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

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Prof. Joep Perk, FESC / Prof. Christi Deaton, FESC

ESC TV 2013 - Village 4: make prevention work

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Prof. John McMurray, FESC / Prof. Gerasimos Filippatos, FESC

ESC TV 2013 - Village 2: Advances in heart failure and LV dysfunction

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Daily wrap-up/expert analysis from ESC 2013: TASTE, TAO, PARIS, Hokusai VTE, RE-ALIGN, Everyday Lifestyle.

ESC13 Daily Wrap-up Sunday Part I

Daily wrap-up/expert analysis from ESC 2013: PRAMI, DECAAF, ACCOAST, LINC, IN-TIME, PRAGUE-14.

ESC 2013 Daily Wrap-up Sunday Part II

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Amsterdam, The Netherlands – Monday 2 September 2013 :A common drug that is used to treat high blood pressure in the general population has been found to significantly reduce a dangerous and frequently fatal cardiac problem in patients with Marfan syndrome.

Results of the COMPARE (COzaar in Marfan PAtients Reduces aortic Enlargement) study reveal that patients treated with losartan (Cozaar) had a significantly reduced rate of aortic enlargement after 3 years compared to patients who did not receive the treatment.

“Our study is the first large, prospective randomized study to assess the effects of losartan on aortic enlargement in adults with Marfan syndrome, and confirms previous findings in a mouse model,” said lead investigator Maarten Groenink MD, PhD from the Departments of Cardiology and Radiology at Academic Medical Centre in Amsterdam, The Netherlands.

“We’re very excited to see that such a commonly used drug that is not expensive and has a familiar side-effect profile could have a significant effect on this very serious and frightening risk factor for these patients. These findings may change standard clinical management.”
  
Marfan syndrome, a heritable connective tissue disorder, affects 2-3 in 10,000 people. It causes progressive enlargement of the aorta, making it prone to rupture, which can be fatal in more than 50% of cases.  Currently, the only effective treatment is prophylactic surgical aortic root replacement.

In addition to lowering blood pressure, the main benefit of losartan is believed to be its interference with the biochemical process that causes aortic enlargement.
To assess this, the COMPARE study included 233 participants (47% female) with Marfan syndrome from all four academic Marfan screening centers in the Netherlands.

Subjects were a mean age of 41 years, 27% had previously undergone prophylactic aortic root replacement, and the majority (73%) were being treated with beta blockers.

A total of 117 subjects were randomized to receive no further treatment, while 116 were randomized to receive losartan 50 mg daily, doubling after 14 days if there were no side effects.

Aortic enlargement was monitored with magnetic resonance imaging (MRI) for three years of follow-up.

During the study period, if patients in either arm required prophylactic aortic root replacement the decision was left to the discretion of the attending cardiologists based on existing guidelines and anticoagulation therapy was initiated when appropriate.

The study showed that after 3 years aortic root enlargement was significantly less in the losartan group than in controls (0.77 mm vs. 1.35 mm, p=0.014), and 50% of losartan patients showed no growth of the aortic root compared to 31% of controls (p=0.022).

In Marfan syndrome aortic enlargement is usually confined to the ‘aortic root’, but may also extend beyond it.  The study showed that aortic enlargement beyond the root was not significantly reduced by losartan. However, among the subset of patients who had already received aortic root replacement, dilation in one section, called the aortic arch, was significantly lower in patients treated with losartan compared to controls (0.50 mm vs. 1.01 mm; p=0.033). “This result should be interpreted with some caution as baseline aortic dimensions of patients with prior aortic root replacement were not completely comparable between the groups, “ said Dr. Groenink.

Although the reduced rate of aortic enlargement in the losartan group suggests this drug may postpone or even prevent aortic rupture as well as the need for prophylactic surgery in Marfan patients, the study did not actually demonstrate this result.

There were no differences in the rate of aortic dissections (0 in the losartan group and 2 controls) or elective aortic surgery (10 in the losartan group and 9 in controls) and no cardiovascular deaths occurred.

