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Medical Research News

Intensified, BNP-guided therapy was no more effective than a standard, symptom-guided approach in elderly heart failure patients in reducing the number of deaths and all-cause hospitalisations. However, the response to this intervention differed significantly between patients aged 60-74 years and those aged ??5 years. This indicates the need for specific data in this large subset of very old heart failure patients who have been largely excluded from large treatment trials.

Our study was carried out in 15 hospitals in Switzerland and Germany and included 499 heart failure patients with reduced pump function of the heart aged ??0 years. The study was called TIME-CHF, standing for the Trial of Intensified (BNP-guided) versus standard (symptom-guided) Medical therapy in Elderly patients with Congestive Heart Failure. Patients in both groups were well treated according to current guidelines, but doses of medication were significantly increased in the BNP-guided group. Increase in medication took place within the first 6 months after study inclusion and patients were followed up for another 12 months. This study has several aspects that may be relevant for the treatment of heart failure patients, particularly since we included a population that is representative for patients as seen in daily practice. Patients were on average 77 years old (82 years in the group aged ??5 years) and had many diseases other than heart failure, i.e. app. 80% had 2 or more additional diseases. Previous studies had largely excluded such patients.

Symptoms and quality of life of patients in both intervention groups improved with treatment, irrespective of age. Death rate in all patients was lower than we expected. This indicates that all patients with heart failure seem to profit from current standard therapy. With more intensified therapy, younger patients showed lower death rate and less hospitalisations due to cardiac reasons, including heart failure, than with standard therapy. However, this was not the case in older patients, where patients with intensified therapy had similar death and hospitalisation rate, but worse quality of life than with standard treatment. Therefore, general treatment recommendations which are based on results in younger patients, may not necessarily be directly applicable to very old patients. This particularly applies to patients with relevant diseases other than heart failure. Studies testing interventions in these very old patients, such as TIME-CHF, are needed to define the best therapies. In addition, it may not be beneficial to push doses to the limits in the very elderly and in those with other relevant health problems.

The intervention reduced the disease specific endpoint of death and heart failure hospitalisations, but not all-cause hospitalisations. The latter is more relevant for patients, which is why we used this as our primary outcome measure. In previous studies, however, disease specific endpoints have been used. Our study indicates that the net benefit of treatment might be smaller than expected from the large treatment trials, particularly in patients who are likely to be hospitalised or die due to reasons other than heart failure. This might explain why death and hospitalisation rates in the general heart failure community over the last two decades decreased at a lesser rate than was expected based on results from studies. In addition, TIME-CHF shows how important it is to study patients as seen in daily practice since the conclusion may not be exactly the same.

Our findings need to be confirmed before it can be generally recommended to use different therapies in heart failure patients depending on their age. Nevertheless, it may help to better define individual needs for heart failure patients and to boost the urgently needed studies in this large heart failure population of very old patients.

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Drug Trials

The results of the much awaited BEAUTIFUL (morBidity-mortality EvAlUaTion of the If inhibitor ivabradine in patients with CAD and left ventricULar dysfunction) trial have shown that coronary artery disease (CAD) patients with left ventricular dysfunction (LVD) and a heart rate more than 70 bpm have a significantly higher risk of cardiovascular death and other cardiovascular events and in these patients (heart rate above 70 bpm) treatment with ivabradine further reduces the risk of the most important coronary events such as fatal and non-fatal myocardial infarction and coronary revascularisation by one third, even when these patients are already receiving optimal therapy.

Commenting after the results presentation, the Chairman of the BEAUTIFUL Executive Committee, Prof Kim Fox said 'Ivabradine was always known to relieve ischemia. With the BEAUTIFUL results, ivabradine is the first antianginal treatment shown to reduce myocardial infarction and revascularisation and to have a good tolerability profile even when used with other drugs. This is the gold standard for any antianginal, anti-ischemic drug'.

