Professional Documents
Culture Documents
Assist Prof. Surarong Chinwong, Ph.D. Department of Pharmaceutical Care 1 Faculty of Pharmacy. Chiang Mai University.
Cavallari LH, DiDomenico RJ. Ischemic Heart Disease. In: CHISHOLM-BURNS MA, G.WELLS B, SCHWINGHAMMER TL, MALONE PM, KOLESAR JM, ROTSCHAFER JC, et al., editors. Pharmacotherapy: Principles & Practice. New York: The McGraw-Hill Companies, Inc.; 2008. p. 63-82
Cavallari LH, DiDomenico RJ. Ischemic Heart Disease. In: CHISHOLM-BURNS MA, G.WELLS B, SCHWINGHAMMER TL, MALONE PM, KOLESAR JM, ROTSCHAFER JC, et al., editors. Pharmacotherapy: Principles & Practice. New York: The McGraw-Hill Companies, Inc.; 2008. p. 63-82
What is atherosclerosis?
Atherosclerosis
7
Comes from the Greek words athero (meaning gruel or paste) and sclerosis (hardness) Condition where vascular smooth muscle cells, inflammatory cells, lipids, cholesterol and cellular waste accumulate in the inner lining of an artery Producing a fibro-fatty plaque Thickening of the arterial wall
TNF, TNF, interferon, IL-1, CRP Matrix metalloproteinase (MMP) fibrogenic mediator, GF
11
12
13
14
15
16
Myocardial ischaemia
T wave inversion, ST segment depression
Myocardial injury
ST segment elevation
abnormal Q-wave (broad (>1mm) and deep (>2mm or more than 25% of the amplitude of the following R wave)
http://www.publicsafety.net/12lead_dx.htm
ST-segment elevation MI
Presentation Working Dx
ECG
Normal
ECG
Markers
+
Biochem. Marker
No ST Elevation NSTEMI
ST Elevation
Diagnosis
Rule-Out
Unstable Angina
Acute MI
1. 2. 3. 4.
ST Elevation
Uns Angina
3.
2.
1.
, , , , , . ; 2007.
ASC
A: Aspirin, Antiplatelet and Antianginal therapy B: Beta blocker and Blood pressure C: Cigarette smoking and Cholesterol D: Diet and Diabetes E: Education and Exercise
(modifiable risk factors) atherosclerosis atherosclerosis plaques plague rupture thrombus embolus acute coronary syndrome
, , , , , . ; 2007.
30
31
29
27
, , , , , . ; 2007.
Aspirin
Indication (secondary prevention) Dosage and administration 160-325 mg. 75-325 mg/ Caution/precaution bronchospasm, angio-edema, anaphylaxis (active bleeding)
33
Clopidogrel, ticlopidine
Indication ASA ( ASA) (coronary stents) ASA 1 (Thai) ASA 1-9 (Thai) Dosage and administration Clopidogrel 300 mg. 75 mg/ Ticlopidine 500 mg. 250 mg. 2
34
Clopidogrel, ticlopidine
Dosage and administration
clopidogrel 75mg/ aspirin 12 acute coronary syndrome (AHA/ACC 2006 I (B) clopidogrel 75mg/ aspirin 1 bare metal stent, 3 sirolimus-eluting stent 6 paclitaxel-eluting stent (AHA/ACC 2006 I (B) rash, severe neutropenia, thrombotic, thrombocytopenic purpura (TTP) ticlopideine clopidogrel
35
Caution/precaution
Number of patients
19,185
CAPRIE1
Clopidogrel vs ASA
CLASSICS2
Clopidogrel* vs ticlopidine*
4 weeks
1,020
CURE3
Clopidogrel* vs placebo*
1 year
12,562
CURE Study
*On
1. CAPRIE Steering Committee. Lancet 1996; 348: 132939. 2. Bertrand NE et al. Circulation 2000; 102: 6249 3. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502.
