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Health See other Health Articles Title: Does Aspirin Prevent Cardiovascular Disease and Cancer? Ignore the Guidelines Medscape ... Opinions on the use of aspirin in the prevention of cardiovascular disease (CVD) have varied over the past 25 years since the Physicians' Health Study (PHS) first demonstrated conclusively that low-dose aspirin (325 mg every other day) prevents a first myocardial infarction (MI) in apparently healthy men.[1] Governmental and health organizations have consistently endorsed the use of aspirin in secondary prevention. In contrast, despite the accumulation of data from several randomized trials that demonstrate that aspirin reduces the risk for a first MI,[2-6] the US Food and Drug Administration (FDA) has not acted on three applications for the use of aspirin as primary prevention.[7] After the third submission, the FDA announced in May 2014 that the data still did not sufficiently support this indication, although FDA conceded that the results from additional ongoing clinical trials "may provide new evidence that could be the basis for changing the current uses (indications) for aspirin."[8-13] The FDA position is based primarily on the fact that virtually all of the trials were in such low-risk subjects that reliable evidence is sparse in the moderate- and high-risk primary prevention subjects in whom the benefits of aspirin will clearly outweigh the risks. Such data are accumulating in ongoing randomized trials such as the Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) trial in subjects who are at moderate to high risk for a first event. Despite the lack of regulatory approval, several randomized trials indicate that aspirin provides the same degree of protection against nonfatal MI as a statin.[14] In addition, in secondary prevention, the benefits of aspirin and statins are, at least, additive. Aspirin was proposed as a basic component of a primary prevention polypill.[15] Clinical practice guidelines were initially and cautiously enthusiastic about low-dose aspirin, stating that it might be appropriate in a proportion of healthy adults.[16-20] As a result, support grew for the use of low-dose aspirin to prevent first MI. Since that time, however, most guidelines have become even more cautious, recommending "a more pragmatic approach."[21] An exception is the most recent guidelines of the American College of Chest Physicians, suggesting low-dose aspirin (75-100 mg/day) over no aspirin in patients older than 50 years without symptomatic CVD.[22] The current guideline of the US Preventive Services Task Force recommends the use of aspirin for men aged 45-79 years to prevent MI and women aged 55-79 years to prevent ischemic strokes, when the potential benefit outweighs the potential harm due to an increase in gastrointestinal hemorrhage.[23] (This guideline is being updated.) Recent reports have concluded that patients have been receiving inconsistent[24] or no advice about taking aspirin for primary prevention.[25] One analysis suggested that between 2007 and 2011, despite the fact that enthusiasm waned in clinical guidelines, more people with CVD equivalents used aspirin for primary prevention.[26] This perceived increase has been attributed to generalization from observational studies[1,27] about the clear benefits of aspirin as high-risk primary prevention in patients who have a prior CV event.[27,28] Another reason is the emergence of data indicating that it may stave off colorectal cancer,[29-31] in addition to reducing the risk for a first MI.[26] Subgroup analyses of randomized trials have suggested that aspirin may help prevent other gastrointestinal cancers as well as breast, lung, and prostate cancers. Although the randomized evidence is strongest for prevention of colorectal cancer, the supporting data for other cancers have, so far, come from retrospective analyses of randomized trials designed to look at the effects on prevention of CVD, and not from randomized trials designed to measure this outcome. Currently, no cancer or other health organization recommends taking aspirin specifically to help prevent cancer. In the meantime, researchers and the guidelines committees of medical societies and governmental agencies are attempting to balance the overall benefits and harms of prophylactic use of aspirin for prevention of CVD and cancer in the general population. Some are awaiting the results of new trials. Several recently concluded and ongoing trials in CVD and cancer that are expected to conclude by 2019 may clarify the extent to which aspirin diminishes cancer incidence and mortality.[32] Analyses of available data continue, with a recent review stating that "for average-risk individuals aged 50-65 years taking aspirin for 10 years, there would be a relative reduction of between 7% (women) and 9% (men) in the number of cancer, MI or stroke events over a 15-year period and an overall 4% relative reduction in all deaths over a 20-year period."[33] At the 2014 Congress of the European Society of Cardiology (ESC) in Barcelona, Spain, Charles Hennekens, MD, DrPH, founding principal investigator of both the PHS and the Women's Health Study (WHS), reviewed the overall benefits and risks of prophylactic aspirin use.