Acupuntura e Cefaleia

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Journal of Clinical Epidemiology 55 (2002) 77–85

0895-4356/02/$ – see front matter © 2002 Elsevier Science Inc. All rights reserved.

PII: S0895- 4356(01)0 0422-X

Should systematic reviews include non-randomizedand uncontrolled studies?

The case of acupuncture for chronic headache

Klaus Lindea,c,*, Michael Scholzb, Dieter Melchartc

, Stefan N. Willich

a

a

Institute for Social Medicine & Epidemiology, Charité Hospital, Humboldt-Universität, 10098 Berlin, Germany

b

Institute for Medical Statistics & Epidemiology, Technische Universität, Ismaningerstr. 22, 81675 Munich, Germany

c

Centre for Complementary Medicine Research, Department of Internal Medicine II, Technische Universität, Kaiserstr. 9, 80801 Munich, Germany

Received 1 December 2000; received in revised form 28 June 2001; accepted 6 July 2001

Abstract

We aimed to investigate: (1) whether patient and intervention characteristics, design-independent quality aspects, and response rates differ be-

tween randomized and non-randomized trials of acupuncture for chronic headache; (2) whether non-randomized studies provide useful additional in-

formation (regarding long-term effects, prognostic factors, adverse effects, and generalizability); (3) reasons for potential differences in response

rates. Studies including at least five patients and reporting clinical outcome data were identified through searches in Medline, Embase, the Cochrane

Controlled Trials Register, other databases and checking of bibliographies. Twenty-four randomized trials and 35 non-randomized studies (five non-

randomized controlled cohort studies, 10 prospective uncontrolled studies, 10 case series, and 10 cross-sectional surveys) met the inclusion criteria.

Studies were heterogeneous regarding patients, interventions, outcome measurements and results. On average, randomized trials had smaller sample

sizes, met more quality criteria, and had lower response rates (0.59 [95% confidence interval 0.48–0.69] vs. 0.78 [0.72–0.83]). Whether randomized

or not, studies meeting more quality criteria had lower response rates. Non-randomized studies did not have significantly longer follow-up periods,

three included an analysis of prognostic variables, only one reported on adverse effects, and the degree of generalizability was unclear. In the case of

acupuncture for chronic headache, non-randomized studies confirmed the finding of a systematic review of randomized trials that the treatment is

likely to be effective but provided little relevant additional information on long-term effects, prognostic factors, and adverse effects. © 2002

Elsevier Science Inc. All rights reserved.

Keywords: Meta-analysis; Acupuncture; Headache; Migraine; Randomized controlled trial

1. Introduction

Systematic reviews play an increasingly important role

in assessing the existing evidence for health care interven-

tions. Most systematic reviews of prophylactic and thera-

peutic interventions include only randomized controlled tri-

als (RCTs) which are generally considered as the gold

standard for evaluation. However, the medical literature isfull of non-randomized and uncontrolled studies. Should the

results of these studies be dismissed completely? Or should

they be considered as useful additional information for sys-

tematic reviews?

It is obvious that it is highly problematic to draw conclu-

sions on causal effects from non-randomized or even un-

controlled studies. However, in other aspects such studies

can—if planned and performed well—provide valid data.

For example, one problem of RCTs is that they often recruit

only a small and non-representative sample of patients who

are then treated and monitored under conditions which do

not necessarily reflect everyday practice [1,2]. As a conse-

quence, the degree to which the results are generalizable

and externally valid is unclear. Therefore, it would be desir-

able to compare patient characteristics, treatments and

course of disease in RCTs and pragmatic non-randomized

studies. Another problem of RCTs (particularly placebo-

controlled) in chronic conditions is the often limited obser-

vation period due to ethical reasons, feasibility or resources

[3,4]. Cohort studies in which patients receive their pre-

ferred treatment can follow patients more easily over longer

periods. Large-scale non-randomized trials could also be

useful to identify potentially relevant prognostic factors (as

well as factors determining why certain people choose cer-

tain treatments) and to evaluate safety.

Furthermore, if the number or quality of available ran-

domized trials is insufficient to draw conclusions, non-ran-

* Corresponding author. Tel.: 089-33041048; fax: 089-393484.

