Lipid lowering trials ppt

LIPID LOWERING TRIALSDR.NAVIN AGRAWAL

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.

Updated ATP III LDL-C Goals and Cutpoints for Therapy

Risk Category

LDL-C (mg/dL)

Goal

Initiation Level for

TLCConsideration Level for

Drug Therapy

High risk: CHD or CHD risk equivalents (10-yr risk >20%)

<100 (optional: <70)

100 100(<100: consider drug

options)

Moderately high risk: 2+ risk factors (10-yr risk 10–20%)

<130 (optional: <100)

130 130(100–129: consider drug

options)

Moderate risk: 2+ risk factors (10-yr risk <10%)

<130 130 160

Lower risk: 0–1 risk factor

<160 160 190 (160–189: LDL-C–lowering

drug optional)

Circulation 2004;110:227-239

RISK FACTORS Cigarette smoking Hypertension (BP 140/90 mm Hg or on antihypertensive medication) Low HDL cholesterol (40 mg/dL),Family history of premature CHD (CHD in male first-degree relative 55 years of age; CHD in female first-degree relative 65 years of age)Age:-men 45 years; women 55 years.

CHD History of myocardial infarction Unstable angina Stable angina Coronary artery procedures (angioplasty or bypass surgery)Evidence of clinically significant myocardial ischemia.

CHD RISK EQUIVALENTS Peripheral Arterial Disease Abdominal aortic aneurysm Carotid artery disease Transient ischemic attacks or stroke of carotid origin 50% obstruction of a carotid artery Diabetes, 2 risk factors with 10-year risk for hard CHD 20%.

0

50

100

150

200

250

300

350

400

450

JUPITER

WOSCOPS

AFCAPS/TexCAPS

HTN - Diuretics

HTN – Beta Blockers

Aspirin - M

en

Aspirin - W

omen

Num

ber N

eede

d to

Tre

at (5

yea

rs)

5-YEAR NNT VALUES FOR PRIMARY PREVENTION OF CVD

Ridker et al from the Jupiter study group

WOSCOPSAFCAPS/Tex CAPSASCOT-LLAALLHAT LLTCARDSASPEN MEGAJUPITER

Primary Prevention

SecondaryPrevention

4S

CARE

LIPIDGREACETNTAVERTIDEAL

MIRACLPROVE IT-TIMI 22A to Z (2004)STATIN STEMIARMYDA-ACSARMYDA-RECAPTURE

ACS

MAJOR STATIN TRIALS IN CAD

STATINS

PRIMARY PREVENTION

WOSCOPSWEST 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

0 1 2 3 4 5 60

2

4

6

8

10

12

Pravastatin 40 mg

Placebo

Years in Study

Percentwith

Events

31%Risk

Reduction

P=0.0001

James Shepherd, et al, N Engl J Med 1995;333:1301-7

AFCAPS/TexCAPS AIR FORCE/TEXAS CORONARY ATHEROSCLEROSIS PREVENTIONSTUDY

5608 MEN,997 WOMEN,MEAN LDL 150//F/U 5.2 YRS

primary end point:-Fatal/Nonfatal MI, Sudden Cardiac Death, Unstable Angina

0.03

0.06

0.04

0.01

0.00

Cu

mu

lati

ve I

ncid

en

ce

Years of Follow-up

>5

0.07

54321

0.05

0.02

37% riskreductionP < .001

Lovastatin (n = 3304)Placebo (n = 3301)

Downs JR, et al. JAMA. 1998;279:1615-1622.

0

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

Colhoun HM et al. Lancet 2004;364:685-696.

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.”

• 17802 men>50 and women >60 yrs• LDL<130• CRP>2• No CVD• No DM• Median Follow Up 1.9 Yrs• Primary End Point:- 1st Mace• Secondary End Point:-revasculariztion,hospitalisation From

Cv Cause,death From Any Cause• Randomized to rosuvastatin 20 mg vs placebo• Trial stopped early at 1.9 yrs of follow up

JUPITER Justification for the Use of statins in Prevention: an Intervention Trial Evaluating Rosuvastatin

Ridker PM et al NEJM 2008;2195

HAZARD RATIO

PRIMARY END POINT(1ST MACE):- 0.56MI,STROKE,DEATH FROM CV CAUSE:- 0.53REVASCULARIZATION OR HOSPITALIZATION:- 0.53DEATH FROM ANY CAUSE- 0.80

CAVEATS

HIGH LDL AND LOW HS CRP PATIENTS NOT INCLUDEDTRIAL STOPPED EARLY IN 2 YRSADVERSE EFFECTS OCCURING IN LATE THERAPY CANNOT BE RULED OUT SMALL INCREASE IN BLOOD GLUCOSE AND HBAIC REPORTED

META ANALYSIS OF PRIMARY PREVENTION TRIALS

J J Brugts et al BMJ 2009;338:b2376

70 388 people, of whom 23 681 (34%) were women and 16 078 (23%) had diabetes mellitus.

