Integrated Biomarker and Imaging Study-2 - IBIS-2

Sep 02, 2008
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Author/Summarized by Author:
Anthony A. Bavry, MD, MPH, FACC
Summary Reviewer:
Deepak L. Bhatt, MD, MPH, MBA, FACC
Trial Sponsor:
GlaxoSmithKline
Date Presented:
01/01/2008
Date Published:
01/01/2008
Date Updated:
09/02/2008
Original Posted Date:
09/02/2008
References

Description:

Lipoprotein-associated phospholipase A2 (Lp-PLA2) is found in necrotic lipid cores and it may contribute to plaque instability. The goal of the trial was to evaluate treatment with the Lp-PLA2 inhibitor darapladib compared with placebo in patients with angiographically documented coronary artery disease.

Hypothesis:

Darapladib will be more effective at improving coronary atheroma deformability and levels of high sensitivity C-reactive protein (hs-CRP).

Study Design

  • Blinded
  • Factorial
  • Placebo Controlled
  • Randomized
  • Parallel

Patients Enrolled: 330
Mean Follow Up: 12 months
Mean Patient Age: 58 years
Female: 18

Patient Populations:

Patients at least 18 years of age undergoing catheterization for stable coronary artery disease or an acute coronary syndrome

Exclusions:

  • Anticipated surgical revascularization
  • Stroke in the last 6 months
  • Liver or renal disease
  • Uncontrolled hypertension
  • Poorly controlled diabetes
  • Congestive heart failure or left ventricular ejection fraction <30%
  • Left main artery narrowing or coronary anatomy not suitable for IVUS

Primary Endpoints:

  • Plaque deformability
  • Reduction in hs-CRP

Secondary Endpoints:

  • Necrotic core volume
  • Plaque composition
  • Plaque size
  • Plasma levels of Lp-PLA2
  • Major adverse cardiac events

Drug/Procedures Used:

Patients with angiographically documented coronary artery disease were randomized to darapladib 160 mg daily (n = 175) versus placebo (n = 155). Patients underwent intravascular ultrasound (IVUS) of a nonintervened segment at baseline and at 12 months.

Concomitant Medications:

The use of aspirin was 89%, ticlopidine or clopidogrel 80%, beta-blockers 80%, and statins 90%.

Principal Findings:

Overall, 330 patients were randomized. There was more hypertension in the darapladib group versus placebo (67% vs. 59%). Approximately 31% of participants had prior myocardial infarction, and 50% of participants had an index diagnosis of acute coronary syndrome. At 12 months of follow-up, low-density lipoprotein cholesterol was 88 mg/dl in the darapladib group versus 84 mg/dl in the placebo group. Lp-PLA2 was reduced 59% by darapladib (p < 0.001).

The first co-primary endpoint, plaque deformability, was similar between the groups at follow-up (p = 0.22). The second co-primary endpoint, hs-CRP, was also similar between the groups (p = 0.35). Patients treated with darapladib had no significant change in necrotic core volume during follow-up (-0.5 mm3, p = 0.71); however, patients treated with placebo expanded their necrotic core volume during follow-up (4.5 mm3, p = 0.009). There was no change in necrotic lipid core for darapladib versus placebo (p = 0.012). The composition of the plaque changed, so that there was no difference in the total atheroma volume between the groups (p = 0.95).

The composite of cardiovascular death, myocardial infarction, stroke, and revascularization was 17% in the darapladib group versus 19% in the placebo group. The incidence of serious adverse events that led to discontinuation of study medication was 4% for darapladib versus 7% for placebo. Patients in the darapladib group more frequently reported malodor or urine and feces (16% vs. 3%), respectively. The mean systolic blood pressure during treatment was 3.0 mm Hg higher in the darapladib group compared with placebo (p = 0.031).

Interpretation:

Among patients with angiographically documented coronary artery disease, treatment with the Lp-PLA2 inhibitor darapladib did not affect plaque deformability or levels of hs-CRP. Darapladib appeared to stabilize the necrotic lipid core by adding fibrous tissue, although there was progression of the necrotic core in the placebo group. On average, systolic blood pressure was 3 mm Hg higher during the treatment period for the darapladib group, compared with placebo. This medicine appeared to be well tolerated, with a similar incidence of discontinuation for adverse events compared with placebo. Major adverse cardiac events were similar between the groups.

This phase II exploratory study showed that darapladib might be able to stabilize necrotic lipid cores on top of good medical therapy. The increase in blood pressure during treatment will need to be carefully monitored. It is unknown how nonvalidated surrogate endpoints (i.e., plaque deformability) relate to clinical outcomes. A larger study examining validated surrogate endpoints may be warranted prior to expanding into larger phase III trials.

References:

Serruys PW, Garcia-Garcia HM, Buszman P, et al., on behalf of the Integrated Biomarker and Imaging Study-2 Investigators. Effects of the direct lipoprotein-associated phospholipase A2 inhibitor darapladib on human coronary atherosclerotic plaque. Circulation 2008;Sep 1:[Epub ahead of print].

Effects of the Direct Lipoprotein-Associated Phospholipase A2 Inhibitor Darapladib on Human Coronary Atherosclerotic Plaque. Presented by Dr. Willem Wijns at the European Society of Cardiology Congress, Munich, Germany, August/September 2008.

Keywords: Coronary Artery Disease, Stroke, Acute Coronary Syndrome, Myocardial Infarction, Plaque, Atherosclerotic, Follow-Up Studies, Benzaldehydes, Lipoproteins, LDL, Cholesterol, C-Reactive Protein, Oximes, Biomarkers, Coronary Angiography, Catheterization, Phospholipase A2 Inhibitors, Hypertension


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