Protocols

DESTINY II: DEcompressive Surgery for the Treatment of

malignant INfarction of the middle cerebral arterY II
Eric Jüttler1,2, Julian Bösel1, Hemasse Amiri1, Petra Schiller3, Ronald Limprecht3,
Werner Hacke1, and Andreas Unterberg4, for the DESTINY II Study Group

maximum number of 160 patients to be enrolled (ISRCTN

Background Patients with severe space-occupying – so-called
21702227).
malignant – middle cerebral artery infarcts have a poor
Discussion In the face of an ageing population, the potential
prognosis even under maximum intensive care treatment.
benefit of hemicraniectomy in older patients is of major
Randomised trials demonstrated that early hemicraniectomy
clinical relevance, but remains controversial.
reduces mortality from about 70% to 20% without increasing
Conclusion The results of this trial are expected to directly
the risk of being very severely disabled. Hemicraniectomy
influence decision making in these patients.
increases the chance to survive completely independent more
than fivefold and doubles the chance to survive at least partly Key words: decompressive surgery, elder stroke patients,
independent. Only patients up to 60-years have been in- hemicraniectomy, ischaemic stroke, malignant MCA infarct,
cluded in these trials. However, patients older than 60-years randomised trial
represent about 50% of all patients with malignant middle
cerebral artery infarcts. Data from observational studies,
suggesting that older patients may not profit from hemicra-
Executive summary
niectomy, are inconclusive, because these patients have gen-
erally been treated later and less aggressively. This leads to
Rationale
great uncertainty in everyday clinical practice.
Aims To investigate the efficacy of early hemicraniectomy in About 50% of all patients with malignant middle cerebral
patients older than 60-years with malignant MCA infarcts. artery (MCA) infarcts are older than 60-years. The benefit of
Materials & Methods DEcompressive Surgery for the Treat- hemicraniectomy in these patients is unclear. Data from
ment of malignant INfarction of the middle cerebral arterY II is observational studies are rare and inconclusive, because older
a randomised controlled trial including patients 61-years and patients in these studies were usually treated later and less
older with malignant middle cerebral artery infarcts. Patients aggressively than younger patients.
are randomised to either maximum conservative treatment
alone or in addition to early hemicraniectomy within 48 h
after symptom onset. The trial uses a sequential design with a Aim and hypothesis
DEcompressive Surgery for the Treatment of malignant IN-
farction of the middle cerebral arterY II (DESTINY II) aims to
Correspondence: Eric Jüttler, Department of Neurology, University of investigate the benefit of early hemicraniectomy in addition to
Heidelberg, Im Neuenheimer Feld 400, D-69120 Heidelberg, Germany. maximum conservative treatment to reduce death and very
E-mail: eric.juettler@med.uni-heidelberg.de
1
Department of Neurology, University of Heidelberg, Heidelberg,
severe disability compared with maximum conservative treat-
Germany ment alone in patients with malignant MCA infarcts, who are
2
Center for Stroke Research Berlin, Charité – Universitätsmedizin Berlin, older than 60-years. The primary aim is to assess whether
Berlin, Germany decompressive surgery reduces mortality without increasing
3
Institute of Medical Biometry and Informatics, University of Heidelberg, the number of very severely disabled – i.e. completely depen-
Heidelberg, Germany
4
Department of Neurosurgery, University of Heidelberg, Heidelberg,
dent and bedridden – survivors.
Germany

Funding: This trial was funded by the German Research Council [Deutsche
Forschungsgemeinschaft (DFG)] – ref. JU2764/1-1.
Conflicts of interest: None declared.
DOI: 10.1111/j.1747-4949.2010.00544.x
Design
DESTINY II is a prospective, randomised, controlled,
open, multicentre, two-armed, comparative trial. Patients
are randomised to either conservative treatment alone or

