Acute coronary syndromes
BMJ 2015; 351 doi: https://doi.org/10.1136/bmj.h5153 (Published 20 October 2015) Cite this as: BMJ 2015;351:h5153
Acute coronary syndrome infographic
Click here to see an infographic, showing how to distinguish between types of ACS, as well as treatment and management of patients.
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We think that the sources and selection criteria for the literature search supporting the Clinical Review “Acute coronary syndromes” (which comprised PubMed, Google, guidelines, and personal experience) missed critical sources of information.1 We also feel that this Clinical Review may mislead readers into believing that ticagrelor is the “agent of choice.” For the newer antiplatelet agents, as for most drug therapies, a more complete story can be found in the publicly accessible drug approval pages on the FDA website.2
For example:
Regarding: “In separate head to head trials prasugrel and ticagrelor reduced the hazard of death from cardiovascular causes, non-fatal myocardial infarction, or non-fatal stroke by 19% and 16%, compared with clopidogrel”.1 Most readers would object to a reporting of results via relative risk reductions but we should also be cautious in inferring anything this assuredly when the reference list includes documents which provide such a limited version of events. In TRITON-TIMI 38, the 2.2% absolute difference in the primary outcome (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke) was driven by a decrease in non-fatal myocardial infarctions in the prasugrel arm, 60% of these were peri-procedural.3 The FDA reviewer states “much of the treatment effect for prasugrel is driven by a decrease in asymptomatic elevations in cardiac enzymes.” The reported reduction in non-fatal myocardial infarction is fragile. First, it was not replicated in a second acute coronary syndrome trial, TRILOGY ACS, not mentioned in this review article.4 Second, the losses to follow up in TRITON-TIMI 38 are twice that of the reported absolute difference in the primary outcome. Last, while a lack of benefit is specifically noted for participants aged 75 or more, it is unclear who would derive meaningful benefit given that cardiovascular death, non-fatal stroke, total mortality, and total serious adverse events were not significantly reduced with prasugrel compared to clopidogrel.
Regarding: “These unwanted bleeding effects were less evident with ticagrelor”.1 According to the FDA Medical review, major or minor bleeds were increased by 1.5% for ticagrelor compared to clopidogrel in PLATO at 12 months (HR 1.11, 95%CI 1.03 to 1.20).5 This compares to an increase in major or minor bleeds of 1.2% for prasugrel compared to clopidogrel in TRITON-TIMI 38 at 15 months (HR 1.31, 95%CI 1.11 to 1.56).3 Patients might identify both major and minor bleeds as unwanted? This month Health Canada reported that “surveys indicated that some prescribers did not present a full understanding of the appropriate ASA doses for co-administration with ticagrelor, as well as bleeding risks associated with the medication”.6 We wonder if an under-emphasis on bleeding events may be a contributor to this. Further, the FDA medical review noted issues with the quality of the mortality data in the PLATO trial noting that “Three patients allegedly withdrew consent after they died…another 12 patients reported their own deaths by telephone.”
It is not clear from this Clinical Review, but when treated with prasugrel or ticagrelor, patients with a prior history of TIA or stroke were more likely to experience a stroke or intracranial hemorrhage compared to patients on clopidogrel.2 The FDA reviewer, when discussing the ticagrelor data stated that "it is disconcerting that drugs that claim to lower heart attack and death, increase risk for stroke and other thrombotic events." This would likely be important information for patients and caregivers/prescribers to be aware of.
Our assessment7 of ticagrelor and prasugrel (based on an extensive appraisal of regulatory documents provided by the FDA2) came to very different conclusions as those presented in this Clinical Review. We concluded that “it is uncertain whether prasugrel or ticagrelor have any therapeutic advantages or disadvantages, compared with clopidogrel.”7 We urge readers of this Clinical Review to be cautious when considering the statement that “NICE recommends ticagrelor, which should now be regarded as the P2Y12 receptor antagonist of choice in patients with ST elevation myocardial infarction.” Implying that ticagrelor is the agent of choice, in the absence of clinical net benefit and with signals of serious harm compared to clopidogrel, would be ill-advised.
References:
1. Timmis A. Acute coronary syndromes. BMJ 2015;351:h5153
2. Drugs@FDA. FDA Approved Drug Products. http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm
3. Wiviott S, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007;357:2001-15
4. Roe M, et al. Prasugrel versus clopidogrel for acute coronary syndromes without revascularization. N Engl J Med 2012;367:1297-309
5. Wallentin L, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndrome. N Engl J Med 2009;361:1045-57
6. Health Canada Product InfoWatch – October 2015. http://www.hc-sc.gc.ca/dhp-mps/medeff/bulletin/hpiw-ivps_2015-10-eng.php...
