EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable Artery coronary disease) is the largest and longest study ever conducted.

Präsentation zum Thema: "EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable Artery coronary disease) is the largest and longest study ever conducted."—  Präsentation transkript:

1 EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable Artery coronary disease) is the largest and longest study ever conducted in patients with stable coronary disease. It was announced at ESC in Vienna on the 31st of August 2003 during an official hotline session. EUROPA is considered as a reference study for the initiation of the ACEI perindopril 8 mg once daily as chronic treatment in all patients with stable coronary artery disease.

2 Studientrends mit ACE Hemmern
Wirksamkeit Behandlung nach Ereignissen Prävention von Ereignissen CONSENSUS 1 SOLVD AIRE SAVE TRACE HOPE PEACE The clinical trials with ACE inhibitors in coronary artery disease patients over the years have proved their benefits in the “treatment” of patients right after the ischemic event (CONSENSUS, SOLVD, AIRE, SAVE, TRACE) and it was less proved on the “prevention” of secondary events (EUROPA, HOPE, PEACE), or even failed to prove (QUIET). GISSI-3 ISIS-4 Administrative Zeit nach Ereignissen vorher QUIET CONSENSUS 2 Diese Studien konnten keinen Erfolg nachweisen

3 Benefits der ACE Hemmung
SOLVD SAVE AIRE TRACE HOPE SOLVD (prev) So far, the benefit of ACE inhibitors were extensively investigated in large cohort of ishemic heart disease patients: post MI, LVSD with EF<40%, HF. The difference between these trials lies in the type of patients selected for each respective trial, which are actually patients of high risk. Coronary artery disease is a progressive condition involving patients with lower and higher risk levels. For cardiologists, according to the investigators from the EUROPA trial, patients involved presented all-risk coronary patients in comparison to other trials conducted in this area, which were patients considered as high risk patients. So, EUROPA was aiming to resolve the question on the benefits of ACE inhibition in the treatment of all risk stable coronary artery disease patients. ALLE KHK PATIENTEN

4 Sekundäre Prävention von KHK Warum ACE Hemmung?
ANGIOTENSINOGEN KININOGEN Renin + + Kallikrein Angiotensin I Bradykinin ACE + + Angiotensin II Desaktivierung B2 Rezeptor AT Rezeptoren Endothelialzelle The rationale of the possible benefits of an ACEI in the treatment of coronary artery disease is based on their anti ischemic properties linked to their mode of action. Angiotensin II (A II) plays a significant role in the mechanisms which underlie the atherosclerotic process: vasoconstriction and cell proliferation. Angiotensin-converting enzyme (ACE) inhibitors, such as perindopril, interrupt the production of A II, leading to antiproliferative and anti atherogenic effect. On the other hand, ACE inhibitors counteract the breakdown of bradykinin. A substance, which is responsible for the improvement in endothelial function, leading to vasodilation and growth inhibition. Bradykinin stimulates nitric oxide (NO) production and prostaglandin release from the endothelium. NO production and prostaglandin release yield beneficial vasodilatory, growth-inhibitory, antiatherogenic, antithrombotic, anti-inflammatory, and antioxidant effects. Glatte Gefäß- muskel zelle Vasokonstriktion Zellproliferation Vasodilation Wachstumshemmung CMF Learning Systems in 2000, “Courtesy CM Ferrario, MD”

5 Sekundäre Prävention von KHK Warum ACE Hemmung?
BRADYKININ SYSTEM ANGIOTENSIN SYSTEM Kininogen Angiotensinogen Kallikrein Renin Ang I Endothel Bradykinin ACE Hemmer Wirkung + + ACE  Thrombo- aggregation + (Enzym) Ang II Prostaglandin NO Indeed, looking more closely at the very important formation of bradykinin and pharmacological mode of action of ACEIs, we can conclude that bradykinin is one of the most important consequence of ACE inhibition. Bradykinin stimulates the release of NO from the endothelium, which not only dilates the vessel but also reduces platelet aggregation, the activity of white cells, and smooth muscle cell hypertrophy, all of which result from the activities of angiotensin II. Damage to the endothelium by smoking, hypercholesterolemia, diabetes, hypertension, or superoxides inhibits NO release, allowing angiotensin II to exert the harmful effects, as represented on the left side of the figure. SMC = glatte Muskelzellen FGF = Fibroblasten Growth Factor PDGF = Platelet Derived Growth Factor Inaktive Peptide Verstärkung der sympathischen Aktivität Vasokonstriktion  SMC Mitogenese Vasodilatation FGF PDGF  Aldosteronfreisetzung

6 Endotheliale Dysfunktion: Plaques im Frühstadium
Permeabilitäts-steigerung Eintritt von Leukozyten Leukozyten- adhäsion The earliest changes that occur within the dysfunctional endothelium include: Increase of the permeability of the endothelium to lipoproteins and plasma constituents. This alteration is mediated by nitric oxide, angiotensin II, endothelin and other compounds. Leukocyte adhesion molecules are produced in greater quantity, thus increasing the uptake of leukocytes and their adhesion to the vessel wall. Adapted from Ross R. N Engl J Med 1999; 340:

