Why do we need antihypertensive combinations?

University Hospital Erlangen
Nephrology and Hypertension
Erlangen, GERMANY

Why do we need antihypertensive combinations?

by R. E. Schmieder, Germany

Hypertension is a worldwide problem and the leading cause of mortality. Most hypertensive patients have additional cardiovascular risk factors or diseases. In most of these patients, more than one antihypertensive drug is necessary to achieve goal levels of blood pressure. Data from several hypertension management clinical trials have shown that on average two or more antihypertensive agents are needed to reach current blood pressure targets. As physiological and pharmacological synergies result in more effective drug combinations, guidelines recommend adding a drug from another class to the initially prescribed drug. According to the European Society of Hypertension and the European Society of Cardiology guidelines, the most rational antihypertensive combinations are combinations involving angiotensin- converting enzyme (ACE) inhibitors, calcium channel blockers (CCBs), angiotensin II receptor blocker (ARBs), and thiazide (-like) diuretics. The combination of an ACE inhibitor with the thiazide-like diuretic indapamide has been shown to be effective in lowering blood pressure and preventing or reducing cardiovascular morbidity in many trials, such as STRATHE (Strategies of Treatment in Hypertension: Evaluation), PROGRESS (Perindopril pROtection aGainst Recurrent Stroke Study), HYVET (HYpertension in the Very Elderly Trial), PICXEL (Perindopril/Indapamide in a Double-Blind Controlled Study versus Enalapril in Left Ventricular Hypertrophy), REASON (PREterax in Regression of Arterial Stiffness in a ContrOlled Double-BliNd study), LIFE (Losartan Intervention For Endpoint reduction in hypertension), and ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation ). Likewise, the combination of an ACE-inhibitor and a CCB has been tested in trials like EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease), ASCOT-BLA (Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm), or ACCOMPLISH (Avoiding Cardiovascular events through COMbination therapy in Patients LIving with Systolic Hypertension) and there is evidence of beneficial effects in the prevention of cardiovascular events and new-onset diabetes, or rehabilitation after stroke. Thus, combination therapy should be individualized according to the comorbidities of hypertensive patients.

Medicographia. 2013;35:385-394 (see French abstract on page 394)

Hypertension is a worldwide problem and the leading cause of mortality.1 In 2001, it was estimated that 7.6 million premature deaths and 92 million disability-adjusted life years could be attributed to high blood pressure (BP) worldwide.1 Most hypertensive patients have additional cardiovascular risk factors or diseases (eg, diabetes). As well as arterial stiffness, endothelial dysfunction, and atherosclerosis, high cholesterol, obesity, smoking, physical inactivity, and oxidative stress also contribute to an increase in systolic BP (SBP) with age, thereby accelerating the aging of the arteries and potentially causing ischemic heart disease and stroke.1-3

Based on extensive prospective observational data, it was shown that both SBP and diastolic BP (DBP) have a strong and linear relationship with adverse cardiovascular events in all age groups.4 Although the relationship varies with age and sex, a 20-mm Hg difference in SBP or a 10-mm Hg difference in DBP is, on average, associated with a doubling of cardiovascular risk.4 Therefore, adequate BP control is considered to be essential in reducing this risk. The benefits of more aggressive therapeutic approaches in hypertension are especially pronounced in high-risk groups such as patients with diabetes mellitus or chronic kidney disease (CKD).5,6

Drugs that have been proven to be particularly useful in the treatment of elevated BP are calcium channel blockers (CCBs), thiazide(-like) diuretics and agents that target the renin-angiotensin system (RAS), ie, angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs).5-9

Management of hypertension

Improvement in cardiovascular outcomes and survival is the ultimate goal of antihypertensive treatment. However, despite the wide range of available antihypertensive drugs, the management of hypertension remains insufficient. About 30% of hypertensive individuals are unaware of their condition and receive no treatment at all. Of the remaining 70% who do, only 34% achieve the recommended target of SBP <140 mm Hg and DBP <90 mm Hg.10 This is of concern because of the proven benefits of reducing BP, which translate into reductions in the incidence of myocardial infarction (MI) (20%-25%), heart failure (>50%), and stroke (35%-40%).10

Large clinical trials have demonstrated that adequate BP control can be achieved and sustained in most patients with hypertension only with the use of multiple antihypertensive drugs.11,12 Both the European Guidelines (ESH-ESC 2007 and ESH-ESC 2013)5,13 and the American Guidelines (JNC 7)6,14 recommend that a significant proportion of hypertensive patients— in fact, the majority of patients—receive treatment with two or more drugs.

