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Current perspectives on combination therapy in the management of hypertension.
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PMID:  23837009     Owner:  NLM     Status:  PubMed-not-MEDLINE    
Hypertension (HTN) is a worldwide health problem and a major preventable risk factor for cardiovascular (CV) events. Achieving an optimal blood pressure (BP) target for patients with HTN will often require more than one BP-lowering drug. Combination therapy is not only needed, but also confers many advantages such as better efficacy and a better tolerability. A better compliance and simplicity of treatment is noted with the single-pill combination (SPC). In addition, for those patients who do not achieve BP target when receiving dual combinations, triple SPCs are now available, and their efficacy and safety have been tested in large clinical trials. BP-lowering drugs used in combination therapy should have complementary mechanisms of action, leading to an additive BP-lowering effect and improvement in overall tolerability, achieved by decreasing the incidence of adverse effects. On the basis of large, outcome-driven trials, preferred dual combinations include an angiotensin receptor antagonist (ARB) or an angiotensin converting enzyme inhibitor (ACEI) combined with a calcium channel blocker (CCB), or an ARB or ACEI combined with a diuretic. Acceptable dual combinations include a direct rennin inhibitor (DRI) and a CCB, a DRI and a diuretic, a beta-blocker and a diuretic, a CCB and a diuretic, a CCB and a beta-blocker, a dihydropyridine CCB and a non-dihydropyridine CCB, and a thiazide diuretic combined with a potassium-sparing diuretic. Some combinations are not recommended and may even be harmful, such as dual renin angiotensin aldosterone system inhibition. Currently available triple SPCs combine a renin angiotensin aldosterone system inhibitor with a CCB and a diuretic. Combination therapy as an initial approach is advocated in patients with a systolic BP more than 20 mmHg and/or a diastolic BP more than 10 mmHg above target and in patients with high CV risk. In addition, using SPCs has been stressed and favored in recent international guidelines. Recently, triple SPCs have been approved and provide an attractive option for patients not achieving BP target on dual combination. The effect of such a strategy in the overall management of HTN, especially on further reducing the incidence of CV events, will have to be confirmed in future clinical and population-based studies.
Samir G Mallat; Houssam S Itani; Bassem Y Tanios
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Publication Detail:
Type:  Journal Article     Date:  2013-06-17
Journal Detail:
Title:  Integrated blood pressure control     Volume:  6     ISSN:  1178-7104     ISO Abbreviation:  Integr Blood Press Control     Publication Date:  2013  
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Created Date:  2013-07-09     Completed Date:  2013-07-09     Revised Date:  2013-07-11    
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Nlm Unique ID:  101562709     Medline TA:  Integr Blood Press Control     Country:  New Zealand    
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Languages:  eng     Pagination:  69-78     Citation Subset:  -    
American University of Beirut, Department of Internal Medicine, Division of Nephrology and Hypertension, Beirut, Lebanon.
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Journal ID (nlm-ta): Integr Blood Press Control
Journal ID (iso-abbrev): Integr Blood Press Control
ISSN: 1178-7104
Publisher: Dove Medical Press
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© 2013 Mallat et al, publisher and licensee Dove Medical Press Ltd
collection publication date: Year: 2013
Electronic publication date: Day: 17 Month: 6 Year: 2013
Volume: 6First Page: 69 Last Page: 78
PubMed Id: 23837009
ID: 3699293
DOI: 10.2147/IBPC.S33985
Publisher Id: ibpc-6-069

Current perspectives on combination therapy in the management of hypertension
Samir G Mallataf1-ibpc-6-069
Houssam S Itaniaf1-ibpc-6-069
Bassem Y Taniosaf1-ibpc-6-069
American University of Beirut, Department of Internal Medicine, Division of Nephrology and Hypertension, Beirut, Lebanon
Correspondence: Correspondence: Samir G Mallat, Department of Internal Medicine, American University of Beirut Medical Center, PO Box 11-0236, Riad El-Solh 1107 2020, Beirut, Lebanon Tel +961 1 350 000 Fax +961 137 0814,