7 Endotheliale Dysfunktion: Plaques im Spätstadium
Migration glatter Muskelz. Lipid- akkumulation Ent- zündung Plättchen-aggregation Eintritt von Leukozyten As the dysfunctional endothelium progresses from early to more mature stages of atherosclerotic lesions, abnormal activity within the blood vessel continues: A fatty streak is formed within the vessel wall (lipid accumulation). Later, smooth muscle cells begin to migrate into the developing plaque. Leukocytes continue to adhere to the endothelium and after penetration move into the vessel wall. Inflammatory response in the atherosclerotic lesion starts. Platelets adhere to the dysfunctional endothelium contributing to the migration and proliferation of smooth muscle cells and monocytes, but also to platelet aggregation. Platelets accumulating on the vessel wall contribute to thrombus formation. As the atherosclerotic plaque progresses to late stages, a fibrous cap forms over the plaque and walls of the lesion from the vessel lumen. This fibrous cap may then become unstable and rupture causing thrombus formation, and often, CV events. Adapted from Ross R. N Engl J Med 1999; 340:

8 ACE Hemmung zur sekundären Prävention von KHK
Grundprinzip Antiarteriosklerotische Wirkung Reduktion von Plaquesrupturen Verbesserung der vaskulären endothelialen Funktion Verstärkte Fibrinolyse Modulation der neurohormonell induzierten arteriellen Vasokonstriktion Blutdrucksenkung Reduktion der LV Hypertrophie Angiotensin II Reduktion / Erhöhung von Bradykinin So,ACEIs, by both decreasing A II and increasing bradykinin levels offer possible anti ischemic effects, which could lead to secondary prevention of cardiovascular events in the treatment of coronary artery disease patients. inhibition in secondary prevention, comes directly from the following properties of perindopril, as demonstrated in human or experimental models: anti-atherosclerotic action, action on plaque rupture reduction, improvement of vascular endothelium, enhanced fibrinolysis, modulation of the neurohormonoally- induced arterial vasoconstriction, blood pressure lowering action in reducing left ventricular hypertrophy

9 Hypothese Die vielfältigen Wege, durch die die ACE-Hemmung
den arteriosklerotischen Prozess beeinflusst, lässt vermuten, dass diese bei allen Patienten mit koronarer Herzkrankheit (KHK) eine signifikante sekundäre Prävention ischämischer Ereignisse bewirkt. Based on the hypothesis that ACE inhibition affects atherosclerotic process in multiple ways, benefits in all patients with coronary artery disease, can be anticipated.

10 Perindopril: Gründe für die Auswahl für EUROPA
Nachgewiesene 24-Stunden Wirksamkeit Hohe Affinität zu Gewebs-ACE Spezifische Erhöhung von Bradykinin Anti-ischämische Eigenschaften: Korrektur der koronaren endothelialen Dysfunktion Normalisierung der Struktur von Widerstandsarterien Normalisierung der fibrinolytischen Balance Anti-arteriosklerotischer Effekt Anti-ischämische Wirksamkeit Gute Verträglichkeit auch bei fragilen Patienten (Herzinsuffizienz, Schlaganfall) EUROPA is investigators led study, where perindopril 8 mg once daily is the ACEI of choice due to its actions ideally suitable for investigating this hypothesis. Looking more specifically at the main reasons why perindopril was chosen for the EUROPA trial, the following properties came under consideration: Reliable 24-hour efficacy in BP reduction following a single tablet daily taken in the morning (as confirmed by its high TPR), with exceptional hemodynamic tolerance, proven when initiated and maintained in all patient types (in heart failure, post MI, as well as in patients with a history of stroke). High tissue affinity. Unique increase of bradykinin. Its anti-ischemic properties proven to: - correct coronary endothelial dysfunction, - normalize the structure of resistance arteries, - normalize fibrinolitic balance and structure of resistance arteries Anti atherosclerotic effect Anti ischemic efficacy Good tolerance even in fragile patients with previous heart failure and strokes.

11 Nachgewiesene 24-Stunden RR Kontrolle
Peak (6 Std. nach Gabe) Trough (24 Std. nach Gabe) RRsys RRdiast RRsys RRdiast 0,7 -2,9 -1,8 -4 -4,8 -4,7 -4 -5,9 -8,4 -7,9 RR Reduktion (mmHg) -8 -9,2 RR Reduktion (mmHg) -8 -11,1 -11,2 The blood pressure reduction over 24 h minimizes the risk of stroke and myocardial infarction in the early morning hours. In the randomized, parallel study, 293 mild-to-moderate essential hypertensive patients were treated with perindopril 4 to 8 mg once daily or placebo for 12 weeks. Trough-to-peak ratio (TPR) in placebo-corrected diastolic blood pressure at 24 h versus 6 h was 100%, and 97% for 4 mg and 8 mg, respectively. A linear relationship in efficacy between the dose of perindopril and the reduction in blood pressure was demonstrated over the range of 4 mg to 8 mg once daily over the 24 h. As with previous studies the higher doses of perindopril were not associated with an increased incidence of adverse effects. Perindopril 4 to 8 mg once daily, provides real 24-h blood pressure control. Myers MG. Can J Cardiol. 1996;12: -12 -12 Plazebo (n=58) Plazebo (n=58) Perindopril 4 mg (n=57) Perindopril 4 mg (n=57) -15,9 Perindopril 8 mg (n=58) Perindopril 8 mg (n=58) -16 -16 Myers MG. Can J Cardiol 1996; 12:

12 Hohe Affinität zu Gewebs-ACE bei KHK-Erkrankten
Kontrolle ACE Up-Regulierung während des ischämischen Zustandes Perindopril Hemmung des endothelialen und adventitialen ACE Perindopril has a very high tissue and plasma ACE affinity, as proven for the first time ever with an ACEI in humans suffering from coronary artery disease. Zhuo et al. studied the in vivo effects of ACE inhibition with perindopril on cellular expression of ACE, in human blood vessels using quantitative in vitro autoradiography and immunocytochemistry. Perindopril decreased plasma ACE by 70% and the plasma angiotensin II to angiotensin I ratio by 57%, and reduced vascular ACE to approximately 65% of control levels in both endothelium and adventitia. Perindopril inhibits both endothelial and advential ACE, this being further proof for reversing endothelial dysfunction, a key role player in the manifestation of cardiovascular diseases and their complications. This is one of the main reasons supporting its choice in the EUROPA study. Zhuo JL et al. Hypertension. 2002;39:

13 Spezifische Erhöhung von Bradykinin
Perindopril The long term treatment of patients with coronary artery disease, with perindopril 8 mg once daily, significantly decreases serum ACE activities (P<0.01) and increases plasma bradykinin concentrations (P<0.05). These results provide the first evidence that long-term treatment with perindopril exerts anti ischemic effects on the myocardial ishemia induced by increased myocardial oxygen demand in patients with . ACE-Hemmung und Erhöhung des Bradykininspiegels bei KHK-Patienten unter Perindoprilbehandlung Morishita T, Tsutsui M, Shimokawa H et al. Jpn J. Pharmacol ;88 :

14 Verbesserung der endothelialen Dysfunktion
Perindopril Perindopril corrects endothelial function as observed in this study, not accomplished by different antihypertensive therapies (ACEI, ARB, CCB and Beta-blockers) in essential hypertensive patients. Only perindopril managed to significantly increase flow mediated dilation after 6 months. AT1 receptor antagonist did not improve endothelial dysfunction leading to the conclusion that the beneficial effect of perindopril is related to bradykinin dependant mechanisms. Ghiadoni L. et al. Hypertension 2003;41:

15 Korrektur endothelialen Dysfunktion
Cold pressor test (CPT) Vasodilatation (%) normoton hyperton 10 +13% +12% 4 mg Perindopril -8% Perindopril, due to its high tissue affinity, corrects endothelial function at the level of the coronary arteries, which is altered in patients suffering from hypertension. This leads to improvement in coronary vasodilatation and heart perfusion. As shown in this study, perindopril restores flow-dependent and cold pressor test-induced dilations in the coronary arteries of hypertensive patients. Coronary blood flow was significantly increased by perindopril from to mL/min (P <0.01) and coronary resistance decreased from to mm Hg.mL-1 .min-1 (P <0.001).3 -10 CPT CPT Vasokonstriktion (%) *P<0.001 Antony I, Lerebours G, Nitemberg A. Circulation.1996;94:

16 Normalisierung der Struktur von Widerstandsarterien
P < 0.01 P < 0.05 NS Normotensiv vorher nachher Arterielles Media/Lumen Verhältnis (%) 8 6 4 5.82 7.94 5.96 7.14 6.79 Perindopril n=13 Atenolol n=12 Normotensiv n=25 Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension was evaluated with perindopril and atenolol. Gluteal biopsies were taken before and after treatment under local anesthetic. A significant change in the media:lumen ratio after the treatment with perindopril was obvious, in contrast to atenolol and besides the similar BP reduction obtained. Mittlerer RR (mmHg) 90 122 101** 126 98** Lumen  (µm) 237 208 247*ii 222 208 vs vorher *P <0.05. **P < vs Atenolol iiP < 0.01 Thybo NK, et al. Hypertension 1995; 25:

17 Normalisierung der Struktur von Widerstandsarterien
Periarteriolare Kollagenschicht Total Interstitial Collagen (m2) (Vv%) 800 p=0.04 8,0 p=0.04 600 558  270 6,0 5.5  3.8 22% 53% 4.3  3.2 400 4,0 Perindopril normalises structure of coronary resistance arteries in patients with hypertensive heart disease. In the study where hypertensive patients with LVH and microvascular angina, were treated with perindopril 4 mg to 8 mg for 1 year, after the treatment period, perindopril had significantly decreased coronary resistance. Perindopril induced the regression of periarteriolar fibrosis of resistance vessels and of the interstitial collagen. This was accompanied by marked improvement in coronary reserve. These findings indicate the beneficial reparative effects of ACE inhibition with perindopril on coronary microcirculation in hypertensive heart disease, beyond BP control. 260  173 200 2,0 0,0 n=14 Patienten Perindopril 4-8 mg/12 Monate Vor Behandlung Nach Behandlung Schwartzkopff B, et al. Hypertension 2000; 36:

18 Verbesserte Koronarreserve
*P = 0.001 n = 14 + 67%* Baseline 2.1 12 Monate Behandlung mit Perindopril 4 mg 3.5 As a result, the coronary reserve increased by 67%. Also, the LV muscle mass index significantly decreased by 11% after a 12-month perindopril treatment. Percent of increase in coronary reserve was more than expected by regression of LVH alone. Regression of fibrosis was demonstrated by perindopril in the non-pressure overloaded right ventricle and independently from local myocyte size. It seems to be due to direct/chronic effects of perindopril on collagen metabolism. Perindopril 4 to 8 mg, once daily, reverses both interstitial fibrosis and LV mass in patients with LVH and significantly restores coronary flow reserve in the long term treatment independently of its anti-hypertensive efficacy. Schwartzkopff B et al. Hypertension. 2000;36:

19 Verstärkte Fibrinolyse
Freisetzung von Tissue-type Plasminogen Aktivator (tPA) in der koronaren Zirkulation 700 Perindopril 4 mg/Tag 500 * ** Losartan 50 mg/Tag Kontrolle tPA Freisetzung (ng/min/100 mL) 300 Hypertoniepatienten (n=34) 100 * P<0.05 vs Kontrolle ** P<0.05 vs Losartan It has been confirmed that in hypertensive and cardiovascular disease the reduced levels of tissue-type plasminogen activator (t‑PA), are contributing to thrombus formation. This plays a role in the pathogenesis of acute myocardial infarction and stroke.  In a recent trial which compared the effects of perindopril and losartan on fibrinolytic balance in coronary artery circulation of the patients with atypical chest pain and hypertension, perindopril increased t-PA enhanced by bradykinin significantly more than losartan. It was concluded that perindopril may have a greater potential to enhance the bradykinin-induced coronary release of t-PA than losartan. Perindopril increases t-PA level and restores fibrinolytic balance acting on a major component of the myocardial ischemia process. Matsumoto T, Minai K, Horie H, et al. J Am Coll Cardiol. 2003;41: -100 0.2 0.6 2.0 Bradykinin (µg/min) Minai K et al. Japanese Circulation Journal. 2001;65(suppl I-A)

20 Antiartheriosklerotischer Effekt
(A) Kontrolle (B) Diabetische apoE-defiziente Mäuse (C) Diabetische apoE-defiziente Mäuse behandelt mit 4 mg Perindopril In a study on diabetic apoE-deficient mice, perindopril shows its ability to oppose the development of atherosclerosis by inhibiting ACE tissue growth factor and vascular cell adhesion molecule-1 overexpression in the aorta. This experimental study clearly proves perindopril’s efficacy on atherosclerosis in at-risk diabetic animal models. Perindopril plays a pivotal role in the opposition of development and acceleration of atherosclerosis in diabetes. Candido R, Jandeleit-Dahm KA, Cao Z, et al. Circulation. 2002;106: Candido R et al. Circulation. 2002;106:

21 Anti-ischämische Wirksamkeit
ST-SEGMENT DEPRESSION BELASTUNGS-INDUZIERTE VENTRIKULÄRE SYSTOLISCHE DYSFUNKTION Veränderung ST-Segment (mm) Left ventricular motion score P < 0,05 - 39% 6 - 42% P < 0,05 5 2,5 42% 39 % 4 2 3 1,5 2 1 Finally and as a final proof of perindopril’s choice for EUROPA it is interesting to look after its anti-ischemic efficacy, as recently proven in humans suffering from stable angina. After 3 months of treatment, perindopril given at the same dosage as used in EUROPA, that is to say 8 mg significantly reduces the time to ST-segment depression, as well as exercise-induced left ventricular systolic dysfunction. A linear relationship exists between the inhibition of plasma ACE by perindopril and the increase in bradykinin concentration. This high concentration is thought to be involved in the anti-ischaemic effects obtained with perindopril. This further emphazises its choice to conduct the EUROPA trial. 1 0,5 vorher 3 Monate Perindopril vorher 3 Monate Perindopril Morishita T et al. Jpn J Pharmacol. 2002;88:

22 Exzellente Verträglichkeit auch bei fragilen Patienten
1 2 3 4 5 6 7 8 9 10 24 5 Zeit (Std) Im Vergleich zu Enalapril und Captopril verursacht Perindopril keine first-dose Hypotonie -5 -10 -15 * * * -20 * * * First dose hypotension in heart failure patients with the initiation of an ACEI may be symptomatic or asymptomatic, which may lead to renal, cardiac, or cerebral hypoperfusion. In the double-blind, randomized, placebo-controlled, parallel-group prospective study of elderly patients with stable chronic heart failure, perindopril demonstrated an excellent hemodynamic tolerance minimizing the risk of hypotension. Perindopril 2 mg produces no more decrease in blood pressure then placebo. On the contrary, enalapril and captopril induce significant and long-lasting reduction in mean arterial pressure. Perindopril once daily provides an excellent hemodynamic profile even in fragile patients. So, for all these reasons perindopril was chosen to conduct EUROPA study. Mc Fadyen r J, Lees K R, Reid J L. Br Heart J. 1991;66: * * * * * * * * Plazebo Perindopril 2 mg Captopril 6,25 mg Enalapril 2,5 mg -25 * * * Veränderungen des mittleren arteriellen Blutdrucks (mmHg) n = 48 * P< 0.05 versus Plazebo -30 MacFadyen RJ, et al. Br Heart J 1991; 66:

23 Exzellente Verträglichkeit – auch bei fragilen Patienten
Perindopril Plazebo Blutdruck (mmHg) Perindopril senkt den RR während die zerebrale Durchblutung erhalten bleibt Coversyl once daily maintains cerebral blood flow in patients with acute ischemic stroke. There is an obvious theoretical concern that Bp lowering agent may also cause an adverse reduction in cerebral blood flow. In patients with already compromised cerebral circulation (ie, those who have had a stroke) this would clearly be highly undesirable. However it appears Coversyl provides BP controls without any adverse effects on cerebral blood flow. In a study of 28 patients with acute stroke and hypertension, between 48 hours and 7 days after a stroke, patients were randomized to either Coversyl once daily or placebo. The comparison with the placebo curve is particularly important in the context of a stroke because of the spontaneous wide variations of blood pressure in the acute phase ( first weeks). Cerebral blood flow was calculated from internal carotid artery Doppler ultrasound measurements. These measurements were undertaken 3 times: before intake of Coversyl, during the first 24 hours, and then repeated after 2 weeks. The results show that Coversyl reduces BP while maintaining cerebral blood flow. Zeit nach der Einnahme Dyker AG, Grosset DG, Lees KR. Stroke. 1997;28:

24 Studienziel Ziel der Studie war die Untersuchung, ob die Langzeitgabe des ACE-Hemmers Perindopril (COVERSUM) - zusätzlich zur state of the art Standardtherapie - zu einer Reduktion von kardiovaskulären Ereignissen bei Niedrigrisiko-Patienten mit nachgewiesener KHK führt. The aim of EUROPA is clear and simple: that is to examine and investigate whether long-term administration of the ACE inhibitor Perindopril added to standard therapy leads to secondary prevention of ischemic events in patients with documented coronary artery disease, with or without signs of myocardial ischemia, and without heart failure.

