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Cardiovascular Safety of Tocilizumab Versus Etanercept in Rheumatoid Arthritis: A Randomized Controlled Trial.
Giles, JT, Sattar, N, Gabriel, S, Ridker, PM, Gay, S, Warne, C, Musselman, D, Brockwell, L, Shittu, E, Klearman, M, et al
Arthritis & rheumatology (Hoboken, N.J.). 2020;(1):31-40
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Abstract
OBJECTIVE To assess the risk of major adverse cardiovascular events (MACE) in patients with rheumatoid arthritis (RA) treated with tocilizumab compared to those treated with the tumor necrosis factor inhibitor etanercept. METHODS This randomized, open-label, parallel-group trial enrolled patients with active seropositive RA (n = 3,080) who had an inadequate response to conventional synthetic disease-modifying antirheumatic drugs and who had at least 1 cardiovascular (CV) risk factor. Patients were randomly assigned 1:1 to receive open-label tocilizumab at 8 mg/kg/month or etanercept at 50 mg/week. All patients were followed up for a mean of 3.2 years. The primary end point was comparison of time to first occurrence of MACE. The trial was powered to exclude a relative hazard ratio for MACE of 1.8 or higher in the tocilizumab group compared to the etanercept group. RESULTS By week 4 of treatment, the serum low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels were a median 11.1%, 5.7%, and 13.6% higher, respectively, in patients receiving tocilizumab compared to those receiving etanercept (each P < 0.001). During follow-up, 83 MACE occurred in the tocilizumab group compared to 78 MACE in the etanercept group. The estimated hazard ratio for occurrence of MACE in the tocilizumab group relative to the etanercept group was 1.05 (95% confidence interval 0.77-1.43). Results were similar in sensitivity analyses and in the on-treatment population analysis. Adverse events occurred more frequently in the tocilizumab group, including serious infection and gastrointestinal perforation. CONCLUSION The results of this trial, which provide insights into the CV safety of tocilizumab as compared to etanercept, ruled out a risk for occurrence of MACE of 1.43 or higher in patients treated with tocilizumab. This result should be interpreted in the context of the clinical efficacy and non-CV safety of tocilizumab.
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Prospective functional classification of all possible missense variants in PPARG.
Majithia, AR, Tsuda, B, Agostini, M, Gnanapradeepan, K, Rice, R, Peloso, G, Patel, KA, Zhang, X, Broekema, MF, Patterson, N, et al
Nature genetics. 2016;(12):1570-1575
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Abstract
Clinical exome sequencing routinely identifies missense variants in disease-related genes, but functional characterization is rarely undertaken, leading to diagnostic uncertainty. For example, mutations in PPARG cause Mendelian lipodystrophy and increase risk of type 2 diabetes (T2D). Although approximately 1 in 500 people harbor missense variants in PPARG, most are of unknown consequence. To prospectively characterize PPARγ variants, we used highly parallel oligonucleotide synthesis to construct a library encoding all 9,595 possible single-amino acid substitutions. We developed a pooled functional assay in human macrophages, experimentally evaluated all protein variants, and used the experimental data to train a variant classifier by supervised machine learning. When applied to 55 new missense variants identified in population-based and clinical sequencing, the classifier annotated 6 variants as pathogenic; these were subsequently validated by single-variant assays. Saturation mutagenesis and prospective experimental characterization can support immediate diagnostic interpretation of newly discovered missense variants in disease-related genes.
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The Association Between Antihypertensive Medication Nonadherence and Visit-to-Visit Variability of Blood Pressure: Findings From the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial.
