Olmesartan:Safety update report by FDA

After reviewing the results of the ROADMAP and ORIENT trials (1), US FDA has determined that the benefits of Benicar (Olmesartan) continue to outweigh its potential risks when used for the treatment of patients with high blood pressure according to the drug label.(2)

Benicar (Olmesartan) is not recommended as a treatment to delay or prevent protein in the urine (microalbuminuria) in diabetic patients.

In November, 2011, US FDA (3) had mentioned that it is evaluating data from two clinical trials in which patients with type 2 diabetes taking the blood pressure medication, Benicar (olmesartan) had a higher rate of death from a cardiovascular cause compared to patients taking a placebo.

ROADMAP and ORIENT are both long-term clinical trials. In both trials, patients with type 2 diabetes were given either Benicar or placebo to determine if treatment with Benicar would slow the progression of kidney disease. An unexpected finding observed in both trials was a greater number of deaths from a cardiovascular cause (heart attack, sudden death, or stroke) in the Benicar-treated patients compared to placebo.
 Benicar (olmesartan) is in the class of drugs called angiotensin II receptor blockers (ARBs). These drugs and a closely related group of drugs called angiotensin-converting enzyme inhibitors (ACEIs) have been evaluated in many studies involving thousands of patients at high-risk for cardiovascular events, such as patients who had a previous heart attack or had heart failure. No increased risk of cardiovascular-related death has been reported in these trials and, in fact, some of these studies indicate ARBs and ACEIs are useful as treatments for certain patients at high-risk for cardiovascular events.

(1)  Haller H, Ito S, Izzo JL, et al. Olmesartan for the delay or prevention of microalbuminuria in Type 2 Diabetes. N Engl J Med 2011;364:907-17

(2)  http://www.theheart.org/article/1211653.do

(3) http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm215222.htm

Screen time has a potential adverse influence on retinal microvascular structure.

The magnitude of arteriolar narrowing associated with each hour daily of TV viewing is similar to that associated with a 10-mm Hg increase in systolic blood pressure in children.

A study mentioning the influence of physical activity and screen time on the retinal microvasculature in young children will be published in May issue of Arterioscler Thromb Vasc Biol. 2011

Gopinath B and colleagues of University of Sydney, Australia have investigated the associations among physical activity (outdoor and indoor sporting activities), sedentary behaviors (including screen time, television [TV] viewing, and computer and videogame usage), and retinal microvascular caliber in schoolchildren.

Six-year-old students (1765/2238) from a random cluster sample of 34 Sydney schools were examined. Parents completed questionnaires about physical and sedentary activities. Retinal images were taken, and retinal vessel caliber was quantified.

After adjusting for age, sex, ethnicity, eye color, axial length, body mass index, birth weight, and mean arterial blood pressure, children who spent more time in outdoor sporting activities (in the highest tertile of activity) had 2.2 μm (95% CI 0.65 to 3.71) wider mean retinal arteriolar caliber than those in the lowest tertile (P(trend)=0.004). Increasing quartiles of time spent watching TV were associated with narrower mean retinal arteriolar caliber ≈2.3 μm (95% CI 0.73 to 3.92), P(trend)=0.003.

The authors concluded that the data suggests that physical activity could have a beneficial influence, whereas screen time has a potential adverse influence on retinal microvascular structure.

http://www.ncbi.nlm.nih.gov/pubmed/21508347

Calcium supplements and cardiovascular events

Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction, according  to a study published in April issue of BMJ (1). 

Bolland BJ and colleagues have reanalysed of WHI CaD Study limited access dataset with incorporation of meta-analysis eight other studies have. WHI CaD Study, a seven year, randomized, placebo controlled trial of calcium and vitamin D (1g calcium and 400 IU vitamin D daily) in 36 282 community dwelling postmenopausal women.

Main outcome measure: Incidence of four cardiovascular events and their combinations (myocardial infarction, coronary revascularisation, death from coronary heart disease, and stroke) assessed with patient-level data and trial-level data.

