Long-term safety and efficacy of anacetrapib in patients with atherosclerotic vascular disease.

AIMS: REVEAL was the first randomized controlled trial to demonstrate that adding cholesteryl ester transfer protein inhibitor therapy to intensive statin therapy reduced the risk of major coronary events. We now report results from extended follow-up beyond the scheduled study treatment period. METHODS AND RESULTS: A total of 30 449 adults with prior atherosclerotic vascular disease were randomly allocated to anacetrapib 100 mg daily or matching placebo, in addition to open-label atorvastatin therapy. After stopping the randomly allocated treatment, 26 129 survivors entered a post-trial follow-up period, blind to their original treatment allocation. The primary outcome was first post-randomization major coronary event (i.e. coronary death, myocardial infarction, or coronary revascularization) during the in-trial and post-trial treatment periods, with analysis by intention-to-treat. Allocation to anacetrapib conferred a 9% [95% confidence interval (CI) 3-15%; P = 0.004] proportional reduction in the incidence of major coronary events during the study treatment period (median 4.1 years). During extended follow-up (median 2.2 years), there was a further 20% (95% CI 10-29%; P < 0.001) reduction. Overall, there was a 12% (95% CI 7-17%, P < 0.001) proportional reduction in major coronary events during the overall follow-up period (median 6.3 years), corresponding to a 1.8% (95% CI 1.0-2.6%) absolute reduction. There were no significant effects on non-vascular mortality, site-specific cancer, or other serious adverse events. Morbidity follow-up was obtained for 25 784 (99%) participants. CONCLUSION: The beneficial effects of anacetrapib on major coronary events increased with longer follow-up, and no adverse effects emerged on non-vascular mortality or morbidity. These findings illustrate the importance of sufficiently long treatment and follow-up duration in randomized trials of lipid-modifying agents to assess their full benefits and potential harms. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 48678192; ClinicalTrials.gov No. NCT01252953; EudraCT No. 2010-023467-18.

Randomized Evaluation of the Effects of Anacetrapib through Lipid-modification (REVEAL)-A large-scale, randomized, placebo-controlled trial of the clinical effects of anacetrapib among people with established vascular disease: Trial design, recruitment, and baseline characteristics.

Patients with prior vascular disease remain at high risk for cardiovascular events despite intensive statin-based treatment. Inhibition of cholesteryl ester transfer protein by anacetrapib reduces low-density lipoprotein (LDL) cholesterol by around 25% to 40% and more than doubles high-density lipoprotein (HDL) cholesterol. However, it is not known if these apparently favorable lipid changes translate into reductions in cardiovascular events. METHODS: The REVEAL study is a randomized, double-blind, placebo-controlled clinical trial that is assessing the efficacy and safety of adding anacetrapib to effective LDL-lowering treatment with atorvastatin for an average of at least 4years among patients with preexisting atherosclerotic vascular disease. The primary assessment is an intention-to-treat comparison among all randomized participants of the effects of allocation to anacetrapib on major coronary events (defined as the occurrence of coronary death, myocardial infarction, or coronary revascularization). RESULTS: Between August 2011 and October 2013, 30,449 individuals in Europe, North America, and China were randomized to receive anacetrapib 100mg daily or matching placebo. Mean (SD) age was 67 (8) years, 84% were male, 88% had a history of coronary heart disease, 22% had cerebrovascular disease, and 37% had diabetes mellitus. At the randomization visit (after at least 8weeks on a protocol-defined atorvastatin regimen), mean plasma LDL cholesterol was 61 (15) mg/dL and HDL cholesterol was 40 (10) mg/dL. INTERPRETATION: The REVEAL trial will provide a robust evaluation of the clinical efficacy and safety of adding anacetrapib to an effective statin regimen. Results are anticipated in 2017.

Edoxaban vs. warfarin in patients with atrial fibrillation on amiodarone: a subgroup analysis of the ENGAGE AF-TIMI 48 trial.

