Angiotensin II antagonists in paroxysmal atrial fibrillation: Results from the ANTIPAF trial

Atrial fibrillation (AF) is the most common cardiac arrhythmia, affecting about 7 million people in Europe. It is a progressive chronic disease in which episodes become more frequent and long-lasting over time. Conventional anti-arrhythmic therapy aims at halting progression and reducing symptoms, but the use of most anti-arrhythmic drugs is compromised by severe side effects, such as pro-arrhythmia or extra-cardiac organ toxicity.
A number of meta-analyses have shown that angiotensin II antagonists (or ARBs) may have the potential to reduce recurrence of AF, with an almost placebo-like tolerability. However, the available evidence from meta-analyses is heterogeneous with respect to the patient populations under investigation, the specific study designs, and the methods used to detect recurrent AF.
The ANTIPAF (ANgiotensin II anTagonists In Paroxysmal Atrial Fibrillation) trial was the first trial to prospectively evaluate the principal hypothesis that the angiotensin II receptor antagonist olmesartan suppresses episodes of paroxysmal AF. The primary endpoint of the trial was the percentage of days with documented episodes of paroxysmal AF throughout 12 months of follow-up. Secondary endpoints included the time to first occurrence of a documented relapse of AF, quality of life, time to first AF recurrence, time to persistent AF, and the number of hospitalisations.
Patients were stratified according to presence of beta-blocker therapy and randomised to placebo or olmesartan (40 mg/day). Concomitant therapy with ARBs, ACE inhibitors, and anti-arrhythmic drugs was prohibited. Patients were followed using daily trans-telephonic ECG recordings (at least one 1-minute ECG/day) independent of symptoms - and were encouraged to submit further tele-ECGs in any case of AF-related symptoms. Follow-up visits were scheduled after 3, 6, 9 and 12 months, which included long-term ECGs, transthoracic echocardiography, laboratory markers, and assessment of quality of life.
425 patients (at least 18 years old) with documented episodes of paroxysmal AF were included from 37 centres in Germany. A total of 87,818 tele-ECGs were analysed during follow-up (44,888 ECGs in the placebo group and 42,930 ECGs in the olmesartan group). Thus, a mean of 207 tele-ECGs were recorded per patient with an average of 1.12 tele-ECGs per patient and day of follow-up.
The study demonstrated no significant difference in the burden of AF (primary endpoint) between both treatment groups. Further secondary outcome parameters such as quality of life, time to first AF recurrence, time to persistent AF, and the number of hospitalisations were also similar between groups. However, the time to prescription of recovery medication (amiodarone) was longer in patients treated with olmesartan than in those receiving placebo.
Commenting on the study results, principal investigator Professor Andreas Götte from St. Vincenz Hospital, Paderborn, Germany, said: "In patients with AF and concomitant structural heart disease such as hypertensive heart disease or systolic heart failure, ARBs are effective adjunct therapies while being highly tolerable. ANTIPAF provides pivotal evidence, however, that ARBs do not reduce the number of AF episodes in patients with paroxysmal AF and without structural heart disease."

* The ANTIPAF study was conducted by the German Competence Network on Atrial Fibrillation (AFNET), an interdisciplinary national research network funded by the German Federal Ministry of Education and Research.

AVERROES trial terminated early: apixaban associated with "important" relative risk reduction for stroke and systemic embolism in AF

