PAPER Influence of Sibutramine on blood pressure: evidence ... - Nature

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Feb 1, 2005 - 6Department of Medicine, McMaster University, Hamilton General ... *Correspondence: Dr J Jordan, Franz Volhard Clinical Research Center,.
International Journal of Obesity (2005) 29, 509–516 & 2005 Nature Publishing Group All rights reserved 0307-0565/05 $30.00 www.nature.com/ijo

PAPER Influence of Sibutramine on blood pressure: evidence from placebo-controlled trials J Jordan1*, J Scholze2, B Matiba3, A Wirth4, H Hauner5 and AM Sharma6 1 Franz-Volhard Clinical Research Center and Helios Klinikum, Medical Faculty of the Charite´, Humboldt-University, Berlin, Germany; 2Outpatient Department, Medical Faculty of the Charite´, Humboldt-University, Berlin, Germany; 3Abbott GmbH & C. KG, Knollstrasse Ludwigshafen, Germany; 4Teutoburger-Wald-Klinik, Bad Rothenfelde, Germany; 5Else-Kro¨nerFresenius-Zentrum fu¨r Erna¨hrungsmedizin der TU Mu¨nchen Klinikum Rechts der Isar, Mu¨nchen, Germany; and 6 Department of Medicine, McMaster University, Hamilton General Hospital, Hamilton, Ontario, Canada

OBJECTIVE: Sibutramine, a serotonin and norepinephrine transporter inhibitor, is widely used as an adjunctive obesity treatment. There have been concerns that norepinephrine reuptake inhibition with sibutramine could exacerbate arterial hypertension. DESIGN: Combined analysis of two placebo-controlled trials. SUBJECTS: The combined data set consisted of 1336 patients. Of these patients, 966 were randomized to sibutramine and 370 were randomized to placebo. MEASUREMENTS: Body weight, blood pressure, heart rate (HR). RESULTS: Sibutramine reduced body weight regardless of basal blood pressure. In the complete set of patients, systolic blood pressure did not change with either intervention over the 48-week period (0.1715.5 mmHg with sibutramine, 0.2715.2 mmHg with placebo, P ¼ 0.9). The change in diastolic blood pressure over the 48 week period was 0.379.5 mmHg with sibutramine and 0.879.2 mmHg with placebo (P ¼ 0.049). The blood pressure response was not exacerbated in patients with grade 1 or 2 hypertension or in patients with isolated systolic hypertension. Sibutramine treatment caused a slight increase in supine HR that was sustained throughout the studies. CONCLUSIONS: Sibutramine treatment is unlikely to elicit a critical increase in blood pressure even in hypertensive patients. However, blood pressure and HR should be monitored closely. In patients who experience a clinically significant and sustained increase in blood pressure, the drug should probably be discontinued. International Journal of Obesity (2005) 29, 509–516. doi:10.1038/sj.ijo.0802887 Published online 1 February 2005 Keywords: autonomic; baroreflex; norepinephrine transporter; sympathetic nervous system; catecholamines

Introduction One-third of the adult population in the United States is obese and has an increased risk for cardiovascular diseases.1–3 Although life-style treatments should be considered first, most patients do not achieve and maintain sufficient weight loss with diet and exercise alone.4 One possible therapeutic approach is a combination of diet and exercise with antiobesity medications. The serotonin and norepinephrine uptake inhibitor sibutramine is a widely used antiobesity drug.5–7 Sibutramine mediates increased satiety, although a

*Correspondence: Dr J Jordan, Franz Volhard Clinical Research Center, Haus 129, Humboldt University, Wiltbergstr. 50, 13125 Berlin, Germany. E-mail: [email protected] This work has not been previously published. Received 4 February 2004; revised 22 September 2004; accepted 4 November 2004; published online 1 February 2005

mild increase in energy expenditure may also contribute to weight loss.8 Norepinephrine uptake inhibition with sibutramine in peripheral tissues could exacerbate arterial hypertension through an increase in synaptic norepinephrine concentrations. Indeed, when applied locally to peripheral tissues, norepinephrine transporter blockade increases norepinephrine overflow.9 However, sibutramine is administered systemically. In the central nervous system, norepinephrine transporter blockade attenuates sympathetic outflow through activation of alpha-2 adrenoreceptors.10 Therefore, the systemic application of any norepinephrine uptake-inhibiting drug is associated with complex and opposing cardiovascular effects.11–14 For example, in normal-weight and normotensive young subjects, sibutramine acutely increases resting blood pressure. Yet, the drug profoundly attenuates the pressor response to sympathetic stimuli through a ‘clonidine-like’ sympatholytic effect.12 The

