Analysis of drug prescription in chronic haemodialysis patients
Masahiko Tozawa,
Kunitoshi Iseki,
Chiho Iseki,
Saori Oshiro,
Yasushi Higashiuesato,
Masanobu Yamazato,
Nozomi Tomiyama,
Takeshi Tana and
Shuichi Takishita
Third Department of Internal Medicine and Dialysis Unit, University of The Ryukyus, Okinawa, Japan
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Abstract
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Background. Information concerning medication use in Asian haemodialysis patients is sparse. We surveyed prescribed medications and examined the relation between the number of medications and mortality and clinical characteristics in chronic haemodialysis patients, in Okinawa, Japan.
Methods. We conducted a cross-sectional multicentre survey in August 1999 and patients were observed during 13 months of follow up.
Results. The clinical demographics of 850 chronic haemodialysis patients in seven dialysis units were obtained. Compared with the mean number of medications prescribed in ambulatory patients treated in general practice reported from Ministry of Health and Welfare of Japan (2.7 (n=20 716)), the mean number medications in haemodialysis patients was larger (7.2 (n=850)). The three most prescribed drug types in haemodialysis patients were those related to calcium and phosphate metabolism (88%), antihypertensive agents (71%), and erythropoietin (60%). Among the 850 patients, 38 died during the 13-month follow-up period. The number of medications was positively associated with mortality after adjusting for age, sex, and other clinical factors: the hazard ratio was 1.14 (95% confidence interval 1.031.26, P=0.007). A multiple linear regression analysis using the number of medications as a dependent factor and sex and other clinical characteristics as independent factors revealed that male sex (P=0.04), diabetes mellitus (P<0.0001), and duplication of drugs (P<0.0001) were positively correlated with the number of medications.
Conclusions. Multiple drug use was observed in haemodialysis patients. The number of prescribed drugs was a significant predictor of short-term mortality. Male sex, diabetes mellitus, and duplication of drugs were correlated with increases in the number of medications.
Keywords: end-stage renal disease; haemodialysis; mortality; multiple drug use
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Introduction
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Chronic haemodialysis patients have multiple complications that require pharmacologic therapy [1], and end-stage renal disease may heighten the risk of unfavourable drug effects [2]. The administration of multiple medications simultaneously, consecutively, or both, as well as poor compliance with drug regimens and drug interactions may contribute to drug-related problems [35]. Despite the frequent use of multiple medications and the high potential of adverse drug reactions, current information on the types and numbers of drugs prescribed for Asian haemodialysis patients is sparse [2,3,6].
The use of numerous medications is a known risk factor for falls in elderly non-haemodialysis patients [7,8]. In addition, multiple drug use may be a marker of frailty. Non-compliance with drug regimens may increase the risk of severe complications [9], and represents a potential problem in haemodialysis patients who tend to take numerous medications [4,5,10]. Although the number of prescribed medications in haemodialysis patients may be associated with mortality, this relationship has not yet been examined.
We conducted a multicentre survey of medications prescribed for patients undergoing chronic haemodialysis to examine the current state of drug use, the relation between the number of drugs and mortality, and the factors related to the number of medications given to haemodialysis patients.
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Subjects and methods
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We invited seven dialysis units (four private hospitals and three private clinics) to participate in the present study, which is part of a prospective cohort analysis. All of the units were located in the vicinity of our university making it possible to frequently discuss the progress of the study. All of the involved physicians, nurses, and technicians were cooperative. Included in the study were all the patients in a given dialysis centre. The 850 patients (489 men, 361 women) that were alive on August 1, 1999 were observed until September 31, 2000. The average group size per centre was 121 patients (range 25233). Patients with end-stage renal disease who survived at least 1 month of dialysis were registered as chronic dialysis patients in the Okinawa Dialysis Study (OKIDS) registry [11]. Clinical data were obtained by reviewing medical records in each dialysis unit. The dialysis sessions occurred two or three times per week per patient for 3.54.0 h per session. The mean KT/V for patients on dialysis three times per week from the survey of the Japanese Society for Dialysis Therapy was 1.33 (1.25 for men and 1.46 for women) [12]. Bicarbonate solutions were used as the dialysate in all patients (re-use of a dialyzer is rare in Japan). Baseline laboratory data and clinical variables were obtained before the first dialysis sessions in August 1999. Similarly, baseline systolic blood pressure and diastolic blood pressure were recorded to establish pre-dialysis blood pressure status [13]. Hypertension was defined as systolic blood pressure
140 mmHg and diasystolic blood pressure
90 mmHg, or the current use of antihypertensive medication. Causes of death were confirmed from medical records. Classification of cause of death in haemodialysis patients was defined as described previously [14].
