Abstract
An open‐label drug substitution study showed that controlled‐release isradipine (Dynacirc‐CR) can be safely substituted for amlodipine on a mg‐for‐mg basis in patients with mild‐to‐moderate hypertension. When controlled‐release isradipine was substituted for amlodipine, blood pressure was more effectively controlled, and edema rates were reduced. When subjects resumed amlodipine therapy, the previous gain in blood pressure reduction and lessening of edema vanished. The basis for this more favorable pattern of efficacy and side‐effects with controlled‐release isradipine, although mechanistically unresolved, may relate to a lesser degree of sympathetic nervous system activation.
Dihydropyridine calcium channel blockers (DHP CCBs) have been widely used for many years to treat mild‐to‐moderate hypertension. 1 , 2 , 3 Numerous clinical trials have also shown their efficacy in improving related outcomes, such as fatal and nonfatal myocardial infarction, heart failure, and stroke. 3 , 4 , 5 , 6 , 7 Despite similarities among these agents, however, recent evidence suggest that not all DHP CCBs are equivalent in terms of blood pressure (BP) control or incidence of treatment‐emergent side effects, such as pedal edema. 8 , 9 , 10 In particular, preliminary studies have found controlled‐release isradipine to produce lower rates of edema than amlodipine and controlled‐release felodipine, both intrinsically long‐lasting DHP CCBs. 8 , 11
OBJECTIVES
To determine whether substituting a controlled‐release form of isradipine (Dynacirc‐CR; Reliant Pharmaceuticals, Liberty Corner, NJ) for amlodipine (Norvasc; Pfizer Pharmaceuticals, New York, NY) modifies the antihypertensive response in hypertensive subjects currently being treated with amlodipine and to compare the tolerability, particularly the incidence of edema, between controlled‐release isradipine and amlodipine.
DESIGN
This was an open‐label, drug substitution study conducted in Cleveland, OH. The study protocol was reviewed and approved by the Institutional Review Board and all study subjects provided written informed consent before participation in the trial. Subjects with documented evidence of coronary heart disease (e.g., used nitrates or had a prior myocardial infarction) or congestive heart failure were excluded. A schematic representation of the study protocol is presented in Figure 1. BP measurements were obtained three times during the 6‐month run‐in period and again 2 weeks before drug substitution. Baseline BP in this study was the average of these four predrug substitution measurements. The patients took their BP medicine approximately 2 hours prior to their visit. BP was measured in a sitting position 15 minutes after the patient was assigned to an examination room. The patient's BP was remeasured 10 minutes later (hence BP was measured twice at each visit).
Figure 1.
Isradipine‐controlled release (CR) substitution study trial design. Following a 6‐month run‐in period, amlodipine‐treated patients were converted to an equivalent dose of isradipine‐CR for 6 weeks. After 6 weeks of isradipine‐CR treatment, patients resumed therapy with amlodipine for an additional 6 weeks. BP=blood pressure
At the end of the run‐in period, subjects who were currently treated with amlodipine 5 mg/d were switched to controlled‐release isradipine 5 mg/d, and those currently treated with amlodipine 10 mg/d were switched to controlled‐release isradipine 10 mg/d. Adjuvant antihypertensive therapy was allowed, provided the drugs and their respective doses remained stable during the study. In particular, the diuretic dose for each patient was maintained constant relative to the class and dose amount. BP was measured at 2‐week intervals during the controlled‐release isradipine treatment period. After 6 weeks of treatment with controlled‐release isradipine, subjects were switched back to amlodipine at their original dose. BP was evaluated 6 weeks later. At each study visit, subjects were assessed for clinically evident lower limb edema. Edema was assessed by the same study coordinator; the patient's shoes and socks were removed and edema was scored as 1+ to 4+ and/or had changed since the patient's initial visit. No assessment of protein excretion was undertaken in these studies.
