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Summary

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background The long-term efficiacy for thiopurinic drugs in Crohn’s disease (CD), and particularly in ulcerative colitis (UC), has been insufficiently studied.

Aim To evaluate prospectively and compare the long-term effectiveness of azathioprine (AZA) in CD and UC.

Methods Three hundred and ninety-four AZA treated patients were included consecutively included. Truelove-modified index and CDAI were used to assess effectiveness. Hospitalizations and surgical procedures were recorded.

Results Two hundred and thirty-eight patients with CD and 156 with UC received AZA for a median of 38 months. Effectiveness: Partial response/remission was achieved in 34%/49% of CD patients and in 47%/42% of UC (nonstatistically significant differences). Steroid treatment: Prior to AZA, 49% of CD patients were receiving steroids, whereas only 8% needed steroids after therapy (P < 0.001). Corresponding figures in UC patients were 39% vs. 9% (P < 0.001). Hospitalizations: Prior to AZA, the rate of hospitalizations in CD was 0.190 per-patient-year, while after treatment, it decreased to 0.099 (P < 0.001). Corresponding hospitalization rates in UC were 0.108 vs. 0.038 (P < 0.001). Surgery: The rate of surgery in CD prior/after AZA was 0.038/0.011 per-patient-year (P < 0.001). The number of surgical interventions in UC prior/after AZA treatment was 26/0 (the rate per-patient-year was 0.018/0) (P < 0.001).

Conclusions Our results confirm the effectiveness of AZA in inflammatory bowel disease, not only in the short term but also in the long term, resulting in a steroid sparing effect and in both a reduction in the number of hospitalizations and surgical procedures. AZA is similarly effective for both CD and UC patients.


Introduction

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Steroids offer efficient and prompt relief of symptoms in a high proportion of inflammatory bowel disease patients, both with Crohn’s disease (CD) and ulcerative colitis (UC). However, although most patients initially respond to corticosteroids, at 1 year, approximately 25% become steroid-dependent.1

Thiopurine drugs azathioprine (AZA) and mercaptopurine (MP) are the gold-standard treatment for steroid-dependent and steroid-resistant CD,2 as these drugs have been shown to be effective both in inducing3 and in maintaining4 remission of the disease. In addition, a clear steroid sparing effect in active or quiescent CD has been observed with AZA/MP therapy.3 However, the long-term efficacy for thiopurinic drugs has been insufficiently studied, as most trials include short-term follow-up of a period of only months or a few years.

On the other hand, debate exists regarding whether thiopurinic therapy is as effective in UC as it is in CD. There have been surprisingly few randomized controlled trials, most of which were performed decades ago and suffered from small sample sizes, inadequate dosing of AZA, ambiguous endpoints, and other methodological limitations.5 Thus, although several (but usually small) uncontrolled studies have subsequently evaluated the role of AZA/MP in UC, and despite the widespread acceptance of these drugs for the treatment of UC patients, the use of thiopurinics remains more controversial in UC than in CD.6–31

Our aim was to evaluate prospectively the long-term effectiveness of AZA therapy in a large group of almost 400 patients with CD or UC, and to compare the beneficial effect on both diseases. We did not only consider clinical remission rates and steroid sparing effect of AZA, but also evaluated and compared hospitalizations and surgical procedures before and after starting AZA in these patients.

Methods

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

All consecutive patients with the diagnosis of inflammatory bowel disease starting AZA treatment at the Gastroenterology Unit from the ‘Hospital Universitario Central de Asturias’ (Oviedo, Spain), were included in this prospective study. Informed consent was obtained from all patients and the study was approved by the Committee of Human Experimentation at our institution. Patients who had started AZA treatment at another hospital were excluded. Patients who received AZA primarily for other indications (renal transplant, rheumatoid arthritis, autoimmune liver disease) were excluded. The choice of the dose of AZA was based, as usually recommended, on the patient’s weight (2.5 mg/kg).

