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CVD I: Risk assessment & Anti-coagulation

CVD I: Risk assessment & Anti-coagulation. G. Michael Allan Associate Professor, Family Med, U of A. Conflict of Interest. Family Doctor for 12+ yrs Academic 8 years Pay from U of A and Alberta Health Research and Speaking Fees

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CVD I: Risk assessment & Anti-coagulation

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  1. CVD I: Risk assessment & Anti-coagulation G. Michael Allan Associate Professor, Family Med, U of A

  2. Conflict of Interest Family Doctor for 12+ yrs Academic 8 years Pay from U of A and Alberta Health Research and Speaking Fees Non-Profit Sources (E.g Canadian Expert Drug Advisory Committee, Alberta College of Family Physicians, etc) No funding from Industry

  3. Objectives • Discuss risk: Primary vs Secondary prevention. • Review Risk Assessment • General Risk Assessment • Special Test like Homocysteine and hsCRP. • Evidence for the use of Anti-Platelet Agents • ASA in primary prevention • ASA in secondary prevention • Clopidogrel in Primary Prevention • Clopidogrel in Secondary Prevention

  4. Opening Quiz • Which of the following risk factors carry the most risk for future CVD. • Diabetes • History of MI • Age • hsCRP • smoking

  5. Opening Quiz • Which of the following risk factors carry the most risk of future CVD in primary prevention; • Smoking • Age • Blood sugar (if diabetic) • Blood pressure • hsCRP

  6. Who really benefit from treatment? • Who gets meds by guidelines? • Who is higher risk?

  7. Who really benefit from treatment? • Mrs Risk would treated with a drug due to her lipid levels while Mr Risk would not (although he would get 10 x the benefit).

  8. How Accurate are Risk Tools Looking at variability (95% CI) within models: Framingham +/- 15% if estimated risk >30% (but only 3% when between 10-20%)1 Reynolds risk +/- 5-6% at 15 or 20%. 2 1. Am Heart J 1991; 121: 293-98. 2. J Cardiovasc Risk 2002; 9: 183-190. 3. Heart 2009;95:125–9.

  9. What Risk Assessment tool is “best”? University of Edinburgh Cardiovascular Risk Calculator – International Units http://cvrisk.mvm.ed.ac.uk/calculator/calc.asp National Cholesterol Education Program – US units http://hp2010.nhlbihin.net/atpiii/calculator.asp?usertype=prof

  10. The Cardiac Crystal Ball*: Biomarkers What do biomarkers add to standard CVD risk models? What might be the role of biomarkers like hsCRP? What did the JUPITER trial add and what did not add? * Brought to you by Nostradamus Labs.

  11. Studies of hsCRP & Biomarkers CRP (& other biomarkers) provide little additional predictive value.1-4 hsCRP (HR ratio 1.19, p < 0.001) vs D-dimer (1.36), interleukin-6 (1.28), lipoprotein-A2 (1.17).3 0.76 without vs 0.77 with Biomarkers2 1) N Engl J Med 2004;350:1387-97. 2) N Engl J Med 2006; 355: 2631-39 3) Arch Intern Med 2006; 166: 1368-73. 4) Int J Epidemiol 2009; 38: 217-31.

  12. Does reducing hsCRP reduce risk? Reducing hsCRP does NOT mean reduced risk 3. Ann Clin Biochem 2002; 39: 85-88. 4. Cardiovasc Drug Rev 2006; 24: 33-50. 5. Lancet 2008; 371: 117-125. 6. JAMA. 2007;297:842-57. 7. JAMA 2007; 298: 1189-1195. 8. Circulation 2004; 110: 934-939. 9. CMAJ 2002; 166: 1649-1650

  13. More hsCRP facts? Median hsCRP = 2.5 mg/l (♀) and 1.5 mg/l (♂).1 Within-subject standard deviation is 1.2 mg/l.2 What about reclassifying? Between 5.6% and 18% of people could move up or down arbitrary risk classes (high-mid-low).3 Sample Patient Female Patient with ~8% risk 8 mg/L: 9% 2.5 mg/L: 8% 1.0 mg/L: 7% 0.5 mg/L: 6% 1. N Engl J Med 2005; 352: 1611-1613. 2. Clin Chem 2001; 47: 444-450. 3 Circulation 2008; 118: 2243-51 & Ann Intern Med 2006; 145: 21-29. Circ Cardiovasc Qual Outcomes 2008; 1: 92-97.

  14. What about Jupiter? Screened ~90,000 patients, took 17,802 Limits: Stop early, funding, run-in, selection Most Patients moderate risk (would benefit) Mean CRP would add about 1-3% to risk2 and less to absolute benefit ASCOT trial already showed statins reduce CVD endpoints from 9.5% to 7.5% (NNT 50) over 3.3 yrs in intermediate risk patients with a low LDL3 1. NEJM 2008;359:2195-207. 2. http://www.reynoldsriskscore.org/ 3. Lancet 2003; 361: 1149–58.

