Κριτική θεώρηση των μεγάλων μελετών και των καλών μεταναλύσεων ως εργαλείου ενδείξεων για τεκμηρίωση συστάσεων στα καρδιαγγειακά νοσήματα Υπερλιπιδαιμία Β. Α. Λαμπαδιάρη Επίκουρη Καθηγήτρια Παθολογίας- Σακχαρώδη Διαβήτη Β Προπαιδευτική Παθολογική Κλινική, Μονάδα Έρευνας και Διαβητολογικό κέντρο του Πανεπιστημίου Αθηνών, Π. Γ.Ν «Αττικόν».
Δήλωση σύγκρουσης συμφερόντων Η ομιλία αντανακλά τις απόψεις του ομιλητή Η Βάϊα Λαμπαδιάρη έχει λάβει τιμητικές αμοιβές (honoraria) για διαλέξεις σε συνέδρια, επιστημονικές ημερίδες/εκδηλώσεις και συμβουλευτική από τις εταιρίες: Novartis, Sanofi, NovoNordisk, MSD, Boehringer
Χαμηλά επίπεδα LDL-c συσχετίζονται με ελάττωση καρδιαγγειακών συμβάντων Η αυξημένη LDL χοληστερόλη αποτελεί παράγοντα κινδύνου για ΣΝ 1 Η μείωση της LDL χοληστερόλης με τις στατίνες μειώνει τον ΚΑ κίνδυνο σε ασθενείς με και χωρίς ΣΝ, συμπεριλαμβανομένων των ασθενών με Οξύ Στεφανιαίο Σύνδρομο (ΟΣΣ) 2,3 ΣΝ = στεφανιαία νόσος, ΚΑ = καρδιαγγειακός, ΟΣΣ = οξύ στεφανιαίο σύνδρομο, IMPROVE-IT = Improved Reduction of Outcomes: Vytorin Efficacy International Trial. 1. Grundy SM et al. Circulation. 2004;110:227 239. 2. Cannon CP et al. Am Heart J. 2008;156:826 832. 3. Cannon CP et al. N Engl J Med. 2004;350:1495 1504.
Scandinavian Simvastatin Survival Study (4S) Randomized trial of cholesterol lowering in 4,444 patients with CAD: The Scandinavian Simvastatin Survival Study. To investigate whether long-term simvastatin therapy reduces total mortality and coronary events in post-mi and or angina patients with total cholesterol between 212-309 mg/dl. The Lancet, Vol 344, November 19, 1994
Summary of Key End-point Results Simvastatin Better Placebo Better Total mortality CAD mortality Major coronary events p=0.0003 p<0.00001 p<0.00001 PTCA/CAB G p<0.00001 Event-free survival 0.2 0.4 0.6 0.8 1.0 1.2 Relative risk (95% CI) Reduced Increased p<0.00001 The Lancet, Vol 344, November 19, 1994
Prevention of Coronary Heart Disease with Pravastatin in Men with Hypercholesterolemia- Woscops This double-blind study was designed to determine whether the administration of pravastatin to men with hypercholesterolemia and no history of myocardial infarction reduced the combined incidence of nonfatal myocardial infarction and death from coronary heart disease N Engl J Med 1995;333:1301-7
WOS Results/Clinical Events Event % Reduction p value Nonfatal MI + CHD death 31% < 0.001 Definite nonfatal MI 31% < 0.001 Definite CHD death 28% 0.13 (NS) Definite and suspected CHD 33% 0.042 death All cardiovascular deaths 32% 0.033 Total mortality 22% 0.051 (NS) CABG/PTCA 37% 0.029 James Shepherd, et al, N Engl J Med 1995;333:1301-7
Primary Prevention of Acute Coronary Events with Lovastatin in Men and Women with Average Cholesterol Levels Results of AFCAPS/TexCAPS To compare lovastatin with placebo for prevention of the first acute major coronary event: unstable angina, fatal and non-fatal MI and sudden cardiac death in a cohort of men and women without clinically evident atherosclerotic CVD, who have average TC and LDL-C and below-average HDL-C. JAMA 1998;279:1615-1622
Cumulative Incidence Primary Endpoint ~ First Acute Major Coronary Event* 0.06 0.05 0.04 *Includes unstable angina, fatal and non-fatal MI & sudden cardiac death Placebo 37% Risk Reduction (p < 0.001) 0.03 0.02 Lovastatin 0.01 0.00 # At Risk Lovastatin Placebo 0 1 2 3 4 5 5+ Years Years of Follow-up N=3304 N=3270 N=3228 N=3184 N=3134 N=1688 N=3301 N=3251 N=3211 N=3159 N=3092 N=1644 JAMA 1998;279:1615-1622
Cumulative Incidence Tertiary Analysis Fatal and Non-Fatal Cancer* 0.08 0.07 0.06 *Excludes non-melanoma skin cancer Placebo P = NS 0.05 0.04 Lovastatin 0.03 0.02 0.01 0.00 # At Risk Lovastatin Placebo 0 1 2 3 4 5 5+ years Years of Follow-up N=3304 N=3249 N=3188 N=3117 N=3059 N=1626 N=3301 N=3234 N=3171 N=3105 N=3043 N=1603 Poster Presentation 1998 ACC Meeting, Atlanta GA
