Cardiovascular risk factors such as hypertension and diabetes are understood to trigger a sequence of pathological events starting from hypertension and atherosclerosis, which if left unmanaged can ultimately progress to end-stage cardiovascular disease. This chain of events is termed the cardiovascular continuum. The angiotensin-converting enzyme inhibitor, perindopril, has marked restorative effects on endothelial dysfunction and this translates into clinical benefits for patients at all stages of the continuum, making it a highly effective treatment in cardiovascular disease. In hypertensive patients, large-scale clinical trials have shown that perindopril-based treatments reduce morbidity and mortality and reduce the onset of stroke, renal failure, and diabetes when compared with other anti-hypertensive therapies. In patients at more advanced stages of the cardiovascular continuum, the use of perindopril on top of other standard management practices further improves long-term prognosis in coronary artery disease. Perindopril also reduces cardiac remodelling following myocardial infarction and improves patient symptoms and prognosis in diastolic heart failure. Current trial evidence confirms the clinical benefits of perindopril throughout the cardiovascular continuum, thus slowing the progression of cardiovascular disease and improving patient prognosis.
The term ‘cardiovascular continuum’ was coined in 1991 by Dzau and Braunwald1 to describe cardiovascular disease as a sequence of related pathological events. In this model, the progression of cardiovascular diseases starts from risk factors such as hypertension and diabetes leading through coronary artery disease (CAD) and myocardial ischaemia, to congestive heart failure (HF) and end-stage heart disease (Figure 1A).1,2 Thus, a hypertensive patient, if left unmanaged, can be predicted to progress down the cardiovascular continuum and develop CAD. Similarly, a CAD patient has a greater risk of more serious cardiovascular outcomes such as myocardial infarction (MI), stroke, or HF. It should be noted, however, that individuals do not progress down the cardiovascular continuum at the same rate. For example, MI may suddenly occur after years of asymptomatic CAD. Appropriate management of patients throughout the cardiovascular continuum is crucial in order to slow—or even arrest—this decline, thereby reducing morbidity and mortality in this population.
In 2001, Dart and Kingwell3 described a second continuum, which appears to underlie the cardiovascular continuum. This ‘pathophysiological continuum’ is a vicious circle of endothelial damage and mechanical fatigue, atherosclerosis, arterial stiffening, increased central wave reflection, and increased pulse pressure (PP) and central aortic blood pressure (BP) (Figure 1B).3 This spirals down the cardiovascular continuum and accelerates the progression of cardiovascular disease (Figure 1A). For example, at the beginning of the cardiovascular continuum, endothelial damage due to increased PP starts a series of events that aggravate hypertension leading to atherosclerosis and CAD. Another example, at a later stage, is continuing endothelial dysfunction in CAD patients, which triggers myocardial ischaemia and MI. The most effective management strategies for patients break the pathophysiological continuum and stop progression down the cardiovascular continuum.
Angiotensin-converting enzyme inhibition and the cardiovascular continuum
Angiotensin-converting enzyme (ACE) inhibitors are widely used for the treatment of hypertension and HF and for secondary prevention in CAD. Among the ACE inhibitor class, perindopril has marked restorative effects on endothelial function,4 thus inhibiting the pathophysiological continuum. In this article, we shall see how this translates into clinical benefits at all stages of the cardiovascular continuum by reviewing the evidence for perindopril in hypertension, diabetes, stroke, CAD, post-MI, and HF.
Hypertension is a major risk factor for the onset of cardiovascular and renal disease and is a triggering factor for entry of individuals into the cardiovascular continuum (Figure 1A). In 2000, hypertension was estimated to be present in 26% of the world's population and, by 2025, this is predicted to increase by 60% and so to affect 1.56 billion people.5,6 Although awareness and management of hypertension have improved during the last two decades, the treatment of many hypertensive patients remains suboptimal,5 and as many as 30% do not achieve adequate BP control.7 Furthermore, 30% of the hypertensive patients remain unaware of their condition, leaving diagnosis to be made at a late stage when accelerated decline down the cardiovascular continuum has already occurred, resulting in end-organ damage.5 The main target of management in hypertension should be to arrest the pathophysiological continuum and prevent entry or decline down the cardiovascular continuum (Figure 1A and B).
