Clopidogrel versus ticagrelor or prasugrel in patients aged 70 years or older with non-ST-elevation acute coronary syndrome (POPular AGE): the randomised, open-label, non-inferiority trial.

BACKGROUND: Current guidelines recommend potent platelet inhibition with ticagrelor or prasugrel in patients after an acute coronary syndrome. However, data about optimal platelet inhibition in older patients are scarce. We aimed to investigate the safety and efficacy of clopidogrel compared with ticagrelor or prasugrel in older patients with non-ST-elevation acute coronary syndrome (NSTE-ACS). METHODS: We did the open-label, randomised controlled POPular AGE trial in 12 sites (ten hospitals and two university hospitals) in the Netherlands. Patients aged 70 years or older with NSTE-ACS were enrolled and randomly assigned in a 1:1 ratio using an internet-based randomisation procedure with block sizes of six to receive a loading dose of clopidogrel 300 mg or 600 mg, or ticagrelor 180 mg or prasugrel 60 mg, and then a maintenance dose for the duration of 12 months (clopidogrel 75 mg once daily, ticagrelor 90 mg twice daily, or prasugrel 10 mg once daily) on top of standard care. Patient and treating physicians were aware of the allocated treatment strategy, but the outcome assessors were masked to treatment allocation. Primary bleeding outcome consisted of PLATelet inhibition and patient Outcomes (PLATO; major or minor bleeding [superiority hypothesis]). Co-primary net clinical benefit outcome consisted of all-cause death, myocardial infarction, stroke, PLATO major and minor bleeding (non-inferiority hypothesis, margin of 2%). Follow-up duration was 12 months. Analyses were done on intention-to-treat basis. This trial is registered with the Netherlands Trial Register (NL3804), ClinicalTrials.gov (NCT02317198), and EudraCT (2013-001403-37). FINDINGS: Between June 10, 2013, and Oct 17, 2018, 1002 patients were randomly assigned to clopidogrel (n=500) or ticagrelor or prasugrel (n=502). Because 475 (95%) patients received ticagrelor in the ticagrelor or prasugrel group, we will refer to this group as the ticagrelor group. Premature discontinuation of the study drug occurred in 238 (47%) of 502 ticagrelor group patients randomly assigned to ticagrelor, and in 112 (22%) of 500 patients randomly assigned to clopidogrel. Primary bleeding outcome was significantly lower in the clopidogrel group (88 [18%] of 500 patients) than in the ticagrelor group (118 [24%] of 502; hazard ratio 0·71, 95% CI 0·54 to 0·94; p=0·02 for superiority). Co-primary net clinical benefit outcome was non-inferior for the use of clopidogrel (139 [28%]) versus ticagrelor (161 [32%]; absolute risk difference -4%, 95% CI -10·0 to 1·4; p=0·03 for non-inferiority). The most important reasons for discontinuation were occurrence of bleeding (n=38), dyspnoea (n=40), and the need for treatment with oral anticoagulation (n=35). INTERPRETATION: In patients aged 70 years or older presenting with NSTE-ACS, clopidogrel is a favourable alternative to ticagrelor, because it leads to fewer bleeding events without an increase in the combined endpoint of all-cause death, myocardial infarction, stroke, and bleeding. Clopidogrel could be an alternative P2Y12 inhibitor especially for elderly patients with a higher bleeding risk. FUNDING: ZonMw.

Patient-Reported Satisfaction with Thyroid Hormone Replacement Therapy for Subclinical Hypothyroidism in Older Adults: A Pooled Analysis of Individual Participant Data from Two Randomized Controlled Trials.