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 Protocols
hemicraniectomy plus conservative treatment within 48 h of
symptom onset. The trial uses a sequential statistical design
analysing statistical significance of the primary endpoint after
every single patient having reached this endpoint. The trial will
be stopped as soon as there is a statistically significant
difference between the two treatment groups.
Study outcomes
The primary endpoint is the patient’s disability after six-months
measured by the modified Rankin Scale (mRS) and dichot-
omised 0–4 vs. 5 or 6. Secondary endpoints are assessed after
one-year including global disability, activities of daily living,
neurological deficit, speech and language disturbance, depres-
sion, quality of life, complications of operative treatment, and
retrospective agreement to treatment.
Discussion
To clarify the potential benefit of hemicraniectomy in older
patients with malignant MCA infarcts, a randomised trial is clearly
needed. The results of this trial are expected to directly influence
decision making in acute ischaemic stroke treatment in the future.
Introduction and rationale
Space-occupying cerebral ischaemic infarcts are associated
with cytotoxic, interstitial, and vasogenic brain oedema of
different extents. Depending on the celerity and extent of
oedema formation, and on individual compensating mechan-
isms of the patient, ischaemic brain oedema in large space-
occupying MCA infarcts may lead to transtentorial or
transforaminal herniation usually after two–five-days (1–3).
Herniation is responsible for 78% of deaths during the first
week (4). For these catastrophic infarcts, the term malignant
MCA infarcts was introduced (2).
Conservative intensive care treatment strategies include
osmotherapy with glycerol, mannitol, or hyperosmolar hydro-
xyl–ethyl starch, intracranial pressure (ICP)-lowering thera-
pies with barbiturates, buffer solutions or hyperventilation,
and neuroprotective therapies such as moderate hypothermia
(5). None of these therapies are supported by adequate
evidence from clinical trials (6, 7). Their benefit in malignant
MCA infarction is doubtful and several authors argue that they
are ineffective or even detrimental (5–8). In particular, ICP-
lowering therapies guided by ICP monitoring seem to have
little effect (9). This may be explained by the fact that
displacement of brain tissue plays the pivotal role in these
infarcts, whereas increased ICP usually occurs late, if it occurs
at all (9, 10). Not surprisingly, this is reflected by clinical
findings: prognosis of patients with malignant oedema for-
mation after MCA infarct is poor despite maximum conser-
vative treatment, and in randomised or larger prospective
observational studies, mortality averages 50–80% (2, 11–16).
Despite their doubtful benefit, conservative treatment options
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E. Jüttler et al.
are currently used in many centres treating patients with
ischaemic infarcts and space-occupying brain oedema (17).
In contrast to therapies targeting ICP, decompressive hemi-
craniectomy is based on mechanical thinking: temporary
removal of a part of the skull would allow oedematous tissue
to stretch outside the neurocranium, thereby avoiding fatal
displacement of brain tissue. Lowering of ICP and consecutive
restoration of cerebral perfusion are probably a secondary
result (9). The procedure can be performed in every neuro-
surgical centre.
The benefit of hemicraniectomy in malignant MCA infarct
has been demonstrated in three randomised trials and a pooled
analysis (13–16): early hemicraniectomy reduces mortality from
71% to 22%. The proportion of patients who remain very
severely disabled is small and is not increased by hemicraniect-
omy compared with conservative treatment (4% vs. 5%). Forty-
three per cent of patients after hemicraniectomy show a good
clinical outcome regarding the severity of these infarcts (mRS
score 2–3), compared with 215% of those treated conservatively.
The proportion of patients who are independent in their
activities of daily living (mRS score 2) increases more than five
times, from 25% to 14%. Likewise, however, the proportion of
patients with moderate-to-severe disability (mRS score 4)
increased more than 12-fold (31% vs. 25%) (13).
The upper age limit in the randomised trials was 60-years and
left the question of a benefit of hemicraniectomy in older patients
unresolved. According to the results of observational trials,
mortality in older patients is not increased after conservative
treatment and amounts 50–80% (2, 11, 12). Data on functional
outcome in these patients, however, are insufficient. Larger case
series on hemicraniectomy show more heterogeneous results: in a
study by Uhl et al. (18), 12% of patients older than 50-years were
independent, 37% died or were severely disabled. Gupta et al. (19)
reported an independent outcome in only 1% of patients older
than 50-years; 80% were severely disabled or died. None of these
studies had a control group. In the largest prospective compara-
tive study, mortality after conservative treatment in patients
older than 60-years was 81% vs. 50% after hemicraniectomy. No
patient was very severely disabled (mRS score 5) (20). However,
of the 53 patients included in this study, only 17 were older than
60-years, and six of these were treated by hemicraniectomy.
None of the published studies including patients older than
60-years with malignant MCA infarcts was randomised, most
were retrospective, and treatment procedures varied con-
siderably. Most of all, possible prognostic factors such as
occlusion of the internal carotid artery, additional infarcts of
the anterior cerebral artery (ACA), and/or the posterior
cerebral artery (PCA), stroke severity, and time to treatment
differed between younger and older patients: older patients in
these studies showed a trend towards more severe infarcts, but
were treated less aggressively, especially when additional
infarcts of the ACA or PCA were present or when they
deteriorated early. In addition, hemicraniectomy in older
patients was performed later and therapy was less often
escalated and/or sooner ceased. Reasons for later intervention
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 E. Jüttler et al. Protocols
may be the belief that compared with younger patients older
patients may less likely proceed to herniation due to more
compensating intracranial space, i.e. lower average brain
volumes and greater CSF space. Altogether, this may have
resulted in a self-fulfilling prophecy with higher mortality rates
of older patients in reported studies (21).

