Association Between Achieved Low-Density Lipoprotein Cholesterol Levels and Long-Term Cardiovascular and Safety Outcomes: An Analysis of FOURIER-OLE.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. METHODS: In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. RESULTS: In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. CONCLUSIONS: In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01764633.

Patient selection for long-term secondary prevention with ticagrelor: insights from PEGASUS-TIMI 54.

AIM: In patients with prior myocardial infarction (MI) on aspirin, the addition of ticagrelor reduces ischaemic risk but increases bleeding risk. The simultaneous assessment of baseline ischaemic and bleeding risk may assist clinicians in selecting patients who are most likely to have a favourable risk/benefit profile with long-term ticagrelor. METHODS AND RESULTS: PEGASUS-TIMI 54 randomized 21 162 prior MI patients, 13 956 of which to the approved 60 mg dose or placebo and who had all necessary data. The primary efficacy endpoint was cardiovascular death, MI, or stroke, and the primary safety outcome was TIMI major bleeding; differences in Kaplan-Meier event rates at 3 years are presented. Post-hoc subgroups based on predictors of bleeding and ischaemic risk were merged into a selection algorithm. Patients were divided into four groups: those with a bleeding predictor (n = 2721, 19%) and then those without a bleeding predictor and either 0-1 ischaemic risk factor (IRF; n = 3004, 22%), 2 IRF (n = 4903, 35%), or ≥3 IRF (n = 3328, 24%). In patients at high bleeding risk, ticagrelor increased bleeding [absolute risk difference (ARD) +2.3%, 95% confidence interval (CI) 0.6, 3.9] and did not reduce the primary efficacy endpoint (ARD +0.08%, 95% CI -2.4 to 2.5). In patients at low bleeding risk, the ARDs in the primary efficacy endpoint with ticagrelor were -0.5% (-2.2, 1.3), -1.5% (-3.1, 0.02), and -2.6% (-5.0, -0.24, P = 0.03) in those with ≤1, 2, and 3 risk factors, respectively (P = 0.076 for trend across groups). There were significant trends for greater absolute risk reductions for cardiovascular death (P-trend 0.018), all-cause mortality (P-trend 0.027), and net outcomes (P-trend 0.037) with ticagrelor across these risk groups. CONCLUSION: In a post-hoc exploratory analysis of patients with prior MI, long-term ticagrelor therapy appears to be best suited for those with prior MI with multiple IRFs at low bleeding risk. CLINICAL TRIAL REGISTRATION: NCT01225562 ClinicalTrials.gov.

Re-adjudication of the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) with study-level meta-analysis of hospitalization for heart failure from cardiovascular outcomes trials with dipeptidyl peptidase-4 (DPP-4) inhibitors.

BACKGROUND: Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) assessed the cardiovascular (CV) safety of sitagliptin versus placebo on CV outcomes in patients with type 2 diabetes and CV disease and found sitagliptin noninferior to placebo. Subsequently, based on feedback from FDA, the Sponsor of the trial, Merck & Co., Inc., engaged a separate academic research organization, the TIMI Study Group, to re-adjudicate a prespecified set of originally adjudicated events. METHODS: TIMI adjudicated in a blinded fashion all potential hospitalization for heart failure (HHF) events, all potential MACE+ events previously adjudicated as not an endpoint event, and a random subset (~10%) of MACE+ events previously adjudicated as an endpoint event. An updated study-level meta-analysis of four randomized, placebo-controlled, CV outcomes trials with dipeptidyl peptidase 4 (DPP-4) inhibitors was then performed. RESULTS: After re-adjudication of potential HHF events in the intent-to-treat population, there were 224 patients with a confirmed event in the sitagliptin arm (1.05/100 person-years) and 239 patients in the placebo arm (1.13/100 person-years), corresponding to a hazard ratio (HR) of 0.94 (95% confidence interval [95% CI]: 0.78-1.13, p = .49). Concordance between the outcome of the original adjudication and the re-adjudication for HHF events was 82.7%. The meta-analysis of CV outcomes trials with DPP-4 inhibitors with placebo and involving 43 522 patients yielded an HR of 1.07 (95% CI: 0.83-1.39), with moderate heterogeneity (p = .45, I2 = 62.07%). CONCLUSION: The results of this independent re-adjudication process and analyses of CV outcomes from TECOS were consistent with the original adjudication results and overall study findings. An updated study-level meta-analysis showed no overall significant risk for HHF with DPP-4 inhibitors, but with statistical heterogeneity.

