1Royal Brompton Hospital, Sydney Street, London SW3 6NP, UK
2Sticares Cardiovascular Research Institute, RotterdamRhoon, The Netherlands
3Cardiology Hospital, Lille, France
4Hospital Santa Anna, Ferrara, Italy
5ThoraxCenter Erasmus Medical Centre, Rotterdam, The Netherlands
Received 13 August 2004; revised 31 January 2005; accepted 17 February 2005; online publish-ahead-of-print 28 April 2005.
* Corresponding author. Tel: +44 20 7351 8626; fax: +44 20 7351 8629. E-mail address: k.fox{at}rbh.nthames.nhs.uk
See page 1347 for the editorial comment on this article (doi:10.1093/eurheartj/ehi308)
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Abstract |
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Methods and results A total of 1502 diabetic patients with known coronary artery disease and without heart failure of 12 218 overall in the EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery (EUROPA) disease were randomized in a double-blinded manner to perindopril 8 mg once daily or placebo. Follow-up was for a median of 4.3 years. The primary end point was cardiovascular death, non-fatal myocardial infarction, and resuscitated cardiac arrest. Perindopril treatment was associated with a non-significant reduction in the primary endpoint in the diabetic population, 12.6 vs. 15.5%, relative risk reduction 19% [(95% CI, 7 to 38%), P=0.13]. This was of similar relative magnitude to the 20% risk reduction observed in the main EUROPA population.
Conclusion Perindopril tends to reduce major cardiovascular events in diabetic patients with coronary disease in addition to other preventive treatments and the trend towards reduction was of a similar relative magnitude to that observed the general population with coronary artery disease.
Key Words: Randomized controlled trial ACE inhibitor Diabetes mellitus Stable coronary disease Secondary prevention
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Introduction |
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Cardiovascular disease is the leading cause of death and morbidity in the diabetic population.12,13 Quite apart from the fact that diabetes places an individual at higher risk than the general population of developing coronary and other cardiovascular disease,12,13 the presence of diabetes in the context of established disease portends a worse clinical outcome. Diabetes in patients with coronary disease is associated with approximately double the rate of major cardiovascular events observed in the non-diabetic population.14 The effects of ACE inhibition in diabetic patients are of particular interest, given the higher prevalence and greater risk associated with cardiovascular disease in the context of diabetes, and potential additional benefits on renal function and progression of diabetes. Although studies suggest that ACE inhibitors may prevent cardiovascular events in some diabetic patients, their role in diabetic coronary patients remains unknown. The PERindopril SUbstudy in Coronary Artery Disease and DiabEtes (PERSUADE) study, the diabetic substudy of EUROPA was planned to investigate the effect of the ACE inhibitor perindopril in reducing cardiovascular death, MI, and other cardiovascular outcomes in diabetic patients with stable coronary disease without heart failure.
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Methods |
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Population
Men and women >18 years of age, with objective evidence of coronary disease, but without clinical heart failure were enrolled in the study. Previous MI, coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI), or angiographically documented coronary stenosis >70% were accepted as objective evidence of coronary disease or a positive stress test in symptomatic males. The main exclusion criteria were clinical evidence of heart failure, planned revascularization, hypotension (sitting systolic blood pressure of <110 mmHg) or uncontrolled hypertension (systolic blood pressure >180 mmHg and/or diastolic blood pressure of >100 mmHg), recent (<1 month) use of ACE inhibitor or angiotensin receptor blockers therapy, and renal insufficiency (creatinine >150 µmol/L) or serum potassium >5.5 mmol/L. Each institution's review board or ethics committee reviewed the protocol and all participants provided informed consent. Of the 12 218 patients randomized in EUROPA, 1502 (12%) had an established diagnosis of diabetes at baseline, based on self-report of physician diagnosis or patient records. These patients form the main population for analysis in the PERSUADE study. PERSUADE was a preplanned substudy of the EUROPA study. However, forced enrollment of diabetics to achieve a pre-specified target proportion of diabetic patients did not occur and the diabetic sample size was not determined prior to the study.
