Planning secondary prevention: Room for improvement

Abstract

The prognosis of patients after acute coronary syndromes is still suboptimal, mainly due to the risk of recurrent adverse coronary events, which is greatest during the first year, but persists over one’s lifetime. Meaningful progress in preventing cardiovascular events has been achieved. However, there remains much room for improvement by embracing innovative therapies and investing in multidisciplinary approaches. Pharmacological interventions focused on optimising antithrombotic and lipid-lowering therapies are both pillars of secondary prevention that have seen recent ground-breaking advances. Moreover, new approaches in diabetic patients with cardiovascular disease and new targets for anti-inflammatory treatment may significantly improve prevention strategies in the future. However, pharmacological treatments are expensive and can have significant side effects. Developing better tools in order to identify high-risk patients and promote more personalised strategies for each patient should be an absolute priority. Furthermore, adherence to medication is still low and represents a real challenge; several strategies to improve low adherence to treatment are currently under discussion. Non-pharmacological interventions are also essential. Improving communication with patients and advanced surveillance for those secondary risk factors that may negatively impact prognosis are crucial. Encouraging multidisciplinary teams that work effectively to optimise all aspects of secondary prevention, including a cardiac rehabilitation programme, is the optimal approach. Current secondary prevention strategies and suggestions for areas of improvement are discussed in this manuscript. However, the question remains: will research in secondary prevention continue to focus on stronger and more expensive drugs, or is it time for us to embrace a more patient-centred clinical and research model?

Keywords

Acute coronary syndrome secondary prevention antithrombotic therapy lipid-lowering cardiac rehabilitation cardiovascular disease

Planning secondary prevention: room for improvement

During recent decades, there has been significant progress in the prevention of recurrent cardiovascular events after acute coronary syndromes (ACSs).¹ Although current secondary prevention therapies have achieved substantial success in reducing the risk of cardiovascular events and mortality after ACSs,² the prognosis of patients who survive ACSs is still far from benign, mainly due to the risk of major adverse coronary events, which increase late mortality.³

The rate of recurrent events is greatest during the first 6–12 months after the acute event,³ during which it is recommended to have a more aggressive pharmacological approach.^4,5 However, the risk of recurrence of ACSs and cardiovascular mortality persists long after the first year. Recent studies have shown that after this time the risk is reduced by more than half, but still remains substantial,⁶ especially when ACS survivors are compared with individuals from the general population matched for age, sex and area of residence.⁷

Reducing long-term residual cardiovascular risk and improving quality of life are primary goals in clinical practice and research. Interventions aiming to modify cardiovascular risk factors and education focused on promoting lifestyle changes should begin during hospitalisation after an ACS. These measures should be based on a comprehensive cardiac rehabilitation (CR) programme that addresses, in a multidisciplinary way, secondary prevention before and after hospital discharge. How secondary prevention should be implemented is summarised in Figure 1. This manuscript aims to review prevention strategies, focusing especially on those that may help to improve current results, including pharmacological and non-pharmacological interventions.

Figure 1.

Summary of secondary prevention interventions after acute coronary syndromes.

Pharmacological strategies

Strengthening secondary prevention

Antithrombotic therapy

Standard antithrombotic treatment during the first 12 months following an ACS is dual antiplatelet therapy (aspirin plus one P2Y₁₂ inhibitor).⁵ Recent studies suggest that a more individualised treatment should be proposed for each patient. On the one hand, in patients with high bleeding risk, the administration of the P2Y₁₂ inhibitor could be shortened to 3–6 months.⁵ On the other hand, new evidence has highlighted different and more effective options for reducing late thrombosis recurrence by potentiating antithrombotic therapy.

The DAPT, PEGASUS-TIMI 54 and ATLAS ACS 2-TIMI 51 studies are three recent investigations (see Table 1) that proved that a more aggressive antithrombotic treatment is effective at reducing coronary events, with the additional cost of a significant increase in the incidence of major bleeding. The answer to the question of whether this reduction in thrombotic risk is worth the cost of increasing bleeding risk is still to be answered. It is clear that a better classification of patients regarding their thrombotic risk for recurrence and their bleeding risk is needed in order to provide each patient with the most appropriate treatment according to their requirements.