Hypertension (HTN) is a highly prevalent disease estimated to be found in around 26% of the adult population worldwide.1 In the United States, it is estimated that about 30% of adults have HTN, as defined by a systolic blood pressure (BP) of 140 mmHg or higher, a diastolic BP of 90 mmHg or higher, or the current use of a BP-lowering drug. Furthermore, among persons aged 65 years or older, the prevalence reached 70%.2

HTN remains one of the major preventable risk factors for coronary events, stroke, heart failure, peripheral vascular disease, and progression of kidney disease.36 Despite recent advances in therapy and increased awareness among both physicians and patients, a large proportion of the hypertensive population continues to have suboptimal BP control, although it is improved when compared with previous data.2,7

To achieve optimal, guideline-recommended BP targets, most hypertensive patients will require a combination of two or more BP-lowering drugs, and monotherapy would likely be sufficient only in a small proportion of patients (about 20%–30%).8

Recent international guidelines recommend initiating a two-drug combination therapy both for patients with a systolic BP more than 20 mmHg and/or a diastolic BP more than 10 mmHg above target and for patients with high cardiovascular (CV) risk.9,10 In addition, single-pill combination (SPC) drugs (SPCs) have also gained ground as the preferred approach to combine BP-lowering drugs in recently updated European guidelines.11

In this article, we review the latest approach to the management of HTN in light of recent advances in combination therapy.

Why is combination therapy needed?

The concept of monotherapy up-titration to achieve BP target has been repetitively challenged.12 Such a strategy is unlikely to achieve the same BP-lowering effect in comparison with combination therapy, as demonstrated in many studies. In a recent meta-analysis, the BP-lowering effect of combining drugs from two different classes was five times more than doubling the dose of a single drug.13 In addition, in a recent retrospective study, hypertensive patients initially begun on combination therapy were more likely to achieve their BP target at 12 months compared with those started on monotherapy.14

One pivotal point in treating HTN in patients with high CV risk is the time to achieve optimal BP control. As demonstrated in a post hoc analysis of the Valsartan Antihypertensive Long-Term Use Evaluation (VALUE) trial, patients who achieved BP target at 6 months had fewer subsequent CV events. Furthermore, an earlier BP response within 1 month was predictive of better outcomes.15 A possible explanation for this finding is that patients who achieved slower BP control might have started with a higher CV risk. As demonstrated in a retrospective analysis by Nasser et al,16 the patients with a higher baseline CV risk (a higher amount of albuminuria, diabetes mellitus, and obesity and a lower estimated glomerular filtration rate) were those who attained BP goals slower. In the same study, it was also shown that therapeutic inertia played an important role, emphasizing the pivotal influence of caring physicians on the speed to BP control. In a recent, randomized controlled trial in patients with HTN and metabolic syndrome, initiating therapy with a combination of an angiotensin receptor antagonist (ARB; valsartan [VAL]) and a calcium channel blocker (CCB; amlodipine [AML]) achieved BP target more rapidly than a strategy starting with a high dose of monotherapy with VAL.17 Moreover, in a recent matched cohort study in patients with HTN, initial combination therapy was associated with a 34% risk reduction in CV events compared with monotherapy, and a more rapid achievement of BP target was the main contributor to this risk reduction.18

Therefore, it is essential and currently recommended that patients with a systolic BP more than 20 mmHg and/or a diastolic BP more than 10 mmHg above target and/or high CV risk (ie, patients with established CV disease or those with multiple CV risk factors such as metabolic syndrome, subclinical organ damage, diabetes, and renal disease) be initiated on combination therapy at diagnosis.9,10

In addition, recent data suggest that initiation of a combination therapy for patients with uncomplicated stage 1 HTN (systolic BP between 140 and 159 mmHg and/or diastolic BP between 90 and 99 mmHg) might be more effective at achieving BP target than up-titrating monotherapy. In a meta-analysis of nine randomized controlled trials that included both stage 1 and stage 2 hypertensive patients, 92% of patients with stage 1 HTN randomly assigned to receive a fixed combination of VAL/hydrochlorothiazide (HCTZ) (160 mg/12.5 mg) achieved their BP target at week 8 versus 74.7%, using a higher dose of VAL (320 mg).19 In fact, in a recent position paper, the American Society of HTN suggested starting with a combination therapy in patients with uncomplicated stage 1 HTN, in particular when one agent will improve the adverse effects profile of the other.20

