TRANSACTIONS
OF THE ROYAL
SOCIETY
OF TROPICAL
MEDICINE
AND
HYGIENE
(2001) 95,637-650
A meta-analysis using individual patient data of trials comparing artemether
with quinine in the treatment of severe falciparum malaria
The Artemether-Quinine
Meta-analysis
Study Group+
Abstract
We conducted a meta-analysis using individual patient data from randomized controlled trials comparing
artemether and quinine in severe falciparum malaria. Eleven trials were identified, of which 8 were clearly
randomized. Original individual patient data on 1919 patients were obtained from 7 trials, representing
85% of the patients in the original 11 studies. Overall there were 136 deaths among the 961 patients
treated with artemether, compared with 164 in the 958 treated with quinine [14% vs 17%, odds ratio
(95% confidence interval) 0.8 (0.62 to 1.02), P= 0.081. There were no differences between the 2
treatment groups in coma recovery or fever clearance times, or the development of neurological sequelae.
However, the combined ‘adverse outcome’ of either death or neurological sequelae was significantly less
common in the artemether group [odds ratio (95% CI) 0.77 (0.62 to 0.96), P= 0.021, and treatment
with artemether was associated with significantly
faster parasite clearance [hazard ratio (95% CI) 0.62
(0.56 to 0.69), P < O*OOl]. In subgroup analyses artemether was associated with a significantly lower
mortality than quinine in adults with multisystem failure. In the treatment of severe falciparum malaria
artemether is at least as effective as quinine in terms of mortality and superior to quinine in terms of
overall serious adverse events. There was no evidence of clinical neurotoxicity or any other major sideeffects associated with its use.
malaria, Plusmodium fulciparum, severe disease, chemotherapy, artemether, quinine, meta-analysis,
individual patient data, neurotoxicity, sequelae
Keywords:
nin
Introduction
The Cinchona alkaloids were introduced for the
treatment of malaria over 3 centuries ago. Quinine
remained the mainstay of treatment for malaria until
the introduction of safer, more effective, synthetic antimalarials, the most important of which was chloroquine. With the extensive spread of chloroquine
resistance since the early 196Os, quinine (and its diastereomer quinidine) once again became the standard
treatment for severe malaria. However, quinine has a
number of drawbacks, including a relatively narrow
therapeutic ratio and the development of low-grade
resistance in Plasmodium falciparum. In uncomplicated
malaria, resistance manifests itself as prolonged parasite
clearance and increased recrudescence rates; the effects
on treatment efficacy in severe malaria are less clear,
but eventually resistance leads to an increase in mortality, and may also increase permanent neurological
morbidity.
More than a thousand years before the curative
powers of Cinchona bark became known to European
explorers and physicians, qinghao (sweet wormwood)
was in use in China as a herbal remedy for fever
(HONG, AD
340). It was not until the 1970s that
Chinese scientists identified the active antimalarial
ingredient, qinghaosu (extract of qinghao), or artemisi-
Address for correspondence: Nicholas Day? Centre for Tropical Medicine, Nuffield Department of Climcal Medicine, John
Radcliffe Hospital, Headington, Oxford OX3 9DU, UK;
phone +44 (0) 1865 220970, fax +44 (0) 1865 220984,
e-mail [email protected]
‘Artemether-Quinine
Writing Committee
Meta-analysis
Study Group
Kasia Stepniewska, Nicholas Day, Abdel Babiker, David Lalloo, David Warrell, Piero Olliaro, Nicholas White (Chair)
Statistical Secretariat
Kasia Stepniewska, Abdel Babiker, Paul Gamer
Advisorv Groub
Nicholas Day; Tim Pete, Peter Winstanley, Michael Boele van
Hensbroek, David Lalloo, Nicholas White
Investigators and other participants ($not included above)
Martin Danis, Cathy Davies, Tran Tinh Hien, Juntra KarbWang, Dominic Kwiatkowski, Kevin Marsh, Heather McIntosh, Malcolm Molyneux, Steven Murphy, Andrew Seaton,
Terrie Taylor, Bill Watkins.
(QINGHAOSU
ANTIMALARIAL
COORDINATING
1979). This was a sesauiteruene lactone seroxide, a che&cal structure hiderto -mknown in &ology. Artemisinin and its derivatives artemether and
artesunate (collectively referred to here as QHS) have
been shown to be the most rapidly acting of all antimalarial drugs in terms of clearance of parasitaemia.
This finding led to the initiation of clinical trials in
Africa and in Asia comparing artemisinin derivatives
with quinine for the treatment of severe malaria. The
aim of these trials was usually to assessdifferences in
mortality, neurological sequelae and serious toxic effects between the 2 drugs. The individual results have
been largely inconclusive, with no one trial sufficiently
powered to show a moderate but clinically important
effect on these primary outcomes. For example the 2
largest trials would have been able to detect only a 50%
reduction in mortality (16% vs 8%). While most of the
studies were underway, enthusiasm for artemether (the
most commonly evaluated of the parenteral derivatives)
was tempered by the finding in animal studies of an
unusual pattern of neurotoxicity and some evidence of
cardiotoxicity with artemether, and the closely related
compound arteether. By then hundreds of thousands of
patients had been treated with the artemisinin derivatives without any reports of such toxic effects occurring
in humans. Potential neurotoxicity in a drug used to
treat a disease commonly associated with coma may be
difficult to assess.Again the clinical trials yielded mixed
results; whereas an early study reported a reduction in
coma duration with artemether, in the 2 largest studies
artemether was associated with coma prolongation. To
establish reliably the magnitude of the differences between these 2 antimalarial treatments in mortality and
major complication rates, including time-to-event variables such as coma clearance, a meta-analysis of individual patient data from all relevant trials was undertaken.
The primary objective of this meta-analysis was to
compare the quinine and artemether treatments with
respect to mortality. The secondary aims were comparisons of the 2 treatments with respect to neurological
sequelae, parasite clearance, fever clearance and coma
recovery.
GROUP,
Methods
Identification
of trills
and collection of data
We planned to include in the meta-analysis all
known, published or unpublished, properly rando-
THE ARTEMETHER-QUININEMETA-ANALYSIS
STUDYGROUP
638
mized trials comparing quinine and artemether in severe malaria. The identification of trials was achieved
(i) through discussions with an international panel of
malaria clinical investigators,
(ii) throunh a search of the National Librarv of Medi’ ’ tine GedLine database, and
(iii) with reference to trials identified previously by the
Cochrane Collaboration.
Letters explaining the nature of the meta-analysis and
requesting collaboration were sent to the Principal
Investigators of all these trials. Principal Investigators
were also asked to identify any other relevant trials they
knew of or were involved in. All investigators were
offered full collaboration as part of the ArtemetherQuinine Meta-analysis Study Group. Individual patient
data from the original databaseswere requested for an
extensive set of clinical and laboratory variables. These
variables were defined a ~riori
bv the Advisorv Committee of the Group following discussions at a preliminary meeting of the clinical investigators. A wide range
of admission variables, categorical outcome variables,
and the raw original serial measurements of coma
score, temperature, and parasite counts were included.
DejGtition of end-points and explanatoy
variables
Five endpoints were studied: death, neurological
sequelae, parasite clearance, coma clearance and fever
clearance. We also defined a derived ‘adverse outcome’
variable, combining death and neurological sequelae.
‘Death’ was defined as any death attributable to the
current episode of malaria infection. The definition of
neurological sequelae varied between studies, mainly
because of variation in the length of patient follow-up.
