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Dr. Ángel Morales-Martinez de Tejada
Dr. María Pilar Abaurrea-Ortiz
In this paper we review current information about secondary prevention in coronary artery disease (CAD) patients which has emerged from recent trials. The REGARDS epidemiological study was a prospective cohort of patients with stable coronary disease between 2003 and 2007. Its key point was the control of certain variables (using similar objectives to those found in the COURAGE trial) where only 1% of patients met all of them. The five-year results of the SYNTAX randomised clinical trial demonstrated that optimal medical treatment (OMT) is more important than the method of revascularisation, especially in those undergoing PCI (HR 0.65, 95% CI: 0.44-0.95; p=0.027) where optimal medical treatment was seen to reduce the combined endpoint of myocardial infarction (MI), stroke and death (HR 0.73, 95% CI: 0.58 -0.92; p=0.007). Results can be different in diabetics and/or patients suffering from multivessel disease (FREEDOM, BARI 2D, MASS II). However, the real problem is lack of adherence to medical treatment, as seen in the REACH registry. Little information is seen about abnormal ejection fraction (STICH).
This paper presents a telescopic review of the different trials involving coronary artery disease (CAD) and secondary prevention. We have found wide methodological and participant/selection variability. Another point of interest was the low representation of some types of individuals.
COURAGE  and REGARDS  variables were the most demanding. Lifestyle-related variables such as weight control (or body mass index [BMI] control) and physical activity were not considered in the vast majority of studies or had a low compliance rate.
Optimal medical treatment (OMT) has been demonstrated to be necessary for the prevention of major adverse cardiac events (MACE), even more so than other strategies, as reflected in the SYNTAX follow-up . Compliance with OMT points a finger straight at patients and their medical systems. The multidisciplinary and special approach needed for complex patients, such as diabetics, was seen in the BARI 2D  and FREEDOM  studies; kidney disease, elderly, multivessel disease were examined in the COURAGE , FREEDOM  and STICH (which also included patients with these conditions “and/or” reduced left ventricular ejection fraction)  studies.
We reviewed a number of studies which represent several complementary approaches to secondary prevention after a coronary event (Table 1).
Non-clinical trial design involving 30,239 subjects. It determined the proportion of subjects with CAD and optimal risk factor levels.
A randomised clinical trial (RCT) that assigned multivessel CAD diabetic patients (DM) to percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). All 1,900 subjects were treated with medical therapy for secondary prevention.
BARI 2D 
RCT in which 2,368 type 2 DM and CAD patients were randomised to prompt revascularisation plus medical therapy or medical therapy alone.
A prospective trial comparing CABG plus medical therapy to medical therapy alone in 1,212 ischaemic cardiomyopathy patients with low ejection fraction.
RCT of 2,287 ischaemic disease patients comparing PCI plus optimal medical treatment (OMT) to OMT alone.
RCT of 1,800 individuals with complex CAD, randomised to PCI or CABG. The entire cohort was treated with OMT. Five-year follow-up is also reviewed here.
MASS II 
RCT comparing a 10-year follow-up of PCI, CABG or medical treatment in 611 patients with multivessel CAD, stable angina and normal ejection fraction.
A registry involving 37,154 patients suffering from atherosclerotic disease. Adherence to secondary prevention treatments was evaluated.
PREVENT IV 
A prospective trial including 2,970 patients who underwent CABG evaluating the effect of secondary prevention medical treatment.
Table 1. List of trials and their aims reviewed in this paper.
We observed a poor representation of some subgroups of individuals, as illustrated in Table 2:
older than 75 years.
female: 15% in COURAGE and 35% in REGARDS.
diabetes mellitus [4,5].
kidney disease: [2,4].
left ventricular systolic dysfunction: STICH complete cohort and 5% of the FREEDOM population.
multivessel disease: 30% in COURAGE, 60% in STICH and 80% in FREEDOM.
prior/recent myocardial variable, displayed in about 50% of individuals.
