Lipoprotein‐Associated Phospholipase A2 Activity Is a Marker of Risk But Not a Useful Target for Treatment in Patients With Stable Coronary Heart Disease

Background: We evaluated lipoprotein‐associated phospholipase A2 (Lp‐PLA2) activity in patients with stable coronary heart disease before and during treatment with darapladib, a selective Lp‐PLA2 inhibitor, in relation to outcomes and the effects of darapladib in the STABILITY trial. Methods and Results: Plasma Lp‐PLA2 activity was determined at baseline (n=14 500); at 1 month (n=13 709); serially (n=100) at 3, 6, and 18 months; and at the end of treatment. Adjusted Cox regression models evaluated associations between Lp‐PLA2 activity levels and outcomes. At baseline, the median Lp‐PLA2 level was 172.4 μmol/min per liter (interquartile range 143.1–204.2 μmol/min per liter). Comparing the highest and lowest Lp‐PLA2 quartile groups, the hazard ratios were 1.50 (95% CI 1.23–1.82) for the primary composite end point (cardiovascular death, myocardial infarction, or stroke), 1.95 (95% CI 1.29–2.93) for hospitalization for heart failure, 1.42 (1.07–1.89) for cardiovascular death, and 1.37 (1.03–1.81) for myocardial infarction after adjustment for baseline characteristics, standard laboratory variables, and other prognostic biomarkers. Treatment with darapladib led to a ≈65% persistent reduction in median Lp‐PLA2 activity. There were no associations between on‐treatment Lp‐PLA2 activity or changes of Lp‐PLA2 activity and outcomes, and there were no significant interactions between baseline and on‐treatment Lp‐PLA2 activity or changes in Lp‐PLA2 activity levels and the effects of darapladib on outcomes. Conclusions: Although high Lp‐PLA2 activity was associated with increased risk of cardiovascular events, pharmacological lowering of Lp‐PLA2 activity by ≈65% did not significantly reduce cardiovascular events in patients with stable coronary heart disease, regardless of the baseline level or the magnitude of change of Lp‐PLA2 activity

Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction

Background: Unfractionated heparin is often used as adjunctive therapy with fibrinolysis in patients with ST-elevation myocardial infarction. We compared a low-molecular-weight heparin, enoxaparin, with unfractionated heparin for this purpose. Methods: We randomly assigned 20,506 patients with ST-elevation myocardial infarction who were scheduled to undergo fibrinolysis to receive enoxaparin throughout the index hospitalization or weight-based unfractionated heparin for at least 48 hours. The primary efficacy end point was death or nonfatal recurrent myocardial infarction through 30 days. Results: The primary end point occurred in 12.0 percent of patients in the unfractionated heparin group and 9.9 percent of those in the enoxaparin group (17 percent reduction in relative risk, P<0.001). Nonfatal reinfarction occurred in 4.5 percent of the patients receiving unfractionated heparin and 3.0 percent of those receiving enoxaparin (33 percent reduction in relative risk, P<0.001); 7.5 percent of patients given unfractionated heparin died, as did 6.9 percent of those given enoxaparin (P=0.11). The composite of death, nonfatal reinfarction, or urgent revascularization occurred in 14.5 percent of patients given unfractionated heparin and 11.7 percent of those given enoxaparin (P<0.001); major bleeding occurred in 1.4 percent and 2.1 percent, respectively (P<0.001). The composite of death, nonfatal reinfarction, or nonfatal intracranial hemorrhage (a measure of net clinical benefit) occurred in 12.2 percent of patients given unfractionated heparin and 10.1 percent of those given enoxaparin (P<0.001). Conclusions: In patients receiving fibrinolysis for ST-elevation myocardial infarction, treatment with enoxaparin throughout the index hospitalization is superior to treatment with unfractionated heparin for 48 hours but is associated with an increase in major bleeding episodes. These findings should be interpreted in the context of net clinical benefit

Impact of Diabetes Mellitus and Chronic Kidney Disease on Cardiovascular Outcomes and Platelet P2Y(12) Receptor Antagonist Effects in Patients With Acute Coronary Syndromes : Insights From the PLATO Trial

Background-There are limited data on how the combination of diabetes mellitus (DM) and chronic kidney disease (CKD) affects cardiovascular outcomes as well as response to different P2Y(12) receptor antagonists, which represented the aim of the present investigation. Methods and Results-In this post hoc analysis of the PLATO (Platelet Inhibition and Patient Outcomes) trial, which randomized acute coronary syndrome patients to ticagrelor versus clopidogrel, patients (n=15 108) with available DM and CKD status were classified into 4 groups: DM+/CKD+ (n=1058), DM+/CKD- (n=2748), DM-/CKD+ (n=2160), and DM-/CKD- (n=9142). The primary efficacy end point was a composite of cardiovascular death, myocardial infarction, or stroke at 12 months. The primary safety end point was PLATO major bleeding. DM+/CKD+ patients had a higher incidence of the primary end point compared with DM-/CKD- patients (23.3% versus 7.1%; adjusted hazard ratio 2.22; 95% CI 1.88-2.63; P Conclusions-In acute coronary syndrome patients, a gradient of risk was observed according to the presence or absence of DM and CKD, with patients having both risk factors at the highest risk. Although the ischemic benefit of ticagrelor over clopidogrel was consistent in all subgroups, the absolute risk reduction was greatest in patients with both DM and CKD.Peer reviewe