Currently recommended targets for the management of hypertension are <140/90 mmHg.5,8 ACE inhibitors are recommended as first-line therapy in the management of hypertension in patients aged <55 years and in those with compelling indications such as HF, left ventricular (LV) dysfunction, MI, diabetes, or recurrent stroke.8 Perindopril has proven anti-hypertensive efficacy and is well tolerated with low rates of cough and first-dose hypotension.9,10 With one of the highest trough-to-peak ratios of the ACE inhibitor class, perindopril provides 24-h anti-hypertensive coverage in a single daily intake.11 A primary healthcare trial in over 13 000 patients demonstrated that monotherapy with perindopril reduces BP by −19.7/10.5 mmHg in the general hypertensive population and by −14.9/8.4 mmHg in patients unresponsive to other anti-hypertensive agents.12,13
Combination therapy in hypertensive patients
The use of more than one anti-hypertensive agent is often necessary to achieve target BP and prevent target-organ damage.14–16 In this context, perindopril has been confirmed as a suitable choice for fixed-combination therapies in hypertension, notably with the thiazide-like diuretic, indapamide.14–16 The potential advantages of combining perindopril with the calcium channel blocker amlodipine were highlighted in the large-scale, randomized, double-blind Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT).17
ASCOT included hypertensive patients (n = 19 257) at moderate cardiovascular risk who were randomly allocated to BP lowering with amlodipine, with the addition of perindopril as required, or beta-blocker, or with the addition of diuretic as required. After a median of 5.5 years, ASCOT was stopped prematurely because the amlodipine/perindopril group showed an 11% reduction in all-cause mortality (P = 0.0247), compared with beta-blocker/diuretic. The early termination of ASCOT reduced the power of the study, and the relative risk reduction (RRR) of −10% in the primary endpoint (non-fatal MI including silent MI and fatal coronary heart disease) with amlodipine/perindopril did not reach statistical significance. Nevertheless, treatment with amlodipine/perindopril significantly reduced a range of other endpoints, including cardiovascular mortality, total coronary events, and total cardiovascular events and procedures.
A review of the ASCOT data highlighted that cardiovascular mortality was slightly higher in the amlodipine/perindopril treatment arm until 2 years into the study, when the arms started to diverge (Figure 2).18 At this time point, the majority of amlodipine-treated patients had also been receiving perindopril for at least 1 year. When the trial was stopped, 68.4% of the patients in the amlodipine/perindopril group were receiving perindopril, and cardiovascular mortality was reduced by 14% (P < 0.05).
The mean BP in the amlodipine/perindopril group was 2.7/1.9 mmHg lower than in the beta-blocker/diuretic group. However, this difference could not entirely account for the differences in outcome.19 The Conduit Artery Functional Evaluation substudy of 2199 patients from ASCOT showed that despite similar reductions in brachial artery BP, both central aortic BP and central aortic PP were significantly reduced with amlodipine/perindopril vs. beta-blocker/diuretic (−4.3 and −3.0 mmHg, respectively, both P < 0.0001).20 Moreover, central aortic PP was significantly associated with an increased risk of cardiovascular events or procedures and the development of renal impairment. These findings suggest that central arterial PP lowering by perindopril and amlodipine combination therapy disrupts the pathophysiological continuum in Figure 1B, thereby slowing progression onto the cardiovascular continuum in hypertensive patients.
The ASCOT trial results overturned established thinking in the treatment of hypertension and prompted an early revision of the treatment and management guidelines for hypertension by the British Hypertension Society.21 The findings of ASCOT also form the rationale behind the new fixed combination of perindopril and amlodipine for the treatment of hypertension. The anti-hypertensive efficacy of this combination is being investigated in ongoing trials.
