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2.  Ischaemic cardiac outcomes in patients with atrial fibrillation treated with vitamin K antagonism or factor Xa inhibition: results from the ROCKET AF trial 
European Heart Journal  2013;35(4):233-241.
We investigated the prevalence of prior myocardial infarction (MI) and incidence of ischaemic cardiovascular (CV) events among atrial fibrillation (AF) patients.
Methods and results
In ROCKET AF, 14 264 patients with nonvalvular AF were randomized to rivaroxaban or warfarin. The key efficacy outcome for these analyses was CV death, MI, and unstable angina (UA). This pre-specified analysis was performed on patients while on treatment. Rates are per 100 patient-years. Overall, 2468 (17%) patients had prior MI at enrollment. Compared with patients without prior MI, these patients were more likely to be male (75 vs. 57%), on aspirin at baseline (47 vs. 34%), have prior congestive heart failure (78 vs. 59%), diabetes (47 vs. 39%), hypertension (94 vs. 90%), higher mean CHADS2 score (3.64 vs. 3.43), and fewer prior strokes or transient ischaemic attacks (46 vs. 54%). CV death, MI, or UA rates tended to be lower in patients assigned rivaroxaban compared with warfarin [2.70 vs. 3.15; hazard ratio (HR) 0.86, 95% confidence interval (CI) 0.73–1.00; P = 0.0509]. CV death, MI, or UA rates were higher in those with prior MI compared with no prior MI (6.68 vs. 2.19; HR 3.04, 95% CI 2.59–3.56) with consistent results for CV death, MI, or UA for rivaroxaban compared with warfarin in prior MI compared with no prior MI (P interaction = 0.10).
Prior MI was common and associated with substantial risk for subsequent cardiac events. Patients with prior MI assigned rivaroxaban compared with warfarin had a non-significant 14% reduction of ischaemic cardiac events.
PMCID: PMC3896862  PMID: 24132190
Atrial fibrillation; Myocardial infarction; Coronary artery disease; Outcomes; Factor Xa; Rivaroxaban; Warfarin
3.  Thioester Bonds of Thiocoraline Can Be Replaced with NMe-Amide Bridges without Affecting Its DNA-Binding Properties 
In the search for new drug candidates for DNA recognition, affinity and sequence selectivity are two of the most important features. NMe-azathiocoraline, a synthetic antitumor bisintercalator derived from the natural marine product thiocoraline, shows similar potency to the parent compound, as well as possessing enhanced stability. Analysis of the DNA-binding selectivity of NMe-azathiocoraline by DNase I footprinting using universal substrates with all 136 tetranucleotides and all possible symmetrical hexanucleotide sequences revealed that, although this ligand binds to all CpG steps with lower affinities than thiocoraline, it displays additional binding to AT-rich sites. Moreover, fluorescence melting studies showed a strong interaction of the synthetic molecule with CACGTG and weaker binding to ACATGT and AGATCT. These findings demonstrate that NMe-azathiocoraline has the same mode of action as thiocoraline, mimicking its DNA-binding selectivity despite the substitution of its thioester bonds by NMe-amide bridges.
PMCID: PMC4027633  PMID: 24900772
Thiocoraline; bisintercalator; DNA binding; antitumor; DNase I footprinting; fluorescence melting
4.  Outcomes of Temporary Interruption of Rivaroxaban Compared With Warfarin in Patients With Nonvalvular Atrial Fibrillation 
Circulation  2014;129(18):1850-1859.
During long-term anticoagulation in atrial fibrillation, temporary interruptions (TIs) of therapy are common, but the relationship between patient outcomes and TIs has not been well studied. We sought to determine reasons for TI, the characteristics of patients undergoing TI, and the relationship between anticoagulant and outcomes among patients with TI.
Methods and Results
In the Rivaroxaban Once Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF), a randomized, double-blind, double-dummy study of rivaroxaban and warfarin in nonvalvular atrial fibrillation, baseline characteristics, management, and outcomes, including stroke, non–central nervous system systemic embolism, death, myocardial infarction, and bleeding, were reported in participants who experienced TI (3–30 days) for any reason. The at-risk period for outcomes associated with TI was from TI start to 30 days after resumption of study drug. In 14 236 participants who received at least 1 dose of study drug, 4692 (33%) experienced TI. Participants with TI were similar to the overall ROCKET AF population in regard to baseline clinical characteristics. Only 6% (n=483) of TI incidences involved bridging therapy. Stroke/systemic embolism rates during the at-risk period were similar in rivaroxaban-treated and warfarin-treated participants (0.30% versus 0.41% per 30 days; hazard ratio [confidence interval]=0.74 [0.36–1.50]; P=0.40). Risk of major bleeding during the at-risk period was also similar in rivaroxaban-treated and warfarin-treated participants (0.99% versus 0.79% per 30 days; hazard ratio [confidence interval]=1.26 [0.80–2.00]; P=0.32).
TI of oral anticoagulation is common and is associated with substantial stroke risks and bleeding risks that were similar among patients treated with rivaroxaban or warfarin. Further investigation is needed to determine the optimal management strategy in patients with atrial fibrillation requiring TI of anticoagulation.
Clinical Trial Registration
URL: Unique identifier: NCT00403767.
PMCID: PMC4206548  PMID: 24552831
anticoagulation; atrial fibrillation; stroke
5.  Factors Associated With Major Bleeding Events 
This study sought to report additional safety results from the ROCKET AF (Rivaroxaban Once-daily oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation).
