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The Value of Observational Research A Case Study Approach. Hal V. Barron, MD. Review what we can learn from observational data Examine associations and attempt to speculate on causality when RCTs are not feasible when RCTs are unethical (Does smoking really cause cancer?)

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Overview

Review what we can learn from observational data

Examine associations and attempt to speculate on causality when RCTs are not feasible

when RCTs are unethical (Does smoking really cause cancer?)

when the sample size needed for a RCT is prohibitive

Examine associations for hypothesis generation

Describe what is happening in the “real world”

Safety surveillance : Identification of rare events or subgroup analysis

Drug utilization patterns

Natural history of disease

Efficacy vs Effectiveness

Overview


Examine associations and attempt to speculate on causality when rcts are not feasible

Studies have demonstrated the importance of establishing and maintaining a patent infarct related artery in the setting of acute myocardial infarction (AMI) complicated by cardiogenic shock.

The purpose of the present study was to determine whether the use of Intra-aortic baloon pumping (IABP) is associated with a survival advantage in patients with AMI complicated by cardiogenic shock.

Why not do a RCT???

Examine associations and attempt to speculate on causality when RCTs are not feasible


National registry of myocardial infarction nrmi iabp use and outcome

Using data from the National Registry of Myocardial Infarction 2 (NRMI 2), we evaluated 23,180 patients who presented with or developed cardiogenic shock during the hospitalization.

National Registry of Myocardial Infarction (NRMI) : IABP Use and Outcome


Nrmi iabp use and outcome
NRMI : IABP Use and Outcome Infarction 2 (NRMI 2), we evaluated 23,180 patients who presented with or developed cardiogenic shock during the hospitalization.


Overview1

Review what we can learn from observational data Infarction 2 (NRMI 2), we evaluated 23,180 patients who presented with or developed cardiogenic shock during the hospitalization.

Examine associations and attempt to speculate on causality when RCTs are not feasible

when RCTs are unethical (Does smoking really cause cancer?)

when the sample size needed for a RCT is prohibitive

Examine associations for hypothesis generation

Describe what is happening in the “real world”

Safety surveillance : Identification of rare events or subgroup analysis

Drug utilization patterns

Natural history of disease

Efficacy vs Effectiveness

Overview


Data from the TIMI 2 Study Infarction 2 (NRMI 2), we evaluated 23,180 patients who presented with or developed cardiogenic shock during the hospitalization.


Examine associations and attempt to speculate on causality when rcts are not feasible1

Do beta-blockers reduce intra-cranial hemorrhage ICH rates when given immediately following tPA for AMI

Does this meet the FINER criteria?

What is the rate of ICH following tPA?

Is a 30% reduction meaningful?

What size trial would need to be conducted?

Examine associations and attempt to speculate on causality when RCTs are not feasible


Nrmi bb use and ich
NRMI: BB Use and ICH when given immediately following tPA for AMI

Unadjusted ICH Rate (%)

AGE


Nrmi bb use and ich1
NRMI: BB Use and ICH when given immediately following tPA for AMI

Unadjusted ICH Rate


Nrmi and beta blocker use

Multivariate Analysis: Effect of Drug Therapy Administered Within 24 Hours on Intracranial Hemorrhage Rate

Medication Adjusted OR (95% Cl)

 blocker 0.69 (0.57-0.84)*

ACE inhibitor 0.75 (0.55-1.03)

Calcium channel antagonist 1.27 (0.98-1.64)

Lidocaine 0.93 (0.76-1.13)

Intravenous magnesium 1.05 (0.76-1.45)

Intravenous nitroglycerin 0.86 (0.69-1.09)

*p<0.001.

Cl = confidence intervals; OR = odds ratio; other abbreviation as in Table 1.

NRMI and Beta-blocker Use


Overview2

Review what we can learn from observational data Within 24 Hours on Intracranial Hemorrhage Rate

Examine associations and attempt to speculate on causality when RCTs are not feasible

unethical studies

sample size is prohibitive

Examine associations for hypothesis generation

Describe what is happening in the “real world”

Safety surveillance : Identification of rare events or subgroup analysis

Drug utilization patterns

Natural history of disease

Efficacy vs Effectiveness

Overview


Immunological mechanisms involved in allergic disease
Immunological Mechanisms Involved in Allergic Disease Within 24 Hours on Intracranial Hemorrhage Rate

Sensitization

Re-Exposure

Allergen

Allergen

Environment

Submucosa

Antigen- Presenting Cell

Productionof Antigen-

Specific IgE

MHC Class II Protein and Epitope

ClinicalEffects

Mast Cell

Degranulation

Asthma, Rhinitis, Urticaria

+

Th2-Cell

B-Cell

Mediators


Ige and asthma relationship in adults
IgE and Asthma Within 24 Hours on Intracranial Hemorrhage RateRelationship in Adults

40

N = 2657

20

Asthma

10

Odds ratio

5

2.5

Rhinitis

1

0.32

1

3.2

10

32

100

320

1000

3200

Serum IgE (IU/mL)

Burrows B, et al. N Engl J Med. 1989;320:271–277.


