aDatabase did not include the number of individuals screened for study participation or the number excluded before randomization.
bReasons were not provided.
cA primary end point event (coronary heart disease death, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) occurred prior to withdrawal of consent in 11 of the 109 in the darapladib group and in 12 of the 111 in the placebo group.
dA primary end point event (coronary heart disease death, myocardial infarction, or urgent coronary revascularization for myocardial ischemia) occurred prior to loss to follow-up in 1 of the 43 in the darapladib group and in 4 of the 41 in the placebo group.
Cumulative incidence curves for the primary end point of coronary heart disease death, myocardial infarction, or urgent coronary revascularization for myocardial ischemia. HR indicates hazard ratio.
Prespecified subgroups of interest for the primary composite end point of coronary heart disease death, myocardial infarction, or urgent coronary revascularization for myocardial ischemia.
eAppendix 1. SOLID-TIMI 52 trial - Trial Leadership & Investigators
eAppendix 2. Inclusion and Exclusion Criteria
eAppendix 3. Clinical End Point Definitions
eFigure 1. Cumulative Incidence Curves for the Secondary Endpoint CV Death, MI or Stroke
eFigure 2. Subgroups of Interest for the Secondary Composite Endpoint of CV Death, MI or Stroke
eTable. Summary of MI According to the Universal Classification of MI by Randomized Treatment Arm
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O’Donoghue ML, Braunwald E, White HD, et al. Effect of Darapladib on Major Coronary Events After an Acute Coronary Syndrome: The SOLID-TIMI 52 Randomized Clinical Trial. JAMA. 2014;312(10):1006–1015. doi:10.1001/jama.2014.11061
Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to be involved in atherogenesis through pathways related to inflammation. Darapladib is an oral, selective inhibitor of the Lp-PLA2 enzyme.
To evaluate the efficacy and safety of darapladib in patients after an acute coronary syndrome (ACS) event.
Design, Setting, and Participants
SOLID-TIMI 52 was a multinational, double-blind, placebo-controlled trial that randomized 13 026 participants within 30 days of hospitalization with an ACS (non–ST-elevation or ST-elevation myocardial infarction [MI]) at 868 sites in 36 countries.
Patients were randomized to either once-daily darapladib (160 mg) or placebo on a background of guideline-recommended therapy. Patients were followed up for a median of 2.5 years between December 7, 2009, and December 6, 2013.
Main Outcomes and Measures
The primary end point (major coronary events) was the composite of coronary heart disease (CHD) death, MI, or urgent coronary revascularization for myocardial ischemia. Kaplan-Meier event rates are reported at 3 years.
During a median duration of 2.5 years, the primary end point occurred in 903 patients in the darapladib group and 910 in the placebo group (16.3% vs 15.6% at 3 years; hazard ratio [HR], 1.00 [95% CI, 0.91-1.09]; P = .93). The composite of cardiovascular death, MI, or stroke occurred in 824 in the darapladib group and 838 in the placebo group (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78). There were no differences between the treatment groups for additional secondary end points, for individual components of the primary end point, or in all-cause mortality (371 events in the darapladib group and 395 in the placebo group [7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Patients were more likely to report an odor-related concern in the darapladib group vs the placebo group (11.5% vs 2.5%) and also more likely to report diarrhea (10.6% vs 5.6%).
Conclusions and Relevance
In patients who experienced an ACS event, direct inhibition of Lp-PLA2 with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events.