The results of WHI CaD Study show that there is an interaction between personal use of calcium supplements and allocated calcium and vitamin D for cardiovascular events. In the 16 718 women (46%) who were not taking personal calcium supplements at randomization the hazard ratios for cardiovascular events with calcium and vitamin D ranged from 1.13 to 1.22 (P=0.05 for clinical myocardial infarction or stroke, P=0.04 for clinical myocardial infarction or revascularisation), whereas in the women taking personal calcium supplements cardiovascular risk did not alter with allocation to calcium and vitamin D.

In meta-analyses of three placebo controlled trials, calcium and vitamin D increased the risk of myocardial infarction (relative risk 1.21 (P=0.04), stroke (P=0.05), and the composite of myocardial infarction or stroke (P=0.02).

Calcium or calcium and vitamin D increased the risk of myocardial infarction (P=0.004) and the composite of myocardial infarction or stroke (P=0.009).

The authors concluded that Calcium supplements with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction. This finding was obscured in the WHI CaD Study by the widespread use of personal calcium supplements.

(1) http://www.bmj.com/content/342/bmj.d2040 

Dietary Guidelines 2010

The US Department of Agriculture (USDA) has released the Dietary Guidelines for Americans, 2010 which are intended for Americans ages 2 years and older, including those at increased risk of chronic disease.

 The main concepts of the guidelines are to maintain calorie balance over time to achieve and sustain a healthy weight and to focus on consuming nutrient-dense foods and beverages.

The key recommendations are:

1.     Balancing calories and manage weight

•                 Prevent and/or reduce overweight and obesity through improved eating and physical activity behaviors.

•                 Control total calorie intake to manage body weight. For people who are overweight or obese, this will mean consuming fewer calories from foods and beverages.

•                 Increase physical activity and reduce time spent in sedentary behaviors.

•                 Maintain appropriate calorie balance during each stage of life—childhood, adolescence, adulthood, pregnancy and breastfeeding, and older age.

2.     Foods and food components to reduce

•                 Reduce daily sodium intake to less than 2,300 milligrams (mg) and further reduce intake to 1,500 mg among persons who are 51 and older and those of any age who are African American or have hypertension, diabetes, or chronic kidney disease. The 1,500 mg recommendation applies to about half of the U.S. population, including children, and the majority of adults.

•                 Consume less than 10 percent of calories from saturated fatty acids by replacing them with monounsaturated and polyunsaturated fatty acids.

•                 Consume less than 300 mg per day of dietary cholesterol.

•                 Keep trans fatty acid consumption as low as possible by limiting foods that contain synthetic sources of trans fats, such as partially hydrogenated oils, and by limiting other solid fats.

•                 Reduce the intake of calories from solid fats and added sugars.

•                 Limit the consumption of foods that contain refined grains, especially refined grain foods that contain solid fats, added sugars, and sodium.

If alcohol is consumed, it should be consumed in moderation—up to one drink per day for women and two drinks per day for men—and only by adults of legal drinking age.
For detalied guidelines refer to http://www.cnpp.usda.gov/Publications/DietaryGuidelines/2010/PolicyDoc/ExecSumm.pdf
http://www.cnpp.usda.gov/DGAs2010-PolicyDocument.htm

HPS trial post hoc analysis

The results of Heart Protection Study  post-hoc analysis have been publishedd in the latest issue of Lancet.(1) The HPS tested the hypothesis that the effects of statin therapy differ according to baseline concentrations of CRP and LDL cholesterol.

Patients were categorised into six baseline CRP groups (<1·25, 1·25—1·99, 2·00—2·99, 3·00—4·99, 5·00—7·99, and ≥8·00 mg/L), each including about 3000 patients.

Results showing the effect of Simvastatin on LDL_C levels have been published earlier. Results of this post-hoc analysis:

·        Allocation to simvastatin produced a significant 24% (95% CI 19—28) proportional reduction in the incidence of first major vascular event after randomisation.

·        There was no significant trend in the proportional risk reduction with increasing baseline CRP, with significant reductions in each of the baseline CRP groups, including in participants with CRP concentration less than 1·25 mg/L (29% risk reduction, 99% CI 12—43; p<0·0001).

·        Indeed, even in those with baseline CRP concentration less than 1 mg/L, there was a significant 27% (99% CI 5—44) reduction in risk (166 [13·7%] allocated to simvastatin vs 218 [18·3%] allocated to placebo; p=0·0022).