The phase 3 AVERROES (Apixaban Versus Acetylsalicylic acid (ASA) to Prevent Strokes) trial, designed to show the superiority of apixaban over aspirin for the prevention of stroke or systemic embolism in high-risk atrial fibrillation patients unsuitable for treatment with a vitamin K antagonist (warfarin), was terminated early following a recommendation from the Data Monitoring Committee. Final study visits took place between 1 July and 15 August this year. A predefined interim analysis had shown clear evidence of a clinically important reduction in stroke and systematic embolism and an acceptable safety profile for apixaban compared to aspirin. The principal investigator, Dr Stuart Connolly from Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada, and the study's sponsors accepted the recommendation to terminate the trial.
AVERROES was a double-blind randomised trial which recruited 5600 patients with atrial fibrillation (mean age 70 years) demonstrated or expected to be unsuitable for treatment with a vitamin K antagonist (because of difficulty in controlling treatment effect, increased risk of haemorrhage, patient refusal to take warfarin or intermediate stroke risk). So far, aspirin is the only effective treatment for stroke prevention in patients unsuitable for warfarin.
Apixaban, a Factor Xa inhibitor, has already been investigated for the prevention of deep vein thrombosis, following orthopaedic surgery, and after acute coronary syndrome - but not so far in patients with atrial fibrillation. The AVERROES trial compared the effects of apixaban and aspirin in these patients. Another trial, ARISTOTLE (not yet completed) is studying apixaban against warfarin in patients suitable for warfarin.
The AVERROES study was performed at 520 sites worldwide and recruitment was completed in December 2009. The primary endpoint was a composite of stroke or systemic embolism, while the primary safety endpoint was major haemorrhage. Secondary and tertiary endpoints were a composite of stroke, systemic embolism, myocardial infarction or vascular death, and total death.
At the interim analysis results showed that the annual rate of stroke or systemic embolism (the primary outcome) was 3.9% per year on aspirin and 1.7% per year on apixaban (HR 0.45, p<0.001). The rate of major haemorrhage was 1.4% per year on aspirin and 1.6% per year on apixaban (HR 1.18, p=0.33). The rate of haemorrhagic stroke was 0.2% per year in both treatment groups and there was no evidence of hepatic toxicity or other major adverse events.
Commenting on the results, Dr Connolly said: "The results of AVERROES are truly impressive. The reduction in stroke and systemic embolism is very important and the increased risk of haemorrhage is small. It appears that apixaban will be an excellent treatment for the many patients with atrial fibrillation who are unsuitable for warfarin. These findings will reduce the burden of stroke in society.”

* Atrial fibrillation is a common heart rhythm disorder in which the upper chamber of the heart beats improperly. Patients with AF are at increased risk of stroke because of the formation of blood clots in the upper chamber. The standard therapy for the prevention of stroke and other embolic events in AF is warfarin.

Nurses can significantly reduce the risk of recurrent complications in heart patients: results from the RESPONSE trial

A six-month outpatient prevention programme conducted by nurses has resulted in significant and sustained improvements in the control of cardiovascular risk factors, including high cholesterol or high blood pressure, in patients hospitalised for a heart attack or impending heart attack.
The programme, applied in addition to standard medical care, led to the improved adherence to current guidelines on prevention, including lifestyle and compliance with drug treatment. The nurses were able to increase the proportion of patients with good control of risk factors by 40% (defined as at least seven out of nine risk factors on target) and to reduce the calculated risk of dying in the next 10 years by about 17%.
RESPONSE (Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists) was an 11-centre randomised study designed to quantify the impact of a nurse-co-ordinated outpatient risk management programme on the risk of future clinical events in patients with symptomatic coronary artery disease. The primary endpoint was patient evaluation according to the SCORE risk score at 12 months, with secondary endpoints assessed according to the Framingham risk score and individual risk factors at 12 months follow-up (including lipid profile, glucose, blood pressure, weight, waist circumference, physical activity, healthy diet, alcohol consumption).
In explaining the background to the trial, principal investigator Professor Ron Peters from the Academic Medical Center, Amsterdam, said: "Patients with coronary artery disease are at high risk of recurrent complications and death. Preventive care can effectively reduce this risk, and guidelines have been issued by the American Heart Association/American College of Cardiology and the European Society of Cardiology which target common risk factors for heart disease such as high blood pressure, smoking, and high cholesterol.
"Together, these risk factors are associated with the development of coronary artery disease, which remains the world's leading cause of death. At present, a considerable gap exists between these guidelines and their application in clinical practice. It is widely believed, both by patients and doctors, that the preventive aspect of treatment is given insufficient priority and that new approaches are needed to realise the full benefits of prevention. A short coaching programme by a nurse, on top of usual care, is such a new approach already found promising in primary care."
The RESPONSE trial, which evaluated an outpatient nursing programme in 11 hospital centres in the Netherlands, included 754 patients hospitalised for an acute coronary complication (MI or impending MI). They were randomised to either usual care alone or usual care plus a six-month nursing intervention that included four extra visits to the outpatient clinic. Nurses gave advice on healthy lifestyle (food choices, physical exercise, non-smoking, weight control), and monitored major risk factors, such as blood pressure, cholesterol and sugar levels, and use of preventive medication. The nurses pursued specific targets as defined by the guidelines, and if necessary drug treatment was adjusted in collaboration with treating physicians.
The primary measurement of the study was performed at 12 months, which was six months after the last visit to the nurse. Results showed a significant improvement in risk factor prevalence at the end of the programme, with no loss of effect at 12 months.
Overall, at 12 months after the start of the programme, 35% of patients in the nursing group and 25% of patients in the control group were classified as having good control of risk factors (defined as at least seven out of nine factors on target). This reflects an increase of 40%. Of the risk factors targeted by the intervention, body weight was the least successful. There was no change in weight or waist circumference between baseline and 12 months, with no difference between the two study groups. "This may indicate that weight loss is not a realistic target in the first year after a coronary event," said Professor Peters, "when priority needs to be given to several other risk factors. It remains to be seen if later attempts might be more successful."
When the risk of death over the next ten years was calculated according to the SCORE risk function, the nurses were able to reduce this risk by 17%.
Professor Peters noted that these results were achieved against a background of medical care that was better than expected, with risk factor levels in the study population more favourable than those reported in the literature - and with excellent adherence to medication in both groups. This high level of care in the control group, he added, may have been influenced by participation in the trial.
"The nurse programme was practical and well attended by the patients," he said. "More than 93% of patients attended all visits to the nurse. These findings are very encouraging and support the initiation of prevention programmes by nurses to help patients reduce their risk of future complications."

