Atorvastatin

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  • Atorvastatin

    1. 1. SPARCL TRIAL: HIGH-DOSE ATORVASTATIN AFTER STROKE OR TRANSIENT ISCHEMIC ATTACK PRESENTED BY: TING CHUONG WEI KENNY GOH WEI CHUAN CHEN SIAW MING 12-12-2007
    2. 2. Atherosclerosis Timeline Phase I: Initiation LDL-C plays a major role in initiating the development of atherosclerotic plaque. Libby P. In: Heart Disease: A Textbook of Cardiovascular Medicine . 6th ed. Philadelphia, Pa: WB Saunders Co; 2001:995-1009; Libby P. J Intern Med . 2000;247:349-358. Media Intima Phase II: Progression Disease progression results in the remodeling of the vascular wall so that the size of the lumen does not change significantly. LDL-C Lumen Unstable Stable Phase III: Complication Extensive lipid accumulation and a greater inflammatory component can pose the threat of plaque rupture.
    3. 3. Mechanism of Action of Statins Cholesterol Synthesis Pathway acetyl CoA HMG-CoA mevalonic acid mevalonate pyrophosphate isopentenyl pyrophosphate geranyl pyrophosphate farnesyl pyrophosphate squalene cholesterol dolichols ubiquinones HMG-CoA synthase HMG-CoA reductase Squalene synthase Statins X
    4. 4. Mechanisms Through Which Statins may Confer Stroke Protection <ul><li>Lipoprotein alterations </li></ul><ul><li>Prevent atherosclerosis </li></ul><ul><li>Improved endothelial function </li></ul><ul><li>Plaque stabilization </li></ul><ul><li>Anti-thrombosis </li></ul><ul><li>Attenuation of the inflammatory cytokine responses that accompany cerebral ischemia </li></ul><ul><li>Antioxidant properties that ameliorate ischemic oxidative stress on the brain </li></ul>
    5. 5. Percentage Reduction of LDL-C by Statin Change in LDL-C from baseline (%) 0 – 10 – 20 – 30 – 40 – 50 – 60 – 5 – 15 – 25 – 35 – 45 – 55 10 mg 20 mg 80 mg 10 mg 20 mg 40 mg 80 mg 10 mg 20 mg 40 mg Atorvastatin Pravastatin 40 mg Drug Information Handbook 13 th Edition 20 mg 40 mg 80 mg Lovastatin Simvastatin
    6. 6. WHAT IS THE BACKGROUND AND RATIONALE BEHIND THIS STUDY? <ul><li>Patients with prior stroke/TIA are at risk for future cardiovascular (CV S ) events . </li></ul><ul><li>Statins  stroke incidence in patients at risk for CV S disease , however, stroke risk reduction with statin therapy has not been demonstrated in patients with a history of stroke or TIA . </li></ul>This study 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 Investigators. N Engl J Med. 2006;355:549-59.
    7. 7. P RIMARY H YPOTHESIS OF THE STUDY <ul><li>Treatment with 80 mg of atorvastatin per day would reduce the risk of fatal or nonfatal stroke among patients with a history of stroke or TIA. </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    8. 8. DEFINITION <ul><li>STROKE - focal clinical signs of central nervous system dysfunction of vascular origin that lasted for at least 24 hours. </li></ul><ul><li>TRANSIENT ISCHEMIC ATTACK (TIA) – the loss of cerebral or ocular for less than 24 hours, presumably owing to atherosclerotic causes. </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    9. 9. <ul><li>6670 SELECTED FOR SCREENING VISIT </li></ul>STUDY DESIGN SPARCL Investigators. N Engl J Med. 2006;355:549-59. 4731 UNDERWENT RANDOMIZATION 1939 EXCLUDED 1591 = DID NOT MEET ENRTY CRITERIA 250 = WITHDREW CONSENT 54 = EXCLUDED FOR OTHER ADMINISTRATION REASONS 44 = HAD AN ADVERSE EVENT OR REACHED AN END POINT DURING SCREENING POINT
    10. 10. STUDY DESIGN SPARCL Investigators. N Engl J Med. 2006;355:549-59. Stroke or TIA in ≤6 months, no known CHD, LDL-C 100–190 mg/dL N = 4731 Atorvastatin 80 mg daily n = 2365 Placebo n = 2366 Randomized Double blind Primary end point: Fatal/nonfatal stroke Secondary end points : Major coronary or CV events Median follow-up: ~ 4.9 years
