31-08-2013 t/m 4-09-2013 ESC Congres 2013 Amsterdam (NH)

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Amsterdam, The Netherlands , Sunday 1 September 2013  – The investigational anticoagulant otamixaban significantly increased bleeding without reducing mortality or new heart attacks compared to currently recommended therapy among patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS) who were scheduled for an early invasive strategy,  according to results of the Treatment of Acute Coronary Syndromes with Otamixaban (TAO) trial.

The TAO study failed to meet its primary endpoint showing superiority of otamixaban,  an injectable factor Xa inhibitor, over a combination of unfractionated heparin (UFH) and eptifibatide in moderate- to high-risk  NSTE-ACS patients scheduled to undergo angiography and potentially percutaneous coronary intervention (PCI) within 3 days of randomization.

“The risk of major or minor bleeding was approximately doubled with otamixaban across all patient subgroups, and a lower dose did not achieve better results,” said the study’s lead investigator Philippe Gabriel Steg, MD, from the Hôpital Bichat, Assistance Publique - Hôpitaux de Paris.

The findings “suggest a narrow therapeutic window for acute injectable Xa inhibition in the setting of ACS treated with modern antiplatelet therapy and routine early intervention, and that raising the intensity of anticoagulation via this mechanism will not achieve a superior efficacy/safety balance in ACS in the modern era of intervention,” said Professor Steg.

In June, the developer, Sanofi, announced its decision to discontinue the investigational program with the drug “due to efficacy lower than expected”.

The multicenter, phase 3 TAO study randomized 13,229 patients to either standard treatment consisting of UFH plus downstream eptifibatide (started only for PCI patients and discontinued 18 to 24 h after PCI ) or otamixaban (0.08 mg/kg intravenous bolus at randomization then 0.100 or 0.140 mg/kg per hour intravenous infusion).  UFH and otamixaban (and their placebos) were started and stopped usually at the end of PCI unless patients required continued anticoagulation for a medical reason.

In addition to the study medication all patients received both aspirin and an oral adenosine diphosphate receptor antagonist.

Rates for the primary outcome, a composite of all-cause death or new myocardial infarction from randomization to day 7, were not significantly different between the two groups (5.5% with otamixaban vs 5.7% with controls, adjusted relative risk 0.99, P =.93).

However, the primary safety outcome, the rate of major or minor bleeding according to Thrombolysis in Myocardial Infarction (TIMI) criteria  through day 7 was more than doubled with otamixaban (3.1% vs 1.5%, relative risk 2.13, P<.001).

Unfractionated heparin (UFH), particularly when combined with a glycoprotein IIb/IIIa inhibitor (GPI) such as eptifibatide at the time of percutaneous coronary intervention (PCI), “remains an effective and widely used therapy, and its use is supported by US and European guidelines,” said Professor Steg.

“However, UFH has limitations, such as a narrow therapeutic window, a somewhat unpredictable anticoagulant response, and activation of the PF4 platelet receptor,” he explained.

Theoretically, otamixaban, seemed an attractive anticoagulant for this patient population because it is an injectable agent with rapid onset and offset, modest renal elimination, and predictable anticoagulant effect that obviates the need for monitoring.

Although a previous phase 2 trial (SEPIA-ACS1 TIMI 42) had suggested a clinical benefit of otamixaban, it was a dose-ranging trial, with an overall low event rate, making risk estimates less accurate. The dosing of eptifibatide was also slightly different.

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Amsterdam, The Netherlands, 1 September 2013 -  Among patients undergoing percutaneous coronary intervention (PCI) with stents, the risk of cardiovascular complications after stopping dual antiplatelet therapy (DAPT) is highly variable depending on the context, and some patients experience no complications at all, according to the results of the Patterns of Non-Adherence to Anti-Platelet Regimens In Stented Patients (PARIS) study.

“Our findings challenge existing paradigms for prolonging antiplatelet therapy in otherwise stable patients after PCI, and show that in a real-world setting physicians are making appropriate decisions in selecting low-risk patients for discontinuation,” said lead investigator Roxana Mehran, MD., Professor of Medicine and Director of Interventional Cardiovascular Research and Clinical Trials, Icahn School of Medicine at Mount Sinai, New York.

“Conversely, when patients simply don’t comply or are forced off antiplatelet therapy because they are bleeding, their risk is significantly elevated,” she added.

