Transcript Prava alone

AHA/ACC Guidelines Update in Patients
with Atherosclerotic CV Disease
 Medication Recommendations as Supplements
to Lifestyle Modification:
– Lipid-lowering therapy to achieve LDL-C of
<100mg/dL
– Antiplatelet therapy, principally aspirin
– Anti-hypertensive therapy to achieve BP of <140/90
– Hypoglycemic therapy to achieve near normal
fasting glucose (HbA1C <7%)
– ACE inhibitor
– Beta-blocker
Source: Circulation (2001) 104: 1577–79.
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Sub-Optimal Usage at Discharge of
CV Therapies with Proven Value
100%
80%
77%
60%
Percent of
CHD Patients
37%
40%
20%
0%
ASA
Statin
Therapy at Hospital Discharge
167,000 patients nationwide, July ’99 to June ’00.
Includes CHD patients with no exclusions for contraindications or intolerance to these drugs.
Source: National Registry of Myocardial Infarction –3.
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OTC Aspirin Use in
Coronary Heart Disease
 Under-utilization: Only 51% of patients with known
cardiovascular disease reported they were taking
aspirin or an ‘equivalent’
 Mis-medication: Among patients who thought they
were taking aspirin for CHD, 15% were actually
taking a non-aspirin analgesic
National Survey 26,976 persons >40 years of age
3818 reported prior CVD
Cook et al, (1999) Med Gen Med, www.medscape.com.
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OTC “Aspirin Only” Products
Brand
No. of Products
ASA Doses (mg)
Aspergum®
1
227
Norwich®
2
325, 500, 650
Bayer®
13
81, 325, 500
St. Joseph®
1
81
Ecotrin®
3
81, 325, 500
Halfprin®
2
81, 162
Ascriptin®
5
81, 325, 500
Bufferin®
4
81, 325, 500
Adprin®
1
325
Alka-Seltzer®
3
325, 500
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OTC “No Aspirin” Products
Tylenol®
acetaminophen
Advil®
ibuprofen
Aleve®
naproxen
Motrin®
ibuprofen
Anacin® (aspirin-free)
acetaminophen
Excedrin® (aspirin-free)
acetaminophen
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Following New AHA/ACC Guidelines
Necessitates High Pill Burden
 A typical CHD patient might be taking:
– aspirin
– ACE inhibitor
– beta-blocker
– statin
 A CHD patient with diabetes might also be taking:
– oral anti-diabetic agents
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U.S. Heart Disease Prevalence Is Projected
to Double in the Next Half Century
15
12.3
12
Number
of CHD
Patients
(Millions)
9
6.3
6
3
0
1970
1980
1990
2000
2010
2020
2030
2040
2050
Sources: ACC/AHA Guidelines 2001, NHLBI Chartbook 2000
and Adapted from Foot et al (JACC 2000).
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Hypothetical 2 x 2 Factorial
Pravigard (Buffered Aspirin and Pravastatin Sodium)
Trial Design
Is Pravachol+Aspirin more effective than both Aspirin
alone and Pravachol alone?
Pravachol
Placebo
Aspirin
Prava+Aspirin
Aspirin alone
Placebo
Prava alone
Placebo
Hennekens CH et al. Archives of Internal Medicine, In Press.
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Efficacy and Safety of Pravigard (Buffered Aspirin and
Pravastatin Sodium)
Based on Meta-analysis of 5 Pravachol trials
Trial
Number of
Subjects*
% on Aspirin
Primary Endpoint
LIPID
9014
82.7
CHD mortality
CARE
4159
83.7
CHD death & non-fatal MI
REGRESS
885
54.4
Atherosclerotic progression
(& events)
PLAC I
408
67.5
Atherosclerotic progression
(& events)
PLAC II
151
42.7
Atherosclerotic progression
(& events)
Totals
14,617
80.4
*99.7% of Pravachol (pravastatin sodium) treated subjects received 40mg dose
Total exposure 79,300 patient years
Hennekens CH et al. Archives of Internal Medicine, In Press.
