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Major coronary event MCE was defined as death from coronary disease, nonfatal myocardial infarction, or cardiac arrest with resuscitation. Major cardiovascular disease indicates MCE plus stroke. Any coronary heart disease indicates MCE plus hospitalization for unstable angina pectoris and coronary revascularization procedures. Any cardiovascular disease indicates any of the above plus peripheral vascular disease and hospitalization for nonfatal congestive heart failure. HR indicates hazard ratio; CI, confidence interval. Dr Bendiksen is in private practice in Hamar, Norway. Context Evidence suggests that more intensive lowering of low-density lipoprotein cholesterol LDL-C than is commonly applied clinically will provide further benefit in stable coronary artery disease. Objective To compare the effects of 2 strategies of lipid lowering on the risk of cardiovascular disease among patients with a previous myocardial infarction MI. Design, Setting, and Participants The IDEAL study, a prospective, randomized, open-label, blinded end-point evaluation trial conducted at ambulatory cardiology care and specialist practices in northern Europe between March and March with a median follow-up of 4. Main Outcome Measure Occurrence of a major coronary event, defined as coronary death, confirmed nonfatal acute MI, or cardiac arrest with resuscitation. A major coronary event occurred in simvastatin patients Nonfatal acute MI occurred in 7. Major cardiovascular events occurred in and in the 2 groups, respectively HR, 0. Occurrence of any coronary event was reported in simvastatin and atorvastatin patients HR, 0. Noncardiovascular death occurred in 3. Death from any cause occurred in 8. Patients in the atorvastatin group had higher rates of drug discontinuation due to nonserious adverse events; transaminase elevation resulted in 43 1. Serious myopathy and rhabdomyolysis were rare in both groups. Conclusions In this study of patients with previous MI, intensive lowering of LDL-C did not result in a significant reduction in the primary outcome of major coronary events, but did reduce the risk of other composite secondary end points and nonfatal acute MI. There were no differences in cardiovascular or all-cause mortality. Patients with MI may benefit from intensive lowering of LDL-C without an increase in noncardiovascular mortality or other serious adverse reactions. Lowering of low-density lipoprotein cholesterol LDL-C with statins has in the last decade become part of the standard treatment regimen in patients with established coronary heart disease CHD. A detailed description of the study design and baseline characteristics of the patients has been published elsewhere. Records of patients previously treated at the centers were screened for the main eligibility criteria. Potentially eligible patients were invited for a screening visit. Written informed consent was obtained from all patients, and the study was approved by the national or regional review board in all countries and by governmental reimbursing institutions in countries where the main sponsor did not cover all costs. Men and women aged 80 years or younger with a history of a definite myocardial infarction and who qualified for statin therapy according to national guidelines at the time of recruitment were eligible. Study medication was assigned via a central interactive voice response system ClinPhone, Nottingham, England. Allocation numbers were given out in blocks of Allocation was balanced by center; no other stratification was used. There was no run-in or washout period. Study medication was provided by prescription except in Finland, where it was dispensed at the expense of the sponsor. Patients were followed up at the centers after 12 and 24 weeks and every 6 months thereafter. All