Variables were recorded systematically but in some cases were collected on a self-reporting basis. Biases were frequent, as there were different inclusion criteria and sometimes specific population areas selected, such as the stroke belt area in REGARDS . Some historical trials provided explicit information on medical treatment [7,8]; however, only one contemporary one did so .
Name of trial
SYNTAX 5 yr
Table 2. Therapeutic control targets in each trial.
ACEI: angiotensin-converting enzyme inhibitor; BMI: body mass index; DAT: diastolic arterial tension; GFR: glomerular filtration rate; HDL: high-density lipoprotein; LDL: low-density lipoprotein; SAT: systolic arterial tension
The COURAGE trial raised an interesting point in relation to the following variables to control: use of acetyl-salycilic acid (ASA), systolic and diastolic blood pressure control (130/85), low-density lipoprotein (LDL), high-density lipoprotein (HDL), triglycerides and glycaemic control (<70, >40, <150, HbA1c <7%), smoking cessation, 10% relative weight loss if the baseline BMI was >27.5 kg/m2, exercise 30-45 minutes five times per week. Based on this, REGARDS goals were even more demanding (aspirin use, systolic blood pressure <130 mmHg, diastolic blood pressure <85 mmHg, LDL <85 mg/dl, HDL >40 mg/dl, triglycerides <150 mg/dl, fasting glucose <126 mg/dl, non-smoking status, BMI <25 kg/m2 and exercise >3 days per week). FREEDOM reduced them to: systolic and diastolic pressure, LDL, HDL and glycaemic control and smoking cessation. Meanwhile, SYNTAX variables considered the use of OMT, such as AAS, statin, beta-blockers and angiotensin-converting enzyme (ACE) inhibitors. The latter trial provides specific information on the medical treatment employed in revascularised patients, but records were based on self-reported information.
Beta-blocker use was considered in a minority of them and exercise and BMI variables only in COURAGE and REGARDS. Other variables were widely represented.
When comparing OMT information and revascularisation, we referred to COURAGE and SYNTAX.
BARI 2D included diabetic subjects and provided systematic glomerular filtration rate (GFR) information too.
Taken together, these results lead us to the following observations, namely that smoking cessation, glycaemic control, blood pressure control, lipid control/using statins and aspirin use were well represented and had a high achievement rate (Table 3).
Table 3. Percentages in trials for patients under control/treatment for each variable.
BMI: body mass index; CABG: coronary artery bypass grafting; HT treat: hypertension treatment; Initial/Fup: initial percentage/follow-up percentage; PCI: percutaneous coronary intervention
Beta-blockade has not been considered as part of OMT in the vast majority of studies analysed. However, the achievement rate, when considered, was high [1,3,9,10].
Physical activity was valued as one medical target in REGARDS (exercise more than three days per week) and COURAGE (at least 30 to 45 minutes of moderate activity five times per week or vigorous activity three times per week), with a low response rate (25%). These studies were not designed to find out causal event-rate relationships related to exercise. BMI was controlled in 22% and 29%, respectively. Inability to reach these goals might be due to their relationship to lifestyle, the most difficult to achieve in our experience.
The SYNTAX trial five-year follow-up has shown that OMT reduces mortality by 36% and is an independent predictor of long-term survival. OMT (defined as the use of antiplatelet agents, statin, ACE inhibitors and beta-blockers) was an overall mortality predictor (HR 0.64, 95% CI: 0.48-0.85; p=0.002), also in the PCI cohort (HR 0.65, 95% CI: 0.44-0.95; p=0.027). In the cardiac surgery group, there was a trend in the same direction (HR 0.71, 95% CI: 0.44-1.05; p=0.159). It also reduced the combined death/MI/stroke rate (HR 0.73, 95% CI: 0.58-0.92; p=0.007).
