Barriers to blood pressure control and angiotensin enzyme inhibitor use in Canadian patients with chronic renal insufficiency{dagger}

Marcello Tonelli1, John Gill2, Sanjaya Pandeya3, Clara Bohm4, Adeera Levin2 and Bryce A. Kiberd1,

1 Department of Medicine, Dalhousie University, Halifax, Nova Scotia, 2 Department of Medicine, University of British Columbia, Vancouver, British Columbia, 3 Department of Medicine, University of Western Ontario, London, Ontario and 4 Department of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada



   Abstract
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix 1: choices available...
 References
 
Background. Current recommendations for the management of chronic renal insufficiency (CRI) include the use of angiotensin-converting enzyme inhibitors (ACEI) and achieving target blood pressure control. We designed this study to describe the use of these therapeutic strategies, and to investigate barriers to their implementation.

Methods. This was a prospective study of 304 consecutive CRI patients, seen at follow-up in four nephrology clinics across Canada. The use of blood pressure control and antihypertensive medication (AHM) in each of these clinics was recorded, and a questionnaire was administered to nephrologists to determine the basis for decisions concerning AHM regimens and ACEI use/non-use.

Results. Mean age was 60.8±15.7 years, mean creatinine clearance was 30.3±18 ml/min, and underlying renal diseases were similar to registry data. Mean arterial pressure (MAP) achieved was 99.4±14.4 and 98.9±11.9 mmHg in individuals with >1 and <=1 g/day proteinuria, respectively. When similarly stratified by proteinuria, mean systolic blood pressures were 141.4±23.5 and 140.9±20.3 mmHg, and mean diastolic blood pressures were 78.4±14.0 and 77.9±11.4 mmHg, respectively. Blood pressure control, according to published guidelines, was achieved in 128 patients (42.1%). A further 86 (28.3%) patients had their AHM increased. The remaining 90 (29.6%) did not have their AHM increased. Of these, 40 were labelled ‘at target blood pressure’ (mean MAP 100.5±5.4 mmHg), 19 ‘office hypertension’ and 11 ‘unfavourable risk/benefit ratios’. There were 108/304 (35.5%) patients who were not taking ACEI or ARB (angiotensin receptor antagonist): 34/108 (31%) had previous ACEI failure due to hyperkalaemia (21/108, 19%) or acute renal failure (17/108, 16%), and 61/108 (55%) were felt ‘unlikely to benefit’ (categories not mutually exclusive). Miscommunication with the primary physician and medication costs were not identified as significant barriers to improved blood pressure control or ACEI use.

Conclusions. Approximately 40% of CRI patients are achieving current blood pressure goals and 64% are prescribed ACEI/ARB in tertiary care nephrology clinics. Although the use of these strategies may be increasing, there remains room for improvement. Physicians should remain aware of the need to use these proven strategies in patients with CRI.

Keywords: angiotensin-converting enzyme inhibitors; angiotensin receptor antagonists; chronic renal insufficiency; hypertension



   Introduction
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix 1: choices available...
 References
 
Chronic renal insufficiency (CRI) is a common condition, associated with variable rates of progression to end-stage renal disease (ESRD). Strategies that delay or prevent ESRD include aggressive control of blood pressure and the use of angiotensin-converting enzyme inhibitors (ACEI) [17]. Although the optimal blood pressure in CRI is unknown, published guidelines suggest a goal mean arterial pressure (MAP) of <92 mmHg (125/75) in patients with >1 g/day proteinuria, and a goal MAP of <98 mmHg (130/80) in patients with CRI and non-proteinuric renal disease [810]. ACEI have been recommended for most patients with CRI, especially in patients with significant proteinuria or with diabetes mellitus [9,11].

Data collected from a previous multicentre Canadian cohort of CRI patients showed that blood pressure control was suboptimal, as 50% had MAP >105 mmHg (equivalent to 145/85). Fifty per cent of patients in this previous prospective study were not taking ACEI [12]. Reasons for use and non-use of ACEI and other antihypertensive strategies were not recorded.