Patients with 1 significant asthma exacerbations

Omalizumab Within 24 Hours on Intracranial Hemorrhage Rate

Placebo

Patients With  1 Significant Asthma Exacerbations

37%

 58%

30%

40

P = .009

P < .001

P = .095

30.5

30

23.3

23.0

Patients, %

20

16.0

14.6

12.8

10

n =268 257 274 272 225 109

0

US (008)

International (009)

Pediatric (010)

Distribution of AEEs per patient

P = .006

P < .001

P = .093

Significant asthma exacerbation = episode requiring course of oral CS or doubling dose of ICS


Background: Within 24 Hours on Intracranial Hemorrhage RatePatients with elevated white blood cell (WBC) counts during acute myocardial infarction (AMI) have a higher risk of adverse outcomes.

Objectives: The goal of this study was to determine the relationship between the WBC count and angiographic characteristics to gain insight into this pathophysiology of this clinical observation.

Methods: Angiographic and clinical data from 936 patients in the TIMI 10A and TIMI 10B trials was used to evaluate these relationships

The Association Between White Blood Cell Count, Epicardial Blood Flow, Myocardial Perfusion, and Clinical Outcomes in the Setting of Acute Myocardial InfarctionHal V. Barron, M.D.; Christopher P. Cannon, M.D.; Sabina A. Murphy, M.P.H.; Susan J. Marble, M.S., R.N.; Eugene Braunwald, M.D.; and C. Michael Gibson, M.S., M.D.; for the TIMI 10 Study Group


Preventing diseases of the endothelium the role of the integrins
Preventing “Diseases” of The Endothelium: Within 24 Hours on Intracranial Hemorrhage RateThe Role Of The Integrins


Results Within 24 Hours on Intracranial Hemorrhage Rate: The development of new congestive heart failure was associated with significantly higher WBC counts (13.3  8.9, n=64 vs 10.8  3.5, p<0.0001), an observation which remained significant in a multivariable model adjusting for all potential confounding variables (O.R. 1.2 per 1 unit increase in WBC count, p<0.001).


Overview3

Review what we can learn from observational data Within 24 Hours on Intracranial Hemorrhage Rate

Examine associations and attempt to speculate on causality when RCTs are not feasible

unethical studies

sample size is prohibitive

Examine associations for hypothesis generation

Describe what is happening in the “real world”

Safety surveillance : Identification of rare events or subgroup analysis

Drug utilization patterns

Natural history of disease

Efficacy vs Effectiveness

Overview


Ich risk following t pa nrmi 2
ICH Risk following t-PA:NRMI 2 Within 24 Hours on Intracranial Hemorrhage Rate

Gurwitz et al. 1998 Annals Int Med. 129; 597-604.


All patients in nrmi 2
All Patients in NRMI 2 Within 24 Hours on Intracranial Hemorrhage Rate


Background

Initial reperfusion therapy (IRT) is beneficial for patients with acute myocardial infarction (AMI)

A minority of patients with AMI receive IRT

Underutilization could be related to:

the absence of clear indications

perceived contraindications

physicians’ reluctance to prescribe IRT

Background


Hypothesis

To determine what percent of patients identified as having with acute myocardial infarction (AMI)clear indications for initial reperfusion therapy (IRT) do not receive this life-saving therapy

To identify patient subgroups who are at greatest risk for not receiving IRT

Hypothesis


Methods study population
Methods - with acute myocardial infarction (AMI)Study Population

SymptomsHosp <6 hrs

ST Segment or LBBB

Contraindications to thrombolytic Rx

No IRT

N=20,319

IRT

N=64,344


Reperfusion Therapy with acute myocardial infarction (AMI)

LBBB

No CP

Age > 75

Prior CHF

Prior MI

Prior Stroke

Killip 3#

Killip 2#

Prior Angina

Diabetes

Female

Prior Revasc.

Anterior MI*

Prior HTN

Caucasian

Current Smoker

Prehospital ECG

Sx < 3 hrs.