Mean follow-up was 4.1 years.

Statin therapy was associated with a significant risk reduction in all cause mortality of 12%, in major coronary events of 30%, and in major cerebrovascular events of 19%.

No evidence of an increased risk of cancer was observed.

In patients without established cardiovascular disease but with cardiovascular risk factors, statin use was associated with significantly improved survival and large reductions in the risk of major cardiovascular events.

CAVEATS

USE OF DIFFERENT TYPES AND DOSES OF STATINSDIFFERENT RISK PROFILE IN DIFFERENT STUDIESBENEFIT STRATIFIACTION FOR DIFFERENT RISK GROUPS NOT DONE

STABLE CAD

4S 4444 PTS WITH CAD,MEAN LDL 188MG DL/MEDIAN F/U 5.4 YRS/PLACEBO CONTROLLED

0.85

0.80

0.00

0.0

1.00

0.95

0.90

Pro

port

ion

Alive

Years Since Randomization

Placebo

Simvastatin

6432 5

Log rank P = .0003

This improvement in survival is accounted for by the 42% reduction in the risk of coronary death.

Scandinavian Simvastatin Survival Study Group. Lancet. 1994;344:1383-1389.

1

PRIMARY ENDPOINT :-TOTAL MORTALITY

CARE4159 CAD PTS (3583 MEN/576 WOMEN)WITH MED LDL 139 /F U 5 YRS

Adapted from Sacks FM, et al. N Engl J Med. 1996;335:1001-1009.

0

5

10

Incid

en

ce (

%)

Years

0

15

54321

Change in risk,24% reductionP = 0.003

Pravastatin(40 mg)

Placebo

Nonfatal MI or CHD Death

ALL CAUSE MORTALITY DECREASED BY 9%

CABG ↓26%PCI ↓23%STROKE↓ 31%TOTAL MI ↓25%FATAL MI ↓37%BENEFIT WOMEN>MEN

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

Pitt B et al. N Engl J Med. 1999;341:70-76.

0

5

10

15

20

25

Atorvastatin Angioplasty/UC

% of patients

with an ischemic

event

13%

21%

- 36% difference*

(P=0.048)

n=22 of 164 n=37 of 177

AVERTPRIMARY 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

CAVEATS

SMALL NUMBER OF PATIENTSHIGH INCIDENCE OF CROSSOVERNUMBER OF EVENTS IN BOTH GROUPS WERE LESSSHORT DURATION OF FOLLOW UPNOT APPLICABLE TO PATIENTS WITH HIGH RISK LESIONS OR TO UNSTABLE PATIENTS

HPS20536 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

TNT TRIAL

mean follow-up of 4.9 years

RRR= 22%

mean follow-up of 4.9 years

RRR= 22%

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

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

MEDIAN LDL 77 mg/dlMEDIAN LDL 77 mg/dl

MEDIAN LDL 101 MG/DLMEDIAN LDL 101 MG/DL

8.7%8.7%

10.9%10.9%

0%0%

4%4%

8%8%

12%12%

High-doseHigh-dose Low-doseLow-doseN = 4995N = 4995 N = 5006 N Engl J Med. 2005;352:1425-1435

HR=0.78 (0.69–0.89)P<0.001

TNT TRIALTNT TRIALThe 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.

2.0%2.0%

4.9%4.9%

0.5%0.5%

2.3%2.3%2.5%2.5%

6.2%6.2%

0.5%0.5%

3.1%3.1%

0%0%

2%2%

4%4%

6%6%

8%8%

CHD deathCHD death Nonfatal MINonfatal MI ResuscitationResuscitationafter cardiacafter cardiac

arrestarrest

StrokeStroke

High-doseHigh-dose Low-DoseLow-DoseN Engl J Med. 2005;352:1425-1435

P=0.004

P=0.02P=0.09

P=0.89

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

Pedersen TR et al. JAMA. 2005;294:2437-45.

Cumulativehazard (%)

Major coronary event*

Time from randomization (years)No. at riskSimvastatin 4449 4293 4165 4037 3917 1200Atorvastatin 4439 4285 4170 4053 3940 1182

16

12

8

4

01 2 3 4 50

Simvastatin(20 -40mg)

Atorvastatin(80 mg)

11% RRRHR = 0.89 (95% CI, 0.78–1.01) P = 0.07

*Death from CAD, nonfatal MI, cardiac arrest with resuscitation

IDEAL INCREMENTAL DECREASE IN ENDPOINTS THROUGH AGGRESSIVE LIPID LOWERING

Reduction in SECONDARY endpoint

Pedersen TR et al. JAMA. 2005;294:2437-45.