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Contribution of Trials to Total
CHD Patient Years of Exposure
LIPID
68%
CARE
28%
REGRESS
2%
PLAC-I
1%
PLAC-II
1%
Total Exposure = 73,900 Patient Years
Hennekens CH et al. Archives of Internal Medicine, In Press.
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Meta-Analysis Comparisons
Randomized Groups
Pravastatin
Placebo
Aspirin Users
Prava-ASA
(n=5888)
ASA alone
(n=5833)
Aspirin
Non-Users
Prava alone
(n=1436)
Placebo
(n=1460)
Subgroups
Model 1:Multivariate Cox proportional hazards model
Model 2: Same as Model 1 except allows for trial
heterogeneity: Bayesian hierarchical
Hennekens CH et al. Archives of Internal Medicine, In Press.
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Greater Relative Risk Reduction for
Pravigard (Buffered Aspirin and Pravastatin Sodium)
Cox Proportional Hazards – All Trials
RRR
Relative Risk (95% CI)
Fatal or Non-Fatal MI
0.69
Prava+ASA vs ASA alone
0.74
Prava+ASA vs Prava alone
0.400
31%
0.600
26%
0.800
1.000
Ischemic Stroke
0.71
Prava+ASA vs ASA alone
0.69
Prava+ASA vs Prava alone
0.400
29%
0.600
31%
0.800
1.000
CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke
0.76
Prava+ASA vs ASA alone
0.87
Prava+ASA vs Prava alone
0.400
RRR = Relative Risk Reduction
24%
0.600
0.800
13%
1.000
Hennekens CH et al. Archives of Internal Medicine, In Press.
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Model 1 - Absolute Event Rates
Fatal and NF-MI
Prava
Placebo
RRR*
Aspirin Users
7.6%
10.7%
31.3%
Aspirin Non-Users
8.7%
10.8%
19.4%
* Relative risk reduction based on Cox PH model
Hennekens CH et al. Archives of Internal Medicine, In Press.
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Model 1 - Absolute Event Rates
Ischemic Stroke
Prava
Placebo
RRR*
Aspirin Users
2.3%
3.1%
29.2%
Aspirin Non-Users
3.1%
3.5%
12.0%
* Relative risk reduction based on Cox PH model
Hennekens CH et al. Archives of Internal Medicine, In Press.
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Model 1 - Absolute Event Rates
CHD Death, NF-MI, CABG, PTCA, Ischemic Stroke
Prava
Placebo
RRR*
Aspirin Users
22.3%
28.5%
24.2%
Aspirin Non-Users
23.8%
27.3%
15.4%
* Relative risk reduction based on Cox PH model
Hennekens CH et al. Archives of Internal Medicine, In Press.
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Model 2 – Hierarchical, Random Effects
Fatal or Non-Fatal MI
0.100
Placebo
ASA alone
Prava alone
0.075
Cumulative
Proportion
of Events
0.050
Prava+ASA
0.025
0.000
0
1
2
3
4
5
Year
Hennekens CH et al. Archives of Internal Medicine, In Press.
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Model 2 – Hierarchical, Random Effects
Ischemic Stroke Only
0.025
Placebo
Prava alone
ASA alone
0.020
0.015
Cumulative
Proportion
of Events
0.010
Prava+ASA
0.005
0.000
0
1
2
3
4
5
Year
Hennekens CH et al. Archives of Internal Medicine, In Press.
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Reported Safety of the Combination in the
Pravachol (pravastatin sodium) Trials
 No increased incidence of
– CK abnormalities
– Liver Function Test abnormalities
– Gastrointestinal bleeds
– Hemorrhagic stroke
Hennekens CH et al. Archives of Internal Medicine, In Press.
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Important Safety Information Pravachol (pravastatin sodium)
Pravachol is contraindicated for patients who are pregnant or nursing and in the presence of active
liver disease or unexplained persistent transaminase elevations.
Myopathy should be considered in any patient with diffuse myalgias, muscle tenderness or
weakness, and/or marked elevation of creatine phosphokinase (CPK). Patients should be advised
to promptly report unexplained muscle pain, tenderness, or weakness, particularly if accompanied
by malaise or fever. The risk of myopathy during treatment with another HMG-CoA reductase
inhibitor is increased with concurrent therapy with erythromycin, cyclosporine, niacin, or fibrates.
