Badanie SIGNIFY – iwabradyna w stabilnej chorobie wieńcowej

Listopad 14, 2014  |  Udostępnij  | 

W ostatnich tygodniach na łamach New England Journal of Medicine opublikowano wyniki badania SIGNIFY[1], w którym oceniano możliwość zastosowania iwabradyny u chorych ze stabilną chorobą wieńcową. Biorąc pod uwagę mechanizm działania tego leku, polegający na obniżaniu częstości akcji serca (bez obniżania siły skurczu mięśnia sercowego, czy obniżania ciśnienia tętniczego), eksperyment ten miał podwójne znaczenie – z jednej strony służył ocenie działania iwabradyny w tej konkretnej jednostce chorobowej, a jednocześnie pokazał, czy zwalnianie rytmu serca powinno być uznawane za cel terapeutyczny u pacjentów z chorobą niedokrwienną.
shutterstock_112836925Badanie SIGNIFY przeprowadzono w 1139 ośrodkach na terenie 51 krajów. Zgodnie z przyjętym protokołem do eksperymentu kwalifikowano chorych leczonych z powodu stabilnej choroby wieńcowej, którzy w ciągu ostatniego roku przebyli ostry zespół wieńcowy i/lub w momencie randomizacji byli w >=II klasie CCS. Ponadto do kryteriów włączenia należały: rytm zatokowy >=70/min oraz brak klinicznych cech niewydolności serca (minimalna EF=40%). Powyższe parametry oceniano w dniu randomizacji oraz w trakcie kontroli po 2 i 4 tygodniach, a następnie rozpoczynano podawanie iwabradyny (oraz placebo w grupie kontrolnej). Lek dawko wanno według schematu: domyślnie 2×7,5mg lub 2x5mg u osób >=75 roku życia, do maksimum 2x10mg pod kontrolą częstości rytmu serca. Jednocześnie preparaty standardowo zalecane w profilaktyce choroby wieńcowej były podawane według wytycznych. Do zdarzeń tworzących pierwszorzędowy punkt końcowy zaliczono zgon z przyczyn sercowo-naczyniowych oraz zawał serca. Leczenie uznawano za źle tolerowane, jeśli u chorego wystąpiła objawowa bradykardia lub gdy przy braku objawów częstość akcji serca spadała poniżej 45/min podczas podawania najmniejszej możliwej dawki iwabradyny. W badaniu udział wzięło łącznie ponad 19,1 tys. pacjentów. U 9550 spośród nich rozpoczęto terapię iwabradyną (grupa badana), natomiast 9552 chorym podawano placebo (grupa kontrolna). Przeciętny okres obserwacji wyniósł niemal 28 miesięcy. Po 3 miesiącach od podania pierwszej dawki leku, w trakcie wizyty kontrolnej, średnia częstość akcji serca uległa zmniejszeniu do 60.7±9.0/min w grupie badanej oraz do 70.7±10.1 w grupie placebo (różnica pomiędzy grupami była istotna statystycznie i utrzymywała się podczas kolejnych pomiarów kontrolnych). Po zakończeniu obserwacji i podsumowaniu wyników okazało się, że terapia iwabradyną nie przyniosła korzyści w zakresie występowania pierwszorzędowego punktu końcowego (6.8% vs. 6.4%; 95% CI0.96-1.20). Nie odnotowano także istotnych statystycznie różnic pod względem ryzyka względnego występowania poszczególnych jego składowych (zgon z przyczyn sercowo-naczyniowych – HR 1.10; 95%CI 0.94-1.28; zawał serca – HR 1.04; 95% CI0.90-1.21). Jednocześnie – zgodnie z oczekiwaniami – przyjmowanie iwabradyny wiązało się ze zwiększonym ryzykiem wystąpienia działań niepożądanych w porównaniu z leczeniem placebo. Do najczęstszych należały: objawowa bradykardia (7.9% vs. 1.2%), bezobjawowa bradykardia (11.0% vs. 1.3%), a także napadowe migotanie przedsionków (5.3% vs. 0.5%) i zaburzenia widzenia (5.4% vs. 0.5%). Obserwowane efekty uboczne były przyczyną odstawieniu przyjmowanego leku przez 13.2% chorych z grupy badanej oraz 7.4% w grupie kontrolnej (p<0.001).

Badanie SIGNIFY wykazało, że podawanie iwabradyny u chorych ze stabilną chorobą wieńcową bez skurczowej niewydolności serca nie wpływa na poprawę rokowania. Jednocześnie przyjmowanie tego leku jest związane z występowaniem działań niepożądanych, z których najczęstszym jest bradykardia. Poczynione obserwacje sugerują ponadto, iż zwalnianie czynności serca u pacjentów z chorobą niedokrwienną najpewniej nie powinno być celem terapeutycznym.

1. Fox K. et al., Ivabradine in Stable Coronary Artery Disease without Clinical Heart Failure. N Engl J Med. 18 Sept 2014; 371:1091-1099


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