Aspirina en prevencion primaria

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Aspirin in Primary Prevention: Interview With Kausik Ray

Linda Brookes, MSc; Kausik Ray, MBChB, MD, MPhil

Posted: 03/08/2012

A Best Evidence Interview With Kausik Ray, MBChB, MD, MPhil

The Best Evidence Study

Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and nonvascular outcomes: meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172:209-216.

About the Interviewee

Kausik Ray, MBChB, MD, MPhil, is professor of cardiovascular disease prevention and honorary consultant cardiologist at St. George’s Hospital NHS Trust, University of London, London, England. He is a clinical cardiologist and cardiovascular epidemiologist with an interest in primary and secondary prevention of cardiovascular disease. His research interests focus on cardiometabolic risk, preventative cardiology, cardiovascular epidemiology, and clinical trials. He is a reviewer for the UK Medical Research Council and an external expert for the National Institute for Health and Clinical Excellence (NICE). He is a member of the European Atherosclerosis Society (EAS) consensus panel evaluating the role of plasma levels of LDL cholesterol (Lp[a]), HDL cholesterol, and triglycerides in the prevention of cardiovascular disease; an expert member of the EAS Therapeutics Committee; and a national lead or member of the steering committee of several large international trials looking at novel drug interventions.

Background to the Interview

Although aspirin is still widely recommended in secondary prevention of cardiovascular disease (CVD) events, support for its use in primary prevention has declined and few guidelines recommend aspirin in healthy individuals or in those whose risk for bleeding is known to outweigh the potential benefit. However,most guideline recommendations for the use of aspirin in primary prevention of CVD are based on evidence from clinical trials published before 2005.[1-3] Professor Ray and his colleagues at St. George’s, University of London, sought to update the evidence by a meta-analysis using new trial data.[4] They also analyzed the effect of aspirin on nonvascular outcomes, specifically cancer, in the same trials, because an increasing number of studies have suggested that aspirin could be beneficial in preventing certain types of cancer. For their investigator-led meta-analysis, Prof. Ray used data from 9 «good quality» randomized, placebo-controlled trials published between 1988 and 2010 that reported on cardiovascular disease, nonvascular outcomes, or death in ≥ 1000 subjects and 1 year of follow-up.[5-14] The trials were identified from searches in MEDLINE and Cochrane Library databases and unpublished trial data. The researchers found that over a mean follow-up of 6.0 years, in a total of 102,621 participants, aspirin treatment was associated with a significant 10% decline in total CVD events, primarily as a result of a 20% reduction in nonfatal myocardial infarction (MI). They saw no beneficial effects on fatal MI, stroke, or CVD death, and modest, nonsignificant reductions in total coronary heart disease (CHD; 14%), total nonvascular mortality (8%), and all-cause mortality (6%). Moreover, they found no «convincing» evidence of benefit with regard to cancer mortality (7% reduction). However, people receiving aspirin showed a 70% excess risk for total bleeding events and a 31% excess risk for nontrivial bleeding events. The researchers found that the net benefit of aspirin treatment for nonfatal MI and total CVD increased as background CVD event rates increased, but that these benefits were offset by higher rates of nontrivial bleeds. For nonfatal MI only, there appeared to be a benefit of aspirin prophylaxis at high baseline event rates.

«This meta-analysis provides the largest evidence to date regarding the wider effects of aspirin treatment in primary prevention,» Prof. Ray and coauthors noted. «In contemporary primary prevention settings, aspirin may add little extra value to other CVD risk-reduction strategies that target lipid levels, blood pressure, and smoking, especially in low-risk individuals. On the other hand, aspirin may be associated with net harm owing to increased potential for bleeding.» They concluded that «routine use of aspirin for primary prevention is not warranted and treatment decisions need to be considered on a case-by-case basis,» and suggested that, «It is perhaps timely to reappraise existing guidelines for aspirin use in primary prevention.»

