Effectiveness of the once-daily calcium antagonist, lacidipine, in controlling 24-hour ambulatory blood pressure

SYSTEMIC HYPERTENSION

Effectiveness of the Once-Daily Calcium Antagonist, Lacidipine, in Controlling 241Hour Ambulatory Blood Pressure Mary E. Heber, MB, MRCP, Paul A. Broadhurst, MB, MRCP, Geoffrey S. Brigden, MB, MRCP, and Edward B. Raftery, MD

The efficacy of the new once-daily dihydropyridine calcium antagonist, lacidipine, in reducing ambulatory intraarterial blood pressure (BP) was examined in 12 untreated hypertensive patients. The intraarterial recording was commenced 24 hours before the first 4-mg dose and was continued for a further 24 hours thereafter. After dose titration and chronic therapy, a second 24-hour ambulatory BP recording was made. There was a steady onset of drug action, maximal at 2 hours, but with a reflex tachycardia after the first dose. Chronic administration reduced BP throughout the 24-hour period, without tachycardia. Mean daytime reduction in BP was 20 mm Hg systolic (p
acidipine is a newdihydropyridine calcium antagonist that has been shown to have typical pharmacologic activity but with a longer duration of action and greater potency on a weight-for-weight basis.It has a selectiveperipheral vasodilatory action that results in a reduction in peripheral vascular resistance,a compensatory increase in heart rate and an increase in stroke volume. In healthy volunteers a significant reduction in blood pressure (BP) has been detected24 hours after dosing on a once-daily dosageregimen. Dose titration studies in patients with mild to moderatehypertension have demonstrated a dose-relatedantihypertensive activity over the range of 2 to 6 mg (data on company file, Glaxo Group Research, Ltd., Greenford, Middlesex, United Kingdom). This study determines the profile of BP reduction by lacidipine over 24 hours after a single daily dose in ambulatory hypertensive patients. The efficacy of the drug in controlling BP during isometric and dynamic exercise,and its effectson postural BP control were also assessed.

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METHODS Patients: Patients were recruited from the Harrow

Hypertension Clinic. They were consideredfor inclusion in the study if their clinical diastolic BP, measured sphygmomanometrically, was 195 mm Hg after 3 consecutivevisits at least 1 week apart, during which period they had not been receiving any medication. Both men and women between the ages of 21 and 75 years were screenedfor inclusion, but women of child-bearing potential were excluded, as were those with secondaryor malignant hypertension, other cardiac disease,or any other clinically important pathologic condition. All patients gave written informed consent,and the study was approved by the Harrow Health Authority ethics committee. Study design: This was an open study, with dose titration from 4 to 8 mg. It has been shown that there is no placebo effect on intraarterial BP measurements’ and we considered a placebo arm to be unethical in an invasive BP monitoring study. From the Cardiology Department and the Division of Clinical Sciences, At entry, BP was measuredusing a mercury-in-glass Northwick Park Hospital, and the Clinical Research Centre, Harrow, Middlesex, United Kingdom. This study was supported in part by a sphygmomanometer.If the entry criteria were satisfied, grant from Glaxo Group Research,Ltd., Greenford, Middlesex, United intraarterial ambulatory recording was begun. The next Kingdom. Manuscript received April 16, 1990;revised manuscript re- day, after 24 hours of monitoring, patients underwent a ceived and accepted July 9, 1990. program of physiologic testing before receiving their Address for reprints: Edward B. Raftery, MD, Cardiology Department, Northwick Park Hospital, Watford Road, Harrow, Middlesex, first dose of lacidipine 4 mg. Monitoring was continued for a further 24 hours, after which the intraarterial canHA1 3UJ, United Kingdom. 1228

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nula was removed. Patients continued to take lacidipine 4 mg once daily at 10 AM for 2 weeks. At the 2-week visit, 3 cuff BP measurementswere recorded. If BP control was satisfactory (average diastolic BP 190 mm Hg, or a decreasein averagediastolic BP of 115 mm Hg) patients continued on the same dosefor at least another 2 weeks,and then underwent a secondperiod of intraarterial BP monitoring, commencing immediately after the morning dose. Physiologic testing was performed at the end of the 24=hour period, before removal of the cannula. Patients whose diastolic BP was not controlled were given 6 mg of lacidipine for another 2=weekperiod, and, if still not controlled, the dosewas then increasedto 8 mg/day. BP was checked by cuff at 2=weekintervals and arrangements made for the secondperiod of monitoring when it had been satisfactorily controlled on a stable dose for 4 weeks. Blood and urine samples were taken for routine hematologic and biochemical screeningat entry, after 4 weeksand at completion of the study. Intraarterial

ambulatory

blood pressure

recording:

The technique of ambulatory BP monitoring used in this laboratory has been previously fully documented.2 A disposable3Fr gaugecannula was introduced into the brachial artery of the nondominant arm under local anesthesia,using a sterile Seldinger technique. This was connectedthrough a l-m length of tubing to a specially designedtransducer-perfusion unit, which infused heparinized saline in a concentration of 10 IU/ml at a rate of 1.5 X ml/hour. The BP signal from the transducer and the electrocardiogram from bipolar chest leads were recorded on a miniature tape recorder (Oxford Medilog MK l), which also incorporated a time channel with an event marker. BP frequency responsewas flat from 0 to 8 Hz. The equipment is designed so that patients may be fully ambulant and carry out their normal daily activities. Physiologic testing: After 24 hours of ambulatory recording, the patients underwent a standardized series of physiologic tests,beginning with 20 minutes of supine rest, followed by 60° head-up tilt maintained for 2 minutes, Isometric exercisewas then performed, using 50% of maximum voluntary contraction on a handgrip dynamometer, maintained for 2 minutes. After L5 minutes rest, patients commencedmaximal dynamic exerciseusing bicycle ergometry, beginning at a work load of 50 W and increasing by 50-W increments. Each work load was maintained for 5 minutes unless stopped at the patient’s request. Analysis of data: The ambulatory tape recordings were replayed and written out on a linear direct-writing recorder (Watanabe) to allow assessmentof analog signal quality and elimination of any artifact3 Hourly sections were analyzed on a dedicated computer to give mean levels of systolic and diastolic BP and heart rate. Hourly mean values for all the patients were pooled, and curves were constructed to show the 24=hour pro= files of BP and heart rate before treatment, after the first dose, and at the completion of lacidipine therapy. Mean daytime and nighttime pressureswere calculated” and the differences between untreated, first dose and

chronic dose values were compared using Student’s paired t test (2-tailed). Becausethere was a slight variation in the exact time of administration of the first dose, the BP for the 6 hours from the time of dosing in each patient was calculated and compared with the same 6 hours from the previous day. BP and heart rate during the last 5 minutes of supine rest, and during tilt, isometric and dynamic exercise were computed using a standard digitizing program, which has been described previously.5Results before and after treatment with lacidipine were compared using Student’s paired t test (2-tailed). Mean values of sphygmomanometric measurementsof BP at entry into the study and on the final day of treatment were pooled and compared, again using Student’s paired t test (2tailed). A p value <0.05 was considered significant. RESULTS Clinical course: Twelve patients (4 men, 8 women), mean age 54 years (range 41 to 70) were entered into the study. One patient had a very severeheadacheafter the first dose (4 mg) of lacidipine and refused to continue. The data from this patient were included in the analysis of the first dose response,but were excluded thereafter. The other 11 patients completed the study. One patient failed to take her first dose of lacidipine until 4 PM, and her data were excluded from analysis for the 24-hour profile after the first dose. She was, however, included in all other analyses. Hypertension in 2 patients was controlled with 4 mg of lacidipine; 7 patients were titrated to 6 mg and 2 to 8 mg. Seven patients complained of headache, flushing or fullness in the head during the course of therapy. In 2 patients this was after the first dose, 1 of whom subsequently withdrew. In 5, it occurred later and persisted, but was not severeenough to causethe patients to withdraw from the study. Three patients developed severe ankle edema when taking a dose of 6 mg. All these patients completed the study, but in 1 an indicated dose increment to 8 mg was withheld. No patient developed

