1 Cardiovascular & Renal Drugs Advisory Committee Meeting Presentation.

1

Cardiovascular & Renal Drugs Advisory Committee

Meeting

Presentation

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Bayer HealthCare’s Citizen Petition for Expanded Aspirin Professional Labeling to Include Moderate Risk Patients

Erica Peitler, RPhSr. VP Global Strategic InitiativesBayer HealthCare LLCMorristown, New Jersey

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Key Points

• Consensus that ASA prevents MI

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Key Points


• ASA is cost effective, yet underutilized

5

Key Points



• Guidelines support ASA use in moderate risk

6

Key Points




• Expanded labeling for ASA can have significant public health impact

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Key Points





• Request FDA recognition of global risk assessment rather than event-based risk

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Key Points






• Totality of evidence advances our understanding of appropriate patient selection

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Key Points






• Totality of evidence advances our understanding of appropriate patient selection

• Bayer is committed to working with the FDA and the health care provider community to reduce MI burden

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Expert Participants

• Investigators J. Michael Gaziano, MD

Tobias Kurth, MD, ScDNancy R. Cook, ScD

Physicians’ Health Study Colin Baigent, BMBCh, MSc

British Doctors’ Study Thomas W. Meade, DM, FRS

Thrombosis Prevention Trial Gianni Tognoni, MD

Primary Prevention Project Alberto Zanchetti, MD

Hypertension Optimal Treatment Trial

• Guidelines Michael P. Pignone, MD, MPH (USPSTF) Thomas Pearson, MD, MPH, PhD (AHA) John A. Colwell, MD, PhD (ADA)

• Cardiology/Epidemiology Stephen Kimmel, MD, MSCE Thomas Pearson, MD, MPH, PhD Randall Stafford, MD, PhD

• Cardiologists C. Noel Bairey Merz, MD Charles L. Curry, MD Eric Topol, MD

• Gastrointestinal Safety David Y. Graham, MD Loren Laine, MD James Lewis, MD

• Neurology Tobias Kurth, MD, ScD

• Labeling Steve Hellebusch

Hellebusch Research

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Agenda

• Rationale for Expanded Aspirin Labeling Thomas Pearson, MD, MPH, PhD

• Safety and Efficacy of Aspirin in Moderate Risk Patients Colin Baigent, MD

• Appropriate Aspirin Use in Women C. Noel Bairey Merz, MD

• Aspirin Utilization: Importance of Labeling Alignment with Medical Practice Randall Stafford, MD, PhD

• Clinical Considerations Eric Topol, MD

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Rationale for Expanded Aspirin Professional Labeling to Include Moderate Risk Patients

Thomas A. Pearson, MD, MPH, PhDAlbert D. Kaiser Professor and Chair of Community Preventive MedicineSenior Associate Dean for Clinical ResearchUniversity of Rochester School of MedicineRochester, New York

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Rationale for Expanded Professional ASA Labeling

To Include Patients at “Moderate Risk”

• Proposal Adopt global risk labeling for ASA patient selection Include patients with 10 year risk of CHD that exceeds 10%

where benefits outweigh the risks

• Rationale Coronary heart disease continues to be a major public

health problem Many patients are at sufficient risk of CHD to warrant ASA

treatment Global CHD risk is the appropriate determinant of the type

and intensity of intervention Professional labeling can define Moderate Risk and High

Risk populations where the benefits of treatment outweigh the risks

There is substantial underutilization of ASA in high/moderate risk patients

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Coronary Heart Disease Overview

• Leading cause of morbidity and mortality in the U.S.

• Despite previous marked reduction in mortality, recent evidence suggests no reduction in MI incidence

• Rising prevalence of CHD carries huge implications to direct and indirect costs

• The first presentation of CHD may be disabling or fatal 20 % of CHD presents as sudden death CHF is one of the only diseases with morbidity, mortality,

incidence and prevalence which has increased annually for the past 25 years

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Trends in Incidence of MI from 1970-1994 inOlmstead County, MN

50

100

150

200

250

300

350

400

450

79' 80' 81' 82' 83' 84' 85' 86' 87' 88' 89' 90 91' 92' 93' 94'

Men Women

Roger VL et al. Arch Intern Med. 2002;136:341-348.