Data on the prescribed medications from the 850 haemodialysis patients in August 1999 were collected from medical records. In each centre, only the unit nephrologist was prescribing medications. Pharmacists were not allowed to change medications or to write prescriptions. In all centres, surveys were conducted under the supervision of one of two authors (M.T. or K.I.). Subsequently, medication records from each patient were reviewed by M.T. or C.I. The number of medications prescribed, category of medication, and duplication of medications were the focus of the review. The number of medications was defined as the total number of prescribed medications for each patient. We categorized the medications according to therapeutic actions including: calcium channel blockers, H2 blockers, and adrenal cortical steroids. Drug duplication was indicated when the same therapeutic agent was contained in more than one medication used [10], e.g. amlodipine and nifedipine.
In the present study, we examined only one parameter for medication compliance. Frequency of missed medication doses was determined from self-administered questionnaires. Patients were asked to grade their level of compliance with medical regimens according to four categories: (i) never missed a dose, (ii) sometimes missed doses, (iii) often missed doses, and (iv) frequently missed doses.
Statistical analysis
Unpaired t-tests or
2 tests were used to analyse differences in data or ratios between two groups. Relative risk was estimated with the Cox proportional hazards regression model. Survival curves were estimated with the KaplanMeier method, and a log-rank test was used to analyse group difference in the survival analysis. Multiple linear regression analysis was used to determine independent predictors of the number of medications. All statistical analyses were performed on StatView 5.0 (SAS Institute, Cary, NC, USA). A P value <0.05 was considered to be significant.
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Results
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Figure 1
shows the distribution of the number of prescribed medications. The mean (SD) number of medications taken was 7.2 (SD 3.1, range 020). Baseline characteristics of patients are shown in Table 1
. The patients were classified into two groups according to the mean number of medications: 07 medications (low-medication group, n=470) and 820 (high medication group, n=380). Age, duplication of drug use, and frequency of diabetes mellitus were significantly higher in the high-medication group than in the low-medication group (P<0.0001). Serum albumin and creatinine were significantly lower in the high-medication group than in the low-medication group (P=0.04 and 0.001). Drug duplication was most frequently observed for calcium channel blocker, benzodiazepines, and stool softeners.
The most frequently used drugs were agents acting on calcium and phosphate metabolism (88%), followed by antihypertensive agents (71%), and erythropoietin (60%) (Figure 2
). As an index of centre variability, we calculated the coefficient of variation [CV=(SD/mean)x100%] for frequency of medication use in the seven dialysis units. Among 10 most frequently used medications, the largest CV was for iron preparations (107%) and the smallest was for calcium and phosphate metabolism (10%). A large degree of inter-unit variability in drug use was observed.

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Fig. 2. Frequency and centre variability of medication use in the 10 most frequently used drugs. CV, coefficient of variation for frequency of medication use in seven dialysis centres. Ca, P Met, agents for calcium and phosphate metabolism; Anti-HT, antihypertensive agents; Epo, erythropoietin; Peptic Ulcer, agents for peptic ulcer; Anti-Coag, anticoagulation and antiplatelet agents; Sedative, sedative and hypnotics drugs; Iron Prep, iron preparations; Antilipid, antilipidemic agents.