lipid and lipoprotein levels were measured from fasting blood samples. Such measurements, along with liver enzymes and other laboratory measurements, were made at baseline, at 12 and 24 weeks, at 1 year, and yearly thereafter. All measurements were made at a central laboratory. The results of lipid and lipoprotein measurements were not revealed to study personnel during the study except in cases of titration of simvastatin at 24 weeks. The primary clinical outcome was time to first occurrence of a major coronary event, defined as coronary death, hospitalization for nonfatal acute myocardial infarction, or cardiac arrest with resuscitation. In addition, individual components of the composite end points were also prespecified as secondary outcomes, as was all-cause mortality. In addition to per-protocol reporting by investigators, monitors reviewed patient records at regular intervals to search for potential end points. An end-point classification committee blindly reviewed reports on potential end points and adjudicated outcomes at regular meetings. All reports were first screened by an independent center Inveresk, Raleigh, NC for blinding of treatment allocation. Because the risk of the patients first recruited was recalculated to be lower than first anticipated, the originally planned sample size of patients was increased to The study was initiated by the investigators and scientifically led by a steering committee consisting of independent researchers and investigators and 3 members employed by the sponsor. Monitoring of data collection was provided by the sponsor. A contract research organization Covance, Horsham, England reviewed the data for errors and inconsistencies and sent queries to the investigators for clarification. This organization provided the interim reports for the data and safety monitoring board. The final statistical analysis was performed by the sponsor. An independent academic statistician of the steering committee I. Kaplan-Meier hazard rates were used to examine incidence over time and the log-rank test was used to assess group differences. All analyses in this report are based on the intention-to-treat principle including all randomized patients. Of these, met the eligibility criteria and were randomized Figure 1. The median follow-up time was 4. Six patients were lost to follow-up and 48 patients withdrew consent prior to study close, but vital status was known for 35 of these at the close of the study. Data for these patients have been included in the analysis for the period prior to loss or withdrawal. Vital status at the end of the trial is thus unknown for 19 patients. Baseline characteristics were well balanced between the 2 treatment groups Table 1. The median time since last myocardial infarction was 22 months in the simvastatin group and 21 months in the atorvastatin group. Most patients who stopped taking the study drug switched to a different statin. In the simvastatin group, patients took a different statin at some point; in 2. In the atorvastatin group, patients took a different statin; in 8. Total cholesterol and triglyceride levels were also significantly lower in the atorvastatin group compared with the simvastatin group, whereas high-density lipoprotein cholesterol HDL-C levels were slightly but significantly higher in the simvastatin group. Apolipoprotein levels changed correspondingly Table 2. In December , reports of patients with a confirmed primary end point had arrived at the coordinating centers. Based on this information, the steering committee decided that the study close-out procedures should be concluded by April , when it was anticipated that the protocol-specified target of patients with a primary end point would have occurred. When all study close-out visits had been performed, a total of patients had actually experienced a primary