Renal function in hypertensive patients
Patients with prolonged and uncontrolled hypertension have increased risk of chronic renal disease due to the development of nephrosclerosis. These structural changes within the kidney cause further increases in BP forming a vicious cycle and accelerating the pathophysiological continuum (Figure 1B). The first sign of renal impairment in hypertensive patients is a reduced glomerular filtration rate. If poorly managed, this stage can rapidly progress to increasing levels of albuminuria and end-stage renal failure. Aggressive and sustained BP lowering in itself provides renal protection, and target BP goals are <130/80 mmHg in hypertensive patients with renal disease. In type 2 diabetics, who are either normotensive or well controlled with other anti-hypertensive agents, perindopril significantly reduces the progression of renal disease when compared with placebo or calcium channel blocker.22,23 This shows a direct renoprotective action of perindopril, which is independent of its anti-hypertensive efficacy.
The risk of development of renal impairment was reduced by 15% with amlodipine/perindopril in the ASCOT trial vs. beta-blocker/diuretic.17 At a later stage of renal impairment, in diabetic hypertensives with microalbuminuria, treatment with perindopril was shown both to maintain BP control and to reduce albuminuria over 3 years.24 Finally, in hypertensive patients with end-stage renal failure, the use of perindopril alone or in combination is significantly associated with reduced cardiovascular and all-cause mortalities (81 and 82%, respectively, both P < 0.001), whereas the use of a beta-blocker or a calcium channel blocker in these patients had no effect on clinical outcome over an average of 4.25 years.25 The renoprotective and BP-lowering effects of perindopril thus appear to have clinical benefits for hypertensive patients at all stages of renal disease.
Patients with type 2 diabetes
Type 2 diabetes mellitus is a major risk factor for the onset of cardiovascular disease. Moreover, over 70% of diabetics also suffer from hypertension, and the primary cause of death in diabetics is cardiovascular disease. For this reason, patients with both hypertension and diabetes need to be aggressively managed, and BP targets are <130/80 mmHg.
Small-scale studies in diabetic hypertensives show that perindopril reverses arterial remodelling and stiffening,26,27 which are important steps on the pathophysiological continuum (Figure 1B). In ASCOT, 27% of the study population (n = 5137) had diabetes at baseline, but no history of cardiovascular disease.17 In this subpopulation, amlodipine/perindopril reduced total cardiovascular events and procedures by 23% when compared with beta-blocker/diuretic (P < 0.05). Further analyses of the diabetic subpopulation showed that amlodipine/perindopril reduced a variety of cardiovascular endpoints vs. beta-blocker/diuretic.28 Importantly, the composite endpoint of fatal and non-fatal stroke was reduced by 25% (P < 0.05), whereas that of peripheral artery disease, fatal coronary heart disease, and non-fatal MI was reduced by 48% (P < 0.001). The endpoint of requirement for revascularization was reduced by 57% (P < 0.001).28
More recently, the Action in Diabetes and Vascular disease: PreterAx and DiamicroN-MR Controlled Evaluation (ADVANCE) study evaluated the clinical benefits of background BP lowering with a fixed combination of perindopril and indapamide on top of standard management in a cohort of 11 140 diabetic patients.29 Over a mean of 4.3 years, treatment with perindopril/indapamide fixed combination reduced the incidence of the composite primary endpoint of macrovascular (non-fatal stroke, non-fatal MI, and cardiovascular death) and microvascular (new or worsening nephropathy and retinopathy) events by 9% vs. placebo (P < 0.05). Cardiovascular and all-cause mortalities were also reduced by 18 and 14%, respectively (both P < 0.05). The beneficial effects of fixed combination of perindopril and indapamide on the primary endpoint were similar in the hypertensive and non-hypertensive patients in ADVANCE.29
Hypertension is often associated with impaired glucose tolerance, insulin resistance, and obesity, and many hypertensive patients develop diabetes. A further complication to this problem is that some classes of anti-hypertensive agents, such as beta-blockers, increase the risk of new-onset diabetes, whereas others, notably ACE inhibitors, reduce the risk.30 In this context, perindopril has been shown to improve insulin sensitivity, glycaemic control, and glucose metabolism in hypertensive patients.31–33 These effects are likely to account for the 30% reduction in the risk of new-onset diabetes with amlodipine/perindopril vs. beta-blocker/diuretic in ASCOT (P < 0.0001).17
In a more recent analysis, Gupta et al.34 assigned a risk score to an ASCOT subpopulation considered to be at risk of developing diabetes. This risk score was based on variables such as baseline fasting plasma glucose >5 mmol/L, body mass index, triglycerides, and lipid levels. The Kaplan–Meier curves for this subpopulation divided according to risk (first quartile, lowest risk and fourth quartile, highest risk) are presented in Figure 3.34 The protective effects of amlodipine/perindopril vs. beta-blocker/diuretic were seen regardless of baseline risk and even appeared as the strongest protective factor against new-onset diabetes.