Background: The benefit of levothyroxine treatment of subclinical hypothyroidism (SCH) is subject to debate. This study compared treatment satisfaction between older adults with SCH using levothyroxine or placebo. Methods: We analyzed pooled individual participant data from two randomized, double-blind, placebo-controlled trials investigating the effects of levothyroxine treatment in older adults with SCH. Community-dwelling participants aged ≥65 years, with SCH (persistent thyrotropin levels 4.60-19.99 mIU/L for >3 months and normal free T4 level), were included. Intervention dose titration until thyrotropin levels normalized, with a mock dose adjustment of placebo. Treatment satisfaction was determined during the final study visit using the Treatment Satisfaction Questionnaire for Medication (TSQM), encompassing perceived effectiveness, side effects, convenience, and global satisfaction, along with the participants' desire to continue study medication after the trial. Results: We included 536 participants. At baseline, the median (interquartile range [IQR]) age was 74.9 (69.7-81.4) years, and 292 (55%) were women. The median (IQR) thyrotropin levels were 5.80 (5.10-7.00) mIU/L at baseline in both groups; at final visit, 4.97 (3.90-6.35) mIU/L in the placebo and 3.24 (2.49-4.41) mIU/L in the levothyroxine group. After treatment, the groups did not differ significantly in global satisfaction (mean difference [CI] -1.1 [-4.5 to 2.1], p = 0.48), nor in any other domain of treatment satisfaction. These results held true regardless of baseline thyrotropin levels or symptom burden. No major differences were found in the numbers of participants who wished to continue medication after the trial (levothyroxine 35% vs. placebo 27%), did not wish to continue (levothyroxine 27% vs. placebo 30%), or did not know (levothyroxine 37% vs. placebo 42%) (p = 0.14). In a subpopulation with high symptom burden from hypothyroid symptoms at baseline, those using levothyroxine more often desired to continue the medication after the trial than those using placebo (mean difference [CI]: -21.1% [-35.6% to -6.5%]). Conclusion: These pooled data from two RCTs showed no major differences in treatment satisfaction between older adults receiving levothyroxine or placebo. This finding has important implications for decision-making regarding initiating levothyroxine treatment for SCH. Our findings generally support refraining from routinely prescribing levothyroxine in older adults with SCH.

The Pharmacogenetics of Statin Therapy on Clinical Events: No Evidence that Genetic Variation Affects Statin Response on Myocardial Infarction.

Background: The pharmacogenetic effect on cardiovascular disease reduction in response to statin treatment has only been assessed in small studies. In a pharmacogenetic genome wide association study (GWAS) analysis within the Genomic Investigation of Statin Therapy (GIST) consortium, we investigated whether genetic variation was associated with the response of statins on cardiovascular disease risk reduction. Methods: The investigated endpoint was incident myocardial infarction (MI) defined as coronary heart disease death and definite and suspect non-fatal MI. For imputed single nucleotide polymorphisms (SNPs), regression analysis was performed on expected allelic dosage and meta-analysed with a fixed-effects model, inverse variance weighted meta-analysis. All SNPs with p-values <5.0 × 10-4 in stage 1 GWAS meta-analysis were selected for further investigation in stage-2. As a secondary analysis, we extracted SNPs from the Stage-1 GWAS meta-analysis results based on predefined hypotheses to possibly modifying the effect of statin therapy on MI. Results: In stage-1 meta-analysis (eight studies, n = 10,769, 4,212 cases), we observed no genome-wide significant results (p < 5.0 × 10-8). A total of 144 genetic variants were followed-up in the second stage (three studies, n = 1,525, 180 cases). In the combined meta-analysis, no genome-wide significant hits were identified. Moreover, none of the look-ups of SNPs known to be associated with either CHD or with statin response to cholesterol levels reached Bonferroni level of significance within our stage-1 meta-analysis. Conclusion: This GWAS analysis did not provide evidence that genetic variation affects statin response on cardiovascular risk reduction. It does not appear likely that genetic testing for predicting effects of statins on clinical events will become a useful tool in clinical practice.

Ticagrelor Versus Clopidogrel in Older Patients with NSTE-ACS Using Oral Anticoagulation: A Sub-Analysis of the POPular Age Trial.

There are no randomised data on which antiplatelet agent to use in elderly patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) and an indication for oral anticoagulation (OAC). The randomised POPular Age trial, in patients of 70 years or older with NSTE-ACS, showed a reduction in bleeding without increasing thrombotic events in patients using clopidogrel as compared to ticagrelor. In this sub-analysis of the POPular AGE trial, we compare clopidogrel with ticagrelor in patients with a need for oral anticoagulation. The follow-up duration was one year. The primary bleeding outcome was Platelet Inhibition and Patient Outcomes (PLATO) major and minor bleeding. The primary thrombotic outcome consisted of cardiovascular death, myocardial infarction and stroke. The primary net clinical benefit outcome was a composite of all-cause death, myocardial infarction, stroke, and PLATO major and minor bleeding. A total of 184/1011 (18.2%) patients on OAC were included in this subanalysis; 83 were randomized to clopidogrel and 101 to ticagrelor. The primary bleeding outcome was lower in the clopidogrel group (17/83, 20.9%) compared to the ticagrelor group (33/101, 33.5%; p = 0.051), as was the thrombotic outcome (7/83, 8.4% vs. 19/101, 19.2%; p = 0.035) and the primary net clinical benefit outcome (23/83, 27.7% vs. 49/101, 48.5%; p = 0.003). In this subgroup of patients using OAC, clopidogrel reduced PLATO major and minor bleeding compared to ticagrelor without increasing thrombotic risk. This analysis therefore suggests that, in line with the POPular Age trial, clopidogrel is a better option than ticagrelor in NSTE-ACS patients ≥70 years using OAC.

