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Abstracts

Life Extension Magazine May 2011
Abstracts

Aspirin

Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.

BACKGROUND: Treatment with daily aspirin for 5 years or longer reduces subsequent risk of colorectal cancer. Several lines of evidence suggest that aspirin might also reduce risk of other cancers, particularly of the gastrointestinal tract, but proof in man is lacking. We studied deaths due to cancer during and after randomised trials of daily aspirin versus control done originally for prevention of vascular events. METHODS: We used individual patient data from all randomised trials of daily aspirin versus no aspirin with mean duration of scheduled trial treatment of 4 years or longer to determine the effect of allocation to aspirin on risk of cancer death in relation to scheduled duration of trial treatment for gastrointestinal and non-gastrointestinal cancers. In three large UK trials, long-term post-trial follow-up of individual patients was obtained from death certificates and cancer registries. RESULTS: In eight eligible trials (25,570 patients, 674 cancer deaths), allocation to aspirin reduced death due to cancer (pooled odds ratio [OR] 0·79, 95% CI 0·68-0·92, p=0·003). On analysis of individual patient data, which were available from seven trials (23,535 patients, 657 cancer deaths), benefit was apparent only after 5 years’ follow-up (all cancers, hazard ratio [HR] 0·66, 0·50-0·87; gastrointestinal cancers, 0·46, 0·27-0·77; both p=0·003). The 20-year risk of cancer death (1,634 deaths in 12,659 patients in three trials) remained lower in the aspirin groups than in the control groups (all solid cancers, HR 0·80, 0·72-0·88, p<0·0001; gastrointestinal cancers, 0·65, 0·54-0·78, p<0·0001), and benefit increased (interaction p=0·01) with scheduled duration of trial treatment (≥7·5 years: all solid cancers, 0·69, 0·54-0·88, p=0·003; gastrointestinal cancers, 0·41, 0·26-0·66, p=0·0001). The latent period before an effect on deaths was about 5 years for oesophageal, pancreatic, brain, and lung cancer, but was more delayed for stomach, colorectal, and prostate cancer. For lung and oesophageal cancer, benefit was confined to adenocarcinomas, and the overall effect on 20-year risk of cancer death was greatest for adenocarcinomas (HR 0·66, 0·56-0·77, p<0·0001). Benefit was unrelated to aspirin dose (75 mg upwards), sex, or smoking, but increased with age-the absolute reduction in 20-year risk of cancer death reaching 7·08% (2·42-11·74) at age 65 years and older. INTERPRETATION: Daily aspirin reduced deaths due to several common cancers during and after the trials. Benefit increased with duration of treatment and was consistent across the different study populations. These findings have implications for guidelines on use of aspirin and for understanding of carcinogenesis and its susceptibility to drug intervention.

Lancet. 2011 Jan 1;377(9759):31-41

Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials.

BACKGROUND: High-dose aspirin (≥500 mg daily) reduces long-term incidence of colorectal cancer, but adverse effects might limit its potential for long-term prevention. The long-term effectiveness of lower doses (75-300 mg daily) is unknown. We assessed the effects of aspirin on incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour.

METHODS: We followed up four randomised trials of aspirin versus control in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TIA Aspirin Trial) prevention of vascular events and one trial of different doses of aspirin (Dutch TIA Aspirin Trial) and established the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data. RESULTS: In the four trials of aspirin versus control (mean duration of scheduled treatment 6·0 years), 391 (2·8%) of 14 033 patients had colorectal cancer during a median follow-up of 18·3 years. Allocation to aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0·76, 0·60-0·96, p=0·02; mortality HR 0·65, 0·48-0·88, p=0·005), but not rectal cancer (0·90, 0·63-1·30, p=0·58; 0·80, 0·50-1·28, p=0·35). Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0·45, 0·28-0·74, p=0·001; 0·34, 0·18-0·66, p=0·001), but not the distal colon (1·10, 0·73-1·64, p=0·66; 1·21, 0·66-2·24, p=0·54; for incidence difference p=0·04, for mortality difference p=0·01). However, benefit increased with scheduled duration of treatment, such that allocation to aspirin of 5 years or longer reduced risk of proximal colon cancer by about 70% (0·35, 0·20-0·63; 0·24, 0·11-0·52; both p<0·0001) and also reduced risk of rectal cancer (0·58, 0·36-0·92, p=0·02; 0·47, 0·26-0·87, p=0·01). There was no increase in benefit at doses of aspirin greater than 75 mg daily, with an absolute reduction of 1·76% (0·61-2·91; p=0·001) in 20-year risk of any fatal colorectal cancer after 5-years scheduled treatment with 75-300 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily on long-term follow-up of the Dutch TIA trial (odds ratio 2·02, 0·70-6·05, p=0·15). INTERPRETATION: Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy.

