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

Evacetrapib and Cardiovascular Outcomes in High-Risk Vascular Disease

BACKGROUND: The cholesteryl ester transfer protein inhibitor evacetrapib substantially raises the high-density lipoprotein (HDL) cholesterol level, reduces the low-density lipoprotein (LDL) cholesterol level, and enhances cellular cholesterol efflux capacity. We sought to determine the effect of evacetrapib on major adverse cardiovascular outcomes in patients with high-risk vascular disease. METHODS: In a multicenter, randomized, double-blind, placebo-controlled phase 3 trial, we enrolled 12,092 patients who had at least one of the following conditions: an acute coronary syndrome within the previous 30 to 365 days, cerebrovascular atherosclerotic disease, peripheral vascular arterial disease, or diabetes mellitus with coronary artery disease. Patients were randomly assigned to receive either evacetrapib at a dose of 130 mg or matching placebo, administered daily, in addition to standard medical therapy. The primary efficacy end point was the first occurrence of any component of the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS: At 3 months, a 31.1% decrease in the mean LDL cholesterol level was observed with evacetrapib versus a 6.0% increase with placebo, and a 133.2% increase in the mean HDL cholesterol level was seen with evacetrapib versus a 1.6% increase with placebo. After 1363 of the planned 1670 primary end-point events had occurred, the data and safety monitoring board recommended that the trial be terminated early because of a lack of efficacy. After a median of 26 months of evacetrapib or placebo, a primary end-point event occurred in 12.9% of the patients in the evacetrapib group and in 12.8% of those in the placebo group (hazard ratio, 1.01; 95% confidence interval, 0.91 to 1.11; P=0.91). CONCLUSIONS: Although the cholesteryl ester transfer protein inhibitor evacetrapib had favorable effects on established lipid biomarkers, treatment with evacetrapib did not result in a lower rate of cardiovascular events than placebo among patients with high-risk vascular disease. (Funded by Eli Lilly; ACCELERATE ClinicalTrials.gov number, NCT01687998 .)

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

EVAR : critical applied aortic morphology relevant to type-II endoleaks following device enhancement in patients with abdominal aortic aneurysms

The original publication is available at http://www.cvja.co.za/Endovascular repair (EVAR) of abdominal aortic aneurysms (AAA) is an established alternative option to conventional surgery for AAA, provided optimal anatomical morphology of the aneurysm sac, neck and outflow exists. In most documented series of EVAR, type-II endoleak occurrence is a universal procedural drawback. This is referred to as the Achilles heel of EVAR. This morphological study, addressing predominantly non-aneurysmal aortic anatomy, reveals the dyssynchronous origins of the renal ostia, ectopia of the superior mesenteric artery and median sacral artery, variations in the length of the infrarenal abdominal aorta, multiple mainstem renal arteries, and the presence of accessory renal arteries (in 13% of cadavers). Such potential vascular anomalies need careful consideration pre-operatively prior to EVAR. In a prospective, clinical study of EVAR in 163 patients over 60 months, using four different aortic stent devices, we demonstrated an intraprocedural type-II endoleak rate, before exclusion, of 3% (5/163). Most were related to patent lumbar arteries. An active policy of intraprocedural aneurysm pressure sac measurement and angiography was used to demonstrate type-I and type-II endoleaks, focusing on the applied anatomy of aortic side branches and variations. Selective intraprocedural coil embolisation and thrombin injection into the sac was utilised to thrombose persisting and large lumbar arteries that predisposed to retroleaks. We recorded a low incidence of persisting type-II endoleaks using this proactive treatment strategy by addressing variant aortic morphology and patent lumbar arteries during EVAR. One aneurysm-related death (0.6%) was observed due to late rupture after EVAR, and a single intraprocedural death was related to unpredictable aneurysm rupture. In conclusion, comprehensive anatomical knowledge of the abdominal aorta and its main collateral side branches, including variations, is a fundamental prerequisite if satisfactory and predictable results are to be achieved after EVAR, especially regarding prevention, diagnosis and treatment of type-II endoleaks. Intraprocedural aneurysm sac pressure monitoring, coil embolisation and the use of injection of thrombin into the aneurysm sac of selected patients is useful in reducing the incidence of post-EVAR type-II persisting endoleaks.Publishers' versio

The water use of selected fruit tree orchards (volume 2) : technical report on measurement and modelling

Final report to the water research commission and department of agriculture, forestry and fisheries. The water use of selected fruit tree orchards (Volume 2) : technical report on measurements and modelling

EVAR: Critical applied aortic morphology relevant to type-II endoleaks following device enhancement in patients with abdominal aortic aneurysms