The intent of the current study was threefold. Our first objective was to describe the blood pressure control and use of antihypertensive medications, especially ACEI, in patients with CRI. Our second objective was to investigate barriers to the tight control of blood pressure and the use of ACEI in this population. Finally, we hoped to identify strategies that may help in achieving these treatment objectives.



   Subjects and methods
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
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 References
 
This was a prospective observational study of consecutive adult patients seen in nephrology outpatient clinics in four Canadian tertiary care centres (Halifax, London, Saskatoon, Vancouver). The nephrologists who participated in the study were all affiliated with major Canadian universities. In Canada, primary care is the responsibility of the family physician. Nephrologists are consultants and direct care through the family physicians. The health care system in Canada is universally available to permanent residents, comprehensive in the services it provides, accessible regardless of income, portable within the country and is publicly funded. All outpatients seen by nephrologists for follow-up of CRI during the pre-specified 4-week study period in 1999 were eligible for enrolment. However, only patients with CRI as defined by creatinine clearance (estimated by the Cockcroft–Gault equation) <75 ml/min documented at least twice (>1 month apart), and with no identified reversible cause were included. The only exclusion criterion was dialysis dependence. The study was purely descriptive and no therapeutic interventions were prohibited.

At each clinic visit for each patient, the attending nephrologist completed a study questionnaire, which indicated a list of potential reasons for prescribing/not prescribing additional antihypertensive medications (AHM) or ACEI. Nephrologists who did not increase AHM and/or start ACEI at the clinic visit were asked to indicate the reason(s) for these decisions; multiple selections were permitted. Every attempt was made to ensure the form was completed immediately following the visit so as to minimize recall bias. One hundred per cent of study forms were completed. Appendix 1 shows the choices available on the study form.

The patients' blood pressures were recorded at the study visit. If multiple blood pressures were recorded, the lowest value obtained was entered in the study. Nurses who measured blood pressures during the study had been trained (for clinical purposes) to take blood pressures in the sitting position after 5 min of rest, and to use blood pressure cuffs that were sized according to arm circumference. Korotkoff phases I and V were used to record systolic and diastolic blood pressures, respectively. However, no special attempt was made to ensure that nurses adhered to this standard clinical protocol during the study. No data from ambulatory blood pressure monitoring was recorded during the study.

The definition of ideal blood pressure control was based on published recommendations for the treatment of hypertension in CRI [810]. Although the Canadian guidelines [8] had not yet been published at the time this study was conducted, they were aimed chiefly at primary care physicians, and were based on other guidelines and clinical trial data that had been available (and well known to nephrologists) for several years. The primary outcome measure was MAP, although data on systolic blood pressure (SBP) and diastolic blood pressure (DBP) were collected and reported.

Study investigators/research assistants collected demographic and other information. Underlying renal disease was based on the attending nephrologist's working diagnosis; renal biopsies were not performed in all cases. For the purposes of this study, loop diuretics were considered AHM. No attempt was made to assess compliance with AHM regimens.

Statistical analysis
Statistical analysis was performed using SAS version 8.0 (SAS Institute, Cary, NC, USA). All statistical tests were two-sided and the level of statistical significance was P<0.05. Frequencies for answers to each question were tabulated. Analyses specific for patient type, centre and other parameters were performed, including t-tests, univariate regression and multivariate regression (linear and logistic).



   Results
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Of the 359 consecutive patients seen in the study period, 55 patients were ineligible and excluded from further analysis (Figure 1Go). Demographic characteristics of the 304 eligible patients at the study visit are shown in Table 1Go. The study visit was, on average, the fourth visit to the nephrologist (4.0±1.3 (mean±SD), range 2–6). No patient was seeing a nephrologist for the first time.



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Fig. 1.  Flow chart indicating distribution of patients in various categories of blood pressure control and ACEI/ARB use. Responses given by nephrologists explaining why AHM had not been increased and/or ACEI had not been started are given where applicable. Multiple answers were permitted in each category.

