CVD I: Risk assessment & Anti-coagulation

G. Michael AllanAssociate 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

– Non-Profit Sources (E.g Canadian Expert Drug Advisory Committee, Alberta College of Family Physicians, etc)

– No funding from Industry

Objectives

1) Discuss risk: Primary vs Secondary prevention. 2) Review Risk Assessment

i. General Risk Assessmentii. Special Test like Homocysteine and hsCRP.

3) Evidence for the use of Anti-Platelet Agentsi. ASA in primary preventionii. ASA in secondary preventioniii. Clopidogrel in Primary Prevention

iv. Clopidogrel in Secondary Prevention

Opening Quiz

• Which of the following risk factors carry the most risk for future CVD.

A. Diabetes

B. History of MI

C. Age

D. hsCRP

E. smoking

Opening Quiz

• Which of the following risk factors carry the most risk of future CVD in primary prevention;

A. Smoking

B. Age

C. Blood sugar (if diabetic)

D. Blood pressure

E. hsCRP

Who really benefit from treatment?

• Who gets meds by guidelines?• Who is higher risk?

Age Smoke BP Total HDL LDL

Mrs Risk

35 No 120 290 (7.5)

40 (1.0)

200 (5.2)

Mr Risky

55 Yes 140 190 (4.9)

40 (1.0)

100 (2.6)

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).

Risk* (x10 yrs)

Med Treating (statin) 5 years

Risk Benefit (~28%)

New risk

Mrs Risk

1.7% Yes 0.6% 0.17% 0.4%

Mr Risky

13.6% No 6.2% 1.7% 4.5%

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.

<5% 5-10% 10-15% 15-20% ≥20%

No CVD (32 K pts)3 2.5% 5.4% 9.5% 11% 20%

Hx CVD (3728 pts) 22% 25% 31% 38% 49%

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?usertyp

e=prof

The Cardiac Crystal Ball*: Biomarkers

1) What do biomarkers add to standard CVD risk models?

2) What might be the role of biomarkers like hsCRP?

3) What did the JUPITER trial add and what did not add?

* Brought to you by Nostradamus Labs.

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

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.

0.76 without vs 0.77 with Biomarkers2

Does reducing hsCRP reduce risk?

• Reducing hsCRP does NOT mean reduced risk

Med Statin Vit E Rosiglitazone Rofecoxib

CRP ↓ (15-50%)4 ↓ (50-80%)4 ↓ (40%)4 ↓ (variable)8

CVD ↓ 5 ↑ (mortality)6 ↑ 7 ↑ 9

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

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.

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.

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

Anti-platelets in Primary Prevention

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?

Primary Prevention- ASA in ♀

• 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.

outcome ♀

CVD 333

Bleed 400

Specific outcomes

stroke 500

MI -

NNT (and NNH)

1. JAMA. 2006;295:306-313.

Primary Prevention – ASA in ♂

• 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.

outcome ♂

CVD 270

Bleed 303

Specific outcomes

Stroke* -

MI 125

NNT (and NNH)

1. JAMA. 2006;295:306-313.

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

When might Benefits outweigh RisksUsed cost-effectiveness to model when to treat (and

got around 15% 10 year risk)

Lancet 2009; 373: 1821-22.

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.

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.

2ndary PreventionClogged Passages

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?

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

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

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

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

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

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.

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.

Adjunctive Issues

Adjunctive Material

• New Anti-platelets

• What about anti-platelet resistance?

• PPI & ASA vs Clopidogrel

• Clopidogrel + PPI

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.

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 allele for 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

clopid Placebo AR RR

Allele 9.5% 13% 3.5% 0.72

No 8% 11.6% 3.6% 0.69

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.

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

Clopidogrel & PPI: What to Do• 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)

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.do Accessed March 26, 2010 with other data from internet & from Circulation 2009;120;2310-2312. 7) Circulation 2009;120;2310-2312 (Dr Juurlink).