end point. The primary end point of coronary death, acute myocardial infarction, or cardiac arrest with resuscitation occurred in patients A post hoc Cox regression analysis of the primary end point with adjustment for sex, age, statin use at randomization, duration since last myocardial infarction, total cholesterol, and HDL-C resulted in an HR of 0. A preliminary analysis of prespecified subgroups defined by sex and age did not reveal any statistically significant treatment group interactions. There were coronary deaths 4. Nonfatal myocardial infarction occurred in patients 7. The composite secondary end point of a major cardiovascular event including stroke was reduced in the atorvastatin group HR, 0. Similarly, there were reductions in the risk of nonfatal myocardial infarction, any CHD event, and any cardiovascular event. Hemorrhagic strokes occurred in 6 patients in each treatment group. Kaplan-Meier hazard rates for selected components of the secondary end points are shown in Figure 3. The risk of death from any cause was similar in both study groups HR, 0. There were no significant differences in noncardiovascular deaths between the treatment groups. In particular, mortality due to cancer was similar in the 2 groups, at 2. There were no significant differences in cancer mortality for any particular body system. There were no significant differences in the frequency of serious clinical adverse experiences between the 2 groups. There were, however, more patients in the atorvastatin group who discontinued study medication because of investigator-reported adverse effects Table 4. Elevation of liver enzyme levels occurred more frequently in the atorvastatin group, but this was not related to any increased incidence of clinical liver disease. Myalgias occurred more frequently in the atorvastatin group, but myopathy rates were exceedingly low in both the atorvastatin and simvastatin groups. There was no difference in all-cause or cardiovascular mortality. There are several possible reasons why statistical significance was not reached for the primary end point. One explanation might be insufficient difference in levels of LDL-C between the groups since the observed difference was slightly smaller than projected. A second possible explanation was that the follow-up duration was only a median of 4. A third possibility is that the effect of simvastatin on HDL-C would attenuate the difference produced by the improved effect of atorvastatin on LDL-C. However, the impact of statins on HDL-C has not yet been shown to influence patient outcomes. However, the end-point classification was conducted by a blinded clinical end-points committee with the idea of minimizing bias. The fact that most patients had to pay part of the cost of the study drug apparently did not affect prescription rates, because the cost for the patients of the 2 study drugs was identical. The apparent adherence to atorvastatin was high and better than that in other comparable trials. This also makes it difficult to make reliable comparisons of reported adverse experiences between the 2 treatment regimens. In the TNT study, the primary end point included stroke. Comparison of the broader end point of any cardiovascular events, however, reveals more similar HRs of 0. This decline in coronary mortality may well reflect improvements in coronary prevention and care during the last decade. While this improvement must be welcomed, it has made it more difficult for trialists to demonstrate further benefit in survival. In the IDEAL study, there was a small and nonsignificant excess of 13 more noncardiovascular deaths in the simvastatin group than in the atorvastatin group. Such small differences are likely to have occurred by chance. There was no difference between the groups in the frequency of adverse events that were rated as