Coronary artery disease: Risk stratification and patient selection for more aggressive secondary prevention

Abstract

In patients with stable coronary artery disease, clinical outcomes are predominantly characterized by the consequences of atherosclerosis on the myocardium, but also by complications of atherosclerosis, notably recurrent acute coronary syndrome or stroke. Secondary prevention therapy is therefore key in this patient population. Intensification of secondary prevention therapy is possible, at the price of a therapeutic risk or a high cost, therefore justifying careful selection of patients with a high residual risk and low therapeutic risk. Two lines of therapy can be intensified, independently of each other, namely anti-thrombotics and lipid-lowering agents. Intensification of anti-thrombotic therapy is efficacious in terms of ischaemic events and cardiovascular mortality, but incurs an excess haemorrhagic risk. Patients aged over 65 years of age and those with a history of intra-cranial haemorrhage are not eligible for intensification of anti-thrombotic therapy. Conversely, patients with prior or recurrent myocardial infarction may benefit from this strategy, especially if they are current smokers or have diabetes mellitus. Intensification of lipid-lowering therapy can be achieved through an association of high-intensity statins with ezetimibe or PCSK9 inhibitors. This strategy engenders little risk, but the cost of PCSK9 inhibition is high, and should be considered based on the level of low-density lipoprotein cholesterol achieved with statin treatment at the maximal tolerated dose. In addition to this patient selection based on low-density lipoprotein cholesterol levels, the presence of diabetes or documented progression of atherosclerosis should be considered.

Keywords

Coronary artery disease acute coronary syndrome atherosclerosis prevention risk stratification anti-thrombotics lipid-lowering therapy statin

Introduction

In patients with stable coronary artery disease, clinical outcomes are predominantly characterized by the consequences of atherosclerosis on the myocardium, namely left ventricular dysfunction, ventricular or atrial arrhythmias and disease progression, but also complications of atherosclerosis, notably recurrent acute coronary syndrome (ACS) or stroke. The PROSPECT study¹ showed that in the three years following an ACS, the risk of cardiovascular events was around 20%; half this risk was attributable to thrombotic complications at the angioplasty site, and the other half to complications of other atheromatous plaques. Before intensifying secondary prevention therapy, reinforcement of all possible lifestyle measures is of paramount importance. After this important first step, intensification of therapy is possible, by reinforcing antiplatelet therapy and by reducing the low-density lipoprotein cholesterol (LDL-C) level. The benefit to be gained from intensifying antithrombotic therapy goes hand in hand with an increase in the risk of bleeding, whereas intensifying lipid-lowering therapy engenders few side effects. However, both strategies can be envisaged, after careful evaluation of the ischaemic and bleeding risks as well as the risk of progression of atherosclerosis.

Residual risk in secondary prevention: individual predictors and scores

Individual factors

After ACS or stroke, the residual risk is time-dependent. The risk is highest during the first 12 months after an acute episode. Beyond one year, the event rate related to atherosclerosis seems to stabilize,^2–5 but numerous other factors may enter into play, either individually or in combination, thereby modifying the residual risk,^2,4,6,7 such as age,^7,8 sex,⁹ diabetes,^7,10 left ventricular dysfunction and recurrent infarction,^2,11 coexisting peripheral artery disease^11,12 or stroke.⁵ In addition to these clinical factors, other parameters also play a role, such as biological factors (renal failure^13,14 or other biological markers^15,16), genetic factors,¹⁷ imaging findings such as the extent of vascular disease^18–21 and, finally, the quality of secondary prevention therapy.^4,7

Risk scores

Due to the large number of factors involved, the interactions between these factors and the relative weight of each in determining a patient’s risk, the use of risk scores is indispensable. Among the many scores developed to assess risk, the majority were designed for the acute phase.^22–25 These scores are thus suboptimal for the chronic phase, even though certain scores have been validated up to one²⁶ and three years.²⁷ The updated version of the GRACE risk score was developed for a period ranging from discharge after ACS to six months, and showed satisfactory external validation up to three years.²⁸ Few risk scores have been developed specifically for secondary prevention in stable patients. The ischaemic risk score based on the population from the REACH registry (developed in 33,419 patients and validated in 16,270 patients) can be used for secondary prevention. The variables included in this score are age (in categories), smoking status, diabetes, extent of arterial disease (number of vascular beds affected), heart failure and treatment with statins and aspirin²⁹ (Figure 1).

Figure 1.

Predictors of ischaemic (left panel) and haemorrhagic (right panel) events among patients with stable atherosclerosis. Data from the REACH registry, adapted from Wilson et al.²⁹ and Ducrocq et al.⁶⁰ In blue: predictors of ischaemic events. In red: predictors of haemorrhagic events. In green: predictors of both ischaemic and haemorrhagic events.

What is ‘aggressive’ secondary prevention treatment?

In the secondary prevention of atherosclerosis, optimal treatment has been well established for several years. In addition to correction of risk factors as well as lifestyle measures, guidelines recommend therapy combining antiplatelets, beta-blockers, angiotensin-converting enzyme inhibitors and statins, known under the acronym ‘BASI’.^30–33 This is the cornerstone of treatment designed to suit the vast majority of patients, and there is little room for tailoring this treatment to meet the needs of individual patients. Yet, this standard secondary prevention therapy has evolved in recent years, with certain therapies called into question (notably, beta-blockers³¹) and the advent of new molecules, in particular antiplatelet and lipid-lowering drugs. The universal ‘BASI’ approach has progressively been replaced by individually tailored treatment, especially for anti-thrombotic therapies^34–37 and lipid-lowering therapy,^38,39 with the potential to intensify lipid-lowering by using high-intensity statins,³⁸ by associating statins with other molecules such as ezetimibe³⁹ or by using PCSK9 inhibitors.⁴⁰

Variations in antiplatelet therapy

With the exception of patients who present allergy or intolerance (generally gastro-duodenal), treatment with aspirin is universally established as the cornerstone of secondary prevention therapy.⁴¹ The first 12 months after an ACS constitute a period of high thrombotic risk, especially if revascularization was achieved by angioplasty with stent implantation. Further to the CURE³⁷ and COMMIT⁴² studies, a combination of aspirin plus clopidogrel for one year was widely adopted and recommended by guidelines, except in patients at high risk of bleeding. During this 12-month period, antiplatelet therapy can be intensified by the use of other agents that are more potent than clopidogrel, without modifying the aspirin treatment. Beyond the first 12 months after ACS, it is potentially possible to prolong the dual antiplatelet therapy, with clopidogrel or other agents.