 

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Table 1.  Demographic and blood pressure characteristics of patients at study visit, stratified by urinary protein and use of ACEI/ARB

 
In the population as a whole, AHM use ranged from no agents in 7.9% of cases to six agents in 0.3%. Percentages of patients on one to five antihypertensive medications were 21.7, 28.0, 30.0, 11.5 and 1.0%, respectively. The most commonly used medications were ACEI (50.3%), followed by diuretics (49%), calcium channel blockers (46%), beta-blockers (34%), direct vasodilators (17%), alpha-blockers (10%) and angiotensin receptor blockers (6%).

Blood pressure control
Table 2Go shows blood pressures recorded at the study visit and at referral. Mean achieved MAP were 99.4±14.4 mmHg and 98.9±11.9 mmHg in individuals with >1 and <=1 g/day proteinuria, respectively. At the study visit, 64.8% of patients had lower MAP compared with their first visit to nephrologists. The mean change in MAP between the first visit and the study visit (all patients) was -7.9±18.1 mmHg (P<0.0001). Table 3Go shows the proportions of patients at various levels of blood pressure. Mean MAP, SBP and DBP were all lower at the study visit compared with the initial visit to the nephrologist. At the study visit, 53.3% had elevated SBP (>=140 mmHg) and 22.4% had elevated DBP (>=90 mmHg). Only 10.2% had isolated systolic hypertension (SBP >=160 mmHg and DBP <90 mmHg).


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Table 2.  Blood pressures and medication data at study visit, stratified by diabetes mellitus, urinary protein and ACEI/ARB use

 

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Table 3.  Levels of blood pressure control at referral and study visit

 
Based on current recommendations for CRI, 42.1% of patients had MAP controlled. Figure 1Go shows that 28.3% of the patients had AHM increased at the study visit and 29.6% had MAP higher than recommended targets for CRI patients, but AHM was not increased. Patients who achieved their MAP target were not otherwise different from those who did not in terms of age, race, sex, diabetic status, residual renal function, mean number of AHM, number of visits to the nephrologist, or underlying renal disease. Multivariate logistic regression, performed using these characteristics as independent variables, found that the number of AHM taken and the goal MAP itself (92 vs 98 mmHg) were the only significant predictors of achieving target MAP. Not surprisingly, patients for whom the target was 92 mmHg were less likely to achieve their goal MAP than those for whom the target was 98 mmHg (34.3 vs 49.4%, respectively; P=0.01).

Reasons for non-adjustment of AHM
Reasons indicated by the attending nephrologists for not increasing AHM in the 28.3% of patients above target were: (i) ‘at target blood pressure’ in 40/90 (44%) cases; (ii) ‘office hypertension’ in 19/90 (21%); and (iii) ‘unfavourable risk/benefit ratio' in 11/90 (12%). In 17/90 cases (19%), no reason was provided. ‘Current antihypertensive regimen unknown’, and concerns about compliance and/or tolerance accounted for the remaining patients. Cost was not identified as a relevant factor in any patient. Orthostatic hypotension or symptoms were not specifically mentioned by any physician, but may have been incorporated into the clinical judgement that the risk outweighed the benefit.

The 50 patients in the ‘at target blood pressure’ or ‘having an unfavourable risk/benefit ratio' subgroups were evaluated further. Although MAP was 100.7±5.6 mmHg, this subgroup of patients was at high risk for renal replacement therapy. Diabetes mellitus was present in 26% of patients, proteinuria was >1 g/day in 58% and the mean creatinine clearance was 27.2±16.0 ml/min.

Use of ACEI
Figure 1Go also shows the breakdown of ACEI use/non-use. In total, 35.5% were not receiving ACEI or angiotensin receptor antagonist (ARB). The reason cited was ‘unlikely to benefit’ from ACEI in 22.9% of cases, a serious adverse reaction (hyperkalaemia, hypotension or worsening renal failure on ACEI) necessitating discontinuation of the medication in 12.0%, unknown or unstable serum creatinine in 3.3%, and cough in 1% (some patients had more than one reason selected). Cost, miscommunication with the patient's primary physician and poor compliance were not cited as significant barriers to ACEI use.

