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J Am Soc Nephrol 14:1006-1011, 2003
© 2003 American Society of Nephrology

Sustained-Release Diltiazem Reduces Myocardial Ischemic Episodes in End-Stage Renal Disease: A Double-Blind, Randomized, Crossover, Placebo-Controlled Trial

Gennaro Cice*, Attilio Di Benedetto{dagger}, Antonello D’Andrea*, Salvatore D’Isa*, Luigi Ferrara*, Pina Elvira Russo*, Aldo Iacono* and Raffaele Calabrò*

*Department of Cardiology, Second University of Naples, Naples, Italy; {dagger}Fresenius Medical Care, Naples, Italy.

Correspondence to Dr. Gennaro Cice, Cattedra di Cardiologia - Seconda Università degli Studi di Napoli, Piazza Luigi Miraglia, 2-80138 Napoli, Italy. Phone: 39-081-5665122; Fax: 39-081-5665122;


   Abstract
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 Abstract
Introduction
 Materials and Methods
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 Discussion
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ABSTRACT. End-stage renal disease (ESRD) patients receiving maintenance hemodialysis and suffering from coronary artery disease (CAD) often receive doses of calcium channel antagonists that are too low. This may be the result of physician’s desire to avoid adverse side effects during hemodialysis. The aim of this study was the assessment of the safety and efficacy of incremental doses of diltiazem for the treatment of myocardial ischemia in ERSD patients with CAD to identify the optimal dose of the drug. A total of 196 chronic hemodialysis patients were enrolled with CAD showing more than 5 min of transient myocardial ischemia during a 48-h Holter ECG monitoring. A double-blind, randomized, crossover, placebo-controlled trial design was used. Incremental doses of diltiazem (120 to 240 mg/d) were administered in 4 mo. With a dose of 120 and 180 mg/d, a significant reduction in the number and duration of total and symptomatic ischemic episodes was observed (P < 0.001), but the number and the duration of silent ischemic episodes were not reduced. Conversely, the efficacy on silent myocardial ischemia was obtained with a dosage of diltiazem of 240 mg/d (P < 0.001). In addition, with a sustained-release formulation (120 mg twice daily), the efficacy was similar to that obtained with four 60-mg tablets, but the safety was improved, especially during hemodialytic session. The circadian variations analysis of transient ischemic episodes showed a significant reduction in both ischemic peaks observed at baseline only with 240 mg/d of diltiazem. The findings emphasize that sustained-release diltiazem (120 mg twice daily) can be largely useful in uremic patients with CAD on maintenance dialysis. Diltiazem reduces the number and the duration of silent ischemic episodes, has a good tolerability, and positively modifies the circadian pattern of ischemic episodes. E-mail: gennarocice@hotmail.com


   Introduction
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 Abstract
 Introduction
Materials and Methods
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 Discussion
 References
 
Coronary artery disease (CAD) has been documented to be one of the main causes of morbidity and mortality in chronic hemodialysis patients with end-stage renal disease (ESRD) (1–3 ). In such patients with concomitant stable chronic angina, as in nonuremic patients (4–5 ), about 80% of ischemic episodes assessed by dynamic 24-h ECG Holter monitoring are asymptomatic (6–9 ). However, the presence of silent ischemia has been reported to negatively influence the prognosis of cardiac events (10–12 ), determining a cumulative effect of subendocardial necrosis, even in case of intermittent ischemic periods (13).

Currently, ERSD patients on hemodialysis suffering from CAD often receive doses of calcium channel antagonists that are too low (14). This may be the result of physician’s desire to avoid adverse side effects during hemodialysis, which prevails over the attempt to achieve the well-documented anti-ischemic activity of the drug (15).

The aim of this study was therefore to evaluate the efficacy and the safety of incremental doses of diltiazem in treating chronic stable angina pectoris in hemodialysis patients with ischemic episodes documented by Holter monitoring. This issue may be critical to the identification of the optimal dose of this drug to be administered in such patients.


   Materials and Methods
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 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Patients
From January 1998 to April 2001, 196 ERSD patients with CAD (135 men and 61 women; mean age, 55.2 ± 3.3 yr) were enrolled by a single center (Fresenius Medical Care Italy) in Naples.

