EXPERT MONOGRAPH ISSUE 44 Title A Real Advantage Or A
EXPERT MONOGRAPHISSUE 44title sub titleOCTOBER 11, 2019A Real Advantage or a Real Problem?The Updated Story of Low-dose AspirinDR STEPHEN GORDON MBBS FRACPDr Stephen Gordon is a graduate in medicine from the University of Western Australia and trained in Cardiologyat Sir Charles Gairdner Hospital and subsequently at the Beth Israel Hospital, Harvard Medical School,Boston, USA. Dr Gordon practises in all areas of adult cardiology, and performs cardiac catheterisation, transoesophageal echo, and has a special interest in echocardiography. Dr Gordon has private practice locationswith Western Cardiology at St John of God Health Care Subiaco, Sanori House, Joondalup and Balcatta.This article summarises, in the light of recent research, the currentbenefits and disadvantages of prescribing low-dose aspirin.IntroductionAspirin (Acetylsalicylic acid or Acetoxybenzoic acid) isa widely lauded derivative of certain types of Willowtree (Salix spp). It has a history of medicinal use datingback thousands of years. As a pharmaceutical, theubiquity, cheapness and multiplicity of benefits of aspirin havein the past earned it the title of ‘The Wonder Drug’. Apart fromits anti-inflammatory, anti-pyretic and analgesic properties, it hasbeen recommended for both primary and secondary preventionof cardiovascular disease, in addition to stroke prevention in atrialfibrillation (historically only) and even for primary prevention ofcolorectal cancers.1 Many healthy Australians are probably takingaspirin daily, likely for its assumed benefits in the prevention ofmyocardial infarction and stroke. However, recent studies andreviews have raised questions about the benefits of, and indicationsfor, aspirin in a healthy population. This article summarises thecurrent advantages and disadvantages of prescribing aspirin forTake Home Messages Low-dose aspirin should no longer be suggestedroutinely in the majority of patients for primarycardiovascular and cerebrovascular prevention. Low-dose aspirin as a primary prevention strategyin older adults resulted in a significantly higherrisk of major haemorrhage and no lower risk ofcardiovascular disease than placebo. Many recent guidelines have removed anyrecommendation for the use of aspirin in patientswith atrial fibrillation. Low-dose aspirin may yet be indicated for high-riskprimary prevention patients and those with highercalcium scores who are at low bleeding risk. Low-dose aspirin remains strongly indicated for thesecondary prevention of cardiovascular events.a number of clinical scenarios, in the light of this recent research.www.healthed.com.au Page 1
HormonalContraceptionTrouble-shootingPart One:StoryThe ofOverweighttitle subA Real Advantageor a RealProblem?ThetitleUpdatedLow-dose WomanAspirinSecondary Prevention of Cardiovascular DiseaseThe place of aspirin is firmly entrenched in the secondary preventionof cardiovascular disease. Patients with clinical cardiovascular,cerebrovascular and peripheral vascular disease continue to havea strong indication for aspirin (and/or other proven antiplateletagents). These indications have been questioned in the modernera, largely because of improved lifestyles and better treatment ofrisk factors such as hypertension, hyperglycaemia and dyslipidemia.Even so, there are unlikely to be any new studies of aspirin forsecondary disease prevention. This is particularly the case as theolder studies2,3 showed marked preventive benefits that significantlyoutweighed the risks.Aspirin, in combination with a second antiplatelet agent, is alsostrongly medically indicated following coronary artery stentplacement. Whilst guidelines have suggested a minimum durationfor dual antiplatelet therapy of twelve months,4 the results of recentstudies5 have suggested that shorter periods of dual antiplatelettherapy may be sufficient. This may also be desirable for patients withhigher risks of bleeding, or when there is a co-existing indication forother types of anticoagulation (such as atrial fibrillation).Low-dose aspirin remainsstrongly indicated for thesecondary prevention ofcardiovascular events.Primary Prevention of Cardiovascular DiseaseThe place of aspirin in primary prevention has recently beensubjected to intensive research. A recent U.S. study6 (2019)suggests that aspirin is being taken by almost 25% of Americansforty years of age and older, and almost 50% of Americansseventy years of age and older, none of whom have a history ofcardiovascular disease or events. Thus millions of Americans (andquite likely a similar percentage of Australians) are taking aspirinfor presumed cardiovascular prevention. It is therefore crucial tohave proof of any benefits and knowledge of the risks relatingto aspirin.Older trials3 of daily aspirin use for primary cardiovascular preventionhave been criticised because of the inclusion of large numbers ofrelatively low-risk patients. This may have diluted the benefitsof aspirin used in patients at higher cardiovascular risk in thosetrials. Hence, new studies