Aim to Reduce RISK not at Target levels

DR.PRAVEEN NAGULA
to reduce atherosclerotic cardiovascular disease(ASCVD)risk
{RCTs,systematic analysis and metaanalysis of RCTs}.

ASCVD coronary heart disease(CHD),stroke,and
peripheral arterial disease,all of presumed atherosclerotic
origin.
to provide strong evidence-based foundation.
only evidence from statin RCTs were used to develop
guidelines.****

Comprehensive approach to lipid management for purposes
with relation to ASCVD reduction only,not for complex lipid
disorders.

.....
Patient centered approach
rather than
one treatment fits all

Benefits of Statins
High intensity therapy lowering LDL cholesterol by >50%.
Moderate intensity therapy - lowering LDL cholesterol by 30-50%.
Reduces ASCVD events across the spectrum of baseline LDL-C
levels > 70 mg/dl.
Relative reduction in ASCVD risk is consistent for primary and
secondary prevention.

Absolute reduction in ASCVD events is proportional to baseline
absolute ASCVD risk.

Statin therapy only for individuals at increased ASCVD risk .



Who are to be benefited
by Statins ?????

Primary prevention of ASCVD
Based on the estimated absolute 10 yr risk of ASCVD
(non fatal MI,CHD death,nonfatal and fatal stroke)

The omnibus CV risk calculator for

Pts without clinical ASCVD and LDL 70-189mg/dl
Estimates 10 yr risk of ASCVD
In diabetics ,for primary prevention

Not in pts with clinical ASCVD

Statin treatment:Recommendations



Primary prevention in patients with
LDL>190mg/dl
Management
Evaluate for cause
Age>21 years
LDL-C
>190mg/dl
primary
High dose
statin
I B
Maximum
tolerated
dose
I B
LDL-C
reduction of
atleast 50%
IIaB
secondary
Evaluate
and treat
accordingly
Primary prevention in patients with
diabetes
Statins
Age
Diabetes
LDLcholesterol
70-189 mg/dl
40-75 yrs
Moderate
intensity
statins
I A
High intensity
statins
with risk >7.5%
IIa B
<40 yrs,
>75yrs
Balance between
ASCVDbenefits and
adverse effects
IIa C
Age of the patient
10 yr ASCVD
risk estimate
Patients without
diabetes,primary
prevention
LDLcholesterol
70-189 mg/dl
>7.5
%
40-75 yrs
Moderate to
high intensity
therapy
I A
>75
yrs
Assess
risk,
benefits
5-7.5%
40-75
yrs
Moderate
intensity
therapy
IIa B
>75
yrs
Assess
risks
benefits
Statins in Heart Failure,
Hemodialysis patients
LDL
cholesterol
>190
mg/dl
Pt had CAD,
HTN,smoker,
not on statins
Age 45
yrs
Start Statins
to the
maximum
tolerated
dose
Age 75
yrs
Assess
risk,benefits
Pt
diabetic,no
CAD,
ASCVDrisk
>7.5%
High
intensity
statins
Pt not
diabetic,
noCAD
Evaluate
secondary
causes
High dose
statin
therapy
70-189
mg/dl
Pt CAD
Statins
Pt
diabetic
Moderat
dose
statins
Pt no
h/o
CAD,
DM2,
risk
<7.5%
Assess
risk,
benefits
Pt having
CKD
No EBT
for
statins
High- Moderate and Low
I ntensity Statin Therapy
Clinical application by Statin dose
STATINS
HIGH INTENSITY THERAPY MODERATE INTENSITY
THERAPY
LOW INTENSITY THERAPY
Daily dose lowers LDL-C
on average,by
approximately 50%
Daily dose lowers LDL C
on average,by
approximately 30-50%
Daily dose lowers LDL C
<30%
Atorvastatin (40) 80 mg Atorvastatin 10 (20) mg Simvastatin 10 mg
Rosuvastatin 20 (40) mg Rosuvastatin (5) 10 mg Pravastatin 10-20 mg
Simvastatin 20-40 mg Lovastatin 20 mg
Pravastatin 40 (80) mg Fluvastatin 20-40 mg
Lovastatin 40 mg Pitavastatin 1 mg
Fluvastatin XL 80 mg
Fluvastatin 40 mg bid
Pitavastatin 2-4 mg
Safety recommendations of statins
NHLBI ACC/AHA
COR
LOE
1.Creatine Kinase,routinely not needed A
III no benefiit A
2.Baseline CK in pts at risk of events E
IIa C
3.Baseline ALT before initiating statins B
I B
4.Decreasing the statin dose,if 2
consecutive values of LDL-C <40
mg/dl.
C
IIb C
5.Simvastatin at 80 mg daily harmful B
III harm A
6.New onset diabetes on statin
therapy,continue statins
B
I B
7.If muscle symtpoms
develop,discontinue,use again
E
II a C
8.Confusional state,see secondary
causes
E
II b C
Monitoring statin treatment
What do guidelines say..