7. Therapeutics Letter #94: Dual antiplatelet therapy: net health benefit or harm? (Accessed November 02, 2015 at http://ti.ubc.ca/letter94)
Competing interests: No competing interests
Editor,
Part of the discharge process for patients who have experienced a coronary syndrome is advice on what activities they can do and, where appropriate, things they should not do. This includes advice as to when they can safely and appropriately return to work and driving. Many patients drive a motor vehicle including for getting to their place of work and for some their driving may be a core component of their work.
In the UK holders of group 1 licences are advised (1) that if successfully treated by coronary angioplasty, driving may recommence after 1/52 provided:
• no other URGENT revascularisation is planned (URGENT refers to within 4/52 from acute event)
• LVEF is at least 40% prior to hospital discharge
• there is no other disqualifying condition
If not successfully treated by coronary angioplasty, driving may recommence after 4/52 provided:
• There is no other disqualifying condition.
Group 2 licence holders (LGV and PCV – Lorries and buses) are told
All Acute Coronary Syndromes disqualify the licence holder from driving for at least 6/52.
Re/licensing may be permitted thereafter provided:
• the exercise or other functional test requirements can be met
there is no other disqualifying condition
Many vocational drivers are self-employed and keen to return to work as soon as possible. It is a frequent surprise to many patients that current regulation disbars them from driving after they feel they have recovered from their cardiac event.
Chris Valentine
Occupational Physician
(1) For medical practitioners At a glance guide to the current medical standards of fitness to drive
November 2014 Edition www.gov.uk/government/publications/at-a-glance.
Competing interests: No competing interests
Although this is a well-written, useful article, it does not refer to the management of older patients with multimorbidity, a common scenario in everyday clinical practice. Patients over the age of 75 make up only 14% of participants in clinical trials1 yet MINAP registry data indicates that figure is closer to 40% in real life.2 As well as being under-represented, those older patients that do feature in clinical trials have fewer co-morbidities and may not have much in common with the frail, older patients that we see in real world clinical practice.2 3
Whilst I do not wish to see older people denied high quality treatment on the basis of age alone, it should be recognised that frail, older people with co-morbidities such as anaemia, heart failure and chronic kidney disease are at higher risk of bleeding, and that bleeding is associated with an increased risk of adverse outcomes and death.4 5 The risk of bleeding may be estimated using a scoring tool such as CRUSADE.6 As an example, an 80 year old woman with stage 4 chronic kidney disease, chronic heart failure and peripheral vascular disease is calculated to have a risk of in-hospital major bleeding of around 20%.7
In frail, older patients, due consideration should be made as to the presence of co-morbidities and polypharmacy, the magnitude of benefit from treatment, the likelihood of harm, the patient's preferences, and life expectancy.8 Future guidelines should take into account multimorbidity to provide patient centred care that takes into account the heterogeneity of clinical practice not represented in randomised controlled trials.9
1. Dodd KS, Saczynski JS, Zhao Y, et al. Exclusion of older adults and women from recent trials of acute coronary syndromes. Journal of the American Geriatrics Society. 2011;59(3):506-11.
2. Zaman MJ, Stirling S, Shepstone L, et al. The association between older age and receipt of care and outcomes in patients with acute coronary syndromes: a cohort study of the Myocardial Ischaemia National Audit Project (MINAP). European Heart Journal. 2014.
3. Alexander KP, Newby LK, Cannon CP, et al. Acute Coronary Care in the Elderly, Part I: Non–ST-Segment–Elevation Acute Coronary Syndromes: A Scientific Statement for Healthcare Professionals From the American Heart Association Council on Clinical Cardiology: In Collaboration With the Society of Geriatric Cardiology. Circulation. 2007;115(19):2549-69.
4. Manoukian SV, Feit F, Mehran R, et al. Impact of major bleeding on 30-day mortality and clinical outcomes in patients with acute coronary syndromes: an analysis from the ACUITY Trial. Journal of the American College of Cardiology. 2007;49(12):1362-8.
5. Eikelboom JW, Mehta SR, Anand SS, et al. Adverse Impact of Bleeding on Prognosis in Patients With Acute Coronary Syndromes. Circulation. 2006;114(8):774-82.
6. Subherwal S, Bach RG, Chen AY, et al. Baseline Risk of Major Bleeding in Non–ST-segment Elevation Myocardial Infarction: The CRUSADE Bleeding Score. Circulation. 2009;119(14):1873-82.
7. CRUSADE bleeding score. Secondary CRUSADE bleeding score. http://www.crusadebleedingscore.org/. Accessed 26th October 2015.
