presented by
Paul St. Laurent, MSN, RN, ACNP, CCRN
Acute Care Nurse Practitioner
Baylor Heart and Vascular Hospital
What Do We Already Know?
TRUE OR FALSE?
 Aspirin reduces the risk of myocardial
infarction
 Antiplatelet therapy reduces stent thrombosis
 Beta blockers reduce post MI mortality
 ACE inhibitors and angiotensin receptor
blockers inhibit LV remodeling
 Statins reduce major coronary events
2
Evidence Based Medicine (EBM)
“The conscientious, explicit and judicious use of
current best evidence in making decisions
about the care of the individual patient. It
means integrating individual clinical expertise
with the best available external clinical evidence
from systematic research."
Sackett DL, BMJ, 1996:312 (7023): 71-72
3
Steps in EBM Process
1: THE PATIENT

Clinical problem arises from care of patient
2: THE QUESTION

Construct question derived from case
3: THE RESOURCE

Select resource, conduct search
4: THE EVALUATION

Appraise evidence for validity and applicability
5: THE PATIENT

Integrate evidence with clinical expertise, patient preferences and
apply it to practice
6: SELF-EVALUATION

Evaluate your performance with this patient
http://www.hsl.unc.edu/services/tutorials/ebm/index.htm
4
Case Scenario
 STEP 1: The patient
 Mrs. Jones
BP is 160/80
 STEP 2: The question
 What
BP medication should she take?
 PMH: DM and chronic kidney disease
 Thiazide, BB, ACEI, ARB, CCB, other?
 STEP 3: The resources
 National
hypertension guidelines
 National Heart, Lung, and Blood Institute
(JNC 7), National Kidney Foundation,
European Society of Hypertension
5
JNC 7
 Published in 2003
 Coalition of 39 major
professional, public, and
voluntary organizations, and
seven federal agencies
 Incorporates results of
many large-scale clinical
trials
6
7
Case Scenario
 STEP 4: The evaluation
 Which ACEI
or ARB is best?
 Review literature for validity and applicability
 STEP 5: The patient
 Prefers
once a day dosing
 Prefers generic
 $4 list
 You prescribe lisinopril 20 mg daily
 STEP 6: Self-evaluation
 Mrs.
Jones returns for follow up in 4 weeks
 BP 140/72
8
Coronary Artery Disease
 Anti-platelet therapy
 Aspirin
 ADP
receptor blockers
(thienopyridines)
 Beta blockers
 ACE inhibitors/angiotensin
receptor blockers
 Lipid-lowering therapy
9
Antiplatelet Medications
10
Aspirin: Mechanism of Action
 Most widely studied antiplatelet drug
 Some of strongest evidence available about
long term effects pertain to patients with
coronary disease
 Irreversibly inhibits COX-1 within platelets,
prevents formation of thromboxane A2,
diminishes platelet aggregation
 Platelet inhibition mechanism for clinical
benefit
11
Antiplatelet Effect of Aspirin
12
Aspirin: The Evidence
 Antithrombotic Trialists’ Collaboration
(2002)
 Collaborative meta-analysis of randomized
trials
 287 studies, 135,000 patients
 25% REDUCTION in combined outcome
of any serious vascular event
 Non-fatal
MI, non-fatal stroke, death from any
vascular cause
Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for
prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2001;324:71-86.
13
Aspirin Dosing
 No trial has compared different doses of ASA
in patients who present with UA/NSTEMI
 Indirect comparisons of doses ranging from less
than 75 mg to up to 1500 mg
 Similar
reductions in the odds of vascular events
 Less than 75 mg daily
 Benefit
reduced by at least half compared with
higher doses
14
Aspirin Dosing
 Analysis from CURE trial suggested no
difference in rate of thrombotic events