This variability did not invalidate the analysis as the
definition of the endpoint was uniform within each
study, and patients were compared directly only within
studies. Only patients who survived to discharge were
analysed for sequelae.
There was considerable variability between trials in
the definitions of ‘time-to-event’ variables, i.e., coma
recovery, fever and parasite clearance times. For this
reason, and also to enable estimation by survival analysis of a summary effect across trials, these measurements for each patient were rederived from the raw
data in accordance with uniform definitions. Parasite
clearance was defined as occurring at the time of the
first negative blood smear. Coma clearance was attained if a Blantyre coma score of 5 (for young children) or a Glasgow coma score of 15 was recorded for
at least 24 h. Only patients with an initial Glasgow
coma score below 11 or Blantyre coma score below 4
were included in the analysis of this endpoint. Similarly, fever clearance was defined as the time after
which the temperature remained normal (axillary temperature below 37.5”C, or rectal temperature below
38°C) for at least 24 h. Only patients with a raised
initial temperature were included in the analysis of this
endpoint. All ‘time-to-event’ measurements were taken
from the time of randomization.
Treatment effects were also studied for patient subgroups pre-defined by the following characteristics: age
(child or adult), sex, severe anaemia (haematocrit
<15% or haemoglobin <5 g/dL), renal failure (serum
creatinine 1265 umol/L). low blood nressure (svstolic
blood pressure <‘SOmmHg), cerebral malaria (Bl&tyre
coma score <3 or Glasgow coma score <8), hypoglycaemia (blood elucose c2.2 mmol/L), jaundice (serum
bilirubin >2.5-mg/dL or clinical ‘jaundice if bilirubin
not measured). These subgroup analyses were specified
a priori by the Advisory Group. The purpose of these
subgroup analyses was to explore any heterogeneity of
treatment effect between groups of patients with differing baseline characteristics (in terms of demography or
clinical presentation) and therefore potentially different
treatment responses.
Data checks
Once these data were centrally located, randomization checks were carried out to ensure that even allocation to treatments took place across the week and
across the whole accrual period. These were achieved
by tabulating the number of patients assigned to each
drug by day of the week, and by plotting the cumulative
number of patients assigned to each drug as the trial
progressed. Individual data were also checked for transmission errors and general quality. For this purpose, all
published analyses of the data were repeated in their
entirety, and any problems encountered were resolved
with the individual trialists.
Statistical methods
The objective of the primary analysis was to obtain
combined estimates of the treatment effect for various
endpoints. For binary endpoints (death, sequelae),
summary odds ratios (ORs) were calculated using the
method of Peto-Mantel-Haenszel, based on the difference between the number of observed (0) and expected (E) events in the artemether treatment group
(EARLYBREASTCANCERTRIAIJSTS'COLLABORATIVE
GROUP, 1990). E was calculated from the 2 X 2 table
giving the numbers with and without the event by
treatment group, assuming a hypergeometric distribution. Then O-E and its variance V were calculated for
each trial separately. These were summed to obtain a
‘grand total’ O-E and V for the overview. The summary log odds ratio is (0-E)/V with variance l/V. In
this way patients in different trials were not compared
directly. For ‘time-to-event’ analyses, hazard ratio
(HR) estimates for each trial were calculated using Cox
regression, and an overall estimate was calculated using
stratified Cox regression (KALEFLEISCH 8z PRENTICE,
1980).
For both types of endpoint, tests of significance of
treatment effect were based on O-E (EARLY BREAST
CANCER‘IRKLISTS’ COLLABORATIVEGROUP, 1990).
However, for time-to-event analyses (parasite, fever
and coma clearance), E was calculated from the logrank
statistic. Two-sided significance levels are reported.
Because there was an imbalance between the numbers
allocated to each treatment group in some trials, an
adjusted total number of patients for each outcome was
calculated for the artemether group given the O-E, V,
and observed totals for the quinine group, and assuming the same number of patients in each group. A test
for heterogeneity of the real effect of the treatment
regimens in the trials was performed using a method
based on O-E and V for binary endpoints (EARLY
BREAST CANCER TRTALISTS’ COLLABORATIVE
GROUP, 1990), and Cox regression models for time-toevent endnoints (KALBFLEISCH& PRENTICE, 1980).
Results*of the-separate trials and the overview were
presented graphically for each endpoint. The position
of a solid square indicates the effect of treatment in that
trial and a horizontal line indicates the 99% confidence
limits for the odds or hazard ratio. The sizes of the solid
squares are directly proportional to the amount of
information each trial contains (the statistical weight of
each trial). The overview result is represented by a
diamond-shaped symbol, which is centred around the
overall odds or hazard ratio estimate and covers the
95% confidence interval (95% CI). The 99% confidence intervals were chosen for individual trials to
compensate for the multiple comparisons being made.
All the above analyses were repeated for subgroups of
patients defined by the characteristics described earlier,
to examine whether the characteristics had any influence on the treatment effect. Additionally, for time-toevent endpoints, adjusted survival graphs by treatment
group were obtained (EARLY BREASTCANCERTRIALISTS' COLLABORATIVEGROUP, 1990). Conditional logistic regression was used for multivariate modelling of
factors affecting outcome. All analyses were on the
639
META-ANALYSISOFARTEMETHER-QUININEFORSEVEREMALARIA
clearance or time to parasite clearance. However, for
fever clearance significant heterogeneity did exist between studies, regions and age-groups (all P < 0.001).
basis of intention to treat. Therefore we included all
patients who were randomized and had confirmed
falciparum malaria. All analyses were performed using
the statistical programme Stata (STATACORP., 1997).
Mortality
The overall mortality was 16% (300 of 1919 patients). There were 136 deaths observed among 961
patients who were given artemether (14%) and 164
deaths among 958 patients who were given quinine
(17%) [summary OR (95% CI) 0.8 (0.62 to 1.02),
P= 0.081.
Figure 1 shows estimated odds ratios and confidence
intervals for each study and for the overview. Results of
the subset analyses for mortality are presented in Figure
2. Although there was no evidence of heterogeneity
between subgroups, artemether was found to be associated with lower mortality than quinine in the subgroup of Asian patients [OR (99% CI) 0.59 (0.35 to
l.Ol), P=O.O12],
adults [0.59 (0.35 to l.Ol), P=
0.0121, males [0.68 (0.44 to 1.04), P= 0.0191, patients with renal failure
[0.36 (0.16 to O.SO),
P= O.OOl], patients with hypoglycaemia [0.53 (0.27 to
1.05), P= 0.0161 and patients with jaundice [0.5 1
(0.29 to 0.90), P= 0.0021. It should be noted that
these subgroup-defining
variables are not mutually independent, as the majority of patients with multisystem
failure are adults from Asia.
After adjusting for admission hypoglycaemia or renal
failure, overall odds ratio for treatment effect decreased
slightly to 0.74, while adjusting for other variables
changed the overall odds ratio very little (Table 4). In a
conditional logistic regression model adjusting for renal
failure, jaundice and hypoglycaemia
simultaneously,
treatment with artemether was associated with an odds
ratio (95% CI) for fatal outcome of 0.69 (0.50 to 0.96)
(P = 0.026).