Lifestyle is the foundation for
ASCVD risk reduction
Adhering to a healthy heart diet,
Regular exercise habits
Avoidance of tobacco products
Maintenance of healthy weight


Remains critical component both prior to and in
concert with the use of cholesterol lowering drug
therapies
What is the fate of
nonstatins in guidelines
are they Ignored??

Niacin
Baseline hepatic
transaminases,FBS,HBA1c
Hepatic transaminases
elevations are higher
>2-3ULN
Persistent severe cutaneous
symptoms,hyperglycemia,
acute gout
New onset AF,
weight loss
Niacin
Start at low dose
Take niacin with food
or aspirin
500 mg ER to
2000mgER
Bile acid
sequestrants
Baseline TG
>300 mg/dl
250-299 mg/dl
Cholesterol
absorption
inhibitors
Baseline hepatic
transaminases
Discontinue if
ALT>3 times
occur
Fibrates
Gemfibrozil in patients
on statin therapy
If TG>500mg/dl and
benefit>risks
GFR<30 ml/min
Omega 3 fatty acids
Severe
hypertriglyceridemia
Evaluate GI
disturbances
I A
IIa/IIbB
III
Secondary causes of hyperlipidemia
Secondary cause Elevated LDL - C ELEVATED TRIGLYCERIDES
DIET Saturated or trans fats,
wt gain,anorexia
Wt gain,
very low fat diets, high intake
of refined carbohydrates,
excessive alcohol intake
DISEASES Biliary obstruction ,
nephrotic syndrome
Nephrotic syndrome, CKD,
lipodystrophies
DRUGS Duiretics,cyclosporine,
glucocorticoids,amiodarone
Oral
estrogens,glucocorticoids,
bile acid sequestrants
protease inhibitors,
retinoic acid,sirolimus,
beta blockers,thiazides
ALTERED
METABOLISM
Hypothyroidism,
Obesity,pregnancy
Diabetes, hypothyroidism,
obesity, pregnancy
Statins,niacin,ezetimbe
C/I in pregnancy,lactation

Evolution of guidelines
NCEP
ATP I
1988

NCEP
ATP II
1993
NCEP
ATPIII
2001
NCEP
ATP III
REVISED
2004
NCEP
ATP IV
2013??
ACC/AHA
2013




Basis for the New Guidelines
RCTs reviewed showed a consistent reduction in ASCVD
events from Statins therapy in secondary and primary
prevention, no ASCVD event reduction in those with NYHA
class II-IV HF or receiving maintenance hemodialysis.
Only fixed doses of statins with placebo or untreated
controls,comparison of high dose with moderate intensity
statins.
No evaluation of the effect of titrated (dose adjusted) statin
treatment to achieve prespecified LDL- C or non HDL-C
goals.
Use of niacin to additionally lower non HDL C,once an LDL
target was achieved,did not further reduce ASCVD
outcomes.(AIM HIGH trial)
The intensity of statin therapy is appropriate on those most
likely to benefit.
Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-207
AFCAPS-TEXCAPS, J AMA 1998;279:16151622
MEGA trial, Lancet 2006;368:11551163.
3 CQs
CQ1 -
secondary,(19RCT)
CQ2 primary
prevention (6RCT)
CQ3 comprehensive
management,safety of
each drug
Why other approaches
ignored???
1.Treat to Target widely used for past 15 yrs
What is the target ?
What is the additional risk reduction beyond one target lower
than other?
adverse effects from multidrug therapy that occur in achieving
goal
undertreatment with statins, overtreatment with nonstatins
2.lowest is best
adverse effects?
3.lifetime risk
long term follow up >15 yrs?
statins>10yrs?
Why Target level therapy
ignored..how came the picture of
statin benefit groups?
Hypothesis or Evidence based..
Myth or reality
A.Secondary Prevention
Evidence high intenisty therapy to maximally lower LDL C than
using a target.

