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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org

Selecting a fixed combination to improve morbidity/mortality: the weight of evidence with ASCOT

Neil R. Poulter*

International Centre for Circulatory Health, NHLI, Imperial College, London, UK

* Corresponding author. Tel: +44 20 7594 3445; fax: +44 20 7594 1145. E-mail address: n.poulter{at}imperial.ac.uk


   Abstract
Top
 Abstract
The ASCOT trial methods
 Results
 Summary/conclusions/discussion
 Funding
 References
 
The Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure-Lowering Arm was designed to compare the effects of a standard combination starting with atenolol and adding a thiazide as needed and a newer combination starting with amlodipine and adding perindopril as needed. Because the newer regimen was associated with a significant reduction in all-cause mortality, the trial was stopped early. Nevertheless, the newer regimen was associated with a significantly superior effect on the primary endpoint excluding silent myocardial infarction, or including revascularization procedures, on total coronary events, cardiovascular (CV) mortality, fatal and non-fatal strokes, unstable angina, total CV events and procedures, new-onset diabetes, and development of renal impairment. The newer regimen was associated with an average blood pressure (BP) which was 2.7/1.9 mmHg lower than that of the standard regimen. Although it seems likely that this BP difference contributed to the superior prevention by the newer regimen, extensive analyses suggested that other advantages of the newer regimen contributed to this superiority. This is in keeping with other findings which suggest that angiotensin-converting enzyme inhibitors may have benefits beyond BP lowering in relation to coronary heart disease events and that calcium channel blockers may have benefits beyond BP lowering in relation to stroke protection.

Key Words: Hypertension • Randomized trial • Amlodipine • Perindopril • Atenolol • Bendroflumethiazide • Cardiovascular benefits

Evidence from randomized trials1,2 are consistent in showing that the majority of patients with hypertension require at least two blood pressure (BP)-lowering agents if currently recommended targets are to be reached.

Although the vast majority of trials of BP management have involved the use of BP-lowering regimens including two or more agents, the choice of the second or third agent has usually been unstructured. Hence, the results of these trials cannot inform recommendations for optimal combinations of antihypertensive agents. Advice is, therefore, based on the theoretical benefits of selecting agents, which have complementary rather than overlapping mechanisms of action. This has given rise to several similar sets of recommendations for drug combinations, and recently, the ESH-ESC guidelines have produced a further version of these earlier models (Figure 1).


Figure 1
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  		Figure 1 The ESH-ESC approach to combining antihypertensive drug Classes.

 
In this latest European version, calcium channel blockers (CCBs) and diuretics are considered a logical combination despite sharing, at least in part, a common mechanism of action. Furthermore, these two agents have, in earlier studies, been shown not to produce optimal BP lowering when used in combination.3 Interestingly, this combination—logical or not—was recently shown to be in common use, at least in the UK.4

In June 2006, the British Hypertension Society (BHS) and NICE published the A/CD algorithm—for how best to combine drugs to achieve optimal BP control5 (Figure 2). Each letter refers to a BP-lowering drug class (A, ACE inhibitor or ARB; C, dihydropyridine CCB; D, diuretic), and the theory underpinning this approach is that hypertension can be broadly classified as ‘high renin’ or ‘low renin’. The former is, therefore, best treated by those drug classes that inhibit the renin–angiotensin system (A), and the latter by those classes that do not (C or D).6,7


Figure 2
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  		Figure 2 The NICE/BHS approach to sequencing antihypertensive drug classes.

 
In general, younger Caucasian people (<55 years) tend to have higher renin status than older people (≥55 years) or black people; hence, the recommended allocation of drugs for step 1 based on age and race is shown in Figure 2. The idea of prescribing initial therapy based on age has recently been challenged by analyses carried out by the Blood-Pressure Lowering Treatment Trialists' Collaboration.8 These analyses suggest that age is not a major determinant of BP response to the major antihypertensive drug classes. However, the collaboration includes virtually no data to allow true comparisons of monotherapy by age because, as mentioned earlier, almost all trials hitherto have involved extensive mixtures (often unstructured) of multiple agents. Once the classes of agents are mixed, age effects would not be expected to be apparent. Furthermore, several trials excluded people below age 55 years and so the critical age effects could not be evaluated and trials, such as VALUE9 and ASCOT,10 which showed clear differences in BP lowering between A and C drugs and B and C drugs, respectively, were not included in the analyses. In contrast, more careful evaluation of drug classes used as monotherapy across the whole age range is consistent in showing that A and B drugs are less effective with increasing age and C and D drugs are less effective with decreasing age.6,7