Lancet. 2010 Nov 20;376(9754):1741-50

Effect of aspirin on long-term risk of colorectal cancer: consistent evidence from randomised and observational studies.

BACKGROUND: Randomised trials have shown that aspirin reduces the short-term risk of recurrent colorectal adenomas in patients with a history of adenomas or cancer, but large trials have shown no effect in primary prevention of colorectal cancer during 10 years’ follow-up. However, the delay from the early development of adenoma to presentation with cancer is at least 10 years. We aimed to assess the longer-term effect of aspirin on the incidence of cancers. METHODS: We studied the effect of aspirin in two large randomised trials with reliable post-trial follow-up for more than 20 years: the British Doctors Aspirin Trial (N=5,139, two-thirds allocated 500 mg aspirin for 5 years, a third to open control) and UK-TIA Aspirin Trial (N=2,449, two-thirds allocated 300 mg or 1,200 mg aspirin for 1-7 years, a third placebo control). We also did a systematic review of all relevant observational studies to establish whether associations were consistent with the results of the randomised trials and, if so, what could be concluded about the likely effects of dose and regularity of aspirin use, other non-steroidal anti-inflammatory drugs (NSAID), and the effect of patient characteristics. RESULTS: In the randomised trials, allocation to aspirin reduced the incidence of colorectal cancer (pooled HR 0.74, 95% CI 0.56-0.97, p=0.02 overall; 0.63, 0.47-0.85, p=0.002 if allocated aspirin for 5 years or more). However, this effect was only seen after a latency of 10 years (years 0-9: 0.92, 0.56-1.49, p=0.73; years 10-19: 0.60, 0.42-0.87, p=0.007), was dependent on duration of scheduled trial treatment and compliance, and was greatest 10-14 years after randomisation in patients who had had scheduled trial treatment of 5 years or more (0.37, 0.20-0.70, p=0.002; 0.26, 0.12-0.56, p=0.0002, if compliant). No significant effect on incidence of non-colorectal cancers was recorded (1.01, 0.88-1.16, p=0.87). In 19 case-control studies (20 815 cases) and 11 cohort studies (1 136 110 individuals), regular use of aspirin or NSAID was consistently associated with a reduced risk of colorectal cancer, especially after use for 10 years or more, with no difference between aspirin and other NSAIDs, or in relation to age, sex, race, or family history, site or aggressiveness of cancer, or any reduction in apparent effect with use for 20 years or more. However, a consistent association was only seen with use of 300 mg or more of aspirin a day, with diminished and inconsistent results for lower or less frequent doses. INTERPRETATION: Use of 300 mg or more of aspirin a day for about 5 years is effective in primary prevention of colorectal cancer in randomised controlled trials, with a latency of about 10 years, which is consistent with findings from observational studies. Long-term follow-up is required from other randomised trials to establish the effects of lower or less frequent doses of aspirin.

Lancet. 2007 May 12;369(9573):1603-13

Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial.

