Editor's Note: Commentary based on Reiner Z, Laufs U, Cosentino F, Landmesser U. The year in cardiology 2018: prevention. Eur Heart J 2019;40:336-44.

Introduction
2018 was an incredible year for preventive cardiology. Numerous observational studies provided insight into the impact lifestyle can have on cardiovascular disease (CVD) risk. New information on the role of SGLT-2 inhibitors in CVD and heart failure became available. Further data on the efficacy and safety of renal denervation in hypertension was provided by randomized clinical trials (RCTs).

Several large-scale studies sought to clarify the role of aspirin in primary prevention of cardiovascular disease. New data for PCSK9 inhibition and recommendations for their use in clinical practice became available and although two RCTs and a large meta-analysis appeared to have signaled the end for n-3 fatty acids in preventive cardiology, one of the most important trials of the year may have found their niche.

Publications in 2018 reported

• Smoking one cigarette a day is associated with approximately 50% of the cardiovascular risk as smoking 20 cigarettes a day.
• Reducing the sodium-potassium ratio in conjunction with lowering dietary sodium intake further decreases the risk of stroke.
• Simple algorithms may assist in the diagnosis of familial chylomicronemia and type III hyperlipidemia.
• Work stress and workplace bullying is associated with increased CVD risk.
• Walking in an urban park has more cardiopulmonary benefit than walking along a busy downtown street.
• Initial antihypertensive therapy with a two-drug combination preferably in a single pill was recommended by the 2018 European guidelines.

Lifestyle
A unique multi-cohort European study (102,633 individuals) assessed the association of work stress with mortality. The presence of job-strain and effort-reward imbalance were indicators of work stress. Increased work stress in men with known cardio-metabolic disease was associated with increased mortality whilst in all women and men without cardio-metabolic disease this association was not present. Similarly, a multi-cohort study of 79,201 individuals from Denmark and Sweden found that being bullied at work and workplace violence were associated with increased CVD, with population attributable risks of 5% and 3% respectively.

Obesity
Further studies demonstrated a near linear relationship between increasing adiposity and CVD, while the DIETFITS (Diet Intervention Examining the Factors Interacting With Treatment Success) trial demonstrated no significant difference in weight loss between a healthy low-fat diet and a healthy low-carbohydrate diet. The CAMELLIA-TIMI 61 (Cardiovascular and Metabolic Effects of Lorcaserin in Overweight and Obese Patients – Thrombolysis in Myocardial Infarction 61) trial again demonstrated the weight loss benefits of lorcaserin in obese and overweight individuals. Reassuringly no increase in CVD risk was found.

Salt
A systematic review and meta-analysis reinforced the association between increased sodium intake and CVD risk. It also highlighted the importance of the sodium-potassium ratio and suggested reducing the Na:K ratio in concert with reducing overall sodium intake to mitigate stroke risk.

The PURE (Prospective Urban Rural Epidemiology) study suggested that not all people need to reduce their salt and "insufficient" salt intake may be harmful. They recommend encouraging salt reduction in communities with sodium intake >5g/day whilst also encouraging most individuals to increase the consumption of potassium rich foods (such as fruits and vegetables).

Environmental Pollution
A rather unique study randomized individuals with stable ischemic heart disease, COPD or matched healthy volunteers to a walk down a busy commercial street in London (Oxford Street) or through a large urban park located less than a mile away (Hyde Park). It found that favorable cardiopulmonary effects of exercise, as determined by augmentation index and pulse wave velocity, were reduced in all groups exposed to traffic pollution.

Smoking
Patients are often concerned about weight gain following smoking cessation. Investigators in Korea grouped a cohort of >100,000 men into sustained smokers, quitters with BMI gain, quitters without BMI change, quitters with BMI loss and non-smokers. Compared with sustained smokers the risk of myocardial infarction was significantly reduced in both quitters with BMI gain (HR 0.33) and without BMI change (HR 0.55) but no significant risk reduction was noted in quitters with BMI loss.

An especially useful study for clinicians to be aware of investigated the belief held by many patients that smoking very few cigarettes is safe. This meta-analysis of 141 cohort studies published in the British Medical Journal surprisingly found that people who smoke one cigarette a day have approximately 50% of the risk of coronary heart disease or stroke as those who smoke 20 cigarettes a day.

