P H Y S I C I A N S ' A C A D E M Y ...Presentation Transcript
AsianCardiovascularMasterClass June 26 -27, 2010 Ho Chi Minh City, Vietnam Presentation topicPractical challenges in optimalCV risk management Slide lecture prepared and held by: Peter Lansberg, MD Academic Medical Centre, Amsterdam, The Netherlands
The lessons learned in the 90ies (Most) Statins are Safe! 25 – 30 % risk reduction Benefit extends to Patients with CAD Stable disease ACS Patients with CVD Patients with diabetes and/or multiple risk factors Majority of patients not adequately treated! More patients need to be treated Patients are not treated aggressively enough
CHD Reduction in Secondary Prevention Trials
LDL-C Reduction across separate studies 0 -10 20 -30 -40 -50 -60 -5 -15 -25 -35 -45 -55 20 mg 40 mg 10 mg rosuvastatin 10 mg 20 mg 80 mg 40 mg atorvastatin simvastatin pravastatin 10 mg 20 mg 40 mg 80 mg 40 mg 10 mg 20 mg Adapted from Law et al bmj.com 2003;326:1423
Cholesterol Goal Attainment in the Real World: The REALITY Asia StudyAsia REALITY Study Current status of cholesterol goal attainment after statin therapy among patients with hypercholesterolemia In Asian countries and region:the Return on ExpenditureAchieved for Lipid Therapyin Asia (REALITY-Asia) study Hyo-SooKima, YangfengWub, Shing-Jong Linc, ChaicharnDeerochanawongd, RobaayahZambaharie, LianchengZhaof, QiaoyiZhangg and Peter Yanh aSeoul National University Hospital, Seoul, South Korea bPeking University School of Public Health, Beijing, China cTaipei Veterans General Hospital, Taipei, Taiwan dRajavithi Hospital, College of Medicine, Rangsit University, Bangkok, Thailand eNational Heart Institute, Kuala Lumpur, Malaysia fFuWai Hospital, Beijing, China gOutcomes Research, Reimbursement & Health Technology Assessment, Merck & Co., Inc., Whitehouse Station, New Jersey, USA hGleneagles Medical Centre, Singapore
Cholesterol Goal Attainment in the Real World: The REALITY Asia StudyLDL-C Goal Attainment by Risk and Country Adapted from: Return on Expenditure Achieved for Lipid Therapy in Asia - REALITY-Asia study
Target lipidlevels Can J CardiolVol 25 No 10 October 2009
Percentage of patients achieving total cholesterol target (< 5.0 mmol/L) Switch cohort Control cohort (n=1,257) (n=4,792) Patients achieving cholesterol target (%) At baseline 60 74 One-year 65 72 post-index Br J Cardiol 2007;14:280-5
Time to Death or First Major Cardiovascular Event Br J Cardiol 2007;14:280-5
Time to Discontinuation of Statin Therapy Br J Cardiol 2007;14:280-5
12 Crystalline vs amorphous atorvastatin Atorvastatin amorphous Atorvastatin crystalline Readily degrades More Stable
The National Lipid AssociationStatin Safety Task Force Report NLA Statin Safety Task Force JM McKenney, Chairman Review of the Literature Review of Drug Interaction Literature Meta-analysis of Randomized, Clinical Trials Analysis of Managed Care Databases Analysis of FDA AERS Database Review of Data from NDA Submissions Independent Analysis by Subspecialist Panels
Muscle Panel (PD Thompson et al.)
Liver Panel (DE Cohen et al.)
Renal Panel (BK Kasiske et al.)
Neurology Panel (LM Brass et al.)
Final Conclusions and Recommendations
Practical Treatment Guidelines
Am J Cardiol 2006; 97 (8, Suppl 1):S1-S98
Transaminases and Liver Disease measuring aminotransferases at baseline cannot adequately identify those who have underlying liver disease There is no sound rationale why statins should not be used in patients with chronic liver disease who otherwise need statin therapy
Use of Atorvastatin or Pravastatin in Patients with NASH 5 patients with NASH 20 mg Prava for 6 months1
Normalization of liver enzymes in all patients
Some improvement in hepatic inflammation and steatosis (liver biopsies)
Significant improvement of hepatic histology in some patietns
Rallidis LS, Drakoulis CK, Parasi AS. Pravastatin in patients with nonalcoholic steatohepatitis: results of a pilot study. Atherosclerosis 2004;174: 193-196. Horlander JC, Kwo PY, Cummings OW. Atorvastatin for the treatment of NASH. Gastroenterology 2001;120:A544.
Use of Simvastatin in Patients with Hepatitis C 219 patients with HCV 17 were identified as using statin Men with a mean age of 58.9 years. All were taking simvastatin Mean dose of 23 (±18 mg) /day Five patients had a LFT = 1.5 x ULN statins are not associated with significant liver enzyme elevations in patients with HCV infection Kimberly Gibson, PharmDa, and Joseph P. Rindone, PharmDb. Experience With Statin Use in Patients With Chronic Hepatitis C Infection Am J Cardiol 2005;96:1278 –1279
Transaminases and Liver Disease Dallas Heart Study1 79% of patients with hepatic steatosis normal LFT Patients with documented NASH2 36% normal LFT but signs of liver cirrhosis Browning JD, et al. Prevalence of hepatic steatosis in an urban population in the United States:impact of ethnicity. HEPATOLOGY 2004;40:1387-1395 Mofrad P et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values HEPATOLOGY 2003;37:1286-1292.
