collection of all important trials of lipid lowering druds

1. LIPID LOWERING TRIALS
DR.NAVIN AGRAWAL

2. INTRODUCTION
 Earliest trials of lipid lowering with bile acid sequestrants
 In 1971, Akira Endo, a Japanese reasoned that certain microorganisms
may produce inhibitors of HMG CoA enzyme to defend themselves, as
mevalonate is a precursor of many substances required by organisms for
the maintenance of cell wall or cytoskeleton.
 The first agent they identified was mevastatin (ML-236B), a molecule
produced by the fungus Penicillium citrinum.
 Mevastatin was never marketed, because of its adverse effects of tumors,
muscle deterioration, and sometimes death in laboratory dogs.
 By 1978, Merck had isolated lovastatin (mevinolin, MK803) from the
fungus Aspergillus terreus first marketed in 1987 as Mevacor.

3. Updated ATP III LDL-C Goals and Cutpoints
for Therapy
LDL-C (mg/dL)
Initiation
RISK FACTORS
Level for
Consideration Level for
Cigarette smoking
Risk Category
TLC
Drug Therapy
 Hypertension (BP 140/90 mm HgGoal antihypertensive medication)
or on
CHD
High risk: CHD or
<100
100
100
 Low HDL cholesterol (40 mg/dL),
History of myocardial infarction <70)
(<100: years of age;
CHD history of premature CHD (CHD in male first-degree relative 55 consider drug
(optional:
Familyrisk equivalents
CHD RISK EQUIVALENTS
 Unstable angina
options)
(10-yr risk >20%)
CHD in female first-degree relative 65 years of age)
 Peripheral Arterial Disease
 Stable angina
Age:-men 45high risk: aortic aneurysm
Moderately years; women 55 years.
<130
130
130
 Abdominal
 Coronary artery procedures (angioplasty or bypass surgery)
(100–129: consider drug
2+ risk factors
(optional: <100)
 Carotid artery significant myocardial ischemia.
Evidence of clinicallydisease
options)
(10-yr risk 10–20%) ischemic attacks or stroke of carotid origin
Transient
 50%
Moderate risk: obstruction of a carotid artery
<130
130
160
2+ risk factors
 Diabetes,
(10-yr risk <10%)
2 risk factors with 10-year risk for hard CHD 20%.
Lower risk:
0–1 risk factor
<160
160
190
(160–189: LDL-C–lowering
drug optional)
Circulation 2004;110:227-239

6. 5-YEAR NNT VALUES FOR PRIMARY PREVENTION OF CVD
Number Needed to Treat (5 years)
450
400
350
300
250
200
150
100
50
0
Ridker et al from the Jupiter study group

7. MAJOR STATIN TRIALS IN CAD
Primary
Prevention
WOSCOPS
AFCAPS/Tex CAPS
ASCOT-LLA
ALLHAT LLT
CARDS
ASPEN
MEGA
JUPITER
Secondary
Prevention
4S
CARE
LIPID
GREACE
TNT
AVERT
IDEAL
ACS
MIRACL
PROVE IT-TIMI 22
A to Z (2004)
STATIN STEMI
ARMYDA-ACS
ARMYDA-RECAPTURE

8. STATINS
PRIMARY PREVENTION

9. WOSCOPS
WEST OF SCOTLANDCORONARY PREVENTION STUDY
6995 MEN WITH NO CAD/ MEAN LDL 192 mg/ dL /F/U 5 YRS
Primary Endpoint:-non fatal MI and CHD death
31%
Risk
Reduction
12
Pravastatin 40 mg
10
Placebo
P=0.0001
8
Percent
with
6
Events
4
2
0
0
1
2
3
4
5
6
Years in Study
James Shepherd, et al, N Engl J Med 1995;333:1301-7

10. AFCAPS/TexCAPS
AIR FORCE/TEXAS CORONARY ATHEROSCLEROSIS PREVENTIONSTUDY
5608 MEN,997 WOMEN,MEAN LDL 150//F/U 5.2 YRS
Cumulative Incidence
primary end point:-Fatal/Nonfatal MI, Sudden Cardiac Death, Unstable Angina
0.07
0.06
Placebo (n = 3301)
Lovastatin (n = 3304)
37% risk
reduction
P < .001
0.05
0.04
0.03
0.02
0.01
0.00
0
1
2
3
4
5
>5
Years of Follow-up
Downs JR, et al. JAMA. 1998;279:1615-1622.

11. CARDS
THE COLLABORATIVE ATORVASTATIN DIABETES STUDY
2838 PATIENTS AGED 40-75 YRS WITH TYPE 2 DIABETES MELLITUS
AND AT LEAST ONE OF: HYPERTENSION, RETINOPATHY, ALBUMINURIA, SMOKING.
PRIMARY ENDPOINT: -ACS, REVASCULARIZATION, OR STROKE.
MEDIAN F/U3.9 YEARS FOLLOW-UP,ATV 10 MG
The trial was terminated 2 years earlier than expected
because the prespecified early stopping rule for efficacy had
been met. Atorvastatin reduced the death rate by 27%.
―The debate about whether all people with this disorder
warrant statin treatment should now focus on whether any
patients are at sufficiently low risk for this treatment to be
withheld.‖
Colhoun HM et al. Lancet 2004;364:685-696.

12. JUPITER
Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin
• 17802 men>50 and women >60 yrs
• LDL<130
• CRP>2
HAZARD RATIO
• No CVD
CAVEATS
PRIMARY END POINT(1ST MACE):0.56
• No DM
MI,STROKE,DEATH PATIENTS NOT INCLUDED
0.53
HIGH LDL AND LOW HS 1.9FROM CV CAUSE:• Median Follow Up CRPYrs HOSPITALIZATION:- 0.53
REVASCULARIZATION OR
TRIAL STOPPED EARLY IN 2 YRS
DEATH FROM ANYst Mace
0.80
• PrimaryEFFECTS OCCURING IN LATE THERAPY CANNOT BE RULED OUT
ADVERSE End Point:- 1 CAUSE SMALL INCREASE IN BLOOD GLUCOSE AND HBAIC REPORTED From
• Secondary End Point:-revasculariztion,hospitalisation
Cv Cause,death From Any Cause
• Randomized to rosuvastatin 20 mg vs placebo
• Trial stopped early at 1.9 yrs of follow up
Ridker PM et al NEJM 2008;2195

13. META ANALYSIS OF PRIMARY PREVENTION TRIALS
 70 388 people, of whom 23 681 (34%) were women and
16 078 (23%) had diabetes mellitus.
CAVEATS
In patients without 4.1 years.
 Mean follow-up was established cardiovascular disease
but with cardiovascular risk factors, statin use was
USE OF DIFFERENT TYPES AND DOSESsurvival and
associated with significantlywith a significant risk
improved OF STATINS
Statin therapyRISKassociated DIFFERENT STUDIES
DIFFERENT was PROFILE IN
large in
of major cardiovascular
reduction reductions in the risk FOR DIFFERENT RISK
BENEFITall cause mortality of 12%, in major coronary
STRATIFIACTION
events.
GROUPS NOT DONE
events of 30%, and in major cerebrovascular events of 19%.
 No evidence of an increased risk of cancer was observed.
J J Brugts et al BMJ 2009;338:b2376

14. STABLE CAD

15. 4S
4444 PTS WITH CAD,MEAN LDL 188MG DL/MEDIAN F/U 5.4 YRS/PLACEBO CONTROLLED
PRIMARY ENDPOINT :-TOTAL MORTALITY
Proportion Alive
1.00
0.95
0.90
0.85
Simvastatin
Placebo
0.80
Log rank P = .0003
This
improvement
in survival is
accounted for
by the 42%
reduction in
the risk of
coronary
death.
0.00
0.0
1
2
3
4
5
6
Years Since Randomization
Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.