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U.S. Heart Disease Prevalence is Projected to Double In the Next Half Century

0

5

10

15

20

25

30

1970 1980 1990 2000 2010 2020 2030 2040 2050

Number of Patients (Millions)

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

12

25

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Rationale for Primary Prevention

• Largely a preventable disease for which simple, and inexpensive options (including ASA) exist

• Use of safe and effective preventive interventions in this population will have significant public health impact

• Aspirin is the most cost-effective pharmacologic option in CHD prevention

• Patients at moderate to high risk can be effectively identified using clinical judgment and risk assessment tools

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Guidelines for Risk Assessment

• AHA (2002) and USPSTF (2002) have adopted clinical guidelines encouraging CHD risk assessment and, in patients at Moderate or High Risk, intervention with aspirin Adults 40 years should have an absolute coronary risk

calculated (AHA guidelines) Guidelines for management are based on absolute risk

Serum lipids (NCEP - ATP III) Aspirin (USPSTF, AHA)

Circulation 2002;106:388-391

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Global Risk Assessment (40 years +)

• Every five years; or more often, especially if 2+ risk factors

• Uses Framingham risk equations

• Uses age, sex, smoking status, systolic BP, total cholesterol, HDL cholesterol

• Diabetes is a CHD risk equivalent

• Calculates 10 year risk of MI or CHD death

• Risk calculator available on NCEP or AHA websites, palm-held devices, color-coded tables, scoring sheets

20

What is This Patient’s Global Risk?

Risk Factor Scenario

Sex Male

Age 52

Smoking Yes

SBP (mmHg) 148

Total Cholesterol (mg/dL) 220

HDL Cholesterol (mg/dL) 38

10 Year Risk of CHD 30%

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Global Risk Labeling Benefits

• Benefits of Risk Assessment-Based Labeling Providers

Tailor individual treatment decisions based on risk (intervention and intensity)

Choose cost effective therapies Patients

Actively involve patient in risk intervention Motivate to comply with non-pharmacologic and

pharmacologic therapies

22

Aspirin and MI Prevention

• Large database supports safety and efficacy of aspirin in secondary prevention of cardiovascular disease

• AHA/ACC secondary prevention guidelines recommend ASA in patients with established cardiovascular disease

• Current FDA approval to reduce risk of MI in patients with history of MI, stroke, angina, PTCA/CABG procedures (risk 20%)

• ADA guidelines (1997) recommend use of aspirin for primary prevention of heart disease in diabetics

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Primary Prevention: Individual Studies

• Robust and clinically informative database 5 trials involving over 55,000 subjects

• High compliance and follow-up

• Diverse patient populations Range of baseline global risks Geographical diversity

• Number of doses, formulations, and primary endpoints

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Primary Prevention: Individual Study Findings

• Five studies provide clinically meaningful data for efficacy and safety Two trials stopped early because of evidence for

aspirin effectiveness (PHS, PPP) Findings consistent in four of five studies

Findings have been used in meta-analysis to more precisely estimate benefit and risk

• Findings consistent with secondary prevention trials

• AHA (2002) and USPSTF (2002) encourage use in moderate risk patients based on these findings

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Benefit Risk Evaluation

• Estimates of benefits and harm of aspirin given for 5 years to 1,000 persons with various levels of baseline risk for coronary heart disease*

*U.S. Preventive Services Task Force. Ann Intern Med 2002;136:157-160 (modified).

Benefits and Harms Baseline Risk for CHD over 10 Years

2% 6% 10%

Total mortality No effect No effect No effect

Coronary heart disease 1-4 avoided 4-12 avoided 6-20 avoided events, n

Hemorrhagic strokes, n 0-2 caused 0-2 caused 0-2 caused

Major gastrointestinal 2-4 caused 2-4 caused 2-4 caused bleeding events, n

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Coronary Heart Disease Risk Continuum

# o

f M

Is P

reve

nte

d(P

er 1

000

pat

ient

s tr

eate

d fo

r 10

ye

ars)

Risk of MI or CHD Death (10 year)

Low Risk Moderate Risk High Risk

10% 20%

• Three risk groups can be identified with a global risk score: low, moderate, high

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• Benefits of intervention accrue to those at greatest underlying risk

