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INDICATIONS OF ASPIRIN IN PRIMARY PREVENTION AMONG HIV-INFECTED PATIENTS
Submit responseThe recommendations on aspirin (A) use for the primary prevention of cardiovascular events (1), based on cardiovascular risk (CVR) calculation according to the Framingham scale, have recently been published (2). Despite the growing interest in CVR among HIV-infected patients (3, 4), the use of A in these subjects has received scant attention to date. However, the gradual aging of these patients means that we are reaching a point where A for primary prevention may be indicated according to the above mentioned recommendations. We have reviewed the indication of A in a group of HIV-infected patients based on the criteria of these recommendations, with calculation of CVR using the Framingham tables
A total of 120 consecutive HIV-infected adults were included in a cross-sectional observational study. Demographic data were recorded, along with information on smoking or diabetes, total cholesterol, HDL-c, LDL-c and blood glucose. Blood pressure was recorded following the consensus recommendations, with confirmation of the new diagnoses based on Holter blood pressure monitoring to rule out white-coat hypertension. The Framingham tables were used to calculate CVR. The indication of A was based on the published criteria for males > 45 years of age and females > 55 years of age. Calculation was also made of the variation in percentage indication over the coming years as the patients gradually exceed this age limit without changes in the risk factors. In our experience primary prevention with A would be indicated in 30,8% of the patients, according to the assessment of the Framingham study. Only two patients were taking the medication. Among the males, the percentage would reach 40 %. Without modification of the CVR factors, over the next 5 years the indication would be expanded to another 15 % as a result of the aging of the group.
Therefore, application of the recently published recommendations on the use of A in HIV-infected patients could help reduce the rise in cardiovascular events described in some studies. Aspirin would be indicated in a large proportion of patients, particularly in males, and this indication moreover may be expected to increase over the coming years.
In the management of CVR among HIV-infected patients it is therefore necessary to also consider aspirin as primary prevention treatment.
References
(1) US preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: US preventive services task force recommendation statement. Ann Intern Med 2009; 150 (6) 396-404
(2) Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation. 1998;97:1837-47.
(3) Friis-Moller N, Sabin CA, Weber R, et al. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl JMed 2003;349:1993-2003.
(4) D:A:D Study group. Class of antiretroviral drugs and the risk of myocardial infarction in HIV infected patients. N Engl. J Med 2007; 356: 1723-1735
Conflict of Interest:
None declared
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The USPSTF Recommendation on Aspirin for the Prevention of Cardiovascular Disease
Submit responseRE: L09-0238 and L09-0239: Aspirin for the Prevention of Cardiovascular Disease: U.S. Preventive Services Task Force Recommendation Statement
To the Editors:
We appreciate the thoughtful letters from Dr. Budhraja and Dr. Mohan regarding the U.S. Preventive Services Task Force (USPSTF) recommendation on aspirin prophylaxis for the prevention of cardiovascular disease (1). Dr. Budhraja calls attention to subgroups of women in whom the effect of aspirin in preventing cardiovascular disease may differ from the general population. In general, the USPSTF is cautious when considering unplanned subgroup analyses of randomized trials, which are the basis for Dr. Budhraja’s comment. The authors of the original report from the Women’s Health Study (2) mention multiple comparisons as an additional caution in interpreting this subgroup analysis. All sub-group analyses should be considered hypothesis-generating rather than independently persuasive.
The possibility suggested by Dr. Budhraja that the higher risk of peptic ulcer disease in smokers might place them at higher risk of hemorrhage when taking aspirin is deserving of further research.
Dr. Mohan raises a number of valuable points. The inadequate and contradictory information derived from web-enabled coronary and cardiovascular disease risk calculators has been a matter of great concern for the USPSTF. The calculator referenced in the recommendation was selected primarily because it is easy to use; also, it does not require information about high-density-lipoprotein cholesterol concentration. As of this writing, the calculator has been removed from the Medical College of Wisconsin’s Website, and reportedly is being revised.
The USPSTF felt that making a recommendation meant to be tailored to estimation of cardiovascular disease risk without making any suggestions to help clinicians use the recommendation would be worse than mentioning an imperfect calculator. Research in this field is sorely needed. The development of a “gold standard” cardiovascular disease risk calculator that would aid in predicting contemporary rates of cardiovascular disease in the United States should be a pressing priority for analysis of data derived from large cohort studies done in the last decade, perhaps pooling individual level-data across studies. AHRQ has funded a project to evaluate the models currently available for use for risk calculation for cardiovascular disease. The results will be available soon. The use of risk prediction models and the tools based these models to guide decisions about use of preventive and therapeutic medications, as well as decisions about screening, will become increasingly important in the emerging era of personalized medicine.
