Journal of Human Hypertension (2002) 16, 199–203 2002 Nature Publishing Group All rights reserved 0950-9240/02 $25.00 www.nature.com/jhh ORIGINAL ARTICLE Impact of calcium antagonists on bleeding time in patients with chronic renal failure K Hayashi, H Matsuda, M Honda, Y Ozawa, H Tokuyama, K Okubo, I Takamatsu, T Kanda, S Tatematsu, K Homma and T Saruta Department of Internal Medicine, School of Medicine, Keio University, Tokyo, Japan Haemorrhagic diathesis develops in chronic renal fail- longation of bleeding time in patients taking calcium ure, in which calcium antagonists are used widely as antagonists was 3.52 (95% CI, 1.01–12.33). In 12 calcium antihypertensive agents. Although calcium antagonists antagonist-treated patients with prolonged bleeding are reported to impair platelet function, it has not been time, the withdrawal of calcium antagonists markedly examined whether calcium antagonists alter bleeding shortened bleeding time (from 11.3 ± 0.8 to 5.4 ± 0.8 min, time. The present study was conducted to clarify P Ͻ 0.05, n = 12). In contrast, in the additional group whether calcium antagonists affect bleeding time in (n = 9), the continued treatment with calcium antagon- chronic renal failure. Patients with chronic renal failure ists had no effect on bleeding time (from 11.7 ± 0.9 to without and with calcium antagonists were enrolled 10.0 ± 1.0 min). Despite the inhibitory effect of calcium (n = 156), and bleeding time (Ivy’s method) as well as antagonists on bleeding time, no clinically serious blood parameters (BUN, creatinine, platelet counts, and events associated with haemorrhagic diathesis haemoglobin) were compared in patients with normal developed. In conclusion, calcium antagonists prolong and prolonged bleeding time. Among patients not taking bleeding time in patients with chronic renal failure. The calcium antagonists (n = 34), three cases manifested subclinical (laboratory) effect of calcium antagonists prolonged bleeding time, whereas abnormal bleeding however is not necessarily associated with haemor- time was observed in 31 patients out of 122. Positive rhagic events of clinical significance. correlations were observed between bleeding time and Journal of Human Hypertension (2002) 16, 199–203. DOI: BUN in both calcium antagonist-untreated (r = 0.46) 10.1038/sj/jhh/1001327 and -treated groups (r = 0.25). The odds ratio for pro- Keywords: calcium antagonists; bleeding tendency; chronic renal failure Introduction widely, and are believed to be safe and effective in patients with chronic renal failure. Although the In advanced renal failure, bleeding diathesis is main action of calcium antagonists is to relax vascu- recognized as a complication leading to serious lar smooth muscle, these agents exert additional haemorrhagic events, including gastrointestinal action. Thus calcium antagonists are reported to bleeding and haemorrhagic pericardial effusion. inhibit platelet aggregation3–6 and elicit pro- Several lines of investigations have attempted to longation of bleeding time.6 These observations sug- elucidate the mechanisms of bleeding tendency in gest that when used in chronic renal failure, calcium chronic renal failure, and it has been documented antagonists might inhibit haemostatic mechanisms. that platelet function is impaired in uremic The effect of calcium antagonists on haemostatic 1,2 patients. Although the increasing incidence of mechanisms in chronic renal failure however bleeding complications as renal failure progresses remains undetermined. suggests the uraemia-induced bleeding tendency, In the present study, we investigated the effects of very few studies have been conducted examining calcium antagonists on bleeding time in the patients the role of other factors in haemorrhagic diathesis with advanced chronic renal failure. Furthermore, in chronic renal failure. In chronic renal failure, sys- whether the effect of calcium antagonists on bleed- temic hypertension develops more frequently. In ing time was associated with haemorrhagic events this circumstance, calcium antagonists are used of clinical significance was also assessed. Patients and methods Correspondence: K Hayashi, MD, Department of Internal Medi- cine, School of Medicine, Keio University, 35 Shinanomachi, Effect of calcium antagonists on bleeding time Shinjuku-ku, Tokyo 160–8582, Japan E-mail: khayashiȰmc.med.keio.ac.jp One hundred and fifty-six patients with moderate to Received 20 August 2001; revised and accepted 11 October 2001 severe chronic renal failure, but not on haemo- Calcium antagonists and bleeding time K Hayashi et al 200 dialysis were enrolled in this study. Most of the comparison of non-parametric data, Wilcoxon patients were admitted to our hospital for surgical signed rank test was applied. Correlation coefficient construction of arterio-venous fistula, the manage- was obtained by the least square method. P values ment of hypertension, and the education of diet. less