ASPIRIN FOR PRIMARY PREVENTION OF CVD
- Gaziano M, Brotons C, Coppolecchia R, Cricelli C, Darius H, Gorelick P, Howard G, Pearson T, Peter M Rothwell P, Ruilope L, MD, Tendera M, Tognoni G. Use of aspirin to reduce risk of initial vascular events in patients at moderate risk of cardiovascular disease (ARRIVE): a randomised, double-blind, placebo-controlled trial. The Lancet 2018, published online August 26, 2018. DOI:https://doi.org/10.1016/S0140-6736(18)31924-X
- Hayden M, Pignone M, Phillips C, Mulrow C. Aspirin for the Primary Prevention of Cardiovascular Events: A Summary of the Evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2002;136:161-172. doi: 10.7326/0003-4819-136-2-200201150-00016
- Ikeda Y, Shimada K, Teramoto T, Uchiyama S, Yamazaki T, Oikawa S, Sugawara M, Ando K, Murata M, Yokoyama K, Ishizuka N. Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Japanese Patients 60 Years or Older With Atherosclerotic Risk Factors: A Randomized Clinical Trial. JAMA. 2014; 312(23):2510-2520. doi:10.1001/jama.2014.15690.
- Antithrombotic Trialists’ (ATT) Collaboration. Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373:1849-1860
- U.S. Preventive Services Task Force Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med 2009; 150:396-404
- Wolff T, Miller T, Ko S. Aspirin for the primary prevention of cardiovascular events: An update of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med 2009; 150:405-410
- Nelson MR, Reid CM, Ames DA, Beilin LJ, Donnan GA, Gibbs P, Johnston CI, Krum H, Storey E, Tonkin A, Wolfe R, Woods R, McNeil JJ. Feasibility of conducting a primary prevention trial of low-dose aspirin for major adverse cardiovascular events in older people in Australia: results from the ASPirin in Reducing Events in the Elderly (ASPREE) pilot study. Med J Aust 2008; 189:105-109
- Ridker PM, Cook NR, Lee I, Gordon D, M.A, Gaziano M, Manson JE, Hennekens CH, Buring JE. A Randomized Trial of Low-Dose Aspirin in the Primary Prevention of Cardiovascular Disease in Women. N Engl J Med 2005; 352:1293-1304 DOI: 10.1056/NEJMoa050613
- The Steering Committee of the Physicians’ Health Study Research Group. Findings from the aspirin component of the ongoing Physicians’ Health Study. N Engl J Med 1988; 318:262-264
ASPIRIN IN 'HIGH' CV RISK' INDIVIDUALS: Type 2 Diabetes, Peripheral Artery Disease
- The ASCEND Study Collaborative Group. Effects of n−3 Fatty Acid Supplements in Diabetes Mellitus. N Engl J Med 2018 DOI: 10.1056/NEJMoa1804989.
- Ong G, Davis TM, Davis WA. Aspirin is associated with reduced cardiovascular and all-cause mortality in type 2 diabetes in a primary prevention setting: the Fremantle Diabetes study. Diabetes Care 2010; 33: 317-321
- Woods RL, Tonkin AM, Nelson MR, Britt HC, Reid CM. Should aspirin be used for the primary prevention of cardiovascular disease in people with diabetes? Med J Aust 2009 190:614-5
- Berger JS, Krantz MJ, Kittelson JM, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients with peripheral artery disease: A meta-analysis of randomized trials. JAMA 2009;301:1909-1919
- Belch J, MacCuish A, Campbell I, Cobbe S, Taylor R, Prescott R, Lee R, Bancroft J, MacEwan S, Shepherd J, Macfarlane P, Morris A, Jung R, Kelly C, Connacher A, Peden N, Jamieson A, Matthews D, Leese G, McKnight J, O’Brien I, Semple C, Petrie J, Gordon D, Pringle S, MacWalter R; Prevention of Progression of Arterial Disease and Diabetes Study Group; Diabetes Registry Group; Royal College of Physicians Edinburgh. The prevention of progression of arterial disease and diabetes (POPADAD) trial: factorial randomised placebo controlled trial of aspirin and antioxidants in patients with diabetes and asymptomatic peripheral arterial disease. BMJ 2008;337:a1840
- Ogawa H, Nakayama M, Morimoto T, Uemura S, Kanauchi M, Doi N, Jinnouchi H, Sugiyama S, Saito Y; Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD) Trial Investigators. Low-dose aspirin for primary prevention of atherosclerosis events in patients with Type 2 diabetes: a randomized controlled trial. JAMA 2008;300:2134-2141.