ASA
ASA 3.6%
4
ASA
12
Clopidogrel
Clopidogrel 2.9%
p = 0.008, n = 19,185
0 0 3 6 9 12 15 18 21 24 27 30 33 36
p = 0.043, n = 19,185
0 0 3 6 9 12 15 18 21 24 27 30 33 36
Months of follow-up
*ITT analysis 1. Gent M. Circulation 1997; 96(suppl 8): I-467.
Months of follow-up
*ITT analysis CAPRIE Steering Committee. Lancet 1996; 348: 132939.
CURE: Design1
C 3 lo do 00m p i d se g og lo re ad l in g
n = 12,562 28 countries
Clopidogrel
75mg o.d. (n = 6,259)
Patients with acute coronary syndrome (unstable angina or non-Q-wave myocardial infarction)
Placebo* (n = 6,303)
Clopidogrel* (n = 6,259)
or 1 2 m fin a l o n th vis it
vis i
vis i
th
th
vis i
th
th
vis i
Placebo
1m on
3m on
6m on
9m on
12
Pl ac
Months of follow-up
*On top of standard therapy (including ASA) 1. The CURE Trial Investigators. N Engl J Med 2001; 345: 494502. 2. Data on file, 2002, p73 internal CSR-EFC 3307.
R = Randomization
Warfarin
Indication
Beta-adrenergic blockers
Indication ( ) AF ventricular rate
45
warfarin INR 2 3 paroxymal chronic atrial fibrillation flutter ( atrial fibrillation, left ventricular thrombus) drug-drug food drug interaction
Caution/precaution
44
Beta-adrenergic blockers
Indication (AHA/ACC 2006)
Start and continue indefinitely in all patients who have had myocardial infarction, acute coronary syndrome, or left ventricular dysfunction with or without heart failure symptoms, unless contraindicated. I (A) Consider chronic therapy for all other patients with coronary or other vascular disease or diabetes unless contraindicated. IIa (C)
46
Beta-adrenergic blockers
Dosage and administration Atenolol 50-200 mg/ Metoprolol 50-200 mg/ Propranolol 20-80 mg. 2 Bisoprolol 5-10 mg/
47
Beta-adrenergic blockers
Caution/precaution -blockers (<60 ) SBP <100 mmHg PR interval >0.24 sec second third degree AV block bifascicular block
48
Diltiazem 120-320 mg/ Verapamil 120-480 mg/ Amlodipine 5-10 mg/ Felodipine 5-10 mg/
51
ACE inhibitors
Indication (secondary prevention) LVEF<0.40, large anterior wall MI, LVEF<0.40 / -blockers nitrates
52 53
ACE inhibitors
Indication (AHA/ACC 2006)
Start and continue indefinitely in all patients with left ventricular ejection fraction 40% and in those with hypertension, diabetes, or chronic kidney disease, unless contraindicated I (A) Consider for all other patients I (B)
ACE inhibitors
Dosage and administration
Captopril 150 mg/ Enalapril 40 mg/ Lisinopril 40 mg/ Fosinopril 40 mg/ Ramipril 10 mg/ Quinapril 40 mg/
54
55
ACE inhibitors
Caution/precaution
56
57
Aldosterone antagonist
Indication
Nitrates
Indication ( ) Dosage and administration NTG 1 1 5 NTG 10 g/min 5 IV NTG 200 g/min long-acting nitrates 24
58 59
Isosorbide dinitrate
Treatment & prophylaxis of angina pectoris Oral tablet: 5 20mg daily 4 maintenance 10 40mg 4 30 Sublingual: 1 2 tab 2 3 Acute angina Sublingual: 1 tab ( 15 )