“The incidence of clinical events was low in our study and therefore the clinical relevance of losartan treatment on aortic surgery and aortic dissection could not be determined,” said Dr. Groenink, adding that only a larger prospective trial with longer follow-up can ultimately determine this outcome.

Funding: This study was funded by a grant from the Dutch Heart Association (2008B115) and supported by the Interuniversity Cardiology Institute of the Netherlands (ICIN).

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Amsterdam, The Netherlands – Monday 2 September 2013 – The search continues for an agent that increases high-density lipoprotein (HDL) and reduces arterial plaque, after the experimental apolipoprotein A1 (apoA1) inducer, RVX-208 failed to do so in the ApoA1 Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation (ASSURE) study.

The lack of efficacy of RVX-208 is “disappointing and surprising, given promising earlier findings,” noted lead investigator Stephen Nicholls MBBS, PhD, Deputy Director at the South Australian Health and Medical Research Institute, Professor of Cardiology at the University of Adelaide and Consultant Cardiologist at the Royal Adelaide Hospital in Adelaide, Australia.

However, the failure of RVX-208 to incrementally impact atherosclerotic plaque should not be interpreted as a failure of the hypothesis that increasing the level and activity of HDL could result in this benefit, he said.

“RVX-208 represents the first epigenetic foray into the metabolic treatment of cardiovascular disease, and ongoing clinical trials will evaluate the potential cardiovascular efficacy of other agents that target HDL.”

ASSURE was a prospective, randomized, double-blind clinical trial carried out at 60 centers.

It randomized 323 patients with low HDL and coronary disease who had a target blood vessel for imaging with less than 50% stenosis.

All patients received treatment with either atorvastatin 10-40 mg daily or rosuvastatin 5-20 mg daily during the study and were also randomized to receive either RVX-208 100 mg (n=244) or placebo (n=80) twice daily for 26 weeks.

The primary and secondary outcomes of the study were change from baseline in percent atheroma volume (PAV) and normalized total atheroma (TAV), both measures of the amount of plaque present in the coronary artery.

Intravascular ultrasonography was used at baseline and the end of the study to measure these outcomes.

Of the 281 patients that remained in the study and had this imaging, while a trend towards plaque regression was observed with RVX-208 compared with baseline, there was no significant difference in efficacy outcomes between the groups, said Dr. Nicholls.

However, there were more discontinuations due to adverse events in the RVX-280 group (3.7% vs. 2.5%) as well as significantly more elevations of liver enzymes at triple the normal limit or more (7.0% vs. 0%, P=0.009).

In terms of efficacy, PAV decreased by 0.40% in the RVX-208 group compared to 0.30% in the placebo group ( P=0.81) and TAV decreased by 4.2 mm3 vs 3.8 mm3 respectively (P=0.86).

HDL cholesterol increased by 10.9% in the RVX-280 group compared to 7.7% in the placebo group (P=0.32), and LDL cholesterol decreased by 16.0% vs 17.6% with placebo (P=0.72).

There were no significant differences in cardiovascular events between the groups (13.8% in the RVX-2008 group vs 7.4% in the placebo; P=0.09), and all liver enzyme elevations occurred within the first 2 months of treatment with spontaneous y  when the study drug was discontinued.

Additionally, the impact of RVX-208 on apoA1 levels from baseline was not significantly different from placebo (P=0.18). The levels increased by 10.6% (P<0.001 compared with baseline) in the placebo group and 12.8% (P<0.001 compared with baseline) in the RVX-208 group.

“We anticipated that RVX-208 might promote regression of atherosclerotic plaque, however it did not demonstrate this benefit,” said Dr. Nicholls. “This is an intriguing therapeutic agent from a small company, and many in the HDL field found it exciting. The preliminary data made them wonder if it would be as good as infusional HDL agents and they elected to test this in a highly provocative fashion, over only 6 months. That is quite a change from the traditional studies of oral agents, which typically take 18-24 months,” he explained.

ASSURE’s lack of positive findings suggests that oral therapies may need longer to show an effect, he added. “We can't make any extrapolations about what might happen with the drug over a longer period because we did not test this, but if you look at longer trials of established therapies, there is a suggestion that, while there may be some early impact on plaque, significant change does not occur quickly and appears take a longer period of time.”