Ex LDL C 78mg/dl on a dose of atorvas 80 mg/dl receiving EBT.

No data to show that adding a nonstatin drug to high intenisty statin
therapy will provide incremental ASCVD risk reduction benefit with
acceptable margin of safety.(AIM HIGH,ACCORD).

This patient may be exposed to adverse effects if started of a drug with
no evidence of benefit,just because his LDLis more than arbitrarily
level.

This is treated as a case of failure..for a lag of 8 mg/dl..Is it justifiable
???



AI M HI GH trial NewEngl J Med 2011;365:2255-67
ACCORD, N Engl J Med 2010;362:156374.
B.FH with LDL C >190 mg/dl
many does not achieve <100mg/dl.
maximum may be 120 mg/dl on 3 drugs.
These pts may have fallen short of target ,but their LDL C
>50% ,more ASCVD risk reduction.
Not treatment failures.
C.Type2Diabetes :
have lower LDL-C than with without diabetes.
goal directed therapy encourages low statin doses,use of drugs
for addressing HDL-C/high TG.
maximally tolerated therapy to be given primary importance.
D.Estimated ASCVD >7.5%
Cholesterol Treatment Trialists Collaboration, Lancet 2012;380:58190.
Taylor F, Ward K, Moore TH et al. 2011:CD004816



Limitations
Clinical judgement required in pts,for whom RCT evidence is
insufficient
Younger adults< 40 yrs with <7.5% ASCVD risk for 10
yrs,high lifetime risk.
HIV pts,rheumatological pts,IBD pts.
RCTS,Systematic reviews,meta analysis of RCTs were taken
into consideration.
New Drugs
Cholesterol ester transfer protein (CETP) inhibitors -
Anacetrapib(DEFINE,REVEAL), dalcetrapib

Ab to pro-protein convertase subtilisin/kexin 9 (PCSK9).

Apolipoprotein B synthesis inhibitors - Mipomersen

Microsomal triglyceride transfer protein (MTP) inhibitors,

Thyroid hormone analogue Eprotirome
Future..
Primary prevention in >75 yrs age
Alternate treatment strategies.
Effectiveness of submaximal doses of statins vs nonstatins in
intolerant pts
Evaluation of the incidence of new onset diabetes associated
with statin therapy.
Outcomes of RCTs of new lipid modifying agents to determine
the incremental ASCVD reduction when added to statin
therapy.
Future updates required for..

1.The treatment of Hypertriglyceridemia.
2.Use of NonHDL-C in decision making.
3.Whether on-treatment markers such as
apoB,Lp(a),LDLparticles are useful in guiding decisions.
4.Best approaches to use noninvasive imaging for refining
risk estimates to guide treatment.
5.Optimal age for starting treatment for reducing lifetime risk
of ASCVD.
6.What to do in pts with HF,hemodialysis.
7.Long term effects of statin associated new onset diabetes and
management.
Conclusions
Patient centered approach is to be given importance rather than
one treatment fits all concept.
Statins to be given at high intenisty,moderate intensity doses but not
with target levels of attainment.
Nonstatins give no ASCVD benefit in pts with high intensity statin
therapy.
Use of lipoprotein a ,non HDLcholesterol levels assessment is not
recommended.
Pts without ASCVD should be started of the statins after assessing 10 yr
risk by omnibus calculators.
New onset diabetes due to statins needs further assessment in future.
New drugs in pipeline,RCT s required for their incremental benefit in
ASCVD risk reduction when added to statins
Lifestyle modification remains the key concept of the management of
blood cholesterol.