrollment
Time since MI
Prior MI ≤ 1 year Prior MI 1 to 3 years Prior MI > 3 years
prior to enrollment
(n=3506) (n=2932) (n=7222)
Calcium No Calcium Calcium No Calcium Calcium No Calcium

Antagonist Antagonist Antagonist Antagonist Antagonist Antagonist
Primary outcome
All-cause death 9.8% 7.1% 1.24 (0.92-1.67) 0.16 8.6% 7.1% 1.09 (0.80-1.50) 0.58 9.7% 9.8% 0.95 (0.80-1.13) 0.56
Secondary outcomes
CV death 6.1% 5.0% 1.12 (0.77-1.63) 0.55 5.5% 4.5% 1.09 (0.73-1.62) 0.68 6.4% 6.5% 0.97 (0.78-1.19) 0.74
CV death/MI 8.8% 7.5% 1.05 (0.77-1.44) 0.74 8.1% 6.9% 1.05 (0.76-1.45) 0.77 9.4% 8.8% 1.05 (0.88-1.26) 0.58
Non-CV death 3.7% 2.1% 1.46 (0.88-2.40) 0.14 3.1% 2.5% 1.10 (0.65-1.87) 0.72 3.3% 3.3% 0.93 (0.69-1.25) 0.58
MI 4.5% 4.2% 0.97 (0.63-1.49) 0.89 3.7% 3.5% 0.95 (0.59-1.53) 0.84 4.4% 3.6% 1.24 (0.96-1.62) 0.10
Stroke 2.7% 1.8% 1.38 (0.78-2.45) 0.27 2.6% 1.9% 1.19 (0.66-2.13) 0.57 2.9% 2.5% 1.00 (0.73-1.38) 0.98
Multivariable adjusted associations according to -blocker use or Calcium antagonist use
taking into account the last status from yearly follow-up
Use over time No Calcium No calcium

-blockers
-blockers Antagonists Antagonists
(n>16150) (n>5810) HR (95%CI) P-value (n>6040) (n>15930) HR (95%CI) P-value
Primary outcome
All-cause death 8.0% 8.0% 0.98 (0.88-1.09) 0.74 8.1% 7.9% 0.96 (0.87-1.07) 0.49
Secondary outcomes
CV death 5.1% 5.1% 0.97 (0.85-1.11) 0.65 5.3% 5.0% 1.00 (0.87-1.14) 0.98
CV death/MI 7.5% 7.0% 1.03 (0.92-1.16) 0.60 7.6% 7.2% 1.00 (0.90-1.12) 0.99
Non-CV death 2.8% 2.9% 1.01 (0.84-1.21) 0.93 2.8% 2.9% 0.90 (0.76-1.08) 0.27
MI 3.4% 2.9% 1.12 (0.94-1.34) 0.20 3.5% 3.2% 1.03 (0.88-1.22) 0.68
Stroke 2.2% 1.6% 1.39 (1.10-1.74) 0.005 2.5% 2.0% 1.05 (0.86-1.29) 0.61
Multivariable adjusted associations according to -blocker doses at baseline
-blocker
-blockers < No -blockers No -blockers No
doses 1/2 dose -blockers

1/2 to full -blockers

full dose -blockers

Primary outcome
All-cause death 7.6% 8.0% 0.95 (0.85-1.06) 0.35 8.2% 8.0% 1.00 (0.89-1.12) 0.94 7.6% 8.0% 0.89 (0.76-1.05) 0.17
Secondary outcomes
CV death 5.1% 5.0% 1.01 (0.87-1.16) 0.92 5.2% 5.0% 1.01 (0.87-1.16) 0.90 4.9% 5.0% 0.92 (0.75-1.13) 0.44
CV death/MI 7.2% 7.1% 1.00 (0.89-1.12) 0.97 7.9% 7.1% 1.08 (0.96-1.22) 0.18 7.8% 7.1% 1.06 (0.90-1.25) 0.46
Non-CV death 2.6% 3.0% 0.85 (0.70-1.02) 0.09 3.0% 3.0% 0.97 (0.81-1.17) 0.77 2.7% 3.0% 0.84 (0.64-1.11) 0.29
MI 3.1% 3.4% 0.91 (0.76-1.09) 0.29 3.9% 3.4% 1.14 (0.96-1.35) 0.14 3.8% 3.4% 1.11 (0.88-1.41) 0.38
Stroke 2.2% 2.0% 1.06 (0.85-1.32) 0.61 2.1% 2.0% 1.00 (0.80-1.26) 0.99 2.5% 2.0% 1.19 (0.89-1.61) 0.17
After exclusion of patients with intolerance or contraindication to -blocker
Survival analysis from Cox proportional hazards models with multivariable adjustment for the REACH cardiovascular event risk score
-blockers and Calcium antagonists in CLARIFY
§ -blockers use and all-cause mortality HR 95% CI P value
Overall 0.94 (0.84-1.06) 0.30
MI ≤ 1 year prior to enrollment 0.68 (0.50-0.91) 0.01

MI 1 to ≤ 3 years prior to enrollment 1.09 (0.76-1.56) 0.63

MI > 3 years prior to enrollment 0.91 (0.84-1.10) 0.33
0.6 0.8 1 1.2 1.4 1.6
-blockers better -blockers worse
§ Calcium Antagonists use and all-cause mortality HR 95% CI P value
Overall 1.02 (0.91-1.13) 0.76
MI ≤ 1 year prior to enrollment 1.24 (0.92-1.67) 0.16

MI 1 to ≤ 3 years prior to enrollment 1.09 (0.80-1.50) 0.58

MI > 3 years prior to enrollment 0.95 (0.80-1.13) 0.56
0.6 0.8 1 1.2 1.4 1.6
Calcium antagonists Calcium antagonists
better worse
Limitations and strengths
§ Limitations: . observational
§ Strengths: . size: 45 countries
. 2898 physicians: GPs and specialists
. 10-15 consecutively enrolled patients
. comprehensiveness
. a few missing data
. baseline / over time / doses
. large multivariable adjustment
. all-cause mortality
Take-home message
➥ In stable CAD:
ü -blockers should be preferentially used in the 1st year following MI
ü >1 year following MI or in patients without prior MI, both -blockers
and Calcium Antagonists may be used for symptom relief but a
mortality benefit should not be assumed
Thank you for your attention

First-Line Anti-Ischaemic Agents Use and Long-Term Clinical Outcomes in Stable Coronary Artery Disease. Insights From The CLARIFY Registry

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First-line anti-ischaemic agents use and long-term clinical

Use at baseline No Calcium No Calcium

Use over time No Calcium No calcium

§ -blockers use and all-cause mortality HR 95% CI P value

Overall 0.94 (0.84-1.06) 0.30

MI ≤ 1 year prior to enrollment 0.68 (0.50-0.91) 0.01

MI 1 to ≤ 3 years prior to enrollment 1.09 (0.76-1.56) 0.63

0.6 0.8 1 1.2 1.4 1.6

§ Calcium Antagonists use and all-cause mortality HR 95% CI P value

Overall 1.02 (0.91-1.13) 0.76

MI ≤ 1 year prior to enrollment 1.24 (0.92-1.67) 0.16

MI 1 to ≤ 3 years prior to enrollment 1.09 (0.80-1.50) 0.58

0.6 0.8 1 1.2 1.4 1.6

Thank you for your attention

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