He suggested the negative finding might either reflect lack of efficacy of RVX-208 “or the inability to improve on benefits produced by statins and other background therapies in the study”.

“In the quarter century following the introduction of statins to clinical practice there has been an intensive, yet unsuccessful, search to identify new strategies to achieve greater cardiovascular risk reductions,” he added. “The search to identify a strategy that promotes HDL functionality, and improve cardiovascular outcomes continues.”

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Amsterdam, The Netherlands Monday 2 September 2013 – Uncertainty persists regarding whether drugs that lower sugar reduce the risk of heart attack, with some concerns that diabetes drugs may actually raise the risks. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) trial was a large international clinical trial that randomized patients to the diabetes drug saxagliptin (Onglyza), a selective dipeptidyl peptidase 4 (DPP-4) inhibitor, or to placebo in order to determine the effect on heart attack risk. The study found no excess, or reduction, in the risk of the primary composite endpoint of heart attacks, stroke, or cardiovascular death, which was the primary safety goal of the study. An increase in hospitalization for heart failure in the saxagliptin arm was noted.

“This large cardiovascular outcome trial sets a new standard for examination of the safety of diabetes drugs,” said trial co-principal investigator, Deepak L. Bhatt, MD, MPH, from the VA Boston Healthcare System and the TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA.

“Saxagliptin demonstrated better control of glucose compared with placebo, reduced the need for insulin therapy, and prevented deterioration in protein spilling from the kidneys to the urine,” added co-principal investigator Itamar Raz, MD, Hadassah Medical Center, Israel.

SAVOR-TIMI 53, a multicenter, randomized, double-blind, placebo-controlled Phase 4 trial conducted at 788 sites in 26 countries, included patients with type 2 diabetes mellitus, HbA1c levels between 6.5% and 12.0%, and either established or multiple risk factors for cardiovascular disease.

A total of 16,492 patients were randomized to receive either saxagliptin 5 mg daily (or 2.5 mg daily in patients with renal impairment) or matching placebo over a median follow-up of 2.1 years. Treatment with all other diabetes and cardiovascular medications was left to the discretion of the treating physician.

The primary endpoint of the study, a composite of cardiovascular death, non-fatal myocardial infarction, or non-fatal ischemic stroke occurred in 7.3% of the saxagliptin group compared with 7.2% of the placebo group (hazard ratio 1.00; P =0.99 for superiority and P <0.001 for non-inferiority).

The major secondary endpoint of cardiovascular death, myocardial infarction, stroke, or hospitalization for heart failure, unstable angina or coronary revascularization was also balanced and occurred in 12.8% of the saxagliptin group and 12.4% of the placebo group (HR 1.02; P=0.66).

“The lack of any excess in heart attack risk is reassuring,” commented Benjamin Scirica, MD MPH, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA, "though the neutral findings are in contrast to the benefit observed in pooled analyses from smaller, prior studies of saxagliptin, and highlight the importance of adequately powered outcome studies with sufficient follow-up to assess more fully cardiovascular effects of therapy.”

In terms of blood sugar control, patients treated with saxagliptin were more likely to achieve a glycated hemoglobin less than 7% at the end of treatment (36.2% vs. 27.9%; P<0.001).

However, significantly more patients in the saxagliptin group reported at least one hypoglycemic event compared with placebo (15.3% vs 13.4%; p<0.001), though there was no significant excess in the rate of hospitalization for hypoglycemia.
Additionally, more patients in the saxagliptin group were hospitalized for heart failure compared with the placebo group (3.5% vs 2.8%; HR 1.27; P=0.007).

“The increase in hospitalization for heart failure was not expected and deserves further study,” stated study chairman Eugene Braunwald, MD, TIMI Study Group, Cardiovascular Division, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA, USA.

“Few diabetes drugs have been studied as thoroughly as saxagliptin was in this trial. Our hope is that these data will help physicians guide future diabetes care in a more data-driven way and improve patient selection for different diabetes drugs,” Dr. Bhatt said.

