Hypertension is the single most important preventable cause of premature death in the Western world. The quest to find the most effective treatment both in terms of blood pressure control and prevention of events, such as heart attacks and strokes, is on-going. The issue of which antihypertensive agent to use first-line has been the subject of debate for over two decades. The lack of a coherent decision has led directly to differing recommendations for first-line hypertension treatment. For example, even within the UK, the British Hypertension Society (BHS)1 and the National Institute for Clinical Excellence (NICE)2 had, until recently, differing viewpoints. However, it seems that the recent landmark Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) study may now offer a solution to this international dilemma. The purpose of this article is to explain the background to the ASCOT study and provide a clear summary of the results and their implications.
The development of angiotensin converting enzyme (ACE) inhibitors came from studies of the venom of the Brazilian viper Bothrops jararaca. This venom potentiated the effect of the vasodilator peptide bradykinin, strongly enhancing its hypotensive effect to cause shock in the snake's prey. Further work with the venom showed that the bradykinin effect was caused by inhibition of its breakdown. It was then realised that this metabolising enzyme also catalysed the conversion of angiotensinogen to active angiotensin II; and so ACE inhibitors were born. The possibility of ACE inhibition as a target for hypertension therapy followed. The first clinical trials of the active peptide extracted from the snake venom were carried out in the UK, and subsequently the US. After successfully reducing blood pressure in 14 of the 17 patients tested, an orally active formulation of the peptide was developed that eventually became captopril, launched in the US in 1981.3 The success of captopril was developed by the pharmaceutical industry and there are now 11 ACE inhibitors licensed in the UK.
Subsequent trials with captopril suggested the possibility that its beneficial effects were not all restricted to an effect on blood pressure. The first studies took place with heart failure (HF) patients. The classic study, Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS) examined the survival benefit of enalapril in patients with severe HF and showed dramatic benefits.4 In the Survival And Ventricular Enlargement (SAVE) study, patients who had survived the acute phase of myocardial infarction (MI) were given captopril or placebo. The group receiving captopril had a 25% decrease in recurrent MI and a 24% reduction in the need for revascularisation.6
The observations that ACE inhibitors had effects beyond blood pressure lowering led to large-scale clinical trials to further investigate these other clinical outcomes.
Ramipril and Perindopril
Following the launch of ramipril the landmark trial Acute Infarction Ramipril Efficacy (AIRE) enrolled patients who had an MI with HF three to 10 days previously. Treatment with ramipril resulted in a 27% reduction in the risk of all-cause mortality.7
The Heart Outcomes Prevention Evaluation (HOPE) trial was the second key study to assess ramipril.8 In HOPE ramipril was given to patients older than 55 at high risk of cardiovascular disease (CVD) events (a history of CVD or diabetes plus at least one other risk factor). Ramipril proved effective in reducing the primary end-point of the combination of MI, stroke or death from CV events by 17.8%. The improvements were seen in the presence of modest blood-pressure (BP) lowering effects. The HOPE investigators concluded that ramipril offered numerous benefits to these high-risk patients, perhaps beyond the effect of a small reduction in BP. HOPE was criticised by some authors because a small ambulatory blood pressure sub-study showed substantial nocturnal BP falls. Nevertheless, the unarguable benefit of ACE inhibitors was confirmed in a population without HF.
The EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease (EUROPA) trial investigated patients at lower risk of developing CVD, regardless of their age or other risk factors.9 This study population was therefore more representative of the general population. EUROPA assessed the effects of perindopril, a long-acting ACE inhibitor that regulates hypertension over a 24-hour period in patients with stable coronary artery disease (CAD) but without HF.
Importantly in the EUROPA trial perindopril was given alongside the patient's standard treatment (aspirin, β-blockers, statins or other lipid-lowering drugs). Perindopril treatment lowered BP by an average of 5/2mmHg, and resulted in a 20% reduction in the combined risk of CV death, non-fatal MI and cardiac arrest, a 24% reduction in fatal and non-fatal MI, and a 39% reduction in HF. EUROPA investigators concluded that perindopril was of benefit to all patients regardless of their baseline BP,10 and with or without HF. Perindopril's benefits were seen in addition to any other preventative treatments the patients may have been taking. Furthermore, perindopril was associated with significant decreases in morbidity and mortality in all patients, whether at low, medium or high risk of cardiac events.11
All This From Lower Blood Pressure
ACE inhibitors were discovered and developed as agents to reduce BP, but the mechanism by which they exert their positive secondary effects on HF, recurrent MI, and stroke remains unestablished. Some researchers have suggested that these effects are nothing more than additional serendipitous consequences of the reduction in BP. However, others suspect they could be directly attributed to the ACE inhibitor itself - an important study published in September 2004 confirmed this.