Sibutramine and blood pressure J Jordan et al

510 complex interaction of peripheral and central nervous mechanisms makes it difficult to predict the cardiovascular response to sibutramine in patients with altered sympathetic activity, such as obese hypertensives.15 A recent post marketing surveillance study suggested a significant decrease in blood pressure with sibutramine in obese hypertensives.16 We pooled data from two recent clinical trials to determine the effect of sibutramine treatment on blood pressure in obese subjects with different degrees of hypertension. Obese patients with hypertension up to a blood pressure of 180/ 110 mmHg were routinely included. We reasoned that this analysis would provide a unique opportunity to assess the role of the norepinephrine transporter function in long-term blood pressure regulation.

Table 1 Study overview

Randomized patients (n) Age 18–65 y Body mass index range Z30 and r40 kg/m2 At least one unsuccessful dietary intervention Willing and motivated to lose weight No contraindications to sibutramine treatment No organic causes of obesity No psychiatric diseases No history of coronary artery disease, decompensated congestive heart failure, tachycardia or other cardiac arrhythmias, peripheral vascular disease, or manifestations of cerebrovascular disease No uncontrolled arterial hypertension

KD9618

KD9706

1001 + + + + + + + +

362 + + + + + + + +

4160/ 95 mmHg

4180/ 110 mmHg

Methods Study design The present study is an analysis of data pooled from the two recently conducted multicenter trials KD9618 (interval study) and KD9706 (SAT).17,18 Both were multi-center, placebo-controlled, double-blind, parallel group trials with treatment periods of 48 and 54 weeks, respectively. In both studies, all patients were submitted to a nonpharmacological treatment program. In KD9618, after a 1-month sibutramine run-in period, patients were randomized to continuous treatment with sibutramine 15 mg, interval treatment with sibutramine 15 mg, or placebo treatment. Patients were randomized to continuous treatment, interval treatment, and placebo in a 2:2:1 ratio. KD9706 compared the effect of continuous therapy with sibutramine 15 mg and placebo. In this study, patients were randomized 1:1 to sibutramine and to placebo. The combined data set consisted of 1349 patients (KD9618: 405 patient continuous sibutramine treatment, 395 interval sibutramine treatment, 201 placebo; KD9706: 174 continuous sibutramine, 174 placebo). Due to grade 3 hypertension, 13 patients were excluded from the statistical analysis. The analysis set consisted of 1336 patients (Table 1). Of these patients, 966 were randomized to sibutramine and 370 were randomized to placebo. In the full set of patients, 274 (20.5%) were treated with antihypertensive medications (32.6% in grade 1 hypertension, 43% in grade 2 hypertension). In this group, 171 were treated with angiotensinconverting enzyme inhibitors or AT1 receptor blockers, 58 with diuretics, 16 with beta-adrenoreceptor blockers, 71 with calcium channel blockers, and 43 with other antihypertensive agents. Written informed consent was obtained before study entry. Both studies were approved by local ethics committees.

Anthropometric measurements Body weight was measured at each study visit with a precision of 0.1 kg on validated scales. During the measurement, patients wore light clothes and no shoes. Body height, International Journal of Obesity

waist circumference (determined in an upright standing position of a normal breathing patient and measured horizontally between the lower border of the ribs and the upper border of the hip bones), and hip circumference (largest circumference above the trochanter major) were measured with a margin of 71 cm. Body mass index was calculated.

Blood pressure measurements Blood pressure was determined in the seated position with both feet on the ground using an appropriately sized brachial cuff and a calibrated mercury sphygmomanometer. After a resting period of 5 min, three measurements were taken and averaged. Heart rate (HR) was determined by palpation of the radial artery.

