EFFECTS OF THE ANGIOTENSINRECEPTOR BLOCKER TELMISARTAN

ON CARDIOVASCULAR EVENTS IN
HIGH-RISK PATIENTS INTOLERANT TO
ANGIOTENSIN-CONVERTING ENZYME
INHIBITORS: A RANDOMIZED
CONTROLLED TRIAL
Palak Parikh
EBM
October 24, 2008

INTRODUCTION

Up to about 20% of patients are unable to

tolerate an ACE inhibitor
ARBs similar in efficacy and better tolerated than
ACE inhibitors in high-risk patients after MI, or in
those with CV disease or high-risk diabetes.
ARBs reduce mortality and rehospitalization for
heart failure, compared to placebo, in patients
intolerant to ACE inhibitors with low EF and heart
failure
ARBs reduce stroke and CV morbidity compared
with beta blockers, in those with moderate HTN
and LV hypertrophy.

Is there any benefit in using an

ARB in reducing major CV events
in broader high-risk
populations?

TRANSCEND TRIAL

Telmisartan Randomized AssessmeNt

Study in ACE iNtolerant subjects with
cardiovascular Disease
Patients intolerant to ACE inhibitors were
enrolled if they had established CAD,
PVD, CVD, or DM w/ end-organ damage.
Intolerance to ACE inhibitors defined as
previous discontinuation by a physcian
b/c of intolerance, with a specific
documented cause.

ACE INHIBITOR INTOLERANCE

Cough (88.2%)
Symptomatic Hypotension (4.1%)
Angioedema or Anaphylaxis (1.3%)
Renal Dysfunction (1.0%)
Other Reasons (8.3%)

TRIAL PROFILE

Patients enrolled between November

2001 and May 2004
Recruitment in 630 centers in 40
countries
Coordinated at Population Health
Research Institute, McMaster University,
and Hamilton Health Sciences, with suboffices at the University of Oxford and
University of Aukland.

EXCLUSION CRITERIA

Known hypersensitivity or
intolerance to ARBs
Need for or inability to
discontinue ARBS
Heart failure
Constrictive pericarditis
Complex congenital heart
disease
Planned cardiac surgery
or cardiac
revascularization w/in
previous 3 months
Significant renal artery
stenosis

Significant primary
valvular or cardiac
outflow tract obstruction
Unexplained syncope
Systolic BP > 160 mm Hg
Heart transplantation
Subarachnoid
hemorrhage
Proteinuria
Hepatic dysfunction
Cr levels > 265
micromol/L

TRIAL PROFILE
Single blind run-in involving placebo daily for 1
week followed by 2 weeks of telmisartan 80 mg.

Randomization performed by central

automated randomization system, with both
patients and trialists blinded to treatment
allocation

BASELINE CHARACTERISTICS

FOLLOW-UP VISITS/SAFETY

Follow-Up Visits

At 6 weeks
At 6 months
Then every 6 months
Median duration of
follow-up was 56
months

Independent data and

safety monitoring
board

Cardiologists
Statisticians
Clinical trial experts

Met twice yearly

Three formal interim
analyses, when 25%,
50%, and 75% of
events had accrued

DISCONTINUATION OF MEDS AND

SPECIFIC REASONS

USE OF TELMISARTAN/NON-STUDY
ARBs

Telmisartan Group

2086 (79.4%) on full dose

36 (1.4%) on reduced dose
54 (1.8%) also on non-study ARBs at 1 year
152 (5.8%) also on non-study ARBs at end of
study

Control Group

84 (2.9%) on non-study ARBs at 1 year

200 (7.6%) on non-study ARBs at end of study

OUTCOMES

Primary Outcome

Secondary Outcome

Composite of CV death, MI, stroke, or hospitalization

for HF
Composite of CV death, MI, or stroke (primary
outcome of HOPE trial)

Other Secondary Outcomes

New HF, development of DM, AFib, cognitive

decline/dementia, nephropathy, and revascularization
Total mortality, angina, TIA, development of LVH,
microvascular complications of DM, changes in BP,
changes in ankle-to-arm BP ratios, and new cancers
Composite of macrovascular and microvascular
disease used in ADVANCE trial.