BACKGROUND: In the ENGAGE AF-TIMI 48 trial, the higher-dose edoxaban (HDE) regimen had a similar incidence of ischaemic stroke compared with warfarin, whereas a higher incidence was observed with the lower-dose regimen (LDE). Amiodarone increases edoxaban plasma levels via P-glycoprotein inhibition. The current pre-specified exploratory analysis was performed to determine the effect of amiodarone on the relative efficacy and safety profile of edoxaban. METHODS AND RESULTS: At randomization, 2492 patients (11.8%) were receiving amiodarone. The primary efficacy endpoint of stroke or systemic embolic event was significantly lower with LDE compared with warfarin in amiodarone treated patients vs. patients not on amiodarone (hazard ratio [HR] 0.60, 95% confidence intervals [CIs] 0.36-0.99 and HR 1.20, 95% CI 1.03-1.40, respectively; P interaction <0.01). In patients randomized to HDE, no such interaction for efficacy was observed (HR 0.73, 95% CI 0.46-1.17 vs. HR 0.89, 95% CI 0.75-1.05, P interaction = 0.446). Major bleeding was similar in patients on LDE (HR 0.35, 95% CI 0.21-0.59 vs. HR 0.53, 95% CI 0.46-0.61, P interaction = 0.131) and HDE (HR 0.94, 95% CI 0.65-1.38 vs. HR 0.79, 95% CI 0.69-0.90, P interaction = 0.392) when compared with warfarin, independent of amiodarone use. CONCLUSIONS: Patients randomized to the LDE treated with amiodarone at the time of randomization demonstrated a significant reduction in ischaemic events vs. warfarin when compared with those not on amiodarone, while preserving a favourable bleeding profile. In contrast, amiodarone had no effect on the relative efficacy and safety of HDE.

Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials.

BACKGROUND: Genetic variants have been associated with the risk of coronary heart disease. In this study, we tested whether or not a composite of these variants could ascertain the risk of both incident and recurrent coronary heart disease events and identify those individuals who derive greater clinical benefit from statin therapy. METHODS: A community-based cohort study (the Malmo Diet and Cancer Study) and four randomised controlled trials of both primary prevention (JUPITER and ASCOT) and secondary prevention (CARE and PROVE IT-TIMI 22) with statin therapy, comprising a total of 48,421 individuals and 3477 events, were included in these analyses. We studied the association of a genetic risk score based on 27 genetic variants with incident or recurrent coronary heart disease, adjusting for traditional clinical risk factors. We then investigated the relative and absolute risk reductions in coronary heart disease events with statin therapy stratified by genetic risk. We combined data from the different studies using a meta-analysis. FINDINGS: When individuals were divided into low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk categories, a significant gradient in risk for incident or recurrent coronary heart disease was shown. Compared with the low genetic risk category, the multivariable-adjusted hazard ratio for coronary heart disease for the intermediate genetic risk category was 1·34 (95% CI 1·22-1·47, p<0·0001) and that for the high genetic risk category was 1·72 (1·55-1·92, p<0·0001). In terms of the benefit of statin therapy in the four randomised trials, we noted a significant gradient (p=0·0277) of increasing relative risk reductions across the low (13%), intermediate (29%), and high (48%) genetic risk categories. Similarly, we noted greater absolute risk reductions in those individuals in higher genetic risk categories (p=0·0101), resulting in a roughly threefold decrease in the number needed to treat to prevent one coronary heart disease event in the primary prevention trials. Specifically, in the primary prevention trials, the number needed to treat to prevent one such event in 10 years was 66 in people at low genetic risk, 42 in those at intermediate genetic risk, and 25 in those at high genetic risk in JUPITER, and 57, 47, and 20, respectively, in ASCOT. INTERPRETATION: A genetic risk score identified individuals at increased risk for both incident and recurrent coronary heart disease events. People with the highest burden of genetic risk derived the largest relative and absolute clinical benefit from statin therapy. FUNDING: National Institutes of Health.

Impact of treatment with saxagliptin on glycaemic stability and ß-cell function in the SAVOR-TIMI 53 study.

