| 1. |
- Hagström, Emil, et al.
(författare)
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Apolipoprotein B, Residual Cardiovascular Risk After Acute Coronary Syndrome, and Effects of Alirocumab
- 2022
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Ingår i: Circulation. - : Ovid Technologies (Wolters Kluwer Health). - 0009-7322 .- 1524-4539. ; 146:9, s. 657-672
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Apolipoprotein B (apoB) provides an integrated measure of atherogenic risk. Whether apoB levels and apoB lowering hold incremental predictive information on residual risk after acute coronary syndrome beyond that provided by low-density lipoprotein cholesterol is uncertain. METHODS: The ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) compared the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome and elevated atherogenic lipoproteins despite optimized statin therapy. Primary outcome was major adverse cardiovascular events (MACE; coronary heart disease death, nonfatal myocardial infarction, fatal/nonfatal ischemic stroke, hospitalization for unstable angina). Associations between baseline apoB or apoB at 4 months and MACE were assessed in adjusted Cox proportional hazards and propensity score-matched models. RESULTS: Median follow-up was 2.8 years. In proportional hazards analysis in the placebo group, MACE incidence increased across increasing baseline apoB strata (3.2 [95% CI, 2.9-3.6], 4.0 [95% CI, 3.6-4.5], and 5.5 [95% CI, 5.0-6.1] events per 100 patient-years in strata <75, 75-<90, >= 90 mg/dL, respectively; P-trend<0.0001) and after adjustment for low-density lipoprotein cholesterol (P-trend=0.035). Higher baseline apoB stratum was associated with greater relative (P-trend<0.0001) and absolute reduction in MACE with alirocumab versus placebo. In the alirocumab group, the incidence of MACE after month 4 decreased monotonically across decreasing achieved apoB strata (4.26 [95% CI, 3.78-4.79], 3.09 [95% CI, 2.69-3.54], and 2.41 [95% CI, 2.11-2.76] events per 100 patient-years in strata >= 50, >35-<50, and <= 35 mg/dL, respectively). Compared with propensity score-matched patients from the placebo group, treatment hazard ratios for alirocumab also decreased monotonically across achieved apoB strata. Achieved apoB was predictive of MACE after adjustment for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol but not vice versa. CONCLUSIONS: In patients with recent acute coronary syndrome and elevated atherogenic lipoproteins, MACE increased across baseline apoB strata. Alirocumab reduced MACE across all strata of baseline apoB, with larger absolute reductions in patients with higher baseline levels. Lower achieved apoB was associated with lower risk of MACE, even after accounting for achieved low-density lipoprotein cholesterol or non-high-density lipoprotein cholesterol, indicating that apoB provides incremental information. Achievement of apoB levels as low as <= 35 mg/dL may reduce lipoprotein-attributable residual risk after acute coronary syndrome.
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| 2. |
- Chiang, Chern-En, et al.
