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Effectiveness of Leech Therapy in Osteoarthritis of the Knee
A Randomized, Controlled Trial
Andreas Michalsen, MD; Stefanie Klotz, RN; Rainer Lu¨dtke, PhD; Susanne Moebus, PhD, MPH; Gu¨nther Spahn, MD;
and Gustav J. Dobos, MD
Background: Leech therapy was commonly used in traditional
arthritis Index and physical sum score of the Medical Outcomes
medicine for treating localized pain. Clinically significant pain
Study 36-Item Short-Form Health Survey with group comparisons
relief after leech therapy for osteoarthritis of the knee has been
at days 3, 7, 28, and 91.
demonstrated by preliminary data.
Results: The primary end point, pain at day 7, was reduced from
Objective: To evaluate the effectiveness of leech therapy for
a mean (±SD) of 53.5 ± 13.7 to 19.3 ± 12.2 after leech therapy
symptomatic relief of osteoarthritis of the knee.
compared with 51.5 ± 16.8 to 42.4 ± 19.7 with topical diclofenac
(estimated group difference, ؊23.9 [95% CI, ؊32.8 to ؊15.1];
Design: Randomized, controlled trial.
P < 0.001). Although the difference between group pain scores
was no longer significant after day 7, differences for function,
Outpatient department for integrative medicine of an
stiffness, and total symptoms remained significant in favor of
academic teaching hospital.
leech therapy until the end of study and for quality of life until
Patients: 51 patients with osteoarthritis of the knee (leech ther-
day 28. Results were not affected by outcome expectation.
apy: 24 patients, mean age [±SD], 62.5 ± 10.2 years; topical di-
clofenac therapy: 27 patients, mean age [±SD], 65.5 ± 6.7 years).
Conclusions: Leech therapy helps relieve symptoms in patients
with osteoarthritis of the knee. The potential of leech therapy for
Intervention: A single treatment with 4 to 6 locally applied
treating osteoarthritis and the pharmacologic properties of leech
leeches (leech therapy group) or a 28-day topical diclofenac reg-
saliva remain to be clarified.
imen (control group).
Ann Intern Med. 2003;139:724-730.
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Measurements: Mean of the pain, function, and stiffness sub-
For author affiliations, see end of text.
scores of the Western Ontario and McMaster Universities Osteo-
See editorial comment on pp 781-783.
The application of medicinal leeches was widely prac- been recommended for symptomatic treatment of osteoar-
ticed in ancient times (1, 2), but their use declined rapidly in Europe and America with the advent of modernsurgery and pharmacology (3). In ancient medical practice,phlebitis and thrombotic states were 2 main indications for leech therapy (4). In more recent times, the polypeptide Protocol
hirudin, one of several biologically active substances in The research protocol, reviewed and approved by our leech saliva, was identified as the most potent known nat- institutional ethics committee, included 6 study visits. Ap- ural inhibitor of coagulation (5, 6). Natural leeches are plicant patients were recruited by press announcements currently used to treat postoperative local congestions after and first screened for eligibility by telephone. Those who reconstructive and plastic surgery (7, 8).
fulfilled the initial enrollment criteria were invited for fur-ther assessment by detailed physical examination, blood Other traditional uses of leeching, such as treating lo- analysis, and radiographs of the knee (first study visit, day calized inflammation and pain, are still part of many eth- Ϫ3). If patients had not had radiographs of the knee in the nomedical systems (9, 10). Besides hirudin, various anti- preceding 3 months, radiography was performed at day inflammatory substances and hyaluronidase have been Ϫ3. All eligible patients who gave written informed con- found in leech saliva. In a nonrandomized pilot study, we sent were included in the study and asked to limit their found that a single treatment with 4 locally applied leeches osteoarthritis medications during the study to rescue med- rapidly relieved pain from osteoarthritis of the knee (11).
ication. No patient took slow-acting substances against os- Because of the lack of randomized, controlled trials of teoarthritis. Baseline measurements were done at visit 2 leech therapy, we designed this trial to assess the symptom- (day 0), when the participant was randomly assigned to atic short-term efficacy of leech therapy in osteoarthritis of either leech or topical diclofenac therapy and the allocated the knee. Topically applied diclofenac was chosen as the treatment was started. During subsequent visits on study control therapy to compare 2 types of local treatment. The days 3, 7, 28, and 91, all outcomes were assessed except effectiveness of topically applied nonsteroidal anti-inflam- quality of life, which was assessed only on days 28 and 91.
matory drugs (NSAIDs) and diclofenac in treating osteo- Each patient was asked to record intake of rescue medica- arthritis has been demonstrated (12, 31, 32); their use has tion, application of study gel, and appearance of adverse 724 2003 American College of Physicians
effects in a medical diary. Patients were screened and re-cruited between January and June 2002. Patient treatments and follow-ups were completed by 1 November 2002.
