In 2007, the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) published their guidelines for the management of arterial hypertension.1 These guidelines covered in detail all aspects of the management of hypertensive patients, from the diagnosis and detection of early subclinical organ damage to the discussion of the various therapeutic strategies in essential and secondary forms of hypertension.
As mentioned in the introduction to these guidelines, the manuscript tries “to offer the best available and most balanced recommendation to all healthcare providers involved in the management of hypertension”. However, the scientific evidence is rapidly developing, and every year new randomised clinical trials, observational studies, meta-analyses and expert opinions are published. These new data either reinforce the recommendations or challenge the concepts elaborated on in existing guidelines.
In this perspective, a reappraisal of the European guidelines on hypertension management was published in 2009.2 This new document was written with the objective of including the results of the newest important clinical studies and critically discussing the 2007 ESH/ESC recommendations in view of the latest developments in the field.
Reappraisal of the European Society of Hypertension/European Society of Cardiology Guidelines – What Are the Important Points?
The detection of subclinical target organ damage and the assessment of the cardiovascular risk of hypertensive patients as precisely as possible are two important initial steps in the management of hypertensive patients, and help to define therapeutic strategies. The number of new methods to assess target organ damage in hypertension is constantly increasing. Some of the measures are easily accessible and cheap, such as the electrocardiogram (ECG) or the determination of urinary protein excretion, whereas others have a high cost and a low availability, such as the measurement of intima-media thickness. Moreover, the prognostic importance of some of the new procedures is not always well documented.3 The reappraisal of guidelines insists on the regular use of techniques that are simple, widely available and cheap, such as urinary protein excretion, calculation of glomerular filtration rate (eGFR) and the ECG. More sophisticated methods can of course be used, provided they add precision to the quantification of the cardiovascular risk.
A major issue in the reappraisal of the 2007 guidelines is the discussion of the blood pressure thresholds for drug treatment in hypertension, with a particular emphasis on grade 1 hypertension and hypertension in the elderly.2 The reappraisal also discusses the blood pressure goals and the evidence available for defining lower BP targets of antihypertensive treatment in some groups of patients, for example in diabetics and in patients with a history of cardiovascular disease.
Interestingly, a critical analysis of clinical trials revealed that the evidence in favour of a recommendation to initiate antihypertensive therapy in patients with a low or moderate cardiovascular risk and a blood pressure (BP) of between 140 and 159mmHg systolic and 90 and 99mmHg diastolic remains scant, and hence could be challenged. In this clinical situation, drug therapy should be initiated only after a suitable period of lifestyle changes. Today, there is no evidence to support treatment in patients with a high to normal BP (130–139/85–89mmHg) uncomplicated by diabetes or a previous cardiovascular event. Similarly, there is no argument to treat patients with a previous cardiovascular complication in the absence of hypertension. Finally, the current recommendations on BP values at which one should initiate a treatment in the elderly (i.e >140/90mmHg) are not supported by the results of clinical trials since none of the published studies included patients with such a low starting BP.4 Therefore, the actual recommendations could be questioned and the BP threshold perhaps set at 160mmHg systolic in the elderly.
There are also many discussions about the necessity of starting antihypertensive therapy in patients with diabetes and a high normal blood pressure and to target lower BP goals (<130/80mmHg) in this patient population. As confirmed recently by the results of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial,5 it does not seem that lowering systolic BP below 120mmHg provides additional clinical benefits in diabetics except perhaps for the prevention of stroke. Thus, it might be sufficient to recommend that in diabetes, systolic BP be reduced well below 140mmHg without additional precision. This critical discussion of BP targets has revived the issue of the J-curve phenomenon, according to which a very low BP may be associated with an increase in coronary events. This phenomenon may particularly relevant in patients with advanced atherosclerotic artery diseases.
When Should We Start a Monotherapy or a Drug Combination?
