Preventing recurrent events in survivors of acute coronary syndromes in Australia: consensus recommendations using the Delphi process

Abstract

Objective: There remain substantial gaps in implementation of evidence-based care in patients with acute coronary syndromes (ACS) in Australia, which contribute to high recurrent event rates. Improved translation of evidence into effective action is a key health-care priority. We engaged cardiovascular experts from across Australia to develop straightforward, easily actionable recommendations on key medications to use following ACS.

Methods: An eight-person steering committee (SC) reviewed the published evidence and developed an initial set of statements to be developed into consensus recommendations using a modified Delphi technique. A panel of 21 expert cardiologists in the ACS field (including the SC) voted on their level of agreement with the statements using a 6 point Likert scale. Statements that did not reach consensus (≥80% agreement) were reviewed by the SC, modified as appropriate based on input from the panel and circulated for re-voting.

Results: Twenty-eight statements were developed by the SC across six classes of medication: low-density lipoprotein (LDL) cholesterol lowering agents, aspirin, dual antiplatelet therapy, renin–angiotensin–aldosterone system inhibitors, beta blockers and “other”. Twenty-six recommendations were endorsed by the voting panel; two statements did not reach consensus.

Conclusions: Despite the extensive evidence base and detailed guidelines outlining best practice post ACS, there remain considerable gaps in translating these into everyday care. We used an internationally recognized technique to develop practical consensus recommendations on medical treatment following ACS. These simple, up-to-date recommendations aim to improve evidence-based medication use and thereby reduce the risk of future cardiovascular events for Australian patients with ACS.

Keywords:

• Acute coronary syndrome
• aspirin
• angiotensin converting enzyme inhibitors
• angiotensin receptor antagonists
• beta adrenergic blockers
• antiplatelet agents
• LDL cholesterol

Introduction

Most patients with acute coronary syndromes (ACS) have chronic underlying atherosclerotic disease that leaves them at high risk of recurrent events¹. In clinical registries, the risk for further cardiovascular events is approximately 20% in the first year after a myocardial infarction (MI), with ongoing risk in the “chronic” phase (a further 20% cardiovascular event rate over the next 3 years)¹. Although some of these events are likely to be non-modifiable (e.g. extreme age, significant comorbidities), or would have occurred despite optimal medical therapy², a significant proportion of these events can be attributed to non-adherence with evidence-based care^3–5.

Despite a considerable evidence base, there are marked gaps in the implementation of secondary prevention strategies in cardiovascular disease⁶. Patients may misunderstand the chronicity of their disease⁶, and both patients and their physicians tend to underestimate the risk of recurrent events⁷. The recently updated Australian ACS guidelines outline the optimal management of patients both during and after their ACS event, and the underlying evidence⁸. However, it has been repeatedly demonstrated in Australia and overseas that adherence with practice guidelines is incomplete and inconsistent^5,9. The challenge remains translating the evidence and guidelines into effective action⁶, which the Australian Commission on Safety and Quality in Health Care recognizes as a key health-care priority¹⁰.

The aim of this consensus document is to bridge the gap between the evidence base from clinical trials and registries, as summarized in published guidelines^8,11–15, and daily clinical practice, based on recommendations that reflect the current state of agreement in Australia. This recognizes that the “art of medicine” acknowledges that trial evidence and practice guidelines cannot address all the complexities, including multiple drug combinations and comorbidities, present in clinical practice. The program brought together cardiovascular experts from across Australia to develop recommendations on the key medications to use following an ACS event. We acknowledge the importance of other aspects of secondary prevention (e.g. systems of care, smoking cessation, cardiac rehabilitation) to patient care; however, guidance on these is outside the scope of this project. The consensus recommendations complement the Australian ACS guidelines by providing practical advice on medication use in contemporary practice, including choice of agents, treatment duration and situations of greatest benefit. They also address situations where medications can be reduced, such as where the incremental benefit of therapy is low, or where patients are reluctant to continue taking multiple medications long term (with a recommendation on what core therapy is considered to be). This article also highlights areas of ongoing uncertainty, where consensus was not reached.

