Darapladib falls short in chronic coronary heart disease

March 31, 2014

The novel inflammation inhibitor darapladib showed no primary-endpoint advantage over placebo in patients with chronic coronary heart disease treated with a high level of background care, although it did suggest possible benefits for more specific coronary artery-related endpoints, according to research presented at the American College of Cardiology's 63rd Annual Scientific Session. STABILITY is the first study to test this inflammation-prevention mechanism for reducing the likelihood that plaque will become an artery-blocking clot.

Darapladib strongly inhibits Lp-PLA2, a biomarker of inflammation in blood vessels. In the bloodstream, Lp-PLA2 is generally found on LDL cholesterol. High Lp-PLA2 levels are a risk factor for coronary heart disease and, in animal models, are linked with vulnerable plaque, an unstable waxy buildup in arterial walls that is associated with heart attacks and strokes.

In this international, phase III double-blind trial, 15,828 patients with chronic coronary (median age 65 years) were randomly assigned to receive a 160-mg darapladib tablet or placebo once daily. No major safety concerns arose; median follow-up was 3.7 years. The primary endpoint of time to first heart attack, stroke and death from cardiovascular causes was not met. Darapladib showed no significant benefit, with 769 events (9.7 percent) compared with 819 events (10.4 percent) for placebo. However, a secondary endpoint looking at a reduction in major related to the arteries (heart attack, urgent need for angioplasty or bypass surgery, or death) was nominally significant. The darapladib group had a 10 percent relative risk reduction, with 737 events (9.3 percent) in major coronary events compared with 814 events (10.3 percent) in the placebo group.

"These events are clinically important, with substantial consequences for patients," said Harvey D. White, M.D., director of Coronary Care Unit, Green Lane Cardiovascular Unit, Auckland City Hospital, New Zealand, and a co-chair of the study. "The effects on these endpoints could support the hypothesis that inhibition of Lp-PLA2 with darapladib may alter the composition of atherosclerotic plaques to a less vulnerable state and reduce ischemic events related to plaque progression and rupture."

Researchers were surprised to see the high rate of background care in this patient population. At baseline, 93 percent of patients were taking aspirin, 97 percent statins, 79 percent beta-blockers and 77 percent ACE inhibitors or angiotensin receptor blockers, compared with similar rates at the end of the study. "We set out to test the incremental effect of darapladib on top of optimal treatment," White said.

One intriguing finding emerged from subgroup analyses: smokers had a greater decrease in major adverse cardiovascular events than non-smokers.

"Previous studies showed that smokers have higher Lp-PLA2 levels, and it's plausible that smokers may be more responsive to Lp-PLA2 inhibition, but this finding may have occurred by chance and should be considered hypothesis generating," White said.

Ongoing analysis of biomarkers, including Lp-PLA2 levels, and genetic sub-studies of STABILITY may help provide insight about darapladib's potential effects on the prevention of coronary events in patients with stable . "As with statins, it may take some time for the anti-inflammatory effect of darapladib to alter the composition of coronary artery plaque, resulting in less vulnerability and fewer coronary events," White said. The modest effect of darapladib on coronary artery-related events seen in this study may heighten interest in SOLID-TIMI 52, a phase III study of darapladib in patients with recent experience of acute coronary disease.

Explore further: More severe heart disease found in patients with vitamin D deficiency

More information: This study will be simultaneously published online in the New England Journal of Medicine at the time of presentation.

Related Stories

More severe heart disease found in patients with vitamin D deficiency

March 27, 2014
Vitamin D deficiency is an independent risk factor for heart disease with lower levels of vitamin D being associated with a higher presence and severity of coronary artery disease, according to research to be presented at ...

Celiac disease linked to increased risk of coronary artery disease

March 29, 2014
People with celiac disease may have a near two-fold increased risk of coronary artery disease compared with the general population, according to research to be presented at the American College of Cardiology's 63rd Annual ...

GlaxoSmithKline drug fails in late-stage study (Update)

November 12, 2013
A potential GlaxoSmithKline heart disease treatment acquired in a key company takeover fell short in a big, late-stage study.

Prognostic value of lipoprotein (a) with low cholesterol unclear

November 22, 2013
(HealthDay)—Lipoprotein (a) (Lp[a]) has utility in assessing cardiovascular risk in patients with coronary artery disease (CAD); however, the prognostic value of Lp(a) in patients with low cholesterol levels remains unclear, ...

Recommended for you

Could aggressive blood pressure treatments lead to kidney damage?

July 18, 2017
Aggressive combination treatments for high blood pressure that are intended to protect the kidneys may actually be damaging the organs, new research from the University of Virginia School of Medicine suggests.

Quantifying effectiveness of treatment for irregular heartbeat

July 17, 2017
In a small proof-of-concept study, researchers at Johns Hopkins report a complex mathematical method to measure electrical communications within the heart can successfully predict the effectiveness of catheter ablation, the ...

Concerns over side effects of statins stopping stroke survivors taking medication

July 17, 2017
Negative media coverage of the side effects associated with taking statins, and patients' own experiences of taking the drugs, are among the reasons cited by stroke survivors and their carers for stopping taking potentially ...

Study discovers anticoagulant drugs are being prescribed against safety advice

July 17, 2017
A study by researchers at the University of Birmingham has shown that GPs are prescribing anticoagulants to patients with an irregular heartbeat against official safety advice.

Protein may protect against heart attack

July 14, 2017
DDK3 could be used as a new therapy to stop the build-up of fatty material inside the arteries

Heart study finds faulty link between biomarkers and clinical outcomes

July 14, 2017
Surrogate endpoints (biomarkers), which are routinely used in clinical research to test new drugs, should not be trusted as the ultimate measure to approve new health interventions in cardiovascular medicine, according to ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.