    11. 11. SAFETY ASSESMENTS FOR THIS STUDY INCLUDE…… <ul><li>Full clinical laboratory assessments were performed </li></ul><ul><li>Electrocardiograms were obtained </li></ul><ul><li>Drug safety also assed by an evaluation of the type, frequency, severity, and duration of any reported adverse event </li></ul><ul><li>And also basis of vital signs, physical examination, laboratory test. </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    12. 12. QS1: DID THE STUDY ASK A CLEARLY FOCUSED QUESTION? YES , from PICO chart <ul><li>Administration of atorvastatin 80mg daily. </li></ul><ul><li>Follow-up visit were scheduled 1, 3 and 6 months after enrollment and every 6 months thereafter </li></ul>I NTERVENTION <ul><li>The patients </li></ul><ul><li>Were men and women over 18 years old who had an ischemic or hemorrhagic stroke or a TIA 1-6 months before randomization. </li></ul><ul><li>had to be ambulatory with a modified Rankin Score of more than 3. </li></ul><ul><li>LDL cholesterol level of at least 100 mg/dL and not more than 190mg/dL. </li></ul>P OPULATION CHARACTERISTICS PICO
    13. 13. <ul><li>Primary end point: </li></ul><ul><li>Fatal and non-fatal stroke </li></ul><ul><li>Secondary end-point: </li></ul><ul><li>Stroke and TIA </li></ul><ul><li>Major coronary events (death from cardiac causes, nonfatal MI or resuscitation after cardiac arrest) </li></ul><ul><li>Major cardiovascular event (stroke + any major coronary events) </li></ul><ul><li>Acute coronary events (major coronary events or unstable angina) </li></ul><ul><li>Revascularization procedures (Coronary, Carotid or Peripheral) </li></ul><ul><li>Any cardiovascular event (Any of the former + clinically significant peripheral vascular disease) </li></ul><ul><li>Any coronary events (Acute coronary event + coronary revascularization procedures, unstable angina or ischemia requiring emergency hospitalization) </li></ul>O UTCOME <ul><li>Treatment group is compared with the placebo group </li></ul>C OMPARISON CHARACTERISTICS PICO
    14. 14. QS2: WAS THIS RANDOMIZED CONTROL-TRIAL AND WAS IT APPROPRIATE? YES, this trial is a Randomized Control-Trial (RCT) to study the comparison of risk reduction incidence of fatal and non-fatal stroke among the patients receiving 80 mg of atorvastatin per day with placebo over median follow up 4.9 years . This RCT is an appropriate research design because this is a clinical question and is the most reliable form of scientific event. SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    15. 15. QS3. WERE THE PARTICIPANTS APPROPRIATELY ALLOCATED TO INTERVENTION AND CONTROL GROUPS? <ul><li>YES, after the patients g iven written informed consent, they are randomly assigned to double-blind therapy with either 80 mg of atorvastatin per day or placebo. </li></ul><ul><li>Patients who were taking lipid-altering drug had to stop these medication 30 days before the screening phase of the study. </li></ul><ul><li>Both groups were well balanced. The baseline characteristics as in Table 1 were similar in the 2 groups. Both groups were well matched with respect relevant clinical parameters. Table 1: Baseline characteristics of patients </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    16. 16. <ul><li>The subjects were men and women > 18 years old who had an ischemic or hemorrhagic stroke or a TIA 1 to 6 months before randomization. </li></ul><ul><li>The mean LDL-C, HDL-C and triglyceride were similar in the both groups at baseline. </li></ul><ul><li>Patient with hemorrhagic stroke were included if they were deemed by the investigator to be at risk for ischemic or coronary heart disease. </li></ul><ul><li>After randomization, the patients in both groups also took </li></ul><ul><li>other medication s . </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    17. 