Methods

Consensus recommendations were developed using a modified Delphi technique¹⁶. The Delphi process is a widely accepted method that enables a group of experts to reach meaningful consensus about a particular topic area. It starts with an open-ended question to solicit themes which are subsequently developed into statements. The statements are voted on and modified during subsequent rounds with the aim of converging towards group consensus. The modified technique included a review of the literature to collate evidence around identified themes.

For the current program, the full Consensus Group voting panel consisted of 21 cardiologists nationally recognized in the field of ACS: a Steering Committee of eight cardiologists, selected on the basis of their expertise in primary and secondary prevention of cardiovascular disease and their involvement in the development of clinical practice guidelines; and an additional group of 13 cardiologists nominated by the Steering Committee. The main steps were: (1) convening of Steering Committee and selection of the Consensus Group; (2) development of open-ended questions and identification of related themes by the Steering Committee (Delphi Round 1); (3) development of each theme identified during Round 1 into structured statements; (4) collation of the evidence to support each statement and presentation to the full Consensus Group at a face-to-face meeting; (5) anonymous voting on statements and discussion by the full Consensus Group (Delphi Round 2); (6) revision by the Steering Committee of statements that did not achieve consensus during Round 2 and repeat voting by the full Consensus Group (Delphi Round 3).

The key question that was posed at the start of the Delphi process was: “Based on current evidence, what are the key medications and how long should they be taken, to reduce the risk of future cardiovascular events in ACS patients?” Statements were developed across six classes of medication: low-density lipoprotein cholesterol (LDL-C) lowering agents, aspirin, dual antiplatelet therapy (DAPT), renin–angiotensin–aldosterone system inhibitors, beta blockers and “other”. A 6 point Likert scale was used for voting on level of agreement or disagreement with each statement (strongly agree; agree; partially agree; partially disagree; disagree; strongly disagree). Consensus was defined a priori as at least 80% of the group voting either “strongly agree” or “agree”.

Results

Twenty-eight statements were developed and twenty-six achieved consensus following voting by the full Consensus Group (Table 1). Voting result details and evolution of statements are shown in the Supplementary material, Table S1, for the 26 consensus recommendations and in Supplementary material, Table S2, for the remaining two voting statements for which consensus was not reached.

Table 1. Consensus recommendations.

