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AHA/ACC Guidelines Update in Patients AHA/ACC Guidelines Update in Patients with Atherosclerotic CV Diseasewith Atherosclerotic CV Disease

Source: Circulation (2001) 104: 1577–79.

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

Medication Recommendations as Supplements to Lifestyle Modification:

– Lipid-lowering therapy to achieve LDL-C of <100mg/dL

– Antiplatelet therapy, principally aspirin

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Sub-Optimal Usage at Discharge of Sub-Optimal Usage at Discharge of CV Therapies with Proven ValueCV Therapies with Proven Value

Source: National Registry of Myocardial Infarction –3.

167,000 patients nationwide, July ’99 to June ’00.Includes CHD patients with no exclusions for contraindications or intolerance to these drugs.

77%

37%

0%

20%

40%

60%

80%

100%

ASA Statin

Therapy at Hospital Discharge

Percent of CHD Patients

A-3A-3

Cook et al, (1999) Med Gen Med, www.medscape.com.

OTC Aspirin Use in OTC Aspirin Use in Coronary Heart DiseaseCoronary 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

A-4A-4

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

OTC “Aspirin Only” ProductsOTC “Aspirin Only” Products

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OTC “No Aspirin” ProductsOTC “No Aspirin” Products

Tylenol® acetaminophen

Advil® ibuprofen

Aleve® naproxen

Motrin® ibuprofen

Anacin® (aspirin-free) acetaminophen

Excedrin® (aspirin-free) acetaminophen

A-6A-6

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

Following New AHA/ACC Guidelines Following New AHA/ACC Guidelines Necessitates High Pill BurdenNecessitates High Pill Burden

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0

3

6

9

12

15

1970 1980 1990 2000 2010 2020 2030 2040 2050

Numberof CHD

Patients (Millions)

Sources: ACC/AHA Guidelines 2001, NHLBI Chartbook 2000and Adapted from Foot et al (JACC 2000).

6.3

12.3

U.S. Heart Disease Prevalence Is Projected U.S. Heart Disease Prevalence Is Projected to Double in the Next Half Centuryto Double in the Next Half Century

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Hypothetical 2 x 2 Factorial Hypothetical 2 x 2 Factorial Pravigard Pravigard (Buffered Aspirin and Pravastatin Sodium)(Buffered Aspirin and Pravastatin Sodium)

Trial DesignTrial Design

PlaceboPravachol

Aspirin

Placebo

Prava+Aspirin

Prava alone

Aspirin alone

Placebo

Is Pravachol+Aspirin more effective than both Aspirin alone and Pravachol alone?

Hennekens CH et al. Archives of Internal Medicine, In Press.

A-9A-9

Trial

LIPID

CARE

REGRESS

PLAC I

PLAC II

Totals

Number of Subjects* % on Aspirin

82.7

83.7

54.4

67.5

42.7

80.4

Primary Endpoint

CHD mortality

CHD death & non-fatal MI

Atherosclerotic progression (& events)

9014

4159

885

408

151

14,617

Atherosclerotic progression (& events)

Atherosclerotic progression (& events)

*99.7% of Pravachol (pravastatin sodium) treated subjects received 40mg doseTotal exposure 79,300 patient years

Efficacy and Safety of Pravigard Efficacy and Safety of Pravigard (Buffered Aspirin and (Buffered Aspirin and

Pravastatin Sodium)Pravastatin Sodium) Based on Meta-analysis of 5 Pravachol trialsBased on Meta-analysis of 5 Pravachol trials

Hennekens CH et al. Archives of Internal Medicine, In Press.

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Contribution of Trials to TotalContribution of Trials to TotalCHD PatientCHD Patient Years of ExposureYears of Exposure

Total Exposure = 73,900 Patient Years

LIPID 68%

CARE28%

REGRESS2%

PLAC-I1%

PLAC-II1%

Hennekens CH et al. Archives of Internal Medicine, In Press.

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Meta-Analysis ComparisonsMeta-Analysis Comparisons

PlaceboPravastatin

Aspirin Users

Aspirin Non-Users

Subgroups

Randomized Groups

Prava-ASA(n=5888)

Prava alone(n=1436)

ASA alone(n=5833)

Placebo(n=1460)

Model 1:Multivariate Cox proportional hazards modelModel 2: Same as Model 1 except allows for trial heterogeneity: Bayesian hierarchical

Hennekens CH et al. Archives of Internal Medicine, In Press.