Stratification In our analysis, we stratified patients according to blood pressure before start of the study drug. Blood pressure was graded according to the current guidelines of the European Society of Hypertension.19 Normotension was defined as blood pressure of o140/90 mmHg, grade 1 hypertension as blood pressure 140–159/90–99 mmHg, grade 2 hypertension as blood pressure 160–179/100–109 mmHg, and grade 3 hypertension as blood pressure of Z180/110 mmHg. In all, 12 patients had grade 3 hypertension at the onset of the study, which was a specified exclusion criterion in both protocols. They were excluded from the statistical analysis. The presence of systolic blood pressure (SBP) Z140 mmHg and a diastolic blood pressure (DBP) o90 mmHg was defined as isolated systolic hypertension. Patients with isolated systolic hypertension were analyzed separately.

Statistical methods If not otherwise indicated, data are presented as mean7s.d. Quantitative differences between treatment groups were

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511 compared with U-tests. Qualitative differences were analyzed with w2 testing. We used an intention to treat analysis. The last observation was carried forward. The combined analysis was designed according to a method by Whitehead and Whitehead.20 The weight change in the placebo group of KD9618 (Intervall) had to be adjusted for the weight change in the sibutramine run-in period. In this group, patients’ body weight was adjusted beginning at week 4. In each of these patients, weight reduction in the sibutramine run-in period was replaced by the maximal weight reduction at any time point of the placebo treatment phase (week 4–48).

Results Study design The overall dropout rate was 21.9% (n ¼ 204) with sibutramine and 31.4% (n ¼ 116) with placebo (Po0.0001). The major reason for this difference was poor efficacy and noncompliance in the placebo group. Treatment was discontinued due to side effects in 5.5% of the sibutramine-treated patients and in 6.2% of the placebo-treated patients.

Body weight response Body weight, body mass index, and waist circumference before treatment were similar in the placebo and in the sibutramine group (Table 2). Hypertensive patients were heavier than normotensive patients (Table 3). Sibutramine treatment elicited a greater decrease in body weight than placebo treatment. In the complete set of patients, weight reduction was 8.077.2 kg (n ¼ 966) with sibutramine and 3.678.0 with placebo (n ¼ 370) over the 48-week period (Po0.0001). Most of the weight change occurred during the first 12 weeks (Figure 1). In normotensives, body weight decreased to 8.176.9 kg with sibutramine and 3.578.2 kg with placebo (Po0.0001). In grade 1 hypertensives, body weight decreased to 7.778.0 kg with sibutramine and 3.778.0 kg with placebo (Po0.0001). In grade 2 hypertensives, the weight reduction was 7.178.6 kg sibutramine and only 1.576.9 kg with placebo (P ¼ 0.0007). In patients with isolated systolic hypertension, body weight decreased to 8.576.8 kg with sibutramine and 4.877.6 kg with placebo (Po0.0001). With sibutramine, body mass decreased to 2.972.6 kg/m2 and waist circumference decreased to 7.977.3 cm. With placebo, body mass decreased to 1.372.8 kg/m2 and waist circumference decreased to 5.077.9 cm (Po0.0001 for the comparisons with sibutramine).

Blood pressure and heat rate changes Baseline blood pressure data for the whole population and in the different blood pressure classes are given in Tables 2 and 3. In the complete set of patients, SBP did not change with either intervention over the 48-week period

Table 2

Baseline characteristics

Patients (n) Patients, who completed the study (%) Age (y) Gender (male/female%) Body weight (kg) Body mass index (kg/m2) Waist circumference (cm) Waist to hip ratio Blood pressure (mmHg) Heart rate (bpm) Triglycerides (mg/dl) Total cholesterol (mg/dl) HDL cholesterol (mg/dl) LDL cholesterol (mg/dl)

Sibutramine

Placebo

966 78.1

370 67.0

42.4711.6 22.9/77.1 110.9714.5 35.073.4 106.7712 0.970.09 133716/8278.5 7679.6 162796 215741 50715 135734

42.9711.5 25.7/74.3 109.9713.1 35.3+3.4 107.3711.3 0.9+0.10 133715/8278.3 7678.9 178799 222744 48713 140737

Data are given as mean7s.d.