Baseline measurements, randomization, and follow-up
Enrolled patients received perindopril 4 mg (or 2 mg in the elderly) titrated up to a maximum of 8 mg once daily over a 4-week run-in period. Patients who completed this run-in period without clinically significant adverse effects were randomized to perindopril 8 mg or placebo. Patients were followed-up at 3, 6, and 12 months and every 6 months thereafter for a median of 4.3 years. Blood pressure was recorded twice in the sitting position using a standard sphygmomanometer after at least 5 min rest at each visit and sodium, potassium, and creatinine were measured during the run-in, at randomization and once yearly from there on. Treatment for diabetes was at the discretion of the patient's physician.
Patient recruitment and randomization was conducted from October 1997 to June 2000. The protocol was modified during the study to redefine the primary endpoint for the following reasons. First, the primary endpoint was defined as total mortality, non-fatal MI, and unstable angina. However, during the course of the study new methods of detection of myocardial injury/infarction were introduced into clinical practice, and new recommendations made jointly by the European Society of Cardiology (ESC) and American College of Cardiology (ACC) regarding definition of MI in 2000. These guidelines recommended that all patients with raised markers of myocardial necrosis (cardiac troponin T, I or CK-MB) should be labelled MI and distinguished from unstable angina without myocardial necrosis. Unstable angina without myocardial necrosis was no longer judged an appropriate endpoint given its subjective diagnosis. Secondly, the contribution of cardiovascular mortality to the overall mortality in the population was lower than expected, that is 60%. As ACE inhibition was not expected to improve non-cardiovascular mortality, cardiovascular mortality was deemed more appropriate to include in the primary endpoint than total mortality. The primary endpoint was therefore redefined as cardiovascular death, non-fatal MI, or successfully resuscitated cardiac arrest in January 2002, more than a year before the trial was completed, with no knowledge of the trial outcome at the time. Power calculations using the new endpoint suggested that the duration of the trail should be extended by 1 year to accrue the required number of events. These modifications were agreed by the EUROPA steering committee.
Thus, for the final analysis, the primary endpoint was a composite outcome of cardiovascular mortality, non-fatal MI, or successfully resuscitated cardiac arrest. A diagnosis of MI was based on the recommendations of the ESC and ACC.15 Cardiovascular mortality was adjudicated by the central critical event committee on the basis of autopsy results if available or documentary evidence from medical records of the immediate clinical history prior to death. Other secondary endpoints included, individually and in various combinations, total mortality, revascularization, stroke, hospitalization for unstable angina, and hospitalization for heart failure. These endpoints were included in analysis only if confirmed by the independent critical event committee. Specific diabetes related endpoints included hospitalization for diabetes or peripheral vascular disease, doubling of serum creatinine, or rise in creatinine >170 µmol/L.
Statistical analysis
We used the log rank test in an intention to treat analysis for the time to first event for the primary and other secondary endpoints. The cumulative distribution of events over time was examined using the KaplanMeier method. Cox's proportional-hazards model was used to measure treatment effect, by deriving relative risks and relative risk reductions [(1RR)x100] with 95% confidence intervals, for the primary and secondary clinical endpoints analysed by time to first event. The proportional hazards assumption was not formally tested. Event rates presented were calculated using appropriate survival analysis techniques.
Tests of significance were two-sided and a significance level of P<0.05 was used. Adjustments were not made for multiple comparisons. Subsidiary comparisons included assessment of the effect of treatment with perindopril not just on first events but on first and subsequent (all) events during the scheduled treatment period. The mean difference in blood pressure over follow-up was calculated as an average of the mean difference between the treatment groups at each time point. Differences in blood pressure between treatment and placebo groups were compared over time using a repeated measures procedure (proc MIXED) in SAS v 8.02. Patients were used as a random factor in the analysis. Time was not included as a continuous variable in the mixed model, as visit was included. Treatment and interaction between visit and treatment were included. Differences between treatment and placebo groups in creatinine and change in creatinine from baseline, which was calculated at randomization and annually thereafter, were also assessed by this procedure.
Role of the funding source
Representatives of the sponsor were non-voting members of the study executive committee and were involved with the executive committee in the study design, interpretation of the data, the writing of the report, and the decision to submit the paper for publication. The sponsor was not involved in the data collection and data analysis.