60
Isosorbide mononitrate
Prophylaxis of angina pectoris Immediate release 5 -20mg 5mg 10mg 2-3 20mg twice/day 7 Sustained release 1 tab 2 tab tab daily
61
Nitrates Caution/precaution
Antidyslipidaemic agents
63
lipoprotein Chylomicrons Low-density lipoprotein cholesterol (LDL-C) Low-density lipoprotein cholesterol (LDL-C) and Very-low-density lipoprotein cholesterol (VLDL-C) Intermediate-density lipoprotein cholesterol (IDL-C) Very-low-density lipoprotein cholesterol (VLDL-C) Very-low-density lipoprotein cholesterol (VLDL-C) Chylomicrons
64
125
United States
100 75
50
25
Existing CHD
Yes
Patients
4444 male and female, aged 3570 6595 male, aged 4564 4159 male and female, aged 2175 9014 male and female, aged 3175 6605 male and female, aged 4573 20536 male and female, aged 4080 10305 male and female, aged 4079
Cholesterol Raised
4S1
WOSCOPS2
Mean LDL-C 4.97 mmol/L, 192 mg/dL Mean LDL-C 3.59 mmol/L, 139 mg/dL Mean LDL-C 3.80 mmol/L, 147 mg/dL Mean LDL-C 3.89 mmol/L, 150 mg/dL
Raised
4.9
CARE3
Average
5.0
LIPID4
Yes
Average
6.1
No
Average
5.2
simvastatin 40 mg od
Yes
Mean LDL-C 3.4 mmol/L, 130 mg/dL Mean LDL-C 3.4 mmol/L, 130 mg/dL
Low/average
Low/average
5.0 3.3 69
ASCOT-LLA7 atorvastatin
10 mg od
In some patients
Spectrum of Risk
30 25
CHD/high cholesterol CHD/average to high cholesterol CHD*/average to high cholesterol CHD/average cholesterol Some patients with CHD/ average cholesterol No MI/high cholesterol No CHD/average cholesterol 70
Before 2001
- Primary prevention Rx - Statin therapy Pl - Placebo
4S1
Increasing absolute CHD risk
20 15
10 5
ASCOT - Rx ALLHAT - Rx ALLHAT - Pl WOSCOPS - Rx AFCAPS/TexCAPS - Pl ASCOT - Pl 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4) WOSCOPS - Pl
AFCAPS/TexCAPS7
*CHD or CHD risk equivalent, e.g. diabetes
0
70 (1.8)
90 (2.3)
130 (3.4)
71
Before 2001
30
- Secondary prevention
Before 2001
30
- Primary prevention - Secondary prevention 4S - Pl 4S - Pl
20 15
LIPID - Rx CARE - Rx PROSPER - Rx HPS - Rx
20 15
LIPID - Rx CARE - Rx PROSPER - Rx HPS - Rx
4S - Rx LIPID - Pl CARE - Pl PROSPER - Pl HPS - Pl ALLHAT - Pl WOSCOPS - Rx AFCAPS/TexCAPS - Pl ASCOT - Pl 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4) WOSCOPS - Pl
10 5 0
10 5
ALLHAT - Rx
ASCOT - Rx
0
90 (2.3) 110 (2.8) 130 (3.4) 150 (3.9) 170 (4.4) 190 (5.0) 210 (5.4) 70 (1.8)
70 (1.8)
90 (2.3)
130 (3.4)
72
73
CHD Risk
Curvilinear: The lower, the better, with diminishing returns Linear: The lower, the better
0
100
LDL-C (mg/dL)
Background
Statin therapy is highly effective vs. placebo in long-term treatment of CHD
l
Are statins effective in reducing events in patients with an acute coronary syndrome (ACS)? Does intensive LDL-C lowering to an average of 65 mg/dL achieve a greater reduction in clinical events than standard LDL-C lowering to an average of 95 mg/dL?