according to ASA dose, but there was a dosedependent increase in bleeding
 Major bleeding rate
 2.0%
in patients taking < 100 mg daily
 2.3% with 100 mg - 200 mg daily
 4.0% with > 200 mg daily
 Therefore, maintenance doses of 75 -162 mg
PREFERRED
Yusuf, S., et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndrome without ST-segment
elevation. N Engl J Med 2001;345:494-502.
15
So What is The Recommended
Dose of Aspirin in CAD?
16
17
ACC/AHA Guidelines
 ACC and AHA jointly engaged in producing
guidelines since1980
 ACC/AHA Task Force on Practice Guidelines
charged to develop, update, or revise guidelines
for important cardiovascular diseases and
procedures
 Current guidelines include:
 STEMI
(2009), USA/NSTEMI (2007), Chronic stable
angina (2007), PCI (2009), chronic heart failure
(2009), valvular disease (2008), PAD (2005)
18
http://www.americanheart.org/presenter.jhtml?identifier=3004542
19
20
21
Aspirin Recommendations
CLASS I
 UA/NSTEMI/STEMI without stenting
 Aspirin
75 – 162 mg indefinitely (LOE: A)
 UA/NSTEMI/STEMI with BMS
 Aspirin
162 – 325 mg at least one month, then 75 –
162 mg indefinitely (LOE: A)
 UA/NSTEMI/STEMI with DES
 Aspirin
162 mg – 325 mg at least 3 months for
sirolimus-eluting, at least 6 months for paclitaxeleluting, then 75 – 162 mg indefinitely (LOE: A)
22
Thienopyridines: Mechanism of Action
 Adenosine diphosphate (ADP) receptor
antagonists
 Prevent adenosine diphosphate from binding to
its receptor on platelets
 Stops activation of glycoprotein IIb/IIIa
complex thereby inhibiting platelet activation
 Prodrugs: require metabolism by cytochrome
P450 enzyme to become active
 Clopidogrel and prasugrel
23
24
Thienopyridines: Clinical Benefits
 Monotherapy and in combination with aspirin
 Clopidogrel: CAPRIE, CURE, CHARISMA
 Prasugrel: TRITON-TIMI
38
 CAPRIE (1996)
 Monotherapy
with clopidogrel vs. aspirin
 Primary end-point composite of vascular death, MI,
stroke
 Favored clopidogrel (5.3% vs. 5.8%)
CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of
ischaemic events (CAPRIE). Lancet 1996;348:1329-1339.
25
Thienopyridines: The Evidence
 CURE (2001)
 Dual
therapy: aspirin + clopidogrel or aspirin + placebo
in ACS patients
 Clopidogrel: 20% REDUCTION in end point of CV
death, MI or stroke at 12 months
 CHARISMA (2006)
 Dual
therapy with clopidogrel + aspirin vs. aspirin alone
in patients at high risk for atherothrombotic events
 No statistical difference overall
 Significant benefit in subset of patients with prior MI
Yusuf, S., et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment
elevation. N Engl J Med 2001;345:494-502.
Bhatt, DL., et al. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med
2006;354:1706-1717.
26
Prasugrel
 FDA approved July 10, 2009
 TRITON-TIMI 38
 Randomized, double-blind
study
 Compared prasugrel (60 mg LD, 10 mg MD) to
clopidogrel (300 mg LD, 75 mg MD) in patients
undergoing PCI
 19% relative risk reduction in primary composite
endpoint of death, nonfatal MI, or nonfatal stroke at
expense of significant increase in the risk of major
bleeding
Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J
Med. 2007;357:2001-2015.
27
Thienopyridine Recommendations
CLASS I
 UA/NSTEMI/STEMI without stenting
 LD: Clopidogrel
300-600 mg/prasugrel (STEMI only) 60
mg (LOE: B)
 MD: Clopidogrel 75 mg/prasugrel 10 mg for 1 month,
ideally for 1 year (LOE: B)
 UA/NSTEMI/STEMI with BMS
 Clopidogrel
75 mg/prasugrel 10 mg (STEMI only) for at
least 1 month (LOE: B)
 UA/NSTEMI/STEMI with DES
