Issue One – China Addendum 2017 – Aspirin Disease Prevention and Current Research Summaries

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The purpose of this report is to provide a relatively concise and current overview of activity, which reflects the depth of expertise and knowledge of the members of the Scientific Advisory Board, from both geographical and scientific areas. This shared information enables The International Aspirin Foundation to provide educational material for medical professionals. It is not meant to be an exhaustive amount of information, rather what the experts regard as the most relevant and topical activity to comment upon. The topics the Scientific Advisory Board considered in their summaries are:

■ Primary disease prevention using aspirin

■ Secondary disease prevention using aspirin

■ Other new trials or recently published science of interest about aspirin

■ New or existing research on aspirin in their geographical locality

■ Relevant conferences or meetings in their geographical locality or scientific area concerning aspirin

■ References of interest for further information

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References 1. Rothwell PM, Algra A, Chen Z, Diener HC, Norrving B, Mehta Z. Effects of aspirin on risk and severity of early recurrent stroke after transient ischaemic attack and ischaemic stroke: time-course analysis of randomised trials. Lancet 2016; 18th May online.


Professor Junbo Ge

MD, FACC, FESC, FSCAI

Shanghai, China

44

Aspirin ASCVD prevention in China

 Update Chinese guideline on ASCVD primary and secondary prevention

Cardiovascular disease has become the leading cause of death in China with the development of China's economy and improvement of living standard and lifestyle changes, the incidence of cardiovascular disease as well as CVD risk factors continues to increase1 .The newly released “Outline of Healthy Chinese 2030” advocated management strategy for chronic disease including cardiovascular disease changed from treatment into prevention. To achieve the early arrival of cardiovascular disease inflection point, the most effective prevention strategy is primary prevention.

Aspirin has been widely used in cardiovascular and cerebrovascular disease which plays an indispensable role in cardiovascular disease primary and secondary prevention with a most cost-effectiveness value. However the awareness of primary prevention needs to be improved. Actual usage rate of aspirin in clinical practice was 14.09% in primary prevention population, and 26.61% in secondary prevention population2. To standardize cardiovascular disease prevention and management, improve the awareness of primary prevention, Chinese society of cardiology updated guideline on ASCVD disease prevention which will be published in second quarter of 2017.

Chinese guidelines recommended whether patients without cardiovascular disease should take aspirin should refer to patients’ baseline CVD risk, those with a 10-years CVD risk> 10% should consider taking aspirin for primary prevention under doctor’s recommendation. According to the epidemiology of cardiovascular risk factors in Chinese, Chinese guideline developed a new stratified ASCVD risk assessment process considering hypertension was the most decisive parameter. For patients younger than55 years old with a moderate CVD risk, assessment of ASCVD lifetime risk was recommended to facilitate the early identification of individuals with high risk of ASCVD during the rest of their lives, and gave actively intervene at the early stage.

For patients with cardiovascular disease, Guideline3 recommended that once patients was diagnosed as cardiovascular disease low dose of aspirin should be the routine of clinical treatment among those without contraindications.

Published 2016 Chinese expert consensus on Aspirin use in patients with ASCVD

For standardized use of aspirin in primary prevention, Chinese consensus led by geriatrics branch of Chinese Medical Association defined 6 target groups for aspirin ASCVD primary prevention4 : 1) those 10 years ASCVD risk higher than 10% ,2) Hyperlipidemia patients, TC ≥7.2mmol/l or LDL-C≥4.9mmol/l, aged≥ 55years old, 3)diabetes patients aged ≥ 50years old, with at least one major risk factor ( family history of premature CVD, hypertension, smoking, Dyslipidemia or albuminuria), 4)hypertension patients with any 2 conditions below: male≥ 45years old or female≥ 55years old, smoking, low HDL-C<1.04mmol/l ,5) CKD patients with eGFR 30-45ml.min-1.1.73m-2, 6) those who do not meet above conditions but have any 4 items below: male≥45years old or female≥ 55years old, smoking, family history of premature CVD, BMI≥ 28Kg/m2, Dyslipidemia.

