title: Effect on the development of ankle edema of adding delapril to manidipine in patients with mild to moderate essential hypertension: a three-way crossover study.
abstract: BACKGROUND
  Use of the combination of an angiotensin-converting enzyme inhibitor (ACEI) and a calcium channel blocker (CCB) is considered a rational approach in patients whose hypertension is not controlled by monotherapy, providing better blood pressure (BP) control than the individual components with a lower incidence of adverse effects. In particular, such combinations have been found to reduce the incidence of ankle edema, the most common adverse effect of dihydropyridine annhypertensives.
  
  
  OBJECTIVE
  The present study was undertaken to evaluate the effect on the development of ankle edema of adding the ACEI delapril to the CCB manidipine in patients with mild to moderate essential hypertension.
  
  
  METHODS
  Patients between the ages of 30 and 70 years who had mild to moderate hypertension (diastolic BP [DBP] >90 and <110 mm Hg) were included in the study. After a 4-week placebo run-in period, eligible patients were randomized to receive 6 weeks each of manidipine 10 mg/d, delapril 30 mg/d, and both in a crossover fashion. There was a 2-week washout period between treatments. Ankle edema was assessed based on ankle-foot volume (AFV) and pretibial subcutaneous tissue pressure (PSTP). Sitting BP, AFV, and PSTP were measured at the end of the placebo run-in period and the end of each active-treatment period.
  
  
  RESULTS
  The study enrolled 40 patients with previously untreated hypertension (21 women, 19 men). Both manidipine and delapril monotherapy were associated with significant reductions from baseline in systolic BP (SBP) (mean [SD], -17.3 [4] and -14.8 [4] mm Hg, respectively; both, P<0.01) and DBP (-14.6 [3] and -12.9 [3] mm Hg; both, P<0.01). Compared with monotherapy, the combination of manidipine and delapril was associated with greater reductions from baseline in SBP (-21.8 [5] mm Hg; P<0.001) and DBP (-18.6 [4] mm Hg; P<0.001). Manidipme monotherapy was associated with significant increases from baseline in both AFV (7.9%; P<0.001) and PSTP (36.6%; P<0.01). Compared with manidipine alone, the combination of manidipine and delapril was associated with less pronounced increases in AFV (3.3%; P<0.05) and PSTP (10.4%; P<0.05). Ankle edema was clinically evident in 3 patients after receipt of manidipine monotherapy and in 1 patient after receipt of combination treatment.
  
  
  CONCLUSIONS
  In these patients with mild to moderate essential hypertension, the addition of delapril to manidipine partially counteracted the manidipine-induced microcirculatory changes responsible for ankle edema.
authors.affiliation: Dipartimento di Medicina Interna, Clinica Medica, IRCCS Policlinico S. Matteo, Università di Pavia, Pavia, Italy. r.fogari@smatteo.pv.it
authors.forename: Roberto
authors.initials: R
authors.lastname: Fogari
authors.forename: GianDomenico
authors.initials: G
authors.lastname: Malamani
authors.forename: Annalisa
authors.initials: A
authors.lastname: Zoppi
authors.forename: Amedeo
authors.initials: A
authors.lastname: Mugellini
authors.forename: Andrea
authors.initials: A
authors.lastname: Rinaldi
authors.forename: Elena
authors.initials: E
authors.lastname: Fogari
authors.forename: Tiziano
authors.initials: T
authors.lastname: Perrone
mesh_terms: D000328:Adult; D000368:Aged; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use*; D000842:Ankle / Q000503:physiopathology; D000959:Antihypertensive Agents / Q000009:adverse effects / Q000627:therapeutic use*; D002121:Calcium Channel Blockers / Q000009:adverse effects / Q000627:therapeutic use*; D018592:Cross-Over Studies; D004095:Dihydropyridines / Q000009:adverse effects / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control*; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007189:Indans / Q000627:therapeutic use*; D008297:Male; D008875:Middle Aged; D009578:Nitrobenzenes; D010879:Piperazines; D016896:Treatment Outcome
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004095:Dihydropyridines; D007189:Indans; D009578:Nitrobenzenes; D010879:Piperazines; C054218:manidipine; C047759:delapril