·        Allocation to simvastatin reduced the incidence of first major coronary event by 27% (95% CI 21—33), of first stroke by 25% (15—34), and of first revascularisation by 24% (17—30), with no significant trend in the proportional risk reduction with increasing baseline CRP concentration for any of these outcomes.

·        There was also no significant trend in the proportional reduction in vascular death with increasing baseline CRP.

·        The proportional risk reduction in participants with low LDL cholesterol and low CRP (27%, 99% CI 11—40; p<0·0001) was statistically similar to that in participants with high LDL cholesterol and high CRP (23%, 10—35; p<0·0001). The authors have mentioned that even when the threshold used to define low LDL cholesterol was reduced to 2·8 mmol/L (which was the median baseline concentration in the JUPITER trial), the proportional reduction in major vascular events in participants with low LDL cholesterol and low CRP (92 [13·6%] vs 128 [18·2%]; risk reduction 0·73, 99% CI 0·52—1·04; p=0·0213) was still similar to the reduction recorded overall.

According to the authors the results of this post-hoc analysis does not lend support to the hypothesis that baseline CRP concentration modifies the vascular benefits of statin therapy materially.

The discussion on the hypothesis has been done on http://www.theheart.org/article/1177999.do

(1) http://www.thelancet.com/journals/lancet/article/PIIS0140-6736(10)62174-5/fulltext?_eventId=login#bib2

Antihypertensive effect of Hydrochlorthiazide

A meta-analysis of use of hydrochlorthiazide (HCTZ) in management of hypertension has been published in the January issue of J Am Coll Cardiol (1) .

The trials with the following criteria were included in the meta-analysis: 1) randomized trials involving patients with hypertension that assessed the antihypertensive efficacy by 24-h Ambulatory Blood Pressure (ABP) monitoring comparing HCTZ with other antihypertensive drug classes; 2) use of HCTZ as a monotherapy in the trial; and 3) trial duration of at least 4 weeks.

The main outcome of the present analysis was BP (systolic/diastolic) reduction from baseline to follow-up.

Results: The antihypertensive efficacy of HCTZ in the dose of 12.5 to 25 mg was assessed from 14 randomized controlled trials.

·       The mean baseline BP in these studies was 148 ± 7.5/92 ± 5.6 mm Hg.

·       After treatment with HCTZ for a mean duration of 17 weeks, systolic ABP decreased by 6.5 mm Hg  and diastolic ABP by 4.5 mm Hg.

·       Other antihypertensive agents such as ACE inhibitors, ARBs, beta-blockers, and calcium antagonists were significantly more efficacious than HCTZ in the dose of 12.5 to 25 mg.

·       In head-to-head comparisons with other antihypertensive drug classes, HCTZ in the usual dose of 12.5 to 25 mg lowered systolic ABP less well than ACE inhibitors by 4.5 mm Hg (p = 0.001), ARBs by 5.1 mm Hg, beta-blockers by 6.2 mm Hg (p < 0.00001), and calcium antagonists by 4.5 mm Hg (p = 0.02).

·        HCTZ lowered diastolic ABP less well than ACE inhibitors by 4.0 mm Hg (p < 0.0001), ARBs by 2.9 mm Hg (p = 0.002), beta-blockers by 6.7 mm Hg (p < 0.00001), and calcium antagonists by 4.2 mm Hg (p = 0.0001)

·   The antihypertensive effect of HCTZ was similar to other antihypertensives in controlling the office BP, whereas it was inferior to other antihypertensives in controlling ABP.

·    The authors have mentioned that assessing the antihypertensive efficacy of HCTZ by office BP measurements only is deceptive and is prone to provide to physicians and patients a false sense of security.

·       At a daily dose of 50 mg and above, HCTZ's antihypertensive efficacy seems to be similar to most other drug classes. However, all biochemical adverse effects such as hypokalemia, hyponatremia, hyperuricemia, insulin resistance, and visceral fat accumulation are dose dependent and become clinically more significant with daily doses exceeding 25 mg (2).  

·       In its commonly used dose of 12.5 to 25 mg once a day, there has been no evidence that HCTZ reduces myocardial infarction, stroke, or death.

