CARDIOVASCULAR JOURNAL OF AFRICA • Vol 21, No 6, November/December 2010
AFRICA
339
TABLE 2. SOLID-ORGAN CANCERS REPORTED IN RANDOMISED CONTROLLED
TRIALS OFANGIOTENSIN RECEPTOR BLOCKERS
Lung cancer
ARB (%)
Control (%)
RR (95% CI)
%
p
-value
All available trials
LIFE
29/4605 (0.6) 12/4588 (0.3) 2.41 (1.23–4.71)
0.01
CHARM-Overall
31/3803 (0.8) 25/3796 (0.7) 1.24 (0.73–2.09)
0.43
TRANSCEND
35/2954 (1.2) 27/2972 (0.9) 1.30 (0.79–2.15)
0.30
ONTARGET
229/17044 (1.3) 101/8576 (1.2) 1.14 (0.90–1.44)
0.27
PROFESS
37/10016 (0.4) 30/10048 (0.3) 1.24 (0.77–2.00)
0.39
Meta-analysis
361/38422 (0.9) 195/29980 (0.7) 1.25 (1.05–1.49) 6.6 0.01
With background ACE-inhibitor treatment
CHARM-Added
12/1276 (0.9) 7/1272 (0.6) 1.71 (0.68–4.33)
0.26
ONTARGET (telmisartan
+
ramipril vs
ramipril)
129/8502 (1.5) 101/8576 (1.2) 1.29 (0.99–1.67)
0.055
Meta-analysis
141/9778 (1.4) 108/9848 (1.1) 1.32 (1.03–1.69) 0 0.031
Without background ACE-inhibitor treatment
LIFE
29/4605 (0.6) 12/4588 (0.3) 2.41 (1.23–4.71)
0.01
TRANSCEND
35/2954 (1.2) 27/2972 (0.9) 1.30 (0.79–2.15)
0.30
ONTARGET (telmisartan vs ramipril) 100/8542 (1.2) 101/8576 (1.2) 0.99 (0.76–1.31)
0.97
CHARM-Alternative
10/1013 (1.0) 3/1015 (0.3) 3.34 (0.93–12.10)
0.066
Meta-analysis
174/17114 (1.0) 143/17151 (0.8) 1.50 (0.93–2.41) 65 0.097
Prostate cancer*
All available trials
LIFE
58/2118 (2.7) 42/2112 (2.0) 1.38 (0.93–2.04)
0.11
CHARM-Overall
32/2617 (1.2) 27/2582 (1.0) 1.17 (0.70–1.95)
0.55
TRANSCEND
35/1674 (1.2) 27/1705 (1.6) 1.32 (0.80–2.17)
0.27
ONTARGET
275/12544 (2.2) 128/6245 (2.0) 1.07 (0.87–1.32)
0.53
PROFESS
36/6455 (0.6) 32/6418 (0.5) 1.12 (0.70–1.80)
0.64
Meta-analysis
436/25408 (1.7) 256/19062 (1.3) 1.15 (0.99–1.34) 0 0.076
With background ACE-inhibitor treatment
CHARM-Added
7/1006 (0.7)
9.1000 (0.9) 0.77 (0.29–2.07)
0.61
ONTARGET (telmisartan
+
ramipril vs
ramipril)
141/6252 (2.3) 128/6245 (2.0) 1.10 (0.87–1.39)
0.43
Meta-analysis
148/7258 (2.0) 137/7245 (1.9) 1.08 (0.86–1.36) 0 0.52
Without background ACE-inhibitor treatment
LIFE
58/2118 (2.7) 42/2112 (2.0) 1.38 (0.93–2.04)
0.11
TRANSCEND
35/1674 (2.1) 27/1705 (1.6) 1.32 (0.80–2.17)
0.27
ONTARGET (telmisartan vs ramipril) 134/6292 (2.1) 128/6245 (2.0) 1.04 (0.82–1.32)
0.75
CHARM-Alternative
8/691 (1.2)
3/691 (0.4) 2.67 (0.71–10.01)
0.15
Meta-analysis
235/10775 (2.2) 200/10753 (1.9) 1.17 (0.97–1.41)
0.10
Breast cancer
†
All available trials
LIFE
37/2487 (1.5) 36/2476 (1.5) 1.02 (0.65–1.61)
0.92
CHARM-Overall
17/1186 (1.4) 17/1214 (1.4) 1.02 (0.52–2.00)
0.95
TRANSCEND
20/1280 (1.6) 17/1267 (1.3) 1.16 (0.61–2.21)
0.64
ONTARGET
60/4500 (1.3) 34/2331 (1.5) 0.91 (0.60–1.39)
0.67
PROFESS
20/3561 (0.6) 15/3630 (0.4) 1.36 (0.70–2.65)
0.37
Meta-analysis
154/13014 (1.2) 119/10918 (1.1) 1.04 (0.82–1.32) 0 0.74
With background ACE inhibitor treatment
ONTARGET (telmisartan
+