Results
Trials ident$Yed
In total 11 trials comparing artemether and quinine
in severe malaria were identified (MYINT & SHWE,
1987; SHWE et al., 1988; WIN et al., 1992; WALKER et
al., 1993; KAR~WANG et al., 1995; DANIS et al., 1996;
HIEN et al., 1996; MURPHY et al., 1996; VAN HENSBROEK etal., 1996; SEATON etal., ~~~~;TAYLoR etal.,
1998) (Table 1). All trials were open label except the
Viet Nam study, which was double blind, and one of
the Burmese studies, which was single blind. Two
published Burmese studies paired patients to receive
alternate treatments and from the published reports it
was not possible to establish whether these were randomized trials (MYINT
& SHWE, 1987; SHWE et al.,
1988). In the later Burmese (Myanmar) study, only
some of the quinine patients were randomized (WIN et
al., 1992). African studies enrolled only children, except for the multicentre study in West Africa which
included 74 adults (28%). All Asian studies were on
adults.
We received individual patient data from 7 of the
trials, representing 86% (1947 of 2264) of the patients
in the identified studies, and it is these trials which
formed the central part of this meta-analysis. Entry
criteria and drug regimens for these trials are given in
Table 2. All of these studies were fully randomized.
A number of patients were excluded from the original
analyses in each of the trials (see Table 1 for numbers).
The most common reason for exclusion was non-compliance with either inclusion criteria or drug regimen.
We included in the overview as many of these patients
as possible and as a result 60 of 88 excluded patients
were added to the data set (3 patients from The
Gambia study, 38 from Kenya and 19 from Malawi).
After these re-inclusions there were 1919 patients with
individual patient data available from the 7 studies
(representing 85% of the patients in all 11 studies).
Table 3 summarizes baseline characteristics for these
studies.
Tests for heterogeneity in the trial results revealed no
significant heterogeneity between the 7 studies, between the 2 regions (Af?ica/Asia), or between adults
and children for mortality, sequelae, time to coma
Table
1. All known trials of quinine
and artemether
Neurolo@cal sequelae
Neur&og&l
sequelae were assessed at discharge in
trials in Viet Nam. Kenva. Panua New Guinea. Malawi
and The Gambia; at 7&days*after admission ;n Thailand, and at 14 days in West Africa. In Papua New
Guinea, only hearing complications were recorded; in
all other trials a similar range of complications was
checked. Neurological sequelae were observed in 11%
of patients (172 out of 1572 patients who survived).
There was no significant difference between treatments
in the incidence of sequelae [lo% in the artemether
group (81/807 patients) and 12% in the quinine group
in severe malaria
Age-group
Years of
accrual
Trial design
>3 months
> 14 years
> 16 years
< 12 years
> 12 years
1993-94
199 l-96
1992
1992-94
1992-95
Open label
Double blind
Open label
Open label
Open label
282
561
102
200
40
14
1
5
39
7
Children
l-9 years
1992-94
1992-94
Open label
Open label
183
579
19
3
Published datab
Burma (Myint & Shwe, 1987)
Burma (Shwe et al., 1988)
> 12 years
>12 years
1985
1987
Myanmar (Win et al., 1992)
Nigeria (Walker et al., 1993)
> 17 years
<5 years
1989-91
1991-92
Patients paired
Patients paired according
to age, sex and
complications
Uni-blind
Open label
Country (reference)
Individual patient data
West Africa (Danis et al., 1996)
Viet Nam (Hien et al., 1996)
Thailand (Karbwang et al., 1995)
Kenya (Murphy et al., 1996)
Papua New Guinea (Seaton et al.,
1998)
Malawi (Taylor et al., 1998)
The Gambia (Van Hensbroek
et al., 1996)
“Number of patients excluded when data were originally analysed.
bNo individual patient data were received on these studies.
Number
randomized
Number
excluded”
62
60
117
99
59
640
THE ARTEMETHER-QUININE META-ANALYSIS STUDY GROUP
Table 2. Entry criteria and drug regimens for trials
pared with quinine for severe falciparum
malaria
Country
Entry criteria
West Africa
l
l
l
l
Viet Nam
l
l
l
Thailand
l
l
l
l
Kenya
l
l
l
Papua New Guinea
l
l
l
Malawi
l
l
l
l
The Gambia
l
l
l
included
in the meta-analysis
of artemether
com-
Study drug dose regimen
Age >3months
Asexual l? falciparum parasitaemia
Temperature >38”C
One or more of the following:
GCS <8 (or Blantyre score <3),
repeated generalized convulsions, severe
anaemia, pulmonary oedema or
respiratory distress, hyperglycaemia,
massive haemoglobinuria, acidosis, or to
have vomited at least 3 times in the 24 h
preceding admission
Quinine dihydrochloride: loading dose
20 mg/kg, maintenance 10 mg/kg”
Artemether: for bodyweight s50 kg,
loading dose 3.2 mg/kg, maintenance dose
1.6 mg/kg; for bodyweight >50 kg,
1oadinF dose 160 mg, maintenance dose
80 mg
Age > 14 years
Asexual P. falciparum parasitaemia
One or more of the followine:
GCS <l 1; haematocrit <21yo/o+
parasitaemia > 100 OOO/mL; jaundice +
parasitaemia > 100 OOO/mL; renal
failure (creatinine >3 mg/dL);
hypoglycaemia (glucose <40 mg/dL);
hyperparasitaemia (X00 OOO/mL or
10%); haemodynamic shock (systolic BP
<80 mmHg)
Quinine dihydrochloride/sulphate:
loading
dose 20 mg/kg, maintenance dose
10 w/W
Artemether: loading dose 4 mg/kg,
maintenance dose 2 mg/kg”
Age > 16 years
Weight exceeding 40 kg
Asexual I? falciparum parasitaemia
One or more criteria of severe malaria:
unarousable coma, severe anaemia, renal
failure, pulmonary oedema,
hypoglycaemia (glucose <40 mg/dL),
spontaneous bleeding, repeated
generalized convulsions, acidaemia,
hyperparasitaemia
Quinine dihydrochloride/sulphate:
loading dose 20 mg/kg, maintenance dose
10 mg/kg
Artemether: loading dose 160 mg daily,
maintenance dose 80 mg daily
Age <12 years
Unarousable coma (Blantyre motor
response <2)
I? falciparum parasitaemia with fever
Quinine dihydrochloride: loading dose
20 mg/kg, maintenance dose 10 mg/kg”
Artemether: loading dose 3.2 mg/kg,
maintenance dose 1.6 mg/kgb
Age > 12 years
Asexual I? falciparum parasitaemia
Fulfilled one or more of the WHO
criteria for severe or complicated malaria
Quinine dihydrochloride: loading dose
20 mg/kg, maintenance dose 10 mg/kg”
Artemether: loading dose 3.2 mg/kg,
maintenance dose 1.6 mg/kgb
Children
Asexual l? falciparum parasitaemia
Altered consciousness with a Blantyre
coma score <2
No alternative or contributing
explanation for coma
Quinine sulphate: loading dose 20 mg/kg,
maintenance dose 10 mg/kg”
Artemether: loading dose 3.2 mg/kg,
maintenance dose 1.6 mg/kgb
Age l-9 years
Blantyre coma score of s2
Asexual I? falci’arum parasitaemia
Quinine dihydrochloridelsulphate:
loading dose 20 mg/kg, maintenance dose
10 mg/kf
Artemether: loading dose 3.2 mg/kg,
maintenance dose 1.6 mg/kgb
GCS, Glasgow coma score. “8 hourly; “daily.
Quinine was given intravenously in the Kenya, Malawi, West Africa, Papua New Guinea and Thailand studies, and intramuscularly
in The Gambia and Viet Nam studies. Artemether was always given intramuscularly.