The PARIS study, a prospective, international, multicenter, observational registry trial, enrolled more than 5-thousand patients with coronary artery disease undergoing PCI with stent implantation at 15 clinical sites in 5 countries between July, 2009 and December, 2010.

Follow-up at 30 days, 6 months, 1 and 2 years determined whether patients had discontinued, interrupted or disrupted antiplatelet therapy and whether this resulted in any major adverse cardiovascular events (MACE).

“Discontinuation” was defined as a physician-recommended cessation of medication for subjects believed to no longer need it, while “interruption” was defined as temporary (up to 14 days) due to surgical necessity, and “disruption” was due to bleeding or non-compliance.  

In a final analysis of 5,018 patients at 2, the study showed a cumulative incidence of discontinuation, interruption and disruption of 40.8%, 10.5% and 14.4%, respectively, while the cumulative incidence of MACE was 11.5%.

At 1-year, which is the duration currently recommended for antiplatelet therapy, the cumulative incidence of discontinuation, interruption and disruption was 11.5%, 4.6% and 9.8% respectively, with a 7.4% cumulative incidence of MACE.

The majority of MACE (74%) occurred in patients who had remained on their recommended antiplatelet therapy, but among those who had not, there was a 50% increased risk of MACE associated with disrupting compared to staying on medication, and a 37% decreased risk associated with discontinuation compared to staying on. In contrast, brief interruptions did not increase risk for thrombotic events such as stent thrombosis or myocardial infarction.

“The findings show that when physicians recommend discontinuation presumably because patients are stable, there is no risk of adverse events, but when patients simply don’t comply or are forced off antiplatelet therapy because they are bleeding, their risk is significantly elevated,” said Dr. Mehran.

For the latter group, a novel finding was that the risk of MACE was highest in the first 7 days of disruption (when there was a 7-fold increase), after which it decreased.

Importantly, the study also showed that sustained antiplatelet therapy was not associated with reduced thrombotic risk compared to recommended discontinuation – a finding that goes against common assumption.

“In fact, there was a slight, though statistically non-significant reduction in risk associated with recommended discontinuation, which contrasts with some previous studies that have suggested a potential protective effect with prolonged antiplatelet therapy,” she said.

The PARIS study results show that the effect of antiplatelet cessation on cardiovascular risk is “modest” – offering insight on this interaction in the modern era of post-PCI therapy.

Previous studies have not included such a broad range of subjects and did not account for the context around antiplatelet cessation, said Dr. Mehran.

“We hope that these novel findings will spur initiatives to standardize and harmonize criteria for DAPT cessation, analogous to previous efforts used for myocardial infarction and bleeding.”

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Science in perspective - Day 1

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Dr David Wald, FESC

ESC TV 2013 - Hot Line II: PRAMI, ACCOAST, and LINC part 1

Prof. Gilles Montalescot, FESC

ESC TV 2013 - Hot Line II: PRAMI, ACCOAST, and LINC part 2

Prof. Sten Rubertsson

ESC TV 2013 - Hot Line II: PRAMI, ACCOAST, and LINC part 3

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Prof. Stephan Windecker, FESC / Prof. Jean-Philippe Collet, FESC

ESC TV 2013 - Village5: All the latest interventional innovations

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http://www.nejm.org/doi/full/10.1056/NEJMoa1308075

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http://www.nejm.org/doi/full/10.1056/NEJMoa1305520

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Amsterdam, The Netherlands – Sunday 1 September 2013: Physical activity decreases the risk of sudden cardiac death in unfit men, reveals research presented at the ESC Congress today by Dr Jari Laukkanen and Dr Magnus Hagnas from Finland.

Dr Laukkanen said: “Sudden cardiac death (SCD) accounts for approximately 50% of deaths from coronary heart disease. SCD typically occurs shortly after the onset of symptoms, leaving little time for effective medical interventions, and most cases occur outside hospital with few or no early warning signs. Finding ways to identify individuals at elevated risk of SCD would allow early interventions on risk factors to be implemented.”

The current study investigated the impact of high leisure-time physical activity (LTPA) combined with cardiorespiratory fitness (CRF) on risk of SCD. It included 2,656 randomly selected men aged 42 to 60 years from the Kuopio Ischemic Heart Disease Risk Factor Study, a Finnish study of risk predictors for cardiovascular outcomes and SCD in the general population. Baseline cycle exercise test and risk factor assessment were performed in 1984-89. SCD was defined as death with cardiac origin within 24 hours after onset of symptoms.

