Dr Tarun Kumar MD Internal Medicine VMMC and Safdarjung Hospital New Delhi

1. JOURNAL CLUB PRESERNTATION
EVOLOCUMAB AND CLINICAL OUTCOMES IN PATIENTS
WITH CARDIOVASCULAR DISEASE

2. NEJM May 4,2017 edition
Presented by – Dr. Tarun Kumar
Moderator –Dr . Smita Mohanty

3. BACKGROUND
 Low-density lipoprotein (LDL) cholesterol is a well-
established and modifiable risk factor for
cardiovascular disease.
 Monoclonal antibodies that inhibit proprotein
convertase subtilisin–kexin type 9 (PCSK9) have
emerged as a new class of drugs that effectively lower
LDL cholesterol levels.
 Evolocumab, a member of this class, is a fully human
monoclonal antibody that reduces LDL cholesterol
levels by approximately 60%.

4. • The LDL receptor (LDLR), present on liver and other cell
membranes, binds and initiates ingestion of LDL-particles
from extracellular fluid into cells, thus reducing LDL particle
concentrations.
• However, when PCSK9 is bound to the LDLR, after the
LDLR & LDL particle combination has been ingested, the
receptor is degraded and is no longer recycled back to the
cell membrane surface to bind and ingest more LDL-
particles.
• If PCSK9 is blocked, more LDLRs are recycled and are
present on the surface of cells to remove LDL-particles from
the extracellular fluid . Therefore, blocking PCSK9 can lower
blood LDL-particle concentrations.

5. PURPOSE OF THIS STUDY
• Genetic studies have shown that carriage of PCSK9 loss-of-function alleles is
associated with lower LDL cholesterol levels and a reduced risk of myocardial
infarction. Moreover, exploratory data from longer-term follow-up in phase 2 and
phase 3 trials of PCSK9 inhibitors showed significant reductions in cardiovascular
outcomes. However, there were little more than 100 events in these studies
combined.
• Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects
with Elevated Risk (FOURIER) was a dedicated cardiovascular outcomes trial that
tested the clinical efficacy and safety of evolocumab when added to high-intensity
or moderate-intensity statin therapy in patients with clinically evident
atherosclerotic cardiovascular disease.

6. Methods
• Trial design –Multunational, Randomized, double blind, placebo- controlled
• Period -february 2013 to november 2016
• Patients recruited from 1242 sites from 49 countries
• From feb 2013 to june 2015 27,564 patients underwent randomization (1:1)out of
them 13,784 in evolocumab
group and 13780 in placebo group

7. Participant population
Inclusion Criteria
1. Patients age between 40-85 year
2. History of clinically evident atherosclerotic cardiovascular disease i.e myocardial
infarction , nonhemorrhagic stroke or symptomatic peripheral artery disease at
high risk for recurrent event i.e additional risk factor ( 1+major or 2+ minor)
Major - a) age>65+yr b) MI/Nonhaemorrhagic stroke in prior 6 months
c)Multiple MI/Nonhaemorrhagic stroke or PAD d) Current daily smoker e) Diabetes
Minor –a) history of MI related coronary revascularisation b)Residual CAD 40+%
stenosis in 2+ large vessels c) HDL (most recent)<40mg/dl for male and <50mg/dl
for female d)LDL-C (most recent) >130mg/dl(3.4mmol/L) or Non-HDL-C
>4.1mmol/L or LDL-C >70mg/dl after 2 weeks of lipid lowering therapy e) Metabolic
syndrome

8. 3. Fasting LDL cholesterol level of 70 mg/dl or higher or a non HDL cholesterol
100mg/dl or higher while they were taking an optimized regimen of lipid lowering
therapy ,which was defined as preferably a high intensity statin but
must have been at least atorvastatin at a dose of 20 mg daily or its equivalent ,with
or without ezetimibe.
4. Fasting triglyceride <400mg/dl