Another important aspect in HTN management is BP variability. Evidence from animal studies suggests that combination therapy is superior to monotherapy in reducing BP variability and may be the preferred approach in this setting.21,22 In an analysis of trials comprising cohorts with previous transient ischemic attack, visit-to-visit systolic BP fluctuations and maximum systolic BP correlated with increased risk for stroke and coronary events.23

Furthermore, monotherapy may fail in controlling BP by triggering a counter-regulatory reaction, diminishing its BP-lowering effect. This reaction can be blocked by a proper combination therapy that will act on several mechanisms involved in the pathophysiology of HTN.24

Finally, high doses of monotherapy may lead to a better control of BP at the expense of increasing the incidence of adverse effects. When combining two drugs from different classes, lower dosages of the individual components will be enough to achieve BP target with fewer dose-related adverse effects.25 In addition, each agent in the combination can counterbalance the adverse effects of the other.26

Which is better, SPC or free combination?

An important question that arises is whether combination therapy should be delivered as a free combination or as a SPC.

In general, whether used as free combination or SPC, combination therapy achieves an equivalent BP-lowering effect.27,28 A 2004 study demonstrated that an SPC composed of the ARB candesartan and HCTZ was equally safe and effective at reducing BP when compared with the addition of HCTZ to previous monotherapy as a free combination.29

However, SPCs offer several advantages compared with a free combination. In a recent meta-analysis, SPCs significantly improved compliance and persistence to therapy compared with corresponding free combinations of the same drugs. It would be logical to extrapolate from this data that because compliance is improved, overall efficacy and BP control would be better when using SPCs. In fact, in the same meta-analysis, using SPCs demonstrated trends toward better BP control and decreased incidence of adverse effects compared with a free combination.30 In a retrospective study, significantly more patients adhered to a prescribed single pill of enalapril/HCTZ at 12 months than to a free combination of the same drugs.31 Previous data have clearly shown that increasing the number of pills had a negative effect on compliance and on persistence on therapy, translating into poor clinical outcomes.3234

On another note, to achieve BP targets, up to 24% to 32% of patients will require three or more drugs, as shown in clinical trials.35,36 SPCs have the potential to simplify the complex task of combining and titrating drugs from several classes.37

Currently available SPC formulations offer a wide range of dosages for the individual components, offering good flexibility for dosage adjustment and titration for optimal BP control. Triple-combination formulations are also emerging and may additionally offer the advantage of further reducing the pill burden.38

Therefore, SPCs clearly offer all the advantages of free combination drugs in addition to improved adherence, simplification of therapy, better efficacy, and better tolerability. In addition, they are currently endorsed by international guidelines as the preferred strategy to combine BP-lowering drugs.11,20

Table 1 illustrates a comparison between different HTN management strategies.

What is required for combination therapy?

HTN is a complex disease in which multiple factors and physiological mechanisms are involved. The primary hemodynamic parameters for BP regulation are intravascular volume, cardiac output, and systemic vascular resistance. The renin angiotensin aldosterone system (RAAS) and the sympathetic nervous system are the the fine-tuners that continuously both regulate and calibrate these parameters.39

Most commonly used BP-lowering drugs include diuretics, beta-adrenoceptor antagonists (beta-blockers), CCBs, angiotensin converting enzyme inhibitors (ACEIs), ARBs, direct renin inhibitors (DRIs), alpha-blockers, and centrally acting agents. Therefore, the possibility of combining drugs is quite large. However, not every combination is beneficial, and some combinations can be potentially dangerous.

For instance, combining a beta-blocker with a centrally acting agent (clonidine, alpha-methyldopa) can lead to bradycardia and heart block, and their abrupt withdrawal can result in a hypertensive crisis.20,40 In addition, in the ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET), the combination of an ACEI and an ARB leads to increased incidence of adverse effects with no improvement in outcomes, and in the recently halted Aliskiren Trial In Type 2 Diabetes Using Cardio-Renal Disease Endpoints (ALTITUDE) trial, the addition of the DRI to an ARB resulted in increased incidence of hypotension, renal impairment, and hyperkalemia, which might have accounted for the significantly higher incidence of cardiac arrest in the combination therapy group.41,42 In addition, the use of beta-blockers with a nondihydropyridine CCB (such as verapamil) can lead to potentiation of the negative inotropic and chronotropic effect of these drugs.43