The combined use of Pravachol and fibrates should be avoided unless the benefit of further
alterations in lipid levels is likely to outweigh the increased risk of this drug combination.
It is recommended that liver function tests be performed prior to initiating therapy, prior to
increasing the dose, and when otherwise clinically indicated.
If a patient develops increased transaminase levels, or signs and symptoms of liver disease, more
frequent monitoring may be required. Withdrawal of Pravachol is recommended if an increase in
AST or ALT of >3x ULN persists.
Pravachol is well tolerated. The most common adverse events are rash, fatigue, headache, and
dizziness.
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Important Safety Information - Aspirin
Aspirin is contraindicated in patients with known allergy to nonsteroidal anti-inflammatory drug
products, in patients with the syndrome of asthma, rhinitis, and nasal polyps, and in nursing
mothers. Aspirin should not be used in children or teenagers for viral infections, with or without
fever, because of the risk of Reye’s syndrome with concomitant use of aspirin in certain viral
illnesses.
Patients who consume three or more alcoholic drinks every day should be counseled about the
bleeding risks involved with chronic, heavy alcohol use while taking aspirin.
Aspirin can inhibit platelet function leading to an increase in bleeding time.
Avoid using aspirin in patients with severe renal failure, severe hepatic insufficiency or a history of
active peptic ulcer disease.
Patients with sodium-retaining states, such as congestive heart failure or renal failure, should avoid
sodium-containing buffered aspirin preparations because of their high sodium content.
Pregnant women should only take aspirin if clearly needed, use during the third trimester of
pregnancy should be avoided.
GI side effects include stomach pain, heartburn, nausea, vomiting, and gross GI bleeding.
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Drug Interactions
 Polypharmacy may increase the potential for drug-drug
interactions.
 The CYP450 3A4 pathway metabolized more than 50%
of all prescription drugs.
 Neither Pravachol nor aspirin are metabolized by
CYP450 3A4 to a clinically significant extent.
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Cardiac Hospital Atherosclerosis
Management Program (CHAMP)
Population:
 Patients with acute myocardial infarction
Methods:
 University-associated teaching hospital
 Before CHAMP (1992 to 1993): no specific
treatment algorithms used
 During CHAMP (1994 to 1995): physician decision
based on national clinical guidelines (ACC/AHA,
NCEP Adult Treatment Panels I and II)
Endpoints:
 Treatment rates and clinical outcome were
compared between the 2 groups
Fonarow GC et al. Am J Cardiol 2001;87:819–22.
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CHAMP: Treatment Rates
Pre-CHAMP
1992/1993
(n=256)
Post-CHAMP
1994/1995
(n=302)
Discharge
1 year
Discharge
1 year
ASA
78%
68%
92%
94%
-blocker
12%
18%
61%
57%
Statin
6%
10%
86%
91%
P<0.01, pre-versus post-CHAMP at discharge and at 1 year
Fonarow GC et al. Am J Cardiol 2001;87:819–822.
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CHAMP: Impact on Clinical Outcomes
Pre-CHAMP
1992/1993
(n=256)
Recurrent MI
Heart Failure
Hospitalization
Sudden Death
Cardiac Mortality
Noncardiac Mortality
Total Mortality
20 (7.8%)
12 (4.7%)
38 (14.8%)
3 (1.2%)
13 (5.1%)
2 (0.8%)
18 (7.0%)
Post-CHAMP
1994/1995
(n=302)
10 (3.1%)*
8 (2.6%)
23 (7.6%)*
2 (0.6%)
6 (2.0%)*
2 (0.6%)
10 (3.3%)*
*p < 0.05
Fonarow GC et al. Am J Cardiol 2001;87:819–822.
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CHAMP: Significance
Patients discharged on secondary prevention
medications from the hospital demonstrate longterm compliance.
This increase in compliance translates into better
long-term clinical outcomes.
Fonarow GC et al. Am J Cardiol 2001;87:819–822.
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