9. Exclusion criteria
1. NYHA class 3 or 4 or last known LVEF<30%
2. Any history of haemorrhagic stroke
3. MI or Stroke within last 4 weeks
4. Planned or expected cardiac surgery or revascularization with in 3 months
5. Uncontrolled HTN(BP>180/110 mmhg
6. Uncontrolled hyperthyroidism or hypothyroidism
7. Uncontrolled or recurrent ventricular tachycardia
8. Homozygous familial hypercholesterolemia
9. Patients undergoing LDLplasmapheresis
10. eGFR <20ml/min/1.73 m2

10. • Eligible patients were randomly assigned in a 1:1 ratio to receive subcutaneous injections of
evolocumab(either 140 mg every 2weeks or 420 mg every month according to patient
preference) or matching placebo
• Randomization was performed in a double blinded manner with the use of a central
computerized system,with stratification according to the final screening LDL cholesterol level
(<85 or >85 mg/dl) and region

11. Primary end points
• The Primary efficacy end points was major cardiovascular events,defined as composite of
cardiovascular death ,myocardial infarction,stroke,hospitalization for unstable angina or
coronary revascularization.
Secondary end points
• The secondary efficacy end point was the composite of cardiovascular death ,myocardial
infarction and stroke

12. Stastical Analysis
1. Primary efficacy analysis was based on the time from randomized study group
assignment to first occurrence of any element of the primary composite end point
2. If rate of primary end point significantly lower in the evolocumab group (p<0.05),
than in a hierarchial fashion , key secondary end point and than cardiovascular
death were tested at a significance level of0.05
3. All efficacy analysis were conducted on an intention to treat basis
4. The size of the patient population in the trial was based on secondary end point,
and they estimated that 1630 such end points events were required to provide
90% power to detect a relative reduction of >15% in this end point with
evolocumab as compared with placebo

13. Results
• The base line characteristics of the patients in the two groups were well matched
• The mean age of the patients was 63 yrs and 24.6% were female
• 81.1 % of patients had history of MI ,19.4% nonhemorrhagic stroke and 13.2%
symptomatic PAD
• At baseline 69.3% of the patients were taking high intensity statin therapy and
30.4% on moderate intensity statin therapy and 5.2% were also taking ezetimibe
• The rate of use of secondary preventive therapies was high with 92.3% on
antiplatelets ,75.6% on beta blockers and 78.2% taking ACE/ARB , an aldosterone
antagonist or both at trial entry
• A total 27525 patients(99.9%) received at least one dose of study agent
• Premature discontinuation of study agent occurrred in12.5% of patients(5.7%per
year) in each group
• Median duration of follow-up was 26 months(IQR 22 to 30)

15. Results
• The median LDL-C level at baseline was 92 mg/dl (IQR 80 to 109mg/dl)
• At 48 weeks , mean percentage reduction in LDL-C level with evolocumab as
compared to placebo was 59%(95%CI,58 to 60;p<0.001) for a mean absolute
reduction of 56mg/dl to a median of 30mg/dl
• The reduction in LDL-C level was maintained over time
• At 48 weeks in the evolocumab group, the LDL-C was redused to<70mg/dl in
87% of patients ,<40mg/dl in 67% ,<25mg/dl in 42% as cmpared to
18%,0.5%,<0.1% respectively in placebo group(p<0.001)
• Evolocumab also redused non-HDL-C and Apo B levels by 52% and
49%(p<0.001)

16. METHODS

17. Results
• Evolocumab significantly redused the risk of primary composite end point of cardiovascular
death ,Stroke ,hospitalization for unstable angina or coronary revascularization
• The primary end point occurred in 1344 patients (9.8%) in the evolocumab group and in
1563 patients (11.3%) in the placebo group
• Likewise ,the secondary composite end point occurred in 816 patient(5.9%) in evolocumab
group and in 1013 patients(7.4%) in placebo group
• The magnitude of risk reduction with regard to primary end point tended to increase over
time from 12 % in the first year to 19% beyond first year
• Likewise the risk reduction for secondary end points increased from 16% in the first year to
25 % beyond first year