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Amsterdam, The Netherlands – Monday 2 September 2013 –  Patients with type 2 diabetes and high cardiovascular risk due to recent acute coronary syndromes had similar rates of cardiovascular events when treated with the anti-diabetic agent alogliptin compared to placebo according to results of the Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care (EXAMINE) trial presented at the European Society of Cardiology Congress.

“Compared with placebo, treatment with alogliptin resulted in similar rates of the primary endpoint, which was a composite of cardiovascular death, myocardial infarction, and stroke ,” said the chair of the study’s steering committee William B. White, MD, from the University of Connecticut School of Medicine in Farmington, Connecticut, USA.

“The findings could guide clinicians to choose among the many anti-diabetic agents available when treating patients with type 2 diabetes and very high cardiovascular risk,” he suggested.
 
EXAMINE, designed as a non-inferiority trial, was undertaken to satisfy U.S. Food and Drug Administration requirements that new diabetes drugs be subjected to studies to rule out cardiovascular risk.

“It represents the first cardiovascular safety trial of an anti-diabetic drug in patients with acute coronary syndromes. Hence, for those who are likely candidates for the drug in clinical practice with elevated CV risk, including those with a recent acute coronary syndrome, it is reassuring that alogliptin does not increase cardiovascular morbidity or mortality,” noted Dr. White.

“However, EXAMINE does not rule out longer-term benefits or risks of alogliptin with respect to cardiovascular end points as the median duration of the trial was approximately 18 months,” he added.

The trial recruited 5,380 patients from 898 centers in 49 countries and randomized them to receive alogliptin or placebo, administered in a double-blind fashion along with standard-of-care treatment for type 2 diabetes mellitus and cardiovascular risk factors.

Due to its renal clearance, alogliptin dosing was modified according to kidney function, with 71.4% of patients receiving 25 mg, 25.7% receiving 12.5 mg, and 2.9% receiving 6.25 mg daily.

After a median follow-up of 18 months, and up to 40 months,  the primary endpoint, which was a composite of cardiovascular death, myocardial infarction, and stroke had occurred at a similar rate in alogliptin and placebo-treated patients (11.3% vs 11.8% respectively; P <0.001 for non-inferiority).

As would be expected with an antihyperglycemic agent, end-of-study glycated hemoglobin levels were significantly lower in patients on alogliptin than placebo with a mean change from baseline of -0.33% and +0.03% respectively.

Incidences of hypoglycemia, malignancy, pancreatitis, and dialysis were similar for both groups.  To date, research has yet to identify a diabetes drug that is not only safe but actually beneficial to the heart – an important issue for diabetic patients who are at high risk for cardiovascular problems.

The EXAMINE trial satisfied FDA requirements to show cardiovascular safety but built into the trial design, as a secondary objective, was an exploration for cardiac benefits which were not found.

“There is a need for safe glucose lowering therapies in patients with diabetes who are at an elevated risk for cardiovascular disease,” he added. “Given the EXAMINE study design and high risk patient population evaluated, these results provide key insights to clinicians treating diabetes patients with cardiovascular disease.”

Funding: Funded by Takeda Development Center Americas, Inc.

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Amsterdam, The Netherlands,  Monday 2 September 2013  – Despite being weighed down by more cardiovascular risk factors, people living in higher income countries are able to avoid many of the severe and even fatal consequences of cardiovascular disease (CVD) compared to their counterparts in lower income parts of the world.

These “surprise” findings, from the PURE (Prospective Urban Rural Epidemiologic) Study underscore the value of a good healthcare system in addition to healthy heart habits, said lead investigator Salim Yusuf, MD, professor of medicine of McMaster University’s Michael G. DeGroote School of Medicine, vice president of research at the Hamilton Health Sciences and director of the Population Health Research Institute (PHRI) in Hamilton, Ontario, Canada.

“What we’ve got is a paradox:  a higher risk factor burden in high-income countries compared to low-income countries, but a lower mortality rate from CVD - and this is not because risk factors don’t matter – they do,” said Dr. Yusuf, who presented the study at the ESC Congress 2013.

