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

Materials and Methods

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.

Results

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.

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 × 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.

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

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:

• The main liver metabolism of diltiazem and its prevalent gastroenteric elimination (65%) fits with the peculiar pharmacokinesis of the uremic patients.

• The favorable peak-valley ratio of serum concentration of the drug determines a better protection from organ damage, with an enhanced control of the ischemic episodes during the whole day.

• The improvement of the compliance of the patient to therapy is easily obtained by the reduction of the number of administrations of the drug (from four to two assumptions per day) and, above all, through a reduction of the incidence and the severity of the adverse side effects.

• The reduction of the number and the duration of silent ischemic episodes in ERSD patients may be clinically relevant in a population of patients at high risk of cardiac events.

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.