Vascular Inflammation Suppression to Treat Acute Coronary Syndrome for 16 Weeks - VISTA-16

Description:

Varespladib methyl is a novel nonspecific pan-secretory phospholipase A2 (sPLA2) inhibitor with favorable effects on atherosclerotic lesions in animal studies. It is considered to be a potent anti-inflammatory agent by interfering with arachidonic acid metabolism. The current trial sought to study the safety and efficacy of varespladib in patients with recent acute coronary syndrome (ACS) who were on atorvastatin.

Hypothesis:

Varespladib would be superior to placebo in reducing adverse cardiovascular events in patients presenting with ACS who also received atorvastatin.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • Men and women ≥40 years of age
  • A diagnosis of unstable angina, NSTEMI, or STEMI
  • All subjects must have the presence of at least one of the following risk factors:
    - Diabetes mellitus, or
  • Presence of any three of the following characteristics of metabolic syndrome:
    - Waist circumference >102 cm in males, >88 cm in females
    - Serum triglycerides ≥150 mg/dl
    - HDL-C <40 mg/dl in males, <50 mg/dl in females
    - Blood pressure ≥130/85 mm Hg
    - Plasma glucose ≥110 mg/dl
  • History of cerebrovascular disease (stroke or transient ischemic attack)
  • History of peripheral vascular disease
  • Previous coronary artery bypass grafting
  • Previous documented MI
  • Previous coronary revascularization
  • Subjects must be randomized within ≤96 hours of hospital admission for the index event, or if already hospitalized, within ≤96 hours of index event diagnosis
  • Revascularization, if required or planned, must occur prior to randomization

    Number of screened applicants: 5,391
    Number of enrollees: 5,145
    Duration of follow-up: 16 weeks
    Mean patient age: 61 years
    Percentage female: 26%

Exclusions:

  • Subjects enrolled in another experimental (interventional) protocol within the past 30 days prior to screening
  • Subjects treated for cancer within the previous 5 years except for skin basal cell carcinoma or carcinoma in situ of the cervix, with measures other than a minor, complete surgical excision, or radiation therapy (e.g., chemotherapy)
  • The presence of any severe liver disease with cirrhosis, active hepatitis, active chronic hepatitis, alanine aminotransferase or aspartate aminotransferase >3 x ULN, biliary obstruction with hyperbilirubinemia (total bilirubin >2 x ULN)
  • Active cholecystitis, gall bladder symptoms, or any hepatobiliary abnormalities
  • The presence of severe renal impairment (creatinine clearance <30 ml/min or creatinine >3 x ULN), nephrotic syndrome, or subjects undergoing dialysis
  • Uncontrolled diabetes mellitus (known glycated hemoglobin >11% within the last 1 month prior to screening)
  • Females who are nursing, pregnant, or intend to become pregnant during the time of the study, or females of childbearing potential who have a positive pregnancy test during screening evaluation (women of child-bearing potential must also use a reliable method of birth control during the study and for 1 month following completion of therapy)
  • Subjects who have a history of alcohol or drug abuse within 1 year of study entry
  • Subjects living too far from participating center or unable to return for follow-up visits
  • Subjects who in the opinion of the investigator are a poor medical or psychiatric risk for therapy with an investigational drug, are unreliable, or have an incomplete understanding of the study, which may affect their ability to take drugs as prescribed or comply with instructions
  • Known human immunodeficiency virus, hepatitis B virus, hepatitis C virus, or tuberculosis infection
    Acute bacterial, fungal, or viral infection
  • Subjects currently taking drugs who are potent inhibitors of cytochrome P450 unless they can be withdrawn
  • Subjects with New York Heart Association class III or IV heart failure, or if known, left ventricular ejection fraction <30
  • Subjects with moderate or severe aortic stenosis, aortic regurgitation, mitral stenosis, or mitral regurgitation
  • Ventricular arrhythmias requiring chronic drug treatment or implantable cardioverter-defibrillator
    Subjects with no stenosis or stenosis <50% on angiography, if known
  • Subjects with a pacemaker or persistent left bundle branch block
  • Fasting triglyceride levels of ≥400 mg/dl (4.5 mmol/L)
  • Subjects who have a history of statin intolerance or a significant myopathy or rhabdomyolysis with any lipid-altering drugs
  • Subjects currently treated with the maximum labeled dose of a statin and not at LDL-C target for their level of risk, as defined by the National Cholesterol Education Program Adult Treatment Program III

Primary Endpoints:

  • Composite of cardiovascular death/myocardial infarction (MI)/stroke/unstable angina requiring hospitalization at 16 weeks

Secondary Endpoints:

  • Composite of cardiovascular mortality, nonfatal MI, and nonfatal stroke
  • Individual components of the primary outcome
  • Total mortality
  • Changes in circulating lipid and inflammatory markers

Drug/Procedures Used:

Patients were randomized within 96 hours of presentation of the index event in a 1:1 ratio to treatment with varespladib (500 mg/d) or matching placebo, stratified by use of any lipid-modifying therapy before the index event and the type of qualifying index event (ST-elevation MI [STEMI], non–STEMI, or unstable angina. The protocol specified that enrolled patients be treated with individualized, evidence-based management of ACS, including diet and atorvastatin at a dose of at least 20 mg (median dose 40 mg).