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The duration of follow-up was 12.7 (1.5) months. During the follow-up period, 38 patients died (nine patients in the low-medication group, 29 patients in the high-medication group). Overall death rate was 38.9 deaths per 1000 patient-years. The most common cause of death was cardiac disease (n=12, 32%), followed by infection (n=10, 26%), stroke (n=5, 13%), sudden death (n=4, 10%), withdrawal from dialysis (n=4, 10%), and other (n=3, 7%). There was no difference in cause of death distribution between the high-medication and the low-medication group. Survival curves of the two groups show that the high-medication group had a poorer chance of survival than the low-medication group (P=0.007, Figure 3
). The relative risk of the high-medication vs the low-medication group, adjusted for age, sex, duration of haemodialysis, diabetes mellitus, hypertension, serum albumin level, serum creatinine level, and body mass index was 2.58 (confidence interval (CI) 1.125.94, P=0.025). Cox proportional hazards regression analysis showed that mortality was positively associated with the number of medications, age, sex, and serum creatinine level (Table 2
).

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Fig. 3. Survival curves by baseline number of medications. The follow-up period was from August 1, 1999 to September 31, 2000. The cut-off value used for the number of medications per group was the mean value of the overall number of medications used.
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Table 2. Results of a multivariate Cox proportional hazards regression analysisa of baseline characteristics related to survival time
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We analysed the relation between the 10 most frequently used drugs at baseline and mortality (Table 3
). Erythropoietin and coronary vasodilator drugs were significant predictors of mortality; erythropoietin use had a negative association with mortality, and coronary vasodilators had a positive relation to death.
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Table 3. Results of Cox regression analysisa of the most frequently used 10 drugs at baseline related to survival time
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In the Cox analysis shown in Table 2
, the addition of erythropoietin and coronary vasodilators to the independent variable still resulted in the number of medications as a significant predictor of mortality with a relative risk of 1.10 (CI 1.011.22, P=0.04).
The KaplanMeier method showed that survival rates in the seven units were different from one another (P=0.023 by log rank test). Therefore, we also calculated the Cox analysis with adjustment for dialysis units in Table 2
and found that the number of medications was a significant predictor of death with a relative risk of 1.12 (CI 1.021.22, P=0.01).
To determine which patient characteristics were correlated with the number of medications used, we performed multiple linear regression analysis with the number of medications as the dependent variable (Table 4
). The explanatory variables included in the analysis appear in Table 4
. Sex, diabetes mellitus, and duplication of drugs were positively correlated with the number of medications.
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Table 4. Results of multiple regression analysisa of baseline characteristics related to the number of medications prescribed
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We also measured the frequency of medication-missed doses. Among the 850 patients, 710 (84%) responded to the self-administered questionnaires: 429 (60%) indicated none missed, 215 (30%) had some missed, 47 (7%) had several missed, and 19 (3%) had many missed.
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Discussion
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In the present study, we found (i) multiple drug use in haemodialysis patients, (ii) that the number of medications had a positive association with mortality in haemodialysis patients, and (iii) that male sex, diabetes mellitus, and duplication of drugs correlated with the number of medications. Haemodialysis patients have multiple complications [1], which often necessitates the use of many drugs [6]. The number of prescribed drugs, by itself, may reflect the severity or multiplicity of comorbid conditions in haemodialysis patients. Prior investigators suggested that total number of medications was a measure of frailty [7,8].
In June 1999, the Statistics and Information Department of the Minister's Secretariat (Ministry of Health and Welfare of Japan), investigated medication use in ambulatory patients treated in the general practice setting. The subjects were randomly selected from patients who were subscribers to three medical insurance plans in Japan (The National Health Insurance, Employees Health Insurance, and Government-Managed Health Insurance). The results of this study are posted on the web (http://wwwl.mhlw.go.jp). According to the report, the mean number of prescribed drugs in 069-year-old patients was 2.7 (n=20 716) and was 3.5 in
70-year-old patients (n=135 390). The mean number of medications used by haemodialysis patients in our study was 7.2, which was similar to that found in other large surveys (Table 5
) [26,10]. The number of drugs prescribed for haemodialysis patients are remarkably higher than that prescribed for ambulatory patients. A positive relation had been reported between the number of medications and the potential for drug-related problems [15]. When a large number of medications are used, the potential for drug-related problems such as drug duplication, significant drug interaction, and use of contraindicated drugs is high [11], and these problems probably increase the risk of adverse drug effects [5].