References
(1) 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.
(2) Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, 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 Mar 31;352(13):1293-304. Epub 2005 Mar 7.
Conflict of Interest:
None declared
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Should Aspirin be Discontinued at Age 80?
Submit responseTo the Editor:
A recent article by the U.S. Preventive Services Task Force in the Annals of Internal Medicine (1) compared the benefits of aspirin in reducing the risk of heart disease to the possible increased incidence of GI bleeding caused by the aspirin. The authors came to the conclusion that before the age of 79 there was a clear advantage due to the aspirin. They left open the issue of ages 80 and above on the basis of insufficient data.
The reader may be tempted to infer that 80 years reprents a break even point between the two different risks, i.e. omitting the aspriin or accepting the risk of GI bleeding due to the aspirin.
But these are not the only options. The addition of a Proton Pump Inhibitor (PPI) heavily biases the decision in favor of continuing the aspirin.
Although there seems to be relatively little data beyond age 80, there is good reason to trust extrapolation, at least for a few years, in the absence of contradictory evidence. One can build considerable safety into this logic by comparing the least likely benefit situation from the aspirin-PPI combination to the maximum risk situation for GI bleeding and showing that even in this worst case, the break even piont is far above 80 and therefore the combination PPI-aspirin therapy is superior to discontinuing the aspirin.
Assume for the moment that 80 is the break even age where the part of the GI risk due to aspirin alone equals or exceeds the reduction of CV risk expected of the aspirin.
Data exists for patients below the age of 80 that indicates about a factor of three reduction in GI risk can be realized by the use of PPI and this number appears roughly independent of age (2).
To be conservative let us assume, for reasons possibly unknown, that the factor of three is overly optimistic. Reduce it to a factor of two. Let us further assume that the CV risk does not increase beyond its value at age 80. This is of course not true but this assuption further penalizes the aspirin-PPI combination. Then the lowest break even age is that for which the GI risk curve without PPI increases by a factor of two from its value at 80. Unless there is some dramatic change occurring in the risk mechanism, one's best estimate is that the GI risk curve continues to tilt up or bend up beyond 80 about the way it does before 80. This moves the break even point up to about 90 years of age. Considering the very conservative assunptions above the estimate of 90 is itself conservative.
In any case, if there exists an age at which the aspirin-PPI GI risk exceeds the reduction in CV risk, it certainly is not 80.
References
1. 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.
2. Sameer D. Saini, et al; Cost-effectiveness of Proton Pump Inhibitor Cotherapy in Patients Taking Long-term, Low-Dose Aspirin for Secondary Cardiovascular Prevention. Arch Intern Med. 2008; 168 (15): 1684 -1690.
Conflict of Interest:
None declared
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USPSTF Guideline on Aspirin
Submit responseTo the Editor.
We were pleased to see an attempt to translate current evidence for aspirin therapy into a clinically useful risk chart in the U.S. Preventive Services Task Force’s (USPSTF) guideline update in the Annals of Internal Medicine March 17 issue (1). Whereas we concur with the guideline’s conservative estimate of the value of aspirin therapy and agree with the need for shared decision making, we think the USPSTF’s approach could be improved.
For their guideline, the authors chose to value Harms and Benefits in terms of the cumulative probability of events over a period of 10 years without consideration of the timing, the severity, and the consequences of these events. Few people would consider a severely disabling stroke within the next year and a mild gastrointestinal bleeding episode 9 years from now as equal, which is in essence the assumption underlying the guideline. Shared decision making is advocated in the guideline to resolve the tough decisions. Although we are strongly in favor of shared decision making it does, however, require information not only about the cumulative probabilities of events but also on competing risks, timing of fatal and non-fatal events, and quality-of-life. This information is missing from the guideline and, if known, is difficult for patients and physicians to combine mentally without decision support. Furthermore, the USPSTF article only covered Myocardial Infarction (MI) in males, and Ischemic Stroke in females, while in females aged 65 or older the effect of aspirin on MI is also relevant (2).
Greving et al.(3) developed a decision analytic simulation model based on a meta analysis by Berger (4), which takes all of these aspects into account. Interestingly, there seems to be a discrepancy between their results and the USPSTF approach. For example, based on Greving’s model, a woman aged 75 and older, not at increased risk for serious bleeding, and with an average cardiovascular risk has a significant net benefit from aspirin use, whereas according to the USPSTF guideline additional risk factors are needed to outweigh potential harm. This example illustrates that omitting both the consequences of events and the effect of aspirin on MI in elderly women, could lead to suboptimal decisions.
