Imperial College London

ProfessorPeterSever

Faculty of MedicineNational Heart & Lung Institute

Professor of Clinical Pharmacology & Therapeutics
 
 
 
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Contact

 

+44 (0)20 7594 1099p.sever

 
 
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Assistant

 

Mrs Yvonne Green +44 (0)20 7594 1100

 
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Location

 

333ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
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831 results found

Sever P, 2020, OBITUARY Michael Schachter, BMJ-BRITISH MEDICAL JOURNAL, Vol: 370, ISSN: 1756-1833

Journal article

Deedwania P, Murphy SA, Scheen A, Badariene J, Pineda AL, Honarpour N, Keech AC, Sever PS, Pedersen TR, Sabatine MS, Giugliano RPet al., 2020, Efficacy and Safety of PCSK9 Inhibition With Evolocumab in Reducing Cardiovascular Events in Patients With Metabolic Syndrome Receiving Statin Therapy: Secondary Analysis From the FOURIER Randomized Clinical Trial., JAMA Cardiol

Importance: The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER randomized clinical trial. Patients with metabolic syndrome (MetS) are at increased cardiovascular risk. Objective: To investigate outcomes with evolocumab in patients with and without MetS. Design, Setting, and Participants: The FOURIER trial randomized patients worldwide with stable atherosclerotic cardiovascular disease receiving statin to evolocumab vs placebo with follow-up for a median of 2.2 years. Data were collected February 2013 to November 2016. For this prespecified analysis, patients with the requisite data were stratified based on the National Cholesterol Education Program Adult Treatment Panel III MetS criteria; in secondary analyses, patients were further substratified by diabetes at baseline. Analysis was intention to treat. Analysis began March 2018 and ended April 2020. Interventions: Patients were randomized to evolocumab or placebo. Main Outcomes and Measures: The primary end point was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary end point was cardiovascular death, myocardial infarction, or stroke. Results: Of 27 342 patients (mean [SD] age, 63 [9] years; 20 623 men [75.4%]) included in this analysis, 16 361 (59.8%) with baseline MetS were, when compared with patients without MetS, at higher risk of cardiovascular events (adjusted hazard ratio [95% CI], 1.31 [1.18-1.46]; P < .001 for the primary and 1.38 [1.20-1.57]; P < .001 for the key secondary end point). Evolocumab reduced low-density lipoprotein cholesterol similarly in patients with MetS (median [interquartile range], 92 [79-109] mg/dL vs 30 [19-48] mg/dL; P < .001) and without MetS (median [interquartile range], 92 [81-108] mg/dL vs 29 [18-44] mg/dl; P < .001). For the primary end point, the hazard rati

Journal article

Gencer B, Mach F, Murphy SA, De Ferrari GM, Huber K, Lewis BS, Ferreira J, Kurtz CE, Wang H, Honarpour N, Keech AC, Sever PS, Pedersen TR, Sabatine MS, Giugliano RPet al., 2020, Efficacy of Evolocumab on Cardiovascular Outcomes in Patients With Recent Myocardial Infarction A Prespecified Secondary Analysis From the FOURIER Trial, JAMA CARDIOLOGY, Vol: 5, Pages: 952-957, ISSN: 2380-6583

Journal article

Wiviott SD, Giugliano RP, Morrow DA, De Ferrari GM, Lewis BS, Huber K, Kuder JF, Murphy SA, Forni DM, Kurtz CE, Honarpour N, Keech AC, Sever PS, Pedersen TR, Sabatine MSet al., 2020, Effect of Evolocumab on Type and Size of Subsequent Myocardial Infarction A Prespecified Analysis of the FOURIER Randomized Clinical Trial, JAMA CARDIOLOGY, Vol: 5, Pages: 787-793, ISSN: 2380-6583

Journal article

Marston NA, Gurmu Y, Melloni GEM, Bonaca M, Gencer B, Sever PS, Pedersen TR, Keech AC, Roselli C, Lubitz SA, Ellinor PT, O'Donoghue ML, Giugliano RP, Ruff CT, Sabatine MSet al., 2020, The Effect of PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) Inhibition on the Risk of Venous Thromboembolism, CIRCULATION, Vol: 141, Pages: 1600-1607, ISSN: 0009-7322

Journal article

Sever P, Johnston SL, 2020, The Renin-Angiotensin system and SARS-CoV-2 infection: A role for the ACE2 receptor?, Journal of the Renin-Angiotensin-Aldosterone System, Vol: 21, Pages: 1-2, ISSN: 1470-3203

Journal article

Giugliano RP, Pedersen TR, Saver JL, Sever PS, Keech AC, Bohula EA, Murphy SA, Wasserman SM, Honarpour N, Wang H, Lira Pineda A, Sabatine MSet al., 2020, Stroke Prevention With the PCSK9 (Proprotein Convertase Subtilisin-Kexin Type 9) Inhibitor Evolocumab Added to Statin in High-Risk Patients With Stable Atherosclerosis, STROKE, Vol: 51, Pages: 1546-1554, ISSN: 0039-2499

Journal article

Sever P, 2020, Renal denervation: An uncertain future, JOURNAL OF THE RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM, Vol: 21, ISSN: 1470-3203

Journal article

Sever P, Gouni-Berthold I, Keech A, Giugliano R, Pedersen TR, Im K, Wang H, Knusel B, Sabatine MS, O'Donoghue MLet al., 2020, LDL-cholesterol lowering with evolocumab, and outcomes according to age and sex in patients in the FOURIER Trial., European Journal of Preventive Cardiology, Pages: 2047487320902750-2047487320902750, ISSN: 2047-4873