Proteomic Bioprofiles and Mechanistic Pathways of Progression to Heart Failure.

Background Identifying the mechanistic pathways potentially associated with incident heart failure (HF) may provide a basis for novel preventive strategies. Methods and Results To identify proteomic biomarkers and the potential underlying mechanistic pathways that may be associated with incident HF defined as the first hospitalization for HF, a nested-matched case-control design was used with cases (incident HF) and controls (without HF) selected from 3 cohorts (>20 000 individuals). Controls were matched on cohort, follow-up time, age, and sex. Two independent sample sets (a discovery set with 286 cases and 591 controls and a replication set with 276 cases and 280 controls) were used to discover and replicate the findings. Two hundred fifty-two circulating proteins in the plasma were studied. Adjusting for the matching variables age, sex, and follow-up time (and correcting for multiplicity of tests), 89 proteins were found to be associated with incident HF in the discovery phase, of which 38 were also associated with incident HF in the replication phase. These 38 proteins pointed to 4 main network clusters underlying incident HF: (1) inflammation and apoptosis, indicated by the expression of the TNF (tumor necrosis factor)-family members; (2) extracellular matrix remodeling, angiogenesis and growth, indicated by the expression of proteins associated with collagen metabolism, endothelial function, and vascular homeostasis; (3) blood pressure regulation, indicated by the expression of natriuretic peptides and proteins related to the renin-angiotensin-aldosterone system; and (4) metabolism, associated with cholesterol and atherosclerosis. Conclusions Clusters of biomarkers associated with mechanistic pathways leading to HF were identified linking inflammation, apoptosis, vascular function, matrix remodeling, blood pressure control, and metabolism. These findings provide important insight on the pathophysiological mechanisms leading to HF. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02556450.

Platelet receptor P2RY12 haplotypes predict restenosis after percutaneous coronary interventions.

The platelet receptor P2Y12 (gene symbol P2RY12) is involved in several processes that contribute to restenosis after percutaneous coronary interventions (PCI). Therefore, common variation in the P2Y12 gene may serve as a useful marker for risk stratification. We studied whether common variation in the platelet receptor P2Y12 gene affects the risk of restenosis after PCI. Comprehensive coverage of common variation in the P2Y12 gene was obtained by genotyping five haplotype-tagging SNPs (ht-SNPs) in 2,062 PCI-treated patients who received a stent and participated in the GENetic DEterminants of Restenosis (GENDER) Study. Haplotypes were inferred and their association with target vessel revascularization (TVR) was studied. Seven P2Y12 haplotypes were identified with an allelic frequency above 5% (designated here H1 to H7) of which two (H5 and H7) were associated with a higher risk of TVR (hazard ratios [HR]=1.4, 95% confidence interval [CI]=1.0-2.0; and HR=1.6, 95% CI=1.2-2.0, respectively) than the reference P2Y12 haplotype (H1), which contains the common alleles of all five P2Y12 ht-SNPs. Our study shows that common variation in the P2Y12 gene predicts restenosis in PCI-treated patients.

Genetic variation in galectin-3 gene associates with cognitive function at old age.

Inflammation plays an important role in the development of cognitive decline and dementia in old age. Galectin-3 is known for its role in acute and chronic inflammation. We assessed whether genetic variation in the LGALS3 gene, encoding for galectin-3, associates with cognitive function in the 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). The rs4644, rs4652, and rs1009977 polymorphisms were genotyped to cover the genomic region of the LGALS3 gene. Subjects carrying the variant alleles of each LGALS3 single nucleotide polymorphism (SNP) had significantly higher baseline C-reactive protein concentrations (p < 0.01). Carriers of the variant alleles had significantly worse performance at baseline compared with carriers of the wild-type allele (all p < 0.05). In the longitudinal analysis, we found that carriers of the variant alleles had worse performance at the attention tasks compared with carriers of the wild-type allele. Although observed differences were small, these data suggest that genetic variation in the LGALS3 gene might be associated with cognitive function in an elderly population. Further research is warranted to confirm these results.

