Atorvastatin: Statins in CVD management. Is just lipid lowering enough
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Transcript of Atorvastatin: Statins in CVD management. Is just lipid lowering enough
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Statins in CVD management : Is just lipid lowering enough?
Dr Vivek BaligaConsultant Internal Medicine
Director, HeartSenseTM
www.heartsense.in
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Preamble• Statins were originally introduced as lipid lowering drugs, but
today they are recommended in many high risk patient groups irrespective of baseline lipid levels.
• This suggests that benefits of statins are beyond and independent of lipid lowering effects.
• So Choice of statin should be based on evidence of CV benefits rather than lipid lowering
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Primary Prevention of CVD• As per AHA 2013, guidelines all T2DM patients of age 40-75
require either moderate or high dose statin therapy
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2016 ADA guidelines for statins in DM
Diabetes Care 2016;39(supple 1): S1-S112
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All DM patients with> 1 CV risk factor require moderate to high dose statin
But what is the evidence that statins reduce CV events in T2DM patients without high LDL-C?
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MI Risk in Diabetics Without Prior MI Equivalent to Nondiabetic With MI
Haffner SM et al. N Engl J Med. 1998;339:229-234.
Numbers in bars represent number of persons in category at baseline.
Finnish population study (7-year follow-up)
3.5
20.218.8
45
0
10
20
30
40
50
60
Patients without diabetes Patients with diabetes
Inci
denc
e of
fata
l/non
fata
l MI
durin
g 7-
year
follo
w-u
p (%
)
No prior MI
Prior MI
P<0.001
P<0.001
P<0.001 for diabetes vs no diabetes
890130469 169
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Diabetes is CHD equivalent
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RM Parikh et al. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 4 (2010) 10–12
85.5%
Dyslipidemia
97.8 %
Dyslipidemia
85.5 %
Prevalence of Dyslipidemia (%) in Male T2 DM
Prevalence of Dyslipidemia (%) in Female T2DM
In India, 90% diabetics have dyslipidemia
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Study Patients Follow up Results
ASCOT LLA * 2532 Atorvastatin 10 mg
3.3 yrs 23% risk reduction
CARDS 2838 Atorvastatin 10 mg
3.9 yrs 37% risk reduction
HPS * 2912 Simvastatin 40 mg
5 yrs 33% risk reduction
Major Statin Primary Prevention Trials In DM
* sub-analysis
Only Atorvastatin and Simvastatin have evidence that statin reduce CV events in Primary prevention.
OTHERS DO NOT HAVE SUCH EVIDENCE!
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4-year follow-up
CARDS: primary prevention in T2DM Atorvastatin 10 mg/day
(n=1428)
Placebo(n=1410)
2838 patients
Primary end point: Incidence of major cardiovascular events:
– Cardiovascular-related death– Nonfatal MI– Stroke– Resuscitated cardiac arrest– Unstable angina– Coronary revascularization procedures
Patient population: Age: 40-75 years LDL-C 160 mg/dL Triglycerides 600 mg/dL Type 2 diabetes No prior MI or CHD 1+ CHD risk factor
C o l h o u n H M e t a l . L a n c e t . 2 0 0 4 ; 3 6 4 : 6 8 5 - 6 9 6 .CARDS: Collaborative Atorvastatin Diabetes Study
At Baseline,LDL-C: 120 mg/dlHDL-C: 54.5 mg/dlNon-HDL-C: 153 mg/dl
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CARDS: Atorvastatin reduces CV events by 37%
*Acute CHD event, coronary revascularization, stroke. RRR: Relative risk reduction
Colhoun HM et al. Lancet. 2004;364:685-696.