Methods

Design
DESTINY II is a prospective, randomised, controlled, open,
multicentre, two-armed, comparative trial (Fig. 1). Patients are
randomised 1 : 1 to either conservative treatment alone or
hemicraniectomy within 48 h of symptom onset plus conser-
vative treatment. The trial uses a sequential statistical design
analysing statistical significance of the primary endpoint after
every single patient having reached this endpoint. The trial
will be stopped as soon as there is a statistically significant
difference between the two treatment groups.
Based on the experience of DESTINY I, blinding is im-
possible for treating physicians and patients as well as for most
of the investigators.

Patient population – inclusion and exclusion criteria

Subjects meeting all of the following criteria will be considered
for inclusion in the trial:
1. age 61-years or older, either sex
2. clinical signs and symptoms of an unilateral MCA infarct
3. National Institutes of Health Stroke Scale (NIHSS) score
414 (infarcts of the nondominant hemisphere) or 419
(infarcts of the dominant hemisphere)
4. level of consciousness on item 1a of the NIHSS40
5. symptom onset before o48 h before operation or initiation Fig. 1 Study flow chart of the DESTINY II trial.
of conservative treatment
6. neuroradiological findings (noncontrast computed tomo-
graphy or magnetic resonance imaging): unilateral ischaemic 5. secondary space-occupying haemorrhage in the area of
infarction of at least two-thirds of the MCA territory, and infarction (PH2)
at least partially including the basal ganglia. Additional 6. known systemic bleeding or coagulation disorder
involvement of the ACA or PCA territories is optional. These 7. life expectancy o3-years
criteria may be evident either in initial neuroimaging or in any 8. other concomitant severe disease that would confound
follow-up with treatment
7. possibility to start treatment within 6 h after randomisa- 9. other clear contraindication for treatment, and
tion, and 10. participation in any other interventional trial.
8. informed consent by the patient him/herself, his/her legal
representative, adjudication by a legally competent judge, or by
an independent physician neither involved in the patient’s
Screening and randomisation
treatment nor the trial.
Subjects presenting with any of the following criteria will not After admission, clinical examination, neuroimaging, verifica-
be included in the trial: tion of inclusion and exclusion criteria, and informed consent,
1. premorbid mRS score 41 or premorbid Barthel Indexo95 patients are randomly assigned to one of the two treatment
2. coincidental or timely associated other brain lesion groups (visit 1): (1) conservative treatment alone or (2)
3. absence of pupil reflexes hemicraniectomy plus conservative treatment within 48 h of
4. Glasgow Coma Scale (GCS) score o6 symptom onset. Randomisation of patients in one of the two

