They also exhibit a somewhat less favourable side effect profile than that of RAS blockers, with a higher rate of treatment discontinuation when assessed in real-life conditions. Finally, beta-blockers are not a homogeneous class. In recent years, the use of vasodilating beta-blockers—such as labetalol, nebivolol, celiprolol, and carvedilol—has increased. Studies on nebivolol have shown that it has more favourable effects on central BP, aortic stiffness, endothelial dysfunction, etc.
Table of Contents
It has no adverse effect on the risk of new-onset diabetes and a more favourable side effect profile than classical beta-blockers, , including less adverse effects on sexual function. Bisoprolol, carvedilol, and nebivolol have been shown to improve outcomes in RCTs in heart failure; however, there are no RCTs reporting patient outcomes with these beta-blockers in hypertensive patients. Centrally active drugs were widely used in the earliest decades of antihypertensive treatment when other treatments were not available, but are less frequently used now, principally because of their poorer tolerability relative to the newer major classes of drugs.
Antihypertensive drugs, other than the major classes already discussed above, are no longer recommended for the routine treatment of hypertension, and are primarily reserved for add-on therapy in rare cases of drug-resistant hypertension where all other treatment options have failed. Guidelines have generated a variety of different strategies to initiate and escalate BP-lowering medication to improve BP control rates.
In previous Guidelines, the emphasis was on initial use of different monotherapies, increasing their dose, or substituting for another monotherapy. However, increasing the dose of monotherapy produces little additional BP lowering and may increase the risk of adverse effects, whilst switching from one monotherapy to another is frustrating, time consuming, and often ineffective. For these reasons, more recent Guidelines have increasingly focused on the stepped-care approach, initiating treatment with different monotherapies and then sequentially adding other drugs until BP control is achieved.
Despite this, BP control rates have remained poor worldwide. Several reasons need to be considered to identify why the current treatment strategy has failed to achieve better BP control rates: Efficacy of pharmacological therapies. Are the best available treatments, in whatever combination, incapable of controlling BP in most patients?
Physician or treatment inertia. Patient adherence to treatment. Evidence is accumulating that adherence is a much more important factor than previously recognised. Studies using urine or blood assays for the presence or absence of medication have shown that adherence to treatment is low. Insufficient use of combination treatment. BP is a multiregulated variable depending on many compensating pathways.
Consequently, combinations of drugs, working through different mechanisms, are required to reduce BP in most people with hypertension. Thus, monotherapy is likely to be inadequate therapy in most patients. Complexity of current treatment strategies. There is also evidence that adherence to treatment is adversely affected by the complexity of the prescribed treatment regimen.
In a recent study, adherence to treatment was strongly influenced by the number of pills that a patient was prescribed for the treatment of hypertension. The above considerations suggest that the most effective evidence-based treatment strategy to improve BP control is one that: i encourages the use of combination treatment in most patients, especially in the context of lower BP targets; ii enables the use of SPC therapy for most patients, to improve adherence to treatment; and iii follows a treatment algorithm that is simple, applies to all patients, and is pragmatic, with the use of SPC therapy as initial therapy for most patients, except those with BP in the high—normal range and in frail older patients see below.
Among the large number of RCTs of antihypertensive therapy, only a few have directly compared different two-drug combinations, with systematic use of the two combinations in both arms. In other trials, treatment was initiated using monotherapy in either arm and another drug and sometimes more than one drug was added, usually in a non-randomized fashion, according to a pre-specified treatment algorithm. In a few trials, the design precluded the use of what might be considered optimal combinations because multiple monotherapies were being evaluated [e.
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With this caveat, Table 21 shows that a variety of drug combinations have been used in at least one active arm of placebo-controlled trials and have been associated with significant benefit on major CV events. In trials comparing different regimens Table 22 , all combinations have been used in a larger or smaller proportion of patients, without major differences in benefits. The only exceptions are two trials in which a large proportion of the patients received either an ARB—diuretic combination or CCB—ACE inhibitor combination, with both regimens being superior to a beta-blocker—diuretic combination in reducing CV outcomes.
However, in six other trials with seven comparisons , beta-blockers followed by diuretics or diuretics followed by beta-blockers were not associated with a significantly different risk of any CV outcome, , , , — and the beta-blocker diuretic combination was significantly more effective than placebo in three trials.
Major drug combinations used in trials of antihypertensive treatment in a stepped approach or as a randomized combination combinations vs. Based on the results of outcome RCTs and recent meta-analyses, and evidence of BP-lowering effectiveness, all five major drug classes can, in principle, be combined with one another, except for ACE inhibitors and ARBs, whose concomitant use may lead to no additional benefit but increased adverse effects and is thus discouraged.
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These combinations are now widely available in a single pill and in a range of doses, facilitating simplification of treatment, flexible prescribing, and uptitration from lower to higher doses. These combinations will also limit potential adverse effects associated with diuretic or CCB monotherapy, reducing the risk of hypokalaemia due to diuretics and reducing the prevalence of peripheral oedema due to CCBs. These combinations also ensure that the RAS is inhibited as part of the treatment strategy, which is an important consideration for many patient groups e.
Beta-blockers in combination should be preferentially used when there is a specific clinical indication for their use e. Initial combination therapy is invariably more effective at BP lowering than monotherapy, indeed even low-dose combination therapy is usually more effective than maximal dose monotherapy. Although no RCT has compared major CV outcomes between initial combination therapy and monotherapy, observational evidence suggests that the time taken to achieve BP control is an important determinant of clinical outcomes, especially in higher risk patients, with a shorter time to control associated with lower risk.
