Lipton RB, Stewart WF, Stone AM, Láinez MJA, Sawyer JPC. Stratified Care vs Step Care Strategies for MigraineThe Disability in Strategies of Care (DISC) Study:A Randomized Trial. JAMA. 2000;284(20):2599-2605. doi:10.1001/jama.284.20.2599
Author Affiliations: Departments of Neurology, Epidemiology, and Social Medicine, Albert Einstein College of Medicine, Bronx, NY, and Innovative Medical Research Inc, Stamford, Conn (Dr Lipton); Department of Epidemiology, Johns Hopkins School of Public Health, and Innovative Medical Research Inc, Baltimore, Md (Dr Stewart); AstraZeneca, Macclesfield, Cheshire, England (Mr Stone and Dr Sawyer); and Hospital Clinico Universitario, Universidad de Valencia, Valencia, Spain (Dr Láinez).
Context Various guidelines recommend different strategies for selecting and
sequencing acute treatments for migraine. In step care, treatment is escalated
after first-line medications fail. In stratified care, initial treatment is
based on measurement of the severity of illness or other factors. These strategies
for migraine have not been rigorously evaluated.
Objective To compare the clinical benefits of 3 strategies: stratified care, step
care within attacks, and step care across attacks, among patients with migraine.
Design and Setting Randomized, controlled, parallel-group clinical trial conducted by the
Disability in Strategies Study group from December 1997 to March 1999 in 88
clinical centers in 13 countries.
Patients A total of 835 adult migraine patients with a Migraine Disability Assessment
Scale (MIDAS) grade of II, III, or IV were analyzed as the efficacy population;
the safety analysis included 930 patients.
Interventions Patients were randomly assigned to receive (1) stratified care (n =
279), in which patients with MIDAS grade II treated up to 6 attacks with aspirin,
800 to 1000 mg, plus metoclopramide, 10 mg, and patients with MIDAS grade
III and IV treated up to 6 attacks with zolmitriptan, 2.5 mg; (2) step care
across attacks (n = 271), in which initial treatment was with aspirin, 800
to 1000 mg, plus metoclopramide, 10 mg. Patients not responding in at least
2 of the first 3 attacks switched to zolmitriptan, 2.5 mg, to treat the remaining
3 attacks; and (3) step care within attacks (n = 285), in which initial treatment
for all attacks was with aspirin, 800 to 1000 mg, plus metoclopramide, 20
mg. Patients not responding to treatment after 2 hours in each attack escalated
treatment to zolmitriptan, 2.5 mg.
Main Outcome Measures Headache response, achieved if pain intensity was reduced from severe
or moderate at baseline to mild or no pain at 2 hours; and disability time
per treated attack at 4 hours for all 6 attacks, compared among the 3 groups.
Results Headache response at 2 hours was significantly greater across 6 attacks
in the stratified care treatment group (52.7%) than in either the step care
across attacks group (40.6%; P<.001) or the step
care within attacks group (36.4%; P<.001). Disability
time (6 attacks) was significantly lower in the stratified care group (mean
area under the curve [AUC], 185.0 mm · h) than in the step care across
attacks group (mean AUC, 209.4 mm · h; P<.001)
or the step care within attacks group (mean AUC, 199.7 mm · h; P<.001). The incidence of adverse events was higher
in the stratified care group (321 events) vs both step care groups (159 events
in across-attack group; 217 in within-attack group), although most events
were of mild-to-moderate intensity.
Conclusion Our results indicate that as a treatment strategy, stratified care provides
significantly better clinical outcomes than step care strategies within or
across attacks as measured by headache response and disability time.