1	Lipid lowering therapy
1.1	In addition to receiving dietary and lifestyle advice, all patients should be commenced on high dose statins as soon as practicable after presenting with ACS.
1.2	Treatment should aim to achieve the lowest possible LDL-C level; current recommended National Heart Foundation targets of less than 1.8 mmol/L appear reasonable.
1.3	Patients should be continued on treatment with the highest tolerated dose of a potent statin indefinitely to try to maintain their LDL-C level below 1.8 mmol/L.
1.4	If the patient does not attain an LDL-C level less than 1.8 mmol/L on high dose potent statin alone, consider the addition of ezetimibe.
1.5	If the patient cannot tolerate statins due to adverse effects then consider temporary discontinuation of statin and re-challenge, or statin sparing approaches such as a lower dose of statin or less frequent dosing. Consider the addition of ezetimibe if LDL-C is not adequately controlled with these measures.
2	Aspirin
2.1	Aspirin should be given acutely to all patients with ACS, and should be continued at a dose of 100–150 mg a day indefinitely unless contraindicated.
2.2	ACS patients who are intolerant of aspirin should be treated acutely with an alternative anti-platelet agent and treatment should be continued indefinitely.
3	Dual antiplatelet therapy
3.1	DAPT should be commenced in all patients with ACS whether they are managed medically or with PCI.
3.2	ACS patients treated with CABG are likely to benefit from starting DAPT following CABG surgery, especially if the patient is considered to be at high risk of further events.
3.3	STEMI patients to be treated with primary PCI should be given DAPT as soon as possible. Aspirin together with either ticagrelor or prasugrel is the preferred option.
3.4	While being treated with thrombolysis, patients with STEMI should be given clopidogrel as the second antiplatelet agent in combination with aspirin.
3.6	Given the high risk of recurrent events, every effort should be made to maintain DAPT for at least 12 months post ACS unless contraindicated.
3.7	In patients with a high ischemic risk and low bleeding risk, DAPT should be considered beyond 12 months post ACS.
4	Angiotensin converting enzyme inhibitors and angiotensin receptor blockers
4.1	ACE inhibitors should be commenced early in hemodynamically stable patients with ACS, unless contraindicated.
4.2	ACS patients with impaired LV function (ejection fraction <40%) should be continued on ACE inhibitors indefinitely.
4.3	In ACS patients with normal LV function, ACE inhibitors should be continued indefinitely in the presence of hypertension, diabetes or chronic kidney disease.
4.4	In low-risk patients with normal LV function, it is reasonable to consider stopping ACE inhibitors 12 months after presentation of ACS unless there is diabetes, chronic kidney disease or blood pressure is not optimal.
4.5	Angiotensin receptor blockers should only be used as an alternative treatment for patients who cannot tolerate ACE inhibitors.
4.6	There is no benefit in combining an ACE inhibitor and an angiotensin receptor blocker for the reduction of cardiovascular events or the treatment of hypertension.
5	Beta blockers
5.1	Beta blockers should be commenced early in hemodynamically stable patients with ACS, unless contraindicated.
5.2	ACS patients with impaired LV function (ejection fraction <40%) should be continued on heart failure specific beta blockers indefinitely.
5.3	In ACS patients with normal LV function who have had complete revascularization beta blockers can be ceased after 6–12 months unless the patient has angina or hypertension.
6	Other
6.1	Nitrates should only be used for symptom relief as they have not been shown to improve survival.
6.2	Calcium channel blockers should not be initiated in the hospital phase of ACS unless specifically indicated for uncontrolled hypertension or coronary spasm.
6.3	Dihydropyridine calcium channel blockers may be considered in later, post-hospital stages of ACS in patients with normal LV function and hypertension or angina not controlled by ACE inhibitors and/or beta blockers.
6.4	At 12 months post MI in a stable, low risk, normotensive, non-diabetic patient with normal LV function, who wishes to reduce their pill burden, it is reasonable to continue therapy with aspirin and LDL-C lowering therapy alone.

Abbreviations. ACE, angiotensin converting enzyme; ACS, acute coronary syndromes; CABG, coronary artery bypass grafting; DAPT, dual antiplatelet therapy; LDL-C, low-density lipoprotein cholesterol; LV, left ventricular; MI, myocardial infarction; NSTEMI, non-ST segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST segment elevation myocardial infarction.

Section 1: lipid lowering therapy

Consensus was achieved on all five voting statements about lipid lowering therapy (Table 1). While guideline recommendations for statin therapy after an episode of ACS are very clear and evidence-based (i.e. all patients after ACS should be commenced on a moderate or high potency statin), the guidelines for monitoring of statin therapy are contradictory, recommending either that the prescribing of a moderate to high potency statin is sufficient¹⁵, or to aim for a target level of LDL-C (e.g. <1.8 mmol/L)¹². Many patients and, indeed, some medical practitioners may be swayed by current media publicity about the side effects of statins¹⁷, resulting in inappropriate cessation of statin therapy¹⁸. There is also some uncertainty about the role of non-statin therapy if a patient is unable to take a statin or if their lipid profile is not well controlled on a moderate to high potency statin.

There were three main areas of contention regarding lipid lowering. First, whether target levels for LDL-C are sensible. The consensus decision was that target levels for LDL-C lowering, while lacking a robust evidence base, were reasonable and a helpful aide-mémoire for post-ACS management. Second, how to balance real and imagined statin side effects. While some patients cannot take statins due to genuine side effects, most patients stop statins for non-specific, non-statin-related reasons¹⁹. The wording of this consensus statement (Statement 1.5, Table 1) was the most challenging. Third, the incomplete evidence for non-statin therapy, with mainly negative results for most agents and a marginal result with only one agent²⁰, required careful wording to reach consensus.