Diagnoses of CD and UC were established by standard clinical, radiological, histological, and endoscopic criteria.32 The Montreal classification of CD based on Age at Diagnosis [16 years or younger (A1), 17–40 years (A2), over 40 years (A3)], Location [terminal ileum (L1), colon (L2), ileocolon (L3), upper gastrointestinal (L4)], and Behaviour [Inflammatory/nonstricturing nonpenetrating (B1), stricturing (B2), penetrating (B3); and perianal disease (p) modifier], was used. For UC, the Montreal classification based on the extent of the disease was used: proctitis, left-sided (up to the splenic flexure), and extensive colitis (proximal to the splenic flexure).

At baseline, the following variables were prospectively extracted in a predefined data extraction form: age, gender, smoking habit, weight, type of inflammatory bowel disease, age at diagnosis, duration of disease, and site of involvement. At the same time, data on AZA treatment (daily dose and treatment duration) and concomitant treatments such as steroids, 5-aminosalicylates, etc., were also recorded. Details regarding the number of prior surgical procedures and hospitalizations resulting from their disease since diagnosis were obtained.

Control visits were performed weekly for the first month, monthly for the following 2 months, and then every 3 months. At these control visits, patients had complete blood counts measured and were clinically reviewed and any adverse effects were recorded.

The activity of the disease and the response to AZA was evaluated by means of Truelove-modified index33, 34 (Table 1) in UC patients, or by means of ‘Crohn’s Disease Activity Index’ (CDAI)35 in CD patients. Steroid dependency was defined as recurrent flare-up on steroids reduction or withdrawal, or as the clinical need for steroid treatment twice within six consecutive months or three times within a year. Finally, hospitalizations and surgical procedures performed during follow-up – after starting AZA treatment – were recorded.

Table 1.   Modified Truelove–Witts index
 1 point2 points3 points
  1. Inactive: <11; mild: 11–15; moderate: 16–21; severe: 22–27.

Number of stools<44–6>6
Blood in stools">−">+/++">++/+++
Haemoglobin (g/dL)>1410–14<10
Albumin (g/L)>3330–32<30
Fever (°C)<3737–38>38
Tachycardia (bpm)<8080–100>100
Erythrocyte sedimentation rate (mm/h)<1515–30>30
White blood cells (×1000)<1010–13>13
Potassium (mmol/L)>3.83–3.8<3

Remission was defined as reduction in the Truelove-modified index to a score below 11 points (defined as inactive disease) in UC patients, and a reduction of CDAI to a score below 150 points in CD patients (also classified as inactive disease). In steroid-dependent patients, remission was defined as remission according to the previous criteria and as complete steroid withdrawal for at least 6 months. In patients with fistulizing disease, remission was defined as the closure of all fistulae.

Partial response was defined as reduction of at least five points in the Truelove-modified index (but without achieving a score <11) in UC patients, and a reduction >70 points of CDAI index (but without achieving a score <150) in CD patients. In steroid-dependent patients, partial response was defined as a significant decrease (at least 50%) in the dose of steroids. In patients with fistulizing disease, partial response was defined as a reduction of 50% or more from baseline in the number of draining fistulae.

Statistical analysis

For continuous variables, mean, median, and standard deviation were calculated. For categorical variables, percentages and corresponding 95% confidence intervals (95% CI) were provided. Categorical variables were compared with the chi-squared test, and quantitative variables with the Student’s t-test (for independent or for paired-samples, depending on the case). A P value <0.05 was considered statistically significant. To evaluate the changes in the number of patients with events (hospitalizations and surgery), the ratio by patient-year was used. The rates were compared by means of rate ratio test. A multiple logistic regression analysis was performed. The dependent variable was clinical response or remission to AZA, and independent variables were: age (categorized as higher or lower than 42 years, which was the median value), gender (male/female), smoking (smokers and nonsmokers), type of inflammatory bowel disease (UC or CD), AZA dose (in mg/kg body weight), and treatment with 5-aminosalicylates, steroids or other therapies. We used a backward modelling strategy, and the log-likelihood ratio was the statistic used for model comparison. Finally, in order to study the ‘time of response to AZA’ the Kaplan and Meier method was used, and differences between curves were evaluated with the log-rank test.