Kronish, IM, Lynch, AI, Oparil, S, Whittle, J, Davis, BR, Simpson, LM, Krousel-Wood, M, Cushman, WC, Chang, TI, Muntner, P
Hypertension (Dallas, Tex. : 1979). 2016;(1):39-45
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Abstract
Low adherence to antihypertensive medication has been hypothesized to increase visit-to-visit variability (VVV) of blood pressure (BP). We assessed the association between antihypertensive medication adherence and VVV of BP in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). VVV of BP was calculated using SD independent of mean, SD, and average real variability across study visits conducted 6 to 28 months after randomization. Participants who reported taking <80% of their antihypertensive medication at ≥1 study visits were categorized as nonadherent. Participants were followed up for cardiovascular events and mortality after the assessment of adherence and VVV of BP. SD independent of mean of BP was higher for nonadherent (n=2912) versus adherent (n=16 878) participants; 11.4±4.9 versus 10.5±4.5 for systolic BP; 6.8±2.8 versus 6.2±2.6 for diastolic BP (each P<0.001). SD independent of mean of BP remained higher among nonadherent than among adherent participants after multivariable adjustment (0.8 [95% confidence interval, 0.7-1.0] higher for systolic BP and 0.4 [95% confidence interval, 0.3-0.5] higher for diastolic BP]. SD and average real variability of systolic BP and diastolic BP were also higher among nonadherent than among adherent participants. Adjustment for nonadherence did not explain the association of VVV of BP with higher fatal coronary heart disease or nonfatal myocardial infarction, stroke, heart failure, or mortality risk. In conclusion, improving medication adherence may lower VVV of BP. However, VVV of BP is associated with cardiovascular outcomes independent of medication adherence.
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Unmeasured confounding in pharmacoepidemiology.
Groenwold, RH, de Groot, MC, Ramamoorthy, D, Souverein, PC, Klungel, OH
Annals of epidemiology. 2016;(1):85-6
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Third-generation zotarolimus-eluting and everolimus-eluting stents in all-comer patients requiring a percutaneous coronary intervention (DUTCH PEERS): a randomised, single-blind, multicentre, non-inferiority trial.
von Birgelen, C, Sen, H, Lam, MK, Danse, PW, Jessurun, GA, Hautvast, RW, van Houwelingen, GK, Schramm, AR, Gin, RM, Louwerenburg, JW, et al
Lancet (London, England). 2014;(9915):413-23
Abstract
BACKGROUND Third-generation, permanent-polymer-based drug-eluting stents with novel, flexible designs might be more easily delivered than previous generations of stents in complex coronary lesions, but might be less longitudinally stable. We aimed to assess the safety and efficacy in all-comer patients of two third-generation stents that are often used clinically, but that have not yet been compared, and one of which has not previously been assessed in a randomised trial. METHODS In this investigator-initiated, single-blind, multicentre, randomised, two-arm, non-inferiority trial, patients aged 18 years and older who required a percutaneous coronary intervention with implantation of a drug-eluting stent were recruited from four study sites in the Netherlands. We randomly assigned patients by independently managed computer-generated allocation sequences in a 1:1 ratio to receive either cobalt-chromium-based zotarolimus-eluting stents (Resolute Integrity, Medtronic, Santa Rosa, CA, USA) or platinum-chromium-based everolimus-eluting stents (Promus Element, Boston Scientific, Natick, MA, USA). Patients and analysts were masked to the allocated stent, but treating clinicians were not. The primary endpoint of target-vessel failure was a composite of safety (cardiac death or target-vessel-related myocardial infarction) and efficacy (target-vessel revascularisation) at 12 months, analysed by intention to treat (with a non-inferiority margin of 3·6%). This trial is registered with ClinicalTrials.gov, number NCT01331707. FINDINGS Between Nov 25, 2010, and May 24, 2012, 1811 eligible all-comer patients, with 2371 target lesions, were enrolled in the study. 370 (20%) patients presented with ST-elevation myocardial infarction and 447 (25%) with non-ST-elevation myocardial infarction. 906 patients were assigned to receive zotarolimus-eluting stents and 905 to receive everolimus-eluting stents. Ease of stent delivery was shown by very low numbers of patients requiring treatment other than their assigned study treatment (six [1%] in the zotarolimus-eluting stent group vs five [1%] in the everolimus-eluting stent group; p=0·22). 12-month follow-up results were available for 1810 patients (one patient in the zotarolimus-eluting stent group withdrew consent). The primary endpoint was met by 55 (6%) of 905 patients in the zotarolimus-eluting stent group and 47 (5%) of 905 in the everolimus-eluting stent group. The zotarolimus-eluting stent was non-inferior to the everolimus-eluting stent (absolute risk difference 0·88%, 95% CI -1·24% to 3·01%; upper limit of one-sided 95% CI 2·69%; non-inferiority p=0·006). We noted no significant between-group differences in individual components of the primary endpoint. Definite stent thrombosis occurred in three (0·3%) patients in the zotarolimus-eluting stent group and six (0·7%) patients in the everolimus-eluting stent group (p=0·34). Longitudinal stent deformation was seen only in the everolimus-eluting stent group (nine [1·0%] of 905 vs 0 of 906, p=0·002; nine of 1591 [0·6%] everolimus-eluting stents implanted became deformed), but was not associated with any adverse events. INTERPRETATION Both stents were similarly efficacious and safe, and provided excellent clinical outcomes, especially in view of the large number of patients who presented with acute myocardial infarctions. FUNDING Boston Scientific, Medtronic.