Section 2: aspirin

Consensus was achieved on both statements about aspirin therapy (Table 1). The recommendations are based on a well accepted – if somewhat aging – evidence base supporting the importance of long-term antiplatelet therapy in the prevention of recurrent cardiovascular events²¹. They are consistent with the Australian ACS guidelines⁸. Points of discussion included: the fact that, more than 1 year following a MI, patients with an indication for anticoagulation may not require continued antiplatelet therapy – this is acknowledged in the Australian ACS guidelines, as well as the AHA/ACC and ESC guidelines; “aspirin intolerance” is not well defined and ranges from true aspirin allergy (for which desensitization can be considered under specific circumstances) to gastrointestinal intolerance (which may be managed through additional therapy with a proton pump inhibitor); more potent antiplatelet agents, such as ticagrelor or prasugrel, may confer additional benefit when administered as a single agent in place of aspirin, however this strategy cannot be recommended in the absence of prospective, randomized trials evaluating its benefits versus harms.

Section 3: dual antiplatelet therapy

Consensus was achieved on six of the seven voting statements regarding DAPT (Table 1). The benefit of DAPT for acute treatment of ACS and subsequent secondary prevention has been established in several trials^2,22–24, and spelled out in national and international practice guidelines for over a decade^11,13,25. Despite this, DAPT is underutilized in Australian patients with ACS, especially in those patients not treated with percutaneous coronary intervention (PCI) (i.e. those receiving either medical treatment or revascularization with coronary artery bypass grafting [CABG])⁵. Our consensus statements expand upon the Australian ACS guidelines, with specific statements concerning DAPT in these groups. Medically treated ACS patients are a high-risk group, for whom both clopidogrel and ticagrelor significantly reduce the risk of recurrent events (with ticagrelor offering superior protection over clopidogrel)^24,26. CABG patients, who are typically treated with aspirin as the sole antiplatelet, also benefit from DAPT, with improved graft patency and a possible mortality benefit^27–29.

The current Australian ACS guidelines do not separately address antiplatelet therapy in ST segment elevation MI (STEMI), and the recommendations and cautions are aimed more towards treatment of non-STEMI (NSTEMI) patients. Our consensus statements recognize the importance of early and optimal antiplatelet therapy in STEMI; for patients undergoing primary PCI we emphasize the use of ticagrelor or prasugrel (both of which have shown a reduction in stent thrombosis and subsequent events when compared with clopidogrel in this setting)^30,31, and the importance of giving these agents as soon as possible³². Conversely, for patients undergoing fibrinolysis, the group agreed a separate statement that clopidogrel is the only P2Y₁₂ inhibitor that we know is safe to use²². It was thought important to highlight the potential risks with prasugrel and ticagrelor in this setting (including a possible increased risk of intracranial hemorrhage), since this is not addressed in the Australian ACS guidelines.

In the current Australian guidelines, DAPT therapy for up to 1 year is recommended for patients at “intermediate to very high risk of a recurrent event”⁸. We felt a more definitive statement was important. There was strong consensus behind making every effort to maintain DAPT for at least 12 months post ACS unless contraindicated. Although a subset of patients need earlier discontinuation of DAPT (e.g. patients requiring long-term anticoagulation therapy for conditions such as atrial fibrillation or mechanical heart valves), early discontinuation is a recognized risk for recurrent events³³, and efforts should be directed to ensure that all other patients understand the benefits of therapy and complete a minimum of 12 months of DAPT.

Recently, two large trials have shown that continuation of DAPT beyond 12 months with either clopidogrel or prasugrel³⁴, or ticagrelor³⁵ reduces cardiovascular events, but increases bleeding. Unsurprisingly, the benefit of continued therapy was highest in those at greatest ischemic risk³⁶. The statement “in patients with a high ischemic risk and low bleeding risk, DAPT should be considered beyond 12 months post ACS” recognizes that there is benefit from ongoing therapy in high-risk patients, but also reflects the fact that prolonged therapy needs to be an informed decision made by the patient and their treating physician, taking into account both the patient’s risk profile and the patient and physician’s opinions on the risks versus benefits of therapy.

One statement, regarding optimal timing of DAPT initiation in NSTEMI, did not reach consensus. This reflects the lack of clear-cut evidence to support either early (i.e. at initial diagnosis) or delayed (i.e. in catheter laboratory) administration of DAPT in NSTEMI¹³, and the consequent variation in clinical practice among the consensus group.