clinicaltrials.gov Identifier: NCT01000727
Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been hypothesized to play a causal role in the development of atherosclerosis and to contribute to plaque instability through pathways related to inflammation.1 A number of epidemiologic studies have shown that higher circulating levels of Lp-PLA2 activity or mass are associated with an increased risk of coronary events in primary and stable secondary prevention cohorts.2 Lp-PLA2 has been shown to be highly concentrated in unstable and ruptured atherosclerotic plaques.3 Further, in 2 case-control studies, natural deficiency of Lp-PLA2 activity due to carriage of the V279F null allele in the Lp-PLA2 gene was associated with a lower risk of developing coronary heart disease (CHD).4
Darapladib is a selective Lp-PLA2 inhibitor that reduces Lp-PLA2 activity in plasma5 and in atherosclerotic plaques.6 In phase 2 testing, darapladib did not modify total coronary atheroma volume when compared with placebo on a background of statin therapy, but it appeared to prevent necrotic core expansion as assessed by intravascular ultrasound virtual histology.7 In the STABILITY trial (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy), darapladib did not significantly reduce the primary end point of cardiovascular death, myocardial infarction (MI), or stroke in patients with stable CHD (hazard ratio [HR], 0.94 [95% CI, 0.85-1.03]; P = .20); however, darapladib nominally reduced the occurrence of secondary end points including major coronary events (HR, 0.90 [95% CI, 0.82-1.00]; P = .045) and total coronary events (HR, 0.91 [95% CI, 0.84-0.98]; P = .02).8 The current phase 3 trial evaluated the efficacy and safety of darapladib on a background of optimal medical therapy in patients recently hospitalized with acute coronary syndrome (ACS).
The study design of the the SOLID-TIMI 52 trial (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52; ClinicalTrials.gov NCT 01000727) has been previously described.9 The design was a double-blind, placebo-controlled phase 3 trial that was conducted at 868 sites in 36 countries (eAppendix in Supplement 1). The protocol (Supplement 2) was approved by the relevant institutional review boards or ethics committees and all participants gave written informed consent.
Patients were considered eligible for enrollment if they had been hospitalized with an ACS event in the 30 days prior to randomization (unstable angina, non–ST-elevation MI, and ST-elevation MI; Figure 1 and eAppendix 2 in Supplement 1). All participants were required to have at least 1 additional predictor of cardiovascular risk including age of at least 60 years, history of MI prior to the qualifying event, significant renal dysfunction (estimated glomerular filtration rate 30-59 mL/min/1.73 m2), diabetes mellitus requiring pharmacotherapy, or polyvascular disease (including carotid or peripheral arterial disease). For patients in whom a percutaneous coronary intervention (PCI) was planned, the procedure was to be completed prior to randomization whenever possible.
Relevant exclusion criteria included planned or completed coronary artery bypass graft (CABG) surgery for the qualifying event (due to an anticipated low event rate during follow-up), current liver disease, severe renal impairment (eGFR<30 mL/min/1.73 m2), New York Heart Association class III or IV heart failure, poorly controlled hypertension or asthma, a history of severe allergic reaction or anaphylaxis, and life expectancy of less than 2 years due to a condition other than cardiovascular disease. Exclusions on the basis of poorly controlled hypertension or asthma or severe allergic reactions were based on theoretical concerns of the study drug that were not confirmed in clinical testing.
After providing informed consent, participants were assigned using a permuted block randomization without stratification through a telephone-based interactive voice response system to once-daily enteric-coated darapladib 160 mg orally or matching placebo to be swallowed whole and taken with food. Since the efficacy of darapladib could vary by ethnicity and race, this information was self-reported by study participants at randomization according to prespecified categories and captured in the electronic case-report form. After randomization, patients were to be seen at clinic visits for routine clinical and laboratory assessments at months 1, 3, 6, and every 6 months thereafter. Beginning at month 9, telephone visits were also conducted every 6 months between clinic visits. The use of guideline-recommended therapies for patients after an ACS event was strongly recommended throughout the course of the trial. Biannual performance reports were provided to investigators that summarized adherence to standard of care therapies and treatment goals.
In December 2013, the SOLID-TIMI 52 executive committee reviewed data from the recently completed STABILITY trial prior to the unblinding or closure of the SOLID-TIMI 52 database.8 Observations from the STABILTY trial suggested that darapladib may modify the incidence of major and total coronary events, but not the incidence of noncoronary vascular events including stroke.