(91/765), OR (95% CI) 0.82 (059 to 1.15), P=
0.241. Estimated odds ratios and confidence intervals
for each study and for the overview are presented in
Figure 3. No differences between treatments were
found in terms of subgroup effects (data not shown) or
adjusted effects (Table 4).
Combined adverse outcome: death or sequelae
In total 472 ‘adverse outcomes’ were observed, 217
(23%) in patients treated with artemether and 255
(27%) in those treated with quinine [OR (95% CI)
0.77 (0.62 to 0.96), P= 0.021 (Fig. 4). On subgroup
analysis the
tality alone
renal failure
significantly
ing quinine
region, age and sex effects seen with morare not apparent, although patients with
or with jaundice receiving artemether had
fewer adverse outcomes than those receiv(Fig. 5).
Parasite clearance
Serial parasite measurements were available for 1542
patients. Artemether cleared parasitaemia more rapidly
than quinine [HR 0.62, 0.56 to 0.69, P < 0.001,
median (95% CI) clearance time 20 (16 to 24) h compared with 32 (28 to 32)] (Figs 6 and 7). This differ-
characteristics
of patients
in trials
(%)
median (80% ICR)
“Total number of patients with data available.
bFor studies in West Africa, Viet Nam and Thailand haematocrit
‘An equivalent of the children’s Blantyre coma score was used.
dEvaluated clinically as bilirubin was not measured.
ICR, interquartile range; ND, not determined.
Anaemia (%)
Hypoglycaemia
median (80% ICR)
median (80% ICR)
Jaundice (%)
Haematocrit/haemoglobinb,
Renal failure (%)
Bilirubin [pal/L],
BP <80 mmHg (%)
Serum creatinine [pmol/L],
Cerebral malaria (%)
Parasite count [/pL] (X lOOO), median (80% ICR)
Patients with follow-up
Male(%)
Age [years], median
Coma score, median (80% ICR)
Characteristic
Table 3. Baseline
90.4
(0.9-675)
7
177
(97-513)
30
58.1
(17.1-246)
61
30
(18-41)
5
7
lo;q5
(6l-; 5)
560
76
(%) is given; otherwise haemoglobin
(lOz974,
32
28.9
(12.2-41.5)
17
7
88.0
(8.0-470)
22
65
(35.4-98)
0
268
51
6.3
3/5
(22i4)
Viet Nam
in the overview
West Africa
included
4)
(g/dL)
is used.
(19YI)
0
6
93.3
(7.7-523)
5
177
(88-513)
33
76.1
(25.7-274)
77
l&5
(3;;
97
90
Thailand
(3.4Jii.2)
24
18
6d
NL
(4OY
11
00)
88.8
(2.2-889)
2k3
(1;;)
199
48
Kenya
(12286)
55
10.6
(8-14.9)
0
7
323
(18.8-1400)
18
140
(100-690)
23
52;5c
(1;;)
Papua New
Guinea
11
13d
8
(5.1-l
1.3)
9
1
ND
(2115)
241
(3.2-691)
3
(;;a
1/25
51
183
Malawi
(5.lY.5)
9
24
(;-;6l)
(13280)
0
11
(2.p540)
1!i7
‘PO;21
579
51
The Gambia
1853
1849
1574
1853
1478
1192
1559
1478
1885
1913
1919
1916
1915
1885
N”
642
THE ARTEMETHER-QUININE META-ANALYSIS STUDY GROUP
Death
Study
Artemether
Quinine
O-E
V
P
81133
81135
0.006
3.78
0.98
Viet Nam
361284
471276
-6.09
17.70
0.15
Thailand
6147
17150
-5.14
4.43
0.01
5.68
0.30
West Africa
Kenya
15/98
Papua New Guinea
ll/lOl
2.20
1115
3118
-0.82
0.90
0.39
Malawi
10195
13188
-1.94
5.05
0.39
The Gambia
601289
65/290
-2.39
24.55
0.63
136/961
14
1641958
17
-14.13
62.08
0.08
Overall
% Dead
0.1
1
2 3
Odds ratio
Artemether better
Quinine better
Fig. 1. Individual patient data analysis of deaths, within trials and overall. The overview diamond represents 95% CI, whereas the
error bars for each trial represent 99% CI.
ence was also observed in nearly all subgroups of patients (data not shown).
Coma clearance
Serial measurements of coma score were available for
1421 patients with impairment of consciousness on
study entry (Glasgow coma score <ll or Blantyre
coma score ~4). Time to recovery from coma was not
Table 4. Treatment
effect adjusted
(95% CI) and probability
(p)
Variable adjusted
for
Sex
Blood pressure
Renal failure
Cerebral
Anaemia
Hypoglycaemia
Jaundice
Unadjusted
NA, not applicable.
Death
0.79
0.61-1.01
P = 0.060
0.78
0.61-1.01
P = 0.063
0.79
0*61-1.02
P = 0.066
0.74
0.58-0.96
P = 0,022
0.80
0.62- 1.03
P = 0.082
0.78
0.61-1.00
P = 0.051
0.74
057-0.96
P = 0.023
0.77
0.60-0.99
P= 0.041
0.80
0*62- 1.02
P = 0.080
for explanatory
Sequelae
0.82
0.58-1.14
P = 0.238
0.81
0.58-1.14
P= 0.231
0.82
0.59-l-15
P = 0,243
0.80
0.57-l-12
P= 0.186
0.82
0.58-1.14
P = 0.242
0.82
O-58-1.14
P= 0.241
0.78
0.55-1.09
P= 0.145
0.83
0.59-1.16
P = O-272
0.82
0.58-1.14
P = 0.240
found to be significantly different for the 2 drugs [HR
1.09, 0.97 to 1.22, P= 0.12, medians 24 (24 to 30)
and 23 (19 to 24) h for artemether and quinine respectively] (Figs 7 and 8). In the subset analyses the hazard
ratio was consistently higher than unity (artemethertreated patients having longer coma durations) but the
results were not statistically significant (data not
shown). After adjusting for subgroup-defining variables
variables:
hazard
ratio
(HR), 95% confidence
Death or
sequelae
Parasite
clearance
Coma
recovery
0.76
0.62-0.95
P= 0.016
0.76
0.61-0.95
P= 0.015
0.76
0~61-0.95
P= 0.016
0.73
0.58-0.9 1
0.61
0.55-0.68
P co.00 1
0.61
0.54-0.68
P <O*OOl
0.61
0*55-0.69
P co.00 1
0.61
0.54-0.68
P <O*OOl
0.61
0.54-0.68
P <o.oo 1
0.62
0.56-0.69
P <O.OOl
0.61
0*54-0.68
P<O*OOl
0.61
0.55-0.68
P <O.OOl
0.62
0.56-0.69
P <o.oo 1
1.09
0.97- 1.23
P = 0.005
0.78
0.63-0.97
P = 0.026
0.76
06-0.95
P= 0.014
0.73
0.58-0.92
P = 0.007
0.76
0.6 l-O.94
P= 0.013
0.79
0.64-0.98
P = 0.034
P = 0.099
1.09
0*97- 1.22
P= 0.124
1.08
0.96-1.21
P= 0.152
1.09
0.97-1.22
P= 0.135
NA
interval
Fever
clearance
l-01
0.89-1.14
P= 0.911
1.01
0.90-1.15
P = 0.742
1.00
0.89-1.14
P = 0.935
1.02
0.90-1.15
P = 0.779
1.02
0*90-1.15
P = 0.769
1.10
0.98-1.24
1.01
0.89-1.14
P = O-078
P = 0.888
1.01
0.90-1.15
P = 0.826
1.07
0.95-1.21
P = 0.201
1.10
O-98-1.23
1.02
0.90-1.16
P = 0.087
P = 0.705
1.09
0.97-l-22
P = 0.120
1.01
0*90-1.15
P = 0.807
META-ANALYSIS
OF ARTEMETHER-QUININE
643
FOR SEVERE MALARIA
Death
O-E
V
Total
A (%)
Q (%)
Region
Africa
Asia
19011229
15
16
-2.56
11 O/690
12
19
- 12.06
38.59
23.03
Age
Child
Adult
18711152
16
17
1 lo/764
11
17
-2.70
- 12.06
38.50
23.03
1211755
176/1159
16
13
16
18
-0.80
- 14.20
24.68
36.78
19711396
31/161
691359
12
16
20
16
23
-13.19
-2.66
41.17
18
1.54
791780
8
12
-8.19
17.22
214/1103
19
4133
2
20
20
-3.59
- 1.70
42.16
0.70
Sex
Female
Male
Systolic BP
>80 mmHg
~80 mmHg
Missing
Cerebral
No
Yes
Missing
Anaemia
No
Yes
Missing
Renal failure
No
Yes
Missing
Hypoglycaemia
No
Yes
Missing
5.83
13.49
I
I
I
I
_
I
I
I
I
I
246/l 673
311178
20165
14
13
23
16
21
35
-9.71
-3.72
-1.81
51.62
6.17
2.96
18711272
14
15
-2.91
571206
531438
18
38
10
14
- 10.37
-4.30
37.50
10.03
11.52
18411592
10
13
-8.52
40.17
-9.21
13168
31
22
46
18
0.51
14.65
2.47
1211995
1081577
681344
12
12
14
18
24
20
-14.16
-1.93
25.53
21.29
13.04
300/1919
14
17
- 14.13
62.08
1001256
Jaundice
No
Yes
Missing
All participants
0.24
Odds ratio
Artemether
better
Fig. 2. Subgroup analysis of deaths. A, artemether; Q, quinine. See ‘Statistical methods’ for description
the hazard ratio remained very close to the unadjusted
value, and no statistically significant differences were
found (Table 4).