Cumulativehazard (%)

Any coronary heart disease*

Time from randomization (years)No. at riskSimvastatin 4449 3937 3920 3527 3370 1002Atorvastatin 4439 3984 3799 3632 3496 1032

40

30

20

10

01 2 3 4 50

Any cardiovascular disease†

Time from randomization (years)

4449 3841 3580 3338 3127 9084439 3902 3671 3469 3299 963

40

30

20

10

01 2 3 4 50

Simvastatin

Atorvastatin

Simvastatin

Atorvastatin

*Major coronary event, hospitalization for UA, coronary revascularizations†CHD endpoints, peripheral vascular disease, hospitalization for nonfatal CHF

Incremental Decrease in End Points Through Aggressive Lipid Lowering

16% RRRHR = 0.84 (95% CI, 0.76–0.91) P < 0.001

16% RRRHR = 0.84 (95% CI, 0.78–0.91) P < 0.001

POST CABG TRIAL1351 PTS 1 TO 11 YRS POST CABG,ANGIOGRAPHIC F/ U FOR 4 YRSANOTHER ARM OF STUDY COMPARED WARFARIN VS PLACEBO

POST CABG TRIAL1351 PTS 1 TO 11 YRS POST CABG,ANGIOGRAPHIC F/ U FOR 4 YRSANOTHER ARM OF STUDY COMPARED WARFARIN VS PLACEBO

AGGRESSIVE GROUP N = 675

MODERATE TREATMENT

N = 675

P VALUE

LDL LEVEL (mg/dL)

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 -

CHOLESTYRAMINE (gm) 8 8 -

Post-CABG Trial Investigators. N Engl J Med. 1997;336:153-162.

Primary end point: Mean per-patient percentage of grafts with significant progression in SVG (³0.6 mm change)Secondary end point: New occlusions, new lesions, lumen narrowing

Mean ldl level in aggressive group was 85mg v/s 135 mg in placebo group

P value

POST-CABG ANGIOGRAPHIC OUTCOMESMRE Difference

Moderate Aggressive %

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.


0

5

10

15

%

Yr after enrollment

Aggressive

Moderate

Event=PTCA or bypass surgery

P=0.03.

POST-CABG

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5


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

Nicholas J. Leeper et al Circulation 2007;116:613-8

No cases of rhabdomyolysis ↑ hepatic transaminase elevations, de novo malignancy or renal insufficiency

Mortality reduction by 35%CAVEATS

NON RANDOMIZED STUDYNON BLINDEDPRIMARY PHYSICIAN DEPENDENT DOSING AND DRUG PROTOCOLHIGH INCIDENCE OF CROSSOVERREDUCTION IN LDL FROM PLACEBO GROUP WAS LESS THAN EXPECTEDMORBID PATIENTS WERE PROBABLY TAKEN OFF STATINS LEADING TO INFLATION OF MORTALITY IN NON STATIN GROUP

MIRACL3086 PTS WITH UA:-24-96 HRS AFTER ADMISSION FOR 16 WEEKS

Relative risk = 0.84p=0.048

Atorvastatin 80 mg + Diet

Placebo + DIET

0

5

10

15

0 4 8 12 16Time since randomization (weeks)

Cu

mu

lati

ve I

nci

den

ce (

%)

Time to first occurrence of:• Death (any cause)• Nonfatal MI• Resuscitated cardiac arrest• Worsening angina with new

objective evidence requiring urgent rehospitalization

17.4%

14.8%

Schwartz GG et al. Jama 2001; 285: 1711-1718

Figure 4 Achieved CRP and LDL vs. Outcomes4500PTS,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

JAMA. 2004;292:1307-1316

FAILED TO ACHIEVE PRIMARY END POINT(P=0.14)BUT FAVOURED EARLYAND AGGRESSIVE STATIN REGIMENS

PROVE IT –TIMI 22PRAVASTATIN OR ATORVASTATIN EVALUATION AND INFECTION THERAPY

4162 ACS (WITHIN 10 DAYS)PTS/STABLE AFTER WITH NO PCI PLANNING/F/U 18-36 MNTHS THERAPY

Cannon CP, Eugene Braunwald, et al. N Engl J Med. 2004;350:1495-1504

16 %

PROVE IT–TIMI 22Clinical Relevance of Achieved LDL-C and Achieved CRP Combined after Statin

Therapy

Recu

rrent

MI or

Coro

nary

Death

(%)

Follow-up (Years)0.0 0.5 1.0 1.5 2.0 2.5

LDL 70 mg/dl, CRP 2 mg/L

LDL 70 mg/dl, CRP <2 mg/LLDL <70 mg/dl, CRP 2 mg/L

LDL <70 mg/dl, CRP <2 mg/L

LDL <70 mg/dl, CRP <1 mg/L

Series10.00

0.02

0.04

0.06

0.08

0.10

Ridker PM et al. N Engl J Med 2005;352:20-28

LUNAR STUDY825 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, andimproved other blood lipid parameters than ATV80 in patients with acute coronary

syndrome.