Osteoarthritis causes pain and disability, but conventional Patients
therapies offer limited relief for many patients. Leech sa- Patients were eligible if they were older than 40 years liva contains anti-inflammatory substances, and leechesshowed promise as an osteoarthritis therapy in a nonran- of age, had definite osteoarthritis of the knee as defined by the American College of Rheumatology (14) without clin-ical evidence of rheumatoid arthritis and systemic joint Contribution
disease, and had not undergone arthroscopy or surgery of This randomized trial compared a single application of 4 to the knee or had intra-articular injections in the previous 3 6 leeches to the affected knee with 28 days of topical di- months. In addition, patients were required to have a pain clofenac treatment. Patients with leech therapy had less rating greater than 40 on 1 of the 5 pain scales of the pain through day 7 than those receiving diclofenac. The Western Ontario and McMaster Universities Osteoarthritis leech therapy group showed benefits in function, stiffness, Index (WOMAC) visual analogue scales (15). Exclusion and total arthritis symptoms through the 91 days of fol- criteria were current anticoagulant treatment or hemo- philia, type 1 diabetes mellitus, anemia, polyneuropathy, Cautions
severe articular inflammation on physical examination (ex-cluded also by an erythrocyte sedimentation rate Ͼ 40 Future studies should evaluate leeches and the substances mm/h and C-reactive protein level Ͼ 5 mg/L), or other in their saliva against various conventional therapies in serious illnesses. Patients regularly taking rescue medica- blinded studies with long-term follow-up.
tion with NSAIDs or analgesics were not excluded if the mean weekly dosage and type of administration had notbeen altered during the preceding 3 months.
Randomization and Treatment Groups
pain score. The WOMAC is a disease-specific question- Patients were randomly allocated to the treatment naire addressing severity of joint pain (5 questions), limi- groups by a nonstratified block randomization with ran- tation of physical function (17 questions), and stiffness (2 domly varying block lengths. Sequentially numbered enve- questions). Each question is assessed by a 100-mm visual lopes containing the treatment assignments were prepared.
analogue scale, and the aggregate WOMAC score is repre- When a patient met the inclusion criteria and consented to sented by the sum of the 24-component item scores (15).
participation, the study physician opened the lowest num- Secondary end points consisted of all other WOMAC sub- bered envelope, which determined the group of assign- scores and the WOMAC total score during the study and the physical sum score of quality of life assessed by the Leech therapy was carried out as previously described Medical Outcomes Study 36-Item Short-Form Survey (SF- and tested in our pilot study (11, 16). In summary, 4 to 6 36) (17) at days 28 and 91. The SF-36 scores were stan- medicinal leeches (Hirudo medicinalis, ZAUG GmbH, dardized, taking the mean of the German population as 0 Biebertal, Germany) were applied once to the periarticular and its SD as 1. The prevalence of adverse effects and the soft tissue of the affected knee, with preference to maxi- use of oral rescue medication were monitored through the mally painful points during examination and palpation.
patients’ diaries from days 0 to 28 and through interviews Leeches were left in place until they detached by them- on days 28 and 91. To control for nonspecific treatment selves, after a mean of 70 minutes. The patient’s knee was effects, outcome expectation was rated by all patients on a then bandaged, and the patient was cautioned not to be 5-point Likert scale ranging from 4 (expecting great pain physically active for the next 12 hours. The patient re- relief) to 0 (expecting no pain relief) immediately after they turned the next day (study day 1) for a change of dressing had been informed of their assigned treatment. Current and a repeated blood count. Control group patients were physical activity was evaluated by a standardized physical given 300 g of diclofenac gel (diclofenac–natrium 10 mg– activity questionnaire and by calculating energy expendi- 1 g gel, Pharmacia, Erlangen, Germany), and the proper ture (kcal/wk) at baseline and days 28 and 91. Initially and use was demonstrated. Patients were instructed to apply at the end of the study, all participants completed a ques- the gel at least twice daily for days 0 through 28 and to tionnaire that included personal data, general medical in- discontinue application thereafter. Adherence to diclofenac formation, and queries about clinical status. Trained, un- gel treatment was assessed from the diaries and cross- blinded research assistants collected patient-reported data, checked by counting used gel tubes and interviewing the and research personnel who were unaware of study group assignments performed data entry and monitoring.