As the therapeutic armamentarium for migraine expands, clinicians and
patients have an unprecedented range of treatment choices.1- 4
Emerging treatment guidelines recommend strategies for selecting and sequencing
acute treatments without empirical evidence.2- 4
Ultimately, the goal of optimal migraine care is to initiate effective treatment
strategies as early as possible, thereby minimizing pain and disability.4
At least 3 different acute treatment strategies have been proposed for
migraine: step care across attacks, step care within attacks, and stratified
In step care across attacks, patients begin with a nonspecific therapy (ie,
a simple or combination analgesic). After treating several attacks, if the
treatment result is unsatisfactory, patients recontact their clinician for
treatment escalation. The process is repeated until a satisfactory treatment
result is achieved. This approach, often advocated in managed care treatment
guidelines, has a number of advantages and disadvantages.5,6
In step care within attacks, patients initially treat an attack with
a nonspecific therapy. At a specific timepoint posttreatment, usually 2 hours,
patients assess their response and, if needed, take another medication, often
migraine-specific. This approach provides patients with a real-time strategy
for managing treatment failure.5
In stratified care, the initial treatment is selected based on the patient's
treatment needs. Variants of stratified care are recommended in various treatment
guidelines.3,4 We have suggested
that headache-related disability (activity limitations in various domains
of function) may serve as the basis for stratification in migraine care.5,6 In clinical simulations, physicians
use headache-related disability to determine severity of illness and to inform
the choice of treatment.7 Although this approach
of matching treatment to severity of illness is intuitive7
and used for other conditions (eg, asthma8),
it has not been tested empirically in migraine.
To date, stratified care based on the Migraine Disability Assessment
Scale (MIDAS) grade and step-care strategies for the acute treatment of migraine
have not been rigorously evaluated. Therefore, we conducted a randomized clinical
trial of 3 treatment strategies. In this study, patients were randomized,
not to a drug, but to a strategy of care.
This was a randomized, parallel group, open-label, multiple attack study
conducted by the Disability in Strategies of Care Study group for patients
with an established diagnosis of migraine based on the International Headache
Society's criteria.9 Patients were recruited
from 88 centers in 13 countries. During the course of the 15-month clinical
trial (December 1997 to March 1999), each participant treated up to 6 moderate
to severe migraine attacks. Aspirin plus metoclopramide was selected as the
nonspecific treatment because it is widely used around the world and has proven
efficacy in migraine.10,11 Zolmitriptan,
2.5 mg, a widely used oral triptan, was selected as the migraine-specific
Patients provided written informed consent during the first clinic visit
(baseline). The trial was designed and monitored in accordance with the ethical
principles of Good Clinical Practice13 as required
by the major regulatory authorities and in accordance with the Declaration
The MIDAS questionnaire measures lost time in 3 domains of activity
due to headaches; it has been extensively validated.15- 17
MIDAS was used to assign a disability grade to each patient (grade I [little
or infrequent disability, score 0-5]; grade II [mild or infrequent disability,
score 6-10]; grade III [moderate disability, score 11-20]; and grade IV [severe
disability, score ≥21]), indicating overall illness severity during a 3-month
recall period. (Disability assessment for each treated migraine attack was
measured as disability time as described below). Patients with grade I headaches
were excluded from the trial because we determined that the majority of patients
in this category do not warrant treatment with a triptan.
Eligible patients with a MIDAS grade of II, III, or IV were randomized
to 1 of 3 treatment groups.
Stratified Care. Patients with grade II headache received aspirin, 800 to 1000 mg (depending
on the standard dose in each country), plus metoclopramide, 10 mg, as their
acute treatment for all 6 attacks. Patients with grade III or IV headache
received zolmitriptan, 2.5 mg, as their acute treatment for all attacks. Patients
were asked not to take rescue medication within the first 4 hours of the attack.
Step Care Across Attacks. Patients treated the first 3 attacks with aspirin, 800 to 1000 mg, plus
metoclopramide, 10 mg. Those who did not have a satisfactory headache response
(defined as a reduction in pain intensity from severe or moderate at baseline
to mild or no pain at 2 hours in at least 2 of the 3 attacks) were instructed
to escalate ("step up") therapy to zolmitriptan, 2.5 mg, for the next 3 attacks.