Section 4: angiotensin converting enzyme inhibitors and angiotensin receptor blockers

Consensus was achieved on six of seven voting statements regarding angiotensin converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs) and aldosterone antagonists (Table 1). The intent of the recommendations was to discuss and evaluate the evidence for indefinite use of inhibitors of the renin–angiotensin–aldosterone system inhibitors (i.e. ACE inhibitors and ARBs) after ACS. Guideline recommendations are often not followed in clinical practice, and it is important to be aware of their evidence base and of new data that can influence clinical practice. In the present program on clinically relevant decisions post ACS, Statements 4.1, 4.2, 4.3, 4.5 and 4.6 generally reflect current guidelines. Regarding Statement 4.5, most participants felt that there is more evidence to support the use of ACE inhibitors than ARBs.

The less than total consensus for Statement 4.6 was surprising considering that there is clear evidence that the combination of an ACE inhibitor and an ARB increases the chance of acute renal failure and hyperkalemia with no evidence of benefit^37,38. Guidelines strongly support this statement¹¹.

There were also areas where there was disagreement with published guidelines: Statement 4.4 is not recommended in AHA/ACC guidelines, which suggest indefinite treatment with ACE inhibitors or ARBs in patients with coronary artery disease who have had an ACS event¹¹. In clinical practice, the patients described in this statement are perceived to be at lower risk, and in the real world ACE inhibitors or ARBs are often stopped 12 months or so after ACS in the absence of the conditions mentioned, because the benefit of long-term use on top of antiplatelet therapy and a statin is dubious. Consensus reflects clinical practice rather than the guidelines.

Statement 4.7 did not achieve consensus (Supplementary material, Table S2). Eplerenone use post ACS in patients with heart failure and ejection fraction below 40% is recommended in guidelines^13,14. It is the only mineralocorticoid receptor antagonist (MRA) that has been studied in this context, and it has significant mortality benefit³⁹. The concept of using an MRA early post ACS with heart failure to improve outcomes was generally accepted, but cost issues were a consideration, especially when there is a cheap alternative (spironolactone) available. Although spironolactone is likely to be as good and is certainly cheaper, there is no evidence for its use after ACS; however, it seems that many are comfortable to extrapolate the results of the EPHESUS study with eplerenone to spironolactone³⁹.

Section 5: beta blockers

Consensus was achieved on all three voting statements regarding beta blockers (Table 1). The evidence for the use of beta blockers after MI is somewhat dated, with most trials coming from the era before acute intervention/fibrinolysis, DAPT, statins and ACE inhibitor therapy⁴⁰. The use of beta blockers is no longer universal after MI, because of perceptions that they give less prognostic benefit compared with other therapies and are associated with fatigue, bradycardia and hypotension. Based on discussion from the current group, many cardiologists are unsure whether beta blockers offer any advantage in patients presenting with limited MI and preserved systolic function who are fully revascularized and treated with other evidence-based therapies. Long-term data in patients with hypertension (LIFE, ASCOT-BPLA) suggest that beta blockers confer less benefit than other therapies such as ACE inhibitors, ARBs and calcium channel blockers^41–43.

The beta blocker recommendations in the 2016 Australian ACS guidelines have changed significantly from the previous 2006 guidelines. In 2006, indefinite beta blocker use was recommended for most patients²⁵. In 2016, caution is voiced for acute therapy, and longer-term therapy is only recommended using vasodilatory beta blockers in those with reduced left ventricular (LV) systolic function⁸. Patients presenting with MI who are managed with early revascularization appear to have fewer ischemic, arrhythmic or hemodynamic complications than similar patients treated in the era when beta blockers were shown to be of benefit⁴⁴.

Our consensus group discussed whether to start all patients on beta blockers after MI and then withdraw them as appropriate, whether to initiate beta blockers only in patients who have a definite indication and how long to continue beta blocker use after MI in a stable patient without alternative indications for this therapy. The resulting recommendations were consistent with, but expanded upon, the updated Australian Guidelines⁸. We differed in recommending that beta blockers should still be commenced at the time of ACS in most hemodynamically stable patients without contraindication. However, we agreed that they could be ceased within the first 12 months for patients without ongoing indications such as hypertension, angina or heart failure. The benefits of beta blockers may be greatest early after MI, and early initiation followed by “considered discontinuation” was thought an appropriate approach. This could reduce adverse effects, reduce “pill burden”, and improve adherence with other, more critical secondary prevention medicines such as aspirin and lipid-lowering therapy⁴⁵.