Since USPSTF recommendations are regarded as the “reference standard” for allocating preventive services to the general population we believe that primary care physicians and patients should be aware of the limitations of the recommended approach in this guideline.
References
1. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009; 150:396-404.
2. Ridker PM, Cook NR, Lee IM, et al. A randomized trial of low-dose aspirin in the primary prevention of cardiovascular disease in women. N Engl J Med. 2005; 352:1293-1304. Epub 2005 Mar 1297.
3. Greving JP, Buskens E, Koffijberg H, Algra A. Cost-effectiveness of aspirin treatment in the primary prevention of cardiovascular disease events in subgroups based on age, gender, and varying cardiovascular risk. Circulation 2008; 117:2875-2883.
4. Berger JS, Roncaglioni MC, Avanzini F, Pangrazzi I, Tognoni G, Brown DL. Aspirin for the primary prevention of cardiovascular events in women and men: a sex-specific meta-analysis of randomized controlled trials. Jama 2006; 295:306-313.
Conflict of Interest:
None declared
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Aspirin for primary prevention: The evidence in women smokers
Submit responseThe recently updated USPSTF guidelines on aspirin for primary prevention of cardiovascular disease are an ideal example evidence-based medicine in action (1). Although we can’t fully explain why aspirin effects differ by gender, the evidence strongly suggests that it does, and now our guidelines, and practices, can reflect that. The concept makes intuitive sense: target aspirin use to those who are most at risk of cardiovascular disease. As cigarette smoking is a major risk factor for stroke and MI, the updated guidelines imply that smokers are more likely to be given aspirin.
However, if we are willing to accept differential effects of aspirin in men and women, we should also accept the possibility of differential effects in other physiologically distinct subgroups. The WHS showed a significant interaction with smoking status (p<0.0001), and somewhat unexpectedly, aspirin use was associated with increased harm in currently smoking women (Relative risk = 1.3 for major CV event) (2).
The question as to weather other studies have shown similar results is complicated by the established gender gap. The Thrombosis Prevention Trial (TPT) employed high risk patients, 44% of whom were smokers, and although a subgroup analysis was not published, benefits of aspirin were consistent with other trials (3). However, the TPT was performed solely in men. Other trials involving women had much fewer patients than WHS, and subgroup analyses from them were not published.
Since smoking is also a risk factor for peptic ulcer (4), and the bulk of the data available suggest harm rather than benefit in smoking women, I believe it may be prudent to take a more cautious approach to aspirin use in this group until further data can clarify the issue.
References
1. US Preventive Services Task Force. Aspirin for the prevention of cardiovascular disease: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009 Mar 17;150(6):396-404.
2. Ridker PM, Cook NR, Lee IM, Gordon D, Gaziano JM, 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 Mar 31;352(13):1293-304. Epub 2005 Mar 7.
3. Thrombosis prevention trial: randomised trial of low-intensity oral anticoagulation with warfarin and low-dose aspirin in the primary prevention of ischaemic heart disease in men at increased risk. The Medical Research Council's General Practice Research Framework. Lancet. 1998 Jan 24;351(9098):233-41.
4. Kurata, JH, Nogawa, AN. Meta-analysis of risk factors for peptic ulcer. Nonsteroidal antiinflammatory drugs, Helicobacter pylori, and smoking. J Clin Gastroenterol 1997; 24:2.
Conflict of Interest:
None declared
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Time of Taking Aspirin Can Have an Effect on the Frequency of Occurence of Coronary Heart Disease
Submit responseWe read the article by Calonge et al.(1) with great interest, in which they recommend aspirin for the prevention of coronary heart disease. The incidence of acute myocardial infarction and stroke assessed by onset of clinical symptoms exhibits a marked circadian variation with a peak period during the morning. Acute myocardial infarction usually occurs unexpectedly or more frequently in the morning hours, between 8-11 a.m. In this morning period there is a higher aggregability of thrombocytes. Patients usually take aspirin for prevention in the morning as the treatment regimen is one tablet per day to be swallowed without chewing at least 30 min before breakfast. It is obvious that highest plasma level of the drug occurs after the morning peak-incidene of the thromboembolic event, suggesting lower profilactic effect of Aspirin. Furthermore, this treatment regimen has its highest protective effect during the day, when synergistically, normal physical activity exerts a protective action on thromboembolic processes. However, this method of daily Aspirin administration has its lowest protective value against cardiovascular events during the night and early morning, when the lack of physical activity further augment the cascade of haemorheological events favoring platelet aggregation and subsequent ischemia. In contrast, highest plasma level of Aspirin taken late evening (10:00 pm) would be reached prior to the peak-incidence of thromboembolic disorders (2). We are confident that this time shift in the administration of Aspirin would better fit in the circadian scheme of the occurrence of cardiovascular events, thus resulting in a significantly more effective prevention.