Investigadores norteamericanos encuentran una base genética clave en el asma severo

Investigadores del Hospital Pediátrico de Cincinnati, en Estados Unidos, han identificado una base genética cuya presencia puede determinar la gravedad del asma, según los resultados de un estudio en ratones cuyos resultados se han publicado en la revista 'Nature Immunology'.
La prevalencia del asma ha aumentado en los últimos años y, pese a que existen numerosos factores ambientales que favorecen su aparición, como el humo del tabaco, algunos alérgenos o la contaminación atmosférica, este estudio ha fijado un posible "punto de inflexión molecular" entre la variante más suave y la más agresiva.

De este modo, los autores de este estudio han descubierto que una proteína preinflamatoria, la interleukina-17 (IL-17A), puede ser la principal culpable de los síntomas más graves de esta enfermedad respiratoria.

Según describe la autora del estudio, Marsha Wills-Karps, el proceso de la enfermedad parece comenzar cuando las vías respiratorias se exponen a los alérgenos ambientales, lo que provoca una mala regulación de un gen llamado factor 3 del complemento (C3), que activa una parte del sistema inmune denominada "cascada de activación del complemento".

Esto conduce a la producción exagerada de IL-17A por las células de las vías respiratorias y pone en marcha lo que los científicos describen como un bucle de amplificación, ya que la IL-17A a su vez induce la producción de más C3 en la superficie de las vías respiratorias.

Al continuar el bucle de amplificación por la exposición constante a estos alérgenos, se aumenta la respuesta inflamatoria, involucrando ya a las células T auxiliares y a otras proteínas interleuquinas (IL-13 e IL-23), lo que provoca en último lugar la obstrucción del flujo nasal.

"Este hallazgo puede ser clave en la búsqueda de futuros tratamientos terapéuticas para combatir esta variante, aunque para ello será necesario precisar si es necesario actuar inhibiendo la producción del IL-17A i sobre las C3", asegura Wills-Karp.

Danish trial demonstrates the benefits of dual-chamber pacing over single-lead atrial pacing in treating sick sinus syndrome

DANPACE, a Danish multicentre randomised trial comparing single lead atrial and dual chamber pacing in patients with sick sinus syndrome, concludes that dual chamber pacing, which was associated with lower rates of atrial fibrillation and re-operation, "should be the preferred pacing mode".
Behind the conclusion lies a 20-site study of 1415 subjects with sick sinus syndrome (a variety of arrhythmias caused by a malfunction of the sinus node, the heart's principal pacemaker) referred for their first pacemaker implantation. Pacemakers are routinely used to treat patients suffering from sick sinus syndrome.
The patients were randomised equally to single-lead atrial or dual-chamber pacemakers* and their progress followed for a mean of 6.4 years, producing over 7000 operational years of evidence. Results showed that all-cause mortality rates were similar in both groups, 29.6% in the single-lead atrial pacemaker group and 27.3% in the dual chamber group. However, the prevalence of paroxysmal atrial fibrillation was lower in the dual chamber group than in the single-lead group (HR 0.79, p=0.024), with significantly fewer dual chamber patients requiring pacemaker re-operation during follow-up (HR 0.50, p<0.001).
Summarising the outcome, principal investigator Dr Jens Cosedis Nielsen from the Department of Cardiology, Skejby Hospital in Aarhus, Denmark, said: “The results showed that, when compared with dual-chamber pacing, single-lead atrial pacing was associated with a 27% increase in the risk of developing atrial fibrillation and a doubling of the risk of having to undergo a pacemaker re-operation.
“In prior trials, ventricular stimulation has been found to increase the incidences of atrial fibrillation and heart failure. However, in this patient group we demonstrated for the first time that dual-chamber pacing actually decreases atrial fibrillation and has no influence on the incidence of heart failure when compared with single-lead atrial pacing without ventricular stimulation.”