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Biodegradable-polymer drug-eluting stents vs. bare metal stents vs. durable-polymer drug-eluting stents: a systematic review and Bayesian approach network meta-analysis.
Kang, SH, Park, KW, Kang, DY, Lim, WH, Park, KT, Han, JK, Kang, HJ, Koo, BK, Oh, BH, Park, YB, et al
European heart journal. 2014;(17):1147-58
Abstract
BACKGROUND The aim of this study was to compare the safety and efficacy of biodegradable-polymer (BP) drug-eluting stents (DES), bare metal stents (BMS), and durable-polymer DES in patients undergoing coronary revascularization, we performed a systematic review and network meta-analysis using a Bayesian framework. METHODS AND RESULTS Study stents included BMS, paclitaxel-eluting (PES), sirolimus-eluting (SES), endeavor zotarolimus-eluting (ZES-E), cobalt-chromium everolimus-eluting (CoCr-EES), platinium-chromium everolimus-eluting (PtCr-EES), resolute zotarolimus-eluting (ZES-R), and BP biolimus-eluting stents (BP-BES). After a systematic electronic search, 113 trials with 90 584 patients were selected. The principal endpoint was definite or probable stent thrombosis (ST) defined according to the Academic Research Consortium within 1 year. RESULTS Biodegradable polymer-biolimus-eluting stents [OR, 0.56; 95% credible interval (CrI), 0.33-0.90], SES (OR, 0.53; 95% CrI, 0.38-0.73), CoCr-EES (OR, 0.34; 95% CrI, 0.23-0.52), and PtCr-EES (OR, 0.31; 95% CrI, 0.10-0.90) were all superior to BMS in terms of definite or probable ST within 1 year. Cobalt-chromium everolimus-eluting stents demonstrated the lowest risk of ST of all stents at all times after stent implantation. Biodegradable polymer-biolimus-eluting stents was associated with a higher risk of definite or probable ST than CoCr-EES (OR, 1.72; 95% CrI, 1.04-2.98). All DES reduced the need for repeat revascularization, and all but PES reduced the risk of myocardial infarction compared with BMS. CONCLUSIONS All DESs but PES and ZES-E were superior to BMS in terms of ST within 1 year. Cobalt-chromium everolimus-eluting stents was safer than any DES even including BP-BES. Our results suggest that not only the biodegradability of polymer, but the optimal combination of stent alloy, design, strut thickness, polymer, and drug all combined determine the safety of DES.
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Imaging of myocardial infarction using ultrasmall superparamagnetic iron oxide nanoparticles: a human study using a multi-parametric cardiovascular magnetic resonance imaging approach.