Fever clearance
Serial temperature
measurements
were available for
Quinine better
of methodology
used.
1302 patients. No difference in the effect of the drugs
was found on fever clearance [overall HR 1.01 (0.90 to
1*15), P= 0.81, medians 42 (32 to 48) and 48 (41 to
54) h for artemether and quinine respectively] (Figs 7
and 9). Adjustment for subgroup-defining variables had
no material effect on the overall hazard ratio (Table 4).
644
THE ARTEMETHER-QUININE
META-ANALYSIS
STUDY
GROUP
Sequelae
Study
Artemether
Quinine
O-E
V
P
West Africa
21125
21127
0.02
0.99
0.99
Viet Nam
31248
l/229
0.92
0.99
0.36
Thailand
o/41
1133
-0.55
0.25
0,27
12165
18161
-3.48
5.75
0.15
-0.48
0.25
0.33
5.62
0.48
Kenya
Papua New Guinea
0114
1115
Malawi
16185
11175
The Gambia
481229
571225
-4.96
20.22
0.27
Overall
% Sequelae
81/807
911765
12
-6.88
34.08
0.24
10
I
I
I
0.1
1
1
I
2
3
1.66
Odds ratio
Artemether better
Quinine better
Fig. 3. Individual patient data analysis of neurological sequelae, within trials and overall. The overview diamond represents 95% CI,
whereas the error bars for each trial represent 99% CL
Death
or sequelae
Study
P
Artemether
Quinine
O-E
V
West Africa
10/133
101135
0.07
4.64
0.97
Viet Nam
391284
481276
-5.12
18.40
0.23
6147
18150
-5.63
4.56
0.008
27180
29172
-0.58
10.11
0.41
Thailand
Kenya
Papua New Guinea
1115
Malawi
0.1
,
, 7
1
-1.27
0.04
1.08
0.22
9.12
0.99
26195
24188
1081289
1221290
-6.80
34.72
0.25
,
, 2;;/961
2;;/958
-19.28
82.64
0.019
2
3
The Gambia
%
Adverse outcome ,
Overall
4118
Odds ratio
Artemether better
Quinine better
Fig. 4. Individual patient data analysis of ‘adverse outcomes’ (deaths or neurological sequelae), within trials and overall. The
overview diamond represents 95% CI, whereas the error bars for each trial represent 99% CI.
Non-individual patient data trials
The mortality results using the published summary
data from the 4 trials for which individual data were
unavailable are shown in Figure 10. There is a significantly lower mortality associated with use of artemether
in these studies. However, the reservations mentioned
above concerning randomization
in 3 of these trials
should be borne in mind.
Discussion
The central result of this meta-analysis is that artemether treatment is associated with a trend towards a
lower mortality compared with quinine, but this difference is not significant at the 5% level. There had been
concern that a reduction in mortality might have been
associated with an increase in the incidence of neurological sequelae but this was not found, and ‘adverse
outcomes’ (combining mortality and sequelae) were
less common in patients treated with artemether (P=
O-02). Artemether was consistently associated with significantly faster clearance of parasitaemia than quinine,
although there were no differences in treatment effects
on fever clearance or coma recovery.
Concerns over potential neurotoxicity with qinghaosu derivatives arose when pre-registration toxicity studies were performed on artemether during the US army
and WHO-sponsored
development of arteether. The
results showed that both arteether and artemether
645
META-ANALYSIS OF ARTEMETHER-QUININE FOR SEVEREMALARIA
Death
or sequelae
Total
A
Q
O-E
V
Africa
Asia
356/l 182
116/690
26
16
31
20
-9.58
-12.02
57.09
24.04
Age
Child
Region
35511108
28
33
-9.25
56.76
Adult
1171764
14
18
-12.50
24.29
Sex
Female
2061736
24
29
-5.83
34.49
Male
26311131
21
25
-16.11
46.48
Systolic BP
X30 mmHg
299/1363
19
24
-17.64
53.51
~80 mmHg
Missing
40/160
1331349
23
32
28
38
-2.64
-1.27
6.64
891767
37611069
11
30
14
36
-10.31
-7.83
19.28
59.47
7136
16
20
-1.70
0.70
39311641
451165
33166
21
27
49
25
33
56
- 14.49
-5.33
-2.21
69.30
7.49
No
Yes
2841125 1
591206
19
33
23
39
-11.11
- IO.47
46.67
10.24
Missing
129/415
26
31
-3.39
21.76
Cerebral
No
Yes
Missing
Anaemia
No
Yes
Missing
Renal failure
Hypoglycaemia
No
46911556
17
21
- 15.09
59.06
Yes
3 1O/249
57
64
-9.21
13.49
Missing
143167
21
25
Jaundice
No
Yes
Missing
2231950
1221575
1271347
19
22
31
23
27
37
-2.89
-15.80
-3.39
37.13
22.63
19.61
All
47211872
23
27
-19.28
82.64
0.68
3.26
I
I
I
0.1
I
1
I
,
2
3
Odds ratio
Artemether
Fig. 5. Subgroup analysis of ‘adverse outcomes’ (deaths or neurological
caused serious neurotoxicity
in beagle dogs and this
was confirmed subsequently in rats (BREWER et al.,
1994), mice (NONTPRASERT et al., 1998) and monkeys
(PETRAS et al., 1997; GENOVESE et al., 1998a, 1998b).