16. CARE
4159 CAD PTS (3583 MEN/576 WOMEN)WITH MED LDL 139 /F U 5 YRS
15
Placebo
Change in risk,
24% reduction
P = 0.003
Incidence (%)
Pravastatin(40 mg)
10
Nonfatal MI or CHD Death
5
0
0
1
2
3
Years
4
CABG ↓26%
PCI ↓23%
STROKE↓ 31%
5 TOTAL MI ↓25%
FATAL MI ↓37%
BENEFIT WOMEN>MEN
ALL CAUSE MORTALITY DECREASED BY 9%
Adapted from Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.

17. LIPID
THE LONG TERM INTERVENTION WITH PRAVASTATIN IN ISCHAEMIC DISEASE(LIPID) STUDY
9014 CAD PTS ,RANDOMIZED TO PRVASTATIN 40G V/S PLACEBO F/U 6.1 YRS
N Engl J Med 1998;339:1349-57

18. AVERT
PRIMARY OUTCOME:-Ischemic Events
341 PTS ANGIOGRAPHICALLY DOCUMENTED CAD WITH EF>40% AND >4 MINUTES EXERCISE ON
BRUCE RANDOMIZED TO HIGH DOSE STATIN/ANGIOPLASTY WITH STANDARD CARE/F / 18 MNTHS
- 36% difference*
25
(P=0.048)
CAVEATS
21%
20
SMALL NUMBER OF PATIENTS
HIGH INCIDENCE OF CROSSOVER
% of
NUMBER OF EVENTS IN BOTH GROUPS WERE LESS
15
13%
patients
SHORT DURATION OF FOLLOW UP
with an
NOT APPLICABLE TO PATIENTS WITH HIGH RISK LESIONS OR TO
10
ischemic
UNSTABLE PATIENTS
event
5
0
Atorvastatin
n=22 of 164
Angioplasty/UC
n=37 of 177
Pitt B et al. N Engl J Med. 1999;341:70-76.

19. HPS
20536 WITH CAD OR DM/ RANDOMIZED TO SIMVASTATIN 40 MG VS PLACEBO/ FU 5 YRS
PRIMARY OUTCOME:- MORTALITY OR FATAL OR NON FATAL CV EVENTS
Among the many types of high-risk individual studied, 5
years of simvastatin would prevent about 70–100 people per
1000 from suffering at least one of these major vascular
events (and longer treatment should produce further benefit).
Lancet 2002; 360: 7–22

20. TNT TRIAL
10000 PTS,STABLE CAD,COMPARING HIGH AND LOW DOSE ATORVASTATIN
Primary Composite of CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal
or nonfatal stroke
12%
10.9%
8.7%
mean follow-up of 4.9
years
8%
4%
0%
MEDIAN LDL
77 mg/dl
High-dose
N = 4995
MEDIAN LDL
101 MG/DL
RRR= 22%
HR=0.78 (0.69–0.89)
P<0.001
Low-dose
N = 5006
N Engl J Med. 2005;352:1425-1435

21. TNT TRIAL
The individual components of the primary endpoint were also lower or tended to be
lower in the high-dose group compared to the low-dose group with the exception of
resuscitation after cardiac arrest, which was the equal in both groups.
8%
P=0.004
6.2%
6%
P=0.09
4.9%
P=0.02
4%
3.1%
2.0%
2.5%
2.3%
P=0.89
2%
0.5%
0.5%
0%
CHD death
Nonfatal MI
High-dose
Resuscitation
after cardiac
arrest
Stroke
Low-Dose
N Engl J Med. 2005;352:1425-1435

22. IDEAL
INCREMENTAL DECREASE IN ENDPOINTS THROUGH AGGRESSIVE LIPID LOWERING
8888 PTS WITH PRIOR MI.F U 4.8 YRS,ATV 80 MG V/S SIMVA 20 MG
Reduction in primary endpoint
Major coronary event*
16
Cumulative
hazard (%)
Simvastatin(20 -40mg)
11% RRR
HR = 0.89 (95% CI, 0.78–1.01)
P = 0.07
12
8
Atorvastatin(80 mg)
4
0
0
2
3
4
5
Time from randomization (years)
No. at risk
Simvastatin
Atorvastatin
1
4449
4439
*Death from CAD, nonfatal MI, cardiac
arrest with resuscitation
4293
4285
4165
4170
4037
4053
3917
3940
1200
1182
Pedersen TR et al. JAMA. 2005;294:2437-45.

23. IDEAL
INCREMENTAL DECREASE IN ENDPOINTS THROUGH AGGRESSIVE LIPID LOWERING
Reduction in SECONDARY endpoint
Incremental Decrease in End Points Through Aggressive Lipid Lowering
Any cardiovascular disease†
Any coronary heart disease*
40
40
16% RRR
HR = 0.84 (95% CI, 0.76–0.91)
P < 0.001
30
16% RRR
HR = 0.84 (95% CI, 0.78–0.91)
P < 0.001
30
Simvastatin
Cumulative
hazard (%)
Simvastatin
20
20
Atorvastatin
10
Atorvastatin
10
0
0
0
1
2
3
4
5
0
Time from randomization (years)
No. at risk
Simvastatin
Atorvastatin
4449
4439
3937
3984
3920
3799
3527
3632
3370
3496
1
2
3
4
5
Time from randomization (years)
1002
1032
4449
4439
3841
3902
3580
3671
3338
3469
3127
3299
908
963
*Major coronary event, hospitalization for UA, coronary revascularizations
†CHD endpoints, peripheral vascular disease, hospitalization for nonfatal CHF
Pedersen TR et al. JAMA. 2005;294:2437-45.

24. POST CABG TRIAL
1351 PTS 1 TO 11 YRS POST CABG,ANGIOGRAPHIC F/ U FOR 4 YRS
ANOTHER ARM OF STUDY COMPARED WARFARIN VS PLACEBO
Mean ldl level in aggressive group was 85mg v/s 135 mg in placebo group
AGGRESSIVE MODERATE
GROUP
TREATMENT
N = 675
N = 675
LDL LEVEL (mg/dL)
P VALUE
93-97
132-136
0.001
GRAFT Ath
PROGRESSION
27
39
0.001
REVASCULARISATION
AT 4 YRS
6.5
9.2
0.03
LOVASTATIN (mg/day)
40,80
2.5, 5mg
-
8
8
-
CHOLESTYRAMINE (gm)
Primary end point: Mean per-patient percentage of grafts with significant progression in
SVG ( 0.6 mm change)
Secondary end point: New occlusions, new lesions, lumen narrowing
Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.

25. POST-CABG ANGIOGRAPHIC OUTCOMES
MRE
Difference
Moderate
Aggressive
%
P value
Progression
39
28
28
<0.001
New occlusions
16
10
40
<0.001
New lesions
21
10
52
<0.001
Mean lumen change
in mm
Minimum diameter
-0.38
-0.20
48
<0.001
Mean diameter
-0.34
-0.16
52
<0.001
MRE=Mean per-patient percentage of grafts.
Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.

26. POST-CABG
Event=PTCA or bypass surgery
15
P=0.03.
10
Moderate
%
Aggressive
5
0
0.5
1.0 1.5 2.0
2.5 3.0 3.5 4.0
4.5
Yr after enrollment
Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.

