This document summarizes guidelines for the treatment of stable coronary artery disease. It discusses recommendations for both the prevention of cardiovascular events and the relief of angina symptoms. For event prevention, it recommends low-dose aspirin daily for all patients, as well as statin therapy. For angina relief, it recommends short-acting nitrates and calcium channel blockers or beta-blockers as first-line treatment. It also discusses the evidence and recommendations for various second-line treatment options. The guidelines provide classifications for each recommendation based on the level of evidence.

1. Lecture F. Arrigo, Messina
Saturday, October, 11-2014 10.00 - 10.30

2. I25.0 Atherosclerotic cardiovascular
disease, so described
I25.1 Atherosclerotic heart disease
Coronary (artery):
• atheroma
• atherosclerosis
• disease
• sclerosis
I25.2 Old myocardial infarction
• Healed myocardial infarction
• Past myocardial infarction diagnosed by ECG
or other special investigation, but currently
presenting no symptoms
I25.3 Aneurysm of heart
Aneurysm: a) mural b) ventricular
I25.4 Coronary artery aneurysm
Coronary arteriovenous fistula, acquired
Excludes congenital coronary (artery) aneurysm
I25.5 Ischaemic cardiomyopathy
I25.
6
Silent myocardial ischaemia
I25.
8
Other forms of chronic ischaemic
heart disease
Any condition in I21-I22 and I24.- specified as
chronic or with a stated duration of more than 4
weeks (more than 28 days) from onset
I25.
9
Chronic ischaemic heart disease,
unspecified
Ischaemic heart disease (chronic) NOS

3.  Stable coronary artery disease (ESC)
 Stable Ischemic Heart Disease (ACC/AHA)
 Stable angina pectoris (NICE)
 Stable coronary Heart disease (Braunwald)
 Some authors include
 Microvascular Angina
 Vasospastic Angina
 Inducible myocardial Ischemia
 Previous revascularization (CABG o PCI)

4. REACH registry
Annual event rates in stable CAD outpatients (n=38602), 1-year follow-up
Steg PG, et al. JAMA. 2007;297:1197-1206

6. The majority of stable CAD outpatients have
neither angina nor ischemia
ESC Congress 2013 Amsterdam
• Presence of both is
associated with the
worst outcome
• The presence of anginal
symptoms in daily life
appears associated with
a higher risk of CV death
or MI than ischemia alone

7. Event prevention
Angina/ischemia relief

8. European Heart Journal (2013) 34, 2949–3003

9. European Heart Journal (2013) 34, 2949–3003
Indication Class Level
General considerations
Optimal medical treatment indicates at least one drug for
angina/ischaemia relief plus drugs for event prevention.
I C
It is recommended to educate patients about the disease, risk factors
and treatment strategy.
I C
It is indicated to review the patient’s response soon after starting
therapy.
I C
Event prevention
Low-dose aspirin daily is recommended in all SCAD patients. I A
Clopidogrel is indicated as an alternative in case of aspirin intolerance. I B
Statins are recommended in all SCAD patients. I A
It is recommended to use ACE inhibitors (or ARBs) if presence of other
conditions (e.g. heart failure, hypertension or diabetes).
I A
ESC GUIDELINES

10. European Heart Journal (2013) 34, 2949–3003
Indication Class Level
Angina/ischaemia relief
Short-acting nitrates are recommended. I B
First-line treatment is indicated with ß-blockers and/or calcium
channel blockers to control heart rate and symptoms.
I A
For second-line treatment it is recommended to add long-acting
nitrates or ivabradine or nicorandil or ranolazine, according to
heart rate, blood pressure and tolerance.
IIa B
For second-line treatment, trimetazidine may be considered. IIb B
According to comorbidities/tolerance is indicated to use second-
line therapies as a first-line treatment it in selected patients.
I C
In asymptomatic patients with large areas of ischaemia (>10%) ß-
blockers should be considered.
IIa C
In patients with vasospastic angina, calcium channel blockers
and nitrates should be considered and beta-blockers avoided.
IIa B
ESC GUIDELINES

11. European Heart Journal (2013) 34, 2949–3003
ACEI = angiotensin converting enzyme
inhibitor; CABG = coronary artery bypass
graft; CCB = calcium channel blockers; CCS =
Canadian Cardiovascular Society; DHP =
dihydropyridine; PCI = percutaneous coronary
intervention.
A Data for diabetics. B if intolerance,
consider clopidogrel
ESC GUIDELINES

12. Long–acting nitrates
what's new

13. anti-ischaemic efficacy of PETN 80 mg b.i.d. (morning and mid-day) over
placebo in 655 patients with chronic stable angina pectoris.