# o

f M

Is P

reve

nte

d(P

er 1

000

pat

ient

s tr

eate

d fo

r 10

ye

ars)



10% 20%

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• Because relative risk reductions (25%) are the same, appropriate to extrapolate benefit across continuum


# o

f M

Is P

reve

nte

d(P

er 1

000

pat

ient

s tr

eate

d fo

r 10

ye

ars)



HOT

PHS

BDT

PPP

TPT

Angina

REVASC. (CABG, PTCA)

2 Prevention

10% 20%

12

4

25

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• Adverse event rate remains constant across underlying risk strata

# o

f M

Is P

reve

nte

d(P

er 1

000

pat

ient

s tr

eate

d fo

r 10

ye

ars)



10% 20%

Adverse Event rate

12

4

25

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• ASA should be indicated for all populations where benefits outweigh the risks (including moderate risk)

# o

f M

Is P

reve

nte

d(P

er 1

000

pat

ient

s tr

eate

d fo

r 10

ye

ars)



HOT

PHS

PPP

TPT

Angina

REVASC.(CABG, PTCA)

2 Prevention

10% 20%

AdverseEvent rate

12

4

12

4

25

BDT

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Extrapolation to Broader Population

• Statistically significant benefit in preventing MI among the trials conducted in secondary and primary prevention

• Homogeneity of Relative Risk Reductions for CHD across the high and low risk populations supports usefulness of aspirin therapy across risk continuum regardless of previous event

• Benefit to risk relationship is enhanced by: Limiting use to patients of at least Moderate Risk (> 10%) Excluding patients with increased risk of bleeding

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Conclusions

• Robust findings support the utility of aspirin in preventing MI across the risk continuum

• A favorable benefit to risk relationship can be demonstrated in Moderate Risk patients Approx. 6-20 MIs can be prevented for every 2-4 GI bleeds

and 0-2 hemorrhagic strokes caused Benefit even greater in higher-risk patients

• Major public health benefits can be expected from proposed label change Increase number of patients assessed for CHD risk Reduce underutilization of treatment (primary and

secondary) Reduce long-term morbidity, mortality and costs

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Evaluation of the Safety and Efficacy of Aspirin by Global Risk of CHD

Dr. Colin BaigentAntithrombotic Trialists’ (ATT) CollaborationUniversity of Oxford, UK

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Presentation Overview

• ATT collaboration, history and objectives Rationale and definitions

• Antiplatelet therapy in HIGH-RISK patients Clear benefits in a wide range of patients

• Identification of MODERATE RISK patients who may benefit from aspirin Assessment of benefits Assessment of bleeding risks

• Conclusions

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Pre-defined ATT outcomes

• ATT outcomes defined in mid 1980s, before most studies had started

• Primary outcome: “Serious Vascular Event” Non-fatal MI OR Non-fatal stroke OR Vascular death

• Secondary outcomes Non-fatal MI, Non-fatal MI or CHD death Stroke (non-fatal, fatal) Death (vascular, non-vascular) Major extracranial bleeding

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ATT Collaboration: 2 sources of evidence

• Effects of antiplatelet therapy among HIGH-RISK patients (BMJ 2002; 324:71-86) One quarter reduction in serious vascular events among

a wide range of HIGH-RISK patients Benefits clearly outweigh bleeding risks Benefits similar irrespective of age, gender, blood

pressure, and presence of diabetes

• Effects of aspirin among MODERATE-RISK individuals in 5 “primary prevention” trials Aim was to assess whether “moderate-risk” individuals

benefit from aspirin Collaboration of study investigators Based on individual patient data Manuscript in preparation

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HIGH-RISK patients

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Benefit per 1000(SE):

A13.5%

A10.4%

A17.8%

A8.1%

C21.4%

C14.2%

C17.0%

C9.0%

C10.2%

0%

10%

20%

Prior MI Acute MI Priorstroke/TIA

Acutestroke

Other highrisk

CATEGORY

A = Antiplatelet therapy

C = Control

Average duration: 27 m

36(5)

1.3 m38(5)

29 m36(6)

0.7 m9(3)

22 m22(3)

