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EUROPA-Studie (Perindopril) (60 Abbildungen)

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FÜR ÖSTERREICH: Weitere Informationen: Servier, Mariahilfer Straße 20/5, 1070 Wien, Tel. 01/524 39 99
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EUROPA-Studie
Abbildung 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.


Keywords: CoversumEUROPA-Studiekardiales EreignisKHKKoronare HerzkrankheitPerindoprilServier Austria GmbHStabile Angina pectoris
 
 
Studientrends - ACE-Hemmer
Abbildung 2: 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).


Keywords: ACE-HemmerCoversumPerindoprilPräventionSchemaServier Austria GmbHStudieTherapie
 
 
ACE-Hemmung - Benefit
Abbildung 3: 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.


Keywords: ACE-HemmungCoversumKHKKoronare HerzkrankheitPerindoprilSchemaServier Austria GmbHStudie
 
 
KHK - Sekundärprävention
Abbildung 4: 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.


Keywords: ACE-HemmerAngiotensinCoversumKHKKininogenKoronare HerzkrankheitPerindoprilSchemaSekundärpräventionServier Austria GmbH
 
 
KHK - Sekundärprävention
Abbildung 5: 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


Keywords: ACE-HemmerAngiotensinbradykininCoversumKHKKoronare HerzkrankheitPerindoprilSchemaSekundärpräventionServier Austria GmbH
 
 
Endotheliale Dysfunktion
Abbildung 6: 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.


Keywords: AtheroskleroseCoversumDysfunktionEndothelGraphische DarstellungPerindoprilPlaqueServier Austria GmbH
 
 
Endotheliale Dysfunktion
Abbildung 7: 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.


Keywords: AtheroskleroseCoversumDysfunktionEndothelGraphische DarstellungPerindoprilPlaqueServier Austria GmbH
 
 
KHK - Sekundärprävention
Abbildung 8: 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.


Keywords: ACE-HemmerKHKKoronare HerzkrankheitSekundärprävention
 
 
EUROPA-Studie - Hypothese
Abbildung 9: Based on the hypothesis that ACE inhibition affects atherosclerotic process in multiple ways, benefits in all patients with coronary artery disease, can be anticipated.


Keywords: ACE-HemmerAtheroskleroseCoversumEUROPA-StudieIschämieKHKKoronare HerzkrankheitPerindoprilSekundärpräventionServier Austria GmbH
 
 
EUROPA-Studie - Perindopril
Abbildung 10: 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.


Keywords: ACE-HemmerAtheroskleroseCoversumEUROPA-StudieIschämiePerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Blutdruck
Abbildung 11: 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.


Keywords: BlutdruckCoversumDiagrammEUROPA-StudiePerindoprilServier Austria GmbH
 
 
Perindopril - Gewebs-ACE
Abbildung 12: 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.


Keywords: ACEACE-HemmungCoversumPerindoprilServier Austria GmbH
 
 
Perindopril - Bradykinin
Abbildung 13: 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.


Keywords: ACE-HemmungbradykininCoversumDiagrammKHKKoronare HerzkrankheitPerindoprilServier Austria GmbH
 
 
Perindopril - Endotheliale Dysfunktion
Abbildung 14: 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.


Keywords: CoversumDiagrammDysfunktionEndothelPerindoprilServier Austria GmbH
 
 
Perindopril - Endothliale Dysfunktion
Abbildung 15: 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 33.7 + 10.0 to 57.9 + 20.5 mL/min (p < 0.01) and coronary resistance decreased from 4.28 + 1.27 to 2.96 + 0.84 mm Hg.mL-1 .min-1 (p < 0.001).3


Keywords: Cold Pressure TestCoversumDiagrammDysfunktionEndothelPerindoprilServier Austria GmbHVasodilatationVasokonstriktion
 
 
Perindopril - Widerstandsarterien
Abbildung 16: 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.


Keywords: CoversumDiagrammHypertonieLumenPerindoprilServier Austria GmbHWiderstandsarterie
 
 
Perindopril - Widerstandsarterien
Abbildung 17: 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.


Keywords: CoversumDiagrammKollagenPerindoprilServier Austria GmbHWiderstandsarterie
 
 
Perindopril - Koronarreserve
Abbildung 18: 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.