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Results |
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The frequency of use of open label ACE inhibitor therapy at any time during the study was significantly greater in the placebo group than in the perindopril treated group in patients known to have diabetes at baseline. Calcium channel blockers and diuretics were also used significantly more frequently in the placebo group (Table 2).
A primary endpoint, either cardiovascular mortality or MI or cardiac arrest occurred in 121 patients in the placebo group and 91 patients in the perindopril group, corresponding to a relative risk reduction of 19% (95% CI 7, 38) P=0.131 (Table 3, Figure 2). This is comparable to a relative risk reduction of 19% (95% CI 8, 29) in primary endpoint with perindopril in patients without a diagnosis of diabetes at the outset of the study, or 20% (95% CI 9, 29) in the EUROPA study as a whole. The benefit is of the same relative magnitude to that reported in EUROPA but the absolute effect is greater because of the higher event rate in the diabetic population. The KaplanMeier curve indicates that the cumulative incidence of the primary endpoint in the perindopril group becomes less than that of the placebo group from about 3 years. From there the separation of the curves persists until the study end. The combined secondary endpoints comprised total mortality, MI, unstable angina, and cardiac arrest; and cardiovascular mortality, MI, and stroke are also reduced by a considerable, but non-statistically significant extent. Relative risk reductions are 15% (5, 32%) and 14% (11, 34), respectively (Table 3). Individual secondary endpoints are also reduced, albeit non-significantly, by perindopril (Figure 3). Although the 23% relative risk reduction in fatal and non-fatal MI failed to meet significance, the incidence of non Q-wave MI was lowered significantly by perindopril, relative risk reduction 34% (95% CI, 0.156%, P=0.048).
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Discussion |
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The high rate of events in the diabetic population, approaching double that in the overall population or those without a diagnosis of diabetes at baseline, means that a relative risk reduction in this population of similar magnitude to that in the overall population is associated with greater absolute risk reduction. Considering that the use of secondary prevention, platelet inhibitors, statins, and beta blockers is so widespread, greater than used in HOPE or observed in large surveys of clinical practice in Europe,17 the additional benefit of ACE inhibitor therapy might be expected to be attenuated, yet the relative magnitude of the effect was maintained. Tight control of blood pressure has been proven to reduce macrovascular complications of diabetes and improve cardiovascular outcome in hypertensive diabetics in a range of studies from UKPDS to HOT,1820 and control of blood pressure may be more important in the diabetic population than in non-diabetics. Targeted multifactorial intervention programmes including intensive blood pressure lowering and the use of ACE inhibition irrespective of blood pressure, have also been shown to be effective in reducing cardiovascular events in diabetic patients.21
It has been discussed if it is the ACE-inhibition per se or the concomitant blood pressure reduction which relates to the beneficial effects of ACE inhibitors on cardiovascular outcome.9,10 The reduction in blood pressure achieved with perindopril treatment during the course of this study (4.6/1.8 mmHg) is within the range (36 mmHg systolic/14 mmHg diastolic) observed in other previous trials of placebo controlled trials of ACE inhibitor therapy (HOPE,9 PART2,22 QUIET,23 and SCAT24). Meta-analysis of the results of these trials has not indicated any heterogeneity in the effects of ACE inhibitors in terms of cardiovascular outcomes at this level of blood pressure reduction.25 Although there are methodological limitations to the analysis, no direct evidence to suggest that higher levels of baseline systolic or diastolic blood pressure, or a greater fall in blood pressure with treatment favourably influenced the effect of treatment with perindopril was observed. This is consistent with the results of the metanalysis of cardiovascular protection and blood pressure reduction by Staessen et al.26 which indicated that blood pressure at baseline contributed less to variance in outcome than blood pressure differences during follow-up. However, it is noteworthy that in the PERSUADE population the benefit of treatment was significant in the lowest tertile of initial reduction in systolic blood pressure, mostly composed of patients who had no fall in blood pressure, maintained over the course of the study in the perindopril group. Although it is not possible to conclude that the blood pressure lowering effect did not play a role in the treatment benefit observed, this finding supports the concept of pleiotropic vasculoprotective effects of ACE inhibition in addition to the blood pressure lowering effects.