The ROCKET AF trial demonstrated similar risks of stroke/systemic embolism and major/nonmajor clinically relevant bleeding (principal safety endpoint) with rivaroxaban and warfarin.
The risk of the principal safety and component bleeding endpoints with rivaroxaban versus warfarin were compared, and factors associated with major bleeding were examined in a multivariable model.
The principal safety endpoint was similar in the rivaroxaban and warfarin groups (14.9 vs. 14.5 events/100 patient-years; hazard ratio: 1.03; 95% confidence interval: 0.96 to 1.11). Major bleeding risk increased with age, but there were no differences between treatments in each age category (<65, 65 to 74, ≥75 years; pinteraction = 0.59). Compared with those without (n = 13,455), patients with a major bleed (n = 781) were more likely to be older, current/prior smokers, have prior gastrointestinal (GI) bleeding, mild anemia, and a lower calculated creatinine clearance and less likely to be female or have a prior stroke/transient ischemic attack. Increasing age, baseline diastolic blood pressure (DBP) ≥90 mm Hg, history of chronic obstructive pulmonary disease or GI bleeding, prior acetylsalicylic acid use, and anemia were independently associated with major bleeding risk; female sex and DBP <90 mm Hg were associated with a decreased risk.
Rivaroxaban and warfarin had similar risk for major/nonmajor clinically relevant bleeding. Age, sex, DBP, prior GI bleeding, prior acetylsalicylic acid use, and anemia were associated with the risk of major bleeding. (An Efficacy and Safety Study of Rivaroxaban With Warfarin for the Prevention of Stroke and Non-Central Nervous System Systemic Embolism in Patients With Non-Valvular Atrial Fibrillation: NCT00403767)
PMCID: PMC4206565  PMID: 24315894
anticoagulants; atrial fibrillation; hemorrhage
6.  The effect of interleukin-1 receptor antagonist therapy on markers of inflammation in non-ST elevation acute coronary syndromes: the MRC-ILA Heart Study 
European Heart Journal  2014;36(6):377-384.
Acute coronary syndromes (ACSs) are driven by inflammation within coronary plaque. Interleukin-1 (IL-1) has an established role in atherogenesis and the vessel-response to injury. ACS patients have raised serum markers of inflammation. We hypothesized that if IL-1 is a driving influence of inflammation in non-ST elevation ACS (NSTE-ACS), IL-1 inhibition would reduce the inflammatory response at the time of ACS.
Methods and results
A phase II, double-blinded, randomized, placebo-controlled, study recruited 182 patients with NSTE-ACS, presenting <48 h from onset of chest pain. Treatment was 1:1 allocation to daily, subcutaneous IL-1receptor antagonist (IL-1ra) or placebo for 14 days. Baseline characteristics were well matched. Treatment compliance was 85% at 7 days. The primary endpoint (area-under-the-curve for C-reactive protein over the first 7 days) was: IL-1ra group, 21.98 mg day/L (95%CI 16.31–29.64); placebo group, 43.5 mg day/L (31.15–60.75) (geometric mean ratio = 0.51 mg/L; 95%CI 0.32–0.79; P = 0.0028). In the IL-1ra group, 14-day achieved high-sensitive C-reactive protein (P < 0.0001) and IL-6 levels (P = 0.02) were lower than Day 1. Sixteen days after discontinuation of treatment (Day 30) high-sensitive C-reactive protein levels had risen again in the IL-1ra group [IL-1ra; 3.50 mg/L (2.65–4.62): placebo; 2.21 mg/L (1.67–2.92), P = 0.022]. MACE at Day 30 and 3 months was similar but at 1 year there was a significant excess of events in the IL-1ra group.
IL-1 drives C-reactive protein elevation at the time of NSTE-ACS. Following 14 days IL-1ra treatment inflammatory markers were reduced. These results show the importance of IL-1 as a target in ACS, but also indicate the need for additional studies with anti-IL-1 therapy in ACS to assess duration and safety.
Clinical Trial Registration
EUCTR: 2006-001767-31-GB:
PMCID: PMC4320321  PMID: 25079365
Myocardial infarction; Drugs; Interleukins
7.  A Mutant of Uracil DNA Glycosylase That Distinguishes between Cytosine and 5-Methylcytosine 
PLoS ONE  2014;9(4):e95394.
We demonstrate that a mutant of uracil DNA glycosylase (N123D:L191A) distinguishes between cytosine and methylcytosine. Uracil DNA glycosylase (UDG) efficiently removes uracil from DNA in a reaction in which the base is flipped into the enzyme’s active site. Uracil is selected over cytosine by a pattern of specific hydrogen bonds, and thymine is excluded by steric clash of its 5-methyl group with Y66. The N123D mutation generates an enzyme that excises cytosine. This N123D:L191A mutant excises C when it is mispaired with A or opposite an abasic site, but not when it is paired with G. In contrast no cleavage is observed with any substrates that contain 5-methylcytosine. This enzyme may offer a new approach for discriminating between cytosine and 5-methylcytosine.
PMCID: PMC3989344  PMID: 24740413
8.  Relationship Between Time in Therapeutic Range and Comparative Treatment Effect of Rivaroxaban and Warfarin: Results From the ROCKET AF Trial 
Time in therapeutic range (TTR) is a standard quality measure of the use of warfarin. We assessed the relative effects of rivaroxaban versus warfarin at the level of trial center TTR (cTTR) since such analysis preserves randomized comparisons.