21%
Pravastatin 40mg
60
49%
40
Atorvastatin 80mg
P<0.001
2x2 Factorial: Gatifloxacin vs. placebo Duration: Mean 2 year follow-up (>925 events)
20
<24h Rand. 30 Days 4 Mos. 8 Mos. 16 Mos. Final
Primary Endpoint: Death, MI, Documented UA requiring hospitalization, revascularization (> 30 days after randomization), or Stroke
Note: Changes in LDL-C may differ from prior trials: 25% of patients on statins prior to ACS event ACS response lowers LDL-C from true baseline
30 Days 17% 1.9% 6.3% 12.2% 22.4%* 2.2% 7.7% 14.1% 26.3%* 90 Days 18% 180 Days 14% End of Follow-up 16%
21 24 27 30 0.5 0.75 Atorvastatin 80mg Better 1.5 1.0 1.25
% with 15 Event
10 5 0 0 3 6 9 12
20
16% RR (P = 0.005)
15
18
Months of Follow-up
Atorvastatin 10 mg (n=5006) Age (mean; years) Male (%) Previous MI (%) Angina (%) Coronary Revascularization (%) Angioplasty Bypass LDL Cholesterol (mean, mg/dl) Total Cholesterol (mean, mg/dl) 60.9 80.8 57.7 81.2
90
Hazard Ratio (95% CI) 0.78 (0.69-0.89) 0.80 (0.61-1.03) 0.78 (0.66-0.93) 0.96 (0.56-1.67) 0.75 (0.59-0.96)
P-value
<0.001
127 (2.5%)
101 (2.0%)
0.09
308 (6.2%)
243 (4.9%)
0.004
26 (0.5%)
25 (0.5%)
0.89
155 (3.1%)
117 (2.3%)
0.02
92
High-dose atorvastatin
HR = 0.78 (0.69-0.89),P<0.001 80 mg/day If LDL was <40 mg/dL at 24 wks dose could be reduced to 40 mg/day
Standard-dose simvastatin
20 mg/day If cholesterol >190 mg/dL at 24 wks dose could be increased to 40 mg/day
n=4,439
n=4,449
Years
93
Primary Endpoint: Composite of major coronary event, defined as coronary death, hospitalization for non-fatal acute MI or resuscitated cardiac arrest. Secondary Endpoint: Major cardiovascular events, anyCHD event, hospitalization with a primary diagnosis of congestive heart failure, peripheral artery disease, any cardiovascular events and all94 cause mortality. Presented at AHA
12
10.4
9.3
9 6 3 0 Atorvastatin Simvastatin
The primary composite endpoint of major coronary event occurred in 9.3% of the atorvastatin group and 10.4% of the simvastatin group.
* Major coronary event defined as coronary death, hospitalization for non-fatal acute MI or resuscitated cardiac arrest.
96
p=0.02
7.2 7.2
32 32
26.5 26.5
30.8 30.8
p=0.90 %
3.9 3.9
4.0 4.0
24 24
p=0.02
Major cardiovascular events, defined as any primary event plus stroke, occurred less often in the atorvastatin group. Any cardiovascular event, defined as major CV event plus hospitalization for CHF and peripheral artery disease, also occurred less often in the atorvastatin 98 group.
Presented at AHA 2005
4 4 2 2 0 0
16 16 8 8
12.0 12.0
13.7 13.7
p=NS
0.2 0.2
0.2 0.2
Nonfatal MI Nonfatal MI
Simvastatin Simvastatin
Presented at AHA 2005
Atorvastatin Atorvastatin
99
100
102
104
20 15 10 5 0 30 50 70 90 110
TNT 80
40
130 150 170 190 210
105
70
100
130
160
190
107
LDL Cholesterol (mg/dl) Updated from - OKeefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.
LDL-C (mg/dL)
Grundy SM et al. Circulation 2004;110:227239.