14. Thomas MunzelT et al. European Heart Journal (2014) 35, 895–903
Treatment with PETN over 12 weeks did
not modify the primary endpoint ofTotal
Exercise Duration (P = 0.423).
In a pre-specified sub-analysis of patients
with reduced exercise capacity (n = 257),
PETN appeared more effective than
placebo (P = 0.054).
In the subgroup of pts with refractory
angina pectoris and symptomatic at low
exercise levels the change inTED at 6 and
12 weeks was markedly larger in the PETN
group than in the control group (P = 0.05
and P = 0.017).
Patients symptomatic at low
exercise levels

15. Betablockers
what's new

16. Meta analysis of 26 trials, including 6,108 patients,
showed no significant survival benefits of beta-
blockers (OR 0.92, 95% CI 0.62 to 1.38) when
compared to placebo in patients with stable
angina.
Shu DF, Dong BR, Lin XF,WuTX, Liu GJ . Eur J Cardiovasc Prev RehabilApr 27 2011
REACH registry, which included 44 708
participants, also showed that beta-blocker
therapy in stable CAD patients did not provide
any benefit.
BangaloreS, et al, on behalf of the REACH Registry Investigators. JAMA. 2012 Oct 3;308(13):1340-9.

17. The purpose of this study was to assess the association of beta-
blockers with outcomes among patients with new-onset CHD.
26,793 consecutive patients discharged after the first CHD
event (ACS or coronary revascularization) who did not use
beta-blockers in the year before entry.
Average follow-up of 3.7 years
Hazard Ratio (HR) for death or MI associated with beta-blocker
Interaction tests to determine whether the association differed
for patients with or without a recent MI.
Andersson C, Shilane D, Go AS, ChangTI, Kazi D, Solomon MD, Boothroyd DB, Hlatky MA.
J Am Coll Cardiol. 2014 Jul 22;64(3):247-52.
Andersson C, Shilane D, Go AS, Chang TI, Kazi D, Solomon
MD, Boothroyd DB, Hlatky MA.2014 Jul 22;64(3):247-52.

18. Association of beta-blocker use with cardiac events, overall and according to
presence or absence of a prior myocardial infarction (MI).
Andersson C, et al J Am CollCardiol. 2014 Jul 22;64(3):247-52.
Andersson C, Shilane D, Go AS, Chang TI, Kazi D, Solomon
MD, Boothroyd DB, Hlatky MA.2014 Jul 22;64(3):247-52.

19. Post hoc analysis from the CHARISMAa trial.
The cohorts were divided into 2 groups based on baseline β-
blocker use. 28 months of follow-up.
 4772 patients with prior MI
 7804 patients with known atherothrombosis
 2101 patients with risk factors alone but without heart failure.
Primary outcome was a composite of nonfatal MI, stroke, or CV
mortality.

20.  PRIOR MI COHORT
 β-blocker use was associated with
▪ lower risk of the primary outcome (HR 0.69; 95% CI, 0.50-0.94;
P=0.021)
▪ lower risk of recurrent MI (HR 0.62; 95% CI, 0.39-1.00; P=0.049)
▪ no difference in mortality (52 [5.3%] versus 66 [6.7%]; P=0.20).
 KNOWN ATHEROTHROMBOSIS AND RISK FACTORS
ALONE COHORTS
 β-blocker use was not associated with lower ischemic
outcomes
 RISK FACTORS ALONE COHORTS
 trend toward a higher risk of stroke (3.5% versus 1.5%;
HR 2.13; 95% CI 0.92-4.92; P=0.079)
Bangalore S, Bhatt DL, Steg PG, et al. Circ CardiovascQual Outcomes 2014; Sep 30. [Epub ahead of print]
a Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance

21. Ivabradine
what's new

22. Presented at ESC Congress 2014 Hotline 2

23.  19,102 patients who had both stable CAD without clinical
heart failure and a heart rate of 70 beats per minute or more.
 After a median follow-up of 27.8 months, there was no
significant difference between the ivabradine group and
the placebo group in the incidence of the primary end
point, death from CV causes and nonfatal Myocardial
Infarction.