Antithrombotic Trialists’ Collaboration, 2002

P-value: <0.00001 <0.00001 <0.00001 0.002 <0.00001

A8.0%

Absolute effects on vascular events in various high-risk groupsR

AT

E

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Antiplatelet Therapy among HIGH-RISK Patients

By GENDER

37 (4) per 1000reduction


02468101214161820

Male Female

Gender

% o

f p

atie

nts

40

0

5

10

15

20

25

<65 65+

Age

% o

f p

atie

nts


By AGE



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By BP



0

5

10

15

20

25

<90 90+

Diastolic Blood Pressure

% o

f p

atie

nts

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0

5

10

15

20

25

No Yes

Diabetes

% o

f p

atie

nts


By DIABETES Status



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Extracranial Bleeding: HIGH-RISK Patients

• 1.6-fold increase in risk of extra cranial bleeds

• Absolute excess risk ~1 per 1000 per year

• Consistent across different high-risk groups

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MODERATE-RISK patients

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Characteristics of “Primary Prevention” Trials

BDS

(1988)

PHS

(1989)

TPT

(1998)

HOT

(1998)

PPP

(2001)

N 5139 22071 5085 18970 4495

Duration (yrs) 6 5 7 4 4

ASA dose (mg/day) 500 325* 75 75 100

Placebo control N Y Y Y N

Age (mean) 61 53 57 61 64

Women - - - 47% 57%

Prior vascular disease 8% 1% <1% 3% 4%

Diabetes 2% 2% 2% 8% 17%

*Alternate day aspirin

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ATT Analysis of Primary Prevention Trials

• Individual patient data 5 trials involving over 55,000 subjects Extensive checking and validation of data

• Diverse patient populations Around one fifth of individuals at MODERATE-RISK

• Outcomes pre-defined by ATT Silent MI specifically excluded

• Pre-specified comparisons with post-MI and post-TIA patients

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ATT: Effects on VASCULAR EVENTS

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ATT: Effects on CHD EVENTS

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ATT: Effects on NON-FATAL MI

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ATT: Effects on STROKE

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ATT: Effects on HEMORRHAGIC STROKE

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ATT: Effects on VASCULAR DEATH

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ATT: Effects on MAJOR EXTRACRANIAL BLEEDS

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Benefit and Risk of Aspirin

In Primary & Secondary Prevention

Outcome Primary Prevention Secondary Prevention

Non-fatal MI 1/3 reduction 1/3 reduction

Any stroke NS 1/5 reduction

Vascular death NS 1/10 reduction

Major bleeds 2/3 increase 2/3 increase

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Absolute Benefits of Aspirin on CHD EVENTS

In Primary and Secondary Prevention

0

1

2

3

4

5

6

Primary prevention

Secondary prevention

<10%* 10-20% >20%

Benefit per 1000 patientstreated per year

1 3 6

*10 year baseline risk

Eve

nts

Pre

ven

ted

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Events Avoided or Caused

Per 1000 Individuals Treated with Aspirin for 5 Years

Avoided Caused

10-year risk CHD Ischemic Hemorrhagic Majorof CHD event event stroke stroke bleed

<10% 5 0 1 5

10-20% 14 0 1 5

>20% 25-50 25-50 1 5

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Conclusions

• High-Risk Benefits clearly outweigh bleeding risks and use should be

encouraged regardless of history of previous event

• Moderate Risk Benefits sufficiently outweigh risks among moderate-risk

individuals (10-20% ten year risk) to warrant treatment Substantial public health benefit if aspirin extended to

moderate-risk individuals

• Low Risk Aspirin use is not appropriate if ten year CHD risk is less

than 10%

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Women, Coronary Heart Disease (CHD) &the Role of Aspirin in Primary Prevention

C. Noel Bairey Merz, M.D.Medical Director and Endowed Chair,Women’s Health and Preventive CardiologyCedars-Sinai Medical CenterScientific Chair, NHLBI-sponsored WISE StudyLos Angeles, CA

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Magnitude and Significance of the Problem• Since 1984, more women than men die annually of CHD

This will worsen with the continued aging of the U.S. population

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Current Status of Primary Prevention in Women

1 http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5106a3.htm , updated 06-15-02; 2 Eaker ED, et al., Circulation. Vol.88,No.4, Part 1, October 1993. 1999-2009; 3 The Women’s Health Book, Third Ed, 2002; 4 Elrodt G, et al. AHA Get with the Guidelines. Circulation 2003;108:IV-446