Summary of Results Clinical benefit Appeared within the first year of treatment and continued Was apparent for all LDL-C tertiles Range 90-235 mg/dl Was consistent for subgroups Women Risk Factors - Age, DM, HTN, Smokers JAMA 1998;279:1615-1622
AFCAPS/TexCAPS Implications Using NHANES III survey data, approximately 8 million Americans without documented cardiovascular disease meet the age and lipid criteria of AFCAPS/TexCAPS. Assuming that only 17% of the reference population would qualify for drug treatment by current NCEP guidelines, we estimate that 6 million Americans currently not recommended for drug treatment may benefit from LDL-C reduction with lovastatin. JAMA 1998;279:1615-1622
HPS: Heart Protection Study Purpose To determine whether simvastatin reduces mortality and vascular events in patients with and without coronary disease, but all at high risk, and with a broad range of baseline cholesterol levels Reference HPS Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7 22.
HPS: Heart Protection Study - RESULTS continued - Cause-specific mortality Cause of death Simvastatin (n=10,269) No. (%) Placebo (n=10,267) No. (%) Death rate ratio (95% CI) Simvastatin better Placebo better Vascular causes Coronary Other vascular Subtotal: any vascular Non-vascular causes Neoplastic Respiratory Other medical Nonmedical Subtotal: any nonvascular ANY DEATH 587 194 781 359 90 82 16 547 1328 (5.7) (1.9) (7.6) (3.5) (0.9) (0.8) (0.2) (5.3) (12.9) 707 230 937 345 114 90 21 570 1507 (6.9) (2.2) (9.1) (3.4) (1.1) (0.9) (0.2) (5.6) (14.7) RR=0.83 (0.75 0.91) P<0.0001 RR=0.95(0.85 1.07) P=0.4 RR=0.87(0.81 0.94) P<0.0003 Dashed line indicates overall RR for a subtotal 0.4 0.6 0.8 1.0 1.2 1.4 HPS Collaborative Group. Lancet 2002;360:7 22.
MEGA Trial Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) Trial Presented at The American Heart Association Scientific Session 2005 Presented by Dr. Haruo Nakamura
MEGA Trial: Background In Japan, the incidence of coronary disease is about one third lower than the US and Europe, where most of the statin trials have been conducted The goal of this study was to examine whether the addition of a low-dose statin to a diet rich in omega-3 fatty acids could reduce the risk of CHD. 7,832 men age 40-70 years and postmenopausal women up to age 70 with total cholesterol 220-270 mg/dl Presented at AHA 2005
# per 1000 patient years MEGA Trial: Primary Composite Endpoint Primary composite endpoint of coronary heart disease events p = 0.01 5 5,0 The primary composite 4 3 3,3 endpoint of coronary heart disease events occurred less frequently in the 2 pravastatin plus diet group 1 (3.3 vs 5.0 per 1000 patient years, hazard ratio [HR] 0 Pravastatin+diet Diet 0.67, p=0.01). Presented at AHA 2005
MEGA Trial: Summary The present study demonstrated that even in this lower risk population, primary prevention with low-dose statin therapy can be effective in reducing cardiac events, with a modest reduction in lipid parameters. There was no difference in the frequency of cancer or elevated liver function abnormalities and no cases of rhabdomyolysis. Presented at AHA 2005
Fatal CHD/nonfatal MI (%) Proportion alive Fatal CHD/nonfatal MI (%) 1.00 0.95 0.90 0.85 0.80 0.00 Early secondary prevention trials only focused on long-term event reductions in stable patients 4S Placebo Simvastatin Risk reduction, 30% Log-rank p=0.0003 0 1 2 3 4 5 6 15 CARE 20 15 10 5 0 0 LIPID Placebo Pravastatin Risk reduction, 24% p<0.001 1 2 3 4 5 6 7 10 Placebo 5 0 Pravastatin Risk reduction, 24% p=0.003 0 1 2 3 4 5 6 Years 4S Study Group. Lancet 1994;344:1383 1389. Sacks FM et al. N Engl J Med 1996;335:1001 1009. LIPID study group. N Engl J Med 1998;339:1349 1357.
Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering MIRACL: Rationale and Results
MIRACL: central hypothesis Early, rapid, and profound cholesterol lowering therapy with atorvastatin can reduce early recurrent ischemic events in patients with unstable angina or non-q-wave acute MI Schwartz GG et al. Am J Cardiol 1998;81:578 581.
MIRACL: occurrence of primary end point events Death Nonfatal Acute MI Resuscitated Cardiac Arrest Worsening angina with new objective evidence of ischemia requiring urgent rehospitalization * *p=0.02 0.25 0.50 0.75 1.00 1.25 1.50 1.75 2.00 Atorvastatin better Placebo better Relative risk Data on file, Pfizer Inc.
Cumulative Incidence (%) MIRACL: fatal or nonfatal stroke 2 1.5 Placebo 1.6% 1 0.5 Atorvastatin Relative risk = 0.50 p=0.045 0.8% 0 0 4 8 12 16 Time since randomization (weeks) Data on file, Pfizer Inc.
MIRACL: conclusions Early, rapid, and profound cholesterol lowering therapy with atorvastatin reduced early recurrent ischemic events in patients with unstable angina or non-q-wave acute MI Atorvastatin reduced the incidence of recurrent ischemic events within 16 weeks Treatment was generally well tolerated Data on file, Pfizer Inc.
To compare the effects on the combined outcome of nonfatal MI (including silent MI) and fatal CHD of atorvastatin 10 mg with those of placebo in hypertensive patients with TC levels of 6.5 mmol/l ( 250 mg/dl) Atorvastatin 10 mg vs placebo No fixed lipid-lowering target Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Cumulative Incidence (%) Primary End Point: Nonfatal MI and Fatal CHD 4 Atorvastatin 10 mg Number of events 100 Placebo Number of events 154 3 36% reduction 2 1 HR = 0.64 (0.50-0.83) p=0.0005 0 0,0 0,5 1,0 1,5 2,0 2,5 3,0 3,5 Years Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Cumulative Incidence (%) 3 2 Secondary End Point: Fatal and Nonfatal Stroke Atorvastatin 10 mg Number of events 89 Placebo Number of events 121 27% reduction 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, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
Summary and Conclusions In hypertensive patients at modest risk of CHD, atorvastatin is associated with a highly significant reduction in the primary end point of CHD, together with significant reductions in the secondary end points of stroke, all cardiovascular events and procedures, and total coronary events These reductions in major cardiovascular events are large given the short follow-up time and occurred earlier than in many other statin trials There was no significant heterogeneity among pre-specified subgroups Sever PS, Dahlöf B, Poulter N, Wedel H, et al, for the ASCOT Investigators. Lancet. 2003;361:1149-58
PRavastatin Or atorvastatin Evaluation and Infection Therapy (TIMI 22) 4,162 patients with an Acute Coronary Syndrome < 10 days Disclosure Statement: Dr. Cannon currently receives research grant support from Bristol-Myers Squibb, Merck and Sanofi-Synthelabo. He serves as a consultant to AstraZeneca, Glaxo Smith Kline, Guilford Pharmaceuticals and Vertex
Background Statin therapy is highly effective vs. placebo in longterm treatment of CHD 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?