Results

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Characteristics of patients

Between 1 January 1991 and 30 March 2004, 238 patients with CD and 156 patients with UC were included in this prospective study. Baseline characteristics of these patients are summarized in Table 2. Mean age was significantly lower in CD than in UC patients (41.2 ± 14 vs. 46.8 ± 13 years; P < 0.001). Montreal classification of CD patients was as follows: Age at Diagnosis (A1, 10%; A2, 77%; A3, 13%), Location (L1, 31.1%; L2, 13.9%; L3, 52.5%; and L3 + L4, 2.5%), and Behaviour (B1, 37.8%; B2, 16.8%; B3, 45.4%; B1p, 15%; B2p, 5%; and B3p, 17.8%). At baseline, mean CDAI score for CD patients was 276 ± 74, while mean modified Truelove index for UC patients was 17.1 ± 2.4.

Table 2.   Patient characteristics at baseline and treatment administration data (n = 394)
 Total (n = 394)CD (n = 238)UC (n = 156)P
  1. CD, Crohn’s disease; UC, ulcerative colitis; AZA, azathioprine; N.S., statistically nonsignificant differences.

Age, years (mean ± standard deviation)">43.4 ± 14">41.2 ± 13">46.8 ± 15"><0.001
Males, N (%)">197 (50)">119 (50)">78 (50)">N.S.
Smoking habit, N (%)">115 (29)">62 (26)">53 (34)">N.S.
Disease duration, years (mean ± standard deviation)">7.5 ± 7.48">8.1 ± 7.1">6.6 ± 7">N.S.
Site of involvement for CD, N (%)
 Terminal ileum (L1) ">74 (31)  
 Colon (L2) ">33 (14)  
 Ileocolon (L3) ">125 (53)  
 L3 + Upper gastrointestinal (L4) ">6 (2)  
Site of involvement for UC, N (%)
 Proctitis  ">9 (6) 
 Left-sided colitis  ">75 (48) 
 Extensive colitis  ">72 (46) 
Treatment administration
 AZA treatment duration, years (mean ± standard deviation)">2.8 ± 2.4">2.8 ± 2.3">2.9 ± 2.6N.S.
 AZA dosage, mg/kg/day (mean ± standard deviation)">2.3 ± 0.5">2.3 ± 0.5">2.2 ± 0.5N.S.

Indications for AZA treatment were: steroid-dependence (in most of the cases, 55%), steroid-refractoriness (17%), isolated fistulizing disease (8.5%), steroid-dependence and fistulae (17.5%), and steroid-refractoriness and fistulae (2%). In particular, among patients with CD, 96 (40%) had at least one active fistula; of these, 36 (15%) had three or more active fistulas at the beginning of the study. Location of fistulae in CD patients was: perianal (75%), enterocutaneous (19.5%) and enterovesical (5.5%).

Treatment data

Data of AZA treatment administration are summarized in Table 2. The median AZA dose was 2.3 mg/kg body weight per day (interquartile range, 2–2.6 mg/kg), and the median AZA duration was 2.8 years (range, 0–14 years). Among patients with CD, the median AZA dose was 2.3 mg/kg (interquartile range, 2.0–2.6 mg/kg), and the median duration of AZA treatment was 2.6 years (range: 0–14 years). Within patients with UC, the median AZA dose was 2.1 mg/kg (interquartile range, 1.9–2.5 mg/kg), and the median duration of AZA treatment was 2.5 years (range, 0–13 years).

Effectiveness data

Clinical response and remission.  Overall, 85% of the patients with inflammatory bowel disease responded to AZA treatment: 46% achieved remission, 39% were considered as partial responders, and 15% were nonresponders (including patients suffering from associated adverse effects). Kaplan–Meier curves showed that median time for partial response or remission after starting AZA treatment was 4.5 months (95% CI, 3.8–5.2 months). Differences were not demonstrated when comparing effectiveness of AZA treatment (% of remission or clinical response) between patients with CD and patients with UC (Table 3). In the multivariate analysis, type of disease (CD vs. UC) did not influence effectiveness of AZA therapy. Differences were neither observed when Kaplan–Meier curves were compared (log-rank test) depending on type of disease (CD vs. UC) (Figures 1 and 2). At the end of the study, clinical relapse was documented in 16 patients (4.7%) during AZA treatment, of whom 11 had CD (5.6%) and five had UC (3.6%).