The remaining patients continued using aspirin plus metoclopramide for the
remaining 3 attacks.
Step Care Within Attacks. Patients initiated treatment with aspirin, 800 to 1000 mg, plus metoclopramide,
10 mg, for all attacks. After 2 hours, if a satisfactory headache response
was not achieved, patients were instructed to step up therapy and take zolmitriptan,
Patients were allocated to treatment groups in balanced blocks and allocated
sequentially by sex and MIDAS grade.
Eligible patients (1) ranged in age from 18 to 65 years, met the International
Headache Society's criteria for migraine with or without aura,9
and had onset of their first migraine before age 50 years; (2) had from 1
to 8 migraine attacks per month for the previous 3 months and had not taken
a triptan (selective serotonin1B/1D agonist) within the last 3
months; (3) had fewer than 10 nonmigraine headache days per month during the
previous 6 months and could differentiate between migraine and nonmigraine
headaches, if they had both; and (4) could not start or change preventive
therapy during the study.
Patients were excluded from the study if they (1) had a medical or psychiatric
condition that might increase the risk of study medication or interfere with
efficacy or safety assessments; (2) had a history of basilar, ophthalmoplegic,
or hemiplegic migraine; or (3) were lactating or pregnant.
During the baseline visit, eligible patients were randomized to 1 of
the 3 treatment groups, provided with diary cards, study medications, and
instructions. Patients used diary cards to track treatment response (intensity,
duration, treatment, and rescue medication). Patients graded pain intensity
of each attack as none, mild, moderate, or severe and were instructed to treat
only moderate or severe migraine attacks. Attacks were not eligible for study
treatment if they were present for more than 12 hours, if an acute analgesic
was used during the previous 6 hours, or if ergotamine or opiates were used
during the previous 24 hours.
A maximum of 2 additional doses of study medication were allowed for
treatment of a single attack (maximum daily dose: zolmitriptan, 7.5 mg, aspirin,
3000 mg, and metoclopramide, 30 mg) for persistent or recurrent migraine.
Rescue medications (eg, nonsteroidal anti-inflammatory drugs, antiemetics,
analgesics, and sedatives) were not permitted within 4 hours, ergotamine was
not permitted for 6 hours, and other triptans were not permitted for 12 hours
following treatment with study medications.
Patients made follow-up visits after treating their third (visit 2)
and sixth attack (visit 3), at which time headache diaries were reviewed.
At visit 2 in the step care across attack group, treatment was escalated in
patients who responded to aspirin plus metoclopramide in only 0 or 1 of the
Patients recorded pain intensity (at baseline, 1, 2, and 4 hours) using
a 4-point scale (0 = no pain, 1 = mild pain, 2 = moderate pain, and 3 = severe
pain). Functional status was recorded on a 0- to 100-point scale in which
0 represented an inability to do any activities and 100 represented perfectly
normal function. Headache response at 2 hours and disability time per treated
attack at 4 hours were the primary outcome measures. Headache response was
achieved if headache pain intensity was reduced from severe or moderate at
baseline to mild or no pain within 2 hours. Disability time was calculated for each attack and defined as the area under disability
vs time curve (AUC). Level of disability was defined
as 100 minus the recorded level of functionality and was measured at baseline,
1, 2, and 4 hours. Secondary efficacy end points included 1-hour or 4-hour
headache response and 2-hour pain-free response.