27. STATINS USE IMPROVES SURVIVAL EVEN IN
PATIENTS WITH EXTREMELY LOW LDL LEVELS
4295 PATIENTS (70%) MEAN AGE WAS 65 YEARS, 43% HAD PRIOR ISCHEMIC HEART
DISEASE, AND 47% HAD DIABETES MELLITUS. FOLLOW-UP OF 2.0+-1.4 YEARS
Mortality reduction by 35%
CAVEATS
NON RANDOMIZED STUDY
NON BLINDED
PRIMARY PHYSICIAN DEPENDENT DOSING AND DRUG PROTOCOL
HIGH INCIDENCE OF CROSSOVER
REDUCTION IN LDL FROM PLACEBO GROUP WAS LESS THAN EXPECTED
MORBID PATIENTS WERE PROBABLY TAKEN OFF STATINS LEADING TO
INFLATION OF MORTALITY IN NON STATIN GROUP
No cases of rhabdomyolysis ↑ hepatic transaminase elevations, de novo
malignancy or renal insufficiency
Nicholas J. Leeper et al Circulation 2007;116:613-8

28. ACS

29. MIRACL
3086 PTS WITH UA:-24-96 HRS AFTER ADMISSION FOR 16 WEEKS
Placebo + DIET
Cumulative Incidence (%)
15
17.4%
14.8%
Atorvastatin 80 mg + Diet
10
Relative risk = 0.84
p=0.048
Time to first occurrence of:
• Death (any cause)
• Nonfatal MI
• Resuscitated cardiac arrest
• Worsening angina with new
objective evidence requiring
urgent rehospitalization
5
0
0
4
8
12
16
Time since randomization (weeks)
Schwartz GG et al. Jama 2001; 285: 1711-1718

30. Figure 4
Achieved CRP and LDL vs. Outcomes
4500PTS,40 MG OF SIMVASTATIN FOR 1 MONTH OF ACS F/B 80 MG THEREAFTER
V/S PLACEBO FOR 4 MONTHS F/B 20 MG SIMVA
FAILED TO ACHIEVE PRIMARY
END POINT(P=0.14)BUT
FAVOURED EARLY
AND AGGRESSIVE STATIN
REGIMENS
JAMA. 2004;292:1307-1316

31. PROVE IT –TIMI 22
PRAVASTATIN OR ATORVASTATIN EVALUATION AND INFECTION THERAPY
4162 ACS (WITHIN 10 DAYS)PTS/STABLE AFTER WITH NO PCI PLANNING/F/U 18-36 MNTHS THERAPY
16 %
Cannon CP, Eugene Braunwald, et al. N Engl J Med. 2004;350:1495-1504

32. PROVE IT–TIMI 22
Recurrent MI or Coronary Death
(%)
Clinical Relevance of Achieved LDL-C and Achieved CRP Combined after Statin
Therapy
0.10
LDL 70 mg/dl, CRP 2 mg/L
0.08
LDL 70 mg/dl, CRP <2 mg/L
LDL <70 mg/dl, CRP 2 mg/L
0.06
LDL <70 mg/dl, CRP <2 mg/L
0.04
LDL <70 mg/dl, CRP <1 mg/L
0.02
0.00
0.0 0.5 1.0 1.5 2.0 2.5
Follow-up (Years)
Ridker PM et al. N Engl J Med 2005;352:20-28

33. LUNAR STUDY
825 PTS WITH ACS WITHIN 48 HOURS OF FIRST SYMPTOMS WERE
RANDOMIZEDTO, ONCE-DAILY TREATMENT WITH RSV20,RSV40 OR ATV80
FOR 12 WEEKS.PRIMARY END POINT:-LDL LEVELS
RSV40 more effectively decreased LDL cholesterol, increased HDL cholesterol, and
improved other blood lipid parameters than ATV80 in patients with acute coronary
syndrome.
Bertram Pitt et al Am J Cardiol 2012;109:1239 –1246

34. PCI

35. ARMYDA
ATORVASTATIN FOR REDUCTION OF MYOCARDIAL DAMAGE DURING ANGIOPLASTY
153 STATIN NAÏVE PTS WITH CHRONIC STABLE ANGINA RANDOMIZED TO 40 MG /DAY
ATORVASTATIN V/S PLACEBO,CARDIAC ENZ MEASURED AT 0,8 AND 24 HRS
PRIMARY END POINT;- PERIPROCEDURAL MI AND 30 DAY MACE
Vincenzo Pasceri et al Circulation. 2004;110:674-678

36. ARMYDA-ACS
191 PTSWITH NSTEMI<48 HRS, ATORVASTATIN 80 MG 12 HRS AND 40 MG 2 HRS BEFORE PROCEDURE
PRIMARY END POINT :-30 DAY MACE,SECONDARY :-PERIPROCEDURAL MI
%
21
18
14/85
(17%)
13/85
(15%)
15
P=0.01
P=0.04
12
88%
9
4/86
(5%)
4/86
(5%)
6
1/85
(2%)
3
Individual and
Combined
Outcome
Measures of
the Primary
End Point at
30 days
0
Death
MI
Atorvastatin
TVR
Placebo
MACE
Composite
Primary End Point
(30-day death, MI, TVR)
J Am Coll Cardiol 2007;49:1272-8

37. ARMYDA-RECAPTURE
80 MG+40 MG BOLUS 12 HRS PRE PCI, EXCLUDED PATIENTS WITH STEMI,HIGH RISK ACS,
DERANGED LFT AND RFT CR>3,EF<30%
PRIMARY ENDPOINT:- OUTCOME MEASURES OF THE AT 30 DAYS
12
%
9.1
8.6
9
P=0.045
Atorvastatin
6
Placebo
3.4
3.4
3
0.5
0
Cardiac
death
0.5
MI
TVR
MACE
Composite
Primary End Point
REDUCTION OF 30 COMPOSITE MACE,NNT 17
Di Sciascio G et al J Am Coll Cardiol 2009

38. NAPLES II
NOVEL APPROACHES FOR PREVENTING OR LIMITING EVENTS
80 MG LOADING 24 HRS BEFORE PCI/PTS WITH CHR STABLE ANGINA/30 DAY MACE
Atorvastatin
Group
(N=338)
Control
Group
(N=330)
P value
Death
1 (0.3%)
0
NS
MI
33 (9.8%)
52 (15.8%)
0.014
Q-wave MI
1 (0.3%)
0
NS
Non Q-wave MI
32 (9.5%)
52 (15.8%)
0.014
Unplanned revasc
0
0
-
Stent thrombosis
2 (0.58%)
1 (0.30%)
0.57
Composite
34 (10%)
52 (15.7%)
0.029
EFFECT MORE PRONOUNCED IN PTS WITH HIGH BASELINE CRP
Carlo Briguori et al J Am Coll Cardiol 2009;54:00–00

39. STATINS IN PERIPROCEDURAL ANALYSIS
PCI META MI
30 DAY MACE
Giuseppe Patti, et al Circulation. 2011;123:1622-1632

40. REGRESSION OF
ATHEROSCLEROSIS

41. REVERSAL
REVERSAL OF ATHEROSCLEROSIS WITH AGGRESSIVE LIPID LOWERING
502 SYMPTOMATIC CORONARY ARTERY DISEASE PATIENTS WITH
ELEVATED LDL/FU 18 MNTHS/PRAVA 40 MG VS ATV 80 MG
NISSEN SE ET AL, JAMA : 291 : 1071-1080 ; 2004

42. REVERSAL
CONTINUOUS RELATIONSHIP BETWEEN LDL, CRP, AND PERCENT ATHEROMA VOLUME
3.5
3
2.5
2
1.5
Change In Percent
Atheroma Volume (%)
1
0.5
0
-100
-75
-50
-25
0
Change In LDL-C (mg/dL)
25
3.5
2.5
1.5
0.5
Change In Percent
Atheroma Volume (%)
-0.5
-1.5
-2.5
-14 -12 -10
-8
-6 -4 -2
0
Change In CRP (mg/L)
2
4
6
Nissen et al. N Engl J Med. 2005;352:29.
Nissen. Am J Cardiol. 2005;96(suppl):61F.