serious. There were, however, more nonserious adverse events resulting in drug discontinuation in the atorvastatin group. This difference may reflect real nontolerance to a high dose of atorvastatin, but the possibility of reporting bias is present given the open-label design of the trial. The proportion of patients in the simvastatin group who developed liver enzyme elevations was exceptionally small and was significantly lower than in the atorvastatin group. This reporting was not subject to bias, since it was performed by the central laboratory that transferred the results directly to the study database. In summary, when comparing standard and intensive LDL-C—lowering therapies in patients with previous myocardial infarction, there was no statistically significant reduction in the primary end point of major coronary events, but there was reduced risk of other composite secondary end points and nonfatal acute myocardial infarction. There were no differences in cardiovascular and all-cause mortality. The results indicate that patients with myocardial infarction may benefit from intensive lowering of LDL-C without increase in noncardiovascular mortality or other serious adverse reactions. Corresponding Author : Terje R. Author Contributions: Dr Pedersen had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Dr Kastelein has received research grants from Pfizer. Drs Olsson and Holme have received honoraria from Pfizer as steering committee members. Dr Bendiksen was previously employed by Pfizer Norway and has received honoraria from Pfizer as a steering committee member. No other disclosures were reported. That analysis confirmed all results reported in this article. Role of the Sponsor: Members of the steering committee employed by Pfizer contributed to the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript. Alsbjerg, Skive; F. Andersen, Silkeborg; L. Andersen, Randers; M. Andersen, Fredericia; N. Andersen, Slagelse; U. Andersen, Slagelse; M. Brockstedt, Silkeborg; J. Buhl, Silkeborg; L. Corell, Frederiksberg; J. Egstrup, Svendborg; P. Frandsen, Fredericia; B. Fruergaard, Roskilde; G. Glintborg, Kalundborg; T. Glud, Middelfart; L. Henriksen, Fredericia; T. Hildebrandt, Frederiksberg; E. Husic, Svendborg; N. Jakobsen, Frederiksberg; J. Jastrup, Odder; G. Jensen, Roskilde; H. Jensen, Odder; P. Jensen, Holstebro; T. Jensen, Fredericia; T. Jensen, Randers; H. Kragelund, Frederiksberg; N. Lessing, Kalundborg; K. Lomholt, Randers; H. Madsen, Kalundborg; L. Madsen, Frederiksberg; L. Madsen, Holstebro; A. Markenvard, Fredericia; A. McNair, Frederikssund; T. Melchior, Roskilde; M. Nielsen, Silkeborg; H. Nielsen, Roskilde; T. Nielsen, Esbjerg; W. Nielsen, Hvidovre; C. Nyvad, Holstebro; J. Olsen, Roskilde; M. Olsen, Frederikssund; M. Pedersen, Odder; E. Poulsen, Middelfart; M. Rasmussen, Hvidovre; V. Rasmussen, Hvidovre; C. Ravens, Fredericia; S. Ravn, Kalundborg; H. Schultz, Frederiksberg; B. Steffensen, Randers; S. Stentebjerg, Skive; T. Terkelsen, Silkeborg; P. Thomsen, Esbjerg; N. Thorball, Roskilde; J. Ulriksen, Skive; M. Vaage-Nilsen, Frederikssund; N. Alanko, Tampere; H. Gylling, Helsinki; R. Hussi, Heinola; R. Jukka, Rauma; A. Ketonen, Joensuu; R. Kettunen, Mikkeli; L. Koivunen, Lohja; A. Koponen, Lappeenranta; P. Korhonen, Rauma; M. Laakso, Kuopio; M. Lampinen, Salo; S. Lehto, Kuopio; C. Luotola, Lappeenranta; J. Miettinen, Helsinki; J. Nurminen, Joensuu; H. Oksa, Tampere; T. Pekkarinen, Vantaa; O. Puhakka, Kuopio; R. Radhakrishnan, Helsinki; M. Relas, Helsinki; J. Rinne, Tammisaari; A. Strandberg, Kerava; T. Strandberg, Helsinki; R. Sulosaari, Kerava; H. Vanhanen, Helsinki; Iceland 82 patients enrolled : J. Oddsson, Reykjavik; G. Sigurdsson, Reykjavik; G. Thorgeirsson, Reykjavik; G. Thorgeirsson, Reykjavik; the Netherlands patients enrolled : W. Aarnoudse, Eindhoven; E. Badings, Deventer; G. Bartels, Groningen; D. Basart, Hoorn; M. Baselier, Breda; G. Bech, Eindhoven; D. Beelen, Delft; P. Bernink, Groningen; E. Birkhoff-Pieters, Rotterdam; L. Bouwens, Deventer; A. Bredero, Utrecht; P. Bruijns, Goes; M. Buijs, Rotterdam; T. Cherpanath, Breda; J. Chin, Weert; P. Chin A Fo, Delft; R. Constantinescu, Breda; J. De Boo, Goes; I. Den Hartog, Ede; J. DeWarrimont-Henquet, Heerlen; H. Dunselman, Breda; R. Entjes, Eindhoven; M. Faverey, Breda; R. Feld, Heerlen; Y. Foolen, Eindhoven; M. Galjee, Enschede; H. Groeneveld, Deventer; D. Groot, Eindhoven; R. Groutars, Amsterdam; J. Hartog, Utrecht; H. Heijmen, Eindhoven; J. Henneman, Alkmaar; W. Hermans, Tilburg; F. Hersbach, Eindhoven; D. Hertzberger, Nijmegen; A. Herweijer, Zwijndrecht; N. Holwerda, Tilburg; J. Hoorntje, Zwolle; P. Huinink, Eindhoven; C. Janus, Hoorn; H. Klomps, Weert; A. Kloppenberg-Oey, Groningen; M. Kofflard, Zwijndrecht; J. Kooistra-Huizer, Delft; H. Koornstra-Wortel, Oss; J. Kragten, Heerlen; K. Krasznai, Eindhoven; P. Kuijer, Oss; K. Levert, Delft; A. Liem, Goes; D. Lok, Deventer; J. Louwerenburg, Enschede; P. Melman, Tilburg; H. Michels, Eindhoven; W. Nierop, Rotterdam; F. Nijland, Amsterdam; S. Oude Ophuis, Nijmegen; J. Peels, Alkmaar; H. Penn, Weert; J. Posma, Groningen; R. Rademaker, Eindhoven; A. Ramdat Misier, Zwolle; S. Roeffel, Eindhoven; H. Roeters Van Lennep, Goes; B. Schaafsma, Ede; J. Schroeder-Tanka, Amsterdam; A. Smeets, Eindhoven; A. Stammen, Breda; H. Suryapranata, Zwolle; L. Takens, Groningen; T. Tan, Amsterdam; F. Tietge, Deventer; P. Tilon, Hoorn; W. Tonino, Eindhoven; M. Trip, Amsterdam; Y. Tuininga, Deventer; V. Umans, Alkmaar; G. Uytdehaag, Breda; P. Van Bergen, Hoorn; B. Van den Branden, Breda; M. Van Der Schaaf, Hoorn; I. Van Eede, Assen; A. Van Es, Enschede; P. Van Kalmthout, Ede; T. Van Loenhout, Ede; R. Van Rijswijk, Tilburg; R. Van Roosmalen, Assen; M. Van Schoot, Enschede; J. Van Wijngaarden, Deventer; L. Van Woerkens, Zwijndrecht; M. Veerhoek, Rotterdam; J. Visser, Amsterdam; A. Weevers, Eindhoven; R. Weidgraaf, Enschede; R. Weijers, Eindhoven; A. Willems, Amsterdam; A. Withagen, Delft; P. Zwart, Oss; Norway patients enrolled : C. Aase, Haugesund; W. Aaser, Rud; K. Andresen, Mysen; P. Aronsen, Hammerfest; O. Aronsen, Karasjok; I. Axelsson, Notodden; M. Baisa, Notodden; H. Dalen, Levanger; R. Dalen, Hammerfest; A. Dimmen, Kristiansund; S. Dyb, Prsgrunn; K. Erchinger, Odda; H. Fadnes, Stord; S. Furnes, Hammerfest; K. Gisholt, Nesttun; S. Gravdal, Bergen; T. Graven, Levanger; S. Gudnason, Bergen; H. Hagen, Moss; B. Halvorsen, Moss; P. Hamre, Stavanger; V. Hansteen, Oslo; S. Hareide, Volda; E. Hauge, Bergen; T. Heese, Odda; K. Helander, Mo i Rana; A. Hervold, Stavanger; A. Herzog, Oslo; A. Heskestad, Molde; S. Hewitt, Oslo; V. Hognestad, Rikshospitalet, Oslo; L. Holst-Larsen, Haugesund; M. Hosseini, Bergen; A. Hurtig, Tynset; K. Janniche, Tynset; K. Johnsen, Karasjok; O. Jordal, Bergen; R. Karlsen, Stavanger; A. Kask, Bergen; J. Kjekshus, Oslo; J. Kleinau, Levanger; B. Klykken, Levanger; F. Kontny, Oslo; S. Kornstad, Sandvika; A. Koss, Jessheim; B. Kulseng, Trondheim; K. Langaker, Oslo; D. Langvoll, Hammerfest; K. Larsby, Hammerfest; T. Lid, Notodden; A. Lied, Molde; F. Lindberg, Oslo; I. Meling, Stavanger; G. Mujic, Kristiansund; L. Munk, Stavanger; S. Nabizadeh, Moss; S. Nadirpour, Haugesund; P. Nesje, Mo i Rana; S. Nitter-Hauge, Oslo; E. Omland, Flekkefjord; A. Oppdal, Bergen; T. Pedersen, Oslo; Z. Radunovic, Bergen; N. Ringdal, Molde; K. Risberg, Skedsmokorset; G. Semb, Oslo; P. Skag, Paradis; G. Skjelvan, Trondheim; J. Solli, Kristiansand; L. Sparby, Kongsvinger; T. Steen, Oslo; T. Svilaas, Kongsberg; K. Thon, Moss; R. Thorshaug, Bergen; H. Toft, Bergen; S. Tonstad, Oslo; T. Torjussen, Kristiansand; T. Torjussen, Mysen; H. Torsvik, Rud; D. Torvik, Prsgrunn; A. Totland, Haugesund; K. Valnes, Oslo; J. Von