The BEAUTIFUL trial was initiated in December 2004, under the guidance of an independent Executive Committee with the first patient being enrolled in early 2005. 10917 CAD patients with LVD, were recruited in 781 centres in 33 countries across 4 continents. The mean heart rate in these patients was 71 bpm and half of the patients had a heart rate more than 70 bpm. The results of the BEAUTIFUL study have shown that these patients with heart rate > 70 bpm are more likely to die or suffer from another cardiovascular event. The increase in risk is 34% for cardiovascular death, 46% for myocardial infarction, 56% for heart failure and 38% for coronary revascularisation.

In the overall study population treatment with ivabradine did not result in a significant reduction of the primary composite end point (Cardiovascular death, admission to hospital for acute MI and admission to hospital for heart failure). However in patients with baseline heart rate more than 70 bpm, ivabradine significantly reduced the risk of hospitalisation for fatal and non-fatal myocardial infarction by 36% (p=0.001) and the risk of coronary revascularisation by 30% (p=0.016). What is important to note is that most of these patients were already receiving the guidelines-recommended cardiovascular therapy: antiplatelet agents (94%), angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (91%), β-blockers (87%), as well as lipid-lowering agents (76%). Hence the results of BEAUTIFUL constitute a step further in the management of these coronary patients with heart rate above 70 bpm because, for the first time it has been shown that pure heart rate reduction with ivabradine further reduces coronary events even in patients receiving the current optimal cardiovascular therapy. This study also confirms that ivabradine is safe and well tolerated and can be used with all routinely prescribed cardiovascular drugs. Commenting on the results the Chairman of the Steering Committee, Prof Roberto Ferrari said 'Often a lot of investigations are performed in coronary patients but a simple heart rate measurement is not done. BEAUTIFUL has reinforced the need to measure heart rate in all CAD patients and if the heart rate is more than 70 bpm to reduce it by using ivabradine on top of background therapy.'

BEAUTIFUL results with ivabradine can be explained by its well documented ability to relieve myocardial ischemia in patients with chronic stable angina.1 New research has demonstrated that ivabradine improves endothelial dysfunction2 and prevents the progression of atherosclerosis.

Despite all the advances, the World Health Organisation reports that till 2030 coronary artery disease will remain the leading healthcare problem worldwide3. Ivabradine would help to reduce this burden because as shown by the BEAUTIFUL study, ivabradine reduces the risk of myocardial infarction and revascularisation. 'Half of the CAD patients have a resting heart rate more than 70 bpm. These patients can now benefit from a treatment that will greatly reduce their chances of having another heart attack or needing further surgery, concluded Professor Kim Fox, the Chairman of the BEAUTIFUL Executive Committee.

References:
1. Tardif J-C, Ford I, Tendera M, et al. Eur Heart J. 2005;26:2529-2536.
2. Florian Custodis, MD*; Magnus Baumh?l, et al Circulation 2008;117:2377-2387.
3. Projections of Global Mortality and Burden of Disease from 2002 to 2030 PLoS Med 3(11): e442. doi:10.1371/journal.pmed.0030442.

Depending on the country, ivabradine is available as Procoralan?, Coralan?, Coraxan?, or Corlentor?

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Drug Trials

Researchers involved in the GISSI trial, concluded that simple, safe and cheap treatment with n-3 PUFA can provide a moderate beneficial advantage in terms of mortality and admission to hospital for cardiovascular reasons in patients with chronic heart failure, in a context of usual care.

Several epidemiological and experimental studies suggested that n-3 PUFA could exert favourable effects on the atherotrombotic cardiovascular disease including arrhythmias. The GISSI team investigated whether n-3 PUFA could improve morbidity and mortality in a large population of patients with symptomatic heart failure of any cause.

The GISSI researchers undertook a randomised, double blind, placebo controlled trial in 357 cardiology sites in Italy. They enrolled 6 975 patients with chronic heart failure of New York Heart Association class II-IV, assigned to n-3 PUFA 1 g daily or placebo. Patients were followed up for a median of 3?9 years. Primary end-points were time to death and time to death or admission to hospital for cardiovascular reasons. Analysis was by intention-to-treat population.