E-mail address

: [email protected] (K. Linde).



78

K. Linde et al. / Journal of Clinical Epidemiology 55 (2002) 77–85

domized studies might be useful to get a better overview of

what is known so far and to inform future research.

This last point might be particularly relevant in system-

atic reviews of complementary therapies. For example,

there are two systematic reviews (one on acupuncture for

induction of labor [5] and one for cranberries to treat uri-

nary tract infections [6]) limited to RCTs in the Cochrane

Database of Systematic Reviews which did not identify a

single trial meeting the inclusion criteria. Many other re-

views restricted to RCTs contain very few trials. Would

these reviews be more informative if they included non-ran-

domized studies? There is a need for empirical studies in-

vestigating under what circumstances the inclusion of non-

randomized trials is adequate and which problems have to

be taken into account.

Parallel to a “conventional” systematic review of the

RCTs of acupuncture for chronic headache [7] we per-

formed a more inclusive analysis to investigate the follow-

ing questions: (1) Do randomized and non-randomized

studies of acupuncture for chronic headache differ in regardto patients, interventions, design-independent quality as-

pects, and response rates? (2) Do non-randomized studies

provide relevant additional information (results on long-

term outcomes, prognostic factors, adverse effects or com-

plications, response rates in representative or well-defined

groups of patients)? (3) In case response rates in random-

ized and non-randomized patients differ, what are possible

explanations?

2. Methods

2.1. Selection criteria

We included reports providing clinical outcome data in

at least five patients with recurrent or chronic headaches

(migraine, tension headache, cluster headache, not precisely

classified chronic or recurrent headaches) who had been

treated with acupuncture (needle insertion at acupuncture

points, pain points, trigger points or other methods of stimu-

lating acupuncture points such as laser acupuncture or elec-

troacupuncture) for prophylaxis of their headaches. We ex-

cluded studies focussing on acute headaches only or solely

reporting physiological outcomes. Studies only available in

Chinese language were not included due to the lack of re-

sources for translation.

2.2. Search strategy

To identify published and unpublished eligible studies we

searched: (1) Medline 1966 to December 1998 (search terms:

acupuncture/acupressure/electroacupuncture and headache/

migraine); (2) Embase 1989 to December 1998 (acupunc-

ture/acupressure and headache/migraine); (3) the Cochrane

Controlled Trials Register (Issue 1, 1999); (4) individual

trial collections and private databases; and (5) bibliogra-

phies of articles obtained. All references identified by the

literature search, and if available their abstracts, were screened

by two reviewers. Full reports of potentially relevant publi-

cations were obtained and checked for eligibility.

2.3. Classification

Included studies were classified into five categories: (1)

Randomized controlled trials; (2) non-randomized con-

trolled cohort studies; (3) uncontrolled prospective studies

(studies apparently based on a preplanned study protocol

and meeting at least one of the following criteria: explicit

in- and exclusion criteria, at least two predefined clinical

outcome measures, predefined treatment intervention); (4)

case series (uncontrolled studies without evidence of a pre-

defined protocol); (5) cross-sectional studies/surveys. The

classification of non-randomized studies was done twice

with a time lag of 5 months by the first author.

2.4. Data extraction

We extracted source details (bibliographic information,

language, country of the first author, whether published in aMedline-listed journal), information on patients (number,

diagnosis, in- and exclusion criteria, use of headache classi-

fication guidelines, setting, mean age, percentage females,

years since onset of disease, resistance to previous treat-

ment), interventions (strategy to choose acupuncture points,

number and duration of sessions), length of follow-up, and

data on response to treatment (definition of response, num-

ber of patients classified as responders after treatment, at

early follow-up, and follow-up of at least 6 months after

treatment; number of patients treated with acupuncture,

time of the earliest available response measurement). Re-

sponse rates for meta-analysis were calculated as number of

responders divided by the number of patients analyzed forthe earliest available time point after treatment. Data from

groups without acupuncture (control groups) were not ana-

lyzed. To assess whether non-randomized studies add rele-

vant information we checked the number of studies: (1)

with at least 6 months follow-up after the last acupuncture

session; (2) which provided outcome data for at least 80%

of treated patients after at least 6 months follow-up; (3)

which systematically investigated prognostic factors; (4)

with data on side effects or complications; (5) with at least

three study centers and a transparent sampling strategy. Se-

lection, extraction and assessments were performed by at

least two reviewers for randomized and non-randomizedcontrolled trials, and by one reviewer for the other studies.