References:
1.Calonge, N., Petitti D. B., DeWitt T. G., et al. Aspirin for the Prevention of Cardiovascular Disease:U.S. Preventive Services Task force Recommendation Statement. Ann Intern Med. 2009;150:396-404.
2.Kriszbacher I., Koppan M., Bodis J. Aspirin for stroke prevention taken in the evening? Stroke. 2004;35:2760-1.
Conflict of Interest:
None declared
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CHD Risk-Assessment Tools May Lead to Inappropriate Use of Aspirin for Primary Prevention
Submit responseTO THE EDITOR: Although we agree with the expanded role of aspirin for primary prevention of coronary heart disease (CHD) recommended by the U.S. Preventive Services Task Force (USPSTF)(1), we are concerned that their designated risk-assessment tool (http://healthlink. mcw.edu/article/923521437.html) - one of many they suggest would be useful - may lead to the inappropriate overuse of aspirin for primary prevention.
Using this calculator, based on Framingham data (2), a 45-year old low-risk male (normotensive, non-diabetic, non-smoker, total cholesterol=160 mg/dL, HDL=50 mg/dL) is assigned a 10-year risk of 4%. This low-risk patient, according to USPSTF would be placed on preventive aspirin. However, calculating the same patient’s risk using the online tool (http://hp2010.nhlbi hin.net/atpiii/calculator.asp) accompanying the National Cholesterol Education Program guidelines(3)– also based on Framingham data –generates a risk of 1%.
Clinicians often exhort patients to be wary of online information, yet medical professionals apparently need to exercise the same caution. The USPSTF committee writes, “Available tools provide estimations of coronary heart disease risk . . .” suggesting that all tools are equivalent and accurate. However, previous research has shown wide variability of equation-based prediction tools (4,5). The Table demonstrates such inconsistency using three readily available risk-assessment tools. Without more specific guidance from the USPSTF, use of any online tool may lead to inappropriate overuse or underuse of aspirin depending on the specific tool chosen.
We encourage the USPSTF to reissue their most recent recommendations with a specific risk- assessment tool that has been thoroughly studied to ensure the clinically appropriate application of these important guidelines.
Table. Predicted 10-year CHD risk of 3 hypothetical patients using 3 different online risk calculatorsHealthLink, %* NCEP, %† PROCAM, %‡ Low- risk§ 411Moderate-risk|| 1375High-risk ¶ 371969* Risk assessment tool can be found at http://healthlink.mcw.edu/article/923521437.html
† Risk assessment tool can be found at http://hp2010.nhlbihin.net/atpiii/calculator.asp
‡ Risk assessment tool can be found at http://www.chd- taskforce.com/
§ Low-risk (45 year-old male, non-smoker, untreated BP = 120/80 mm Hg, total cholesterol = 160 mg/dL, LDL = 90 mg/dL, HDL = 50 mg/dL, triglyceride = 100 mg/dL, no family history of CHD)
||Moderate-risk (55 year-old male, non-smoker, untreated BP = 130/90 mm Hg, total cholesterol = 200 mg/dL, LDL = 140 mg/dL, HDL = 50 mg/dL, triglyceride = 150 mg/dL, no family history of CHD)
¶High-risk (65 year-old male, smoker, treated BP = 120/80 mm Hg, total cholesterol = 240 mg/dL, LDL = 200 mg/dL, HDL = 30 mg/dL, triglyceride = 200 mg/dL, no family history of CHD)REFERENCES
1. U.S. Preventive Task Force. Aspirin for the Prevention of Cardiovascular Disease: U.S. Preventive Task Force Recommendation Statement. Ann Intern Med. 2009; 150:396-404.
2. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:1837–1847.
3. National Cholesterol Education Program. 10-year CVD Risk Calculator. 19 March 2009. National Heart Lung and Blood Institute. <http://hp2010.nhlbihin.net/atpiii/calculator.asp>
4. Lenz M, Mühlhauser I. [Cardiovascular risk assessment for informed decision making. Validity of prediction tools]. Med Klin (Munich) 2004;99:651- 61.
5. Brindle P et al. Accuracy and impact of risk assessment in the primary prevention of cardiovascular disease: a systematic review. Heart. 2006 Dec;92(12):1752-9Conflict of Interest:
None declared