Beta blockers should be continued in patients in whom there is a strong indication, such as in the setting of heart failure/LV dysfunction, atrial fibrillation, ongoing myocardial ischemia/incomplete revascularization or ongoing hypertension.

Section 6: other

Consensus was achieved on all four statements about other treatments (Table 1). Nitrates should be used only for symptomatic relief. Calcium channel blockers have no direct role in the management of MI, but they can be used for other conditions such as hypertension, coronary spasm or possibly rate control in atrial fibrillation. Dihydropyridines can be used in patients with hypertension with normal LV function, but as third-line therapy after ACE inhibitors and/or beta blockers. In well patients with normal LV function who have undergone complete revascularization, the long-term use of only aspirin and a statin is supported.

Discussion

Twenty-six consensus recommendations were developed as a practical and easily referenced key medication guide to reduce the risk of future cardiovascular events in ACS patients. Our intention is for these recommendations to complement and expand upon the recent Australian ACS guidelines, and to bridge the gap between evidence-based guideline recommendations and real-world practice. The process was driven by two concerns: the persistent high recurrent event rate in ACS survivors, and the surprisingly low use of evidenced-based treatments documented in studies of contemporary Australian practice^3,5. Several factors may contribute to this evidence-treatment gap: a concern that the guidelines are too prescriptive and impractical; a belief that the evidence does not extend to a significant proportion of patients in real-world practice; or a skepticism about the strength of the evidence on which the guidelines are based⁴⁶. Consensus recommendations go beyond the trial evidence, melding it with clinical experience to give practical and pragmatic advice on best therapy in various scenarios.

Development of the consensus recommendations included a literature review that also incorporated relevant local and international studies. In the local setting, rates of cardiovascular disease and associated adverse outcomes are disproportionately high in Aboriginal Australians and Torres Strait Islanders compared with non-Indigenous Australians^47–49. Australian ACS guidelines emphasize the importance of culturally and linguistically appropriate communication of secondary prevention advice for Indigenous Australians⁸. Many risk assessment tools used in ACS care (e.g. GRACE, CRUSADE) still remain to be validated in the Indigenous Australian population⁸. A framework for overcoming disparities in the management of ACS highlights the importance of developing a targeted care plan with the patient and their Indigenous cardiac coordinator⁴⁷.

Our consensus recommendations were developed across six classes of medication; however, many post-ACS patients will also be receiving medications for other concurrent morbidities such as diabetes. Such multi-morbidity will increase the complexity of the treatment regimen and also the risk of medication non-adherence⁵⁰. Strategies to improve adherence include patient education, ongoing follow-up and reminder aids (e.g. calendar notifications, pill-boxes, mobile devices apps). The treatment regimen complexity may also be reduced by choosing regimens that require fewer doses or that have less stringent dosing needs.

Two of our 28 statements did not reach consensus, despite consideration of feedback from the voting panel and subsequent rewording (Supplementary material, Table S2). Statement 3.5 (“NSTEMI patients should be treated with DAPT as soon as possible. The preferred option is with aspirin and ticagrelor unless contraindicated. It is reasonable to delay DAPT until anatomy is known for patients being taken early to the cardiac catheter laboratory”) achieved agreement from 71% of the group, but one expert disagreed and five only partially agreed. Some felt that therapy should be withheld in all cases until the coronary anatomy is known, others preferred early administration in all. This reflects clinical uncertainty from lack of clear evidence. The only trial to address the question directly utilized prasugrel⁵¹, which does not have a role in medically treated ACS⁵². There was no benefit and increased bleeding with early compared to in-lab administration of prasugrel in this trial, although time to cardiac catheterization was remarkably quick (median time 4 hours⁵¹) and not comparable with standard practice in Australia (median time 46 hours⁵³). The majority opinion favored routine early treatment unless going directly to the cardiac catheter laboratory, the rationale being that DAPT is effective regardless of whether patients undergo medical or invasive management²⁶, and a concern that without adequate background antithrombotic and antiplatelet therapy events including vessel occlusion and transition to STEMI could occur while waiting to get to the lab.