AIMS: To study the effects of saxagliptin, a dipeptidyl peptidase-4 inhibitor, on glycaemic stability and ß-cell function in the SAVOR-TIMI 53 trial. METHODS: We randomized 16,492 patients with type 2 diabetes (T2D) to saxagliptin or placebo, added to current antidiabetic medications, and followed them for a median of 2.1 years. Glycaemic instability was defined by: (i) a glycated haemoglobin (HbA1c) increase of ≥ 0.5% post-randomization; (ii) the initiation of new antidiabetic medications for ≥ 3 months; or (iii) an increase in dose of oral antidiabetic medication or ≥ 25% increase in insulin dose for ≥ 3 months. ß-cell function was assessed according to fasting homeostatic model 2 assessment of ß-cell function (HOMA-2ß) values at baseline and at year 2 in patients not treated with insulin. RESULTS: Compared with placebo, participants treated with saxagliptin had a reduction in the development of glycaemic instability (hazard ratio 0.71; 95% confidence interval 0.68-0.74; p < 0.0001). In participants treated with saxagliptin compared with placebo, the occurrence of an HbA1c increase of ≥ 0.5% was reduced by 35.2%; initiation of insulin was decreased by 31.7% and the increases in doses of an oral antidiabetic drug or insulin were reduced by 19.5 and 23.5%, respectively (all p < 0.0001). At 2 years, HOMA-2ß values decreased by 4.9% in participants treated with placebo, compared with an increase of 1.1% in those treated with saxagliptin (p < 0.0001). CONCLUSIONS: Saxagliptin improved glycaemia and prevented the reduction in HOMA-2ß values. Saxagliptin may reduce the usual decline in ß-cell function in T2D, thereby slowing diabetes progression.

Baseline characteristics of the patient population in the Saxagliptin Assessment of Vascular Outcomes Recorded in patients with diabetes mellitus (SAVOR)-TIMI 53 trial.

BACKGROUND AND AIMS: SAVOR-TIMI 53 was designed to study the effects of the DPP-4 inhibitor saxagliptin on cardiovascular outcomes in high risk type 2 diabetes patients with diverse levels of diabetes control and background anti-diabetic drugs. The goal of this article is to describe the baseline characteristics of this hypothesis driven study. MATERIALS AND METHODS: A total of 16 496 diabetic patients from North America (31.9%), Western Europe (26.0%), Eastern Europe (17.3%), Latin America (16.4%) and Asia (8.3%), with either established cardiovascular disease (78.3%) or with ≥two additional cardiovascular risk factors (21.7%) were randomised to saxagliptin or placebo. Biomarkers of inflammation and insulin resistance were taken at baseline and 2 years later in order to correlate saxagliptin effect on cardiovascular outcome to its effect on inflammation and insulin resistance. RESULTS: Mean [+/-standard deviation (SD)] age was 65.0 (+/-8.6) years, 66.9% were male, body mass index was 31.2 kg/m² (+/-5.6), mean diabetes duration was 11.9 years (+/-8.9) and the mean HbA1c 8.0% (+/-1.4%). HbA1c < 7% was most prevalent among North Americans (30.8%) and least among Asians (15.1%), whereas HbA1c > 9% was 30.7% in Latin America 27.0% in Asia and 15.1% in North America. Diabetic retinopathy was reported in 12.3% of patients, nephropathy in 17.7% and amputation in 2.5%. Diabetic treatments categories were as follows: no medication (5.4%), 1 oral anti-diabetic drug (OAD) (25.0%), ≥2 OAD (27.7%) and/or insulin (40.9%). The prevalence of micro-albuminuria was twice as high among insulin users compared with users of ≥2 OAD. Baseline statin use (78.3% overall) varied by region. CONCLUSION: The SAVOR-TIMI 53 patient population, with differing background diabetes control and anti-diabetic treatment, provides global representation of diabetic patients with established cardiovascular disease or at high risk for cardiovascular disease and is well-positioned to determine the effect of saxagliptin on cardiovascular events.

Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial.