Patients with stroke
Although BP lowering in hypertensive patients is an effective primary prevention, the risks of stroke and major cardiovascular events are greater in patients with established cerebrovascular disease and there have been few clinical studies investigating the effects of BP lowering in this high-risk group. Perindopril is a useful treatment in this scenario as it maintains cerebral blood flow, even in normotensive patients.35,36 The Perindopril pROtection aGainst REcurrent Stroke Study (PROGRESS) was the first large-scale study to investigate the role of ACE inhibition in secondary prevention of stroke in patients with cerebrovascular disease.37 Patients (n = 6105) with a history of stroke or transient ischaemic attack were randomized to treatment with either a perindopril-based regimen or placebo, on top of standard management. There were no BP entry criteria, although subjects with uncontrolled hypertension could receive anti-hypertensive agents other than ACE inhibitor.
After a mean of 3.9 years, the RRR of stroke was 28% in the perindopril-based regimen vs. placebo (P = 0.0001). All stroke subtypes were significantly reduced, including a reduction of 50% in haemorrhagic stroke and 24% in ischaemic stroke. The perindopril-based regimen also was associated with a 27% reduction in major cardiovascular events (non-fatal MI or death from cardiovascular disease) and a 38% reduction in non-fatal MI. The reductions in stroke and major coronary events with the perindopril-based regimen were similar in the hypertensive and normotensive patient subgroups and were independent of the reduction in BP. Protection against stroke was also seen in the amlodipine/perindopril arm of ASCOT, which showed a 23% reduced risk of fatal and non-fatal stroke vs. beta-blocker/diuretic (P < 0.0005).17 These findings show that perindopril-based BP-lowering regimens have protective actions against stroke and should be considered for routine use as secondary prevention in patients with established cerebrovascular disease.
Patients with coronary artery disease
CAD is a consequence of endothelial dysfunction and atherosclerosis, i.e. the effects of the pathophysiological continuum on the cardiovascular continuum (Figure 1A and B). The prevalence of CAD is higher in men than in women and rises sharply with age after the fourth decade.38,39 CAD may first manifest as myocardial ischaemia and angina pectoris and can ultimately progress to MI.
The management of CAD targets both symptomatic treatment and secondary prevention.38 The findings of the EUropean Trial on Reduction of Cardiac Events with Perindopril in stable CAD (EUROPA) provided clear evidence for the efficacy of perindopril in secondary prevention in patients with stable CAD.40 Patients with documented evidence of CAD, but without uncontrolled hypertension or HF (n = 12 218), were randomly allocated to either perindopril or placebo on top of other standard preventative therapies (beta-blockers, lipid-lowering agents, and antiplatelet agents). After a mean of 4.2 years, there was a significant 20% reduction in primary endpoint (cardiovascular mortality, non-fatal MI, or resuscitated cardiac arrest) in favour of perindopril (P < 0.0005). This beneficial effect was seen in different subgroups of patients according to age, presence of hypertension, diabetes, previous MI, and concomitant treatments (beta-blockers or lipid-lowering agents).40,41 The results of EUROPA were in agreement with the earlier Heart Outcomes Prevention Evaluation (HOPE) trial, which demonstrated the protective effects of ramipril in a cohort of high-risk stable CAD patients without HF.42
Subsequent to the HOPE and EUROPA trials, the findings of the Prevention of Events with Angiotensin-Converting Enzyme inhibition (PEACE) trial questioned the efficacy of ACE inhibition in certain types of patients with stable CAD.43 The PEACE trial examined the effects of trandolopril in patients aged >50 years with stable CAD and preserved LV function. After a median of 4.8 years, there was no difference in the incidence of the primary combined endpoint (death from cardiovascular causes, MI, and coronary revascularization) vs. placebo.