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 Protocols
treatment groups is carried out online (http://www.randomizer.
at). In order to ensure a balanced distribution of both therapies
in each participating centre, randomisation is stratified for the
centre. In case of failure to randomise a patient online, a 24-h/
7-day phone service is provided for alternative randomisation
by sealed envelopes.
Treatment or intervention
Treatment is started in each group within not later than 48 h
after symptom onset and not later than 6 h after randomisation
(visit 2).
Decompressive hemicraniectomy consists of a large hemi-
craniectomy and a duraplasty. In summary, a large (reversed)
question-mark-shaped skin incision based at the ear is made
from the ipsilateral ear to the occiput, sparing the facial nerve.
After separating the temporal muscle and preparation of the
galea periost, a bone flap with a diameter of at least 12 cm is
removed, including the frontal (up to the middle pupilar line),
parietal (up to 2 cm lateral of the sinus sagittalis superior),
temporal (down to the base of the middle cranial fossa), and
parts of the occipital (up to 4 cm behind the outer ear canal)
squamae. If necessary, additional temporal bone is removed so
that the floor of the middle cerebral fossa can be explored. The
dura is opened and an augmented dural patch, consisting of
homologous periost, temporal fascia, or lyophylised cadaver
dura is inserted. The dura is fixed at the margin of the
craniotomy to prevent epidural bleeding. The temporal muscle
and the skin flap are then reapproximated and secured.
Resection of necrotic tissue is not recommended, but optional.
Insertion of an ICP probe or other monitoring probes is
optional but not obligatory. After surgery, patients are trans-
ferred to the ICU. In surviving patients, cranioplasty is
performed after six-weeks to six-months, using the stored
bone flap (at 801C) or an artificial bone flap.
Conservative treatment: So far, no mode of conservative
treatment in malignant MCA infarction has been proven to
be effective or superior to another. As a result, treatment
options may vary between institutions. The following recom-
mendations are the result of a consensus protocol of all
participating centres:
1. Osmotherapy: osmotherapy may be started at any time
point after randomisation. The use of mannitol (20%, 100 ml
or 05–10 g/kg every 4–6 h, maximum 25 g/kg/day), glycerol
(10%, 250 ml, four times per day), or hydroxyl–ethyl starch
(6% in 09% saline, 100–250 ml every 8 h, maximum 750 ml/
day) is left at the discretion of the treating physician. Dosage
depends on serum osmolality, which should reach 315–
320 mOsm. In particular, in combination with mannitol and
under rigorous control of serum sodium levels, 10% saline
(repeatedly administered as 75 ml boluses) may be used.
2. Intubation and mechanical ventilation: patients should be
intubated at a GCS score o8, when there are any signs of respi-
ratory insufficiency (arterial pO2o60 mmHg and/or pCO24
48 mmHg), reduced swallowing or coughing reflexes, or when
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the airway is compromised. Earlier intubation and mode of
ventilation are left at the discretion of the treating physician.
3. Hyperventilation: the use of hyperventilation is discour-
aged in the early phase of treatment. In the case of further
neurological deterioration and/or uncontrolled increase in
ICP, hyperventilation may be started as an ultima ratio. It is
advised to monitor venous oxygenation with jugular bulb
oxymetry and to maintain saturation above 50%. Arterial
pCO2 may be reduced to 28–32 mmHg.
4. Buffer solution may be used as the last option when other
therapeutic attempts have failed. Trimethamin (THAM, Tris
buffer) is recommended (1 mmol/kg as bolus over 45 min,
followed by 025 mmol/kg/h, arterial target pH 75–755). If
ICP does not decrease 10–15 mmHg within 15 min, treatment
should be considered as ineffective.
5. Hypothermia is not recommended within this trial, but is
optional.
6. ICP monitoring: the use and mode of invasive ICP mon-
itoring are left at the discretion of the treating physician. If
used, measurement should be performed in the ipsilateral side.
7. Sedation: the mode of sedation is left at the discretion of the
treating physician. The use of barbiturates is discouraged,
because they may reduce cerebral perfusion pressure and often
do not lead to sustained control of ICP. The use of muscle
relaxants is left at the discretion of the treating physician.
8. Blood pressure control: blood pressure is controlled accord-
ing to the latest recommendations of the treatment of acute
ischaemic stroke (22). The use of catecholamines or antihy-
pertensive drugs is left at the discretion of the treating
physician. An exception is made in patients after decompres-
sive surgery. Blood pressure during the first 8 h after surgery is
kept at 140–160 mmHg to avoid severe bleedings.
9. Positioning: flat head positioning is recommended. In
patients at risk for aspiration or pneumonia, or after intuba-
tion, elevation of the head of 15–301 is recommended.
10. Body core temperature: normothermia is recommended.
Elevated body temperature is treated as soon as it exceeds 3751C
(22). The use of antipyretics, external cooling, or intravasal
cooling is left at the discretion of the treating physician.
11. Blood glucose level: blood glucose level should not exceed
140 mg/dl (8 mmol/l), with a target level of 80–110 mg/dl using
insulin if necessary. Hypoglycaemia is treated with infusion of
10% or 20% glucose solution (22).
12. Haemoglobin concentration should be above 10 g/dl using
erythrocyte concentrates, if necessary.
13. For prophylaxis of deep venous thrombosis, low-molecu-
lar-weight heparins s.c. are recommended.
Intensive care treatment may vary between centres, but has
to be standardised within each participating centre. All treat-
ments in the ICU are documented for postprotocol analysis.
The total duration of acute treatment (visits 1 and 2)
is individual, usually o2-weeks, but may be longer. According
to the trial protocol, visit 2 is followed by two further visits at
six-months (visit 3) and one-year (visit 4) after randomisation.
These two visits are part of the trial and are performed by
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 E. Jüttler et al.
investigators, who were not involved in the patient’s treatment.
The last follow-up will be after one-year for all arms (Table 1).
Primary outcome
Functional outcome according to the mRS score and dichot-
omised 0–4 vs. 5 or 6, recorded six-months714-days after
randomisation (23).
Secondary outcomes
All secondary endpoints are recorded one-year714-days after
randomisation.
 median survival time (time from randomisation to death by
any reason on the basis of Kaplan–Meier estimation)
 overall mortality (death of any reason)
 time from surgery to bone flap reimplantation
 rate of surgery-related complications (after initial surgery
and after bone flap reimplantaion including surgery-related
haemorrhage requiring blood transfusions, anaesthesia-re-
lated incidents, pain requiring pharmacological treatment,
impaired wound healing or wound infection, liquor fistula,
hygroma, or any other secondary complication leading to
prolongation of hospitalisation or rehospitalisation)
 neurological status (NIHSS score) (24)
 disability (mRS score, distribution, and dichotomisation at
0–4 vs. 5 or 6 and at 0–3 vs. 4–6)
Protocols
 activities of daily living (Barthel Index) (25)
 quality of life (SF-36 and EuroQoL 5D) (26–28)
 speech and language disturbance (Aachen Aphasia Test) (29)
 retrospective consent to treatment, and
 depression (Hamilton Depression Rating Scale) (30).
Data management and monitoring body
All data specified in the trial protocol will be documented in
the patient’s records and on standardised case report forms
(CRFs), available as original with two copies. The investigating
physician is responsible for appropriate completion of the
form. The Institute of Medical Biometry and Informatics
Heidelberg is responsible for database development, data
acquisition via double entry, data storage, and validation.
Data validation includes controls of completeness, consis-
tence, and plausibility of the data documented in the CRF
using a query system between the data management and the
investigating physician. After resolution of all queries con-
cerning enrolled patients, the databank is closed (end of the
trial) and forwarded to the biometrician for the purpose of
evaluation. After finalisation of all evaluations, the final report
and all original CRFs are delivered to the principal investigator.
The trial is supervised and monitored by the Coordination
Center for Clinical Trial (KKS) Heidelberg including initiation
and regular site visits, source data verification, and reports of

