Ezetimibe Added to Statin Therapy After Acute Coronary Syndrome
NEJM 2015; 372(25):2387-2397
Mentor: Dave L. Dixon, PharmD, AACC, FNLA, CDE, CLS, BCPS-AQ Cardiology
Presented: September 25, 2015
Kyle D. Thorner, PharmD
WakeMed Health & Hospitals
Article Summary
Background: Ezetimibe reduces serum LDL-cholesterol via
inhibition of intestinal cholesterol absorption via the NiemannPick C1 transporter (NPC1). It is hypothesized that ezetimibe
should provide cardiovascular benefit in addition to LDL
cholesterol reduction. Mutations resulting in inactive or partially
inactive NPC1 have been associated with a reduction in
cardiovascular disease (CVD). However, previous trials have
failed to show cardiovascular benefit beyond LDL cholesterol
reduction and the SEAS trial introduced a potential cancer
signal associated with ezetimibe.
Objective: To evaluate the effect of ezetimibe combined with
simvastatin, as compared with that of simvastatin alone, in
stable patients who had an acute coronary syndrome and
whose LDL cholesterol values were within guideline
recommendations.
Study Population:
Results:
- Baseline Characteristics: Average age 63.6 years,
~76% male, ~84% white, mean baseline LDL-C of
93.8 mg/dL, index event UA (~29%), NSTEMI
(~47%), or STEMI (~24%). Baseline medications:
statin (~35%), aspirin (~42%), post-ACS medications:
aspirin (~97%), thienopyridine (~86%), BB (~87%),
and ACEI (75%)
- Median follow-up: 6 years
- Total follow-up: 7 years
Outcome
LDL-C at 1 year
(mg/dL)
Primary
composite (%)
Nonfatal MI (%)
Inclusion Criteria
Age ≥ 50 years,
hospitalization within previous
10 days for ACS, LDL
cholesterol ≥ 50 mg/dL, LDL
≤125 mg/dL for patients naïve
to lipid-lowering therapy, LDL
≤100 mg/dL for patients on
lipid-lowering therapy
Exclusion Criteria
Planned CABG, CrCl < 30
ml/min, active liver disease,
use of statin therapy with
LDL-lowering potency greater
than 40 mg of simvastatin
Study Design: IMPROVE-IT was an international, multicenter,
double-blind, placebo-controlled trial. Patients were
randomized to receive simvastatin 40 mg once daily plus
ezetimibe 10 mg daily or simvastatin 40 mg once daily plus
placebo.
Outcomes:
- Primary: Composite of death from CVD, major
coronary event (nonfatal myocardial infarction,
unstable angina requiring hospitalization, or coronary
revascularization after 30 days) or nonfatal stroke
- Secondary: Various composite outcomes
- Tertiary: Individual components of the composite
outcomes
- Safety: Liver enzyme levels, creatinine kinase levels,
incidence of myopathy, incidence of rhabdomyolysis,
gallbladder-related adverse events, and incidence of
cancer
Ischemic Stroke
(%)
ALT, AST or
both ≥3 x ULN
Rhabdomyolysis
Myopathy
Cancer
*Yearly NNT = 350
-
Simvastatin
(n=9077)
SimvastatinEzetimibe
(n=9067)
HR (95%
CI)
p-Value
(NNT)
69.9
53.2
-
<0.001
2742 (34.7)
2572 (32.7)
1083 (14.4)
945 (12.8)
297 (4.1)
236 (3.4)
0.936
(0.89-0.99)
0.87
(0.8-0.95)
0.79
(0.67-0.94)
0.016
(50)*
0.002
(63)
0.008
(143)
208 (2.3)
224 (2.5)
-
0.43
18 (0.2)
10 (0.1)
732 (10.2)
13 (0.2)
15 (0.2)
748 (10.2)
-
0.37
0.32
0.57
Subgroup Analysis: Significant difference observed in
the primary endpoints for patients with diabetes
(NNT=19) and patients age ≥75 (NNT=12)
By the end of the study, 42% of patients in each study
arm were no longer taking originally assigned
treatment.
