Frågedatum: 2018-03-15
RELIS database 2018; id.nr. 59, ULIC
www.svelic.se
Utredningen som riktar sig till hälso- och sjukvårdspersonal, har utformats utefter tillgänglig litteratur och resurser vid tidpunkten för utredning. Innehållet i utredningen uppdateras inte. Hälso- och sjukvårdspersonal är ansvarig för hur de använder informationen vid rådgivning eller behandling av patienter.


Risk för perifera ödem och lerkandipin, amlodipin, felodipin och nifedipin



Fråga: Fick fråga angående risken för perifera ödem och Lerkandipin (tredje generationens kalciumkanalblockerare) jämfört med Amlodipin, Felodipin, Nifedipin. Jag har fått för mig att det finns stora studier som talar för att det är mindre risk för perifera ödem jämfört med de andra kalciumkanalblockerarna då det är en något bättre kärlselektivtet för Lerkanidipin. Hur ser evidensläget ut?

Svar: SVAR
Several studies have investigated the incidence of ankle edema during treatment with lercanidipine compared with other calcium channel blockers. The results of these investigations are briefly described below.

A newly published critical review (1) on the efficacy and safety of lercanidipine in the treatment of hypertension reported that globally, the incidence of ankle edema during lercanidipine treatment is between 0.6% and 9%, which is much lower than the 23%–29% reported with other dihydropyridine calcium channel blocker (DHP-CCBs).

The “lercanidipine challenge trial” (2), performed in patients with adverse events during treatment with different DHP-CCBs and who switched to lercanidipine, showed lercanidipine treatment to be associated with a significant reduction of particularly ankle edema.

In a randomized, double-blind study of post-menopausal women with mild to moderate hypertension (n=92), leg edema occurred in 9.8% of lercanidipine-treated patients compared to 33.3% of the amlodipine-treated subjects after 8 weeks of treatment (1, 3, 4).

A meta-analysis of randomized trials (5) showed that lercanidipine was associated with a significantly lower percentage of patients with peripheral edema (7.0% vs. 14.0%, P < 0.001), compared with the pooled data reported for the first generation DHP-CCBs amlodipine, nifedipine, and felodipine, with 56% relative risk reduction. Compared with the pooled data of the second generation drugs lacidipine and manidipine, however, there were no significant differences (8.5% vs. 6.6%).

A meta-analysis by Makani H et al (6) included six trials with a total of 2648 patients and reported edema rates in head-to-head comparisons of newer lipophilic DHPs (lacidipine, lercanidipine and manidipine) compared to older, traditional DHPs. The analysis found that lipophilic DHP-CCBs induce a significant 57% risk reduction for ankle edema compared with hydrophilic DHP-CCBs. The low incidence of ankle edema with lercanidipine is independent of age, gender, ethnic group, presence of concomitant cardiovascular disease, or blood pressure reduction (1).

A multicenter, double-blind, randomized, parallel group study (7), including 324 patients who were treated for 24 weeks with either lercanidipine, lacidipine, or nifedipine, reported an incidence of edema of 2.8% for lercanidipine compared with 7.5% for lacidipine and 10.1% for nifedipine group, which was a trend in favor of lercanidipine (P<0.10). In another multicenter, double-blind, randomized, parallel group study (8) that included 250 patient who were treated for 8 weeks with either lercanidipine, felodipine, or nifedipine, it was reported that the incidence of edema for lercanidipine was 5.5% compared to 13% for felodipine and 6.6% for nifedipine. The study was not powered to show statistical differences among individual adverse reaction, but the number of adverse reaction was significantly lower in the lercanidipine-treated and nifedipine-treated patients than in the felodipine-treated patients, while no statistically significant differences were found between lercanidipine and nifedipine.

UK Medicines Information (UKMi) pharmacists for NHS healthcare professionals (9) answered a question about the reported incidences of ankle oedema with different calcium channel blockers and made a table that is available through NICE Evidence Search at www.evidence.nhs.uk. They concluded that the potential to cause ankle oedema appears to exist for all CCBs, and that it is caused by increasing capillary pressure leading to leakage of fluids into the surrounding tissues. This occurs in spite of the diuretic nature of some CCBs. Ankle oedema appears to occur more frequently in CCBs from the DHP group, although some agents such as lacidipine and lercanidipine may cause it less frequently than nifedipine and amlodipine. Diltiazem, a non-DHP agent, seems to be associated with the lowest incidence of ankle oedema.

Different hypothetical mechanisms have been suggested to explain the lower incidence of ankle edema during treatment with lercanidipine in comparison with other DHP CCBs (8): a smaller discrepancy between arteriolar and venular vasodilation due to a lower sympathetic activation and a smaller venoconstriction; a smaller effect on vascular permeability with consequent fluid extravasation; the experimental findings that lercanidipine dilates both afferent and efferent glomerular arterioles.

Referenser:
  1. Guido Grassi, Nicolàs R. Robles, Gino Seravalle, and Francesco Fici. Lercanidipine in the Management of Hypertension: An Update. J Pharmacol Pharmacother. 2017 Oct-Dec; 8(4): 155–165.
  2. Borghi C, Prandin MG, Dormi A, Ambrosioni E. Improved tolerability of the dihydropyridine calcium-channel antagonist lercanidipine: The lercanidipine challenge trial. Study Group of the Regional Unit of the Italian Society of Hypertension. Blood Press Suppl. 2003;1:14–21
  3. Micromedex, DrugDex, Thomson Reuters.
  4. Lund-Johansen P, Stranden E, Helberg S, et al: Quantification of leg oedema in postmenopausal hypertensive patients with lercanidipine or amlodipine. J Hypertens 2003; 21(5):1003-1010.
  5. Makarounas-Kirchmann K, Glover-Koudounas S, Ferrari P. Results of a meta-analysis comparing the tolerability of lercanidipine and other dihydropyridine calcium channel blockers. Clin Ther. 2009 Aug; 31(8):1652-63.
  6. Makani H, Bangalore S, Romero J, Htyte N, Berrios RS, Makwana H, Messerli FH. Peripheral edema associated with calcium channel blockers: incidence and withdrawal rate--a meta-analysis of randomized trials. J Hypertens. 2011 Jul; 29(7):1270-80.
  7. Cherubini A, Fabris F, Ferrari E, Cucinotta D, Antonelli Incalzi R, Senin U. Comparative effects of lercanidipine, lacidipine, and nifedipine gastrointestinal therapeutic system on blood pressure and heart rate in elderly hypertensive patients: the ELderly and LErcanidipine (ELLE) study. Arch Gerontol Geriatr 2003; 37:203–212.
  8. Romito R, Pansini MI, Perticone F, Antonelli G, Pitzalis M, Rizzon P. Comparative effect of lercanidipine, felodipine, and nifedipine GITS on blood pressure and heart rate in patients with mild to moderate arterial hypertension: the Lercanidipine in Adults (LEAD) Study. J Clin Hypertens (Greenwich) 2003; 5:249–253
  9. NHS, UK Medicines Information, 2013. https://www.surreyandsussex.nhs.uk/wp-content/uploads/2013/04/UKMi-Ankle-Oedema-incidence-with-different-CCBs1.pdf