Table 1 Procedures of the DESTINY II trial

Visit 1: Visit 2: conservative Visit 3: Visit 4:

screening/ treatment/ follow-up: follow-up:
randomisation hemicraniectomy six-months714-days one-year714-days

Age, gender, height, weight Xa

Time and date of symptom onset and admission Xa
Modified Rankin Scale Xa,b X X
Barthel Index Xa,b X
NIH Stroke Scale Xa X
Glasgow Coma Scale Xa
Neuroimaging (CT, MRT): time and date, Xa
infarct localization, infarct size, involvement of
ACA/PCA territory, involvement of basal ganglia,
contralateral infarct, and parenchymal hematoma
Inclusion/exclusion criteria X
Informed consent X Xc Xc
Randomisation: time and date, random number, X
and treatment arm
Treatment: time and date of treatment start, X
treatment arm
Skull reimplantation: time and date X
SF-36 X
EuroQoL 5D X
Hamilton Depression Rating Scale X
Aachener Aphasia Test X
Agreement to remain in trial X X
SAE X X X
a
Routine examination. bPremorbid status. cIf patient was not capable of giving informed consent previously and has regained his/her capability of giving
informed consent.

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 Protocols
adverse events. All data management and supervising proce-
dures are performed according to standard operation proce-
dures (SOPs) and in accordance to ICH-GCP Guidelines (E6)
and the Declaration of Helsinki.
Statistical methods
Hypotheses
The primary endpoint is a dichotomised endpoint, score on the
mRS 0–4 ( 5 success) vs. 5 or 6 ( 5 failure) six-months after ran-
domisation. The two-sided test problem is described as follows:
H0 : pdecompression ¼ pconservative
vs: H1 : pdecompression ¼
6 pconservative
or
H0 : y ¼ 0 vs: H1 : y ¼ 6 0;
 
