24. USPSTF 2015 DRAFT
RECOMMENDATIONS
• Key changes:
• No differentiation of GENDER
• No differentiation of DIABETES status
• Incorporates CRC benefit
• Key points:
• Currently, ASA therapy NOT recommended in cancer
prevention WITHOUT increased CVD risk
• Life expectancy ≥ 10 years to see CRC benefit
26. USPSTF 2015 DRAFT
RECOMMENDATIONS
Low-dose ASA for CVD and CRC primary
prevention if:
10-year CVD risk ≥ 10%
Low risk for bleeding
Life expectancy ≥ 10 years
Willing to take ASA daily for ≥ 10 years
29. Guirguis-Blake JM, Evans CV, Senger CA, et al. Aspirin for
the Primary Prevention of Cardiovascular
Events: A Systematic Evidence Review for the U.S. Preventive
Services Task Force. Evidence Synthesis No. 131. AHRQ
Publication No. 13-05195-EF-1. Rockville, MD: Agency for
Healthcare Research and Quality; 2015. PMID: 26491760
30. CV EVENTS PRIMARY PREVENTION
• 10 RCTs
• N = 103,787
• Total MI, total stroke, CVD mortality: 11% reduction
(RR 0.89, 95% CI 0.84-0.95)
• Non-fatal MI/coronary events: 20% reduction (RR
0.80, 95% CI 0.72 – 0.88)
• Total stroke with 100 mg ASA daily or less: 15%
reduction (RR 0.85, 95% CI 0.76 – 0.96)
• CVD mortality: no change with ASA therapy
• All-cause mortality: insufficient evidence
• Diabetes: no additional CVD benefit
31. Chubak J, Kamineni A, Buist DS, et al. Aspirin Use for
the Prevention of Colorectal Cancer: An Updated
Systematic Evidence Review for the U.S. Preventive Services
Task Force. Evidence Synthesis No. 133. AHRQ Publication No.
15-05228-EF-1. Rockville, MD: Agency for Healthcare Research
and Quality; 2015.
32. CRC PREVENTION
• 6 RCTs primary and secondary CVD prevention (N =
75,980)
• Invasive CRC incidence: no effect within first 10 years,
40% reduction after 10 years (RR 0.60, 95% CI 0.47-
0.76), 20-24% reduction over 20 years
• 4 RCTs (N = 14,033)
• CRC mortality: 33% reduction with 20+ years
• 11 RCTs (N = 25,570)
• All-cause mortality: 6% reduction within first 10 years
(RR 0.94, 95% CI 0.89-0.99)
33. Whitlock EP, Williams SB, Burda BU, et al. Aspirin Use in
Adults: Cancer, All-Cause Mortality, and
Harms. A Systematic Evidence Review for the U.S. Preventive
Services Task Force. Evidence Synthesis No. 132. AHRQ
Publication No. 13-05193-EF-1. Rockville, MD: Agency for
Healthcare Research and Quality; 2015.
44. KEY POINTS
• Narrower range of use
• Age 50 - 59 versus 45/55 - 79
• Lower strength of recommendation
• B versus A
• Varying guideline recommendations
• Age ≥ 50 (ACCP, 2012)
• 10-year ASCVD ≥ 10% and benefits >> risks (AHA/ASA, 2014)
• Different risk assessment tools
• AHA/ACC Pooled Cohort CVD Risk Estimator
• Framingham’s Risk Calculator
• CVD benefit in those < 10 years life expectancy??
• < 5 years (CVD) versus >10 years (CRC)
45. KEY POINTS
• Narrower range of use
• Age 50 - 59 versus 45/55 - 79
• Lower strength of recommendation
• B versus A
• Varying guideline recommendations
• Age ≥ 50 (ACCP, 2012)
• 10-year ASCVD ≥ 10% and benefits >> risks (AHA/ASA, 2014)
• Different risk assessment tools
• AHA/ACC Pooled Cohort CVD Risk Estimator
• Framingham’s Risk Calculator
• CVD benefit in those < 10 years life expectancy??
• < 5 years (CVD) versus >10 years (CRC)
46. KEY POINTS
• Narrower range of use
• Age 50 - 59 versus 45/55 - 79
• Lower strength of recommendation
• B versus A
• Varying guideline recommendations
• Age ≥ 50 (ACCP, 2012)
• 10-year ASCVD ≥ 10% and benefits >> risks (AHA/ASA, 2014)
• Different risk assessment tools
• AHA/ACC Pooled Cohort CVD Risk Estimator
• Framingham’s Risk Calculator
• CVD benefit in those < 10 years life expectancy??
• < 5 years (CVD) versus >10 years (CRC)
47. KEY POINTS
• Narrower range of use
• Age 50 - 59 versus 45/55 - 79
• Lower strength of recommendation
• B versus A
• Varying guideline recommendations
• Age ≥ 50 (ACCP, 2012)
• 10-year ASCVD ≥ 10% and benefits >> risks (AHA/ASA, 2014)
• Different risk assessment tools
• AHA/ACC Pooled Cohort CVD Risk Estimator
• Framingham’s Risk Calculator
• CVD benefit in those < 10 years life expectancy??
• < 5 years (CVD) versus >10 years (CRC)
48. KEY POINTS
• Narrower range of use
• Age 50 - 59 versus 45/55 - 79
• Lower strength of recommendation
• B versus A
• Varying guideline recommendations
• Age ≥ 50 (ACCP, 2012)
• 10-year ASCVD ≥ 10% and benefits >> risks (AHA/ASA, 2014)
• Different risk assessment tools
• AHA/ACC Pooled Cohort CVD Risk Estimator
• Framingham’s Risk Calculator
• CVD benefit in those < 10 years life expectancy??