In contrast to American and British hypertension guidelines, European guidelines are relatively flexible regarding which antihypertensive drug class should be used as first-line therapy in hypertensive patients. This position is based on the principle that the main benefits of antihypertensive therapy reside in the lowering of BP per se. Thus, the five major classes of antihypertensive agents, i.e. diuretics, angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, angiotensin receptor blockers (ARB) and beta-blockers, do not differ in their overall ability to lower BP in hypertension and hence to reduce the cardiovascular risk of patients. In recent years, there have been many discussions concerning the place of beta-blockers, which have been downgraded in the British recommendations based on the results of a meta-analysis suggesting a slight inferiority in preventing stroke. However, beta-blockers are similar to other classes in preventing coronary events and heart failure, and may even be superior to some other classes in patients who have suffered a recent coronary event.6 The reappraisal of the 2007 ESH guidelines recognises the fact that beta-blockers have been found to be less powerful than ACE inhibitors, ARBs and calcium antagonists in reducing left ventricular hypertrophy, aortic stiffness and carotid intima-media thickness, but also consider the fact that beta-blockers are not an homogenous class of antihypertensive drugs. Thus, the majority of the observations have been made with atenolol and the properties of this agent might not be shared by other beta-blockers such as nebivolol or carvedilol,7 although one must admit that there is clearly less information on the effect of these beta-blockers in hypertension. Today, the main reason why beta-blockers and, to a certain degree, diuretics are less popular as initial therapies is their tolerability profile with an increased incidence of adverse metabolic effects such as new-onset diabetes. With the increased incidence of obesity in the general population, the risk of developing type 2 diabetes is increasing and may be promoted by the use of beta-blockers and diuretics. To avoid this trend, physicians tend to favour the use of blockers of the renin–angiotensin system (RAS) and calcium channel blockers.
Today, considering an equivalent antihypertensive efficacy for the five classes, the main arguments to choose one drug class rather than another one in a given individual are the tolerability profile, the compelling indications and contraindications and the recognised efficacy in specific clinical conditions as illustrated in Tables 1 and 2. Thus, the prescription of the antihypertensive therapy will increasingly be individualised, taking into account not only the tolerability profile but also the associated diseases, the other cardiovascular risk factors and, most importantly, the patient’s expectations and willingness to accept the proposed treatment.
Interestingly, the concept of first-line therapy has rightly been challenged by the 2009 reappraisal of guidelines. A ranking of drugs for management is not really useful for several good reasons. The first is that the response to a monotherapy is highly unpredictable in a given individual. In addition, all classes of drugs have their advantages and possible side effects. Finally, only 30–50% of hypertensive patients will normalise their BP with the administration of a single-drug therapy. Therefore, the likelihood that hypertensive patients will be treated with multiple agents is very high, and hence the concept of first-line therapy becomes irrelevant.
Single-pill Combinations – The Future of Hypertension Management
Clinical trials have clearly demonstrated that to achieve the BP targets defined in the actual guidelines, the majority of hypertensive patients will need more than one antihypertensive agent, and on average between two and three drugs.8 In the 2007 guidelines, the ESH recognised the possibility of prescribing a single-pill combination as initial therapy. This recommendation was based on several practical arguments. The immediate use of a single-pill combination increases the likelihood of controlling BP in 60% of hypertensive patients. BP will be controlled more rapidly and a more rapid control of BP associated with a simplified therapeutic regimen might result in a lower incidence of treatment discontinuations. The association of drugs with different mechanisms of action enables counter-regulatory processes to be blunted. Finally, the use of combination therapies enables doctors to prescribe lower doses of each agent and hence induces fewer side effects. The only major limitation of this approach would be the loss of flexibility of upward and downward treatment strategies.
In 2007, before the Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial was published, the most popular fixed-dose combination of antihypertensive drugs was the association of a blocker of the RAS (ACEI or ARB) and a low dose of thiazide. Associations of beta-blockers and calcium antagonists and beta-blockers and diuretics were also quite popular in some countries. The association of an ACE inhibitor and a diuretic will certainly remain a very commonly prescribed single-pill combination: new data from the Action in Diabetes and Vascular disease-preterAx and DiamicroN Controlled Evaluation (ADVANCE) and Hypertension in the Very Elderly Trial (HYVET) studies using perindopril and indapamide, respectively, in patients with type 2 diabetes and in very elderly patients have confirmed the clinical benefits of this association to lower cardiovascular outcomes.
