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Ramipril

Klassificering: C

Preparat: Ramipril Actavis, Ramipril Arrow, Ramipril Aurobindo, Ramipril HEXAL, Ramipril Krka, Ramipril Orifarm, Ramipril Ranbaxy, Ramipril ratiopharm, Ramipril Sandoz, Ramipril STADA, Ramipril Teva, Ramipril Winthrop, Ramipril/Hydrochlorothiazide Krka, Ramipril/Hydroklortiazid 2care4, Ramipril/Hydroklortiazid Actavis, Ramipril/Hydroklortiazid Alternova, Ramipril/Hydroklortiazid Ebb, Ramipril/Hydroklortiazid HEXAL, Ramipril/Hydroklortiazid Orifarm, Riprosil, Triatec®, Triatec® comp, Triatec® comp mite

ATC kod: C09AA05, C09BA05

Substanser: ramipril

Sammanfattning

Ramipril minskar risken för död och allvarlig hjärtsvikt. Nyttan av behandling är lika för båda könen.
Män som behandlas med ramipril vid kronisk nefropati verkar löpa en ökad risk för sjukdomsprogression på grund av lägre behandlingseffekt av ramipril, jämfört med kvinnor.
En vanlig icke-dosberoende biverkan av ACE-hämmare är hosta som förekommer oftare hos kvinnor. Angiotensinreceptorblockerare kan då vara ett alternativ.

Additional information

Pharmacokinetics and dosing

In a pharmacokinetic study (18 men, 18 women), patients received a single 5 mg oral dose of ramipril. Cmax and half-lives of the active metabolite ramiprilat were identical in both sexes, but women showed a higher AUC/kg than men. Since both men and women received a fixed dose, the differences were explained by a higher dose/kg in women, as a consequence of their lower body weight [19].

Effects

Heart failure

A European multicentre cohort study of patients with heart failure with reduced ejection fraction (HFrEF) (3609 men, 1114 women) found similar all-cause mortality for patients treated with ACE inhibitors (enalapril, lisinopril, or ramipril) given at equivalent doses. No differences between men and women or between age groups were seen [1].

In a large cohort study comparing angiotensin converting enzyme (ACE) inhibitors with angiotensin receptor blockers (ARBs) in patients with congestive heart failure (9 475 men, 10 223 women), women on ARBs had better survival than women on ACE inhibitors (HR 0.69, 95%CI 0.59-0.80) while men on ARBs had similar survival as men on ACE inhibitors (HR 1.10, 95%CI 0.95-1.30). However, other anti-hypertensive agents were more common in those on ARBs, especially women, leading to a larger blood pressure reduction and thus larger reduction in risk of death. Also, more of those on ARBs were hypertensive than those on ACE inhibitors, and more of those on ACE inhibitors had a history of myocardial infarction than those of ARBs [2]. Additional confounding by indication cannot be excluded. 

 Hypertension

In general, the activity level of the endogenous renin-angiotensin system (RAS), which regulates blood pressure, is higher in men than in premenopausal women. Postmenopausal women have higher activity than premenopausal women. This suggests that the efficacy of an RAS inhibitor would be lower in premenopausal women. However, studies on sex differences in the effect of RAS inhibition are contradictory [3, 4]. It has been suggested that black hypertensive patients have a smaller antihypertensive efficacy of ACE inhibitors than non-blacks, possibly due to a higher prevalence of low renin state in black hypertensive patients [5-7]. 

 Acute myocardial infarction

In the large randomized double-blind AIRE trial (1461 men, 525 women), 2.5 mg ramipril daily was compared with placebo, 2-9 days after acute myocardial infarction. Ramipril reduced the risks of death from any cause by 27%. The benefits of ramipril therapy were similar in both men and women [20, 21].

Non-diabetic nephropathy

Another randomized clinical trial (269 men, 83 women) investigated the impact of sex on the outcome of non-diabetic chronic proteinuric nephropathy and effect of ramipril treatment. Ramipril decreased proteinuria less effectively in men than in women (-7.8 ± 4.2% vs. -21.9 ± 5.7%). Compared to conventional treatment (placebo plus antihypertensive therapy), ramipril decreased the difference in GFR (-52% vs. -19%) and progression to end-stage renal disease (-74% vs. -40%) more effectively in women than in men. Among patients with chronic proteinuric nephropathies, men are at increased risk of progression due to their lower response to ACE inhibitor treatment. ACE inhibition is similarly renoprotective in women regardless of the ACE polymorphism, and in men with a certain genotype (double deletion of the ACE gene) [22].

Adverse effects

Several studies have reported a female predominance in the prevalence of ACE inhibitor induced cough [8-16]. The pathogenesis of the cough reaction is unknown. Different thresholds for coughing in men and women have been proposed [17], as well as ethnic differences in cough tendency [18]. One study suggests that sex hormones do not have any influence on cough, since most of the women in the study were postmenopausal [6].A pharmacoepidemiological study (5259 men, 5111 women) of ramipril found an incidence of ramipril-induced cough of 7.1%. Female sex was significantly and independently associated with the onset of ramipril-related cough (odds ratio 1.35) [23].

It is suggested that ACE inhibitors cause angioedema to a greater extent in black patients than in non-black patients [7].

Reproductive health issues

ACE inhibitors should not be used in pregnant women. Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).

Försäljning på recept

Fler män än kvinnor hämtade ut tabletter innehållande ramipril (ATC-kod C09AA05) på recept i Sverige år 20181, totalt 75 894 män och 39 330 kvinnor. Det motsvarar 15 respektive 8 personer per tusen invånare. Andelen som hämtat ut läkemedel ökade med stigande ålder hos båda könen. I genomsnitt var tabletter innehållande ramipril 2,6 gånger vanligare hos män [24].