8. American Geriatrics Society Expert Panel on the Care of Older Adults with M. Guiding Principles for the Care of Older Adults with Multimorbidity: An Approach for Clinicians. Journal of the American Geriatrics Society. 2012;60(10):E1-E25.
9. Guthrie B, Payne K, Alderson P, et al. Adapting clinical guidelines to take account of multimorbidity. BMJ. 2012;345.
Competing interests: No competing interests
Very good review and a practical Infograph. However, there is no mention about the risk stratification in patients presenting to the ED with chest pain and normal ECG. According to the infograph, patients with atypical chest pain with no heart failure or arrhythmias and negative Troponin can be discharged. Any consideration to the risk factors at this point?
Competing interests: No competing interests
The fourth sentence under the heading "Non-ST elevation myocardial infarction and unstable angina" should read: "Anticoagulation with subcutaneous fondaparinux 2.5 mg daily . . . ." [not, "Anticoagulation with oral fondaparinux 2.5 mg daily . . . ." as published].
Competing interests: No competing interests
Thank you Professor Timmis for an excellent update.
In the paragraph "Non-ST elevation myocardial infarction and unstable angina" you mention the use of oral fondaparinux 2.5mg daily. I believe this is an error and "oral" should be replaced with "subcutaneous".
Competing interests: No competing interests
Timmin’s review on the management of acute coronary syndrome is timely and comprehensive but fails to make any reference to the role of primary care in the aftercare of patients discharged from hospital.[1] The review acknowledges that with recent advances, patients admitted with acute myocardial infarction are discharged home after 48-72 hours and secondary prevention aimed at reducing the risk of recurrent acute coronary syndrome should be initiated early. However, although nearly 90 percent of acute post MI patients are discharged with appropriate cardio protective medications, there is steady decline in medication adherence over a period of five years [2]. To realise the long term benefits of secondary prevention there should be good communication between secondary and primary care.[3] For over a decade, GPs in the UK have been incentivised to provide long term care for people with coronary heart disease through nurse led clinics in their practices.[4]
The review gives a guarded endorsement of cardiac rehabilitation quoting evidence from a Dutch observational study and a controversial negative trial from the UK.[1] We know of two positive RCTs of cardiac rehabilitation in ACS patients.[5,6] Participation in cardiac rehabilitation also confers a significant improvement in adherence to cardio-protective medications over three years.[7]
Furthermore, our clinical review on cardiac rehabilitation, published last month in the BMJ, reported the findings of the recently updated Cochrane systematic review that confirms the benefits of exercise-based rehabilitation in terms of a reduction cardiovascular mortality (relative risk 0.74, 95% CI: 0.64 to 0.85) and hospital readmissions (relative risk 0.86, 95% CI: 0.77 to 0.95) together with an improvement in health-related quality of life in post-MI and revascularised patients.[8] We highlighted the reasons for the less than 50% uptake of cardiac rehabilitation despite the increasing evidence and one of the key factors was lack of endorsement by a clinician.[8,9]
It is not enough to discharge patients with acute coronary syndrome on secondary prevention medication without referral to a comprehensive cardiac rehabilitation programme and emphasising the need for long term follow up in primary care.
References
1. Timmis A. Acute coronary syndromes .BMJ 2015;351:h5153
doi: 10.1136/bmj.h5153 (Published online 20 October 2015)
2.Arnold SV, Spertus JA, Masoudi FA, et al. Beyond medication prescription as performance measures: optimal secondary prevention medication dosing after acute myocardial infarction. J Am Coll Cardiol. 2013;62:1791-801.
3. Dalal HM, Evans PH. Achieving national service framework standards for cardiac rehabilitation and secondary prevention. BMJ 2003; 326: 481-484. PubMed
.
4 Dalal H, Evans PH, Campbell JL. Recent developments in secondary prevention and cardiac rehabilitation after acute myocardial infarction. BMJ 2004;328:693-7
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5 Bettencourt N, Dias C, Mateus P, Sampaio F, Santos L, Adão L, Mateus C, Salomé N, Miranda F, Teixeira M, Simões L, Ribeiro VG. Impact of cardiac rehabilitation on quality of life and depression after acute coronary syndrome. Rev Port Cardiol. 2005;24:687-96.
6 Houle J, Doyon O, Vadeboncoeur N, Turbide G, Diaz A, Poirier P. Effectiveness of a pedometer-based program using a socio-cognitive intervention on physical activity and quality of life in a setting of cardiac rehabilitation. Can J Cardiol. 2012 Jan-Feb;28(1):27-32
7 Shah ND, Dunlay SM, Ting HH, et al. Long-term medication adherence after myocardial infarction: experience of a community. Am J Med. 2009;122:961-13
8.Dalal HM , Doherty P and Taylor RS. Cardiac rehabilitaion. BMJ 2015;351:h5000 doi: 10.1136/bmj.h5000 (Published 29 September 2015.