These findings entered the public domain when most
of the trials featured in this meta-analysis were under-
better
Quinine better
sequelae).
way. As no case of clear-cut neurotoxicity
had been
described amongst the hundreds of thousands of documented patients who had received qinghaosu drugs, the
trials continued, although with increased vigilance and,
in some cases, increased nervous system evaluation.
Detecting drug neurotoxicity in a disease which itself
646
THE ARTEMETHER-QUININE
Parasite
META-ANALYSIS
STUDY
GROUP
clearance
Study
MA-Ma*
HR
CI
P
-8
0.72
0.52 to 1.00
0.002
Viet Nam
-18
0.65
0.52 to 0.82
CO.001
Thailand
-24
0.58
0.32 to 1.04
0.007
-8
0.61
0.41 to 0.92
0.001
-12
0.50
0.18 to 1.37
0.058
-8
050
0.33 to 0.75
‘Co.001
The Gambia
-12
0.62
0.38 to 0.88
<O.OOl
Overall
-12
0.62
0.56 to 0.69
CO.001
West Africa
Kenya
Papua New Guinea
Malawi
Hazard ratio
Artemether better
Quinine better
*Difference between medians.
Fig. 6. Individual patient data analysis of parasite clearance times, within trials and overall. The overview diamond represents 95%
CI, whereas the error bars for each trial represent 99% CI.
(a)
Days from
Number
hemether
Quinine
starung
treannent
at nsk
765
777
Number
at risk
Anemerher
707
Qumine
714
Number
at nsk
Anemether
667
QUiNlX
635
601
642
250
373
72
150
Days from
584
587
294
274
410
429
255
248
188
155
13
27
sramnS
~eatment
100
94
54
40
172
159
Days from
621
584
27
66
starting
135
100
111
72
46
21
37
17
28
IO
treatment
82
49
67
34
57
32
45
22
37
15
Fig. 7. Kaplan-Meier plots of time-to-event outcome variables, calculated using individual patient original measurements. Time to (a) parasite clearance, (b) coma recovery, and
(c) fever clearance. Circles, artemether; triangles, quinine.
has serious neurological manifestations is difficult, but
the finding of prolonged duration of coma in the
artemether arm of the only double-blind artemetherquinine comparison generated further concern. It was
unclear whether this was caused by a chance occurrence, was putatively neuroprotective
coma, or artemether neurotoxicity.
In the light of this uncertainty
the results of the combined coma recovery survival
analysis in the current meta-analysis are reassuring.
Neurotoxicity
in the animal models has affected particularly the brainstem centres involved in hearing, but
no residual hearing abnormalities were documented in
any of the trials-including
those with audiometric testing. In addition the characteristic neuropathological
features of toxicity have not been observed on close
histological examination of the brainstems of patients
who died following severe malaria treated with artemether (G. Turner, personal communication).
The
way in which the QHS class of drugs has been introduced into medicine has been unusual. The discovery
of neurotoxicity in experimental animals followed the
widespread use of these compounds in humans, and in
these circumstances the detailed evaluation of clinical
trials is critically important for assessment of the therapeutic ratio.
Qinghaosu derivatives that can be given parenterally
include artemether, arteether (both oil soluble), artesunate, and artelinic acid (both water soluble). Of these,
only artemether and artesunate, which were synthesized and developed for clinical use by Chinese scientists, are currently in extensive clinical use. Only artemether has been studied systematically in severe malaria, and for this reason was chosen as the qinghaosu
derivative representative in this meta-analysis. Subsequent animal studies have demonstrated that watersoluble QHS drugs such as artesunate are considerably
less neurotoxic than oil-soluble derivatives such as
artemether (NONTPRASERT
et al., 1998; T. Brewer,
personal communication).
This observation suggests
that artesunate might be preferred to artemether on
META-ANALYSIS
OF ARTEMETHER-QUININE
647
FOR SEVERE MALARIA
Coma recovery
HR
CI
P
0
0.98
0.70 to 1.36
0.82
18
1.39
0.97 to 1.99
0.013
0.46
0.18 to I.15
0.017
1.32
0.80 to 2.20
0.15
-28
0.72
0.07 to 7.34
0.71
-4
0.91
0.58 to 1.43
0.57
1.10
0.86 to 1.41
0.29
MA-MQ*
Study
West Africa
Viet Nam
Thailand
-24
Kenya
5
Papua New Guinea
Malawi
The Gambia
8
Overall
Artemether
*Difference
Hazard ratio
better
Quinine better
between medians.
Fig. 8. Individual patient data analysis of coma recovery times, within trials and overall. The overview diamond represents 95% CI,
whereas the error bars for each trial represent 99% CI.
Fever clearance
Study
MA-MP*
HR
CI
P
0
1.05
0.72 to 1.55
0.70
Viet Nam
31
1.38
1.05 to 1.82
0.002
Thailand
-5
0.75
0.34 to 1.64
0.33
Kenya
-4
0.97
0.59 to 1.58
0.86
Papua New Guinea
-28
0.31
0.09 to 1.10
0.008
Malawi
-12
0.58
0.36 to 0.93
0.001
The Gambia
-6
0.99
0.71 to 1.38
0.90
Overall
-6
1.01
0.90 to 1.15
0.81
West Africa
0.1
1
2
3
Hazard ratio
Artemether
*Difference
better
Quinine better
between medians.
Fig. 9. Individual patient data analysis of fever clearance times, within trials and overall. The overview diamond represents 95% CI,
whereas the error bars for each trial represent 99% CL
648
THEARTEMETHER-QUININJZMETA-ANALYSISSTUDYGROUP
Death
Q
A
O-E
V
P
I
Studies wnh IPD
West Africa
Viet Nam
Thailand
81133
81135
3.78
0.98
361284
471276
-6.09
17.70
0.15
6147
17150
-5.14
4.43
0.01
5.68
0.30
0.90
0.39
15198
Kenya
Papua New
Guinea
ll/lOl
1115
0.06
2.20
3/18
-0.82
Malawi
10195
13/88
-1.94
Gambia
601289
651290
-2.39
Overall
1361961
1641958
14.13
5.05
0.63
62.08
0.08
Studxs
with published
Burma
‘87
0130
2130
-1.00
0.49
Burma
‘85
013 1
2131
-1.00
0.49
7150
23167
-5.82
5.51
Nigeria
11152
13147
-1.61
4.58
Overall
181163
401175
-9.43
11.07
Myanmar
0.39
2455
data
I
I
O!l
;
Hazard
Artemether
better
1
:.
Quinine
better
rauo
Fig. 10. Comparison of individual patient data (IPD) analysis of deaths for the 7 trials for which these data were available, with an
analysis of published data from the 4 trials from which individual patient data could not be obtained. The overview diamonds
represent 95% CI, whereas the error bars for each trial represent 99% CI.
toxicological grounds, but there is no clinical basis for
this and both drugs have been very widely used without
any conclusive evidence of neurotoxicity in humans. A
meta-analysis of published summary data from trials in
severe malaria conducted using any QHS drug (i.e.,
not restricted to artemether) showed a significant survival advantage associated with QHS drugs compared
with quinine [OR (95% CI) 0.68 (055 to 0*84)],
although this was less significant if the analysis was
restricted to trials reporting adequate concealment of
allocation [OR 0.77 (0.61 to 0.98)] (MCINTOSH &
OLLIARO, 1998). Overall adverse effects with QHS
drugs were mild and not more common than with
quinine. Although the majority of patients were in trials
comparing artemether with quinine (and hence included in the current individual patient data metaanalysis), it is reassuring that there was no evidence of
heterogeneity in treatment effect between the QHS
drugs. At present neither artemether nor artesunate is
licensed for general parenteral use in Europe or North
America.
