The PERFECT study was designed to evaluate whether long-term administration of perindopril improves endothelial dysfunction in patients with stable CAD and without clinical heart failure. Our findings, analysed in two ways, indicate that long-term use of perindopril is compatible with an improvement in FMD, although these findings were not statistically significant. The rate of change in endothelial function per 6 months showed a significant improvement over time in the perindopril group, where the comparison with placebo showed that these improvements bordered on statistical significance (p of 0.07).
The mechanisms underlying the beneficial effects of ACE inhibition are complex, and include inhibition of angiotensin II production with, subsequently, a reduction of its negative effects on the vascular system. Through coupling to the angiotensin II type 1 receptor, angiotensin II leads to vasoconstriction, vascular inflammation with an increase in pro-inflammatory genes, adhesion molecules and macrophage recruitment, an increased uptake and oxidation of LDL by endothelial cells and oxyradical production leading to endothelial dysfunction. Furthermore, it stimulates sympathetic activation and aldosterone release, adding to vasoconstriction and endothelial dysfunction. ACE inhibitors may positively affect endothelial dysfunction by decreasing angiotensin II production alone. However, equally or possibly more important is their effect on bradykinin. Through coupling to the bradykinin B2 receptor bradykinin results in NO and endothelial-derived hyperpolarizing factor. In addition it promotes prostacyclin release. As a consequence, bradykinin is not only a strong vasodilator, it also inhibits, through NO production, vascular smooth muscle cell growth and migration, improves endothelial function, inhibits the expression of cell adhesion molecules, prevents platelet adhesion, and restores the fibrinolytic balance by tPA production. As such, bradykinin effectively counteracts the deleterious effects of angiotensin II. The improvement of endothelial function with ACE inhibition is bradykinin-dependent . Of importance, not all ACE inhibitors increase bradykinin production to a similar extent. This depends, amongst other factors, on tissue affinity of the ACE inhibitor. Perindopril is one of the few ACE inhibitors with profound tissue affinity . It increases bradykinin significantly more than enalapril despite similar effects on circulating angiotensin II . Also, perindopril increases bradykinin levels at lower doses than needed to reduce angiotensin II levels . Indirectly, the pivotal role of bradykinin on endothelial function is suggested by the observation that perindopril, but not an angiotensin receptor antagonist telmisartan, improves endothelium-dependent vasodilatation, after long-term treatment despite similar anti-hypertensive effects . The PERTINENT study, another sub-study of EUROPA, provides further evidence in support for the improvement in endothelial function observed in the PERFECT study . PERTINENT studied the effect of 8 mg perindopril versus placebo after one year treatment on plasma markers of atherosclerosis, neurohormonal activation and apoptosis. A significant reduction in angiotensin II and cytokine levels was found together with a reduction in apoptosis. Of importance, bradykinin increased significantly accompanied by an increase in ecNO synthase in perindopril but not in placebo treated patients. These data from a similar patient population as in PERFECT provide evidence that pivotal mechanisms in endothelial function are improved by perindopril treatment and could lead to an improvement in endothelial function, as indicated in PERFECT.
There have been several studies performed on the effect of ACE inhibition and endothelial function as measured by FMD of the brachial artery (Table 2) [30–42]. Most studies were single centre studies, had a limited number of subjects enrolled (varying from 9 to 46), and were of short duration (from postprandial effect to 6 months). The designs applied were mostly cross-over trials. Overall, the effects varied from beneficial effects on FMD response to no effect at all without consistency in patient groups. That severely limits direct comparison with our results. In PERFECT the first FMD measurement after randomisation was at 6 months. No difference in FMD was found at 6 months between treatment groups. Our study is unique in that we studied long term effects of intervention on FMD. A recent review of studies on the long term effect of ACE inhibition on endothelial function, as assessed by a variety of measurements (vascular response and/or plasma markers) concluded that for CAD patient results are consistently showing an improvement in endothelial function . This is substantiated by the results from trials showing that coronary endothelial dysfunction improves after 6 months of treatment with ACE inhibitors .