All the patients were on periodic hemodialytic treatment from a mean period of 80.3 ± 25.6 mo. The diagnosis of CAD was made on the basis of the following:

  1. Previous myocardial infarction documented by clinical history, ECG signs, and increase of specific serum markers of cardiac damage
  2. Angiographic evidence of significant coronary artery stenosis (>70%) of at least one coronary vessel
  3. Previous percutaneous coronary angioplasty (PTCA) or by-pass graft (CABG)

History and clinical data of our population are listed in Table 1. To be included in the study, patients had to be clinically stable and show at least 5 min of myocardial ischemia (1.0 mm or more transient ST segment depression) by 48-h ECG Holter monitoring.


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  		Table 1. Baseline clinical characteristics of study populationa
 
Exclusion criteria from the study protocol were as follows: unstable angina pectoris, acute myocardial infarction, PTCA or CABG < 3 mo, extreme bradycardia (heart rate < 50 bpm), significant first-degree atrioventricular block (PQ > 0.24 s), second- or third-degree atrioventricular block, heart failure with third or forth NYHA class, arterial hypotension (systolic BP < 100 mmHg).

Drug Selection and Study Design
All patients were dialyzed three times a week in the afternoon for a mean time of 240 ± 30 min with a bicarbonate dialysate (32 mEq/L), 144 ± 2 mEq/L Na, and 2 to 3 mEq/L K. Dry weight was defined as a lack of edema or physical signs of volume overload and cramping, without nausea or vomiting or with a fall in systolic BP to less than 90 mmHg. Real-time monitoring allowed for an exact and constant control of the weight reduction per hour. During the dialytic session, the following parameters were also evaluated: systolic and diastolic arterial BP, heart rate, and serum electrolytes (potassium, sodium). BP was measured while the patients was sitting and had rested for at least 5 min by a trained nurse with a sphygmomanometer. The mean of three consecutive readings was used, with additional readings if required. The values of arterial pressure reported in our study are referred in the pre-dialytic period. At the end of each hemodialysis, therapy with recombinant human erythropoietin was administered if necessary to maintain a mean hemoglobin value of 11.2 ± 0.5 g/dl.

After a careful history and physical examination, in patients receiving other antihypertensive or anti-ischemic therapy, the treatment was progressively reduced over 1 wk and suspended for 15 d, except the use of nitrates in case of angina. After a detailed explanation of the protocol and the purpose of the study, the patients gave their informed consent. A double-blind, randomized, single-center, crossover, placebo-controlled trial design was used, and patients were divided into two groups, receiving either diltiazem (102 patients) or placebo (94 patients). The randomization was administered centrally with the use of permuted blocks. Determination of whether a patient would be treated by either diltiazem or placebo was made by reference to a statistical series based on random sampling numbers drawn up by a statistician of the center. The details of the series were unknown to any of the investigators and were contained in similar envelopes. After acceptance of a patient by the panel, the appropriate envelope was opened and the card inside told if the patient was to be a diltiazem or a placebo case. The placebo was presented similarly to diltiazem in blister packs with tablets similar for form and color. Each patient collected tablets directly from the pharmacy department. All study participants were blinded to treatment assignment for the duration of the study. Only the study statisticians and the data monitoring personnel saw unblinded data, but none had any contact with study participants. During the treatment, a questionnaire asked patients to indicate which treatment they believed they had received (diltiazem, placebo, or don’t know), to evaluate patient blinding.

During four following periods of four weeks each, diltiazem was administered at incremental doses: first 120 mg/d in two administrations; then 180 mg/d in three administrations; next 240 mg/d in four administrations; and finally 240 mg/d in a sustained-release formulation (two administrations of 120 mg). At the end of these four periods, after a 15-d wash-out, the two groups were inverted to receive either placebo or incremental doses of diltiazem (Figure 1). At the end of each phase of the protocol, the 48-h ECG Holter monitoring was repeated. The results observed at the end of each period were compared with the basal one and with the previous phase to assess the incremental efficacy and the safety of each dose.



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  		Figure 1. Flow diagram of the study.

 
ECG Holter Monitoring
Two-lead (D2 and V5) ECG Holter monitoring (CardioData Inc, Marlborough, MA) was performed for 48 h, with patients recording in a diary the activities during the day and any relevant symptoms. In particular, patients were asked to annotate the experience of possible anginal attacks and the possible assumption of sublingual nitrates. The tool was calibrated on the electrocardiogram to twelve derivations, with correction for ST depression without pathologic meaning. The analysis of the ECG layout was performed using a CardioData Mk4 system. An ST depression (measured 60 to 80 msec after J point) > 1.0 mm in comparison with baseline ECG for a duration of at least 60 s was considered ischemic. The duration of every ischemic episode was obtained from the total number of seconds with an ST depression >1.0 mm in comparison with the basal layout. The total ischemic burden was calculated as the product between the maximum ST depression in the 48 h (mm) and the total duration of the ischemia (min).