The rationale for steps 2, 3, and 4 in the A/CD algorithm are less soundly based and are recommended on the logical grounds of selecting combinations of agents, which do not have overlapping mechanisms. At first sight, it seems obvious that two drugs will be more effective than one drug in lowering BP. However, the fact that two lower doses of drugs in combination may be more effective than a full dose of one drug is perhaps less well established and intuitive. Nevertheless, best data suggest that adding a second drug (of whatever class) is more effective than uptitrating monotherapy.11 A striking example supporting this approach was a recently published comparison of the BP-lowering effects of each of four drugs at full dose vs. a quarter dose of the same four drugs in combination in one tablet.12 The combination of four drugs at quarter dose was far superior to any of the monotherapy agents at full dose.

Whether the choice of second drug matters in terms of BP-lowering efficacy is less clear, but a recent meta-analysis suggests that some combinations produce more than additive BP-lowering effects whereas others produce less than additive effects.13 Among those producing better additive effects are A and C, and A and D drug classes. These are the two pairs of drug classes recommended as the second-line approaches in the British A/CD algorithm (Figure 2).5 Until very recently, A plus C has been less commonly used than A plus D. However, two recent studies are likely to impact on current clinical practice.14,15 Firstly, the STAR study14 showed that in patients with impaired glucose tolerance, the use of trandolapril and verapamil produced significantly less type 2 diabetes than losartan and thiazide, during up to 52 weeks of follow-up. Perhaps more importantly, the ACCOMPLISH trial established that benazapril plus amlodipine was clearly superior to benazapril plus thiazide in terms of preventing all major cardiovascular (CV) events, despite achieving very similar levels of clinical BP reduction.15 It seems likely therefore that an A plus C combination should be preferred to A plus D, except where compelling indications and/or side-effects preclude this preference.

The A/CD algorithm has the unique advantage of providing advice on how best to control more severe levels of raised BP. For those patients with apparently resistant hypertension (uncontrolled despite the use of three agents—one of which should be a diuretic), the use of aldosterone antagonists (e.g. spironolactone 25 mg o.d.) appears to provide (albeit based on observational data) dramatic BP-lowering effects.16 Whether other diuretics would be equally successful in this context is controversial and currently under investigation. Note that β-blockers have been relegated to fourth-line agents based on the results of a series of meta-analyses that were consistent in showing this drug class to be inferior to A, C, and D drugs in terms of preventing CV events.17,18

British,19 American,20 and European21 guidelines have all moved towards recommending the use of fixed low-dose combinations of drugs. Historically, the use of such agents has been considered infra dig, but in light of the real need for more than one agent for most patients and for several other reasons, it seems a logical approach that should improve BP lowering. With this in mind, the American (JNC7)20 and the latest European guidelines21 formally recommend combination therapy as first-line treatment (Figures 3 and 4).


Figure 3
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  		Figure 3 JNC 7: algorithm for the treatment of hypertension.

 

Figure 4
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  		Figure 4 ESH–ESC: algorithm for the treatment of hypertension.

 
Despite the need to use two or more drugs for BP control in most patients, trials specifically designed to compare the effects of different combinations of antihypertensive treatment are relatively rare.

The LIFE trial22 compared an ARB and diuretic with a β-blocker and diuretic, whereas the VALUE trial10 compared an ARB and diuretic with a CCB and diuretic. More recently, as described earlier, the ACCOMPLISH trial15 has reported a comparison of an ACE inhibitor plus thiazide vs. an ACE inhibitor plus CCB, but the ASCOT trial10 is almost unique in comparing two different pairs of drug classes—β-blocker and diuretic vs. CCB and ACE inhibitor. The results of this trial are discussed in more detail below.