The objective of the study of Corrao et al15 was to assess whether antihypertensive combination therapy provides greater cardiovascular protection in daily clinical practice. This population- based study was carried out in a cohort of 209 650 patients aged 40 to 79 who were newly treated with antihypertensive drugs.15 Patients who were started on combination therapy had an 11% reduction in cardiovascular risk compared with those who received mono-therapy. This was also the case for coronary (–8%) and cerebrovascular (–12%) events, when considered separately.15 In a study by Neutel et al,16 combination therapy showed greater efficacy than high doses of the individual agents in increasing arterial compliance and reducing left ventricular mass.11 Furthermore, a meta-analysis of 42 factorial trials of antihypertensive agents (10 968 patients) showed that combining drugs from two different classes is approximately fivefold more effective than doubling the dose of one drug.17 Compared with patients who received mono-therapy during follow-up, those who were started on combination therapy and remained on it for the entire period of observation had a 26% reduction in cardiovascular risk. As such, the indication for using a combination of BP drugs should be broadened.15,18


Treatment with a two-drug antihypertensive combination is especially recommended in high risk patients to minimize the development or progression of target organ damage or vascular complications,19 and also in patients with stage 2 hypertension.5,14 The JNC 7 guidelines recommend initial combination therapy when BP is >20/10 mm Hg above goal BP. Moreover, results from controlled clinical trials have shown that two or more antihypertensive drugs are required for most hypertensive patients to achieve BP control.6,20 The recommendation for a combination of two agents as initial therapy is reflected in current hypertension guidelines, including the consensus statement by the Hypertension in African Americans Working Group (HAAWG),21 the Guidelines of the Task Force for the Management of Arterial Hypertension,13 and JNC 7.14

Antihypertensive combinations offer the possibility of combining agents with different pharmacological profiles to achieve additive effects with enhanced tolerability.13,22 The US National Health and Nutrition Examination Survey (NHANES) recommends the use of two or more drug classes to achieve the goal of BP control.

Compliance – the importance of treatment adherence

Compliance represents a major problem in hypertension because of the asymptomatic nature of this chronic disease (at least at the onset), and because in the majority of patients, more than one agent is required to achieve BP targets.

Compared with free combinations, fixed-dose combinations offer better treatment adherence because the treatment regimen is simplified.23,24 Two meta-analyses reported reductions in noncompliance of 26% and 21%, respectively, with fixed dose combinations compared with a regimen of the same two agents given separately.25,26 A further advantage of combination therapy is the ability to reach BP control more rapidly than with mono-therapy or free-combination,27 due to its expected positive impact on compliance, which should improve long term clinical outcomes.10,28

Table I
Table I. Preferred drugs according to clinical conditions in the 2007
ESH/ESC Guidelines.

Abbreviations: ACE inhibitor, angiotensin-converting enzyme inhibitor; ARB,
angiotensin receptor antagonist; CA, calcium antagonist; ISH, isolated systolic
hypertension; MI, myocardial infarction.
After reference 5: Mancia G, et al. J Hypertens. 2007.25(6):1105-1187. © 2007,
The European Society of Cardiology (ESC) and European Society of Hypertension


Which antihypertensive combinations for which patients?

JNC7 is not specific as regards which drug combinations should be used but it does state that ‘‘thiazide-type’’ diuretics are often used as one of the components. According to the European Society of Hypertension and the European Society of Cardiology Guidelines, the most rational antihypertensive combinations are combinations involving ACE inhibitors, CCBs, ARBs, thiazide (-like) diuretics (ie, hydrochlorothiazide [HCTZ], chlorthalidone, or indapamide), depending on clinical conditions (Table I, and Figure 1 [ page 388]).5,13

The recently updated British Hypertension Society/National Institute for Health and Clinical Excellence (BHS/NICE) recommendations of 2011 show a simple algorithm. These recommendations are based on the fact that, on average, younger people have higher renin levels and respond better (in terms of BP reduction) to “A” drugs (ACE inhibitors or ARBs), whereas older people or black people of African origin tend to have lower renin levels and respond better in terms of BP reduction to “C” drugs (CCBs).4 When combination is required, “A+C” is recommended but if a diuretic is considered, in patients who are intolerant to CCBs for instance, use of thiazide-like diuretics such as indapamide is advised, as these drugs are safer than older drugs such as HCTZ.

Figure 1
Figure 1. Recommended combinations of antihypertensive

Panel A. Antihypertensive drug combinations recommended as
preferred (thick lines) or possible (dash lines) in the 2007 ESH/ESC
Guidelines. Panel B. The five combinations retained for priority
use in the 2009 reappraisal of the 2007 ESH/ESC Guidelines.
Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin
receptor blockers; CCB, calcium channel blockers, ESC, European Society of Cardiology; ESH, European Society
of Hypertension.
After reference 4: Poulter NR. J Hypertens. 2011.29(suppl 1):
S15-S21. © 2011, Lippincott Williams & Wilkins.

