Scientific Sessions 2011
Again this year, clinical trials evaluating lipoprotein-modifying
therapies are in the spotlight at the American Heart Association Scientific
Sessions 2011, with concurrent publications in The New England Journal of
The Study of Coronary Atheroma by Intravascular Ultrasound: Effect of
Rosuvastatin Versus Atorvastatin (SATURN) is a prospective, randomized,
multicenter, double blind clinical trial led by Stephen J. Nicholls, MD,
Steven E. Nissen, MD, and colleagues. These investigators performed
serial IVUS at baseline and after 104 weeks of treatment in 1,039 patients with
Patients were randomly assigned to treatment with atorvastatin (Lipitor,
Pfizer) 80 mg daily or
rosuvastatin (Crestor, AstraZeneca) 40 mg daily. The
rosuvastatin group attained lower LDL levels than the atorvastatin group (63
mg/dL vs. 70 mg/dL; P,.001) and slightly higher levels of HDL (50 mg/dL
vs. 49 mg/dL; P=.01); however, the primary efficacy endpoint —
percent atheroma volume — did not differ between the groups. Coronary
atherosclerosis regressed with both treatment strategies: by 0.99% (95% CI,
–1.19 to –0.63) with atorvastatin and by 1.2% (95% CI, –1.52 to
–0.90) with rosuvastatin. Both agents induced regression in most patients:
63% with atorvastatin and 68.5% with rosuvastatin.
In the Atherothrombosis Intervention in Metabolic Syndrome with Low HDL
Cholesterol/High Triglyceride and Impact on Global Health Outcomes (AIM-HIGH) trial, 3,414 patients with established CVD were
randomly assigned to extended-release niacin 1,500 mg to 2,000 mg daily or
matching placebo with 50 mg of niacin per tablet to mask treatment identity.
Both groups received simvastatin (Zocor, Merck) 40 mg to 80 mg and ezetimibe
(Vytorin, Merck/Schering-Plough) 10 mg daily, as needed, to maintain LDL levels
between 40 mg/dL and 80 mg/dL.
The trial was stopped for a lack of efficacy after an average follow-up
of 3 years. Despite an improvement in the lipid profile, including a
significant increase in median HDL from 35 mg/dL to 42 mg/dL, there was no
difference between the groups in the incidence of the primary composite
endpoint of CHD death, nonfatal MI, ischemic stroke, hospitalization for an
acute coronary syndrome or symptom-driven coronary or cerebral
It was clearly a challenge to end the AIM-HIGH trial after a mean
follow-up of 3 years. The rise in strokes may have been a chance finding
because many of the participants assigned niacin who sustained a stroke had
stopped their niacin a number of months before. The Coronary Drug Project did
not find an excess rate of stroke with niacin but did report an excess
incidence of atrial fibrillation, a major risk factor for stroke. The rate of
AF was not reported in the AIM-HIGH participants by treatment group. The other
point to consider is that the event curves in the Cholesterol and Recurrent
Events (CURE) study did not separate until after 2 years; this trial compared
pravastatin (Pravachol, Teva Pharmaceuticals) vs. placebo. The 3-year follow-up
may not have been long enough in AIM-HIGH because the trial mandated equal LDL
levels that were accomplished by a greater use of ezetimibe in those not
receiving niacin. Only HDL and triglyceride levels differed between treatment
Trials viewed in tandem
SATURN and AIM-HIGH address opposite sides of the coin in some respects
— SATURN aimed low with potent statin therapy, whereas AIM-HIGH did as its
name implies with add-on niacin. The primary endpoint of SATURN was
imaging-based and the primary endpoint of AIM-HIGH was clinical outcomes.
However, at the core, both trials assessed two competing lipoprotein management
strategies for patients with atherosclerotic vascular disease, with modest
differential results on patients’ lipid profiles, and found neutral
effects on the primary endpoints.
Some may be surprised, and others may not. Either way, as both camps
reconvene back down on planet Earth, two key questions are:
- How do we reconcile these studies with existing literature?
- What is the bottom line when it comes to managing our patients?
Reconciling data with existing literature
Reconciling these studies may have a lot to do with endpoints. Painting
with broad strokes, there is a ladder of endpoints, starting with hard clinical
points, running down to soft clinical endpoints, to imaging endpoints, on down
to biomarker endpoints. Ultimately, we want to be confident that if we see a
change in an endpoint in response to a therapy, then this means we are
benefiting patients. As it turns out, this is easier said than done. SATURN and
AIM-HIGH raise important questions about surrogate imaging endpoints because
SATURN employs one and AIM-HIGH was immediately preceded by a positive trial
based on one: Arterial Biology for the Investigation of the Treatment Effects
of Reducing Cholesterol 6-HDL and LDL Treatment Strategies (ARBITER-6-HALTS).