pdecompression ð1  pconservative Þ
y ¼ log
pconservative ð1  pdecompression Þ
pdecompression represents the success rate (mRS score 0–4) after
decompressive hemicraniectomy plus conservative treatment,
pconservative represents the success rate (mRS score 0–4) after
conservative treatment alone, and y represents the log odds ratio.
Analyses
Planning and analysis of the primary endpoint is performed
using the software pest 44 (Planning and Evaluation of
Sequential Trials, John Whitehead, Hazel Brunier, 1989, The
PEST project, University of Reading). The trial is planned as a
sequential trial with an inspection after each patient that
reaches the primary endpoint.
Before each interim analysis, the assignment to the analysis
populations (full analysis set, per protocol set, safety analysis
set) will be decided according to the specification given in the
analysis plan.
As soon as an interim analysis shows a significant difference of
success rates, and at the recommendation of the Data Safety and
Monitoring Board (DSMB), the steering committee will stop the
trial. Depending on the intermediate results of the sequential
analysis, the trial will include a maximum of 160 patients.
According to the concept of the triangular test, early stopping
of the trial with a nonsignificant result is also possible.
All trial participants who have not reached the primary
endpoint at the moment of preliminary evaluation-related or
premature termination of the trial are considered as over-
running patients. Their treatment will be continued and
evaluated separately. Their data are not part of the final
confirmatory analysis but will be evaluated separately and
the results will be appended to the results of the final analysis.
For the primary analysis, the triangular test for a binary
endpoint according to Whitehead will be applied with a two-
sided significance level of a 5 005 and a power of 90%. The
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confirmatory analysis will be performed on the basis of the full
analysis set. Additionally, a per protocol analysis will be carried
out that includes all patients without major protocol violations.
Secondary endpoints will be evaluated descriptively. De-
pending on the scales of the variables, the following character-
istics are indicated: mean, standard deviation, median,
minimum and maximum, first and third quartile, or absolute
and relative frequency. Additional descriptive P-values for
group comparisons and corresponding 95% confidence inter-
vals will be given where indicated. Comparability of both
treatment groups will be evaluated by a comparison of demo-
graphic data and baseline values.
Sample size calculation
According to the available data based on observational studies
and case reports until 2007 (90 publications, 1834 patients, 386
of those with individual outcome data, including 106 older
than 61-years, 35 of those treated conservatively and 71 by
hemicraniectomy), the expected success rate is 86% in the
conservative arm and 310% in the surgical arm, respectively.
The absolute difference of success rate is 224%, the log odds
ratio y is 156.
In a classic study design, the expected difference of the
primary endpoint would require the inclusion of 65 patients
per arm corresponding to a total number of 130 patients.
According to the triangular test for the binary endpoint, the
sequential design requires a lower number of patients: a
significant difference is expected with a probability of 50%
after enrolment of 66 patients (33 per arm), and with a
probability of 90% after inclusion of less than 130 patients.
The maximum number of cases is 160 (80 per arm).
Duration
Based on the number of patients treated in the participating
centres within the past three-years, the estimated number of
recruited patients averages five per month after activation of
all attending centres. Thus, the duration of the trial is estimated
four-years, including initiation and evaluation, or three-years
starting with the inclusion of the first patient, respectively.
Study organisation
Steering committee
The steering committee consists of the neurological (Professor
Eric Jüttler, principal investigator) and the neurosurgical
(Professor Andreas Unterberg) project manager along with
the director of the leading trial centre (Professor Werner
Hacke). The Steering Committee is responsible for planning
of the trial including funding, development of the trial proto-
col in cooperation with the participating centres, design
of patient’s and legal representative’s information and in-
formed consent, approval of the trial protocol and informed
consent including later amendments by legal authorities and
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 E. Jüttler et al.
ethics committees, selection, verification, and recruitment of
potential trial centres, design of the CRF, and organisation of a
randomisation system on a 24-h/7-days basis including a trial-
phone hotline. Based on the results of the sequential design and