BACKGROUND: Rivaroxaban is an oral direct factor Xa inhibitor that has been effective in prevention of venous thromboembolism in patients undergoing elective orthopaedic surgery. However, its use after acute coronary syndromes has not been investigated. In this setting, we assessed the safety and efficacy of rivaroxaban and aimed to select the most favourable dose and dosing regimen. METHODS: In this double-blind, dose-escalation, phase II study, undertaken at 297 sites in 27 countries, 3491 patients stabilised after an acute coronary syndrome were stratified on the basis of investigator decision to use aspirin only (stratum 1, n=761) or aspirin plus a thienopyridine (stratum 2, n=2730). Participants were randomised within each strata and dose tier with a block randomisation method at 1:1:1 to receive either placebo or rivaroxaban (at doses 5-20 mg) given once daily or the same total daily dose given twice daily. The primary safety endpoint was clinically significant bleeding (TIMI major, TIMI minor, or requiring medical attention); the primary efficacy endpoint was death, myocardial infarction, stroke, or severe recurrent ischaemia requiring revascularisation during 6 months. Safety analyses included all participants who received at least one dose of study drug; efficacy analyses were by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00402597. FINDINGS: Three patients in stratum 1 and 26 in stratum 2 never received the study drug. The risk of clinically significant bleeding with rivaroxaban versus placebo increased in a dose-dependent manner (hazard ratios [HRs] 2.21 [95% CI 1.25-3.91] for 5 mg, 3.35 [2.31-4.87] for 10 mg, 3.60 [2.32-5.58] for 15 mg, and 5.06 [3.45-7.42] for 20 mg doses; p<0.0001). Rates of the primary efficacy endpoint were 5.6% (126/2331) for rivaroxaban versus 7.0% (79/1160) for placebo (HR 0.79 [0.60-1.05], p=0.10). Rivaroxaban reduced the main secondary efficacy endpoint of death, myocardial infarction, or stroke compared with placebo (87/2331 [3.9%] vs 62/1160 [5.5%]; HR 0.69, [95% CI 0.50-0.96], p=0.0270). The most common adverse event in both groups was chest pain (248/2309 [10.7%] vs 118/1153 [10.2%]). INTERPRETATION: The use of an oral factor Xa inhibitor in patients stabilised after an acute coronary syndrome increases bleeding in a dose-dependent manner and might reduce major ischaemic outcomes. On the basis of these observations, a phase III study of low-dose rivaroxaban as adjunctive therapy in these patients is underway. FUNDING: Johnson & Johnson Pharmaceutical Research & Development and Bayer Healthcare AG.

Recent trials of lipid lowering.

The global burden of coronary artery disease has pushed lipid-lowering therapy to the forefront of medical management of this condition. Recent clinical trials have compared the efficacy of more intensive lipid lowering with statins against the normal standard of care. Other agents such as fibrates, glitazones, which also favourably modify lipid levels have also been assessed recently. This narrative review summarises the key recent clinical trials of lipid lowering since 2004 and their implications for future patient care.

Determinants of improvement in epicardial flow and myocardial perfusion for ST elevation myocardial infarction; insights from TIMI 14 and InTIME-II.

BACKGROUND: When evaluating new reperfusion regimens for ST elevation MI, it is important to adjust for factors that influence the likelihood of achieving normal epicardial flow and complete ST resolution. METHODS AND RESULTS: A total of 610 patients from TIMI 14 contributed to the angiographic analyses. The electrocardiographic analyses were based on 544 patients from TIMI 14 and 763 patients from InTIME-II. For each hour from onset of symptoms to initiation of pharmacological reperfusion, the odds of achieving TIMI 3 flow at 90 min or complete ST resolution at 60-90 min decreased significantly (P=0.03). Anterior location of infarction was associated with a reduction in the odds of achieving TIMI 3 flow or complete ST resolution. The use of abciximab as part of the reperfusion regimen significantly increased the odds of TIMI 3 flow (P=0.01) and ST resolution (P<0.001). The fibrinolytic administered (alteplase, reteplase, lanoteplase) did not influence the odds of TIMI 3 flow or ST resolution after adjusting for time to treatment, infarct location, and use of abciximab. CONCLUSIONS: The influence of time from symptoms on epicardial flow and STRES reinforces the need for increased efforts to reduce treatment delays in patients with ST elevation MI. The significant benefits of abciximab with respect to facilitation of epicardial and myocardial reperfusion are evident even after adjusting for time to treatment and infarct location. To adjust for determinants of success of reperfusion regimens, phase II trials evaluating new drug combinations should consider using a randomization scheme that stratifies patients based on infarct location and time from symptoms.