Statement 4.7 (“Post ACS in patients with heart failure and ejection fraction <40%, a MRA should be added early to standard therapy to reduce mortality, unless contraindicated due to hyperkalemia or severe renal dysfunction. The preferred evidence-based MRA is eplerenone”) also achieved 71% agreement, with one expert disagreeing and five only partially agreeing. In this case, the trial evidence and guideline recommendations failed to translate into agreed practice. Eplerenone is the only MRA which has been studied post ACS. It has been shown to have a significant mortality benefit in patients with heart failure and ejection fraction below 40%³⁹, and is the guideline-recommended therapy in this setting^13,14. However, some experts felt cost should be taken into consideration and preferred the use of spironolactone (which is likely to be effective, but does not have trial data in the post-ACS setting). This demonstrates how considerations beyond the trial data and guidelines play an important part in determining patient treatment. The general need for further research into the cost-effectiveness of approaches to secondary prevention is also noted in the Australian ACS guidelines⁸.

Only two statements reached unanimous agreement – Statement 1.5 (steps to take for statin intolerance) and Statement 2.1 (indefinite aspirin use). This speaks to the limitations of the evidence base – and, by extension, the guidelines⁴⁶ – in informing everyday practice for all patients and all clinical scenarios. It also highlights the importance of consensus recommendations to translate the guidelines into practice, and achieve greater uniformity of care and improved patient outcomes.

We reached consensus (>80% agreement) on 26 of 28 statements using the Delphi process. The resulting recommendations are broad-ranging; they encourage more widespread use of effective agents where trial evidence has not yet translated into routine practice (e.g. use of DAPT in ACS patients managed medically or with CABG; continuation of DAPT beyond 12 months in high-risk patients) and reduction in the use of agents where current practice is no longer supported by firm evidence (e.g. cessation of beta blockers after 12 months in stable asymptomatic patients with normal LV function). They also specifically address strategies to de-escalate therapy and improve adherence with the medicines of greatest benefit (aspirin and statin alone beyond 12 months in stable patients without additional risk factors). In this respect the recommendations go beyond the evidence and the guidelines, and give practical advice to tailor best therapy to the individual patient. Potential future plans to disseminate and implement the consensus recommendations include direct peer-to-peer communications, medical education programs and local congress presentations. It is envisioned that the recommendations will be regularly reviewed, and updated if required, taking into consideration newly available treatments, efficacy and safety evidence, and management guideline updates.

In conclusion, survivors of an ACS remain at high risk of recurrent events, attributable in part to non-adherence with evidence-based care^3–5. Despite the existence of excellent treatment-evidence guidelines, including the recently updated Australian ACS guidelines⁸, there remain significant barriers in translating these into everyday practice^5,9. This may be driven in part by a belief that the evidence is incomplete, impractical or does not extend to a significant proportion of patients seen in everyday practice. Using the internationally recognized Delphi technique, we developed 26 practical consensus recommendations on secondary prevention medications following an ACS event. These recommendations complement and expand upon the ACS guidelines, emphasizing areas where there are considerable treatment gaps, outlining situations where some medications may not be necessary, giving practical advice on managing medication side effects and recommending what to use as core therapy when adherence is an issue. It is intended that these recommendations be used alongside the ACS practice guidelines, to give practical advice on medication use, promote more uniform use of effective treatments and reduce the risk of recurrent events in ACS survivors.

Transparency

Declaration of funding

Administrative and medical writing support was provided by Ms Donna Bartlett (Allori Pty Ltd, Australia) and Dr Anja Becher (Sydney, Australia) and was funded by AstraZeneca Australia. The sponsor had no role in the preparation of this article.

Author contributions: All authors were involved in the conception of the study, the design, analysis and interpretation of the data, the drafting of the paper and revising it critically for intellectual content. All authors approved the final version to be published and agree to be accountable for all aspects of the work.