Endovascular repair (EVAR) of abdominal aortic aneurysms (AAA) is an established alternative option to conventional surgery for AAA, provided optimal anatomical morphology of the aneurysm sac, neck and outflow exists. In most documented series of EVAR, type-II endoleak occurrence is a universal procedural drawback. This is referred to as the Achilles heel of EVAR. This morphological study, addressing predominantly non-aneurysmal aortic anatomy, reveals the dyssynchronous origins of the renal ostia, ectopia of the superior mesenteric artery and median sacral artery, variations in the length of the infrarenal abdominal aorta, multiple mainstem renal arteries, and the presence of accessory renal arteries (in 13% of cadavers). Such potential vascular anomalies need careful consideration pre-operatively prior to EVAR. In a prospective, clinical study of EVAR in 163 patients over 60 months, using four different aortic stent devices, we demonstrated an intraprocedural type-II endoleak rate, before exclusion, of 3% (5/163). Most were related to patent lumbar arteries. An active policy of intraprocedural aneurysm pressure sac measurement and angiography was used to demonstrate type-I and type-II endoleaks, focusing on the applied anatomy of aortic side branches and variations. Selective intraprocedural coli embolisation and thrombin injection into the sac was utilised to thrombose persisting and large lumbar arteries that predisposed to retroleaks. We recorded a low incidence of persisting type-II endoleaks using this proactive treatment strategy by addressing variant aortic morphology and patent lumbar arteries during EVAR. One aneurysm-related death (0.6%) was observed due to late rupture after EVAR, and a single intraprocedural death was related to unpredictable aneurysm rupture. In conclusion, comprehensive anatomical knowledge of the abdominal aorta and its main collateral side branches, including variations, is a fundamental prerequisite if satisfactory and predictable results are to be achieved after EVAR, especially regarding prevention, diagnosis and treatment of type-II endoleaks. Intraprocedaral aneurysm sac pressure monitoring, coil embolisation and the use of injection of thrombin into the aneurysm sac of selected patients is useful in reducing the incidence of post-EVAR type-II persisting endoleaks.Conference Pape

Carotid stenosis and carotid plaque analysis relevant to carotid endarterectomy and stent-assisted angioplasty

The primary objective of this cadaveric study was to review the morphological variations of the anatomy of the human carotid artery bifurcation relevant to carotid endarterectomy (CEA) and carotid artery stent-supported angioplasty (CSSA). We quantify carotid bifurcation plaque morphology. Results showed that the angle of deviation at the origin of the internal carotid artery (ICA), in relation to the common carotid artery (CCA), measured a mean of 21.8 degrees with a range from seven to 45 degrees. This anatomical finding is important for the interventionalist concerned with insertion of a carotid stent. The angle of the ICA origin may be an independent risk factor for early atherosclerotic changes at the ICA bulb. Carotid bifurcation plaque was observed in a small, random cohort of seven out of 13 cadavers, and contributed to a mean stenosis of 15.2% (range 5.0-34.8%). Plaque morphology (n = 7) showed haemorrhage (29%), superficial thrombosis (57%), calcification (71%), areas of focal necrosis (71%), neovascularisation (14%) and infiltrates (29%). Ulcerations were not detected. Although four out of 13 patients (31%) died of a cerebrovascular accident, the cause of cerebral apoplexy was thought not to be associated with the carotid bifurcation pathology. 'Re-boring' of occluding plaque, as in CEA, offers potential volumetric anatomical advantage over CSSA within the carotid bifurcation and bulb. In conclusion, precise and applied knowledge of carotid bifurcation anatomy is critical to reduce technical complications during CEA or CSSA. This information may reduce potential dangers of iatrogenic thrombo-embolism and ensuing neurologic deficits. Patients with low-grade carotid stenosis, evidence of focal plaque necrosis, are at risk of spontaneous plaque cap rupture, distal thrombo-embolism and stroke.Revie

Alirocumab and cardiovascular outcomes after acute coronary syndrome

BACKGROUND Patients who have had an acute coronary syndrome are at high risk for recurrent ischemic cardiovascular events. We sought to determine whether alirocumab, a human monoclonal antibody to proprotein convertase subtilisin-kexin type 9 (PCSK9), would improve cardiovascular outcomes after an acute coronary syndrome in patients receiving high-intensity statin therapy. METHODS We conducted a multicenter, randomized, double-blind, placebo-controlled trial involving 18,924 patients who had an acute coronary syndrome 1 to 12 months earlier, had a low-density lipoprotein (LDL) cholesterol level of at least 70 mg per deciliter (1.8 mmol per liter), a non-highdensity lipoprotein cholesterol level of at least 100 mg per deciliter (2.6 mmol per liter), or an apolipoprotein B level of at least 80 mg per deciliter, and were receiving statin therapy at a high-intensity dose or at the maximum tolerated dose. Patients were randomly assigned to receive alirocumab subcutaneously at a dose of 75 mg (9462 patients) or matching placebo (9462 patients) every 2 weeks. The dose of alirocumab was adjusted under blinded conditions to target an LDL cholesterol level of 25 to 50 mg per deciliter (0.6 to 1.3 mmol per liter). The primary end point was a composite of death from coronary heart disease, nonfatal myocardial infarction, fatal or nonfatal ischemic stroke, or unstable angina requiring hospitalization. RESULTS The median duration of follow-up was 2.8 years. A composite primary end-point event occurred in 903 patients (9.5%) in the alirocumab group and in 1052 patients (11.1%) in the placebo group (hazard ratio, 0.85; 95% confidence interval [CI], 0.78 to 0.93; P<0.001). A total of 334 patients (3.5%) in the alirocumab group and 392 patients (4.1%) in the placebo group died (hazard ratio, 0.85; 95% CI, 0.73 to 0.98). The absolute benefit of alirocumab with respect to the composite primary end point was greater among patients who had a baseline LDL cholesterol level of 100 mg or more per deciliter than among patients who had a lower baseline level. The incidence of adverse events was similar in the two groups, with the exception of local injection-site reactions (3.8% in the alirocumab group vs. 2.1% in the placebo group). CONCLUSIONS Among patients who had a previous acute coronary syndrome and who were receiving highintensity statin therapy, the risk of recurrent ischemic cardiovascular events was lower among those who received alirocumab than among those who received placebo

Evolocumab and clinical outcomes in patients with cardiovascular disease

peer reviewedBACKGROUND Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. © 2017 Massachusetts Medical Society