Assessing the risks of bleeding from antithrombotic therapy

Antithrombotic therapy using antiplatelet and anticoagulant agents is the cornerstone of treatment for acute and chronic coronary artery disease (CAD), yet it is also associated with an increased risk of bleeding. It is paradoxical that elderly patients, the most likely population to develop CAD, are those that suffer most from bleeding complications. Research has been carried out at OLVG Hospital in the Netherlands into the stratification of risk for all patients requiring this type of therapy.
Professor Freek Verheugt led the research. “Until relatively recently, aspirin used to be the only effective antiplatelet drug, but now CAD patients can get increased protection from ADP receptor antagonists added to aspirin,” he said. “Previous studies showed us that, compared to younger patients, the elderly seemed to benefit more from single antiplatelet therapy with aspirin that from dual antiplatelet therapy. This data, however, should be treated with caution since it is derived from post-hoc analysis of randomised control trials.”
The TRITON and PLATO clinical trials demonstrated that newer ADP blockers such as prasugrel and ticagrelor are more effective that clopidogrel. But in both trials, the benefits seemed to reduce in patients over 75 years, although this observation comes from post-hoc analyses of the mega-trials. Other research has also shown that the elderly do not get the full benefit from platelet glycoprotein IIb/IIIa receptors, include abciximab, eptifibatide and tirofiban.
For anticoagulants, there is less data available on the risk of bleeding in relation to age. In elderly patients with fibrinolysis, low molecular weight heparin increases the bleeding risk in the elderly significantly over un-fractionated heparin. So, if chosen as the most effective treatment, low molecular weight heparin should be administered in lower doses for older patients. Bleeding associated with the newer anticoagulant bivalirudin also increased in the elderly, when compared to younger patients.
The research concludes that the risk of bleeding is increased by antiplatelet and anticoagulant therapy when applied to the treatment of acute and chronic CAD. Professor Verheugt explained the findings, “For aspirin, it was clearly shown that the risk reduction of ischemic endpoints applies equally to the elderly, but for clopidogrel this benefit is less apparent. Neither was it clearly seen from use of newer ADP receptor blockers such as prasugrel and ticagrelor. Additionally, no clear benefit was observed for elderly patients treated with glycoprotein receptor blockers for acute coronary syndromes.”
Antiplatelet therapies carry an increased risk of bleeding, especially in the elderly. This is probably also true for anticoagulant drugs, but data that specifically covers the elderly is relatively scarce.

Should antiplatelet response be tested?

The effectiveness of dual antiplatelet therapy (DAT) with clopidogrel in cardiovascular (CV) patients is highly variable, and the degree of residual platelet aggregation can significantly influence the prognosis. A number of clinical and genetic risk factors contribute to this observation, and the contribution of genetic polymorphisms has been addressed. To date, however, common genetic clusters have not been identified that reliably predict a patient’s response to antiplatelet therapy. The challenge faced by researchers at University Hospital, Tuebingen in Germany is to determine ways of balancing the thrombotic risk, with the risk of bleeding when using DAT. The outcomes of the research includes a conclusion that platelet function testing (PFT), while an important component in risk evaluation, should not be relied on to adjust antiplatelet therapy regimes.
New antiplatelet agents have been developed – and will continue to be developed – that overcome low responsiveness to clopidogrel. These agents have a higher antiplatelet effect and are less susceptible to genetic inheritance. But, according to Professor Meinrad Gawaz of the University Hospital in Tuebingen, Germany, there are important factors to consider before prescribing them. “These new agents offering higher platelet inhibition come with an increased risk of bleeding,” he says. “So far, these drugs have mostly been studied in patients with acute coronary syndromes, but their role in stable CV patients has yet to be fully characterised.”

It is therefore essential to identify sub-groups of patients who could benefit from novel treatment regimes. Platelet function testing (PFT) can help to monitor and guide antiplatelet therapy for patients in at-risk groups more likely to respond to additional antiplatelet therapy. These groups include diabetics and patients suffering from stent thrombosis. Major concerns have been expressed, however, about the transferability of results obtained by different PFT methodologies. Near-patient testing methods have been evaluated in the clinical setting and show reproducible results, but consensus has to be reached upon the appropriate cut-off values to differentiate between thrombotic and bleeding risk.
The results of ongoing trials will show whether adjustment on behalf of routine PFT will lead to improved outcomes. Until then, PFT represents an important component to evaluate the thrombotic risk but adjustment of antiplatelet therapy based on PFT cannot be recommended in a routine fashion but can only be considered as an off-label indication in individual cases bearing in mind the bleeding risk.