Methods and Results
TTR was calculated using the Rosendaal method, without exclusion of international normalized ratio (INR) values performed during warfarin initiation. Measurements during warfarin interruptions >7 days were excluded. INRs were performed via standardized finger‐stick point‐of‐care devices at least every 4 weeks. The primary efficacy endpoint (stroke or non‐central nervous system embolism) was examined by quartiles of cTTR and by cTTR as a continuous function. Centers with the highest cTTRs by quartile had lower‐risk patients as reflected by lower CHADS2 scores (P<0.0001) and a lower prevalence of prior stroke or transient ischemic attack (P<0.0001). Sites with higher cTTR were predominantly from North America and Western Europe. The treatment effect of rivaroxaban versus warfarin on the primary endpoint was consistent across a wide range of cTTRs (P value for interaction=0.71). The hazard of major and non‐major clinically relevant bleeding increased with cTTR (P for interaction=0.001), however, the estimated reduction by rivaroxaban compared with warfarin in the hazard of intracranial hemorrhage was preserved across a wide range of threshold cTTR values.
The treatment effect of rivaroxaban compared with warfarin for the prevention of stroke and systemic embolism is consistent regardless of cTTR.
PMCID: PMC4187517  PMID: 24755148
rivaroxaban; time in therapeutic range; warfarin
9.  Outcomes among non-ST-segment elevation acute coronary syndromes patients with no angiographically obstructive coronary artery disease: observations from 37,101 patients 
Limited data exist concerning outcomes of patients with non-ST-segment elevation acute coronary syndromes (NSTE ACS) with no angiographically obstructive coronary artery disease (non-obstructive CAD). We assessed the frequency of clinical outcomes among patients with non-obstructive CAD compared with obstructive CAD.
Methods and results:
We pooled data from eight NSTE ACS randomized clinical trials from 1994 to 2008, including 37,101 patients who underwent coronary angiography. The primary outcome was 30-day death or myocardial infarction (MI). Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for 30-day death or MI for non-obstructive versus obstructive CAD were generated for each trial. Summary ORs (95% CIs) across trials were generated using random effects models. Overall, 3550 patients (9.6%) had non-obstructive CAD. They were younger, more were female, and fewer had diabetes mellitus, previous MI or prior percutaneous coronary intervention than patients with obstructive CAD. Thirty-day death or MI was less frequent among patients with non-obstructive CAD (2.2%) versus obstructive CAD (13.3%) (ORadj 0.15; 95% CI, 0.11–0.20); 30-day death or spontaneous MI and six-month mortality were also less frequent among patients with non-obstructive CAD (ORadj 0.19 (0.14–0.25) and 0.37 (0.28–0.49), respectively).
Among patients with NSTE ACS, one in 10 had non-obstructive CAD. Death or MI occurred in 2.2% of these patients by 30 days. Compared with patients with obstructive CAD, the rate of major cardiac events was lower in patients with non-obstructive CAD but was not negligible, prompting the need to better understand management strategies for this group.
PMCID: PMC3932771  PMID: 24562802
Acute coronary syndromes; angiography; atherosclerosis; coronary disease; infarction
10.  Should patients with acute coronary disease be stratified for management according to their risk? Derivation, external validation and outcomes using the updated GRACE risk score 
BMJ Open  2014;4(2):e004425.
Risk scores are recommended in guidelines to facilitate the management of patients who present with acute coronary syndromes (ACS). Internationally, such scores are not systematically used because they are not easy to apply and some risk indicators are not available at first presentation. We aimed to derive and externally validate a more accurate version of the Global Registry of Acute Coronary Events (GRACE) risk score for predicting the risk of death or death/myocardial infarction (MI) both acutely and over the longer term. The risk score was designed to be suitable for acute and emergency clinical settings and usable in electronic devices.
Design and setting
The GRACE risk score (2.0) was derived in 32 037 patients from the GRACE registry (14 countries, 94 hospitals) and validated externally in the French registry of Acute ST-elevation and non-ST-elevation MI (FAST-MI) 2005.
Patients presenting with ST-elevation and non-ST elevation ACS and with long-term outcomes.
Outcome measures
The GRACE Score (2.0) predicts the risk of short-term and long-term mortality, and death/MI, overall and in hospital survivors.
For key independent risk predictors of death (1 year), non-linear associations (vs linear) were found for age (p<0.0005), systolic blood pressure (p<0.0001), pulse (p<0.0001) and creatinine (p<0.0001). By employing non-linear algorithms, there was improved model discrimination, validated externally. Using the FAST-MI 2005 cohort, the c indices for death exceeded 0.82 for the overall population at 1 year and also at 3 years. Discrimination for death or MI was slightly lower than for death alone (c=0.78). Similar results were obtained for hospital survivors, and with substitutions for creatinine and Killip class, the model performed nearly as well.
The updated GRACE risk score has better discrimination and is easier to use than the previous score based on linear associations. GRACE Risk (2.0) performed equally well acutely and over the longer term and can be used in a variety of clinical settings to aid management decisions.
PMCID: PMC3931985  PMID: 24561498
12.  Euro Heart Survey 2009 Snapshot: regional variations in presentation and management of patients with AMI in 47 countries 
Detailed data on patients admitted for acute myocardial infarction (AMI) on a European-wide basis are lacking. The Euro Heart Survey 2009 Snapshot was designed to assess characteristics, management, and hospital outcomes of AMI patients throughout European Society of Cardiology (ESC) member countries in a contemporary ‘real-world’ setting, using a methodology designed to improve the representativeness of the survey.