Publication: Aspirin 100 Q&A for clinical doctors

Standardized use of aspirin is a prerequisite for clinical benefit. For better understanding the preventive role of aspirin in ASCVD and appropriate use in clinical practice, Aspirin 100 Q&A for clinical doctors was published5. The brochure included common questions doctors were interested in, contents including basic pharmacological knowledge of aspirin, effect on primary and secondary prevention of cardiovascular disease, aspirin adverse effect and how to overcome, drug interactions, and matters needing attention in clinical use.

New research on antiplatelet therapy in Chinese

In a randomized trials conducted at 114 centers in China, clopidogrel with aspirin in acute minor stroke or transient ischemic attack concluded the combination of clopidogrel and aspirin is superior to aspirin alone for reducing the risk of stroke in the first90 days and does not increase the risk of hemorrhage. Among 2933 patients who underwent CYP2C19 analysis, 58.8% patients were carriers of loss of function alleles which was higher than western countries. And compare to aspirin alone, clopidogrel plus aspirin did not reduce the risk of new stroke in the subgroup of patients who were the carriers of CYP2C19 loss of function alleles6.

References

1. Chen Weiwei, Gao Runlin, Liu Lisheng, et al. “Report on Cardiovascular Diseases in China (2015)" Abstract. Chinese Circulation Journal, 2016, 31(6):521-528.

2. Yang Zhaojun, Shan Zhongyan, Tian Haoming, et al. Current status of aspirin use in cardiovascular prevention in some areas of China. Chinese Journal of Diabetes Mellitus, 2011,3(1):22-26.

3. Chinese Society of Cardiology. Guidelines for diagnosis and treatment of ST-segment elevation myocardial. Chinese Journal of Cardiology, 2015,43:380-393.

4. The Geriatrics Branch of Chinese Medical Association, Aspirin use in patients with atherosclerotic cardiovascular disease:2016 Chinese expert consensus statement. Chinese Journal of Internal Medicine, 2017,56(1):1-13.

5. Xiaoying Li. Aspirin 100 Q&A for clinical doctors. People’s military medical press.

6. Yilong Wang, Xingquan Zho, Jinxi Lin, et al. Association between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction among Patients with Minor Stroke or Transient Ischemic Attack. JAMA. 2016 Jul 5;316:70-8

1. Chen Weiwei, Gao Runlin, Liu Lisheng, et al. “Report on Cardiovascular Diseases in China (2015)" Abstract. Chinese Circulation Journal, 2016, 31(6):521-528. 2. Yang Zhaojun, Shan Zhongyan, Tian Haoming, et al. Current status of aspirin use in cardiovascular prevention in some areas of China. Chinese Journal of Diabetes Mellitus, 2011,3(1):22-26. 3. Chinese Society of Cardiology. Guidelines for diagnosis and treatment of ST-segment elevation myocardial. Chinese Journal of Cardiology, 2015,43:380-393. 4. The Geriatrics Branch of Chinese Medical Association, Aspirin use in patients with atherosclerotic cardiovascular disease: 2016 Chinese expert consensus statement. Chinese Journal of Internal Medicine, 2017,56(1):1-13. 5. Xiaoying Li. Aspirin 100 Q&A for clinical doctors. People’s military medical press. 6. Yilong Wang, Xingquan Zho, Jinxi Lin, et al. Association between CYP2C19 Loss-of-Function Allele Status and Efficacy of Clopidogrel for Risk Reduction among Patients with Minor Stroke or Transient Ischemic Attack. JAMA. 2016 Jul 5;316:70-8
For patients with cardiovascular disease, Guideline3 recommended that once patients was diagnosed as cardiovascular disease low dose of aspirin should be the routine of clinical treatment among those without contraindications.
Aspirin ASCVD prevention in China Update Chinese guideline on ASCVD primary and secondary prevention
Recently published science of interest about aspirin: aspirin mechanism In an Opinion article in press at Nature Reviews Cancer, we review the weight of the evidence supporting aspirin’s chemo preventive potential and highlight advances in our understanding of aspirin’s mechanisms of action. We challenge the notion that aspirin prevents cancer through a single, dominant pathway and propose an integrative multi-pathway model for its mode of action. We highlight how these pathways can be leveraged to develop mechanistic biomarkers for personalised risk stratification. Such biomarkers may then be translated clinically in a precision medicine approach critical to the future of aspirin chemoprevention.