ATP III LDL-C Goals and Cutpoints for TLC and Drug Therapy in Different Risk Categories and Proposed Modifications Based on Recent Clinical Trial Evidence
Risk Category High risk: CHD or CHD risk equivalents (10-year risk >20%) Moderately high risk: 2+ risk factors (10-year risk 10% to 20%) Moderate risk: 2+ risk factors (10 year risk <10%) Lower risk: 0-1 risk factor LDL-C Goal <100 mg/dL (optional goal: <70 mg/dL) Initiate TLC Consider Drug Therapy 100 mg/dL (<100 mg/dL: consider drug options) 130 mg/dL (100-129 mg/dL: consider drug options) 160 mg/dL 190 mg/dL (160-189 mg/dL: LDL-lowering drug optional) 108
100 mg/dL
<130 mg/dL
130 mg/dL
CHD in male first-degree relative < 55 years CHD in female first-degree relative < 65 years
Age
<130 mg/dL
130 mg/dL
<160 mg/dL
160 mg/dL
Aggressive lipid lowering therapy with statins is effective in preventing cardiovascular events Intensive lipid lowering with highdose statin therapy provides a significant benefit over standard-dose therapy Evidences support the concept that lower is better
111
Doses of Currently Available Statins Required to Attain an Approximate 30% to 40% Reduction of LDL-C Levels (Standard Doses)
Drug
Atorvastatin Lovastatin Pravastatin Simvastatin Fluvastatin Rosuvastatin
Dose, mg/d
All of these are available at doses up to 80 mg. For every doubling of the dose above the standard dose, an approximate 6% decrease in LDL-C level can be obtained. For rosuvastatin, doses available up to 40 mg; the efficacy for 5 mg is estimated by subtracting 6% from the FDA reported efficacy at 10 mg
114
Liao JK, et al. Annual Review of Pharmacology and Toxicology 2005;45: 89-118.
117
Endres M. Statins: Potential new indications in inflammatory conditions. Atherosclesis 118 Supplement 2006;7: 31-35.
Failure to achieve LDL-C goal Each doubling of a statin dose provides only 6% additional LDL-C reduction Rule of six
inhibit Rac1 mediated NAD(P)H oxidase activity
119 121
Liao JK, et al. Annual Review of Pharmacology and Toxicology 2005;45: 89-118.
SPARCL was designed to evaluate whether high-dose statin treatment reduces risk of stroke in patients with a recent stroke or TIA and no history of coronary heart disease
SPARCL Trial
SPARCL Investigators. Cerebrovasc Dis. 2003;16:389-95. Heart Protection Study Collaborative Group. Lancet. 2004;363:757-67.
Placebo n = 2366
Primary end point: Fatal/nonfatal stroke Secondary end points: Major coronary or CV events Follow-up: ~5 years (until >540 primary end points)
SPARCL Investigators. N Engl J Med. 2006;355:549-59.
2 (0.1)
Atorvastatin
<0.001 0.004
TIA
*Adjusted
*Adjusted
Placebo
Placebo
10
Atorvastatin
Atorvastatin
SPARCL: Summary
Atorvastatin 80 mg yielded: Primary end point
16% fatal/nonfatal stroke (P = 0.03)
Significant benefit despite small hemorrhagic stroke with atorvastatin (2.3%) vs placebo (1.4%)
SPARCL: Implications
Aggressive statin therapy should be strongly considered soon after stroke or TIA Magnitude of benefit may vary depending on baseline stroke subtype SPARCL results support the concept of stroke or TIA as a CHD risk equivalent
35% major coronary events (P = 0.003) 20% major CV events (P = 0.002) 42% any coronary events (P < 0.001) 26% any CV events (P < 0.001) 45% revascularizations (P < 0.001)
SPARCL Investigators. N Engl J Med. 2006;355:549-59.
Investigate whether an acute atorvastatin reload before percutaneous coronary intervention (PCI) protects patients receiving chronic statin therapy from periprocedural myocardial damage.
ASTEROID Trial
Patients with coronary artery disease who require coronary angiography
Open-label; mean age 58.5 years; mean follow-up at 2 years; 29% female.
All enrolled patients: 40 mg rosuvastatin, IVUS of a single vessel not intervened upon at baseline n=507
Withdrawn consent, withdrawn for other reasons, adverse event (n=63), n=158
Primary Endpoint: 1) Change in percent atheroma volume and 2) change in nominal atheroma volume in the 10 mm subsegment with the greatest disease severity at baseline. Secondary Endpoint: Change in normalized total atheroma volume for the entire artery.