STATISTICAL ANALYSIS
BP within each dose group was compared with its baseline value by analysis of variance. Controlled BP was defined as systolic BP (SBP) below 140 mm Hg and diastolic BP below 90 mm Hg. The BP control rates within each dose group were compared by χ2. All values are expressed as mean ± SEM unless otherwise stated and p<0.05 was held as significant.
RESULTS
Subject Disposition
A total of 114 subjects with mild‐to‐moderate hypertension who had been treated with a stable dose of amlodipine for at least 4 months were eligible for inclusion in the study. Other subject characteristics are presented in Table I. On average, subjects receiving a daily dose of amlodipine 10 mg were older (57.4 vs. 53.1 years), heavier (body mass index, 31 vs. 27), with a higher average serum creatinine value (1.2 vs. 1.5 mg/dL) and required more drugs to control their hypertension than was the case for those receiving amlodipine 5 mg/d: 81% of subjects were receiving adjuvant therapy to control BP (43% received one additional drug and 38% received two additional drugs). The majority of patients in both dose groups were not at goal BP as defined by values of <140/90 mm Hg, which was more an issue of suboptimal control of SBP.
Table II presents BP measurements for 5 mg and 10 mg treatment groups. Subjects treated with 10 mg of controlled‐release isradipine had significantly lower SBP than those treated with amlodipine 10 mg from 2 weeks through 6 weeks, with levels dropping from 154.4±8.8 mm Hg at baseline to 146.5±7.4 mm Hg at 6 weeks (p<0.05). Diastolic BP also fell in the 10 mg controlled‐release isradipine group, but the change did not reach statistical significance. In the 5 mg treatment groups, both SBP and diastolic BP trended downwards in the controlled‐release isradipine arm, but this did not reach statistical significance. Seven additional patients achieved goal BP while on controlled‐release isradipine, primarily because of a reduction in SBP. In both the 5 mg and 10 mg treatment limbs BP returned toward its baseline level of elevation 6 weeks after discontinuing controlled‐release isradipine and resuming treatment with amlodipine.
Table II.
Baseline and 6‐Week Blood Pressure Measurements (mm Hg) (Mean ± SD)
| Dose | n | Amlodipine Baseline | Isradipine 6 Weeks | Amlodipine 6 Weeks | |
|---|---|---|---|---|---|
| 5 mg | 51 | SBP | 147±6.6 | 143.1±5.9 | 146.2±7.2 |
| DBP | 86.2±5.7 | 82.8±5.3 | 87.1±6.1 | ||
| 10 mg | 63 | SBP | 154.4±8.8 | 146.5±7.4* | 151.7±8.5 |
| DBP | 85.9±6.8 | 81.7±6.4 | 85.4±7.2 | ||
| SBP=systolic blood pressure; DBP=diastolic blood pressure; *p<0.05 | |||||
No clinically significant adverse events were spontaneously reported. Examination by the investigator revealed clinically evident edema (1–2+) in 8/51 and 13/63 of those subjects receiving amlodipine 5 mg and 10 mg, respectively, in the amlodipine run‐in period. After switching to controlled‐release isradipine, 6/51 and 6/63 still had ankle edema. This improvement in edema grade and/or resolution of the same was statistically significantly lower in African Americans receiving the 10 mg substitution dose of controlled‐release isradipine (Figure 2). Less edema was also observed among Caucasians in the 10 mg treatment group, but the treatment groups were not large enough to allow this particular trend to reach statistical significance. No new cases of ankle edema were observed in any subjects who were edema‐free while being treated with controlled‐release isradipine; moreover, edema recurred in 54% of the patients (five patients in whom it had previously resolved with controlled‐release isradipine) within the 2‐week period of resuming treatment with amlodipine.
Figure 1.