43. INTRAVASCULAR ULTRASOUND IMAGES AT
BASELINE AND FU
NISSEN SE ET AL, JAMA : 291 : 1071-1080 ; 2004

44. ARBITER
ARTERIAL BIOLOGY FOR THE INVESTIGATION OF THE TREATMENT EFFECTS OF REDUCING CHOLESTEROL*
COMPARISON OF ATV 80 mg, N = 79 VS PRAVASTATIN 40 mg, N = 82 ON CIMT 1 YEAR
ATORVASTATIN
 LDL ( mg/L) AT 1 YR
 CIMT REGRESSION
PRAVASTATIN
P VALUE
76 23
( - 48.5%)
110 30
( - 27.2%)
P = 0.001
- 0.034
0.02
0.025 + 0.017
p = 0.03
MARKED LDL REDUCTION WITH ATORVASTATIN PROVIDES SUPERIOR
EFFICACY OR ATHEROSCLEROSIS REGRESSION AT 1 YR
TAYLOR AJ ET AL : CIRCULATION 2002 ; 106 : 2055 – 2060

45. METEOR
MEASURING EFFECTS ON INTIMA-MEDIA THICKNESS: AN EVALUATION OF ROSUVASTATIN
984 INDIVIDUALS,LOW RISK FACTORS MODEST CIMT THICKENING (1.2-3.5 MM),
AND LDL MEAN, 154 mg/dl/F/U 2 YEARS/40 MG RSV VS PLACEBO
Rosuvastatin resulted in statistically significant reductions in
the rate of progression of maximum CIMT over 2 years vs
placebo in pts of low cardiovascular risk(Framingham risk
score<10%).
Rosuvastatin did not induce disease regression.
John R. Crouse IIIet al JAMA. 2007;297:1344-1353

46. ASTEROID
• 507 patients randomized to Rosuvastatin 40mg/d vs placebo
and atheroma volume measured by IVUS (349 pts followed up
at 2y)
• LDL-C decreased from 130mg/dL to 61mg/dL and HDL
increased by 14.7%
• Median change in atheroma volume – 0.79% with 5.6%
decrease in the most diseased subsegments (p<0.001)
• Well tolerated (1.8% patients had transaminase rise, none had
CK >10 times)
• Atheroma regression occurred in most patients and was not
linked to the LDL cholesterol achieved
Stephen D. Wiviott et al Am J Cardiol 2009;104:29–35

47. SATURN
1039 SUBJECTS ESTABLISHED CORONARY ARTERY DISEASE (CAD) ON
ANGIOGRAPHY RSV40 MG OR ATV80 MG 24 MONTHS
OTHER ATHEROSCLEROSIS REGRESSION STUDIES
Maximal doses of rosuvastatin and atorvastatin resulted
in significant regression of PLACEBO FOR 6 MONTHS IN ACS
ESTABLISH-ATORVASTATIN 20 MG V/Scoronary atherosclerosis.
COSMOS-LOW DOSE RSV IN JAPANESE PTS FOR 76 WKS
Despite the lower level of 20 MG-EQUIVALENT
JAPAN ACS-PITAVASTAIN 4 MG VS ATV LDL cholesterol and the
TOGETHAR-52higher level of HDL cholesterol achieved END POINTS ACHIEVED
WKS OF 2MG PITAVASTATIN-SOME with
rosuvastatin, a similar degree of regression of PAV was
HATS:-COMBINATION OF STATIN AND NIACIN
observed in the two treatment groups.
ASAP:-SIMVASTATIN IN HYPERCHOLESTEROLEMIC PTS DECREASED CIMT
STUDY IN DANISH MEN:-40 MG SIMVASTATIN
Stephen J. Nicholls et al N Engl J Med 2011;365:2078-87.

48. HIGH DOSE STATINS
META ANALYSIS
10 RCTs enrolling a total of 41778 participants.
Trials followed patients for a mean of 2.5 years.
Did not find statistically significant effects on all-cause mortality [relative risk
(RR) 0.92]or cardiovascular disease (CVD) deaths (RR 0.89)
Significant effect on non-fatal MIs (RR 0.82, P ≤ 0.0001) and a significant
reduction in the composite of fatal and non-fatal strokes reported in 10 RCTs
(RR 0.86,P=0.006).
 A subgroup analysis of three trials examining ACS patients found significant
effects on all-cause (RR 0.75 P ¼ 0.005) and CVD mortality (RR 0.74,P=
0.013) with intensive dosing.
Edward J. Mills et al European Heart Journal (2011) 32, 1409–1415

49. Across all 26 trials, all-cause mortality was reduced by 10% per 1·0
mmol/L LDL reduction (p<0·0001), largely reflecting significant
reductions in deaths due to coronary heart disease (p<0·0001) and
other cardiac causes (p=0·002), with no significant effect on deaths
due to stroke (p=0·5) or other vascular causes (p=0·8).
MACE
Cholesterol Treatment Trialists’ (CTT) Collaboration Lancet 2010; 376: 1670–81

50. ESC/EAS GUIDELINES European Heart Journal (2011) 32, 1769–1818

51. SPECIFIC SUBSETS
DIABETES
HYPERTENSION
STROKE
CONGESTIVE CARDIAC FAILURE
PERIPHERAL AETERIAL DISEASE
CHRONIC KIDNEY DISEASE
AORTIC STENOSIS
PERIOPERTIVE MORBIDITY
ATRIAL FIBRILLATION
WOMEN V/S MEN
ELDERLY

52. EFFICACY OF CHOLESTEROL-LOWERING IN DIABETES
META-ANALYSIS
DIABETES
Cholesterol Treatment Trialists’ (CTT) Collaborators,Lancet 2008; 371: 117–25

53. STATINS AND RISK OF INCIDENT DIABETES
META-ANALYSIS
13 statin trials with 91140 participants, of whom 4278 (2226 assigned
statins and 2052 assigned control treatment) developed diabetes during a
mean of 4 years.
Statin therapy is associated with a slightly increased risk of development of
Statin therapy was associated in absolute terms and when incident
diabetes, but the risk is low both with a 9% increased risk for compared with
diabetes (odds coronary events.
the reduction in ratio [OR] 1·09; 95% CI 1·02–1·17), with little
heterogeneity (I²=11%) between trials.
Clinical practice in patients with moderate or high cardiovascular risk or
Meta-regression showed that risk of development
existing cardiovascular disease should not change. of diabetes with
statins was highest in trials with older participants, but neither baseline
body-mass index nor change in difference between various statins
Analyses also showed no clear LDL-cholesterol concentrations in terms
accounted for
of diabetes risk.residual variation in risk.
Treatment of 255 (95% CI 150–852) patients with statins for 4 years
resulted in one extra case of diabetes.
Naveed Sattar et al Lancet 2010; 375: 735–42

54. EFFECT OF DIFFERENT STATINS ON INSULIN SENSITIVITY
META ANALYSIS
16 studies (n = 1146) were included, with patients receiving
Euglycemic three
pravastatin inclamp trials (n =164), atorvastatin in five trials (n
Minimum model (MIDMOD)
= 315), rosuvastatin in five trials (n = 419),and simvastatin in
Fasting (n = 369).
five trialssampled intravenous glucose tolerance test (FSIVGTT)
Insulin suppressiontest
Quantitative
When pooled insulin sensitivity check no significant impact on IS
as a class, statins had index (QUICKI)
Homeostasis model assessment (HOMA)
as compared with placebo/control[ p = 0.19].
Matsuda index
Stumvoll index
Pravastatin was found to significantly improved IS [p
Avignon index
=.03], whereas simvastatin significantly worsened [p = 0.03].
William L. Baker Et Al Diabetes Research And Clinical Practice 87 (2010 ) 98 – 107