Disagreements were resolved by discussion.

In addition, using a list of 16 items proposed by White

and Ernst [8] we investigated how detailed the acupuncture

treatment was described (results presented in [9]).

2.5. Assessment of quality aspects relevant for headache

The aim of the quality rating was to assess the accuracy

of observation and reporting, as far as possible indepen-

dently from the specific design chosen. Whether random-

ized or not a study with good quality in this respect should




79

allow a health care professional treating headache patients

to have an idea of the patients in the study and the course of

symptoms. The criteria were partly derived from the guide-

lines for clinical trials in migraine and tension-type head-

ache from the International Headache Society [10,11]. The

following 10 items could be answered yes, no or unclear:

(1) Sampling method clear and clearly described? (2) Clear

headache diagnosis? (3) Patients characterized (at least age,

sex, duration, severity of symptoms)? (4) At least 4 weeks

baseline period? (5) At least two clinical headache out-

comes? (6) Use of a headache diary? (7) Cointerventions

described? (8) At least 90% of patients included analyzed

after treatment? (9) At least 80% of patients treated ana-

lyzed at early (

6 months) follow-up? (10) At least 80% of

patients treated analyzed at late (

6 months) follow-up? In

case of cross-sectional studies items 9 and 10 were scored

when the survey took place at least 6 months after acupunc-

ture treatment and the response rate was greater than 80%.

2.6. Analyses

Characteristics and fulfillment of the quality criteria

among RCTs and other studies were compared with the chi-

square test and the Mann-Whitney test (no adjustment for

multiple comparisons).

Responder proportions were estimated by a generalized

linear mixed model (random effects model) as implemented

in the SAS® Macro GLIMMIX [12]. In particular, we used

a linear logistic regression model with an additional random

intercept term to reflect the heterogeneity between the stud-

ies. GLIMMIX uses restricted pseudo-likelihood (REPL) to

find the parameter estimates of the linear mixed logistic

model we specified. The approach allows for trial-specificand treatment-averaged inference. This estimation proce-

dure was utilized for univariate as well as for multivariate

analysis.

3. Results

From a total of 97 acupuncture studies on headache iden-

tified, 59 met the inclusion criteria. The most frequent rea-

son for exclusion was the mixing of data of a variety of

chronic pain patients without separate reporting of results in

those with chronic headache. Twenty-four of the 59 included

studies were RCTs and 35 studies were non-randomized (5

non-randomized controlled cohort studies, 10 prospective

uncontrolled studies, 10 case series, and 10 cross-sectional

studies). Table 1 provides an overview of basic features of

the included studies which were heterogeneous regarding

patients, interventions, type and timing of outcome mea-

surements.

The median number of patients treated with acupuncture

was significantly smaller in RCTs than in other studies (see

Table 2). A total of 535 patients received acupuncture treat-

ment in the 24 RCTs compared to 2695 in the 35 non-ran-

domized studies. RCTs were performed more often in mi-

graine patients and slightly more often in specialized

outpatient pain departments. Age, sex distribution and the

duration of headache complaints were similar. Only 14

studies (seven RCTs and seven other studies) made state-

ments whether patients had been resistant to previous ther-

apy; in four RCTs and four other studies this had been the

case. Acupuncture sessions lasted significantly longer in the

non-randomized studies while the number of treatment ses-

sions and the proportion of studies using an individualized

treatment strategy was similar.

RCTs met criteria for accuracy of observation and re-

porting much more often than non-randomized studies but

in both groups the number of criteria met covered the full

range indicating that there were very low and good quality

studies in both groups (see Table 3). Ten of the 24 RCTs

and 26 of the 35 non-randomized studies met less than five

quality criteria. RCTs significantly more often described a

clear headache diagnosis, a pre-treatment baseline observa-

tion period, at least two clinically relevant outcome mea-

sures, and the use of headache diaries. Sampling strategies

and cointerventions (such as treatment for headache attacks)were rarely well described regardless of the type of study.