“But it’s telling us that there’s something that’s even more important, or at least as important, and that is healthcare – healthcare access, equity, and efficiency – a lot of the positives of the Canadian and Swedish and other European healthcare systems.”

The PURE study enrolled 155,245 subjects from 17 countries to assess the influence of cardiovascular (CV) risk factors on CV disease and mortality.

The study population included 16,110 subjects from high income countries (primarily Canada but also Sweden and the United Arab Emirates), 104,260 subjects from 10 middle-income countries, and 34,875 subjects from 4 low-income countries (India, Bangladesh, Pakistan, and Zimbabwe). Subjects were between 35 and 70 years old, from both rural and urban areas, and were surveyed and followed for a mean of 3.9 years.

Cardiovascular risk was calculated for each subject using the INTERHEART Risk Score (IHRS), and based on age, sex, smoking, diabetes, blood pressure, family history of heart disease, working heart rate, psychosocial assessment, diet and physical activity.

Treatment and prevention practices were also noted such as hypertension control, smoking cessation, use of lipid lowering drugs and secondary prevention.

The study found that CVD risk factors were highest in high-income countries and lowest in low-income countries, but treatment and preventive measures also followed this pattern (p<0.0001).

Overall, hospitalisations for CVD were highest in the high versus middle and low-income countries (P<0.05), but in examining the reasons for hospitalisation the study showed that compared to low-income countries, both fatal and other major CVD (myocardial infarction, stroke and heart failure) were less common in high-income countries and non-major CVD was more common ((P<0.001 for all).

Specifically, major CVD occurred at a rate of 4.3 per 1,000 person years in high-income countries, compared to 5.1 and 6.4 in middle and low-income countries respectively. And fatal CVD occurred at a rate of 0.6 per 1,000 person years in high-income countries compared to 1.7, 3.8 in middle and low-income countries respectively.

In contrast, the rate of non-major CVD in high-income countries was 4.3 per 1,000 person years, compared to 5.1, and 6.4 in middle and low-income countries (P<0.001).

“In countries like Canada, when people get even a relatively mild condition, they are generally treated for it – things are being picked up early resulting in less severe disease – whereas in poorer countries mild CVD doesn’t get picked up until its severe or patients die,” explained Dr. Yusuf.

“What this is telling us is that healthcare matters. The gurus of cardiovascular disease prevention have kept emphasising the control of risk factors, with very little recognition that healthcare matters, but this is telling us that healthcare matters at least as much as risk factor control. Now the challenge is to identify those key aspects of health care that are effective and apply them to low and middle-income countries in a much more frugal manner."

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Amsterdam, The Netherlands – Monday 2 September 2013: Metabolically healthy women have the same cardiovascular disease risk regardless of their BMI, according to research presented at the ESC Congress today by Dr Søren Skøtt Andersen and Dr Michelle Schmiegelow from Denmark. The findings in more than 260,000 subjects suggest that obese women have a window of opportunity to lose weight and avoid developing a metabolic disorder, which would increase their CVD risk.

Dr Schmiegelow said: “Obesity and/or metabolic disorders (hypertensive disorders [hypertension, gestational hypertension or pre-eclampsia], disorders in glucose-metabolism [diabetes, gestational diabetes] and elevated cholesterol levels [dyslipidemia]) are well known cardiovascular risk factors. Studies in middle aged men have found that obese and normal weight men have the same cardiovascular risk if they are metabolically healthy. Our study aimed to find out if the same was true for young fertile women.”

The study used Danish national health databases and followed 261,489 women who had given birth during 2004-2009 with no prior history of cardiovascular disease. The women were divided into four categories according to their pre-pregnancy body mass index (BMI, kg/m2) and presence of metabolic disorders (present/not present) (see figure). The women’s mean age was 31 years.