Member countries of the ESC were invited to participate in a 1-week survey of all patients admitted for documented AMI in December 2009. Data on baseline characteristics, type of AMI, management, and complications were recorded using a dedicated electronic form. In addition, we used data collected during the same time period in national registries in Sweden, England, and Wales. Data were centralized at the European Heart House.
Overall, 4236 patients (mean age 66±13 years; 31% women) were included in the study in 47 countries. Sixty per cent of patients had ST-segment elevation myocardial infarction, with 50% having primary percutaneous coronary intervention and 21% fibrinolysis. Aspirin and thienopyridines were used in >90%. Unfractionated and low-molecular-weight heparins were the most commonly used anticoagulants. Statins, beta-blockers, and angiotensin-converting enzyme inhibitors were used in >80% of the patients. In-hospital mortality was 6.2%. Regional differences were observed, both in terms of population characteristics, management, and outcomes.
In-hospital mortality of patients admitted for AMI in Europe is low. Although regional variations exist in their presentation and management, differences are limited and have only moderate impact on early outcomes.
PMCID: PMC3821830  PMID: 24338295
Acute myocardial infarction; Europe; hospital outcomes; survey
13.  Secretory Phospholipase A2-IIA and Cardiovascular Disease 
Holmes, Michael V. | Simon, Tabassome | Exeter, Holly J. | Folkersen, Lasse | Asselbergs, Folkert W. | Guardiola, Montse | Cooper, Jackie A. | Palmen, Jutta | Hubacek, Jaroslav A. | Carruthers, Kathryn F. | Horne, Benjamin D. | Brunisholz, Kimberly D. | Mega, Jessica L. | van Iperen, Erik P.A. | Li, Mingyao | Leusink, Maarten | Trompet, Stella | Verschuren, Jeffrey J.W. | Hovingh, G. Kees | Dehghan, Abbas | Nelson, Christopher P. | Kotti, Salma | Danchin, Nicolas | Scholz, Markus | Haase, Christiane L. | Rothenbacher, Dietrich | Swerdlow, Daniel I. | Kuchenbaecker, Karoline B. | Staines-Urias, Eleonora | Goel, Anuj | van 't Hooft, Ferdinand | Gertow, Karl | de Faire, Ulf | Panayiotou, Andrie G. | Tremoli, Elena | Baldassarre, Damiano | Veglia, Fabrizio | Holdt, Lesca M. | Beutner, Frank | Gansevoort, Ron T. | Navis, Gerjan J. | Mateo Leach, Irene | Breitling, Lutz P. | Brenner, Hermann | Thiery, Joachim | Dallmeier, Dhayana | Franco-Cereceda, Anders | Boer, Jolanda M.A. | Stephens, Jeffrey W. | Hofker, Marten H. | Tedgui, Alain | Hofman, Albert | Uitterlinden, André G. | Adamkova, Vera | Pitha, Jan | Onland-Moret, N. Charlotte | Cramer, Maarten J. | Nathoe, Hendrik M. | Spiering, Wilko | Klungel, Olaf H. | Kumari, Meena | Whincup, Peter H. | Morrow, David A. | Braund, Peter S. | Hall, Alistair S. | Olsson, Anders G. | Doevendans, Pieter A. | Trip, Mieke D. | Tobin, Martin D. | Hamsten, Anders | Watkins, Hugh | Koenig, Wolfgang | Nicolaides, Andrew N. | Teupser, Daniel | Day, Ian N.M. | Carlquist, John F. | Gaunt, Tom R. | Ford, Ian | Sattar, Naveed | Tsimikas, Sotirios | Schwartz, Gregory G. | Lawlor, Debbie A. | Morris, Richard W. | Sandhu, Manjinder S. | Poledne, Rudolf | Maitland-van der Zee, Anke H. | Khaw, Kay-Tee | Keating, Brendan J. | van der Harst, Pim | Price, Jackie F. | Mehta, Shamir R. | Yusuf, Salim | Witteman, Jaqueline C.M. | Franco, Oscar H. | Jukema, J. Wouter | de Knijff, Peter | Tybjaerg-Hansen, Anne | Rader, Daniel J. | Farrall, Martin | Samani, Nilesh J. | Kivimaki, Mika | Fox, Keith A.A. | Humphries, Steve E. | Anderson, Jeffrey L. | Boekholdt, S. Matthijs | Palmer, Tom M. | Eriksson, Per | Paré, Guillaume | Hingorani, Aroon D. | Sabatine, Marc S. | Mallat, Ziad | Casas, Juan P. | Talmud, Philippa J.
This study sought to investigate the role of secretory phospholipase A2 (sPLA2)-IIA in cardiovascular disease.
Higher circulating levels of sPLA2-IIA mass or sPLA2 enzyme activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy.
We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events [MVE] in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2-IIA isoenzyme, as an instrumental variable.
PLA2G2A rs11573156 C allele associated with lower circulating sPLA2-IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval [CI]: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2-IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE.
Reducing sPLA2-IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
PMCID: PMC3826105  PMID: 23916927
cardiovascular diseases; drug development; epidemiology; genetics; Mendelian randomization; ACS, acute coronary syndrome(s); CI, confidence interval; LDL-C, low-density lipoprotein cholesterol; MI, myocardial infarction; MVE, major vascular events; OR, odds ratio; RCT, randomized clinical trial; SNP, single-nucleotide polymorphism; sPLA2, secretory phospholipase A2
14.  Management and outcomes of patients presenting with STEMI by use of chronic oral anticoagulation: results from the GRACE registry 
To describe the characteristics, treatment, and mortality in patients with ST-elevation myocardial infarction (STEMI) by use of chronic oral anticoagulant (OAC) therapy.