Follow-up was either short or incomplete in most studies as

well. A total of 50 studies presented some sort of responder

data for at least one of the three predefined time-points.

RCTs more often used a clearly defined response criterion.

The pooled response rate was 59% in RCTs [95% confi-

dence interval (CI) 48–69%) and 78% in non-randomized

studies (72–83%; P

0.001).

Ten (42%) RCTs and 14 (40%) non-randomized studies

measured outcome data at least 6 months after completion

of the treatment (see Table 4. However, only two (8%)

RCTs and six non-randomized (17%) studies actually pro-vided data for more than 80% of treated patients. In the two

RCTs and in two non-randomized studies reliable data on

frequency of headache was available from patient diaries.

All these studies suggest that improvements achieved after

treatment last in the majority of patients. The role of prog-

nostic factors was investigated in two (8%) RCTs and three

(9%) non-randomized studies. Due to the small sample sizes

and the exploratory character of the analyses the results can

at best be considered hypothesis generating. Only nine non-

randomized studies (and eight RCTs) gave information

(number of centers, selection process) on how they recruited

their patients. In all these studies acupuncture was provided

within a single practice or unit. Data on adverse effects

(number of patients reporting adverse effects and/or explicit

description of the events observed) was reported in four

(17%) RCTs and one (3%) non-randomized study.

In the univariate analysis diagnosis, sex distribution,

mean age, number and duration of treatment sessions, type

and timing of response measurement as well as complete-

ness of follow-up did not have a significant impact on the

response rates observed (see Table 5). Instead, studies de-

scribing their sampling strategy, a clear headache diagnosis,

having a baseline period and using a headache diary had

significantly lower response rates. Fig. 1 shows that both a



80


Table 1

Overview of studies of acupuncture treatment for recurrent headaches

First author (ref) Type of headache Quali ty criteria met Response definition

n

treated with acupuncture

Response rates (%)

After treatment

Follow-up

Early

6 mo.

RCTs

Ahonen [25] Tension 4 Improved at least 2 mo* 12 n.a. 58 n.a.

Baust [26] Migraine 4

50% index reduction 23 61 n.a. n.a.Carlsson [27] Tension 5 — 30 n.a. n.a. n.a.

Ceccherelli [28] Migraine 5

50% index reduction 15 87 n.a. n.a.

Doerr-Proske [29] Migraine 7 — 10 n.a. n.a. n.a.

Dowson [30] Migraine 8

50% frequency reduct. 25 32 n.a. n.a.

Hansen [31] Tension 2


Henry [32] Migraine 5 Patient assessment 20 65 n.a. n.a.

Hesse [33] Migraine 8 — 42 n.a. n.a. n.a.

Heydenreich [34] Migraine 3 Unclear 20 n.a. n.a. 80

Heydenreich [35] Migraine 3 Unclear 50 n.a. n.a. 80

Johansson [36] Tension 0 — 17 n.a. n.a. n.a.

Kubiena [37] Migraine 4


Lehmann [38] Migraine 3 — 21 n.a. n.a. n.a.

Lenhard [39] Migraine 7

33% frequency reduct. 16 n.a. 56 n.a.

Loh [40] Various 3 Patient assessment 23 35 n.a. n.a.

Okazaki [41] Migraine 1 Unclear 20 75 n.a. n.a.

Pintov [42] Migraine 7 — 11 n.a. n.a. n.a.

Tavola [43] Tension 10

50% index reduction 15 53 n.a. 40Vincent [44] Migraine 9


Vincent [45] Tension 9

50% index reduction 14 64 43 n.a.

Weinschütz [46] Migraine 5 Single case statistics 20 50 65 n.a.

Weinschütz [47] Migraine 5 Single case statistics 20 45 75 n.a.

White [48] Tension 5 — 5 n.a. n.a. n.a.

Non-randomized controlled cohort studies

Borglum-J. [49] Unclear 8 Unclear 32 79 n.a. n.a.

Guccione [50] Migraine 1 — 24 n.a. n.a. n.a.

Sold-Darseff [51] Migraine 1 Unclear 30 93 n.a. n.a.