AIMS: Some trials have reported diminished efficacy for statins in the elderly, and in women compared with men. We examined the efficacy and safety of evolocumab by patient age and sex in the FOURIER trial, the first major cardiovascular outcome trial of a PCSK9 inhibitor. METHODS AND RESULTS: FOURIER was a randomised, double blind trial, comparing evolocumab with placebo in 27,564 patients with atherosclerotic cardiovascular disease receiving statin therapy (median follow-up 2.2 years). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina or coronary revascularisation. Cox proportional hazards models were used to assess the efficacy of evolocumab versus placebo stratified by quartiles of patient age and by sex. There were small variations in the cardiovascular event rate across the age range (for the primary endpoint, Kaplan-Meier at 3 years 15.6%, >69 years, vs. 15.1%, ≤56 years, P = 0.45); however, the relative efficacy of evolocumab was consistent regardless of patient age (for the primary endpoint (Q1 hazard ratio, 95% confidence interval) 0.83, 0.72-0.96, Q2 0.88, 0.76-1.01, Q3 0.82, 0.71-0.95, Q4 0.86, 0.74-1.00; Pinteraction = 0.91), and the key secondary endpoint (cardiovascular death, myocardial infarction, stroke) (Q1 0.74 (0.61-0.89), Q2 0.83 (0.69-1.00), Q3 0.78 (0.65-0.94), Q4 0.82 (0.69-0.98)); Pinteraction = 0.81). Women had a lower primary endpoint rate than men (Kaplan-Meier at 3 years 12.5 vs. 15.3%, respectively, P < 0.001). Relative risk reductions in the primary endpoint and key secondary endpoint were similar in women (0.81 (0.69-0.95) and 0.74 (0.61-0.90), respectively) compared with men (0.86 (0.80-0.94) and 0.81 (0.73-0.90), respectively), Pinteraction = 0.48 and 0.44, respectively. Adverse events were more common in women and with increasing age but, with the exception of injection site reactions, ther

Journal article

Marston NA, Kamanu FK, Nordio F, Gurmu Y, Roselli C, Sever PS, Pedersen TR, Keech AC, Wang H, Pineda AL, Giugliano R, Lubitz SA, Ellinor PT, Sabatine MS, Ruff CTet al., 2019, Use of a Genetic Risk Score to Predict Coronary and Vascular Events and Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease From the FOURIER Trial, Resuscitation Science Symposium (ReSS), Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: E977-E977, ISSN: 0009-7322

Conference paper

Sever P, 2019, William Stanley Peart: MB BS (London) 1943, FRCP 1974, FRS 1969, KBE 1985, clinician, scientist, and teacher (Born 31 Mar 1922, Died 14 Mar 2019), Hypertension, Vol: 74, Pages: 1226-1228, ISSN: 0194-911X

Among the great British clinician scientists of the 20th century, Stanley Peart was a giant. His international fame was based on a remarkable scientific contribution for research on the autonomic nervous system and the renin-angiotensin system—2 systems that play a vital role in the regulation of the circulation and the kidney. He was responsible for demonstrating that noradrenaline was the sympathetic neurotransmitter—the nature of which had eluded scientists for >3 decades and, subsequently, the nature of angiotensin, the key effector peptide hormone of the renin-angiotensin aldosterone system, and its isolation, purification, and sequencing—an outstanding achievement given the limitations imposed by the technologies of the time.

Journal article

Sever P, 2019, William Stanley Peart OBITUARY, BMJ: British Medical Journal, Vol: 367, Pages: 1-2, ISSN: 0959-535X

Journal article

Gencer B, Mach F, Murphy SA, De Ferrari GM, Huber K, Lewis BS, Ferreira J, Kurtz CE, Wang H, Honarpour N, Keech AC, Sever PS, Pedersen TR, Sabatine MS, Giugliano RPet al., 2019, Evolocumab and Cardiovascular Outcomes in Patients With Recent Myocardial Infarction: Analysis From FOURIER, Scientific Sessions of the American-Heart-Association, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Marston NA, Kamanu FK, Nordio F, Gurmu Y, Roselli C, Sever PS, Pedersen TR, Keech AC, Wang H, Lira Pineda A, Giugliano RP, Lubitz SA, Ellinor PT, Sabatine MS, Ruff CTet al., 2019, Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial., Circulation Journal, ISSN: 0047-1828

Journal article

Clark DW, Zhang W, Gao H, Afaq S, Elliott P, Elliott J, Poulter N, Scott W, Sever P, Tzoulaki I, Lehne B, Chambers J, Evangelou E, Kooner J, Walters R, Wilson Jet al., 2019, Associations of autozygosity with a broad range of human phenotypes, Nature Communications, Vol: 10, ISSN: 2041-1723