·       Numerous, mostly factorial design studies have shown that when combined with these drug classes, HCTZ, even at low doses, elicits a distinct incremental fall in BP. That indicates that HCTZ is more useful as an "enhancer" or "sensitizer" for the antihypertensive effect of renin-angiotensin system blockers than as a monotherapeutic agent. The ACCOMLISH trial shows HCTZ to be inferior to amlodipine.(3)

·       The authors concluded that HCTZ in its commonly used dose of 12.5 to 25 mg daily lowers BP significantly less well than do all other drug classes as measured in head-to-head studies by ABP monitoring.

The meta-analysis has also been discussed on: http://www.theheart.org/article/1176571.do#bib_2

References:

1.     http://content.onlinejacc.org/cgi/content/long/57/5/590

2.     Messerli FH, Bangalore S, Julius S. Risk/benefit assessment of beta-blockers and diuretics precludes their use for first-line therapy in hypertension Circulation 2008;117:2706-2715discussion 2715

3.     Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients N Engl J Med 2008;359:2417-2428.

Budesonide for eosinophilic esophagitis

Results of a  randomized, double-blind, placebo-controlled trial to evaluate the effect of oral budesonide (1 mg twice daily for 15 days) in adolescent and adult patients with active EoE. Eosinophilic esophagitis has been published in November 2010 issue of Gastroenterology journal.(1)

 (EoE) is a chronic inflammatory disease of the esophagus characterized by dense tissue eosinophilia; it is refractory to proton pump inhibitor therapy.

EoE affects all age groups but most frequently individuals between 20 and 50 years of age. Topical corticosteroids are effective in pediatric patients with EoE, but no controlled studies of corticosteroids have been reported in adult patients.

METHODS: A pretreatment and post-treatment disease activity was assessed clinically, endoscopically, and histologically.

 The primary end point was reduced mean numbers of eosinophils in the esophageal epithelium (number per high-power field [hpf] = esophageal eosinophil load). Esophageal biopsy and blood samples were analyzed using immunofluorescence and immunoassays, respectively, for biomarkers of inflammation and treatment response.

RESULTS:

·       A 15-day course of therapy significantly decreased the number of eosinophils in the esophageal epithelium in patients given budesonide (from 68.2 to 5.5 eosinophils/hpf; P < .0001) but not in the placebo group (from 62.3 to 56.5 eosinophils/hpf; P = .48).

·       Dysphagia scores significantly improved among patients given budesonide compared with those given placebo (5.61 vs 2.22; P < .0001).

·       White exudates and red furrows were reversed in patients given budesonide, based on endoscopy examination. Budesonide, but not placebo, also reduced apoptosis of epithelial cells and molecular remodeling events in the esophagus; no serious adverse events were observed.

The authors concluded that a 15-day course of treatment with budesonide is well tolerated and highly effective in inducing a histologic and clinical remission in adolescent and adult patients with active EoE.

(1) http://www.ncbi.nlm.nih.gov/pubmed/20682320?dopt=Abstract

Consumption of Added Sugars and Risk of cardiovascular diseases

In the January issue of Circulation, a cross-sectional study ‘Consumption of Added Sugars and Indicators of Cardiovascular Disease Risk among US Adolescents’ has been published.(1)

Methods: In a cross-sectional study of 2157 US adolescents in the National Health and Nutrition Examination Survey (NHANES) 1999 to 2004, dietary data from one 24-hour recall were merged with added sugar content data from the US Department of Agriculture MyPyramid Equivalents databases.

Measures of cardiovascular disease risk were estimated by added sugar consumption level (<10%, 10 to <15%, 15 to <20%, 20 to <25%, 25 to <30%, and 30% of total energy).

Multivariable means were weighted to be representative of US adolescents and variances adjusted for the complex sampling methods.

Results:

·       Daily consumption of added sugars averaged 21.4% of total energy.

·       Added sugars intake was inversely correlated with mean high-density lipoprotein cholesterol levels (mmol/L) which were 1.40 (95% confidence interval [CI] 1.36 to 1.44) among the lowest consumers and 1.28 (95% CI 1.23 to 1.33) among the highest (P trend =0.001).

·       Added sugars were positively correlated with low-density lipoproteins (P trend =0.01) and geometric mean triglycerides (P trend =0.05).