La depresión se relaciona con la alteración de regiones cerebrales

En la población general, la depresión está frecuentemente asociada con un estilo de vida poco saludable, falta de voluntad propia y "debilidad psicológica". Sin embargo, los resultados de un estudio presentado en el 23 Congreso Anual del Colegio Europeo de Neuropsicofarmacología, que se celebra estos días en Amsterdam (Holanda), ha demostrado que la depresión es una enfermedad cerebral tangible, asociada con la disfunción de áreas cerebrales específicas.

En concreto, un equipo de investigadores franceses ha demostrado mediante la utilización de imágenes por resonancia magnética (RM) que las personas deprimidas muestran alteraciones en las regiones cerebrales encargadas de regular el control cognitivo y las respuestas emocionales e, incluso, comprobar que dicha alteración se mantiene hasta ocho semanas después de comenzar el tratamiento antidepresivo con fármacos.

Así, los científicos han identificado cómo los pacientes depresivos presentan una activación 'anormal' de la corteza prefrontal medial del cerebro que podría explicar algunos complejos de las personas deprimidas, como la visión negativa de si mismos, el sentimiento de culpa o la continua reflexión personal.

En este sentido, el estudio ha descubierto que, a pesar de que estos síntomas remitan, algunos pacientes seguían presentando alteraciones en las regiones cerebrales. Según explican los autores, estas alteraciones anormales podrían indicar la necesidad de tratamientos complementarios dirigidos a modificar la conducta cognitiva para reducir el riesgo de que la depresión reaparezca en el paciente.

Asimismo, la identificación de biomarcadores mediante el estudio de las imágenes por RM permitiría a los psiquiatras a ajustar el tratamiento antidepresivo para que actúe sobre determinados procesos neurológicos que provocan la enfermedad en el paciente.

Al menos el 40 por ciento de las personas diagnosticadas por depresión reciben tratamiento farmacológico, aunque entre el 20 y el 30 por ciento de estos pacientes sufre recurrencias y convierte su trastorno en crónico por la ineficacia del tratamiento.

**Foto de Reuters

Amsterdam Molecular Therapeutics Reports Half-Year Results 2010

Amsterdam Molecular Therapeutics (Euronext: AMT), a leader in the field
of human gene therapy, today reported its results for the first half year of
2010.

Highlights:

- Glybera(R):
- EMA initiated MAA review in 01/2010
- Approval progressing on schedule for decision mid 2011
- Novel biomarker for Glybera(R) activity identified

- Hemophilia B: Phase I/II started

- Duchenne Muscular Dystrophy: to benefit from EUR 4 million
innovation credit

- sRNA: silencing gene therapy technology achieves 80% cholesterol
reduction
- Supervisory Board nominations: 3 new industry professionals
slated to join board
- Key financial figures in line with guidance
- Cash & cash equivalents of EUR 13.5 million at June 30, 2010

"We are very pleased with the key milestones we have achieved
in the first half year of 2010 in the Glybera(R) approval process which seems
firmly on track. Our dialogue with the EMA is very encouraging and we look
forward to the Agency's decision with confidence. We also continue to make
progress with our pipeline, not only on the partnership front for programs
such as Hemophilia B, but also in our early stage efforts," said Jorn Aldag,
chief executive officer of AMT.

Operations

Glybera(R) for Lipoprotein Lipase Deficiency (LPLD)

In January 2010, the European Medicines Agency (EMA) commenced
review of AMT's Marketing Authorization Application. In May 2010 AMT received
questions (Day 120 questions) regarding the application. In July we met with
the EMA, to clarify the questions they raised, enabling AMT to align its
response strategy. We are now working towards an official response to the EMA
Day 120 questions, due by the end of 2010.

As of today we remain confident in the approvability of
Glybera(R). Our assessment is based on the following:

- Our response to the EMA does not require further clinical
trials with additional new to be treated patients. We expect to be
able to formulate our response satisfactorily by submitting data and
further analyses from already treated patients.
- More, highly relevant, data from our last clinical trial
CT-AMT-011-02 AMT strongly suggest that Glybera's effects are lasting
(one year) via a mechanism that causes clearance of chylomicrons, the
fat carrying particles which are responsible for pancreatitis in LPLD
patients.
- Overall we have developed a clear response strategy, which,
if executed with no unforeseen adverse events or delays, should allow
us to remain on track for a positive EMA decision in the middle of
2011.