Bertram Pitt et al Am J Cardiol 2012;109:1239 –1246

ARMYDA ATORVASTATIN FOR REDUCTION OF MYOCARDIAL DAMAGE DURING ANGIOPLASTY

Vincenzo Pasceri et al Circulation. 2004;110:674-678

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

Individual and Combined Outcome

Measures of the Primary

End Point at 30 days

ARMYDA-ACS191 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

Death MI TVR MACE0

3

6

9

12

15

18

21

Atorvastatin Placebo

4/86(5%)

13/85 (15%)

1/85(2%)

14/85(17%)

4/86(5%)

P=0.04 P=0.01

%

CompositePrimary End Point

J Am Coll Cardiol 2007;49:1272-8

(30-day death, MI, TVR)

88%

8.69.1

P=0.045

ARMYDA-RECAPTURE

%

CompositePrimary End Point

3.4

0

3

6

9

12

Cardiac death

MI TVR MACE

Atorvastatin

Placebo

0.5 0.5

3.4

80 MG+40 MG BOLUS 12 HRS PRE PCI, EXCLUDED PATIENTS WITH STEMI,HIGH RISK ACS,DERANGED LFT AND RFT CR>3,EF<30%

REDUCTION OF 30 COMPOSITE MACE,NNT 17

Di Sciascio G et al J Am Coll Cardiol 2009

PRIMARY ENDPOINT:- OUTCOME MEASURES OF THE AT 30 DAYS

NAPLES IINOVEL APPROACHES FOR PREVENTING OR LIMITING EVENTS

80 MG LOADING 24 HRS BEFORE PCI/PTS WITH CHR STABLE ANGINA/30 DAY MACE

AtorvastatinGroup

(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

PERIPROCEDURAL MI

30 DAY MACE

STATINS IN PCI META ANALYSIS

Giuseppe Patti, et al Circulation. 2011;123:1622-1632

REGRESSION OF ATHEROSCLEROSIS

REVERSAL REVERSAL OF ATHEROSCLEROSIS WITH AGGRESSIVE LIPID LOWERING

NISSEN SE ET AL, JAMA : 291 : 1071-1080 ; 2004

502 SYMPTOMATIC CORONARY ARTERY DISEASE PATIENTS WITH ELEVATED LDL/FU 18 MNTHS/PRAVA 40 MG VS ATV 80 MG

REVERSALCONTINUOUS RELATIONSHIP BETWEEN LDL, CRP, AND PERCENT ATHEROMA VOLUME

Nissen et al. N Engl J Med. 2005;352:29.Nissen. Am J Cardiol. 2005;96(suppl):61F.

3.5

3

2.5

2

1.5

1

0.5

00 25-25-50

Change In LDL-C (mg/dL)-75-100

Change In PercentAtheroma Volume (%)

3.5

2.5

1.5

0.5

-0.5

-1.5

-2.50 642-2-6

Change In CRP (mg/L)-10 -4-8-12-14

Change In PercentAtheroma Volume (%)

INTRAVASCULAR ULTRASOUND IMAGES AT BASELINE AND FU

NISSEN SE ET AL, JAMA : 291 : 1071-1080 ; 2004

ARBITER ARTERIAL BIOLOGY FOR THE INVESTIGATION OF THE TREATMENT EFFECTS OF REDUCING CHOLESTEROL*

ATORVASTATIN PRAVASTATIN P VALUE

LDL ( mg/L) AT 1 YR76 23

( - 48.5%)110 30

( - 27.2%)P = 0.001

CIMT REGRESSION - 0.034 0.02 0.025 + 0.017p = 0.03

COMPARISON OF ATV 80 mg, N = 79 VS PRAVASTATIN 40 mg, N = 82 ON CIMT 1 YEAR

MARKED LDL REDUCTION WITH ATORVASTATIN PROVIDES SUPERIOR

EFFICACY OR ATHEROSCLEROSIS REGRESSION AT 1 YR

TAYLOR AJ ET AL : CIRCULATION 2002 ; 106 : 2055 – 2060

METEORMEASURING EFFECTS ON INTIMA-MEDIA THICKNESS: AN EVALUATION OF ROSUVASTATIN

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

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

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

SATURN 1039 SUBJECTS ESTABLISHED CORONARY ARTERY DISEASE (CAD) ON

ANGIOGRAPHY RSV40 MG OR ATV80 MG 24 MONTHS

Maximal doses of rosuvastatin and atorvastatin resulted in significant regression of coronary atherosclerosis.

Despite the lower level of LDL cholesterol and the higher level of HDL cholesterol achieved with rosuvastatin, a similar degree of regression of PAV was observed in the two treatment groups.

Stephen J. Nicholls et al N Engl J Med 2011;365:2078-87.