Dual antiplatelet therapy in the first 12 months after ACS

Antithrombotic therapy during the first year after an ACS can be intensified by replacing clopidogrel by either prasugrel⁴³ or ticagrelor.³⁴ Both these drugs have been shown to have net clinical benefit, despite an excess of bleeding events. The use of prasugrel is restricted to patients who undergo angioplasty and who have no prior history of stroke. In patients aged over 75 years or weighing less than 60 kg, the excess risk of bleeding as compared with clopidogrel is such that the net clinical benefit of prasugrel is nil. Ticagrelor has wider indications, including patients treated without percutaneous coronary intervention, that is, medically or by surgical revascularization, and there are no age or weight limits. The only patients not eligible for ticagrelor are those with a history of intra-cranial bleeding. A strategy of intensifying the standard antithrombotic combination of aspirin and clopidogrel with the addition of a direct oral anticoagulant (anti Xa) at low dose was tested in the ATLAS-ACS2 TIMI 51 study, with the use of rivaroxaban 2.5 or 5.0 mg twice daily. After an average follow-up of 13 months, rivaroxaban reduced the risk of the composite end point of death from cardiovascular causes, myocardial infarction or stroke, at the price of an increased risk of major bleeding and intracranial haemorrhage.⁴⁴ Therefore, secondary prevention therapy can be intensified in the first year after an ACS by replacing clopidogrel either with ticagrelor (except in patients with a history of ischaemic stroke) or with prasugrel (subject to the restrictions cited above). The addition of rivaroxaban at a dose of 2.5 mg twice daily is a potentially useful option that can be considered for patients at low haemorrhagic and high thrombotic risk.

Beyond the first 12 months after ACS or angioplasty, what is aggressive antithrombotic therapy, and which patients should have it?

Beyond the first year after an ACS or angioplasty with stent implantation, single antiplatelet therapy is the rule, generally using low-dose aspirin.³³ In a meta-analysis of 95,000 patients, aspirin was shown to reduce the relative risk of cardiovascular death by 21%.⁴⁵ As for the acute phase, antiplatelet therapy can be intensified, not by increasing the dose of aspirin above 100 mg/day, but rather by prolonging the duration of the dual antiplatelet therapy (DAPT), combining aspirin with clopidogrel or another antiplatelet agent.

Four clinical trials have tested the utility of DAPT beyond 12 months, testing associations of aspirin with one of clopidogrel, prasugrel, vorapaxar or ticagrelor.

The CHARISMA study included high-risk patients in primary prevention or (predominantly) secondary prevention, with 9478 of the 15,603 patients having suffered from documented infarction, stroke or peripheral arterial disease before inclusion.⁴⁶ Although the results did not find any significant benefit with the association of aspirin and clopidogrel compared with aspirin alone in the overall population, pre-defined subgroup analysis of secondary prevention patients showed a 17% reduction in relative risk of cardiovascular events with DAPT, without an increase in the risk of bleeding.¹¹

The ‘DAPT’ study confirmed a reduction of thrombotic complications with prolonged DAPT in patients undergoing angioplasty with implantation of an active stent (40% in the context of ACS), and treated for one year with DAPT without bleeding complications. In the intervention arm of the study, patients pursued DAPT for a further 18 months with either clopidogrel (63.5%) or prasugrel (34.7%). After the 18 additional months’ treatment, patients in this group had a reduction in thrombotic events,⁴⁷ albeit with an unexplained excess in mortality and a higher rate of bleeding complications. There was a statistically significant interaction (p = 0.03) between prasugrel and clopidogrel, suggesting that prasugrel yielded greater protection against major adverse cardiovascular events than clopidogrel.

The use of vorapaxar, an inhibitor of the protease-activated receptor PAR-1, at a dose of 2.5 mg/day, on top of aspirin alone, or aspirin plus clopidogrel, for an average of 30 months, was tested versus placebo in the TRA-2P TIMI 50 study, in patients with a history of recent (<1 year) infarction or stroke.⁴⁸ The study was prematurely discontinued due to an excess of bleeding complications (moderate and severe bleeding, including intracranial haemorrhage), but the study nonetheless reported a reduction in cardiovascular mortality.

The PEGASUS-TIMI 54 study compared ticagrelor versus placebo, in association with aspirin in patients aged over 50 years with a history of infarction (on average, 1.7 years prior) and presenting at least one additional high-risk feature (i.e. age > 65 years, diabetes, a second prior spontaneous myocardial infarction, multivessel disease or chronic renal dysfunction). After an average follow-up of 33 months, DAPT was associated with a reduction in thrombotic events at the cost of an increase in major bleeding, and there was a trend towards a reduction of cardiovascular mortality with the dose of 60 mg twice daily.³⁶ Age (above or below 75 years) was not shown to have an effect on the risk of bleeding at either the 60 mg twice daily or the 90 mg twice daily dose. The patients who seemed to yield the most benefit were those in whom the interval between myocardial infarction (MI) and randomization was the shortest.⁴⁹

Based primarily on the CHARISMA, DAPT and PEGASUS studies, the ACC-AHA guidelines published in 2016 stipulated that patients with previous MI may benefit from prolonged DAPT.⁵⁰