On the basis of these external results that potentially informed upon the efficacy of darapladib, the executive committee voted to revise the statistical analysis plan for the SOLID-TIMI 52 trial to amend the primary end point. This decision was made without communication from the independent data monitoring committee to the executive committee and while all members remained blinded to the SOLID-TIMI 52 results; the independent data monitoring committee was subsequently informed of the decision. The prior secondary end point of major coronary events (CHD death, MI, or urgent coronary revascularization for myocardial ischemia) became the primary end point of the trial. In turn, the composite of cardiovascular death, MI, or stroke became a secondary end point. The number of reported primary end point events was relatively comparable under both definitions and therefore the end point change did not substantially affect the power to evaluate the primary hypothesis. The study protocol was amended to reflect these changes. All interim analyses were conducted prior to the amendment. The sponsor informed the US Food and Drug Administration, the European Medicines Agency, and the Japanese Pharmaceuticals and Medical Devices Agency of the change.
An independent and blinded clinical events committee adjudicated all reported deaths (including deaths reported through vital status searches), cardiac ischemic events (including urgent coronary revascularization for myocardial ischemia), cerebrovascular events, hospitalizations for heart failure, and gastrointestinal neoplasms and polyps. Cardiovascular end point definitions are provided in eAppendix 3 in Supplement 1. All deaths that were unwitnessed were assumed to be cardiovascular in etiology unless a noncardiovascular cause could be determined. As prespecified, coronary revascularization events that were planned prior to randomization but occurred postrandomization were excluded from the coronary revascularization end point definition.
The primary efficacy analysis was conducted in the intention-to-treat population and included all randomized participants. Patients who were event free and who subsequently withdrew consent or were lost to follow-up were censored for the primary end point on the date that primary end point events were last assessed. Complete details are provided in the Reporting and Analysis Plan in Supplement 2. Safety analyses were conducted among patients who received at least 1 dose of study drug. Cox proportional hazards regression models were used to assess the effect of darapladib on the primary end point and additional time-to-event outcomes. For the on-treatment analysis, patients who took the study drug and did not experience an end point event were censored 1 day following the last dose of the study drug. A prespecified landmark analysis examined the rates of the primary end point from randomization to 12 months and beyond 12 months of follow-up. Patients with a primary end point event prior to 12 months were excluded from the post 12-month analysis. A generalized estimating equations model with repeated measures was used to assess the change in blood pressure over time with covariates that included treatment group, study visit, baseline value, treatment group by visit, and baseline value by visit interactions.
When the study was initially designed, it was determined that 1500 events would be required to yield 90% power to detect a 15.5% reduction in the risk of the primary end point (HR = 0.845) for participants treated with darapladib compared with placebo. On the basis of 2 planned interim analyses, the primary end point was assessed at a threshold of significance of P value less than .049 after applying a flexible α-spending function. At the time of study design, the median duration of follow-up was anticipated to be approximately 3 years. Cumulative event rates were calculated using the Kaplan-Meier method at 3 years. All CIs were 2-sided with a 95% confidence level. Tests for subgroup interaction were considered exploratory and assessed at a prespecified nominal P value of less than .10. All reported P values were 2-sided. Statistical analyses were conducted at the TIMI Study Group and sponsor using SAS statistical software, version 9.
From December 7, 2009, until October 28, 2011, a total of 13 026 participants were randomized into the SOLID-TIMI 52 trial at 868 centers in 36 countries. The longest duration of follow-up was 3.8 years with a median follow-up of 2.5 years (interquartile range [IQR], 2.1-2.8 years). There were 31 167 total patient-years of follow-up.
The final disposition of all study participants is summarized in Figure 1. Vital status after July 1, 2013, was ascertained in 99.6% of all randomized participants. At study conclusion, there were 13 participants who were lost to follow-up without known vital status. Vital status was ascertained for an additional 71 patients who were classified as lost prior to the close out period; of these patients, 10 had died. During the course of the study, 220 patients withdrew consent (0.7 per 100 person-years) of whom vital status at the end of the trial was obtained in 186 using publically available records (wherever permitted by local law). The numbers of patients who were lost to follow-up or who withdrew consent was similar between treatment groups (Figure 1).