Declaration of financial/other relationships

C.J.H. has disclosed that he has received research support, honoraria, or is a member of advisory boards: Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Janssen, The Medicines Company, Medtronic and Merck Sharp and Dohme. J.A. has disclosed that he has received research support, honoraria, or is a member of advisory boards: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myer Squibb, Merck Sharp and Dohme, Pfizer and Sanofi Aventis. D.B. has disclosed that he has received research support, honoraria, or is a member of advisory boards: AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myer Squibb, Merck Sharp and Dohme, Pfizer and Sanofi Aventis. A.S. has disclosed that he has received honoraria, speaker fees, consultancy fees, is a member of advisory boards or has appeared on expert panels for: Abbott, Aspen, AstraZeneca, Bayer, Biotronik, Boehringer Ingelheim, Bristol Myer Squibb, CSL, Janssen Cilag, Menarini, Merck Sharp and Dohme, Novartis, Pfizer, Sanofi Aventis, Servier and Vifor. P.L.T. has disclosed that he has received honoraria for presentations and advisory boards from AstraZeneca, Boehringer Ingelheim and Pfizer, and research funding from AstraZeneca, Pfizer, Amgen and Bristol Myers Squibb. M.I.W. has disclosed that he has received honoraria, speaker fees, consultancy fees, is a member of advisory boards or has appeared on expert panels for: Abbott, Amgen, AstraZeneca, Bristol Myer Squibb, Eli Lilly, GlaxoSmithKline, Merck Sharp and Dohme, Pfizer and St Jude Medical. P.E.A. has disclosed that he has received research grants and honoraria for advisory boards from AstraZeneca, Elli Lilly, Sanofi Aventis, Boehringer Ingelheim, Amgen, CSL, Merck Sharp and Dohme, Bristol Myer Squibb, Bayer and Pfizer.

CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Full consensus group: John Amerena (Geelong Cardiology Research Centre, Barwon Health, Deakin University, VIC), Philip E. Aylward (Flinders University and Medical Centre, Adelaide, SA; and South Australian Health and Medical Research Institute, Adelaide, SA), Andrew Boyle (John Hunter Hospital, NSW), David Brieger (Cardiology Department, Concord Hospital and Sydney Medical School, The University of Sydney, Sydney, NSW), Clara K. Chow (The George Institute for Global Health, Sydney Medical School, Australia), David Cross (Heartcare Partners, QLD, and Royal Brisbane and Women’s Hospital, QLD), Deepak Haikerwal (Western Hospital, VIC), Christopher J. Hammett (Department of Cardiology, Royal Brisbane and Women's Hospital, QLD), Karam Kostner (Mater Hospital Brisbane and University of Queensland, QLD), Kumaril Mishra (Calvary Central Districts Hospital, SA), Allison Morton (St John of God Hospital, Bunbury, WA), Andrew T.L. Ong (Department of Cardiology, Westmead Hospital and Westmead Clinical School, University of Sydney, NSW), Rohan Poulter (Nambour General Hospital, QLD), Peter Psaltis (University of Adelaide and South Australian Health and Medical Research Institute, Adelaide, SA), Sharmalar Rajendran (University of Adelaide, SA), Jamie Rankin (Fiona Stanley Hospital, WA), Andrew Sindone (Cardiology Department, Concord Hospital and Sydney Medical School, The University of Sydney, Sydney, NSW), Peter L. Thompson (Heart Research Institute, Sir Charles Gairdner Hospital and Harry Perkins Institute of Medical Research, University of Western Australia, Perth), Philip Tideman (Country Health SA LHN and Southern Adelaide LHN, SA), Bill Van Gaal (Northern Hospital, VIC), Matthew I. Worthley (University of Adelaide, Royal Adelaide Hospital, Adelaide, SA; and South Australian Health and Medical Research Institute, Adelaide, SA).

Acknowledgements

We thank Professor Clara K. Chow (The George Institute for Global Health, Sydney Medical School, Australia) for her participation in this project as a member of the PERMIT Program Steering Committee. Administrative and medical writing support was provided by Ms Donna Bartlett (Allori Pty Ltd, Australia) and Dr Anja Becher (Sydney, Australia) and was funded by AstraZeneca Australia. The sponsor was given the opportunity to comment on the final version of the article.