Sipahi I, Nicholls S, Tuzcu E, Nissen S. Interpreting the ASTEROID trial: Coronary atherosclerosis can regress with very intensive statin therapy. Cleve Clin J Med, 2006; 73:937-944. Reprinted with permission. Copyright 2006. Cleveland Clinic Foundation. All rights reserved.
Before
After
- 6.8%
*
- 9.1%
*p<0.001 for difference from baseline values. Wilcoxon signed rank test
ASTEROID Trial
For patients with CHD, Very high-intensity statin therapy using rosuvastatin 40 mg/d achieved an average LDL-C of 60.8 mg/dL and increased HDL-C by 14.7%, resulting in significant regression of atherosclerosis. Treatment to LDL-C levels below currently accepted guidelines, when accompanied by significant HDL-C increases, can regress atherosclerosis in coronary disease patients.
JUPITER
Multi-National Randomized Double Blind Placebo Controlled Trial of Rosuvastatin in the Prevention of Cardiovascular Events Among Individuals With Low LDL and Elevated hsCRP
Rosuvastatin (N = 8901)
hsCRP, mg/L LDL, mg/dL 4.2 108 49 118 186 94 5.7 (2.8 - 7.1) (94 - 119) (40 60) (85 - 169) (168 - 200) (87 102) (5.4 5.9)
Placebo (n = 8901)
4.3 108 49 118 185 94 5.7 (2.8 - 7.2) (94 - 119) (40 60) (86 - 169) (169 - 199) (88 102) (5.5 5.9)
No Prior CVD or DM
Men >50, Women >60
Rosuvastatin 20 mg (N=8901)
4-week run-in
Placebo (N=8901)
HDL, mg/dL Triglycerides, mg/L Total Cholesterol, mg/dL Glucose, mg/dL HbA1c, %
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica, Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands, Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland, United Kingdom, Uruguay, United States, Venezuela
150
151
JUPITER
Primary Trial Endpoint
0.08
140 120
60 50
LDL (mg/dL)
100 80 60 40 20 0
HDL (mg/dL)
40
0.06
30
10 0
Cumulative Incidence
20
- 44 %
140 120
hsCRP (mg/L)
0.04
TG (mg/dL)
3 2 1
80 60 40 20 0
0.00
0.02
100
0
Number at Risk
2 Follow-up (years)
12
24
36
48
Months
Months
152
Rosuvastatin Placebo
8,901 8,901
8,631 8,621
8,412 8,353
6,540 6,508
3,893 3,872
1,958 1,963
1,353 1,333
983 955
544 534
157 174
153
0.06
Rosuvastatin 142 22 31 30 33 76 83
0.03
0.04
0.05
- 20 %
0.00 0
0.01
0.02
1
8,787 8,775 6,999 6,987
2 Follow-up (years)
4,312 4,319 2,268 2,295
3
1,602 1,614 1,192 1,196
4
683 684 227 246
154
155
HR
WOSCOPS PROSPER HPS ASCOT-LLA PROVE-IT Pravastatin Pravastatin Simvastatin Atorvastatin Atorvastatin Pravastatin JUPITER Rosuvastatin
0.25 0.5 1.0 2
VS
(95% CI)
0.70 (0.500.98) 1.34 (1.061.68) 1.20 (0.981.35) 1.20 (0.911.44) 1.11 (0.671.83)
1.25 (1.051.54)
4
Neuvonen PJ, Niemi M, Backman JT. Drug interactions with lipid-lowering drugs: mechanisms and clinical relevance. Clin Pharmacol Ther. 2006;80(6):565-81.
Statin Better
Statin Worse
156 157
158
159
Atorvastatin Fluvastatin
Fold increase of statin AUC by Cyclosporin Gemfibrozil Grapefruit juice 6-8 2-3 2-10 6-15 1.5 1-4 2-4 ~ ~ 5-10 2 ~ 5-10 2 ~ 5 1.5 ~
Pravastatin
Rosuvastatin Simvastatin
Percentage decrease of statin AUC by potent inducer Rifampin, carbamazepine 7095 6090 50 30 ? ?