Keywords: CoversumDiagrammKoronarreservePerindoprilServier Austria GmbH
 
 
Perindopril - Fibrinolyse
Abbildung 19: 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.


Keywords: bradykininCoversumDiagrammFibrinolyseHypertonieLosartanPerindoprilServier Austria GmbHTissue-type plasminogen activatortPA
 
 
Perindopril - Antiatheriosklerotischer Effekt
Abbildung 20: 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: 246-53.


Keywords: AtheroskleroseCoversumDiabetesGraphische DarstellungPerindoprilServier Austria GmbH
 
 
Perindopril - Antiischämische Wirksamkeit
Abbildung 21: 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.


Keywords: BelastungCoversumDiagrammDysfunktionIschämiePerindoprilServier Austria GmbHST-SegmentStabile Angina pectorisSystole
 
 
Perindopril - Verträglichkeit
Abbildung 22: 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 J, Lees K R, Reid J L. Br Heart J. 1991; 66: 206-11.


Keywords: BlutdruckcaptoprilCoversumDiagrammEnalaprilHerzinsuffizienzHypotoniePerindoprilServier Austria GmbHVerträglichkeit
 
 
Perindopril - Verträglichkeit
Abbildung 23: 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.


Keywords: BlutdruckCoversumDiagrammHypertoniePerindoprilServier Austria GmbHVerträglichkeit
 
 
EUROPA-Studie - Studienziel
Abbildung 24: 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.


Keywords: ACE-HemmerCoversumEUROPA-Studiekardiovaskuläres EreignisKHKKoronare HerzkrankheitPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Endpunkte
Abbildung 25: 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.


Keywords: CoversumEndpunktEUROPA-StudiePerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Studiendesign
Abbildung 26: 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.


Keywords: CoversumDiagrammEUROPA-StudiePerindoprilServier Austria GmbHStudiendesign
 
 
EUROPA-Studie - Patientenauswahl
Abbildung 27: 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.


Keywords: CoversumEUROPA-StudieKHKKoronare HerzkrankheitPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - KHK
Abbildung 28: 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


Keywords: Angina pectorisCABGCoversumEUROPA-StudieKHKKoronare HerzkrankheitMyokardinfarktPCIPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Charakteristik
Abbildung 29


Keywords: CoversumEUROPA-StudiePerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Patientenrekrutierung
Abbildung 30: 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.


Keywords: CoversumEUROPA-StudiePatientPerindoprilSchemaServier Austria GmbH
 
 
EUROPA-Studie - Zentren
Abbildung 31: 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.


Keywords: CoversumEuropaEUROPA-StudieGraphische DarstellungPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Ausschlußkriterien
Abbildung 32: 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.


Keywords: AusschlusskriterienCoversumEUROPA-StudiePerindoprilRandomisierungServier Austria GmbH
 
 
EUROPA-Studie - Charakteristika
Abbildung 33: 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: 68 + 10 and they had normal blood pressure. Importantly, there were no differences between these two groups, perindpril and placebo, almost identically matched.


Keywords: CharakteristikaCoversumEUROPA-StudiePatientPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Anamnese
Abbildung 34: 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.


Keywords: AnamneseCoversumEUROPA-StudiePerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Risikofaktoren
Abbildung 35: 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.


Keywords: CoversumEUROPA-StudiePerindoprilRisikofaktorServier Austria GmbH
 
 
EUROPA-Studie - Medikation
Abbildung 36: 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.


Keywords: CoversumEUROPA-StudieMedikamentPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Resultate
Abbildung 37


Keywords: CoversumEUROPA-StudiePerindoprilResultatServier Austria GmbH
 
 
EUROPA-Studie - Primärer Endpunkt
Abbildung 38: 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.


Keywords: CoversumDiagrammEUROPA-StudieHerzstillstandMyokardinfarktPerindoprilprimärer EndpunktServier Austria GmbHTod
 
 
EUROPA-Studie - Endpunkte
Abbildung 39: 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 %.


Keywords: CoversumDiagrammEndpunktEUROPA-StudieHerzstillstandinstabile Angina pectorisMortalitätMyokardinfarktPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Subgruppenanalyse
Abbildung 40: 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.


Keywords: AlterCoversumDiagrammEUROPA-StudieFrauMannPerindoprilServier Austria GmbHSubgruppe
 
 
EUROPA-Studie - Subgruppenanalyse
Abbildung 41: 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.