Dissociating the thrombotic risk from the haemorrhagic risk

A meta-analysis combining six randomized trials that evaluated the benefit of prolonged DAPT beyond one year in patients with MI (totalling 33,435 patients) found a relative reduction of 22% in major adverse cardiac events with prolonged DAPT, as well as a 15% reduction in cardiovascular mortality, albeit without a reduction in overall mortality, and at the price of a relative increase of 73% in major bleeding (Figure 2).⁵¹ A Bayesian network meta-analysis including 31,666 patients showed that prolongation of DAPT beyond one year was associated with a 42% higher hazard ratio for bleeding, and an 18% higher hazard ratio for all-cause mortality, driven by a 49% higher hazard ratio for non-cardiac mortality, without any change in cardiovascular mortality, and despite a reduction in MI, stroke and stent thrombosis.⁵² The CHARISMA, DAPT, PEGASUS and TRA2P studies suggest that patients with one or more previous MIs are consistently a population at high thrombotic risk who benefit from intensification of the antiplatelet therapy. Conversely, the higher bleeding risk associated with the more aggressive antithrombotic strategy obliges us to exclude patients at high haemorrhagic risk. Thus, although patients with a history of intracranial bleeding can easily be identified and excluded due to the potential risk of recurrence, other predictors of bleeding risk are more difficult to determine.

Figure 2.

Meta analysis from six randomized trials comparing short versus prolonged dual antiplatelet therapy (adapted from Udell et al.⁵¹). Upper panel: odds ratios (and 95% confidence intervals) for major cardiovascular events. Lower panel: odds ratios (and 95% confidence intervals) for individual cardiovascular endpoints.

Estimating haemorrhagic risk

As with the estimation of ischaemic risk, several scores have been developed to evaluate the risk of bleeding, and most were designed for use in the acute phase,^53–56 in the context of coronary angioplasty^57,58 or in patients treated with vitamin K antagonists.⁵⁹ The predictors of bleeding retained in these scores include age, low body weight, renal failure, heart failure and anti-thrombotic treatment. One of the few scores developed in a cohort of patients with stable disease is the bleeding score from the REACH cohort, based on 68,106 patients included in the REACH registry and validated in 15,603 patients included in the CHARISMA study.⁶⁰ Age, peripheral arterial disease, congestive heart failure, diabetes, hypertension, smoking, antiplatelets, oral anticoagulants and hypercholesterolaemia were the nine items retained for the final score.

Sub-group analysis of patients with a history of MI in the TRA2P TIMI 50 study, including 17,779 patients, showed that in this population, the addition of vorapaxar reduced the risk of major adverse events by 20% after an average follow-up of 2.4 years (1.6% absolute risk reduction), with an excess of moderate and severe bleeding, including intra-cranial haemorrhage.⁶¹ Analysis of stable patients in the placebo group who had a history of MI but no history of intra-cranial haemorrhage showed that patients at risk of an ischaemic event (death, MI or stroke) were those aged over 75 years and those with a history of peripheral, cerebral and coronary arterial disease, renal failure, diabetes and smoking⁶² (Figure 3).

Figure 3.

Factors associated with the risk of death, myocardial infarction and stroke by multivariate analysis in the placebo group of the TRA2P TIMI 50 study (adapted from Bohula et al.⁶²).

The comparison of the ischaemic and haemorrhagic scores from the REACH registry shows how difficult it is to dissociate these two types of risk. Age, renal failure, smoking status, heart failure and peripheral arterial disease are predictors of both thrombosis and bleeding. Only diabetes, lack of statins, and recent history of vascular events orient the profile towards ischaemic risk, while hypertension, renal dysfunction and prolongation of DAPT increase the bleeding risk (Figure 1). Similarly, the DAPT study enabled the construction of a score combining both thrombotic and haemorrhagic risk, in which only variables with discriminant capacity were retained (Figure 4). The main inclusion criterion in the DAPT study was that patients had to have been treated with antiplatelet therapy for at least one year without any bleeding complications. Age was found to be a predictor of bleeding, whereas a history of prior MI, heart failure, or diabetes, current smoking, implantation of multiple stents, stents of small diameter, taxol-eluting stents or stents placed on a vein graft were predictors of thrombotic events.⁶³ Although not strictly identical to the REACH score, the DAPT score does confirm certain factors as being of prime importance, and gives important pointers for patient selection (Figure 4).

Figure 4.

Predictors of thrombotic (in blue), haemorrhagic (in red) and both thrombotic and haemorrhagic (in green) events in the DAPT population (adapted from Yeh et al.⁶³).

What are the conclusions for the reinforcement of antithrombotic therapy?

Intensifying antiplatelet therapy is possible, either by modifying DAPT, or by replacing clopidogrel with a more potent agent (i.e. prasugrel 10 mg/day, or ticagrelor 90 mg twice daily, or rivaroxaban 2.5 mg twice daily). Beyond the first 12 months, intensification of antiplatelet therapy is possible by prolonging the prescription for DAPT, up to 30 months, using either clopidogrel 75 mg/day, or ticagrelor 60 mg twice daily, or rivaroxaban 2.5 mg twice daily.

Even when the prerequisite that the patient had no bleeding complication during the first year is respected, this reinforced DAPT regime reduces ischaemic events, but the increased haemorrhagic risk persists. Therefore, patient selection cannot be on the basis of previous MI alone,⁵⁰ but patients at high bleeding risk, such as those aged over 65 or those with prior intracranial bleeding, are not suitable candidates for this strategy and must therefore be excluded. Conversely, patients with a history of one or more prior MIs are potentially suitable candidates, and two additional criteria can also be taken into account, namely ongoing smoking, and diabetes, which in some studies were associated with higher thrombotic risk than bleeding risk.