[34-36] After the meeting, Dr Hennekens explained to Linda Brookes, for Medscape, how he views the evidence and how he believes it should be interpreted by healthcare providers. High-Dose Aspirin After MI FDA Questions Use of Aspirin to Prevent First Heart Attack Weighing Benefits and Risks of Aspirin for Primary Cardiovascular Prevention Medscape: You were the first to demonstrate that taking low-dose aspirin will prevent a first MI. Despite all the debate over the years, your opinion on the use of aspirin in primary CV prevention doesn't seem to have changed. Dr Hennekens: My position has never wavered: For practicing clinicians, the role of aspirin in primary prevention has to be viewed in light of the totality of evidence. A consistent body of evidence shows conclusively that in the highest-risk people, such as those experiencing an MI, taking an aspirin during or up to 24 hours after the onset of symptoms and continuing it daily will reduce their risk for death by 23%, as well as risks for reinfarction, stroke, and death from CVD.[37] The findings are similar among those who have survived a prior MI or other occlusive CV event. In all such high-risk patients, the absolute risk for an event is so high compared with the absolute risk for side effects of aspirin, that aspirin needs to be routinely used, almost without exception. In that context, if you look at the data on primary prevention, since the PHS, all of the trials over the years have shown that aspirin prevents a first MI, but virtually all have been conducted in very low-risk men and women. The problem in primary prevention is twofold. Number one is that those same absolute risks associated with aspirin, when given during or after an MI as secondary prevention, are present in primary prevention, but the absolute benefit of aspirin in primary prevention is lower because the absolute risk for an event is lower. So the question for the doctor or healthcare provider in primary prevention is: What to do about primary prevention if the absolute benefit is lower than that seen with use for secondary prevention, because the absolute risk for an event is lower but that absolute hazard of aspirin is the same? This is complicated by the fact that even though around 100,000 people have been studied in primary prevention trials, over 95% of them were at very low risk, so we don't have data in the population that we probably want to give aspirin to, which is the intermediate-risk people—ie, those who have a 10-year risk for an event of less than 10%. Only about 5000 patients of the 100,000 randomized in trials were in that group, so these data on their own are not reliable. So, in my opinion, it isn't that the quality of the evidence in primary prevention is a concern. Rather, the quantity is less in the population in which we would want to give aspirin. In the previous primary prevention trials, that 10-year risk was around 5%, so it was very low. In contrast, in the ARRIVE trial, 10-year risk for an event is 10%-20%, which corresponds to a mean 10-year CVD risk of approximately 30%.[9] ARRIVE is one of several trials in moderate- and high-risk primary prevention subjects that will provide direct randomized evidence on the risk-benefit ratio of aspirin in primary prevention subjects at intermediate risk. Medscape: That seems very clear. So why didn't everyone see it like that? Dr Hennekens: I believe that what happened over the past two decades was that people were initially emphasizing the benefit of aspirin and not considering the risks. Alternatively, there were also people who were emphasizing the risks of aspirin without considering the benefit. If you look at the totality of evidence in primary prevention, the decision to use aspirin should never be a routine, knee-jerk response the way it is in secondary prevention or during an MI. It ought to be an individual clinical judgment that weighs the absolute benefit of aspirin in a particular patient against the absolute risk. Our Rollercoaster Relationship With Aspirin Weighing Benefits and Risks of Aspirin for Primary Cardiovascular Prevention Waiting for the Right Evidence Making an Informed Clinical Judgment Gender Differences in Aspirin's Effects? Conclusions: Making Decisions About Use and Dose Waiting for the Right Evidence Medscape: So the clinical trial data cited in support of the overall benefit of aspirin in primary prevention[1-6] didn't constitute sufficient evidence to convince you? Dr Hennekens: Frankly, I don't really understand why there was a regulatory submission for this indication again. Aspirin was first submitted to the FDA for primary prevention in 1989 (I was involved in that submission), and the Cardiorenal Drugs Advisory Committee voted 6-2 in favor of the routine use of aspirin in men without risk factors, though this recommendation was never acted on by FDA. The same reasons apply today: namely that the data are insufficient in the intermediate- and high-risk subjects who will be the population for which aspirin is likely to be prescribed in primary prevention. At that time, there were only two primary prevention trials—the PHS and the British Doctors' Trial (BDT).[2] Subsequent data from three more trials—the Thrombosis Prevention Trial (TPT),[3] the Hypertension Optimal Treatment (HOT) trial,[4] and the Primary Prevention Project (PPP) trial[5] —were the basis for a similar submission made in 2003, which was rejected by a vote of 11-3.[38] The average risk for a first event in these six trials is less than 5%, whereas the likely cutpoint for aspirin use may be about 10%.[1-6] So it's not a question of whether aspirin works in secondary prevention but doesn't work in primary—that's not true. The data are quite consistent, in my view, that aspirin does prevent MIs, and I feel that the accumulating randomized evidence in moderate- and high-risk primary prevention subjects will allow regulatory authorities and clinicians to make more informed decisions about aspirin use in primary prevention. The main trial that will provide that evidence will be the ARRIVE trial,[9] but there are other trials in the United Kingdom and Europe: • ASCEND (A Study of Cardiovascular Events in Diabetes), where people are defined as being at moderate risk because of having diabetes alone with no prior CV events [10]; • ACCEPT-D (Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes) trial [13]; and • The ASPREE (Aspirin in Reducing Events in the Elderly) trial.