·       Among the lowest and highest consumers, respectively, low-density lipoproteins (mmol/L) were 2.24 (95% CI 2.12 to 2.37) and 2.44 (95% CI 2.34 to 2.53), and triglycerides (mmol/L) were 0.81 (95% CI 0.74, 0.88) and 0.89 (95% CI 0.83 to 0.96).

·       Among those overweight/obese ( 85th percentile body-mass-index), added sugars were positively correlated with the homeostasis model assessment (P linear trend =0.004).

The authors concluded that the consumption of added sugars among US adolescents is positively associated with multiple measures known to increase cardiovascular disease risk.



(1) http://circ.ahajournals.org/cgi/content/abstract/123/3/249?etoc

ACCELERATE results

The results of a randomized, parallel group trial comparing Aliskiren and the calcium channel blocker amlodipine combination as an initial treatment strategy for hypertension control (ACCELERATE) have been published in the recent issue of Lancet.(1)

The researchers tested whether a combination of aliskiren and amlodipine is superior to each monotherapy in early control of blood pressure without excess of adverse events, and if initial control by monotherapy impairs subsequent control by combination therapy.

Methods:

·       It was a double-blind, randomised, parallel-group, superiority trial at 146 primary and secondary care sites in ten countries, with enrolment from Nov 28, 2008, to July 15, 2009.

·       Eligible patients were suffering from essential hypertension, aged 18 years or older, and had systolic blood pressure between 150 and 180 mm Hg.

·       Patients were randomly assigned (1:1:2) to treatment with

o   150 mg aliskiren plus placebo,

o   5 mg amlodipine plus placebo,

o   or 150 mg aliskiren plus 5 mg amlodipine.

·       From 16-32 weeks, all patients received combination therapy with 300 mg aliskiren plus 10 mg amlodipine.

·       The primary endpoints, assessed on an intention-to-treat basis (ie, in patients who received the allocated treatment), were the adjusted mean reduction in systolic blood pressure from baseline over 8 to 24 weeks, and then the final reduction at 24 weeks.

Results:

·       318 patients were randomly assigned to aliskiren, 316 to amlodipine, and 620 to aliskiren plus amlodipine.

·       Patients given initial combination therapy had a 6·5 mm Hg (95% CI 5·3 to 7·7) greater reduction in mean systolic blood pressure than the monotherapy groups (p<0·0001).

·        At 24 weeks, when all patients were on combination treatment, the difference was 1·4 mm Hg (95% CI -0·05 to 2·9; p=0·059).

·       Adverse events caused withdrawal of 85 patients (14%) from the initial aliskiren plus amlodipine group, 45 (14%) from the aliskiren group, and 58 (18%) from the amlodipine group. Adverse events were peripheral oedema, hypotension, or orthostatic hypotension.

The authors have concluded that routine initial reduction in blood pressure (>150 mm Hg) with a combination such as aliskiren plus amlodipine can be recommended.

(1) http://www.ncbi.nlm.nih.gov/pubmed/21236483?dopt=Abstract 

Rivaroxaban

In the recent issue of NEJM results of two studies involving Rivaroxaban have been published. One was an open-label, randomized study that compared oral Rivaroxaban alone (15 mg twice daily for 3 weeks, followed by 20 mg once daily) with subcutaneous Enoxaparin followed by a vitamin K antagonist (either Warfarin or Acenocoumarol) for 3, 6, or 12 months in patients with acute, symptomatic DVT. 

 The second parallel study was a double blind, randomized, event-driven superiority study that compared rivaroxaban alone (20 mg once daily) with placebo for an additional 6 or 12 months in patients who had completed 6 to 12 months of treatment for venous thromboembolism.

The primary efficacy outcome for both studies was recurrent venous thromboembolism. The principal safety outcome was major bleeding or clinically relevant nonmajor bleeding in the initial-treatment study and major bleeding in the continued-treatment study.

The study of rivaroxaban for acute DVT included 3449 patients: 1731 given rivaroxaban and 1718 given enoxaparin plus a vitamin K antagonist. Rivaroxaban had noninferior efficacy with respect to the primary outcome (36 events [2.1%], vs. 51 events with enoxaparin–vitamin K antagonist [3.0%]; hazard ratio, 0.68; 95% confidence interval [CI], 0.44 to 1.04; P<0.001).