24. 24.81
0.31
19.43
0.55
0
5
10
15
20
25
30
Improvement in CCS class at M3 Worsening in CCS class at M3
Ivabradine
Placebo
Patients(%)
P<0.01
Elective revascularization
• Ivabradine 2.8%
• Placebo 3.5%
• HR 0.82 (p=0.058)
Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. N Eng J Med. 2014 August 31. DOI:10.1056/NEJMoa1406430.

25. Ranolazine
what's new

26. The late inward Na
current is increased in
ischemic myocardium
direct antiischemic
effect
not dependent on
changes in cardiac
work

27. Meta analysis of Six trials (9223 patients)
- 0,53
Int J Cardiol. 2013 Nov 15;169(4):262-70

28. Meta analysis of Six trials (9223 patients)
- 0,53
Int J Cardiol. 2013 Nov 15;169(4):262-70
- 0,69

29.  Patients (N = 92) answered a survey evaluating
their perceptions of angina prior to ranolazine
initiation (based on recall of previous experience)
and during ranolazine treatment.
 Change in QoL was assessed using the Patient
Global Impression of Change scale.
J. B. Muhlestein, S. Grehan. Drugs, 2013; 13:2007-213

30. N = 92 respondents
Patient-reported
changes in quality of
life on the Patient
Global Impression of
Change scale since
initiating ranolazine
treatment.
79,4 %
J. B. Muhlestein, S. Grehan. Drugs, 2013; 13:2007-213

31.  46 patients with stable microvascular angina pectoris (effort
angina, positive exercise stress test [EST], normal coronary
angiography, coronary flow reserve <2.5), whith symptoms
inadequately controlled by standard anti-ischemic therapy
 Ivabradine (5 mg twice daily), Ranolazine (375 mg twice
daily), or placebo for 4 weeks.
 The Seattle Angina Questionnaire (SAQ), EuroQoL scale, and
EST were assessed at baseline and after treatment.
 Coronary microvascular dilation in response to adenosine
and to cold pressor test and peripheral endothelial function
(by flow-mediated dilation) were also assessed.
VillanoA, Di FrancoA, Nerla R, SestitoA,Tarzia P, Lamendola P, Di MonacoA, Sarullo FM, Lanza GA, Crea F.
Am J Cardiol. 2013 Jul 1;112(1):8-13

32.  Both drugs improved SAQ items and EuroQoL scale
 (p <0.01)
 Time to 1-mm ST-segment depression and EST
duration improved by ranolazine.
 No effects on coronary microvascular function and
on flow-mediated dilation with drugs or placebo.
 In conclusion, ranolazine and ivabradine may have a
therapeutic role in MVA patients with inadequate
control of symptoms with usual anti-ischemic therapy.
VillanoA, Di FrancoA, Nerla R, SestitoA,Tarzia P, Lamendola P, Di MonacoA, Sarullo FM, Lanza GA, Crea F.
Am J Cardiol. 2013 Jul 1;112(1):8-13

33.  Ranolazine Refractory Angina Registry was designed to evaluate
the safety, tolerability, and effectiveness in RA patients.
 100 patients were enrolled.
 Angina class, medications, major adverse cardiac events including
death, myocardial infarction, and revascularization were obtained
at 1, 6, and 12 months.
 Overall 43% of patients had a ≥2 class improvement in
angina.
 At 1 year, 57% patients remained on ranolazine
 Reasons for discontinuation included: side effects (n = 16), major
adverse cardiac events (n = 10), cost (n = 5), ineffective (n = 6), cost
and ineffective (n = 3), and unknown (n = 3).
Bennett NM et al. Crit Pathw Cardiol. 2014 Sep;13(3):96-8.

34. The combination of ranolazine and dronedarone
appeared to lower the burden of atrial fibrillation (AF) by
>70% over three months in 45% to 60% of patients with
the paroxysmal form of the arrhythmia.
A placebo-controlled limited size and phase 2 study

35. Optimal MedicalTherapy
what's new

36.  Many trials do not include “second line
treatments”.
 Adherence to prolonged and multiple
treatments is very poor.
 Observational studies (Reach, Euro Heart
Survey, Clarify) showed underutilization of
preventive and antianginal drugs.

37. Garg P et al. J Am Heart Assoc. 2014;3:e000882
Prior to PCI following PCI
OMT 8023 (33.9%) 11 149 (47.1%)
suboptimal therapy 11 891 (50.2%) 11 591 (48.9%)
none 3766 (15.9%) 940 (4.0%)
Population-based cohort of 23 680 patients >65
years old with stable CAD undergoing PCI
“optimal medical therapy” defined as prescription for bblocker,
statin, and either ACE-inhibitor or ARB in the 90 days prior to PCI,
and the same medications along with a thienopyridine in the 90 days
following PCI.

