Fig. 41.1
Schematic representation of therapeutic algorithm proposed by ESH/ESC guidelines on hypertension (Modified from Mancia et al. [12])
Fig. 41.2
Schematic representation of therapeutic algorithm proposed by JNC 8 guidelines on hypertension (Modified from James et al. [13])
Table 41.1
Potential combination therapies for the clinical management of hypertension
A. Dual combination therapies |
1. Based on thiazide diuretics |
ACE inhibitors + thiazide diuretics (hydrochlorothiazide, indapamide) |
ARBs + thiazide diuretics (hydrochlorothiazide, chlorthalidone) |
Calcium channel blockers + thiazide diuretics (hydrochlorothiazide, indapamide) |
2. Based on calcium channel blockers |
ACE inhibitors + calcium channel blockers |
ARBs + calcium channel blockers |
Calcium channel blockers + thiazide diuretics (hydrochlorothiazide, indapamide) |
B. Triple combination therapies |
ACE inhibitors + calcium channel blockers + thiazide diuretics (hydrochlorothiazide, indapamide) |
ARBs + calcium channel blockers + thiazide diuretics (hydrochlorothiazide) |
In those hypertensive patients who do not achieve satisfactory BP control under monotherapy, a combination strategy based on the use of two classes of antihypertensive drugs including RAS-blocking agents with either CCBs or thiazide diuretics (dual combination therapy) should be used. Randomized clinical trials [22–24] and large meta-analyses [25, 26] confirmed that dual combination therapy is characterized by an antihypertensive efficacy about five times greater than the doubling of the dose of monotherapy. In particular, among different combination therapies, those based on RAS blockers and CCBs are now viewed as the most effective and better tolerated antihypertensive strategy compared to other drug classes in several clinical settings [12, 13].
In those hypertensive patients who do not achieve satisfactory BP control under dual combination therapy, a combination strategy based on the use of three classes of antihypertensive drugs, including RAS blocking agents, CCBs and thiazide diuretics (triple combination therapy) should be used [16]. If the recommended BP targets are not achieved under triple combination therapy, a fourth antihypertensive drug class should be added. The addition of any antihypertensive class different from the previous three classes (beta-blockers, alpha-blockers, aldosterone antagonists, centrally acting agents) has demonstrated to be able to provide additional BP reductions and to achieve effective BP control in a number of patients with moderate-to-severe hypertension and in hypertensive patients who are difficult to be treated. Currently available evidence in the medical literature suggests the additional use of aldosterone antagonists [27, 28]. It should also be acknowledged that some combination therapies with specific drug classes should not be used for the treatment of hypertension. In particular, the use of combination therapy based on ARBs plus ACE inhibitors should not be used in the treatment of essential hypertension because of the additive antihypertensive effect and the potential risk of adverse effects (worsening renal function) [29]. Several studies suggest the use of this combination therapy in order to obtain greater antiproteinuric effect than that achieved with monotherapy with either ARBs or ACE inhibitors; however, a careful monitoring of renal function and plasma electrolytes is always required (Chap. 36).
The use of combination therapies based on ACE inhibitors or ARBs plus direct renin inhibitor (aliskiren) is currently not recommended, since analysis of recent clinical trials reported an increased risk of adverse events (worsening renal function and nonfatal cerebrovascular events) in normotensive patients with diabetic renal failure [30] or congestive heart failure [31]. On the other hand, this potential safety issue does not seem to be confirmed by data derived from extensive monitoring of the clinical practice. In fact, it was reported that in patients with treated uncontrolled hypertension, the addition of aliskiren to an optimal antihypertensive strategy including at least two drug classes may improve BP control rates in the absence of relevant side effects and with the possibility of reducing the use of other concomitant classes of antihypertensive drugs [32].
Combination therapies based on beta-blockers plus diuretics should not be used in the treatment of essential hypertension, unless there are specific indications, because of the potential risk of new-onset diabetes in predisposed patients [33], except for those beta-blockers with vasodilating action [34, 35] and beta1-selective blockers [36].
