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Macrovascular Residual Risk THROUGH LANDMARK STUDY

8 October 2013
ESC 2013 Hotline: ASSURE fails to reassure about HDL

In the ASSURE (ApoA-I Synthesis Stimulation and Intravascular Ultrasound for Coronary Atheroma Regression Evaluation) trial, treatment with RVX-208, a first-in-class agent that induces apolipoprotein A-I (apoA-I), a precursor to high-density lipoprotein (HDL), did not meet its primary endpoint in high-risk patients with low plasma levels of HDL cholesterol (HDL-C).

Nicholls SJ, Ballantyne CM, Barter PJ, Brewer B, Kastelein JJP, Gordon A, Johansson J, Wong N, Puri R, Borgman M, Wolski K, Nissen S: ASSURE: Effect of an oral agent inducing apo A-I synthesis on progression of coronary atherosclerosis: Results of the ASSURE Study [abstract 708] [].
Slides available at:]
Comments & References
Objective: RVX-208 is a novel agent which upregulates apoA-I production via an epigenetic mechanism, leading to increased formation of prebeta-HDL, the key functional particle for cellular cholesterol efflux. The aim of ASSURE was to investigate the effect of treatment with RVX-208 on atherosclerosis progression in statin-treated patients with angiographic evidence of coronary artery disease (CAD).
Study design: Phase IIb randomized, placebo-controlled imaging trial
Study population: 323 patients with symptomatic CAD (>20% and <50% stenosis in target blood vessel) and low plasma HDL-C concentration (
Primary variable:

• -0.6% change in percent atheroma volume (PAV) from baseline to follow-up 26-weeks later, as determined by intravascular ultrasound (IVUS).
• Secondary variables included the change in total atheroma volume in the target segment


All patients received treatment with either atorvastatin (10-40 mg daily) or rosuvastatin (5-20 mg daily) during the study. Eligible patients completed a 4-week screening period before randomization to oral 100 mg RVX-208 (n=243) or placebo (n=80) twice daily for 26 weeks. IVUS was performed at baseline (start of screening period) and the end of the 26-week randomization period.

Main results:

At the end of the study, both groups showed similar increases in plasma HDL cholesterol concentration (10.9% in the RVX-208 group versus 7.7% in the placebo group, p=0.32) and apoA-I (12.8% versus 10.6%, respectively). Reductions in low-density lipoprotein cholesterol (LDL-C) at the end of the study were also similar in each group (-16.0% versus -17.6%, p=0.56). There was a trend to regression in the primary end point (PAV) at 26 weeks, although this was not statistically significant. There was no significant difference between the groups in the change in total atheroma volume at 26 weeks. There were more discontinuations due to adverse events in the RVX-208 group (3.7% vs. 2.5%). RVX-208 was associated with serum transaminase elevations (>3 x upper limit of normal [ULN]), as previously reported (Table 1).(1) All transaminase elevations occurred within the first 2 months of treatment and resolved spontaneously when the drug was discontinued.

Table 1. Median change from baseline in atheroma measures after 26 weeks treatment with RVX-208 or placebo

End point



Between group

PAV (%)




Total atheroma volume (mm3)








Cardiovascular events








AST/AL elevations
> 3 X ULN





Authors’ conclusion: Although ASSURE failed to achieve its primary endpoint, there was a trend to regression with RVX-208 (in combination with statin). The magnitude of benefit observed in the placebo group and short duration of treatment may be contributory factors to the non-significant benefit with RVX-208.


The ASSURE trial was designed to test whether treatment with RVX-208, which induces the synthesis of apoA-I, the lipid-poor precursor of HDL, translates to atherosclerosis regression. However, it must be acknowledged that the short duration of treatment was a limitation of the trial. Indeed, it should be borne in mind that in the previous SATURN (Study of Coronary Atheroma by InTravascular Ultrasound: Effect of Rosuvastatin versus Atorvastatin) study, the largest IVUS study to date, the duration of follow-up was 2 years.(2)

Moreover, it is highly relevant in the context of strategies for managing residual cardiovascular risk that definitive trials have so far failed to show the benefit of HDL-C raising on hard clinical endpoints in patients with well controlled LDL-C levels. There are also continuing questions regarding the relevance of low plasma HDL-C concentration per se as unconditional CV risk factor and therapeutic target. Indeed, data from the LURIC (Ludwigshafen Risk and Cardiovascular Health) study show that HDL-C plasma concentration is not an appropriate biomarker for cardiovascular risk in the secondary prevention setting.(3) This may relate to emerging reports suggesting that HDL becomes ‘dysfunctional’ in the inflammatory setting of CAD, arising from changes in the lipids and proteins of HDL.(4,5)
However, such compositional changes would not be revealed by measurement of HDL cholesterol concentration. Debate continues as to whether HDL functionality is a more appropriate biomarker, supported by ‘proof of concept’ studies.6 However, measures of HDL functionality still remain within the realm of research and require validation before they can be adapted to the routine clinical practice setting.


1. Nicholls SJ, Gordon A, Johannson J et al. ApoA-I induction as a potential cardioprotective strategy: rationale for the SUSTAIN and ASSURE studies. Cardiovasc Drugs Ther 2012;26:181-7.
2. Nicholls SJ, Ballantyne CM, Barter PJ et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011;365: 2078-87.
3. Silbernagel G, Schöttker B, Appelbaum S et al. High-density lipoprotein cholesterol, coronary artery disease, and cardiovascular mortality. Eur Heart J 2013;Epub ahead of print 7 September 2013.
4. Riwanto M, Rohrer L, Roschitzki B et al. Altered activation of endothelial anti- and pro-apoptotic pathways by high-density lipoprotein from patients with coronary artery disease: Role of HDL-proteome remodeling. Circulation 2013;127:891-904.
5. Alwaili K, Bailey D, Awan Z et al. The HDL proteome in acute coronary syndromes shifts to an inflammatory profile. Biochim Biophys Acta 2012;1821:405-15.
6. Khera AV, Cuchel M, de la Llera-Moya M et al. Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 2011;364:127-35.

Key words

HDL cholesterol, apolipoprotein A-I, imaging, atherosclerosis regression