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). Effect of withdrawal of calcium antagonists on bleeding time lations were noted between bleeding time and Among 156 patients taking calcium antagonists, 21 serum creatinine, platelet counts or haemoglobin patients with prolonged bleeding time were ran- (Figure 2). Of note, the regression line for the corre- domly assigned to two groups. In one group (BUN, lation between bleeding time and BUN in patients 9.8 ± 1.1 mmol/l (58.7 ± 6.5 mg/dl); platelet, 18.8 ± with calcium antagonists was shifted leftward, com- 2.4 × 104/mm3, n = 12], treatment with calcium pared with that in patients without these agents (y- Ͻ antagonists was discontinued, and bleeding time intercept, 2.99 vs 1.27, P 0.05); the slopes were not was examined during the treatment with calcium different between these lines (0.029 vs 0.036, Ͼ antagonists and after cessation of these agents at an P 0.5). interval of 7 to 10 days. Thus, the withdrawal of cal- The types of calcium antagonists used in this cium antagonists shortened bleeding time (from study were summarised in Table 2. Although nifedi- 11.3 ± 0.8 to 5.4 ± 0.8 min, P Ͻ 0.05 by Wilcoxon pine and amlodipine were used more frequently, no signed rank test; Figure 3, left). In contrast the predilection of calcium antagonists was noted with remaining group [BUN, 10.5 ± 1.4 mmol/L regard to the effect on bleeding time. (62.9 ± 8.2 mg/dl); platelet, 16.8 ± 2.3 × 104/mm3, Despite the inhibitory action of calcium antagon- n = 9] continued to receive calcium antagonists ists on bleeding time, the incidence of the events throughout the study. Bleeding time was repeatedly associated with bleeding tendency did not differ evaluated at nearly the same interval, and proved to be unchanged (from 11.7 ± 0.9 to 10.0 ± 1.0 min; Figure 3, right).

Discussion It is well established that patients with advanced chronic renal failure are at an increased risk for haematological complications. Although anaemia is a commonly observed complication, haemorrhagic events such as gastrointestinal bleeding and haemor- rhagic pericardial effusion may ensue, and their incidence increases as renal function deteriorates.7 It is traditionally believed that impaired renal func- tion constitutes a central determinant of bleeding diathesis in chronic renal failure. Most of these patients however are on the antihypertensive ther- apy, of which calcium antagonists are the most Figure 2 Correlation between bleeding time and blood urea nitro- widely prescribed in this circumstance. Despite sev- gen (BUN), creatinine, platelet counts, or haemoglobin in patients with chronic renal insufficiency taking calcium antagonists. eral lines of studies reporting the inhibitory effect of 3–6 Bleeding time was correlated with BUN (r = 0.25, P Ͻ 0.05, calcium antagonists on platelet function, no n = 122), but not creatinine, platelet counts, or haemoglobin. investigations have been conducted examining the

Journal of Human Hypertension Calcium antagonists and bleeding time K Hayashi et al 202 Table 3 Number of patients manifesting clinical symptoms associated with haemorrhagic diathesis in chronic renal failure

Bleeding time Calcium antagonists (−) Calcium antagonists (+)

Normal Prolonged Total Normal Prolonged Total

No. of patients 31 3 34 91 31 122

Stool occult blood 4 1 5 7 4 10 Haemorrhagic gastritis 2 0 2 3 1 4 Ocular fundic haemorrhage 6 1 7 9 2 11 Haemorrhagic pericarditis 0 0 0 0 0 0 Oral mucosal bleeding 0 0 0 1 0 0 Skin petechiae 2 0 2 5 2 7

BUN levels (Figure 2). Since hypertension is one of the most common complications in chronic renal failure, and end-stage renal failure favours the use of calcium antagonists rather than other antihyper- tensive agents (eg, ACE inhibitors), it is extremely important to evaluate the clinical relevance of the calcium antagonist in advanced chronic renal failure. We propose that the calcium antagonist aug- ments the impaired nature of the haemostatic mech- anism in advanced chronic renal failure. Recently, it has been a matter of great interest that calcium antagonists affect haemostasis and vaso- motor tone via mechanisms independent of the inhibition of voltage-dependent calcium channels. Thus, Takahara et al3 reported that nifedipine Figure 3 Changes in bleeding time after withdrawal of calcium inhibited platelet aggregation induced by ADP and antagonists in patients with chronic renal failure. The discontinu- ation of the treatment with calcium antagonists markedly short- collagen. Similarly, amlodipine prevented platelet 10 ened bleeding time (left, P Ͻ 0.05, n = 12). No changes were adhesion. In addition to these findings observed in noted, however, when calcium antagonists were continued (right, vitro, the calcium antagonist is recently reported to n = 9). Ca-A, calcium antagonists. increase nitric oxide from vascular endothelium.11,12 Additionally, Ding et al13 have demonstrated that role of calcium antagonists in the impaired haemo- calcium antagonists enhance nitric oxide synthase stasis in chronic renal failure. expression in cultured endothelial cells. In this The present study demonstrates that the number regard, Noris and Remuzzi14 suggest that the of patients with prolonged bleeding time is accumulation of guanidinosuccinic acid, which increased when calcium antagonists are given (odds stimulates endothelial nitric oxide production,15,16 ratio, 3.52). Furthermore, the withdrawal of calcium is responsible for uraemic bleeding; the nitric oxide antagonists corrected the bleeding time (Figure 3). synthase inhibition normalised platelet dysfunction These findings clearly indicate that calcium antag- and bleeding time in uraemic rats.17 It therefore is onists affect bleeding time in patients on calcium intriguing to speculate that calcium antagonists and antagonist therapy. It is traditionally believed that the mechanism that underlies chronic renal failure retention of uraemic toxins is responsible in large act in concert to lengthen bleeding time via a com- part for the haemorrhagic diathesis in chronic renal mon factor, ie, nitric oxide. Further investigations failure.1 Horowitz et al8,9 demonstrated that are required to determine this issue. accumulation of uraemic toxins including guanidi- Of utmost importance, the present study indicates nosuccinic acid is associated with impaired platelet that the calcium antagonist does not cause clinically aggregation and prolongation of bleeding time. serious events associated with haemorrhagic diath- Indeed, the present study shows that bleeding time esis. In this regard, Pahor et al18 have recently dem- is prolonged as BUN elevates (Figure 1). In addition onstrated that calcium antagonists are associated to the impaired haemostatic mechanism underlying with an increased risk of gastrointestinal haemor- chronic renal failure, calcium antagonists are rhage in hypertensive patients over 67 years old. reported to impair platelet aggregation,3,4 prevent Our present findings, indicating the calcium antag- platelet adhesion,10 and prolong bleeding time.3 In onist-related prolongation of bleeding time, however the present study, during the treatment with cal- do not necessarily support the clinical finding by cium antagonists, the correlation between bleeding Pahor et al18 but rather may simply reflect the modu- time and BUN is preserved, but shifted to lower lation of renal insufficiency-related bleeding tend-

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