The A Coronary disease Trial Investigating Outcome with Nifedipine (ACTION) study investigated the effects of long-acting nifedipine gastrointestinal therapeutic system (GITS) (Adalat┬« LA in the UK) in stable coronary heart disease (CHD) patients.12 Nifedipine has been a mainstay of treatment for angina and hypertension for many years. The criteria for inclusion and exclusion in the ACTION study were similar to those used in EUROPA. Although nifedipine successfully lowered BP by an average of 6/3mmHg, it had no effect on major cardiac events. Some secondary end-points were improved, mainly through an important reduction in the need for coronary procedures and interventions, confirming the value of nifedipine GITS for symptom control. There was also a benefit in transient ischaemic attack (TIA) prevention. The contrast in results between ACTION and EUROPA offers support to the idea that the CV benefits provided by ACE inhibitors do not arise solely from their BP lowering activity. Similar levels of BP lowering were achieved among similar patients in ACTION and EUROPA, yet perindopril reduced CV events by 21%.13 Furthermore, in EUROPA similar results were seen in patients with low or high BP at entry, and among those in whom BP did not fall during the study.
The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)14 has attracted much attention amongst healthcare professionals since its early cessation in December 2004. The announcement of the preliminary results in March 2005, suggesting that the treatment combination of amlodipine/ perindopril offered superior benefits over the more traditional first-line treatment of atenolol/ bendroflumethiazide in terms of reducing the risk of death, MI, stroke and new-onset diabetes means that many doctors have been eagerly awaiting the full results to find out exactly what the long-term implications of these results are for the future of hypertension management. The full results were presented at the European Society of Cardiology (ESC) Annual Congress in early September 2005 to great scientific acclaim.
ASCOT - How it All Began
By 1990 it was clear that lowering BP in hypertensive patients with the drugs available at that time, principally β-blockers and diuretics, reduced stroke risk but had much less effect on CHD events. There was a belief, although no data, that the new drugs for hypertension could be more effective than the older ones. Moreover, it was becoming apparent that combination therapy might be required.
ASCOT recruited 19,257 patients from the UK, Ireland and the Nordic countries. The study set out to test whether a newer antihypertensive combination treatment, comprising the calcium channel blocker amlodipine and the ACE inhibitor perindopril, was more effective at preventing CHD than an older combination regimen consisting of the β-blocker atenolol and the diuretic bendroflumethiazide.
The patients recruited to ASCOT were men and women between the ages of 40 and 79 years, who were all hypertensive (an untreated systolic/diastolic BP of ≥160/100mmHg, or a treated systolic/diastolic BP of ≥140/90mmHg). As well as high BP they all had at least three other risk factors for future CV events (see Box 1).
Patients were excluded if they were contraindicated to any of the treatments used in the study, or if they had a previous MI, current angina, recent stroke or TIA, congestive HF (CHF) or uncontrolled arrythmias.
Patients received treatment towards a target BP of ≤140/90mmHg (non-diabetic patients) and ≤130/80mmHg (diabetic patients) following the treatment algorithm outlined in Table 1. The treatment was planned to continue for five years or until 1,150 primary events had occurred - whichever was longer. Follow-up visits took place after six weeks, three months, six months, and subsequently six-monthly.
The primary end-point of the study was the effect of treatment on combined risk of non-fatal MI and fatal CHD.
There were a number of critical secondary end-points for the trial, including:
- all-cause mortality;
- CV mortality;
- fatal and non-fatal stroke;
- total coronary end-points; and
- total CV events and procedures.