Study links male Y chromosome variants with the risk of coronary heart disease

Scientists in the UK have shown that genetic variations in the Y chromosome affect a male’s risk of coronary heart disease. It is well known that males have a higher incidence of coronary heart disease than females due, in part, to the Y chromosome they inherit from their fathers. To investigate the role of the Y chromosome further, a team from the University of Leicester carried out research to determine whether genetic variations in the Y-chromosome affect risk for males.
Not all Y chromosomes are the same. There are variants within the male gender called “Y-haplogroups”, which are usually associated with specific geographic regions and tend to indicate the origin of the ancestral line. Professor Nilesh Samani explains the background to the project that was funded by the British Heart Foundation, “We set out to determine if men with differing types of Y chromosome were at differing risk of heart disease. We tested nearly 3,000 British males, and found that those carrying the I-haplogroup variant had a 55 percent higher risk of coronary heart disease.”
Of the 3,000 men tested, 1,295 were the cohort group of those with coronary heart disease and the rest were the control group. The Y-haplogroup was identified in all men, and the results showed that those in the I-haplogroup had an approximately 55 percent higher risk of coronary heart disease compared to the others. The association of the I-haplogroup with coronary heart disease was independent of, and not explained by, traditional heart risk factors such as cholesterol, high blood pressure and smoking.
Commonly found in central, eastern and northern Europe, the I-haplogroup is carried by about 13 percent of British men. Its origin is thought to be of the Gravettian culture, which arrived in Europe from the Middle East about 25,000 years ago. Since the I-haplogroup is not so prevalent in southern parts of Europe, an interesting speculation is whether it contributes to the higher levels of coronary heart disease in the north compared to the south – however, this requires further research and testing.
What is clear from this study though, is that men carrying the I-haplogroup are more likely to suffer from coronary heart disease than men with other Y-haplogroups.

A single bolus of erythropoietin does not improve cardiac function after an acute myocardial infarction: results from the HEBE III trial

Results from the HEBE III study, a prospective, randomised, multicentre trial performed in seven centres in the Netherlands, suggest that the promising effects of erythropoieitin seen in previous smaller studies cannot be confirmed for the improvement of clinical outcome in patients with a first ST-elevation myocardial infarction.
MI remains a major hazard for millions of patients in Europe. Despite improvements in treatment, the majority still end up with reduced cardiac function, and strategies to improve post-MI cardiac function are strongly needed. One approach, suggested in experimental and smaller clinical studies, is the administration of erythropoietin (EPO), currently used for the treatment of anemia caused by renal disease. The HEBE III study was designed to study the effects of a single intravenous bolus of EPO on clinical outcome in patients with a first ST-elevation MI. The primary endpoint of the trial - as a measure of cardiac function - was left ventricular ejection fraction (LVEF) after six weeks, with secondary endpoints assessed according to infarct size and major adverse cardiovascular events (MACE).
The trial was conducted in 529 randomised STEMI patients and headline results showed that this single IV bolus of EPO did not improve cardiac function. However, patients who received EPO had fewer major cardiac events, such as heart failure, compared with the control group.
The HEBE III trial studied the effect of a single bolus of 60,000 IU epoetin alfa on LVEF. EPO was administered intravenously within three hours after a successful PCI for a first STEMI. The study aimed to find a 3% increase of LVEF in patients treated with EPO compared to standard care. In total, 529 patients were included in the study, in which 263 patients were assigned to the EPO group and 266 to the control group. After six weeks, LVEF was 53% in the EPO group and 52% in the control group, but this 1% difference was too small to be statistically or clinically significant. Furthermore, infarct size, measured by proteins in the blood, was also not significantly different between the two groups. However, in the EPO group, only eight patients suffered a major cardiac adverse event, compared to 19 in the control group.
Commenting on the results, principal investigator Dr Adriaan Voors from the University Medical Center, Groningen, the Netherlands, said: "The promising effects of erythropoieitin in previous smaller studies could not be confirmed in this large clinical trial. The reduction of major cardiac effects is of interest, but, since the study was not primarily designed to reduce cardiac effects, and the numbers are small, we should be careful with its interpretation. Larger clinical trials powered to detect a reduction in hard clinical endpoints should be performed before EPO can be routinely used in patients with an acute heart attack."