OTHER ATHEROSCLEROSIS REGRESSION STUDIES

ESTABLISH-ATORVASTATIN 20 MG V/S PLACEBO FOR 6 MONTHS IN ACSCOSMOS-LOW DOSE RSV IN JAPANESE PTS FOR 76 WKSJAPAN ACS-PITAVASTAIN 4 MG VS ATV 20 MG-EQUIVALENTTOGETHAR-52 WKS OF 2MG PITAVASTATIN-SOME END POINTS ACHIEVEDHATS:-COMBINATION OF STATIN AND NIACINASAP:-SIMVASTATIN IN HYPERCHOLESTEROLEMIC PTS DECREASED CIMTSTUDY IN DANISH MEN:-40 MG SIMVASTATIN

HIGH DOSE STATINS META ANALYSIS

Edward J. Mills et al European Heart Journal (2011) 32, 1409–1415

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.

Cholesterol Treatment Trialists’ (CTT) Collaboration Lancet 2010; 376: 1670–81

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

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

SPECIFIC SUBSETSDIABETESHYPERTENSIONSTROKECONGESTIVE CARDIAC FAILUREPERIPHERAL AETERIAL DISEASECHRONIC KIDNEY DISEASEAORTIC STENOSISPERIOPERTIVE MORBIDITYATRIAL FIBRILLATION WOMEN V/S MENELDERLY

EFFICACY OF CHOLESTEROL-LOWERING IN DIABETES

META-ANALYSIS

Cholesterol Treatment Trialists’ (CTT) Collaborators,Lancet 2008; 371: 117–25

DIABETES

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 was associated with a 9% increased risk for incident diabetes (odds ratio [OR] 1·09; 95% CI 1·02–1·17), with little heterogeneity (I²=11%) between trials.

Meta-regression showed that risk of development of diabetes with statins was highest in trials with older participants, but neither baseline body-mass index nor change in LDL-cholesterol concentrations accounted for 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

Statin therapy is associated with a slightly increased risk of development of diabetes, but the risk is low both in absolute terms and when compared with the reduction in coronary events.

Clinical practice in patients with moderate or high cardiovascular risk or existing cardiovascular disease should not change.

Analyses also showed no clear difference between various statins in terms of diabetes risk.

Euglycemic clampMinimum model (MIDMOD)Fasting sampled intravenous glucose tolerance test (FSIVGTT)Insulin suppressiontestQuantitative insulin sensitivity check index (QUICKI)Homeostasis model assessment (HOMA)Matsuda indexStumvoll indexAvignon index

EFFECT OF DIFFERENT STATINS ON INSULIN SENSITIVITYMETA ANALYSIS

16 studies (n = 1146) were included, with patients receiving pravastatin in three trials (n =164), atorvastatin in five trials (n = 315), rosuvastatin in five trials (n = 419),and simvastatin in five trials (n = 369).

When pooled as a class, statins had no significant impact on IS as compared with placebo/control[ p = 0.19].

Pravastatin was found to significantly improved IS [p =.03], whereas simvastatin significantly worsened [p = 0.03].

William L. Baker Et Al Diabetes Research And Clinical Practice 87 (2010 ) 98 – 107

ALLHAT LLT10355 HT PTS ,AGE >55 ,MEAN LDL 146,PRAVASTATIN40 MG V/S USUAL CARE/FU 8 YRS

CAVEATS

NON BLINDED DESIGNSMALLER THAN EXPECTED DECREASE IN CHOLESTROL IN THE 2 GROUPS30% CROSS OVER RATESUBSTANTIAL CHOLESTROL REDUCTION IN THE PLACEBO GROUPASSESSMENT ONLY IN HYPERTENSIVE POPULATIONPRAVASTATIN WAS USED

HYPERTENSION

Series10

1

2

3

4

Cu

mu

lati

ve I

nci

den

ce (

%)

Years

ASCOT 10305 PTS WITH HTN AND 3 OTHER RISK FACTORS, FU FOR 5.5 YRS

PRIMARY ENDPOINT—NONFATAL MI AND FATAL CHD

0.0 0.5

1.0

1.5

2.0

2.5

3.0

3.5

Atorvastatin 10 mg Number of events 100

Placebo Number of events 154

36%reduction

HR = 0.64 (0.50–0.83); p = 0.0005

Sever PS et al. Lancet 2003;361:1149–1158.

Excluded patients with MI, current angina or Cerebrovascular events within 3 months

Series10

1

2

3

Cu

mu

lati

ve I

nci

den

ce (

%)

Years

ASCOTSECONDARY ENDPOINT—FATAL MI AND NONFATAL STROKE

0.0 0.5

1.0

1.5

2.0

2.5

3.0

3.5



27%reduction

HR = 0.73 (0.56–0.96); p = 0.0236


Series10

2

4

6

8

10

12

Cu

mu

lati

ve I

nci

den

ce (

%)

Years

ASCOT SECONDARY ENDPOINT—ALL CV EVENTS AND PROCEDURES

0.0 0.5

1.0

1.5

2.0

2.5

3.0

3.5



21%reduction

HR = 0.79 (0.69–0.90); p = 0.0005


Stopped prematurely after 3.3 y of f/u due to early benefits noted

META ANALYSIS OF STATINS IN STROKE

Pierre Amarenco et al Lancet Neurol 2004; 3: 271–78

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.