56. ALLHAT LLT
HYPERTENSION
10355 HT PTS ,AGE >55 ,MEAN LDL 146,PRAVASTATIN40 MG V/S USUAL CARE/FU 8 YRS
CAVEATS
NON BLINDED DESIGN
SMALLER THAN EXPECTED DECREASE IN CHOLESTROL IN THE 2 GROUPS
30% CROSS OVER RATE
SUBSTANTIAL CHOLESTROL REDUCTION IN THE PLACEBO GROUP
ASSESSMENT ONLY IN HYPERTENSIVE POPULATION
PRAVASTATIN WAS USED

57. ASCOT
10305 PTS WITH HTN AND 3 OTHER RISK FACTORS, FU FOR 5.5 YRS
PRIMARY ENDPOINT—NONFATAL MI AND FATAL CHD
Cumulative Incidence (%)
Atorvastatin 10 mg
100
Placebo
4
Number of events
Number of events
154
36%
reduction
3
2
1
0
0.0
HR = 0.64 (0.50–0.83); p = 0.0005
0.5
1.0
1.5
2.0
Years
Excluded patients with MI, current
angina or Cerebrovascular events within
3 months
2.5
3.0
3.5
Sever PS et al. Lancet 2003;361:1149–1158.

58. ASCOT
SECONDARY ENDPOINT—FATAL MI AND NONFATAL STROKE
Cumulative Incidence (%)
3
Atorvastatin 10 mg
Number of events
89
Placebo
Number of events
121
27%
reduction
2
1
HR = 0.73 (0.56–0.96); p = 0.0236
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Sever PS et al. Lancet 2003;361:1149–1158.

59. ASCOT
SECONDARY ENDPOINT—ALL CV EVENTS AND PROCEDURES
Cumulative Incidence (%)
12
Atorvastatin 10 mg
389
Placebo
10
Number of events
Number of events
486
21%
reduction
8
6
Stopped prematurely after 3.3 y of f/u
due to early benefits noted
4
2
HR = 0.79 (0.69–0.90); p = 0.0005
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
Years
Sever PS et al. Lancet 2003;361:1149–1158.

60. STROKE
META ANALYSIS OF STATINS IN STROKE
Statins is not associated with an increase in haemorrhagic stroke
Statins reduce the incidence of stroke in high-risk populations (mainly patients with
coronary heart disease, diabetes, or hypertension) even with a normal baseline cholesterol
concentration.
Whether they actually reduce the incidence of recurrent strokes in secondary prevention is
unproved.
Pierre Amarenco et al Lancet Neurol 2004; 3: 271–78

61. SPARCL
(Stroke Prevention by Aggressive Reduction in Cholesterol Levels)
HR=0.58 (95% CI, 0.46-0.73)
P<.001; NNT/yr=144
HR=0.84 (95% CI, 0.71-0.99) P=.03;
NNT/yr=257
Any Coronary Event (%)
Fatal or Nonfatal Stroke (%)
Placebo
13.1%
Stroke (14.5%)
Placebo
8.6%
Coronary Event
Cause-specific adjusted hazard ratios in the atorvastatin
(33%)
group, as compared with the placebo group, were 0.78 for
ischemic stroke, 1.66 for hemorrhagic stroke, and 0.55
for unclassified stroke.
Atorvastatin, 80 mg
11.2%
0
Atorvastatin, 80 mg
5.2%
0
0
1
2
3
4
5
6
0
1
2
3
4
5
6
Years since Randomization
N=4731 patients with stroke or TIA within 1 to 6 months; Median follow-up: 4.9 years; Exclusion: patients with atrial
fibrillation, and other cardiac sources of embolism, subarachnoid hemorrhage
SPARCL Investigators. N Engl J Med. 2006;355:549-559.

62. Included published and unpublished data from 23 randomized trials and 19 observational
studies.
No evidence that statins were associated with intracerebral Hemorrhage; if
The complete data set comprised 248 391 patients is likely to intracerebral hemorrhages.
such a risk is present, its absolute magnitude and 14 784 be small and
outweighed by the other cardiovascular benefits of these drugs
Statins were not associated with an increased risk of intracerebral hemorrhage in
randomized trials (risk ratio, 1.10)cohort studies (risk ratio, 0.94), or case-control studies (risk
ratio, 0.60).
Daniel G. Hackam et al Circulation2011;124:2233-2242

63. ESC/EAS GUIDELINES European Heart Journal (2011) 32, 1769–1818

64. HEART FAILURE
Ten studies (10,192 patients) with follow-up from 3 to 47 months were
included. Three trials randomized patients to rosuvastatin, 1 tosimvastatin, and
6 to atorvastatin.
Overall, statins did not affect all-cause or cardiovascular mortality but did
CAVEATS
significantly decrease hospitalization for worsening HF during follow-up
In conclusion, 0.008).
(odds ratio [OR] 0.67, p meta-analysis of randomized controlled
GISSI and CORONA study showed no benefit
trials demonstrated trials are less
The number of subjects in otherthat statins are safe and improve
Patients randomized decrease had a significant 4.2% increase inHF. at
LVEF and to statins hospitalization for worsening LVEF
LVEF was not available for GISSI and CORONA studies and end of protocol.
follow-up (95% confidence interval 1.3 to 7.1, p 0.004).
No pathophysiological reason available to discriminate against rosuvastatin
Heterogenous group of pts including iscaemic and non ischaemic HF patients
Furthermore, post hoc analyses showed heterogeneity among different statins
and demonstrated that randomization to atorvastatin significantly decreased
all-cause mortality (OR 0.39, p 0.004), decreased hospitalization for
worsening HF (OR 0.30, p <0.000 01), and randomization to atorvastatin and
simvastatin led to a significant improvement in LVEF, whereas these benefits
were not observed in patients randomized to rosuvastatin.
Michael J. Lipinski et al Am J Cardiol 2009;104:1708–1716

65. EFFICACY OF STATIN THERAPY IN CHRONIC SYSTOLIC
CARDIAC INSUFFICIENCY: META-ANALYSIS
The pooling analysis showed that statin treatment did not significantly reduce the
risk of all-cause death (RR=0.93, p=0.31), death for cardiovascular cause or pump
failure (p=0.10), and rehospitalization for heart failure (RR=0.90, p=0.15).
Although statin has little impact on clinical outcomes in
overall CHF patients, non-significant trend towards is
In addition, statin therapy had astatin administration if neededreduced risk of
feasible to CHF patients, and the treatment might be
nonfatal myocardial infarction (RR=0.84, p=0.08).
effective when restricted to specific statins or populations.
When restricted to various statins and patients' age, the analysis demonstrated
that atorvastatin was associated with reduced all cause mortality (p=0.009) and
readmission rate for heart failure (p=0.005), and the superiority of statin therapy was
significant in CHF patients less than 65 years (both p=0.01).
Shuning Zhang et al European Journal of Internal Medicine 22 (2011) 478–484