[11] When the totality of evidence is incomplete, it is appropriate to remain uncertain. Meanwhile, it is interesting to note that, as a founding member of the Antithrombotic Trialists' Collaboration, the meta-analysis we published in The Lancet a few years ago, which concluded that aspirin is "of uncertain net value in primary prevention,"[39] was not intended to tell people not to use aspirin; rather, it meant to tell them to avoid using it routinely. Making an Informed Clinical Judgment Medscape: Has the message or the mechanism been misinterpreted over all these years? Dr Hennekens: Aspirin is as old as medicine itself, and in the 20th century it was the most widely used drug in the entire world. But it really wasn't until Sir John Vane showed in 1971 how aspirin inhibits prostaglandins[40] and how even small amounts of aspirin irreversibly acetylate the active site of cyclooxygenase-1 in platelets, inhibiting formation of thromboxane A2 from arachidonic acid. Vane was awarded the Nobel Prize 10 years later because he was the first to explain why aspirin might have net benefits in the treatment and prevention of CVD. So we have to remember that it's relatively recently in the history of aspirin that that mechanism has been described. When people say, "Don't use it at all," they are overinterpreting the risk for side effects, when in fact what we should be telling healthcare providers is that appropriate use requires an informed clinical judgment because that professional knows more than anyone about balance of benefits and risks for each of his or her particular patients. Medscape: So how should the assessment as to whether a patient needs aspirin as primary prevention best be made? Dr Hennekens: Way back when I participated in the first guidelines for aspirin,[16] we said then what I still believe is true now: Look at the absolute risk for a CV event for the patient. If the absolute risk in a patient is high, then that patient will have a net benefit from aspirin; if it is low, then the patient might not have an absolute benefit. It is also necessary to evaluate the absolute risk for side effects for the patient, which is mainly extracranial bleeding, primarily gastrointestinal. We don't have enough evidence to know exactly where the dividing line is, so we will leave it to the judgment of the clinician until the ongoing trials are completed. I'm not in agreement with all of the complicated algorithms that clinicians are told to follow; I think that nobody knows more about the benefit and risk for the patient than his or her clinician, whose judgment should be based on the totality of evidence. For example, the Framingham Risk Score (FRS) is often used as the basis for calculating the risk to a patient. It is a very good tool, developed to help categorize high, medium, and low. The FRS is based on data from the landmark Framingham Heart Study, a prospective cohort study of largely middle-class white people. Thus, a black or Hispanic patient is going to be at higher absolute risk than that predicted by their FRS. In addition, obesity and physical inactivity are also major risk factors for occlusive events, but they are not included in the risk score. Last but not least, you find that no matter what the risk factor score is, people with a positive family history—by which I mean an event in a man younger than 55 years and in a woman younger than 65 years—have about double the risk for CVD, independent of other risk factors. Thus, my message to the clinician is: Don't rely on any calculator to help you decide a patient's risk. Look at the totality of evidence about your patient and weigh the absolute risk for an occlusion against the absolute risk for a bleed with aspirin. In the next few years the data will speak for themselves because we will have some tens of thousands of randomized subjects at intermediate and high risk in primary prevention. Right now, the evidence is incomplete, so until that happens, let's leave it at individual judgment and weigh the absolute benefit against the absolute risk for individual patients. The overall message should be: Don't give aspirin to people who don't need it, and don't withhold it from people who would benefit. Gender Differences in Aspirin's Effects? Medscape: Are there gender differences in the effects of aspirin in CVD prevention, as suggested after the WHS results were published?[41] Dr Hennekens: Absolutely not. I was founding principal investigator of the PHS, which was the first to show a statistically significant and clinically important benefit of aspirin in men with first MI,[1] as well as the WHS, which was the first to show a statistically significant and clinically important benefit of aspirin in women with first stroke.[27] Some erroneously concluded gender differences from this finding. Several lines of reasoning do not support this hypothesis. For example, in the secondary prevention trials, which have far larger numbers of endpoints, subsequent risks for MI or stroke are the same in men and women. In primary prevention, MI becomes the leading killer in men by age 45 years, but it doesn't become the leading killer in women until age 65 years. But by the end of life, 1 in 3 men and 1 in 3 women die from coronary heart disease. An occlusive event in a middle-aged man is most likely to be an MI, whereas in a woman, until age 65, it is more likely to be a stroke. In the WHS, 90% of the women were under age 65. In a subgroup analysis useful to formulate the hypothesis, women aged 65 years or older accounted for over 30% of the endpoints, and there were statistically significant benefits of aspirin during a first stroke as well as during a first MI. So, in my opinion, the benefits of aspirin are the same in men and women. Premenopausal women who are nonsmokers are extremely unlikely to experience an MI, but cigarettes increase their risk 13-fold.