Possible variations in lipid lowering therapy

Standard treatment, and achieving the target LDL-C value

Randomized and observational studies have successively shown that for secondary prevention, treatment with statins is beneficial,⁶⁴ regardless of the initial LDL-C value.⁶⁵ Furthermore, it has been shown that high-intensity statin therapy is preferable to low³⁸ or moderate intensity.⁶⁶ In both primary and secondary prevention, for every reduction of 1 mmol/l (38 mg/dl) in LDL-C, there is a 20% reduction in cardiovascular events per year,⁶⁷ justifying the recommendation for systematic treatment with high-intensity statins.³² A target value of LDL-C <70 mg/dl (or a 50% decrease if the baseline LDL-C level is between 70 and 135 mg/dl) is recommended in the guidelines of the European Society of Cardiology in order to facilitate efficacy and compliance with treatment. Although the threshold of 70 mg/dl is not strongly supported by scientific evidence, it corresponds to the values found in studies that compared different intensities of statin treatment, and it is critical in clinical practice to have a fixed threshold to recommend in order to achieve better compliance.⁶⁸ The IMPROVE IT study tested two hypotheses, namely the benefit of adding ezetimibe to statin treatment after ACS over a prolonged duration; but also the idea of lowering LDL-C below the 70 mg/dl value.⁶⁹ In terms of LDL-C values, the IMPROVE IT study compared patients with an average LDL-C of 69 mg/dl versus those with an average value of 54 mg/dl, and showed that this additional reduction of 20% in LDL-C resulted in a 6% reduction in events over six years³⁹ (even reaching a reduction of 9%, if cumulative events are taken into account⁷⁰). The results of the FOURIER and SPIRE-2 trials confirm that treatment with a PCSK9 inhibitor yields a 50% to 60% reduction in LDL-C, and this reduction is associated with a corresponding decrease in major adverse cardiovascular events.^40,71 The SPIRE trials were stopped early after the sponsor elected to discontinue the development of bococizumab owing in part to the development of high rates of antidrug antibodies observed in biological studies. The magnitude of reduction in clinical events per decrease of 1 mmol/l of LDL-C seems to be similar with PCSK9 inhibitors as with statins or ezetimibe. Importantly, the benefit of LDL-C reduction is observed for LDL-C levels far below 70 mg/dl, since patients in whom the LDL-C level on treatment was below 25 mg/dl had the greatest reduction in events.⁴⁰

In parallel to clinical criteria, the impact of the reduction in LDL-C has also been demonstrated in terms of progression or regression of the volume of atherosclerotic coronary plaque in studies using intravascular ultrasound. The REVERSAL⁷² and GLAGOV studies,⁷³ as well as a meta-analysis,⁷⁴ have shown that the development of plaque volume within 12 to 24 months has a linear relation with the level of LDL-C achieved. An LDL-C value above 70 to 100 mg/dl is associated with plaque progression, whereas plaque regression of around 1% over 12 months is likely with LDL-C values between 36 and 70 mg/dl.^72,73

In summary, the level of LDL-C achieved under treatment therefore identifies patients at risk and a greater reduction in LDL-C yields a greater reduction in events, without any clear lower threshold.

Patients with high residual risk, linked to LDL-C

Registry studies have shown in secondary prevention that the therapeutic target is achieved in only 28% of patients.⁷⁵ Three primary causes have been cited for this failure to achieve target LDL-C values: (1) insufficient efficacy of statins because of very high LDL-C levels, and this is particularly true in patients suffering from familial hypercholesterolaemia,⁷⁶ and also in poor responders to statin therapy;⁷⁷ (2) patients who are intolerant to statins, particularly because of muscle symptoms, and in whom treatment intensity has to be reduced, or even requiring treatment discontinuation;⁷⁸ and (3) patient non-compliance with treatment,⁷⁹ for which the predictive factors are well established. History-taking and LDL-C measurement generally make it possible to distinguish between these three causes, and each situation requires a specific management strategy:

For patients with elevated LDL-C values, and for those showing poor response to statin therapy, the addition of ezetimibe or a PCSK9 inhibitor should be considered.^80–82 In the IMPROVE IT study, diabetic patients and those with prior coronary artery bypass graft⁸³ yielded a particular benefit from reduction of the LDL-C value below 70 mg/dl with ezetimibe. The mechanism of action of this improved efficacy in diabetics is related to their higher risk profile and a more favourable biological response.⁸² If the LDL-C is still not at the desired target, despite a combination of highest tolerated statin dose plus ezetimibe, then PCSK9 inhibitors should be considered.

Muscle intolerance should be verified by ensuring that symptoms improve when statin therapy is discontinued (even temporarily). In this case, statins can be re-introduced at a lower intensity and/or lower dose.⁷⁸ Patients at risk of intolerance are those who are initiating statin therapy for the first time, those with a personal or family history of muscle symptoms, elevation of muscle creatine kinase and those treated by simvastatin or atorvastatin. Conversely, well tolerated statin therapy for the previous three months or prescription of fluvastatin are factors that render muscle intolerance unlikely.⁸⁴

Premature discontinuation of secondary prevention treatments is frequent, and is not limited to statins only, but concerns all secondary prevention drugs.⁷⁹Unwarranted discontinuation, often at the patient’s own initiative, of antiplatelet drugs⁸⁵ or statins is responsible for an excess of mortality and recurrent MI.^86,87 Factors influencing non-compliance are mainly economic reasons, but also include younger age, male sex, lower socio-economic status, current smoking, and low body weight.⁸⁸

What are the conclusions for the reinforcement of lipid lowering therapy?