Omega-3 Fatty Acids
The effects of omega-3 fatty acids on CVD risk were heavily assessed this year and have been recently discussed in detail elsewhere on acc.org. In brief, a meta-analysis of 78,000 patients showed no reduction in cardiovascular events with n-3 fatty acids compared with placebo. Consistent with this were the VITAL (Vitamin D and Omega-3) and ASCEND (A Study of Cardiovascular Events iN Diabetes) studies both of which failed to demonstrate a benefit in primary prevention in a broad population and individuals with diabetes, respectively. Both studies used a 1g per day fish oil capsule containing 840mg of n-3 fatty acids, including 460mg of eicosapentaenoic acid (EPA) and 380mg of docosahexaenoic acid (DHA) as recommended by the American Heart Association for secondary cardiovascular prevention. Of course, REDUCE-IT (Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial) discussed below put the attention back on higher doses of pure EPA.

Dyslipidemia
A major headline RCT of 2018 was REDUCE-IT, which assessed the effects of high dose icosapent ethyl (a derivative of the n-3 fatty acid EPA) in 8,179 high CVD risk patients with hypertriglyceridemia who were also receiving a statin. The study's primary endpoint was a composite of CV death, MI, stroke, coronary revascularization and unstable angina. There was a 25% relative risk reduction (HR 0.75; 95% CI 0.68–0.83). Key to this trial were the specific population included and the specific formulation of drug used, both of which may explain the better outcomes than seen in the other n-3 fatty acid trials discussed above.

The ODYSSEY Outcomes (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) study was the second major clinical outcomes trial assessing the effect of PCSK9 inhibitors. It found that the addition of alirocumab to a statin in patients post-acute coronary syndrome with an LDL-C level ≥70 mg/dL, non-HDL-C level ≥100 mg/dL or apolipoprotein B ≥80 mg/dL reduced the relative risk of recurrent ischemic cardiovascular events by 15% (HR 0.85; 95%CI 0.73-0.98). Similar to the recently published 2018 ACC/AHA Guideline on the Management of Blood Cholesterol, a pragmatic recommendation for the use of the PCSK9 inhibitors in clinical practice, including both alirocumab and evolocumab, were published by a joint task force of the European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS).

Further analysis of the ORION-1 (LDL-C Reduction From 6 to 9 Months Following Single or Second Injection of Inclisiran a Novel siRNA Compound) trial originally published in 2017 demonstrated that inclisiran, a small interfering RNA, produced significant reductions in a number of atherogenic lipoproteins. This supports the potential future use of an alternative modality of PCSK9 inhibition to the monoclonal antibodies evolocumab and alirocumab currently available.

Familial chylomicronemia (Fredrickson's Type I hyperlipidemia) is a rare inherited disorder resulting from lipoprotein lipase deficiency and is associated with increased risk of hypertriglyceridemia and pancreatitis. Guidance for the diagnosis using an algorithmic based diagnosis tool was published by a panel of European experts to assist with identification of high-risk individuals and limit the need for systematic genotyping. Interestingly a similar algorithmic approach to diagnose Type III hyperlipidemia was also recently published utilising apoB levels and a standard lipid panel.

Arterial Hypertension
The 2018 European Society of Cardiology and European Society of Hypertension (ESC/ESH) guidelines on arterial hypertension did differ in some ways than the 2017 ACC/AHA counterparts. The definitions, treatment thresholds, and treatment targets, were more conservative. In a somewhat controversial move, a class I recommendation was given to initiate anti-hypertensive treatment with a two-drug combination, preferably in a single pill (exceptions being those who are frail, at lower CVD risk and those with grade I hypertension).

A class I recommendation was also given to the addition of low-dose spironolactone to current therapy or the addition of further diuretic therapy if intolerant of spironolactone. The guidelines did not recommend the use of device-based therapies unless in the setting of a clinical trial; in fact there were plenty of such trials published in 2018.

The SPYRAL HTN OFF-MED and RADIANCE-HTN SOLO studies assessed the effects of different renal artery ablation techniques on patients with mild hypertension off pharmacologic therapy. Likewise, SPYRAL HTN ON-MED studied a cohort of patients with uncontrolled hypertension who continued their pharmacologic therapy. All 3 studies were randomized with sham procedure controls and each demonstrated statistically significant reductions in blood pressure in the short term.