Morphine and Cardiovascular Outcomes Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Undergoing Coronary Angiography.

BACKGROUND: Mechanistic studies have shown that morphine blunts the antiplatelet effects of oral adenosine diphosphate receptor blockers. However, the clinical relevance of this interaction is controversial. OBJECTIVES: This study sought to explore the association between morphine and ischemic events in 5,438 patients treated with concomitant clopidogrel presenting with non-ST-segment elevation acute coronary syndromes (NSTEACS) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome) trial. Patients not treated with clopidogrel (n = 3,462) were used as negative controls. METHODS: Endpoints were the composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout at 96 h (4-way endpoint) and the composite of death or MI at 30 days. RESULTS: In patients treated with clopidogrel, morphine use was associated with higher rates of the 4-way endpoint at 96 h (adjusted odds ratio [OR]: 1.40; 95% confidence interval [CI]: 1.04 to 1.87; p = 0.026). There was a trend for higher rates of death or MI at 30 days (adjusted OR: 1.29; 95% CI: 0.98 to 1.70; p = 0.072), driven by events in the first 48 h (adjusted hazard ratio: 1.54; 95% CI: 1.07 to 2.23; p = 0.021). In patients not treated with clopidogrel, morphine was not associated with either the 4-way endpoint at 96 h (adjusted OR: 1.05; 95% CI: 0.74 to 1.49; p = 0.79; pinteraction = 0.36 ) or death or MI at 30 days (adjusted OR: 1.07; 95% CI: 0.77 to 1.48; p = 0.70; pinteraction = 0.46). CONCLUSIONS: When used concomitantly with clopidogrel pre-treatment, morphine was associated with higher rates of ischemic events in patients with NSTEACS. (EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome; NCT00089895).

Long-term ticagrelor for secondary prevention in patients with prior myocardial infarction and no history of coronary stenting: insights from PEGASUS-TIMI 54.

AIMS: PEGASUS-TIMI 54 demonstrated that long-term dual antiplatelet therapy (DAPT) with aspirin and ticagrelor reduced the risk of major adverse cardiovascular events (MACE), with an acceptable increase in bleeding, in patients with prior myocardial infarction (MI). While much of the discussion around prolonged DAPT has been focused on stented patients, patients with prior MI without prior coronary stenting comprise a clinically important subgroup. METHODS AND RESULTS: This was a pre-specified analysis from PEGASUS-TIMI 54, which randomized 21 162 patients with prior MI (1-3 years) and additional high-risk features to ticagrelor 60 mg, 90 mg, or placebo twice daily in addition to aspirin. A total of 4199 patients had no history of coronary stenting at baseline. The primary efficacy outcome (MACE) was the composite of cardiovascular death, MI, or stroke. Patients without history of coronary stenting had higher baseline risk of MACE [13.2% vs. 8.0%, adjusted hazard ratio (HR) 1.41, 95% confidence interval (CI) 1.15-1.73, in the placebo arm]. The relative risk reduction in MACE with ticagrelor (pooled doses) was similar in patients without (HR 0.82, 95% CI 0.68-0.99) and with prior stenting (HR 0.85, 95% CI 0.75-0.96; P for interaction = 0.76). CONCLUSION: Long-term ticagrelor reduces thrombotic events in patients with prior MI regardless of whether they had prior coronary stenting. These data highlight the benefits of DAPT in prevention of spontaneous atherothrombotic events and indicate that long-term ticagrelor may be considered in high-risk patients with prior MI even if they have not been treated with stenting. CLINICALTRIALS.GOV IDENTIFIER: NCT01225562.

Efficacy and Safety of Further Lowering of Low-Density Lipoprotein Cholesterol in Patients Starting With Very Low Levels: A Meta-analysis.