38. PCI / CABG

40. 39,131 stable IHD patients, of whom 15,139 were treated medically, and 23,992
were revascularized (PCI = 15,604; CABG = 8,388). F.U. 2.5 years.
 The revascularization patients had higher uptake of clopidogrel (70.3 % vs
27.2 %; p < 0.001), β-blockers (78.2 % vs 76.7 %; p = 0.010), and statins (94.7
% vs 91.5 %, p < 0.001) in the 1-year post-angiogram.
 CONCLUSIONS: Stable IHD patients treated with revascularization had
improved risk-adjusted outcomes in clinical practice, potentially due to
under-treatment of medical therapy patients.
J Gen Intern Med. 2014 Jul;29(7):1031-9.
12,362 well-
matched pairs
Revascula-
rized
medical
therapy
HR p
deaths 8.6 % 12.7 % HR 0.75 p < 0.001
MIs 11.7 % 14.4 % HR 0.84 p < 0.001
repeat PCI/CABG 17.4 % 24.1 % HR 0.67 p < 0.001
Wijeysundera HC et al. J Gen Intern Med. 2014 Jul;29(7):1031-9.

41.  The optimal medical therapy or revascularization
with PCI are equivalent in terms of major
coronary events.
 In the presence of inducible ischemia, PCI
reduces the ischemic burden, but does not
fundamentally alter the outcome.
 The optimal medical therapy is not really such:
it is applied in almost one third of patients and
treatment goals are not achieved in
approximately 20-25% of cases.

42. 2014 ESC/EACTS Guidelines on myocardial revascularization

43. FFR-guided PCI
what's new

44. Downloaded from nejm.org by FRANCESCO ARRIGO on September 7, 2014.
N Engl J Med September 1, 2014
This report describes the prespecified 2-year
results for the primary end point , a composite
of death from any cause, nonfatal myocardial
infarction, or urgent revascularization.

45. Downloaded from nejm.org by FRANCESCO ARRIGO on September 7, 2014.
N Engl J Med September 1, 2014
 1220 patients with stable coronary artery disease.
 FFR in all stenoses that were visible on angiography.
 Patients who had at least one stenosis with an FFR ≤ 0.80
were randomly assigned to undergo FFR-guided PCI plus
OMT or to receive medical therapy alone.
 The rate of the primary end point was significantly lower in
the PCI group than inthe medical-therapy group (HR 0.39;
P<0.001).
 This reduction was driven by a lower rate of urgent
revascularization in the PCI group (HR 0.23; P<0.001), with no
significant between-group differences in the rates of death
and myocardial infarction.

46. Downloaded from nejm.org by FRANCESCO ARRIGO on September 7, 2014.
N Engl J Med September 1, 2014
 In conclusion, among patients with stable CAD and ischemia,
as shown by the presence of at least one stenosis with an
FFR ≤ 0.80 in a large epicardial artery, the clinical outcome at
2 years was improved by FFR-guided PCI with second-
generation DES plus the best available medical therapy, as
compared with medical therapy alone.
 In patients without hemodynamically significant
stenosis, the best available medical therapy alone
was associated with an excellent 2-year clinical
outcome, regardless of the angiographic appearance
of the stenoses.

47. Appropriate Use
Criteria
what's new

48.  Coronary revascularization is appropriate when
the expected benefits, in terms of survival or
health outcomes (symptoms, functional status,
and/or quality of life) exceed the expected
negative consequences of the procedure.

49. A appropriate; I inappropriate; U uncertain.

51. Complete
Revascularization
what's new

52.  Preventive Angioplasty in Myocardial Infarction
(PRAMI)
▪ N Engl J Med. 2013;369:1115-1123
 65% reduction in adverse events if complete
revascularization was performed at the time of initial
PCI
 Complete versus Lesion-only Primary PCITrial
(CvLPRIT)
▪ ESC Congress 2014
 55% reduction in major adverse CV events in patients
presenting for primary PCI when non-infarct related
artery is treated on the index admission

54.  Chronic IHD is a very heterogeneous disease
 With symptoms
 Without symptoms
 Treatment is aimed to
 prevent acute events
 reduce symptoms
 To achieve these goals
 no choice between OMT and PCI, but ..
…appropriate use of both.