25 Studienendpunkte Primärer Endpunkt Sekundäre Endpunkte .
CV Mortalität + nicht tödl. MI + Herzstillstand Gesamtmortalität + nicht tödl. MI + Angina Pectoris + Herzstillstand Herzinsuffizienz Revaskularisierung (PCI/CABG) Schlaganfall Primärer Endpunkt Sekundäre Endpunkte The EUROPA study was designed to determine whether adding perindopril to optimal therapy decreased the rate of: CV mortality, non fatal MI, cardiac arrest – primary endpoint In addition, selected secondary end points of the study were: total mortality + non fatal MI + unstable angina + cardiac arrest; heart failure; revascularisation (PCI/CABG) and stroke.

26 Studien-Design Randomisierung Run-in Periode Follow-up
Perindopril 8 mg 1x täglich Perindopril 4 mg 8 mg Plazebo -1 -1/2 12 24 36 48 60 Monate Randomisierung After the run-in period of 2 weeks patients received 4 mg of perindopril once daily in the morning in addition to their usual medication. At 4 weeks, the thrid visit, patients were randomized double-blind to perindopril 8 mg or placebo, and continued their treatment until the last patients included complete the 4-year follow-up period. Run-in Periode Follow-up

27 Patientenauswahlkriterien
Männlich oder weiblich > 18 Jahre alt Nachgewiesene koronare Herzkrankheit (=KHK) Keine geplante Revaskularisierung Keine klinischen Zeichen einer Herzinsuffizienz According to these selection criteria, some important points can be highlighted: the patient profile is very close to the general population met in clinical practice in terms of age and risk factors. Patients include were older than 18 years, had documented coronary disease, were not scheduled for revascularisation and had no clinical signs of heart failure.

28 Nachgewiesene KHK Vorangegangener MI > 3 Monate
PCI / CABG > 6 Monate Angiographischer Nachweis einer KHK ( 70% Stenose mindestens einer Koronararterie) Männliche Angina pectoris Patienten: positiver Belastungs- oder Stresstest EUROPA includes 100% of patients with proven 100% coronary artery disease. 12,218 patients aged 26 to 89 years (mean age 60 years) without heart failure were recruited and randomised if they had documented CAD, which was defined as either: A history of previous MI at least three months before selection A history of PTCA or CABG at least 6 months old Significant coronary stenosis on coronary angiogram In males with a history of chest pain, by a positive exercise test, stress echo or scintiography

29 Baseline Charakteristika
J:\artem\F151097\Europa 10/24/97 Baseline Charakteristika 1

30 Patienten Rekrutierung
Abgeschlossen 6.107 6.108 Perindopril 6.110 Plazebo Randomisiert 12.218 Nicht randomisiert 1.437 Einschluss 13.655 Patients were followed up at 3, 6, and 12 months, and every 6 months thereafter. After randomisation, withdrawals from treatment were similar to those for placebo, and only 3 patients were lost to follow up amongst 12,218 patients.

31 424 Zentren: Patienten 102 176 141 130 57 1251 2176 115 94 300 399 285 511 890 17 22 2068 1772 277 134 209 65 197 830 EUROPA trail is a true pan-European trial. Therefore, the results were applicable across all Europe, including 12,218 patients that were randomised from 424 centers in 24 Europeen countries, involving 525 investigators.

32 Nicht randomisiert Gesamt: 1.437 von 13.655 Pat. 10.5
Unverträglichkeit Hypotonie Kreatinin/Kalium Erhöhung Schlechte Compliance Wichtige klin. Ereignisse Keine med. Gründe Unspezifisch 2.4 2.1 1.1 0.6 0.5 3.3 % Perindopril 8 mg once daily was well tolerated. Around 10% of patients were not randomised after the open-label dose-titration phase for various reasons.

33 Baseline Charakteristika
Perindopril (mittlerer  SD) Plazebo Alter (Jahre) 60  9 männlich (%) 86 85 Gewicht (kg) 81  12 80  12 HF (bpm) 68  10 SBD (mmHg) 137  16 137  15 DBD (mmHg) 82  8 The analysis of the baseline characteristics of patients recruited into the study showed that: Patients were at least 18 years without clinical evidence of heart failure and with evidence of coronary artery disease. In average they were 60 years old which is not old for coronary artery disease. They were largely men: 86%, weight: 81+12, heart rate: and they had normal blood pressure. Importantly, there were no differences between these two groups, perindpril and placebo, almost identically matched.

34 Anamnese Perindopril Plazebo Myokardinfarkt 64.9 64.7
(%) Plazebo Myokardinfarkt 64.9 64.7 Revaskularisierung 54.7 55.2 Schlaganfall / TIA 3.4 3.3 Herzinsuffizienz 1.3 1.2 Periphere Gefäßkrankheiten 7.1 7.4 There were 65% of patients with previous history of MI, 83% of those with MI was more than 1 year in the past, 1/3 of them had an MI 5 years before study started. Half of the patients randomised had revascularisation, and small % of patients had peripheral vascular disease, history of stroke or TIA and 1.3 had heart failure as it was the exclusion criteria, all equally balanced between perindopril and placebo group.