Concomitant Medications:

At randomization: aspirin (91.5%), thienopyridine (76%), and beta-blockers (83%)

Principal Findings:

The trial was terminated early due to futility. A total of 5,145 patients were randomized, 2,572 to varespladib and 2,573 to placebo. Baseline characteristics were fairly similar between the two arms. Approximately 33% were current smokers, 64% had metabolic syndrome, 31% had diabetes, and 18% had undergone prior percutaneous coronary intervention. The index diagnosis was STEMI in 47% and NSTEMI in 38%. A total of 81% underwent revascularization during the index event. The mean baseline low-density lipoprotein cholesterol (LDL-C) was 105 mg/dl and high-density lipoprotein cholesterol (HDL-C) 43 mg/dl.

Between randomization and week 16 of the study, LDL-C decreased by 28.8% in the varespladib group and 25.1% in the placebo group (p = 0.008). At week 16, the mean LDL-C was significantly lower in the varespladib arm (69.l vs. 73.8 mg/dl). No significant differences were noted in HDL-C and triglycerides.

The primary outcome of cardiovascular mortality, nonfatal MI, nonfatal stroke, or unstable angina requiring hospitalization was similar between the varespladib and placebo arms (6.1% vs. 5.1%; hazard ratio [HR], 1.25; 95% confidence interval [CI], 0.97-1.61; p = 0.08). The composite secondary outcome of cardiovascular mortality, MI, and stroke was higher in the varespladib arm (4.6% vs. 3.8%, HR, 1.36; 95% CI, 1.02-1.82; p = 0.04). This was due primarily to a greater incidence of MI in the varespladib arm (3.4% vs. 2.2%; p = 0.005). Other outcomes including cardiovascular mortality (1.5% vs. 1.4%, p = 0.54), stroke (0.4% vs. 0.6%, p = 0.81), and unstable angina (1.9% vs. 1.4%, p = 0.47) were similar between the two arms. All-cause mortality at 6 months (n = 1,588) was similar (2.7% vs. 2.0%, p = 0.15). ALT elevation x 3 upper limit of normal (ULN) was higher in the varespladib arm (38 vs. 6 patients).

Interpretation:

The results of the VISTA-16 trial indicate that nonselective inhibition of sPLA2 with varespladib was not associated with improved cardiovascular outcomes at 16 weeks in patients with recent ACS as compared with placebo. There was also an excess of MIs in the varespladib arm during follow-up. These findings are important since the higher MI risk was noted despite a significant reduction in LDL and C-reactive protein with varespladib as compared with placebo. This again highlights the importance of randomized controlled trials focused on clinical endpoints rather than on surrogate endpoints such as LDL reduction. The exact reason for the higher MI risk with varespladib is unclear, but may be due to its nonselective inhibition of all sPLA2 isoforms (group X for example, is anti-atherogenic). Trials with agents that inhibit lipoprotein-associated PLA2 are ongoing.

References:

Nicholls SJ, Kastelein JJ, Schwartz GG, et al., on behalf of the VISTA-16 Investigators. Varespladib and Cardiovascular Events in Patients With an Acute Coronary Syndrome: The VISTA-16 Randomized Clinical Trial. JAMA 2014;311:252-62.

Presented by Dr. Steve Nicholls at the American Heart Association Scientific Sessions, Dallas, TX, November 18, 2013.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Diabetes and Cardiometabolic Disease, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), ACS and Cardiac Biomarkers, Aortic Surgery, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Triglycerides, Interventions and ACS, Interventions and Vascular Medicine, Diet

Keywords: Phospholipases A2, Secretory, Follow-Up Studies, Ischemic Attack, Transient, Blood Pressure, Risk Factors, Glucose, Waist Circumference, Biological Markers, Cholesterol, HDL, Confidence Intervals, Acute Coronary Syndrome, Stroke, Cholesterol, LDL, Protein Isoforms, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Heptanoic Acids, Peripheral Vascular Diseases, Percutaneous Coronary Intervention, Metabolic Syndrome X, Pyrroles, C-Reactive Protein, Indoles, Medical Futility, Phospholipases A, Diet, Triglycerides, Coronary Artery Bypass, Diabetes Mellitus


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