ramipril vs
ramipril)
33/2250 (1.5) 34/2331 (1.5) 1.00 (0.61–1.66)
>
0.99
Without background ACE inhibitor treatment
LIFE
37/2487 (1.5) 36/2476 (1.5) 1.02 (0.65–1.61)
0.93
TRANSCEND
20/1280 (1.6) 17/1267 (1.3) 1.16 (0.61–2.21)
0.64
ONTARGET (telmisartan vs ramipril)
27/2250 (1.2) 34/2331 (1.5) 0.83(0.50–1.36)
0.45
CHARM-Alternative
5/322 (1.6)
4/324 (1.2)
1.26 (0.34–4.64)
0.73
Meta-analysis
89/6339 (1.2) 91/6398 (1.4) 0.99 (0.74–1.32) 0 0.93
ARB
=
angiotensin receptors blocker. RR
=
risk ratio. ACE
=
angiotensin converting enzyme. *Analysis
limited to men.
†
Analysis limited to women, all breast cancers were assumed to have occurred in women.
Breast cancer data were not available for the CHARM-Added trial.
•
the analyses did not take into account
the effect of gender, age, smoking or
other known risk factors for malignan-
cies.
Boehringer-Ingelheim had conducted a
comprehensive internal safety data analy-
sis including malignancy data, which has
formed part of the submission package to
regulatory bodies since 2008. This analy-
sis includes patient level time-to-event
data, which are presented as malignancies
per 100 patient years, and no statistically
significant difference was observed.
The
Cardiovascular Journal of Africa
obtained comment from Dr Carl
Lombard, director of the Biostatistics
Unit at the South African Medical
Research Council (MRC) and Dr Adam
Nosworthy, senior specialist physician
and medical oncologist, University of
the Witwatersrand, Charlotte Maxeke
Johannesburg Academic Hospital, and
clinical adviser to the South African
Oncology Consortium. They reviewed
the published and Boehringer-Ingelheim
data for the Journal, and their comments
follow.
Comment from Dr Carl Lombard
on Boehringer-Ingelheim analysis
Systematic reviews, which evaluate
different trials around the same question
often lead to a formal pooled analysis of
the relevant information through a meta-
analysis. This is often a crude analysis
since only the summarised data from
trials are available from the publications.
The methodology of meta-analysis is
well established and is a useful tool
to pick up small signals of benefit or
risk across trials with varying levels and
direction of effect sizes. Sipahi
et al
.
1
utilised the meta-analysis methodology
to look at the risk of solid-organ cancers
in randomised, controlled trials of angio-
tensin receptor blockers. The conclusions
reached from this analysis are balanced
and qualified and clearly outline the limi-
tations and need for further analysis.
Three of the trials involved in this
analysis used the Boehringer-Ingelheim
ARB, telmisarton. Boehringer-Ingelheim
has provided additional information
involving patient-level information on the
incidence and progression of cancers in
the study participants of these trials (Fig.
1, Table 3).