Pre-infarction angina predicts thrombus burden in patients admitted for ST-segment elevation myocardial infarction.

AIMS: In patients with ST-elevation myocardial infarction (STEMI), high thrombotic burden, subsequent distal embolisation and myocardial no-reflow remain a large obstacle that may negate the benefits of urgent coronary revascularisation. We aimed at assessing the predictors of: 1) thrombus grade in patients undergoing primary percutaneous coronary intervention (PPCI) and 2) infarct size, in order to optimise therapy to reduce thrombus burden. METHODS AND RESULTS: One-hundred and fifty-three consecutive patients presenting with STEMI and undergoing PPCI were included. Thrombus was evaluated by angiography and scored according to the TIMI study group score. Next, patients were categorised into two groups that had either high thrombus grade (HTG; score 4-5) or low thrombus grade (LTG; score 1-3). We evaluated predictors of angiographic thrombus grade among a number of clinical, angiographic and laboratory data. We also assessed infarct size and scintigraphic left ventricular ejection fraction (LVEF) at three months in both patient groups. Ninety-four patients (58±11 years; 75% males) presented with HTG, whereas 59 patients (58±12 years; 78% males) presented with LTG. Pre-infarction angina (PIA) was more frequently encountered in the LTG group than in the HTG group (25% vs. 10%, p=0.009). Pre-procedural TIMI flow was significantly lower in the HTG group (p<0.001), and thrombosuction was more frequently applied in the HTG group (p<0.001). Absence of PIA (OR=0.29, 95% CI=0.11-0.75, p=0.01) and proximal culprit lesion (OR=2.10, 95% CI=1.02-4.36, p=0.04) were the only independent predictors of HTG. HTG proved an independent predictor of higher peak levels of creatine kinase (CK) (p<0.001) and troponin T (p<0.001), as well as lower LVEF (p=0.05) along with male gender and absence of prior statin therapy. CONCLUSIONS: Absence of PIA and proximal culprit lesions are associated with higher thrombus grade. Higher thrombus grade is associated with larger infarct size and slightly worse LV function. This may have clinical implications in planning strategies, particularly regarding pharmacotherapy, that aim to decrease thrombus burden prior to stent implantation.

Assessment of obstruction length and optimal viewing angle from biplane X-ray angiograms.

Three-dimensional quantitative coronary angiography (3D QCA) has been encouraged by the increasing need to better assess vessel dimensions and geometry for interventional purposes. A novel 3D QCA system based on biplane X-ray angiograms is presented in this paper. By correcting for the isocenter offset and by improving the epipolar constraint for corresponding two angiographic projections, accurate and robust reconstruction of the vessel centerline is achieved and the reproducibility of its applications, e.g., the assessments of obstruction length and optimal viewing angle, is guaranteed. The accuracy and variability in assessing the obstruction length and optimal bifurcation viewing angle were investigated by using phantom experiments. The segment length assessed by 3D QCA correlated well with the true wire segment length (r (2) = 0.999) and the accuracy and precision were 0.04 +/- 0.25 mm (P < 0.01). 3D QCA slightly underestimated the rotation angle (difference: -1.5 degrees +/- 3.6 degrees , P < 0.01), while no significant difference was observed for the angulation angle (difference: -0.2 degrees +/- 2.4 degrees , P = 0.54). In conclusion, the new 3D QCA approach allows highly accurate and precise assessments of obstruction length and optimal viewing angle from X-ray angiography.

Coronary angiography enhancement for visualization.

High quality visualization on X-ray angiograms is of great significance both for the diagnosis of vessel abnormalities and for coronary interventions. Algorithms for improving the visualization of detailed vascular structures without significantly increasing image noise are currently demanded in the market. A new algorithm called stick-guided lateral inhibition (SGLI) is presented for increasing the visibility of coronary vascular structures. A validation study was set up to compare the SGLI algorithm with the conventional unsharp masking (UM) algorithm on 20 still frames of coronary angiographic images. Ten experienced QCA analysts and nine cardiologists from various centers participated in the validation. Sample scoring value (SSV) and observer agreement value (OAV) were defined to evaluate the validation result, in terms of enhancing performance and observer agreement, respectively. The mean of SSV was concluded to be 77.1 +/- 11.9%, indicating that the SGLI algorithm performed significantly better than the UM algorithm (P-value < 0.001). The mean of the OAV was concluded to be 70.3%, indicating that the average agreement with respect to a senior cardiologist was 70.3%. In conclusion, this validation study clearly demonstrates the superiority of the SGLI algorithm in the visualization of coronary arteries from X-ray angiograms.