In many species, the offspring of related parents suffer reduced vigor, survival and reproductive success, a phenomenon known as inbreeding depression1. In humans, the importance of this effect has remained unclear2, partly because reproduction between close relatives is both rare in many cultures and frequently associated with confounding social factors3. Here, using genomic inbreeding coefficients4 (FROH) for >1.3 million individuals, we show that FROH is significantly associated (P < 0.0005) with apparently deleterious changes in 32 out of 100 traits analysed. Increased FROH is associated with reduced reproductive success (decreased number and likelihood of having children, older age at first sex and first birth, decreased number of sexual partners), as well as reduced risk-taking behaviour (alcohol intake, ever-smoked, self-reported risk taking) and increased disease risk (self-reported overall health, and risk factors including grip strength and heart rate). The effect on fertility is striking: FROH equivalent to the offspring of first cousins is associated with a 55% decrease [95% CI 44-66%] in the odds of having children. These effects are associated with runs of homozygosity (ROH), but not with common variant homozygosity, suggesting that genetic variants causing inbreeding depression are predominantly rare. For a subset of traits, the effect of FROH differs significantly between men and women. Indeed, an increased FROH is associated with decreased total and LDL cholesterol in men, raising the possibility that increases in these traits may have benefited evolutionary fitness, despite being known coronary risk factors. Finally, the effects of FROH are confirmed within full-sibling pairs, where the variation in FROH is independent of environmental confounding. We conclude that inbreeding depression influences a broad range of human phenotypes through the action of rare, recessive variants.

Journal article

Cappuccio FP, Sever PS, British and Irish Hypertension Society, 2019, Reply to Chiolero: Salt intake monitoring at a population level, Journal of Human Hypertension, Vol: 34, Pages: 666-667, ISSN: 0950-9240

Journal article

Erzurumluoglu AM, Chambers JC, Elliott P, Evangelou E, Kooner JS, Poulter N, Sever P, Zhang W, Howson JMM, Wells Jet al., 2019, Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci, Molecular Psychiatry, Vol: 25, Pages: 2392-2409, ISSN: 1359-4184

Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10−8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10−8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10−3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.

Journal article

Charytan DM, Sabatine MS, Pedersen TR, Park J-G, Pineda AL, Wasserman SM, Deedwania P, Olsson AG, Sever PS, Keech AC, Giugliano RPet al., 2019, Correction: Efficacy and Safety of Evolocumab in Chronic Kidney Disease in the FOURIER Trial (vol 73, pg 2961, 2019), Journal of the American College of Cardiology, Vol: 74, Pages: 1162-1166, ISSN: 0735-1097

Journal article

Sung YJ, de Las Fuentes L, Winkler TW, Chasman DI, Bentley AR, Kraja AT, Ntalla I, Warren HR, Guo X, Schwander K, Manning AK, Brown MR, Aschard H, Feitosa MF, Franceschini N, Lu Y, Cheng C-Y, Sim X, Vojinovic D, Marten J, Musani SK, Kilpeläinen TO, Richard MA, Aslibekyan S, Bartz TM, Dorajoo R, Li C, Liu Y, Rankinen T, Smith AV, Tajuddin SM, Tayo BO, Zhao W, Zhou Y, Matoba N, Sofer T, Alver M, Amini M, Boissel M, Chai JF, Chen X, Divers J, Gandin I, Gao C, Giulianini F, Goel A, Harris SE, Hartwig FP, He M, Horimoto ARVR, Hsu F-C, Jackson AU, Kammerer CM, Kasturiratne A, Komulainen P, Kühnel B, Leander K, Lee W-J, Lin K-H, Luan J, Lyytikäinen L-P, McKenzie CA, Nelson CP, Noordam R, Scott RA, Sheu WHH, Stančáková A, Takeuchi F, van der Most PJ, Varga TV, Waken RJ, Wang H, Wang Y, Ware EB, Weiss S, Wen W, Yanek LR, Zhang W, Zhao JH, Afaq S, Alfred T, Amin N, Arking DE, Aung T, Barr RG, Bielak LF, Boerwinkle E, Bottinger EP, Braund PS, Brody JA, Broeckel U, Cade B, Campbell A, Canouil M, Chakravarti A, Cocca M, Collins FS, Connell JM, de Mutsert R, de Silva HJ, Dörr M, Duan Q, Eaton CB, Ehret G, Evangelou E, Faul JD, Forouhi NG, Franco OH, Friedlander Y, Gao H, Gigante B, Gu CC, Gupta P, Hagenaars SP, Harris TB, He J, Heikkinen S, Heng C-K, Hofman A, Howard BV, Hunt SC, Irvin MR, Jia Y, Katsuya T, Kaufman J, Kerrison ND, Khor CC, Koh W-P, Koistinen HA, Kooperberg CB, Krieger JE, Kubo M, Kutalik Z, Kuusisto J, Lakka TA, Langefeld CD, Langenberg C, Launer LJ, Lee JH, Lehne B, Levy D, Lewis CE, Li Y, Lifelines Cohort Study, Lim SH, Liu C-T, Liu J, Liu J, Liu Y, Loh M, Lohman KK, Louie T, Mägi R, Matsuda K, Meitinger T, Metspalu A, Milani L, Momozawa Y, Mosley TH, Nalls MA, Nasri U, O'Connell JR, Ogunniyi A, Palmas WR, Palmer ND, Pankow JS, Pedersen NL, Peters A, Peyser PA, Polasek O, Porteous D, Raitakari OT, Renström F, Rice TK, Ridker PM, Robino A, Robinson JG, Rose LM, Rudan I, Sabanayagam C, Salako BL, Sandow K, Schmidt CO, Schreiner PJ, Scott WR, Sever P, Sims M, Sitet al., 2019, A multi-ancestry genome-wide study incorporating gene-smoking interactions identifies multiple new loci for pulse pressure and mean arterial pressure, Human Molecular Genetics, Vol: 28, Pages: 2615-2633, ISSN: 0964-6906