Patients on ACEI and/or ARB tended to be younger (58.4 vs 65.2 years, P<0.003), to have higher creatinine clearance (33.8 vs 23.9 ml/min, P<0.001), and to have higher MAP at the study visit (100.4 vs 96.8 mmHg, P=0.02). Nearly three-quarters of patients with diabetes mellitus were prescribed ACEI/ARB, a higher proportion than in non-diabetics (73.7 vs 59.0%, P=0.009). Age (P<0.0001) and renal function (P<0.0001), but not diabetes mellitus (P=0.14) or MAP at the study visit (P=0.07), remained significant predictors of ACEI/ARB use in a multivariate model. The prevalence of proteinuric renal disease was not higher among ACEI/ARB users than non-users (51 vs 49%, P=NS). The proportion of patients taking ACEI/ARB was 74.8% when creatinine clearance was >=25 ml/min, but only 53.7% when creatinine clearance was <25 ml/min.

Of the patients felt to be ‘unlikely to benefit’ from ACEI, 25% (15/61) had diabetes mellitus and 46% (28/61) had >1 g/day of urinary protein. In addition, 13% (8/61) had MAP >110 mmHg and 34% (21/61) had a history of vascular disease. However, 62% (38/61) of these patients had adequately controlled blood pressure (their mean MAP was 94.0±12.8 mmHg) and 7% (4/61) had previously failed therapy with an ACEI.

Other findings
Clinic location was an independent predictor of MAP (linear model, P<0.006), but not ACEI use (logistic model, P<0.17) by univariate regression. The centre with the best blood pressure control (mean MAP 96.9±14.7 mmHg, 57.8% at target MAP) also had patients with lower mean creatinine clearance, in whom control of hypertension is often more difficult. We were unable to identify any differences in patient populations that might explain these findings.

Mean achieved blood pressure control was improved in this study compared with previous analysis of a similar patient group [12]. The mean MAP in the previous cohort was 105±13 mmHg, significantly higher than in the present study (P<0.0001). Similarly, the proportion of patients with very poor control (defined arbitrarily as MAP >110 mmHg) was significantly lower in the current study (17%) compared with the earlier report (31%).



   Discussion
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix 1: choices available...
 References
 
Blood pressure control
Our first objective was to describe blood pressure control in the population with CRI. Mean achieved MAP were 98.9±11.9 and 99.4±14.4 mmHg in individuals with >1 and <=1 g/day proteinuria, respectively. Approximately 42% of the patients had controlled MAP, and another 28% had their AHM increased at the study visit. At first glance, this level of care appears exemplary, since hypertension in CRI is often difficult to manage and a substantially lower proportion of hypertensive individuals in the general population achieve this level of control [13]. The observation that nearly half of patients not at target had their AHM increased is also notable compared with the proportion of medication increases that were reported in an unselected population of poorly controlled hypertensive men [14]. However, the potential benefits of blood pressure control are greater in patients with CRI, so performance standards should be set higher than in the general population.

The mean achieved blood pressure in the current analysis was similar to that in a 1998 German study of patients with CRI [15]. However, the current study appears to have a higher proportion of patients with more advanced disease, in whom blood pressure control is often more difficult. This, together with the modest reduction in blood pressures compared with the previous Canadian study, suggests that overall performance is improving. Since achieved blood pressures were lower in some centres than others, our data suggests that continued improvement is possible. Although Canadian recommendations for the treatment of hypertension were published in 1999 [8], American guidelines [9], and the data on which both sets of guidelines were based [16], had been available for several years at the time we conducted our study. A future re-evaluation of achieved blood pressure control in this population might yield an insight into whether management of hypertension in CRI is improving with time.

Our second objective was to identify the barriers to ideal blood pressure control. Based on current recommendations, a substantial proportion (30%) of patients with suboptimal blood pressure control did not have AHM increased. The reason for not increasing AHM was most commonly assigned to three categories: ‘at target’, ‘risks exceed benefits’ or ‘office hypertension’. The majority of the patients in the ‘at target’ and ‘risks exceed benefits’ groups had levels of blood pressure historically considered acceptable. We can only surmise that the attending nephrologists were basing their assessment on prior blood pressure recommendations, prior blood pressure recordings, or were incorporating other factors beside blood pressure into their decision making.