• Women are more likely to die of sudden death prior to hospital arrival (52%), compared with 42% for men1, and account for a disproportionate share of cardiovascular healthcare costs2

• 50% of women greater than 55 years old have serum cholesterol levels that are high risk ( 240 mg/dL); 1/3 of women in this group have a global CHD risk score of greater than 6%2

• Women see primary care physicians more often than men for both routine and symptom-related care, and are more compliant with preventive healthcare recommendations.3

• Yet, women are less likely to receive appropriate preventive care, including aspirin therapy, when indicated4

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Efficacy of Low Dose Aspirin in Women

• Issues to Consider in Evaluating the Data:• “Special Population” treatment where women are

considered a minority subgroup, despite comprising the majority of both the general and CHD populations

• “Pedestal Treatment” for women where risk avoidance is factored relatively higher, shifting the perceived risk/benefit ratio such that effective treatments are less utilized

• No significant differences in magnitude of risk or benefit between women and men in either the primary or secondary prevention aspirin trials that included women

• No biological basis for a gender difference in aspirin benefit or risk

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Women, CHD & the Role of Aspirin in Primary Prevention

• Conclusions The aging of America necessitates a focus on the

majority (women) for CHD prevention - not just politically correct

Risk stratification exists, women are amenable to preventive practices, yet therapies are underutilized compared to men

Similar favorable risk/benefit ratios for women and men for ASA as primary prevention

Opportunity exists today to close the evidence-based/practice gap, as well as to rectify “special population” and “pedestal” treatment for the largest group afflicted by CHD - women

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Enhancing Appropriate Aspirin Utilization with CHD Risk-Based Therapy

Randall S. Stafford, MD, PhDAssistant Professor of MedicineProgram on Prevention Outcomes and Practices,Stanford Prevention Research CenterStanford, CA

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Presentation Overview

• Rationale and Methods for Examining Aspirin Utilization

• Aspirin Use in Low, Moderate and High Risk Groups Disparities in Aspirin Use Explanation for Suboptimal Use Strategies for Enhancing Appropriate Utilization

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Rationale for Study

• Concept of global risk implies that a continuum of risk exists that can be used to tailor intensity of management Patients at higher global risk should be treated more

aggressively across multiple risk reduction strategies

• Aspirin’s role in secondary prevention is well-established, but also of benefit in moderate risk patients without known CVD event Need to solidify physician recognition of risk stratification

as a key tool in disease management

• Little is known about current physician aspirin utilization practices

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Specific Project Aims

• Evaluate 1992-2001 trends in aspirin use by cardiovascular disease risk status, focusing on moderate risk patients

• Identify patient and physician characteristics associated with aspirin use

67

Data Sources

• Federally-Conducted National Care Surveys Private physician offices (NAMCS) and hospital

OPD (NHAMCS) Patient visits as the unit of analysis Annual samples of 45-50,000 visits

• Visit-Specific Information About: Patient demographics and diagnoses Physician activities (tests, advice, referrals) New or continuing medications

• Validated against other national data sources

• Limitations

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Definition of Cardiovascular Risk

• High Risk : Existing coronary heart disease or other clinical forms of

atherosclerosis (5% of total annual visits)

• Moderate risk : Diabetes mellitus (5%)

> 2 CHD risk factors among men < 45 and women < 55 or > 1 risk factors among men > 45 and women > 55 (15%)

• Low risk : (75%)

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The Likelihood of Aspirin Use by Cardiovascular Risk

0%

10%

20%

30%

40%

50%

1992-93 1994-95 1996-97 1998-99 2000-01

Low Moderate Diabetes High

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% Aspirin Use among Visits with Statins

by Cardiovascular Risk

0%

10%

20%

30%

40%

50%

1992-93 1994-95 1996-97 1998-99 2000-01

Moderate High

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Factors Independently Associated with Aspirin Use

Significant Factors Odds Ratios

Cardiovascular Risk (ref: Low) Multiple risk factors 2.2 (1.7 3.0) Diabetes 3.3 (1.8 5.9) High 9.0 (6.4 12.7)