In the context of secondary prevention, all patients should have high-intensity statins, regardless of their baseline LDL-C level.^32,78 Lipid-lowering therapy can be intensified by increasing the statin intensity where possible, or by adding ezetimibe or a PCSK9 inhibitor. A decision-making algorithm for optimizing lipid-lowering therapy in the context of secondary prevention after MI has recently been published, and considers that all patients after MI are at high risk as long as treatment has not reached the maximum tolerated dose, and it also allows for the possibility of adding ezetimibe if the LDL-C value remains above the target of 70 mg/dl.⁸⁹

The place of PCSK9 inhibitors in the treatment armamentarium needs to be discussed, given the cost of this treatment. The American College of Cardiology (ACC)⁹⁰ and the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS)⁹¹ have recently published consensus statements for the use of these new agents. Both consensus positions use risk evaluation to propose an LDL-C threshold under statin and ezetimibe therapy at which PCSK9 inhibitors treatment should be initiated. According to the ACC consensus,⁹⁰ in stable patients with atherosclerotic cardiovascular disease (ASCVD), the proposed threshold is LDL-C > 100 mg/dl, and >70 mg/dl in patients with ‘severe ASCVD’. In the ESC/EAS statement,⁹¹ a more conservative position is chosen, namely LDL-C > 100 mg/dl in very high risk patients, and LDL-C > 135 mg/dl in stable secondary prevention patients. Interestingly, the definition of ‘severe ASCVD’ is comparable for both the ACC and ESC/EAS, and includes patients with a recent ACS, those with progressing disease, such as recurrent ACS, unplanned revascularization or stroke, or those with diabetes and organ damage, or those with major risk factors (Table 1).

Table 1.

LDL-C criteria for considering the use of a PCSK9 inhibitor, on top of maximally tolerated statins and ezetimibe treatment (adapted from Sabatine⁹³).

Category	ACC 2016 Expert Panel⁹⁰	ESC/EAS consensus⁹¹
Severe ASCVD	≥1.8 mmol/l (70 mg/dl)	≥2.6 mmol/l (100 mg/dl)
ASCVD	≥2.6 mmol/l (100 mg/dl)	≥3.6 mmol/l (135 mg/dl)
Diabetes with target organ damage, without ASCVD		≥3.6 mmol/l (135 mg/dl)
Heterozygous familial hypercholesterolaemia or baseline LDL-C >4.9 mmol/l without ASCVD	≥2.6 mmol/l (100 mg/dl)	≥4.5–5 mmol/l (170–190 mg/dl), according to risk

LDL-C: low-density lipoprotein cholesterol; ACC: American College of Cardiology: ESC/EAS: European Society of Cardiology/European Atherosclerosis Society; ASCVD: atherosclerotic cardiovascular disease

This treatment escalation does not appear to expose the patient to a risk of major adverse events, other than the risk of intolerance (mainly muscle symptoms), which is reversible and occurs at a frequency of around 10%.⁸⁴ To a lesser extent, there is a risk of development of diabetes, which is higher in pre-diabetic patients, and a low risk of intra-cranial haemorrhage.⁶⁷ Last but not least, there is no signal for cognitive decline with statins, ezetimibe and PCSK9 inhibitors, even at very low LDL-C levels, as shown by the results of the Ebbinghaus study.⁹² However, it should be noted that in this study, the duration of exposure to PCSK9 inhibitors was quite limited.

Conclusion: what aggressive secondary prevention, and for whom?

Intensification of secondary prevention therapy is possible, at the price of a therapeutic risk or a high cost, therefore justifying careful selection of patients with a high residual risk and low therapeutic risk. Two lines of therapy can be intensified, independently of each other, namely antithrombotics and lipid-lowering agents. Intensification of antithrombotic therapy is efficacious in terms of ischaemic events and cardiovascular mortality, but incurs an excess haemorrhagic risk. Patients aged over 65 years of age, and those with a history of intra-cranial haemorrhage are not eligible for intensification of antithrombotic therapy. Conversely, patients with prior MI or recurrent MI may benefit from this strategy, especially if they are current smokers or have diabetes mellitus. Intensification of lipid-lowering therapy can be achieved through an association of high-intensity statins with ezetimibe or PCSK9 inhibitors. This strategy engenders little or no actual risk, but a high cost with PCSK9 inhibition, and therefore, its use should be considered based on the level of LDL-C achieved with statin treatment at the maximal tolerated dose. In addition to this patient selection based on LDL-C levels, the presence of diabetes or documented progression of atherosclerosis under treatment also identifies suitable candidates for treatment intensification.

Footnotes

Author contribution

FS and RC contributed to the conception of the work. All authors contributed to the acquisition, analysis and interpretation of literature data for the work. FS and FE drafted the manuscript. RC critically revised the manuscript. All gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

References

Stone

Maehara

Lansky

. A prospective natural-history study of coronary atherosclerosis. N Engl J Med 2011; 364: 226–235.

Jernberg

Hasvold

Henriksson

. Cardiovascular risk in post-myocardial infarction patients: Nationwide real world data demonstrate the importance of a long-term perspective. Eur Heart J 2015; 36: 1163–1170.

Smolina

Wright

Rayner

. Long-term survival and recurrence after acute myocardial infarction in England, 2004 to 2010. Circ Cardiovasc Qual Outcomes 2012; 5: 532–540.

Nakatani

Sakata

Suna

. Incidence, predictors, and subsequent mortality risk of recurrent myocardial infarction in patients following discharge for acute myocardial infarction. Circ J 2013; 77: 439–446.

Amarenco

Lavallee

Labreuche

. Coronary artery disease and risk of major vascular events after cerebral infarction. Stroke 2013; 44: 1505–1511.

Rapsomaniki

Shah

Perel

. Prognostic models for stable coronary artery disease based on electronic health record cohort of 102 023 patients. Eur Heart J 2014; 35: 844–852.

Bhatt

Eagle

Ohman

. Comparative determinants of 4-year cardiovascular event rates in stable outpatients at risk of or with atherothrombosis. JAMA 2010; 304: 1350–1357.

Roe

Goodman

Ohman

. Elderly patients with acute coronary syndromes managed without revascularization: Insights into the safety of long-term dual antiplatelet therapy with reduced-dose prasugrel versus standard-dose clopidogrel. Circulation 2013; 128: 823–833.