A-12A-12RRR = Relative Risk Reduction

Relative Risk (95% CI) RRR

Prava+ASA vs ASA alone

Prava+ASA vs Prava alone

Fatal or Non-Fatal MI

0.400 0.800 1.0000.600

0.400 0.800 1.0000.600

CHD Death, Non-Fatal MI, CABG, PTCA, or Ischemic Stroke

Prava+ASA vs ASA alone

Prava+ASA vs Prava alone

24%0.76

13%0.87

31%0.69

26%0.74

Prava+ASA vs ASA alone

Prava+ASA vs Prava alone

29%0.71

31%0.69

Ischemic Stroke

0.400 0.800 1.0000.600

Greater Relative Risk Reduction for Greater Relative Risk Reduction for Pravigard Pravigard (Buffered Aspirin and Pravastatin Sodium)(Buffered Aspirin and Pravastatin Sodium)

Cox Proportional Hazards – All TrialsCox Proportional Hazards – All Trials

Hennekens CH et al. Archives of Internal Medicine, In Press.

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Model 1 - Absolute Event RatesModel 1 - Absolute Event Rates

Fatal and NF-MI

PlaceboPrava RRR*

7.6%

8.7%

10.7%

10.8%

31.3%

19.4%

* Relative risk reduction based on Cox PH model

Aspirin Users

Aspirin Non-Users

Hennekens CH et al. Archives of Internal Medicine, In Press.

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Ischemic Stroke

PlaceboPrava RRR*

2.3%

3.1%

3.1%

3.5%

29.2%

12.0%

* Relative risk reduction based on Cox PH model

Aspirin Users

Aspirin Non-Users

Model 1 - Absolute Event RatesModel 1 - Absolute Event Rates

Hennekens CH et al. Archives of Internal Medicine, In Press.

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CHD Death, NF-MI, CABG, PTCA, Ischemic Stroke

PlaceboPrava RRR*

22.3%

23.8%

28.5%

27.3%

24.2%

15.4%

* Relative risk reduction based on Cox PH model

Aspirin Users

Aspirin Non-Users

Model 1 - Absolute Event RatesModel 1 - Absolute Event Rates

Hennekens CH et al. Archives of Internal Medicine, In Press.

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0.000

0.025

0.050

0.075

0.100

0 1 2 3 4 5

Year

Model 2 – Hierarchical, Random EffectsModel 2 – Hierarchical, Random Effects

Fatal or Non-Fatal MI

Placebo

Prava alone

ASA alone

Prava+ASA

Cumulative Proportion of Events

Hennekens CH et al. Archives of Internal Medicine, In Press.

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0.000

0.005

0.010

0.015

0.020

0.025

0 1 2 3 4 5

Model 2 – Hierarchical, Random EffectsModel 2 – Hierarchical, Random Effects

Ischemic Stroke Only

ASA alone

Prava+ASA

Year

Cumulative Proportion of Events

Prava alonePlacebo

Hennekens CH et al. Archives of Internal Medicine, In Press.

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Reported Safety of the Combination in the Reported Safety of the Combination in the Pravachol Pravachol (pravastatin sodium)(pravastatin sodium) Trials 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 - Important Safety Information - Pravachol Pravachol (pravastatin sodium)(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 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 InteractionsDrug 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 Cardiac Hospital Atherosclerosis Management Program (CHAMP)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

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.

A-23A-23

CHAMP: Treatment Rates CHAMP: Treatment Rates

Fonarow GC et al. Am J Cardiol 2001;87:819–822.

P<0.01, pre-versus post-CHAMP at discharge and at 1 yearP<0.01, pre-versus post-CHAMP at discharge and at 1 year

Discharge 1 year Discharge 1 year

ASA 78% 68% 92% 94%

-blocker 12% 18% 61% 57%

Statin 6% 10% 86% 91%

Pre-CHAMP Post-CHAMP1992/1993 1994/1995

(n=256) (n=302)

Pre-CHAMP Post-CHAMP1992/1993 1994/1995

(n=256) (n=302)

A-24A-24

Recurrent MI 20 (7.8%) 10 (3.1%)*Heart Failure 12 (4.7%) 8 (2.6%)Hospitalization 38 (14.8%) 23 (7.6%)*Sudden Death 3 (1.2%) 2 (0.6%)Cardiac Mortality 13 (5.1%) 6 (2.0%)*Noncardiac Mortality 2 (0.8%) 2 (0.6%)Total Mortality 18 (7.0%) 10 (3.3%)*

*p < 0.05*p < 0.05

Pre-CHAMP Post-CHAMP1992/1993 1994/1995

(n=256) (n=302)

Pre-CHAMP Post-CHAMP1992/1993 1994/1995

(n=256) (n=302)

Fonarow GC et al. Am J Cardiol 2001;87:819–822.

CHAMP: Impact on Clinical Outcomes CHAMP: Impact on Clinical Outcomes

A-25A-25

Patients discharged on secondary prevention medications from the hospital demonstrate long-term compliance.

This increase in compliance translates into better long-term clinical outcomes.

Fonarow GC et al. Am J Cardiol 2001;87:819–822.

CHAMP: Significance CHAMP: Significance