41.4 Rationale for Combination Therapies Based on RAS Antagonism
The benefits of RAS-inhibiting drugs in different clinical conditions have been demonstrated in different clinical settings, from asymptomatic patients with cardiac disease to severe refractory heart failure, end-stage renal disease and cardiovascular death [37]. In particular, the favourable effects of RAS-blocking agents, including both ACE inhibitors and ARBs, as compared to conventional treatment (mostly including beta-blockers and diuretics) have been extensively tested in a large, representative population and corroborated by the achievement of reduced cardiovascular morbidity and mortality [37]. On the basis of the observation that in most cases both ACE inhibitors or ARBs were systematically associated with other classes of antihypertensive drugs, mostly thiazide diuretics or CCBs, it has been suggested that implementing the use of combination therapies based on drugs able to inhibit the deleterious effects of abnormal RAS activation may also improve BP control and tolerability, beyond the favourable effects on cardiovascular protection in the clinical management of hypertension.
The rationale of combination therapy based on RAS blockers in hypertension should not be limited only to an increased BP-lowering efficacy due to the synergistic and additive effects on BP reduction provided by different compounds [38–40]. In addition, it may be linked to the favourable impact on several pathophysiological mechanisms of hypertension, as well as to the inhibition of the contra-regulatory mechanisms, thus leading to a reduced incidence of drug-related side effects and hence improved tolerability [38–40]. In addition, these combination strategies can be effectively and safely applied in a number of hypertension-related clinical conditions, such as patients with obesity, metabolic syndrome or diabetes mellitus, coronary artery disease, cerebrovascular disease and renal failure with or without proteinuria [41, 42].
Nowadays, because of the above-mentioned evidence, dual or triple combination therapies based on RAS-blocking agents, thiazide diuretics and/or CCBs appear to be rational for a number of pharmacologic, therapeutic and clinical reasons, as compared to those combinations including beta-blockers and thiazide diuretics. First, these strategies are based on the concomitant use of the most documented antihypertensive agents. Secondly, they are substantially neutral or favourable from the metabolic perspective (i.e. reduced incidence of new-onset diabetes mellitus) when compared with traditional combination therapy. Finally, they have important clinical advantages in terms of tolerability, by providing a substantial reduction of the adverse effects of one component through the antagonistic actions of RAS-blocking agents [43].
41.5 Experience with Combination Therapies in Randomized Clinical Trials: Proven Benefits for Cardiovascular Protection
Results of international, randomized, controlled clinical trials have consistently demonstrated that a reduced incidence of major cardiovascular events is strictly related to the degree of BP reduction. In the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, the largely prevalent use of monotherapy at the beginning of the trial was associated with only 25 % of patients controlled, whereas 70 % of patients were controlled with the use of combination therapy which progressively prevailed during the course of the study [23]. The same trend was observed in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA) trial [22], in which the progressive titration protocol for the use of a combination therapy based on either an ACE inhibitor and indapamide or a beta-blocker and a thiazide diuretic resulted in very high proportions of hypertensive patients who achieved BP control. Despite similar BP reductions between two treatment arms, antihypertensive therapy based on an ACE inhibitor and indapamide induced substantial advantages in terms of reduced incidence of cardiovascular events compared to beta-blocker and thiazide diuretic therapy [22]. More recently, in the Avoiding Cardiovascular events through Combination therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial [24], the use of combination therapy (benazepril plus amlodipine or benazepril plus hydrochlorothiazide) from the beginning of the study resulted in a very high percentage (72.4–75.4 %) of patients with controlled BP levels at the end of the trial. Even in this trial, antihypertensive therapy based on benazepril (ACE inhibitor) plus amlodipine (CCB) resulted in significantly lower incidence of major cardiovascular events than that of benazepril (ACE inhibitor) plus hydrochlorothiazide (diuretic) [24].