Yilmaz, A, Dengler, MA, van der Kuip, H, Yildiz, H, Rösch, S, Klumpp, S, Klingel, K, Kandolf, R, Helluy, X, Hiller, KH, et al
European heart journal. 2013;(6):462-75
Abstract
AIMS: The purpose of this clinical trial was to investigate whether cardiovascular magnetic resonance imaging (CMR) using ferumoxytol (Feraheme™, FH), an ultrasmall superparamagnetic iron oxide nanoparticle (USPIO), allows more detailed characterization of infarct pathology compared with conventional gadolinium-based necrosis/fibrosis imaging in patients with acute myocardial infarction. METHODS AND RESULTS Fourteen patients who had experienced an acute ST-elevation myocardial infarction were included in this study. Following coronary angiography, a first baseline study (pre-FH) was performed followed by subsequent CMR studies (post-FH) 48 h after intravenous ferumoxytol administration. The CMR studies comprised cine-CMR, T(2)-weighted short tau inversion recovery spin echo imaging, T(2)-mapping, and T(1)-weighted late gadolinium enhancement (LGE) imaging. The median extent of short-axis in-plane LGE was 30% [inter-quartile range (IQR) 26-40%]. The median in-plane extent of T(2)-weighted 'hypoenhancement' in the region of myocardial infarction, which was not present prior to ferumoxytol administration in any patient, was 19% (IQR 14-22%; P < 0.001 compared with the extent of LGE). The median in-plane extent of areas showing signal void in T(2)-mapping images post-FH in the region of myocardial infarction was 16% (IQR 12-18%; P < 0.001 compared with the extent of LGE; P = 0.34 compared with the extent of T(2)-weighted hypoenhancement). A substantial drop in absolute T(2)-values was observed not only in the infarct core and peri-infarct zone, but also in the remote 'healthy' myocardium, although there was only a minor change in the skeletal muscle. Substantial ferumoxytol uptake was detected only in cultured macrophages, but not in peripheral blood monocytes from study patients. CONCLUSION We could demonstrate in humans that USPIO-based contrast agents enable a more detailed characterization of myocardial infarct pathology mainly by detecting infiltrating macrophages. Considering the multi-functionality of USPIO-based particles and their superior safety profile compared with gadolinium-based compounds, these observations open up new vistas for the clinical application of USPIO.
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Comparison of the reperfusion efficacy of thrombus aspiration with and without distal protection during primary percutaneous coronary intervention in patients with acute ST-segment elevation myocardial infarction.
Satoh, S, Inoue, H, Omura, S, Ejima, E, Shimozono, K, Hayashi, M, Mori, T, Takenaka, K, Kawamura, N, Numaguchi, K, et al
The American journal of cardiology. 2013;(11):1725-9
Abstract
We evaluated a hypothesis that thrombus aspiration with distal protection is superior to simple thrombus aspiration in patients treated with primary percutaneous coronary intervention (PCI). A total of 176 consecutive patients with ST-segment elevation myocardial infarction were enrolled in this study and assigned to either the thrombus aspiration group (A, n = 104) or the thrombus aspiration with distal protection group using a filter device system (A + DP, n = 72). We compared the angiographic reperfusion grade, left ventricular (LV) function, and clinical outcomes between the 2 groups. There were no significant differences in age, gender distribution, the onset-to-reperfusion time, the peak levels of creatine kinase, or 6-month mortality between the 2 groups. The rate of achieving a Thrombolysis In Myocardial Infarction flow grade of 3 and a myocardial blush grade of 3 was higher in the A + DP group than in the A group. Among the patients who underwent follow-up catheterization 6 months after PCI (A, n = 62; A + DP, n = 52), there were no significant differences in the LV end-diastolic volume index, LV end-systolic volume index, or LV ejection fraction between the 2 groups at the time of PCI or 6 months after PCI. In conclusion, thrombus aspiration with distal protection may be more effective in initially restoring the coronary blood flow than thrombus aspiration alone, although it may not be superior to thrombus aspiration in preventing LV remodeling or preserving the LV function in patients with ST-segment elevation myocardial infarction.
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Bare metal stents, durable polymer drug eluting stents, and biodegradable polymer drug eluting stents for coronary artery disease: mixed treatment comparison meta-analysis.