160
Effects of renal/hepatic impairment Plasma levels not affected by renal disease; markedly increased with chronic alcoholic liver disease. Potential drug accumulation with hepatic insufficiency Potential drug accumulation with renal or hepatic insufficiency. Mean AUC varied 18-fold in cirrhotic patients and peak values varied 47fold. Increased plasma concentrations with severe renal impairment and hepatic disease Higher systemic exposure may occur in hepatic and severe renal insufficiency
164
Ezetimibe
Liver
Synthesis*
(~800 mg/day) (~1000 mg/day) (~300700 mg/day)
Biliary cholesterol
Extrahepatic tissues
Intestine
Resins
Plant stanols
NPC1L1
NPC1L1=Niemann-Pick C1 Like 1
Adapted from Champe PC, Harvey RA. In Biochemistry. 2nd ed. Philadelphia: Lippincott Raven, 1994; Ginsberg HN, Goldberg IJ. In Harrisons Principles of Internal Medicine. 14th ed. New York: McGraw-Hill, 1998:21382149; Shepherd J Eur Heart J Suppl 2001;3(suppl E):E2E5; Hopfer U. In Textbook of Biochemistry with Clinical Correlations. 5th ed. New York: Wiley-Liss, 2002:1082 166 1150; Davis JP et al Genomics 2000;65:137145.
Ezetimibe
Ezetimibe monotherapy is an option for adults with primary (heterozygous-familial or non-familial) hypercholesterolaemia (at 20% or greater 10year CVD risk) in whom statins are contraindicated or not tolerated Ezetimibe, co-administered with initial statin therapy, is an option for patients with primary hypercholesterolaemia taking statins when: TC or LDL is not appropriately controlled either after dose titration of initial statin therapy or because dose titration is limited by intolerance to the statin therapy
167
Ezetimibe
??????? Although ezetimibe effectively lowers LDL levels, there is currently no published evidence that ezetimibe alone or added to a statin helps patients live longer or live better ENHANCE study (January 2008): no significant difference in carotid intima-media thickness with ezetimibe versus placebo, added to simvastatin 80mg, in familial hypercholesterolaemia SEAS study (September 2008): no significant difference in major CV events with ezetimibe + simvastatin 40mg, versus placebo in patients with aortic stenosis. Hazard Ratio (HR) for new cancer 1.55, P=0.01 168
Ezetimibe 10 mg-Simvastatin 80 mg
Simvastatin 80 mg
IMT assessment
-10 to -7
-6
Weeks
12
Months
15
18
21
24
Inclusion criteria
Men and women Age 45 - 85 years Asymptomatic Valvular AS:
Aortic valve thickening on echocardiographic evaluation Doppler jet velocity 2.5 - 4.0 m/sec
Fatal Cancer
20 Cumulative percentage
Intention-to-Treat Population
15
10
Hazard ratio: 1.67 P=0.05 Unadjusted P=0.06 With Log-rank continuity correction Ezetimibe/Simvastatin 10/40 mg n=39 (4.1%) n=23 (2.5%) Placebo 0 1
930 916
0
No. at risk Ezetimibe/Simvastatin 10/40 mg Placebo
2 3 Years in study
912 890 884 865
4
855 835
5
89 94
: (formulation) Micronised formulations: 67mg 3 200mg Non-micronised formulation: 200 300mg/day , 200 400mg/day bioavailability ( nanoparticles) 40 160mg/day : 5mg/kg/day 180
transaminase 3 (upper limit of normal) statins fibrates creatinine 2.0 mg/dl fibrates creatinine 4 mg/dl fibrates
181 182
6 -12 3 6 statins fibrates transaminase 6 12 1 2 2 3 6
183
transaminase 3 CPK 10 myopathy rhabdomyolysis statin fibrate transaminases creatinine SGOT, SGPT CPK 1 2 6 rhabdomyolysis hepatitis
184