The number of medications is higher in patients having significantly shorter periods on dialysis (Table 1
). Patients with a higher number of medications should have a larger number of complications and a poorer prognosis than those with lower numbers of medications. If age and other confounding patient factors are not considered, patients with a better prognosis may have a larger duration of haemodialysis. However, in a multivariate analysis adjusted for age and other variables (Table 4
), we found no significant relation between duration of haemodialysis and the number of medications.
Erythropoietin therapy improves both quality of life [16] and prognosis in dialysis patients [17]. However, there is no beneficial effect of haematocrit normalization on all-cause mortality in dialysis patients with cardiac disease [18]. In the present study, use of erythropoietin significantly reduced the risk of death (Table 3
) and the mean level of haematocrit in patients receiving erythropoietin was not normalized (30.2%).
Table 3
also shows that use of coronary vasodilators significantly increased the risk of mortality. Coronary vasodilator drugs are mostly used for coronary heart disease states associated with increased risk of death. The prognosis of haemodialysis patients after the onset of acute myocardial infarction was poor [19].
Diabetes mellitus is a significant predictor of long-term survival in dialysis patients [12]. Because the observational period in the present study was relatively short and the number of patients was not large, diabetes mellitus was not a significant predictor of death in the Cox analysis (Table 2
).
Non-compliance with medication use in haemodialysis patients includes missing doses of medications and not filling a prescription, both of which may increase with the use of numerous drugs [35]. In one study, the number of drugs used to treat chronic disease was associated with the risk of hospitalization in elderly ambulatory patients by 31% [20]. An association between non-compliance with medications and clinical visits, emergency department visits, and healthcare cost has been reported [21,22]. Non-compliance is also associated with hospitalization [21,22], and hospitalized haemodialysis patients have a poor prognosis [1]. These findings may explain the relation between the number of drugs used and the poor prognosis of haemodialysis patients.
In the present study, 60% of patients reported no missing doses of medication. Blanchard et al. [23] reported that 70% of 80 dialysis patients never missed a dose of their medications. Thus, compliance with drug use in our patients was comparable with that of Blanchard et al. [23]. In the study by Kaplan et al. [5], only 10 (33%) of their haemodialysis patients never missed doses. The number of missing doses reported by our patients may have been underestimated. Finally, differences in the type of medications could influence the differences in compliance between studies [4].
Centre variability in the use of certain drugs was found in the present study (Figure 2
). Anderson et al. [10] reported a similar variability, and they proposed that a contributing factor might have been variability in patients between dialysis centres. Centre variability might also depend on physical preferences for special drugs and medications. In our study, survival rates in the seven units were also different. However, even after adjustment for drug use and for dialysis units, the number of medications was a significant predictor of mortality, suggesting that medication number was a predictor of mortality independent of specific drug use and unit variability.
We found that diabetes mellitus and duplication of drug use correlated positively with the number of medications (Table 4
). Diabetic patients have a high incidence of comorbid conditions [11,24], including high rates of hypertension [25,26]. This may account for the relatively high number of drugs used in diabetic patients. In the present study, drug duplication was observed in 20% of patients. In a previous study, drug duplication was found in 12% of 1023 patients on long-term dialysis therapy [10].
Clinical pharmacists have provided successful therapeutic care for haemodialysis patients. Of 205 interventions by clinical pharmacist in a dialysis unit, 90.5% produced positive patient outcomes [27]. In addition, 126 drug-related problems in 46 haemodialysis patients were identified by a pharmacist in training in nephrology units [3]. Overall, the healthcare system may save an estimated $3.98 for every $1 spent on pharmaceutical care [28]. Pharmaceutical care was shown to improve improved clinical outcomes of dialysis patients through the development of specialized skills in pharmacists [29]. In dialysis units, the provision of pharmacists with professional skills in nephrology should be beneficial for both clinical and economic outcomes in dialysis patients [28].
The results from both large studies in the USA [6,10] and the present study indicate that calcium and phosphate metabolism agents, erythropoietin, and antihypertensive agents are prescribed most frequently for haemodialysis patients. This indicates that hyperphosphataemia, secondary hyperparathyroidism, renal anaemia, and hypertension have been common problems in many haemodialysis patients during the past two decades.