In an accompanying commentary,[15] Samia Mora, MD, MHS (Brigham & Women’s Hospital, Harvard Medical School, Boston) noted that the results of the study, showing a net benefit of aspirin among high-risk individuals, were consistent with a previous meta-analysis of aspirin trials by the Antithrombotic Trialists’ (ATT) Collaboration.[16] «To date, the data argue against the routine use of aspirin for primary prevention of CVD for individuals at low absolute risk of CVD. As the current guidelines recommend, it is reasonable to consider using aspirin for primary prevention in higher-risk individuals without known CVD (above 1% CVD event rate per year) if they are deemed to have a greater benefit-to-risk ratio and after taking into account patient preferences,» Dr. Mora concluded.

Prof. Ray spoke with Linda Brookes, MSc, for Medscape Cardiology, about the clinical implications of the findings of this latest meta-analysis and how they could impact the way aspirin is used in primary prevention.

The Interview

Medscape: Why did you examine nonvascular as well as cardiovascular outcomes in the same meta-analysis?

Prof. Ray: Considering all the recent debate about both the cardiovascular and the nonvascular benefits of aspirin, we wanted to look at those outcomes in their entirety.

Medscape: Your study included data from 3 more recent clinical trials: The prevention of progression of arterial disease and diabetes (POPADAD)[12] and Japanese Primary Prevention of Atherosclerosis With Aspirin for Diabetes (JPAD),[13] both carried out in diabetic subjects, and the Aspirin for Asymptomatic Atherosclerosis (AAA) trial, in patients with peripheral artery disease.[14]

Prof. Ray: Yes. A previous meta-analysis, the ATT collaborative study,[16] looked at vascular events and bleeds but did not include these 3 studies. That study examined the relative risks and benefits of aspirin in both primary and secondary prevention. It did not really give one a feeling for net benefit when trying to weigh individual risks and benefits in primary prevention, which is what we wanted to do. We know that in secondary prevention, if patients have had an MI or a stroke, taking aspirin does reduce cardiovascular deaths and therefore, because cardiovascular deaths contribute a significant proportion of the deaths that occur in such a population, [secondary prevention] results in an impact on all-cause mortality. Although there is a bleeding risk, the overall benefit vs risk ratio favors taking the drug, because it is preventive; events are so common it reduces them. That is the first important point for the basis of our study. The second was that about 1 year ago, Rothwell and colleagues reported a meta-analysis of the effect of aspirin on cancer deaths in more than 25,000 people.[17] This analysis included a mixed population of primary and secondary prevention; it suggested that daily aspirin might have beneficial effects in preventing death from a range of common cancers, but that the effect might take years to emerge — about 5 years for esophageal, pancreatic, brain, and lung cancer, but longer for stomach, colorectal, and prostate cancer. Some of the studies included in that meta-analysis had a duration of follow-up as long as 20 years. This is an important question. If you are already taking a drug such as aspirin as secondary prevention, and there is a beneficial effect on [preventing] cancer, then that is added value or added benefit, because you have another indication to take a drug you are already taking. We tried to answer a broader question: Is taking aspirin regularly beneficial in a healthy population who have no particular reason to take the drug?

Medscape: What is your definition of «healthy» in that scenario?

Prof. Ray: By «healthy» we mean that people may have risk factors but they are free from [established] cardiovascular disease, either MI or stroke.

Medscape: Obviously, some of the people in the studies in your meta-analysis had diabetes, high cholesterol, hypertension, and they were at higher risk of having an event than others who did not [have these risk factors].

Prof. Ray: They had risk factors, but they had not had a cardiovascular event. The process of atherothrombosis starts off with atherosclerosis and finally a thrombus forms. Drugs work in different ways, so if you take a statin or antihypertensive medication, you are modifying the disease process; by modifying the plaque, you are modifying something upstream. If you take aspirin, that will not modify the plaque, it will modify the thrombotic complications downstream. So these drugs work in 3 different ways. What you, as a patient, want to know about a drug is: Will it prolong life? Is it going to affect fatal or nonfatal events? And what is the cost? That is how we approached this study. In patients who have risk factors like hypertension or diabetes, in that context, risk is risk; it is actually quite generalizable.