STROKE

SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels)

SPARCL Investigators. N Engl J Med. 2006;355:549-559.

Fata

l or N

onfa

tal S

trok

e (%

)

Years since Randomization

0 1 2 3 4 5 60

4

8

12

16

Placebo 13.1%

Atorvastatin, 80 mg11.2%

HR=0.84 (95% CI, 0.71-0.99) P=.03; NNT/yr=257

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

0 1 2 3 4 5 60

4

8

12

16

HR=0.58 (95% CI, 0.46-0.73)P<.001; NNT/yr=144

Placebo 8.6%

Atorvastatin, 80 mg5.2%

Any

Coro

nary

Eve

nt (%

)

Stroke (14.5%) Coronary Event

(33%) Cause-specific adjusted hazard ratios in the atorvastatingroup, as compared with the placebo group, were 0.78 for ischemic stroke, 1.66 for hemorrhagic stroke, and 0.55 for unclassified stroke.

Included published and unpublished data from 23 randomized trials and 19 observational studies.

The complete data set comprised 248 391 patients and 14 784 intracerebral hemorrhages.

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).

No evidence that statins were associated with intracerebral Hemorrhage; if such a risk is present, its absolute magnitude is likely to be small and outweighed by the other cardiovascular benefits of these drugs

Daniel G. Hackam et al Circulation2011;124:2233-2242

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 significantly decrease hospitalization for worsening HF during follow-up (odds ratio [OR] 0.67, p 0.008).

Patients randomized to statins had a significant 4.2% increase in LVEF at follow-up (95% confidence interval 1.3 to 7.1, p 0.004).

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.

In conclusion, meta-analysis of randomized controlled trials demonstrated that statins are safe and improve LVEF and decrease hospitalization for worsening HF.

Michael J. Lipinski et al Am J Cardiol 2009;104:1708–1716

HEART FAILURE

CAVEATS

GISSI and CORONA study showed no benefitThe number of subjects in other trials are lessLVEF was not available for GISSI and CORONA studies and end of protocol.No pathophysiological reason available to discriminate against rosuvastatinHeterogenous group of pts including iscaemic and non ischaemic HF patients

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).

In addition, statin therapy had a non-significant trend towards reduced risk of nonfatal myocardial infarction (RR=0.84, p=0.08).

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).

Although statin has little impact on clinical outcomes in overall CHF patients, statin administration if needed is feasible to CHF patients, and the treatment might be effective when restricted to specific statins or populations.

Shuning Zhang et al European Journal of Internal Medicine 22 (2011) 478–484

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 MACE significantly decreased• Benefit only present with statins. • The greatest evidence was with simvastatin in people with a

blood cholesterol level of at least 3.5 mmol/litre• 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

LEADER PQRSTHPSST THOMAS TRIAL

Aung PP et al. Cochrane Database of Systematic Reviews 2007

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

AURORAROSUVASTATIN IN SUBJECTS ON REGULAR HEMODIALYSIS: AND ASSESSMENT OF

SURVIVAL AND CARDIOVASCULAR EVENTS

MAJOR CARDIOVASCULAR EVENT

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

CAVEATS

BASELINE LDL 100 MG10 MG ROSUVASTATINEXCLUDED PATIENTS ALREADY ON STATINLOWER 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 YRSHIGH PROPORTION OF DISCONTINUATION4D ON DIALYSIS DEPENDENT DIABETIC PATIENTS AND ALERT ON RENAL TRANSPLANT PATIENTS CORROBORATED THE FINDINGS

CHRONIC KIDNEY DISEASE

SHARP TRIALSTUDY 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

Colin Baigent et al Lancet 2011; 377: 2181–92

CAVEATS

NOT ENOUGH POWER TO COMPARE DIALYSIS AND NON DIALYSIS PATIENTSONE THIRD OF PATIENTS CROSSED OVER TO THE DIALYSIS GROUPTHE TRENDS OF DIFFERENCE IN MACE IN VARIOUS STAGES OF CKD WITH T/T WAS NOT DIFFERENT

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

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.

No significant 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.

Currently available data do not support the use of statins to improve outcomes and to reduce disease progression in non-rheumatic calcific aortic valve stenosis.

Alessandro Parolaret al Heart 2011;97:523e529.

NON RHEUMATIC AORTIC STENOSIS

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.

Oliver J. Liakopoulos et al European Heart Journal (2008) 29, 1548–1559

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 all-cause 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).