Before the results of the ACCOMPLISH trial, the preferential choice of ACE inhibition with a CCB has been proposed for renal protection, for the potential complementary effects of co-administering both drug classes on the microcirculation and the mesangium.

Once any given drug combination has been identified as ‘optimal’, the issue of whether the drugs should be produced as a fixed-dose combination (FDC) (albeit potentially with various dose combinations) arises.

There seems to be no reason for FDCs to be considered poor quality medicine when used for hypertension, anymore than in the fields of respiratory medicine, diabetes, or oncology where the use of such products is the norm.

Concerns that FDCs are expensive are frequently ill-founded in that, for example in the UK, when diuretics are combined with ARBs or ACE inhibitors, the products are flat-priced against the RAS-blocker. Furthermore, up-titration costs and prescription costs and hence overall direct costs may be reduced when FDCs are used.

Although data are limited, evidence suggests that compliance with two drugs delivered as an FDC is greater than with the two agents provided separately.23,24 Hence, it is a reasonable assumption, supported by some data, that BP lowering is superior with the use of FDCs and hence CV events and thereby indirect healthcare costs are reduced.

Currently, these potential benefits of FDCs are under-utilized in the UK and provide a relatively simple way of improving BP control.


   The ASCOT trial methods
Top
 Abstract
 The ASCOT trial methods
Results
 Summary/conclusions/discussion
 Funding
 References
 
The study design, organization, and main results of the study have been published previously.10,25 Patients eligible for inclusion in ASCOT were men and women aged between 40 and 79 years, with either untreated hypertension, defined as systolic BP of 160 mmHg or more and/or diastolic BP of 100 mmHg or more, or treated hypertension with systolic BP of 140 mmHg or more and/or diastolic BP 90 mmHg or more. In addition, the study population was required to have at least three of the following additional risk factors for CV disease (CVD): male sex, age 55 years or older, smoking, type 2 diabetes, peripheral arterial disease, previous stroke or transient ischaemic attack, microalbuminuria or proteinuria, ratio of plasma total cholesterol to HDL cholesterol of 6 or higher, or family history of premature coronary heart disease (CHD).

Exclusion criteria included previous myocardial infarction (MI), currently treated angina, a cerebrovascular event within the previous 3 months, fasting triglycerides >4.5 mmol/L, heart failure, uncontrolled arrhythmias, or any clinically important haematological or biochemical abnormality on routine screening.

Patients were randomized to a regimen based on amlodipine ± perindopril or atenolol ± bendroflumethiazide and treated according to a pre-specified algorithm outlined in Figure 5. At each follow-up visit, antihypertensive drug therapy was titrated to achieve target BPs (<130/80 mmHg for diabetic patients and <140/90 mmHg for all other patients).


Figure 5
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  		Figure 5 The ASCOT-BPLA trial: treatment steps in the two randomized groups.

 
Patients with a non-fasting total cholesterol of 6.5 mmol/L or less currently untreated with a statin or fibrate were randomized to atorvastatin 10 mg daily or matching placebo in the Lipid-Lowering Arm of the study (ASCOT-LLA).26 The primary endpoint was fatal CHD and non-fatal (including silent) MI.


   Results
Top
 Abstract
 The ASCOT trial methods
 Results
Summary/conclusions/discussion
 Funding
 References
 
In October 2004, the Data Safety Monitory Board recommended that the BP-lowering arm (BPLA) of the trial should be stopped on the grounds that, compared with those allocated amlodipine ± perindopril therapy, those allocated the atenolol ± thiazide therapy had significantly higher all-cause mortality as well as worse outcomes on several secondary endpoints including stroke.

After a median follow-up of 5.5 years, the CV benefits associated with allocation to the amlodipine ± perindopril regimen are apparent in Figure 5. Having stopped this limb of the study earlier than planned due to benefits in all-cause mortality, the study had become underpowered to evaluate the primary endpoint that was non-significantly reduced by 10% (P = 0.105). However, all coronary events and the primary endpoint minus silent MI and the primary endpoint plus coronary revascularizations were significantly reduced (Figure 6).