Effects of pravastatin on mortality in patients with and without coronary heart disease across a broad range of cholesterol levels. The Prospective Pravastatin Pooling project.

AIMS: To assess the effects of pravastatin on all-cause mortality and cause-specific mortality and to compare the effects for patients with prior coronary heart disease with those for patients without, using pooled data from the Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) study, the Cholesterol and Recurrent Events (CARE) study, and the West of Scotland Coronary Prevention Study (WOSCOPS). METHODS AND RESULTS: 13 173 patients with coronary heart disease and 6595 men with elevated cholesterol and no prior coronary disease received pravastatin, 40 mg daily, or placebo for an average of 5 to 6 years. Data were analysed according to a pre-specified, published protocol. For all three trials combined, the mortality among patients assigned pravastatin was significantly lower, at 7.9%, than the 9.8% among those assigned placebo, a relative risk reduction of 20% (95% confidence interval (CI) 12-27%, P<0.0001). Active treatment was associated with a reduction in coronary mortality (24%, 95% CI 14-33%). Larger reductions in absolute risk were estimated in those with prior coronary heart disease than in those without. CONCLUSION: Treatment with pravastatin over 5 years reduces all-cause mortality and coronary mortality in patients with and those without a history of coronary heart disease. The size of the benefit was related principally to the baseline risk.

An integrated clinical approach to predicting the benefit of tirofiban in non-ST elevation acute coronary syndromes. Application of the TIMI Risk Score for UA/NSTEMI in PRISM-PLUS.

AIMS: We evaluated the TIMI Risk Score for Unstable Angina and Non-ST Elevation Myocardial Infarction for predicting clinical outcomes and the efficacy of tirofiban in non-ST elevation acute coronary syndromes. METHODS AND RESULTS: Developed in TIMI 11B, the risk score is calculated as the sum of seven presenting characteristics (age > or =65 years, > or =3 cardiac risk factors, documented coronary disease, recent severe angina, ST deviation > or =0.5 mm, elevated cardiac markers, prior aspirin use). The risk score was validated in the PRISM-PLUS database (n=1915) and tested for interaction with the efficacy of tirofiban+heparin vs heparin alone. The risk score revealed an increasing gradient of risk for death, myocardial infarction or recurrent ischaemia at 14 days ranging from 7.7-30.5% (P<0.001). Dichotomized at the median, patients with a score > or =4 derived a greater relative risk reduction with tirofiban (P((Interaction))=0.025). Among patients with normal creatine kinase myocardial bands, the risk score showed a 3.5-fold gradient of risk (P<0.001) and identified a population that derived significant benefit from tirofiban (RR 0.73, P=0.027). CONCLUSION: The TIMI Risk Score is a simple clinical tool for risk assessment that may aid in the early identification of patients who should be considered for treatment with potent antiplatelet therapy.

Enoxaparin is superior to unfractionated heparin for preventing clinical events at 1-year follow-up of TIMI 11B and ESSENCE.