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BP and heart rate responseto the first doseof lacidipine is shown in Figure 2. BP decreasedsteadily from dosing and a significant reduction was demonstrated 2 hours No. after dosing. Pts. Untreated Treated p Value The 24-hour profiles plotted from consecutivemean Supine rest (last 5 of 20 min) 9 hourly BPSand heart rates in 11 patients, untreated and Systolic BP (mm Hg) 161 136 <0.05 after their first 4-mg dose of lacidipine, are shown in Diastolic BP (mm Hg) 90 78 NS Figure 3A, and similar profiles for 11 patients, untreatHeart rate (beats/min-‘) 83 84 NS ed and after 4 weeksof therapy at their maximal titratHead-up tilt ed dose,are shown in Figure 3B. A significant reduction 15 seconds 9 Systolic BP (mm Hg) 170 136 <0.02 in daytime pressure was observed after the first dose, Diastolic BP(mm Hg) 99 81 <0.005 but the curves coincided by 8 PM. A similar coincidence Heart rate (beats/mW) 90 89 NS was seen after full dose titration, but in this case the 30 seconds 9 curves then divided again and a significant reduction in Systolic BP (mm Hg) 170 138 <0.05 Diastolic BP (mm Hg) 102 82 <0.05 both systolic and diastolic BP was observedat 9 AM, 23 Heart rate (beats/minwl) 87 89 NS hours after the last dose of the drug. After full dose 60 seconds 9 titration, there was a reduction in mean daytime BP of Systolic BP (mm Hg) 169 144 NS 20/12 mm Hg (p <0.05 systolic, p <0.02 diastolic) and Diastolic BP (mm Hg) 104 86 <0.05 Heart rate (beats/min-‘) 90 91 a reduction in mean nighttime pressureof 8/6 mm Hg NS 90 seconds 9 (p <0.05 systolic, difference not significant for diastolSystolic BP (mm Hg) 172 144 <0.05 ic). No significant change in heart rate was demonDiastolic BP (mm Hg) 104 86 (0.05 strated. Heart rate (beats/min-‘) 90 92 NS BP and heart rates during rest and for 90 secondsof BP = blood pressure: NS = not significant. 60” head-up tilt are listed in Table 1. BP at peak of isometric handgrip in untreated patients and approxiany significant hematologic or biochemical derange- mately 22 hours after the last titrated doseof the drug is shown in Figure 4. BP was significantly reduced by ment during the course of the study. Pooled systolic and diastolic BP measurements for therapy in all these physiologic tests, but no significant 11 patients at entry and completion of the study are postural drop occurred on tilting. BP and heart rates shown in Figure 1. Both systolic and diastolic BPSwere during bicycle dynamic exercisebefore and at complesignificantly reduced, and no change in heart rate was tion of therapy are shown in Figure 5. BP was significantly reduced (p <0.05) during bicycle exerciseup to noted. Intraarterial ambulatory blood pressure: Technical- the fifth minute, when 9 patients were still exercising. ly adequate BP recordings were obtained in all patients. The trend was continued throughout exercise,but insufficient numbers of patients exercisedlonger than 5 minutes for the differences to be meaningful. There was no p
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The effect of calcium antagonist drugs in reducing BP is mediated by a reduction in vascular smooth muscle tone,6 thereby reducing the raised peripheral vascular resistance,which is the consistenthemodynamicabnormality in essential hypertension.7,8This vasodilation may, however, result in a reflex tachycardia, orthostatic hypotension, flushing and headache.These adverseeffects may be reduced by the use of long-acting or slowrelease preparations, which achieve a smooth plasma level without sudden peaks9 Moreover, it has beensuggestedthat compliance is improved by once-daily therapies,rOespecially in asymptomatic conditions such as hypertension.l1 Thus, a calcium antagonist with an effective 24-hour duration of action should be useful in the treatment of this condition. Our results show that BP decreasedgradually after the first dose of lacidipine, with no acute decreasein pressure, and, after optimal dose titration to suit individual patient requirements, lacidipine effected a

FIGURE 3. Twenty-four

sure curves in 11 patients. left panel, untreated and after their first 4 mg dose of lacidipine; right panel, untreated and after full-dose titration (4 to 8 weeks treatment).

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smooth reduction in BP throughout 24 hours, with a mean daytime reduction of the same order as other calcium antagonists.9J2,13 Although a reflex tachycardia occurred after the first dose of the drug, heart rate at the end of the treatment period was similar to the rate at baseline,suggestinga “resetting” of the baroreceptor reflex. This is consistent with the suggestion outlined above-that vasodilatory side effects may be reduced oncea steady plasma level is achieved.Firm conclusions about the incidence of headacheand ankle-swelling that persisted at the end of the treatment period cannot be made, as only a small number of patients were studied. We believe it is prognostically important to reduce BP throughout 24 hours, both at rest and during stress, although data to confirm this are not available. Other investigators have suggested that basal BP,14 early morning increase in BP15and the BP responseto normal daily stressI are more closely associatedwith cardiovascular events than is the casual daytime BP. Nevertheless,it is by casual clinical BPS,measured sphygmomanometrically, that BP control must of necessity be assessed.Thus, we measured mean daytime and mean nighttime intraarterial pressures,and the BP response to isometric and dynamic exercise and also cuff BPs at

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entry and completion of the study. Like other calcium antagonists, lacidipine did not affect diurnal variation, or the proportional increase in BP during exercise, as would be expected with a drug that doesnot alter autonomic tone. Nevertheless, 24-hour BP reduction is achieved with this drug.

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