Adverse events were recorded on patient diary cards and defined as mild,
moderate, or severe. Any detrimental changes in the patient's condition that
occurred between taking the first dose of study medication and up to 24 hours
after taking the last dose of trial medication (for the treatment of the same
migraine headache) was defined as an adverse event. A serious
adverse event was defined as fatal, life-threatening, requiring prolonged
hospitalization, resulting in disability or incapacity, resulting in a congenital
abnormality, or requiring medical intervention to prevent permanent impairment
Power calculations indicated that 300 participants were needed per study
group to detect a difference of 15% in headache response at 2 hours. This
was based on 2 assumptions: that approximately 20% of the patients would not
be evaluable or would be withdrawn from the trial and that headache response
rates of 50% would be achieved for the 2 step care strategies. Treatment efficacy
rates at 2 hours for patients with grade III or IV headaches in the stratified
care group were based on published reports for zolmitriptan (62% to 65%)12,18 and for aspirin plus metoclopramide
Data were analyzed for the efficacy population, defined as all participants
who were randomized and treated at least 1 migraine attack and reported at
least 1 efficacy assessment. All statistical testing was 2-tailed at the 5%
type I error.
A random effects analysis of variance model was used to analyze continuous
measures. Discrete data were analyzed using a generalized linear mixed model
(using SAS macro GLIMMIX19). Both analyses
allowed for the fixed effects of treatment regimen (stratified care, step
care within attacks, step care across attacks), baseline MIDAS grade, attack
baseline headache intensity/disability as appropriate, country, attack group
(1-3 vs 4-6), attack number within an attack group, interaction between treatment
and attack group (this allowed separate treatment effects to be produced for
each attack group), and a random patient effect. Analysis of data revealed
the most appropriate variance/covariance matrix was unstructured. Effect sizes
are presented as either odds ratios (OR) (for discrete data) or differences
in least squares means (for continuous data), with 95% confidence intervals
(CIs). In studies of common outcomes, the OR should not be interpreted as
a measure of relative risk.
The efficacy population totaled 835 migraine patients (Figure 1) who completed 2-hour efficacy data taken from the patient
diary data on at least 1 attack and excluded those patients who did not complete
diary cards (n = 129), but who received the study medication, or who were
affected by a MIDAS grade protocol amendment (n = 98). (This procedure for
scoring and grading disability was modified based on reliability studies.15,17)
The safety and tolerability population included all participants who
were randomized to treatment and received at least 1 dose of study medication
for a migraine attack.
The 3 treatment groups were well balanced with respect to demographic
and headache characteristics (Table 1),
and no differences were observed between treatment groups. Of the 1062 patients,
a total of 219 patients (20.6%) were withdrawn from the study because of loss
to follow-up (n = 90, 8.5%), withdrawal of informed consent (n = 35, 3.3%),
protocol noncompliance (n = 33, 3.1%), adverse event/concurrent illness (n
= 32, 3.0%), deterioration in patient condition (n = 2, 0.2%), and for other
reasons (n = 27, 2.5%). No significant differences were observed in the number
of withdrawals between stratified care and step care across attacks groups
(P = .91) or stratified care and step care within
attacks groups (P = .92). The reasons for withdrawal
were evenly distributed across treatment groups and MIDAS grades.
Stratified Care vs Step Care Across Attacks. The proportion of all attacks responding at 2 hours was significantly
greater for stratified care than for step care across attacks for all 6 attacks
(OR, 1.67; CI, 1.31-2.12; P<.001; Figure 2). Similar results were evident for headache response at
1 hour (OR, 1.61; CI, 1.20-2.15; P = .001) and 4
hours (OR, 1.76; CI, 1.38-2.24; P<.001).
For the first 3 attacks, the stratified care group showed a significantly
higher 2-hour headache response than the step care across attacks group (OR,
2.91; CI, 2.18-3.87; P<.001; Table 2). In the step care across attacks group, treatment was escalated
for attacks 4 to 6 in those patients who did not respond (ie, in at least
2 of the 3 attacks treated with aspirin plus metoclopramide). Treatment was
escalated in 56.4% of patients with MIDAS grade II, 68.9% of patients with
grade III, and 74% of patients with grade IV headache. The proportion of patients
needing to step up treatment significantly increased with increasing MIDAS
grade (χ2 for trend, P = .03). For
attacks 4 to 6, stratified care vs step care treatment strategies did not
differ for 2-hour headache response rates (P = .79; Table 2).