We looked at approximately 102,000 people with an average of more than 6 years, or more than 700,000 person years, of follow-up. The first important finding was that there was no effect on cardiovascular death — it did not reduce that. The only benefit we observed was a reduction in nonfatal MI, a significant 20% reduction in nonfatal MI during that period of time. The number needed to treat to prevent 1 nonfatal MI event over 6 years was about 162. The flip side was that the cost was extra bleeds. We defined the bleeds as being significant or «nontrivial,» which included nonfatal intracerebral bleeds, retinal bleeds, fatal bleeds, and bleeds that required admission to hospital and/or a transfusion. These are not minor events and, by this definition, 1 of these nontrivial bleeds occurred for every 73 people treated with aspirin for about 6 years. Thus, for every nonfatal MI prevented, there were about 2.5 extra bleeds. [During the 6 years of the study], we did not see a significant reduction in cancer deaths; even if it had been significant, the bleeding risk [weighed against] the cancer benefit was about 3.5 to 1.

When we reviewed the data, we found that the trials published up to the year 2000 suggested more benefit for aspirin than those published post-2000. One reason for this, we believe, may be that background therapy has changed and there is now a greater use of statins and antihypertensive drugs. That scenario may also explain why the more recent trial results have shown less benefit for aspirin and might be contributing to the confusion about whether aspirin is useful or not. That fits closely with a finding of the ATT collaborative, which hypothesized a scenario in which aspirin was added to primary prevention therapy that theoretically reduced background CVD risk by 50%.[16] By that calculation, the effect of aspirin was about one-half that suggested by the trials in the meta-analysis. In that scenario you would actually see much less benefit.

Our study showed that in the general population it is very hard to predict who is going to benefit from aspirin therapy vs net bleeding risk. When we plotted the number of extra bleeds caught against the number of events prevented in each trial we found a [fairly] straight line, showing that if you are looking at people in whom you might see a favorable net benefit, where aspirin is really going to prevent a nonfatal MI or a cardiovascular death, it is probably going to be at a much higher level of cardiovascular risk than we previously perceived. But you also need to have a population with a low bleeding risk. This suggests that we need to move toward working out an individual, personalized bleeding risk vs individual risk for a nonfatal MI.

The other important finding from our analysis was that although the effect on MI was consistent when aspirin was taken daily or on alternate days, the bleeding risk diminished significantly, so that in relative terms there would have been a 48% increase in risk if you were taking aspirin daily vs a 16% increased bleeding risk if you took it on alternate days. Therefore, one of the implications is that rather than treating everybody at a population level, there may be individuals at very high level of risk for MI whom you choose to treat with aspirin, and if you were to do that, an alternate-day aspirin would probably be better.

Medscape: Your findings on cancer were different from what the Rothwell meta-analysis reported.[17]

Prof Ray: We were looking at cancer overall. We do not exclude the possibility of a long-term benefit on cancer, and there may be different effects with different types of cancer. A study published in 2011, the Colorectal Adenoma/Carcinoma Prevention Programme 2 (CAPP2), indicated that if you have a predisposition to a particular type of hereditary colorectal cancer, Lynch syndrome, which is a faster developing cancer, taking 600-mg aspirin per day reduces the risk for this disease.[18] It would suggest that for other types of cancers, a longer duration of treatment might have a beneficial effect on incidence.