Outcome Measures
Statistical Analysis
The primary outcome measure was change in knee We initially planned the trial as a sequential trial by pain from day 0 to 7 as derived from the mean WOMAC using the triangular test with preset boundaries to permit www.annals.org
4 November 2003 Annals of Internal Medicine Volume 139 • Number 9 725
termination of the trial if the efficacy or inefficacy of leech Figure. Western Ontario and McMaster Universities
therapy was established or if there was evidence of no dif- Osteoarthritis Index (WOMAC) pain score.
ference in outcome between the 2 treatment groups (18).
According to the test design with preplanned repeated dataevaluations, the trial was designed to be terminated whenthe path of the t statistic, measuring imbalance between theoutcome for the 2 randomized groups, crossed 1 of thepreset termination boundaries (efficacy, inefficacy, or nodifference in outcome) of the sequential design. In thetriangular test, design blinding of the data evaluation is notfeasible.
A between-group difference of 0.625 SD on the WOMAC pain scale was the anticipated effect size, and theminimum statistical power was fixed at 80%. With theseassumptions, we expected to enroll approximately 60 pa-tients to detect the above-mentioned difference with a2-sided type I error of 5%. Data were evaluated weekly on Mean course of the WOMAC pain score in both groups in the study the basis of a recruitment rate of 3 to 4 patients each week.
course (means [ϩSD] are based on raw [not imputed] data; P values Unexpectedly, the efficacy boundary of the sequential de- were calculated from repeated-measurement analysis of variance). Com-plete WOMAC patient data in the leech therapy and topical diclofenac sign was crossed early when 21 patients had been evaluated treatment group were available for 24 and 26 patients, respectively (day at day 7; thus, within the triangular study design, the pri- 7); 24 and 24 patients, respectively (day 28); and 23 and 23 patients, mary study hypothesis that leeches are more efficacious than topical diclofenac was accepted (P ϭ 0.004). Thestudy review board stopped recruitment according to the multiply imputed following the suggestions of Rubin (20).
protocol. At that time, 30 more patients were already in- In detail, we used the Monte Carlo Markov chain method cluded or on the waiting list for study inclusion. The study of SAS software, version 8.02 (SAS Institute, Inc., Cary, review board decided to follow these 30 patients to com- North Carolina), and imputed missing values for each pletion. Otherwise, the sample size would have been too treatment group separately. In total, we created 20 multi- small to detect any other group differences with the sec- ple imputed data sets and analyzed them with the SAS Thus, we were compelled to change our preplanned All statistical analyses were based on all randomly as- data analysis. Instead of applying a triangle test, we fitted signed patients, including patients who dropped out for general repeated-measurement analyses of variance to the nonadherence to the treatment or withdrew for other rea- WOMAC scores. In detail, we modeled a day-to-group sons (intention-to-treat sample). All tests were 2-sided, and interaction as an 8-level factor and assumed an exponential P values less than 0.05 were considered to be statistically correlation function (19). Missing WOMAC scores were Subsequent analyses on the WOMAC pain score were done to adjust for the effects of possibly confounding vari- Table 1. Baseline Characteristics of Study Patients*
ables: outcome expectation, use of rescue medication, and Characteristic
WOMAC scores at baseline. We included these variables as Diclofenac
covariates in the analyses of variance and estimated the group differences in the presence of these factors.
Role of the Funding Source
The funding source had a role in the design and con- Previous regular NSAID intake, n (%) duct of the study but not in the interpretation of data or in Duration of knee osteoarthritis, y the decision to submit the manuscript for publication.
Of 112 patients screened by telephone interview, 61 patients were invited for further assessment. After detailed examination, 51 patients fulfilled all study criteria, agreed to study participation, and underwent randomization.
