STRAIGHT TALK
STEVEN E. NISSEN, MD, MACC
ACC 2016: Interpreting the
Prevention Trials
T
he 2016 Annual Scientific Sessions of the
American College of Cardiology provided an
unusually impactful series of insights into
the treatment of hyperlipidemia and hypertension.
The long awaited HOPE-3 trial was finally reported,
accompanied by an unprecedented three manuscripts in the New England Journal of Medicine. (1-3)
The trial randomized 12,705 “intermediate risk”
individuals to either low-dose rosuvastatin (10 mg
daily), the combination of candesartan 16 mg plus
hydrochlorothiazide 12.5 mg, or both therapies for a
median follow-up of 5.6 years. The stated goal of the
trial was to provide a “proof of concept” validation of
the “polypill”, an often advocated approach to cardiovascular (CV) prevention that combines lose doses
of several therapies into a single low-cost multi-drug
combination product intended for administration
to patients at high risk of CV morbidity/mortality.
Some of the most ardent advocates of the polypill
have suggested adopting this approach on a population-wide basis without customization to individual
patient risk profiles.
The results of HOPE-3 clearly demonstrate the
irrationality of the polypill concept. Although the
rosuvastatin treatment group showed a statistically
robust benefit (an approximately 25% reduction in
death, stroke, and myocardial infarction), the blood
pressure (BP) lowering arm yielded unimpressive
results, a non-significant 7% reduction in the primary
endpoint, p = 0.40. The authors emphasized the
significant benefits in the patients within the upper
tertile of BP (>143.5 mm Hg systolic), but didn’t
emphasize the potential harm in patients within the
lower tertile (≤131.5 mm Hg). Although the results
for the lowest BP tertile didn’t reach statistical
significance because of the limited statistical power,
the hazard ratio (HR) for the broadest coprimary
endpoint was 1.25, compared with 0.76 for the highest BP tertile. These data show that overly aggressive
BP lowering in these patients is likely harmful rather
than helpful. Accordingly, administering polypill
therapy to a broad swath of the population would
likely yield both benefits and hazards, depending on
the patient’s risk profile. HOPE-3 reveals what most
clinicians already know, individualization of treatment is best, rather than “one size fits all.”
Two other clinical trials generated important
58 CardioSource WorldNews
insights. We presented the GAUSS-3 Trial, simultaneously published in JAMA, that addressed the challenging clinical problem of statin intolerance due to
muscle-related adverse effects. (4) The trial design
was unusual, enrolling 511 patients with a strong
history of intolerable muscle symptoms when
administered multiple statins (82% failed 3 or more
statins). These patients were initially randomized to
atorvastatin or placebo for 10 weeks and asked to
report whether they experienced intolerable muscle
symptoms. Then, after a 2-week washout, patients
crossed over to the alternative treatment group so
that each patient had 10 weeks of statin and 10
weeks of placebo. Only patients with symptoms of
atorvastatin, but not placebo, entered the second
phase of the trial. During the blinded atorvastatin
rechallenge, 42.6% of patients had intolerable
muscle symptoms on the statin, but not placebo,
while 26.5% had symptoms on placebo, but not
atorvastatin.
These findings provide two key insights. First,
muscle-related statin intolerance is a real phenomenon affecting a substantial fraction of patients.
Second, there is a strong psychosomatic component of statin intolerance with about a quarter of
patients having symptoms on placebo, a phenomenon sometimes called the “nocebo effect.” For the
42.6% of patients with confirmed statin intolerance,
we subsequently randomized patients to receive
ezetimibe or the new PCSK9 inhibitor, evolocumab.
Not surprisingly, the evolocumab-treated patients
had a much more robust lowering of low-density
lipoprotein cholesterol (LDL-C), 52-54% compared
with 16.7% for ezetimibe. Despite baseline LDLC levels of about 220 mg/dL, approximately two
thirds of evolocumab-treated patients achieved an
LDL-C < 100 mg/dL, compared with less than 2% of
ezetimibe-treated patients.
A third study presented at ACC 2016 stunned
the lipidology community, the ACCELERATE Trial,
presented by Stephen Nicholls, MD. This study was
presented prior to final closeout, but represented
nearly 99% complete data. This was a 12,092 patient
trial that randomized statin-treated patients at high
risk for cardiovascular events to a cholesteryl ester
transfer protein (CETP) inhibitor, evacetrapib, or
placebo. This drug yielded lipid-modulating benefits
exactly as expected, a 130% increase in high-density
lipoprotein cholesterol (HDL-C) and a 37% decrease
in LDL-C. Despite these large lipid benefits, the study
was terminated for futility on the recommendation
of the Data Monitoring Committee after a median
study participation of 29 months. The primary
endpoint was a composite of cardiovascular death,
MI, stroke, coronary revascularization, or hospitalization for unstable angina. A total of 774 events
occurred in the evacetrapib group and 768 events in
the placebo group, HR 1.01, p = 0.85. None of the
components of the primary endpoint showed statistically significant benefits, although there was a trend
toward benefit for all-cause mortality, p = 0.06. A
small increase in BP (0.9 mm) and C-reactive protein
(4.6%) do not likely explain the lack of benefit.
The results represent the third CETP inhibitor to
fail to show evidence of meaningful clinical benefits
(torcetrapib, dalcetrapib, and now evacetrapib).
These findings represent a stunning failure of favorable lipid effects to translate into an improvement
in clinical outcomes. Once again, the use of surrogate endpoints like cholesterol levels, reduction in
glycemia, or BP lowering, have proven unreliable in
predicting reductions in the intended cardiovascular
benefits. ACCELERATE should serve as a warning
and a reminder that excessive faith in biochemical
“benefits” has frequently mislead the cardiovascular
community. Despite the high costs and time-consuming nature of clinical outcome trials, large, carefully
conducted randomized controlled trials represent
the only reliable approach to determining whether
therapies are beneficial, neutral, or harmful. ■
References
1. Lonn EM, Bosch J, López-Jaramillo P, et al. N Engl J Med. 2016 Apr.
[Epub ahead of print]
2. Yusuf S, Bosch J, Dagenais G, et al. N Engl J Med. 2016 Apr 2.
[Epub ahead of print]
3. Yusuf S, Lonn E, Pais P, et al. N Engl J Med. 2016 Apr 2. [Epub
ahead of print]
4. Nissen SE, Stroes E, Dent-Acosta RE, et al. JAMA. 2016 Apr 3. doi:
10.1001/jama.2016.3608. [Epub ahead of print]
Steven E. Nissen, MD, is Chair of the Department of
Cardiovascular Medicine at the Cleveland Clinic and
co-author of Heart411: The Only Guide to Heart Health
You’ll Ever Need.
May 2016