41.6 Experience with Combination Therapy in Clinical Studies in Hypertension: Proven Benefits for Blood Pressure Reductions
41.6.1 Dual Combination Therapy
Several clinical studies, although with limited sample size, duration of the follow-up and different treatment protocol or study design, have demonstrated the efficacy, safety and tolerability of different combination therapies in achieving effective and sustained BP control in hypertensive patients at different risk profile. Potential combination therapies that can be applied for hypertension management and control are listed in Table 41.1. As shown in this table, the choice of drugs in combination therapy is based on their pharmacological properties, lack of pharmacokinetic interaction and their clinical effectiveness. The basis for a combination is twofold (in addition to patient convenience and compliance): synergistic or additive effect (increases efficacy) and antagonism of other drug’s adverse effect(s), e.g. the increase in sodium and fluid excretion induced by hydrochlorothiazide leads to a reflex activation of the RAS characterized by a significant increase in plasma renin and angiotensin. Therefore, RAS inhibitors would indirectly antagonize angiotensin effects and potentiate the antihypertensive effects of hydrochlorothiazide. Hypokalemia, an adverse effect with hydrochlorothiazide, is reduced by ACEi; on the other hand, hyperkalaemia by RAS inhibitors is counterbalanced by diuretics. Also, peripheral oedema induced by CCB is reduced by RAS inhibitors and diuretics. Additionally, reduction of circulating angiotensin II levels and calcium channel blockade has additive effects in lowering BP levels. It may be noted, however, that European guidelines on hypertension recommend the use of combination therapy based on diuretics and dihydropyridine CCBs only in elderly hypertensive patients with isolated systolic hypertension [12]. As previously discussed, despite the availability of numerous clinical trials and observational registries demonstrating the antihypertensive efficacy of aliskiren, both in monotherapy and in combination therapy, in patients with different degrees of hypertension and global cardiovascular risk profile, the same guidelines do not recommend the use of aliskiren as first-line antihypertensive therapy. This is because of the report of increased incidence of serious adverse events in the aliskiren arm of two large, randomized, controlled clinical trials, performed in high-risk normotensive patients with diabetic renal impairment [30] and congestive heart failure [31], respectively.
Overall data confirm that a treatment algorithm based on dual combination represents an effective, safe and well-tolerated therapeutic strategy for improving BP control and achieving BP normalization in the clinical management of patients with mild-to-moderate hypertension. To further improve BP control and achieve BP normalization, triple combination therapy can be implemented. This strategy, in fact, has been tested in open-label extensions of the above-mentioned studies or in randomized clinical trials, which included patients with apparently resistant or challenging hypertension under dual combination therapy or grade 2–3 hypertension, respectively.
41.6.2 Triple Combination Therapy
Several clinical studies have tested the antihypertensive efficacy and safety of triple combination therapy based on the use of dihydropyridine CCBs (mostly amlodipine besylate), thiazide diuretic (hydrochlorothiazide) and ARBs (losartan [44, 45], valsartan [46, 47] and olmesartan [48, 49]).
In the 12-week prospective, open-label, titrate-to-goal Blood Pressure Control in All Subgroups With Hypertension (BP-CRUSH) study [50], treated uncontrolled hypertensive patients on monotherapy were switched to fixed-dose dual combination therapy with olmesartan/amlodipine and subsequently up-titrated every 4 weeks to full-dose dual (i.e. olmesartan/amlodipine) or triple (i.e. olmesartan/amlodipine/hydrochlorothiazide) combination therapies, if BP control was not achieved. At the end of the study, an overall proportion of more than 75 % of patients reached the systolic BP target.
In the TRIple Therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in HyperteNsIve PatienTs StudY (TRINITY), a 12-week, multicenter, randomized, double-blind, parallel-group study, performed by Oparil et al. [51], triple combination therapy was compared with dual combination therapy of the individual components in fixed-dose formulations, including olmesartan/amlodipine 40/10 mg, olmesartan/hydrochlorothiazide 40/25 mg and amlodipine/hydrochlorothiazide 10/25 mg in patients with moderate-to-severe hypertension [51]. At the end of the study period, triple combination treatment was associated with markedly greater reductions in seated systolic and diastolic BP levels as compared with dual combination therapy. The number of patients reaching the recommended BP target at week 12 was 69.9 % in the triple combination treatment group and 52.9 %, 53.4 % and 41.1 % in the dual combination treatment groups receiving olmesartan/amlodipine 40/10 mg, olmesartan/hydrochlorothiazide 40/25 mg and amlodipine/hydrochlorothiazide 10/25 mg, respectively (P < 0.001, triple combination versus each dual combination therapy) [51].