Table 3.   Evaluation of effectiveness of azathioprine treatment: response and remission rates
EffectivenessCrohn’s disease n = 238Ulcerative colitis n = 156P
  1. * See text for definitions.

  2. N.S., statistically nonsignificant differences.

Remission* (%)">117 (49.2)">65 (41.7)N.S.
Partial response* (%)">81 (34.0)">73 (46.8)N.S.
No response* (%)">40 (16.8)">18 (11.5)N.S.
image

Figure 1.  Comparison of Kaplan–Meier curves for clinical response or remission to azathioprine treatment depending on the type of inflammatory bowel disease: Crohn’s disease (CD) vs. ulcerative colitis (UC). Top: first 12 months of follow-up; bottom: complete follow-up.

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image

Figure 2.  Comparison of Kaplan–Meier curves for remission to azathioprine treatment depending on the type of inflammatory bowel disease: Crohn’s disease (CD) vs. ulcerative colitis (UC). Top: first 12 months of follow-up; bottom: complete follow-up.

Download figure to PowerPoint

Steroid treatment.  At the beginning of the study, 49% of CD patients were receiving treatment with steroids, whereas this therapy was needed by only 8% of the patients at the end of the study (P < 0.001) (Table 4). Corresponding figures for steroid-dependence in UC patients were 39% and 9%, respectively before and after AZA treatment (P < 0.001) (Table 4).

Table 4.   Evaluation of effectiveness of azathioprine treatment: effect on steroid treatment, hospitalizations, and surgical procedures
 Previous to azathioprine, N (%)After azathioprine, N (%)P
Crohn’s disease patients (n = 238)
 Steroid treatment116 (49)18 (8)P < 0.001
 Hospitalization/patient-years476/2503 = 0.19064/647 = 0.099P < 0.001
 Surgical procedures/patient-years94 / 2503 = 0.0387/647 = 0.011P < 0.001
Ulcerative colitis patients (n = 156)
 Steroid treatment60 (39)14 (9)P < 0.001
 Hospitalization/patient-years154/1420 = 0.10817/450 = 0.038P < 0.001
 Surgical procedures/patient-years26/1420 = 0.0180/450 = 0P < 0.011

Hospitalizations.  Prior to AZA treatment, the rate for hospitalization was 0.190 per patient-year for CD patients, while after AZA treatment, this figure decreased to 0.099 per patient-year (P < 0.001) (Table 4). Hospitalization rates in UC patients, before and after starting AZA treatment, were 0.108 and 0.038 per patient-year respectively (P < 0.001) (Table 4).

Surgical procedures.  The cumulative number of surgical interventions performed in all CD patients prior to and after AZA treatment was 94 and 7, respectively. Thus, for patients with CD before AZA, this rate was 0.038 per patient-year, whereas after AZA treatment it was 0.011 per patient-year. As a consequence, surgery in this group of patients was significantly less frequent after AZA treatment than before (P < 0.001) (Table 4). The number of surgical interventions (colectomy) performed in UC patients prior to and after AZA treatment was 26 and 0, respectively (the rate per patient-year was 0.018 and 0, respectively) (P < 0.001; Table 4).

Adverse effects

Overall, adverse effects were reported in 74 patients treated with AZA, which represents 18.8% of the cases. The frequency of each particular adverse effect is summarized in Table 5. As shown, the most frequent side effects were gastrointestinal intolerance (9.1%), and myelotoxicity (4.3%). AZA treatment had to be interrupted due to adverse effects in 63 patients (16%), due to the following reasons: myelotoxicity (17 patients), nausea/vomiting (25 patients), acute pancreatitis (10 patients), hepatotoxicity (four patients) and others (seven patients).

Table 5.   Adverse effects in patients treated with azathioprine
Adverse effectPatients, N (%)
  1. Leucopenia was defined as a leucocyte count <3 × 109/L, and neutropenia was defined as <1.5 × 109/L neutrophils. Hepatotoxicity was defined as an increase of transaminases at least two times higher the normal values. Pancreatitis was diagnosed when compatible symptoms (abdominal pain) were present and serum amylase was increased three times above the upper normal limit.