 Clopidogrel
75 mg/prasugrel 10 mg (STEMI only) for at
least 1 year (LOE: B)
28
Loading Doses
 Clopidogrel 300 mg loading dose
 Well
established for use in patients with acute
coronary syndrome
 Inhibition of platelet aggregation 30% - 40%
 Time to peak effect 4 to 6 hours
 Clopidogrel 600 mg loading dose
 Inhibits
platelet aggregation > 40%
 Time to peak effect 2 to 3 hours
 Reduces clopidogrel hyporesponsiveness
29
Loading Doses: The Evidence
 Meta-analysis of 10 studies
 1,567
patients undergoing PCI, variety of loading doses
(300 mg – 900 mg)
 Result: high loading doses significantly reduce early
ischemic events in patients scheduled for PCI
 HORIZONS-AMI
 3,311
patients with STEMI receiving either 300 mg or
600 mg loading dose
 600 mg:  30-day mortality, subacute stent thrombosis,
major adverse cardiac events, with no increase in
bleeding
Lotrionte, M., et al. Meta-analysis appraising high clopidogrel loading in patients undergoing percutaneous coronary intervention. Am J
Cardiol 2007;100:1199-1206.
Dangas, G., et al. Role of clopidogrel loading dose in patients with ST-segment elevation myocardial infarction undergoing primary
angioplasty. J Am Coll Cardiol 2009;54:1438-1446.
30
Loading Doses: The Evidence
 ARMYDA-5 PRELOAD Trial
 409 patients randomized to 600 mg clopidogrel
4-8 hours before PCI or in the cath lab after
angiography but prior to PCI
 No difference in primary end-point of 30-day
incidence of cardiac death, myocardial infarction,
or unplanned target vessel revascularization
Sciascio, G., et al. Effectiveness of in-laboratory high-dose clopidogrel loading versus routine pre-load in patients undergoing
percutaneous coronary intervention. J Am Cardio 2010;56:550-557.
31
Beta-Blockers: Mechanism of Action
 Block the action of adrenergic catecholamines
(norepinephrine and epinephrine) on adrenergic receptors
 1 receptor mainly in heart
 2 receptor mainly in lungs, vascular smooth
muscle, skeletal muscle
 Cardioselective “selectively” block 1
 Nonselective block 1 and 2
32
Beta Blockers: Clinical Benefits
 Decreased oxygen demand due to reduction in
BP, HR, contractility, and relief of chest pain
 Decreased risk of VF and sudden cardiac death
 Decreased HR prolongs diastole, and enhances
coronary artery perfusion
 Reduces remodeling, and enhances
hemodynamic function
33
Beta Blockers: The Evidence
 US Carvedilol Study (1996)
 Carvedilol
vs placebo in HF patients
 65% REDUCTION IN MORTALITY
 CIBIS-II and MERIT-HF (1999)
 Bisoprolol
and metoprolol vs placebo in HF patients
 34% REDUCTION IN MORTALITY
 CAPRICORN (2001)
 Carvedilol
vs placebo in AMI patients with EF ≤ 40%
 23% REDUCTION IN MORTALITY
34
Beta Blockers: The Evidence
 EPIC (1994), EPILOG (1997), EPISTENT (1998),
CAPTURE (1997), RAPPORT (1998)
 Pooled
results of 2894 patients with UA and AMI
undergoing PCI
 1939 patients received BB, 934 did not
 50% REDUCTION IN MORTALITY at 30 days
and 6 months
Ellis, K. et al. Mortality benefit of beta blockade in patients with acute coronary syndromes undergoing coronary intervention. J
Interven Cardiol 2003;16;2999-305
35
Beta Blocker Recommendations
CLASS I
 UA/NSTEMI/STEMI
 It
is beneficial to start and continue beta-blocker
therapy indefinitely in all patients who have had MI,
acute coronary syndrome, or LV dysfunction with or
without HF symptoms, unless contraindicated
(LOE: A)
36
Beta Blocker: Selection
 Cardio-selective vs nonselective
 Contraindications
 Marked
1st degree, 2nd/3rd degree AVB, significant sinus