35 Risikofaktoren Perindopril Plazebo Hypertonie 27.0 27.2
(%) Plazebo Hypertonie 27.0 27.2 Diabetes Mellitus 11.8 12.8 Hypercholesterinämie 63.3 Raucher 15.4 15.1 Patients randomised in EUROPA trial involved: hypertensive patients, which presented 27% of the study population, 11.8% of patients had diabetes, 63.3% were hypercholesterolemic and 15.4% declared themselves as smokers. Again, a very balanced population was maintained between perindopril and placebo groups of patients.

36 Baseline Medikation Perindopril Plazebo Plättchenhemmer 91.9 92.7
(%) Plazebo Plättchenhemmer 91.9 92.7 -Blocker 62.0 61.3 Lipidsenker 57.8 57.3 Nitrate 42.8 43.0 Ca-Antagonisten 31.7 31.0 Diuretika 9.1 9.4 Orale Antikoagulantien 4.4 4.2 Of particular importance when it comes to interpretation of this study is the background treatment. Demographic data clearly demonstrate that the EUROPA patients were receiving perindopril or placebo on top of optimal preventive therapy. Most of the randomised coronary artery disease patients were treated with platelet inhibitors, B-blockers, lipid lowering drugs, nitrates, Ca-blockers, diuretics and oral anticoagulants. Homogeneity was maintained between these two groups of patients.

37 J:\artem\F151097\Europa 10/24/97 Resultate

38 % CV Tod, nicht tödlicher MI oder Herzstillstand
Primärer Endpunkt % CV Tod, nicht tödlicher MI oder Herzstillstand Jahre 2 4 6 8 10 12 14 1 3 5 Plazebo Perindopril p = 0,0003 RRR: 20% RRR = relative Risikoreduktion Perindopril reduced the combined primary endpoint of cardiovascular death, myocardial infarction and cardiac arrest by 20% (p=0.0003) after 4 years follow up. Reduction of the primary end-point reached significance even earlier and curves diverged after one year of treatment. Jährliche Plazebo-Ereignisrate: 2,4% n =

39 Primärer und 1. sekundärer Endpunkt
0,5 1,0 2,0 20 14 22 46 RRR (%) Perindopril besser Plazebo besser CV Mortalität, MI, Herzstillstand CV Mortalität Nicht tödlicher MI Herzstillstand Gesamtmortalität, MI, Instabile Angina pectoris, All components of the primary end point were reduced in favour of perindopril.CV mortality was reduced by 14%, non fatal MI by 22% and cardiac arrest by 46%. Composite of total mortality, non-fatal MI, unstable angina, cardiac arrest was significantly reduced by 14%.

40 Subgruppenanalyse RRR (%) Mit vorangegangenem MI Ohne MI 22,4 12,1
0,5 1,0 2,0 Perindopril besser Placebo Mit vorangegangenem MI Ohne MI 22,4 12,1 Alter  56 J. Alter 57 – 65 J. Alter > 65 J. 27,3 14,3 18,2 Männlich Weiblich 19,3 22,0 Sub-group analysis demonstrated that all patients benefited from perindopril 8 mg once daily. Regardless of gender, age or history of MI, the cardiovascular death, MI or cardiac arrest was always in favor of perindopril group.

41 Subgruppenanalyse Mit Hypertonie RRR (%) Ohne Hypertonie
0,5 1,0 2,0 Mit Hypertonie RRR (%) Perindopril besser Placebo besser Ohne Hypertonie Mit Diabetes Mellitus Ohne Diabetes Mellitus Mit Schlaganfall/TIA Ohne Schlaganfall /TIA 18,6 19,9 18,9 19,0 15,8 Sub-group analysis, also, showed that perindopril 8 mg once daily reduced morbidity and mortality in all patients irrespective of previous history of hypertension, diabetes or stroke and/or TIA.

42 Subgruppenanalyse RRR (%) Mit Lipidsenker Ohne Lipidsenker
Perindopril besser Placebo besser 0,5 1,0 2,0 Ohne Lipidsenker Mit -Blocker Ohne -Blocker Mit Ca-Antagonisten Ohne Ca-Antagonisten 16,3 22,3 26,4 7,0 15,8 22,2 Consistency of benefits with perindopril is shown in all patients whether they were using lipid lowering drugs, b-blockers and Calcium-channel blockers, or not. Almost all patients were using platelet inhibitors and more than half of them, lipid lowering drugs. By further analysis, no drug interaction was found meaning that benefits with perindopril are independent of other drugs. 92% der Patienten erhielten Thrombozytenaggregationshemmer

43 Sekundäre Endpunkte RRR (%) Tödl. & nicht tödl. MI, Angina pectoris
0,5 1,0 2,0 Perindopril besser Placebo besser Gesamtmort., MI, inst. Angine p.,Herzstillstand CV Mortalität & MI CV Mortalität , MI & Schlaganfall CV Mortalität , MI, Revaskularisation CV Mortalität , MI, Angina pectoris Tödl. & nicht tödl. MI Gesamtmortalität CV Mortalität Angina pectoris Herzstillstand Schlaganfall Revaskularisierung Herzinsuffizienz RRR (%) 14,0 19,3 17,4 11,3 15,5 16,5 23,9 11,0 13,9 7,1 45,6 4,3 4,2 39,2 Beneficial effect of treatment with perindopril on all prespecified secondary endpoints was shown in EUROPA.