Table 1.

Studies suggesting a benefit of more aggressive antithrombotic treatments for secondary prevention after acute coronary syndromes.

Trial	Design	Main findings
DAPT study²²	After placing DES randomized to: – Aspirin + clopidogrel or prasugrel – Aspirin + placebo Follow-up: 12–30 months	Continuation with thienopyridine treatment beyond 12 months reduced: – Risk of stent thrombosis (HR 0.29, 95% CI 0.59–0.85) – Major adverse CV and cerebrovascular events (HR 0.71, 95% CI 0.17–0.48) – Increased risk of moderate or severe bleeding (2.5% vs. 1.6%, p = 0.001)
PEGASUS-TIMI 54²³	Double-blind 1:1:1 After a MI 1–3 years previously, randomised to aspirin plus: – Ticagrelor 90 mg b.i.d. – Ticagrelor 60 mg b.i.d. – Placebo Median follow-up: 33 months	Active treatment: – Reduced CV death, MI or stroke: ○ Ticagrelor 90 mg (HR 0.85, 95% CI 0.75–0.96) ○ Ticagrelor 60 mg (HR 0.84, 95% CI 0.74–0.95) – Increased risk of TIMI major bleeding ○ Ticagrelor 90 mg (2.60%, p < 0.001) ○ Ticagrelor 60 mg (2.30%, p < 0.001) ○ Placebo (1.06%)
ATLAS ACS 2-TIMI 51²⁴	Double-blind After an ACS, randomised to: – Rivaroxaban 2.5 mg b.i.d. – Rivaroxaban 5 mg b.i.d. – Placebo Follow-up: mean of 13 months, up to 31 months	Active treatment (2.5 mg and 5 mg): – Reduced death from CV, MI or stroke (HR 0.84, 95% CI 0.74–0.96) – Increased risk of major bleeding and intracranial haemorrhage (2.1% vs. 0.6%, p < 0.001), without a significant increase in fatal bleeding

DES: drug-eluting stent; MI: myocardial infarction; b.i.d.: twice daily; ACS: acute coronary syndrome; HR: hazard ratio; CI: confidence interval; CV: cardiovascular; TIMI: thrombolysis in myocardial infarction.

Lipid control

Lipid-lowering drugs are considered to be another essential pillar of secondary prevention. It is well established that patients with proven coronary artery disease (CAD) are considered to be at very high cardiovascular risk, and therefore the low-density lipoprotein cholesterol (LDL-C) goal in these patients must be under 70 mg/dL (or a reduction of at least 50% if the baseline is between 70 and 135 mg/dL). Intensive lipid-lowering strategies focused on reducing LDL-C decrease the recurrence of cardiovascular events; hence, this must be an absolute priority within the proposed targets. Statin therapy is fully established and has strongly demonstrated its benefits. However, in a non-negligible proportion of patients who are treated with statins alone, it is not possible or is insufficient to achieve adequate cholesterol control. In these cases, using ezetimibe or a PCSK9 inhibitor (in monotherapy or in combination) is recommended.^5,8

Ezetimibe lowers LDL-C levels by reducing intestinal cholesterol absorption. The IMPROVE-IT trial showed that ezetimibe added to statin therapy also improves cardiovascular outcomes (Table 2). The impressive reduction in LDL-C provided by PCSK9 inhibitors led to the belief that these could be useful therapies for secondary cardiovascular prevention. The recently published FOURIER trial confirmed that the addition of evolocumab to statin therapy after an ACS could further decrease a combined end point of cardiovascular death, myocardial infarction, stroke, hospitalisation for unstable angina or coronary revascularisation compared to statin therapy alone (hazard ratio [HR] 0.85; 95% confidence interval 0.79–0.92) (Table 2).

Table 2.

Studies suggesting a benefit of more aggressive lipid-lowering therapy beyond statins after acute coronary syndromes.

