Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Cratonic basin formation: a case study of the Parnaíba Basin of Brazil

Cratonic basins comprise a significant component of the Earth's continental crust and surface geology. Their subcircular form and large areas of flat-lying, largely undeformed sedimentary rocks characterize the central regions of many continents, and are also a significant habitat for water, mineral and petroleum resources. These basinal regions have been extensively studied, yet there is little consensus on the driving mechanism of their subsidence or their greater tectonic context. Here we present the results of an integrated basin analysis of the Paleozoic–Early Mesozoic Parnaíba cratonic basin of NE Brazil. The analysis integrates existing geological and geophysical data, and a new deep-crustal geophysical dataset, to determine the deep structure of the basin and the underlying crust and mantle. Several major features have emerged from this which constrain the basins genesis: (1) continental–shallow-marine stratigraphy characterized by an exponentially decreasing tectonic subsidence with a relatively long time constant of the order of 70–90 myr; (2) a complex Proterozoic–Early Paleozoic basement that comprises at least three major crustal blocks defined by seismic facies and conductivity contrasts with no evidence of an extensive rift system beneath the basin; (3) a mid-crustal fabric that appears to define the top of a dense and seismically fast lower crust (Vp 6.7–6.8 km s−1 and Vs 3.7–3.8 km s−1) and upper mantle (Vp 8.2–8.4 km s−1) directly beneath the basin, and which correlates with a sediment-corrected Bouger gravity anomaly high of +40–60 mGal; (4) a Moho that is generally as deep or deeper beneath the basin (40–45 km) than its surrounding region (34–40 km), and which appears stepped at the terrane boundaries; (5) a relatively conductive crust and upper mantle beneath the basin, and relatively resistive crust along the boundaries of the basement blocks; and (6) igneous events immediately before and after formation of the cratonic megasequence and a geochemically enriched mantle beneath the basin that sourced two major episodes of Mesozoic igneous intrusions. These latter events are responsible for the development of an atypical gas-prone petroleum system dependent on local magmatic events for heat generation and trapping configurations. The data describing these features are presented and discussed, and their implications used to draw conclusions about the formation of the Parnaíba Basin specifically and cratonic basins more generally

Cratonic basin formation: a case study of the Parnaíba Basin of Brazil

Cratonic basins comprise a significant component of the Earth's continental crust and surface geology. Their subcircular form and large areas of flat-lying, largely undeformed sedimentary rocks characterize the central regions of many continents, and are also a significant habitat for water, mineral and petroleum resources. These basinal regions have been extensively studied, yet there is little consensus on the driving mechanism of their subsidence or their greater tectonic context. Here we present the results of an integrated basin analysis of the Paleozoic–Early Mesozoic Parnaíba cratonic basin of NE Brazil. The analysis integrates existing geological and geophysical data, and a new deep-crustal geophysical dataset, to determine the deep structure of the basin and the underlying crust and mantle. Several major features have emerged from this which constrain the basins genesis: (1) continental–shallow-marine stratigraphy characterized by an exponentially decreasing tectonic subsidence with a relatively long time constant of the order of 70–90 myr; (2) a complex Proterozoic–Early Paleozoic basement that comprises at least three major crustal blocks defined by seismic facies and conductivity contrasts with no evidence of an extensive rift system beneath the basin; (3) a mid-crustal fabric that appears to define the top of a dense and seismically fast lower crust (Vp 6.7–6.8 km s−1 and Vs 3.7–3.8 km s−1) and upper mantle (Vp 8.2–8.4 km s−1) directly beneath the basin, and which correlates with a sediment-corrected Bouger gravity anomaly high of +40–60 mGal; (4) a Moho that is generally as deep or deeper beneath the basin (40–45 km) than its surrounding region (34–40 km), and which appears stepped at the terrane boundaries; (5) a relatively conductive crust and upper mantle beneath the basin, and relatively resistive crust along the boundaries of the basement blocks; and (6) igneous events immediately before and after formation of the cratonic megasequence and a geochemically enriched mantle beneath the basin that sourced two major episodes of Mesozoic igneous intrusions. These latter events are responsible for the development of an atypical gas-prone petroleum system dependent on local magmatic events for heat generation and trapping configurations. The data describing these features are presented and discussed, and their implications used to draw conclusions about the formation of the Parnaíba Basin specifically and cratonic basins more generally

Deep marine slide and channel deposits from the Jurassic-Cretaceous Fossil Bluff Group, Alexander Island, Antarctica

The Fossil Bluff Grqup (FBG: ?Bathpnian-Albian) is the fill of a forearc basin which lay between the Antarctic Peninsula volcanic arc and an accretionary complex (LeMay Group) to the west (Figs 8.1 and 8.2). Volcanism in the arc, and accretion and deformation in the LeMay Group, were contemporaneous with sedimentation in the forearc basin. The basin was inverted during Late Cretaceous or Tertiary times during an episode of dextral transpressive deformation (Storey and Nell 1988). Tertiary igneous rocks in central and northern Alexander Island reflect arc migration, followed by Neogene extension