Among the GISSI findings: 955 (27%) patients died from any cause in the n-3 PUFA group and 1014 (29%) in the placebo group (relative risk reduction 9%, p=0?041). 1981 (57%) patients in the n-3 PUFA group and 2053 (59%) in the placebo group died or were admitted to hospital for cardiovascular reasons (relative risk reduction 8%, p=0?009). In absolute terms, 56 patients needed to be treated for 3.9 years to avoid one death or 44 to avoid one event like death or admission to hospital for cardiovascular reasons. In a per-protocol analysis performed in about 5000 full complier patients, the relative risk of death was reduced by 14% (p 0.004). Safety was excellent.

GISSI is endorsed by theAssociazione Nazionale Medici Cardiologi Ospedalieri (ANMCO), Firenze, Italy; Ist.Ricerche Farmacologiche Mario Negri, Milan, Italy and the Consorzio Mario Negri Sud, Santa Maria Imbaro, Italy.

The GISSI-HF trial was planned, conducted and analyzed by the GISSI group which has full ownership of the data.

This study is registered with Clinical trials.gov., number: NCT00336336.

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Medical Research News

Young competitive athletes are perceived by the general population to be the healthiest members of society. The possibility that highly trained athletes may have a potentially serious cardiac condition that can predispose to life-threatening tachyarrhythmias or sudden cardiac death seems paradoxical.

However, high-risk ventricular tachyarrhythmias and sudden cardiac death in the athlete although uncommon, are extremely visible events due to the high profile of elite and professional athletes. In athletes under the age of 35 years, the incidence of sudden death is low and in most cases occurs in individuals with inherited heart disease, such as hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia and congenital anomalies of coronary arteries. In older athletes, sudden death is more common and is generally due to arrhythmias in the context of coronary artery disease.

A crucial point is the role played by physical exercise and training in the genesis of ventricular arrhythmias and, therefore, whether exercise can enhance the risk of arrhythmic cardiac arrest in athletes. Indeed, regular exercise training is associated with morphologic and functional cardiac changes that may create ambiguity with cardiac pathologic conditions and differentiating the benign, exercise-induced physiologic changes from true pathological conditions with risk of sudden death is critical to developing appropriate screening strategies to reduce such adverse events.

Recent studies showed that the risk for sudden death in young competitive athletes with cardiovascular disease was 2.5-fold greater than in non-athletes. These data suggest that sports activity itself may act as a trigger for life-threatening ventricular tachyarrhythmias in susceptible individuals with underlying, even silent cardiovascular disease, thereby predisposing to cardiac arrest. Therefore, polymorphic and malignant ventricular tachycardia triggered by intensive athletic conditioning should raise suspicion and greater scrutiny for an underlying inherited electrophysiological disorder (such as channelopathies), or an underlying structural disease (like arrhythmogenic right ventricular dysplasia or hypertrophic cardiomyopathy). These findings are in agreement with results of our previous study on physical de conditioning, in which we observed that none of the athletes with frequent and complex ventricular arrhythmias (with or without cardiovascular abnormalities) disqualified from training and competition, experienced clinical events or cardiac arrest in the follow-up and all showed a marked reduction, or even disappearance of the premature ventricular depolarizations.

Therefore, the reduction/disappearance of ventricular arrhythmias is a potential mechanism by which disqualification from competitive sports may reduce the risk for sudden cardiac death. These data support the restriction from competitive sport and intense exercise training in athletes with frequent and complex ventricular arrhythmias and structural heart disease and explains the 89% decline in the incidence rate of sudden cardiovascular death among young competitive athletes aged 12 to 35 years in the Veneto region of Italy over a 26-year period.

These data support the conclusion that the reduction in the incidence of sudden cardiovascular death is the result of the introduction in 1982 of a nationwide pre participation screening program. There was coincident timing between decline of sudden cardiovascular death in young competitive athletes and implementation of pre participation cardiovascular screening in Italy. Athletes with cardiovascular abnormalities need a thorough clinical assessment and therapeutic options for sudden cardiac death prevention, such as ICD. However, in athletes with documented malignant ventricular tachyarrhythmias, competitive sports are contraindicated. A possible exception is represented by ventricular arrhythmias occurring in the context of acute and transient myocardial lesion, such as myocarditis, commotio cordis, acute electrolytic depletion, when the cause has proven to be completely resolved.