44 Tödl. und nicht tödl. MI RRR: 24% p < 0,001 Plazebo Perindopril (%)
2 4 6 8 10 p < 0,001 RRR: 24% Plazebo Perindopril Perindopril 8 mg once daily reduced myocardial infarction (fatal or non-fatal) by 24 % (p<0.001). This is one of the most impressive results as curves separated early and there was a tendency for the gap between curves to widen more in time even after the end of the study follow up. As Dr Harvey White, from Cardiology Dept. Green Lane hospital, NZ commented in the EUROPA editorial: “Although the blood pressure reduction in EUROPA was small (5mm Hg systolic and 2 mm Hg diastolic), the systolic pressure reduction might be expected to translate into a 10% reduction in myocardial infarction, whereas the actual reduction in non-fatal MI was 24%”. This demonstrates that BP reduction should not be the predominant mechanism of benefit with perindopril. 1 2 3 4 5 Jahre

45 Hospitalisierung bei Herzinsuffizienz
RRR: 39% Plazebo 0,0 0,5 1,0 1,5 2,0 (%) Perindopril Another very significant result was reduction of hospitalisation for heart failure by 39% (p=0.002). There is a clear evidence that the patients assigned to perindopril 8 mg once daily benefited right after the onset of the study. 5 1 2 3 4 Jahre

46 Blutdruck Perindopril 8mg Plazebo RRsys: 5 mmHg RRdiast: 2 mmHg
-1 -1/2 3 6 12 18 24 30 36 42 48 54 60 Monate 70 80 90 100 110 120 130 140 mmHg RRsys: 5 mmHg RRdiast: 2 mmHg During the run-in period during where all patients received perindopril, blood pressure was reduced from 137/82 to 128/78 mm Hg. After randomisation, systolic and diastolic blood pressures among patients treated with perindopril were maintained until the study end and the average blood pressure during double-blind treatment was 5/2 mm Hg higher in the placebo group. Also, it was shown that reduction of fatal and non-fatal MI was reduced more then due to the reduction of BP alone (ref. EUROPA editorial).

47 Compliance Plazebo Perindopril 8mg (%) 6 12 18 24 30 36 Monate 20 40
6 12 18 24 30 36 Monate 20 40 60 80 100 120 (%) Plazebo Perindopril 8mg After randomisation, study medication was well tolerated. At 3 years, 81% of patients assigned perindopril and 84% of placebo patients, were taking study medication. Most of the patients assigned to perindopril continued on 8 mg, only 7% had dropped to 4 mg at 3 years. The average use of study medication was 3.7 years of 4.2 years follow-up.

48 Absetzen der Behandlung
Perindopril % Plazebo Husten 2.7 0.5 Hypotonie 1.0 0.3 Niereninsuffizienz Unverträglichkeit 2.4 1.3 Studienendpunkt 6.2 7.5 Hypertonie 0.4 0.8 Verweigerung der Einnahme 4.3 4.2 Sonstige Gründe 5.7 5.8 As perindopril 8 mg once daily was very well tolerated, the reasons for permanent withdrawal from treatment were comparable to placebo.

49 Klinische Aussagen J:\artem\F151097\Europa 10/24/97
Clinical implications from EUROPA trial are important for all at-risk coronary artery disease patients in the clinical practice.

50 Belastung durch KHK Weltweit 56 Mio. Todesfälle (2001)
29% durch CV Erkrankungen (~ 16 Mio.) (Prognose für 2020: 37%) EU: 20 Mio. Menschen leiden unter KHK Out of 56 million deaths worldwide in 2001, burden of coronary disease is accounted for 29% of them, causing deaths in total for 16 million people. In 2020, 37% of deaths are foreseen as CV deaths. In the European Union, there are 20 million people at risk who have coronary artery disease. Prof. Kim Fox, at the EUROPA study presentation commented that “investigators were particularly excited because the disease they are talking about is the most important disease, and every improvement they can make will have a great impact on the health care in the western world.

51 Klinische Auswirkungen der KHK
Instabile Angina pectoris MI KHK Stabile Angina pectoris Herz- insuffizienz Coronary artery disease encompasses all major cardiovascular complications. Clinical expression of coronary disease is presented through:silent ischemia, stable angina, unstable angina, MI, HF and sudden death. Stille Ischämie Plötzlicher Herztod

52 Benefits pro Population
% CV Tod, MI oder Herzstillstand 15,2 Perindopril Plazebo 12,7 8,1 6,2 6,2 5,2 niedriges In EUROPA study, all at-risk patients benefited, whether they were in low, medium or high risk group of patients. Perindopril 8 mg once daily reduced primary end-point (CV death, MI or cardiac arrest) regardless of age, gender, previous history of coronary artery disease (MI, CABG/PTCA, PVD, stroke), risk factors (smoking, diabetes) or preventive therapy (platelet inhibitors, lipid lowering drugs or B-blockers). durchschnittliches hohes Risiko Die Benefits von Perindopril zeigen sich unabhängig von Alter, Geschlecht, vorangegangener MI, verschied. Erkrankungender Koronaraterien, Schlaganfall, Hypertonie, Diabetes, Rauchen, Hypercholesterinämie, Einnahme von Lipidsenkern oder  -Blockern.