Importance: In the Cholesterol Treatment Trialists Collaboration (CTTC), in patients starting with low-density lipoprotein cholesterol (LDL-C) levels of approximately 3.4 mmol/L (131.5 mg/dL), there was a 22% reduction in major vascular events per 1-mmol/L (38.7-mg/dL) lowering of LDL-C. The magnitude of clinical benefit of further LDL-C lowering in patients already with very low LDL-C levels remains debated. Objective: To evaluate efficacy and safety of further lowering LDL-C levels in patient populations presenting with median LDL-C levels of 1.8 mmol/L (70 mg/dL) or less. Data Sources and Study Selection: The CTTC was used for statin data. For nonstatin therapy, Medline database was searched (2015-April 2018). Key inclusion criteria were a randomized, double-blind, controlled cardiovascular outcome trial of LDL-C lowering with data in populations starting with LDL-C levels averaging 1.8 mmol/L (70 mg/dL) or less. Data Extraction and Synthesis: Two authors independently extracted data into standardized data sheets, and data were analyzed using meta-analysis. Main Outcomes and Measures: The risk ratio (RR) of major vascular events (a composite of coronary heart death, myocardial infarction, ischemic stroke, or coronary revascularization) per 1-mmol/L (38.7-mg/dL) reduction in LDL-C level. Results: In the subgroup of patients from the CTTC meta-analysis of statins with a mean LDL-C in the control arm of 1.7 mmol/L (65.7 mg/dL), 1922 major vascular events occurred and the RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C was 0.78 (95% CI, 0.65-0.94). For 3 trials of nonstatin LDL-C-lowering therapies added to statins, there were 50 627 patients, the median LDL-C in the control arms ranged from 1.6 mmol/L to 1.8 mmol/L (63 mg/dL to 70 mg/dL), and 9570 major vascular events occurred. Nonstatin therapy lowered LDL-C by 0.3 to 1.2 mmol/L (11 mg/dL to 45 mg/dL), and the RR for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C was 0.79 (95% CI, 0.70-0.88). For statins and nonstatins combined, the RR was 0.79 (95% CI, 0.71-0.87; P < .001). Low-density lipoprotein cholesterol lowering was not associated with an increased risk of serious adverse events, myalgias and/or myositis, elevation in the level of aminotransferases, new-onset diabetes, hemorrhagic stroke, or cancer. Conclusions and Relevance: There is a consistent relative risk reduction in major vascular events per change in LDL-C in patient populations starting as low as a median of 1.6 mmol/L (63 mg/dL) and achieving levels as low as a median of 0.5 mmol/L (21 mg/dL), with no observed offsetting adverse effects. These data suggest further lowering of LDL-C beyond the lowest current targets would further reduce cardiovascular risk.

Efficacy and Safety of Ticagrelor Over Time in Patients With Prior MI in PEGASUS-TIMI 54.

BACKGROUND: Ticagrelor reduces ischemic risk in patients with prior myocardial infarction (MI). It remains unclear whether ischemic risk and the benefits of prolonged P2Y12 inhibition in this population remain consistent over time. OBJECTIVES: The study sought to investigate the pattern of ischemic risk over time and whether the efficacy and safety of ticagrelor were similar early and late after randomization. METHODS: The PEGASUS-TIMI (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction) 54 trial randomized patients with prior MI (median 1.7 years prior) to ticagrelor 90 mg, ticagrelor 60 mg, or placebo on a background of aspirin. The rates of cardiovascular (CV) death, MI, and stroke as well as TIMI major bleeding were analyzed at yearly landmarks (years 1, 2, and 3). RESULTS: A total of 21,162 patients were randomized and followed for 33 months (median), with 28% of patients ≥5 years from MI at trial conclusion. The risk of CV death, MI, or stroke in the placebo arm remained roughly constant over the trial at an ∼3% annualized rate. The benefit of ticagrelor 60 mg was consistent at each subsequent landmark (year 1 hazard ratio [HR]: 0.82; 95% confidence interval [CI]: 0.67 to 0.99; year 2 HR: 0.90; 95% CI: 0.74 to 1.11; and year 3 HR: 0.79; 95% CI: 0.62 to 1.00). TIMI major bleeding was increased with ticagrelor 60 mg at each landmark, but with the greatest hazard in the first year (year 1 HR: 3.22; year 2 HR: 2.07; year 3 HR: 1.65). CONCLUSIONS: Patients with a history of MI remain at persistent high risk for CVD, MI, and stroke as late as 5 years after MI. The efficacy of low-dose ticagrelor is consistent over time with a trend toward less excess bleeding. (Prevention of Cardiovascular Events in Patients with Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562).

Long-term Tolerability of Ticagrelor for the Secondary Prevention of Major Adverse Cardiovascular Events: A Secondary Analysis of the PEGASUS-TIMI 54 Trial.