Patient Age (years) (ref: 20-44) 45-64 1.9 (1.4 2.7) 65-79 2.5 (1.8 3.6) 80 3.2 (2.1 5.0)

72

Factors Independently Associated with Aspirin Use

Significant Factors Odds Ratios

Patient Sex (ref: Male) Female 0.8 (0.7 0.9)

Medical Insurance (ref: Private) Medicare 1.2 (1.0 1.5) Medicaid 1.1 (0.9 1.5) Self-Pay 0.6 (0.4 1.0) Other 0.9 (0.6 1.4)

Physician Specialty (ref: Cardiology) IM 0.3 (0.2 0.5) GP/FP 0.2 (0.1 0.4) Other 0.2 (0.1 0.2)

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Summary of Study Findings

• Aspirin is dramatically underused in the prevention of CHD in appropriate patients Minimal inappropriate use in low risk patients

• The extent of underutilization has improved only modestly in the past decade in spite of evidence

• Greater aspirin use was independently associated with higher cardiovascular risk, advanced age, male gender, health insurance coverage, and cardiologist care

74

Limitations

• Possible under-reporting of aspirin use

• While not perfect, best data available shows that aspirin is underused

75

What Causes Suboptimal Use Aspirin Use?

• Lack of knowledge about existing evidence

• Lack of incentives and/or accountability for evidence-based practice

• Patients and physicians focus on acute issues

• Balancing costs, risks and benefits not always straightforward

• Aspirin is not labeled for primary prevention despite available evidence of its benefits

76

How to Improve Appropriate Aspirin Use?

• Unambiguous aspirin labeling supporting appropriate use Expanded labeling to include intermediate-risk patients

• Physician and patient education and encouragement Better incentives for attaining recommended practices

• Employ case management to manage chronic issues and improve patient adherence

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Aspirin in Primary Prevention For Risk

Eric J. Topol, MDProvost and Chief Academic Officer, Cleveland Clinic

Chairman, Department of Cardiovascular Medicine

Professor of Medicine and Genetics

78

The Body of Data

• 55,580 patients from 5 RCTs

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The Body of Data


• Diverse populations at risk is a major strength

80

The Body of Data



• Unequivocal (>30%) of MI endpoint

81

The Body of Data



• Unequivocal (>30%) of MI endpoint

• Post-hoc subgroup analysis is counter-productive

82

Professional Societies and Groups Supporting

• American Heart Association

• American College of Cardiology

• American Diabetes Association

• US Preventive Services Task Force

• Antithrombotic Trialists’ Collaboration

83

“Real World” Issues

• Empowered American consumers already accept low dose ASA for prevention

• > 20 Million Americans currently take ASA for prevention of MI

• Inconsistent message - Physician experts to lay community via Good Housekeeping, Reader’s Digest, Prevention, Ladies Home Journal, etc.

84

Acute MI in 2003 and the Future

• The pathophysiology involves platelet-thrombus as the proximate cause

• No sig. reduction in mortality in the past 10 yrs despite multiple treatments assessed in RCTs

• Once the MI has initiated, bad outcomes result

• The only meaningful strategy is to prevent the events

85

Who Should Be Recommended to Take Aspirin?

• Risk of > 0.6% per year recommended by USPSTF,

• Risk of > 1% per year recommended by AHA, ACC [35% reduction NFMI, 3/1000 /yr]

• Risk of > 2% per year has a striking benefit/risk ratio [43% reduction NFMI, 6/1000 /yr]

86

The Trade-Off Continues to Get Better

• Overriding MI vs. GI Bleeding events, which are not

• Preservation of efficacy for ASA at doses as low as 75 - 81 mg

• Less than half bleeding events encountered at low dose ASA (BRAVO, CURE)

87

Anchoring Issues for Primary Prevention

• The most important direction in the future of medicine

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• Ongoing large RCTs are assessing therapies in addition to ASA---the “runaway” concept

89



• Ongoing large RCTs are assessing therapies in addition to ASA---the “runaway” concept

• ASA is the cornerstone of prevention of MI—not just 2° !

1 Cardiovascular & Renal Drugs Advisory Committee Meeting Presentation.

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Transcript of 1 Cardiovascular & Renal Drugs Advisory Committee Meeting Presentation.