17. <ul><li>Patient who had a stroke or TIA within 1 - 6 months before study entry . </li></ul><ul><li>Had low-density lipoprotein (LDL) cholesterol levels of 100-190 mg/dL (2.6-4.9 mmol/L) . </li></ul><ul><li>Had no known coronary heart disease . </li></ul>Inclusion criteria : SPARCL Investigators. N Engl J Med. 2006;355:549-59. Exclusion Criteria: <ul><li>Atrial filbrillation </li></ul><ul><li>Other cardiac sources of embolism </li></ul><ul><li>Subarachnoid hemorrhage </li></ul>
    18. 18. Table 1: Baseline characteristics of patients SPARCL Investigators. N Engl J Med. 2006;355:549-59. 17 17 Diabetes 61 62 Hypertension 39 41 Former smoker 19 19 Current smoker Risk factors (%) 143 144 Triglycerides 50 50 HDL-C 134 133 LDL-C Lipid profile (mg/dL) 138 139 Systolic BP (mm Hg) 63 63 Age (years) 59 60 Male (%) Placebo n = 2366 Atorvastatin n = 2365
    19. 19. Table 2: Entry events *Ischemic stroke or TIA in >97% of patients N = 4731 SPARCL Investigators. N Engl J Med. 2006;355:549-59. (<0.1 ) 1 (0.1) 2 Unknown (32) 752 (30) 708 TIA (68) (66) (2) (0.3) 1613 1559 48 6 (70) (67) (2) (0. 6 ) 1655 1595 45 15 Entry event* Stroke Ischemic Hemorrhagic Other type or not determined (%) n (%) n Placebo Atorvastatin
    20. 20. Table 3: Concomitant medications N = 4731 SPARCL Investigators. N Engl J Med. 2006;355:549-59. 154 (7) 139 (6) Vitamin K antagonist, including warfarin BACK 63 (3) 57 (2) Prior statin therapy 102 (4) 110 (5) ARB 422 (18) 414 (18) β -blocker 359 (15) 350 (15) Dihydropyridine derivative 667 (28) 683 (29) ACE inhibitor 2063 (87) 2067 (87) Antiplatelet agent Concomitant therapy Placebo n (%) Atorvastatin n (%)
    21. 21. QS4. WERE THE PARTICIPANTS, STAFF AND STUDY PERSONNEL BLIND TO PARTICIPANTS STUDY GROUP? <ul><li>YES, eligible patients were randomly assigned to double-blind therapy with either 80 mg of atorvastatin per day or placebo. </li></ul><ul><li>All patients were counseled to follow the National Cholesterol Education Program Step 1 (or similar) diet throughout the study. </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    22. 22. <ul><li>If LDL-C level  below 40 mg/dL (1.0 mmol/L) in patient treated with atorvastatin, the investigator for a randomly chosen placebo patient was notified. And LDL-C level were remeasured in both patients. </li></ul><ul><li>Only nine of patients (3 assigned to atorvastatin group and 6 assigned to placebo group) was revealed to the study physician. And they were unblinded to their study physician during the study. </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    23. 23. QS5. WERE ALL THE PARTICIPANTS WHO ENTERED TO THE TRIAL ACCOUNTED FOR ITS CONCLUSION? <ul><li>YES . </li></ul><ul><li>Complete follow-up achieved for 96% atorvastatin (2365 patients) vs. 95% placebo groups (2253 patients), all randomized patients analyzed by intention to treat . </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    24. 24. QS6. WERE THE PARTICIPANTS IN ALL GROUPS FOLLOWED UP AND DATA COLLECTED IN THE SAME WAY? <ul><li>Yes. At the end of the study the median period of follow-up was 4.9 years </li></ul><ul><li>Both groups were treated in exactly the same way with follow-up visits at 1 , 3 , and 6 months after enrolment and every six months thereafter. </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    25. 