(författare)
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Alirocumab and Cardiovascular Outcomes in Patients With Previous Myocardial Infarction : Prespecified Subanalysis From ODYSSEY OUTCOMES
- 2022
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Ingår i: Canadian Journal of Cardiology. - : Elsevier. - 0828-282X .- 1916-7075. ; 38:10, s. 1542-1549
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: After acute coronary syndrome (ACS), patients with a previous myocardial infarction (MI) may be at particularly high risk for major adverse cardiovascular events (MACE) and death. We studied the effects of the PCSK9 inhibitor alirocumab in patients with recent ACS according to previous history of MI.METHODS: The ODYSSEY OUTCOMES trial compared alirocumab with placebo, beginning 1 to 12 months after ACS with median 2.8-year follow-up. The primary MACE outcome comprised death from coronary heart disease, nonfatal MI, fatal or nonfatal ischemic stroke, and hospitalization for unstable angina. Of 18,924 patients, 3633 (19.2%) had previous MI.RESULTS: Patients with previous MI were older, more likely male, with more cardiovascular risk factors and previous events. With placebo, 4-year risks of MACE and death were higher among those with vs without previous MI (20.5% vs 8.9%, P < 0.001; 7.4% vs 3.4%, P < 0.001, respectively). Alirocumab reduced the risk of events regardless of the presence or absence of a history of MI (MACE, adjusted hazard ratio [aHR] 0.90, 95% confidence interval [CI], 0.78-1.05 vs 0.82, 0.73-0.92; Pinteraction = 0.34; death, aHR 0.84; 95% CI, 0.64-1.08 vs 0.87, 0.72-1.05; Pinteraction = 0.81). Estimated absolute risk reductions with alirocumab were numerically greater with vs without previous MI (MACE, 1.91% vs 1.42%; death, 1.35% vs 0.41%).CONCLUSIONS: A previous history of MI places patients with recent ACS at high risk for recurrent MACE and death. Alirocumab reduced the relative risks of these events consistently in patients with or without previous MI but with numerically greater absolute benefit in the former subgroup. (ODYSSEY OUTCOMES: NCT01663402).
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| 3. |
- Mauritsen, Thorsten, et al.
(författare)
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Developments in the MPI-M Earth System Model version 1.2 (MPI-ESM1.2) and Its Response to Increasing CO2
- 2019
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Ingår i: Journal of Advances in Modeling Earth Systems. - 1942-2466. ; 11:4, s. 998-1038
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Tidskriftsartikel (refereegranskat)abstract
- A new release of the Max Planck Institute for Meteorology Earth System Model version 1.2 (MPI-ESM1.2) is presented. The development focused on correcting errors in and improving the physical processes representation, as well as improving the computational performance, versatility, and overall user friendliness. In addition to new radiation and aerosol parameterizations of the atmosphere, several relatively large, but partly compensating, coding errors in the model's cloud, convection, and turbulence parameterizations were corrected. The representation of land processes was refined by introducing a multilayer soil hydrology scheme, extending the land biogeochemistry to include the nitrogen cycle, replacing the soil and litter decomposition model and improving the representation of wildfires. The ocean biogeochemistry now represents cyanobacteria prognostically in order to capture the response of nitrogen fixation to changing climate conditions and further includes improved detritus settling and numerous other refinements. As something new, in addition to limiting drift and minimizing certain biases, the instrumental record warming was explicitly taken into account during the tuning process. To this end, a very high climate sensitivity of around 7 K caused by low-level clouds in the tropics as found in an intermediate model version was addressed, as it was not deemed possible to match observed warming otherwise. As a result, the model has a climate sensitivity to a doubling of CO2 over preindustrial conditions of 2.77 K, maintaining the previously identified highly nonlinear global mean response to increasing CO2 forcing, which nonetheless can be represented by a simple two-layer model.
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| 4. |
- Schwartz, Gregory G, et al.
(författare)
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Lipoprotein(a) and Benefit of PCSK9 Inhibition in Patients With Nominally Controlled LDL Cholesterol.