Baseline characteristics were well balanced between treatment groups (Table 1). The median age of the study population was 64 years and 74.5% of patients were men. The qualifying ACS event was ST-elevation MI in 45.2%, non–ST-elevation MI in 42.7%, and unstable angina in 12.2% of participants. In the course of treatment for the index event, 86.0% underwent cardiac catheterization and 76.7% underwent PCI prior to randomization. The median time between the date of hospitalization for the qualifying event and randomization was 14 days. At the baseline visit, 94.6% of patients were receiving a statin and 46.1% were recorded to have been taking a statin for at least 8 weeks prior to randomization. The median low-density lipoprotein (LDL) cholesterol concentration was 74.9 mg/dL (interquartile range [IQR], 57.1-96.9 mg/dL). The use of other evidence-based therapies for patients after ACS was comparably high (>85% for each type of medication, including high proportions of patients using aspirin, a β-blocker, and a P2Y12 inhibitor at randomization), and well-balanced between treatment groups (Table 1).
At the end of follow-up, the primary end point of major coronary events (CHD death, MI, or urgent coronary revascularization for myocardial ischemia) had occurred in 903 of 6504 participants in the darapladib group and 910 of 6522 participants in the placebo group (16.3% vs 15.6% at 3 years; HR, 1.00 [95% CI, 0.91-1.09]; P = .93; Figure 2, Table 2). The secondary end point of cardiovascular death, MI, or stroke occurred in 824 darapladib-assigned participants and 838 placebo-treated patients (15.0% vs 15.0% at 3 years; HR, 0.99 [95% CI, 0.90-1.09]; P = .78; eFigure 1 in Supplement 1). There were no statistically significant differences between treatment groups in the incidence and number of events for the individual components of the primary end point or additional secondary end points (Table 2). The risk of all-cause mortality was similar between the treatment groups and occurred in 371 patients in the darapladib group and 395 patients in the placebo group (7.3% vs 7.1% at 3 years; HR, 0.94 [95% CI, 0.82-1.08]; P = .40). Additional efficacy end points are reported in Table 2. The number of MI events by treatment group, according to the Universal Classification of MI,10 is shown in the eTable in Supplement 1.
At a prespecified threshold of P value less than .10, there was no evidence of heterogeneity across the majority of prespecified subgroups including age, region, renal dysfunction, and other comorbid conditions for the primary end point (Figure 3). An interaction of nominal significance was observed on the basis of sex (P value for interaction = .04) and race (P value for interaction = .07). No gradient of efficacy for darapladib vs placebo was observed for patients with higher baseline LDL cholesterol concentrations (P value for interaction = .17) or higher baseline Lp-PLA2 activity (P value for interaction = .98). The treatment interaction on the basis of sex was no longer significant when the secondary end point of cardiovascular death, MI, or stroke was examined (P value for interaction = .29; eFigure 2 in Supplement 1).
The incidence of any serious adverse event was similar between treatment groups (Table 3). Any adverse event leading to drug discontinuation was 17% in the darapladib group and 12% in the placebo group. Consistent with prior studies, patients treated with darapladib were more likely to report an odor-related concern than those in the placebo group (predominantly odor of the feces, urine, and skin; 11.5% vs 2.5%) and diarrhea (10.6% vs 5.6%) and these concerns contributed to a higher rate of study drug discontinuation in the darapladib group. The incidence of malignancy was similar for patients randomized to darapladib or placebo (Table 3). The change in blood pressure was similar between treatment groups with a trend toward a smaller increase in systolic blood pressure over time for patients taking darapladib compared with those in the placebo group (adjusted mean difference between treatment groups, −0.8 mmHg [95% CI, −1.4 to −0.2]; P = .01). Darapladib did not have a significant effect over time on LDL cholesterol (P = .98), HDL cholesterol (P = .25), or triglycerides (P = .97), as compared with placebo.
As a sensitivity analysis, an ontreatment analysis was conducted; darapladib did not reduce the risk of major coronary events (CHD death, MI, or urgent coronary revascularization for myocardial ischemia) for patients while taking the study drug (HR, 0.98 [95% CI, 0.89-1.08]; P = .67).