There are several putative mechanisms by which ACE inhibition may delay progression of atherosclerosis and reduce cardiovascular events. First, ACE inhibition may retard the accelerated atherosclerotic progression typical of diabetes. Murine models using Apo-E deficient mice as experimental models of atherosclerosis have shown that induction of diabetes is associated with a four-fold increase in atherosclerotic plaque area over a 20 week period. Treatment with perindopril in the diabetic mice results in significantly less plaque development, similar to control animals. In addition to effects on plaque volume, plaque composition is also adversely affected by diabetes with increased macrophage infiltration of the plaque, which is ameliorated by perindopril treatment. Connective tissue growth factor and cellular adhesion molecules such as VCAM and ACE gene expression are all increased in diabetic atherosclerosis and reduced by perindopril.27 ACE inhibitors also exert a positive effect on the endothelial dysfunction, which is often a feature of coronary disease. Perindopril can acutely correct the endothelial dysfunction seen in hypertensive coronary arteries and at long-term increase coronary reserve and reduce myocardial vascular resistance.28 This effect may be caused indirectly by reduction in angiotensin II or an increase in bradykinin, which serve to inactivate and augment release of nitric oxide, respectively. A more recent discovery of increased constituitive NO synthase expression in the coronary endothelium in response to perindopril suggest that there may also be a more direct effect on nitric oxide production.29 This in turn has other beneficial effects including a reduction in platelet adhesion and aggregation. Finally ACE inhibition may exert further antithrombotic effects by reducing angiotensin II, which exerts its prothrombotic effect by increasing PAI-1 and fibrinogen. 30,31
In this group of diabetics with well-controlled blood pressure, the incidence of overt renal dysfunction or doubling of serum creatinine was rare. This is in keeping with previous findings indicating that, although diabetes is one of the most frequent causes of end stage renal disease, in fact cardiovascular events constitute a far greater morbidity burden and mortality risk to the type 2 diabetic population than renal disease.32,19 It is not surprising therefore that no significant treatment effect was observed when serum creatinine levels were used as the indicator of renal disease.
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Limitations |
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Conclusions |
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Acknowledgements |
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Appendix |
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EUROPA Executive Committee
Fox K. (Chairman, UK), Bertrand M. (France), Ferrari R. (Italy), Remme W.J. (The Netherlands), Simoons M.L. (The Netherlands)
EUROPA Steering Committee
Remme W.J. (Chairman, The Netherlands), Aldershvile J. and Hildebrandt P. (Denmark), Bertrand M. (France), Bassand J.P. (France), Cokkinos D. and Toutouzas P. (Greece), Eha J. (Estonia), Erhardt L. (Sweden), Erikssen J. (Norway), Grybauskas P. (Lithuania), Kalnins U. (Latvia), Karsch K. and Sechtem U. (Germany), Keltai M. (Hungary), Klein W. (Austria), Lüscher T. (Switzerland), Mulcahy D. (Ireland), Nieminen M. (Finland), Oto A. and Ozsaruhan O. (Turkey), Paulus W. (Belgium), Providencia L. (Portugal), Riecansky I. (Slovakia), Ruy
o W. (Poland), Santini U. and Tavazzi L (Italy), Soler-Soler J. (Spain), Widimsky P. (Czech Republic), Fox K.M. (UK)
Data Safety Monitoring Board
Julian D. (Chairman, UK), Dargie H. (UK), Kübler W. (Germany), Murray G. (UK)
Clinical Event Committee
Thygesen K. (Chairman, Denmark), Duprez D. (Belgium), Steg G. (France)
Investigators
Austria: Drexel H., Gombotz G., Klein W.
Belgium: Duprez D., Heyndrickx G.H., Legrand V., Materne P., Van Mieghem W.
Czech Republic: Bocek P., Branny M., Cech M., Charouzek J., Drazka J., Fabik L., Florian J., Francek L., Groch L., Havranek P., Hradec J., Jansky P., Jirmar R., Jokl I., Krejcova H., Kvasnak M., Maratka T., Marcinek G., Moravcova J., Nedbal P., Peterka K., Povolny J., Rosolova H., Semrad B., Sochor K., Spacek R., Spinar J., Stipal R., Stuchlik K., Sulda M., Ulman J., Vaclavicek A., Vojtisek P.