than 0.05 were considered statistically signifi- These include the patients not taking (age 60 ± 3 cant. years old; n = 34) and taking calcium antagonists (age 60 ± 1 years old; n = 122). Patients on antiplate- let therapy were excluded from the study. The infor- Results mation on clinical symptoms for haemorrhagic Effect of calcium antagonists on bleeding time diathesis during the previous 3 months was obtained from all patients, and the laboratory exam- Table 1 summarises patient profiles enrolled in this inations were conducted, including faecal occult study (n = 156). Calcium antagonists were pre- blood test, ocular fundoscopy, cardiac ultrasound, scribed in a large proportion of cases (n = 122). and gastrointestinal endoscopy if required. Among the patients not taking calcium antagonists Bleeding time was evaluated by well-trained lab- (n = 34), only three patients (ie, 8.8%) manifested oratory technicians with a modified Ivy method, prolonged bleeding time. In contrast, variable using the Simplate II bleeding time device (normal degrees of prolongation in bleeding time were range, 3–8 min). Blood urea nitrogen (BUN), serum observed in 25.4% of the patients treated with cal- creatinine, platelet counts and blood haemoglobin cium antagonists. The odds ratio for prolongation of levels were evaluated as factors affecting bleeding bleeding time in patients taking calcium antagonists time. BUN and serum creatinine were measured was 3.52 (95% CI, 1.01–12.33). by autoanalyzer. In the patients not treated with calcium antagon- ists, BUN, serum creatinine, platelet counts, or hae- moglobin, did not differ between the subgroup with Effect of withdrawal of calcium antagonists on normal bleeding time and that with prolonged bleeding time bleeding time (Table 1). Similarly, in patients Among patients taking calcium antagonists, 21 treated with calcium antagonists, no differences patients were randomly assigned to two groups. In were observed between these subgroups for any of one group (n = 12), bleeding time was examined dur- the parameters examined. There was no gender dif- ing the treatment with calcium antagonists and after ference in the development of prolonged bleeding the withdrawal of these agents, at an interval of 7– time in any of the groups. 10 days. In the remaining group (n = 9), bleeding Figure 1 summarises the relationship between time was repeatedly evaluated at nearly the same bleeding time and other parameters including BUN, interval during the continued use of calcium antag- serum creatinine, platelet counts and haemoglobin onists. The laboratory technicians who conducted in patients not taking calcium antagonists. Bleeding bleeding time were not informed of whether calcium time was positively correlated with BUN (r = 0.46, antagonists had been withdrawn or not. Informed P Ͻ 0.05). No correlations however were observed consent was obtained from these patients. between bleeding time and serum creatinine or platelet counts. Blood haemoglobin levels were negatively correlated with bleeding time, with a Statistics correlation coefficient of 0.36 (P Ͻ 0.05). Results were expressed as the mean ± s.e.m. Statisti- In patients treated with calcium antagonists, a cal analysis was evaluated by two-way ANOVA fol- weak correlation was observed between bleeding lowed by multiple comparison post hoc test. For time and BUN (r = 0.25, P Ͻ 0.05), whereas no corre- Table 1 Patients profiles Bleeding time Calcium antagonists(−) Calcium antagonists (+) Normal Prolonged Total Normal Prolonged Total n 31 3 34 91 31 122 male/female 17/14 1/2 18/16 58/33 17/14 73/49 Age (years) 60 ± 361± 10 60 ± 360± 157± 260± 1 BUN (mg/dl) 82.2 ± 4.9 106.0 ± 15.2 84.3 ± 4.7 67.2 ± 2.4 80.0 ± 5.2 70.4 ± 2.3 Creatinine (mg/dl) 8.9 ± 0.5 10.7 ± 3.6 9.0 ± 0.5 7.4 ± 0.3 8.4 ± 0.7 7.7 ± 0.3 Platelet counts (×104/mm3) 23.6 ± 1.6 21.7 ± 5.2 23.4 ± 1.5 21.2 ± 0.8 19.6 ± 1.4 20.8 ± 0.7 Hemoglobin (g/dl) 8.1 ± 0.2 6.4 ± 1.0 8.0 ± 0.3 8.8 ± 0.3 8.1 ± 0.3 8.6 ± 0.2 Systolic BP (mm Hg) 151 ± 9 150 ± 7 146 ± 14 157 ± 4 158 ± 4 156 ± 7 Diastolic BP (mm Hg) 80 ± 581± 485± 284± 283± 292± 5 Results are mean ± s.e.m. BUN, blood urea nitrogen; BP, blood pressure. Journal of Human Hypertension Calcium antagonists and bleeding time K Hayashi et al 201 Table 2 Type of calcium antagonists used in the study Bleeding time Total (n) р8min Ͼ8min Nifedipine-SR 28 8 36 Amlodipine 28 10 38 Benidipine 10 4 14 Efonidipine 10 1 11 Manidipine 8 2 10 Nicardipine-SR 4 0 4 Balnidipine 3 0 3 Diltiazem-SR 5 2 7 Verapamil 1 2 3 Figure 1 Correlation between bleeding time and blood urea nitro- gen (BUN), creatinine, platelet counts, or haemoglobin in patients with chronic renal insufficiency not taking calcium antagonists. between the patients without calcium antagonists A positive correlation was observed between bleeding time and and those with calcium antagonists (Table 3). BUN (r = 0.46, P Ͻ 0.05, n = 34) or haemoglobin (r = 0.35, P Ͻ 0.05).