MASS II data revealed that MACE at 10-year follow-up in relation to primary endpoints was more frequent in the medical treatment group vs. PCI vs. CABG (59%, 42% and 33%) and p (log-rank) <0.001 . Nowadays, secondary prevention goals are more aggressive  and new DES have appeared . These limit the contributions mentioned. However, one idea has not changed, namely the importance of OMT after revascularisation by either PCI or CABG [1,4,6,11] and the efforts to be made to improve compliance.
The need for a complete revascularisation loses importance if the left anterior vessel has been treated [4,11,14].
The event rate at five years for stable coronary disease diabetic displayed no differences between medical treatment and revascularisation, without significant differences in MACE, except in the subgroup of patients who had a CABG indication .
In the case of multivessel disease and low ejection fraction, the addition of CABG to medical therapy reduced sudden death (HR 0.73, 95% CI: 0.54-0.99; p=0.041), pump failure and fatal events (HR 0.64, 95% CI: 0.41-1.00; p=0.05) .
For treatment in multivessel disease diabetic patients, we can be guided by the results of FREEDOM. It demonstrated that OMT plus DES was less effective than CABG (primary outcome - combined death/MI/stroke - p=0.005 by log-rank test at five years, event rate 26.6% vs. 18.7%), although the CABG group showed a higher stroke rate (2.4 vs. 5.2%, p=0.03). In multivessel disease non-diabetic patients, we used COURAGE. It showed that OMT matched the results of PCI (HR 1.05, 95% CI: 0.87-1.27; p=0.62) with a large and demanding therapeutic target limitation (Table 1). The whole cohort comprised patients with stable CAD, and only 30% had multivessel disease, excluding unprotected left main and patients with abnormal LVEF. It looked very different from our clinical practice.
Overall patient profile was as follows: white, male, under 75 years old, not including diabetics, renal failure, ventricular dysfunction, multivessel disease or recent MI. These make up the higher event risk group, so, for these trials, external validity is poor. Things must change, if we do not want any surprises.
Preventing a new coronary event requires control of the variables recognised in secondary prevention. Some of these are related to changes in lifestyle (physical activity, BMI, smoking cessation) and some are control variables such as blood pressure, lipids, glucose, beta-blockade and antiplatelet therapy. No doubt the underlying issue is the metabolic syndrome. We face a progressively older polymedicated population and aggregation of an increasing number of risk factors that are largely unrepresented in population studies. We need a real and simplified therapeutic approach.
Demanding OMT objectives are required to be set by the medical profession and therapeutic commitment is required of patients in order to obtain the same good long-term results in patients receiving OMT as those obtained in patients revascularised by CABG and PCI. Novel treatments and the development of new DES  could change the results previously obtained.
Unfortunately, less than 50% of patients meet all the objectives in secondary prevention . When the objectives are more demanding , only 1% reach them - quite amazing when you consider that this occurs within clinical trials.
In those who fulfilled initial treatment requirements but did not maintain adherence, the results were consistently worse without differences from non-adherents. This was reflected in MACE rates at one and four years in REACH, where the term negative converters was used. It is our job to avoid such conversions and facilitate positive converters.
As described by some authors , "our model of socio-demographic factors only partially explains the variability in controlling risk factors", resulting in the need for a multidisciplinary approach and government support for implementation and development.
Dr Ángel Morales-Martinez de Tejada1, MD
Dr María Pilar Abaurrea-Ortiz2, MD
1. Cardiologist, Acute Cardiac Care Unit, Cardiology Department, Badajoz University Hospital, Badajoz, Spain
2. Family and Community Medicine Specialist, San Juan de Aznalfarache Community Center, Seville, Spain
Author for correspondence:
Dr Angel Morales-Martinez de Tejada, Calle Ramón Fernández Moreno, número 12, bloque 3, portal 1, primero A, 06006 Badajoz, Spain
Conflict of interest:
The authors have no conflicts of interest.
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