Conclusions: The addition of ezetimibe to statin therapy in
stable patients with recent ACS and who had LDL cholesterol
levels within guideline recommendations further lowered the
risk of cardiovascular events.
Discussion:
- First clinical trial to show cardiovascular benefit from
the addition of a non-statin to statin therapy. Benefit
seen without an increase in adverse events.
- Utilization of moderate intensity statin for
monotherapy arm does not reflect current practice.
- The significant lowering of LDL cholesterol combined
with reduction in cardiovascular endpoints, albeit
modest, lends support to the LDL hypothesis, but
does not disprove the statin hypothesis.
Ezetimibe Added to Statin Therapy After Acute Coronary Syndrome
NEJM 2015; 372(25):2387-2397
Mentor: Dave L. Dixon, PharmD, AACC, FNLA, CDE, CLS, BCPS-AQ Cardiology
Presented: September 25, 2015
Questions:
1) Would you include ezetimibe as step therapy before a
PCSK-9 inhibitor?
After maximizing statin therapy, I would include the addition of
ezetimibe ahead of PCSK-9 inhibitors for step therapy.
However, there are several factors to consider. While
IMPROVE-IT demonstrated significant LDL lowering and
modest cardiovascular benefit with the addition of ezetimibe to
simvastatin, PCSK-9 inhibitors have been shown to
dramatically decrease LDL cholesterol by as much as 60% in
in addition to statin therapy and provide benefit in
cardiovascular outcomes as well. (1,2) Patient compliance may
be higher with ezetimibe despite additional pill burden if
patients are unwilling to subject themselves to injections.
Financially, ezetimibe will eventually be the far less expensive
option when generic versions become available in April 2017,
which will include the combination of simvastatin and
ezetimibe. (3)
2) What are your thoughts about the additional cost of
ezetimibe? Is the higher cost worth the achieved outcomes?
If a patient is able to tolerate high-intensity statin therapy, I do
not think the additional cost of ezetimibe would make up for the
residual benefit of adding ezetimibe. The PROVE-IT TIMI 22
study demonstrated the benefit of high intensity statin therapy
compared to moderate intensity statin therapy in patients with
recent ACS for reducing the primary endpoint of death, MI,
unstable angina requiring hospitalization, stroke or
revascularization. (4) Therefore, it is likely that a high intensity
statin monotherapy arm would produce at least the same
outcomes as the addition of ezetimibe added to moderate
intensity statin therapy. The average wholesale prices (AWP)
for a thirty-day supply of ezetimibe and ezetimibe/simvastatin
are $283.85 and $281.26, respectively. (5) While this does
represent a financial obstacle, the cardiovascular outcome
benefit seen in IMPROVE-IT may justify the additional expense
in patients only able to tolerate moderate-intensity statin
therapy. Specifically, the addition of ezetimibe to statin therapy
reduced non-fatal MI and ischemic stroke, which represent a
substantial economic burden themselves. Lastly, generic
versions of ezetimibe will be available in the near future. (3)
Kyle D. Thorner, PharmD
WakeMed Health & Hospitals
3) What are your thoughts regarding the pill burden due to the
addition of ezetimibe?
I believe that the pill burden with the addition of ezetimibe to
statin therapy is negligible. Ezetimibe does not require more
than once daily dosing and can be taken at the same time of
day as the statin therapy without fear of any kind of drug
interaction. Also, if an addition tablet was of concern, the
combination tablet of simvastatin/ezetimibe is approximately
the same price as the ezetimibe alone. (5)
4) Clarify what your opinion of the discontinuation rates seen in
IMPROVE-IT?