bradycardia, hypotension, history of asthma, low
output state, severe LV dysfunction
 Significant COPD: short-acting B1 agent at low dose
 Reassess when acute problems have resolved
37
Beta-Blocker Selection
 Dosing considerations
 Daily: metoprolol
succinate, carvedilol phosphate,
atenolol, nevibolol
 BID: metoprolol tartrate, carvedilol, labetalol
 Evidence-based beta blockers
 HF: metoprolol
succinate, carvedilol, bisoprolol
38
ACE Inhibitors: Mechanism of Action
 Angiotensin converting enzyme inhibitors
 Block the enzyme that converts antiogensin I to
angiotensin II
 Block bradykinin, which increases nitric oxide
release, promotes vasodilation
 Block aldosterone
39
ACE Inhibitors: Clinical Benefit
 Inhibits LV remodeling, preserves
LV function
 Afterload reduction (vasodilation)
 Reduces
blood pressure
 Reduce infarct size
 Improves endothelial function
 Reduces overall cardiovascular
mortality
40
41
ACE Inhibitors: The Evidence
 SAVE(1992), AIRE (1993),TRACE (1999)
 5966
patients after with LV dysfunction post MI
 26% REDUCTION in death, MI, hospital admission
for HF
 HOPE (2003), QUIET (2001), PART-2 (2000),
SCAT (2000), EUROPA (2003), PEACE (2004),
CAMELOT (2004)
 14%
REDUCTION in death, MI
42
ACE Inhibitor Recommendations
CLASS I
 UA/NSTEMI/STEMI
 Should
be given and continued indefinitely for
patients with HF, LV dysfunction (LVEF < 40%),
hypertension, diabetes, and chronic kidney disease,
unless contraindicated (LOE: A)
43
ACE Inhibitor Selection
 Contraindications
 Hypotension, angioedema,
hyperkalemia, bilateral renal
artery stenosis, acute renal
insufficiency
 Dosing considerations
 Daily: lisinopril, ramipril,
enalapril, benazepril, fosinopril,
quinapril
 BID/TID: captopril
44
Angiotensin Receptor Blockers (ARBs):
Mechanism of Action
 Angiotensin II causes potent vasoconstriction,
aldosterone secretion and sympathetic
activation
 ARBs bind to specific membrane-bound
receptors that displace angiotensin II from its
type 1 receptor subtype (AT1)
45
ARBs: The Evidence
 VALIANT (2003)
 Valsartan
vs captopril
 Valsartan equally effective at reducing mortality, CV
morbidity
 Can be used as alternative if ACEI not
tolerated
 ACEI
cough secondary to inhibition of bradykinin
pathway
Pfeffer, M., et al.Valsartan, captopril, or both in myocardial infraction complicated by heart failure, left ventricular dysfunction,
or both. N Engl J Med 2003:349:1893-1906.
46
ARB Recommendations
CLASS I
 UA/NSTEMI/STEMI
 Angiotensin
receptor blocker should be prescribed
at discharge to those UA/NSTEMI patients who are
intolerant of an ACE inhibitor and who have either
clinical or radiological signs of HF and LVEF < 40%
(LOE: A)
 It is beneficial to use angiotensin receptor blocker
therapy in other patients who are ACEI intolerant
and have hypertension (LOE: B)
47
ARB Selection
 Contraindications
 Same
as for ACEI
 Dosing considerations
 Candesartan, irbesartan,
losartan, olmesartan,
telmisartan, valsartan
 All can be given daily
 None available in generic form
48
Statins: Mechanism of Action
 HMG CoA reductase inhibitors competitively
inhibit the activity of HMG CoA reductase,
which reduces cellular cholesterol
concentration
 Reduced cholesterol causes up regulation of
LDL receptors, and increased uptake of plasma
LDL
 End result: decreased plasma LDL
49
Statins: Clinical Benefits
 Plaque stabilization
 Unstable
 stable plaque
 Reduces inflammation
 Contributor
of atherosclerosis and plaque rupture
 Reduces CRP levels
 Reverses endothelial dysfunction