META ANALYSIS OR >30000 PATIENTSPERI OPERATIVE MORBIDITY

In published data from 13 short term trials (4414randomised patients, 659 events), statin treatmentseemed 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.

In contrast,among 22 longer term and mostly larger trials of statin versus control (105 791 randomised patients, 2535events), statin treatment was not associated with a significant reduction in atrial fibrillation (0.95, 0.88 to 1.03; P=0.24) (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).

The suggested beneficial effect of statins on atrial fibrillation from published shorter term studies is not supported by a comprehensive review of published and unpublished evidence from larger scale trials.

Kazem Rahimi et al BMJ 2011;342:d1250

ATRIAL FIBRILLATION

META ANALYSIS

The cardiovascular event rate similar in womenand men (OR: 0.81 and 0.77 respectively).

The benefit of statins was statistically significant in both sexes, regardless of the type of control, baselinerisk, or type of endpoint and in both primary and secondary prevention.

All-cause mortality was also lower withstatin therapy both in women and men without significant interaction by sex (p for interaction 0.4457).

Statin therapy is associated with significant decreases in cardiovascular events and in all-cause mortality in women and men.

Statin therapy should be used in appropriate patients without regard to sex.

William J. Kostis et al J Am Coll Cardiol 2012;59:572–82

WOMEN V/S MEN

SECONDARY PREVENTION META -ANALYSIS

Jonathan Afilalo et al J Am Coll Cardiol 2008;51:37–45

ELDERLY (AGE>65)

NIACIN

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% increasein HDL-C

reduces CHD risk by2-3%

Series1-50

-40

-30

-20

-10

0

10

20

30

Efficacy of Extended-Release NiacinC

han

ge f

rom

Base

line

2500 mg

3000 mg

Goldberg A et al. Am J Cardiol 2000;85:1100-1105.

2000 mg

1500 mg

1000 mg

500mg

HDL-C

LDL-CLp(a)

TG

–9%–14%

–22% –21%–17%

29.5%30%26%

22%15%

10%

–28%

–35% –44%–39%

–11%

–5%

–26%

–3%

–12%

–30%

–24%–17%

RANDOMIZED CONTROLLED CLINICAL TRIALS OF NICOTINIC ACID

SourceImaging 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

Singh IM et al. JAMA. 2007;298:786–798.

increase HDL-C by 21–24%

Arterial Biology for the Investigation of theTreatment Effects of Reducing Cholesterol

AIM HIGHADDITIONAL 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 LDL<80 mg /dl low HDL-C(35 mg/dl), and high TG(164 mg), all of them on simvastatin and ezetimibe were randomized to either niacin in gradually increasing doses up to 2000 mg per day (n=1718) or placebo (n=1696).

• Of the participants, 515 were given a second LDL-

cholesterol-lowering drug, ezetimibe , in order to maintain LDL-cholesterol levels at the target range between 40 and 80 mg/dL.

The AIM-HIGH Investigators N Engl J Med 2011;365:2255-67

FALLACIES

STOPPED PREMATURELY PLACEBO GROUP ALSO RECEIVED 50 MG IMMEDIATE RELEASE NIACIN TO MASK THE IDENTITY DISCLOSURE DUE TO FLUSHINGSTROKE INCIDENCE INCREASE WAS NOT SIGNIFICANTNO CAUSAL RELATION OF NIACIN IN STROKE WAS ESTABLISHEDOTHER STUDIES AND META ANALYSIS DO NOT CORROBORATE THE FINDINGS LDL LEVELS WERE VERY LOW AT ENTRY AS 94% PTS WERE ON STATINSLESS GENERALIZABLE RESULTS DUE TO LOW WOMEN PERCENTAGE -15%

Eric Bruckerta et al Atherosclerosis 210 (2010) 353–361

MACE

STROKE

ANY CARDIOVASCULAR EVENT

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

CETP INHIBITORS

RADIANCE850 PTS WEITH HETEROZYGOUS FAMILIAL

HYPERCHOLESTEROLEMIA/ATORVA+-TORCETRAPIB,F/U 2 YRS

N Engl J Med 2007;356:1620-30.

Series10

0.1

0.2

0.3

ILLUSTRATE1188 CAD PTS ON ATV WITH LDL<100,RANDOMIZED,24 MONTH ,IVUS GUIDED FOLLOW UP

PRIMARY ENDPOINT

Torcetrapib

p=0.72

0.12%

0.19%

The percent

change in

atheroma volume

did not differ

between

treatment groups

Placebo

Ch

an

ge in

Ath

ero

ma V

olu

me

from

Base

line (

%)

N = 591 N = 597

Nissen SE et al. N Engl J Med 2007;356:1304–1316.