Disability time (from 0-4 hours) averaged across all 6 attacks was significantly
lower for stratified care (AUC = 185 mm · h) than step care across
attacks (AUC = 209.4 mm · h; treatment effect, −21.25; CI, −31.44
to −1.07; P<.001; Figure 3). The difference was explained by a significantly greater
disability time for attacks 1 to 3 in the step care across attacks group compared
with the stratified care group (treatment effect, −42.61; CI, −54.01
to −31.21; P<.001). Following treatment
escalation in this group, no differences were observed with stratified care
for attacks 4 to 6 (P = .99).
The proportion of attacks achieving a 2-hour pain-free response was
significantly greater for the stratified care group than the step care across
attacks group (OR, 1.66; CI, 1.18-2.32; P = .003; Table 2). Again, the statistically significant
difference during the first 3 attacks (OR, 3.05; CI, 2.01-4.62; P<.001; Table 2) accounts
for much of the advantage of stratified care over step care treatment strategy.
Stratified Care vs Step Care Within Attacks. Across all 6 attacks, the proportion of attacks with a headache response
at 2 hours was significantly higher for the stratified care treatment group
than for the step care within attacks group (OR, 2.14; CI, 1.66-2.77; P<.001; Figure 2).
This was evident for attacks 1 to 3 (OR, 2.05; CI, 1.55-2.72; P<.001) and attacks 4 to 6 (OR, 2.24; CI, 1.64-3.07; P<.001; Table 2). Patients
who did not achieve a headache response at 2 hours had the option of taking
zolmitriptan, 2.5 mg, as a rescue medication. Comparing the stratified care
and step care within attacks groups, significant differences in the proportion
of attacks that responded to treatment were evident at 1 hour (OR, 1.77; CI,
1.33-2.36; P<.001). Between-group differences
were not evident at 4 hours (P = .21); patients in
the step care group who did not respond by 2 hours could escalate their treatments
to zolmitriptan, 2.5 mg (Figure 2).
Disability time from 0 to 4 hours was significantly lower in the stratified
care treatment group (AUC = 185 mm · h) compared with the step care
within attacks group (AUC = 200 mm · h; all attacks, treatment effect, −
19.43; CI, −29.73 to −9.14; P<.001).
Separation between the 2 treatment groups was most evident up to 2 hours prior
to rescue with zolmitriptan. By 4 hours (Figure 3), though the AUC was lower for step care, the between-group
differences in disability time also had decreased.
Stratified care provided more effective treatment than step care within
attacks for the proportion of attacks that were pain-free at 2 hours (6 attacks,
OR, 1.68; CI, 1.20-2.36; P = .003). Similar trends
were evident at 1 and 4 hours.
The safety and tolerability population included 930 patients treating
4945 migraine attacks. Adverse events were reported in 697 attacks (14.1%).
Many of the most common adverse events (defined as those occurring with a
frequency >2.0%), including asthenia, dizziness, and paresthesia, were those
usually seen with triptan treatment (Table
3). Adverse events in all treatment groups were predominantly mild
to moderate and not severe (Table 3).
One patient reported 7 serious adverse events during the course of an attack,
defined as the period within 24 hours of taking the last dose of study medication.
This patient was in the step care within attack treatment group and experienced
2 episodes of abdominal pain, 3 episodes of parasthesia, and 2 reports of
somnolence and was withdrawn from the study after the third attack.
Six patients reported serious adverse events that started more than
24 hours after receiving the initial dose of treatment medication: 2 in the
stratified care treatment group, 3 in the step care across attacks group,
and 1 in the step care within attacks group. Adverse events leading to withdrawal
from the trial were similar across the 3 treatment groups (stratified care
3.3%, step care across attacks 2.9%, and step care within attacks 3.8%).