- Nicolucci A. Aspirin for primary prevention of cardiovascular events in diabetes: still an open question. JAMA 2008;300:2180-2181.
ASPIRIN AND CANCER
ASPIRIN AND BLEEDING
ASPIRIN AND COGNITIVE FUNCTION
ASPIRIN AND DEPRESSION
- Almeida, O P et al. “Aspirin Decreases the Risk of Depression in Older Men with High Plasma Homocysteine.” Translational Psychiatry 2.8 (2012): e151–. PMC. Web. 30 Mar. 2015.
- Berk, M., Dean, O., Drexhage, H., McNeil, J.J., Moylan, S., O’Neil, A., Davey, C.G., Sanna, L., Maes, M.H., Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Medicine (2013) 11 (1): 1-17
- Berk M et al., So depression is an inflammatory disease, but where does the inflammation come from? BMC Med. 2013 Sep 12;11:200. doi: 10.1186/1741-7015-11-200.
- Berk M et al., Aspirin: a review of its neurobiological properties and therapeutic potential for mental illness. BMC Med. 2013 Mar 18;11:74. doi: 10.1186/1741-7015-11-74
- Dodd S et al., Putative neuroprotective agents in neuropsychiatric disorders. Prog Neuropsychopharmacol Biol Psychiatry. 2013 Apr 5;42:135-45
- Köhler O, Petersen L, Mors O, Gasse C. Inflammation and depression: combined use of selective serotonin reuptake inhibitors and NSAIDs or paracetamol and psychiatric outcomes. Brain and Behavior. 2015;5(8):e00338. doi:10.1002/brb3.338.
- Laan W, Grobbee DE, Selten JP, Heijnen CJ, Kahn RS, Burger H.Adjuvant aspirin therapy reduces symptoms of schizophrenia spectrum disorders: results from a randomized, double-blind, placebo-controlled trial. J Clin Psychiatry. 2010 May;71(5):520-7.
- Moylan S, Maes M, Wray NR, Berk M. The neuroprogressive nature of major depressive disorder: pathways to disease evolution and resistance, and therapeutic implications. Mol Psychiatry. 2013; 18: 595-606.
- Pasco JA et al., Clinical implications of the cytokine hypothesis of depression: the association between use of statins and aspirin and the risk of major depression. Psychother Psychosom. 2010;79(5):323-5.
- Watson S, Horton K, Bulmer S, Carlile J, Corcoran C, Gallagher P, Ferrier IN.Effect of aspirin on hypothalamic-pituitary-adrenal function and on neuropsychological performance in healthy adults: a pilot study.Psychopharmacology (Berl). 2009 Jul;205(1):151-5.
ASPIRIN AND SEPSIS
- Eisen DP, McBryde ES. An association between aspirin use in human cases of infective endocarditis and reduced systemic embolism is shown in meta-analysis of observational studies. J Infect Dis. 2015. Epub 2015/03/11.
- Falcone M, Russo A, Cangemi R, Farcomeni A, Calvieri C, Barilla F, et al. Lower mortality rate in elderly patients with community-onset pneumonia on treatment with aspirin. Journal of the American Heart Association. 2015;4(1):e001595. Epub 2015/01/08.
- Chen W1, Janz DR, Bastarache JA, May AK, O’Neal HR Jr, Bernard GR, Ware LB. Prehospital Aspirin Use Is Associated With Reduced Risk of Acute Respiratory Distress Syndrome in Critically Ill Patients: A Propensity-Adjusted Analysis. Crit Care Med. 2014 Dec 31.