[42] From the time of conception, men have higher absolute risks for death compared with women until about age 105! Medscape: How do factors such as diabetes or obesity weigh against gender in terms of risk? Dr Hennekens: It's interesting that you mention that, because the clinical adage is that long-standing diabetes in a woman basically neutralizes the gender benefit on MI because diabetes doubles the risk in men but increases the risk three- to sixfold in women. With respect to the use of aspirin in diabetics, the ASCEND trial[10] has enrolled over 10,000 people with diabetes. In regard to obesity, this risk factor is emerging in the United States and worldwide as perhaps the leading avoidable cause of premature death in men and women. Medscape: What about the role of aspirin in prevention of cancer? There is direct randomized evidence that aspirin prevents colon polyps and recurrent colon cancer. With respect to other cancers, there has been a reliance on observational studies, which cannot be used to test hypotheses of small benefits, as well as subgroups of particular trials, which are also useful to formulate but not test hypotheses. In that regard, in ISIS-2 (Second International Study of Infarct Survival), aspirin conferred a 23% reduction in mortality when given during acute MI. Subgroups that appeared to benefit equally included men and women, the elderly and middle aged, diabetics and nondiabetics, and hypertensives and non-hypertensives. There was one subgroup that aspirin didn't benefit: patients born under the star sign of Gemini or Libra.[37] Thus, ISIS-2 formulated a hypothesis that the only birth sign that did not benefit was Scorpios. In regard to aspirin in cancer prevention, we shouldn't be overemphasizing particular subgroups or particular categories rather than looking at all the evidence, in particular those trials with longer durations of treatment and follow-up. Conclusions: Making Decisions About Use and Dose Medscape: When a decision is made that a patient should be taking aspirin, what dose is appropriate for primary prevention? The trials seem to use different doses. Dr Hennekens: The risk of aspirin increases with the dose, but the Antithrombotic Trialists' Collaboration showed that there is no significant difference in the risks between 75 mg and 325 mg, and there is the same benefit.[42] We have assumed that the lowest dose is the best because the side effects might be less. That complicates the situation more for the clinician because randomized trial evidence that used 325 mg suggests that aspirin prevents colon polyps from developing,[43] and as secondary prevention in people with colon cancer, it reduces subsequent colon cancer risk.[28-31] Medscape: At the ESC Congress, there was a question about how to evaluate the accumulating evidence for aspirin as protection again cancer, particularly colorectal cancer, and incorporate that with current recommendations in primary prevention of CVD. Dr Hennekens: My position on cancer is the same as on CVD. I wouldn't want to see people so enthused about the early findings as to start giving people aspirin to prevent cancer, and then later on realize that the findings are not so conclusive. I believe that the cancer findings are not nearly as conclusive as they are in CVD, because the trials were not designed a priori to test cancer. Medscape: Presumably we will also learn more about aspirin in cancer prevention in the coming years. The ASPREE trial, also looking at nonfatal cancer as a secondary endpoint,[11] and a couple of other trials, including AspECT (Aspirin Esomeprazole Chemoprevention Trial),[44] are focused on cancer prevention. Until then, mightn't physicians be tempted to give aspirin to people who are at increased risk for cancer, especially colorectal cancer? Dr Hennekens: I would certainly consider it, but I would consider the cancer evidence as adjunctive to the CV evidence, not in isolation. Medscape: For primary care providers, do you think it will be possible to produce a general guideline combining the benefits and risks of aspirin in preventing CVD and cancer? Dr Hennekens: I have said—and I believe this to be over the course of decades—that guidelines for the use of aspirin in primary prevention are premature until we have the evidence. We don't have evidence yet for CVD, let alone in cancer, to, in my view, warrant routine guidelines. So I don't think we're helping clinicians at all to give them guidelines, let alone give them several that are not consistent with each other. Leave it up to individual clinical judgment. Medscape: So would you advise clinicians to ignore current guidelines? Dr Hennekens: The key thing about the guidelines is that we don't yet have a sufficient totality of evidence. Even when the totality of evidence is complete, guidelines should inform but not dictate the actions of clinicians. Medscape: But we may expect to get evidence in a few years' time? Dr Hennekens: Exactly. At present, let's just accept the uncertainties, and in a few years' time there is likely to be a more complete totality of evidence on aspirin in primary prevention. Until then, to paraphrase Voltaire, "Let's not let the perfect be the enemy of the possible."[45] Poster Comment: the only birth sign that did not benefit was Scorpios. Sunshine vitamin may have done the trick. Post Comment Private Reply Ignore Thread
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