Elevated blood pressure (BP), a leading cause of global morbidity and mortality, is influenced by both genetic and lifestyle factors. Cigarette smoking is one such lifestyle factor. Across five ancestries, we performed a genome-wide gene–smoking interaction study of mean arterial pressure (MAP) and pulse pressure (PP) in 129 913 individuals in stage 1 and follow-up analysis in 480 178 additional individuals in stage 2. We report here 136 loci significantly associated with MAP and/or PP. Of these, 61 were previously published through main-effect analysis of BP traits, 37 were recently reported by us for systolic BP and/or diastolic BP through gene–smoking interaction analysis and 38 were newly identified (P < 5 × 10−8, false discovery rate < 0.05). We also identified nine new signals near known loci. Of the 136 loci, 8 showed significant interaction with smoking status. They include CSMD1 previously reported for insulin resistance and BP in the spontaneously hypertensive rats. Many of the 38 new loci show biologic plausibility for a role in BP regulation. SLC26A7 encodes a chloride/bicarbonate exchanger expressed in the renal outer medullary collecting duct. AVPR1A is widely expressed, including in vascular smooth muscle cells, kidney, myocardium and brain. FHAD1 is a long non-coding RNA overexpressed in heart failure. TMEM51 was associated with contractile function in cardiomyocytes. CASP9 plays a central role in cardiomyocyte apoptosis. Identified only in African ancestry were 30 novel loci. Our findings highlight the value of multi-ancestry investigations, particularly in studies of interaction with lifestyle factors, where genomic and lifestyle differences may contribute to novel findings.

Journal article

Noordam R, Young WJ, Salman R, Kanters JK, van den Berg ME, van Heemst D, Lin HJ, Barreto SM, Biggs ML, Biino G, Catamo E, Concas MP, Ding J, Evans DS, Foco L, Grarup N, Lyytikainen L-P, Mangino M, Mei H, van der Most PJ, Mueller-Nurasyid M, Nelson CP, Qian Y, Repetto L, Said MA, Shah N, Schramm K, Vidigal PG, Weiss S, Yao J, Zilhao NR, Brody JA, Braund PS, Brumat M, Campana E, Christofidou P, Caulfield MJ, De Grandi A, Dominiczak AF, Doney ASF, Eiriksdottir G, Ellervik C, Giatti L, Gogele M, Graff C, Guo X, van der Harst P, Joshi PK, Kahonen M, Kestenbaum B, Lima-Costa MF, Linneberg A, Maan AC, Meitinger T, Padmanabhan S, Pattaro C, Peters A, Petersmann A, Sever P, Sinner MF, Shen X, Stanton A, Strauch K, Soliman EZ, Tarasov KV, Taylor KD, Thio CHL, Uitterlinden AG, Vaccargiu S, Waldenberger M, Robino A, Correa A, Cucca F, Cummings SR, Doerr M, Girotto G, Gudnason V, Hansen T, Heckbert SR, Juhl CR, Kaeaeb S, Lehtimaki T, Liu Y, Lotufo PA, Palmer CNA, Pirastu M, Pramstaller PP, Ribeiro ALP, Rotter JI, Samani NJ, Snieder H, Spector TD, Stricker BH, Verweij N, Wilson JF, Wilson JG, Jukema JW, Tinker A, Newton-Cheh CH, Sotoodehnia N, Mook-Kanamori DO, Munroe PB, Warren HRet al., 2019, Effects of Calcium, Magnesium, and Potassium concentrations on ventricular repolarization in unselected individuals, Journal of the American College of Cardiology, Vol: 73, Pages: 3118-3131, ISSN: 0735-1097

BackgroundSubclinical changes on the electrocardiogram are risk factors for cardiovascular mortality. Recognition and knowledge of electrolyte associations in cardiac electrophysiology are based on only in vitro models and observations in patients with severe medical conditions.ObjectivesThis study sought to investigate associations between serum electrolyte concentrations and changes in cardiac electrophysiology in the general population.MethodsSummary results collected from 153,014 individuals (54.4% women; mean age 55.1 ± 12.1 years) from 33 studies (of 5 ancestries) were meta-analyzed. Linear regression analyses examining associations between electrolyte concentrations (mmol/l of calcium, potassium, sodium, and magnesium), and electrocardiographic intervals (RR, QT, QRS, JT, and PR intervals) were performed. The study adjusted for potential confounders and also stratified by ancestry, sex, and use of antihypertensive drugs.ResultsLower calcium was associated with longer QT intervals (−11.5 ms; 99.75% confidence interval [CI]: −13.7 to −9.3) and JT duration, with sex-specific effects. In contrast, higher magnesium was associated with longer QT intervals (7.2 ms; 99.75% CI: 1.3 to 13.1) and JT. Lower potassium was associated with longer QT intervals (−2.8 ms; 99.75% CI: −3.5 to −2.0), JT, QRS, and PR durations, but all potassium associations were driven by use of antihypertensive drugs. No physiologically relevant associations were observed for sodium or RR intervals.ConclusionsThe study identified physiologically relevant associations between electrolytes and electrocardiographic intervals in a large-scale analysis combining cohorts from different settings. The results provide insights for further cardiac electrophysiology research and could potentially influence clinical practice, especially the association between calcium and QT duration, by which calcium levels at the bottom 2% of the population distribution led to cl