Using data from the Global Registry of Acute Coronary Syndromes (GRACE), patient characteristics, treatment, and reperfusion strategies of STEMI patients on chronic OAC are described, and relevant variables compared with patients not on chronic OAC. Six-month post-discharge mortality rates were evaluated by Cox proportional hazard models.
Of 19,094 patients with STEMI, 574 (3.0%) were on chronic OAC at admission. Compared with OAC non-users, OAC users were older (mean age 73 vs. 65 years), more likely to be female (37 vs. 29%), were more likely to have a history of atrial fibrillation, prosthetic heart valve, venous thromboembolism, or stroke/transient ischaemic attack, had a higher mean GRACE risk score (166 vs. 145), were less likely to be Killip class I (68 vs. 82%), and were less likely to undergo catheterization/percutaneous coronary intervention (52 vs. 66%, respectively). Of the patients who underwent catheterization, fewer OAC users had the procedure done within 24 h of admission (56.5 vs. 64.5% of OAC non-users). In propensity-matched analyses (n=606), rates of in-hospital major bleeding and in-hospital and 6-month post-discharge mortality were similar for OAC users and OAC non-users (2.7 and 3.7%, p=0.64; 15 and 13%, p=0.56; 15 and 12%, p=0.47, respectively), rates of in-hospital recurrent myocardial infarction (8.6 and 2.0%, p<0.001) and atrial fibrillation (32 and 22%, p=0.004) were higher in OAC patients, and rates of 6-month stroke were lower (0.6 and 4.3%, p=0.038). Patients in both groups who underwent catheterization had lower mortality than those who did not undergo catheterization.
This is the largest study to describe the characteristics and treatment of STEMI patients on chronic OAC. The findings suggest that patients on chronic OAC are less likely to receive guideline-indicated management, but have similar adjusted rates of in-hospital and 6-month mortality.
PMCID: PMC3821815  PMID: 24222840
Acute coronary syndrome; anticoagulant; guidelines; myocardial infarction
15.  A Cyclic Peptide Inhibitor of HIF-1 Heterodimerization That Inhibits Hypoxia Signaling in Cancer Cells 
Journal of the American Chemical Society  2013;135(28):10418-10425.
Hypoxia inducible factor-1 (HIF-1) is a heterodimeric transcription factor that acts as the master regulator of cellular response to reduced oxygen levels, thus playing a key role in the adaptation, survival, and progression of tumors. Here we report cyclo-CLLFVY, identified from a library of 3.2 million cyclic hexapeptides using a genetically encoded high-throughput screening platform, as an inhibitor of the HIF-1α/HIF-1β protein–protein interaction in vitro and in cells. The identified compound inhibits HIF-1 dimerization and transcription activity by binding to the PAS-B domain of HIF-1α, reducing HIF-1-mediated hypoxia response signaling in a variety of cell lines, without affecting the function of the closely related HIF-2 isoform. The reported cyclic peptide demonstrates the utility of our high-throughput screening platform for the identification of protein–protein interaction inhibitors, and forms the starting point for the development of HIF-1 targeted cancer therapeutics.
PMCID: PMC3715890  PMID: 23796364
16.  An assessment of composite measures of hospital performance and associated mortality for patients with acute myocardial infarction. Analysis of individual hospital performance and outcome for the National Institute for Cardiovascular Outcomes Research (NICOR) 
To investigate whether a hospital-specific opportunity-based composite score (OBCS) was associated with mortality in 136,392 patients with acute myocardial infarction (AMI) using data from the Myocardial Ischaemia National Audit Project (MINAP) 2008–2009.
Methods and results:
For 199 hospitals a multidimensional hospital OBCS was calculated on the number of times that aspirin, thienopyridine, angiotensin-converting enzyme inhibitor (ACEi), statin, β-blocker, and referral for cardiac rehabilitation was given to individual patients, divided by the overall number of opportunities that hospitals had to give that care. OBCS and its six components were compared using funnel plots. Associations between OBCS performance and 30-day and 6-month all-cause mortality were quantified using mixed-effects regression analysis. Median hospital OBCS was 95.3% (range 75.8–100%). By OBCS, 24.1% of hospitals were below funnel plot 99.8% CI, compared to aspirin (11.1%), thienopyridine (15.1%), β-blockers (14.7%), ACEi (19.1%), statins (12.1%), and cardiac rehabilitation (17.6%) on discharge. Mortality (95% CI) decreased with increasing hospital OBCS quartile at 30 days [Q1, 2.25% (2.07–2.43%) vs. Q4, 1.40% (1.25–1.56%)] and 6 months [Q1, 7.93% (7.61–8.25%) vs. Q4, 5.53% (5.22–5.83%)]. Hospital OBCS quartile was inversely associated with adjusted 30-day and 6-month mortality [OR (95% CI), 0.87 (0.80–0.94) and 0.92 (0.88–0.96), respectively] and persisted after adjustment for coronary artery catheterization [0.89 (0.82–0.96) and 0.95 (0.91–0.98), respectively].
Multidimensional hospital OBCS in AMI survivors are high, discriminate hospital performance more readily than single performance indicators, and significantly inversely predict early and longer-term mortality.