have been needed to focus on higher-riskpatients in order to determine the magnitude of benefit of dailyaspirin use. These studies should also better assess the risks oftaking aspirin, particularly in relation to the risk of major bleeding.www.healthed.com.au Since late 2018, three large, high-quality randomised primaryprevention trials comparing daily low-dose aspirin with placebohave been reported. All focused on patients who are expected to beat moderate or high cardiovascular risk.The ARRIVE Trial7 included 12,546 patients, approximately half ofwhom were randomised to take 100mg of enteric-coated aspirindaily. They were all considered to be of moderate cardiovascular riskand were followed for five years. On the ‘intention to treat’ analysisof the ARRIVE Trial there was no benefit in taking aspirin for theprimary endpoint (essentially cardiac events: 4.3% versus 4.5%P 0.6). There was a significant increase in bleeds (1.0% versus0.5%, P 0.0007), but only a few were judged ‘severe’.The ASCEND Trial8 included 15,480 patients over forty years ofage who had diabetes. Approximately half were given 100mgof aspirin daily and all subjects were followed for a mean of 7.4years. Significant vascular events occurred in 8.5% of the aspiringroup, compared with 9.6% of the placebo group (12% relative riskreduction). However, that benefit was balanced by an increase inmajor bleeding events (mostly gastrointestinal) occurring in 4.1%of the aspirin group, compared with 3.2% of the placebo group(29% relative risk increase). Despite some data that suggests abenefit in reducing colorectal cancer risk, there was interestinglyno difference between the two groups regarding gastrointestinalor other malignancies, although the patients will be followed uplonger term to detect any possible late benefit.The ASPREE Trial9 included 19,114 Australian and American patientsover seventy years of age (or over 65 years of age if African Americanor Hispanic). These subjects did not have any overt cardiovasculardisease, cerebrovascular disease or atrial fibrillation. Approximatelyhalf were given 100mg of enteric-coated aspirin daily and the trialcontinued for 4.7 years. The primary endpoint was actually death,dementia or persistent physical disability. Secondary endpoints weremajor haemorrhage, cardiovascular and cerebrovascular events orhospitalisation for heart failure.By the end of the study, the rate of cardiovascular events was10.7 events per 1000 person-years in the aspirin group and 11.3events per 1000 person-years in the placebo group (no significantreduction). The rate of major haemorrhage was 8.6 events per1000 person-years in the aspirin group and 6.2 events per 1000person-years in the placebo group (a significant increase in majorbleeding, P 0.001). Just under half of these haemorrhages weregastrointestinal, but there was also a significant increase in all typesof intracranial bleeds. The conclusion of the authors was that ‘Theuse of low-dose aspirin as a primary prevention strategy in olderadults resulted in a significantly higher risk of major haemorrhageand did not result in a significantly lower risk of cardiovasculardisease than placebo.’A subsequent meta-analysis10 of all the major high-quality aspirintrials in primary cardiovascular prevention was recently published.Page 2
A Real Advantage or a Real Problem? The Updated Story of Low-dose AspirinThis incorporated the three recent large studies above and includedover 184,000 patients. The review showed a modest (11%)reduction in cardiovascular events for subjects taking low-doseaspirin. This was balanced by a 43% increase in serious bleeding,including a 33% increase in intracerebral haemorrhage. Once again,there was no net benefit for the patients assigned to aspirin.and dyslipidaemia), and reduced rates of smoking, particularly indeveloped countries. It has further raised the possibility that thewidely used cardiovascular risk calculators utilising conventionalrisk factors may actually be overestimating cardiovascular risk inthis modern era.11,12These large clinical trials have turned around our thinking aboutaspirin for primary prevention. Not all the trials showed a reductionin cardiovascular events. In the one that did, the reduction incardiovascular events was balanced by a significant increase inbleeding. Most of these were gastrointestinal, however, a smallnumber were intracerebral bleeds. Any reduction in cardiovascularevents noted did not produce a lower mortality in the patientstreated with aspirin (and in fact, patients in the ASPREE trialactually had an increased all-cause mortality).Low-dose aspirin should nolonger be suggested routinely foruse in the majority of patientsfor primary cardiovascularand/or cerebrovasculardisease prevention.The use of low-dose aspirin asa primary prevention strategyin older adults resulted in asignificantly higher risk ofmajor haemorrhage and did notresult in a significantly lowerrisk of cardiovascular diseasethan placebo.The majority of low-risk to moderate-risk healthy patients takinglow-dose