Keywords: CoversumDiabetes mellitusDiagrammEUROPA-StudieHypertoniePerindoprilSchlaganfallServier Austria GmbHSubgruppe
 
 
EUROPA-Studie - Subgruppenanalyse
Abbildung 42: 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.


Keywords: BetablockerCoversumDiagrammEUROPA-StudieKalziumantagonistLipidsenkerPerindoprilServier Austria GmbHSubgruppe
 
 
EUROPA-Studie - Sekundäre Endpunkte
Abbildung 43: Beneficial effect of treatment with perindopril on all prespecified secondary endpoints was shown in EUROPA.


Keywords: CoversumDiagrammEUROPA-StudiePerindoprilsekundärer EndpunktServier Austria GmbH
 
 
EUROPA-Studie - Myokardinfarkt
Abbildung 44: 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 (5 mm 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.


Keywords: CoversumDiagrammEUROPA-StudieMyokardinfarktPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Hospitalisierung
Abbildung 45: 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.


Keywords: CoversumDiagrammEUROPA-StudieHerzinsuffizienzHospitalisationPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Blutdruck
Abbildung 46: 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).


Keywords: BlutdruckCoversumDiagrammEUROPA-StudiePerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Compliance
Abbildung 47: 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.


Keywords: ComplianceCoversumDiagrammEUROPA-StudiePerindoprilServier Austria GmbHTherapietreue
 
 
EUROPA-Studie - Non Compliance
Abbildung 48: As perindopril 8 mg once daily was very well tolerated, the reasons for permanent withdrawal from treatment were comparable to placebo.


Keywords: AbbruchCoversumEUROPA-StudiePerindoprilServier Austria GmbHTherapie
 
 
EUROPA-Studie - Klinische Aussagen
Abbildung 49: Clinical implications from EUROPA trial are important for all at-risk coronary artery disease patients in the clinical practice.


Keywords: CoversumEUROPA-StudieIVFPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - KHK
Abbildung 50: 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."


Keywords: CoversumEuropaEUROPA-StudieKHKKoronare HerzkrankheitPerindoprilServier Austria GmbHTodesfallWelt
 
 
EUROPA-Studie - KHK
Abbildung 51: 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.


Keywords: CoversumEUROPA-StudieKHKKoronare HerzkrankheitPerindoprilSchemaServier Austria GmbH
 
 
EUROPA-Studie - Perindopril - Benefit
Abbildung 52: 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).


Keywords: BenefitCoversumDiagrammEUROPA-StudieHerzstillstandMyokardinfarktPerindoprilServier Austria GmbHTod
 
 
EUROPA-Studie - Interaktionsanalyse
Abbildung 53: 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.


Keywords: BehandlungBetablockerCoversumEUROPA-StudieInteraktionsanalyseKalziumantagonistLipidsenkerPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Benefits
Abbildung 54: 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".


Keywords: BenefitCoversumEUROPA-StudieKHKKoronare HerzkrankheitPerindoprilSchemaServier Austria GmbHStudie
 
 
EUROPA-Studie - HOPE-Studie
Abbildung 55: 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.


Keywords: CoversumEUROPA-StudieHOPEPerindoprilPopulationServier Austria GmbH
 
 
EUROPA-Studie - HOPE-Studie
Abbildung 56: 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.


Keywords: BasistherapieCoversumEUROPA-StudieHOPEMedikamentPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - HOPE-Studie
Abbildung 57: 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.


Keywords: CoversumEUROPA-StudieHOPEMortalitätMyokardinfarktPerindoprilPlaceboServier Austria GmbH
 
 
EUROPA-Studie - Ergebnisse
Abbildung 58: 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 %


Keywords: CoversumErgebnisEUROPA-StudieKHKKoronare HerzkrankheitPerindoprilRisikoServier Austria GmbH
 
 
EUROPA-Studie - Benefit
Abbildung 59: 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.


Keywords: CoversumEUROPA-StudieKHKKoronare HerzkrankheitNutzenPerindoprilServier Austria GmbH
 
 
EUROPA-Studie - Ergebnisse
Abbildung 60: 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".


Keywords: BenefitCoversumEUROPA-StudieKHKKoronare HerzkrankheitNutzenPerindoprilServier Austria GmbH
 
 
 
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