IMPORTANCE: In the PEGASUS-TIMI 54 trial, treatment with ticagrelor reduced the incidence of cardiovascular death, myocardial infarction, or stroke by 15% to 16% among stable patients compared with placebo. However, more patients prematurely discontinued treatment with ticagrelor than with placebo. OBJECTIVE: To investigate the reasons and timing of discontinuation of treatment with ticagrelor among stable patients prior myocardial infarction. DESIGN, SETTING, AND PARTICIPANTS: In the PEGASUS-TIMI 54 trial, 21 162 stable outpatients with prior myocardial infarction were randomly assigned to 90 mg of ticagrelor twice daily, 60 mg of ticagrelor twice daily, or placebo, with all of the patients receiving a low dose of aspirin. These participants were followed up for a median of 33 months (study start date: October 2010; completion date: December 2014). Discontinuation of treatment was evaluated by treatment arm, cause, and timing. This analysis was initiated in May 2015. MAIN OUTCOME AND MEASURE: Discontinuation of treatment. RESULTS: Over 33 months, 32%, 29%, and 21% of patients receiving 90 mg of ticagrelor, 60 mg of ticagrelor, and placebo, respectively, discontinued treatment (P < .001). Discontinuation of treatment due to an adverse event occurred in 19%, 16%, and 9% of patients, respectively (P < .001). The most frequent adverse events leading to discontinuation of treatment were bleeding (with Kaplan-Meier event rates of 7.8%, 6.2%, and 1.5% of patients, respectively; P < .001) and dyspnea (6.5%, 4.6%, and 0.8% of patients, respectively; P < .001). Eighty-six percent of bleeding events that led to the discontinuation of treatment with ticagrelor were nonmajor, and 86% of adverse events due to dyspnea that led to discontinuation of treatment with ticagrelor were mild or moderate in severity. The discontinuation rates are annualized for patients who received 90 mg of ticagrelor twice daily (hazard ratio [HR], 2.00 [95% CI, 1.84-2.16] for the first year; HR, 1.12 [95% CI, 1.00-1.26] for the second and third years) and patients who received 60 mg of ticagrelor twice daily (HR, 1.59 [95% CI, 1.46-1.73] for the first year; HR, 1.18 [95% CI, 1.06-1.32] for the second and third years) compared with patients who received placebo. CONCLUSIONS AND RELEVANCE: When initiated among stable patients with prior myocardial infarction, discontinuation of treatment with ticagrelor was driven primarily by nonserious adverse events occurring primarily early after randomization. For patients completing 1 year of treatment, the subsequent discontinuation rate was low. These data demonstrate how adverse events considered "nonserious" by traditional trial criteria may have an effect on quality of life and, thus, may precipitate the discontinuation of treatments and underscore the need for patient education and counseling on the timing and nature of adverse effects with the aim of improving adherence when appropriate. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01225562.

Reduction in Ischemic Events With Ticagrelor in Diabetic Patients With Prior Myocardial Infarction in PEGASUS-TIMI 54.

BACKGROUND: Patients with diabetes appear to be at elevated risk of atherothrombotic events. OBJECTIVES: The purpose of this study was to determine the effect of antiplatelet therapy with ticagrelor on recurrent ischemic events in patients with diabetes and prior myocardial infarction (MI). METHODS: We examined the subgroups of patients with diabetes (n = 6,806) and without diabetes (n = 14,355) from PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin-Thrombolysis In Myocardial Infarction 54), in which 21,162 patients with a history of MI 1 to 3 years prior and with additional risk factors were randomized to ticagrelor (90 or 60 mg twice daily) or placebo. Patients were followed for a median of 33 months. The primary efficacy endpoint was major adverse cardiovascular events (MACE) (cardiovascular death, MI, stroke) and the primary safety endpoint was TIMI (Thrombolysis In Myocardial Infarction) major bleeding. RESULTS: The relative risk reduction in MACE with ticagrelor was consistent for the pooled doses versus placebo in patients with diabetes (hazard ratio [HR]: 0.84; 95% confidence interval [CI]: 0.72 to 0.99; p = 0.035) and without diabetes (HR: 0.84; 95% CI: 0.74 to 0.96; p = 0.013; p interaction = 0.99). As patients with diabetes were at higher risk of MACE, the absolute risk reduction tended to be greater in patients with versus without diabetes (1.5% vs. 1.1%, with corresponding 3-year number needed to treat of 67 vs. 91). In patients with diabetes requiring pharmacological therapy (n = 5,960), the absolute risk reduction was 1.9% with a 3-year number needed to treat of 53. Additionally, in patients with diabetes, ticagrelor reduced cardiovascular death by 22% and coronary heart disease death by 34%. Similar to patients without diabetes, there was increased TIMI major bleeding in patients with diabetes (HR: 2.56; 95% CI: 1.52 to 4.33; p = 0.0004). CONCLUSIONS: In patients with diabetes with prior MI, adding ticagrelor to aspirin significantly reduces the risk of recurrent ischemic events, including cardiovascular and coronary heart disease death. (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin [PEGASUS]; NCT01225562).