53 Interaktion Formale Interaktionsanalyse untersuchte die Wirksamkeit von Perindopril in Bezug auf: -Blocker Lipidsenker Ca-Antagonisten Interaktionseffekt in allen 3 Analysen nicht signifikant. Although patients were treated with perindopril 8 mg once daily on top of standard, preventive therapy, there were no significant interactions reported between the perindopril and all background medications. Der Behandlungseffekt von Perindopril ist unabhängig von anderen Sustanzen.

54 Benefits für alle KHK Patienten
SOLVD SAVE AIRE TRACE EUROPA HOPE SOLVD (prev) EUROPA trial demonstrated benefit for all coronary artery disease patients including large cohort of low, but also, medium and high risk patients randomised in the previous trials (I.e. HOPE, SOLVD, SAVE, AIRE, TRACE). Prof. Kim Fox, the EUROPA chairman commented: “The results from the EUROPA trial demonstrate some of the largest benefits ever seen in the prevention of chronic disease”. ALLE KHK PATIENTEN

55 HOPE vs. EUROPA Studien-Population HOPE EUROPA Alter (Jahre) 66 60
Weiblich (%) 27 15 Dokumetierte KHK (%) 80 100 Vorangegangener MI (%) 53 65 Periph. Gefäßerkr. (%) 43 7 Schlaganfall / TIA (%) 11 3 Diabetes (%) 38 12 Hypertonie (%) 47 Hypercholesterinämie (%) 63 EUROPA study with perindopril 8 mg once daily extends the observations of HOPE, in which cardiovascular events were reduced with ACE inhibition in high-risk patients with coronary heart disease. The risk of patients in EUROPA was lower than in HOPE, which selected older patients (66 vs 60), who had higher percentage of cardiovascular risk disease PVD, hypertension), stroke or diabetes.

56 HOPE vs. EUROPA Baseline HOPE EUROPA Thrombozyten-aggr.-hemmer* 76 %
92 % -Blocker 39 % 62 % Lipidsenker 29 % 58 % EUROPA: umfassendere Basistherapie als in HOPE At baseline,patients randomised in EUROPA were using more extensive therapy. More patients in EUROPA used optimal preventive therapy: aspirin, ß-blockers, and lipid-lowering drugs. * hauptsächlich Aspirin

57 HOPE: jährliche Plazebo-Ereignisrate 50 bis 80 % höher als bei EUROPA
HOPE vs. EUROPA Plazebo Outcomes standardisiert für 4,5 Jahre follow-up HOPE EUROPA Gesamtmortalität 12.2% 7.4 % CV Mortalität 8.1% 4.4% Q-wave MI 3.2% 2.1% HOPE: jährliche Plazebo-Ereignisrate 50 bis 80 % höher als bei EUROPA At a mean follow-up of 4.5 years, HOPE reported a placebo mortality of 12%, cardiovascular mortality of 8%, and Q-wave myocardial infarction of 3%, compared with 7%, 4%, and 2%, respectively, in EUROPA study at 4.2 years of follow-up. Thus, the major annual event rates in HOPE were 40% to 80% higher than those in EUROPA.

58 Zusammenfassung EUROPA, die größte und bisher längste Studie bei
Patienten mit stabiler KHK zeigt, dass - unabhängig von deren Risiko - 8 mg Perindopril täglich folgende Ereignisse signifikant reduziert: CV Mortalität + nicht tödl. MI + Herzstillstand: - 20% CV Mortalität und nicht tödl. MI : - 19% Tödl. MI und nicht tödl. MI : - 24% Herzinsuffizienz: - 39% As prof. Willem Remme, EUROPA Chairman added: “The EUROPA results are profound. Cardiovascular deaths, myocardial infarction and heart failure were all significantly reduced in patients given treatment based on ACE inhibitor perindopril, in addition to standard optimal therapy including aspirin, statins and ß -blockers”. In this largest and longest trial of stable CAD patients, perindopril 8 mg once daily reduced significantly: CV mortality, non-fatal MI and cardiac arrest by 20% CV mortality and non fatal MI by 19% Fatal and non fatal MI by 24% Heart failure by 39%

59 Absoluter Nutzen Mit Perindopril 8mg 1mal täglich kann ein schweres kardiovaskuläres Ereignis (Tod, nicht tödlicher MI oder Herzstillstand) bei jedem 50. KHK-Patienten, der 4 Jahre behandelt wird, verhindert werden. Once again, the absolute benefits were achieved with perindopril 8 mg once daily in the EUROPA trial: “Adding perindopril to standard optimal therapy over a four year period would stop 50,000 heart attacks or cardiovascular deaths in a country with a population of 60 million” concluded prof. Kim Fox, the study chairman. “The EUROPA trial provides clear evidence of major health gains for these patients. If the findings are applied worldwide then many millions of lives could be saved” added prof. Willem Remme, the study chairman.

60 Nutzen der Resultate Die Vorteile waren unabhängig von der state of the art Standardtherapie (92% Aggregations- hemmer, 58% Lipidsenker, 62% -Blocker) nach- weisbar und konsistent in allen vordefinierten Patientengruppen. Perindopril sollte zur Langzeit-Behandlung aller KHK-Patienten in Betracht gezogen werden. Last but not least, all these benefits demonstrated with perindopril 8 mg once daily in EUROPA trial, were achieved on top of standard optimal treatment (platelet inhibitors, lipid lowering drugs and ß -blockers) and are consistent in all sub-groups of patients. Perindopril should be used in chronic therapy in all patients with coronary disease: As prof. Willem Remme concluded: “We now have sufficient evidence to show that perindopril, due to its anti-atherogenic effects and blood pressure lowering properties is beneficial and should be used in treating all patients with coronary artery disease”.