Mueller

Neumann

Roskamm

. Women do have an improved long-term outcome after non-ST-elevation acute coronary syndromes treated very early and predominantly with percutaneous coronary intervention: A prospective study in 1,450 consecutive patients. J Am Coll Cardiol 2002; 40: 245–250.

10.

Silvain

Vignalou

Barthelemy

. Coronary revascularization in the diabetic patient. Circulation 2014; 130: 918–922.

11.

Bhatt

Flather

Hacke

. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol 2007; 49: 1982–1988.

12.

Diehm

Allenberg

Pittrow

. Mortality and vascular morbidity in older adults with asymptomatic versus symptomatic peripheral artery disease. Circulation 2009; 120: 2053–2061.

13.

James

Budaj

Aylward

. Ticagrelor versus clopidogrel in acute coronary syndromes in relation to renal function: Results from the Platelet Inhibition and Patient Outcomes (PLATO) trial. Circulation 2010; 122: 1056–1067.

14.

Shlipak

Fried

Cushman

. Cardiovascular mortality risk in chronic kidney disease: Comparison of traditional and novel risk factors. JAMA 2005; 293: 1737–1745.

15.

Beygui

Silvain

Pena

. Usefulness of biomarker strategy to improve GRACE score’s prediction performance in patients with non-ST-segment elevation acute coronary syndrome and low event rates. Am J Cardiol 2010; 106: 650–658.

16.

Schiele

Meneveau

Chopard

. Prognostic value of albuminuria on 1-month mortality in acute myocardial infarction. Am Heart J 2009; 157: 327–333.

17.

Wauters

Carruthers

Buysschaert

. Influence of 23 coronary artery disease variants on recurrent myocardial infarction or cardiac death: The GRACE Genetics Study. Eur Heart J 2013; 34: 993–1001.

18.

Bhatt

Peterson

Harrington

. Prior polyvascular disease: Risk factor for adverse ischaemic outcomes in acute coronary syndromes. Eur Heart J 2009; 30: 1195–1202.

19.

Sianos

Morel

Kappetein

. The SYNTAX Score: An angiographic tool grading the complexity of coronary artery disease. EuroIntervention 2005; 1: 219–227.

20.

Palmerini

Caixeta

Genereux

. Comparison of clinical and angiographic prognostic risk scores in patients with acute coronary syndromes: Analysis from the Acute Catheterization and Urgent Intervention Triage StrategY (ACUITY) trial. Am Heart J 2012; 163: 383–391, 391 e1-5.

21.

Palmerini

Genereux

Caixeta

. Prognostic value of the SYNTAX score in patients with acute coronary syndromes undergoing percutaneous coronary intervention: analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage StrategY) trial. J Am Coll Cardiol 2011; 57: 2389–2397.

22.

Antman

Cohen

Bernink

. The TIMI risk score for unstable angina/non-ST elevation MI: A method for prognostication and therapeutic decision making. JAMA 2000; 284: 835–842.

23.

Boersma

Pieper

Steyerberg

. Predictors of outcome in patients with acute coronary syndromes without persistent ST-segment elevation. Results from an international trial of 9461 patients. The PURSUIT Investigators. Circulation 2000; 101: 2557–2567.

24.

Granger

Goldberg

Dabbous

. Predictors of hospital mortality in the global registry of acute coronary events. Arch Intern Med 2003; 163: 2345–2353.

25.

Morrow

Antman

Snapinn

. An integrated clinical approach to predicting the benefit of tirofiban in non-ST elevation acute coronary syndromes. Application of the TIMI Risk Score for UA/NSTEMI in PRISM-PLUS. Eur Heart J 2002; 23: 223–229.

26.

Eagle

Lim

Dabbous

. A validated prediction model for all forms of acute coronary syndrome: Estimating the risk of 6-month postdischarge death in an international registry. JAMA 2004; 291: 2727–2733.

27.

Simms

Weston

West

. Mortality and missed opportunities along the pathway of care for ST-elevation myocardial infarction: A national cohort study. Eur Heart J Acute Cardiovasc Care 2015; 4: 241–253.

28.

Fox

Fitzgerald

Puymirat

. Should patients with acute coronary disease be stratified for management according to their risk? Derivation, external validation and outcomes using the updated GRACE risk score. BMJ Open 2014; 4: e004425–e004425.

29.

Wilson

D’Agostino

Sr Bhatt

. An international model to predict recurrent cardiovascular disease. Am J Med 2012; 125: 695–703.e1.

30.

Steg

James

Atar

. ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force on the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J 2012; 33: 2569–2619.

31.

Roffi

Patrono

Collet

. 2015 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: Task Force for the Management of Acute Coronary Syndromes in Patients Presenting without Persistent ST-Segment Elevation of the European Society of Cardiology (ESC). Eur Heart J 2016; 37: 267–315.

32.

Piepoli

Hoes

Agewall

. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts): Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37: 2315–2381.

33.

Montalescot

Sechtem

. Task Force Members. ESC guidelines on the management of stable coronary artery disease: The Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013; 34: 2949–3003.

34.

Wallentin

Becker

Budaj

. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2009; 361: 1045–1057.

35.

Wiviott

Desai

Murphy

. Efficacy and safety of intensive antiplatelet therapy with prasugrel from TRITON-TIMI 38 in a core clinical cohort defined by worldwide regulatory agencies. Am J Cardiol 2011; 108: 905–911.

36.

Bonaca

Bhatt

Cohen

. Long-term use of ticagrelor in patients with prior myocardial infarction. N Engl J Med 2015; 372: 1791–1800.

37.

Yusuf

Zhao

Mehta

. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 2001; 345: 494–502.

38.

Cannon

Braunwald

McCabe

. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350: 1495–1504.

39.

Cannon

Blazing

Giugliano

. Ezetimibe added to statin therapy after acute coronary syndromes. N Engl J Med 2015; 372: 2387–2397.