1.           Gaciong Z. The real dimension of analgesic activity of aspirin. Thromb Res. 2003;110(5-6):361-4.

2.           Seymour RA, Hawkesford JE, Sykes J, Stillings M, Hill CM. An investigation into the comparative efficacy of soluble aspirin and solid paracetamol in postoperative pain after third molar surgery. Br Dent J. 2003;194(3):153- 7; discussion 49.

3.           Lampl C, Voelker M, Steiner TJ. Aspirin is first-line treatment for migraine and episodic tension-type headache regardless of headache intensity. Headache. 2012;52(1):48-56.

4.           Lecchi M, D’Alonzo L, Negro A, Martelletti P. Pharmacokinetics and safety of a new aspirin formulation for the acute treatment of primary headaches. Expert Opin Drug Metab Toxicol. 2014;10(10):1381-95.

5.           Eccles R, Loose I, Jawad M, Nyman L. Effects of acetylsalicylic acid on sore throat pain and other pain symptoms associated with acute upper respiratory tract infection. Pain Med. 2003;4(2):118-24.

6.           Bachert C, Chuchalin AG, Eisebitt R, Netayzhenko VZ, Voelker M. Aspirin compared with acetaminophen in the treatment of fever and other symptoms of upper respiratory tract infection in adults: a multicenter, randomized, double-blind, double-dummy, placebo-controlled, parallel-group, single-dose, 6-hour dose-ranging study. Clin Ther. 2005;27(7):993-1003.

7.           Leonards JR. The influence of solubility on the rate of gastrointestinal absorption of aspirin. Clin Pharmacol Ther. 1963;4:476-9.

8.           Davison C. Salicylate metabolism in man. Ann N Y Acad Sci. 1971;179:249-68.

9.           Fonseca MD, Cunha FQ, Kashfi K, Cunha TM. NOSH-aspirin (NBS-1120), a dual nitric oxide and hydrogen sulfide-releasing hybrid, reduces inflammatory pain. Pharmacol Res Perspect. 2015;3(3):e00133.

1.       Final Recommendation Statement: Aspirin Use to Prevent Cardiovascular Disease and Colorectal Cancer: Preventive Medication. U.S. Preventive Services Task Force. April 2016.

2.       Bibbins-Domingo K; U.S. Preventive Services Task Force. Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2016;164:836-45. doi:10.7326 /M16-0577

3.       U.S. Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: recommendation statement. Ann Intern Med 2009;150:396-404.

4.       Dehmer SP, Maciosek MV, Flottemesch TJ, LaFrance AB, Whitlock EP. Aspirin for the Primary Prevention of Cardiovascular Disease and Colorectal Cancer: A Decision Analysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2016 Jun 21;164(12):777-86.

5.       EA, Whitlock EP. 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]

6.       Chubak J, Kamineni A, Buist DSM, Anderson ML, Whitlock EP. 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. [PMID: 26491758]

7.       Whitlock EP, Williams SB, Burda BU, Feightner A, Beil T. 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.[PMID: 26491756]

8.       Guirguis-Blake JM, Evans CV, Senger CA, O’Connor EA, Whitlock EP. Aspirin for the primary prevention of cardiovascular events: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:804-13. doi:10.7326/M15-2113

9.       Chubak J, Whitlock EP, Williams SB, Kamineni A, Burda BU, Buist DSM, et al. Aspirin for the prevention of cancer incidence and mortality: systematic evidence reviews for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:814-25. doi:10.7326 /M15-2117

10.    Whitlock EP, Burda BU, Williams SB, Guirguis-Blake JM, Evans CV. Bleeding risks with aspirin use for primary prevention in adults: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2016;164:826-35. doi:10.7326/M15-2112

Table 1 Studies examining PIK3CA mutation, aspirin use and colorectal cancer outcomes.