The analysis of the circadian variation of the ischemic episodes was performed dividing ECG Holter data on a time-scale and calculating the number of ischemic episodes during each daily period. The primary endpoints of the study were the reduction of the number and the duration of total and silent ischemic episodes documented by Holter monitoring. The secondary endpoint was the reduction of total ischemic burden.

Statistical Analyses
The analyses were performed by SPSS for Windows release 10.0 (Chicago, IL). Descriptive statistical procedures were used to assess the distribution of each variable. Data are presented as mean ± SD. We believed that the incidence of silent ischemia in ESRD patients would be 23% (9). On the basis of a 0.9 power to detect a significant difference, (P < 0.05, two-sided), 165 patients were required for the study group. To compensate for nonevaluable patients, we enrolled 197 patients. Patients groups were compared by t test for continuous variables. When appropriate, between-group comparisons were also performed using the two-way ANOVA with treatment as one factor and time as the other factor. Comparisons to determine the significance of changes within the same group over time and between groups at each time point were performed with the Newman-Keul test after the samples were tested for normal distribution. {chi}2 tests were used for categorical variables. Differences were significant at P < 0.05.


   Results
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 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
The results of our study are listed in Table 2. The administration of diltiazem at the dose of 120 mg/d significantly reduced the number of total ischemic episodes during 48 h (P < 0.001) as well as the mean duration of total ischemia compared with baseline control (P < 0.001). However, the number of symptomatic ischemic episodes was significantly reduced (P < 0.001), whereas no significant differences were observed for silent ischemic episodes. Similarly, patients on treatment with diltiazem showed significantly reduced time duration of symptomatic myocardial ischemia (P < 0.001), but not of silent ischemia.


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  		Table 2. Effects of increasing doses of diltiazem on myocardial ischemic parameters
 
When diltiazem was administered at a dose of 180 mg/d, the number of total, symptomatic, and silent ischemic episodes, as well as of the mean duration of ischemia, was comparable to the results of the 120-mg administration with respect to the basal control. However, in comparison with the previous phase of the drug administration, a significant reduction of the duration of the total (P < 0.05) and symptomatic (P < 0.001) myocardial ischemia was observed.

The administration of rapid-release diltiazem at a dose of 240 mg (60 mg x 4)/d determined a further significant reduction of the number and of the duration of the total and symptomatic ischemic episodes (all < 0.001). In addition, a significant reduction of the number (P < 0.05) and of the time duration of silent ischemic episodes (< 0.001) was evidenced. Using the same daily dose of diltiazem (240 mg), with a sustained-release formulation (two administrations of 120 mg), the anti-ischemic effects resulted comparably to the ones achieved with four 60-mg tablets/d.

The safety of the drug was substantially good, with the appearance of few minor side effects (Table 3). Only when diltiazem was administered with a daily dose of 240 mg in rapid-release formulation, 22 patients (11.2%) experienced major drug side effects determining the withdrawal of the treatment: six patient (3.3%) with extreme symptomatic bradycardia, six patients (3.3%) with second-degree atrioventricular block (Mobitz type I), and ten patients (5.1%) with arterial hypotension during the hemodialytic session. Conversely, when the sustained-release diltiazem was administered, only five patients (2.5%) experienced major side effects: three patients (1.5%) with arterial hypotension during the dialytic session, and two (1.1%) patients with severe symptomatic bradycardia.


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  		Table 3. Minor adverse drug side effects of diltiazem
 
The circadian variations of transient ischemic episodes at the baseline control outlined the presence of two main ischemic peaks: the first during the early hours of the morning (from 6.00 to 9.00), and the second in the afternoon, during the hemodialytic session (from 16.00 to 20.00). The diltiazem, at doses of both 120 and 180 mg, although reducing the global number of ischemic episodes, did not modify their circadian variation. Conversely, the administration of 240 mg of diltiazem, both in rapid-release and in sustained-release formulation, significantly reduced the number of ischemic episodes during the two ischemic daily peaks (Figure 2).



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  		Figure 2. Circadian pattern of ischemic episodes at the baseline control and after treatment with incremental doses of diltiazem.