Turk [52] Migraine 1 Unclear 100 86 n.a. n.a.

Zibin [53] Migraine 0 Unclear 340 99 n.a. n.a.

Uncontrolled prospective studies

Baischer [54] Migraine 10

33% index reduction 31 70 n.a. 58

Boivie [55] Migraine 10 Unclear 30 n.a. 56 56

Börglum-J. [56] Tension 6 Unclear 21 67 57 n.a.

Börglum-J. [57] Tension 5 Unclear 16 63 n.a. n.a.

Ceccherelli [58] Various 4

50% index reduction 12 100 n.a. n.a.Ceccherelli [59] Various 6


Kim [60] Migraine 3 Meeting defined criteria* 25 n.a. 80 n.a.

Major [61] Migraine 8


Tolksdorf [62] Various 5

50% index reduction 70 59 n.a. 38

Zwölfer [63] Tension 3 Patient assessment 20 80 n.a. n.a.

Case series

Batra [64] Migraine 3 At least 50% improvem.* 20 n.a. 65 n.a.

Cheng [65] Various 2 No headache at all 33 91 n.a. n.a.

Fischer [66] Unclear 2

50% symptom reduct.* 189 75 n.a. n.a.

Heydenreich [67] Migraine 0 At least 50% improvem.* 320 n.a. n.a. 88

Heydenreich [68] Migraine 3 At least 50% improvem.* 296 n.a. n.a. 76

Laitinen [69] Migraine 5 Meeting defined criteria* 39 92 n.a. 46

Lawrence [70] Various 1 Alleviation symptoms* 96 92 n.a. n.a.

Spoerel [71] Various 2 Severity & freq. reduct.* 38 n.a. 84 n.a.

Stux [72] Migraine 0 Unclear 50 88 n.a. n.a.

Yamauchi [73] Various 2 Unclear 7 71 n.a. n.a.

SurveysCarlsson [74] Various 4 Patient assessment 79 57 n.a. 23

Chen [75] Unclear 1 Patient assessment 44 n.a. n.a. 68

Haug [76] Unclear 1 Patient assessment 49 n.a. n.a. 84

Junilla [77] Unclear 2

30% symptom reduct.* 115 n.a. n.a. 77

Junilla [78] Various 2 Patient assessment 69 81 n.a. n.a.

Kubiena [79] Migraine 1 Patient assessment 118 n.a. 62 n.a.

Maxion [80] Migraine 1 Patient assessment 13 15 n.a. n.a.

McKibbin [81] Various 4 — 107 n.a. n.a. n.a.

Pöntinen [82] Migraine 2 Patient assessment 107 n.a. n.a. 57

Shifman [83] Various 0 Patient assessment 33 58 n.a. n.a.

n.a.

not available; *operationalization unclear.

Patient assessments performed with various categorizations (without use of headache diaries).




81

randomized trial design and a higher number of quality cri-

teria met were associated with lower response rates. We

were unable to specify an adequate model for multiple re-

gression analysis. Apart from design (randomized or not)

other factors had little consistent effects.

4. Discussion

Our results show that in the case of acupuncture for

chronic headache: (1) RCTs and non-randomized studies

differ in regard to patients included, interventions provided,

and response rates reported; (2) RCTs have in average bet-

ter accuracy of observation and reporting, but a relevantproportion of RCTs has very low and some prospective un-

controlled trials have acceptable accuracy of observation

and reporting; (3) the available non-randomized studies pro-

vide only limited useful additional information in regard to

long-term response and prognostic factors, and no addi-

tional information regarding adverse effects and generaliz-

ability; (4) better study design (randomized vs. not random-

ized) and better accuracy of observation and reporting

(regardless whether a study is randomized or not) are asso-

ciated with lower response rates.