ALPHA OMEGA: Beneficial effect of low doses of n-3 fatty acids only found in sub-groups of post-MI patients

Results from the Alpha Omega Trial, a multicentre, placebo-controlled trial in men and women following myocardial infarction (MI), suggest that low doses of n-3 fatty acids given in the form of enriched margarines do not reduce the overall rate of major cardiovascular events.
Results from the study - in which patients received a 400 mg per day supplement of the fish oil fatty acids EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) and 2 grams of the plant-derived fatty acid alpha-linolenic acid (ALA) via enriched margarines - showed that these supplementary n-3 fatty acids did not reduce major cardiovascular events in the overall patient population. Among sub-groups, there was a borderline significant reduction in major cardiovascular events in women who received ALA, and, in patients with diabetes, n-3 fatty acids were protective against ventricular arrhythmia-related events.
N-3 (or omega-3) fatty acids can be divided in two main classes: EPA and DHA from fish; and ALA from plant foods such as soybean oil and walnuts. "Several intervention studies in cardiac patients have shown that a daily intake of 1-2 grams of EPA + DHA via fish oil capsules reduced mortality from coronary heart disease by 20%," said principal investigator Professor Daan Kromhout from Wageningen University, the Netherlands.
"Epidemiological studies in healthy populations have also suggested that 250 mg EPA + DHA or eating fish once or twice a week can lower the risk of CVD by a similar amount. For ALA, there is less evidence of a cardioprotective effect. We designed the Alpha Omega Trial as a dietary intervention study to examine the effect of low doses of n-3 fatty acids on major cardiovascular events."
A total of 4837 men and women aged 60-80 years were enrolled in the trial. They had all suffered a myocardial infarction approximately four years before the study began. They were randomly assigned to daily use of one of four margarines for 40 months: containing extra EPA + DHA (400 mg/day); ALA (2 g/day); both EPA + DHA and ALA; or placebo. The margarines were similar in taste and appearance for all four treatment groups and were used by the trial participants on bread instead of their regular margarine or butter; compliance and double-blinding were maintained throughout the study period.
The primary endpoint of the trial, which was completed in November 2009, was major cardiovascular events (MACE) of morbidity and mortality, and cardiac procedures (PCI and CABG). Important secondary endpoints were fatal coronary heart disease and ventricular arrhythmia-related events defined as sudden death, cardiac arrest and cardioverter-defibrillator placement.
"The patients in this trial were very well treated," said Professor Kromhout, "with 98% on antithrombotic agents, 90% on antihypertensive drugs, and 86% on lipid lowering drugs. We found that cardiovascular mortality rate in the study population was only half that expected, probably because of their excellent treatment. This may also be why the rate of major cardiovascular events during follow-up was no lower in the fatty acid groups than in the placebo group.
"However, we did see a 27% borderline significant reduction in primary endpoint in women who received ALA. We also carried out an exploratory analysis in patients with diabetes, and this showed a significant 50% reduction in CHD mortality in patients who received EPA + DHA. For both, EPA + DHA and ALA a similar 50% reduction was observed in the number of arrhythmia-related events in diabetic patients."

ESC Estocolmo: presentación del Estudio SHIFT por parte de Servier

Procoralan(R) reduce el riesgo de muerte y hospitalización en pacientes por insuficiencia cardiaca

El mayor estudio de morbi-mortalidad con tratamientos para la insuficiencia cardiaca ha demostrado que añadir el agente reductor específico de la frecuencia cardiaca Procoralan(R) (ivabradina) a la terapia estándar reduce significativamente el riesgo de muerte y hospitalización por insuficiencia cardiaca. (1) Los resultados de este nuevo estudio, SHIFT (Systolic Heart Failure Treatment with the If Inhibitor Ivabradine Trial), se han presentado hoy en el Congreso Europeo de Cardiología1 celebrado en Estocolmo y se han publicado en The Lancet(2).