The discontinuation rate in IMPROVE-IT was substantial with
42% of patients in each arm not taking their originally assigned
treatment by the end of the trial. (1) I do think this makes the
interpretation of the trial’s results difficult. However, an ontreatment analysis of the IMPROVE-IT trial showed similar
LDL-cholesterol lowering and the primary endpoint remained
statistically significant, HR 0.92 (CI 0.868-0.983, p=0.012). (5) I
think this report makes it easier to trust that the benefit seen in
IMPROVE-IT was due to the addition of ezetimibe and not
from other lipid-lowering regimens that patients may have been
on throughout the trial.
5) Would you still add ezetimibe to a patient on atorvastatin
80mg who had an LDL > 70mg/dL?
I am hesitant to recommend the addition of ezetimibe to highintensity statin therapy, like atorvastatin 80 mg, due to a lack of
evidence for this practice and the additional financial burden
that would be placed upon the patient. Utilizing the results of
the PROVE-IT TIMI 22 study, which showed the benefit of high
intensity statins over moderate-intensity statins in patients with
recent ACS, it may be postulated that a monotherapy high
intensity statin arm in IMPROVE-IT very well may have
produced equal, if not improved, outcomes as the
ezetimibe/simvastatin arm. (1,4) Therefore, I would conclude
that the addition of ezetimibe to high intensity statin therapy
would likely provide modest benefit while increasing
medication expenditure. In accordance with the most recent
hyperlipidemia guidelines, if it was felt that high-intensity statin
therapy did not reduce LDL cholesterol sufficiently then I think
it may be reasonable to consider the addition of non-statin
therapy as long as this does not result in the reduction of statin
intensity secondary to new adverse events. (7)
Ezetimibe Added to Statin Therapy After Acute Coronary Syndrome
NEJM 2015; 372(25):2387-2397
Mentor: Dave L. Dixon, PharmD, AACC, FNLA, CDE, CLS, BCPS-AQ Cardiology
Presented: September 25, 2015
6) Would you recommend re-instating the LDL thresholds postthis trial?
The reduction in LDL cholesterol and improvement in
cardiovascular outcomes observed in IMPROVE-IT lend
support to the “LDL hypothesis” that more benefit is gained
with every decrease in LDL cholesterol. (1) If this is true, then it
would make sense to have targets for LDL reduction included
in clinical guidelines. However, there is no evidence to date to
suggest LDL cholesterol can be lowered pharmacologically to
a point that results in adverse effects. Therefore, I would
recommend minimum LDL targets to be achieved without a
limit on the degree of LDL lowering.
References
1) Cannon CP, Blazing MA, Giugliano RP et al.
Ezetimibe added to statin therapy after acute
coronary syndrome. NEJM 2015; 372(25):2387-2397.
2) Sabatine MS, Giugliano RP, Wiviott SD et al. Efficacy
and safety of evolocumab in reducing lipids and
cardiovascular events. NEJM 2015;372(16):15001509.
3) Anticipated availability of first-time generics.
Pharmacist’s Letter 2015;Detait-Document #310944.
Accessed October 10, 2015.
4) Cannon CP, Braunwald E, McCabe CH et al.
Intensive versus moderate lipid lowering with statins
after acute coronary syndromes. NEJM
2004;350(15):1495-1504.
5) Micromedex. RED BOOK Online. Ann Arbor (MI):
Truven Health Analytics; 2013 [cited 10 Oct 2015].
Available from: www.micromedexsolutions.com.
6) Cannon CP, Blazing MA, Giugliano RP et al. OnTreatment Analysis of the IMProved Reduction of
Outcomes: Vytorin Efficacy International Trial
(IMPROVE-IT). Available from:
http://my.americanheart.org/idc/groups/ahamahpublic/@wcm/@sop/@scon/documents/downloadable
/ucm_469611.pdf.
7) Stone NJ, Robinson JG, Lichtenstein AH et al. 2013
ACC/AHA Guideline on the Treatment of Blood
Cholesterol to Reduce Atherosclerotic Cardiovascular
Risk in Adults. Circulation 2013;129:S1-S45.
Kyle D. Thorner, PharmD
WakeMed Health & Hospitals