CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 6, November/December 2010
340
AFRICA
TABLE 3. NUMBER OF PATIENTSWITH MALIGNANCIES
BY ORGAN PER 100 PATIENTYEARS BY STUDY
ONTARGET
TRANSCEND
TR
T
R
∆
T-R T
P
∆
T-P
Randomised (
n
)
8502 8542 8576
2954 2972
Patients with neoplasms
1
2.14
1.96
1.88
0.08
1.72
1.48
0.25
Gastrointestinal
0.33
0.28
0.28
0
0.28
0.28 –0.01
Skin
0.39
0.34
0.37 –0.03 0.23
0.21
0.02
Prostate
0.36
0.33
0.31
0.01
0.25
0.2
0.05
Lung
0.32
0.23
0.25 –0.01 0.25
0.17
0.07
Genito-urinary
0.1
0.14
0.12
0.03
0.15
0.13
0.02
Blood
0.12
0.09
0.08
0.01
0.09
0.09
0
Breast
0.09
0.07
0.09 –0.02 0.14
0.13
0.01
Gynaecological
0.09
0.09
0.07
0.02
0.07
0.02
0.04
Head and neck
0.06
0.08
0.05
0.03
0.04
0.04
0
Metastases
0.05
0.05
0.03
0.02
0.02
0.01
0.01
Liver
0.05
0.06
0.05
0
0.04
0.03
0.01
Pancreas
0.05
0.05
0.05
0.01
0.06
0.05
0.01
CNS
0.03
0.03
0.04 –0.01 0.02
0.03 –0.01
Benign
0.01
0.01
0.01
0.01
0.01
0.01
0
NOS
0.03
0.03
0.02
0.01
0.03
0.01
0.01
Melanoma
0.04
0.04
0.04
0.01
0.01
0.03 –0.02
Endocrine
0.01
0.01
0.01 –0.01 0.01
0
0.01
Bone
0.01
0.01
0.01
0
0.01
0.01
0
Sarcoma
0.01
0.01
0
0
0.01
0.01
0.01
Abdominal
0.01
0.01
0
0
0
0.01 –0.01
Neuroendocrine
0
0
0
0
0
0
0
∆
represents the difference between treatment arms:
+
occurred more frequently and – less frequently
in telmisartan group; T
=
telmisartan, R
=
ramipril, P
=
placebo.
The information provided across the
three trials is differential and limited,
which does not allow an appropriate
pooled analysis across them. For the
TRANSCEND and ONTARGET trials
for example, the patient years of follow
up is absent, whereas it is provided for
the PRoFESS trial. The report reviews the
results of the three trials separately.
(telmisartan vs placebo), ONTARGET
(telmisartan
+
ramipril, telmisartan vs
ramipril)], the incidence rate ratio was
1.07; 95% CI: 0.99–1.14.
2. With background ACE inhibitor treat-
ment [ONTARGET (telmisartan +
ramipril vs ramipril)], the incidence
rate ratio was 1.14; 95% CI: 1.03–1.16.
3. Without background ACE inhibitor
treatment [PRoFESS (telmisartan vs
placebo), TRANSCEND (telmisartan
vs placebo), ONTARGET (telmisartan
vs ramipril)], the incidence rate ratio
was 1.03; 95% CI: 0.96–1.12.
These analyses still have some limitations
in that they utilise only patient follow up
and do not adjust for latency and other
confounders. However, the comparisons
are between large groups of patients that
have been properly randomised, and with
the same intensity of follow up and malig-
nancy ascertainment.
From analysis 3 in which monotherapy
telmisartan was compared to either place-
bo or ramipril, there is no evidence of
risk for overall malignancy with regard to
this product. With regard to the telmisar-
tan/ramipril combination arm, there is
evidence of risk with regard to the inci-
dence of overall malignancies.
The conclusion made by Boehringer-
Ingelheim in their safety report is there-
fore objective: ‘There was a modest
imbalance in malignancies seen in some
of the recently completed cardiovascu-
lar outcome studies with telmisartan.
This imbalance was primarily in the
telmisartan/ramipril combination arm in
ONTARGET, as opposed to monotherapy
arms of telmisartan vs rampipril.’
However, the call for further analysis
by Sipahi
et al
.
1
still stands, since the
safety report of Boehringer-Ingelheim
does not utilise the full potential of the
available individual-level data for pooled
analyses.
Comment from Dr Adam
Nosworthy
The findings published by Sipahi
et al
.
1
in
the 14 June issue of the
Lancet
raise the
concern of most doctors involved in clini-
cal trials. (1) Do the treatments intended
to offer benefit result in long-term harm
to patients? (2) The latest trend of regula-
tory bodies to grant fast-track approval
to new medications needs to be carefully
reviewed.
In an attempt to offer patients the latest
Making approximate estimates for
the patient years in TRANSCEND and
ONTARGET from the information
provided, and performing pooled analyses
for overall malignancies, similar to that
done by Sipahi
et al
.,
1
the following was
found:
1. In all three trials [PRoFESS (telmisar-
tan vs placebo), TRANSCEND
Fig. 1. Fatal and non-fatal malignancies: ONTARGET and TRANSCEND
12
8
4
0
T/R
8502
T
8542
R
8576
T
2954
P
2972
Patients %
9.7
8.9
8.0
6.9
1.14 (1.03–1.26)*
1.17 (0.97–1.41)
This analysis clearly proves that there is no significant increase of telmisartan
vs ramipril or placebo in ONTARGET and TRANSCEND. There is however a
significant increase in the combination arm (telmisartan
+
ramipril) vs ramipril.
ONTARGET
TRANSCEND
Total
n
Randomised
8.6
824
762
735
236
204
1.09 (0.99–1.21)
1.05 (0.94–1.16)
* Significant HR (95% CI).
T
=
telmisartan, R
=
ramipril, P
=
placebo