Figure 6
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  		Figure 6 The ASCOT-BPLA trial: summary of effects of all endpoints.

 
Despite strenuous efforts to lower BP equally in both limbs of BPLA (and BP was lowered very effectively in both groups), those allocated the amlodipine ± perindopril regimen had lower average BP reductions of 2.7/1.9 mmHg throughout the trial. Analyses were carried out to evaluate the vexed question of how far these BP differences explain the superior CV protection afforded by the amlodipine ± perindopril therapy.27

Differences in CV events between BP-lowering regimens were adjusted for the combined effect of differences in BP, weight, heart rate, and biochemical variables, which appeared during the trial associated with the two BP-lowering regimens. Adjustment, however, accounted for only ~50% and 40% of the differences in coronary and stroke events, respectively. BP differences were the biggest contributor to stroke event differences, but HDL-cholesterol differences were the biggest contributor to coronary event differences.

We concluded, therefore, that BP was an unlikely explanation for all the CV advantages of the amlodipine ± perindopril regimen. Subsequently, the CAFE substudy of ASCOT28 provided interesting data which suggested that the bigger effects of the amlodipine ± perindopril regimen on central BP may have also contributed to the different CV outcomes.

One of the tertiary outcomes of the ASCOT-BPLA trial was the evaluation of the impact of two regimens on new-onset diabetes (NOD). The initially reported 31%* reduction in NOD associated with the amlodipine ± perindopril regimen (Figure 7) was more rigorously scrutinized.29 These analyses revealed a 34% reduction in NOD associated with an amlodipine ± perindopril regimen, compared with the atenolol ± thiazide regimen. This variable in multiple regression analyses was the most-powerful protective factor against the development of NOD in this population.


Figure 7
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  		Figure 7 New-onset diabetes by treatment group in the ASCOT-BPLA trial.

 
Having confirmed the superiority of the newer BP-lowering regimen, it was critical to evaluate the cost-efficacy of this regimen. This was addressed in a health-economic analysis30 of the cost per CV event or procedure avoided and the cost per quality-adjusted life year gained in both the UK and Sweden. Compared with the thresholds applied by NICE and the relevant Swedish Board, the amlodipine ± perindopril regimen was found to be cost-effective compared with the atenolol ± thiazide regimen.

Clearly, the CV effects associated with the amlodipine ± perindopril regimen were compared with another active regimen in the ASCOT trial. Hence, the differential beneficial effects of amlodipine ± perindopril are over and above those which can reasonably be expected to have accrued in the atenolol ± thiazide limb by virtue of large BP reductions achieved (~27/17 mmHg). Therefore, it seems a reasonable assumption that had the amlodipine/perindopril combination been compared with placebo, even larger and more significant and important impacts on CV events would have accrued from the use of this antihypertensive regimen.


   Summary/conclusions/discussion
Top
 Abstract
 The ASCOT trial methods
 Results
 Summary/conclusions/discussion
Funding
 References
 
Despite having the results of more than 30 major morbidity and mortality trials,31 many outstanding questions relating to hypertension management remain unanswered.

Confusion remains as to optimal first-line therapy and although it may seem reasonable to recommend diuretics as a starting point for many patients, the trial evidence to support using low-dose thiazides in this context is non-existent and can only be condoned for cost reasons. Furthermore, it is inherently unlikely, given the heterogeneity of the hypertensive population, that any one drug is the best for all subgroups and types of patient. However, given the need in most patients for at least two agents to control BP effectively, more trials of pairs of antihypertensive agents are required, and ideally they are required in the setting of different patient subgroups (e.g. those with LVH, diabetes, and so on).

It seems unlikely that validation of treating low-risk patients with a systolic BP in the range of 140–159 mmHg in a placebo-controlled trial will be carried out. However, the randomized trial evidence for doing so is not available, and the cost implications of this policy (already effectively a worldwide recommendation) are massive. The tradeoff of risk and benefit in this group should be evaluated in a trial.