Since early events after ACS may not have been modifiable with an antiinflammatory therapeutic, a prespecified landmark analysis was conducted. Darapladib did not reduce the incidence of major coronary events from the time of randomization to 12 months (HR, 1.04 [95% CI, 0.92-1.16]) or events that occurred from 12 months through long-term follow-up (HR, 0.94 [95% CI, 0.81-1.09]).
In patients who were stabilized after an ACS event, darapladib did not reduce the risk of recurrent major coronary events through a median of 2.5 years of follow-up when added to existing guideline-recommended therapies. Further, darapladib did not reduce the risk of any cardiovascular end point, including any of the individual components of the primary end point. These results were consistent across key subgroups including those stratified by baseline LDL cholesterol concentration and baseline Lp-PLA2 activity level. Our findings therefore do not support a strategy of targeted Lp-PLA2 inhibition with darapladib in patients stabilized after an ACS event who are similar to those enrolled into this trial.
Prior to the current study, there was evidence to support the theory that inhibition of the Lp-PLA2 enzyme would translate into clinical benefit. LpPLA2 is known to hydrolyze oxidized LDL particles leading to the production of byproducts that have been shown through in vitro experiments to exert proinflammatory and proapoptotic effects.11-13 Lp-PLA2 has been identified in unstable and ruptured plaques3 and is strongly expressed in macrophages in lesions prone to rupture.14 Further, direct inhibition of Lp-PLA2 activity has been shown to inhibit progression to advanced coronary atherosclerotic lesions in diabetic and hypercholesterolemic swine.15 In phase 2 testing, darapladib appeared to stabilize the necrotic core size in coronary atherosclerotic plaques as compared with placebo; however, it did not modify atheroma volume.7 Although not a demonstration of causality, epidemiologic data have shown that higher Lp-PLA2 activity and mass are associated with an increased risk of cardiovascular events in stable individuals, independent of clinical risk factors.2 However, the epidemiologic data have not always been consistent and the role that Lp-PLA2 may play in atherogenesis has often been disputed. Although 2 large case-control studies in South Korean males demonstrated that individuals with reduced Lp-PLA2 activity due to carriage of the V279F null allele were at lower risk of developing CHD,4 prior genetic studies yielded conflicting results.1 In addition, inhibition of Lp-PLA2 with darapladib has not been shown to significantly reduce other markers of inflammation such as C-reactive protein.5,7
Despite the aforementioned preclinical and observational data that suggested that Lp-PLA2 may contribute to the progression of atherosclerosis, the current study of more than 13 000 patients with ACS demonstrated no clinical efficacy for the Lp-PLA2 inhibitor darapladib. Therefore, a key question is whether these findings definitively inform upon the role that Lp-PLA2 may play in atherogenesis.
In the STABILITY trial, darapladib also did not achieve a reduction in the primary end point of cardiovascular death, MI, or stroke (HR, 0.94 [95% CI, 0.85-1.03]; P = .20), yet directionally favorable signals were observed to suggest that darapladib may reduce the risk of coronary events in patients with stable CHD. Specifically, in the STABILITY trial, darapladib reduced the risk of major coronary events (HR, 0.90 [95% CI, 0.82-1.00]; P = .045) and total coronary events (HR, 0.91 [95% CI, 0.84-0.98]; P = .02).8 Although a nominal reduction in these 2 secondary end points could only be considered exploratory, the findings appeared biologically plausible.
However, these observations were not confirmed in the current study. Moreover, a signal of efficacy was not observed when a landmark analysis was conducted to evaluate the drug’s efficacy once patients were stabilized for 12 months beyond their ACS event. Nonetheless, it remains possible that differences in the study populations and the duration of follow-up between the 2 phase 3 trials of darapladib may have contributed to the lack of apparent benefit in the current clinical trial. Prior studies have demonstrated that Lp-PLA2 mass and activity are not prognostic when assessed early after hospitalization with ACS,16,17 but are associated with an increased risk of cardiovascular events in patients with stable CHD.16,18-20 Supporting these prior observations, baseline Lp-PLA2 activity levels were not associated with a treatment benefit with darapladib in the current study; although tests for subgroup interactions were relatively underpowered.
