Cardiovascular

1
Cardiovascular Renal Drugs Advisory Committee
Meeting

• Presentation

2
Bayer HealthCares Citizen Petition for Expanded
Aspirin Professional Labeling to Include Moderate
Risk Patients
Erica Peitler, RPh Sr. VP Global Strategic
Initiatives Bayer HealthCare LLC Morristown, New
Jersey
3
Key Points

• Consensus that ASA prevents MI

4
Key Points

• Consensus that ASA prevents MI
• ASA is cost effective, yet underutilized

5
Key Points

• Consensus that ASA prevents MI
• ASA is cost effective, yet underutilized
• Guidelines support ASA use in moderate risk

6
Key Points

• Consensus that ASA prevents MI
• ASA is cost effective, yet underutilized
• Guidelines support ASA use in moderate risk
• Expanded labeling for ASA can have significant
  public health impact

7
Key Points

• Consensus that ASA prevents MI
• ASA is cost effective, yet underutilized
• Guidelines support ASA use in moderate risk
• Expanded labeling for ASA can have significant
  public health impact
• Request FDA recognition of global risk assessment
  rather than event-based risk

8
Key Points

• Consensus that ASA prevents MI
• ASA is cost effective, yet underutilized
• Guidelines support ASA use in moderate risk
• Expanded labeling for ASA can have significant
  public health impact
• Request FDA recognition of global risk assessment
  rather than event-based risk
• Totality of evidence advances our understanding
  of appropriate patient selection

9
Key Points

• Consensus that ASA prevents MI
• ASA is cost effective, yet underutilized
• Guidelines support ASA use in moderate risk
• Expanded labeling for ASA can have significant
  public health impact
• Request FDA recognition of global risk assessment
  rather than event-based risk
• 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

10
Expert Participants

• Investigators
• J. Michael Gaziano, MD
• Tobias Kurth, MD, ScD
• Nancy 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)

• 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

11
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

12
Rationale for Expanded Aspirin Professional
Labeling to Include Moderate Risk Patients
Thomas A. Pearson, MD, MPH, PhD Albert D. Kaiser
Professor and Chair of Community Preventive
Medicine Senior Associate Dean for Clinical
Research University of Rochester School of
Medicine Rochester, New York
13
Rationale for Expanded Professional ASA
LabelingTo 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

14
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

15
(No Transcript)
16
U.S. Heart Disease Prevalence is Projected to
Double In the Next Half Century
17
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

18
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 ³ 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 2002106388-391
19
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 Patients 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
21
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

23
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

24
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

25
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

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
U.S. Preventive Services Task Force. Ann Intern
Med 2002136157-160 (modified).
26
Coronary Heart Disease Risk Continuum

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

of MIs Prevented (Per 1000 patients treated
for 10 years)
Risk of MI or CHD Death (10 year)
27
Coronary Heart Disease Risk Continuum

• Benefits of intervention accrue to those at
  greatest underlying risk

of MIs Prevented (Per 1000 patients treated
for 10 years)
Risk of MI or CHD Death (10 year)
28
Coronary Heart Disease Risk Continuum

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

of MIs Prevented (Per 1000 patients treated
for 10 years)
Risk of MI or CHD Death (10 year)
29
Coronary Heart Disease Risk Continuum

• Adverse event rate remains constant across
  underlying risk strata

of MIs Prevented (Per 1000 patients treated
for 10 years)
Risk of MI or CHD Death (10 year)
30
Coronary Heart Disease Risk Continuum

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

of MIs Prevented (Per 1000 patients treated
for 10 years)
Risk of MI or CHD Death (10 year)
31
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

32
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

33
Evaluation of the Safety and Efficacy of Aspirin
by Global Risk of CHD
Dr. Colin Baigent Antithrombotic Trialists (ATT)
Collaboration University of Oxford, UK
34
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

35
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

36
ATT Collaboration 2 sources of evidence

• Effects of antiplatelet therapy among HIGH-RISK
  patients (BMJ 2002 32471-86)
• 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

37
HIGH-RISK patients
38
Antithrombotic Trialists Collaboration, 2002
Absolute effects on vascular events in various
high-risk groups
36(5)
Benefit per 1000(SE)
38(5)
36(6)
9(3)
22(3)
Average duration
27 m
29 m
22 m
1.3 m
0.7 m
P-value