LTPA was assessed using a 12-month physical activity questionnaire. One third of subjects had low LTPA (energy consumption <191 kcal/day, equal to around 35 minutes of slow walking or 25 minutes of jogging for a 70 kg male). CRF was assessed with a maximal symptom limited cycle exercise test and peak oxygen uptake was calculated in metabolic equivalents (MET). One third of men had a low CRF (<7.9 METs).

For the analyses the study population was divided into 4 groups: 1) high CRF and high LTPA, 2) high CRF and low LTPA, 3) low CRF and high LTPA and 4) low CRF and low LTPA. Group 1 was used as a reference. The risk of SCD was adjusted for previously established cardiovascular risk factors (age, smoking, alcohol consumption, body mass index, systolic blood pressure, low density lipoprotein cholesterol, C-reactive protein, prevalent type 2 diabetes and previously diagnosed coronary heart disease).

During the mean 19 years of follow-up 193 SCDs occurred. There was a 2-fold increased risk of SCD in men with low CRF and LTPA (group 4, see figure) compared to men with high CRF and high LTPA (hazard ratio 2.0, 95% confidence interval [CI] 1.3-2.9). Men with low CRF and high LTPA (group 3) did not have a statistically significant increased SCD risk compared to men with high CRF and high LTPA (HR 1.3, 95% CI 0.9-1.8 ). Dr Laukkanen said: “This indicates that a higher amount of leisure-time physical activity might reduce the risk of SCD among men with low cardiorespiratory fitness.”

The amount of LTPA did not affect the risk of SCD among the men with high CRF (groups 1 and 2).

Dr Laukkanen said: “Our study shows that CRF is a risk factor for SCD. High leisure-time physical activity exerts a protective effect on the risk of SCD among men with low cardiorespiratory fitness but does not affect risk in men with high baseline CRF.”

He added: “It is widely believed that the level of CRF is determined by physical exercise, genetics and other lifestyle factors. Our study shows that exercise training and LTPA may be especially important in individuals with low CRF. One possible explanation is that CRF can be improved with regular exercise training.”

Dr Laukkanen concluded: “The importance of CRF has often been neglected in the equation of SCD risk, despite appearing to be one of the most important correlates of overall health status. Our study emphasises the importance of regular physical exercise, especially among men with low CRF. An exercise test could be used to identify individuals with low CRF and high risk of SCD, who should then be urged to exercise more.”

Cumulative survival from SCD according to CRF and LTPA

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Amsterdam, The Netherlands – Sunday 1 September 2013 : Cold weather leads to more heart attacks, according to research presented at ESC Congress 2013 today by Professor Marc Claeys from Belgium. The multifactorial study of nearly 16,000 patients found no relationship between heart attacks and air pollution.

Professor Claeys said: “Air pollution and temperature changes are the most frequently reported environmental triggers for acute myocardial infarction (AMI). Epidemiologic studies have focused mainly on one environmental condition, but most environmental triggers are related to each other and may attenuate or reinforce the triggering effect of a single environmental factor.”

He added: “Better knowledge of the impact of environment on AMI will help medical care providers and policy makers to optimise prevention strategies for a target risk population.”

The present study evaluated the independent environmental triggers of AMI in a multifactorial nationwide environmental model. Weekly counts of AMI patients that underwent primary percutaneous coronary intervention (pPCI) during 2006-2009 in 32 Belgian PCI centres were extracted from the national PCI database.

AMI counts were correlated with average weekly meteorological data obtained from daily measurements in 73 meteorological sites, equally distributed in Belgium. The following meteorological measures were investigated: air pollution expressed as particulate matter both less than 10µM (PM10) and less than 2.5µM (PM2.5), black smoke, temperature and relative humidity.

During the study period a total of 15,964 AMI patients (mean age 63 years, 24.8% female) were admitted with a weekly average admission rate of 77 +/- 11 patients. Time series and univariate analysis revealed a significant positive correlation between AMI and air pollution and an inverse correlation between AMI and temperature.