Less Likely More Likely

0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8


Underutilizing of irt in high risk patients
Underutilizing of IRT In High Risk Patients with acute myocardial infarction (AMI)


At least 31% of patients presenting with AMI are appropriate for IRT

1 in 4 patients appropriate for IRT do not receive this life-saving therapy

The underutilization is particularly evident in the elderly, women and other patients at increased risk for in-hospital mortality

Conclusions


Overview4

Review what we can learn from observational data for IRT

Examine associations and attempt to speculate on causality when RCTs are not feasible

when RCTs are unethical (Does smoking really cause cancer?)

when the sample size needed for a RCT is prohibitive

Examine associations for hypothesis generation

Describe what is happening in the “real world”

Safety surveillance : Identification of rare events or subgroup analysis

Drug utilization patterns

Natural history of disease

Efficacy vs Effectiveness

Overview



Data Source after MI is higher in women than in men after adjusting for age and other prognostic factors

Second National Registry of Myocardial Infarction (NRMI-2)

1,658 participating U.S. hospitals

N=691,995 MI patients enrolled up to 1/31/98

Methods of Analysis :Multiple logistic regression with hospital death as outcome

Traditional analysis approach: main effect of female sex after adjusting for age

Test for sex-age interaction

Sequential adjustment for other covariables

  • Specific Aims

    • To test the following hypotheses:

      1. the mortality of women relative to men is not constant across ages

      2. the younger the age of the patients, the higher the risk of death in women relative to men

    • To identify factors that may account for the higher mortality rates of women compared with men


Results selected patient characteristics by sex

Women after MI is higher in women than in men after adjusting for age and other prognostic factorsMen

Mean age 72 66

History of MI (%) 24 28

History of CHF (%) 21 13

History of HTN (%) 59 47

History of diabetes (%) 33 25

Chest pain (%) 63 72

ST elevation (%) 38 42

CHF or cardiog. shock (%) 27 19

Hospital mortality (%) 17 11

RESULTSSelected Patient Characteristics by Sex


Overall effect of female sex on mortality traditional approach

OR of Mortality after MI is higher in women than in men after adjusting for age and other prognostic factors

Women Vs. Men (95% CI)

Unadjusted 1.54 (1.51-1.57)

Age adjusted 1.14 (1.12-1.17)

Overall Effect of Female Sex on Mortality (traditional approach)


History of diabetes
History of Diabetes after MI is higher in women than in men after adjusting for age and other prognostic factors


Presentation after 6 hrs from symptom onset
Presentation After 6 hrs from Symptom Onset after MI is higher in women than in men after adjusting for age and other prognostic factors


Hypotension on admission
Hypotension on Admission after MI is higher in women than in men after adjusting for age and other prognostic factors


Factors disproportionately more common in women at younger ages

Demographic factors after MI is higher in women than in men after adjusting for age and other prognostic factors

Non-White race

Medicaid insurance

Medical history

Hx of CHF

Hx of diabetes

Hx of stroke

Admission data

Delay to presentation >6 hrs

No ST elevation

CHF, pulmonary edema

Hypotension or cardiogenic shock

Treatments

No coronary reperfusion therapy

No use of IV beta-blockers

Factors Disproportionately more Common in Women at Younger Ages


Hospital mortality rates by sex and age unadjusted
Hospital Mortality Rates by Sex and Age after MI is higher in women than in men after adjusting for age and other prognostic factors(Unadjusted)

Sex-Age Interaction: P<0.001


Effect of female sex on mortality by age unadjusted
Effect of Female Sex on Mortality by Age after MI is higher in women than in men after adjusting for age and other prognostic factors(Unadjusted)

30 35 40 45 50 55 60 65 70 75 80 85 90

Age


Impact of overall adjustment
Impact of Overall Adjustment after MI is higher in women than in men after adjusting for age and other prognostic factors

Unadjusted

OR (Women Vs. Men)

Adjusted

30 35 40 45 50 55 60 65 70 75 80 85 90

Age


Summary / Conclusions after MI is higher in women than in men after adjusting for age and other prognostic factors

  • A higher risk of death in women relative to men is seen in the younger age groups only

  • There is a linear increase of risk for women relative to men going from older to younger age

  • The younger the patients’ age, the higher the risk of death of women relative to men

  • Adjustment for covariables explains only 1/3 of the higher mortality risk for women at younger ages


Overview5

Review what we can learn from observational data after MI is higher in women than in men after adjusting for age and other prognostic factors

Examine associations and attempt to speculate on causality when RCTs are not feasible

when RCTs are unethical (Does smoking really cause cancer?)

when the sample size needed for a RCT is prohibitive

Examine associations for hypothesis generation

Examine associations to identify treatment modifiers

Describe what is happening in the “real world”

Safety surveillance: Identification of rare events or subgroup analysis

Drug utilization patterns

Natural history of disease

Efficacy vs Effectiveness

Overview


Trials comparing primary ptca with fibrinolytic therapy pami cohort
Trials Comparing Primary PTCA With Fibrinolytic Therapy: PAMI Cohort

12.0

P=0.06

P=0.02

Grines CL, et al. N Engl J Med. 1993;328:673-679.