- Eisen DP, McBryde ES, Walduck A. Low-dose aspirin and ibuprofen’s sterilizing effects on Mycobacterium tuberculosis suggest safe new adjuvant therapies for tuberculosis. J Infect Dis. 2013 Dec 1;208(11):1925-7.
- Valerio-Rojas JC, Jaffer IJ, Kor DJ, Gajic O, Cartin-Ceba R. Outcomes of severe sepsis and septic shock patients on chronic antiplatelet treatment: a historical cohort study. Critical care research and practice. 2013;2013:782573. Epub 2013/03/20.
- Otto GP, Sossdorf M, Boettel J, Kabisch B, Breuel H, Winning J, et al. Effects of low-dose acetylsalicylic acid and atherosclerotic vascular diseases on the outcome in patients with severe sepsis or septic shock. Platelets. 2013;24(6):480-5. Epub 2012/09/22.
- Eisen DP. Manifold beneficial effects of acetyl salicylic acid and nonsteroidal anti-inflammatory drugs on sepsis. Intensive Care Med. 2012 Aug;38(8):1249-57. Epub 2012/04/26.
- Eisen DP1, Reid D, McBryde ES. Acetyl salicylic acid usage and mortality in critically ill patients with the systemic inflammatory response syndrome and sepsis. Crit Care Med. 2012 Jun;40(6):1761-7.
- Losche W, Boettel J, Kabisch B, Winning J, Claus RA, Bauer M. Do aspirin and other antiplatelet drugs reduce the mortality in critically ill patients? Thrombosis. 2012;2012:720254. Epub 2011/11/24.
- Winning J, Neumann J, Kohl M, Claus RA, Reinhart K, Bauer M, et al. Antiplatelet drugs and outcome in mixed admissions to an intensive care unit. Crit Care Med. 2010;38(1):32-7. Epub 2009/09/23.
ASPIRIN AND AGE-RELATED MACULAR DEGENERATION (AMD)
- Christen WG, Chew EY. Does long-term aspirin use increase the risk of neovascular age-related macular degeneration? Expert Opinion on Drug Safety 2014;13:421-9
- Chong EW, Guymer RH, Robman LD. Does aspirin increase the risk of age-related macular degeneration? Expert Opinion on Drug Safety 2014;13:691-3 doi:10.1517/14740338.2014.914169
- Liew G, Mitchell P, Wong T, Rochtchina E, Wang J. The Association of Aspirin Use With Age-Related Macular Degeneration. JAMA Intern Med 2013;173:258-264
- Cheung N, Tay WT, Cheung GC, Wang JJ, Mitchell P, Wong TY. Is aspirin intake associated with early age-related macular degeneration? The Singapore Indian Eye Study. Br J Ophthalmol 201;97:785-8
- Zhu W, Wu Y, Xu D, Li YH, Jun B, Zhang XL, Wang F, Yu J. Aspirin use and risk of age-related macular degeneration: a meta-analysis. PLoS One 2013; 8: e58821
- de Jong PT, Chakravarthy U, Rahu M, Seland J, Soubrane G, Topouzis F, Vingerling JR, Vioque J, Young I, Fletcher AE. Associations between Aspirin Use and Aging Macula Disorder The European Eye Study. Ophthalmology 2012;119:112-8
- Klein BE, Howard KP, Gangnon RE, Dreyer JO, Lee KE, Klein R. Long-term use of aspirin and age-related macular degeneration. JAMA 2012 Dec 19;308:2469-78
- Kiernan DF, Hariprasad SM, Rusu IM, Mehta SV, Mieler WF, Jager RD. Epidemiology of the association between anticoagulants and intraocular hemorrhage in patients with neovascular age-related macular degeneration. Retina 2010;30:1573-8
- Christen WG, Glynn RJ, Chew EY, Buring JE. Low-dose aspirin and medical record-confirmed age-related macular degeneration in a randomized trial of women. Ophthalmology 2009;116:2386-92
- Christen WG, Glynn RJ, Ajani UA, Schaumberg DA, Chew EY, Buring JE, Manson JE, Hennekens CH. Age-related maculopathy in a randomized trial of low-dose aspirin among US physicians. Arch Ophthalmol 2001 Aug;119:1143-9
- Tilanus MA, Vaandrager W, Cuypers MH, Verbeek AM, Hoyng CB. Relationship between anticoagulant medication and massive intraocular hemorrhage in age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2000;238:482-5
ASPIRIN AND BONE FRACTURES
- Vestergaard P, Hermann P, Jensen JE, Eiken P, Mosekilde L. Effects of paracetamol, non-steroidal anti-inflammatory drugs, acetylsalicylic acid, and opioids on bone mineral density and risk of fracture: results of the Danish Osteoporosis Prevention Study (DOPS). Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA 2012; 23(4): 1255-65.