Relationship Between Early and Late Nonsustained Ventricular Tachycardia and Cardiovascular Death in Patients With Acute Coronary Syndrome in the Platelet Inhibition and Patient Outcomes (PLATO) Trial.

BACKGROUND: Nonsustained ventricular tachycardia (NSVT) is common after acute coronary syndrome (ACS) and a marker of increased risk of arrhythmogenic death. However, the prognostic significance of NSVT when evaluated with other contemporary risk markers and at later time points after ACS remains uncertain. METHODS AND RESULTS: In the Platelet Inhibition and Patient Outcomes (PLATO) trial, continuous ECGs were performed during the first 7 days after ACS (n=2866) and repeated for another 7 days at day 30 (n=1991). Median follow-up was 1 year. There was a time-varying interaction between NSVT and cardiovascular death such that NSVT was significantly associated with increased risk within the first 30 days after randomization (22/999 [2.2%] versus 16/1825 [0.9%]; adjusted hazard ratio, 2.84; 95% confidence interval, 1.39-5.79; P=0.004) but not after 30 days (28/929 [3.0%] versus 42/1734 [2.4%]; P=0.71). Detection of NSVT during the convalescent phase (n=428/1991; 21.5%) was also associated with an increased risk of cardiovascular death, and was most marked within the first 2 months after detection (1.9% versus 0.3%; adjusted hazard ratio, 5.48; 95% confidence interval, 1.07-28.20; P=0.01), and then decreasing over time such that the relationship was no longer significant by ≈5 months after ACS. CONCLUSIONS: NSVT occurred frequently during the acute and convalescent phases of ACS. The risk of cardiovascular death associated with NSVT was the greatest during the first 30 days after presentation; however, patients with NSVT detected during the convalescent phase were also at a significantly increased risk of cardiovascular death that persisted for an additional several months after the index event. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00391872.

Efficacy and safety of ticagrelor for long-term secondary prevention of atherothrombotic events in relation to renal function: insights from the PEGASUS-TIMI 54 trial.

AIMS: We evaluated the relationship of renal function and ischaemic and bleeding risk as well as the efficacy and safety of ticagrelor in stable patients with prior myocardial infarction (MI). METHODS AND RESULTS: Patients with a history of MI 1-3 years prior from PEGASUS-TIMI 54 were stratified based on estimated glomerular filtration rate (eGFR), with <60 mL/min/1.73 m(2) pre-specified for analysis of the effect of ticagrelor on the primary efficacy composite of cardiovascular death, MI, or stroke (major adverse cardiovascular events, MACE) and the primary safety endpoint of TIMI major bleeding. Of 20 898 patients, those with eGFR <60 (N = 4849, 23.2%) had a greater risk of MACE at 3 years relative to those without, which remained significant after multivariable adjustment (hazard ratio, HRadj 1.54, 95% confidence interval, CI 1.27-1.85, P < 0.001). The relative risk reduction in MACE with ticagrelor was similar in those with eGFR <60 (ticagrelor pooled vs. placebo: HR 0.81; 95% CI 0.68-0.96) vs. ≥60 (HR 0.88; 95% CI 0.77-1.00, Pinteraction = 0.44). However, due to the greater absolute risk in the former group, the absolute risk reduction with ticagrelor was higher: 2.7 vs. 0.63%. Bleeding tended to occur more frequently in patients with renal dysfunction. The absolute increase in TIMI major bleeding with ticagrelor was similar in those with and without eGFR <60 (1.19 vs. 1.43%), whereas the excess of minor bleeding tended to be more pronounced (1.93 vs. 0.69%). CONCLUSION: In patients with a history of MI, patients with renal dysfunction are at increased risk of MACE and consequently experience a particularly robust absolute risk reduction with long-term treatment with ticagrelor.

Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y12 inhibitor withdrawal in patients with prior myocardial infarction: insights from PEGASUS-TIMI 54.

AIMS: Ticagrelor reduced major adverse cardiovascular event (MACE) by 15-16% in patients with prior myocardial infarction (MI) in PEGASUS-TIMI 54. We hypothesized that patients who recently discontinued P2Y12 inhibition, even years after MI, may be at particular risk of MACE and may derive particular benefit from continuation or reinitiation of therapy. METHODS AND RESULTS: Patients in PEGASUS-TIMI 54 were categorized by time from last P2Y12 inhibitor (days: ≤30, >30-360, >360). The risk of MACE and the efficacy of ticagrelor were compared across categories. In the placebo arm, patients who more recently stopped P2Y12 inhibitor therapy had a greater number of risk factors but still had a higher risk of MACE after multivariable adjustment [≤30 days, hazard ratio (HR)adj 1.47, 95% confidence interval (CI) 1.12-1.93, P = 0.0051; 30 days-1 year, HRadj 1.28, 95% CI 0.98-1.67, P = 0.073] compared with those who stopped >1 year prior (P-trend = 0.0097). The benefit of ticagrelor depended on the time from last dose, with HRs (95% CI) for ticagrelor (pooled doses) vs. placebo of 0.73 (0.61-0.87), 0.86 (0.71-1.04), and 1.01 (0.80-1.27), respectively, by category (P-trend for interaction < 0.001). The benefit in those ≤30 days of stopping was similar regardless of time from MI (<2 years, HR 0.73, 95% CI 0.60-0.89 vs. ≥2 years, HR 0.71, 95% CI 0.50-1.00). CONCLUSION: The benefit of ticagrelor for long-term secondary prevention in patients with prior MI and at least one additional risk factor appeared more marked in patients continuing on or re-starting after only a brief interruption of P2Y12 inhibition, when compared with patients who had proved themselves stable more than 2 years from their MI and off P2Y12 inhibitor therapy for more than a year. The increase in bleeding events with ticagrelor was similar regardless of this time interval. For clinicians considering a strategy of prolonged P2Y12 inhibitor therapy in high-risk patients, these data suggest greater benefit in the continuation of such therapy without interruption after MI, rather than re-initiating such therapy in patients who have remained stable for an extended period. Future analyses may help to clarify further the profile of post-MI patients most likely to benefit from uninterrupted dual antiplatelet therapy. CLINICAL TRIAL REGISTRATION INFORMATION: http://www.clinicaltrials.gov NCT01225562.

Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes.

BACKGROUND: Statin therapy reduces low-density lipoprotein (LDL) cholesterol levels and the risk of cardiovascular events, but whether the addition of ezetimibe, a nonstatin drug that reduces intestinal cholesterol absorption, can reduce the rate of cardiovascular events further is not known. METHODS: We conducted a double-blind, randomized trial involving 18,144 patients who had been hospitalized for an acute coronary syndrome within the preceding 10 days and had LDL cholesterol levels of 50 to 100 mg per deciliter (1.3 to 2.6 mmol per liter) if they were receiving lipid-lowering therapy or 50 to 125 mg per deciliter (1.3 to 3.2 mmol per liter) if they were not receiving lipid-lowering therapy. The combination of simvastatin (40 mg) and ezetimibe (10 mg) (simvastatin-ezetimibe) was compared with simvastatin (40 mg) and placebo (simvastatin monotherapy). The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, unstable angina requiring rehospitalization, coronary revascularization (≥30 days after randomization), or nonfatal stroke. The median follow-up was 6 years. RESULTS: The median time-weighted average LDL cholesterol level during the study was 53.7 mg per deciliter (1.4 mmol per liter) in the simvastatin-ezetimibe group, as compared with 69.5 mg per deciliter (1.8 mmol per liter) in the simvastatin-monotherapy group (P<0.001). The Kaplan-Meier event rate for the primary end point at 7 years was 32.7% in the simvastatin-ezetimibe group, as compared with 34.7% in the simvastatin-monotherapy group (absolute risk difference, 2.0 percentage points; hazard ratio, 0.936; 95% confidence interval, 0.89 to 0.99; P=0.016). Rates of prespecified muscle, gallbladder, and hepatic adverse effects and cancer were similar in the two groups. CONCLUSIONS: When added to statin therapy, ezetimibe resulted in incremental lowering of LDL cholesterol levels and improved cardiovascular outcomes. Moreover, lowering LDL cholesterol to levels below previous targets provided additional benefit. (Funded by Merck; IMPROVE-IT ClinicalTrials.gov number, NCT00202878.).