In this regard, the outcome of these real-life studies of the impact of initial combination therapy on adherence, BP control, and CV outcomes may be especially relevant. A consideration in the current Guidelines was to persist with the current stepped-care approach to BP treatment, which has been interpreted as recommending monotherapy as initial therapy for most patients, reflecting current practice. In fact, the previous Guidelines did acknowledge the possibility of initial combination therapy for patients with grade 2 or 3 hypertension, or patients at high or very high risk.
In other words, initial monotherapy was only recommended for grade 1 hypertension and low- or moderate-risk patients. Thus, in reality, the shift in emphasis in this new guidance is subtle. However, normalizing the concept of initiating therapy with a two-drug combination for most patients with hypertension is likely to have a major effect on clinical practice and the speed and quality of BP control.
Moreover, the possibility of starting with a low-dose combination of two antihypertensive drugs, even in grade 1 hypertensive patients with low—moderate-risk, is supported by the reduction of CV events obtained by combination therapy in the upper tertile grade 1 hypertension in the HOPE-3 trial. Studies suggest that two-drug combination therapy will control BP in approximately two-thirds of patients. We do not recommend three-drug combinations as initial therapy.
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It is further supported by data from recent studies using various methods to assess adherence to treatment, including the quantification of antihypertensive drugs in urine and blood, , and estimates such as pill counting or prescription refills, which, although indirect, allow the measurement of adherence on a prolonged basis, thereby accounting for its time-variable nature. This approach is now facilitated by the availability of several SPCs with a range of dosages, which eliminates the often-stated disadvantage of SPC therapy i.
It is also convenient that the most widely available SPCs mirror the major drug class combinations recommended by these Guidelines. The major advantage of an SPC as the usual therapeutic approach for hypertension is that patients can progress from 1, 2, or 3 drug treatments whilst remaining on a simple treatment regimen with a single pill throughout, increasing the likelihood of adherence to therapy and achieving BP control. Although, at present, the availability of two-drug SPCs is largely limited to a RAS blocker with either a CCB or diuretic, it would be desirable to see the development of an expanded range of low-cost SPCs in different drug formulations, tailored to different clinical requirements.
Polypills have also emerged as SPCs i. Studies of bioequivalence suggest that when combined in the polypill, different agents maintain all or most of their expected effect.
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Nevertheless, the advantage of treatment simplification and adherence suggests that use of the polypill may be considered in patients with hypertension as substitution therapy, when the need and effectiveness of each polypill component has been previously established by their administration in separate tablets. When BP remains uncontrolled with three-drug combination therapy, the patient is classified as having resistant hypertension, assuming that secondary causes of hypertension and poor adherence to treatment have been excluded, and that the elevation in BP has been confirmed by repeated office BP measurement, ABPM, or HBPM see section 8.
Such patients should be considered for specialist evaluation.
Reflecting on the evidence above, and recognizing the urgent need to address the factors contributing to the poor control of BP in treated hypertensive patients see section 7. A beta-blocker in combination with a diuretic or any drug from the other major classes is an alternative when there is a specific indication for a beta-blocker, e.
The addition of spironolactone for the treatment of resistant hypertension, unless contraindicated see section 8.
Abbreviations and acronyms
The use of other classes of antihypertensive drugs in the rare circumstances in which BP is not controlled by the above treatments. Information on availability and recommended doses of individual drugs, as well as SPCs and free combinations, can be found in national formularies. The algorithm recommends initial therapy for most patients with a two drug-combination, ideally as an SPC. Variations from the core drug treatment algorithm for uncomplicated hypertension shown in Figure 4 are specified in Figures 5 to 8.
Recommended BP target ranges for treated hypertension are shown in Table Refers to patients with previous stroke and does not refer to blood pressure targets immediately after acute stroke. Treatment decisions and blood pressure targets may need to be modified in older patients who are frail and independent. Core drug treatment strategy for uncomplicated hypertension. Drug treatment strategy for hypertension and coronary artery disease.
Drug treatment strategy for hypertension and chronic kidney disease. Drug treatment strategy for hypertension and hear failure with reduced ejection fraction.
Do not use non-dihydropyridine CCBs e. Consider a loop diuretic as an alternative in patients with oedema. Drug treatment strategy for hypertension and atrial fibrillation. The drug treatment strategy for patients with hypertension should be based on the algorithm shown Figures 4 to 8 , unless there are contraindications to these drugs Table 20 , or concomitant conditions or diseases are present that require specific modification of the drugs, as outlined in the recommendations below.
Various device-based therapies have emerged, principally targeted at the treatment of resistant hypertension. These are discussed below. Carotid baroreceptor stimulation or baroreflex amplification therapy—externally via an implantable pulse generator or internally via an implantable device designed to increase the strain on the carotid bulb—can lower BP in patients with resistant hypertension. An RCT with the first generation of an implantable pulse generator showed sustained BP-lowering efficacy and sympathetic nervous system inhibition , but with some concerns about procedural and longer term safety.
A propensity score-matched comparison of the first- and second-generation systems revealed that BP at 12 months post-implantation was similar, with a better safety profile for the second-generation device. Another consideration is that implantation is costly and requires a complex surgical intervention. This has led to the development of an endovascular carotid baroreflex amplification device using a dedicated stent-like device designed to stretch the carotid bulb and increase baroreflex sensitivity.
Preliminary data in humans have shown evidence of BP-lowering efficacy of this new approach, but data from ongoing RCTs are needed to definitively understand its longer-term efficacy and safety.
The rationale for renal denervation lay with the importance of sympathetic nervous system influences on renal vascular resistance, renin release, and sodium reabsorption, the increased sympathetic tone to the kidney and other organs in hypertensive patients, and the pressor effect of renal afferent fibres documented in experimental animals. Several observational studies and national and international registries support the BP-lowering efficacy of renal denervation originally reported in the Symplicity HTN-1 and HTN-2 trials.