The CAPP2 report did not provide any information on bleeding, however, and what I would say about cancer deaths is that one potential confounding factor might be that if aspirin increases the risk for bleeding, you might get so-called «detection bias.» Cancer is often present with bleeding. It might present insidiously, so you might notice hematuria or blood in the stool, and that might lead to investigation. If the bleeding risk is increased in that group, the disease might be detected much earlier, treatment begins earlier, and the patient is more likely to survive. That might be one possible explanation for the reduction in cancer deaths. We need to look at cancer incidence rather than cancer deaths. The trials in our analysis were not designed to look at that, so suggesting using them as a basis for changing cancer guidelines does not make sense. What we now need is a trial looking at cancer incidence that is appropriately powered with appropriate screening on all arms of the trial, where everyone undergoes colonoscopy and MRI, to reduce detection bias. That is a different question, and the answer to it does not exist yet. Our study suggested that if you are going to conduct such a trial, then you might want to look at dose, alternative day vs every day regimens, and regular vs enteric-coated aspirin. The enteric-coated formulation will probably reduce bleeding risk to some extent. Although we did not see any effect of aspirin on cancer in our study, we did see a stronger signal for a reduction in cancer deaths for patients taking aspirin daily vs placebo, compared with alternate day treatment; at least numerically (22%), not statistically — that is an important caveat.[4] However, a big problem with that is that the bleeding risk is increased with both doses, so that has to be weighed in properly. Again, this may be related to the detection bias I referred to. So what is important to look at is incident cancers, not cancer deaths, which I think is the wrong end point.

Medscape: I think a few trials of aspirin in cancer prevention are ongoing, correct?

Prof Ray: Yes, there are a couple of ongoing trials. One that is about to start in the UK is CAPP3, which is an extension of the CAPP2 trial. CAPP3 will focus first on identifying the appropriate dose of aspirin for prevention in about 5000 people with a mismatch repair gene defect for Lynch syndrome who will take placebo or enteric-coated aspirin 100, 300, or 600 mg per day for 5 years. It makes sense to do a trial in individuals at high risk for cancer rather than general populations; if there is a signal, that population is where you will see it first. But it should always be done on the basis of net benefit as well, so the risks of any of these treatments and the benefits should never be overstated or understated. And the trials need to be appropriately powered, obviously.

Medscape: Could aspirin be taken with esomeprazole, as in the Aspirin Esomeprazole Chemoprevention Trial (AspECT)[19]?

Prof. Ray: The bleeding risk with aspirin is not just gastrointestinal. Taking aspirin with esomeprazole might reduce gastrointestinal bleeds, but it wouldn’t affect retinal or intracerebral bleeds.

Medscape: But you do believe that there may be a role in primary prevention of some cancers?

Prof Ray: Routine use of aspirin does not make sense in prevention of cardiovascular disease, but the whole of the cancer story needs a lot more evidence. For prevention of colorectal cancer, the story might well be true — a body of evidence suggests benefit — but for the man or woman in the street, that is a different matter. If bleeds occur early and more commonly, then people might stop the drug, and for good reason if they have had a major adverse event. These people might not be taking it for 20-odd years to see a benefit. Again, whatever benefit you see in individual trials, at a population level you are likely to see less benefit because if you do not take the drug you cannot get the benefit. Thus, one of the key factors that you have to consider is individualized risk: who is at high risk for MI, who is potentially at very high risk for cancer, and then weigh their bleeding risk. In that scenario we will probably move toward some people using this drug appropriately. So there is some risk at a population level, and if you are an average man or woman with some risk factors, probably the net benefit is not there. One or 2 people might benefit from this, but that requires individualized [screening], and that is where we have gone with our study.

Medscape: Some have suggested that bleeding complications are more frequent at doses of aspirin ≥ 100 mg.[20] You did not see any differences with different doses of aspirin or with different formulations (enteric-coated vs regular)?

Prof. Ray: We did not.

Medscape: Was this a surprise?