Journal article

Charytan DM, Sabatine MS, Pedersen TR, Im K, Park J-G, Pineda AL, Wasserman SM, Deedwania P, Olsson AG, Sever PS, Keech AC, Giugliano RPet al., 2019, Efficacy and safety of evolocumab in chronic kidney disease in the FOURIER trial, Journal of the American College of Cardiology, Vol: 73, Pages: 2961-2970, ISSN: 0735-1097

BackgroundData on PCSK9 inhibition in chronic kidney disease (CKD) is limited.ObjectivesThe purpose of this study was to compare outcomes with evolocumab and placebo according to kidney function.MethodsThe FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized individuals with clinically evident atherosclerosis and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl or non–high-density lipoprotein cholesterol ≥100 mg/dl to evolocumab or placebo. The primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization), key secondary endpoint (cardiovascular death, myocardial infarction, or stroke), and safety were analyzed according to chronic kidney disease (CKD) stage estimated from CKD-epidemiology estimated glomerular filtration rate.ResultsThere were 8,077 patients with preserved kidney function, 15,034 with stage 2 CKD, and 4,443 with ≥stage 3 CKD. LDL-C reduction with evolocumab compared with placebo at 48 weeks was similar across CKD groups at 59%, 59%, and 58%, respectively. Relative risk reduction for the primary endpoint was similar for preserved function (hazard ratio [HR]: 0.82; 95% CI: 0.71 to 0.94), stage 2 (HR: 0.85; 95% CI: 0.77 to 0.94), and stage ≥3 CKD (HR: 0.89; 95% CI: 0.76 to 1.05); pint = 0.77. Relative risk reduction for the secondary endpoint was similar across CKD stages (pint = 0.75)—preserved function (HR: 0.75; 95% CI: 0.62 to 0.90), stage 2 (HR: 0.82; 95% CI: 0.72 to 0.93), stage ≥3 (HR: 0.79; 95% CI: 0.65 to 0.95). Absolute RRs at 30 months for the secondary endpoint were −2.5% (95% CI: -4.7% to -0.4%) for stage ≥3 CKD compared with −1.7% (95% CI: -2.8% to 0.5%) with preserved kidney function. Adverse events, including estimated glomerular filtration rate decline, were infrequent and similar regardless of CKD stage.ConclusionsLDL-C lowering and relative clini

Journal article

Nault P, Bonaca M, Giugliano RP, Honarpour N, Keech AC, Sever PS, Pedersen TR, Sabatine Met al., 2019, Risk of Major Adverse Limb Events and Benefits of Evolocumab in Patients With Peripheral Artery Disease by History of Prior Peripheral Revascularization, Vascular Annual Meeting of the Society-for-Vascular-Surgery (SVS), Publisher: MOSBY-ELSEVIER, Pages: E195-E195, ISSN: 0741-5214

Conference paper

Brazel DM, Jiang Y, Hughey JM, Turcot V, Zhan X, Gong J, Batini C, Weissenkampen JD, Liu MZ, Surendran P, Young R, Barnes DR, Nielsen SF, Rasheed A, Samuel M, Zhao W, Kontto J, Perola M, Caslake M, de Craen AJM, Trompet S, Uria-Nickelsen M, Malarstig A, Reily DF, Hoek M, Vogt T, Jukema JW, Sattar N, Ford I, Packard CJ, Alam DS, Majumder AAS, Di Angelantonio E, Chowdhury R, Amouyel P, Arveiler D, Blankenberg S, Ferrières J, Kee F, Kuulasmaa K, Müller-Nurasyid M, Veronesi G, Virtamo J, EPIC-CVD Consortium, Frossard P, Nordestgaard BG, Saleheen D, Danesh J, Butterworth AS, Howson JMM, Erzurumluoglu AM, Jackson VE, Melbourne CA, Varga TV, Warren HR, Tragante V, Tachmazidou I, Harris SE, Evangelou E, Marten J, Zhang W, Altmaier E, Luan J, Langenberg C, Scott RA, Yaghootkar H, Stirrups K, Kanoni S, Marouli E, Karpe F, Dominiczak AF, Sever P, Poulter N, Rolandsson O, Baumbach C, Afaq S, Chambers JC, Kooner JS, Wareham NJ, Renström F, Hallmans G, Marioni RE, Corley J, Starr JM, Verweij N, de Boer RA, van der Meer P, Yavas E, Vaartjes I, Bots ML, Asselbergs FW, Grabe HJ, Völzke Het al., 2019, Exome chip meta-analysis fine maps causal variants and elucidates the genetic architecture of rare coding variants in smoking and alcohol use, Biological Psychiatry, Vol: 85, Pages: 946-955, ISSN: 0006-3223

Background: Smoking and alcohol use have been associated with common genetic variants in multiple loci. Rare variants within these loci hold promise in the identification of biological mechanisms in substance use. Exome arrays and genotype imputation can now efficiently genotype rare nonsynonymous and loss of function variants. Such variants are expected to have deleterious functional consequences and to contribute to disease risk. Methods: We analyzed ∼250,000 rare variants from 16 independent studies genotyped with exome arrays and augmented this dataset with imputed data from the UK Biobank. Associations were tested for five phenotypes: cigarettes per day, pack-years, smoking initiation, age of smoking initiation, and alcoholic drinks per week. We conducted stratified heritability analyses, single-variant tests, and gene-based burden tests of nonsynonymous/loss-of-function coding variants. We performed a novel fine-mapping analysis to winnow the number of putative causal variants within associated loci. Results: Meta-analytic sample sizes ranged from 152,348 to 433,216, depending on the phenotype. Rare coding variation explained 1.1% to 2.2% of phenotypic variance, reflecting 11% to 18% of the total single nucleotide polymorphism heritability of these phenotypes. We identified 171 genome-wide associated loci across all phenotypes. Fine mapping identified putative causal variants with double base-pair resolution at 24 of these loci, and between three and 10 variants for 65 loci. Twenty loci contained rare coding variants in the 95% credible intervals. Conclusions: Rare coding variation significantly contributes to the heritability of smoking and alcohol use. Fine-mapping genome-wide association study loci identifies specific variants contributing to the biological etiology of substance use behavior.