Primary Endpoint Over Time 30 Days 90 Days 180 Days End of Follow-up 40 RR Events Rates Atorva 80 Prava 17% 1.9% 2.2% 18% 6.3% 7.7% 14% 12.2% 14.1% 16% 22.4%* 26.3%* 0.5 0.75 1.0 1.25 1.5 Atorvastatin 80mg Better Pravastatin 40mg Better *2-year event rates
Summary In patients recently hospitalized within 10 days for an acute coronary syndrome: Intensive high-dose LDL-C lowering (median LDL-C 62 mg/dl) compared to moderate standard-dose lipidlowering therapy (median LDL-C 95 mg/dl) reduced the risk of all cause mortality or major cardiac events by 16% (p=0.005) Benefits emerged within 30 days post ACS with continued benefit observed throughout the 2.5 years of follow-up Benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups
PROVE-IT Conclusion MARCH 8, 2004 These findings indicate that patients recently hospitalized for an acute coronary syndrome benefit from early and continued lowering of LDL-C to levels substantially below current target levels. Cannon CP, Braunwald E, McCabe CH, et al. N Engl J Med 2004;350:15 www.nejm.org
Collaborative Atorvastatin Diabetes Study (CARDS) Patient Population Type 2 diabetes mellitus Men and women 40 75 years of age Primary CHD and stroke prevention LDL-C 160 mg/dl ( 4.14 mmol/l) TG 600 mg/dl ( 6.78 mmol/l) 1 additional RF HTN (or on HTN treatment) Retinopathy Albuminuria Current smoking 2838 patients Atorvastatin 10 mg (n=1428) 4-year follow-up Double-blind placebo (n=1410) Primary endpoint: time to first major CV event (CHD death, nonfatal MI, unstable angina, resuscitated cardiac arrest, coronary revascularization, stroke Secondary endpoints: total mortality, any CV endpoint, lipids, and lipoproteins Colhoun HM et al. Lancet 2004;364:685-696.
CARDS: Effect of Atorvastatin on the Primary Endpoint: Major CV Events Including Stroke Cumulative Hazard, (%) 15 10 Relative Risk Reduction 37% (95% CI, 17 52) P = 0.001 Placebo 127 events 5 Atorvastatin 83 events Placebo Atorvastatin 0 0 1 2 3 4 Years 1410 1428 1351 1392 1306 1361 1022 1074 651 694 4.75 305 328 Colhoun HM et al. Lancet 2004;364:685-696.
TNT Trial Treating to New Targets Study Presented at The American College of Cardiology Scientific Sessions 2005
TNT Trial 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 years All received atorvastatin 10 mg during 8 week open-label run-in period Atorvastatin 80 mg n=4,995 Atorvastatin 10 mg n=5,006 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. Secondary Endpoint: Major coronary events, cerebrovascular events, hospitalization for congestive heart failure (CHF), all-cause mortality, peripheral artery disease, any cardiovascular event, any coronary event Presented at ACC 2005
TNT Trial: Primary endpoint 12% 8% 4% Primary Composite of CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke Hazard Ratio [HR]=0.78 p<0.001 8,7% 10,9% The primary composite endpoint of CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal or nonfatal stroke was lower in the high-dose atorvastatin 80 mg group at a mean followup of 4.9 years. 0% High-dose Low-dose Presented at ACC 2005
TNT Trial: Summary The results from TNT confirm what was observed in PROVE-IT / TIMI 22 and suggest that aggressive lipid lowering to LDL levels <75 mg/dl reduces cardiovascular events in patients with stable coronary artery disease. Presented at ACC 2005
The results of the Study of Heart and Renal Protection (SHARP) Colin Baigent, Martin Landray on behalf of the SHARP Investigators Disclosure: SHARP was sponsored, designed, run, and analysed by the University of Oxford. Funding was received from Merck, the UK MRC, British Heart Foundation, and Australian NHMRC.
SHARP: Assessment of LDL-lowering this study has been used by clinicians to justify the prescribing of statins ±ezetimibe in patients with chronic kidney disease.