When interpreting our results, a number of limitations

have to be kept in mind. While extractions and assessments

for the RCTs were performed by at least two reviewers the

non-randomized studies were analyzed by a single reviewer.Although each study was read at least two times it cannot be

Table 2

Comparison of randomized and non-randomized studies of acupuncture for chronic headache: Patient and intervention characteristics

RCTs (

n

24) Other studies (

n

35) P-value

Patient characteristics

N treated with acupuncture (median, range) 20 (5–100) 39 (7–340)

0.001

Diagnosis

Migraine 16 (67%) 16 (46%)

Tension-type headache 7 (29%) 3 (8%)various/unclear 1 (4%) 16 (46%) 0.002

Mean age (median, range) 40 (32–46; mi: 7) 40.5 (22–53, mi: 19) 0.515

% proportion female (median, range) 80 (57–100, mi: 3) 78 (33–100, mi: 10) 0.667

Onset of headache

5 years ago 18 (94%, mi: 6) 18 (100%, mi: 17) 0.866

Setting mi: 5 mi: 6

Specialized outpatient dpt. etc. 17 (89%) 20 (69%)

Practice 2 (11%) 9 (31%) 0.161

Intervention characteristics

Number of acupuncture sessions (median; range) 8 (4–14; mi: 3) 10 (1–30; mi: 11) 0.731

Duration of sessions in minutes (median; range) 15 (1–30; mi: 7) 22.5 (10–45; mi: 10) 0.001

Intervention individualized 9 (43%, mi: 3) 14 (48%, mi: 6) 0.631

mi

number of studies with missing information.

Table 3

Comparison of randomized and non-randomized studies of acupuncture for chronic headache: accuracy of observation and reporting, outcome characteristics

and response rates

RCTs (

n

24) Other studies (

n

35) P-value

Accuracy of observation and reporting

Sampling described 8 (33%) 9 (26%) 0.559

Clear headache diagnosis 16 (67%) 8 (23%) 0.001

Patients characterized 17 (71%) 17 (49%) 0.112

At least 4 wks baseline 15 (63%) 5 (14%)

0.001

Cointerventions described 7 (29%) 10 (29%) 1.000

At least two outcomes 20 (83%) 18 (51%) 0.014

Headache diary used 18 (75%) 8 (23%)

0.001

Complete after treatment 11 (46%) 19 (54%) 0.601

Complete at early follow-up 6 (25%) 10 (29%) 1.000

Complete at late follow-up 2 ( 8%) 6 (17%) 0.453

Median number (range) of items met 5 (0–10) 2 (0–10) 0.008

At least 5 quality crit. met 14 (58%) 9 (26%) 0.016

Subjective quality weak 6 (25%) 29 (83%)

0.001

Outcome characteristics

Response data available 16 (67%) 33 (94%) 0.024

Measurement within 3 months after treatment 16 (89%) 21 (64%) 0.634

Complete at response measurement 10 (56%) 21 (64%) 0.765

Response rates (95% confidence intervals) 0.59 (0.48–0.69) 0.78 (0.72–0.83)

0.001

mi

number of trials with missing information.



82


ruled out that coding errors occurred or that some details

would have been interpreted differently by a second re-

viewer. The list for assessing the accuracy of observation

and reporting was not formally validated. It can only be

considered as a trial to operationalize quality aspects whichgo beyond methodological criteria covered in commonly

used scales [13–15]. We did multiple statistical testing;

therefore, the significant P-values reported have to be inter-

preted with caution.

A number of empirical analyses have addressed the ques-

tion whether effect size estimates from RCTs and non-ran-

domized controlled studies differ (e.g., [16–18] for newer

original work and [19,20] for reviews of older studies). The

findings of these studies are variable. Among randomized

trials there is evidence that trials with better quality yield

less optimistic results. Particularly, adequate concealment

of randomization and double-blinding seem to be associatedwith less optimistic outcomes [21–23]. We are not aware of

studies comparing characteristics, design-independent qual-

ity aspects and outcomes of RCTs and non-randomized (in-

cluding uncontrolled) studies.

We believe that the current discussion of quality of clini-

cal trials over-emphasizes methodological aspects and disre-

gards clinical aspects. This might have pragmatic reasons as

methodological criteria of good quality are valid in most in-

stances while clinical quality criteria strongly differ among

conditions and interventions. Nevertheless, in our opinion

the quality of a trial on a complex treatment for chronic

headache cannot be assessed in a valid manner by checking

only whether there are the words randomized, double-blind

and a description of drop-outs and withdrawals in the text.