Journal article

Poulter NR, Dolan E, Gupta AK, O'Brien E, Whitehouse A, Sever PSet al., 2019, Efficacy and safety of incremental dosing of a new single-pill formulation of perindopril and amlodipine in the management of hypertension, American Journal of Cardiovascular Drugs, Vol: 19, Pages: 313-323, ISSN: 1175-3277

BACKGROUND: Angiotensin-converting enzyme inhibitors and calcium channel blockers in combination are widely recommended in hypertension guidelines. The advantages of single-pill combinations (SPCs) are increasingly recognized, so a dosage-adapted combination of perindopril and amlodipine was developed for the initial management of hypertension. OBJECTIVE: This randomized trial evaluated the blood pressure (BP)-lowering efficacy of four incremental doses of perindopril/amlodipine SPC in adults with mild-to-severe hypertension. METHODS: Eligible patients (N = 1617) were randomized to SPC perindopril 3.5 mg/amlodipine 2.5 mg (i.e., 3.5/2.5 mg) daily, uptitrating as required on a monthly basis up to 14/10 mg until BP < 140/90 mmHg (< 130/80 mmHg in patients with diabetes). The primary endpoint (proportion with controlled BP at each uptitrated dose) was evaluated at 6 months, and safety was evaluated at 9 months; 24-h ambulatory BP measurement and BP variability were also investigated. Control-arm participants (n = 1653) were randomized to irbesartan 150 mg daily, uptitrating over 3 months to irbesartan/hydrochlorothiazide 300/25 mg. RESULTS: Significant increases in BP control were observed with each dosage increment of perindopril/amlodipine, which was well tolerated, rising from 21% (3.5/2.5 mg) to 30% (7/5 mg), 37% (14/5 mg), and 42% (14/10 mg) after 1, 2, 3, and 6 months, respectively. Reductions in mean systolic and diastolic BP occurred with each incremental dose of perindopril/amlodipine. After 6 months, mean BP had fallen by 24.8/10.8 mmHg. Irbesartan-based therapy reduced clinic and 24-h BP similarly to perindopril/amlodipine, but perindopril/amlodipine reduced BP variability more in comparison. CONCLUSIONS: Incremental uptitration with dosage-adapted perindopril/amlodipine SPC is a safe and effective strategy for mana

Journal article

de Vries PS, Brown MR, Bentley AR, Sung YJ, Winkler TW, Ntalla I, Schwander K, Kraja AT, Guo X, Franceschini N, Cheng C-Y, Sim X, Vojinovic D, Huffman JE, Musani SK, Li C, Feitosa MF, Richard MA, Noordam R, Aschard H, Bartz TM, Bielak LF, Deng X, Dorajoo R, Lohman KK, Manning AK, Rankinen T, Smith AV, Tajuddin SM, Evangelou E, Graff M, Alver M, Boissel M, Chai JF, Chen X, Divers J, Gandin I, Gao C, Goel A, Hagemeijer Y, Harris SE, Hartwig FP, He M, Horimoto ARVR, Hsu F-C, Jackson AU, Kasturiratne A, Komulainen P, Kühnel B, Laguzzi F, Lee JH, Luan J, Lyytikäinen L-P, Matoba N, Nolte IM, Pietzner M, Riaz M, Said MA, Scott RA, Sofer T, Stancáková A, Takeuchi F, Tayo BO, van der Most PJ, Varga TV, Wang Y, Ware EB, Wen W, Yanek LR, Zhang W, Zhao JH, Afaq S, Amin N, Amini M, Arking DE, Aung T, Ballantyne C, Boerwinkle E, Broeckel U, Campbell A, Canouil M, Charumathi S, Chen Y-DI, Connell JM, de Faire U, de Las Fuentes L, de Mutsert R, de Silva HJ, Ding J, Dominiczak AF, Duan Q, Eaton CB, Eppinga RN, Faul JD, Fisher V, Forrester T, Franco OH, Friedlander Y, Ghanbari M, Giulianini F, Grabe HJ, Grove ML, Gu CC, Harris TB, Heikkinen S, Heng C-K, Hirata M, Hixson JE, Howard BV, Ikram MA, InterAct Consortium, Jacobs DR, Johnson C, Jonas JB, Kammerer CM, Katsuya T, Khor CC, Kilpeläinen TO, Koh W-P, Koistinen HA, Kolcic I, Kooperberg C, Krieger JE, Kritchevsky SB, Kubo M, Kuusisto J, Lakka TA, Langefeld CD, Langenberg C, Launer LJ, Lehne B, Lemaitre RN, Li Y, Liang J, Liu J, Liu K, Loh M, Louie T, Mägi R, Manichaikul AW, McKenzie CA, Meitinger T, Metspalu A, Milaneschi Y, Milani L, Mohlke KL, Mosley TH, Mukamal KJ, Nalls MA, Nauck M, Nelson CP, Sotoodehnia N, O'Connell JR, Palmer ND, Pazoki R, Pedersen NL, Peters A, Peyser PA, Polasek O, Poulter N, Raffel LJ, Raitakari OT, Reiner AP, Rice TK, Rich SS, Robino A, Robinson JG, Rose LM, Rudan I, Schmidt CO, Schreiner PJ, Scott WR, Sever P, Shi Y, Sidney S, Sims M, Smith BH, Smith JA, Snieder H, Starr JM, Strauch K, Tan N, Taylor KDet al., 2019, Multi-ancestry genome-wide association study of lipid levels incorporating gene-alcohol interactions, American Journal of Epidemiology, Vol: 188, Pages: 1033-1054, ISSN: 1476-6256