Study

%

PIK3CA Mutant

End­point

PIK3CA Mutant

PIK3CA Wild-Type

No aspirin

Aspirin

HR (p value)

No aspirin

Aspirin

HR (p value)

Nurses' Health Study ft Health Professionals Follow-up Study (Liao 2012)

16.7%

OS

95

66

0.54 (0.01)

466

337

0.94 (0.96)

CSS

-

-

0.18 (<0.001)

-

-

0.96 (0.76)

VICTOR trial
(Domingo 2013)

11.6%

OS

90

14

0.29 (0.19)

681

111

0.95 (0.26)

RFS

-

-

0.11 (0.027)

-

-

0.94 (0.79)

Moffitt Cancer Centre & Royal Melbourne Hospital (Kothari 201S)

12.4%

OS

136

49

0.96 (0.86)

-

-

-

CSS

-

-

0.60 (0.14)

-

-

-

Eindhoven Cancer Registry (Reimen 2014)

15.8%

OS

73

27

0.73* (0.4)

348

147

0.55 (<0.001)

Characteristic

No. of Patients

No. of Deaths

Univariate RR (95% CI)

P Value"

Adjusted RR (95% Ci)c

P Value"

HLA class I antigen

 

 

 

 

 

 

Loss

 

 

 

 

 

 

No aspirin use

263

123

1 (Reference)

.74

1 (Reference)

.91

Aspirin use

57

26

1.08 (0.70-1.64)

1.03 (0.66-1.61)

Expression

 

 

 

 

 

 

No aspirin use

521

257

1 (Reference)

.003

1 (Reference)

<.001

Aspirin use

122

42

0.61 (0.44-0.85)

0.53 (0.38-0.74)

 

1.     Langley RE, Burdett S, Tierney JF, Cafferty F, Parmar MK, Venning G. Aspirin and cancer: has aspirin been overlooked as an adjuvant therapy? Br J Cancer. 2011; 105(8): 1107-13.

2.     Rothwell PM, Wilson M, Elwin CE, Norrving B, Algra A, Warlow CP, et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet. 2010; 376(9754): 1741-50.

3.     Rothwell PM, Fowkes FG, Belch JF, Ogawa H, Warlow CP, Meade TW. Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials. Lancet. 2011; 377(9759): 31-41.

4.     Rothwell PM, Price JF, Fowkes FG, Zanchetti A, Roncaglioni MC, Tognoni G, et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomised controlled trials. Lancet. 2012; 379(9826): 1602-12.

5.     Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis: a study of incident cancers during randomised controlled trials. Lancet. 2012.

6.     Coyle C, Cafferty FH and Langley RE. Aspirin and Colorectal Cancer Prevention – Is it for everyone? Curr Colorectal Cancer Rep (2016) 12:27–34

7.     Reimers MS, Bastiaannet E, Langley RE, van Eijk R, van Vlierberghe RL, Lemmens VE, et al. Expression of HLA Class-I Antigen, Aspirin Use, and Survival After a Diagnosis of Colon Cancer. JAMA Intern Med, 2014 174(5) 732-739.

Current clinical trials of aspirin in Italy include ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes), a primary prevention trial coordinated by Dr. Nicolucci at the Mario Negri Institute in Milan, and ASAMET, a randomized, 2x2 biomarker prevention trial of low-dose aspirin and metformin in colon cancer patients coordinated by Dr. De Censi at the E.O. Ospedali Galliera in Genova. Moreover, investigators in Rome, Chieti, Verona, Siena and Bari, coordinated by Prof. Paola Patrignani, are collaborating in investigating the role of platelet activation in intestinal tumorigenesis. They will test the hypothesis that inhibition of platelet activation may explain the efficacy of low-dose aspirin as a chemopreventive agent.
Besides the references quoted in the text, the following may be of interest: Patrono C (2015) The multifaceted clinical readouts of platelet inhibition by low-dose aspirin. J Am Coll Cardiol 66:74-85. Scavone M, Femia EA, Caroppo V, Cattaneo M. Inhibition of the platelet P2Y12 receptor for adenosine diphosphate does not impair the capacity of platelet to synthesize thromboxane A2.Eur Heart J. 2015 Oct 29. pii: ehv551. [Epub ahead of print] Chan AT, Ladabaum U. Where do we stand with aspirin for the prevention of colorectal cancer? The USPTF recommendations. Gastroenterology. 2015 Nov 18. pii: S0016-5085(15)01665-0. doi: 10.1053 / j.gastro.2015.11.018. [Epub ahead of print]

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For further information please contact International Aspirin Foundation Bower House 34 Bower Mount Road Maidstone Kent ME16 8AU Tel: +44(0) 1622 320118 Fax: +44(0) 1436 840194 Email: aspirin@aspirin-foundation.com www.aspirin-foundation.com