0.002

20
A Antiplatelet therapy
C Control
RATE
10
A 13.5
A 10.4
A 17.8
A 8.1
C 21.4
C 14.2
C 17.0
C 9.0
C 10.2
A 8.0
0
Acute MI
Prior
Acute
Other high
Prior MI
stroke/TIA
stroke
risk
CATEGORY
39
Antiplatelet Therapy among HIGH-RISK PatientsBy
GENDER
33 (7) per 1000 reduction
37 (4) per 1000 reduction
40
Antiplatelet Therapy among HIGH-RISK PatientsBy
AGE
45 (7) per 1000 reduction
32 (4) per 1000 reduction
41
Antiplatelet Therapy among HIGH-RISK PatientsBy
BP
41 (7) per 1000 reduction
32 (6) per 1000 reduction
42
Antiplatelet Therapy among HIGH-RISK PatientsBy
DIABETES Status
36 (3) per 1000 reduction
38 (12) per 1000 reduction
43
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

44
MODERATE-RISK patients
45
Characteristics of Primary Prevention Trials
Alternate day aspirin
46
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

47
ATT Effects on VASCULAR EVENTS
48
ATT Effects on CHD EVENTS
49
ATT Effects on NON-FATAL MI
50
ATT Effects on STROKE
51
ATT Effects on HEMORRHAGIC STROKE
52
ATT Effects on VASCULAR DEATH
53
ATT Effects on MAJOR EXTRACRANIAL BLEEDS
54
Benefit and Risk of AspirinIn 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
55
Absolute Benefits of Aspirin on CHD EVENTSIn
Primary and Secondary Prevention
Benefit per 1000 patients treated per year
3
1
6
Events Prevented
10-20
20
Secondary prevention
Primary prevention
10 year baseline risk
56
Events Avoided or Caused Per 1000 Individuals
Treated with Aspirin for 5 Years
57
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

58
Women, Coronary Heart Disease (CHD) the Role
of Aspirin in Primary Prevention

• C. Noel Bairey Merz, M.D.
• Medical Director and Endowed Chair,
• Womens Health and Preventive Cardiology
• Cedars-Sinai Medical Center
• Scientific Chair, NHLBI-sponsored
• WISE Study
• Los Angeles, CA

59
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

60
Current Status of Primary Prevention in Women

• 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 62
• 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

1 http//www.cdc.gov/mmwr/preview/mmwrhtml/mm5106a
3.htm , updated 06-15-02 2 Eaker ED, et al.,
Circulation. Vol.88,No.4, Part 1, October 1993.
1999-2009 3 The Womens Health Book, Third Ed,
2002 4 Elrodt G, et al. AHA Get with the
Guidelines. Circulation 2003108IV-446
61
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

62
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

63
Enhancing Appropriate Aspirin Utilization with
CHD Risk-Based Therapy
Randall S. Stafford, MD, PhD Assistant Professor
of Medicine Program on Prevention Outcomes and
Practices, Stanford Prevention Research
Center Stanford, CA
64
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

65
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
• Aspirins 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

66
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

68
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 55 or 1 risk factors among men 45 and women
  55 (15)
• Low risk
• (75)

69
The Likelihood of Aspirin Use by Cardiovascular
Risk
70
Aspirin Use among Visits with Statinsby
Cardiovascular Risk
71
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)
73
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

77
Aspirin in Primary Prevention For ? Risk
Eric J. Topol, MD Provost 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

79
The Body of Data

• 55,580 patients from 5 RCTs
• Diverse populations at risk is a major strength

80
The Body of Data

• 55,580 patients from 5 RCTs
• Diverse populations at risk is a major strength
• Unequivocal (30) ? of MI endpoint

81
The Body of Data

• 55,580 patients from 5 RCTs
• Diverse populations at risk is a major strength
• 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, Readers 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

88
Anchoring Issues for Primary Prevention

• The most important direction in the future of
  medicine
• Ongoing large RCTs are assessing therapies in
  addition to ASA---the runaway concept

89
Anchoring Issues for Primary Prevention

• The most important direction in the future of
  medicine
• Ongoing large RCTs are assessing therapies in
  addition to ASA---the runaway concept
• ASA is the cornerstone of prevention of MInot
  just 2 !