Trial	Design	Main findings
IMPROVE-IT²⁵	Double-blind After an ACS, randomized to: – Simvastatin 40 mg + ezetimibe 10 mg – Simvastatin 40 mg + placebo Median follow-up: 6 years	Active treatment: – Further reduced LDL-C level by 16.7 mg/dl (p < 0.001) – Reduced CV death, nonfatal MI, unstable angina, coronary revascularisation or nonfatal stroke (HR 0.93; 95% CI 0.89–0.99)
FOURIER²⁶	Double-blind With atherosclerotic CV disease, LDL-C above 70 mg/dL with statin therapy, randomised to: – Evolocumab 140 mg every 2 weeks or 420 mg monthly – Placebo Median follow-up: 2.2 years	Active treatment: – Further reduced LDL-C level by 59% (p < 0.001) – Reduced CV death, MI, stroke, hospitalisation for unstable angina or coronary revascularisation (HR 0.85, 95% CI 0.79–0.92) – No difference in adverse effects (including new-onset diabetes or neurocognitive events)

ACS: acute coronary syndrome; CV: cardiovascular; LDL-C: low-density lipoprotein cholesterol; MI: myocardial infarction; HR: hazard ratio; CI: confidence interval.

Special issues in diabetic patients with CAD

Patients with diabetes mellitus (DM) and cardiovascular disease (CVD) will benefit from innovative therapeutic options in the coming years. Currently, clinical practice guidelines advise a multifactorial approach in patients with DM after an ACS, but no specific recommendations are available for glucose-lowering drugs.⁵ However, this could change substantially after the results of the EMPA-REG and LEADER trials. The EMPA-REG trial studied cardiovascular morbidity and mortality in patients with type 2 diabetes and established CVD who were treated with empagliflozin, an SGLT-2 inhibitor. The empagliflozin group showed a significant reduction in number of deaths from cardiovascular causes (38% relative risk reduction) and hospitalisation for heart failure (35% relative risk reduction) compared with placebo.⁹ Consequently, experts suggest that SGLT-2 inhibitors should be considered early in diabetic patients with CVD.⁵ However, there is a demand for more studies that establish whether or not the results obtained with empagliflozin extrapolate to other SGLT-2 inhibitors and that help us to understand their mechanisms of benefit.

The LEADER trial had a similar approach with liraglutide, a GLP-1 agonist. This study compared liraglutide versus placebo in patients with type 2 diabetes and high cardiovascular risk and revealed lower rates of death from cardiovascular causes, nonfatal myocardial infarction and nonfatal stroke (HR of 0.87).¹⁰ Nevertheless, more research on the benefits and cost–effectiveness of GLP-1 agonists is needed.

Prevention of inflammation or anti-inflammatory treatment

There is a strong relationship between inflammation and cardiovascular risk. Inflammation occurs in the arterial wall as a response to injury caused by different cardiovascular risk factors and is one of the mechanisms of atherosclerosis. It is suspected that a state of systemic inflammation (secondary to acute infections or unbalanced inflammatory diseases) plays a role in the rupture and thrombosis of vulnerable plaques and can precede an ACS.¹¹ Consequently, several strategies aiming to stop an inflammatory condition that can trigger or perpetuate CVD are being tested, and may be considered as new therapies for secondary prevention. Based on the observation of the association between acute respiratory infections (e.g. during peak influenza virus circulation) and ACSs, some studies propose annual influenza vaccinations in patients with established CVD.⁵ More evidence is needed in order to make a firm recommendation on this issue.

Canakinumab is a specific monoclonal antibody that inhibits IL-1β and can potentially hinder inflammatory pathways. It is approved for the treatment of several rheumatic diseases and there is an ongoing trial assessing whether inhibition of IL-1β with canakinumab could reduce the recurrence of cardiovascular events in patients with ACSs and persisting inflammation. The results of the CANTOS trial will clarify whether there is a role for this new strategy in order to improve secondary cardiovascular prevention.¹²

Advances in treatment efficiency

Just as important as advancing research into better drugs that are focused on reducing residual risk after an ACS is to enable patients to benefit from these treatments. It is known that adherence to medication in individuals with CVD is low.¹³ This is one of the major problems in secondary prevention.⁵ Improving adherence to treatment is a persistent challenge and more efforts are needed in order to identify the reasons underlying poor adherence to medication. Generally, these are asserted to be multifactorial. Some examples are cost-related problems, non-detected or non-treated depression and patient’s poor understanding of their disease and the importance of treatment.¹⁴ Simplifying the treatment regime to the lowest acceptable level is strongly recommended.