Multivariate analysis showed that only temperature was significantly correlated with AMI, which increased by 7% for each 10°C decrease in minimal temperature (odds ratio [OR]=1.07, 95% confidence interval [CI]=1.04-1.11), and that there was no significant effect of air pollution (OR=1.01, 95%CI=1.00-1.02).

Professor Claeys said: “Additional analysis showed that the triggering effect of low temperature was also present outside the winter period. Apparently, smaller differences in temperature between indoor and outdoor can also precipitate AMI. In addition, below a minimal temperature of 10°C there is no additional effect of temperature decrease on the occurrence of AMIs.” (see figure 1)

He added: “A potential mechanism to explain the increased risk of coronary events associated with decreasing temperature is the stimulation of cold receptors in the skin and therefore the sympathetic nervous system, leading to a rise in catecholamine levels. Moreover, increased platelet aggregation and blood viscosity during cold exposure promotes thrombosis and clot formation.”

Professor Claeys concluded: “In a global environmental model, low temperature is by far the most important environmental trigger for AMI, whereas air pollution has a negligible effect. People at risk of AMI (for example elderly patients with diabetes and hypertension) can minimise their risk by avoiding big changes in temperature. This means wearing suitable clothes when going from the warm indoors to the colder outdoors, even beyond winter time.”

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Amsterdam, The Netherlands – Sunday 1 September 2013: Listening to favourite music improves endothelial function in patients with coronary artery disease (CAD), according to research presented at ESC Congress 2013 today by Professor Marina Deljanin Ilic from Serbia. Music and exercise training combined produced the most benefit.

Professor Deljanin Ilic said: “In the setting of cardiovascular risk factors and cardiovascular disease the endothelium loses its normal function.1 Since endothelium derived nitric oxide is necessary to maintain an adequate vascular response, correction of endothelial dysfunction has become a goal of therapy.”

She added: “Exercise training has been shown to improve endothelial function and is the cornerstone of a multifaceted programme of cardiovascular rehabilitation. However, little is known about the role of music in cardiovascular rehabilitation or the effects of listening to favourite music on endothelial function.”

The current study evaluated the effects of listening to favourite music on endothelial function through changes of circulating blood markers of endothelial function: the stable end products of nitric oxide (NOx), asymmetric dimethylarginine (ADMA), symmetric dimethylarginine (SDMA) and xanthine oxidase (XO) in 74 patients with stable CAD.

Patients were randomised to trained (T, n=33), music and trained (MT, n=31) and music (M, n=10) groups. Patients in the T and MT groups underwent 3 weeks of supervised aerobic exercise training at a residential centre. In addition to exercise training, patients in the MT group listened to their favourite music for 30 minutes every day.

Patients in the M group received usual community care and listened to their favourite music for 30 minutes every day. Markers were measured and an exercise test performed at baseline and 3 weeks.

After 3 weeks the value of NOx increased in groups T (from 33.0±13.0 to 42.8±11.0 µmol/l, p< 0.005) and MT (from 34.5±7.1 to 49.6±12.6 µmol/l, p<0.0005) (table 1). The increase in NOx was higher in the MT group than in the T and M groups (p=0.0246 and p<0.005) and in the T than in the M group (p<0.05).

XO significantly decreased in all 3 groups after 3 weeks (p<0.0005 for all groups), but at the end of the study XO was significantly lower in the MT than in the T and M groups (p<0.005 and p<0.0005) and in the T than in the M group (p<0.001). After 3 weeks exercise capacity had increased by 39% in MT, 29% in T and 19% in M compared to baseline values (table 2). ADMA and SDMA decreased in all 3 groups (most pronounced in MT) after 3 weeks but the findings were not significant.

Professor Deljanin Ilic said: “The combination of music and exercise training led to the most improvement in endothelial function. Improvements in endothelial function were associated with significant improvements in exercise capacity.”

She added: “Listening to joyful music for 30 minutes has been associated with improved endothelial function, possibly by β-endorphin mediated activation of endothelium derived nitric oxide.2 The vascular health benefits of music may be due to endorphins or endorphin like compounds released from the brain when we hear music we like.”


Professor Deljanin Ilic concluded: “Listening to favourite music alone and in addition to regular exercise training improves endothelial function and therefore may be an adjunct method in the rehabilitation of patients with CAD. There is no an ‘ideal’ music for everybody and patients should choose music which increases positive emotions and makes them happy or relaxed.”