SHIFT reclutó a más de 6.500 pacientes de 37 países con insuficiencia cardiaca de moderada a severa y una frecuencia cardiaca de más de 70 lpm que fueron controlados durante una media de 23 meses. Los resultados mostraron que Procoralan(R) reduce el objetivo primario compuesto de muerte cardiovascular u hospitalización por agravamiento de la insuficiencia cardiaca en un 18% (p<0,0001). p="0,014)">

"Veinte años después de los inhibidores de la enzima convertidora de angiotensina y diez años después de los betabloqueantes, tenemos ahora un nuevo fármaco que salva vidas disponible para nuestros pacientes", señaló el co-presidente del comité ejecutivo de SHIFT, el profesor Michel Komajda, profesor de Cardiología de la Universidad Pierre et Marie Curie París 6 de Francia.

La insuficiencia cardiaca crónica es un problema común y en aumento que afecta a 15 millones de pacientes en Europa (entre el 2% y el 3% de la población general). La insuficiencia cardiaca dificulta la capacidad del corazón parar bombear sangre correctamente y mantener una circulación suficiente para cubrir las necesidades del organismo. La insuficiencia cardiaca es una importante carga sanitaria y económica, representa el 10% de todos los ingresos hospitalarios y la mitad de los pacientes con insuficiencia cardiaca mueren al cabo de 4 años.

Procoralan(R) es un tratamiento innovador que se utiliza actualmente en pacientes con angina estable ya que alivia los síntomas, la isquemia de miocardio y reduce el riesgo de eventos coronarios. El estudio SHIFT ha demostrado ahora también los beneficios pronósticos de Procoralan(R) en pacientes con insuficiencia cardiaca.

El estudio SHIFT es también el primer estudio que confirma específicamente que, gracias a Procoralan(R), la reducción exclusiva de la frecuencia cardiaca reduce el riesgo de muerte u hospitalización por insuficiencia cardiaca. Este descubrimiento confirma que la frecuencia cardiaca juega un papel clave en la progresión de la enfermedad.

El co-presidente del SHIFT, el profesor Karl Swedberg, de la dirección del Departamento de Emergencia y Medicina Cardiovascular de la Universidad de Gothenburg, Suecia, indicó: "El estudio SHIFT tiene importantes implicaciones para nuestra práctica clínica. Nos indica que tener una frecuencia cardiaca alta es perjudicial para los pacientes con insuficiencia cardiaca. De modo que deberíamos medir rutinariamente la frecuencia cardiaca en todos los pacientes con insuficiencia cardiaca y, si es superior a 70 latidos por minuto, debería considerarse reducirla con Procoralan(R), independientemente del tratamiento de base".

--Diseño del ensayo SHIFT
SHIFT es un estudio aleatorizado, doble ciego que compara Procoralan(R) con placebo en el pronóstico de los pacientes con insuficiencia cardiaca de moderada a severa (más frecuentemente de causa isquémica), fracción de inyección del ventrículo izquierdo disminuida y frecuencia cardiaca superior a 70 lpm. El estudio se diseñó para evaluar si Procoralan(R), puede mejorar los eventos cardiovasculares, los síntomas y la calidad de vida al añadirse a la terapia estándar en pacientes con ICC y disfunción sistólica.

Los pacientes recibieron Procoralan(R) o placebo además de su tratamiento estándar para la insuficiencia cardiaca. Estos incluyeron inhibidores ECA y/o ARA II, betabloqueantes, diuréticos y antagonistas de la aldosterona. Un total de 89% de los pacientes en el estudio recibió IECAs y betabloqueantes, y más de la mitad de ellos recibieron al menos un 50% de la dosis objetivo.
SHIFT está patrocinado por Servier, compañía farmacéutica independiente líder en Francia con un largo historial en el desarrollo de fármacos para las enfermedades cardiovasculares, y está coordinado por el comité ejecutivo del SHIFT, un grupo internacional de expertos en insuficiencia cardiaca.

Procoralan(R) se desarrolló por Servier y está indicado para el tratamiento de la angina estable. Es el primer agente de una nueva clase terapéutica conocida como los inhibidores If selectivos y específicos.

*En función de cada país