There has been much debate surrounding the differences in the results of EUROPA, HOPE, and PEACE.44 One hypothesis was that the negative result in PEACE was associated with the lower overall risk of the population. However, further analysis of EUROPA showed a population heterogeneous in terms of cardiovascular risk. Deckers et al.45 investigated this point by classifying EUROPA patients according to baseline cardiovascular risk, i.e. high (>3%), medium (1–3%), or low (<1%) risk of reaching the primary endpoint at the end of the trial. Within each subgroup, perindopril treatment significantly reduced the risk of the primary endpoint by 17, 32, and 12%, respectively, compared with placebo (Figure 4). Importantly, the cardiovascular risk of the lowest tertile of EUROPA (n = 3976) was lower than the average cardiovascular risk in the PEACE population.45 Moreover, the primary endpoint was also reduced by perindopril in EUROPA subgroups with preserved LV function (n = 6878; RRR 16%, P < 0.05)46 and with previous coronary revascularization (n = 6709; RRR 17%, P < 0.05).47 Notably, patients with previous coronary revascularization in HOPE had a similar 15% reduction in the primary endpoint, although this failed to reach statistical significance.48 Considering these results, we can be confident that the differences between the three studies are not linked to baseline risk of the populations.44
The other hypothesis is that ACE inhibitors are not equally effective against cardiovascular disease, and the positive results of HOPE and EUROPA are, therefore, due to the ACE inhibitors used in the trials. In this context, the PERTINENT (PERindopril—Thrombosis, InflammatioN Endothelial dysfunction and Neurohormonal activation Trial) substudy of EUROPA has given us some insight into the action of perindopril on the endothelium.4 Compared with placebo, 1 year's treatment with perindopril significantly reduced plasma levels of von Willebrand factor, which is a marker of endothelial damage (P < 0.001). When human endothelial cells were cultured in plasma samples obtained from EUROPA subjects, 1 year of perindopril vs. placebo was found to significantly increase endothelial nitric oxide synthase activity by 27% (P < 0.05), reduce endothelial apoptosis by 31% (P < 0.05), and reduce endothelial tumour necrosis factor alpha (an inducer of apoptosis) by 13% (P < 0.05). The findings of PERTINENT show that the results of the EUROPA trial may be at least partially a result of perindopril's restorative action on endothelial function and inhibition of the pathophysiological continuum (Figure 1B). This is also supported by pre-clinical studies testing the effect of various ACE inhibitors on endothelial dysfunction.49
The endothelial effects of perindopril have also been investigated in two other EUROPA substudies.50,51 The PERFECT (Perindopril-Function of the Endothelium in Coronary Artery Disease Trial) study assessed 333 EUROPA patients at baseline and after 3 years of perindopril and showed a greater increase in ischaemia-induced flow-mediated dilatation in the coronary arteries vs. placebo, providing further support for the findings of PERTINENT.50 Similarly, the PERSPECTIVE (PERindopril's proSPpective Effect on Coronary aTherosclerosis by angiography and IntraVascular ultrasound Evaluation) study evaluated progression of atherosclerosis using quantitative coronary angiography and intravascular ultrasound to measure lumen diameter and plaque area in 194 EUROPA patients. After 3 years, PERSPECTIVE failed to detect the progression of CAD in either the treatment or the placebo group.51 However, post hoc analyses of the PERSPECTIVE data showed that perindopril significantly reduced coronary vessel cross-sectional area compared with placebo (P < 0.05), with no effect on the lumen. This was significantly correlated with a change in the plaque dimension (r = 0.48, P < 0.0001).52 The data from PERSPECTIVE, therefore, show that perindopril has beneficial effects on coronary remodelling and plaque stabilization.