- Vestergaard P, Steinberg TH, Schwarz P, Jorgensen NR. Use of the oral platelet inhibitors dipyridamole and acetylsalicylic acid is associated with increased risk of fracture. Int J Cardiol 2012; 160(1): 36-40.
- Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with use of nonsteroidal anti-inflammatory drugs, acetylsalicylic acid, and acetaminophen and the effects of rheumatoid arthritis and osteoarthritis. Calcif Tissue Int 2006; 79(2): 84-94.
- Carbone LD, Tylavsky FA, Cauley JA, et al. Association between bone mineral density and the use of nonsteroidal anti-inflammatory drugs and aspirin: impact of cyclooxygenase selectivity. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2003; 18(10): 1795-802.
- Morton DJ, Barrett-Connor EL, Schneider DL. Nonsteroidal anti-inflammatory drugs and bone mineral density in older women: the Rancho Bernardo study. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 1998; 13(12): 1924-31.
- Bauer DC, Orwoll ES, Fox KM, et al. Aspirin and NSAID use in older women: effect on bone mineral density and fracture risk. Study of Osteoporotic Fractures Research Group. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 1996; 11(1): 29-35.
ASPIRIN AND OSTEOARTHRITIS
- Wlukaa A, Dinga C, Wanga Y, Jones G, Urquharta D, Cicuttinia F. Aspirin is associated with reduced cartilage loss in knee osteoarthritis: Data from a cohort study. Maturitas 2015; http://dx.doi.org/10.1016/j.maturitas.2015.04.015
MAJOR ASPIRIN TRIALS (CURRENT)
Consorzio Mario Negri Sud, Italy (Sponsor – Italian Ministry of Health (Italy))
Study population: 5,170 individuals with diabetes (Type 1 or 2), currently taking or candidate for statin treatment (i.e. LDL cholesterol ≥ 100 mg/dL persisting after 3 months of dietary advice), no history of CVD, aged ≥ 50 years.
Study design: Primary prevention, open-label RCT of low-dose aspirin (100mg) + simvastatin (starting at 20mg/day) versus simvastatin alone, for approximately 5 years
Aim: To evaluate whether, in a setting of controlled LDL cholesterol levels (through treatment with simvastatin), low-dose aspirin is effective in the primary prevention of major cardiovascular events in patients with diabetes.
The primary outcome is a composite endpoint of CV death, non-fatal heart attack, non-fatal stroke, and hospital admission for cardiovascular causes.