aspirin for primary prevention will likely not see anyoverall benefit and will have little or no reduction in futurecardiovascular events. For some, there will be an increased risk ofmajor bleeding, especially for those over seventy years of age, orthose who have diabetes.Based on these results, low-dose aspirin should no longer besuggested routinely for use in the majority of patients for primarycardiovascular and/or cerebrovascular disease prevention. Patientswith no definite medical reason for taking low-dose aspirin, and aredoing so anyway, should be counselled accordingly.However, it is important to note that the number of cardiovascularevents that occurred in patients taking part in the three largerecent low-dose aspirin studies (ARRIVE, ASCEND and ASPREE) wassignificantly lower than expected.11 In other words, the patientsin all three trials did not appear to be at as high a risk as theinvestigators had expected or planned. It has been hypothesised11,12that this may reflect a general improvement in lifestyle and bettermanagement of risk factors (such as hypertension, hyperglycaemiawww.healthed.com.au It is therefore still possible that there may still be a place forlow-dose aspirin in patients at very high risk of cardiovascularand cerebrovascular disease in primary prevention, particularly ifthey are considered to be at an acceptably low risk of bleedingcomplications. That level of risk at which treatment benefitoutweighs treatment risk, however, has not been defined by thesestudies. Whether another trial of very high risk patients will bedone is uncertain. In the absence of any evidence for these highrisk patients, a decision based on careful clinical judgement, on acase by case basis, will be required. This should take into accountthe patient’s individual cardiovascular risk and also, of course, anassessment of bleeding risk.Computerised Tomography Coronary ArteryCalcium ScoringRecently, the increasing utilisation of coronary artery calciumscoring, derived by computerised tomography to better predictcardiovascular disease risk, has raised the question of whetherlow-dose aspirin should be routinely used for patients with highercoronary artery calcium scores. There are no published randomisedtrials about the use of low-dose aspirin based on coronary arterycalcium scoring. Recent Australian National Heart Foundation/Cardiac Society of Australia and New Zealand Guidelines13 havesuggested the consideration of low-dose aspirin for patients whohave calcium scores over 400, or scores of 100 to 400 that fallabove the 75th percentile for age and sex. Those recommendationswere based on extrapolation of risk from older studies14 publishedbefore the recent negative low-dose aspirin trials. There may nowbe some uncertainty regarding these recommendations, given thenew data. Once again, without hard evidence, a decision to uselow-dose aspirin based on a coronary artery calcium score mustbe made case by case and through clinical judgement, takinginto account both potential benefits and again, an assessment ofindividual bleeding risk.Page 3
A Real Advantage or a Real Problem? The Updated Story of Low-dose AspirinAtrial FibrillationRecently published guidelines15 have reconsidered the place ofaspirin for patients who have atrial fibrillation. Guidelines in thepast have suggested the use of aspirin, particularly for patientswho have a lower thromboembolic stroke risk, or for higher-riskpatients in whom full anticoagulation has been refused or hasbeen felt to be contraindicated. More recent randomised trialsand reanalysis of older studies,16, 17 however, have indicated thataspirin has probably little or no benefit in the prevention of strokedue to atrial fibrillation. It does, however, carry a bleeding riskalmost as high as the novel oral anticoagulants (NOACs).18 Manyrecent guidelines (including the 2018 National Heart FoundationAustralian Atrial Fibrillation Guidelines15) have therefore removedany recommendation for the use of aspirin in patients with atrialfibrillation. Patients at low thromboembolic risk (i.e. a CHA2DS2VA score of zero) should not be treated with antiplatelet drugs oranticoagulation (see Table 1).Patients at higher thromboembolic risk (CHA2DS2-VA scores oftwo or more, and possibly scores of one) ought to be treated withfull anticoagulation (if this is not contraindicated). This shouldpreferably be achieved with a NOAC, or alternatively, with warfarin(see Table 2).This really leaves no place for aspirin in the modern managementof atrial fibrillation.Prevention of Colorectal CancerAnalyses of older studies21 of aspirin used for primary andsecondary prevention have suggested a possible benefit in thereduction of colorectal cancer. Even so, those studies do not proveany advantage due to aspirin because of the confounding issue ofthem being secondary analyses of previously published trials.Table 2: Annual Stroke Risk by the older CHA2DS2VASC Score (prior to 2018)*CHA2DS2-VASC2ScoreStroke Risk %(95% Confidence e CHA2DS2-VASc Score and approximate risk shown in this