High Innate Production Capacity of Proinflammatory Cytokines Increases Risk for Death from Cancer: Results of the PROSPER Study.

PURPOSE: Various lines of evidence suggest that proinflammatory factors may play a role in tumor growth and metastasis, the leading cause of cancer-related mortality. However, most evidence originates from animal models, only few human studies reported an association between proinflammatory cytokines and death from cancer. Here, we investigated the association between circulating levels and innate production capacity of proinflammatory cytokines and cancer incidence and mortality in the PROspective Study on Pravastatin in the Elderly at Risk (PROSPER). EXPERIMENTAL DESIGN: Circulating levels of interleukin 6 (IL-6) and C-reactive protein were measured in all 5,804 participants of the PROSPER study. The innate production capacity of IL-6, IL-1beta, and tumor necrosis factor alpha (TNF-alpha) were measured in a random sample of 403 subjects. RESULTS: We showed that high circulating inflammatory markers were associated with an increased risk for cancer incidence and death from cancer during follow-up (all P < 0.05). Moreover, high innate proinflammatory cytokine production capacity is associated with an increased risk for death from cancer (all P < 0.04) but not with higher cancer incidence during follow-up (all P > 0.6). CONCLUSIONS: High innate production capacity of proinflammatory cytokines is associated with an increased risk for death from cancer, probably because of increased tumor growth and metastasis. Because there was no association between innate production capacity and cancer incidence, the association between circulating levels and cancer incidence at least partially reflects reversed causality. (Clin Cancer Res 2009;15(24):7744-8).

Anti-atherosclerotic effect of amlodipine, alone and in combination with atorvastatin, in APOE*3-Leiden/hCRP transgenic mice.

We investigated the pleiotropic effects of a calcium antagonist (amlodipine) on early atherosclerosis development in the presence and absence of an HMG-CoA-reductase inhibitor (atorvastatin) in apolipoprotein E*3-Leiden/human C-reactive protein (E3L/CRP) transgenic mice. Male E3L/CRP transgenic mice were fed a cholesterol-containing diet either with or without amlodipine and/or atorvastatin. After 31 weeks, atherosclerosis in the aortic root area was quantified. Treatment with amlodipine did not significantly lower blood pressure, but resulted in a 43% reduction (P < 0.03) of lesion area as compared with the untreated group. Treatment with atorvastatin resulted in an 80% reduction of lesion area as compared with the untreated group (P < 0.001). Combined treatment with amlodipine and atorvastatin decreased the lesion area by 93%, significantly more than either treatment alone (P < 0.008). Plasma C-reactive protein levels were mildly elevated, on average 10 +/- 6 mg/L, and did not differ between groups, neither on baseline nor during treatment. Treatment with amlodipine, independently of blood pressure lowering, reduced atherosclerosis development in E3L/CRP mice. Atorvastatin had a strong anti-atherosclerotic effect, whereas co-treatment with amlodipine enhanced this effect significantly. Plasma C-reactive protein levels were not affected by any of the three treatments.

Local Cre-mediated gene recombination in vascular smooth muscle cells in mice.

Here we describe a means to conditionally modify genes at a predefined and localized region of the vasculature using a perivascular drug delivery device (PDD). A 4-hydroxytamoxifen (4-OHT)-eluting PDD was applied around the carotid or femoral artery of a mouse strain carrying both the tamoxifen-inducible and smooth muscle cell (SMC)-specific Cre-recombinase (SM-Cre-ER(T2)) transgene and a stop-floxed beta-galactosidase gene in the Rosa26 locus: the SM-CreER(T2)(ki)/rosa26 mouse. A dose and time curve of 0-10% (w/w) 4-OHT and 0-14 days application of the PDD in SM-CreER(T2)(ki)/rosa26 mice showed optimal gene recombination at 1% (w/w) 4-OHT loading at 7 days post application (carotid artery 2.4+/-1.8%; femoral artery 4.0+/-3.8% of SMCs). The unique 4-OHT-eluting PDD allowed us to achieve SMC-specific recombination in the same order of magnitude as compared to systemic tamoxifen administration. In addition, recombination was completely confined to the PDD-treated vessel wall segment. Thus, local application of a 4-OHT-eluting PDD results in vascular SMC-specific Cre-mediated recombination in SM-CreER(T2)(ki)/rosa26 mice without affecting additional SMCs.