Mixed results for Lp-PLA2 inhibitor as a hoped-for stabilizer of coronary plaques

September 02, 2008

Munich, Germany - Intravascular ultrasound (IVUS) of coronary lesions after a year of treatment with an agent that suppresses lipoprotein-associated phospholipase A2 (Lp-PLA2), an enzyme with proatherogenic properties found in the bloodstream and abundantly in lipid-rich atheroma, failed in a small randomized study to show that the drug can improve indirect, novel measures of plaque stability[1,2] Other IVUS readings, representing secondary end points in the study, which was conducted in patients with ACS or other symptomatic coronary disease, suggested the drug may stem expansion of the necrotic core of plaques.

Dr Patrick W Serruys

The latter finding offers some hope, at least, that the investigational drug, darapladib (GlaxoSmithKline), may have a potential role in the treatment of coronary disease, according to researchers from the second Integrated Biomarkers and Imaging Study (IBIS-2). They reported their results here at the European Society of Cardiology Congress 2008 and in a Circulation article published online the same day.

"This study demonstrated that necrotic-core expansion occurs despite contemporary cardiovascular therapies, even in the absence of overall plaque size increase," according to the authors, led by IBIS-2 steering committee chair Dr Patrick W Serruys (Erasmus University Medical Center, Rotterdam, the Netherlands). "This unabated necrotic-core expansion could be responsible, in part, for the recurrent cardiovascular events in high-risk patients. Lp-PLA2 inhibition with darapladib halted this process and therefore may represent a new approach for the treatment of atherosclerosis if the benefit of this intervention is confirmed by the results of future event-driven outcomes trials."

After the presentation of IBIS-2 in Munich by coauthor Dr William Wijns (OLV Hospital Aalst, Belgium), the featured discussant, Dr Filippo Crea (Catholic University of Sacred Heart, Rome, Italy), lauded the trial for its tight randomized, placebo-controlled, double-blind design but also had criticisms, partly about its IVUS-oriented "nonvalidated surrogate end points . . . rather than validated surrogate end points, such as carotid intima-media thickness, flow-mediated dilation, or coronary plaque volume, [which are] known to be correlated with clinical end points."

Dr Filippo Crea

Of the study's 155 patients randomized to placebo and 175 assigned to receive darapladib 160 mg/day for 12 months, 130 and 152 patients, respectively, completed the year of therapy; 11 placebo patients and seven of those on active therapy withdrew due to adverse effects. All patients had been referred for angiography. The two groups were similar with respect to Lp-PLA2 activity, treatment with statins and other drugs commonly used in coronary disease, LDL and total cholesterol, and history of CV disease.

IVUS was performed and yielded evaluable images at baseline and at the 12-month follow-up in 121 controls and 146 patients in the darapladib group.

After one year, the two groups showed similar changes (p=0.22) in "density of high strain per 10 mm," an IVUS measure of atheroma deformability observed along a target-vessel segment; the authors called the technique "IVUS-based palpography."

Levels of high-sensitivity C-reactive protein (hs-CRP) declined in both groups and showed no significant difference at the end of the year (p=0.22). Actively treated patients, as expected, showed significant Lp-PLA2 inhibition over 12 months compared to the placebo group (p<0.001).

The IVUS-palpography and hs-CRP changes represented the study's co-primary end points.

Secondary end points went both ways. There was no significant 12-month difference between the groups in change in total atheroma volume as measured by conventional IVUS imaging. On the other hand, IVUS radiofrequency (RF) analysis, which the group termed "virtual histology," showed significant target-lesion progression in the placebo group, as indicated by expanded volume of the target-plaque necrotic core. Darapladib-treated patients showed no such significant change, suggesting that the drug halted lesion progression by at least that IVUS measure.

Mean changes in necrotic core parameters from baseline to 12 months by IVUS in IBIS-2 imaging cohort subset

Parameter Placebo, n=110 Darapladib, n=129 p
Change in necrotic core volume (mm3) +4.5a -0.5 0.012
Change in necrotic core volume as proportion of total plaque (absolute percentage points) +2.5b +0.5 0.047
a. p=0.009 for change in placebo group b. p=0.006 for change in placebo group

IVUS-RF also showed that expansion in necrotic core in controls compared with actively treated patients was accompanied reciprocal decreases in plaque fibrous tissue, according to the authors. "These findings suggest that in the placebo group a larger amount of fibrous tissue was converted into necrotic core, whereas in the darapladib group this process was significantly attenuated."

The current study wasn't powered for clinical outcomes; no darapladib effect on platelet activity was seen, and there was no suggestion of a difference between the groups in thrombotic complications, according to Serruys et al.

The most common adverse event was a blood-pressure increase into the hypertensive range, which, like most other adverse events, occurred at comparable rates. Malodor, primarily from feces or urine, was reported by 3% of controls but 16% of patients on darapladib, according to the group, which also notes that it wasn't a noteworthy cause of patient withdrawal.

Referring to the parameters that the drug did seem to influence, Wijns said to heart wire that "these positive results using sophisticated intermediate end points actually give a lot of support for launching the outcome-driven trial. So if that trial proves to be positive, then one would look at subsets that would benefit the most." Subgroup analyses in IBIS-2 had suggested, though not very strongly, that the drug might work better in diabetics and younger patients, for example.

Dr William Wijns

To heartwire , Serruys speculated that the drug may not have had as much effect in older patients because their lesions were less likely to contain large lipid-rich necrotic cores. "You can imagine that the elderly's necrotic core has probably evolved to dense calcium, so that might be a reason." Theoretically, he said, the drug could prove especially useful in younger patients or those with earlier-stage disease.

In his critique of the trial, Crea pointed to "the lack of internal coherence of findings obtained using different imaging techniques. The authors do not explain why the reduction of necrotic core at virtual histology observed in patients randomized to darapladib did not translate into improvement of plaque deformability at palpography, thus casting some shadows on the clinical interpretation of the study."

In the current trial, "darapladib failed to affect the two primary end points of the trial," Crea observed. "So I think in this regard, I'd like to disagree with William Wijns, that, in spite of the important contribution made by this seminal study, further studies using validated surrogate end points are needed before considering large trials with clinical end points."

The study was funded by GlaxoSmithKline.Several of the coauthors are GlaxoSmithKline employees or work and own equity interest in Volcano Therapeutics, which makes the IVUS sys tems that were exclusively used.The remaining coauthors, including Serruys and Wijns, "report no conflicts."


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