Long-term use of ticagrelor in patients with prior myocardial infarction.

BACKGROUND: The potential benefit of dual antiplatelet therapy beyond 1 year after a myocardial infarction has not been established. We investigated the efficacy and safety of ticagrelor, a P2Y12 receptor antagonist with established efficacy after an acute coronary syndrome, in this context. METHODS: We randomly assigned, in a double-blind 1:1:1 fashion, 21,162 patients who had had a myocardial infarction 1 to 3 years earlier to ticagrelor at a dose of 90 mg twice daily, ticagrelor at a dose of 60 mg twice daily, or placebo. All the patients were to receive low-dose aspirin and were followed for a median of 33 months. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The primary safety end point was Thrombolysis in Myocardial Infarction (TIMI) major bleeding. RESULTS: The two ticagrelor doses each reduced, as compared with placebo, the rate of the primary efficacy end point, with Kaplan-Meier rates at 3 years of 7.85% in the group that received 90 mg of ticagrelor twice daily, 7.77% in the group that received 60 mg of ticagrelor twice daily, and 9.04% in the placebo group (hazard ratio for 90 mg of ticagrelor vs. placebo, 0.85; 95% confidence interval [CI], 0.75 to 0.96; P=0.008; hazard ratio for 60 mg of ticagrelor vs. placebo, 0.84; 95% CI, 0.74 to 0.95; P=0.004). Rates of TIMI major bleeding were higher with ticagrelor (2.60% with 90 mg and 2.30% with 60 mg) than with placebo (1.06%) (P<0.001 for each dose vs. placebo); the rates of intracranial hemorrhage or fatal bleeding in the three groups were 0.63%, 0.71%, and 0.60%, respectively. CONCLUSIONS: In patients with a myocardial infarction more than 1 year previously, treatment with ticagrelor significantly reduced the risk of cardiovascular death, myocardial infarction, or stroke and increased the risk of major bleeding. (Funded by AstraZeneca; PEGASUS-TIMI 54 ClinicalTrials.gov number, NCT01225562.).

Incidence of pancreatitis and pancreatic cancer in a randomized controlled multicenter trial (SAVOR-TIMI 53) of the dipeptidyl peptidase-4 inhibitor saxagliptin.

OBJECTIVE: To determine the incidence of pancreatitis and pancreatic cancer in the SAVOR-TIMI 53 trial. RESEARCH DESIGN AND METHODS: A total of 16,492 type 2 diabetic patients ≥40 years old with established cardiovascular (CV) disease or CV risk factors were randomized to saxagliptin or placebo and followed for 2.1 years. Outcome measures were investigator reported with blinded expert adjudication of total pancreatitis (acute and chronic) and reported cases of pancreatic cancer. RESULTS: Trial investigators reported 35 events of pancreatitis in each treatment arm in 63 patients (33 [0.40%] in the saxagliptin arm and 30 [0.37%] in control arm), with a hazard ratio (HR) of 1.09 (95% CI 0.66-1.79, P = 0.80). Adjudication confirmed pancreatitis in 24 patients (26 events) in the saxagliptin arm (0.29%) and 21 patients (25 events) in placebo arm (0.26%), with an HR of 1.13 (0.63-2.06, P = 0.77). Cases of definite acute pancreatitis were confirmed in 17 (0.2%) vs. 9 (0.1%) (HR 1.88 [0.86-4.41], P = 0.17), definite plus possible pancreatitis in 22 vs. 16 (HR 1.36 [0.72-2.64], P = 0.42), and chronic pancreatitis in 2 vs. 6 (HR 0.33 [0.05-1.44], P = 0.18) in the saxagliptin and placebo arms, respectively. No differences in time to event onset, concomitant risk factors for pancreatitis, investigator-reported causality from study medication or disease severity, and outcome were found between treatment arms. The investigators reported 5 and 12 cases of pancreatic cancer in the saxagliptin and placebo arms, respectively (HR 0.42 [0.13-1.12], P = 0.09). CONCLUSIONS: In the SAVOR-TIMI 53 trial, within 2.1 years of follow-up, risk for pancreatitis in type 2 diabetic patients treated with saxagliptin was low and apparently similar to placebo, with no sign of increased risk for pancreatic cancer. Further studies are needed to completely resolve the pancreatic safety issues with incretin-based therapy.