Results and Discussion
Most patients (77.8%) required an average of 2.2 antihypertensive agents to reach their target BP. Only 14.5% and 8.9% were taking amlodipine and atenolol monotherapy, respectively. This supports previous findings that most hypertensive patients need at least two agents to reach currently recommended targets. This insight is pertinent given the BHS and NICE guidelines. Until recently NICE2 has recommended initial treatment with a low-dose diuretic with the addition of a β-blocker when necessary (this would be most patients). However, they do warn against this approach in those patients at an increased risk of new-onset diabetes. The BHS1 bases therapy on the scientific premise of individual renin status. The BHS proposes the AB/CD system of treatment - in patients younger than 55 and non-black patients, treatment starts with an ACE inhibitor, angiotensin receptor blocker (ARB) or β-blocker, before adding a calcium channel blocker (CCB) or diuretic (avoiding β-blocker/diuretic combinations); black patients or patients older than 55 should start with a CCB or diuretic and add in an ACE inhibitor, ARB or β-blocker.
ASCOT was terminated early because of a large difference in mortality between the older drugs and the newer ones. The early cessation of the study meant that there was not enough statistical power for the planned primary end-point to quite reach statistical significance. The study was powered for 1,150 individuals to experience the primary end-point, whereas this had only occurred in 903 people at the final follow-up. Critically, there were a number of important and substantial reductions in the secondary and tertiary end-points, as outlined in Table 2.
On a broader scale, the extent of the CV benefits seen across all 18 subgroups (see Figure 1) demonstrates that the reduction in CV outcomes associated with amlodipine/perindopril applies to a wide range of patients, regardless of the underlying risk factors observed in the study.
At baseline, over 80% of patients were on antihypertensive treatment, although BP levels were still quite high (164/95mmHg). BP fell to 136.9/78.3mmHg across both treatment groups during the course of the trial; an average reduction of 26.6/16.6mmHg. Throughout the trial, patients allocated to the amlodipine/perindopril strategy had a consistently lower BP than those allocated to the atenolol/thiazide strategy. The average difference throughout the trial was 2.7/1.9mmHg and the difference was largest (5.9/2.4mmHg) at three months.
A 2.7mmHg systolic BP difference would be expected to generate a difference of 4-8% in coronary events and 11-14% in strokes, based on the findings observed in previous randomised trials,15,16 as opposed to the 13% and 23% benefits seen in ASCOT. The effects of the newer drugs do therefore seem greater than would be expected from BP reduction alone. One possible explanation is the higher body mass index (BMI), serum triglyceride, creatinine levels and fasting blood glucose levels, and lower high-density lipoprotein (HDL)-cholesterol levels found among those allocated to the atenolol/thiazide strategy. This would tie in with previous research that has questioned the use of β-blockers in hypertensive patients compared with other antihypertensive treatments, in terms of their lack of CV benefits.
Atenolol and Hypertension
Atenolol in particular has come under scrutiny. The Losartan Intervention For Endpoint reduction in hypertension study (LIFE) study17 found that patients on the angiotensin receptor blocker (ARB) losartan-based regimen had significantly reduced end-points of CV death, MI and stroke compared with those being treated with atenolol. More recently, in 2004, a meta-analysis of nine studies18 found that when atenolol was compared with placebo it was effective at lowering BP and reduced the incidence of stroke, but offered no reduction in risk of death from heart attack or stroke. When atenolol was compared with other antihypertensives it offered no major differences in terms of lowering BP, and if anything was associated with a slightly greater risk of death due to CVD, strokes and heart attacks.
These studies would suggest that poor performance of atenolol in comparison with the amlodipine-perindopril combination may offer a partial explanation for the results seen in ASCOT. An alternative explanation is that amlodipine and perindopril, on top of their superior BP ability, have 'special' effects that extend beyond BP lowering. This would corroborate previous research that has found cardioprotective effects, particularly for ACE inhibitors.
Extra Benefits of ACE Inhibitors Beyond Blood Pressure Lowering
Although there have been some studies, most notably Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial (PREVENT)19 and Comparison of Amlodipine vs Enalapril to Limit Occurrences of Thrombosis (CAMELOT),20 which have found a reduction in CV events with amlodipine, its ACE inhibitors and ARBs that have amassed the most evidence for cardioprotective effects on top of their BP lowering ability.
This suggests that inhibition of the renin-angiotensin-aldosterone system may be a critical factor in achieving the kind of benefits seen in ASCOT. Trials such as HOPE,8 EUROPA9 (previously mentioned) and PROGRESS21 have all achieved reductions in CV end-points with ACE inhibitors in different patient populations.
