Positive results for drug treatments presented at the European Society of Cardiology Congress in Stockholm, Sweden, are set to change clinical practice. In the landmark SHIFT trial, ivabradine reduced the risk of death and hospitalisation in chronic heart failure patients by more than a quarter. Another large study, the phase III EINSTEIN-DVT trial, has shown that the anticoagulant rivaroxaban achieved the primary efficacy and safety outcomes in the treatment of patients with acute, symptomatic deep vein thrombosis. At least other six drugs took centre stage at the ESC meeting with positive results for heart disease patients.
Fausto Pinto, outgoing chairman of the Congress Programme Committee, described the SHIFT and EINSTEIN-DVT studies as the highlights of the ESC 2010 hot lines sessions. “We are all very excited by the results from SHIFT. Ivabradine is not a new drug but it is a new use in moderate to severe heart failure. The SHIFT trial – and the sub-study – both showed for the first time that reducing heart rate is beneficial for patients with heart failure.”
The largest-ever morbi-mortality study of treatments for chronic heart failure has shown that adding the specific heart rate lowering agent ivabradine (Procoralan, Servier) to standard therapy significantly reduces the risk of death and hospitalisation for heart failure.
Results from this new study, SHIFT (Systolic heart failure treatment with the I(f) inhibitor ivabradine trial), were presented at the ESC Congress and published in The Lancet.
SHIFT involved over 6,500 patients from 37 countries with moderate to severe heart failure and heart rate above 70bpm who were followed up for an average of 23 months. The results showed that ivabradine reduces the primary endpoint, a composite of cardiovascular death or hospitalisation for worsening heart failure, by 18% (p<0.0001).
Ivabradine also reduced the likelihood of death from heart failure by over a quarter (26%, p=0.014) and the risk of hospitalisation due to worsening heart failure by the same amount (26%, p<0.0001). These benefits were evident in just three months of treatment with Procoralan and despite the fact that patients were already receiving guideline recommended therapy (betablockers, angiotensin converting enzyme [ACE] inhibitors, diuretics or aldosterone antagonists). The study also confirmed that ivabradine has a good tolerability profile in these fragile patients.
“Twenty years after angiostensin converting enzyme inhibitors and 10 years after betablockers, we now have a new life-saving drug available for our patients,” said SHIFT executive committee co-chairman Michel Komajda, professor of Cardiology, University Pierre et Marie Curie Paris 6, France.
Ivabradine is currently used in angina patients as it relieves symptoms, myocardial ischaemia and reduces the risk of coronary events. The SHIFT study has now also demonstrated the prognostic benefits of ivabradine in chronic heart failure patients.
The SHIFT study is also the first study to specifically confirm that, due to ivabradine, isolated heart rate reduction reduces the risk of death or hospitalisation for heart failure. This finding confirms that heart rate plays a key role in the progression of disease.
SHIFT co-chairman, Karl Swedberg from the Head of the Department of Emergency and Cardiovascular Medicine at University of Gothenburg, Sweden, said: “The SHIFT study has important implications for our clinical practice. It tells us that having a high heart rate is bad for heart failure patients. So we should routinely measure heart rate in all heart failure patients and, if it is above 70 beats per minute, heart rate lowering with ivabradine should be considered, irrespective of their background treatment.”
Patients received Procoralan or placebo in addition to their standard chronic heart failure treatment. These included ACE inhibitors and/or ARBs, betablockers, diuretics and aldosterone antagonists. A total of 89% of patients in the study received ACE inhibitors and betablockers, with more than half of them who received at least 50% of the target dose.
Inder Anand, University of Minnesota, USA, who discussed the results of the trial, said that unfortunately, a quarter of the heart failure population would be excluded because of the presence of atrial fibrillation where ivabradine is unlikely to have an effect.
“SHIFT investigators should be congratulated for conducting a very important study. SHIFT confirms the importance of heart rate in the pathophysiology of heart failure and supports the concept that reduction in heart rate contributes significantly to beneficial outcomes in patients with heart failure. In patients with systolic heart failure in SR with heart rate >70 bpm, receiving usual clinical care and unable to tolerate higher doses of beta-blockers, the addition of the pure heart rate reducing agent ivabradine is likely to improve heart failure outcomes,” Anand said.
SHIFT was funded by Servier, and coordinated by the SHIFT executive committee, an international group of heart failure experts.
Results of the phase III EINSTEIN-DVT study show that the oral anticoagulant rivaroxaban (Xarelto, Bayer) achieved the primary efficacy and safety outcomes in the treatment of patients with acute, symptomatic deep vein thrombosis (DVT).
The study showed that rivaroxaban demonstrated non-inferior efficacy in the treatment of DVT compared with initial enoxaparin treatment followed by a vitamin K antagonist (VKA), the current standard therapy for the treatment of DVT. Recurrent symptomatic venous thromboembolism (ie, the composite of recurrent DVT, non-fatal or fatal pulmonary embolism) occurred in 2.1% of the rivaroxaban recipients and 3% of the subjects receiving standard therapy (p<0.0001 for non-inferiority).
The EINSTEIN-DVT study also demonstrated similar rates of major and clinically relevant non-major bleeding, the principal safety outcome, for rivaroxaban compared with the current standard therapy (8.1% vs. 8.1%, respectively). No liver signal attributable to rivaroxaban was observed in the study.
“The results of the EINSTEIN-DVT trial indicate that rivaroxaban is an effective and safe treatment for acute symptomatic DVT,” said principal investigator, Harry R Büller, Academic Medical Center, Amsterdam, The Netherlands. “The single-drug approach with rivaroxaban will provide clinicians and patients with an attractive, simple, alternative regimen for the initial and long-term treatment of deep vein thrombosis.”
The multinational EINSTEIN-DVT study was designed to investigate a new single-drug approach with rivaroxaban in comparison to standard therapy in a randomised, open-label, non-inferiority study. The trial involved more than 3,400 patients with acute symptomatic DVT, but without any symptoms of pulmonary embolism, across 253 sites in 32 countries worldwide. Patients received either oral rivaroxaban (15mg twice-daily for the first three weeks, followed by 20mg once daily) or body weight-adjusted subcutaneous enoxaparin followed by warfarin or acenocoumarol (dose adjusted to maintain a therapeutic normalised ratio) for three, six or 12 months, based on the attending physician’s assessment at baseline.
The primary efficacy outcome was the cumulative incidence of symptomatic recurrent venous thromboembolism (non-fatal or fatal). The principal safety outcome was the composite of major and clinically relevant non-major bleeding.
The EINSTEIN DVT study was sponsored by Bayer Schering Pharma.