Comparative edema rate at 5‐ and 10‐mg doses of amlodipine and controlled‐release (CR) isradipine. CR=contolled release; *p<0.01
DISCUSSION
This open‐label drug substitution study showed that controlled‐release isradipine (Dynacirc‐CR) can be safely substituted for amlodipine in patients with mild‐to‐moderate hypertension, and that controlled‐release isradipine was more effective in controlling BP than amlodipine. This greater anti‐hypertensive effect, particularly as related to SBP, was particularly evident among subjects who had been switched from amlodipine 10 mg.
The superior antihypertensive response to controlled‐release isradipine 10 mg is important in that 81% of the 10 mg/d subjects were using three medications during the run‐in period and their mean SBP was higher than that seen in the 5 mg/d group. Six weeks after switching to controlled‐release isradipine, the mean SBP among subjects in the 10 mg/d group fell nearly to the level seen in the 5 mg/d group. The difference in antihypertensive efficacy between controlled‐release isradipine and amlodipine is probably not explainable based on pharmacokinetic differences, per se. Both compounds in their current delivery systems maintain their effectiveness for 24 hours, which is pertinent in these current studies since BP was measured at trough. 12 , 13 In both treatment groups, the greater antihypertensive efficacy of controlled‐release isradipine was most evident for SBP.
There are several possible explanations for these differences in BP response favoring controlled‐release isradipine. First, these studies were not placebo‐controlled and a placebo‐effect may have entered into play; however, the fact that BP rose once again when patients reverted back to amlodipine (from controlled‐release isradipine) makes a placebo effect less likely. Second, the doses used for each compound in these studies may not have been equipotent. If so, it is not likely to explain differences of this magnitude since prior studies have shown that amlodipine and controlled‐release isradipine are equipotent on a mg‐to‐mg basis. 8 Third, there may have been a greater level of sympathetic nervous system activation with amlodipine in this study group (not formally evaluated, per se). If this were the case, controlled‐release isradipine would then be likely to produce a greater reduction in BP absent the counterproductive effects of sympathetic activation. 14
Calcium channel blocker therapy has been associated with the development of lower extremity edema, a finding of this study as well 15 , 16 ; however, its occurrence at presumably equipotent doses of each drug was less so with controlled‐release isradipine than amlodipine. In this regard, isradipine therapy (in either immediate‐release 17 , 18 or controlled‐release formulations) has been associated with lower rates of peripheral edema than several other calcium channel blockers.
For example, in a study comparing immediate‐release isradipine with nifedipine retard in 159 subjects with mild hypertension, no subjects treated with isradipine reported peripheral edema, whereas 7.3% of those treated with nifedipine reported edema. 17 This difference in edema rate was present despite the doses of nifedipine and isradipine being comparably potent in how they reduced BP. Similarly, in a study of 143 hypertensive subjects, ankle edema was reported by 14% of those treated with immediate‐release isradipine and by 30% of those receiving immediate‐release felodipine. 18
Lohmann et al. 19 studied another pharmacologically similar controlled‐release form of isradipine (isradipine‐SRO) and found no ankle edema among subjects treated with isradipine‐SRO compared with 7.7% of those treated with nitrendipine. Finally, in a study conducted by Hermans and coworkers, 8 ankle edema was spontaneously reported by 5.8% (6/103) of subjects treated with isradipine‐SRO and by 14.7% (15/102) of subjects treated with amlodipine. In this study, the severity and duration of edema with amlodipine was also greater with amlodipine than with isradipine. Although these observations suggest that the risk of treatment‐emergent lower‐limb edema may be lower among subjects treated with isradipine than those treated with other DHP CCBs, more studies are needed to confirm these observations.
CONCLUSION
In subjects with mild‐to‐moderate hypertension receiving multi‐drug therapy, substituting controlled‐release isradipine for amlodipine resulted in a significantly greater reduction in SBP and a better BP control rate in the 10 mg treatment group. Fewer subjects taking controlled‐release isradipine experienced lower extremity edema compared with those receiving amlodipine; therefore, switching patients from amlodipine to an equivalent dose of controlled‐release isradipine may provide greater efficacy and fewer side effects, particularly among African Americans.
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