Transcript Dosage of enalapril for congestive heart failure in USA

Thrombolysis and the
elderly
Eugene Braunwald MD
Professor of Medicine
Harvard University
Robert Califf MD
Professor of Cardiology
Duke University
Eric Peterson MD
Associate Professor of Cardiology
Duke University
Thrombolysis and the elderly
Lack of benefit for thrombolysis in
patients > 75 years
This retrospective cohort was taken from a database
compiled by the Health Care Financing Administration
(HCFA) for the Cooperative Cardiovascular Project (CCP)
detailing a nationwide sample of elderly patients with MI.
From 210 996 original patients, a cohort of 5191 patients
aged 65-75 and 2673 patients aged 76-86 was obtained.
Among exclusion criteria were the following: direct
admission to hospitals with on-site angioplasty
capabilities, inappropriate ECG criteria on presentation,
and contraindications to thrombolysis.
Thiemann DR, et al. Circulation 2000;101:2239-2246
An increase in mortality?
Observed 30-day mortality
Age 65-75
Age 76-86
without
thrombolysis
(n=1330)
with
thrombolysis
(n=3861)
without
thrombolysis
(n=1066)
with
thrombolysis
(n=1607)
Crude
9.8%
6.8%
15.4%
18.0%
Predicted*
9.6%
7.8%
15.3%
13.6%
*predicted in the absence of thrombolysis
Thiemann DR, et al. Circulation 2000;101:2239-2246
Multivariate adjustment
Adjusted hazard ratios for 30-day
mortality after receiving thrombolysis
Age 65-75
(n=5113)
Age 76-86
(n=2634)
First
model
0.76 (0.61-0.95)
1.29 (1.06-1.58)
Second
model*
0.88 (0.69-1.12)
1.38 (1.12-1.71)
*second, or comprehensive model, adjusts for multiple
variables in addition to those present in the first model
Thiemann DR, et al. Circulation 2000;101:2239-2246
Increasing hazard with age
Hazard ratios for thrombolytic therapy
increase with increasing age
Age
65
74.3
80
Hazard ratio
0.60
95% CI
0.44-0.82
~ 1.00
1.36
1.13-1.64
Thiemann DR, et al. Circulation 2000;101:2239-2246
Thrombolysis and the elderly
Observational studies
This study is observational in nature, and not a
substitute for a randomized, controlled, clinical trial.
In observational studies it is difficult to adjust for all
possible variables and to control bias.
Observational studies are, when well designed, able to
raise and highlight important questions.
The safety and efficacy of thrombolytics in an older
population (76-86 years old) is indeed an important
question.
Thiemann DR, et al. Circulation 2000;101:2239-2246
Thrombolysis and the elderly
Observation vs randomization
Real-world experiences (observational studies) often tell
us things that a randomized clinical trial cannot.
However, real world experiences can't compare
treatments in high risk groups of patients where
treatment selection is based on major prognostic
factors that are difficult to quantify.
One concern is that such observational studies may
impact clinical practice “beyond reasonableness”.
In the world's compilation of placebo vs active
treatment there is a trend toward benefit for those > 75
(approximately 2000 patients ).
Thrombolysis and the elderly
Need for additional studies?
An observational study is notable because of the lack of
information in > 75 age group in prior randomized
trials.
Although a trend toward benefit exists in those > 75
under active treatment (world data), this trend is a lot
less than that seen in younger age groups.
Earlier thrombolytic trials used different agents than
those studied today.
In performing a randomized controlled trial, sufficient
numbers of patients of age greater than 75 need to be
enrolled.
The role of observation
“If you think about how we accumulate
medical evidence, we first make an
observation…from that observation you set
up a design to study a large number of
patients prospectively. Sometimes the first
observation that you’ve made bears out in a
trial, and at other times it does not.”
Dr Eugene Braunwald
Professor of Medicine
Harvard University
The role of databases
Approach databases in a manner similar to that for the
unusual or interesting patient. You may not be able to
draw many conclusions, but you may glean some hints.
eg, analysis of the database for
patients with rheumatoid arthritis
revealed that patients on ASA had a
lower incidence of death from MI
large number of ASA trials in MI
prevention and treatment
ASA accepted in MI management
The ideal patient
Placebo controlled trials can no longer be performed
with patients who are otherwise ideal candidates for
thrombolytic therapy.
Ideal thrombolysis candidate
50 years old
marked ST elevation
45 min crushing chest pain
no contraindications to lysis
Thrombolysis and the elderly
CCP database
Characteristics of the CCP database:
comorbidity
some functional status data
dementia variables
Variables often provided as yes/no.
Subtleties are not available in any database, hence
unmeasured confounding is possible.
SHOCK trial
Methodology
Patients with MI and left ventricular failure were
randomized to emergency revascularization (n=152) or
initial medical stabilization (n=150).
Revascularization was defined as either coronary artery
bypass grafting or coronary angioplasty.
The primary endpoint was all-cause 30-day mortality.
All-cause 6-month mortality and additional subgroup
analyses were investigated.
Mean age of the patients was 66 + 10 years and 32%
were women.
Hochman JS, et al. New Engl J Med 1999;341:625-634
SHOCK trial
Results
Overall mortality (%)
Revascularization
n=152
Medical therapy
n=150
Relative risk
(95% CI)
30-day
46.7
56.0
0.83 (0.67-1.04)
6-month
50.3
63.1
0.80 (0.65-0.98)
Mortality in age group > 75 (%)
Revascularization
n=24
Medical therapy
n=32
p-value
30-day
75.0
53.1
1.41 (0.95-2.11)
6-month
79.2
56.3
1.41 (0.97-2.03)
Hochman JS, et al. New Engl J Med 1999;341:625-634
GUSTO-I trial data
Outcomes in the elderly
Analysis of the GUSTO-I trial data revealed that 30-day
mortality increased markedly with age:
<65
65 to 74
75 to 85
>85
n=24 708
n=11 201
n=4625
n=412
3.0%
9.5%
19.6%
30.3%
30-day
mortality
Combined death or disabling stroke appeared to occur
less often with TPA than with streptokinase in all but the
oldest patients who demonstrated a weak trend
suggesting a lower incidence with streptokinase and s/c
heparin: odds ratio 1.13; 95% CI 0.6, 2.1.
White HD, et al. Circulation 1996;94:1826-1833
Clinical trials in the elderly
Importance in health policy
The need for ongoing clinical trials in the elderly is
apparent, especially given the aging of the baby-boomer
population.
Although current evidence supports the idea of giving
thrombolysis, specific trials in this age group become
ethical and very important.
The role of percutaneous intervention is also at issue.
Patients > 75 make up 1/3 of all patients with MI, but
over 1/2 of all deaths.
Clinical trials in the elderly
Early hazard with thrombolytics
30-day mortality data in a thrombolytic trial of the
elderly may reflect an early hazard due to an increase in
both intracranial hemorrhage and cardiac rupture.
Benefit might therefore not be seen for 6-12 months.
Clinical trials in the elderly
General implications
The establishment of randomized controlled trials in
thrombolysis might aid in informing the medical
community that the elderly are being undertreated.
Practicing physicians should STOP undertreating the
elderly, and SHOULD continue to look for opportunities
to participate in clinical trials.