Effect of enoxaparin versus unfractionated heparin in diabetic patients with ST-elevation myocardial infarction in the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction study 25 (ExTRACT-TIMI 25) trial

Background Patients with diabetes mellitus (DM) are at higher risk for complications after ST-elevation myocardial infarction (STEMI) than patients without DM. Potent antithrombotic therapies may offer particular benefit for these high-risk patients and must be balanced against the potential for increased bleeding

Abstract 16662: GDF-15: Association With Pulmonary Hemodynamic Indices and Reduction With Serelaxin in Acute Heart Failure

Background: Growth differentiation factor 15 (GDF-15) appears to have a role in regulating inflammation and apoptosis and is up-regulated following injury to the liver, kidney, heart and lung. Elevated baseline (BL) levels of GDF-15 and increases over time have been shown to be associated with adverse events in heart failure (HF). GDF-15 was decreased following LVAD implantation and cardiac unloading in end stage HF. As previously reported, serelaxin improved Pulmonary Capillary Wedge Pressure (PCWP), mean Pulmonary Artery Pressure (mPAP), and Pulmonary Vascular Resistance (PVR) during a 20 h infusion period (all p&lt;0.005 vs. placebo [PBO]). A post-hoc analysis was performed to explore serelaxin effects on GDF-15 in acute HF (AHF) and whether GDF-15 is associated with pulmonary hemodynamics. Methods: Following serelaxin (30 ug/kg/d) or PBO infusion for 20 h in AHF patients, PCWP, mPAP, PVR, NTproBNP (Roche Diagnostics) and GDF-15 (pre-commercial kit, Roche Diagnostics) were measured in 32 serelaxin and 31 PBO treated patients. The effect of serelaxin on GDF-15 and NTproBNP was analyzed and the potential association of GDF-15 or NTproBNP with selected hemodynamic indices was explored combining treatment data from the two treatment arms. Results: Following the 20 h infusion period, serelaxin reduced GDF-15 vs BL (BL median 3192 pg/ml) by 16% (serelaxin vs PBO p=0.021) and reduced NTproBNP (BL median 3262 pg/ml) by 13% (serelaxin vs PBO p=0.021). GDF-15 at BL and 20 h was significantly associated with BL and 20 h NTproBNP (both p&lt;0.001), mPAP (both p&lt;0.025), and PVR (both p&lt;0.001). At 20 h GDF-15 and PCWP were significantly associated (p&lt;0.02) but their association at BL was not statistically significant (p=0.70). The association of NTproBNP at BL and 20 h was not statistically significant for BL or 20 h PCWP, mPAP or PVR (all p &gt;0.05). Conclusions: In this small invasive hemodynamic study in patients with AHF, serelaxin significantly reduced GDF-15 and NTproBNP and had favorable effects on pulmonary hemodynamics. GDF-15 levels at BL and 20 h showed a strong correlation with BL and 20 h values of mPAP and PVR. Additional studies measuring GDF-15 levels in acute HF patients with pulmonary congestion appear warranted. </jats:p

A randomized, double-blind, placebo-controlled, multicentre study to assess haemodynamic effects of serelaxin in patients with acute heart failure

The aim of this study was to evaluate the haemodynamic effects of serelaxin (30 µg/kg/day 20-h infusion and 4-h post-infusion period) in patients with acute heart failure (AHF)

Randomized, Double-Blind Study Comparing Saruplase With Streptokinase Therapy in Acute Myocardial Infarction: The COMPASS Equivalence Trial fn1fn1This study was supported by Grünenthal GmbH, the manufacturer of saruplase.

AbstractObjectives. This study sought to demonstrate the equivalence of saruplase and streptokinase in terms of 30-day mortality.Background. The use of thrombolytic agents in the treatment of acute myocardial infarction is well established and has been shown to substantially reduce post-myocardial infarction mortality.Methods. Three thousand eighty-nine patients with symptoms compatible with those of acute myocardial infarction for <6 h entered the study at a total of 104 centers and were randomized to receive streptokinase (1.5-MU infusion over 60 min) or saruplase (20-mg bolus and 60-mg infusion over 60 min). In the saruplase group, a bolus of heparin (5,000 IU) was administered before saruplase, and a corresponding blinded double-dummy placebo bolus was administered before streptokinase. All patients received intravenous heparin infusions for ≥24 h starting 30 min after the end of the thrombolytic infusions; the infusions were titrated to maintain an activated partial thromboplastin time at 1.5 to 2.5 times that of normal.Results. Death of any cause up to 30 days after randomization occurred in 88 (5.7%) of 1,542 patients randomized to receive saruplase and 104 (6.7%) of 1,547 patients randomized to receive streptokinase (odds ratio 0.84, p < 0.01 for equivalence). Hemorrhagic strokes occurred more often in patients receiving saruplase (0.9% vs. 0.3%), whereas thromboembolic strokes were more prevalent in the streptokinase-treated patients (0.5% vs. 1.0%). The rate of bleeding was similar in the two treatment groups (10.4% vs. 10.9%). Hypotension and cardiogenic shock occurred less frequently in the saruplase group. Reinfarction rates were similar.Conclusions. Saruplase is a clinically safe and effective thrombolytic medication. This profile ranks saruplase favorably among the currently available thrombolytic agents