0
5
10
15
0 1 2 3 4 5 6
RRR=37% p=0.001
Cum
ulati
ve in
cide
nce
of e
vent
s (%
of p
atien
ts)
127 events
83 events
Time (years)
Atorvastatin 10 mg (n=1428)Placebo (n=1410)
median follow-up 3.9 years
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0
1
2
3
4
5
6
0 1 2 3 4 5 6
CARDS: Atorvastatin Reduces Stroke by 48% in T2DM
Newman C et al. American Heart Association 78th Scientific Sessions, 2005.
RRR= 48% (95% CI: 31%-89%)P=0.016
Cum
ulati
ve in
cide
nce
of e
vent
s (%
of p
atien
ts)
39 events
21 events
Time (years)
Atorvastatin 10 mg (n=1428)Placebo (n=1410) Median follow-up 3.9 years
Stroke was a component of the primary endpoint, evaluated individually as a secondary survival analysis.
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AHA and ADA guidelines for statin therapy in T2DM for primary prevention are based on
Atorvastatin’s CARDS trial
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Atorvastatin for Primary Prevention in High risk patients: ASCOT-LLA
A double-blind, placebo-controlled trial of atorvastatin 10 mg Vs Placebo in 10305 hypertensive patients studied
Median follow up: 3.3 years
Study end pointsPrimary: Combined nonfatal MI (including silent MI) and fatal CHD
Secondary: Fatal and nonfatal stroke
Total cardiovascular events and procedures
Total coronary events
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Atorvastatin 10 mg Number of events 89Placebo Number of events 121
0
1
2
3
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5
Years
Cum
ulati
ve In
cide
nce
(%)
HR = 0.73 (0.56-0.96)P = .0236
27% reduction
ASCOT-LLA
Primary Endpoint:Nonfatal MI and Fatal CHD
Secondary Endpoint:Fatal and Nonfatal Stroke
0
1
2
3
4
0.0 0.5 1.0 1.5 2.0 2.5 3.0 3.5Years
Cum
ulat
ive
Inci
denc
e (%
)
Atorvastatin 10 mg Number of events 100Placebo Number of events 154
36% reduction
HR = 0.64 (0.50-0.83)P = .0005
Sever PS, et al. Lancet. 2003;361:1149-1158.
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ASCOT-LLA: Primary prevention– DM Sub-analysis (yellow cells)
Highlighted boxes indicate diabetes patients enrolled in lipid-lowering arm.
-blocker ± diuretic CCB ± ACE inhibitor
TC >250 mg/dL (>6.5 mmol/L)
2532 TC 250 mg/dL(6.5 mmol/L)
TC >250 mg/dL (>6.5 mmol/L)
Open lipid lowering 1258 Atorvastatin 10 mg
1274Placebo Open lipid lowering
19,342 patients
Randomized
Randomized
Primary end point: Composite of fatal CHD and nonfatal MI
ASCOT: LLA: Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm Sever PS et al. J Hypertens. 2001;19:1139-1147. CCB: Calcium Channel Blocker ACE: Angiotension Convertase Inhibitor TC: Total Cholesterol
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ASCOT-LLA :23% RRR for total CV events in DM patients with atorvastatin
Sever PS et al. Diabetes Care. 2005;28:1151-1157.
0
5
10
15
0 1 2 3 4 5 6
RRR=23% P=0.036
151 events
116 events
median follow-up 3.3 years
Cum
ulati
ve in
cide
nce
of e
vent
s (%
of p
atien
ts)
Time (years)
Atorvastatin 10 mgPlacebo
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Statin in CKD patients
Alterations in Lipid Profiles in CKD
Clin J Am Soc Nephrol 2007; 2(4):766-85.
Triglycerides
HDL
Lipoprotein (a)
Normal or low LDL
Normal or low TC
VLDL remnants
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Dose of statins in patients with CKD
• Atorvastatin: No dose adjustment required• Rosuvastatin: In patients severe CKD with creatinine
clearance < 30 ml/min (not on hemodialysis), Maximum dose: 10 mg/day
• Pitavastatin: in patients with moderate/severe CKD (GFR: 15-59 ml/min) Maximum dose: 2 mg/day,
GFR: Glomerular Filtration Rate
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• Patients: 325 DM nephropathy patients urinary protein/creatinine ratios (UPCR): 500-5000 mg/g, LDL >90 mg/dL, and on ACEIs/ARBs for > 3 months.