Add-Aspirin (A phase III double-blind placebo-controlled randomised trial assessing the addition of aspirin after standard primary therapy in early stage common solid tumours (Sponsor – University College London (UK))
Start date – May 2014
Status – Currently ongoing, expected publication date 2026
Study population: Approximately 10,000 cancer survivors who have had (or are currently having) treatment for an early stage cancer of the breast, bowel, stomach, oesophagus or prostate in the UK and India
Study Design: RCT of 100mg aspirin, 300mg aspirin or a placebo (dummy) tablet for five years Aim: To assess whether regular aspirin use after standard therapy, including surgery and neo-adjuvant/adjuvant chemotherapy and/or radiotherapy, can prevent recurrence and prolong survival in participants with common solid tumours
MAJOR ASPIRIN TRIALS (PAST)
ASPREE (ASPirin in Reducing Events in the Elderly) Monash University, Berman Center for Clinical Research & Outcomes Funded by National Institute on Aging (National Institutes of Health (US)), National Health and Medical Research Council of Australia (NHMRC), Victorian Cancer Agency (VCA, Australia)
Start date – March 2010 – 2017
Status – Completed, expected publication 2018
Study Population: 16,700 Australians aged ≥ 70 years and 2,400 Americans aged ≥ 65 years for minority populations (55% of US recruitment) and ≥ 70 years for non-minority. Participants are able-bodied and have no history of CVD or a contraindication to take aspirin or placebo.
Study design: Primary prevention, double-blinded, placebo-controlled RCT of 100 mg daily enteric-coated aspirin or a matching placebo for an average of 5 years. Clinical health measures are undertaken annually.
The primary objective is to determine whether low-dose aspirin prolongs life, or life free of dementia, or life free of significant, persistent physical disability in the healthy elderly. Secondary objectives relate to the effects of low-dose aspirin on the key outcome areas of death, cardiovascular disease, dementia and cognitive decline, cancer, physical disability, depression and major bleeding episodes.
ASPREE will determine the true balance of risks and benefits of low dose aspirin for primary prevention in the elderly
ARRIVE (Aspirin to Reduce Risk of Initial Vascular Events)
International Multi-Centre RCT
Sponsor – Bayer
Start date – September 2007
Status – Completed. Findings published 2018
Study population: Approximately 12,000 participants at moderate cardiovascular disease (CVD) risk (Germany, Italy, Spain, UK, and USA).
Men aged ≥ 55 years with 2 – 4 CVD risk factors*
Women aged ≥ 60 years with 3 or more risk factors*
*Please note – CVD risk factors refers to: elevated total LDL cholesterol and/or low HDL cholesterol, cigarette smoking, elevated blood pressure, current use of medication to treat high blood pressure, and a family history of early coronary heart disease (CHD).
Study design: Primary prevention, double-blind randomised control trial (RCT) of low-dose aspirin (100mg) versus placebo for approximately 5 years.
Aim: The ARRIVE study is aiming to demonstrate the efficacy and safety of low-dose aspirin in preventing initial events associated with CVD in individuals with no known history of CVD, but who are at moderate risk.
The primary outcome of ARRIVE is a composite CVD/cerebrovascular endpoint, where time to first occurrence of either non-fatal heart attack, non-fatal ischaemic stroke or CVD death (including fatal heart attack, fatal ischaemic stroke).
ASCEND (A Study of Cardiovascular Events iN Diabetes)
(Sponsor – University of Oxford Clinical Trial Service Unit, UK Jane M Armitage, BSc, MBBS, MRCP, FFPH, Principal Investigator, Clinical Trial Service Unit, University of Oxford)
Start date – March 2005
Status – Completed. Findings published 2018
Study population: 15,400 individuals with diabetes (Type 1 or Type 2), no known vascular disease, aged >= 40 years
Males or females with type 1 or type 2 diabetes mellitus.
Aged ≥ 40 years.
No previous history of vascular disease.
Study design: Primary prevention, double-blind RCT, 2 x 2 factorial design of low-dose, enteric-coated aspirin (100mg) versus placebo, and of omega-3 fatty acid supplementation versus placebo, once daily for an average of 5 years
Aim: To determine whether or not low-dose aspirin and/or omega-3 fatty acid supplementation helps to reduce the development of circulatory problems (e.g. heart attack, stroke) in people with diabetes.