Selective decrease in hepatitis C virus-specific immunity among African Americans and outcome of antiviral therapy.

UNLABELLED: Hepatitis C virus (HCV) infection is a leading cause of chronic hepatitis, end-stage liver disease, and hepatocellular carcinoma throughout the world. Considerable evidence indicates that the risk of viral persistence, natural history, and response to antiviral therapy varies among racial groups, but limited data exist on potential mechanisms to account for these differences. Type 1 helper (Th1) responses to HCV proteins and cytomegalovirus (CMV) antigens were examined using a sensitive interferon (IFN)-gamma enzyme-linked immunospot (ELISPOT) assay in 187 Caucasian American (CA) and 187 African American (AA) patients with chronic genotype 1 infection. ELISPOT responses were examined relative to human leukocyte antigen (HLA) class II alleles and outcome of therapy with pegylated IFN and ribavirin. Th1 responses specific to hepatitis C core protein and combined HCV antigens were significantly lower in AAs compared to CAs, but CMV responses were comparable in the 2 races. The HCV difference in immunity remained after adjusting for gender, serum alanine aminotransferase, histologic severity, and viral level, and was not accounted for by the differential prevalence of human leukocyte antigen class II alleles. Pretreatment total HCV-specific CD4+ T cell response was associated with sustained virologic response (SVR) to pegylated IFN and ribavirin; 43% of patients who had more than 168 ELISPOTs/10(6) peripheral blood mononuclear cells (above background) experienced SVR compared to 28% of those who did not (P= 0.007). ELISPOT response was independently associated with SVR by multivariable analysis. CONCLUSION: Compared to CAs, AAs have weaker HCV-specific immunity. Pretreatment HCV-specific immunity is associated with response to combination antiviral therapy.

Time-related risk of the St. Jude Silzone heart valve.

OBJECTIVE: The St. Jude Medical Silzone heart valve had a silver-impregnated sewing ring designed to reduce the incidence of prosthetic valve endocarditis. Recruitment to the randomized AVERT study comparing Silzone valves with non-Silzone Control valves was stopped because of an increased risk of reoperation for paravalvular leak, but patient follow-up continues. Determining the time-related risk profile of the Silzone valve is important for helping physicians manage the approximately 28,000 patients currently alive with a Silzone valve. METHODS: Between 1998 and 2000, 403 Silzone and 404 Control patients were enrolled in AVERT. As of July 2005, there were 1819 Silzone and 1842 Control patient-years of follow-up (mean 4.5, median 5.1 years). Analysis emphasized the use and interpretation of hazard functions, since they are more meaningful than event-free percentages to currently surviving patients. To this end, instead of Cox regression, which estimates the hazard ratio, assuming it is constant over time, we employed primarily Aalen additive regression, which measures the hazard difference, and produces a plot of it over time. We assessed the risks of major paravalvular leak, endocarditis, bleeding and thrombo-embolism. RESULTS: The Silzone valve had a higher initial risk of major paravalvular leak than Control in the mitral (p=0.02) position, but not in the aortic (p=0.42) position. Analysis of this risk using additive regression, with all valve positions combined, showed that the initial risk due to Silzone lost statistical significance by 2 years and disappeared by 4 years after implant. In the mitral position, the Silzone valve had a higher initial risk of thrombo-embolism plus bleeding than Control; this risk also lost statistical significance by 2 years and subsided to zero by 4 years. The risks for death and endocarditis were similar for Slizone and Control valves. CONCLUSIONS: The additional risks of the Silzone valve, compared to Control, diminish over time and disappear by 4 years after implant. The minimum time after implant of the patients currently alive with Silzone is now well beyond 5 years; thus, these current patients now have a risk profile similar to that of patients with a standard St. Jude valve.