PMCID: PMC3760578  PMID: 24062929
Acute myocardial infarction; composite performance indicators; mortality; performance; quality of care
17.  Impact of Global Geographic Region on Time in Therapeutic Range on Warfarin Anticoagulant Therapy: Data From the ROCKET AF Clinical Trial 
Vitamin K antagonist (VKA) therapy remains the most common method of stroke prevention in patients with atrial fibrillation. Time in therapeutic range (TTR) is a widely cited measure of the quality of VKA therapy. We sought to identify factors associated with TTR in a large, international clinical trial.
Methods and Results
TTR (international normalized ratio [INR] 2.0 to 3.0) was determined using standard linear interpolation in patients randomized to warfarin in the ROCKET AF trial. Factors associated with TTR at the individual patient level (i‐TTR) were determined via multivariable linear regression. Among 6983 patients taking warfarin, recruited from 45 countries grouped into 7 regions, the mean i‐TTR was 55.2% (SD 21.3%) and the median i‐TTR was 57.9% (interquartile range 43.0% to 70.6%). The mean time with INR <2 was 29.1% and the mean time with an INR >3 was 15.7%. While multiple clinical features were associated with i‐TTR, dominant determinants were previous warfarin use (mean i‐TTR of 61.1% for warfarin‐experienced versus 47.4% in VKA‐naïve patients) and geographic region where patients were managed (mean i‐TTR varied from 64.1% to 35.9%). These effects persisted in multivariable analysis. Regions with the lowest i‐TTRs had INR distributions shifted toward lower INR values and had longer inter‐INR test intervals.
Independent of patient clinical features, the regional location of medical care is a dominant determinant of variation in i‐TTR in global studies of warfarin. Regional differences in mean i‐TTR are heavily influenced by subtherapeutic INR values and are associated with reduced frequency of INR testing.
Clinical Trial Registration
URL: Unique identifier: NCT00403767.
PMCID: PMC3603243  PMID: 23525418
anticoagulants; arrhythmia; embolism; prevention; risk factors
18.  Effect of PSI‐697, a Novel P‐Selectin Inhibitor, on Platelet–Monocyte Aggregate Formation in Humans 
Platelet activation is central to the pathogenesis of acute coronary syndromes. Surface expression of P‐selectin on activated platelets induces formation of platelet–monocyte aggregates and promotes vascular inflammation and thrombosis. P‐selectin antagonism may represent a novel therapeutic strategy in vascular disease. We aimed to investigate the effects of the novel P‐selectin antagonist PSI‐697 on platelet–monocyte aggregate formation in humans.
Methods and Results
In a double‐blind, randomized, placebo‐controlled crossover study, healthy smokers were randomized to receive either oral PSI‐697 600 mg or matched placebo. The sequence of treatment was also randomized, with all subjects receiving both PSI‐697 and placebo. Platelet–monocyte aggregates were measured by flow cytometry at 4 and 24 hours in the presence and absence of thrombin receptor‐activating peptide (TRAP; 0.1 to 1.0 μm/L). The ex vivo addition of TRAP caused a concentration‐dependent increase in platelet–monocyte aggregates from 8.2% to 94.8% (P<0.001). At 4 and 24 hours, plasma concentrations of PSI‐697 increased to 1906 and 83 ng/mL, respectively (P<0.001). PSI‐697 had no demonstrable effect on either stimulated or unstimulated platelet–monocyte aggregates at 4 or 24 hours (P>0.05). P‐selectin‐blocking antibody (CLB‐Thromb6), but not PSI‐697, inhibited both stimulated and unstimulated platelet–monocyte aggregate formation in vitro (P<0.001).
The novel small‐molecule P‐selectin antagonist PSI‐697 did not inhibit basal or stimulated platelet–monocyte aggregate formation in humans at the dose tested. Its clinical efficacy remains to be established.
Clinical Trial Registration
URL: Unique identifier: 2007‐005695‐14.
PMCID: PMC3603266  PMID: 23525448
platelets; P‐selectin; thrombosis
19.  Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study 
Voight, Benjamin F | Peloso, Gina M | Orho-Melander, Marju | Frikke-Schmidt, Ruth | Barbalic, Maja | Jensen, Majken K | Hindy, George | Hólm, Hilma | Ding, Eric L | Johnson, Toby | Schunkert, Heribert | Samani, Nilesh J | Clarke, Robert | Hopewell, Jemma C | Thompson, John F | Li, Mingyao | Thorleifsson, Gudmar | Newton-Cheh, Christopher | Musunuru, Kiran | Pirruccello, James P | Saleheen, Danish | Chen, Li | Stewart, Alexandre FR | Schillert, Arne | Thorsteinsdottir, Unnur | Thorgeirsson, Gudmundur | Anand, Sonia | Engert, James C | Morgan, Thomas | Spertus, John | Stoll, Monika | Berger, Klaus | Martinelli, Nicola | Girelli, Domenico | McKeown, Pascal P | Patterson, Christopher C | Epstein, Stephen E | Devaney, Joseph | Burnett, Mary-Susan | Mooser, Vincent | Ripatti, Samuli | Surakka, Ida | Nieminen, Markku S | Sinisalo, Juha | Lokki, Marja-Liisa | Perola, Markus | Havulinna, Aki | de Faire, Ulf | Gigante, Bruna | Ingelsson, Erik | Zeller, Tanja | Wild, Philipp | de Bakker, Paul I W | Klungel, Olaf H | Maitland-van der Zee, Anke-Hilse | Peters, Bas J M | de Boer, Anthonius | Grobbee, Diederick E | Kamphuisen, Pieter W | Deneer, Vera H M | Elbers, Clara C | Onland-Moret, N Charlotte | Hofker, Marten H | Wijmenga, Cisca | Verschuren, WM Monique | Boer, Jolanda MA | van der Schouw, Yvonne