20. Results
• In terms of individual outcomes , evolocumab had no observed effect on
cardiovascular mortality
• However there were reductions of 21 to 27% in the risk of MI ,stroke and
coronary revascularization but no observed effect on the rates of hospitalization
for unstable angina, cardiovascular death or hospitalization for worsening heart
failure

21. Safety
• No significant between group differences were seen in the overall rates of adverse
events,serious adverse events or adverse events thought to be related to the study
agent and leading to discontinuation of the study regimen
• Likewise ,the rates of muscle related events,cataract ,neurocognitive adverse
events and hemorrhagic stroke did not differ significantly between the two groups
• Injection site reactions(2.1% vs 1.9%) and allergic reactions (3.1% vs 2.9%)did not
differ significantly between two groups
• In the evolocumab group, new binding antibodies developed in 43 patients (.3%)
and development of neutralizing antibodies did not occur in any patients

22. Discussion
• When added to statin therapy,the PCSK9 inhibitor evolocumab lowered LDL cholesterol
levels by 59% from baseline levels as compared with placebo.This effect was sustained without
any evidence of attenuation.
• In this dedicated cardiovascular outcomes trial , they found that the addition of evolocumab
to statin therapy significantly redused the risk of cardiovascular outcomes ,with a 15%
reduction in risk of primary composite end points of cardiovascular death,myocardial
infarction ,stroke,hospitalization for unstable angina or coronary revascularization and a 20 %
reduction in the risk of secondary end points
• During a median of 26 months of follow-up ,the only adverse events that were noted to be
nominally significant more common in association with evolocumab were injection site
reactions(2.1% vs 1.6%), but these were rare and rate of discontinuation of the study regimen
was no higher as compared to placebo

23. • The data from our trial provide insight into the benefit of decreasing LDL cholesterol levels to
median levels lower than those in previous trials
• Previously, significant reductions in major cardiovascular events were found in the
Pravastatin or Atorvastatin Evaluation and Infection Therapy–Thrombolysis in Myocardial
Infarction 22 (PROVE IT–TIMI 22) and Treating to New Targets (TNT) trials, in which the
more intensive statin regimen lowered LDL cholesterol levels from approximately 100 mg
per deciliter (2.6 mmol per liter) to 70 mg per deciliter (1.8 mmol per liter)
• More recently, the addition of ezetimibe to statin therapy in the Improved Reduction of
Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) lowered LDL cholesterol
levels from 70 mg per deciliter (1.8 mmol per liter) to 54 mg per deciliter (1.4 mmol per liter)
and significantly reduced major cardiovascular events.
• In extending this concept further in FOURIER, we found consistent reductions in rates of
cardiovascular events across the range of baseline LDL cholesterol levels.
• These observations align well with the effects of evolocumab on coronary atherosclerotic
plaque volume in the Global Assessment of Plaque Regression with a PCSK9 Antibody as
Measured by Intravascular Ultrasound (GLAGOV) trial and show that continued
cardiovascular benefit can be accrued even when LDL cholesterol levels are reduced to 20 to
25 mg per deciliter (0.52 to 0.65 mmol per liter), a range that is well below current targets.

24. • The major limitation of this trial was a relatively short duration of follow-up as
compared with that in other lipid lowering trials ,in which follow-up periods have
averaged approximately 5 years
• Although the median follow-up period in FOURIER was originally planned to be
approximately 4 years , but an event rate that was approximately 50% higher
than had been postulated led to a shorter required duration of follow up to accure
the prespecified number of events
• Most but not all of the patients in the trial received high intensity statin therapy ,
and ezetimibe use was frequent
• However ,the benefit of evolocumab was consistent regardless of the intensity of
statin therapy or ezetimibe use

25. Conclusion
In conclusion, inhibition of PCSK9 with evolocumab on a
background of statin therapy lowered LDL cholesterol levels to
a median of 30 mg per deciliter (0.78 mmol per liter) and
reduced the risk of cardiovascular events. These findings show
that patients with atherosclerotic cardiovascular disease benefit
from the lowering of LDL cholesterol levels below current
targets.

27. THANK YOU