None">320 (81.2)
Myelotoxicity">17 (4.3)
Nausea/vomiting">36 (9.1)
Pancreatitis">11 (2.8)
Hepatotoxicity">4 (1)
Dermatitis">3 (0.8)
Other">3 (0.8)

Follow-up (withdrawals and dropouts)

Thirty-three patients (8.4%) voluntarily abandoned AZA treatment: 18 (7.6%) with CD and 15 (9.6%) with UC (a nonstatistically significant difference). Time until AZA withdrawal on a voluntary basis ranged from 4 to 374 days, with a median value of 16 days, both for CD and for UC (a nonstatistically significant difference). Half of the patients who abandoned AZA treatment did so during the first 2 months of treatment. Physician’s decision of AZA withdrawal occurred in 63 patients (16%), being more frequent in CD patients (19.3%) than in UC patients (10.9%) (P < 0.05). Mean time of physician’s decision of AZA withdrawal was of 29 days, which occurred during the first 2 months of treatment in 50% of the patients.

Discussion

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Azathioprine and MP have been shown to be effective both in inducing3 and in maintaining4 remission of CD. Although the efficacy of thiopurinic drugs in UC is usually assumed, data are surprisingly scarce in this setting. Thus, there remain limited evidence-based data to support the efficacy of AZA/MP in UC.36 Two early double-blind, randomized, placebo-controlled trials evaluating AZA as an induction therapy for the treatment of patients with active UC reported conflicting results9, 14 and, to date, there are only a few controlled trials evaluating the effectiveness of thiopurinic drugs for the treatment of active UC.8, 9, 12, 14, 17, 22, 26, 27 On the other hand, randomized placebo-controlled studies of AZA for the maintenance of remission in patients with UC have also been limited.12, 14, 27

At least three reasons exist as to why clinicians are not particularly prone to prescribe immunosuppressants in UC, which may explain the time taken to find evidence for the use of this drug in UC: the lack of sufficient evidence of efficacy provided by a limited number of studies with questionable methodologies, the fact that surgical cure of UC is theoretically possible, and fear of an increased risk of colonic cancer.5, 18, 37

Our study is, to our knowledge, the largest study to evaluate prospectively the effectiveness of AZA treatment in inflammatory bowel disease patients, as we show the results of 394 patients treated with this drug. We found that 85% of the patients with inflammatory bowel disease responded to AZA treatment (46% achieved remission and 39% were considered as partial responders). Adverse effects were reported in 19% of the patients and, as previously published, the most frequent were gastrointestinal intolerance (9.1%) and myelotoxicity (4.3%).38

The long follow-up of our study – patients received AZA over a median period of 38 months – allowed us to confirm the beneficial effect of this drug in the long-term, demonstrating that the efficacy of AZA is relatively well sustained over several years. The appropriate duration of AZA/MP treatment, once remission of inflammatory bowel disease has been achieved with these drugs, remains controversial. An early retrospective study suggested that treatment for longer than 4 years was no better than withdrawal of AZA treatment;39 however, this observation was based on very small numbers. Further studies have confirmed the beneficial effect of AZA/MP maintenance treatment in those who have achieved remission with these drugs, both in CD and in UC, while suggesting that discontinuing AZA/MP would accelerate relapse.10–12, 19, 40–42 Furthermore, no difference in relapses of patients with inflammatory bowel disease treated with AZA for less or more than 4 years duration has been shown in more recent studies.10 Finally, it has recently been found that while in CD AZA discontinuation after 3–4 years did not lead to reactivation, this was the case in UC, suggesting that, at least in UC patients, continuation of AZA treatment seems beneficial.43 Therefore, at present, many authors recommend to keep most patients who sustained remission with AZA/MP on the medication indefinitely.19, 41

Few studies have directly compared thiopurinic drug efficacy between UC and CD. Differences were not demonstrated in our study when comparing effectiveness of AZA treatment between patients with CD and patients with UC, both in the univariate and in the multivariate analyses. This suggests that this drug is at least as effective in UC as in CD. Kull and Beau18 compared the 6-month efficacy of AZA in patients with UC (only 30 patients) and CD and found that clinical remission rates were slightly higher for UC than for CD patients (77% vs. 70%); furthermore, complete corticosteroids weaning was obtained significantly more often in UC patients than in CD patients (59% vs. 30%). Verhave et al.31 concluded that patients with UC treated with AZA responded similarly to their CD counterparts; moreover, they determined that the beneficial effect occurred 1 month sooner in UC than in CD patients. Finally, Fraser et al.10 showed that AZA was more likely to achieve remission in patients with UC than with CD (58% vs. 45%), but was equally effective for maintenance of remission. In summary, it may be concluded that AZA is at least as effective in UC as in CD patients.