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Drug Trials

An international study led by Canadian researchers has found that telmisartan, a medication used to lower blood pressure, reduced the outcome of cardiovascular death, heart attack or stroke in people who are unable to tolerate a widely available and effective standard treatment.

Dr. Salim Yusuf and Dr. Koon Teo, professors in the Michael G. DeGroote School of Medicine at McMaster University and clinicians at Hamilton Health Sciences, led the study. Results were presented today at the European Society of Cardiology Congress in Munich, Germany.

ACE inhibitors, or angiotensin-converting-enzyme inhibitors, are widely used and effective medications used to lower blood pressure. They work by helping to widen blood vessels to improve blood flow. Approximately 20 per cent of patients who could benefit from an ACE inhibitor stop taking it because of cough, kidney problems, swelling or symptomatic low blood pressure.

Telmisartan is a type of angiotensin-receptor blocker, or ARB. Like ACE inhibitors, telmisartan also lowers blood pressure, but works in a different manner. ARBs block the receptor sites in the body for angiotensin II, a naturally occurring hormone that constricts blood vessels and increases blood pressure.

The TRANSCEND (Telmisartan Randomized AssessmeNt Study in ACE iNtolerant subjects with cardiovascular Disease) study enrolled nearly 6,000 people worldwide who are intolerant to ACE inhibitors, and evaluated whether telmisartan - compared to placebo - would reduce the risk of major cardiovascular events. A high proportion of patients received proven therapies, such as statins, anti-platelet agents and beta-blockers. Physicians were also free to use other medications that could lower blood pressure.

The researchers found that the outcome of cardiovascular death, heart attack or stroke was modestly reduced when patients took telmisartan. In addition, fewer patients receiving telmisartan were hospitalized for any cardiovascular reason compared to placebo. Telmisartan was also remarkably well tolerated, and fewer patients on telmisartan discontinued the medication compared to placebo.

Telmisartan reduced the outcome of cardiovascular death, heart attack, stroke or hospitalization for heart failure by a relative eight per cent (17 per cent in the placebo experienced those cardiac events compared to 15.8 per cent in the telmisartan group). This difference was not statistically significant.

However, when the outcome included cardiovascular death, heart attack or stroke (and not hospitalization for heart failure), telmisartan reduced that outcome by a significant 13 per cent (14.8 per cent in the placebo group experienced those cardiac events compared to 13 per cent with telmisartan).

"The TRANSCEND study demonstrates the value of telmisartan in people who are unable to tolerate angiotensin converting enzyme inhibitors," said principal investigator Dr. Yusuf, director of the Population Health Research Institute at McMaster University.

"Although the benefit is of moderate size, there is an impact on a range of outcomes including the composite of cardiovascular death, myocardial infarction and strokes, as well as cardiovascular hospitalizations. Given the large proportion of people who are unable to tolerate an ACE inhibitor, the use of telmisartan would be clinically important."

"The remarkable tolerability of telmisartan is emphasized by the fact that fewer individuals stop medication if they were receiving telmisartan compared to placebo," said Dr. Teo, the project director. "This is particularly noteworthy, as all the individuals enrolled in the study were unable to tolerate an ACE inhibitor, which is a closely related class of agents."

The TRANSCEND study enrolled people with a history of cardiovascular disease or diabetes with end-organ damage who were intolerant to ACE inhibitors.

The study was conducted in 630 hospitals in 40 countries. It was coordinated by the Population Health Research Institute at McMaster University and Hamilton Health Sciences. The study was sponsored by Boehringer-Ingelheim, the manufacturers of telmisartan.

About the Population Health Research Institute:

The Population Health Research Institute conducts clinical and population research in 79 countries involved over 1,500 hospitals. This institute has coordinated and completed over 50 major international trials in the last 15 years. It is based at McMaster University and Hamilton Health Sciences, which are world-renowned research-intensive institutions, fostering a culture of innovation and commitment to discovery and learning.

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