Similarly, some classes of drugs should not be combined because they can antagonize each other; for example, combining an α1-antagonist (ie, doxazosin) with a sympathetic modulator α-agonist (ie, clonidine).43

Therefore, drug combinations in HTN must fulfill certain requirements to be approved for use. First, the agents to combine should have an additive BP-lowering effect by acting on complementary mechanisms involved in the pathogenesis of HTN and blocking the counter-regulatory pathways triggered by one another.25 For example, diuretics and CCBs will activate RAAS; therefore, the addition of a RAAS inhibitor to any of these agents will lead to potentiation of their BP-lowering effect.44,45 The same rationale applies to the combination of a beta-blocker with a diuretic where the BP-lowering effect will also be additive, as beta-blockers also inhibit the RAAS.46 Another example to illustrate this complementary action is the beta-blocker/CCB combination. On one hand, the CCB-induced activation of the sympathetic nervous system can be blunted by the beta-blocker effect, but on the other hand, the alpha-mediated reflex vasoconstriction induced by beta-blockers can be attenuated by the vasodilatory effect of the CCB.47,48 In contrast, and because of the overlap in their mechanism of action (RAAS inhibition), the combination of a RAAS inhibitor with a beta-blocker is not recommended for management of HTN, as this combination will produce only a modest incremental BP-lowering effect.49 However, these agents are commonly combined and are recommended in patients with heart failure and in those who suffered a myocardial infarction because of their established effects in reducing mortality in these populations.50,51

Second, each agent of the combination therapy should neutralize the adverse effects of the other, thus improving the overall tolerability. A CCB-induced peripheral edema secondary to arteriolar vasodilation can be attenuated by the postcapillary venodilation exerted by the RAAS inhibitor.26,52 Similarly, thiazide diuretic-induced hypokalemia can be counterbalanced by addition of a RAAS inhibitor or a potassium-sparing diuretic such as amiloride, triamterene or spironolactone.44,53 More importantly, the choice of components for any combination therapy should be based on the best available evidence from clinical trials concerning their efficacy in achieving optimal BP targets with a beneficial effect on CV outcomes.

Specific combinations

As stated earlier, not all combinations are equal, and international guidelines classify various combinations as preferred, acceptable, or not acceptable on the basis of large, outcome-driven clinical trials on safety and on the efficacy of the combination (Table 2).10,20

Preferred combinations RAAS inhibitors-CCB

The addition of an ACEI, ARB, or DRI to a CCB has a fully additive BP-lowering effect.24 The superiority of this specific combination in reducing CV events has been illustrated in several clinical trials.

In the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA) trial, 19,257 patients with HTN and at least three CV risk factors were randomly assigned to receive either AML, adding an ACEI (perindopril) as required, versus atenolol, adding bendroflumethiazide (diuretic) as required. After 5.5 years of follow-up, the trial was halted early, as there was a significant 26% reduction in all CV events, 23% reduction in stroke, and 11% reduction in all-cause mortality in the CCB/ACEI group. This difference in outcome between the two groups could be partly explained by the 2.7 mmHg average systolic BP difference throughout the trial, favoring the CCB/ACEI group. However, and as discussed by the authors, this difference in BP would be expected then to generate a difference up to 8% in coronary events and up to14% in strokes, based on the results of randomized trials and long-term prospective observational data.54 The Avoiding Cardiovascular Events in Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial was a randomized, double-blind trial that aimed to compare the use of a fixed combination ACEI (benazepril)/CCB (AML) with an ACEI/thiazide combination in 11,506 hypertensive patients with high CV risk. After 36 months, the ACEI/CCB fixed combination resulted in a 20% greater risk reduction in the primary outcome (a composite of CV events and death from CV causes). Interestingly, the difference in systolic BP between the two groups was less than 1 mmHg over the course of the trial, suggesting a benefit on CV outcomes of the ACEI/CCB combination that went beyond BP lowering.35

A substudy of the ASCOT trial suggested that the advantage seen with this specific combination on CV outcomes might be explained by its ability to reduce central aortic pressures.55