25. QS7. DID THE STUDY HAVE ENOUGH PARTICIPANTS TO MINIMIZE THE PLAY OF CHANCE? <ul><li>Yes. The design of the study provide 90% power to detect an absolute 25% reduction in the 4.9 years (median follow up ) primary outcome measure between treatment groups and placebo group, with a two-sided 5% level of significance (p<0.05). </li></ul><ul><li>These conditions were met the study was sufficiently powered to make reliable conclusions. </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    26. 26. QS 8 : WHAT WAS THE MAIN RESULT AND HOW WERE THE RESULTS PRESENTED? <ul><li>Primary outcome: fatal and non-fatal stroke </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59. CER = 311/2366 x 100% = 13.1% 2055 311 2366 Placebo EER = 265/2365 x100% = 11.2% 2100 265 2365 Atorvastatin % Participants without fatal and non-fatal stroke Participants with fatal and non-fatal stroke Total participants
    27. 27. <ul><li>ARR = CER – EER </li></ul><ul><li>= 13.1% - 11.2% </li></ul><ul><li>= 1.9% ~ 2% </li></ul><ul><li>Interpretation: </li></ul><ul><li>Treatment with atorvastatin (80mg per day) reduces the risk of fatal and non-fatal stroke by 2% . </li></ul><ul><li>In every 100 persons treated with atorvastatin, 2 persons can avoid fatal and non-fatal stroke due to the treatment of atorvastatin. </li></ul>Absolute Risk Reduction (ARR ) SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    28. 28. <ul><li>RRR = 1 – EER/CER </li></ul><ul><li>= 1 – 11.2/13.1 </li></ul><ul><li>= 0.145 </li></ul><ul><li>= 14.5% </li></ul><ul><li>Interpretation </li></ul><ul><li>The treatment reduces the probability of fatal and non-fatal stroke by 14.5%. </li></ul>Relative Risk Reduction (RRR) SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    29. 29. <ul><li>NNT = 1/ARR </li></ul><ul><li>= 1/0.019 </li></ul><ul><li>= 52.63 ~ 53 </li></ul><ul><li>Interpretation </li></ul><ul><li>In order to avoid 1 case of fatal or non-fatal stroke, 5 3 persons need to be treated. </li></ul>Number Needed to Treat (NNT) SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    30. 30. Time since randomization (years) High-dose statin treatment reduces fatal/nonfatal stroke SPARCL Investigators. N Engl J Med. 2006;355:549-59. Fatal/ nonfatal stroke (%) 0 0 1 2 3 4 5 6 16 12 8 4 14.5% RRR HR 0.84 (0.71–0.99) P = 0.03 Placebo Atorvastatin NNT = 53 patients for median f/u 4.9 years Primary outcome
    31. 31. Secondary outcomes: 24 4.2 20.1 15.9 1. Stroke or TIA 44 2.3 8.8 6.5 a. TIA The result is statically not significant (P = 0.98) 6.6 2.9 3.4 2.1 3.1 1.7 ARR (%) - 15 34 29 48 33 59 NNT 8.9 9.1 8. Death 29.0 22.4 7. Any CVS event 6.9 4.0 6. Revascularization 8.6 5.2 5. Any coronary events 6.4 4.3 4. Acute coronary events 17.2 14.1 3. Major CVS event 5.1 3.4 2. Major coronary events CER (%) EER (%) Outcomes
    32. 32. High-dose statin reduces major cardiovascular events SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Cardiac death, MI, resuscitated cardiac arrest, and stroke 0 0 30 20 10 1 2 3 4 5 6 Time since randomization (years) Major CVS events* (%) 18% RRR HR 0.80 (0.69–0.92) P = 0.002 Placebo Atorvastatin NNT = 33 patients for median 4.9 years
    33. 33. Reductions in major coronary events SPARCL Investigators. N Engl J Med. 2006;355:549-59. *Cardiac death, MI, resuscitated cardiac arrest 0 0 10 6 2 1 2 3 4 5 6 Time since randomization (years) Major coronary events* (%) 33% RRR HR 0.65 (0.49–0.87) P = 0.003 Placebo Atorvastatin 8 4
    34. 34. Treatment effect on stroke and TIA Hazard ratio SPARCL Investigators. N Engl J Med. 2006;355:549-59. HR* (95% CI) 0.84 (0.71–0.99) 0.57 (0.35–0.95) 0.87 (0.73–1.03) 0.77 (0.67–0.88) 0.74 (0.60–0.91) <ul><li>Primary outcome </li></ul><ul><li>Stroke (total) </li></ul><ul><ul><li>Fatal </li></ul></ul><ul><ul><li>Nonfatal </li></ul></ul><ul><li>Secondary outcomes </li></ul><ul><li>Stroke or TIA </li></ul><ul><ul><li>TIA </li></ul></ul>P 0.03 0.03 0.11 <0.001 0.004 0.3 1.0 1.7 N = 4731 Aggressive statin therapy Better Worse