Statin Tolerability and Safety– Liver Effects
Elevations in liver transaminaselevels are infrequent but recognised complication of treatment with statins*
Before statin therapy:
Liver function tests recommended
Caution in patients who consume excessive quantities of alcohol and/or have a historyof liver disease
Contraindicated in patients with active liver disease
*ALT >3 x ULN on 2 successive occasions
Some Definitions… Myalgia:Muscle symptoms reported by the patient Myopathy:Muscle symptoms with CK elevation >10xULN Rhabdomyolysis:Widespread muscle injury with CK >10xULN andaccompanying organ (renal) damage. Myoglobinuria/emia feature
Reported Cases of Serious Rhabdomyolysis for Statins: AERS Davidson MH et al. Am J Cardiol. 2006;97:32C-43C
In Summary…The Risk is Small! There were only 73 reported cases of fatal rhabdomyolysis associated with 484,273,000 prescriptions of statinsin the USA
FDA WarningMarch 2010
No Simvastatin with itraconazole, ketoconazole, erythromycin, clarithromycin, telithromycin, HIV protease inhibitors, or nefazodone.
No simvastatin >10 mg with gemfibrozil, cyclosporine, or danazol
No simvastatin >20 mg with amiodarone or verapamil
No simvastatin >40 mg with diltiazem
Patients of Chinese descent should not receive simvastatin 80 mg with cholesterol-modifying doses of niacin-containing products.
caution when such patients are treated with simvastatin 40 mg or less in combination with cholesterol-modifying doses of niacin-containing products
The interim HPS2 results showed that the incidence of myopathy was higher in patients of Chinese descent (0.43%) compared with patients not of Chinese descent (0.03%) taking 40 mg simvastatin plus cholesterol-modifying doses (≥1 g/day) of a niacin-containing product. It is not known if the increased risk for myopathy observed in these patients applies to other patients of Asian descent.
Atorvastatin 2003 and 2006 Safety Meta-analyses* American Journal of Cardiology Newman et al, 2006
Analysis of 49 studies
N = 14,236 (atorvastatin & placebo patients)
10 mg, 80 mg, and placebo
Newman et al, 2003
Analysis of 44 studies
N = 9416 (atorvastatin patients)
10 mg-80 mg and placebo
Newman C et al. Am J Cardiol. 2003;92:670-676; Newman C et al. Am J Cardiol. 2006;97:61-67.
Increased Patient Exposure to Atorvastatin 80 mg in Clinical Trials 4925 4681 5000 3910 3000 Patient-years 1780 1388 1000 167 1996 2001 2004 Atv 10 mg Atv 80 mg >121 million patient-years of exposure to atorvastatin in the real world Newman C et al. Am J Cardiol. 2006;97:61-67.
Musculoskeletal Adverse Events With the 80-mg Dose NR, not reported *Studies not included in 2006 safety meta-analysis †Investigator-reported cases: did not meet criteria for definition of myopathy (persistent CPK elevations >10 x ULN with muscle symptoms) Newman C et al. Am J Cardiol. 2006;97:61-67; Cannon CP et al. N Engl J Med. 2004;350:1495-1504; LaRosa JC et al. N Engl J Med. 2005;352:1425-1435; Pedersen TR et al. JAMA. 2005;294:2437-2445.
Placebo 13,365 (98%) 609 (25%) 920 (31%) 20 (1.1%) 145 (10%) Adverse and Serious Adverse Events in CARDS Atorvastatin 10mg Type of Event No of events (% of patients with event) 13,238 (97%) Any adverse event 599 (23%) Associated AE 835 (29%) Serious AE 19 (1.1%) Associated SAE 122 (8.5%) Discontinued for AE
High Dose Statins after ACS Dept. of Cardiology Stoke on trent September/October 2005 Suspension of Atorvastatin due to costs Audit patients with UA or MI December 2004 – February 2005 Atorvastatine 80 – 40 mg December 2005 – February 2006 Simvastatin 20 – 40 mg
Acute coronary syndrome event
Non cardiac readmissions
High Dose Statins after ACS Rob Butler, James Wainwright . Lancet 2007;369:27
Incidence of Musculoskeletal Adverse Events Were Similar Across Dose Range Data from 2003 safety meta-analysis involving 11,205 patients from 44 trials Newman CB et al. Am J Cardiol. 2003;93:670-676.
Factors that Increase the Risk of Statin Induced Myopathy Patient characteristics Increasing age Female gender Renal insufficiency Hepatic dysfunction Hypothyroidism Diet (i.e. grapefruit juice) Polypharmacy Statin properties High systemic exposure Lipophilicity High bioavailability Limited protein binding CYP 450 3A4 metabolism Am J Cardiol 2006; 97 (8, Suppl 1):S1-88c
Statin Safety in Perspective Number needed to treat for 1 year to: Cause a GI Bleed1 Cause a Fatal GI Bleed1 Aspirin Cause Severe Myositis2 Cause Fatal Myositis2 Statins 248 2066 100,000 1,000,000 1Derry S, Loke YK. 2000 2Thompson PD, et al. 2003