Ten of the 24 RCTs met less than half of our criteria for ac-

curacy of observation and reporting which seem to us quite

basic. This indicates that a relevant proportion of the RCTs

reviewed are unlikely to provide clinically useful results.

The conclusion of our systematic review of RCTs [7]

was that the available evidence suggests that acupuncture is

effective in migraine and tension-type headache but that

further trials with better methodology and larger sample

sizes are urgently needed. The non-randomized studies in-

cluded in the analysis presented here reinforce the impres-

sion of effectiveness. However, the amount of relevant new

information they add is disappointing. The differences be-

tween RCTs and non-randomized studies suggest that pa-

tients and interventions in RCTs are not representative for

routine acupuncture practice. But the sampling strategies in

non-randomized studies—when described at all—did not

allow assessment of generalizability either. Both RCTs and

non-randomized studies almost completely neglected the

question of safety. The majority of non-randomized studies

had very low quality and the potential advantages of using a

non-randomized design were rarely ever used. If we would

have included the non-randomized studies in our original

systematic review [7] the conclusions regarding implica-

tions for practice would not have been different. The con-

clusions regarding future research are obvious: apart from

better RCTs better non-randomized studies with long-term

follow-up and data about safety are needed.

Including non-randomized studies increases the workload

of a systematic review considerably. As efficient search strat-

egies to identify non-randomized studies have not been de-

veloped yet the search has to be very broad. Both during

screening for eligibility and when coding included studies

Table 4

Comparison of randomized and non-randomized studies of acupuncture for

chronic headache: information on long-term results, prognostic factors,

generalizability, and safety

RCTs

(

n

24)

Other studies

(

n

35) P-value

At least 6 months follow-up after

treatment 10 (42%) 14 (40%) 1.000Outcome data for at least 80% of

included patients at follow-up

(at least 6 months) 2 (8%) 6 (17%) 0.453

Analysis of prognostic factors 2 (8%) 3 (9%) 1.000

At least three study centers and

transparent sampling strategy – –

Data on adverse effects 4 (17%) 1 (3%) 0.148

Table 5

Pooled response rates (random effects model) in all studies (both RCTs and

non-randomized) meeting or not meeting defined criteria (univariate mixed

logistic regression model)

Variable

Response rates

(95% confidence intervals)

Criterion not met vs. criterion met P-value

Clinical featureOnly migraine patients 0.72 (0.63–0.79) vs. 0.73 (0.65–0.81) 0.7543

Intervention feature

10 sessions of 15

minutes 0.76 (0.63–0.86) vs. 0.69 (0.60–0.78) 0.3414

Accuracy of observation

and reporting

Sampling described 0.76 (0.71–0.82) vs. 0.62 (0.50–0.72) 0.0138

Clear headache

diagnosis 0.78 (0.72–0.83) vs. 0.62 (0.52–0.72) 0.0037

Patients characterized 0.78 (0.70–0.84) vs. 0.68 (0.60–0.75) 0.0581

At least 4 wks baseline 0.77 (0.72–0.82) vs. 0.61 (0.49–0.72) 0.0099

Cointerventions

described 0.74 (0.67–0.80) vs. 0.69 (0.57–0.79) 0.4695

At least two outcomes 0.77 (0.68–0.83) vs. 0.70 (0.62–0.77) 0.2256

Headache diary used 0.78 (0.73–0.83) vs. 0.61 (0.51–0.70) 0.0015Complete after

treatment 0.75 (0.68–0.82) vs. 0.69 (0.60–0.77) 0.2208

Complete at early

follow-up 0.75 (0.68–0.80) vs. 0.66 (0.54–0.77) 0.1735

Complete at late

follow-up 0.73 (0.66–0.79) vs. 0.72 (0.58–0.82) 0.8816

At least 5 quality crit.

met 0.77 (0.71–0.82) vs. 0.63 (0.53–0.73) 0.0186

Outcome features

Response criterion

50% reduction 0.74 (0.68–0.80) vs. 0.70 (0.57–0.80) 0.4966

Early response

measurement 0.71 (0.64–0.77) vs. 0.79 (0.66–0.88) 0.2383

Complete at response

measurement 0.75 (0.66–0.82) vs. 0.71 (0.63–0.78) 0.4425



84


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