Large clinical trials also have shown comparable efficacy on hard clinical outcomes when using an ARB as compared with ACEIs, but with better overall tolerability.41 In a recent multicenter, randomized prospective trial in Japanese patients with HTN at high CV risk, the addition of VAL to achieve BP target reduced the incidence of stroke by 45% compared with non-RAAS-based add-on therapy.56 No data with the DRI aliskiren (ALI) are available from large, outcome-driven clinical trials.57

RAAS inhibitors and diuretics

The addition of a diuretic to a RAAS inhibitor also leads to the additive BP-lowering effect and, as discussed earlier, to a better tolerability profile as opposed to that of each agent used alone.20 Furthermore, the addition of a RAAS inhibitor will reduce the incidence of thiazide-induced new-onset diabetes.58

Most outcome trials have used the thiazide-like diuretic chlorthalidone in head-to-head comparisons with other agents.59,60 Chlorthalidone has been shown to be more effective than HCTZ in maintaining 24-hour BP control, including better nighttime BP control.61 Therefore, chlorthalidone might be the preferred diuretic to combine with a RAAS inhibitor; however, most available SPCs use HCTZ. Recently, an SPC combining chlorthalidone and the ARB azilsartan was approved.62

Another thiazide-like diuretic, indapamide, was tested in two clinical trials. The Hypertension in the Very Elderly Trial (HYVET) was conducted to assess the benefits and risks of BP-lowering agents in the elderly population. This randomized, double-blind, placebo-controlled trial included around 4000 patients aged 80 years or older with persistent HTN (systolic BP > 160 mmHg). Patients in the active-treatment group received indapamide (sustained release, 1.5 mg) and perindopril (2 mg and 4 mg) as needed to reach the target BP (<150/80 mmHg). At the end of the trial, BP targets were reached in 20% of patients in the placebo group and 48% in the active treatment group. In addition, 73.5% of patients in the active-treatment group were receiving combination therapy (indapamide/perindopril) at trial closure. The active treatment group achieved a 30% reduction in the rate of stroke, a 39% reduction in the rate of death from stroke, and a 21% reduction in the rate of death from any cause.63 The ADVANCE trial was also a randomized, double-blind, placebo-controlled trial that aimed to assess the effects of an SPC of an ACEI (perindopril) and indapamide in a large population of patients with type 2 diabetes. The mean entry BP of randomized patients was 145/81 mmHg, and 41% had a BP less than 140 mmHg systolic and 90 mmHg diastolic. During follow-up, BP was reduced by an average of 5.6 mmHg systolic and 2.2 mmHg diastolic in patients assigned to the active treatment. After a mean follow-up of 4.3 years, the group assigned to perindopril/indapamide achieved a 9% relative risk reduction in major macrovascular and microvascular events. The relative risk for death from CV causes was reduced by 18%, and that for death from any cause by 14%.64

Acceptable combinations

The use of beta-blockers and diuretics is well-established in the management of HTN, and their combination leads to an additive BP-lowering effect.46 However, this specific combination has recently fallen out of favor because of an increased risk for new-onset diabetes. It has been shown that diuretics are associated with a 32% increased risk for new-onset diabetes compared with placebo or non-beta-blocker antihypertensive agents; beta-blockers also have a 32% increased risk compared with placebo or nondiuretic antihypertensive agents.65 This combination is therefore not recommended in patients with metabolic syndrome or prediabetes or who are at high risk for diabetes.10 In addition, both diuretics and beta-blockers are known to negatively affect erectile function.66


Because of the natriuretic properties of CCBs, the combination of a CCB and a diuretic results in a partially additive BP-lowering effect.67 However, in the VALUE trial, the addition of HCTZ as a second step to AML achieved similar BP reduction compared with that seen in the VAL/HCTZ group, was well-tolerated, and resulted in a similar reduction in the primary composite outcome of CV mortality and morbidity.68 Therefore, this combination is classified as acceptable; however, it is not currently available as an SPC.


The addition of a dihydropyridine CCB to a beta-blocker will result in a complementary and additive BP-lowering effect.48 No large outcome trial assessed this specific combination; however, a beta-blocker added to felodipine was the second combination used to achieve BP targets in the Hypertension Optimal Treatment (HOT) study. The HOT study was one of the largest trials in HTN to establish the benefits of tight BP control on CV outcomes.36 A combination of bisoprolol and AML as an SPC is currently available in many countries.