Nearly two-thirds of the EUROPA patients (n = 7190) had a history of MI. In these patients, perindopril significantly reduced the primary endpoint vs. placebo (RRR 22.4%, P < 0.001).53 The main long-term complications following MI are further progression down the cardiovascular continuum starting with changes in ventricle size, shape, and function: a process referred to as cardiac remodelling that can result in HF (Figure 1A). Numerous studies have shown that ACE inhibition reduces morbidity and mortality in patients with residual LV dysfunction following MI through prevention of remodelling, and ACE inhibitors are, therefore, administered as prophylactic treatment 24 h following MI.54 However, up to 40% of the MI patients admitted to hospital have preserved LV function and, until recently, the benefits of ACE inhibitors for this patient subset were unclear. The Perindopril and Remodeling in Elderly with Acute Myocardial Infarction (PREAMI) trial has shown that LV remodelling occurs in elderly post-MI patients with preserved LV function and that these changes can be prevented by perindopril.55 Patients aged >65 years with recent MI and LV ejection fraction >40% (n = 1252) were randomized to treatment with either perindopril or placebo on top of standard management. After 12 months, the composite primary endpoint of death, hospitalization for HF, and LV remodelling showed an RRR of 38% in favour of perindopril (P < 0.001). Furthermore, the mean increase in the LV end-diastolic volume (which is an indicator of cardiac remodelling) was significantly higher in the placebo group than in the perindopril group (4.0 vs. 0.7 mL, P < 0.001). The PREAMI investigators also cited analyses of the subgroup of EUROPA patients aged ≥65 years with a history of MI and LV ejection fraction ≥40%, which showed an RRR of 36.1% (P < 0.05) for the primary endpoint after 3 years of perindopril treatment.55 These beneficial clinical effects of perindopril in PREAMI and EUROPA were seen, despite the use of other standard post-MI therapies such as beta-blockers.
Patients with HF
Although HF represents one of the final stages of the cardiovascular continuum (Figure 1A), successful management of patients here can still improve prognosis. ACE inhibitors are indicated in HF and have beneficial effects on mortality, hospital admission rates, symptoms, and cardiac performance in patients with systolic HF.56 However, it is estimated that 20–50% of the HF patients have diastolic rather than systolic HF. Diastolic HF patients are less likely to have a history of MI, more likely to have a history of hypertension, are more often female, and are usually older. The Perindopril in Elderly People with Chronic Heart Failure (PEP-CHF) trial was set up to understand more about the effects of ACE inhibition in diastolic HF.57 Patients aged >70 years diagnosed with diastolic HF (n = 870) received either perindopril or placebo, on top of standard management. After 1 year, the event rate was lower than expected and reduced the statistical power of the study, but perindopril still showed a strong tendency to reduce the primary endpoint (all-cause mortality, unplanned HF-related hospitalization with a minimum follow-up of 1 year) (RRR 31%; P = 0.055). Of the secondary endpoints, patients treated with perindopril showed RRRs of 37% in hospital admissions for HF (P < 0.05) and 38% for cardiovascular death or unplanned hospitalization for HF (P < 0.05). Perindopril also improved exercise capacity in patients vs. placebo as assessed by the 6-min walking test (P = 0.001). These findings show that perindopril can be an important component of the management strategy in diastolic HF to significantly improve both patient prognosis and quality of life.
The cardiovascular continuum is a well-established concept within the field of cardiology. Improvement in outcomes in cardiovascular disease is achieved through treatments that can disrupt this continuum at multiple points. Evidence from large-scale clinical trials shows that perindopril has a major role in such management strategies throughout the cardiovascular continuum (Figure 1A): at entry in hypertensive or diabetic patients; later in CAD patients with established atherosclerosis and/or endothelial damage; later still, in preventing recurrent stroke; and during the final stages of the continuum with congestive HF. The beneficial effects of perindopril can be linked to its actions in improving endothelial function and breaking the pathophysiological continuum. This slows the rate of progression of cardiovascular disease and consequently improves patient prognosis.
Conflict of interest: K.F. has received research grants and honoraria from Servier.
The author has received funding from Servier.