This randomized clinical trial demonstrated that the stratified care
strategy produced better outcomes than the step care across attacks and the
step care within attacks strategies for migraine. Stratified care treatment
is based on the principle that patient characteristics (ie, headache disability)
can be used to help determine the patient's treatment need, thereby increasing
the chance of successful therapy from the outset.4- 6
Step care across attacks is a strategy that is frequently recommended
in treatment guidelines.3,4 In
practice, step care usually includes multiple steps beginning with, for example,
a simple analgesic, followed by various combination analgesics, a trial of
isometheptene or a butalbital-containing agent, and then triptans. One difficulty
with the step care treatment strategy is that effective treatment may be delayed
far more than in the present study. In addition, patients may not follow-up
with their physician when a treatment fails and instead they may lapse from
medical care.5,18- 20
This approach to discovering the most effective treatment may prolong morbidity
and add to health care costs if several clinical contacts (in-person or by
telephone) and several failed prescriptions are required.5
Stratified care increases the probability of selecting appropriate treatment
as the first intent.
Step care within attacks can delay the use of effective medication within
an attack. Among the 72% of persons with migraine who are less than fully
satisfied with their migraine treatment, 87% say that pain relief takes too
long.21 While step care within attacks may
be an appropriate treatment strategy for patients who usually respond to nonspecific
therapy, it delays the onset of pain relief and restoration of function for
In the stratified care group in our study, treatment was selected based
on severity of illness, as measured by MIDAS grade. In the step care across
attack group, the proportion of patients who needed to escalate treatment
because of lack of response to aspirin plus metoclopramide significantly increased
with MIDAS grade from 56% for patients with grade II to 74% for patients with
grade IV headaches. This finding supports the hypothesis that MIDAS grade
predicts treatment need and suggests that aspirin plus metoclopramide effectively
treats only about one fourth of patients in the highest disability grade.
The 3 different treatment strategies were generally well tolerated.
Adverse events were more frequent in the stratified care treatment arm. This
was mostly attributed to an increase in mild or moderate events, reflecting
the higher numbers of subjects exposed to zolmitriptan as opposed to aspirin
This study was designed as an open-label, randomized trial because of
the complexity of the treatment groups. As a consequence, knowledge of treatment
may have influenced study results. Open-label, randomized designs have been
used in studies of treatment strategy for other conditions22
and more closely simulate clinical practice than double-blind studies.
Aspirin plus metoclopramide and zolmitriptan were selected as study
treatments based on their frequent use, proven efficacy, and worldwide availability.
Choice of these specific medications is not an intrinsic aspect of the stratified
care approach. Had other agents been selected, however, the results may have
Stratification based on individual attacks was an alternative treatment
strategy.4 Using this approach, patients would
opt for a nonspecific therapy or triptan drug based on their assessment of
their own treatment needs for each attack. Given that the patient's ability
to optimally select treatment may change with experience, more than 6 attacks
would have been required; despite difficulties in study design, this approach
merits empirical testing.
In some respects, the treatment strategies used herein differ from those
used in clinical practice. In clinical practice using stratified care, if
an initial migraine-specific therapy failed after 3 attacks, treatment might
be switched to another migraine-specific agent.23
Similarly, rescue medication is often given at 2 hours instead of 4 hours
after receiving the initial medication. Thus, we may have underestimated the
relative benefits of stratified care. For step care across attacks, treatment
escalation was probably more consistent and rapid than in routine practice,
possibly overestimating the benefits of step care across attacks. Finally,
in the future, stratification based on factors other than migraine-related
disability may be possible. Ultimately, symptom profiles, biological markers,
or genetics may identify patient subgroups likely to respond to particular
To the best of our knowledge, this is the first study comparing strategies
of care in acute migraine management. The results favor stratified care based
on MIDAS grades vs step care within and across attacks. The results generally
support recommendations regarding the use of stratified care as the more effective
treatment strategy compared with traditional step care approaches.4- 6 Use of clinically tested
treatment strategies should improve the outcomes of care for patients with