Fler män än kvinnor hämtade ut tabletter innehållande kombination av ramipril och hydroklortiazid (ATC-kod C09BA05) på recept i Sverige år 2018, totalt 1 943 män och 1 379 kvinnor. Det motsvarar 0,4 respektive 0,3 personer per tusen invånare. Andelen som hämtat ut läkemedel var högst i åldersgruppen 70-84 år hos båda könen. I genomsnitt var tabletter innehållande kombination av ramipril och hydroklortiazid 1,8 gånger vanligare hos män [24].

Uppdaterat: 2019-10-08

Litteratursökningsdatum: 2019-05-16

Referenser

  1. Fröhlich H, Henning F, Täger T, Schellberg D, Grundtvig M, Goode K et al. Comparative effectiveness of enalapril, lisinopril, and ramipril in the treatment of patients with chronic heart failure: a propensity score-matched cohort study. Eur Heart J Cardiovasc Pharmacother. 2018;4(2):82-92. PubMed
  2. Hudson M, Rahme E, Behlouli H, Sheppard R, Pilote L. Sex differences in the effectiveness of angiotensin receptor blockers and angiotensin converting enzyme inhibitors in patients with congestive heart failure--a population study. Eur J Heart Fail. 2007;9(6):602-9. PubMed
  3. Coulter DM, Edwards IR. Cough associated with captopril and enalapril. Br Med J (Clin Res Ed). 1987;294:1521-3. PubMed
  4. Strocchi E, Valtancoli G, Ambrosioni E. The incidence of cough during treatment with angiotensin converting enzyme inhibitors. J Hypertens Suppl. 1989;7:S308-9. PubMed
  5. Kostis JB, Shelton B, Gosselin G, Goulet C, Hood WB, Kohn RM et al. Adverse effects of enalapril in the Studies of Left Ventricular Dysfunction (SOLVD) SOLVD Investigators. Am Heart J. 1996;131:350-5. PubMed
  6. Sharma S, Gupta U, Bapna JS, Sahai A. Tolerability of enalapril in mild to moderate hypertension. J Assoc Physicians India. 1995;43:475-6. PubMed
  7. Yeşil S, Yeşil M, Bayata S, Postaci N. ACE inhibitors and cough. Angiology. 1994;45:805-8. PubMed
  8. Yeo WW, Ramsay LE. Persistent dry cough with enalapril: incidence depends on method used. J Hum Hypertens. 1990;4:517-20. PubMed
  9. Just PM. The positive association of cough with angiotensin-converting enzyme inhibitors. Pharmacotherapy. 1989;9:82-7. PubMed
  10. Gibson GR. Enalapril-induced cough. Arch Intern Med. 1989;149:2701-3. PubMed
  11. Os I, Bratland B, Dahlöf B, Gisholt K, Syvertsen JO, Tretli S. Female sex as an important determinant of lisinopril-induced cough. Lancet. 1992;339:372. PubMed
  12. Dykewicz MS. Cough and angioedema from angiotensin-converting enzyme inhibitors: new insights into mechanisms and management. Curr Opin Allergy Clin Immunol. 2004;4:267-70. PubMed
  13. Morimoto T, Gandhi TK, Fiskio JM, Seger AC, So JW, Cook EF et al. An evaluation of risk factors for adverse drug events associated with angiotensin-converting enzyme inhibitors. J Eval Clin Pract. 2004;10:499-509. PubMed
  14. Zapater P, Novalbos J, Gallego-Sandín S, Hernández FT, Abad-Santos F. Gender differences in angiotensin-converting enzyme (ACE) activity and inhibition by enalaprilat in healthy volunteers. J Cardiovasc Pharmacol. 2004;43(5):737-44. PubMed
  15. Komukai K, Mochizuki S, Yoshimura M. Gender and the renin-angiotensin-aldosterone system. Fundam Clin Pharmacol. 2010;24(6):687-98. PubMed
  16. Renitec (enalapril). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-05-14, cited 2019-05-16].
  17. Zestril (lisinopril). Summary of Product Characteristics. Medical Products Agency Sweden; 2016.
  18. Triatec (ramipril). Summary of Product Characteristics. Swedish Medical Products Agency [updated 2019-05-14, cited 2019-05-16].
  19. Vree TB, Dammers E, Ulc I, Horkovics-Kovats S, Ryska M, Merkx et al. Lack of male-female differences in disposition and esterase hydrolysis of ramipril to ramiprilat in healthy volunteers after a single oral dose. ScientificWorldJournal. 2003;3:1332-43. länk
  20. Altace (ramipril) DailyMed 2018. DailyMed [www]. US National Library of Medicine. [updated 2018-02-15, cited 2019-05-16]. länk
  21. [No authors listed]. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Lancet. 1993;342(8875):821-8. länk
  22. Ruggenenti P, Perna A, Zoccali C, Gherardi G, Benini R, Testa A et al. Chronic proteinuric nephropathies II Outcomes and response to treatment in a prospective cohort of 352 patients: differences between women and men in relation to the ACE gene polymorphism Gruppo Italiano di Studi Epidemologici in Nefrologia (Gisen). J Am Soc Nephrol. 2000;11:88-96. PubMed
  23. Wyskida K, Jura-Szołtys E, Smertka M, Owczarek A, Chudek J. Factors that favor the occurrence of cough in patients treated with ramipril--a pharmacoepidemiological study. Med Sci Monit. 2012;18:PI21-8. PubMed
  24. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2018 [cited 2019-03-08.] länk

Författare: Linnéa Karlsson Lind

Faktagranskat av: Mia von Euler

Godkänt av: Karin Schenck-Gustafsson