The apparent benefits of ACE inhibition were also found in PROGRESS. Patients with a history of stroke or TIA who received a perindopril-based therapy (┬▒ the diuretic indapamide), had a reduced risk of non-fatal MI (by 38%) and major coronary events (by 26%) with a BP drop of 9/4mmHg. The study found that these percentages are proportionally approximately twice as great as that which would have been predicted from trials of mainly diuretic-and β-blocker-based regimens where a BP reduction of 10-12/ 5-6mmHg was associated with a 16% reduction in major coronary events.13,14
A recently published meta-analysis of 28 outcome trials comparing ACE inhibitors or CCBs with diuretics, β-blockers or placebo confirmed that BP lowering is fundamental for the prevention of CHD and stroke.22 However, over and above BP reduction, ACE inhibitors were found to be superior to CCBs for prevention of CHD and CCBs appear superior to ACE inhibitors for the prevention of stroke. The study investigators did state that the benefits of ACE inhibitors for the prevention of stroke might have been underestimated.
A Class Effect
Not all ACE inhibitors necessarily exhibit the same cardioprotective effects. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT),23 lisinopril was no better than amlodipine or chlortalidone at reducing CV events. Examining the four large trials of ACE inhibitors in CHD patients, firstly in the Quinapril Ischaemic Event Trial (QUIET) study,24 quinapril did not significantly affect clinical outcomes or progression of coronary atherosclerosis. The much larger Prevention of Events with Angiotensin Converting Enzyme Inhibition (PEACE) Trial25 also found no evidence that the addition of trandolapril to standard therapy in patients with CAD and without HF provided further benefits in terms of death from CV causes, MI or coronary revascularisation. There are arguments that the patients in the QUIET and PEACE had better other secondary prevention strategies and more revascularisation, although randomisation ought to take care of this. The truth is that EUROPA8 with perindopril and HOPE8 using ramipril have demonstrated unquestionable benefits. There is therefore convincing evidence for perindopril and ramipril, but not for other ACE inhibitors, in these large studies of CHD patients.
Implications of ASCOT
There is no doubt that β-blockers have established benefits in patients with CHD, MI, certain arrhythmias, cardiac failure, anxiety and migraine, and for these patient groups, β-blockers remain a recommended treatment.
However, the use of β-blockers as routine first-line therapy for patients with hypertension is now in question. Following the preliminary results, ASCOT study clinicians were advised to gradually withdraw atenolol from all relevant participants in the trial and replace it with a CCB and/or an ACE inhibitor (or ARB, in the case of ACE intolerance).
β-blockers and diuretics are currently the most commonly prescribed treatments among the 7.68 million people in the UK who receive treatment for hypertension, and the ASCOT results have huge implications for these patients if their BP is not absolutely optimally controlled. For example, if the amlodipine-perindopril combination was now prescribed in only half of these instead of a β-blocker/diuretic combination, over five and a half years there would be nearly 100,000 fewer CV events and procedures, nearly 40,000 fewer strokes and 35,000 fewer deaths from CVD. There would also be over 90,000 fewer patients who develop type 2 diabetes. These huge figures could still underestimate the potential impact and could even be doubled again as they do not take into account the eight million hypertensive patients who are currently undiagnosed and are not receiving treatment. Hypertensive patients who have their BP optimally controlled (<130/80mmHg) on a β-blocker-thiazide combination are probably fine (although the risk of diabetes persists); those with sub-optimally controlled pressures may well find the new combination more effective.
The increased incidence of new-onset diabetes seen in the atenolol-bendroflumethiazide group is consistent with recommendations outlined in the BHS AB/CD algorithm, where the increased risk with β-blocker/diuretic therapy is highlighted. In the ASCOT there was also better renal protection with amlodipine-perindopril, and better results in diabetic patients as well as among older patients.
ACE inhibitors are fundamentally effective drugs. It is known that most patients require more than one drug to control their hypertension, and the most commonly used combination to date in the UK has been that of a β-blocker plus a diuretic. ASCOT is a landmark trial that has clearly shown that there are significant CV health benefits to be gained from using a different treatment combination - that of the calcium channel blocker amlodipine and the ACE inhibitor perindopril. In fact, the final conclusion of the ASCOT investigators was that the β-blocker/diuretic combination should not be recommended for routine use in patients with hypertension, but rather for specific circumstances.
The findings of ASCOT imply that there are important CV benefits available to hypertensive patients on an amlodipine-perindopril treatment combination and, in the light of ASCOT, doctors may need to rethink their current choice of drugs and treatment plans. ACE inhibitors have a big future, and patients will live longer and healthier thanks to these excellent drugs.