More recently, in a 10-week, multicenter, randomized, double-blind, parallel-group study, performed by Volpe et al. [52], patients with moderate-to-severe hypertension were randomized to receive thiazide diuretic as add-on therapy to a range of doses of different combination therapies based on olmesartan/amlodipine. At the end of the follow-up period, all triple combination therapy induced substantially greater reductions of both systolic and diastolic BP levels compared to the corresponding dual combination therapy. Patients treated with triple combination therapy also had a significantly improved (>70 %) BP control rate by week 10 [52].
Overall, these data demonstrate the efficacy, safety and tolerability of triple combination therapy relative to dual combination or a single antihypertensive agent in patients with moderate-to-severe hypertension or challenging hypertension. Based on these findings, such therapeutic approach is now recommended by international guidelines for the clinical management of high BP levels, even as first-line approaches, when appropriate.
41.7 Fixed-Dose or Free-Combination Therapy for the Clinical Management of Hypertension
Few ‘head-to-head’ clinical trials directly compared the efficacy, safety and tolerability between fixed-dose and free-combination therapies. A recent meta-analysis [14] based on a limited number of randomized and controlled clinical trials demonstrated that fixed-dose combination therapy provides slightly better results than free-combination therapy in terms of a reduction in systolic and diastolic clinic BP levels but without achieving a statistically significant difference. In the same analysis [14], when fixed-dose and free-combination therapies were compared in terms of compliance with the prescribed antihypertensive treatment, no statistically significant differences were observed. Based on clinical efficacy, the results were slightly favourable to the use of fixed-dose over free-combination therapy. However, this difference was observed mainly in non-randomized clinical trials, whereas no statistically significant difference could be demonstrated in nearly all of the randomized clinical trials that had been considered [14].
A fixed-dose combination strategy has the advantage of providing patients with a simpler therapeutic regimen to be taken in a single dose and therefore, it is absolutely competitive and a winner from the point of view of patient compliance, which is in any case the first and foremost target in the clinical management of hypertension. In other words, no treatment can ever be effective if the patient does not take the prescribed medications, in the correct manner and at the correct dose and time. However, the use of fixed-dose combination therapy often requires progressive dose titration of each medication, in order to achieve and maintain effective and sustained BP control over time. This titration may lead to the onset of dose-related side effects and adverse events, for which physicians may be unable to determine which component of the combination therapy is responsible. In light of these considerations, the use of a free-combination therapy with progressive dose titration may provide a gradual reduction of BP values until effective and sustained BP control is achieved, without resulting in self-discontinuation of the prescribed antihypertensive therapy because of the onset of dose-related side effects or adverse events.
Fixed-dose combination therapy has the advantage of requiring a single daily dose, which also makes it highly competitive in terms of patient compliance. However, it should be mentioned that the use of fixed-dose combination therapy should be able to ensure effective and sustained antihypertensive effects throughout a 24-h period [53]. Also, the use of free-combination therapy may be associated with a higher risk of ‘futility’ compared with fixed-dose combination therapy, particularly when using not rational and not recommended combination of different antihypertensive drugs [12, 13].
Evidence available to date with respect to the treatment of hypertension has been obtained almost exclusively through the use of free rather than fixed-dose combinations. This evidence does not confirm higher patient compliance with the use of fixed-dose combination therapies versus free-combination therapies, as could be expected, although the studies used are adequately large and rigorously controlled. This could also be attributed to a certain ‘mistrust’ in patients, when they see that their BP is poorly controlled over the 24-h period, and consequently tend to lose confidence in the treatment. Finally, no evidence exists to date from randomized, ‘head-to-head’ clinical studies comparing therapies based on fixed-dose combinations versus therapies based on free combinations; this represents a significant limitation that must be taken into account before drawing definitive conclusions.
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