Proportion suffering event (%) Μελέτη SHARP: Μείωση στα Μείζονα αθηροσκληρωτικά συμβάντα 25 20 15 10 Risk ratio 0.83 (0.74 0.94) Logrank 2P=0.0022 Placebo 17% Eze/simv 5 0 0 1 2 3 4 5 Baigent C, et al, Lancet. 2011 Jun 25;377(9784):2181-92 Years of follow-up
Proportion suffering event (%) Μελέτη SHARP: Μείωση στα Μείζονα αθηροσκληρωτικά συμβάντα 25 Exploratory analyses from SHARP suggest that lowering LDL-C with statin-based therapy 20 Risk may improve ratio 0.83 vascular (0.74 access patency, 0.94) but there was no evidence of benefit Logrank in AURORA. 2P=0.0022 Taken together, the available evidence suggests that any benefits of lowering LDL-C on vascular access patency are likely to be modest. Clin J Am Soc Nephrol. 2014 May;9(5):914-9. 15 questionable clinical benefit to lipid-lowering therapy in patients with chronic 10 kidney disease. Clin Ther. 2014 Nov 20. Placebo 17% Eze/simv 5 0 0 1 2 3 4 5 Baigent C, et al, Lancet. 2011 Jun 25;377(9784):2181-92 Years of follow-up
JUPITER Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin Rosuvastatin is not indicated for the treatment of patients with high C-Reactive Protein (CRP). For complete therapeutic and safety information please consult the CRESTOR Product Monograph.
JUPITER JUPITER is the first large-scale, prospective study to examine the role of statin therapy in individuals with low to normal LDL-C levels, but with increased cardiovascular risk identified by elevated CRP The primary objective was to investigate whether long-term treatment with rosuvastatin 20 mg decreases the rate of first major cardiovascular events compared with placebo in patients with low to normal LDL-C but at increased cardiovascular risk as identified by elevated CRP levels Ridker P et al. N Eng J Med 2008;359: 2195-2207 For complete therapeutic and safety information please consult the CRESTOR Product Monograph.
JUPITER Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death Cumulative Incidence 0.00 0.02 0.04 0.06 0.08 HR 0.56, 95% CI 0.46-0.69 P < 0.00001 Number Needed to Treat (NNT 5 ) = 25 0 1 2 3 4 Placebo 251 / 8901-44 % Rosuvastatin 142 / 8901 Number at Risk Rosuvastatin Placebo Follow-up (years) 8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 157 8,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
JUPITER Primary Endpoint Understudied or Low Risk Subgroups Understudied Subgroups Women Age > 70 Black, Hispanic, Other N HR (95%CI) 6,801 0.54 (0.37-0.80) 5,695 0.61 (0.46-0.82) 5,117 0.63 (0.41-0.98) Low Risk Subgroups Framingham Risk < 10 % LDLC < 100 mg/dl BMI < 25 mg/m2 No Hypertension 8,882 0.56 (0.38-0.83) 6,269 0.66 (0.47-0.92) 4,073 0.59 (0.40-0.87) 7,586 0.62 (0.44-0.87) No metabolic Syndrome 10,296 0.49 (0.37-0.65) Elevated hscrp Only 6,375 0.63 (0.44-0.92) All Participants 17,802 0.56 (0.46-0.69) 0.25 0.5 1.0 2.0 4.0 Rosuvastatin Superior Rosuvastatin Inferior
The Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Trial FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Primary endpoint CHD events (nonfatal MI, CHD death) Cumulative risk (%) 10 8 6 HR = 0.89 95% CI = 0.75 1.05 p = 0.16 Placebo 4 2 Fenofibrate 0 0 1 2 3 4 5 6 Years from randomization Placebo Fenofibrate 4,900 4,895 4,835 4,837 4,741 4,745 4,646 4,664 4,547 4,555 2,541 2,553 837 850 Number of patients still followed-up at the given year FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Microvascular disease Retinopathy Percentage of patients Need for laser treatment for retinopathy 6 5 4 3 2 1 5.2% -30% 3.6% P=0.0003 This effect cannot be explained by changes in HbA 1c or concomitant medications, or by the minor reduction in blood pressure in the fenofibrate group 0 Placebo Fenofibrate FIELD Study Investigators. Lancet 2005 ; 366 (9500) : 1849-61