Regarding SATURN, as pioneered by Drs. Nicholls and Nissen, and accepted
by the expert community, IVUS quantifies plaque burden by percent atheroma
volume, subtracting lumen area from the total area within the external elastic
membrane divided by the total area. If different calculations are used, as in
the secondary endpoint of SATURN, then a signal is seen for rosuvastatin
trumping atorvastatin in atherosclerosis regression, but the clinical
significance is unclear. Also unclear is the fact that the Reversal of
Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial failed to show
plaque regression with high-dose atorvastatin, whereas SATURN showed such an
Moreover, from the perspective of the individual patient, we are left
with the question: Why do some patients regress on potent statin therapy,
whereas others only stabilize and others even progress? Also, how much does
atherosclerosis regression actually have to do with increases in HDL (15% in
ASTEROID and 4% in SATURN)? This was highlighted as a possible mechanism in the
publication of the A Study to Evaluate the Effect of Rosuvastatin on
Intravascular Ultrasound-Derived Coronary Atheroma Burden (ASTEROID) trial, but
why was the same magnitude of HDL increase not seen in SATURN?
The limitations of IVUS in assessment of atherosclerosis progression
were discussed by Navin Kapur, MD, and Roger Blumenthal, MD, in
an editorial on the ASTEROID in the Journal of the American Medical
Association in April 2006. Indeed, we simply do not know how reliably an
IVUS measurement or serial IVUS measurements track with clinical outcomes.
The same can be said for serial carotid intima-media thickness data.
ARBITER-6-HALTS showed a 0.014-mm improvement in carotid
intima-media thickness with niacin, this did not translate into a clinical
outcomes benefit during a 3-year period in AIM-HIGH. This is a disappointing
result, but there were a number of reasons for tempered enthusiasm after
ARBITER-6-HALTS, including its premature termination and the small number of
patients studied, as laid out in an editorial by Erin Michos, MD,
and Blumenthal accompanying publication of the original manuscript in
NEJM. The discordance between ARBITER-6-HALTS and AIM-HIGH implies
that we should not be relying on serial carotid intima-media thickness testing
to determine the best therapies.
Rather, we should rely on clinical outcomes data. Although AIM-HIGH did
not show benefit, this does not mean that the HDL hypothesis is dead. Indeed,
several clinical trials of novel agents that raise HDL are undergoing
investigation. AIM-HIGH also does not mean that niacin itself should dig an
It remains to be seen whether a modest incremental benefit can be
detected in the much larger ongoing niacin trial, Treatment of HDL to Reduce
the Incidence of Vascular Events (HPS-2-THRIVE), with results expected in 2013.
Although a clinical outcomes trial, it is notable that AIM-HIGH patients were
not the highest risk, and events were less than expected, so the original
primary composite endpoint was amended to include hospitalization for an ACS
(softened from “high-risk ACS”) or symptom-driven coronary or
cerebral revascularization, which ended up accounting for most of the primary
endpoints in the trial.
In some respects, the inclusiveness of the composite endpoint is a good
thing because doctors, patients and payers care about hospitalizations and
revascularizations; however, in other respects, it is a bad thing because it is
a “softer” or less reliable endpoint because more subjectivity enters
It is not unrealistic to think that HPS-2-THRIVE could show a benefit.
Even if it does, we must point out that it does not necessarily follow that the
benefit is from HDL raising. Although niacin is associated with increased HDL
concentrations, this does not tell us about reverse cholesterol transport and
Niacin also lowers LDL or, perhaps more importantly, atherogenic
lipoprotein particles. Through the particle lens, a clinical effect of niacin
may be more clearly understood because the impact on atherogenic particles is
modest, so a very large trial may be needed to detect an effect, especially in
patients who are already aggressively treated.
The bottom line
At the end of the day, in our humble opinion, the message boils down to
the same message that was loud and clear before these studies: In managing
high-risk patients with atherosclerotic vascular disease, the primary emphasis
should be on atherogenic lipoprotein-lowering through appropriately potent
statin therapy. We predict that atorvastatin will continue to be the dominant
statin given physicians’ and patients’ comfort with it, its
compatibility with calcium channel blockers and because it approaches
rosuvastatin in potency. Cost is a huge issue for patients and the health care
system, especially today, and is tied to adherence, so the transition of
atorvastatin to generic form will be another factor that makes this medication
the dominant one in the statin market for many years to come.
As for niacin, for the time being, although it did not show a benefit as
an add-on therapy in patients with low LDL in AIM-HIGH, it is still a
reasonable agent for lipoprotein-lowering in patients who cannot tolerate a
statin and as an add-on agent for patients above treatment targets despite
maximally tolerated statin therapy.
Seth S. Martin, MD, is a cardiology fellow at The Johns
Hopkins Ciccarone Center for the Prevention of Heart Disease. Roger S.
Blumenthal, MD, is professor of medicine and director of The Johns Hopkins
Ciccarone Center for the Prevention of Heart Disease.
Disclosure: Drs. Martin and Blumenthal report no relevant
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