• Patients divided in 3 groups: Rosuvastatin 10 mg, Rosuvastatin 40 mg and Atorvastatin 80 mg for duration of 52 weeks
• Baseline eGFR: 69-72 ml/min Baseline UPCR: 1160-1260 mg/g • The primary end point: Change in urinary protein/ creatinine ratio
from baseline to week 52
Atorvastatin vs Rosuvastatin in DM+ CKDPLANET I study
The Lancet Diabetes & Endocrinology 2015;3(3):181-90
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PLANET I: % Change in UPCR and eGFR
UPCR Change (%)
-14
-12
-10
-8
-6
-4
-2
0
2
4
-13
2
-4
Atorvastatin 80 mg
Rosuvastatin 10 mg
Rosuvastatin 40 mg
p=0.033
p=0.83
p=0.53
The Lancet Diabetes & Endocrinology 2015;3(3):181-90
Change in eGFR
-8
-7
-6
-5
-4
-3
-2
-1
0
-1.61
-3.7
-7.29
Atorvastatin 80 mgRosuvastatin 10 mg Rosuvastatin 40 mg
Conclusion: Atorvastatin seems to have more renoprotective effects for the studied chronic kidney disease population.
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de Zeeuw D. 2010European Renal Association-European Dialysis and Transplant Association Congress; June 27, 2010; Munich, Germany.
Atorvastatin vs Rosuvastatin for renal function PLANET I:
Adverse event
Rosuvastatin10 mg/day(n = 116)
Rosuvastatin 40 mg/day(n = 123)
Atorvastatin 80 mg/day(n = 110) p
Any renaladverse event
7.8 9.8 4.5 NS
Acute renal failure 0.0 4.1 0.9 <0.05
Serum creatininedoubling
0.0 4.9 0.0 <0.01
Serum creatininedoubling or acute
renal failure
0.0 7.3 0.9 <0.01
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• A meta-analysis of 5 clinical trials head to head comparing atorvastatin vs rosuvastatin
Atorvastatin Vs Rosuvastatin For Proteinuria: A Meta-analysis
Circ J 2012;76:1259-66
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Atorvastatin is safer than Rosuvastatin in DM patients with proteinuria
Atorvastatin is better than Rosuvastatin for reduction in proteinuria
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2013 KDIGO Guidelines for dyslipidemia management in CKD
• In adults aged > 50 years with eGFR< 60 ml/min/1.73 m2 but not treated with chronic dialysis or kidney transplantation (GFR categories G3a-G5), we recommend treatment with a statin or statin/ezetimibe combination. (1A)
• In adults aged > 50 years with CKD and eGFR> 60 ml/min/1.73m2 (GFR categories G1-G2) we recommend treatment with a statin. (1B)
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Rosuvastatin 20 mg (N=8901) MIStroke
Unstable Angina
CVD DeathCABG/PTCA
4-week run-in
Ridker PM et al, Circulation 2003;108:2292-2297
No Prior CVD/CKD/D
MMen >50, Women
>60 LDL <130 mg/dL hsCRP >2 mg/L
Placebo (N=8901)
Follow up: 1.9 yrs
Can we consider rosuvastatin for primary prevention in DM/CKD based on JUPITER?
Patients with DM and CKD were excluded from JUPITER, So there is no evidence for primary CV
prevention with rosuvastatin in DM/CKD!!!