BACKGROUND: Enoxaparin treatment is associated with a 20% reduction in clinical events during the acute phase of management of patients with unstable angina/non ST elevation myocardial infarction. Interest in the use of enoxaparin would be enhanced further if evidence of a durable treatment benefit over the long term could be provided. METHODS: Event rates at 1 year for the composite end-point of death/non-fatal myocardial infarction/urgent revascularization and its individual components were ascertained from the TIMI 11B and ESSENCE databases. RESULTS: There was no evidence of heterogeneity between TIMI 11B and ESSENCE in tests for interactions between treatment and trial. A significant treatment benefit of enoxaparin on the rate of death/non-fatal myocardial infarction/urgent revascularization was observed at 1 year (hazard ratio 0.88;P=0.008). The event rate was 25.8% in the unfractionated heparin group and 23.3% in the enoxaparin group, an absolute difference of 2.5%. A progressively greater treatment benefit of enoxaparin was observed as the level of patient risk at baseline increased. Treatment effects for the individual end-point elements ranged from 9-14%, favouring enoxaparin. CONCLUSIONS: The stable absolute difference in event rates of 2.5% seen at 8 days and again at 1 year favouring enoxaparin may be due to more effective control of the thrombotic process surrounding the index event. Once the pharmacological effect of enoxaparin had dissipated there was no rebound increase in events. Thus, those patients who had received enoxaparin acutely were protected from experiencing a deterioration of the original therapeutic benefit. These findings regarding enoxaparin add to the data to be considered by clinicians when selecting an antithrombin for the acute phase of management of unstable angina/non-ST elevation myocardial infarction.

Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial.

CONTEXT: Cardiac troponins I (cTnI) and T (cTnT) are useful for assessing prognosis in patients with unstable angina and non-ST-segment elevation myocardial infarction (UA/NSTEMI). However, the use of cardiac troponins for predicting benefit of an invasive vs conservative strategy in this patient population is not clear. OBJECTIVE: To prospectively test whether an early invasive strategy provides greater benefit than a conservative strategy in acute coronary syndrome patients with elevated baseline troponin levels. DESIGN: Prospective, randomized trial conducted from December 1997 to June 2000. SETTING: One hundred sixty-nine community and tertiary care hospitals in 9 countries. PARTICIPANTS: A total of 2220 patients with acute coronary syndrome were enrolled. Baseline troponin level data were available for analysis in 1821, and 1780 completed the 6-month follow-up. INTERVENTIONS: Patients were randomly assigned to receive (1) an early invasive strategy of coronary angiography between 4 and 48 hours after randomization and revascularization when feasible based on coronary anatomy (n = 1114) or (2) a conservative strategy of medical treatment and, if stable, predischarge exercise tolerance testing (n = 1106). Conservative strategy patients underwent coronary angiography and revascularization only if they manifested recurrent ischemia at rest or on provocative testing. MAIN OUTCOME MEASURE: Composite end point of death, MI, or rehospitalization for acute coronary syndrome at 6 months. RESULTS: Patients with a cTnI level of 0.1 ng/mL or more (n = 1087) experienced a significant reduction in the primary end point with the invasive vs conservative strategy (15.3% vs 25.0%; odds ratio [OR], 0.54; 95% confidence interval [CI], 0.40-0.73). Patients with cTnI levels of less than 0.1 ng/mL had no detectable benefit from early invasive management (16.0% vs 12.4%; OR, 1.4; 95% CI, 0.89-2.05; P<.001 for interaction). The benefit of invasive vs conservative management through 30 days was evident even among patients with low-level (0.1-0.4 ng/mL) cTnI elevation (4.4% vs 16.5%; OR, 0.24; 95% CI, 0.08-0.69). Directionally similar results were observed with cTnT. CONCLUSION: In patients with clinically documented acute coronary syndrome who are treated with glycoprotein IIb/IIIa inhibitors, even small elevations in cTnI and cTnT identify high-risk patients who derive a large clinical benefit from an early invasive strategy.

Acute coronary syndrome without ST elevation: implementation of new guidelines.

Unstable angina and non-ST-segment-elevation myocardial infarction have in recent years been recognised as frequent and important clinical manifestations of coronary-artery disease. The European (ESC) and American (ACC/AHA) professional societies last year released guidelines on diagnosis, risk stratification, and treatment of these disorders. These guidelines summarise similarly the current evidence and translate them to clinical practice. Most important changes relate to the inclusion of troponins into the risk stratification algorithm, the addition of low-molecular-weight heparin and glycoprotein IIb/IIIa antagonists to medical treatment, and the role of invasive management for improved long-term outcome. Guidelines are constantly challenged by newly emerging study results. Recently, early invasive management and clopidogrel have been found to exert further benefit to this high-risk group of patients. Accordingly, the societies on both sides of the Atlantic will work together closely to update and implement these guidelines.