Bangalore, S, Toklu, B, Amoroso, N, Fusaro, M, Kumar, S, Hannan, EL, Faxon, DP, Feit, F
BMJ (Clinical research ed.). 2013;:f6625
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Abstract
OBJECTIVE To compare the efficacy and safety of biodegradable polymer drug eluting stents with those of bare metal stents and durable polymer drug eluting stents. DESIGN Mixed treatment comparison meta-analysis of 258,544 patient years of follow-up from randomized trials. DATA SOURCES AND STUDY SELECTION PubMed, Embase, and Central were searched for randomized trials comparing any of the Food and Drug Administration approved durable polymer drug eluting stents (sirolimus eluting, paclitaxel eluting, cobalt chromium everolimus eluting, platinum chromium everolimus eluting, zotarolimus eluting-Endeavor, and zotarolimus eluting-Resolute) or biodegradable polymer drug eluting stents, with each other or against bare metal stents. OUTCOMES Long term efficacy (target vessel revascularization, target lesion revascularization) and safety (death, myocardial infarction, stent thrombosis). Landmark analysis at more than one year was evaluated to assess the potential late benefit of biodegradable polymer drug eluting stents. RESULTS From 126 randomized trials and 258,544 patient years of follow-up, for long term efficacy (target vessel revascularization), biodegradable polymer drug eluting stents were superior to paclitaxel eluting stents (rate ratio 0.66, 95% credibility interval 0.57 to 0.78) and zotarolimus eluting stent-Endeavor (0.69, 0.56 to 0.84) but not to newer generation durable polymer drug eluting stents (for example: 1.03, 0.89 to 1.21 versus cobalt chromium everolimus eluting stents). Similarly, biodegradable polymer drug eluting stents were superior to paclitaxel eluting stents (rate ratio 0.61, 0.37 to 0.89) but inferior to cobalt chromium everolimus eluting stents (2.04, 1.27 to 3.35) for long term safety (definite stent thrombosis). In the landmark analysis after one year, biodegradable polymer drug eluting stents were superior to sirolimus eluting stents for definite stent thrombosis (rate ratio 0.29, 0.10 to 0.82) but were associated with increased mortality compared with cobalt chromium everolimus eluting stents (1.52, 1.02 to 2.22). Overall, among all stent types, the newer generation durable polymer drug eluting stents (zotarolimus eluting stent-Resolute, cobalt chromium everolimus eluting stents, and platinum chromium everolimus eluting stents) were the most efficacious (lowest target vessel revascularization rate) stents, and cobalt chromium everolimus eluting stents were the safest with significant reductions in definite stent thrombosis (rate ratio 0.35, 0.21 to 0.53), myocardial infarction (0.65, 0.55 to 0.75), and death (0.72, 0.58 to 0.90) compared with bare metal stents. CONCLUSIONS Biodegradable polymer drug eluting stents are superior to first generation durable polymer drug eluting stents but not to newer generation durable polymer stents in reducing target vessel revascularization. Newer generation durable polymer stents, and especially cobalt chromium everolimus eluting stents, have the best combination of efficacy and safety. The utility of biodegradable polymer stents in the context of excellent clinical outcomes with newer generation durable polymer stents needs to be proven.
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Rationale and design of the EXAMINATION trial: a randomised comparison between everolimus-eluting stents and cobalt-chromium bare-metal stents in ST-elevation myocardial infarction.
Sabaté, M, Cequier, A, Iñiguez, A, Serra, A, Hernández-Antolín, R, Mainar, V, Valgimigli, M, Tespili, M, den Heijer, P, Bethencourt, A, et al
EuroIntervention : journal of EuroPCR in collaboration with the Working Group on Interventional Cardiology of the European Society of Cardiology. 2011;(8):977-84
Abstract
AIMS: To assess the performance of the everolimus-eluting stent (EES) versus cobalt chromium bare-metal stent (BMS) in the setting of primary percutaneous coronary intervention for treatment of patients presenting with ST-segment elevation myocardial infarction (STEMI). The implantation of a drug-eluting stent in the setting of an acute myocardial infarction is still controversial. In several registries this clinical scenario has been associated with the development of stent thrombosis. The EES has demonstrated to reduce the stent thrombosis rate as compared to paclitaxel-eluting stent in randomised controlled trials, mainly performed in patients in stable clinical conditions. There are however few data regarding the effectiveness of EES in the context of STEMI. METHODS AND RESULTS This is an investigator-driven, prospective, multicentre, multinational, randomised, single blind, two-arm, controlled trial (ClinicalTrials.gov number: NCT00828087). This trial, with an all comer design, randomises approximately 1,500 patients 1:1 to EES or BMS. Overall, any patient presenting with STEMI up to 48 hours who requires emergent percutaneous coronary intervention can be included. The primary endpoint is the patient-oriented combined endpoint of all-cause death, any myocardial infarction and any revascularisation at 1-year according to the Academic Research Consortium. Clinical follow-up will be scheduled at 30 days, six months, one year and yearly up to five years. No angiographic follow-up is mandated per protocol. CONCLUSIONS This trial with broad inclusion and few exclusion criteria will shed light on the performance of the second generation EES in the complex scenario of STEMI.