In our study, median time for clinical response after starting AZA treatment was 4.5 months. This result confirms that AZA may be effective in a relatively early period of treatment, a finding also observed by others.6, 11, 25, 31, 44–49 Thus, a remarkable proportion of patients with steroid-refractory or -dependent UC achieve remission on AZA after only a few months. Nevertheless, a longer time to achieve the positive response has also been reported in other studies.15, 18, 19, 21, 40, 50, 51

In addition to standardized disease activity indexes such as the CDAI or Truelove index to assess AZA efficacy, we used the rate of consumption of steroids, the number of hospitalizations, and the rate of surgical procedures performed to evaluate effectiveness of thiopurinic treatment, as these end-points are highly relevant from a clinical point of view. By comparing these variables before and after starting AZA treatment, patients were controls of themselves, which limits possible biases.

A clinically meaningful steroid sparing effect was achieved by the thiopurinic treatment, not only in CD patients but also in UC patients; at the beginning of the study, 39% of UC patients were receiving treatment with steroids, while this therapy was necessary by only 9% of the patients at the end of the study. Ardizzone et al.40 retrospectively evaluated the outcome of 56 patients who received AZA for either steroid-resistant of steroid-dependent UC; when compared with the 2 years before AZA treatment, a significant decrease was observed of about 75% in steroid consumption during the 3 years of AZA therapy.

Our results also showed that the number of cumulative hospitalizations and surgical procedures significantly decreased during AZA treatment, both in CD and in UC patients. As an example, hospitalization rates in UC patients, before and after starting AZA treatment, were 0.108 vs. 0.038 per patient-year respectively. Similarly, although with a retrospective design, Actis et al.52 compared the frequency of hospital admission for patients with UC before and after beginning of a maintenance regimen with AZA; although only 17 patients were included in this study, the maintenance treatment with AZA showed a reduction in the number of hospitalizations, decreasing from a mean of 2.1 in the preceding 4 years to a mean of 0.12 in the following 6 years.

Finally, the cumulative number of surgical interventions in our patients was also significantly lower after starting AZA treatment than before. In particular, the number of surgical interventions performed in UC patients prior to and after AZA treatment was 26 and 0, respectively (the rate per patient-year was 0.018 and 0, respectively). In summary, it can be concluded that inflammatory bowel disease patients (and specifically UC patients) undergoing maintenance therapy with AZA will have fewer relapses needing hospitalization, and fewer surgical procedures.

A postal survey was sent in 1996 to consultant gastroenterologist members of the British Society of Gastroenterology to evaluate the prescription of immunosuppressive therapy in UC.53 In particular, AZA use for UC patients was frequent, with 93% of consultants reporting previous use. However, there was a marked variation in duration of use, with 46% prescribing AZA for <2 years. Consultants with more experience of AZA in UC used it at higher maintenance doses for longer periods. In this respect, the median AZA dose in our patients was 2.2 mg/kg body weight per day, and we prescribed indefinite treatment with AZA in most patients.

In summary, our results confirm the effectiveness of AZA in inflammatory bowel disease, not only in the short-term but also in the long-term, resulting in a steroid sparing effect and in both a reduction in the number of hospitalizations and of surgical procedures. Furthermore, our results show that AZA is similarly effective for the treatment of both CD and UC, supporting the conclusion that thiopurinic immunosuppressants represent the first option in the management of steroid-resistant and steroid-dependent UC, and argue in favour of more widespread and earlier use of AZA/MP in these patients.

Acknowledgements

  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We thank Michel Bourgois (Business & Decision, Belgium) and Cécile Dubois (Head of Biometrics, UCB, Belgium) for statistical support. Declaration of personal interests: None. Declaration of funding interests: CIBEREHD is funded by the Instituto de Salud Carlos III.

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  1. Top of page
  2. Summary
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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