CONTEXT: Basic research and observational evidence as well as results from trials of colon polyp recurrence suggest a role for aspirin in the chemoprevention of cancer. OBJECTIVE: To examine the effect of aspirin on the risk of cancer among healthy women. DESIGN, SETTING, AND PARTICIPANTS: In the Women’s Health Study, a randomized 2 x 2 factorial trial of aspirin and vitamin E conducted between September 1992 and March 2004, 39,876 US women aged at least 45 years and initially without previous history of cancer, cardiovascular disease, or other major chronic illness were randomly assigned to receive either aspirin or aspirin placebo and followed up for an average of 10.1 years. INTERVENTION: A dose of 100 mg of aspirin (n=19,934) or aspirin placebo (n=19,942) administered every other day. MAIN OUTCOME MEASURES: Confirmed newly diagnosed invasive cancer at any site, except for nonmelanoma skin cancer. Incidence of breast, colorectal, and lung cancer were secondary end points. RESULTS: No effect of aspirin was observed on total cancer (n = 2,865; relative risk [RR], 1.01; 95% confidence interval [CI], 0.94-1.08; P = .87), breast cancer (n = 1,230; RR, 0.98; 95% CI, 0.87-1.09; P = .68), colorectal cancer (n = 269; RR, 0.97; 95% CI, 0.77-1.24; P = .83), or cancer of any other site, with the exception of lung cancer for which there was a trend toward reduction in risk (n = 205; RR, 0.78; 95% CI, 0.59-1.03; P = .08). There was also no reduction in cancer mortality either overall (n = 583; RR, 0.95; 95% CI, 0.81-1.11; P = .51) or by site, except for lung cancer mortality (n = 140; RR, 0.70; 95% CI, 0.50-0.99; P = .04). No evidence of differential effects of aspirin by follow-up time or interaction with vitamin E was found. CONCLUSIONS: Results from this large-scale, long-term trial suggest that alternate day use of low-dose aspirin (100 mg) for an average 10 years of treatment does not lower risk of total, breast, colorectal, or other site-specific cancers. A protective effect on lung cancer or a benefit of higher doses of aspirin cannot be ruled out.

JAMA. 2005 Jul 6;294(1):47-55

Aspirin chemoprevention of gastrointestinal cancer in the next decade. A review of the evidence.

Together, gastrointestinal (GI) cancers now account for 25% of neoplastic deaths in the West. In Poland, GI cancer rates are likely to increase further as westernization progresses. Given that conventional cancer therapies have made only modest reductions in cancer mortality, there is a great interest in chemoprevention to prevent or slow malignant transformation from premalignant lesions. The financial pressures in the immediate future require even more stringent criteria for chemopreventive agents - they must be cheap but also safe and efficacious. In this regard, several reviews have indicated that aspirin possesses many favorable qualities for chemoprevention. Furthermore, meta-analyses indicate that aspirin may decrease cancer by approximately 30%. Several large clinical trials are underway, including AspECT (Aspirin and Esomeprazole Chemoprevention Trial) that aims not only to prevent cancer but also decrease the gastric side effects by combining aspirin with potent acid-suppressing drugs. In conclusion, whether aspirin will be the world’s first proven chemopreventive agent is currently unknown but the evidence looks hopeful.

Pol Arch Med Wewn. 2010 Oct;120(10):407-12

Aspirin, salicylates, and cancer.

Evidence from a wide range of sources suggests that individuals taking aspirin and related non-steroidal anti-inflammatory drugs have reduced risk of large bowel cancer. Work in animals supports cancer reduction with aspirin, but no long-term randomised clinical trials exist in human beings, and randomisation would be ethically unacceptable because vascular protection would have to be denied to a proportion of the participants. However, opportunistic trials of aspirin, designed to test vascular protection, provide some evidence of a reduction in cancer, but only after at least 10 years. We summarise evidence for the potential benefit of aspirin and natural salicylates in cancer prevention. Possible mechanisms of action and directions for further work are discussed, and implications for clinical practice are considered.

Lancet. 2009 Apr 11;373(9671):1301-9

Protective association of aspirin/NSAIDs and esophageal cancer: a systematic review and meta-analysis.

BACKGROUND & AIMS: Esophageal carcinomas have high fatality rates, making chemoprevention agents desirable. We performed a systematic review with meta-analysis of observational studies evaluating the association of aspirin/nonsteroidal anti-inflammatory drug (NSAID) use and esophageal cancer. METHODS: We evaluated the MEDLINE, BIOSIS, and Web of Science electronic databases (1980-2001); manually reviewed the literature; and consulted with experts. Studies were included if they: (1) evaluated exposure to NSAIDs, aspirin, or both; (2) evaluated esophageal cancer; and (3) reported relative risks or odds ratios or provided data for their calculation. Data were independently abstracted by 2 investigators. The primary and sensitivity analyses used both fixed and random-effects models. RESULTS: Nine studies (2 cohort, 7 case control) containing 1,813 cancer cases were identified. All primary summary estimates were homogeneous. Statistical pooling showed a protective association between any use of aspirin/NSAID and esophageal cancer (odds ratio [OR] = 0.57; 95% confidence interval [CI], 0.47-0.71). Both intermittent (OR = 0.82; CI, 0.67-0.99) and frequent medication use were protective (OR = 0.54; CI, 0.43-0.67), with greater protection with more frequent use. Stratified by medication type, aspirin use was protective (OR = 0.5; CI, 0.38-0.66), and NSAIDs had a borderline protective association (OR = 0.75; CI, 0.54-1.0). Any use was protective against both esophageal adenocarcinoma (OR = 0.67; CI, 0.51-0.87) and squamous cell carcinoma (OR = 0.58; CI, 0.43-0.78). CONCLUSIONS: Pooled results support a protective association between aspirin and NSAIDs and esophageal cancer (of both histological types) and provide evidence for a dose effect. These findings support evaluating these agents in clinical trials of high-risk patients.