JPPP (Japanese Primary Prevention Project)
Keio University School of Medicine, Japan,
(Sponsors – Japan Heart Foundation & Bayer)
Start date – March 2005
Status – Prematurely terminated after a median follow-up of 5.02 years due to likely futility
Study population: 14,400 participants with asymptomatic atherosclerosis (ABI <= 0.95), no evidence of previous CV events, aged 60 – 85 years diagnosed with one or more of these conditions: hypertension, hyperlipidemia or diabetes
Study design: Primary prevention, open-label, randomised, parallel-group trial of low-dose, enteric-coated aspirin (100mg) versus control, once daily for an average of 8 years
Aim: To determine whether treatment of individuals with asymptomatic atherosclerosis using low-dose aspirin for 8 years prevents cardiovascular events (heart attack, stroke).
Conclusion: The study found once-daily, low-dose aspirin did not significantly reduce the risk of the composite outcome of cardiovascular death, nonfatal stroke, and nonfatal myocardial infarction among Japanese patients 60 years or older with atherosclerotic risk factors. (Ikeda Y, Shimada K, Teramoto T et al. Low-Dose Aspirin for Primary Prevention of Cardiovascular Events in Japanese Patients 60 Years or Older With Atherosclerotic Risk Factors: A Randomized Clinical Trial. JAMA. 2014;312(23):2510-2520. doi:10.1001/jama.2014.15690.)
PHS (Physicians’ Health Study)
Collaborators: Harvard University, Brigham and Women’s Hospital
Funded by: National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)
Start date – September 1981
Status – Completed December 1996
Study population: 22,071 male American physicians between 40-84 years of age (mean = 53 +/- 9.5 years at enrolment), without a history of CVD or cancer (other than non-melanoma skin cancers), renal or liver disease or having a contraindication to take aspirin or beta-carotene.
Study design: Primary prevention, 2X2 factorial designed RCT (double-blind, placebo-controlled) of 325mg aspirin and 50mg beta-carotene versus placebo on alternate days, provided four possible arms: active aspirin and active beta-carotene, active aspirin and beta-carotene placebo, aspirin placebo and active beta-carotene, or aspirin placebo and beta-carotene placebo. Compliance and health outcomes were measured by questionnaires. Primary endpoints included total cancer, prostate cancer, CVD and eye disease
Aim: To assess the effect on cardiovascular mortality of alternate-day consumption of 325 mg of aspirin and, secondarily, the effect on cancer incidence of alternate-day consumption of 50 mg of beta-carotene.
Conclusion: The aspirin arm was stopped early as aspirin was shown to significantly reduced the risk of a first myocardial infarction (1989. New England Journal of Medicine), although the effect on stroke was inconclusive. Results from the beta-carotene arm did not show harm or benefit. (1996. New England Journal). It is estimated more than 400 papers have been written on findings from this trial.
WHS (Women’s Health Study) Brigham and Women’s Hospital
Collaborators: Brigham and Women’s Hospital. Funded by: National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)
Collaborators: Harvard University, Brigham and Women’s Hospital
Funded by: National Cancer Institute (NCI), National Heart, Lung, and Blood Institute (NHLBI)
Start date – September 1992
Status – Completed February 2005, currently participants are being followed on an observational basis (annual questionnaires)
Study population: 39,876 health professional women aged 45 years and over without a history of cancer or CVD
Study design: Primary prevention, double-blind RCT of alternate day Vitamin E (600 IU every other day) or placebo; and to aspirin (100 mg every other day) or placebo.low-dose aspirin (100mg) versus placebo. Compliance was measured by questionnaires. The primary outcome is a composite endpoint of CV death, non-fatal heart attack, non-fatal stroke, and malignant neoplasms of epithelial cell origin.
Aim: To evaluate the effects of low-dose aspirin and vitamin E in primary prevention of cardiovascular disease and cancer in apparently healthy women aged 45 years and over.
Conclusion: The study showed that aspirin lowered the risk of stroke, but had no effect on the risk of AMI (Ridker PM 2005 NEJM) or cancer (2005 Cook NR et al, JAMA). WHS researchers estimate 400 reports on the study have been published since it began.