• Interaction with e-NOS lead to BP rise (RAAS)

• Enlarged HDL with impaired interaction with SR-B1 of the liver

• Induction of Endothelin-1 secretion

• Interfere with the reverse cholesterol transport

• Aldosterone Like Effect

ILLUSTRATEPotential mechanism of adverse outcomes associated with

Torcetrapib

Series10

1

2

1.2

0.8

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•

Series10

2

4

6

8

6.2

5.0

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.

Torcetrapib + Atorvastatin

Atorvastatin

Major CV Event(HR 1.25,p = 0.001)

Death(HR 1.58,p = 0.006)

N Engl J Med 2007;357:2109-22

DAL VESSEL/OUTCOMES TRIAL

Thomas F. Lu¨scher1et al European Heart Journal (2012) 33, 857–865

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.

• 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

FIBRATES

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

LDL HDL TG Nonfatal MI or CHD

Death

CHD Death

Stroke-35-30-25-20-15-10

-505

10

0%

6%

-31%

-22% -22%

-29%

% C

han

ge

Rubins HB et al. N Engl J Med. 1999

Gemfibrozil therapy resulted in a significantreduction in the risk of major cardiovascularevents in patients with coronary disease whose primarylipid abnormality was a low HDL cholesterol level.

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 poweredto 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-arterydisease in type 2 diabetes.

FIELD9795PTS 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

Keech A, et al. Lancet. 2005;366:1849-1861.

CHD events Nonfatal MI CHD Death Total CVD Coronary0

2

4

6

8

10

12

14

5.9

4.2

1.9

13.9

7.4

5.2

3.22.2

12.5

5.9

Eve

nt

Rat

e, % 11% Reduction

P=.16

24% ReductionP=.01

11% ReductionP=.035

21% ReductionP=.003

19% IncreaseP=.22

PlaceboFenofibrate

*Nonfatal MI and CHD death†CHD events, stroke, CVD death, revascularizations

revascularization

Fenofibrate was associated with less albuminuria progression (p=0·002), and less retinopathy needing laser treatment (5·2% vs 3·6%, p=0·0003).

There was a slight increase in pancreatitis (0·5% vs 0·8%, p=0·031) and pulmonary embolism (0·7% vs 1·1%, p=0·022), but no other significant adverse effects.

Fenofibrate did not significantly reduce the risk of the primary outcome of coronary events. It did reduce total cardiovascular events, mainly due to fewer non-fatal myocardial infarctions and revascularisations.

ACCORD5518 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.

FIBRATES IN RISK REDUCTION META ANALYSIS

Fibrate therapy reduced risk of vascular events (RR0.75, P < 0.001); and in 5068 subjects with both high triglycerides and low HDL-C (RR0.71, P < 0.001).

Among 9872 subjects with neither high triglycerides nor low HDL-C,fibrate therapy did not reduce subsequent vascular events (RR 0.96, 95% CI 0.85 to 1.09, P = 0.53).

Fibrate treatment directed at markers of atherogenic dyslipidemia substantially reduce subsequent vascular event risk.

Meng Lee et al Atherosclerosis 217 (2011) 492– 498

NUMBER OF CASES OF RHABDOMYOLYSIS IN COMBINATION THERAPY WITH STATINS*

0.58

8.6

0

1

2

3

4

5

6

7

8

9

10

Fenofibrate Gemfibrozil

No

. C

ases

Rep

ort

ed

Per

Mil

lio

n P

resc

rip

tio

ns

15-Fold Increase

Jones PH, et al. Am J Cardiol. 2005;95:120-122.

*Excludes cases involving cerivastatin

EZETIMIBE

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

ARBITER 6-HALTS315CAD 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

ENHANCE720 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

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

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

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 sulfonylurea-based therapy, respectively,

TG (15%)and APOA I increased and HDL was constant.

Ishwarlal Jialal METABOLIC SYNDROME AND RELATED DISORDERS Volume 7, Number 3, 2009

A total of 29 RCTs (n = 35,144) with 25 reporting mortality and 14 reporting restenosis.

Omega-3 fatty acids were not associated with a statistically significant decreased mortality (relative risk [RR]= 0.88) or with restenosis prevention (RR = 0.89,), though the probability of some benefit remains high (0.93 and 0.90, respectively).

No serious safety issues were identified.

Although not reaching conventional statistical significance, the evidence to date suggests that omega-3 fatty acids may result in a modest reduction in mortality and restenosis

Possible mechanisms of benefitReduction of arrhythmiasHeart rate Ischemia/reperfusion-induced injury Serum triglyceride levels Inflammation Improved endothelial function

OMEGA 3 FATTY ACIDS IN HIGH-RISK CV PATIENTS META-ANALYSIS

LIPID AND SIDE EFFECTS MONITORING

Adult Treatment Panel III guidelines 2003

SUMMARY OF GUIDELINES OF PHARMACOTHERPY


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)

THANK YOUTHANK YOU

Lipid lowering trials ppt

Education

Transcript of Lipid lowering trials ppt