(0.1715.5 mmHg with sibutramine, 0.2715.2 mmHg with placebo, P ¼ 0.9). The change in DBP over the 48week period was 0.379.5 mmHg with sibutramine and 0.879.2 mmHg with placebo (P ¼ 0.049). The time course of the change in systolic and DBP in the different blood pressure classes is illustrated in Figures 2 and 3. In normotensives, blood pressure increased to 4.7715/ 2.378.8 mmHg with sibutramine (Po0.0001/Po0.0001 vs baseline) and 3.8713/1.578.6 mmHg with placebo (Po0.0001/P ¼ 0.02 vs baseline); the blood pressure increase was similar in both groups (P ¼ 0.58/0.32 between interventions). In grade 1 hypertensives, blood pressure changed to 2.8715/4.579.8 mmHg with sibutramine (P ¼ 0.02/ Po0.0001 vs baseline) and 1.4714/5.779.0 mmHg with placebo (P ¼ 0.39/Po0.0001 vs baseline); the response was similar in both groups (P ¼ 0.53/P ¼ 0.33 between interventions). In grade 2 hypertensives, pressure decreased to 7.7715/4.279.2 mmHg with sibutramine (Po0.0001/ Po0.0001 vs baseline) and 11722/6.6712 mmHg with placebo (P ¼ 0.02/P ¼ 0.008 vs baseline); the response was similar in both groups (P ¼ 0.15/0.30 between interventions). In patients with isolated systolic hypertension, blood pressure changed to 8.1713/1.978.7 mmHg with sibutramine (Po0.0001/P ¼ 0.005 vs baseline) and 5.0715/ 0.576.9 mmHg with placebo (P ¼ 0.004/P ¼ 0.53 vs baseline); the response was not significantly different between sibutramine and with placebo (P ¼ 0.14/P ¼ 0.08 between interventions). Patients who were not treated with antihypertensive medications exhibited a blood pressure change of 0.3715/ 0.479.5 mmHg with sibutramine (n ¼ 781) and 0.8715/ 1.079.0 mmHg with placebo (n ¼ 281) (P ¼ 0.45/P ¼ 0.03). In patients who were treated with any antihypertensive medication, blood pressure changed to 1.8716/ 0.379.2 mmHg with sibutramine (n ¼ 185) and 1.9717/ 0.079.7 mmHg with placebo (n ¼ 89) (P ¼ 0.14/P ¼ 0.08). In patients who were treated with angiotensin-converting International Journal of Obesity

Sibutramine and blood pressure J Jordan et al

512 Table 3

Baseline characteristics according to blood pressure class Hypertension Normotension

Grade I

Grade II

ISH

Patients (n) Age (y) Gender (male/female%)

707 39.2710.7 18.8/81.2

267 45.8710.8 25.8/74.2

107 47.9710.9 34.6/65.4

255 46.2712.0 30.2/69.8

Body weight (kg) Men Women

109.6714.4 93.9712.0

110712.6 97.3712.8

116.5715.8 98.1713.7

110.1713.3 95.8714.6

34.573.2

35.873.2

36.373.7

115.8710 101.9710

118.079.0 106.5711

120.7710 107.1710

Body mass index (kg/m2) Waist circumference (cm) Men Women Blood pressure (mmHg) Heart rate (bpm)

12179.2/7776.1 7578.9

14179.7/9172.3 7779.4

15879.7/9675.2 78710

35.2+3.8

115.6710 105.5711 14677.1/8174.2 7879.9

ISH ¼ isolated systolic hypertension. Data are given as mean7s.d.

Figure 1 Body weight changes with sibutramine or placebo in normotensive patients, grade 1 hypertensives, grade 2 hypertensives, and in patients with isolated systolic hypertension. Sibutramine lowered body weight in each group. Data are given as mean7s.e.m.

enzyme inhibitors or AT1 receptor blockers, the blood pressure change over time was similar with sibutramine and with placebo. The number of patients was too small to further explore the interaction between antihypertensive medications and sibutramine. A formal analysis did not reveal a difference in concomitant antihypertensive medications throughout the studies between placebo- or sibutramine-treated patients. International Journal of Obesity

Figure 2 SBP over time in normotensive patients, grade 1 hypertensives, grade 2 hypertensives, and in patients with isolated systolic hypertension. Data are given as mean7s.e.m.

We conducted a shift analysis to assess whether or not patients changed the blood pressure class during treatment as shown in Table 4. For example, worsening of the blood pressure class of normotensive patients at week 0 compared to week 48 was observed in 27.4% of sibutramine-treated patients and in 23.8% of the placebo-treated patients. The shift in higher blood pressure classes was statistically similar with placebo and with sibutramine treatment.