* Values with plus/minus signs are expressed as means Ϯ SD. NSAID ϭ nonsteroidal Twenty-four patients were assigned to leech therapy, and anti-inflammatory drug; SF-36 ϭ Medical Outcomes Study 36-Item Short-Form Sur- 27 patients were assigned to topical diclofenac treatment.
vey; WOMAC ϭ Western Ontario and McMaster Universities Osteoarthritis In- One patient (receiving diclofenac) declined to return for 726 4 November 2003 Annals of Internal Medicine Volume 139 • Number 9
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Table 2. Group Differences for Change in Western Ontario and McMaster Universities Osteoarthritis Index Scores Compared
with Baseline*
End Point
Leech Therapy
Topical Diclofenac
Estimated Difference (95% CI)
* Values are means Ϯ SD. Means indicate mean changes from baseline based on raw data; because of multiple imputations of missing values, the estimated difference is not equal to the difference of means. WOMAC ϭ Western Ontario and McMaster Universities Osteoarthritis Index.
further visits to the study center and withdrew from the with a nonsignificant group difference of Ϫ9.9 (CI, Ϫ20.3 study immediately at day 1. Two more patients in the to 0.5; P ϭ 0.061) at day 28 and Ϫ9.4 (CI, Ϫ20.0 to 1.3; diclofenac group withdrew from the study after day 7 be- P ϭ 0.084) at day 91 (Figure).
cause of persisting symptoms. One patient in each group In addition, joint function improved and stiffness de- dropped out before the last study visit (day 91) because creased rapidly and statistically significantly with leech they received unallowed co-interventions after day 28.
therapy. These effects were maintained until day 91 and Table 1 shows the baseline demographic and clinical
resulted in significant group differences favoring leech ther- characteristics of the study patients. Treatment groups apy, including the WOMAC total score (Table 2). The
were similar with the exception of a higher mean stiffness physical dimension of quality of life improved only for the score in the leech therapy group than in the topical diclofe- leech therapy group on day 28 (group difference, 0.49 [CI, nac group (P ϭ 0.017). All patients had radiographically 0.07 to 0.91]; P ϭ 0.023); at day 91, these group differ- confirmed stage II to III osteoarthritis of the knee accord- ences were no longer detectable (difference, 0.13 [CI, ing to the classification of Kellgren and Lawrence (21).
Ϫ0.31 to 0.56]; P Ͼ 0.2). Calculated physical activity in- Forty-two (82%) of all study patients had received regular creased nonsignificantly in the leech therapy group com- NSAID or acetaminophen therapy in the last 3 years. Fif- teen patients (63%) in the leech group and 19 patients No study patient was receiving stable therapy with (70%) in the topical diclofenac group were currently hav- NSAIDs or analgesics during the study course. Table 3
ing physiotherapy or were exercising quadriceps strength- shows the type and frequency of rescue medication use in ening on a regular basis. Adherence to diclofenac applica- each treatment group. In the first 7 days (that is, before the tion was good, with regular application in 24 of the 26 primary outcome was evaluated), 8 patients in the diclofe- patients analyzed at day 7. One patient did not use diclofe-nac after the fifth day because of an ongoing local skinreaction.
Table 3. Rescue Medication Use from Days 0 to 28 and Days
29 to 91 in the Treatment Groups*
Outcome Measures
Leech therapy provided a greater benefit than topical Medication
Days 0 to 28
Days 29 to 91
diclofenac in the primary outcome measure, change in knee pain after 1 week. The mean WOMAC pain score Diclofenac
Diclofenac
(ϮSD) was reduced from 53.5 Ϯ 13.7 (n ϭ 24) to 19.3 Ϯ 12.2 (n ϭ 24) at 7 days in the leech therapy group and from 51.5 Ϯ 16.8 (n ϭ 27) to 42.4 Ϯ 19.7 (n ϭ 26) in the diclofenac group. After multiple imputing of miss- ing values, there was a highly significant estimated be- tween-group difference (Ϫ23.9 [CI, Ϫ32.8 to Ϫ15.1]; P Ͻ 0.001, repeated-measurement analysis of variance).
The estimated group difference for pain relief in favor of leech therapy was most pronounced at day 3 (Ϫ29.5 [CI, Ϫ36.3 to Ϫ22.6]; P Ͻ 0.001) and diminished over time, * Data are number of patients/medication days.