- 2021
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Ingår i: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 78:5, s. 421-433
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Guidelines recommend nonstatin lipid-lowering agents in patients at very high risk for major adverse cardiovascular events (MACE) if low-density lipoprotein cholesterol (LDL-C) remains ≥70 mg/dL on maximum tolerated statin treatment. It is uncertain if this approach benefits patients with LDL-C near 70 mg/dL. Lipoprotein(a) levels may influence residual risk.OBJECTIVES: In a post hoc analysis of the ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) trial, the authors evaluated the benefit of adding the proprotein subtilisin/kexin type 9 inhibitor alirocumab to optimized statin treatment in patients with LDL-C levels near 70 mg/dL. Effects were evaluated according to concurrent lipoprotein(a) levels.METHODS: ODYSSEY Outcomes compared alirocumab with placebo in 18,924 patients with recent acute coronary syndromes receiving optimized statin treatment. In 4,351 patients (23.0%), screening or randomization LDL-C was <70 mg/dL (median 69.4 mg/dL; interquartile range: 64.3-74.0 mg/dL); in 14,573 patients (77.0%), both determinations were ≥70 mg/dL (median 94.0 mg/dL; interquartile range: 83.2-111.0 mg/dL).RESULTS: In the lower LDL-C subgroup, MACE rates were 4.2 and 3.1 per 100 patient-years among placebo-treated patients with baseline lipoprotein(a) greater than or less than or equal to the median (13.7 mg/dL). Corresponding adjusted treatment hazard ratios were 0.68 (95% confidence interval [CI]: 0.52-0.90) and 1.11 (95% CI: 0.83-1.49), with treatment-lipoprotein(a) interaction on MACE (Pinteraction = 0.017). In the higher LDL-C subgroup, MACE rates were 4.7 and 3.8 per 100 patient-years among placebo-treated patients with lipoprotein(a) >13.7 mg/dL or ≤13.7 mg/dL; corresponding adjusted treatment hazard ratios were 0.82 (95% CI: 0.72-0.92) and 0.89 (95% CI: 0.75-1.06), with Pinteraction = 0.43.CONCLUSIONS: In patients with recent acute coronary syndromes and LDL-C near 70 mg/dL on optimized statin therapy, proprotein subtilisin/kexin type 9 inhibition provides incremental clinical benefit only when lipoprotein(a) concentration is at least mildly elevated. (ODYSSEY Outcomes: Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab; NCT01663402).
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| 5. |
- Schwartz, Gregory G, et al.
(författare)
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Relation of Lipoprotein(a) Levels to Incident Type 2 Diabetes and Modification by Alirocumab Treatment.
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 0149-5992 .- 1935-5548. ; 44:5, s. 1219-1227
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: In observational data, lower levels of lipoprotein(a) have been associated with greater prevalence of type 2 diabetes. Whether pharmacologic lowering of lipoprotein(a) influences incident type 2 diabetes is unknown. We determined the relationship of lipoprotein(a) concentration with incident type 2 diabetes and effects of treatment with alirocumab, a PCSK9 inhibitor.RESEARCH DESIGN AND METHODS: In the ODYSSEY OUTCOMES trial alirocumab was compared with placebo in patients with acute coronary syndrome. Incident diabetes was determined from laboratory, medication, and adverse event data.RESULTS: Among 13,480 patients without diabetes at baseline, 1,324 developed type 2 diabetes over a median 2.7 years. Median baseline lipoprotein(a) was 21.9 mg/dL. With placebo, 10 mg/dL lower baseline lipoprotein(a) was associated with hazard ratio 1.04 (95% CI 1.02-1.06, P < 0.001) for incident type 2 diabetes. Alirocumab reduced lipoprotein(a) by a median 23.2% with greater absolute reductions from higher baseline levels and no overall effect on incident type 2 diabetes (hazard ratio 0.95, 95% CI 0.85-1.05). At low baseline lipoprotein(a) levels, alirocumab tended to reduce incident type 2 diabetes, while at high baseline lipoprotein(a) alirocumab tended to increase incident type 2 diabetes compared with placebo (treatment-baseline lipoprotein(a) interaction P = 0.006). In the alirocumab group, a 10 mg/dL decrease in lipoprotein(a) from baseline was associated with hazard ratio 1.07 (95% CI 1.03-1.12; P = 0.0002) for incident type 2 diabetes.CONCLUSIONS: In patients with acute coronary syndrome, baseline lipoprotein(a) concentration associated inversely with incident type 2 diabetes. Alirocumab had neutral overall effect on incident type 2 diabetes. However, treatment-related reductions in lipoprotein(a), more pronounced from high baseline levels, were associated with increased risk of incident type 2 diabetes. Whether these findings pertain to other therapies that reduce lipoprotein(a) is undetermined.
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