Henry N. Ginsberg, MD College of Physicians & Surgeons, Columbia University, New York For The ACCORD Study Group
ACCORD Study Design Designed to independently test three medical strategies to reduce cardiovascular disease in diabetic patients Lipid Trial question: whether combination therapy with a statin plus a fibrate would reduce cardiovascular disease compared to statin monotherapy in people with type 2 diabetes mellitus at high risk for cardiovascular disease. Randomized, placebo-controlled, double-blind clinical trial conducted in 77 clinical sites in the U.S. and Canada
Primary Outcome By Treatment Group and Baseline Subgroups
Conclusion (1) ACCORD Lipid does not support use of the combination of fenofibrate and simvastatin, compared to simvastatin alone, to reduce CVD events in the majority of patients with T2DM who are at high risk for CVD
Conclusion (2) Subgroup analyses suggesting heterogeneity in response to combination therapy by gender or by the presence of significant dyslipidemia require further investigation Approximately 30% of news and biomedical journal articles described fenofibrate as ineffective, whereas nearly 20% concluded it was effective. Among articles making a recommendation, approximately 50% of news and 67% of biomedical journal articles supported continued fibrate use. The ACCORD-Lipid trial was described inconsistently in news and biomedical journal articles, possibly creating uncertainty among patients and physicians. In addition, conflicts of interest were associated with more favorable trial interpretation. JAMA Intern Med. 2014;174(7):1176-1182.
Niacin Reduces CVD Pre-AIM-HIGH Trials stat sig 27% Many of these trials were tests of drug combinations that included niacin. Bruckert E et al. Atherosclerosis. 2010;210:353-361.
AIM-HIGH Design Purpose: [A] rigorous test of the HDL hypothesis Subjects: N=3414 men/women (85%/15%) w/ prior CVD event and HDL-C 35 (<42/53) LDL-C 74 (algorithm), TG 163 (100-400) [median (range)] Randomized Therapy Extended-release niacin (1500-2000 mg hs) vs Placebo (immediate-release niacin 100-150 mg hs) Open-label titration/addition (keep LDL-C in 40-80 mg/dl) Simvastatin 5-80 mg/d Ezetimibe 10 mg/d + extended release niacin (1500-2000 mg) AIM-HIGH Investigators. N Engl J Med. 2001;365:2255-267. AIM-HIGH Investigators. Am Heart J. 2011;161:471-477.e2.
AIM-HIGH Results Primary Outcome 1 o Endpoint: CHD Death, nonfatal MI, ischemic stroke, high-risk ACS, hospitalization for coronary or cerebrovascular revascularization Boden WE. N Engl J Med. epub 15 Nov 2011; doi 10.1056/NEJMoa1107579.
AIM-HIGH Early Termination Lipids Baseline: LDL-C 71 mg/dl w/ prior stain Rx (94% of subjects) On Rx: HDL-C 25% ERN vs 10% placebo (<2/3 of projected) Data, Safety and Monitoring Board chose early termination Due to futility (likely lack of efficacy) - 1 Endpoint HR 1.05 Early concern about possible increased stroke rate signal Potential explanations for lack of observed efficacy: Placebo arm received IR niacin, statin dose & ezetimibe (poor test of HDL hypothesis w/ just 15% net HDL-C) Early study termination (VA HIT also negative at 3 y) Sl lower than expected event rate (but still >5%/yr) High prior statin use (94%, 40%>5y), prior niacin use (20%) Press conference transcript; May 26, 2011. Available at: www.nhlbi.nih.gov/new/remark/aim-high-transcript.htm. Brinton EA. J Clin Lipi. 2011. Rosenson RS. Curr Athero Rep. 2012 (in press).