‘Office hypertension’ was also cited as a reason for not increasing AHM in a smaller proportion of patients. While this phenomenon is well described in the general population, clinic and patient-measured blood pressures may not differ substantially in patients with CRI [15]. We believe that physicians should consider the use of ambulatory blood pressure monitors before making the diagnosis of office hypertension in patients with CRI, although we did not consider data from such monitoring in our study. Importantly, nephrologists did not identify concerns about communication with the primary physician, cost or compliance as major barriers to blood pressure control. Unfortunately, the patients who did not have their AHM increased constituted a high-risk group, with a substantial proportion having diabetes mellitus, significant proteinuria and advanced renal insufficiency.

Our third objective was to identify strategies that would help achieve targets. Since the number of AHM prescribed was an important predictor of achieving target blood pressures, adding additional agents may improve control. In addition, there were some AHM that could have been used more frequently. For example, the use of beta-blockers in this cohort was relatively low (33.9%). Given the high prevalence of coronary disease in CRI and the efficacy of these agents in reducing cardiovascular mortality, physicians should consider the use of beta-blockers as additional antihypertensives [17]. Similarly, the use of diuretics in this study was <50%, and these agents enhance the antihypertensive effect of ACEI [18,19]. Although excessive diuresis may compromise renal function, judicious use of these agents is safe in CRI [20].

Although we did not attempt to assess dietary prescription or compliance with dietary modification, salt-restricted diets are known to be synergistic with AHM [21]. A concerted effort to implement sodium-restricted diets may therefore increase the number of CRI patients that achieve blood pressure targets.

Use of ACEI
In parallel to describing the level of blood pressure control, we examined the use of ACEI. Approximately 60% of our patients were taking or were started on ACEI, a modest improvement over the previous Canadian cohort study (50%). An additional 6% of the patients in the current analysis were taking ARB, which appear to confer similar benefits, especially in diabetics [22,23]. Many of the patients with diabetes mellitus were on ACEI/ARB (73.7%). Among the roughly one-third of patients who were not taking ACEI or ARB, 31% (11.1% of the entire cohort) had previously failed therapy with ACEI. This indicates that the maximum achievable ACEI use in this population may be as high as 90%.

Twenty per cent of patients were deemed ‘unlikely to benefit’ from ACEI. Mean MAP in this group was only 94 mmHg, and many had non-proteinuric renal disease, in whom the specific benefits of ACEI/ARB are less clear. It is therefore possible that nephrologists chose to focus on achieving blood pressure targets in these patients, rather than on introducing ACEI/ARB specifically. However, ACEI may slow renal loss in patients with <1 g/day proteinuria compared with alternate regimens of AHM, suggesting that their use should be considered even in non-proteinuric disease [24]. Finally, the association between age and renal function with ACEI/ARB non-use, even when adjusted for other factors, may reflect a perception that older patients may be at greater risk for the adverse events associated with these agents.

The incidence of hyperkalaemia or acute renal failure necessitating discontinuation of ACEI was substantially more common in our study than in several large randomized trials [6,7,25]. For example, 2% of ramipril recipients in the AIPRI study stopped treatment due to hyperkalaemia as compared with ~10% of ACEI recipients in the current analysis. However, the AIPRI participants had more residual renal function than those in our study, and their select nature (compared with patients seen in day-to-day practice) may have made them less prone to adverse events due to ACEI use. In support of this hypothesis, data obtained in unselected medical outpatients found the incidence of ACEI-related hyperkalaemia to be 11% overall, and higher in those with renal insufficiency [26]. Although we found the incidence of serious side effects in clinical practice to be substantially higher than in controlled trials, it is worth re-emphasizing that such side effects were implicated only in a minority of ACEI/ARB non-users.