Certain study limitations may have affected interpretation of the results in the present study. Because our seven units are only a part of all the units in Okinawa, selection bias for dialysis units may have been present. In fact, prognosis of patients in the present seven units was better than that for all patients in the OKIDS: overall death rate in the present study was 39 deaths per 1000 patient-years vs 60 for patients of the OKIDS [11]. This indicates that our data may have underestimated the relation between drug number and survival rate. Although centre variability was present as described previously, bias may have been ameliorated by the multicentre nature of the present study. Data for dialysis frequency was not available in the present survey. However, when we studied 1243 patients from OKIDS in 1991 [30], the number of patients receiving haemodialysis treatment thrice weekly was 84%. Most of the patients in the present study were probably receiving thrice-weekly haemodialysis.
In summary, multiple drug use was observed in haemodialysis patients. The number of prescribed drugs had a positive association with short-term mortality. Male sex, diabetes mellitus, and duplication of drugs were correlated with an increase in the number of medications used. The prescription of multiple drugs may reflect the severity or multiplicity of comorbid conditions in haemodialysis patients, and non-compliance could be a factor in the risk of death. The clinical implications arising form the present results should be studied further.
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Acknowledgments
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We thank our medical staff colleagues of the Study Group from the Seven Okinawa Dialysis Units. Physicians that cooperated in the study are as follows: Drs K. Tokuyama (Urasoe Sogo Hospital), S. Toma (Toma Clinic), Y. Shiohira (Tomishiro Chuo Hospital), T. Asato (Adachi Clinic), S. Nakazato (Nakagami Hospital), T. Oura (Oura Clinic), and S. Yoshi (Okinawa Dai-ichi Hospital).
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Notes
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Correspondence and offprint requests to: Masahiko Tozawa, MD, Third Department of Internal Medicine, University of The Ryukyus, 207 Uehara, Nishihara-cho, Okinawa 903-0215, Japan. Email: mtozawa{at}eb.mbn.or.jp 
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References
|
---|
- Tozawa M, Iseki K, Fukiyama K. Prevalence of hospitalization and prognosis of patients on chronic dialysis. Clin Exp Nephrol2000; 4: 236240
- Possidente CJ, Bailie GR, Hood VL. Disruptions in drug therapy in long-term dialysis patients who require hospitalization. Am J Health Syst Pharm1999; 56: 19611964[ISI][Medline]
- Grabe DW, Low CL, Bailie GR, Eisele G. Evaluation of drug-related problems in an outpatient hemodialysis unit and the impact of a clinical pharmacist. Clin Nephrol1997; 47: 117121[ISI][Medline]
- Cleary DJ, Matzke GR, Alexander AC, Joy MS. Medication knowledge and compliance among patients receiving long-term dialysis. Am J Health Syst Pharm1995; 52: 18951900[ISI][Medline]
- Kaplan B, Mason NA, Shimp LA, Ascione FJ. Chronic hemodialysis patients. Part I: characterization and drug-related problems. Ann Pharmacother1994; 28: 316319[Abstract]
- Medication use among dialysis patients in the DMMS. United States Renal Data System. Dialysis Morbidity and Mortality Study. Am J Kidney Dis1998; 32 [Suppl 1]: S60S68[Medline]
- Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med1988; 319: 17011707[Abstract]
- Campbell AJ, Borrie MJ, Spears GF. Risk factors for falls in a community-based prospective study of people 70 years and older. J Gerontol1989; 44: M112M117[ISI][Medline]