 

   Discussion
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The progressive improvement of hemodialytic techniques guarantees a good quality of life in patients with ESRD. However, the gradual increase of the duration of the dialysis, the prolongation of the mean age, and the peculiar clinical characteristics of such patients (arterial hypertension, left ventricular hypertrophy and diastolic dysfunction, diabetes mellitus, and dyslipidemia), determined a simultaneous increase in the incidence of myocardial ischemic disease. As a result, CAD represents the first cause of morbidity and mortality in the uremic patients (1–3 ).

The incidence and the prognostic impact of silent myocardial ischemia in CAD is largely recognized (4–13 ). In our previous reports, we already observed (7,16 ), perhaps inadequately underlining, that many uremic hemodialysis patients with diagnosed CAD assumed too low doses of anti-ischemic drugs in general and of calcium channel antagonists in particular. This phenomenon was partly justified by the physician’s attempt to avoid adverse side effects during hemodialytic session (for example, extreme bradycardia in case of arterial hypotension). Thus, the aim of our study was to establish the adequate dose of diltiazem determining the best safety and efficacy in a population of ESRD patients with diagnosed CAD.

An initial dose of 120 mg/d (60 mg twice daily) of diltiazem, commonly used in uremic patients, appeared to be inadequate in our patients with CAD. In fact, our findings showed that such dose, even if reducing symptomatic ischemic episodes, did not demonstrate any significant effect on silent ischemia, whose presence is largely considered a negative prognostic factor in ischemic patients (4–12 ). As expected, the incidence of adverse side effects with these doses of the drug was very low.

A daily dose of 180 mg of diltiazem (60 mg thrice daily), in comparison with the basal control, showed similar safety and efficacy. However, the doses of 180 mg/d determined a significant reduction of the duration (in min) of total and symptomatic ischemic episodes in comparison to the effects of 120 mg/d, while the reduction of their total number was NS.

On the other hand, in accordance with previous reports on the use of diltiazem in CAD, the results of our study emphasized a significant effect on silent ischemia only by the administration of 240 mg/d of diltiazem (17–19 ). Even if no previous trial has evaluated the prognostic effect of silent ischemia in hemodialysis patients, such reduction of the number and the duration of both total and silent ischemic episodes in our ERSD patients may be clinically relevant. In fact, evidence of asymptomatic ischemia during ambulatory Holter monitoring has been associated with increased risk of myocardial infarction, serious arrhythmias, and sudden death in patients without renal disease (4–13 ). Therefore, an enhanced control of silent ischemic episodes during the whole day may improve the prognosis particularly in the population of uremic patients at high risk of cardiac events (1–3 ).

The dose of 240 mg/d with four daily rapid-release administrations determined remarkable adverse side effects like severe bradycardia, atrioventricular block, and arterial hypotension, that required in some cases the withdrawal of the treatment. Of note, this increased incidence of side effects represents the main reason why such administration is not commonly used by the nephrologist in uremic patients with CAD. Conversely, the administration of 240 mg/d of sustained-release diltiazem showed the same efficacy on the total ischemic burden with a reduced incidence of side effects.

Our findings can be explained by the close relationship between the dose-response curve of diltiazem and the incidence and the severity of its side effects. In fact, it is well known that the final effect of a drug represents the direct consequence of its increased plasmatic concentration up to a plateau, beyond which only an increase of adverse side effects can be observed. The rapid-release formulation of diltiazem determines an abrupt liberation of the active principle with a peak-effect after 1 to 1.5 h from the administration (19,20 ). In addition, at least three daily administrations are necessary to maintain the plasmatic concentration in effective levels, because of its low bioavailability by oral way (30 to 40%) (21–23 ). Conversely, the oral administration of sustained-release formulation of diltiazem determines a reduced plasmatic peak concentration compared with that of the rapid-release, with a more prolonged time to the peak (7 to 8 h versus 1 to 1.5 h, respectively) and slower elimination from the plasma (midlife of elimination: 5 to 8 h) (24). As a consequence, this method of administration can reach a therapeutically effective steady-state concentration with only two daily administrations (25). Furthermore, with the sustained-release formulation the interdose variation of both the plasmatic levels and the peak of serum concentration of diltiazem are reduced, as well as the incidence and the severity of the side effects.