Prof. Ray: No, that is what you would expect. We know that for secondary prevention, 75, 80, or 81 mg of aspirin is pretty much the same as taking 300 or 500 mg. We did not see any significant differences in nonfatal MI, total cardiovascular disease events, or nontrivial bleeds between ≥ 100 and < 100 mg of aspirin daily. Obviously, the 9 studies used different regimens, but we saw no statistically significant differences between them. The only significant difference in nontrivial bleeds between aspirin regimens was between daily dosing and alternate-day dosing.

Medscape: How would you assess bleeding risk vs benefit?

Prof. Ray: In our analysis, we had only summary data.One thing I would advocate is that where individual data sets are available, we look at the bleeding risk and a complete benefit score as European guidelines do for warfarin, with the HAS-BLED and CHA2DS2-VASc scores.[21] Then we can try and move toward individualizing risk/benefit at the level of the individual. I believe that is important. If you are a patient, you want to know, «Well, doctor, you have advised me to take aspirin long-term, what does it do for me?» You can look at this, hand on heart, and answer, «It is not going to prolong your life by reducing cardiovascular deaths, but it is going to reduce your risk of having a nonfatal MI by 20%.» Remember, [aspirin] did not reduce the risk for fatal or nonfatal strokes either. It is going to provide that distinct benefit, but at a price. At the individual level, physicians can have that discussion, with that information, and if a patient believes that prevention of nonfatal MI is more important, the patient will at least understand what they are getting for taking aspirin including the risk, and they will be able to make that choice with informed consent rather than being told that they should be taking it because it is beneficial overall. By assessing the risk and the benefit per person, physicians will be able to truly inform patients and allow them to make an informed choice.

Medscape: Would it be fair to say that even before your study came out guidelines were moving toward a position of recommending against using aspirin in low-risk patients, and for using it in high-risk patients,[22-25] and recommending shared-decision-making in patients in intermediate risk?[26]

Prof. Ray: We are doing that now, but we might need to rethink how we look at high risk, because again, «at high risk» is not informative if you put together a multitude of cardiovascular end points, ie, if you are a «lumper.» You want to know whether aspirin is going to prolong life, prevent a nonfatal event, and what the types of events are, because they all carry different weights in terms of patients’ perspectives of how they wish to be exposed to that risk and to the treatments.

Medscape: If all the guidelines are headed toward individualized treatment, how will general practitioners, family practitioners, etc, find the time to do this?

Prof. Ray: It is a lot to deal with. My routine practice for about 2 years has been not to offer aspirin to my patients for primary prevention based on the analyses that we already started. It did not look as though it made sense and that has not changed. We have to address the question of individualized risk and identify who is at very high risk. This is not like a statin or an antihypertensive. What you have to do for aspirin is to get some understanding of bleeding risk and work out the risk. We have moved toward that with warfarin and we need to do that with aspirin. Then, if we can provide that information, I think that is the next step toward informing the physician. At this point in time, I do not think our general physicians have the tools.

Medscape: Reports from the United States,[27] Canada,[28] and other countries[29,30] indicate that many doctors are prescribing aspirin inappropriately for CVD prevention, ie, not as needed in secondary prevention and too often in primary prevention. It seems that many physicians already have a problem keeping up with the guidelines on aspirin.

Prof. Ray: That is where education comes in. Our paper generated a lot of interest, and we have tried to bring a different nuance of risk/benefit to something that has a public health message and to rethink «What is aspirin?» Quite frankly, if you are a healthy man or woman, there are seconds between primary and secondary prevention. We know the benefit of aspirin in secondary prevention, so keep 75 or 81 mg in your pocket, and when you get the prolonged chest pain and you are having an ischemic event, that is when you take it. But taking it on a daily basis probably does not make sense for the average individual.

Medscape: Even in the people who have a lot of risk factors such as diabetes?

Prof. Ray: Remember, we have not seen a single trial in diabetics where it has shown benefit.