PRIMARY OUTCOME DEFINITIONS

CV Death

MI

CK levels twice the normal upper limit

CK-MB above normal
Troponin T or I levels above abnormal range for lab, except after a PCI or
CABG
New Q waves (or new prominent R waves in V1 or V2)
New LBBB
Ischemic ST-T changes in ECG
Typical clinical presentation c/w MI

Stroke

Considered cause of death unless unequivocal non-CV cause established, as

most of the patients had pre-existing CV disease

New focal neurological deficits ov vascular origin w/ signs or symptoms

lasting longer than 24 hrs, or death if this occurred earlier.

Hospitalization for HF (or attendance in acute care setting)

2 of 3 criteria required

IV diuretic administration
Escalation of diuretic doses or inotropes
Radiological evidence of HF

PRIMARY OUTCOME RESULTS

Hazard Ratio ~ Ratio of experimental hazard rate over control
hazard rate over the time period of evaluation

Relative Risk = EER / CER

A relative risk of 1 means there is no difference in risk between the two groups.
A RR of < 1 means the event is less likely to occur in the experimental group than in the control group.
A RR of > 1 means the event is more likely to occur in the experimental group than in the control group.

PRIMARY ANALYSIS

Time-to-event approach, counting

the first occurrence of any
component of composite outcome.
Cox regression model used.

OTHER SECONDARY EVENTS

SUBGROUP ANALYSES

KAPLAN MEIER CURVES

PRIMARY
OUTCOME

KAPLAN-MEIER CURVE:
Used for estimating the probability of surviving a unit of time.
Used to develop a survival curve when not all survival times are exactly known.

SECONDARY
OUTCOME

COMBINED RESULTS OF
TRANSCEND AND PRoFESS TRIALS

PRoFESS Trial compared telmisartan w/ placebo over 2.5 years in pts after
a recent stroke. Trial showed that telmisartan did not significantly lower the
rate of recurrent stroke, major CV events, or DM.

ODDS RATIOS

Ratio of the odds of an event occurring in

one group (eg. experimental) to the odds
of it occurring in another group (eg.
control)
An odds ratio of 1 implies that the event is
equally likely in both groups.
An odds ratio > 1 implies that the event is
more likely in the first group.
An odds ratio < 1 implies that the event is
less likely in the first group.
a / b or
axd
Event
No Event
c/d
cxb
Experimental
a
b
Control

STUDY VALIDITY

Was the assignment of patients to

treatment randomized?

Were all the patients who entered the trial

properly accounted for at its conclusion?

Yes.

Yes.

Were patients analyzed in the groups to

which they were (originally) randomized?

Yes.

STUDY VALIDITY

Were patients, clinicians, and study personnel

blind to treatment allocation?

Were the groups similar at the start of the trial?

Yes.

Aside from the experimental intervention, were

the groups treated equally?

Yes.

Yes.

Are the results of this study valid?

Yes.

SUMMARY OF STUDY RESULTS

465 of 2944 patients from telmisartan

group experienced the primary outcome
(CV death, MI, stroke, or hospitalization
for HF) compared with 504 of 2964
patients from the placebo group.
15.7%

(telmisartan) vs 17.0% (placebo)

Hazard ratio 0.92, 95% CI 0.81 1.05,
p=0.216
NOT STATISTICALLY SIGNIFICANT

No difference in mortality between the

two groups.

SUMMARY OF RESULTS

Median BP was lower in telmisartan group than

in placebo group by:

6.2/3.6
4.7/2.4
4.2/2.3
3.2/1.3

mm
mm
mm
mm

Hg
Hg
Hg
Hg

at
at
at
at

6 weeks
1 year
2 years
study end

Mean weighted difference between groups in BP

during the study was 4.0/2.2 mm Hg.
Physicians were allowed to use any BP meds
they deemed necessary (other than
telmisartan).
BP meds (eg. diuretics and beta blockers) used
more frequently in placebo group than in
telmisartan group.

SUMMARY OF RESULTS

Adherence to telmisartan was high

and better than with placebo.
Patients with angioedema and other
side-effects (eg cough) on ACE
inhibitors can be given telmisartan.

FUNDING SOURCE

Boehringer Ingelheim Pharmaceuticals,

which did not receive any data until after
the study was completed.
All data was received, checked, and
analyzed independently by the Population
Health Research Institute.
All statistical analysis also done by the
staff of the above institute.

DO THESE RESULTS APPLY TO MY

PATIENTS?

These are relatively low-risk

patients.
These patients had borderline high
BP and blood sugars.
From this study, ARBs did not offer
any significant benefit in a low-risk
patient population.

QUESTIONS?