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513 HR regulation In the complete set of patients, HR increased to 3.3711.2 bpm with sibutramine and 0.4710.8 bpm with placebo (Po0.0001). The HR increase was evident in all blood pressure classes and was sustained throughout the treatment period (Figure 5). We divided the patients in to

We analyzed blood pressure changes in patients who responded to sibutramine or placebo treatment with a clinically significant weight loss (Figure 4). In the full set of patients with at least 5% reduction in body weight at end point, blood pressure changed to 1.2715/0.379.3 mmHg with sibutramine and 0.9716/2.578.5 mmHg with placebo (P ¼ 0.8/P ¼ 0.03). In patients with at least 10% body weight reduction, blood pressure changed to 2.1715/ 0.879.5 with sibutramine and 2.0718/3.078.1 with placebo (P ¼ 0.9/P ¼ 0.09). The difference in blood pressure between sibutramine- and placebo-treated patients was consistent throughout the different blood pressure classes (Figure 4).

Figure 4 Changes in SBP and DBP with placebo or with sibutramine treatment in patients with an at least 5% reduction in body weight during the study. The changes are given in the complete set of patients (all), in normotensives (NTN), grade 1 hypertensives (HTN 11), grade 2 hypertensives (HTN 21), and in patients with isolated systolic hypertension. Data are given as mean7s.e.m.

Figure 3 DBP over time in normotensive patients, grade 1 hypertensives, grade 2 hypertensives, and in patients with isolated systolic hypertension. Data are given as mean7s.e.m.

Table 4

Shift analysis of blood pressure classes Sibutramine treatment (n ¼ 966)

Baseline Normotensive ISH grade 1 grade 2

Placebo treatment (n ¼ 370)

Normotensive

ISH

Grade 1

Grade 2

Grade 3

Normotensive

ISH

Grade 1

Grade 2

Grade 3

376 77 75 7

62 57 25 15

57 32 54 30

20 10 31 22

3 2 4 7

144 31 31 9

27 33 14 5

15 6 24 5

3 6 7 4

F 1 2 3

The table gives the number of patients in each blood pressure class at baseline and the disposition of the same patients during the treatment with placebo or sibutramine in different blood pressure classes. ISH ¼ isolated systolic hypertension; grade 1: grade 1 hypertension; grade 2: grade 2 hypertension. Data are given as absolute numbers.

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514

Figure 5 HR changes over time in normotensive patients, grade 1 hypertensives, grade 2 hypertensives, and in patients with isolated systolic hypertension. Data are given as mean7s.e.m.

three groups according to the HR at study entry (r71, 72–79, Z80 bpm). The HR response to sibutramine was similar in each group (mean HR increase 2.2–3.3 bpm compared with placebo). Interestingly, in the terzile of patients with a heart beat of Z80 bpm at week 0, both in the sibutramine and in the placebo group a decrease of the HR to 2.6711.1 and 5.9710.7 bpm could be observed at the end of the study (Po0.0009).

Ancillary metabolic parameters Triglyceride levels changed to 10.3783 mg/dl with sibutramine and 0.6795 g/dl with placebo (P ¼ 0.04). Total cholesterol changed to 3.1730 mg/dl with sibutramine and 0.1734 mg/dl with placebo (P ¼ 0.16). HDL cholesterol levels increased to 6.1712 mg/dl with sibutramine and 3.6711 mg/dl with placebo (Po0.0001). LDL cholesterol decreased 3.0727 mg/dl with sibutramine and 5.4729 mg/dl with placebo (P ¼ 0.15).