However, the trend may change in the future after the publication of the ACCOMPLISH trial, which compared two fixed-dose combination therapies in >11,000 hypertensive patients with a high cardiovascular risk, i.e. the combination of benazepril plus amlodipine and that of benazepril plus hydrochlorothiazide.9 Both therapeutic regimens controlled BP adequately in close to 80% of patients with only a 1mmHg difference in BP between groups. The tolerability profile was excellent with both treatments. Surprisingly, the incidence of the primary end-point (a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, hospitalisation for unstable angina, coronary revascularisation procedures and resuscitated sudden death) was 20% lower in the benazepril plus amlodipine group than in the benazepril plus hydrochlorothiazide group. The studied population was characterised by a large proportion of obese patients (50%) and patients with diabetes (60%). Interestingly, a post hoc analysis of renal events in ACCOMPLISH has also demonstrated a lower incidence of renal complications with the benazepril plus amlodipine combination, suggesting that this single-pill combination may become an interesting approach to prevent renal as well as cardiovascular complications.10
Thus, today, significant outcome reductions have been demonstrated with several combinations of antihypertensive drugs, including ACE inhibitors and ARBs and a diuretic, an ACE inhibitor and a calcium antagonist and a calcium antagonist and a diuretic. One question that could be asked is: which combination should be preferred and for which patient? So far, there are no clear answers to these two questions as few studies except for ACCOMPLISH have really compared combination therapies in various hypertensive populations. The favourable metabolic profile of the combination of an RAS blocker and a calcium antagonist makes this association very suitable for the management of patients at a high risk of developing metabolic problems, such as obese hypertensives or patients with a metabolic syndrome.
In all other patient groups the association of an RAS-blocker and a low-dose diuretic will remain an excellent therapeutic choice. In anticipation of the predicted obesity epidemic, several associations of RAS blocker and a calcium antagonist are being developed by the industry and should reach the market within a couple of years. Thus, besides the single-pill combination of benazepril and amlodipine, which is already available on the American market, several new combinations are under clinical investigation combining for example the ACE inhibitor enalapril and the dihydropyridine lercanidipine,11 or an ARB (valsartan12 or olmesartan13) and amlodipine and eventually the renin inhibitor aliskiren and amlodipine.14 The antihypertensive efficacy and the excellent tolerability profile of these new associations have been demonstrated in clinical studies. As mentioned previously, one important characteristic of these associations is the reduction of the incidence of peripheral oedema induced by the calcium antagonist. Indeed, blockade of the RAS effectively prevents the development of leg oedema caused by the peripheral vasodilatation promoted by calcium antagonists.
Conclusions
The development of drugs combining two and even three antihypertensive drugs represents the future of hypertension management. Since very few new classes of BP-lowering drugs are being developed, it is now necessary to focus our attention on how to improve hypertension management by interfering with other factors limiting the long-term success of antihypertensive therapy. The simplification of treatment regimens with the use of single-pill combinations should have a very positive impact on the persistence of treatment in hypertension. It is well recognised that, after a couple of years of treatment, close to 50% of patients interrupt their treatment.15 Besides the occurrence of side effects, the complexity of the treatment and the need to take several tablets daily in an asymptomatic condition have been identified as major limitations to the long-term results of hypertension management because of a low long-term adherance to therapy. A more general use of single-pill combinations could also help to fight against the physicians’ therapeutic inertia and hence improve the percentage of patients reaching the goals of therapy.16 Indeed, despite abundant evidence that hypertension is a major cardiovascular risk factor and that controlling BP enables the risk of cardiovascular and renal events to be reduced, surveys consistently show that high BP remains a leading cause of death and cardiovascular morbidity worldwide. In this respect, a periodic critical reappraisal of our approaches of the management of hypertension is of the utmost importance.