As for the analysis of the circadian variation of ischemia, our patients, unlike nonuremic ischemic patients, showed two separate ischemic peaks at baseline control: the first during early morning, between 6:00 and 9:00 am, and the second in the late afternoon, between 4:00 and 8:00 pm. It is essential to emphasize that this second ischemic peak and the hemodialytic session are contemporary and that this peak is higher than the first one, probably due to an additional negative effects of the dialytic session itself, as reported by others. After continuative anti-ischemic treatment, only the use of 240 mg/d of diltiazem was able to reduce both the ischemic peaks. Conversely, lower doses allowed only a reduction of the number of ischemic episodes, not modifying the course of the curves. These results are in accordance with previous studies on ischemic nonuremic patient, which showed that the real anti-ischemic effectiveness of the diltiazem could be reached with a daily dose ranging from 240 to 360 mg/d (26–28 ).

Our last observation concerns the highly feared intra-dialytic hypotensive crisis. In contrast with a percentage of 5.1% of patients that experienced hypotensive intra-dialytic episodes during treatment with 240 mg of rapid-release diltiazem, only 1.5% of patients experienced such collateral effect during treatment with sustained-release diltiazem. The gradual achievement and maintenance of the target plasmatic dose, in addition to the significantly reduced side effects, may represent the basis that guarantees this enhanced hemodynamic stability during the same dialytic bath.

In conclusion, the use a therapeutic scheme with 240 mg of sustained-release diltiazem in two daily administrations determines at least three important effects in ESRD patients with CAD:

Our findings therefore emphasize that the administration of a daily dose of at least 240 mg of sustained-release diltiazem to ESRD patients with CAD is essential to determine the complete anti-ischemic activity of the drug without increasing the incidence of adverse side effects.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. US Renal Data System: 1999 Annual Data Report. Am J Kidney Dis 34: S1, 1999[Medline]
  2. de Lemos JA, Hillis LD: Diagnosis and management of coronary artery disease in patients with end-stage renal disease on hemodialysis. J Am Soc Nephrol 7: 2044–2054, 1996[Abstract]
  3. Goldsmith DJ, Covic A: Coronary artery disease in uremia: Etiology, diagnosis, therapy. Kidney Int 60: 2059–2078, 2001[CrossRef][Medline]
  4. Mulcahy D, Keegan J, Crean P, Quyyumi A, Shapiro L, Wright C, Fox K: Silent myocardial ischemia in chronic stable angina: A study of its frequency and characteristics in 150 patients. Br Heart J 60: 417–423, 1988[Abstract/Free Full Text]
  5. Cecchi AC, Dovellini EV, Marchi F, Pucci P, Santoro GM, Fazzini PF: Silent myocardial ischemia during ambulatory electrocardiographic monitoring in patients with effort angina. J Am Coll Cardiol 1: 934–939, 1983[Abstract]
  6. Gonsorcik j, Szakacs M, Palko S, Mydlik M: Pharmacotherapy of silent myocardial ischemia in patients on hemodialysis. Vnitr Lek 42: 837–841, 1996[Medline]
  7. Cice G, Di Benedetto A, Aquino D, Tagliamonte E, Ferrara L, Sorice P, Iacono A: Angina silente in pazienti uremici dializzati: studio di comparazione tra carvedilolo e diltiazem. Giorn It Nefrol 14: 389–396, 1997
  8. Cice G, Di Benedetto A, Sarubbi B, Tedesco MA, Iacono A: Ischemia silente in pazienti in trattamento dialitico. Cardiologia 39: 629–632, 1994[Medline]
  9. Conlon PJ, Krucoff MW, Minda S: Incidence and long-term significance of transient ST segment deviation in hemodialysis patients. Clin Nephrol 49: 236–242, 1998[Medline]
  10. Deedwania P, Carbajal E, Nelson J, Linn L: Silent ischemia during daily life is an indipendent predictor of survival in stable angina. Circulation 81: 748–756, 1990[Abstract/Free Full Text]
  11. Yeung AC, Barry J, Orav J, Bonassin E, Raby KE, Selwyn AP: Effects of asymptomatic ischemia on long term prognosis in chronic stable coronary disease. Circulation 83: 1598–1604, 1991[Abstract/Free Full Text]
  12. Gottlieb SO, Gottlieb SH, Achuff SC, Baumgardner R, Mellits ED, Weisfeldt ML, Gerstenblith G: Silent ischemia on Holter monitoring predicts mortality in high-risk postinfarction patients. JAMA 259: 1030–1035, 1988[Abstract]
  13. Geft IL, Fishbein MC, Ninomiya K, Hashida J, Chaux E, Yano J, Y-Rit J, Genov T, Shell W, Ganz W: Intermittent brief periods of ischemia have a cumulative effect and may cause myocardial necrosis. Circulation 66: 1150–1153, 1982[Abstract/Free Full Text]
  14. Matsumoto N, Ideishi M, Sasaguri M, Nii T, Nakashima Y, Arakawa K: Effects of slow-release nifedipine on 24-hour ambulatory blood pressure and ischemic changes on 24-hour ambulatory electrocardiogram in patients with severe coronary artery disease. Cardiology 94: 36–43, 2000[CrossRef][Medline]
  15. Elsner D: How to diagnose and treat coronary artery disease in uremic patients: an update. Nephrol Dial Transplant 16: 1103–1108, 2001[Free Full Text]
  16. Cice G, Di Benedetto A, Tagliamonte E, Ferrara L, Sorice P, Iacono A: Efficacia e tollerabilità di bisoprololo e nifedipina in pazienti con cardiopatia ischemica in trattamento dialitico. Cardiologia 42: 397–403, 1997[Medline]
  17. Hossack KF, Pool PE, Steele P, Crawford MH, De Maria AN, Cohen LS, Ports TA: Efficacy of diltiazem in angina on effort: a multicenter trial. Am J Cardiol 49: 567–572, 1982[CrossRef][Medline]
  18. Go M, Hollenberg M: Improved efficacy of high-dose versus medium- and low-dose diltiazem therapy for chronic stable angina pectoris. Am J Cardiol 53: 669–673, 1984[CrossRef][Medline]
  19. Juneau M, Theroux P: Effect of diltiazem slow-release formulation on silent myocardial ischemia in stable coronary artery disease. Am J Cardiol 69: 30B–35B, 1992[CrossRef][Medline]
  20. Morselli Pl, Rovel V, Mitchard M, Durand A, Gomeni R: Pharmacokinetics and metabolism of diltiazem in man (observation on healthy volunteers and angina pectoris patients). In: New Drug Therapy with a Calcium Antagonist, edited by Bing RJ, Amsterdam, Princeton, Expcerpta Medica, 1979, pp 152–168
  21. Bighley LD, Dimmit DC, KcGraw BF: Bioavailability of diltiazem hydrochloride formulations. Clin Res 28: 587A, 1980
  22. Koiwaya Y, Ashiara T, Nakamura M, Etoh A: Plasma concentration of diltiazem after oral administration in normal volunteers. Clin Ther 3: 436–440, 1981[Medline]
  23. Zelis R, Kinney EL: The pharmacokinetics of diltiazem in healthy American men. Am J Cardiol 49: 529–532, 1982[CrossRef][Medline]
  24. Gordin A, Photo P, Sundberg S, Nykanen S, Haataja H: Pharmacokinetics of slow-release diltiazem and its effect on atrioventricular conduction in healthy volunteers. Eur J Clin Pharmacol 31: 423–426, 1986[CrossRef][Medline]
  25. Campistron G, Rostin M, Coulais Y, Caillard C, Zarrouk G, Frances J, Thiercellin JF, Montastruc JL, Houin G: Effect of size and dosage strength on the bioavailability of two diltiazem formulations during repeated administrations in humans. Fund Clin Pharm 1: 67–75, 1987
  26. Stone PH, Gibson RS, Glasser SR, De Wood MA, Parker JD, Kawanishi DT, Crawford MH, Messineo FC, Shook TL, Raby K: Comparison of propranolol, diltiazem and nifedipine in the treatment of ambulatory ischemia in patients with stable angina. Circulation 82: 1962–1972, 1990[Abstract/Free Full Text]
  27. Frischman W, Charlap S, Kimmel B, Teicher M, Cinnamon J, Allen L, Strom J: Diltiazem, nifedipine and their combination in patients with stable angina pectoris: Effects of angina, exercise tollerance and the ambulatory electrocardiographic ST segment. Circulation 77: 774–786, 1988[Abstract/Free Full Text]
  28. Theroux P, Baird M, Juneau M, Warnica W, Klinke P, Kostuk W, Pflugfelder P, Lavallee E, Chin C, Dempsey E: Effect of diltiazem on symptomatic and asymptomatic episodes of ST segment depression occurring daily life and during exercise. Circulation 84: 15–22, 1991[Abstract/Free Full Text]
Received for publication July 11, 2002. Accepted for publication December 20, 2002.




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