Denmark: Bjerregaard-Andersen H., Hildebrandt P., Kristensen K., Madsen J.K., Markenvard J., Meibom J., Norgaard A., Scheibel M.
Estonia: Eha J., Leht A., Teesalu R., Vahula V.
Finland: Itkonen A., Juvonen J., Karmakoski J., Kilkki E., Koskela E., Melin J., Nieminen M.S., Savola R., Terho T., Voipio-Pulkki L.M.
France: Apffel F., Attali P., Barjhoux C., Baron B., Bassand J.P., Berthier Y., Dambrine P., Decoulx E., Deshayes P., Fouche R., Genest M., Godard S., Guillot J.P., Hanania G., Khattar P., Leroy F., Mansourati J., Piquemal R., Quiret J.C., Raynaud P., Rondepierre D., Roynard J.L., Sudhibhasilp S., Van Belle E.
Germany: Bilbal A., Lauer B., Rettig-Stürmer G., Riessen R., Rutsch W., Sechtem U., Sigel H.A., Simon R., Von Schacky C., Winkelmann B.R.
Greece: Avgeropoulou C., Christakos S., Feggos S., Floros S., Fotiadis I., Goudevenos I., Kardara D., Karidis C., Koliopoulos N., Kremastinos D., Lekakis I., Manolis A., Pyrgakis V., Papanikolaou C., Papasteriadis E., Skoufas P., Stravrati A., Stavridis A., Syribeis S., Vardas P., Vassiliadis I., Voudris V., Zobolos S.
Hungary: Berenyi I., Edes I., Janosi A., Kalo E., Karpati P., Kornel S., Pap I., Polak G., Reiber I., Rusznak M., Tarjan J., Timar S., Toth K.
Ireland: Barton J., Crean P., Daly K., Kearney P., Meany T.B., Mulcahy D., Quigley P.
Italy: Antolini R., Azzolini P., Bellone E., Branzi A., Brunelli C., Capponi E., Capucci A., Casaccia M., Cecchetti E., Ceci V., Celegon L., Colombo A., Corsini G., Cucchini F., Dalla Volta S., De Caterina R., De Luca I., De Servi S., Di Donato M., di Giacomo U., Di Pasquale G., Fiorentini C., Gaddi O., Giannetto M., Giannuzzi P., Giordano A., Giovannini E., Guarnierio M., Iacono A., Inama G., Leghissa R., Lorusso R., Marinoni G., Marzilli M., Mauri F., Mosele G.M., Papi S., Pela G., Pettinati G., Polimeni M.R., Portaluppi F., Proto C., Renaldini E., Riva S., Sanguinetti M., Santini M., Severi S., Sinagra G., Tantalo L., Tavazzi L., Vajola S.F., Volterrani M.
Latvia: Ansmite B., Gailiss E., Gersamija A., Kalnins U., Ozolina M.A.
Lithuania: Baubiniene A., Berukstis E., Grigoniene L., Kibarskis A., Kirkutis A., Marcinkus R., Milvidaite I., Vasiliauskas D.
The Netherlands: Aalders J.C.A., Bruggeling W.A.J., De Feyter P.J., De Leeuw M.J., De Waard D.E.P., De Weerd G.J., De Zwaan C., Dijkgraaf R., Droste H.T., Freericks M.P., Hagoort-Kok A.W., Hillebrand F., Jap W.T.J., Jochemsen G.M., Kiemeney F., Kuijer P.J.P., Mannaerts H.F.J., Piek J.J., Saelman J.P.M., Slob F.D., Smits W.C.G., Suttorp M.J., Tan T.B., Van Beek G.J., Van Den Merkhof L.F.M., Van Der Heyden R., Van Hessen M.W.J., Van Langeveld R.A.M., Van Nierop P.R., Van Rey F.J.W., Van Straalen M.J., Vos J., Werner H.A., Westendorp J.J.C.
Norway: Erikssen J.