40.

Sabatine MS, Giugliano RP, Keech AC, et al. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. Epub ahead of print 17 March 2017. DOI: 10.1056/NEJMoa1615664.

41.

Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002; 324: 71–86.

42.

Chen

Jiang

Chen

. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: Randomised placebo-controlled trial. Lancet 2005; 366: 1607–1621.

43.

Wiviott

Braunwald

McCabe

. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med 2007; 357: 2001–2015.

44.

Mega

Braunwald

Wiviott

. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med 2012; 366: 9–19.

45.

Baigent

Blackwell

. Antithrombotic Trialists Collaboration. Aspirin in the primary and secondary prevention of vascular disease: Collaborative meta-analysis of individual participant data from randomised trials. Lancet 2009; 373: 1849–1860.

46.

Bhatt

Fox

Hacke

. Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med 2006; 354: 1706–1717.

47.

Mauri

Kereiakes

Yeh

. Twelve or 30 months of dual antiplatelet therapy after drug-eluting stents. N Engl J Med 2014; 371: 2155–2166.

48.

Morrow

Braunwald

Bonaca

. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med 2012; 366: 1404–1413.

49.

Bonaca

Bhatt

Steg

. Ischaemic risk and efficacy of ticagrelor in relation to time from P2Y12 inhibitor withdrawal in patients with prior myocardial infarction: Insights from PEGASUS-TIMI 54. Eur Heart J 2016; 37: 1133–1142.

50.

Bittl

Baber

Bradley

. Duration of dual antiplatelet therapy: A systematic review for the 2016 ACC/AHA Guideline focused update on duration of dual antiplatelet therapy in patients with coronary artery disease: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2016; 68: 1116–1139.

51.

Udell

Bonaca

Collet

. Long-term dual antiplatelet therapy for secondary prevention of cardiovascular events in the subgroup of patients with previous myocardial infarction: A collaborative meta-analysis of randomized trials. Eur Heart J 2016; 37: 390–399.

52.

Palmerini

Benedetto

Bacchi-Reggiani

. Mortality in patients treated with extended duration dual antiplatelet therapy after drug-eluting stent implantation: A pairwise and Bayesian network meta-analysis of randomised trials. Lancet 2015; 385: 2371–2382.

53.

Mathews

Peterson

Chen

. In-hospital major bleeding during ST-elevation and non-ST-elevation myocardial infarction care: Derivation and validation of a model from the ACTION Registry(R)-GWTG. Am J Cardiol 2011; 107: 1136–1143.

54.

Mehran

Pocock

Nikolsky

. A risk score to predict bleeding in patients with acute coronary syndromes. J Am Coll Cardiol 2010; 55: 2556–2566.

55.

Moscucci

Fox

Cannon

. Predictors of major bleeding in acute coronary syndromes: The Global Registry of Acute Coronary Events (GRACE). Eur Heart J 2003; 24: 1815–1823.

56.

Subherwal

Bach

Chen

. Baseline risk of major bleeding in non-ST-segment-elevation myocardial infarction: The CRUSADE (Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines) bleeding score. Circulation 2009; 119: 1873–1882.

57.

Cantor

Mahaffey

Huang

. Bleeding complications in patients with acute coronary syndrome undergoing early invasive management can be reduced with radial access, smaller sheath sizes, and timely sheath removal. Catheter Cardiovasc Interv 2007; 69: 73–83.

58.

Nikolsky

Mehran

Dangas

. Development and validation of a prognostic risk score for major bleeding in patients undergoing percutaneous coronary intervention via the femoral approach. Eur Heart J 2007; 28: 1936–1945.

59.

Pisters

Lane

Nieuwlaat

. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest 2010; 138: 1093–1100.

60.

Ducrocq

Wallace

Baron

. Risk score to predict serious bleeding in stable outpatients with or at risk of atherothrombosis. Eur Heart J 2010; 31: 1257–1265.

61.

Scirica

Bonaca

Braunwald

. Vorapaxar for secondary prevention of thrombotic events for patients with previous myocardial infarction: A prespecified subgroup analysis of the TRA 2 degrees P-TIMI 50 trial. Lancet 2012; 380: 1317–1324.

62.

Bohula

Bonaca

Braunwald

. Atherothrombotic risk stratification and the efficacy and safety of vorapaxar in patients with stable ischemic heart disease and previous myocardial infarction. Circulation 2016; 134: 304–313.

63.

Yeh

Secemsky

Kereiakes

. Development and validation of a prediction rule for benefit and harm of dual antiplatelet therapy beyond 1 year after percutaneous coronary intervention. JAMA 2016; 315: 1735–1749.

64.

Scandinavian Simvastatin Survival Study Investigators. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: The Scandinavian Simvastatin Survival Study (4S). Lancet 1994; 344: 1383–1389.

65.

Collins

Armitage

Parish

. MRC/BHF Heart Protection Study of cholesterol-lowering with simvastatin in 5963 people with diabetes: A randomised placebo-controlled trial. Lancet 2003; 361: 2005–2016.

66.

Rodriguez

Maron

Knowles

. Association between intensity of statin therapy and mortality in patients with atherosclerotic cardiovascular disease. JAMA Cardiol 2017; 2: 47–54.

67.

Collins

Reith

Emberson

. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388: 2532–2561.

68.

Wei

MacDonald

Watson

. Effectiveness of two statin prescribing strategies with respect to adherence and cardiovascular outcomes: Observational study. Pharmacoepidemiol Drug Saf 2007; 16: 385–392.

69.

Blazing

Giugliano

Cannon

. Evaluating cardiovascular event reduction with ezetimibe as an adjunct to simvastatin in 18,144 patients after acute coronary syndromes: Final baseline characteristics of the IMPROVE-IT study population. Am Heart J 2014; 168: 205–212.e1.

70.