Dual calcium channel blockade

The addition of a dihydropyridine CCB to a nondihydropyridine CCB such as diltiazem or verapamil results in an additive BP-lowering effect.69 In a recent meta-analysis, this strategy of dual calcium channel blockade was more effective at lowering BP, compared with CCB monotherapy, and was well-tolerated. However, long-term outcome data on safety and efficacy of this specific combination are currently lacking.70

Triple SPCs

As mentioned earlier, about 24% to 32% of patients with HTN will require more than two drugs to achieve their BP target.35,36 On the basis of the inherent advantages of an SPC, as described earlier, using SPCs containing three BP-lowering drugs may be a good alternative for these patients, although it is not currently recommended as initial therapy. On the basis of available evidence and beneficial clinical outcome data as outlined earlier, a rational combination in this setting would be an RAAS inhibitor, a CCB, and a diuretic.11 In fact, three SPCs combining these agents have been approved for use, based on large clinical trials composed of VAL/AML/HCTZ, olmesartan (OM)/AML/HCTZ, and ALI/AML/HCTZ.

A prospective, randomized, double-blind trial aimed to assess the efficacy and safety of an SPC containing VAL/AML/HCTZ compared with a dual-combination SPC of the same components (VAL/AML, VAL/HCTZ, and AML/HCTZ) in 2271 patients with stage 2 HTN. At the end of this 12-week study, significantly more patients achieved BP target in the triple-therapy group (about 70% of patients) compared with in the dual-combination groups (around 50% of patients). In addition, the triple-combination therapy was well-tolerated, with reportedly less peripheral edema.71

In the TRINITY (triple therapy with Olmesartan Medoxomil, Amlodipine, and Hydrochlorothiazide in hypertensive patients study) trial, the efficacy and tolerability of a triple SPC containing OM/AML/HCTZ was compared with the components’ dual combinations (OM/AML, OM/HCTZ, and AML/HCTZ) in patients with moderate to severe HTN. At 12 weeks, the triple-combination therapy resulted in significantly more BP reduction when compared with dual therapy, with no significant difference in adverse events.72 The 24-hour ambulatory BP substudies of the two trials discussed here confirmed significantly larger reductions in mean 24-hour, daytime, and nighttime systolic and diastolic BP in the triple-combination groups.73,74 Furthermore, in an open-label extension of the TRINITY trial, the triple-combination therapy allowed up to 80% of patients to achieve BP target after 52 weeks and was well-tolerated.75 In another trial, similar results were observed with an SPC containing ALI/AML/HCTZ.76

These trials provide proof of the safety and efficacy of triple SPCs in the management of HTN and provide the rationale for their use in patients who fail initial dual-combination therapy. Bearing in mind the inherent advantages of a single pill, as discussed earlier, these combinations might be an attractive option in patients with HTN who do not achieve BP target on dual drug combinations. The long-term benefit of this strategy on CV outcomes will have to be confirmed by clinical trials.


In conclusion, and based on the best available evidence, combination therapy will eventually be needed for a vast majority of patients with HTN and should be the first-line treatment for patients with a systolic BP more than 20 mmHg and/or a diastolic BP more than 10 mmHg above target and for those with high CV risk. Low-dose combination therapy may be the preferred initial approach for most newly diagnosed patients with HTN.911,20

It also should be emphasized that using SPCs might be the best way to deliver combination therapy, given their inherent advantages, particularly increased compliance and better overall tolerability. Currently approved SPCs (Table 3), composed of components that are well established as monotherapy and in combination in large clinical trials, offer to the treating physician a wide array of dual- and triple-combination therapies that will help patients achieve BP targets. Figure 1 provides a practical strategy for HTN management. The effect of such a strategy on overall BP control and its effect on further reducing CV events and targetorgan damage in the hypertensive population, as compared with the conventional approach, will need to be confirmed by future clinical and population-based studies.



The authors report no conflicts of interest in this work.

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Keywords: hypertension, combination therapy, single pill, dual combination, triple combination.

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