tableincorporates the risk of female sex. Similar risk analysis for the CHA2DS2VA score is not yet available. Removal of female sex from the risk estimates,however, would likely have only a slight effect on the quoted risk and littleif any effect at the lower risk levels.20‘Lynch syndrome’ is a strongly hereditary condition in whichpatients are genetically predisposed to very high cancer risk at ayoung age to early middle age. One randomised trial22 of patientswith this syndrome did show a reduction in colorectal cancer riskwith the use of 600mg of aspirin daily. There are, however, norandomised trials in lower risk patients or at lower aspirin doses.The three large recent trials of low-dose aspirin used in primaryprevention discussed above did not show a benefit in colorectalcancer reduction. It has been hypothesised though that at leastten years’ exposure to daily aspirin may be required to see anyreduction in cancer risk. ASCEND Trial is ongoing in this regard, butTable 1: The CHA2DS2-VA Score (updated from the CHA2DS2-VASC Score in 2018)19ConditionPointsCongestive heart failure: recent signs, symptoms or admission for decompensated heart failure; thisincludes both HFREF* and HFPEF**, or moderately to severely reduced systolic left ventricular function,whether or not there is a history of heart failure.1HA2History of hypertension, whether or not blood pressure is currently elevated.1Age 75 years or older2DS2Diabetes Mellitus1Stroke in the past, or a history of transient ischaemic attack or thromboembolism.2VVascular disease, defined as prior myocardial infarction or peripheral arterial disease or complex aorticatheroma or plaque on imaging (if performed).1AAge 65 to 74 years1C*Heart failure with reduced ejection fraction **Heart failure with preserved ejection fractionwww.healthed.com.au Page 4
A Real Advantage or a Real Problem? The Updated Story of Low-dose Aspirinthe other trials may not have been long enough to see a benefit.More studies are required for definitive guidelines in this area, butnone appear to be forthcoming in the near future.SummaryLow-dose aspirin remains strongly indicated for the secondaryprevention of cardiovascular events. There is now little or noevidence for the use of aspirin in patients with atrial fibrillation.The place of aspirin for colorectal cancer prevention remainslargely unproven. Patients felt to be at high risk of colorectal cancer(especially those who have Lynch Syndrome) might benefit, if theirbleeding risk is low and the patients are prepared to take aspirinfor at least ten years. There appears to be no net benefit for themajority of patients in the primary prevention setting. There mayyet be a place for high-risk primary prevention patients and patientswith higher calcium scores who are at low bleeding risk. However,in the absence of trial evidence, a decision to use low-dose aspirinin such patients should be carefully considered on an individualbasis. The level of risk should be taken into account, and of course,the potential for harm, especially that of serious bleeding.Given the rather negative results for aspirin in the recent primaryprevention studies, it would appear that if one wishes to reducevascular risk in this group, it would be more rewarding to focuson improvements in lifestyle factors (e.g. improved diet, activityand exercise, weight control, smoking cessation). There shouldbe medical surveillance and treatment of risk factors (such ashypertension, hyperglycaemia, dyslipidemia). Such interventionswould appear now to have greater benefit and substantially lesspotential risk than the use of low-dose aspirin, at least for themajority of patients in the primary prevention setting.Aspirin the ‘Wonder Drug’ then has lost some its allure. There areimportant lessons here, particularly from the recent large primaryprevention studies researching low-dose aspirin. Large numbers ofthe healthy population may have been putting themselves at risk formany years for little or no gain. Large, high quality, well-designedand executed clinical trials are essential before we recommendany pharmaceutical therapy for significant numbers of people. Thisapplies not just to the cardiovascular field, but to the whole gamutof preventive medicine.DeclarationDr Stephen Gordon was commissioned by Healthed for this article.The ideas, opinions and information presented are solely those ofthe author. The advertiser does not necessarily endorse or supportthe views expressed in this article. Dr Gordon declares no significantcompeting financial, professional or personal interests that mightinfluence this article.References1.Cancer Council Australia Colorectal Cancer Guidelines WorkingParty. Clinical practice guidelines for the prevention, earlydetection and managemen
The Updated Story of Low-dose Aspirin EXPERT MONOGRAPH ISSUE 44 Introduction A spirin (Acetylsalicylic acid or Acetoxybenzoic acid) is a widely lauded derivative of certain types of Willow tree (Salix spp). It has a history of medicinal use
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