Diabetes
A post-hoc analysis of the landmark EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial assessing patients with diabetes and established CVD found almost 30% of the patients had a high or very high 5-year risk for heart failure. The study suggested that SGLT2 inhibitors could be effective in the prevention of heart failure.

Support for this finding came from the DECLARE-TIMI 58 (Dapagliflozin Effect on Cardiovascular Events – Thrombolysis in Myocardial Infarction 58) trial. Whilst there was a reduction in cardiovascular death and hospitalizations for heart failure, the trial failed to demonstrate a reduction in major adverse cardiac events with dapagliflozin compared with placebo. Furthermore, a meta-analysis including the three major CVOTs (assessing empagliflozin, canagliflozin and dapagliflozin) reiterated the robust benefits SGLT2 inhibitors have on reducing heart failure hospitalizations and progression of renal disease in patients with diabetes regardless of existence of known CVD or prior HF.

Aspirin
The role of aspirin in primary prevention was one of the most studied topics of 2018. One of three major randomized clinical trials, ASCEND, compared aspirin with placebo in patients with diabetes mellitus without CVD. Aspirin led to a significant reduction in serious vascular events including myocardial infarction, stroke, transient ischemic attack or death from any vascular cause excluding confirmed intracranial hemorrhage (rate ratio 0.88; 95% CI 0.79-0.97). This came at a cost of major bleeding, driven primarily by gastrointestinal bleeding (rate ratio 1.29; 95% CI 1.09-1.52). The conclusion was that there was a significant reduction in cardiovascular events which was counterbalanced by the bleeding hazard. It is worth noting that only one in four patients were being treated with a proton pump inhibitor (PPI) by the end of the study and a meta-analysis also published this year found that PPIs substantially protect from upper GI bleed with an odds ratio of 0.20, although these drugs are not without risks themselves.

ARRIVE (A Randomized Trial of Induction Versus Expectant Management) assessed the role of aspirin for primary prevention in individuals >55-60 years old at intermediate risk for CVD. However, the event rate was much lower than expected which made the study more representative of a low-risk population. There was no reduction in MACE and although numbers of bleeding complication were low, increased bleeding was noted in the aspirin group.

ASPREE (Aspirin in Reducing Events in the Elderly) assessed the effects of aspirin on all-cause mortality in 19,114 community dwelling healthy individuals >70 years old. Aspirin "did not prolong disability-free survival but led to a higher rate of hemorrhage than placebo". However, it is worth noting that the higher all-cause mortality was mostly due to a higher cancer-related death, which was unexpected and therefore should be interpreted cautiously.

Although a summary statement for these three randomized clinical trials could be that aspirin is not indicated in primary CVD prevention including individuals with diabetes without very high cardiovascular risk and the elderly it is worth remembering the caveats that have come with each trial.

In contrast to primary prevention, the protective role of aspirin in secondary CVD prevention is clear and the enormous COMPASS (Rivaroxaban for the Prevention of Major Cardiovascular Events in Coronary or Peripheral Artery Disease) trial found a reduction in mortality (HR 0.77 95% CI 0.65-0.90) with the addition of low dose rivaroxaban to aspirin.

Inflammation
Further studies investigated the findings of the landmark CANTOS (Cardiovascular Risk Reduction Study) trial, originally published in 2017, which demonstrated a reduction in cardiovascular events in individuals post-acute coronary syndrome and an hsCRP >2mg/L. These studies found that patients with elevated CRP have a higher risk of CVD and therefore might derive more benefit from PCSK9 inhibitors and confirmed the effects of canakinumab in chronic kidney disease patients.

Conclusion
2018 was remarkable for the numerous headline-grabbing preventive cardiology studies involving aspirin, omega-3 fatty acids, diabetes mellitus and dyslipidemia. Further studies provided critical insight into how minimal smoking, potassium intake and the environment can affect cardiovascular disease. The role for novel antithrombotic, lipid and anti-diabetic drugs and strategies in reducing cardiovascular risk are becoming clearer which will help us guide our patients to avoid and minimize the impact of cardiovascular disease.

Keywords: Dyslipidemias, Primary Prevention, Secondary Prevention, Life Style, Obesity, Salts, Sodium, Dietary, Environmental Pollution, Smoking, Smoking Cessation, Fatty Acids, Omega-3, Hypertension, Hypertension, Pulmonary, Diabetes Mellitus, Diabetes Mellitus, Type 2, Aspirin, Inflammation, Acute Coronary Syndrome

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