The shortcomings of the Hypertension Optimal Treatment (HOT) trial1 highlight the need for a more definite trial focused on systolic targets given the greater predictive value of systolic BP for most patients with hypertension. The need for such a trial was highlighted in the WHO-ISH guidelines produced in 1999,32 as one of eight areas of further research still required. Another glaring omission is work in the developing world. This is the critical target for preventing the anticipated increase in the burden of hypertension and CVD in the next two decades. The potential for primordial prevention and improved BP management remains, but only if suitable research is designed, resourced, and carried out urgently.

In the most recent hypertension guidelines (except JNC 7), thresholds for treating hypertension are increasingly based on estimated CV risk. It should be acknowledged, however, that no trials have been designed to include patients on the basis of a specific level of risk. Hence, it is difficult and perhaps inappropriate, pending such information, to replace BP levels by risk levels when making treatment recommendations.

At a population level, the advice given to the general public and those responsible for healthcare delivery needs to improve dramatically if we are to lower the healthcare burden due to raised BP. Public education on health is achievable. Despite some cynical views regarding large population-based interventions, startling beneficial effects on CVD and mortality have been demonstrated at the population level. For example, in Finland, the reduction in CV deaths over a 20-year period, following a broad-based national campaign to improve diet and lifestyles, appears to have been almost completely attributable to the healthy life changes that were made.33

The improved implementation of guidelines necessitates more effective communication between those producing the guidelines and the healthcare professionals charged with managing patients. It may also be useful to produce documents—written, visual, or electronic—designed to inform the general public. In the interests of optimal broad-based uptake of guidelines, a pivotal component required is simplicity. Brief, simple messages (despite the inevitable tradeoff of a degree of inaccuracy) are required.

There is a continuing need for more effective agents from among currently available drug classes, ideally with fewer side effects. Perhaps, more importantly, newer classes of agents are required and several new classes of agents are being developed. To provide real advances over currently available agents, such products will be required to have long duration of action and low side effect rates, with BP-lowering efficacy associated with commensurate reduction in CV events. The benefits of pharmacogenetics whereby drugs may be targeted on the basis of genetic profiling are considered by some to be on the horizon, whereas others believe that it is a rather distant horizon. Meanwhile with the increasing need and use of polypharmacy in an ageing population, the trends are likely to move further towards the use of combination therapies. This is likely to involve not just the combination of two (or more) antihypertensive agents but also the combination of various products that act on different CV risk factors.

Meanwhile, pending further evidence from randomized trials to further guide drug selection and sequencing, the combination of A and C drug classes appears to be logical from a mechanistic viewpoint,34 metabolically beneficial (or at worst neutral),35 cost effective,30 well tolerated,10 supported by extensive trial evidence of the individual components,31 and in combination in the ASCOT trial,10 and may produce greater benefits in terms of coronary and stroke protection than the BP reduction so-produced would predict.36

Based on trials in which any of the currently recommended pairs of agents5,19,26 have been compared, ACE inhibitors plus CCBs probably have the best evidence to support their use for the management of hypertension.

Conflict of interest: I confirm that the above manuscript is the work of the authors as stated, and declare that I participated in the design, execution, and analysis of the paper. I also declare that I have the following potential conflicts of interest in connection with this paper. (a) Speaker honoraria: I have and continue to receive honoraria for speaking at industry-sponsored meetings including those organised by Servier. (b) I am currently co-ordinating a randomized trial of up to 3000 patients with hypertension. This trial is funded by Servier Laboratories and employs approximately 20 people in my research unit. (c) I intermittently receive payment for appearing on ad hoc advisory boards for drug and food companies. I own no stock of any kind and have no academic or intellectual commitments that would bias the work submitted for publication.


   Funding
Top
 Abstract
 The ASCOT trial methods
 Results
 Summary/conclusions/discussion
 Funding
References
 
N.R.P. has received funding from Servier to present data at several international symposia and as in this case for producing an associated brief article.


   Footnotes
 
* In earlier publication, by error, 30% reduction was mentioned. Back


   References
Top
 Abstract
 The ASCOT trial methods
 Results
 Summary/conclusions/discussion
 Funding
 References
 

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