66. PERIPHERAL ARTERIAL DISEASE
• Eighteen randomised controlled trials were included in the
review, involving a total of 10,049 participants (78% were men).
• Lipid-lowering therapies improved walking distance.
• No mortality benefit.
• CardiovascularLEADER
MACE significantly decreased
PQRST
• Benefit only present with statins.
HPS
• The greatest evidence was with simvastatin in people with a blood
cholesterol level of at least 3.5 mmol/litre
ST THOMAS TRIAL
• An improvement in total walking distance (Mean Difference152
m) and pain-free walking distance (MD 89.76 m) but no
significant impact on ankle brachial index.(MD 0.04)
• Results on Disease progression are inconclusive
Aung PP et al. Cochrane Database of Systematic Reviews 2007

67. AURORA
CHRONIC KIDNEY DISEASE
ROSUVASTATIN IN SUBJECTS ON REGULAR HEMODIALYSIS: AND ASSESSMENT OF
SURVIVAL AND CARDIOVASCULAR EVENTS
MULTICENTER RCT,2776 PTS B/N 50-80 YRS ON MAINTAINENCE HD,BASELINE LDL
100 MG,RSV 10 MG V/S PLACEBO,F/U 3.8 YRS
END POINT DEATH,NONFATAL MI AND STROKE
MAJOR CARDIOVASCULAR EVENT
CAVEATS
BASELINE LDL 100 MG
10 MG ROSUVASTATIN
EXCLUDED PATIENTS ALREADY ON STATIN
LOWER PRIMARY END POINT SUGGESTS THAT SELECTION BIAS IN
EXCLUDING PTS WHO WERE BELIEVED BY INVESTIGATORS TO REQUIRE
STATINS
INCLUDED ONLY PTS IN AGE GROUP OF 50-80 YRS
HIGH PROPORTION OF DISCONTINUATION
4D ON DIALYSIS DEPENDENT DIABETIC PATIENTS AND ALERT ON RENAL
TRANSPLANT PATIENTS CORROBORATED THE FINDINGS
Bengt C. Fellstrom et al N Engl J Med 2009;360:1395-407

68. SHARP TRIAL
STUDY OF HEART AND RENAL PROTECTION
9270CKD PTS,3023ON DIALYSIS,6427 NOT ON ,SIMVA 20 MG +EZETIMIBE 10 MG V/S
PLACEBO /F/U 4.9 YRS
CAVEATS
NOT ENOUGH POWER TO COMPARE DIALYSIS AND NON DIALYSIS
PATIENTS
ONE THIRD OF PATIENTS CROSSED OVER TO THE DIALYSIS GROUP
THE TRENDS OF DIFFERENCE IN MACE IN VARIOUS STAGES OF CKD
WITH T/T WAS NOT DIFFERENT
Colin Baigent et al Lancet 2011; 377: 2181–92

69. Bengt C. Fellstrom et al N Engl J Med 2009;360:1395-407

70. ESC/EAS GUIDELINES European Heart Journal (2011) 32, 1769–1818

71. NON RHEUMATIC AORTIC STENOSIS
Meta-analysis identified 10 studies with a total of 3822 participants (2214
non-statin-treated and 1608statin-treated); five studies were classified as
prospective and five as retrospective; three trials were randomised whereas
seven were not.
Currently available data do not support the use of statins to improve outcomes and
toNo significantprogression in non-rheumatic calcific aortic valve stenosis.
reduce disease differences were found in all-cause mortality, cardiovascular
mortality or in the need for aortic valve surgery.
Statins did not significantly affect the progression over time of peak and
mean aortic gradient.
Alessandro Parolaret al Heart 2011;97:523e529.

72. SEAS SIMVASTATIN AND EZETIMIBE IN AORTIC STENOSIS
1873 PATIENTS WITH MILD-TOMODERATE,ASYMPTOMATIC AORTIC STENOSIS.
40 MG OF SIMVASTATINPLUS 10 MG OF EZETIMIBE OR PLACEBO DAILY/FU 53.3 MONTHS
N Engl J Med 2008;359:1343-56.

73. META ANALYSIS OR >30000 PATIENTS
PERI OPERATIVE MORBIDITY
19 studies were identified [three RCT , 16 observational] that
reported outcomes of 31725 cardiac surgery patients with (n ¼ 17
201; 54%) or without (n ¼ 14 524; 46%) preoperative statin therapy.
Preoperative statin therapy resulted in a 1.5% absolute risk reduction
(2.2 vs. 3.7%; P , 0.0001) and 43% odds reduction for early allcause mortality (OR 0.57; 95%CI: 0.49–0.67).
A significant reduction (P , 0.01) in statin pretreated patients was
also observed for AF (OR 0.67,), stroke (OR-0.74,), but not for MI
(OR 1.11) or renal failure (OR 0.78, 95%CI: 0.46–1.31).
Oliver J. Liakopoulos et al European Heart Journal (2008) 29, 1548–1559

74. ATRIAL FIBRILLATION
In published data from 13 short term trials (4414
randomised patients, 659 events), statin treatment
seemed to reduce the odds of an episode of atrial fibrillation
by 39% (odds ratio 0.61, P<0.001), but there was significant
heterogeneity (P<0.001) between the trials.
The suggested beneficial effect of statins on atrial
fibrillation from publishedterm and mostly studies is not
In contrast,among 22 longer shorter term larger trials of
statin versus a comprehensive review of published
supported bycontrol (105 791 randomised patients, 2535
events), statin treatment was not associated with a significant
and unpublished evidence from larger to 1.03; P=0.24)
reduction in atrial fibrillation (0.95, 0.88 scale trials.
(P<0.001 for test of difference between the two sets of trials).
Seven longer term trials of more intensive versus standard
statin regimens (28 964 randomised patients and 1419 events)
also showed no evidence of a reduction in the risk of atrial
fibrillation(1.00, 0.90 to 1.12; P=0.99).
Kazem Rahimi et al BMJ 2011;342:d1250

75. WOMEN V/S MEN
META ANALYSIS
The cardiovascular event rate similar in women
and men (OR: 0.81 and 0.77 respectively).
Statin therapy is associated with significant decreases in
The benefit of statins in all-cause mortality in women
cardiovascular events and was statistically significant in both and men.
sexes, regardless of the type of control, baseline
risk, or type should be and in appropriate patients without
Statin therapyof endpoint usedin both primary and secondary
prevention.
regard to sex.
 All-cause mortality was also lower with
statin therapy both in women and men without significant
interaction by sex (p for interaction 0.4457).
William J. Kostis et al J Am Coll Cardiol 2012;59:572–82

76. SECONDARY PREVENTION META -ANALYSIS
ELDERLY (AGE>65)
Jonathan Afilalo et al J Am Coll Cardiol 2008;51:37–45

77. NIACIN

78. Meta-analysis: Predictive Value of HDL Cholesterol
CPPT: Coronary Primary Prevention Trial
LRCF: Lipid Research Clinics Prevalence Mortality
Follow-up Study
MRFIT: Multiple Risk Factor Intervention Trial
FHS:
Framingham Heart Study
1% increase
in HDL-C reduces
CHD risk by
2-3%

79. Efficacy of Extended-Release Niacin
HDL-C
Change from Baseline
30
20
10
0
-10
-20
10%
–3%
–5%
-30
15%
22%
–9%
–14% –17%
–12%
–22%
–17%
–11%
–24%
–28%
-40
-50
500
mg
26%
30% 29.5%
–21%
LDL-C
Lp(a)
–30%
–26%
–35%
–44%
TG
–39%
1000 1500 2000 2500 3000
mg
mg
mg
mg
mg
Goldberg A et al. Am J Cardiol 2000;85:1100-1105.