However, 2 large clinical trials of darapladib have now failed to significantly reduce the risk of future cardiovascular events. Although these results do not support a role for Lp-PLA2 as a direct therapeutic target, it may be challenging to demonstrate incremental benefit for an Lp-PLA2 inhibitor beyond existing therapies for the management of ACS. In particular, in addition to their favorable effects on lipid parameters, statins reduce Lp-PLA2 activity and mass to an extent that cannot be predicted based on the change in LDL concentration alone.15 In addition, although unlikely, the possibility that Lp-PLA2 remains an important target cannot be excluded, but variable plaque penetration of the drug or unidentified off-target effects of darapladib could be responsible for the absence of efficacy in the current study.
Although the current trial did not demonstrate clinical efficacy for darapladib, there are limitations that can be considered. The study design did not screen patients on the basis of their Lp-PLA2 activity levels; therefore, this study cannot exclude the possibility that patients with higher baseline levels of Lp-PLA2 activity would benefit from treatment. However, a gradient of efficacy was not observed when groups were stratified on the basis of Lp-PLA2 activity. The study also did not target a specific degree of Lp-PLA2 inhibition; however, the 160-mg dose of darapladib is anticipated to achieve an approximate 66% reduction in Lp-PLA2 activity on a background of statin therapy. In addition, many cardiovascular events occurring early after ACS may relate more to thrombotic mechanisms and may not be modifiable through Lp-PLA2 inhibition, which could have limited the ability of this study to detect a difference. However, clinical efficacy was not observed through 2.5 years of follow-up.
Overall, these results highlight some of the challenges that may occur during the development of novel therapeutics that are directed toward the inflammatory cascade. In particular, inflammation acts along many complex and redundant pathways that may attenuate the utility of blocking highly specific targets. Further, reliable surrogate end points are lacking to gain insights into a drug’s efficacy prior to phase 3 testing. Although promising advances have been made in imaging modalities that allow for detailed plaque assessment, whether these surrogate end points can be translated into clinical events remains unknown.
Among patients who experienced an ACS event, direct Lp-PLA2 inhibition with darapladib added to optimal medical therapy and initiated within 30 days of hospitalization did not reduce the risk of major coronary events through 2.5 years of follow-up.
Group Information: A list of the SOLID-TIMI 52 Investigators is included in Supplement 1.
Corresponding Author: Michelle L. O’Donoghue, MD, MPH, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, 350 Longwood Ave, First Floor, Boston, MA 02115 (firstname.lastname@example.org).
Published Online: August 31, 2014. doi:10.1001/jama.2014.11061.
Author Contributions: Dr O’Donoghue 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.
Study concept and design: O’Donoghue, Braunwald, White, Lukas, Tarka, Hochman, Bode, Davies, Crugnale, Watson, Serruys, Cannon.
Acquisition, analysis, or interpretation of data: O’Donoghue, Braunwald, Steen, Lukas, Tarka, Steg, Im, Shannon, Davies, Murphy, Wiviott, Bonaca, Watson, Weaver, Cannon.
Drafting of the manuscript: O’Donoghue, Steen, Im, Murphy.
Critical revision of the manuscript for important intellectual content: O’Donoghue, Braunwald, White, Steen, Lukas, Tarka, Steg, Hochman, Bode, Shannon, Davies, Murphy, Wiviott, Bonaca, Weaver, Serruys, Cannon.
Statistical analysis: O’Donoghue, Steen, Im, Shannon, Davies, Murphy, Cannon.
Obtained funding: Braunwald, Cannon.
Administrative, technical, or material support: Steen, Crugnale, Bonaca, Watson, Cannon.