    35. 35. <ul><li>The incident of fatal hemorrhagic stroke did not </li></ul><ul><li>differ significantly between groups (17 in </li></ul><ul><li>atorvastatin and 18 in placebo group). </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59. 12 7 19 Unclassified stroke 33 55 88 Hemorrhagic stroke 274 218 492 Ischemic stroke Placebo Group Atorvastatin Group Total Stroke Types
    36. 36. SAFETY ASSESSMENT: ADVERSE EVENTS SPARCL Investigators. N Engl J Med. 2006;355:549-59. N = 4731 0 11 3 7 141 n Placebo Atorvastatin 2 51 2 7 129 n (0.5) (2.2) ALT or AST > 3x ULN (0.1) Creatine kinase >10x ULN (6.0) (5.5) Myalgia (0.3) (0.3) Myopathy (0.1) (0.1) Rhabdomyolysis Musculoskeletal AE (%) (%)
    37. 37. ADVERSE EVENTS SPARCL Investigators. N Engl J Med. 2006;355:549-59. <ul><li>discontinuation of study treatment due to adverse effect reported in 17.5% atorvastatin vs. 14.5% placebo patients . </li></ul>58 1.7 0.5 2.2 Serious adverse effect - elevation in alanine or aspartate aminotransferase > 3 times upper limit of normal NNH ARR CER EER Outcomes
    38. 38. <ul><li>Median follow up: 4.9 years </li></ul><ul><li>Dosage: 2 tablets daily (1 tablet 40 mg) </li></ul><ul><li>Cost: 1 tablet (40mg) = ~ RM 5 </li></ul><ul><li>Total Cost of Drug Expenditure required for beneficial effect: </li></ul><ul><li>Dosage x 365 days x years of follow up x price of the drugs x NNT </li></ul><ul><li>= 2 x 365 days x 4.9 years x RM 5 x 53 </li></ul><ul><li>= RM 947,905 </li></ul>RM 17,885 is needed per person SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    39. 39. QS9: W HAT OTHER FACTORS NEED TO BE CONSIDERED? <ul><li>Other concomitant medications eg. Aspirin, beta-blockers? </li></ul><ul><li>Costs? </li></ul><ul><li>Risk of recurrent hemorrhage?? </li></ul><ul><li>Different lifestyle and diet among the participant s? </li></ul><ul><li>Safety? </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    40. 40. APPLICABLE? <ul><li>Translating trial results into clinical practice is often difficult, and application of the SPARCL results may be very hard. Physicians treating a patient with recent stroke but without known coronary heart disease may have difficulty prescribing a presumably lifelong drug such as high-dose atorvastatin, which may have harmful side effects . </li></ul>
    41. 41. COMMENTS <ul><li>Statin hepatotoxicity is dose-related, information about the specific liver enzyme elevations that occurred in these studies should be provided. </li></ul><ul><li>Further reassurance to the safety of this approach is needed . </li></ul><ul><li>Atorvastatin reduces the risk of nonfatal stroke from 11.8% to 10.4% over a period of median follow up 4.9 years, but it does so without improving survival. </li></ul>
    42. 42. C ONCLUSION <ul><li>Based on the findings in this journal: </li></ul><ul><li>In patient with a recent stroke or TIA, without known coronary heart disease, treatment with 80mg of atorvastatin per day decreased the risk of stroke, major coronary events and revascularization procedures. </li></ul><ul><li>The results support the initiation of atorvastatin treatment soon after a stroke or TIA. </li></ul><ul><li>However, some factors need to be considered, for example, risk of recurrent hemorrhage, before the initiation of treatment. </li></ul>SPARCL Investigators. N Engl J Med. 2006;355:549-59.
    43. 43. THANK YOU!!!!

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