  15. Biomarkers Bottom-line Recommendations to include biomarker testing based on conflicting evidence. And Jupiter misinterpreted/exaggerated If any use, perhaps in patients at the borderline of needing or not needing Tx, but Cut-offs arbitrary Absolute change small If not willing to take drug, testing unnecessary

  16. Anti-platelets in Primary Prevention

  17. Case: Primary Prevention • Mrs Clot is in. She is 55, generally well but on diuretic for mild hypertension. • Her risk of CVD is 6% (CHD is 3%). • A number of her friends at Curves are on ASA. She has started a baby aspirin once a day and wants to know your thoughts. • What are the risks & benefits of ASA?

  18. Primary Prevention- ASA in ♀ NNT (and NNH) • Study details: Meta-analysis1 • 3 RCT (51 K women), • all low risk (most no risk factors). • Dose 100mg q2days – 100mg OD • Mean 6.4 years f/u • Outcomes: No diff in mortality • risk balance benefits. 1. JAMA. 2006;295:306-313.

  19. Primary Prevention – ASA in ♂ NNT (and NNH) 1. JAMA. 2006;295:306-313. • Study details: Meta-analysis1 • 5 RCT (44 K men), • all low risk (most no risk factors). • Dose 75mg – 500mg OD (most low) • Mean 6.4 years f/u • Outcomes: No diff in mortality • Stat sign more hemorrhagic strokes but actual numbers small (0.28% vs 0.15%) • Overall: risk balance benefits.

  20. Primary Prevention- ASA A meta-analysis of primary (patient level data)1 6 trials (95,000 patients), ~ 6.9 yrs 12% RRR CVD Absolute event rates = 0.57 vs 0.51%/yr on ASA NNT =~286 over 5 years no effect on mortality ↑ major GI bleeds (transfusion or death), NNH ~560 What about hypertensive patients2 Benefits of ASA do not outweigh risks. 1. Lancet 2009; 373: 1849–602. 2. Cochrane 2004;3:CD003186

  21. When might Benefits outweigh RisksUsed cost-effectiveness to model when to treat (and got around 15% 10 year risk) Lancet 2009; 373: 1821-22.

  22. What about adding Clopidogrel CHARISMA1 RCT: High risk 1° or 2° 15,603 pts x 28 month, Clopid 75mg +/- ASA No difference in composite CVD If trend continued, About 5 CVD avoided for 3 Major bleeds2 In 1° prevention1 (3284 pts) population Non-significant increase in CVD events & death Significant increase in death overall (1.6% higher, NNH= 63) Reanalysis3 (more selective classifying 1º prevention patients): no longer statistical significant but borderline trend 1.2% increase Evidence: Do not add Clopid to ASA in 1° prevention 1. NEJM 2006;354:1706-17. 2. Cochrane 2007, 3: CD005158. 3. ACP journal club 2007; 148: 34. Eur Heart J. 2007;28:2200-7.

  23. Case: Primary Prevention • Mrs Clot is too low risk to benefit from ASA. • Bottom-line: The majority of primary prevention patients will not benefit from daily ASA therapy. It is possible there is net benefit in higher-risk primary prevention patients.

  24. 2ndary PreventionClogged Passages

  25. Case: Secondary Prevention • Mr Defiant (64 y.o. ♂) is in after his heart attack. He announces they put him on “a crap load of drugs.” He is concerned about “all those blood thinners” (he includes ASA, clopidogrel & atorvastatin). • He wants to know what they do? • What are the benefits and risks of ASA and/or clopidogrel after MI?

  26. What about ASA Alone? Meta-analysis: All Anti-platelet meds (with combo) 195 RCT, ASA alone ~60% patients Absolute Reduction (for ASA) over mean 2 yrs At 75-325mg, 3.5% reduction in CVD outcomes (NNT 29) Statistical significant mortality reduction (but ASA rates could not be pulled out from all anti-platelets together) Benefits similar regardless of initial event (MI or CVA) No benefit from doses > 75-325 mg (& lower dose ?) Other antiplatelets not stat sign superior to ASA. BMJ 2002;324:71–86

  27. What about ASA Alone? Second meta-analysis (Better absolute numbers) Just ASA (50-325): 6 Trials, 9835 patients 2 CAD & 4 post stroke studies Stat Sign Absolute Reductions at 33 months CVD events = 3.3% less (NNT = 31) Death = 1.4% (NNT = 72) Major Bleed = 0.9% (NNH = 112) Bottom-line: ASA offers a statistical and clinically important advantage. 1) Am J Med 2008; 121: 43-49

  28. What about Clopidogrel Alone? CAPRIE: clopidogrel 75mg OR ASA 325mg 19K pts with recent stroke, MI or PAD given Mean 1.91 yrs Yearly rate of stroke, MI or vascular death Clopidogrel 5.32% vs ASA 5.83% (p=0.043) AR = 0.51, NNT= 197 No other outcome (even grouped) Stat sign Clopid alone little advantage over ASA alone Lancet 1996; 348: 1329–39

  29. What about ASA + Clopidogrel? Meta-Analysis (ASA + Clopid: 91,744 pts) Best data for ACS and PCI (6 of 8 trials) F/U was 28 days to 18 months Outcomes clopidogrel & ASA vs ASA alone ↓ combined: death, reinfarction, & stroke In ACS by 0.85 (0.77-0.94) In PCI by 0.65 (0.55 -0.77) All Bleeds* increased by 1.80 (1.40 to 2.30) Lots of Flaws,… Am J Cardiol 2008;101:960 –966