80. RANDOMIZED CONTROLLED CLINICAL TRIALS
OF NICOTINIC ACID
Arterial Biology for the Investigation of the
Treatment Effects of Reducing Cholesterol
Source
Imaging
Studies
Special
Agent(s)
Patients Receiving
Treatment n/Total
(%)
Follow-up
Duration,
years
Outcomesa
ARBITER 2
Niacin + statin
87/167 (52.1)
1
Decreased carotid IMT (P>0.05)
ARBITER 3
Niacin + statin
87/167 (52.1)
2
Decreased carotid IMT
ARBITER 6
Niacin + statin
97/208 (46.6)
1.2
Decreased carotid IMT
increase HDL-C by 21–24%
Singh IM et al. JAMA. 2007;298:786–798.

81. AIM HIGH
ADDITIONAL INVESTIGATORS IN THE ATHEROTHROMBOSISINTERVENTION IN METABOLIC SYNDROME WITH LOW HDL/HIGH
TRIGLYCERIDES: IMPACT ON GLOBAL HEALTH OUTCOMES
• 3414 participants with a history of CVD, LOW
FALLACIES
LDL<80 mg /dl low HDL-C(35 mg/dl), and high
TG(164 mg), all of them on simvastatin and
STOPPED PREMATURELY
ezetimibe were randomized to either niacin in
PLACEBO GROUP ALSO RECEIVED 50 MG IMMEDIATE RELEASE
gradually increasing doses DISCLOSURE DUE TO day
NIACIN TO MASK THE IDENTITY up to 2000 mg per FLUSHING
(n=1718) or placebo (n=1696).
STROKE INCIDENCE INCREASE WAS NOT SIGNIFICANT
•
NO CAUSAL RELATION OF NIACIN IN STROKE WAS ESTABLISHED
OTHER STUDIES AND META ANALYSIS DO NOT CORROBORATE THE
FINDINGS
 LDL LEVELS WERE VERY LOW AT ENTRY AS 94% PTS WERE ON
Of the participants, 515 were given a second
STATINS
LDL-cholesterol-lowering drug, ezetimibe , in order
LESS GENERALIZABLE RESULTS DUE TO LOW WOMEN PERCENTAGE
to maintain LDL-cholesterol levels at the target range
-15%
between 40 and 80 mg/dL.
The AIM-HIGH Investigators N Engl J Med 2011;365:2255-67

82. MACE
STROKE
ANY CARDIOVASCULAR
EVENT
Eric Bruckerta et al Atherosclerosis 210 (2010) 353–361

83. HPS 2- THRIVE
EXTENDED RELEASE NIACIN/LAROPIPRANT VERSUS MATCHING PLACEBO
Primary endpoints:-heart attack or coronary death, stroke, or the
need for revascularisation.
Secondary endpoints:- is to assess the effects on heart
attack, coronary death, stroke, and revascularisation separately
and to assess the effects on mortality both overall and in
various categories of causes of death, and of the effects on
major cardiovascular events in people with a history of
different diseases at the beginning of the study.
Enrollment: 25673
Start Date: January 2007
Estimated Study Completion Date: January 2013

84. CETP INHIBITORS

85. RADIANCE
850 PTS WEITH HETEROZYGOUS FAMILIAL
HYPERCHOLESTEROLEMIA/ATORVA+-TORCETRAPIB,F/U 2 YRS
N Engl J Med 2007;356:1620-30.

86. ILLUSTRATE
1188 CAD PTS ON ATV WITH LDL<100,RANDOMIZED,24 MONTH ,IVUS GUIDED FOLLOW UP
PRIMARY ENDPOINT
Change in Atheroma Volume
from Baseline (%)
0.3
p=0.72

0.19%
0.2
0.12%
0.1
The percent
change in
atheroma volume
did not differ
between
treatment groups
0
Torcetrapib
Placebo
N = 591
N = 597
Nissen SE et al. N Engl J Med 2007;356:13041316.

87. ILLUSTRATE
Potential mechanism of adverse outcomes associated with
Torcetrapib
• Interaction with e-NOS
lead to BP rise (RAAS)
• Enlarged HDL with
impaired interaction
with SR-B1 of the liver
• Induction of Endothelin1 secretion
• Interfere with the
reverse cholesterol
transport
• Aldosterone Like Effect

88. ILLUMINATE TRIAL
RCT OF TORCETRAPIB+ATORVASTATIN (N = 7,533) VS. ATORVASTATIN ALONE (N = 7,534) IN
PATIENTS AT HIGH RISK FOR CV EVENTS.
PRIMARY ENDPOINT WAS MAJOR CV EVENT.
Major CV Event
Death
8
(HR 1.25,
p = 0.001)
2
(HR 1.58,
p = 0.006)
6.2
6
5.0
%
1.2
1
4
0.8
2
Results
• Trial stopped early due to ↑ events in torcetrapib
group
• Increase in HDL at 12 months ↑ in torcetrapib
group (+34.2 mg/dl vs. +0.5 mg/dl, p < 0.001)
• SBP increase at 12 months ↑ in torcetrapib
group (5.4 mm Hg vs. 0.9 mm Hg, p < 0.001)
Conclusions
• Torcetrapib in addition to atorvastatin was
associated with increased major CV events and
increased mortality compared with atorvastatin
alone, despite being highly effective in raising
HDL
• Increase in blood pressure with torcetrapib did
not fully explain the increased mortality
•
0
0
Torcetrapib +
Atorvastatin
Atorvastatin
N Engl J Med 2007;357:2109-22

89. DAL VESSEL/OUTCOMES TRIAL
The dal-VESSEL trial has established the tolerability and safety of
CETP-inhibition with dalcetrapib in patients with or at risk of CHD.
Dalcetrapib reduced CETP activity and increased HDL-C levels
without affecting NO-dependent endothelial function, blood
pressure, or markers of inflammation and oxidative stress.
Thomas F. Lu scher1et al European Heart Journal (2012) 33, 857–865

90. • 30,000 patients with occlusive arterial disease in
North America, Europe and Asia
• Background LDL-lowering with atorvastatin
• Randomized to anacetrapib 100 mg vs. placebo
• Scheduled follow-up: 4 years
• Primary outcome: Coronary death, myocardial
infarction or coronary revascularization

91. FIBRATES

92. VA-HIT
VETERANS AFFAIRS HIGH-DENSITY LIPOPROTEIN CHOLESTEROL INTERVENTION TRIAL (HIT)
2351 MALE PTS WITH CAD LOW HDL(MEAN 32 MG) AND MODERATE
LDL(MEAN 111 MG)/GEMFIBROZIL1200 MG/ F U 5.1 YRS
% Change
10
6%
5
0
0%
-5
Gemfibrozil therapy resulted in a significant
-10
reduction in the risk of major cardiovascular
-15
events in patients with coronary disease whose primary
-20
lipid abnormality was a low HDL cholesterol level.
-25
-22%
-22%
-30
-29%
-35
-31%
LDL HDL TG NonfatalCHD Stroke
MI or Death
CHD
Death
Rubins HB et al. N Engl J Med. 1999

93. DAIS
DIABETES ATHEROSCLEROSIS INTERVENTION STUDY
418 DIABETIC WITH GOOD GLYCEMIC CONTROL ,MILD LIPID ABNORMALITY AND
DOCUMENTED CAD/50% PTS ASYMPTOMATIC,FENOFIBRATE V/S PLACEBO,FU 3YRS
The trial was not powered
to examine clinical endpoints, but there were
fewer in the fenofibrate group than the placebo
group (38 vs 50)
DAIS suggests that treatment with
fenofibrate reduces the angiographic
progression of coronary-artery
disease in type 2 diabetes.