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4 November 2003 Annals of Internal Medicine Volume 139 • Number 9 727
Table 4. Adverse Events
The observed improvements confirm the results of our pilot study and are most likely attributable to the therapeu- Adverse Event
tic intervention. Slightly higher symptom scores of the pa- Diclofenac
tients in the leech therapy group at the outset could have biased the results. Yet, baseline differences were not statis- tically significant for pain and functional ability, and sta- tistical adjustment for baseline WOMAC scores did not Different mechanisms may explain the observed ef- fects. First, various pharmacologically active substances be- sides the thrombin-inhibitor hirudin have been found inleech saliva, such as histamin-like vasodilators, kallikreinand tryptase inhibitors, various other proteinase inhibitors,and anesthetics (24 –27). Through the concomitant activ- nac group and 6 patients in the leech therapy group took a ity of a further leech saliva component, hyaluronidase (28), rescue medication. On average, patients needed rescue these substances might reach deeper tissue zones and pos- medication on less than 1 of every 5 days throughout the sibly the joint space. However, it is not clear whether pain- study; differences between groups were not statistically sig- relieving therapy in osteoarthritis needs to affect the carti- lage and subchondral bone directly. The various bioactive Outcome expectation was slightly higher in the leech substances in leech saliva may also be as pharmacologically therapy group (mean [ϮSD], 2.4 Ϯ 0.8 vs. 1.9 Ϯ 0.6; P ϭ potent as hirudin and thus exert substantial effects in peri- 0.008). Yet after adjustment for outcome expectation, articular tissue and adjacent structures.
medication use, and other predefined variables, including Second, nociceptive activation contributes to chronic all WOMAC baseline scores, the group difference between pain (29). Leech therapy could induce pain relief through the pain score of the 2 treatment groups remained signifi- antinociceptive effects and counterirritation. However, it is cant; the trend favored leech therapy at day 7 (P Ͻ 0.001), not known to what extent leech bites may induce such and pain was still nonsignificantly reduced at day 28 (Ϫ9.9 mechanisms, and it seems unlikely that reduction of noci- [CI, Ϫ20.3 to 0.6]; P ϭ 0.064) and day 91 (Ϫ9.3 [CI, ceptive input on a single occasion would result in the ob- served lasting effect, such as improved joint function.
Table 4 summarizes the adverse events in the study
Third, placebo effects might be responsible for the treatment groups. Neither group experienced serious ad- symptomatic benefit. The principal limitation of this study verse effects. A common minor adverse effect of leech ther- is that the placebo-like effects of this invasive and uncom- apy was mild to moderate itching at the leech bite sites, mon treatment cannot be precisely assessed. All invasive which lasted for a mean of 4 days. All patients in that treatments of osteoarthritis of the knee are subject to rele- group rated pain associated with the leeching procedure as vant placebo-like effects; for example, in a recent trial, not severe. Twenty-four hours after leeching, the mean sham arthroscopy was not inferior to arthroscopic debride- hemoglobin level (ϮSD) decreased from 8.9 Ϯ 0.7 ment and lavage (30). Currently, a sham leech treatment is mmol/L to 8.5 Ϯ 0.4 mmol/L (P Ͻ 0.001), but in no pa- not available and treatment blinding is not feasible. We tient did it decrease below 6.8 mmol/L. At the end of the assessed outcome expectation to approximate the placebo- study period, 21 of 23 patients in the leech therapy group like effects, but despite higher scores in the leech therapy stated that they would like to undergo repeated therapy in group, adjustment for the confounding effect of outcome expectation did not change the overall results. Future trialsshould include treatment groups with other invasive pro- DISCUSSION
cedures or use genetically modified leeches.
Since long-term therapy for osteoarthritis of the knee Further study limitations are due to nature of the con- has limited options and treatment carries substantial risk trol treatment. In the present study, leech therapy was for serious adverse effects (22), new therapeutic approaches compared with 4-week topical diclofenac treatment. Ran- should be considered. Leech therapy, although extensively domized, controlled trials showed the pain-relieving effect used for treating pain throughout medical history (9, 23), of topical diclofenac in knee osteoarthritis (31, 32). Topi- has never been evaluated in a modern scientific context.