There are also pharmacological measures aimed at improving adherence to treatment. The best example is study of the role of a polypill in simplifying secondary prevention treatments in order to improve compliance, which could lead to long-term clinical benefits in high-risk patients. This hypothesis is currently being investigated in the international multicentre clinical trial Secondary prEvention of CardiovascUlaR disease in the Elderly (SECURE; ClinicalTrials.gov identifier: NCT02596126).

Improving patient selection

Advances in pharmacological treatment are promising, yet all of these treatments are expensive and can have significant side effects. We need to emphasise the necessity of developing better tools that allow us to identify, in an accurate way, the highest-risk patients who are most likely to benefit from a very intensive preventive approach, thereby improving risk–benefit and cost–effectiveness ratios. It is known that factors indicating increased overall residual risk after the first year differ slightly from risk factors of recurrence during the first 12 months. Those patients who, after an ACS, continue to smoke, have major vascular disease burden or renal impairment or who do not receive initial coronary revascularisation are at greater risk of long-term recurrence.¹⁵

Moreover, there is a need to clarify the power of different genetic markers when differentiating high-risk patients. However, the generally used DNA-based test for cardiovascular risk assessment is currently not recommended due to a lack of agreement regarding which genetic markers should be included or calculated.⁵ Therefore, future studies should assess the clinical benefits and cost–effectiveness of the inclusion of genetic data in risk assessments or scores.

Non-pharmacological strategies

Despite sophisticated advances in new drugs aimed at reducing residual cardiovascular risk in patients with previous ACSs, a significant number of patients live in highly toxic environments that increase vascular risk. The situations that may negatively influence the prognosis of CVD are mainly due to fundamental issues that are usually underestimated or omitted in daily clinical practice. For example, patients with a lack of social support, low socioeconomic status, excessive stress at work and/or undetected depression or anxiety are at greater risk of continuing to smoke, making unhealthy food choices, achieving inadequate physical activity and having poor adherence to medication. These factors place them at greater risk of recurrence of vascular events.^16,17 Consequently, more efforts are needed in order to reinforce non-pharmacological strategies.

Investing more time and developing better skills that effectively communicate to patients their diagnosis and prognosis may improve their understanding of the chronic nature of their condition and the vital importance of lifestyle modification in order to reduce future adverse events and improve quality of life. Therefore, it is essential to encourage the creation of multidisciplinary teams that work together to optimise all aspects of secondary prevention: cardiologists, rehabilitators, psychiatrists, psychologists, specialised nurses, dieticians, physiotherapists and social services should be coordinated with the same focus.

The appropriate framework for the organisation and coordination of such multidisciplinary teams and the centrepiece of secondary prevention should be a CR programme. CR is an efficacious and cost-effective intervention for reducing mortality, morbidity and improving quality of life in patients with CAD. Therefore, CR is recommended with the highest level of scientific evidence by international guidelines.¹⁸ However, there is still suboptimal utilisation of CR, and almost 50% of patients after experiencing an ACS do not participate in a CR programme. Recent publications highlight independent predictors of non-referral as being older age, female sex, past stroke, heart or renal failure, prior myocardial infarction and lack of an in-hospital CR centre.¹⁹ Systematic referral and participation in CR must increase and should be encouraged by the acute care team. It is important to start with an appropriate prevention strategy before hospital discharge, as greater benefits have been achieved in adherence and prognosis when this occurs.^13,20

A CR programme should be designed and developed as a multifaceted and multidisciplinary intervention that must include not only supervised physical activity, but also every other aspect of secondary prevention (see Box 1). Planning for CR should provide sufficient time for giving advice and accomplishing health education for patients, and the opportunity should be taken to evaluate social support and screen patients for psychosocial risk factors that may worsen their prognosis. The establishment of cognitive–behavioural strategies in order to facilitate lifestyle modifications in patients with difficulties is strongly recommended.⁵ The longer the duration and more general the intervention programme is, the better the results that are obtained.²¹

Box 1.

Cardiac rehabilitation components and targets.