the recommendations of the DSMB, the steering committee
decides on preliminary termination or continuation of the
trial. The steering committee can also stop the trial prelimin-
ary, if advised so for other reasons by the DSMB. Furthermore,
the steering committee has to give consent to reports and
publication of trial results.
DSMB
Safety aspects of the trial are supervised by the DSMB. The
DSMB consists of an independent stroke physician (Professor
Kennedy Lees, University of Glasgow, UK), neurosurgeon
(Professor Peter Hutchinson, University of Cambridge, UK),
and epidemiologist (Professor Ale Algra, University of Utrecht,
the Netherlands), not involved in the planning or conduction
of the trial. The DSMB independently elects a chairman. The
DSMB is responsible for critical evaluation and suggestions for
improvement of the trial protocol and supervision of the trial
course. The DSMB has to be informed about the results of
the sequential analysis of the primary endpoint after every
10 patients having reached this endpoint, but at least every six-
months starting with the day of inclusion of the first patient,
and immediately when there is a statistically significant result
concerning the primary endpoint by the responsible bio-
statistician including the result of the sequential analysis
and number of severe adverse events in each of both treat-
ment groups. In case of a significant result ahead of time, the
responsible biostatistician has to inform the DSMB immedi-
ately. Based on these results of the sequential trial design
and safety aspects, the DSMB will recommend to continue
or stop the trial. The members of the DMSB confer personally
or via telephone and report their recommendations to the
steering committee.
The DESTINY II study group
Ten centres are currently participating, eight others are under way:
University of Heidelberg (J. Bösel, Department of Neu-
rology; A. Unterberg, Department of Neurosurgery);
Charité – Universitätsmedizin Berlin [T. Nowe, Center for
Stroke Research Berlin (CSB); J. Woitzik, Department of
Neurosurgery];
University of Dresden (H. Schneider, Department of
Neurology; T. Pinzer, Department of Neurosurgery);
University of Leipzig (D. Schneider, Department of Neurol-
ogy; J. Meixensberger, Department of Neurosurgery);
University of Erlangen (H.B. Huttner, Department
of Neurology; O. Ganslandt, Department of Neurosurgery);
University of Mainz (S. Klimpe, Department of Neurology,
T. Kerz, Department of Neurosurgery);
University of Münster (M. Ritter, Department of Neurology,
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International Journal of Stroke & 2011 World Stroke Organization Vol 6, February 2011, 79–86
Protocols
W. Stummer, Department of Neurosurgery);
Medizinische Hochschule Hannover (K. Weissenborn,
Department of Neurology, E. Herrmann, Department of
Neurosurgery);
University of Freiburg (W.-D. Niessen, Department of
Neurology, M. Shah, Department of Neurosurgery);
University of Frankfurt (C. Foerch, Department of Neuro-
logy, H. Vatter, Department of Neurosurgery);
University of Munich (LMU) (T. Pfefferkorn, Department
of Neurology, A. Peraud, Department of Neurosurgery); and
University of Munich (TU) (H. Poppert, Department of
Neurology, M. Stoffel, Department of Neurosurgery).
The DESTINY trial team
J. Bösel, H. Amiri, A. Dormann, P. Beck, Department of
Neurology, University of Heidelberg.
Summary and conclusions
The benefit of hemicraniectomy after malignant MCA infarc-
tion in reducing death, without increasing most severe dis-
ability, and increasing independency has been demonstrated
in patients under 60-years by randomised controlled trials.
Although available data from observational studies suggest a
reduced benefit of hemicraniectomy in older patients, these
data are insufficient for decision making in clinical practice.
Owing to the fact that about 50% of patients with malignant
MCA infarction are older than 60-years, this question is of
great clinical relevance, especially with regard to our ageing
population. DESTINY II aims to investigate the benefit of early
hemicraniectomy plus conservative treatment vs. conservative
treatment alone in a randomised, controlled, multicentre,
sequential trial design. The results are expected to answer
one of the most urgent questions in the treatment of malignant
MCA infarction, thereby directly influencing recommenda-
tions for acute stroke treatment. Many open questions such as
long-tem retrospective agreement of patients with malignant
MCA infarcts and the impact of chronic disability or predicting
factors for the development of space-occupying oedema and
the benefit from hemicraniectomy, such as neuroimaging
findings, timing, and operating techniques, are still unre-
solved. In order to answer these questions, studies including
much larger numbers are needed. Currently, a prospective
registry including all patients with large MCA infarcts irre-
spective of treatment is in a planning status (31).
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