Lercanidipine Vs Lacidipine in Isolated Systolic Hypertension
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Journal of Human Hypertension (2003) 17, 799–806 & 2003 Nature Publishing Group All rights reserved 0950-9240/03 $25.00 www.nature.com/jhh ORIGINAL ARTICLE Lercanidipine vs lacidipine in isolated systolic hypertension M Millar-Craig1, B Shaffu2, A Greenough3, L Mitchell3 and C McDonald3 1Department of Cardiology, Derbyshire Royal Infirmary, London Road, Derby, UK; 2Station Road Surgery, 152 Station Road, Wigston, Leicester, UK; 3Napp Pharmaceuticals Limited, Cambridge Science Park, Milton Road, Cambridge, UK This randomised, double-blind, double-dummy, parallel blood pressure was À0.81 (À4.45, 2.84) mmHg. These group, multicentre study compared the efficacy and confidence intervals were within the limits specified for tolerability of lercanidipine with lacidipine. Elderly equivalence, that is, (À5, 5) mmHg. Ambulatory blood patients with isolated systolic hypertension (supine pressure monitoring showed that the antihypertensive blood pressure X160/o95 mmHg) were enrolled and effects of both drugs lasted for the full 24-h dosing underwent a placebo run-in period of 14–27 days before period and followed a circadian pattern. Both treatments random allocation to lercanidipine tablets 10 mg once were well tolerated with a low incidence of adverse drug daily (n ¼ 111) or lacidipine tablets 2 mg once daily reactions and a low withdrawal rate. Significantly fewer (n ¼ 111) for the assessment period (112–160 days). patients withdrew from treatment with lercanidipine Titration to lercanidipine 20 mg once daily (two 10 mg (P ¼ 0.015). Neither treatment had any clinically signifi- tablets) or lacidipine 4 mg once daily (two 2 mg tablets) cant effect on pulse rate or cardiac conduction. In was allowed after 8 weeks, if required. Both treatments conclusion, both treatments were equally effective in decreased supine and standing systolic and diastolic controlling supine systolic blood pressure in patients blood pressure between the end of the run-in period and with isolated systolic hypertension. the end of the assessment period (Po0.0001). At the end Journal of Human Hypertension (2003) 17, 799–806. of the assessment period, the estimated mean treatment doi:10.1038/sj.jhh.1001614 difference (95% confidence intervals) in supine systolic Keywords: hypertension blood pressure determination; blood pressure monitoring, ambulatory; calcium channel blockers; elderly Introduction lercanidipine tablets are more effective than placebo The British Hypertension Society defines isolated in lowering BP and are as effective as other systolic hypertension (ISH) as a systolic blood antihypertensive agents such as atenolol, hydro- pressure (SBP) X160 mmHg and a diastolic BP chlorothiazide, captopril, and slow release nifedi- 7–11 (DBP) 90 mmHg.1 SBP increases with age, there- pine. There is also evidence that lercanidipine o 12 fore ISH is a particular problem in the elderly. tablets are effective in the treatment of ISH. Treatment of ISH has been shown to reduce stroke, Like lercanidipine, lacidipine is a dihydropyri- coronary events, and major cardiovascular events.2,3 dine calcium channel blocker with a slow onset and Lercanidipine is a dihydropyridine calcium chan- long duration of action. The efficacy of lacidipine in nel blocker. It has an unusual pharmacokinetic mild to moderate hypertension has been shown in profile resulting from its high lipophilicity. It binds studies comparing it with hydrochlorothiazide, 13–15 strongly to the lipid bilayer of cell membranes close atenolol, and nifedipine. The efficacy of lacidi- to the calcium channel from where it is slowly pine in the treatment of ISH is currently being released over subsequent hours. This slow release assessed in the Systolic Hypertension in the Elderly 16 from cell membranes gives a gradual onset and 24-h Long-term Lacidipine (SHELL) trial. duration of action despite the drug’s short plasma Studies have shown that there is a role for long- half-life of 2–5 h.4–6 Studies have shown that acting dihydropyridine calcium channel blockers in the treatment of ISH,2,17 so we designed this study to compare the efficacy, tolerability, and 24-h BP Correspondence: Dr C McDonald, Napp Pharmaceuticals Limited, control profile of lercanidipine tablets with lacidi- Cambridge Science Park, Milton Road, Cambridge CB4 0GW, UK. E-mail. [email protected] pine tablets in patients with ISH. We wanted to Received 28 August 2002; revised 30 May 2003; accepted 13 June show equivalence between the two treatments in 2003 terms of supine SBP. Lercanidipine vs lacidipine in ISH M Millar-Craig et al 800 Materials and methods go a washout period of 14–20 days before entering the single-blind, placebo run-in period. Patients Patients who were not receiving any antihypertensive ther- We carried out this study in general practices and apy proceeded straight to the run-in period, which hospital outpatient hypertension clinics in the UK. lasted for 