HPS2-THRIVE: Randomized placebo-controlled trial of ER niacin and laropiprant in 25,673 patients with pre-existing cardiovascular disease. Jane Armitage on behalf of the HPS2-THRIVE Collaborative Group Financial Disclosure: Grant to Oxford University. Designed, conducted and analysed independently of the grant source (Merck & Co). No honoraria or consultancy fees accepted. N Engl J Med 2014; 371:203-212July 17, 2014
Patients suffering events (%) Effect of ERN/LRPT on MAJOR VASCULAR EVENTS 20 15 Risk ratio 0.96 (95% CI 0.90 1.03) Logrank P=0.29 15.0% 14.5% 10 5 Placebo ERN/LRPT 0 0 1 2 3 4 Years of follow-up
Effect of ERN/LRPT on SERIOUS adverse events (median follow-up 3.9 years) Diabetic complication Excess p value 3.7% <0.0001 New onset diabetes Infection Gastrointestinal Musculoskeletal Heart failure Bleeding Skin Active ERN/LRPT Placebo 1.8% <0.0001 1.4% <0.0001 1.0% <0.0001 0.7% 0.0008 0.4% 0.05 0.7% 0.0002 0.3% 0.0026 0 2 4 6 8 10 12 Percentage of patients
Conclusions Neither niacin, fibrates, nor CETP inhibitors, reduced all cause mortality, coronary heart disease mortality, myocardial infarction, or stroke in patients treated with statins. in the current era of widespread use of statins in dyslipidaemia, substantial trials of these three agents do not support this concept.
IMPROVE-IT Η μείωση της LDL-C από χαμηλά (<70 mg/dl) σε πολύ χαμηλά επίπεδα (<55 mg/dl) θα αποφέρει επιπρόσθετο όφελος στη μείωση του καρδιαγγειακού κινδύνου; Αυτό το πολύ χαμηλό εύρος μείωσης της LDL χοληστερόλης δεν έχει αξιολογηθεί άμεσα σε προηγούμενες μελέτες θεραπείας με υψηλές δόσεις στατινών 2,3 Σε ασθενείς με Οξύ Στεφανιαίο Σύνδρομο η προσθήκη εζετιμίμπης σε αγωγή με στατίνη, ως συνδυασμός εζετιμίμπη/σιμβαστατίνη, βελτιώνει τις ΚΑ εκβάσεις συγκριτικά με τη μονοθεραπεία σιμβαστατίνης; 1 ΣΝ = στεφανιαία νόσος, ΟΣΣ = οξύ στεφανιαίο σύνδρομο, ΚΑ = καρδιαγγειακός. 1. Cannon CP et al. Am Heart J. 2008;156:826 832. 2. Califf RM et al. Am Heart J. 2010;159:705 709. 3. Blazing MA et al. Am Heart J. 2014; doi: 10.1016/j.ahj.2014.05.004.
IMPROVE-IT: Σχεδιασμός της Μελέτης 1-3 Ασθενείς Υψηλού Κινδύνου με Οξέα Στεφανιαία Σύνδρομα (NSTEMI, Ασταθής Στηθάγχη και STEMI Υψηλού Κινδύνου (STEMI όχι πάνω από το 30% του πληθυσμού) Χορήγηση Τυχαιοποιημένης Θεραπείας 10 Ημέρες από την Προσέλευση στο Νοσοκομείο EZ/Simva 10/40 mg Simva 40 mg N = 18.141 2 Ελάχιστη Διάρκεια Παρακολούθησης 2,5 Έτη α Διακόπηκε η τιτλοποίηση μετά την τυχαιοποίηση ακολούθως της επικαιροποίησης της επισήμανσης από τον FDA για τη σιμβαστατίνη 80 mg. Η αρχική τιμή (κατά την έναρξη) της LDL χοληστερόλης ήταν 97 mg/dl στους πρώτους 10.000 ενταχθέντες ασθενείς. IMPROVE IT = IMProved Reduction of Outcomes: Vytorin Efficacy International Trial. 1. Cannon CP et al. Am Heart J. 2008;156:826-832. 2. Califf RM, et al. Am Heart J. 2010;159:705-709. 3. http://clinicaltrials.gov/ct2/show/nct00202878?term=improve-it&rank=1