endothelial nitric oxide
 Decreased thrombogenicity
 Decreased
generation
prothrombin activation and thrombin
50
Statins: The Evidence





LIPID trial
9014 patients with CAD
Pravastatin vs placebo
22%  MORTALITY
24%  cardiac death,
nonfatal myocardial
infarction
51
Statins: The Evidence
4S Trial
 4444 patients with CAD
 Simvastatin vs placebo
 30%  MORTALITY

52
Statin Recommendations
CLASS I
 Statins, in the absence of contraindications, regardless
of baseline LDL-C and diet modification, should be
given to post-UA/NSTEMI/STEMI patients, including
post revascularization patients (LOE: A)
 For hospitalized patients, lipid-lowering medications
should be initiated before discharge (LOE: A)
53
Statin Recommendations
CLASS I
 For UA/NSTEMI/STEMI patients with elevated
LDL-C (≥100 mg per dL), cholesterol-lowering
therapy should be initiated or intensified to
achieve an LDL-C < than 100 mg per dL
(LOE: A)
CLASS IIa
 Further titration to < than 70 mg per dL is
reasonable (LOE: A)
54
STATIN
LDL
LOWERING
Atorvastatin
 35-60%
Fluvastatin
 20-35%
Lovastatin
 25-40%
Pitavastatin
 39-45%
Pravastatin
 20-35%
Rosuvastatin
 40-65%
Simvastatin
 35-50%
DRUG CLASS
LIPID EFFECTS
Bile Acid
Sequestrants
LDL  15-30%
HDL 3-5%
TG No change or increase
Nicotinic acid
LDL  5-25%
HDL  15-35%
TG  20-50%
Fibric acids
LDL  5-20%
HDL 10-20%
TG  20-50%
56
Statin Selection
 Contraindications
 Absolute: active
or chronic liver disease
 Adverse effects
 Myopathy, increased
liver transaminases
 Dosing considerations
 Generic: lovastatin, pravastatin, simvastatin
 Take
any time: atorvastatin, pitavastatin, pravastatin,
rosuvastatin
 Take in the evening: all others
57
58
Impact of Combination Therapy
 Antiplatelet drugs, -blockers, ACE
inhibitors/ARBs, and lipid-lowering agents
reduce mortality
 Aspirin: 25%
 Thienopyridines:  20 %
 BB:  35%
 ACEI:  20 %
 Statins:  25%
59
Impact of Combination Therapy
1264 patients with acute coronary
syndrome
Compared number of discharge drugs and
6-month mortality
What was the overall reduction in
mortality between patients on all
evidence-based medications?
Mukherjee, D et al, Impact of Evidence-Based Combination Therapy on Mortality in patients With Acute Coronary
Syndromes. Circulation, 2004;109;745-749
60
What Was the Reduction in Mortality?
A: 30%
B: 40%
C: 50%
D: > 60%
61
So, How are We Doing?
186,000 eligible patients with AMI
between July 1, 2000 and June 30, 2002
National Registry of Myocardial Infarction
4 (NRMI-4) database
1247 hospitals
Early and discharge medications
Roe, M. et al. Quality of care by classification of myocardial infarction. Arch Intern Med. 2005;165:1630-1636
62
Results
5533
misses
21,394
misses
276,277
MISSED
OPPORTUNITIES
63
What About After Discharge?
 National Disease and Therapeutic Index and
National Ambulatory Medical Care Survey
(physician prescribing practices)
 1990 to 2002
 35,295 patients with CAD
 Aspirin use increased from 18% in 1990, to
19% in 1995, to 38% in 2001
Stafford, R., et al. The underutilization of cardiac medications of proven benefit, 1990 to 2002. J Am Coll Cardiol 2003:41:56-61
64
What About After Discharge?
Duke Databank for Cardiovascular
Disease 1995 to 2002
Self-reported
22,539 patients
Consistently used
 71%
aspirin, 46% ββ, 44% lipid-lowering
Newby, K., et al. Long-Term Adherence to Evidence-Based Secondary Prevention Therapies in Coronary Artery Disease.
Circulation. 2006;113:203-212.
65
Key Strategies
 Ensure patients receive all 5 EVIDENCEDBASED MEDICATIONS
 “Missing” medications should be identified, and
action taken
 Education to providers in all clinical settings
 Inpatient, outpatient, cardiologists, primary
care
providers, physicians, nurses, etc.
66
67
Why Does it Matter?
 5 medications can prevent a heart attack
 5 medications can prevent stent thrombosis
 5 medications can prevent heart failure
 5 medications can save a life
68
At What Cost?
69
$4 Drugs
BBs
Carvedilol
Metoprolol tartrate
Atenolol
Propranolol
ACEIs
Lisinopril
Benazepril
Enalapril
Captopril
STATINS
Lovastatin
Pravastatin
Bisoprolol (with HCTZ only)
70
Take 5, Costs $6
 Aspirin = $0.02/day
 BB = $0.13/day
 ACEI = $0.13/day
 Statin = $0.13/day
 Plavix = $5.50/day (www.drugstore.com)
 TOTAL =
71
Take Home Message
 OVERWHELMING body of evidence
supports use of
 Aspirin
 Thienopyridines
 Beta
blockers
 ACE inhibitors/ARBs
 Lipid-lowering therapy
72
 5 medications can significantly impact patient
outcomes
 Share this message with your patients and
colleagues
73
74