T | Rasheed, Asif | Frossard, Philippe | Demissie, Serkalem | Willer, Cristen | Do, Ron | Ordovas, Jose M | Abecasis, Gonçalo R | Boehnke, Michael | Mohlke, Karen L | Daly, Mark J | Guiducci, Candace | Burtt, Noël P | Surti, Aarti | Gonzalez, Elena | Purcell, Shaun | Gabriel, Stacey | Marrugat, Jaume | Peden, John | Erdmann, Jeanette | Diemert, Patrick | Willenborg, Christina | König, Inke R | Fischer, Marcus | Hengstenberg, Christian | Ziegler, Andreas | Buysschaert, Ian | Lambrechts, Diether | Van de Werf, Frans | Fox, Keith A | El Mokhtari, Nour Eddine | Rubin, Diana | Schrezenmeir, Jürgen | Schreiber, Stefan | Schäfer, Arne | Danesh, John | Blankenberg, Stefan | Roberts, Robert | McPherson, Ruth | Watkins, Hugh | Hall, Alistair S | Overvad, Kim | Rimm, Eric | Boerwinkle, Eric | Tybjaerg-Hansen, Anne | Cupples, L Adrienne | Reilly, Muredach P | Melander, Olle | Mannucci, Pier M | Ardissino, Diego | Siscovick, David | Elosua, Roberto | Stefansson, Kari | O'Donnell, Christopher J | Salomaa, Veikko | Rader, Daniel J | Peltonen, Leena | Schwartz, Stephen M | Altshuler, David | Kathiresan, Sekar
Lancet  2012;380(9841):572-580.
High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian randomisation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.
Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher, p=8×10−13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with non-carriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84–0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88–1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58–0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93, 95% CI 0·68–1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45–1·63) was concordant with that from genetic score (OR 2·13, 95% CI 1·69–2·69, p=2×10−10).
Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.
US National Institutes of Health, The Wellcome Trust, European Union, British Heart Foundation, and the German Federal Ministry of Education and Research.
PMCID: PMC3419820  PMID: 22607825
20.  Anticoagulation in atrial fibrillation: the present and the future 
JRSM Cardiovascular Disease  2012;1(5):cvd.2012.012018.
Atrial fibrillation (AF) is the most common form of cardiac arrhythmia and associated with significant mortality and morbidity. It is a powerful predictor of future embolic stroke, such that anticoagulation is recommended in the majority of patients. For many years this has predominantly been in the form of vitamin K antagonists. However, there are well-documented difficulties with their administration that result in poor compliance and high discontinuation rates. Over recent years several oral alternative anticoagulant agents have become available with the potential to overcome many of these pitfalls. In this review, we discuss current recommendations for anticoagulant therapy in AF and how these may change in the future with the introduction of novel therapeutic options.
PMCID: PMC3738362  PMID: 24175070
21.  Antistaphylococcal activity of DNA-interactive pyrrolobenzodiazepine (PBD) dimers and PBD-biaryl conjugates 
Pyrrolobenzodiazepine (PBD) dimers, tethered through inert propyldioxy or pentyldioxy linkers, possess potent bactericidal activity against a range of Gram-positive bacteria by virtue of their capacity to cross-link duplex DNA in sequence-selective fashion. Here we attempt to improve the antibacterial activity and cytotoxicity profile of PBD-containing conjugates by extension of dimer linkers and replacement of one PBD unit with phenyl-substituted or benzo-fused heterocycles that facilitate non-covalent interactions with duplex DNA.
DNase I footprinting was used to identify high-affinity DNA binding sites. A staphylococcal gene microarray was used to assess epidemic methicillin-resistant Staphylococcus aureus 16 phenotypes induced by PBD conjugates. Molecular dynamics simulations were employed to investigate the accommodation of compounds within the DNA helix.
Increasing the length of the linker in PBD dimers led to a progressive reduction in antibacterial activity, but not in their cytotoxic capacity. Complex patterns of DNA binding were noted for extended PBD dimers. Modelling of DNA strand cross-linking by PBD dimers indicated distortion of the helix. A majority (26 of 43) of PBD-biaryl conjugates possessed potent antibacterial activity with little or no helical distortion and a more favourable cytotoxicity profile. Bactericidal activity of PBD-biaryl conjugates was determined by inability to excise covalently bound drug molecules from bacterial duplex DNA.
PBD-biaryl conjugates have a superior antibacterial profile compared with PBD dimers such as ELB-21. We have identified six PBD-biaryl conjugates as potential drug development candidates.
PMCID: PMC3370821  PMID: 22547662
pyrrolobenzodiazepine dimers; pyrrolobenzodiazepine-biaryl conjugates; DNA adduct formation; MRSA
22.  Identifying Acute Coronary Syndrome Patients Approaching End-of-Life 
PLoS ONE  2012;7(4):e35536.
Acute coronary syndrome (ACS) is common in patients approaching the end-of-life (EoL), but these patients rarely receive palliative care. We compared the utility of a palliative care prognostic tool (Gold Standards Framework (GSF)) and the Global Registry of Acute Coronary Events (GRACE) score, to help identify patients approaching EoL.