Μεμονωμένα Καρδιαγγειακά Τελικά σημεία και KA θάνατος/έμφραγμα Μυοκαρδίου/Εγκεφαλικό Επεισόδιο HR Simva* EZ/Simva* p-value All-cause death 0.99 15.3 15.4 0.782 CVD 1.00 6.8 6.9 0.997 CHD 0.96 5.8 5.7 0.499 MI 0.87 14.8 13.1 0.002 Stroke 0.86 4.8 4.2 0.052 Ischemic stroke 0.79 4.1 3.4 0.008 Cor revasc 30d 0.95 23.4 21.8 0.107 UA 1.06 1.9 2.1 0.618 CVD/MI/stroke 0.90 22.2 20.4 0.003 0.6 1.0 1.4 Ezetimibe/Simva Better Simva Better *7-year event rates (%) http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469669.pdf
Συμπεράσματα Μελέτη IMPROVE-IT: Η πρώτη μελέτη που έδειξε επιπρόσθετο όφελος με την προσθήκη εζετιμίμπης σε θεραπεία με στατίνη: Ναι: Ναι: Ναι: Η ελάττωση της LDL-C με εζετιμίμπη ελαττώνει τα καρδιαγγειακά συμβάντα Ακόμα Χαμηλότερα είναι Ακόμα Καλύτερα (επίτευξη μέσης τιμής LDL-C 53 vs. 70 mg/dl στον 1 χρόνο) Επιβεβαίωση του προφίλ ασφάλειας της εζετιμίμπης Επιβεβαίωση της υπόθεσης για την LDL-C, σχετικά με το ότι η ελάττωση προλαμβάνει καρδιαγγειακά συμβάντα Τα αποτελέσματα μπορούν να ληφθούν υπ όψιν για μελλοντικές συστάσεις http://my.americanheart.org/idc/groups/ahamah-public/@wcm/@sop/@scon/documents/downloadable/ucm_469669.pdf
Πως τοποθετείται η Εζετιμίμπη μετά την ανακοίνωση των αποτελεσμάτων στις ACC/AHA συστάσεις; Low is good but lower is better The earlier lipids are lowered, the better.
Is there evidence for a benefit of statin therapy in people at low risk of vascular disease? Interpretation: In individuals with 5-year risk of major vascular events lower than 10%, each 1 mmol/l reduction in LDL cholesterol produced an absolute reduction in major vascular events of about 11 per 1000 over 5 years. This benefit greatly exceeds any known hazards of statin therapy. Under present guidelines, such individuals would not typically be regarded as suitable for LDL-lowering statin therapy. The present report suggests, therefore, that these guidelines might need to be reconsidered. Cholesterol Treatment Trialists' (CTT) Collaborators; Lancet. 2012 Aug 11; 380(9841):581-90
Efficacy of Intensive Lowering of LDL-C in Subjects with Low Baseline LDL-C Meta-analysis of RCT s of >1000 participants and 2 years treatment duration of more versus less intense statin trials involving 169,138 subjects The major vascular event reduction, among in those with baseline LDL-C <77mg/dL per further 39 mg/dl reduction was 29% (99% CI 2-48, p=0.007); in those with baseline LDL-C <70 mg/dl, similar reduction in LDL-C continued to demonstrate MVE reduction (RR 0.63, 99% CI 0.41-0.95, p=0.004). Cholesterol Treatment Trialists Collaboration. Lancet 2010;376:1670-81
Συσχέτιση του απόλυτου ΚΑ κινδύνου με τη σχετική ελάττωση της LDL-C βάσει της μεταανάλυσης CTT Για την ίδια σχετική ποσοστιαία ελάττωση της LDL-C η μείωση του καρδιαγγειακού κινδύνου συνεχώς ελαττώνεται. Δηλαδή όταν ξεκινάμε από χαμηλά επίπεδα LDL-C αναμένουμε μικρό ποσοστό ελάττωσης του απόλυτου καρδιαγγειακού κινδύνου Laufs U et al. Eur Heart J. 2014;doi:10.1093/eurheartj/ehu228.
Very Low LDL-C and Non-HDL-C in Statin Trials and Major CVD Event Risk LDL-C Non-HDL-C 1,00 1,00 0,89 0,44 0,57 0,51 0,60 0,56 0,64 0,58 0,69 0,64 0,75 0,71 <50, <75 50-74, 75-99 75-99, 100-124 100-124, 125-149 125-149, 150-174 150-174, 175-199 >=175, >=200 On Treatment LDL- C, Non-HDL-C mg/dl Boekholdt et al. JACC 2014;64:485-494