Medscape: The 2 trials with diabetic subjects[12,13] in the meta-analysis were described as underpowered, with lower event rates than anticipated.[15]

Prof. Ray: Absolutely. We haven’t had many data for primary prevention in patients with diabetes, but we did not see any difference in nonfatal MI or CVD events or differences in nontrivial bleeds when we analyzed the data in patients with diabetes at baseline compared with the overall population.[4] A Study of Cardiovascular Events iN Diabetes (ASCEND) is a large ongoing trial by the University of Oxford that is looking at low-dose, enteric-coated aspirin, with or without omega-3 fatty acids, in about 10,000 patients with diabetes.[31] The Aspirin and Simvastatin Combination for Cardiovascular Events Prevention Trial in Diabetes (ACCEPT-D) is another trial looking at low-dose aspirin in about 5000 subjects with diabetes mellitus who are receiving treatment with statins.[32] We hope these trials will clarify the risk/benefits of aspirin in primary prevention in diabetic individuals. Meanwhile, the ATT meta-analysis showed us that the risk factors for bleeding are the same as the risk factors for cardiovascular disease,[14] so it is very unlikely that aspirin is going to show a reduction in cardiovascular death in diabetic subjects. However, we also found that bleeding risk was higher at higher systolic blood pressure. So, again, this suggests that in a patient population with hypertension, the net benefit of aspirin isn’t actually in their favor either.

Medscape: Are any other trials of aspirin in primary prevention still ongoing?

Prof. Ray: Two trials are looking at low-dose aspirin in older patients: the ASPirin in Reducing Events in the Elderly (ASPREE) trial, in the United States and Australia,[33,34] and the Japanese Primary Prevention Project (JPPP), with aspirin in elderly patients with one or more risk factors for vascular events.[35] The Aspirin to Reduce Risk of Initial Vascular Events (ARRIVE) trial is enrolling 12,000 patients in 6 European countries and the United States to investigate the efficacy and safety of low-dose (100 mg daily) aspirin in preventing first CVD events in individuals at moderate risk for coronary heart disease.[36]

Medscape: After the results of the ATT meta-analysis were published, and now with these new data just published, the prevailing message already seems to be that aspirin should be abandoned as primary prevention altogether. But other investigators have suggested that the benefits of long-term use of daily aspirin for prevention of chronic disease may outweigh the consequences associated with the increased risk for bleeding, particularly gastrointestinal bleeding.[17]

Prof. Ray: They are wrong. If you had a bleed in your eye I would say that is pretty important. If you had a bleed into your brain that didn’t kill you, I would say that is also important, and obviously fatal bleeds are included as well. And if you come into hospital needing a blood transfusion, are you likely to take aspirin again? No. What is your risk? It is preventing a heart attack that wouldn’t have killed me; that is how people need to think about this. People are getting hung up on combining things, ie, being a lumper rather than a splitter. Cardiovascular disease manifests in all sorts of ways, so having data on 102,000 people enabled us to begin teasing out what is driving each of these. If you give someone a statin, you are reducing cardiovascular deaths and you are also reducing nonfatal MIs. There is really no flip side, apart from dysglycemia and nonfatal side effects like myalgia. That is not the same as bleeding. This is the information patients should be given. Hopefully, it is very clear: aspirin is not the same as the antihypertensive, and it is not the same as the statin.

Medscape: Do you think the message of your study will get through to physicians and patients?

Prof. Ray: We have had quite a good discussion here. Most people in the lay press want to use the top line. For Medscape, I have gone into a lot of the nuances in our thinking when we designed the analysis and wrote the paper. We have approached it as, «When I see my patients, what is my dilemma, what is their dilemma?» What information do I want to provide them with? It is about informed consent. If something prolongs life, that is a whole different matter. But if it is preventing morbidity, then it is a choice for patients to give informed consent. You have to discuss that with them, and at the level of the individual, people will have different reactions. Some patients might think, «I’m really scared of an MI, I will take [aspirin] and I will take the bleeding risk,» but at least you will have explained to them what that is.


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