Hemophilia B

Further to their 2009 agreement to co-develop a vector-gene
combination for the treatment of Hemophilia B, AMT and St. Jude Children's
Research Hospital in the USA have successfully transferred Factor IX to AMT's
manufacturing platform and have demonstrated proof of concept in animals in
2010. The multicenter, dose escalation study with this vector-gene
combination began in March, 2010 at University College London Hospital in the
United Kingdom guided by Prof. Amit Nathwani. The first patient has been
dosed successfully and demonstrated good results both in terms of clinical
benefit and side effects. Further enrolment of patients is expected in the
second half of 2010.

Duchenne Muscular Dystrophy

In support of its program to treat Duchenne Muscular
Dystrophy, AMT received an investment credit from SenterNovem (now
Agentschap.nl), the Dutch government innovation agency, in January 2010. The
credit comprises a loan covering 35% of the costs of the project through to
2013 with a maximum of EUR 4 million. The loan is repayable only if AMT
successfully commercializes the program. AMT has shown proof of concept in a
pre-clinical model with its optimized construct for exon skipping using its
proprietary AAV technology.

Parkinson's Disease

Together with the University of Lund, Sweden, AMT is
diligently working on the preclinical development of a gene therapy for
delivery of the GDNF gene to the brain. Efficacy data in an animal model of
PD is anticipated to be available by the end of the current year

sRNA

Elevated levels of cholesterol are a major risk factor and
contributor to the development of atherosclerosis and cardiovascular disease
(CVD). Early research at AMT demonstrates that after a single intravenous
injection of a silencing gene therapy in animal models, the serum cholesterol
levels were reduced by 80% with no signs of toxicity. It is therefore
reasonable to expect a similar effect in patients, resulting in reduced risk
for atherosclerosis or CVD. Such a long-term, perhaps life-long active gene
therapy could eliminate the need for maintenance statin therapy.

Supervisory Board changes

During the period ended June 30, 2010, Alexander Ribbink and
George Morstyn retired from the Supervisory Board and AMT thanks them for
their substantial contributions. On April 28, 2010, AMT's co-founder Sander
van Deventer was appointed to the Supervisory Board, and in addition Joseph
M. Feczko, Steven H. Holtzman and Francois Meyer were nominated to the
Supervisory Board for consideration at the Extraordinary General Meeting to
be held on September 20, 2010.

Financials

Results comparison

Total net loss for the period ended June 30, 2010 amounted to
EUR 9.4 million, in line with the net loss for the period ended June 30, 2009
which also amounted to EUR 9.4 million.

The main item within operating costs reflects the investment
in Glybera(R) to support the registration process. Development of our
Duchenne Muscular Dystrophy program, which is 35% funded by a research credit
from SenterNovem through to completion of a Phase I clinical study continues.
Expenditure on our other development projects has been reduced as we are
constrained by our current resources and are focusing on the successful
completion of the Glybera registration process. Research and development
costs increased to EUR 8.1 million for the period ended June 30, 2010 from
EUR 7.1 million in the same period of 2009. At the same time, general and
administrative costs decreased to EUR 1.8 million in the period ended June
30, 2010 from EUR 2.9 million in the same period of 2009.

Net interest income/(cost) decreased to EUR (0.0) million for
the period ended June 30, 2010 from EUR 0.5 million in the same period in
2009 as a result of the Company's decreasing cash balance combined with
continuing low market interest rates for deposits.

Cash and cash equivalents amounted to EUR 13.5 million at June
30, 2010, a decrease of EUR 9.1 million compared to EUR 22.6 million at
December 31, 2009. The decrease in cash and cash equivalents mainly stems
from the operational cash outflow which amounted to EUR 8.9 million for the
period ended June 30, 2010 (compared to an operating cash outflow of EUR 9.5
million for the period ended June 30, 2009).

Outlook

The Company's expenditure continues in line with budget.
However, as AMT has not yet reached the point of generating significant
revenues that could fund operations we continue to explore additional
opportunities for funding, including non-dilutive sources such as grants
and/or collaborations with partners. In addition, AMT is also tracking
opportunities for raising additional capital in conjunction with its bankers.
The outlook for the year remains unchanged.