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Statin for secondary prevention• Current guidelines recommend moderate to high dose of
statins for secondary prevention.• Atorvastatin has multiple landmark trials for secondary
prevention
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771 pts with NSTE-ACS sent to early coronary angiography (<48 hours)
Random
ization (N=191)
Atorvastatin 80 mg 12 hrs pre-angio;
further 40 mg 2 hrs before
N=96
Coronaryangiography
Placebo 12 hrs pre-angio;
further dose 2 hrs
before N=95
Primary end point:
30-day death, MI,
TVR
1st blood sample
(pre-PCI)
CK-MB, troponin-I, myoglobin, CRP
High dose Atorvastatin in ACSARMYDA-ACS trial
2nd and 3rd blood samples(8 and 24 hrs
post-PCI)
30 days
580 pts excluded for: - 451 statin therapy - 41 emergency angiography - 43 LVEF <30% - 30 contraindications to statins - 15 severe renal failure
PCI atorvastatin N=86
PCI placebo N=85
20 pts excluded for indication to: - medical therapy (N=8) - bypass surgery (N=12)
atorvast
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ARMYDA-ACS: Secondary end point
Post-PCI percent increase of CRP levels from baseline
%
63
147
P=0.01
JACC 2007:49:1272-78
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ARMYDA-ACS trialComposite primary end-point (30-day death, MI, TVR)
%
5
17
P=0.01
JACC 2007:49:1272-78
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• 383 patients with stable angina (53%) or NST-ACS (47%) and on chronic statin therapy (55% atorvastatin) undergoing PCI were randomized to atorvastatin reload (80 mg 12 h before intervention, 40-mg pre-procedural dose or placebo (n=191).
• All patients received long-term atorvastatin treatment thereafter (40 mg/day).
• The primary end point was 30-day incidence of major adverse cardiac events (cardiac death, myocardial infarction, or unplanned revascularization).
Loading atorvastatin in patients already on statin ARMYDA-RECAPTURE
J. Am. Coll. Cardiol. 2009;54;558-565
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ARMYDA-RECAPTURE: PRIMARY ENDPOINT
Series10
3
6
9
12
3.4
9.1
P=0.045
MA
CE
( %)
PlaceboAtorvastatin
Loading of Atorvastatin high dose before PCI can reduce the CV events
J. Am. Coll. Cardiol. 2009;54;558-565
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Atorvastatin 80 mg n=4,995
Primary Endpoint: Major cardiovascular event defined as coronary heart death (CHD), nonfatal M, resuscitated cardiac arrest, and fatal or nonfatal stroke at a mean follow-up of 4.9 years.
Atorvastatin for stable CAD TNT Trial
Presented at ACC 2005
Atorvastatin 10 mg n=5,006
10,003 patients with stable coronary heart disease Age 35-75 years, LDL between 130 and 250 mg/dL, triglyceride ≤ 600 mg/dL
19% female, mean age 60.3 yearsAll received atorvastatin 10 mg during 8 week open-label run-in period
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TNT Trial: Primary endpointHazard Ratio [HR]=0.78
p<0.001
Presented at ACC 2005
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4,162 patients with an Acute Coronary Syndrome < 10 days
ASA + Standard Medical Therapy
“Standard Therapy”Pravastatin 40 mg
“Intensive Therapy”Atorvastatin 80 mg
Duration: Mean 2 year follow-up (>925 events)
Atorvastatin in ACS: PROVE IT - TIMI 22
2x2 Factorial: Gatifloxacin vs. placebo
Double-blind
Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke
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CV events in PROVE IT study
Cannon et al. NEJM 2004 Ray et al. Am J Cardiol 2006
Death/MACEDeath/MI/Urg. Revascu.
↓33%↓16%
Intensive statin therapy provides more benefits than low/moderate Intensity statin
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Take Home Message
• CV protection with statin is not completely dependent on lipid lowering.
• Though rosuvastatin is slightly more effective than atorvastatin for lipid lowering, Atorvastatin has stronger evidence for CV protection
• Atorvastatin is approved in both primary and secondary prevention, while rosuvastatin is approved only in primary prevention in patients with hsCRP > 2 mg/L WITHOUT DM/CKD