- Akpaffiong MJ. Non-compliance with antihypertensive drug therapy: a risk factor for stroke among black hypertensives. J Natl Med Assoc1990; 82: 816[ISI][Medline]
- Anderson RJ, Melikian DM, Gambertoglio JG et al. Prescribing medication in long-term dialysis units. Arch Intern Med1982; 142: 13051308[Abstract]
- Iseki K, Kawazoe N, Osawa A, Fukiyama K. Survival analysis of dialysis patients in Okinawa, Japan (19711990). Kidney Int1993; 43: 404409[ISI][Medline]
- Iseki K, Tozawa M, Iseki C, Takishita S. Demographic trends in the Okinawa Dialysis Study (OKIDS) registry (19712000). Kidney Int2002; 61: 668675[ISI][Medline]
- Tozawa M, Iseki K, Fukiyama K. Hypertension in dialysis patients: a cross-sectional analysis. Nippon Jinzo Gakkai Shi (Jap J Nephrol)1996; 38: 129135[Medline]
- Mailloux LU, Bellucci AG, Wilkes BM et al. Mortality in dialysis patients: analysis of the causes of death. Am J Kidney Dis1991; 18: 326335[ISI][Medline]
- Shimp LA, Ascione FJ, Glazer HM, Atwood BF. Potential medication-related problems in noninstitutionalized elderly. Drug Intell Clin Phrarm1985; 19: 766772
- Barany P, Pettersson E, Konarski-Svensson JK. Long-term effects on quality of life in haemodialysis patients of correction of anaemia with erythropoietin. Nephrol Dial Transplant1993; 8: 426432[Abstract]
- Mocks J. Cardiovascular mortality in haemodialysis patients treated with epoetin betaa retrospective study. Nephron2000; 86: 455462[ISI][Medline]
- Besarab A, Bolton WK, Browne JK et al. The effects of normal as compared with low hematocrit values in patients with cardiac disease who are receiving hemodialysis and epoetin. N Engl J Med1998; 27; 339: 584590
- Iseki K, Fukiyama K. Long-term prognosis and incidence of acute myocardial infarction in patients on chronic hemodialysis. Am J Kidney Dis2000; 36: 820825[ISI][Medline]
- Stroupe KT, Murray MD, Stump TE, Callaban, CM. Association between medication supplies and healthcare costs in older adults from an urban healthcare system. J Am Geriatr Soc2000; 48: 760768[ISI][Medline]
- Sclar DA, Chin A, Skaer TL, Okamoto MP, Nakahiro RK, Gill MA. Effect of health education in promoting prescription refill compliance among patients with hypertension. Clin Ther1991; 13: 489495[ISI][Medline]
- Bond WS, Hussar DA. Detection methods and strategies for improving medication compliance. Am J Hosp Pharm1991; 48: 19781988[ISI][Medline]
- Blanchard R, Berger W, Bailie GR, Eisele G. Knowledge of hemodialysis and CAPD patients about their prescribed medicines. Clin Nephrol1990; 34: 173178[ISI][Medline]
- Collins AJ, Hanson G, Umen A, Kjellstrand C, Keshaviah P. Changing risk factor demographics in end-stage renal disease patients entering hemodialysis and the impact on long-term mortality. Am J Kidney Dis1990; 15: 422432[ISI][Medline]
- Tozawa M, Oshiro S, Iseki C et al. Multiple risk factor clustering of hypertension in a screened cohort. J Hypertens2000; 18: 13791385[ISI][Medline]
- Tozawa M, Oshiro S, Iseki C et al. Family history of hypertension and blood pressure in a screened cohort. Hypertens Res2001; 24: 9398[ISI][Medline]
- Tang I, Vrahnos D, Hatoum H, Lau A. Effectiveness of clinical pharmacist interventions in a hemodialysis unit. Clin Ther1993; 15: 459464[ISI][Medline]
- Manley HJ, Carroll CA. The clinical and economic impact of pharmaceutical care in end-stage renal disease patients. Semin Dial2002; 15: 4549[ISI][Medline]
- Matzke GR, St Peter WL, Comstock TJ, Foote EF. Nephrology pharmaceutical care preceptorship: a programmatic and clinical outcomes assessment. Ann Pharmacother2000; 34: 593599[Abstract]
- Tozawa M, Iseki K, Iseki C, Takishita S. Pulse pressure and risk of total mortality and cardiovascular events in patients on chronic hemodialysis. Kidney Int2002; 61: 717726[ISI][Medline]
Received for publication: 12.11.01
Accepted in revised form: 6. 5.02