  30. What about ASA + Clopidogrel? CURE: Acute Coronary Syndrome (without ST elevation), 12,562 patients. Given Clopiogrel & ASA vs ASA alone 3-12 months of drugs (mean 9 months) Outcomes (All statistically significant) Primary: clopid 9.3% vs 11.4%, NNT= 48 Above or refractory ischemia: 2.3% AR, NNT=44 Major Bleed: 3.7% (clopid) vs 2.7%, NNH=100 Total mortality data not presented 1. NEJM 2001;345: 494-502

  31. What about ASA + Clopidogrel? COMMIT study1: 45K MI pts RCT, Clopidogrel or placebo (all got ASA) Duration f/u & clopid admin = while in hosp or max 28d (mean 15 d) Reduced: CVD outcome 0.9% & death 0.6% No diff in bleeding CHARISMA: Secondary only (12,153 pts) x 28 mon Clopid + ASA vs ASA led to,.. Statistically significant reduction in CVD (1%, NNT 100) 1 Lancet 2005; 366: 1607–21.

  32. Case: Secondary Prevention Mr Defiant will get reduction of 3-3.5% in CVD events (+ 1.4% in mortality), ASA x3 yrs. 1-2% in CVD, Clopidogrel ≤1 year. Bleeds will increase up to 1% for each. Clopidogrel + ASA has role for ACS and/or PCI pts. Duration varies but about 1 yr post PCI Clopidogrel added to ASA no role in Primary prevention Or arterial origin ischemic stroke (non cardio-embolic). Ann Pharmacother 2008;42:550-7.

  33. Adjunctive Issues

  34. Adjunctive Material New Anti-platelets What about anti-platelet resistance? PPI & ASA vs Clopidogrel Clopidogrel + PPI

  35. Coming Soon to MI near you,… • Ticagrelor: PLATO study, 2% CVD ↓ over clopidogrel (& ↓ 1% mortality). • Approval North America delayed (no better here?) • Prasugrel: TRITON-TIMI 38 study, 2% CVD ↓ over clopidogrel (but NO mortality). • Diabetes subgroup did better (~4.8% CVD ↓ ) • Bleeding up 0.6% • Cancer up about 0.5% 1) N Engl J Med. 2009;361:1045-57. 2) N Engl J Med 2007;357:2001-15.

  36. Anti-platelet Resistance • Meta-analysis of 20 studies (2930 pts)1 • Multiple tests for ASA res, 28% of pts ASA resistant • CVD events: resistant (39%) vs sensitive (16%). • No effect with dose (?) or changing to Clopidogrel. • Lots of Uncertainty: For example2 • CYP2C19 loss of function allelefor Clopidogel RCT • Bottom-line: Likely exists, no great strategy, maybe new agents? Arch Intern Med 2007;167:1593-9. G Pare et al NEJM 2010

  37. Primary Prevention & GI Bleeds • ?: In a patient with a past GI bleed on ASA, should we switch to Clopidogrel or add a PPI? • Evidence: RCT, Clopiogrel vs ASA + Esomeprazole • Recurrent Ulcer bleed: Clopidogrel (8.6%) vs ASA + PPI (0.7%) with NNH=13 (8-30) at 1 yr • Bottom-line: If anti-platelet agent required, better to add PPI to ASA then switch to clopid NEJM 2005; 352: 238-44.

  38. Clopidogrel & PPI: What to Do • ?: In patients needing both clopidogrel and PPI, what should we do? • Starting evidence: Case-Control,1 Canada, post MI & Cohort,2 US (vet): post ACS, • Odds Ratio of increase risk of MI if on PPI: 1.27 (1.03 – 1.57)1 • Adjusted Odds Ratio for Mortality/ACS admission: 1.25 (1.11 – 1.41)2 • Since then • Non-randomized data RCTs3: No effect on CVD events • Cohort (population data: BC, New Jersey, Penn)4: adjusted RR, MI & death = 1.22 (0.99-1.51), • Tennessee Cohort Study5:No difference but some  GI • COGENT: RCT, stopped early (bankrupt)6: No difference but some  GI

  39. Clopidogrel & PPI: What to Do 1. CMAJ. 2009;180(7):713-8. 2. JAMA. 2009;301(9):937-944 3. Lancet 2009; 374: 989–97. 4. Circulation 2009;120:2322-29. 5. Ann Intern Med.2010;152:337-345. 6. http://www.theheart.org/article/1007145.doAccessed March 26, 2010 with other data from internet & from Circulation 2009;120;2310-2312. 7) Circulation 2009;120;2310-2312 (Dr Juurlink). • Bottom-line: Determine if need PPI • If on ‘just because’  D/C • If do need PPI  Pantoprazole • If need ‘some’ acid suppression  H2Antagonist • Separate timing of PPI and Plavix by 4 hours • ? Use Plavix for a ‘reasonable amount of time’ (not indefinitely for most)

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