Trials comparing primary ptca with fibrinolytic therapy gusto iib cohort
Trials Comparing Primary PTCA With Fibrinolytic Therapy: GUSTO-IIb Cohort

Composite Outcome (%)

P=0.033

P=NS

GUSTO-IIb Angioplasty Substudy Investigators. N Engl J Med. 1997;336:1621-1628


Meta analysis of mortality benefit with primary ptca versus fibrinolytic therapy
Meta-analysis of Mortality Benefit With Primary PTCA Versus Fibrinolytic Therapy

Rate %

Study Group

Absolute Risk Reduction, %

(95% CI)

Lytic Therapy

Odds Ratio (95% CI)

PTCA

Streptokinase

4.0

5.9

0.66 (0.29 to1.50)

1.9 (-2.7 to 4.1)

3- to 4-hour t-PA

3.5

5.7

0.60 (0.24 to1.41)

2.2 (-2.2 to 4.3)

Accelerated t-PA

5.0

7.2

0.68 (0.42 to 1.08)

2.2 (-0.5 to 4.0)

Total

4.4

6.5

0.66 (0.46 to 0.94)

2.1 (0.4 to 3.4)

Weaver WD, et al. JAMA. 1997;678:2093-2098.


Trials comparing primary ptca with fibrinolytic therapy miti cohort
Trials Comparing Primary PTCA With Fibrinolytic Therapy: MITI Cohort

P=NS

0

0.5

1

1.5

2

2.5

3

3.5

4

Time After Discharge (years)

Every NR, et al. N Engl J Med.1996;335:1253-1260.


Pptca versus tpa nrmi 2

4,939 nontransfer pts underwent PPTCA within 12 hrs from Sx onset

24,705 pts received tPA

Lytic ineligable and shock pts were excluded

PPTCA versus tPA :NRMI 2


Randomized trial results versus community setting results nrmi 2 cohort
Randomized Trial Results Versus Community-Setting Results: NRMI-2 Cohort

n=2958, lytic eligible, no shock at presentation

Percent

P=NS

P=NS

Tiefenbrunn AJ, et al. J Am Coll Cardiol. 1998;31:1240-1245.


Mortality (%) NRMI-2 Cohort

Odds Ratio and 95% CI

rt-PA PTCA

Overall 5.4 5.2

STE or LBBB 1st ECG 5.3 5.5

Age < 75 yr. 3.4 3.5

Age > 75 yr. 16.5 14.4

Male 4.5 5.2

Female 9.6 8.9

Inferior MI 3.9 3.9

Anterior MI 7.6 7.1

Low Risk 2.9 2.8

Not Low Risk 7.5 7.4

0.5 1.0 1.5

rt-PA better

PTCA better


Pptca versus tpa death and nonfatal stroke
PPTCA versus tPA NRMI-2 Cohort(Death and Nonfatal Stroke)


Efficacy vs effectiveness

Why might they differ? NRMI-2 Cohort

Efficacy vs Effectiveness


Importance of door to balloon time 30 day mortality in the gusto iib cohort
Importance of Door-to-Balloon Time: NRMI-2 Cohort30-Day Mortality in the GUSTO-IIb Cohort

P=0.001

Mortality (%)

<

Door-to-Balloon Time (minutes)

Berger PB, et al. Circulation. 1999;100:14-20.


Treatment effect modifiers
Treatment effect modifiers NRMI-2 Cohort

Death during Hospitalization (%)

Hospital-specific primary angioplasty volume category

Rates of Death during Hospitalization for Myocardial Infarction among patients treated with thrombolytic therapy versus primary angioplasty. The interaction between reperfusion strategy and primary angioplasty volume was significant (p<.01).


Overview6

Review what we can learn from observational data NRMI-2 Cohort

Examine associations and attempt to speculate on causality when RCTs are not feasible

when RCTs are unethical (Does smoking really cause cancer?)

when the sample size needed for a RCT is prohibitive

Examine associations for hypothesis generation

Describe what is happening in the “real world”

Safety surveillance : Identification of rare events or subgroup analysis

Drug utilization patterns

Natural history of disease

Efficacy vs Effectiveness

Overview


Conclusions

Observational research studies can be NRMI-2 Cohortvery valuable

They provide information not obtainable from RCTs

They provide important information when RCTs are not feasible

Observational research studies can be very misleading as well

They can never really clarify causality (only associations)

Measured and especially unmeasured confounders can be a VERY BIG problem!-more to come on this

Conclusions


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