Poland: Achremczyk P., Adamus J., Baska J., Boliska-So
tysiak H., Bubi
ski R., Ceremu
y
ski L., Cie
li
ski A., Dariusz D., Drozdowski P., Dubiel J.S., Galewicz M., Halawa B., Janion M., Jaworska K., Kaszewska I., Kleinrok A., Kornacewicz-Jach Z., Krawczyk W., Krynicki R., Krzciuk M., Krzemi
ska-Paku
a M., Kuch J., Ku
niar J., Liszewska-Pfejfer D.,
oboz-Grudzie
K., Musia
W., Opolski G., Pasyk S., Piwowarska W., Pulkowski G., Ru
y
o W., Rynkiewicz A., Sinkiewicz W., Skura M., S
owi
ski S.,
mielak-Korombel W., Targo
ski R., Templin W., Tendera M., Tracz W., Trusz-Gluza M., Wodniecki J., Zalewski M., Zinka E.
Portugal: Carrageta M., Coelho Gil J., Ferreira R., Leitao Marques A., Santos Andrade C.M., Seabra-Gomes R.
Slovakia: Bada V., Belicova M., Dukat A., Kaliska G., Kamensky G., Micko K., Mikes Z., Palinsky M., Pella D., Renker B., Riecansky I., Sefara P., Sojka G., Sulej P., Szakacs M.
Spain: Aguirre Salcedo J.M., Alonso Orcajo N., Ancillo Garcia P., Auge Sanpera J.M., Ayuela Azcarate J., Bardaji Mayor J.L., Bertomeu Martinez V., Blanco Coronado J.L., Bosa-Ojeda F., Bros Caimari R., Bruguera Cortada J., Caparros Valderrama J., Del Rio Ligorit A., Espinosa Caliani J.S., Fernandez Aviles F., Garcia Guerrero J.J., Garcia Lopez D., Gonzalez Cocina E., Guallar Urena C., Jodar Lorente L., Lopez Garcia-Aranda V., Macaya De Miguel C., Maroto Montero J., Martinez Romero P., Mate Benito I., Navarro Lopez F., Noriega Peiro F., Olague De Ros J., Orellana Mas J., Paz Bermejo M.A., Placer Peralta L.J., Rodriguez Padial L., Salvador Sanz A., Segui Bonnin J., Simarro Martin E., Valles Belsue F.
Sweden: Ekdahl S., Erhardt L., Forslund L., Ohlin H.
Switzerland: Pieper M., Moccetti T.
Turkey: Acartürk E., Guzelsoy D., Oto A., Özsaruhan O., Turkoglu C.
UK: Adgey A.A.J., Ahsan A., Al-Khafaji M., Ball S.G., Birkhead J., Boon N., Brack M., Bridges A., Buchalter M., Calder B., Cooke R.A., Corr L., Cowell R., Curzen N.P., Davidson C., Davies J., De Belder M.A., Dhiya L., Doig J.C., Findlay I.N., Fox K.M., Francis C.M., Glancy J.M., Greenwood T.W., Groves P., Hall A.S., Hamilton G., Haq I., Hillman R., Hubbard W., Hudson I., Hutton I., Ilsley C., Innes M., James M., Jennings K., Johnston G., Jones C.J.H., Joy M., Keeling P., Kooner J., Lawson C., Levy R.D., Lip G., Mclachlan B., Montgomery H.E., Morley C.A., Murdoch D. L., Muthusamy R., Oakley G.D.G., Penny W., Percival R., Purvis J., Pye M.P., Ramsdale D., Roberts D. H., Rozkovec A., Salmassi A.M., Saltissi S., Sardar S., Shapiro L.M., Schofield P. M., Stephens J., Shakespeare C., Srivastava S., Swan J.W., Tildesley G., Travill C., Wilkinson P.R.
Study Organisation
Interact, Brescia, Italy, London, UK, Rhoon, The Netherlands (monitoring), Cardialysis, Rotterdam, The Netherlands (data management) and Servier, Paris-France (study management and Sponsor)
Servier Management Group
Fratacci M.D., Lerebours G.
Data Management Group (Cardialysis)
Jaap Deckers
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