IMPROVE-IT results in acute coronary syndromes
Adding another type of cholesterol-lowering drug to statin therapy can better prevent heart attacks and strokes in high-risk patients with acute coronary syndrome (ACS), according to the IMPROVE-IT study presented at the American Heart Association’s (AHA) Scientific Sessions in Chicago, USA.
IMPROVE-IT is the first study to show that reducing low-density lipoprotein (LDL) cholesterol with a combination of a statin and non-statin to levels lower than those achieved with the statin alone was associated with significant clinical benefit.
The study enrolled 18,144 patients with ACS aged 50 years or older with LDL levels at or less than 125—or at or less than 100 if they were already using a statin.
Results found that patients given both simvastatin and the non-statin drug, ezetimibe, had a 6.4% lower risk of all cardiovascular events, a 14% lower risk of all heart attacks, a 14% lower risk of stroke, and a 21% lower risk of ischaemic stroke. This was compared to patients with coronary heart disease given the drug simvastatin plus a placebo.
Deaths from cardiovascular disease were statistically the same in both groups. Patients were followed for an average of approximately six years, and some as long as 8.5 years. Approximately two patients out of every 100 patients treated for seven years avoided a heart attack or stroke.
Christopher P. Cannon, lead author and a professor of medicine at Harvard Medical School and physician at Brigham and Women’s Hospital, said: “The study is the first to show that adding a non-statin drug to a statin to improve cholesterol levels can help patients with specific heart problems do better.”
Acute coronary syndrome, such as a heart attack or unstable angina, is an umbrella term for situations where the blood supplied to the heart muscle is suddenly blocked.
The patients, enrolled within 10 days of hospitalisation for a heart attack or unstable angina, were high risk. About 5,000 of them had suffered a full-thickness heart attack known as an ST-segment elevation myocardial infarction, or STEMI.
The remaining 13,000 had suffered a non-STEMI heart attack or had unstable angina, defined by new or worsening chest pain. Patients also had at least one feature putting them at high risk for a further cardiovascular event, including a previous heart attack, diabetes, peripheral artery or cerebrovascular disease, coronary disease in multiple arteries, or bypass surgery in the past.
Statins, such as simvastatin, block cholesterol production in the liver, while ezetimibe, a cholesterol absorption inhibitor, reduces the body’s absorption of cholesterol in the intestine. In the study, the dual therapy reduced patients’ LDL to an average of 54mg/dL, compared with 69 for those treated with the statin and placebo.
The addition of ezetimibe did not raise patients’ risk of ill effects, such as liver or muscle problems, or cancer. Over a decade ago, researchers from the TIMI Study Group, based at Brigham and Women’s Hospital (BWH) demonstrated that a high dose statin, which lowered cholesterol further than a regular dose statin, provided better clinical outcomes. But questions remained about whether further reducing cholesterol would be even more effective in reducing cardiovascular-related events.
Edoxaban was associated with lower risks of bleeding compared with warfarin
The oral factor Xa inhibitor edoxaban was as effective in preventing strokes and safer than warfarin in patients with atrial fibrillation, according to a late-breaking clinical trial presented at the AHA.
The ENGAGE AF-TIMI 48 Trial included more than 21,000 atrial fibrillation patients in 46 countries in 1,400 hospitals. Participants were randomly assigned to receive a high dose of edoxaban at 60mg per day, a low dose of edoxaban at 30mg per day or warfarin.
Edoxaban performed as well as warfarin in preventing strokes, while significantly reducing the risk of bleeding and cardiovascular disease-related death. Compared with warfarin, major bleeding was 20% lower among patients taking the high dose of edoxaban and 53% lower among those taking the low dose. Compared with warfarin, the high dose of edoxaban was associated with a 14% reduction in cardiovascular death; the low dose was associated with a 15% reduction.
Instead of depleting the body’s clotting proteins like warfarin, edoxaban singles out one key clotting protein called Xa, to prevent clots.
Robert P Giugliano, lead author of the study and a researcher and physician at Brigham and Women’s Hospital in Boston, said: “Edoxaban is a more targeted, simpler approach to preventing blood clots. It inhibits the body’s ability to form a clot at a very critical juncture of the clotting pathway and behaves in a more predictable way.”
During the trial, the assigned dose of edoxaban was reduced for some patients based on their kidney function, body weight or because they were taking certain medications. Some patients who started out on the 60mg of edoxaban were lowered to 30mg, and some who began the study at 30mg of edoxaban were switched to 15mg.
A study investigating the reversal of edoxaban’s effects on bleeding measures and biomarkers using a 4-factor prothrombin complex concentrate (4F-PCC) was also published recently in Circulation.
It found the 4F-PCC dose-dependently reversed the effects of edoxaban (60mg), with complete reversal of bleeding duration and endogenous thrombin potential and partial reversal of prothrombin time following 50IU/kg. Edoxaban alone and in combination with 4F-PCC was safe and well tolerated in these healthy subjects. A dose of 50 IU/kg 4F-PCC may be suitable for reversing edoxaban anticoagulation. The phase 1 study was conducted at a single site.
PARADIGM HF: new results on sudden death
New data from PARADIGM-HF, the largest-ever heart failure study showed that LCZ696 has the potential to change the course of the disease for patients with heart failure with reduced ejection fraction.