An individual's lipid profile is influenced by genetic variants and alcohol consumption, but the contribution of interactions between these exposures has not been studied. We therefore incorporated gene-alcohol interactions into a multi-ancestry genome-wide association study of levels of high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and triglycerides. We included 45 studies in Stage 1 (genome-wide discovery) and 66 studies in Stage 2 (focused follow-up), for a total of 394,584 individuals from five ancestry groups. Genetic main and interaction effects were jointly assessed by a 2 degrees of freedom (DF) test, and a 1 DF test was used to assess the interaction effects alone. Variants at 495 loci were at least suggestively associated (P < 1 × 10-6) with lipid levels in Stage 1 and were evaluated in Stage 2, followed by combined analyses of Stage 1 and Stage 2. In the combined analysis of Stage 1 and Stage 2, 147 independent loci were associated with lipid levels at P < 5 × 10-8 using 2 DF tests, of which 18 were novel. No genome-wide significant associations were found testing the interaction effect alone. The novel loci included several genes (PCSK5, VEGFB, and A1CF) with a putative role in lipid metabolism based on existing evidence from cellular and experimental models.

Journal article

Mora S, Chang CL, Moorthy MV, Sever PSet al., 2019, Association of nonfasting vs fasting lipid levels with risk of major coronary events in the Anglo-Scandinavian cardiac outcomes trial-lipid lowering arm, JAMA Internal Medicine, Vol: 179, Pages: 898-905, ISSN: 2168-6114

Importance: Recent guidelines have recommended nonfasting for routine testing of lipid levels based on comparisons of nonfasting and fasting populations. However, no previous study has examined the association of cardiovascular outcomes with fasting vs nonfasting lipid levels measured in the same individuals. Objective: To compare the association of nonfasting and fasting lipid levels with prospectively ascertained coronary and vascular outcomes and to evaluate whether a strategy of using nonfasting instead of fasting lipid level measurement would result in misclassification of risk for individuals undergoing evaluation for initiation of statin therapy. Design, Setting, and Participants: This post hoc prospective follow-up of a randomized clinical trial included 8270 of 10 305 participants from the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) with nonfasting and fasting lipid levels measured 4 weeks apart (including 6855 participants with no prior vascular disease) (median follow-up, 3.3 years; interquartile range, 2.8-3.6 years). Data were collected from February 1, 1998, to December 31, 2002, and analyzed from February 1, 2016, to November 30, 2018. Multivariable Cox models, adjusted for cardiovascular risk factors, were calculated for 40-mg/dL (1-mmol/L) higher values of nonfasting and fasting lipids. Main Outcomes and Measures: The trial's primary end point consisted of major coronary events (nonfatal myocardial infarction [MI] and fatal coronary heart disease [212 events]). Secondary analyses examined atherosclerotic cardiovascular disease (ASCVD) events (including MI, stroke, and ASCVD death [351 events]). Results: Among the 8270 participants (82.1% male; mean [SD] age, 63.4 [8.5] years), nonfasting samples had modestly higher triglyceride levels and similar cholesterol levels compared to fasting samples. Associations of nonfasting lipid levels with coronary events were similar to those for fasting lipid levels. For example, adjuste

Journal article

Murphy SA, Pedersen TR, Gaciong ZA, Ceska R, Ezhov MV, Connolly DL, Jukema JW, Toth K, Tikkanen MJ, Im K, Wiviott SD, Kurtz CE, Honarpour N, Giugliano RP, Keech AC, Sever PS, Sabatine MSet al., 2019, Effect of the PCSK9 inhibitor evolocumab on total cardiovascular events in patients with cardiovascular disease: A prespecified analysis from the FOURIER Trial, JAMA Cardiology, Vol: 4, Pages: 613-619, ISSN: 2380-6583

Importance: The PCSK9 inhibitor evolocumab reduced low-density lipoprotein cholesterol and first cardiovascular events in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, but patients remain at high risk of recurrent cardiovascular events. Objective: To evaluate the effect of evolocumab on total cardiovascular events, given the importance of total number of cardiovascular events to patients, clinicians, and health economists. Design, Setting, and Participants: Secondary analysis of a randomized, double-blind clinical trial. The FOURIER trial compared evolocumab or matching placebo and followed up patients for a median of 2.2 years. The study included 27 564 patients with stable atherosclerotic disease receiving statin therapy. Data were analyzed between May 2017 and February 2019. Main Outcomes and Measures: The primary end point (PEP) was time to first cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary end point was time to first cardiovascular death, myocardial infarction, or stroke. In a prespecified analysis, total cardiovascular events were evaluated between treatment arms. Results: The mean age of patients was 63 years, 69% of patients were taking high-intensity statin therapy, and the median LDL-C at baseline was 92 mg/dL (to convert to millimoles per liter, multiply by 0.0259). There were 2907 first PEP events and 4906 total PEP events during the trial. Evolocumab reduced total PEP events by 18% (incidence rate ratio [RR], 0.82; 95% CI, 0.75-0.90; P < .001) including both first events (hazard ratio, 0.85; 95% CI, 0.79-0.92; P < .001) and subsequent events (RR, 0.74; 95% CI, 0.65-0.85). There were 2192 total primary events in the evolocumab group and 2714 total events in the placebo group. For every 1000 patients treated for 3 years, evolocumab prevented 22 first PEP events