The women were followed for an average of 5 years following childbirth. Discharge diagnoses and data on cause of death were used to determine if the women had a heart attack, a stroke, or died. Metabolic disorders were defined using claimed prescription data related to hypertension, diabetes and dyslipidemia; thus, only disorders being treated were taken into account. The pregnancy-associated metabolic disorders were defined using diagnosis codes.

The researchers found that being overweight (BMI≥25 kg/m2) but metabolically healthy was not associated with an increased risk of a heart attack, stroke or a combination of heart attack/stroke/death in comparison with normal weight, metabolically healthy women.

Dr Schmiegelow said: “Being overweight but free of metabolic disorders does not seem to be associated with an increased risk in young women in the short term. However, development of metabolic disorders, for which obesity is a major determinant, is associated with a marked increase in cardiovascular risk, especially in overweight women even in the short term.”

The investigators found that the metabolically unhealthy, overweight women had an almost 7-fold increased risk of heart attack and a 4-fold increased risk of stroke.

Dr Schmiegelow said: “It is important to note that the absolute risks were still low in this young population, but the key message from this study is that the consequences of obesity become apparent even in a young, low-risk population within a relatively short period of follow-up.”

She added: “Our results clearly show that being overweight but metabolically healthy is not associated with an excess cardiovascular risk in comparison with normal weight healthy women. However being normal weight or overweight with metabolic disorders is associated with a marked increase in risk that is present in a young female population with a mean age of only 31 years and within a short span of follow up.”

Dr Schmiegelow concluded: “Our results indicate that obesity might not be all bad if the overweight woman has not developed any hypertensive disorders, disorders in glucose-metabolism or elevated cholesterol levels. But because obesity markedly increases the risk of developing these metabolic disorders, these women most likely have a window of opportunity to lose weight and change their prognosis.”

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Amsterdam, The Netherlands – Monday 2 September 2013 : Pacemakers implanted for slow heart rhythm restore life expectancy to normal levels, reveals research presented at ESC Congress 2013 today by Dr Erik O. Udo from the Netherlands. The findings provide a new reference point for the prognosis of modern pacemaker patients.

Dr Udo said: “Previous studies describing the survival of pacemaker patients used data that is more than 20 years old and cannot be used anymore for patient counselling and benchmarking. There have been considerable changes in pacemaker technology and in the profile of pacemaker patients and a new reference point of prognosis in modern day cardiac pacing was needed.”

FollowPace was a nationwide multicentre prospective cohort study in 23 Dutch hospitals. It included 1,517 patients who received their first pacemaker for bradycardia (slow or irregular heart rhythm) between 2003 and 2007. Patients were followed for an average of 5.8 years.

The researchers found survival rates of 93%, 81%, 69% and 61% after 1, 3, 5 and 7 years respectively. Patients without cardiovascular disease (such as heart failure or coronary artery disease) at the time of pacemaker implantation had a survival rate similar to age and sex matched controls from the general Dutch population (see figure 1).

Dr Udo said: “Our results suggest that the prognosis of today’s pacemaker patient is primarily determined by whether or not they also have cardiovascular disease, and not by the rhythm disorder itself. Patients who have heart failure or coronary artery disease when the pacemaker is implanted have the highest risk of death. On the other hand, patients without cardiovascular disease at the time of implantation have the best survival, which is comparable to the survival of the general population.”

He added: “In earlier studies we showed that in cases of too slow heart rhythm, permanent pacing relieves symptoms and improves quality of life and therefore a pacemaker is the appropriate device. In this study we could document that other cardiovascular problems, such as coronary artery disease or heart failure, determine the prognosis of pacemaker patients rather than the slow heart rhythm itself.”

He continued: “After pacemaker implantation for a too slow heart rhythm, more attention should be paid to the detection and treatment of other cardiovascular problems. Thus, next to the regular technical follow-ups of the pacemaker, the cardiologist should also regularly check the pacemaker recipient to improve the prognosis by treating potentially diagnosed cardiovascular diseases.”

Dr Udo concluded: “The FollowPace study provides detailed documentation of current standard pacemaker care in a large representative sample of western pacemaker clinics. The results can therefore be considered a new benchmark of life expectancy of patients treated with today’s cardiac pacing.”