14–27 days (one run-in week lasted for 7–9 Patients were of either sex, aged 60–85 years, days). To enter the run-in period, patients had to inclusive, with ISH. Patients with secondary hyper- have a mean supine SBP/DBP of X160 /o95 mmHg. tension, angina, or any other significant cardiac During this period, they received placebo lercanidi- condition were excluded, as were patients whose BP pine tablets and placebo lacidipine tablets and their was not adequately controlled with antihyperten- BP was assessed at each study visit (every 7–9 days). sive monotherapy, and patients who had an SBP To enter the assessment period, patients had to have 4200 mmHg. Other exclusion criteria included: a SBP/DBP of X160 /o95 mmHg at the start of the signs of postural hypotension; hypovolaemia; myo- run-in period and at two visits during the run-in cardial infarction, stroke, or a transient ischaemic period. attack in the last 3 months; clinically significant The double-blind assessment period lasted for hepatic or renal dysfunction; diabetes mellitus. 112–160 days (one assessment week lasted for 7–10 Local research ethics committees approved the days). Patients received either active lercanidipine study and patients gave written informed consent. and placebo lacidipine tablets, or placebo lercani- All staff involved in the study followed the dipine and active lacidipine tablets. They attended sponsor’s standard operating procedures. study visits every 28–40 days. There were two dose levels of study medication. Level 1 was 10 mg lercanidipine tablets or 2 mg lacidipine tablets. Study design Level 2 was 20 mg lercanidipine tablets (two 10 mg tablets) or 4 mg lacidipine tablets (two 2 mg tablets). This was a randomised, double-blind, double- These are the recommended doses according to the dummy, parallel group study. Patients who were Summary of Product Characteristics for each pro- currently receiving antihypertensives had to under- duct. All patients started treatment on Dose Level 1. Entry for patients currently Washout (14 - 20 days) receiving antihypertensive Entry for patients not currently therapy receiving antihypertensive therapy Placebo run-in period (14 - 27 days) Withdrawn if did not have blood pressure ≥160/<95 mmHg at start of run-in and at two visits during run-in Randomisation to active treatment Lercanidipine tablets 10 mg, once daily Lacidipine tablets 2 mg, once daily Eight weeks Eight weeks Dose increased to 20 mg, once daily if Dose increased to 4 mg, twice daily if not responded to treatment not responded to treatment Four weeks Four weeks Dose increased to 20 mg, once daily if Dose increased to 4 mg, once daily if SBP not normalised, or decreased to SBP not normalised, or decreased to 10 mg, once daily if patient suffered 2 mg, once-daily if patient suffered severe adverse event caused by severe adverse event caused by hypotension. hypotension Four weeks Four weeks End of study End of study 28 - 35 days 28 - 35 days Follow-up visit Follow-up visit Figure 1 Study design. Journal of Human Hypertension Lercanidipine vs lacidipine in ISH M Millar-Craig et al 801 Patients took their study medication once daily. used the smoothness index to assess the homogene- Dose titration was allowed as follows: ity of 24-h BP reduction.18 Investigators measured patients’ pulse rate (radial * After approximately 8 weeks in the assessment pulse) at each study visit, and recorded a standard period, the investigator could increase the pa- 12-lead electrocardiogram at the start of the run-in tient’s dose from Level 1 to Level 2 if he/she had period and at the end of the assessment period. They not responded to treatment (i.e. if he/she had not also took a 10 ml blood sample from each patient at achieved an SBP of p140 mmHg or a decrease in the start of the run-in period and at the end of the SBP of X20 mmHg). assessment period for biochemical and haematolo- * After approximately 12 weeks in the assessment gical screening, and recorded any volunteered period, the investigator could increase the pa- adverse events at each study visit. tient’s dose from Level 1 to Level 2 if he/she had not achieved normalised SBP (p140 mmHg), or decrease the patient’s dose from Level 2 to Level 1 Statistical analyses if he/she had experienced a severe adverse event caused by hypotension. If the patient was already We designed this as an equivalence study, so the per receiving Level 2, no further increase in dose was protocol population was used in the primary allowed, but the investigator could withdraw the analysis. Unless otherwise stated, data are presented patient if he/she felt that the patient’s BP was not for the per protocol population. We used analysis of adequately controlled. variance (ANOVA) to compare patients’ age and the w2 test to compare patients’ sex between treatment The study design is shown in Figure 1. groups. We compared patients’ BP and electrocar- Investigators measured patients’ supine and diogram results between treatment groups using standing SBP/DBP at each study visit.