Murphy

Cannon

Blazing

. Reduction in total cardiovascular events with ezetimibe/simvastatin post-acute coronary syndrome: The IMPROVE-IT trial. J Am Coll Cardiol 2016; 67: 353–361.

71.

Ridker PM, Revkin J, Amarenco P, et al. Cardiovascular efficacy and safety of bococizumab in high-risk patients. N Engl J Med. Epub ahead of print 17 March 2017. DOI: 10.1056/NEJMoa1701488.

72.

Nissen

Tuzcu

Schoenhagen

. Effect of intensive compared with moderate lipid-lowering therapy on progression of coronary atherosclerosis: A randomized controlled trial. JAMA 2004; 291: 1071–1080.

73.

Nicholls

Puri

Anderson

. Effect of evolocumab on progression of coronary disease in statin-treated patients: The GLAGOV randomized clinical trial. JAMA 2016; 316: 2373–2384.

74.

Nicholls

Wolski

Sipahi

. Rate of progression of coronary atherosclerotic plaque in women. J Am Coll Cardiol 2007; 49: 1546–1551.

75.

Ferrieres

Rouyer

Lautsch

. Improvement in achievement of lipid targets in France: Comparison of data from coronary patients in the DYSIS and DYSIS II studies. Int J Cardiol 2016; 222: 793–794.

76.

Nordestgaard

Chapman

Humphries

. Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: Guidance for clinicians to prevent coronary heart disease: Consensus statement of the European Atherosclerosis Society. Eur Heart J 2013; 34: 3478–3490a.

77.

Boekholdt

Hovingh

Mora

. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: A meta-analysis of statin trials. J Am Coll Cardiol 2014; 64: 485–494.

78.

Catapano

Graham

De Backer

. 2016 ESC/EAS Guidelines for the Management of Dyslipidaemias: The Task Force for the Management of Dyslipidaemias of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS). Developed with the special contribution of the European Assocciation for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37: 2999–3058.

79.

Chowdhury

Khan

Heydon

. Adherence to cardiovascular therapy: A meta-analysis of prevalence and clinical consequences. Eur Heart J 2013; 34: 2940–2948.

80.

Cannon

Cariou

Blom

. Efficacy and safety of alirocumab in high cardiovascular risk patients with inadequately controlled hypercholesterolaemia on maximally tolerated doses of statins: The ODYSSEY COMBO II randomized controlled trial. Eur Heart J 2015; 36: 1186–1194.

81.

Nissen

Stroes

Dent-Acosta

. Efficacy and tolerability of evolocumab vs ezetimibe in patients with muscle-related statin intolerance: The GAUSS-3 randomized clinical trial. JAMA 2016; 315: 1580–1590.

82.

Farnier

Jones

Severance

. Efficacy and safety of adding alirocumab to rosuvastatin versus adding ezetimibe or doubling the rosuvastatin dose in high cardiovascular-risk patients: The ODYSSEY OPTIONS II randomized trial. Atherosclerosis 2016; 244: 138–146.

83.

Eisen

Cannon

Blazing

. The benefit of adding ezetimibe to statin therapy in patients with prior coronary artery bypass graft surgery and acute coronary syndrome in the IMPROVE-IT trial. Eur Heart J 2016; 37: 3576–3584.

84.

Bruckert

Hayem

Dejager

. Mild to moderate muscular symptoms with high-dosage statin therapy in hyperlipidemic patients – the PRIMO study. Cardiovasc Drugs Ther 2005; 19: 403–414.

85.

Mehran

Baber

Steg

. Cessation of dual antiplatelet treatment and cardiac events after percutaneous coronary intervention (PARIS): 2 year results from a prospective observational study. Lancet 2013; 382: 1714–1722.

86.

Nielsen

Nordestgaard

. Negative statin-related news stories decrease statin persistence and increase myocardial infarction and cardiovascular mortality: A nationwide prospective cohort study. Eur Heart J 2016; 37: 908–916.

87.

Bezin

Francis

Nguyen

. Impact of a public media event on the use of statins in the French population. Arch Cardiovasc Dis 2017; 110: 91–98.

88.

Yusuf

Islam

Chow

. Use of secondary prevention drugs for cardiovascular disease in the community in high-income, middle-income, and low-income countries (the PURE Study): A prospective epidemiological survey. Lancet 2011; 378: 1231–1243.

89.

Schiele F, Farnier M, Krempf M, et al. A consensus statement on lipid management after acute coronary syndrome. Eur Heart J Acute Cardiovasc Care. Epub ahead of print 17 November 2016. pii: 2048872616679791.

90.

Lloyd-Jones

Morris

Ballantyne

. 2016 ACC Expert Consensus Decision Pathway on the role of non-statin therapies for LDL-cholesterol lowering in the management of atherosclerotic cardiovascular disease risk: A report of the American College of Cardiology Task Force on Clinical Expert Consensus Documents. J Am Coll Cardiol 2016; 68: 92–125.

91.

Landmesser U, John Chapman M, Farnier M, et al. European Society of Cardiology/European Atherosclerosis Society Task Force consensus statement on proprotein convertase subtilisin/kexin type 9 inhibitors: Practical guidance for use in patients at very high cardiovascular risk. Eur Heart J. Epub ahead of print 27 October 2016. pii: ehw480.

92.

Giugliano

Mach

Zavitz

. Design and rationale of the EBBINGHAUS trial: A phase 3, double-blind, placebo-controlled, multicenter study to assess the effect of evolocumab on cognitive function in patients with clinically evident cardiovascular disease and receiving statin background lipid-lowering therapy – a cognitive study of patients enrolled in the FOURIER trial. Clin Cardiol 2017; 40: 59–65.

93.

Sabatine MS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors: Comparing and contrasting guidance across the Atlantic. Eur Heart J. Epub ahead of print 21 January 2017. pii: ehw572. DOI: 10.1093/eurheartj/ehw572.