Some aspects of the study need some consideration to appreciate the findings. Firstly, the initial sample size estimation was based on assumptions that came from cross-sectional studies, since longitudinal data were not available. When we perform a posterior power calculation based on the availability of 240 subjects using actually observed data on the difference between baseline and 36 months in FMD in the control arm (0.35% with a SD 3.63), we had a 80% power to detect a difference in change from baseline between the perindopril group and the placebo group of 1.3%, assuming a two sided alpha of 0.05. Our power to detect a 2% difference, as was originally proposed, was even higher. However, our power to detect the currently observed difference of 0.55% was only 20%, suggesting that we can not really exclude the fact that perindopril may have an effect on endothelial function. Secondly, it has been documented that the value of FMD measurement may be affected considerably by life style habits, such as recent physical activity, smoking, and food intake, technical aspects of the measurement, such as cuff location, and concomitant drug treatment, such as statins [45–48]. Furthermore, the reproducibility of the FMD measurement in situations where lifestyle factors were controlled optimally, may be moderate with coefficients of variation between 25–50%, indicating that within person variability may be considerable . This in general leads to attenuation of the magnitude of the relations under study. Although in PERFECT a uniform training and FMD methodology was used, the study was a multicenter trial, which compared to single center studies generally increases variability as shown by our reproducibility findings. This was one of the reasons we applied a random effect model to increase the power of the study to detect meaningful differences between treatment arms.
The baseline FMD value in our population was low, similar to that found in other studies in CAD patients , and may indicate the presence of endothelial dysfunction in this group. The effect of ACE inhibition on FMD over time was modest, although significant. This may be partially attributed to the fact that most of our patients were using multiple drugs that improve endothelial function as well, for example statins . This may have reduced our ability to demonstrate the full benefit of ACE inhibition per se.
In conclusion, appreciating the variability in the FMD measurement and the widespread use of other drugs that may affect FMD, our findings are compatible with the notion that the beneficial effects of perindopril on cardiovascular morbidity and mortality in the EUROPA study may be at least partly explained by an improvement in endothelial function.
Participating PERFECT centers
CZECH REPUBLIC: CESKY KRUMLOV: J. Florian, MD (principal investigator), V. Kuchar, MD; BRNO: B. Semrad, MD (principal investigator), J. Ziembova, MD, J. Schildberger, MD; PILSEN, H. Rosolova, MD (principal investigator), V. Jankovych, MD; PRAQUE: R. Spacek, MD (principal investigator), P. Stanka; PRAQUE: J. Hradec, MD (principal investigator), J. Malik, MD; TABOR: J. Charouzek, MD (principal investigator) V. Jirka, MD; PRAGUE: P. Jansky (principal investigator), Koelbel, MD; SLANY: G. Marcinek, MD (principal investigator), M. Votypka-Pecha; BRNO: L. Groh (principal investigator), I. Hofirek, L. Nechvatal. GERMANY: MUNICH: C. von Schacky, MD, PhD (principal investigator), S. Stoerk, MD, P. Markov. GREECE: ATHENS: Gialavos, MD, (principal investigator), A. Androulakis, MD; ATHENS: J. Lekakis, MD, C. Papamichael, MD. NETHERLANDS: HARDERWIJK: R. Dijkgraaf, MD (principal investigator), Y.Jansen-Timmer, H. Bralts; HENGELO: J.J.J. Bucx, MD (principal investigator until 01/01/2000), H. Droste, MD (principal investigator from 01/01/2000), G. Assink; EMMEN: L.F.M. van de Merkhof, MD (principal investigator), R. Vinke; ROTTERDAM: van Nierop, MD (principal investigator), I.M. Toonder, E. Korten. POLAND: KRAKOW: A.Gackkowski, MD (principal investigator); KRAKOW: T. Zielinsky, MD (principal investigator), T. Rywik, MD; KATOWICE: A.M. Wnuk-Wonjar, MD (principal investigator), C. Vita; KATOWICE: M. Tendera, MD (principal investigator), M. Kazmierski; SWEDEN: MALMO: J. Persson, MD (principal investigator), G. Osting;
Endothelial function core laboratory
Vascular Imaging Center Utrecht, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. Michiel Bots, MD, PhD; Ronald P. Stolk, MD, PhD; Rudy Meijer, Dicky Mooiweer-Bogaerdt ; Frank Leus, Brigitte Wernert, Eefje Spithoven, (http://www.juliuscenter.nl/research facilities/vascular imaging center)
EUROPA Executive Committee
Bertrand M, Ferrari R, Fox K, Remme W.J, Simoons M.
EUROPA Steering Committee
Aldershville J, Denmark; Hildebrandt P, Bassand JP, France; Cokkinos D, Greece; Toutouzas P, Greece, Eha J, Estonia; Erhardt L,Sweden; Erikssen J, Noway; Grybauskas R, Lithuania; Kalnins U, Latvia; Karsch K, Sechtem U, Germany; Keltai M, Hungary; Klein W, Austria; Luescher T, Switzerland; Mulcahy D, Ireland; Nieminen M, Finland; Oto A, Ozsaruhan O, Turkey; Paulus W, Belgium; Providencia L, Portugal; Remme W J, the Netherlands; Riecansky I,Slovakia; Ruzyllo W, Poland; Santini U, Tavazzi L, Italy; Soler-Soler J, Spain; Widimsky P, Czech Republic.