LCZ696 is an ARNI (Angiotensin Receptor Neprilysin Inhibitor) and has a unique mode of action, which is thought to reduce stress and damage on the failing heart and has been shown to cut deaths and hospitalisations by 20% compared to the gold standard ACE inhibitor, enalapril.
New analyses presented at the AHA Scientific Sessions show that LCZ696 cuts the incidence of sudden deaths, accident and emergency (A&E) visits, hospitalisations, worsening symptoms and the need for more intensive treatment in heart failure patients with reduced ejection fraction versus the ACE inhibitor enalapril.
Data presented earlier this year at the European Society of Cardiology meeting announced LCZ696 demonstrated a 20% reduction in cardiovascular deaths and a 21% reduction in heart failure hospitalisations on top of current best standard of care.
Heart failure has a poor prognosis with around 60% of patients dying within five years of diagnosis.
Professor Iain Squire, lead UK trialist for the PARADIGM-HF study, said: “LCZ696 works in a new way to the treatments that have been the mainstay of heart failure management for over two decades. LCZ696 acts to enhance the protective neurohormonal systems of the heart (Natriuretic peptide [NP] system), while also reducing the detrimental effects of the harmful Renin-Angiotensin-Aldosterone System (RAAS). This appears to slow progression of the disease, meaning fewer deaths and hospitalisations and also a better quality of life for patients.”
Analysis of the safety data from PARADIGM-HF showed that fewer patients on LCZ696 discontinued study medication for any adverse event compared to those on enalapril (10.7% versus 12.3%, respectively, p=0.03). The LCZ696 group had more hypotension although this did not lead to greater discontinuation of therapy. The LCZ696 group had less renal impairment, hyperkalaemia and cough than the enalapril group. There was no statistically significant difference in angioedema between the two groups.
PARADIGM-HF is a randomised, double-blind, phase III study that evaluated the efficacy and safety profile of LCZ696 versus enalapril (a widely studied ACE inhibitor) in 8,442 patients with heart failure with reduced ejection fraction. The baseline characteristics showed the patients enrolled were typical heart failure patients with reduced ejection fraction patients with NYHA Class II-IV heart failure. It was specifically designed to see if LCZ696 could decrease CV mortality by at least 15% versus enalapril.
Patients received LCZ696 or enalapril in addition to a current best treatment regimen. The primary endpoint was a composite of time to first occurrence of either CV death or heart failure hospitalisation, and it is the largest heart failure study ever done.
Secondary endpoints were a change in the clinical summary score for heart failure symptoms and physical limitations (as assessed by Kansas City Cardiomyopathy Questionnaire) at eight months; time to all-cause mortality; time to new onset atrial fibrillation; and time to occurrence of renal dysfunction. PARADIGM-HF was initiated in December 2009, and in March 2014, the Data Monitoring Committee (DMC) confirmed that patients given LCZ696 were significantly less likely to die from CV causes, leading to the trial being stopped early. The DMC also confirmed the primary endpoint had been met.
Trials show that alirocumab significantly reduces LDL-C
The results from six phase 3 ODYSSEY trials that showed alirocumab significantly reduced low-density lipoprotein cholesterol (LDL-C) were also presented at the AHA.
Alirocumab is an investigational fully human monoclonal antibody targeting the protein PCSK9 (proprotein convertase subtilisin/kexin type 9) that is being evaluated for its ability to lower LDL-C.
All six trials, ODYSSEY LONG TERM, COMBO I, ALTERNATIVE, OPTIONS I, OPTIONS II, and HIGH FH, met their primary efficacy endpoint of a greater reduction in LDL-C at 24 weeks, versus either active comparator or placebo, which included standard-of-care therapy.
“In these trials patients treated with alirocumab achieved significant and robust LDL-C reductions compared to baseline,” said Jennifer Robinson, Director of the Prevention Intervention Center, Professor, Departments of Epidemiology & Medicine, College of Public Health at the University of Iowa. “New interim results from ODYSSEY LONG TERM provide further support for alirocumab’s consistent safety profile, including in more than 500 patients who achieved LDL-C levels lower than 25mg/dL.”
The trials assessed alirocumab in hypercholesterolemic patients who were at high cardiovascular (CV) risk, had an inherited form of high cholesterol known as heterozygous familial hypercholesterolemia (HeFH), and/or a history of intolerance to two or more statins, including one at the lowest dose. All patients received alirocumab in addition to standard-of-care lipid-lowering therapy, with the exception of some patients in ODYSSEY ALTERNATIVE.
Patients in all six randomised, double-blind, phase 3 ODYSSEY trials received alirocumab via a single, self-administered 1-mL subcutaneous injection, every two weeks. Alirocumab-treated patients received the 150mg dose in ODYSSEY LONG TERM and HIGH FH, and the 75mg dose (increasing to 150mg if needed to reach pre-specified LDL-C levels) in ODYSSEY ALTERNATIVE, OPTIONS I, OPTIONS II, and COMBO I.
In the trials that used an individualised approach with 75mg and 150mg doses, the majority of patients reached their LDL-C goal while remaining on the 75mg dose. Average baseline LDL-C levels in all six trials were between approximately 100–120mg/dL, with the exception of ODYSSEY ALTERNATIVE and HIGH FH where baseline LDL-C levels were greater than 190mg/dL.