Journal article

Rahimi K, Canoy D, Nazarzadeh M, Salimi-Khorshidi G, Woodward M, Teo K, Davis BR, Chalmers J, Pepine CJ, Rahimi K, Teo K, Davis BR, Chalmers J, Pepine CJ, Agodoa L, Algra A, Asselbergs FW, Beckett N, Berge E, Black H, Brouwers FPJ, Brown M, Bulpitt CJ, Byington B, Chalmers J, Cutler J, Devereaux RB, Dwyer D, Fagard R, Fox K, Fukui T, Gupta AJ, Holman RR, Imai Y, Ishii M, Julius S, Kanno Y, Kjeldsen SE, Kostis J, Kuramoto K, Lanke J, Lewis E, Lievre M, Lindholm LH, Lueders S, MacMahon S, Matsuzaki M, Mehlum MH, Nissen S, Ogawa H, Othisgihara T, Ohkubo T, Palmer C, Patel A, Pepine C, Pfeffer M, Poulter NR, Rakugi H, Remuzzi G, Ruggenenti P, Saruta T, Schrader J, Schrier R, Sever P, Sleight P, Staessen JA, Suzuki H, Thijs L, Ueshima K, Umemoto S, van Gilst WH, Verdecchia P, Wachtell K, Yui Y, Yusuf S, Baigent C, Collins R, de Zeeuw D, Neal B, Perkovic V, Rahman M, Remme WJ, Rodgers A, Sundstrom J, Turnbull Fet al., 2019, Investigating the stratified efficacy and safety of pharmacological blood pressure-lowering: an overall protocol for individual patient-level data meta-analyses of over 300 000 randomised participants in the new phase of the Blood Pressure Lowering Treatment Trialists' Collaboration (BPLTTC), BMJ Open, Vol: 9, Pages: 1-7, ISSN: 2044-6055

Introduction Previous research from the Blood Pressure Lowering Treatment Trialists’ Collaboration (BPLTTC) and others has shown that pharmacological blood pressure (BP)- lowering substantially reduces the risk of major cardiovascular events, including ischaemic heart disease, heart failure and stroke. In this new phase, the aim is to conduct individual patient-level data (IPD) meta-analyses involving eligible BP-lowering randomised controlled trials (RCTs) to address uncertainties relating to efficacy and safety of BP-lowering treatment.Methods and analysis RCTs investigating the effect of pharmacological BP-lowering, with a minimum of 1000 patient-years of follow-up in each trial arm, are eligible. Our systematic review identified 100 potentially eligible trials. We requested their investigators/sponsors to contribute baseline, follow-up and outcomes data. As of June 2018, the collaboration has obtained data from 49 trials (n=315 046 participants), with additional data currently in the process of being transferred from four RCTs (n=34 642 participants). In addition, data harmonisation has commenced. Scientific activities of the collaboration are overseen by the Steering Committee with input from all collaborators. Detailed protocols for individual meta-analyses will be developed and registered on public platforms.Ethics and dissemination Ethics approval has been obtained for this new and extended phase of the BPLTTC, the largest collaboration of de-identified IPD from RCTs. It offers an efficient and ethical manner of re-purposing existing data to answer clinically important questions relating to BP treatment as well as methodological questions relating to IPD meta-analyses. Among the immediate impacts will include reliable quantification of effects of treatment modifiers, such as baseline BP, age and prior disease, on both vascular and non-vascular outcomes. Analyses will further assess the impact of BP-lowering on important, but less well und

Journal article

Cappuccio FP, Sever PS, 2019, The importance of a valid assessment of salt intake in individuals and populations. A scientific statement of the British and Irish Hypertension Society, Journal of Human Hypertension, Vol: 33, Pages: 345-348, ISSN: 0950-9240

High salt (salt is sodium chloride – 2.5 g of salt contain 1 g of sodium) intake is a major determinant of blood pressure (BP) in individuals and populations [1]. A reduction of salt intake leads to a reduction in BP and is associated with a reduction in the incidence of cardiovascular disease (CVD) [1,2,3]. However, in the past few years, some epidemiological studies suggested the presence of a J-shaped association between salt (sodium) consumption and CVD [4,5,6,7,8,9]. These results sparked both scientific and media interest and opened a debate on the wisdom of pursuing population-wide salt reduction policies to reduce CVD, as currently recommended by most national and international health organizations, including the World Health Organization (WHO) [10]. Systematic appraisal of these studies identified a variety of pitfalls, suggesting that their results were based on flawed methodologies [11, 12]. The present scientific statement aims to briefly discuss only one such flaw, the use of biased methods of assessing salt consumption, and the consequences of using such biased estimates of exposure (salt intake) when assessing both individual salt intake (for associations with CVD) and population salt consumption (to evaluate population salt reduction programmes).

Journal article

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