The principal safety outcome occurred in 8.1% of the patients in each group. In the continued-treatment study, which included 602 patients in the rivaroxaban group and 594 in the placebo group, rivaroxaban had superior efficacy (8 events [1.3%], vs. 42 with placebo [7.1%]; hazard ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001).

 Four patients in the rivaroxaban group had nonfatal major bleeding (0.7%), versus none in the placebo group (P=0.11).

The authors have concluded that Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation.

http://www.nejm.org/doi/full/10.1056/NEJMoa1007903

Anzemet (dolasetron mesylate)

The U.S. Food and Drug Administration (FDA) has informed that the injection form of Anzemet (dolasetron mesylate) should no longer be used to prevent nausea and vomiting associated with cancer chemotherapy (CINV) in pediatric and adult patients.

New data demonstrate that Anzemet injection can increase the risk of developing an abnormal heart rhythm (torsade de pointes), which in some cases can be fatal. Patients at particular risk are those with underlying heart conditions or those who have existing heart rate or rhythm problems. Anzemet causes a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram (ECG).

Anzemet injection may still be used for the prevention and treatment of postoperative nausea and vomiting (PONV) because the lower doses used for PONV are less likely to affect the electrical activity of the heart and result in abnormal heart rhythms. 

Anzemet tablets may still be used to prevent CINV because the risk of developing an abnormal heart rhythm with the oral form of this drug is less than that seen with the injection form.

However, a stronger warning about this potential risk is being added to the Warnings and Precautions sections of the Anzemet tablet label. Anzemet tablets may also still be used for prevention of PONV. 

Nausea and vomiting are common side effects of chemotherapy and general anesthesia used in surgery. Additional highlights:

• Torsade de pointes, an abnormal heart rhythm, has been reported in some patients receiving Anzemet injection.
• Anzemet should not be used in patients with congenital long-QT syndrome.
• Hypokalemia and hypomagnesemia should be corrected before administering Anzemet. These electrolytes should be monitored after administration as clinically indicated.
• Use electrocardiogram (ECG) monitoring in patients with congestive heart failure, patients with bradycardia, patients with underlying heart disease, the elderly and in patients who are renally impaired who are taking Anzemet.
• No dose adjustment is necessary for renal-impaired patients, hepatic-impaired patients, or the elderly.
• Anzemet also causes dose-dependent PR and QRS prolongation. Drugs known to prolong the PR interval (such as verapamil) or QRS interval (such as flecainide or quinidine) should be avoided in patients taking Anzemet.

http://www.fda.gov/Drugs/DrugSafety/ucm237081.htm

Avastin (bevacizumab): Process for Removal of Breast Cancer Indication Begun

FDA recommended removing the breast cancer indication for Avastin (bevacizumab) because the drug has not been shown to be safe and effective for that use.

The drug itself is not being removed from the market and today’s action will not have any immediate impact on its use in treating breast cancer. Today’s action will not affect the approvals for colon, kidney, brain, and lung cancers.

FDA has made this recommendation after reviewing the results of four clinical studies of Avastin in women with breast cancer and by determining that the data indicate that the drug does not prolong overall survival in breast cancer patients or provide a sufficient benefit in slowing disease progression to outweigh the significant risk to patients.

 None of the studies demonstrated that patients receiving Avastin lived longer and patients receiving Avastin experienced a significant increase in serious side effects. These risks include severe high blood pressure; bleeding and hemorrhage; the development of perforations (or “holes”) in the body, including in the nose, stomach, and intestines; and heart attack or heart failure.

FDA recommends that the Oncologists currently treating patients with Avastin for metastatic breast cancer should use their medical judgment when deciding whether a patient should continue treatment with the drug or consider other therapeutic options.

Patients currently receiving Avastin for breast cancer should speak with their oncologists about whether to continue their treatment or explore other treatment options. 

http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm237172.htm

Long-term effect of aspirin on colorectal cancer incidence and mortality

In the November issue of Lancet, a study assessing the effect of aspirin (low doses i.e. 75-300 mg daily) on the incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour was published.

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) were followed and the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data was established.

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).

The authors concluded that 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.

http://www.lancet.com/journals/lancet/article/PIIS0140-6736(10)61543-7/abstract