Gastroenterology. 2003 Jan;124(1):47-56

Aspirin and cancer risk: a summary review to 2007.

Aspirin has been associated with a reduced risk of colorectal cancer and—based on limited evidence—to cancers of the oesophagus, stomach, breast, ovary and lung. The role of aspirin on other cancers, such as pancreatic, prostate and bladder cancer and non-Hodgkin’s lymphomas and myeloma is less clear, and an increase of risk has been suggested for kidney cancer. For most cancer sites, however, significant heterogeneity between studies, and particularly between study design, was found, with a reduction in risk generally stronger in case-control studies than in cohort ones.

Recent Results Cancer Res. 2009;181:231-51

Long-term aspirin use and the risk of total, high-grade, regionally advanced and lethal prostate cancer in a prospective cohort of health professionals, 1988-2006.

Experimental studies suggest a role for aspirin in the chemoprevention of prostate cancer and epidemiological evidence supports a modest inverse association between regular aspirin use and prostate cancer risk, especially for advanced disease. In a prospective cohort study of 51,529 health professionals aged 40-75 years at baseline, we evaluated long-term aspirin use and the incidence of total, high-grade (Gleason 8-10, n=488), regionally advanced (T3b-T4 or N1, n=228) and lethal prostate cancer (M1, bony metastases or prostate cancer death, n=580) from 1988-2006. We used Cox proportional hazards regression to evaluate risk associated with frequency (days/week), quantity (tablets/week), recency and duration of aspirin use after multivariable adjustment for confounders and other predictors of prostate cancer risk. A total of 4,858 men were diagnosed with prostate cancer during the 18-year study period. Men taking ≥ 2 adult-strength aspirin tablets a week had a 10% lower risk of prostate cancer (p-for-trend=0.02). For regionally advanced cancer, we observed no significant associations with aspirin use. For high-grade and lethal disease, men taking ≥ 6 adult-strength tablets/week experienced similar reductions in risk (HR=0.72 (95% CI: 0.54, 0.96) and HR=0.71 (95% CI: 0.50, 1.00)). Analytical approaches to address bias from more frequent PSA screening among aspirin users did not yield different conclusions. We observed reductions in the risk of high-grade and lethal prostate cancer associated with higher doses of aspirin, but not with greater frequency or duration, in a large, prospective cohort of health professionals. Our data support earlier observations of modest inverse associations with advanced prostate cancer.

Int J Cancer. 2010 Dec 2

Use of aspirin and other nonsteroidal antiinflammatory medications in relation to prostate cancer risk.

Recent interest has focused on the role that inflammation may play in the development of prostate cancer and whether use of aspirin or other nonsteroidal antiinflammatory drugs (NSAIDs) affects risk. In a population-based case-control study designed to investigate the relation between these medications and prostate cancer risk, detailed exposure data were analyzed from 1,001 cases diagnosed with prostate cancer between January 1, 2002, and December 31, 2005, and 942 age-matched controls from King County, Washington. A significant 21% reduction in the risk of prostate cancer was observed among current users of aspirin compared with nonusers (95% confidence interval (CI): 0.65, 0.96). Long-term use of aspirin (>5 years: odds ratio = 0.76, 95% CI: 0.61, 0.96) and daily use of low-dose aspirin (odds ratio = 0.71, 95% CI: 0.56, 0.90) were also associated with decreased risk. There was no evidence that the association with aspirin use varied by disease aggressiveness, but there was effect modification (P(interaction) = 0.02) with a genetic variant in prostaglandin-endoperoxide synthase 2 (PTGS2) (rs12042763). Prostate cancer risk was not related to use of either nonaspirin NSAIDs or acetaminophen. These results contribute further evidence that aspirin may have chemopreventive activity against prostate cancer and highlight the need for additional research.

Am J Epidemiol. 2010 Sep 1;172(5):578-90