Brandis, Stavanger; B. Von Hoff, Kristiansund; F. Wandel, Odda; M. Wolff, Stavanger; A. Zalmai, Oslo; Sweden patients enrolled : L. Akravi, Fagersta; M. Alam, Stockholm; J. Appelqvist, Uddevalla; B. Atmer, Stockholm; I. Axelsson, Stockholm; J. Bastani, Stockholm; A. Berglund, Falun; P. Bhuiyan, Uddevalla; E-B. Bjurman, Lycksele; K. Carlsson, Karlstad; T. Carlsson, Vargberg; C. Dalima, Uddevalla; C. Ekholm, Ljungby; J. Ericsson, Fagersta; U-B. Fahlhammar, Sala; L. Finnas, Katrineholm; B. Frisell, Ludvika; G. Frithz, Eskilstuna; A-M. Henning, Uddevalla; J. Ingmar, Karlstad; J-H. Jamil, Karlskoga; D. Javid, Uddevalla; S. Jensen, Karlshamn; T. Jernberg, Stockholm; H. Kareld, Skene; B. Karlsson, Halmstad; B. Karlsson, Kristinehamn; J-E. Linde, Falun; M. Lindgren, Halmstad; B. Lindvall, Karlskoga; P. Lundkvist, Hudiksvall; B. Moberg, Kristinehamn; D. Moum-Nordlund, Uddevalla; P. Nilsson, Fagersta; J. Nyman, Helsingborg; K. Osika, Karlskoga; A-M. Pedersen, Helsingborg; B. Pischel, Uddevalla; B. Reinius, Kalmar; G. Renklint, Lycksele; A. Rindevall, Ludvika; A. Rindner, Skene; M. Rosenqvist, Motala; G. Salovaara, Katrineholm; R. Skarfors, Halmstad; M. Svensson, Ljungby; O. Viidas, Uddevalla; F. Wagner, Helsingborg; S. Westbom, Karlstad; C. Winger, Sala; P. Wodlin, Motala; R. Pedersen chair , O. Faergeman, J. Kastelein, A. Olsson, M. Tikkanen, I. Holme, M. Lytken Larsen, F. Bendiksen, C. Lindahl, S. Maehlum, J. Julian chair , C. Ballantyne, K. Rasmussen, H. Wedel; End Point Committee : C. Thygesen chair , B. Johannesen, P. Lund Johansen; Data Analysis : S. Auster, T. Karam, R. Chan, M. Tsai, N. Cater, B. Suri, C. Elliott, T. Thomas United States , B. Nicolaisen, I. Stenersen Norway , J. Versteden the Netherlands , B. Steenberg Denmark , P. Kindblom Sweden , P. Figure 1. Figure 2. Figure 3. Table 1. Table 2. Table 3. Table 4. Randomized trial of cholesterol-lowering in patients with coronary-heart-disease: the Scandinavian Simvastatin Survival Study 4S. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med. Intensive lipid lowering with atorvastatin in patients with stable coronary disease. Pitt B. Low-density lipoprotein cholesterol in patients with stable coronary heart disease: is it time to shift our goals? Eur Heart J. Blood Press. Am J Cardiol. Cox DR. Regression models and life-tables. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 participants in 14 randomised trials of statins. By how much and how quickly does reduction in serum-cholesterol concentration lower risk of ischemic heart disease? Holme I. Cholesterol reduction and its impact on coronary artery disease and total mortality. Cholesterol reduction yields clinical benefit: impact of statin trials. Lipid Research Clinics Program. Lipoprotein changes and reduction in the incidence of major coronary heart disease events in the Scandinavian Simvastatin Survival Study. Clinical outcomes in managed-care patients with coronary heart disease treated aggressively in lipid-lowering disease management clinics: the ALLIANCE study. J Am Coll Cardiol. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: a randomized controlled trial. Save Preferences. Privacy Policy Terms of Use. This Issue. Citations 1, View Metrics. X Facebook More LinkedIn. Original Contribution. Terje R. Study Design and Participants. Study Outcomes. Statistical Analysis. Design and Adherence. Comparison With Other Trials. Back to top Article Information. Access your subscriptions. Access through your institution. Add or change institution. Free access to newly published articles. Purchase access. Rent article Rent this article from DeepDyve. Sign in to access free PDF. Save your search. Customize your interests. Create a personal account or sign in to:. Privacy Policy. Make a comment.

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