94. FIELD
9795PTS WITH DM TYPE 2 /78% PTS WITH NO CAD/PRIMARY CHD DEATH OR NON
FATAL MI,ALSO ASSESSED PROGRSSION OF COMPLCATIONS/F/U 5 YRS
11% Reduction
P=.035
14
Event Rate, %
12
10
8
6
4
2
0
13.9
Placebo
Fenofibrate was associated with less albuminuria progression
12.5
Fenofibrate
(p=0·002), and less retinopathy needing laser treatment (5·2% vs
3·6%, p=0·0003).
21% Reduction
P=.003
11% Reduction
There was a slight increase in pancreatitis (0·5% vs 0·8%, p=0·031)
P=.16
7.4
and pulmonary embolism (0·7% vs 1·1%, p=0·022), but no other
24% Reduction
P=.01
5.9
5.9
significant adverse effects. 19% Increase
5.2
P=.22
4.2
Fenofibrate did not 3.2
significantly reduce the risk of the primary
outcome of coronary events. It did reduce total cardiovascular
2.2
1.9
events, mainly due to fewer non-fatal myocardial infarctions and
revascularisations.
CHD events Nonfatal MI
CHD Death
Total CVD
Coronary
revascularization
*Nonfatal MI and CHD death
†CHD events, stroke, CVD death, revascularizations
Keech A, et al. Lancet. 2005;366:1849-1861.

95. ACCORD
5518 DIABETIC PTS,SIMVASTATIN +/- FENOFIBRATE FU FOR 4.6 YRS
PRIMARY OUTCOME OCCURNCE OF FIRST MACE
The ACCORD Study Group N Engl J Med 2010;362:1563-74.

96. FIBRATES IN RISK REDUCTION
META ANALYSIS
Fibrate therapy reduced risk of vascular events (RR
0.75, P < 0.001); and in 5068 subjects with both high
triglycerides and low HDL-C (RR0.71, P < 0.001).
Fibrate treatment directed at markers of atherogenic
dyslipidemia substantiallyneither high triglycerides
Among 9872 subjects with reduce subsequent
nor low event risk.
vascularHDL-C,fibrate therapy did not reduce
subsequent vascular events (RR 0.96, 95% CI 0.85 to
1.09, P = 0.53).
Meng Lee et al Atherosclerosis 217 (2011) 492– 498

97. NUMBER OF CASES OF RHABDOMYOLYSIS IN
COMBINATION THERAPY WITH STATINS*
No. Cases Reported
Per Million Prescriptions
10
8.6
9
8
7
6
5
15-Fold Increase
4
3
2
1
0.58
0
Fenofibrate
Gemfibrozil
*Excludes cases involving cerivastatin
Jones PH, et al. Am J Cardiol. 2005;95:120-122.

98. EZETIMIBE

99. EXTENDED-RELEASE NIACIN OR EZETIMIBE AND
CAROTID INTIMA–MEDIA THICKNESS
Allen J. Taylor, M.D et al N Engl J Med 2009;361:2113-22

100. ARBITER 6-HALTS
315CAD PTS WITH LDL<100 AND HDL<50,F /U 14 MONTHSNIACIN/EZETIMIBE AS ADD ON
THERAPY TO BASELINE STATINS/END POINT CHANGE IN CIMT
Todd C. Villines, MD et al Am Coll Cardiol2010;55:2721–6

101. ENHANCE
720 PTS OF FAMILIAL HYPERCHOLESTEROLEMIA ON SIMVASTATIN+- EZETEMIBE/F/U 24 MONTHS
END POINT –B MODE USG GUIDED MEASUREMENT OF CIMT
John J.P. Kastelein Et Al N Engl J Med 358;14

102. IMPROVE IT
IMPROVED REDUCTION OF OUTCOMES: VYTORIN EFFICACY INTERNATIONAL TRIAL
• A multicenter, double-blind, randomized study to establish the
clinical benefit and safety of vytorin (ezetimibe/simvastatin
tablet) vs simvastatin monotherapy in high-risk subjects
presenting with acute coronary syndrome
• Primary Outcome Measures: death due to any cardiovascular
events, non-fatal coronary events, and non-fatal strokes
• Time Frame: Trial will continue until a minimum of 5,250
subjects have a primary endpoint event and each subject is
followed for a minimum of 2.5 years
• Enrollment: 18141 Study
• Start Date: October 2005
• Estimated Study Completion Date: June 2013

103. BILE ACID SEQUESTRANTS
• WHO CO-OPERATIVE TRIAL:-Pts randomized to clofibtrate had
significantly higher mortality during 9.3 yr follow up . Cause unknown.
Lancet. 1980 Aug 23;2(8191):379-85
• CORONARY DRUG PROJECT:-8341 post MI Men. Patients
randomized to 5 groups.2 arms of estrogen,1 of thyroxine,1 arm of niacin
and clofibrate1ST 3 arms discontinued,clofibrate had no benefit .only niacin
showed 11% lower mortality compared to placebo.JAm Coll CardioI1986;8:1245-55
• LIPID RESEARCH CLINICS PRIMARY PREVENTION
STUDY:-3806 Asymptomatic Pts With Familial Hypercholestrolemia
randomized to cholestyramine v/s placebo.24% risk in CHD death.19%
reduction in non fatal MI. This trial provided correlation of LDL and
mortality.
JAMA. 1984 Jan 20;251(3):351-64

104. META ANALYSIS ON COLSEVALAM
(N = 1018). THIS INCLUDED 301( COL + METFORMIN TRIAL,)280 (COL + INSULIN TRIAL),
AND 437 (COL + SULFONYLUREA TRIAL.
 Three double-blind, placebo-controlled trials in T2DM have now
independently confi rmed the HbA1c and LDL-C reductions with
COL.
 In each of the primary studies, a significant mean treatment
difference in HbA1c (−0.54%, −0.50%, and −0.54%) and LDL-C
(−15.9%, −12.8%, and −16.7%) resulted from the addition of 3.75
grams/day of COL to existing metformin, insulin, or sulfonylureabased therapy, respectively,
 TG (15%)and APOA I increased and HDL was constant.
Ishwarlal Jialal METABOLIC SYNDROME AND RELATED DISORDERS Volume 7, Number 3, 2009

105. OMEGA 3 FATTY ACIDS IN HIGH-RISK CV PATIENTS
META-ANALYSIS
A total of 29 RCTs (n = 35,144) with 25 reporting mortality and
Possible
14 reporting restenosis. mechanisms of benefit
Although not reaching conventional
Reduction of arrhythmias
statisticalrate
Heart significance, the evidence to a statistically
Omega-3 fatty acids were not associated with date
suggests that omega-3(relative riskinjury 0.88) or with
significant  Ischemia/reperfusion-inducedmay result
decreased mortality fatty acids [RR]=
in a Serum triglyceride levels
 modest (RR = 0.89,), though and
restenosis prevention reduction in mortalitythe probability of
restenosis
Inflammation
some benefit remains high (0.93 and 0.90, respectively).
 Improved endothelial function
No serious safety issues were identified.

106. LIPID AND SIDE EFFECTS
MONITORING

107. Adult Treatment Panel III guidelines 2003

108. ESC/EAS GUIDELINES European Heart Journal (2011) 32, 1769–1818

110. SUMMARY OF GUIDELINES OF
PHARMACOTHERPY
ESC/EAS
GUIDELINES
European Heart
Journal (2011)
32, 1769–1818

111. TAKE HOME MESSAGE
 In coronary artery disease ,stroke,perioperative morbidity the role
of statins is unquestionable
 Role of statins in heart failure, aortic stenosis, and atrial
fibrillation needs further evaluation.
 Ezetimibe lowers cholesterol but not the primary end points
 Niacin are rather underused.
 CETP inhibitors are not recommended(as of now)