Study supervision: O’Donoghue, Braunwald, White, Steen, Lukas, Tarka, Steg, Bonaca, Watson, Weaver, Serruys, Cannon.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr O’Donoghue reports institutional grants from GlaxoSmithKline, Eisai, and AstraZeneca; honoraria from diaDexus; and consulting fees from Aegerion. Dr Braunwald reports grants to his institution from GlaxoSmithKline during the conduct of the study; and for outside the submitted work, a grant to his institution from Merck Sharpe & Dohme, Bristol-Myers-Squibb, Duke University, AstraZeneca, Johnson & Johnson, and Sanofi-Aventis; uncompensated consultancies and lectures for Merck Sharpe & Dohme; consultancies with The Medicines Company and Sanofi-Aventis; and honoraria for lectures from Menarini International, Medscape, Bayer, and Daiichi Sankyo. Dr White reports receipt of grants from Sanofi-Aventis, Eli Lilly, The Medicines Company, National Institutes of Health, Roche, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, and Daiichi Sankyo; and consultancies with AstraZeneca, Merck Sharpe & Dohme, Roche, and Regado Biosciences. Dr Steen reports receipt of consulting fees from Regeneron and Sanofi-Aventis. Drs Tarka and Lukas, and Messrs Davies and Watson report receipt of personal fees from GlaxoSmithKline during the conduct of the study and also receipt of personal fees from GlaxoSmithKline outside the submitted work. Drs Tarka and Lukas, Messrs Davies and Watson, and Ms Shannon report being employees of GlaxoSmithKline. Dr Steg reports receipt of honoraria from GlaxoSmithKline for steering committee membership; and personal fees from Amarin, AstraZeneca, Bayer, Boehringer-Ingelheim, Bristol-Myers-Squibb, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck Sharpe & Dohme, Novartis, Otsuka, Pfizer, Roche, Sanofi-Aventis, Servier, The Medicines Company, and Vivus; research grants from the NYU School of Medicine, Sanofi-Aventis, and Servier; and stockholdership in Aterovax. Dr Hochman reports receipt of honoraria from GlaxoSmithKline during the conduct of the study. Dr Bode reports receipt of personal fees from AstraZeneca, Bayer, Boehringer-Ingelheim, Daiichi Sankyo, and Sanofi-Aventis. Dr Maggioni reports receipt of honoraria from GlaxoSmithKline; and grants for steering committee participation from Novartis, Bayer, Abbott Vascular, Cardiorentis. Mss Murphy and Crugnale report receipt of grants from GlaxoSmithKline, during the conduct of the study. Dr Wiviott reports receipt of research grants and consulting fees from AstraZeneca, Bristol-Myers-Squibb, Eisai, Arena, and Eli Lilly/Daiichi Sankyo; research grants from Merck Sharpe & Dohme and Sanofi-Aventis; consulting fees from Aegerion, Angelmed, Janssen, Xoma, ICON Clinical, and Boston Clinical Research Institute; and grants from GlaxoSmithKline during the conduct of the study. Dr Bonaca reports receipt of a research grant to the TIMI Study Group from GlaxoSmithKline and consulting fees from AstraZeneca and Merck Sharpe & Dohme. Dr Weaver reports receipt of personal fees from GlaxoSmithKline for the cost of attending study meetings and from the TIMI Group for executive steering committee meetings. Dr Cannon reports receipt of grant support from Accumetrics, Arisaph, AstraZeneca, Boehringer-Ingelheim, Janssen, Merck Sharpe & Dohme, and Takeda; and receipt of personal fees from CSL Behring, Essentialis, Merck Sharpe & Dohme, Regeneron, Sanofi-Aventis, Takeda, Lipimedix, BMS, and Pfizer. No other disclosures were reported.
Funding/Support: The SOLID-TIMI 52 trial was funded by GlaxoSmithKline.
Role of the Sponsors: The trial was sponsored by GlaxoSmithKline and the protocol was designed by the TIMI Study Group jointly with the executive steering committee and study sponsor. The sponsor developed the statistical analysis plan jointly with the TIMI Study Group. In addition to the sponsor, the TIMI Study Group conducted all primary analyses independently using raw data (K.I. and S.A.M.) and assumes responsibility for the accuracy of the data reported in this manuscript. The manuscript was drafted by the TIMI Study Group (M.L.O.) and reviewed for intellectual content by all of the coauthors. The sponsor reviewed the manuscript and made nonbinding suggestions for consideration.
Correction: This article was corrected online September 15, 2014, for an error in the byline and in the Figure 2 title and legend.