Routine clinical assessment ○ Clinical history: cardiovascular symptoms, adherence to medication ○ Screening for unknown/suboptimal cardiovascular risk factor and comorbidities: ▪ Blood pressure monitoring ▪ Lipid control and medication optimization ▪ Diabetes mellitus screening and medication adjustment ○ Electrocardiogram and cardiac imaging

Exercise training and physical activity counselling and supervision ○ Guided by exercise testing and occurring in hospital during initial phases

Promote lifestyle changes and cognitive–behavioural strategies that help to incorporate changes into daily routine ○ Advice and health education on the chronic nature of coronary artery disease ○ Diet and nutritional counselling ○ Weight control management ○ Smoking cessation

Psychosocial management ○ Social support when experiencing social isolation or of low socioeconomic status ○ Stress and anxiety ○ Depression ○ Sexual dysfunction

There is no definitive evidence for determining which is the best CR schedule. New alternatives in CR models that achieve the more cost-effective profiles and that ensure the participation of all patients during the programme and their continuity once it is finished should be explored. For example, nurse-led programmes or home-based rehabilitation (with or without tele-monitoring) may offer greater flexibility and, as a result, may increase patient participation. Moreover, long-term support and maintenance programmes may be needed in order to increase the possibilities of patients successfully achieving lifestyle changes.

In addition to all of interventions that are focused on the individual level, we cannot forget all of the possibilities for improvement that exist at the population level. Small changes in the risk of disease across a whole population lead to greater reductions in disease burden than larger changes on an individual level.⁵ For this reason, it is crucial that health professionals, through individual actions and professional associations, advocate to promote a healthy lifestyle throughout the population.

Conclusions

Secondary prevention of CVD should be implemented and carried out at any location and at any time, from pharmacological treatments in each individual to policies at the national level. A range of diverse approaches has proven to be a clinical necessity. Therefore, health care professionals have the responsibility of continuing with research into developing future prevention strategies that lead to the definition of better tactics in long-term prevention. The direction that this investigation will take in the future is not clear. Will it continue searching for stronger and more expensive drugs, or is it possible that this clinical research model is approaching the threshold of acceptable complications and economic cost for the additional benefits it provides to patients? Probably a key for success will be to learn how to identify which patients are at very high risk of recurrent events after an ACS, so that greater efforts can be focused on them. Notwithstanding the potential for innovation in personalised medicine, there is still huge room for improvement in secondary prevention at personal and societal levels, and efforts should focus on the development of the innovative strategies discussed in this article.

Footnotes

Acknowledgements

The Centro Nacional de Investigaciones Cardiovasculares is supported by the Spanish Ministry of Economy and Competitiveness (MINECO) and the Pro-CNIC Foundation, and is a Severo Ochoa Center of Excellence (MINECO award SEV-2015-0505).

Author contribution

AC-B contributed to the conception and design of the study, contributed to data acquisition, drafted the manuscript, critically revised the manuscript and gave final approval. DF contributed to the conception and design of the study, contributed to data acquisition, drafted the manuscript, critically revised the manuscript and gave final approval. AP contributed to the conception and design of the study, contributed to data acquisition, drafted the manuscript, critically revised the manuscript and gave final approval. GM contributed to data acquisition, analysis and interpretation, critically revised the manuscript and gave final approval. RM-A contributed to data acquisition, analysis and interpretation, critically revised the manuscript and gave final approval. HB contributed to the conception and design of the study, contributed to data acquisition, drafted the manuscript, critically revised the manuscript and gave final approval.

All agree to be accountable for all aspects of the work, ensuring its integrity and accuracy.

Declaration of conflicting interests

The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: AC-B has no conflicting interests. DF has no conflicting interests. AP has no conflicting interests. GM has no conflicting interests. RM-A has received consulting fees from Astra-Zeneca. HB receives research funding from the Instituto de Salud Carlos III (PIE16/00021), Astra-Zeneca, BMS, Janssen and Novartis; is Scientific Coordinator of the SECURE trial; has received consulting fees from Abbott, Astra-Zeneca, Bayer, BMS-Pfizer and Novartis; and has received speaking fees or support for attending scientific meetings from Astra-Zeneca, Bayer, BMS-Pfizer, Ferrer, Novartis, Servier and MEDSCAPE-theheart.org.

Funding

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

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