The individual patient data approach to meta-analyses has a number of major strengths, including the
ability to undertake formal survival analysis of time-toevent variables such as coma recovery. However, such
an approach is relatively time consuming and expensive
compared with the more commonly used systematic
review of published data. A further minor problem of
the individual patient data approach concerns the
handling of studies from which such data are unavailable. In the current study this was true of only 4
relatively small trials. Analysis of published data from
these trials, 3 of which were probably not properly
randomized, reveals a significant mortality result in
favour of artemether. This result should be treated with
caution, although it is reassuring that no deleterious
effects of the ‘new’ drug were found compared with the
‘gold standard’ quinine. Meta-analyses restricted to
published summary data can be less reliable than those
incorporating both published and unpublished data for
several reasons: they cannot include trials that have not
been published in full; randomized patients inappropriately excluded from analyses cannot be included; combining different reported endpoints can be problematic;
and analyses based on time-to-event data are not possible (STEWART & PARMAR, 1993). Furthermore, the
trial groups do not have the opportunity to be involved
in the interpretation
of their trial data. A recently
published meta-analysis of published data comparing
artemether and quinine produced a similar odds ratio
(95% CI) for overall mortality as the present individual
patient data meta-analysis [0.76 (0.50 to 1.14)], but
was unable to address the important issues of neurological sequelae, combined adverse outcomes, and
coma and fever recovers times (PITILER & ERNST,
1999).
This meta-analysis covers trials conducted on several
different types of patient population. There is a striking
difference in the clinical nresentation of severe malaria
between sub-Saharan Africa and South-East Asia/
Oceania. In parts of tropical Africa where Phsmodium
fdciparum is holoendemic the main clinical manifestation of malaria is severe anaemia in children aged l-3
years, and cerebral malaria is considered rare, although
recent detailed studies challenge this (SCHELLENBERG
et al., 1999). In other areas of Africa, where transmission is less intense, the predominant severe disease
syndrome is cerebral malaria occurring in slightly older
children (BREWSTER & GREENWOOD, 1993; SNOW et
al., 1994). Severe malaria seldom occurs in African
adults living in holoendemic or hyperendemic areas,
but does occur in areas where transmission is sporadic
(ENDESHAW & ASSEFA, 1990). In contrast in SouthEast Asia, where falciparum malaria transmission is
generally unstable and low, severe malaria in (nonimmune) adults is relatively common (HIEN et al.,
1996), and takes the form of a multi-system disorder in
which cerebral manifestations, jaundice, and renal failure are all common. Hence at a population level there
is a difference in clinical presentation between the
META-ANALYSIS
OF ARTEMETHER-QUININE
649
FOR SEVERE MALARIA
severe malaria seen in Africa and that described in
South-East Asia, and this geographical difference is
mirrored bv differences in age. In the 7 studies included
in the meta-analysis, 4 were conducted on African
children. and 3 on South-East Asian adults. Further
differences between these 2 groups of trials include the
presence of low-grade quinine resistance in South-East
Asia, which, in theory, may lead to heterogeneity in the
treatment effect of artemether compared with quinine,
and the sex distribution, as the maioritv of South-East
Asian patients are men (who are more likely to migrate
to malarious areas for work). Subgroup analyses by age
and region suggest that in adults and in Asian patients
artemether is significantly more effective than quinine
in reducing mortality, although, as in the overall analysis, there is no significant treatment effect overall after
adjusting for the subgroup factor (and no significant
heterogeneity between subgroups). The reasons for the
mortality differences in favour of artemether in these
subgroups is unclear. Increased effectiveness in areas of
quinine resistance is a possibility, as is an age-speciiic
variation in efficacy. The natural evolution of severe
malaria in adults tends to be slower than in children,
and this could result in a greater time-window
of
opportunity for an effective drug to salvage the patient.
Malaria-specific immunity, which is related to both age
and geographical region, may attenuate the clinical importance of any drug anti-malarial effect. Hence nonimmune Asian adults (and travellers from developed
countries) may be more dependent on drug effects than
semi-immune African children. The results of subgroup analyses of the presence of the extra-cerebral
complications jaundice and renal failure (both more
common in non-immune adult patients) yielded similar
differences in treatment effect in favour of artemether.
The presence of so many closely linked covariates
makes identification
of the factor(s) underlvina the
difference in treatment effects between the 2 grocps of
trials very difficult.
The results of this meta-analysis can be interpreted
in several ways. The difference in mortality observed (a
relative reduction of 20% in artemether recipients) did
not reach statistical significance. However, we can be
reasonably confident that artemether is at least as effective as quinine, if not better, and if a 20% reduction in
mortality were the true effect this would be of considerable importance. Antimalarial drugs reduce the mortality of severe malaria by killing malaria parasites or
preventing their multiplication.
Artemether acts at an
earlier stage of parasite development compared with
quinine-and
cleared parasites more rapidly. This result should not be interpreted as indicating parasite
clearance is unrelated to life-saving efficacy. The failure
of chloroquine as high-grade resistance develops and
the concomitant increase in mortality suggests that it is.
Many patients who die from severe malaria do so within hours of admission to hospital. They may not be
salvageable. The window of opportunity for improved
antimalarial drug treatments to affect outcome may be
small. The patients who might be saved are, by detinition, the most seriously ill. Yet it is these patients,
whose microcirculatory
function is impaired, who are
most likely to malabsorb the intramuscular oil injection
of artemether (MURPHY et al., 1997). It could be
argued that what artemether gained through its intrinsically greater activity, it lost through inadequate or slow
absorption following intramuscular injection.
These trials provide us with reassuring information
on the safety of both drugs. No adverse effects were
noted with artemether. It was simple and safe to administer. Quinine was associated with hypoglycaemia, but
not with hypotension, deafness or blindness despite use
of a loading dose (20 mg/kg) even to patients who had
already received quinine before admission to hospital.
Artemether is a safe, simple, and effective treatment for
severe falciparum malaria.
Acknowledgements
This meta-analysis was jointly funded by the UNDPWorld
BankWHO Special Programme for Research and Training in
Tropical
Britain.
Diseases (TDR)
and the Wellcome
Trust of Great
References
Brewer, T. G., Peggins, J. O., Grate, S. J., Petras, J. M.,
Levine, B. S., Weina, P. J., Swearengen, J., Heiffer, M. H.
& Schuster, B. G. (1994). Neurotoxicity
in animals due to
arteether and artemether. Transactions of the Royal Society of
Tropical Medicine and Hygiene, 88, supplement 1,33-36.
Brewster, D. R. & Greenwood, B. M. (1993). Seasonal variation of paediatric diseases in The Gambia, west Africa.
Annals of Tropical Paediatrics, 13, 133- 146.
Danis, M., Chandenier, J., Doumbo, O., Kombila, M.,
Kouame, J., Louis, F., Roche, G. & Gentilini, M. (1996).
Results obtained with i.m. artemether versus i.v. quinine in
the treatment of severe malaria in a multi-centre study in
Africa. JapaneseJournal of Tropical Medicine and Hygiene, 24,
93-96.
Early Breast Cancer Trialists’ Collaborative
Group (1990).