9.Ghisi GL, Polyzotis P, Oh P, Pakosh M, Grace SL. Physician factors affecting cardiac rehabilitation referral and patient enrollment: a systematic review. Clin Cardiol 2013;36:323-35.5
Competing interests: No competing interests
Thank you, Dr Timmis, for a thorough update on ACS management, and for a useful infographic. However, I think the article would have provided better guidance on evaluation of low-risk patients if both the text and the infographic had included more discussion of validated tools for managing the low-risk patient.
While the article by Weinstock et al (1) is interesting as a retrospective review of data (and it certainly corroborates other literature on determination of who is at low short-term risk of having a major adverse cardiac event [MACE]), it is far less useful than other literature describing validated tools for determining which patients with chest pain are at low-risk of MACE.
Both the ADAPT (2) and Vancouver (3) rules incorporate clinical assessment, electrocardiography, and troponin assays to allow determination as to which patients with chest pain can be discharged after a short period of observation, for further outpatient assessment. These tools provide validated decision rules, and if appropriately summarized and incorporated into the infographic could provide the user with more confidence in an evidence-based determination as to who can be discharged for outpatient evaluation of chest pain.
Appropriate timely evaluation and management of the patient with ACS is important, but it is just as important to take a soundly evidence-based and validated approach to the low-risk patient to avoid unnecessary testing, expense, and anxiety for the patient.
(1) Weinstock MB, Weingart S, Orth F, et al. Risk for clinically relevant adverse cardiac events in patients with chest pain at hospital admission. JAMA Intern Med2015;175:1207-12. (http://archinte.jamanetwork.com/article.aspx?articleid=2294235)
(2) See https://lessismoreebm.wordpress.com/2015/07/15/a-new-improved-accelerate... and https://sites.google.com/site/clinicalcalculators/home/adapt
(3) See https://sites.google.com/site/clinicalcalculators/home/vancouver
Competing interests: No competing interests
Re: Acute coronary syndromes
Aaron M Tejani, believes that ultimate wisdom around choice of P2Y12 receptor antagonists is to be found in the FDA website, apparently ignoring the errors of judgement that have plagued that organisation over recent years - including the approval of drugs such as troglitazone and rofecoxib that were later withdrawn on grounds of safety. I made it clear in my review that there was uncertainty about the relative merits of different P2Y12 receptor antagonists, stating that "Guidelines have been inconsistent about which P2Y12 receptor antagonist to choose". In stating that ticagrelor is now the drug of choice I was merely quoting the view expressed by NICE based on its evaluation of all the evidence cited by Aaron M Tejani. I have no reason to believe that NICE is more or less reliable than the FDA in its pronouncements.
Chris Valentine reminds us that heart disease has implications for activities such as driving. Clearly these will vary from country to country but in the UK the government document he cites lays out the national rules and should be read by all who treat patients with acute coronary syndromes.
Sean G Ninan reminds us that very elderly frail patients with acute coronary syndromes may have different preferences compared with more robust patients about the treatment they are offered. He is careful to rule against denying such patients high quality treatment but is, I am sure, correct when he recommends that care should be patient-centred. Certainly, in treating acute coronary syndromes, prolonging the process of dying should play no part in our approach to patient care.
Medhat Michail believes that it is not good enough to send home the patient with atypical chest pain, negative troponin and a normal ECG without further risk stratification to determine (presumably) the need for primary prevention of cardiovascular disease. Hard to disagree, although this would add considerably to the workload of emergency departments and might not always be seen as legitimate emergency business.
Hasnain M Dalal emphasises the importance of the aftercare of patients following acute coronary syndromes. If my review gave the impression of "guarded endorsement" of rehabilitation courses it is only because their evaluation has always been difficult and while it seems clear they have a positive effect on quality of life, convincing evidence of direct survival benefit is unavailable. Nevertheless, I agree with the main thrust of Hasnain M Dalal's response that rehabilitation courses and primary care physicians play a vital role in secondary prevention through life-style education and prescription of evidence-based treatments.
Finally, William Cayley wants a means of identifying the low-risk patient with chest pain who can safely be discharged from the emergency room. The algorithm summarised in my review is somewhat more laborious compared with the tools referenced in William Cayley's response but they all share similar criteria. Nevertheless there is now a real expectation, as mentioned in my review, that high sensitivity troponin assays will allow rapid rule-out of acute coronary syndromes, identifying patients who can safely be sent home within an hour or two of presenting to the emergency department.
Competing interests: No competing interests