Discussion As expected, sibutramine caused a significantly greater weight loss than placebo.5,6,21,22 The beneficial effect on body weight was similar in normotensive patients and in patients with different degrees of hypertension. The reduction in body weight with sibutramine was not associated with a critical change in SBP compared with placebo International Journal of Obesity

regardless of the blood pressure class. However, the response to sibutramine was variable. Numerically, we found a 0.1 mmHg difference in SBP between sibutramine and placebo. DBP was 1.1 mmHg greater with sibutramine treatment than with placebo. The blood pressure response was not augmented in hypertensive patients. These results support the findings from smaller previous studies conducted in obese subjects with controlled hypertension.23,24 Sibutramine treatment caused a slight increase in supine HR that was sustained throughout the study. These findings may provide some guidance for the clinical use of sibutramine. Furthermore, the data give important new insights into norepinephrine transporter physiology. Sibutramine’s effects on blood pressure regulation in the chronic treatment of obese patients differ from its acute application in normal-weight subjects. With short-term sibutramine application in healthy subjects, resting blood pressure increases, whereas blood pressure during sympathetic stimulation decreases.12–14 The latter effect may be related to a ‘clonidine-like’ sympatholytic effect of norepinephrine transporter inhibition in the brain.10–12,14 In contrast, in the present study, chronic sibutramine treatment in obese patients increased blood pressure slightly or not at all. Body weight reduction with chronic treatment is an obvious difference between acute and long-term sibutramine application. Body weight reduction is known to decrease the blood pressure.25–27 The sibutramine-induced weight loss may have offset the direct effect of sibutramine on resting blood pressure. Chronic reduction in renal sympathetic activity with norepinephrine transporter inhibition11 may also be contributory. Finally, the sympatholytic ‘clonidinelike’ effects of sibutramine on the sympathetic nervous system might be more prominent in obese patients than in young normal weight subjects. In a large subgroup of obese patients, sympathetic activity is increased even at rest.15,28 Our analysis has several limitations. The analysis was retrospective. Furthermore, body weight change, rather blood pressure response, was the primary end point of both included studies. We cannot exclude completely that blood pressure measurements were less accurate than in a hypertension trial. Another limitation is that the design of the included studies differed substantially.17,18 In KD9618 (Intervall),17 a subgroup of the sibutramine-treated patients were not treated continuously (interval treatment). The interval group was on active treatment in weeks 1–12, in weeks 19–30, and in weeks 37–48. Thus, at the end of both trials that were included in our analysis, patients were on their assigned medications. We used established statistical methods to account for these methodological differences. Despite all these limitations, we believe that our findings may have important clinical implications. For example, our present analysis suggests that initiation of sibutramine treatment is unlikely to elicit a critical increase in blood pressure even in hypertensive patients. However, the response can be variable. Therefore, blood pressure and HR should be monitored carefully during sibutramine treatment.

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515 In patients who experience a clinically significant and sustained increase in blood pressure, the drug should probably be discontinued. In a recent analysis of long-term sibutramine studies (412 months), 1.1% of the sibutraminetreated patients and 0.6% of the placebo-treated patients withdrew from the studies due to hypertension.29 We do not have sufficient data on patients with grade III hypertension. Sibutramine treatment cannot be recommended in this group before blood pressure control is achieved with antihypertensive medications. In obese hypertensive patients, sibutramine may have to be combined with antihypertensive medications. In acute studies, the increase in HR and blood pressure with sibutramine was completely reversed with beta adrenoreceptor blockade.12 However, beta-adrenoreceptor blockade also diminished resting energy expenditure, which may attenuate weight loss.12 Nonetheless, in chronic studies, sibutramine reduced body weight in obese hypertensive patients treated with a beta-adrenoreceptor blocker.30 In the present study, patients who were treated with either angiotensinconverting enzyme inhibitors or AT1 receptor blockers had a similar weight loss response to sibutramine as patients who were untreated. In our analysis, we did not see a major difference in the blood pressure response to sibutramine in patients with or without antihypertensive medications. Further prospective studies are needed to address this issue and to define the ‘ideal’ antihypertensive for the combination therapy with sibutramine. The weight loss with sibutramine leads to an improvement in the lipid profile, glycemic control, blood pressure, and other cardiovascular risk factors irrespective of baseline blood pressure levels. Prospective studies have been initiated to answer the question whether the improvement of these cardiovascular risk factors by sibutramine-induced weight loss is associated with decreased cardiovascular morbidity and mortality.

Acknowledgements This work was supported by Abbott GmbH Co. KG, Germany. The statistical analysis was conducted by the Institute of ¨ rg Schnitker GmbH, Artur-LadebeckApplied Statistics, Dr Jo Str 155, 33647 Bielefeld, Germany. JJ, JS, AW, HH, and AS received research support and lecturer fees from Abbott GmbH.

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