cal NSAIDs in general have been evaluated as an effective In this randomized, controlled trial, patients with os- but secondary treatment in osteoarthritis (12). In our cur- teoarthritis of the knee who were treated with leech therapy rent study, topical diclofenac was preferred over oral experienced clinically significant improvements in self-per- NSAIDs to compare 2 types of local treatment. The mech- ceptions of pain for a limited period. Moreover, a single anisms of topical diclofenac include local accumulation in application of leeches improved functional ability and joint synovial fluid and periarticular tissue, as well as systemic distribution (33, 34). Compared with leech therapy, the 728 4 November 2003 Annals of Internal Medicine Volume 139 • Number 9
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observed improvement with topical diclofenac in our study 38). So far, there are no reported cases of Aeromonas infec- was modest, but the 20% to 25% reduction in pain and tion when leeches were applied for treating osteoarthritis or disability corresponds to treatment effects seen in previous trials with topical NSAIDs (31, 35). However, leech ther- In summary, traditional leech therapy seems to be an apy might be less effective if compared with standard ther- effective symptomatic treatment for osteoarthritis of the apies for osteoarthritis pain, such as intra-articular steroids knee. However, because only subjective, patient-reported or oral NSAIDs, and its superiority compared with these end points were evaluated and the patients were not blinded to the intervention, we emphasize the preliminary We do not know whether our findings may be gener- nature of this study. The effectiveness and safety of this alized to all patients with knee osteoarthritis. Age and sex treatment, especially when applied repeatedly, should be ratio of the study sample are typical for patients with knee further evaluated in larger randomized studies. In addition, osteoarthritis. A selection bias might be introduced by the the active compounds in leech saliva and their local release fact that patients who agree to participate in a leech ther- (that is, in the synovial fluid) deserve further study. Cur- apy study may have had high treatment expectations and rently, no pharmacologic agent has similar lasting effects thus be more susceptible to a placebo effect than the gen- after a single local administration. Further research into the eral patient population with osteoarthritis of the knee.
anti-inflammatory compounds of leech saliva could lead to Finally, this study may not have been long or large the development of new effective substances for treating enough to exactly assess the clinical value and long-term effect of leech therapy. Pain reduction diminished within 4weeks, but the beneficial effects on joint function and stiff- From the Kliniken Essen-Mitte, Academic Teaching Hospital of the ness persisted until the end of the 3-month study period.
University of Duisburg-Essen, Karl and Veronica Carstens Foundation, Because of the sequential design of the study and the clear and Institute for Medical Informatics, Biometry and Epidemiology, Uni-versity of Duisburg-Essen, Essen, Germany.
effect of leech therapy on the primary outcome, the result-ing study groups were rather small for the analysis of sec- Grant Support: By a research grant from the Karl and Veronica Carstens
ondary outcomes. Day-to-day symptom variation may be considerable in patients with osteoarthritis, pointing also tothe need for larger study groups in future trials. In our Potential Financial Conflicts of Interest: None disclosed.
pilot study, the pain-relieving effect of leech therapy wasmore pronounced after 4 weeks than after 1 week. Non- Requests for Single Reprints: Gustav J. Dobos, MD, Kliniken Essen-
randomization could have biased the results of the pilot Mitte, Department of Internal Medicine V, Am Deimelsberg 34 a, study in favor of leech therapy, but these patients were also 45276 Essen, Germany; e-mail, gustav.dobos@uni-essen.de.
treated actively with physiotherapy. This possibly sup- Current author addresses and author contributions are available at www Our present data suggest that re-treatments will be necessary for leech therapy to become clinically valuable inthe long-term management of osteoarthritis of the knee.
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www.annals.org
Current Author Addresses: Drs. Michalsen, Spahn, and Dobos and Ms.
Analysis and interpretation of the data: A. Michalsen, R. Lu¨dtke, S.
Klotz: Kliniken Essen-Mitte, Department of Internal Medicine V, Am Deimelsberg 34 a, 45276 Essen, Germany.
Drafting of the article: A. Michalsen, G. Spahn.
Dr. Lu¨dtke: Karl and Veronica Carstens Foundation, Am Deimelsberg Critical revision of the article for important intellectual content: S. Moe- Dr. Moebus: Institute for Medical Informatics, Biometry and Epidemi- Final approval of the article: A. Michalsen, G.J. Dobos.
ology, Medical Faculty, University of Essen, Hufelandstrasse 55, Obtaining of funding: G.J. Dobos.
Administrative, technical, or logistic support: A. Michalsen, S. Klotz, G.
Author Contributions: Conception and design: A. Michalsen, R.
Collection and assembly of data: S. Klotz, S. Moebus.
Annals of Internal Medicine Volume • Number www.annals.org

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