Methods and Findings
172 unselected consecutive patients with confirmed ACS admitted over an eight-week period were assessed using prognostic tools and followed up for 12 months. GSF criteria identified 40 (23%) patients suitable for EoL care while GRACE identified 32 (19%) patients with ≥10% risk of death within 6 months. Patients meeting GSF criteria were older (p = 0.006), had more comorbidities (1.6±0.7 vs. 1.2±0.9, p = 0.007), more frequent hospitalisations before (p = 0.001) and after (0.0001) their index admission, and were more likely to die during follow-up (GSF+ 20% vs GSF- 7%, p = 0.03). GRACE score was predictive of 12-month mortality (C-statistic 0.75) and this was improved by the addition of previous hospital admissions and previous history of stroke (C-statistic 0.88).
This study has highlighted a potentially large number of ACS patients eligible for EoL care. GSF or GRACE could be used in the hospital setting to help identify these patients. GSF identifies ACS patients with more comorbidity and at increased risk of hospital readmission.
PMCID: PMC3329478  PMID: 22530044
23.  Secondary binding sites for heavily modified triplex forming oligonucleotides 
Nucleic Acids Research  2011;40(8):3753-3762.
In order to enhance DNA triple helix stability synthetic oligonucleotides have been developed that bear amino groups on the sugar or base. One of the most effective of these is bis-amino-U (B), which possesses 5-propargylamino and 2′-aminoethoxy modifications. Inclusion of this modified nucleotide not only greatly enhances triplex stability, but also increases the affinity for related sequences. We have used a restriction enzyme protection, selection and amplification assay (REPSA) to isolate sequences that are bound by the heavily modified 9-mer triplex-forming oligonucleotide B6CBT. The isolated sequences contain An tracts (n = 6), suggesting that the 5′-end of this TFO was responsible for successful triplex formation. DNase I footprinting with these sequences confirmed triple helix formation at these secondary targets and demonstrated no interaction with similar oligonucleotides containing T or 5-propargylamino-dU.
PMCID: PMC3333850  PMID: 22180535
24.  Clopidogrel discontinuation after acute coronary syndromes: frequency, predictors and associations with death and myocardial infarction—a hospital registry-primary care linked cohort (MINAP–GPRD) 
European Heart Journal  2011;32(19):2376-2386.
Adherence to evidence-based treatments and its consequences after acute myocardial infarction (MI) are poorly defined. We examined the extent to which clopidogrel treatment initiated in hospital is continued in primary care; the factors predictive of clopidogrel discontinuation and the hazard of death or recurrent MI.
Methods and results
We linked the Myocardial Ischaemia National Audit Project registry and the General Practice Research Database to examine adherence to clopidogrel in primary care among patients discharged from hospital after MI (2003–2009). Hospital Episode Statistics and national mortality data were linked, documenting all-cause mortality and non-fatal MI. Of the 7543 linked patients, 4650 were prescribed clopidogrel in primary care within 3 months of discharge. The adjusted odds of still being prescribed clopidogrel at 12 months were similar following non-ST-elevation myocardial infarction (NSTEMI) 53% (95% CI, 51–55) and ST-elevation myocardial infarction (STEMI) 54% (95% CI, 52–56), but contrast with statins: NSTEMI 84% (95% CI, 82–85) and STEMI 89% (95% CI, 87–90). Discontinuation within 12 months was more frequent in older patients [>80 vs. 40–49 years, adjusted hazard ratio (HR) 1.50 (95% CI, 1.15–1.94)] and with bleeding events [HR 1.34 (95% CI, 1.03–1.73)]. 18.15 patients per 100 person-years (95% CI, 16.83–19.58) died or experienced non-fatal MI in the first year following discharge. In patients who discontinued clopidogrel within 12 months, the adjusted HR for death or non-fatal MI was 1.45 (95% CI, 1.22–1.73) compared with untreated patients, and 2.62 (95% CI, 2.17–3.17) compared with patients persisting with clopidogrel treatment.
This is the first study to use linked registries to determine persistence of clopidogrel treatment after MI in primary care. It demonstrates that discontinuation is common and associated with adverse outcomes.
PMCID: PMC3184230  PMID: 21875855
ACS; Myocardial infarction; Clopidogrel; Anti-platelet; Observational
25.  Delay to reperfusion in patients with acute myocardial infarction presenting to acute care hospitals: an international perspective 
European Heart Journal  2010;31(11):1328-1336.
To examine the extent of delay from initial hospital presentation to fibrinolytic therapy or primary percutaneous coronary intervention (PCI), characteristics associated with prolonged delay, and changes in delay patterns over time in patients with ST-segment elevation myocardial infarction (STEMI).
Methods and results
We analysed data from 5170 patients with STEMI enrolled in the Global Registry of Acute Coronary Events from 2003 to 2007. The median elapsed time from first hospital presentation to initiation of fibrinolysis was 30 min (interquartile range 18–60) and to primary PCI was 86 min (interquartile range 53–135). Over the years under study, there were no significant changes in delay times to treatment with either strategy. Geographic region was the strongest predictor of delay to initiation of fibrinolysis >30 min. Patient's transfer status and geographic location were strongly associated with delay to primary PCI. Patients treated in Europe were least likely to experience delay to fibrinolysis or primary PCI.
These data suggest no improvements in delay times from hospital presentation to initiation of fibrinolysis or primary PCI during our study period. Geographic location and patient transfer were the strongest predictors of prolonged delay time, suggesting that improvements in modifiable healthcare system factors can shorten delay to reperfusion therapy even further.
PMCID: PMC2878967  PMID: 20231154
Percutaneous coronary intervention; ST-segment elevation myocardial infarction; Reperfusion; Fibrinolysis

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