In the current study, patients on ACEI/ARB had more residual renal function than those not taking these medications. Although many complications of their use, such as hyperkalaemia, acute renal failure and anaemia, occur more commonly in advanced CRI, there is evidence that even patients with very low levels of renal function may benefit from ACEI [27] with careful monitoring. Finally, although ARB have been available for clinical use in Canada since 1995, additional information on their renal benefits has accrued since our study was conducted [22,23,28], and these agents may be less likely to cause hyperkalaemia than ACEI [29]. It is therefore possible that the new data will affect the relative distribution of ACEI to ARB use, or increase the total proportion of patients with CRI who receive one or the other, but this remains to be determined.

Limitations
Limitations of our study include the relatively small number of patients and the absence of any long-term follow-up. Although the forms were filled out after the nephrologists had made treatment decisions, it is possible that our study influenced their clinical practice and our data must be regarded as a best-case estimate. In addition, our findings may not be applicable to non-tertiary settings. We attempted to reduce selection bias by studying consecutive patients. However, since patients with poorly controlled blood pressure may be scheduled for more frequent office visits, such patients may have been over-represented in our study.

Finally, blood pressure was only taken on one occasion, and additional blood pressure measurements would have been helpful. Nonetheless, all of these patients were being seen at follow-up by nephrologists who had seen them previously, and who were making decisions on the basis of available clinical data. We therefore feel that our study accurately represents the conduct of nephrologists in day-to-day clinical practice. In addition, nephrologists could make the conditional recommendation to intensify the AHM regimen if the blood pressure remained at current levels at follow-up with the primary care physician. This recommendation was treated as equivalent to the decision to increase medications immediately, which we believe partially offsets the limitations of the single blood pressure measurement.

Conclusions
Reducing the burden of ESRD is a major public health initiative, which requires the effective dissemination and implementation of effective therapeutic strategies. The task is particularly difficult because the appropriate management of CRI is in constant evolution. Our data suggests that the attitude of physicians about the likelihood that a given patient will derive benefit is an important determinant of ACEI/ARB use and blood pressure control. Physicians caring for patients with CRI should therefore redouble their efforts to implement these therapies, in an attempt to reduce rates of progression to ESRD.



   Appendix 1: choices available on the study form
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix 1: choices available...
 References
 
A. Reasons for not increasing AHM
Patient at his/her target blood pressure, benefit less than risk, non-compliance, intolerance, recent change by another physician, cost, office hypertension, conservative measures more appropriate, current antihypertensive regimen unknown, and other (blank space provided). Multiple selections were permitted.

B. Reasons for not starting ACEI or ARB
Benefit less than risk, benefit of ACEI unlikely, previous ACEI failure (cough, hyperkalaemia, worsening renal failure, hypotension), recent change by another physician, cost, unstable or unknown serum creatinine, current medications unknown, use of an angiotensin-receptor blocker, and other (blank space provided). Multiple selections were permitted.



   Acknowledgments
 
The authors are grateful to Mr Anu Jindal for assistance with data entry, to Drs Joanne Kappel and Catherine Clase for their suggestions on study design, and to the nephrologists who kindly participated in the study: C. Clase, C. Dipchand, D. Hirsch, K. Jindal, B. Kiberd, K. West and M. West (Halifax); D. Hollomby, A. House and N. Muirhead (London); R. Dyck, J. Kappel, J. Klassen and A. Shoker (Saskatoon); and C. Chan-Yan, T. Chiu, L. Deluca, D. Landsberg, A. Levin, D. Taylor and R. Werb (Vancouver). Drs Tonelli and Gill were supported by Kidney Foundation of Canada Biomedical Research Fellowships. Dr Tonelli also received support from Baxter Corporation.



   Notes
 
{dagger}This work was presented in part at the Canadian Society of Nephrology Meeting in March 2000, and in an invited commentary in the primary care publication the Canadian Medical Association Journal. Back

Correspondence and offprint requests to: Bryce A. Kiberd, Room 5076, Dickson Building, 5820 University Avenue, Halifax, Nova Scotia, Canada B3H 1V8. Email: bkiberd{at}is.dal.ca Back



   References
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 Appendix 1: choices available...
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Received for publication: 10.10.01
Accepted in revised form: 6. 3.02