Treatment of Ear& Breast Cancer. Volume 1. Worldwide
Evidence 1985-1990. Oxford: Oxford Medical Publications.
Endeshaw, Y. & Assefa, D. (1990). Cerebral malaria. Factors
affecting outcome of treatment in a suboptimal clinical
setting. Journal of Tropical Medicine and Hygiene, 93,44-47.
Genovese, R. F., Newman, D. B., Li, Q., Peggins, J. 0. &
Brewer, T. G. (1998a). Dose-dependent brainstem neuropathology following repeated arteether administration
in
rats. Brain Research Bulletin, 45, 199-202.
Genovese, R. F., Newman, D. B., Petras, J. M. & Brewer,
T. G. (1998b). Behavioral and neural toxicitv of arteether in
rats. ‘Phamzhcology, Biochemistry
and behaviour,
60,
449-458.
Hien, T. T., Day, N. P. J., Phu, N. H., Mai, N. T. H., Chau,
T. T. H., Lot, I’. I’.. Sinh. D. X., Chuona. L. V.. Wailer.
D., Pete,-T. E: A. &White; N. J. (1996). Kcontrolled
trial
of artemether or quinine in Vietnamese adults with severe
falciparum malaria. New England Journal of Medicine, 335,
7h-RZ
Hong, G. (AD 340). Handbook of Emergency Treatments.
Kalbfleisch, J. & Prentice, R. (1980). The Statisrical Analysis of
Failure Time Data. New York: Wiley.
.-
“_.
Karbwang, J., Tin, T., Rimchala, W., Sukontason, K., NamV., Thanavibul,
A., Na-Bangchang,
K.,
siripongpun,
Laothavom, P., Bunnag, D. & Harinasuta, T. (1995). Comparison of artemether and quinine in the treatment of severe
falciparum malaria in south-east Thailand. Transacrions of
the Royal Society of Tropical Medicine and Hygiene, 89,
668-671.
McIntosh, H. & Olliaro, P. (1998). Artemisinin derivatives in
the treatment of severe malaria. In: Infectious Diseases Module of The Cochrane Database of Systematic Reviews, Garner,
P., Gelband, H., Olliaro, P., Salinas, R., Volmink, J. &
Wilkinson, D. (editors). London: BMJ Publishing.
Murphy, S., English, M., Waruiru, C., Mwangi, I., Amukoye,
E., Crawley, J., Newton, C., Winstanley, P., Peshu, N. &
Marsh, K. (1996). An open randomized trial of artemether
versus quinine in the treatment of cerebral malaria in African children. Transactions of the Royal Sociey of Tropical
Medicine and Hygiene, 90,298-301.
Murphy, S., Mberu, E., Muhia, D., English, M., Crawley, J.,
Waruiru, C., Lowe, B., Newton, C., Winstanley, P., Marsh,
K. & Watkins, W. (1997). The disposition of intramuscular
artemether in children with cerebral malaria: a preliminary
study. Transactions of the Royal Society of Tropical Medicine
and Hygiene, 91,331-334.
Myint, P. & Shwe, T. (1987). A controlled trial of artemether
(qinghaosu derivative) versus quinine in complicated and
severe falciparum malaria. Transactions ojthe Royal Society of
Tropical Medicine and Hygiene, 81, 559-561.
Nontprasert, A., Nosten-Bertrand,
M., Pukrittayakamee,
S.,
Vanijanonta, S., Angus, B. J. & White, N. J. (1998). Assessment of the neurotoxicity
of parenteral artemisinin derivatives in mice. American Journal of Tropical Medicine and
Hygiene, 59,519-522.
Petras, J. M., Kyle, D. E., Gettayacamin, M., Young, G. D.,
Bauman, R. A., Webster, H. K., Corcoran, K. D., Peggins,
J. O., Vane, M. A. & Brewer, T. G. (1997). Arteether: risks
of two-week administration
in Macaca mulatta. American
Joumalof Tropical Medicine and Hygiene, 56,390-396.
Pittler, M. H. & Ernst, E. (1999). Artemether for severe
malaria: a meta-analysis of randomized clinical trials. Clinical Infectious Diseases, 28, 597-60 1.
650
THE ARTEMETHER-QUININE
Qinghaosu Antimalarial Coordinating Group (1979). Amimalarial studies on qinghaosu. Chinese Medical Journal, 98,
811-816.
Schellenberg, D., Menendez, C., Kahigwa, E., Font, F.,
Galindo, C., Acosta, C., Schellenberg, J. A., Aponte, J. J.,
Kimario, J., Urassa, H., Mshinda, H., Tanner, M. & Alonso, I’. (1999). African children with malaria in an area of
intense Plasmodium falcipamm transmission: features on
admission to the hospital and risk factors for death. American Journal of Tropical Medicine and Hygiene, 61,43 l-438.
Seaton, R. A., Trevett, A. J., Wembri, J. I’., Nwokolo, N.,
Naraqi, S., Black, J., Laurenson, I. F., Kevau, I., Saweri, A.,
Lalloo, D. G. & Warrell, D. A. (1998). Randomized comuarison of intramuscular artemether and intravenous auihine in adult, Melanesian patients with severe -or
complicated Plasmodiumfalciparum malaria in Papua New
Guinea. Annals of Tropical Medicine and Parasilology, 92,
__- --_.
111-119
Shwe, T., Myint, I’., Htut, Y., Myint, W. & Soe, L. (1988).
The effect of mefloquine-artemether compared with quinine on patients with complicated falciparum malaria.
Transactions of the Royal Society of Tropical Medicine and
Hygiene, 82,665666.
Snow, R. W., Bastos de Azevedo, I., Lowe, B. S., Kabiru,
E. W., Nevill, C. G., Mwankusye, S., Kassiga, G., Marsh,
K. & Teuscher. T. (1994). Severe childhood malaria in two
areas of markehly different falciparum transmission in east
Africa. Acta Tropica, 57,289-300.
StataCorp (1997). Stata Statistical Software Reference Manual.
College Station, Texas: StataCorp.
META-ANALYSIS
STUDY GROUP
Stewart, L. A. & Parmar, M. K. (1993). Meta-analysis of the
literature or of individual patient data: is there a difference?
Lancet, 341,418-422.
Taylor, T. E., Wills, B. A., Courval, J. M. & Molyneux, M. E.
(1998). Intramuscular artemether vs intravenous quinine:
an open, randomized trial in Malawian children with cerebral malaria. Tropical Medicine and Internatiunal Health, 3,
3-8.
Van Hensbroek, M. B., Onyiorah, E., Jaffar, S., Schneider,
G., Palmer, A., Frenkel, J., Enwere, G., Forck, S., Nusmeijer, A., Bennett, S., Greenwood, B. & Kwiatkowski, D.
(1996). A trial of artemether or quinine in children with
cerebral malaria. New England Journal of Medicine, 335,
69-75.
Walker, O., Salako, L. A., Omokhodion, S. I. & Sowunmi,A.
(1993). An open randomized comparative study of intramuscular artemether and intravenous quinine in cerebral
malaria in children. Transactions of the Royal Society of
Tropical Medicine and Hygiene, 87,564-566.
Win, K:, Than, M. & Thwe, Y. (1992). Comparison of
combmations of parenteral artemisinin derivatives plus oral
mefloquine with intravenous quinine plus oral tetracycline
for treating cerebral malaria. Bulletin of the World Health
Organization, 70, m-782.
Received 13 June 2000; revised 2 Februa y 2001; accepted
for publication 28 Februa y 2001
Fondazione Ivo de Carneri
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