• < 5 years (CVD) versus >10 years (CRC)
50. REFERENCES
• Guirguis-Blake JM, Evans CV, Senger CA, et al. Aspirin for the Primary Prevention of Cardiovascular Events: A
Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 131. AHRQ
Publication No. 13-05195-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015. PMID:
26491760
• Chubak J, Kamineni A, Buist DS, et al. Aspirin Use for the Prevention of Colorectal Cancer: An Updated
Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 133. AHRQ
Publication No. 15-05228-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
• Whitlock EP, Williams SB, Burda BU, et al. Aspirin Use in Adults: Cancer, All-Cause Mortality, and Harms. A
Systematic Evidence Review for the U.S. Preventive Services Task Force. Evidence Synthesis No. 132. AHRQ
Publication No. 13-05193-EF-1. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
• Alfonso L, Ai G, Spitale RC, Bhat GJ. Molecular targets of aspirin and cancer prevention. British Journal of Cancer
(2014) 111, 61-67. Doi: 10.1038/bjc.2014.271
• Paez Espinosa EV, Murad JP, Khasawneh FT. Aspirin: Pharmacology and Clinical Applications. Thrombosis. 2012;
173124. Doi: 10.1155/2012/173124.
• Knights KM, Mangoni AA, Miners JO. Defining the COX Inhibitor Selectivity of NSAIDs: Implications for
Understanding Toxicity. Expert Rev Clin Pharmacol. 2010;3(6):769-776.
Acetylation is a normal biochemical process
Dysregulation of acetylation has been implicated in cancer and other diseases
AA prostanoids, prostacyclines, thromboxane
AA prostanoids, prostacyclines, thromboxane
ASA acetylates Ser530 inhibits aa from access to tyrosine 385 (COVALENT BOND)
ASA MOA: ionic bond with Arg120, then transacetylated SER530 (unique to ASA)
COX-selective:
Lack carboxyl group (no charged interaction with argenine 120)
Large methylsulfonylphenyl group – situates itself in the hydrophobic pocke within the active site hydrophobic channel
COX-nonselective:
- Ionic interaction with ARG120
AA prostanoids, prostacyclines, thromboxane
ASA acetylates Ser530 inhibits aa from access to tyrosine 385 (COVALENT BOND)
ASA MOA: ionic bond with Arg120, then transacetylated SER530 (unique to ASA)
COX-selective:
Lack carboxyl group (no charged interaction with argenine 120)
Large methylsulfonylphenyl group – situates itself in the hydrophobic pocke within the active site hydrophobic channel
COX-nonselective:
- Ionic interaction with ARG120
AA prostanoids, prostacyclines, thromboxane
ASA acetylates Ser530 inhibits aa from access to tyrosine 385 (COVALENT BOND)
ASA MOA: ionic bond with Arg120, then transacetylated SER530 (unique to ASA)
COX-selective:
Lack carboxyl group (no charged interaction with argenine 120)
Large methylsulfonylphenyl group – situates itself in the hydrophobic pocket within the active site hydrophobic channel
COX-nonselective:
- Ionic interaction with ARG120
AA prostanoids, prostacyclines, thromboxane
ASA acetylates Ser530 inhibits aa from access to tyrosine 385 (COVALENT BOND)
ASA MOA: ionic bond with Arg120, then transacetylated SER530 (unique to ASA)
COX-selective:
Lack carboxyl group (no charged interaction with argenine 120)
Large methylsulfonylphenyl group – situates itself in the hydrophobic pocke within the active site hydrophobic channel
COX-nonselective:
- Ionic interaction with ARG120
COX-1 gene and protein expression NOT affected
COX-2 predominantly in tumor tissue – epithelial cells, mononuclear cells, endothelial and stromal cells BUT not nearby tissue
COX-1 gene and protein expression NOT affected
COX-2 predominantly in tumor tissue – epithelial cells, mononuclear cells, endothelial and stromal cells BUT not nearby tissue
ASA preferentially blocks COX-1, while salicylate blocks both
Primary COX-2 product
PGE2-EP receptor binding
Deletion of EP1, EP2 and EP3 = antineoplastic effects
CVD benefit seen within first 5 years
Average 3.6-10.1 years follow up
10 trials – UK, US, Japan, Italy, multinational
7 trials – 100 mg ASA or less daily or every other day
1 trial – 325 mg ASA every other day
1 trial – 500 mg daily
1 trial – 650 mg daily
Studies conducted in Europe, UK, Japan, North America
Daily aspirin:
6 trials 75 – 100 mg/day
1 trial - 300 mg/day
1 trial – 500 mg/day
1 trial – 625 mg/day
1 trial with both 300 and 1,200 mg/day
Data on ASA therapy with prior adenoma/carcinoma limited and conflicting results
Benefit in cancer prevention alone unclear due to inconsistent data
Modest benefit in all-cause mortality cannot be attributed solely to CRC and CVD prevention alone
Risk of bleeding with and without ASA may be more than actually reported (GI bleed, intracranial hemorrhage, etc.)
ACCP = American College of Chest Physicians
AHA = American Heart Association
ASA = American Stroke Association
ACCP = American College of Chest Physicians
AHA = American Heart Association
ASA = American Stroke Association
ACCP = American College of Chest Physicians
AHA = American Heart Association
ASA = American Stroke Association
ACCP = American College of Chest Physicians
AHA = American Heart Association
ASA = American Stroke Association
ACCP = American College of Chest Physicians
AHA = American Heart Association
ASA = American Stroke Association
Primary COX-2 product
PGE2-EP receptor binding
Deletion of EP1, EP2 and EP3 = antineoplastic effects
APC and beta-catenin mediated oncogenic Wnt pathway
APC gene/APC protein (tumor suppressor) mutations B-catenin dysregulation
Thought that ASA “replaces” functional APC