Drug combinations and their studies

◆ RAS inhibition and thiazide-like diuretics
Inhibitors of the RAS, including ACE inhibitors and ARBs, have demonstrated efficacy in treating hypertension and preventing or reducing cardiovascular morbidity, such as strokes (Table II).10,19,29 In the STRATHE trial (Strategies of Treatment in Hypertension: Evaluation), a randomized, controlled study in patients with uncomplicated essential hypertension, 9 months of treatment with perindopril/indapamide lowered SBP by 26.6 mm Hg and led to normalization of BP in 62% of patients.30 The combination of a RAS inhibitor and a diuretic, an effective BP-lowering regimen, protects against hypertension-associated complications, such as cardiovascular events and stroke. This has been demonstrated in interventional studies, such as PROGRESS (Perindopril pROtection aGainst Recurrent Stroke Study), where the combination of the ACE inhibitor perindopril and the thiazidelike diuretic indapamide reduced the risk of stroke, MI, and heart failure in patients with previous stroke or transient ischemic attack (Table II).31

Beneficial effects on mortality have also been noted in elderly patients in the HYVET stroke trial.33 HYVET (Hypertension in the Very Elderly Trial) proved the benefits of effective BP reduction with indapamide (in combination with perindopril in the majority of patients) on cardiovascular outcomes in very elderly hypertensive patients.33 This trial demonstrated that even in patients aged 80 or older, antihypertensive treatment not only reduced BP by 15.0/6.1 mm Hg compared with placebo, but also prevented cardiovascular events, thereby contributing to prolonging life.13,33 Indapamide and perindopril reduced all-cause mortality by 21%, cardiovascular mortality by 23%, and stroke-related mortality by 39% when compared with treatment with placebo. There was also a 30% improvement in stroke rates and a 64% improvement in heart failure rates.41

Table II
Table II. Different antihypertensive combinations and their effects in cardiovascular and other end points in major clinical trials.

Abbreviations: ACCOMPLISH, Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension; ADVANCE, Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation; ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm; CKD, chronic kidney disease; EUROPA, EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease; HCTZ,
hydrochlorothiazide, HYVET; HYpertension in the Very Elderly Trial, LIFE, Losartan Intervention For Endpoint reduction in hypertension; LVH, left ventricular hypertrophy;
NA, not applicable; PICXEL, Perindopril/Indapamide in a Double-Blind Controlled Study versus Enalapril in Left Ventricular Hypertrophy; PREMIER, PREterax in
albuMInuria rEgRession; PROGRESS, Perindopril pROtection aGainst Recurrent Stroke Study; REASON, PREterax in Regression of Arterial Stiffness in a ContrOlled
Double-BliNd study; RR, relative risk; TIA, transient ischemic attack.

The choice of a combination should be based on systematic effects (ie, ACE-inhibitors/ARBs and thiazide [-like] diuretics) as well as on comorbidities and other cardiovascular risk factors (Table I) as specified by the ESH-ESC 2007 and 2013 guidelines.5,13

More recently, in the ADVANCE trial (Action in Diabetes and Vascular Disease),32 a fixed combination of perindopril/indapamide (4 mg/1.25 mg) was used for 4.3 years on top of standard antihypertensive therapy in both normotensive and hypertensive patients with type 2 diabetes mellitus.42 With a total of 11 140 patients, this was the largest trial ever carried out in this type of population. BP reduction was significantly greater with the perindopril/indapamide combination throughout the study: –15.6 mm Hg for SBP and –2.2 mm Hg for DBP.43 This effect was associated with a reduced incidence (–19%) of diabetes- related complications and a reduction in the incidence of coronary events and cardiovascular and all-cause death.32 Perindopril/indapamide reduced cardiovascular mortality by 18%, all-cause mortality by 14%, and new-onset microalbuminuria by 21% (Figure 2, Table II).32,44-46 With regard to treatment tolerability, this combination appeared well tolerated in more than 80% of patients. This result has important practical implications for health services delivery, since only one follow- up visit is needed to establish a patient’s suitability for long term treatment with this regimen.32

The echocardiographic substudy of the ADVANCE trial demonstrated that treatment with perindopril and indapamide resulted in a reduction in left ventricular mass (LVM) over 4 years, but did not improve left ventricular diastolic function.43 The results of the ADVANCE study also showed that the reductions in relative cardiovascular risk, and diabetic and renal events achieved with a perindopril/indapamide combination were consistent among subgroups of patients with diabetes defined by CKD stage.42 As a mirror of their substantially increased cardiovascular risk, the aldosterone/renin ratio (ARR) was greater in patients with CKD stage ≥3, underlining the importance of early recognition of CKD in patients with diabetes and the value of this preventive therapy.42

Figure 2
Figure 2.
effects on primary
and selected
secondary trial
end points.

ADVANCE, Action in
Diabetes and Vascular
disease: PreterAx
and DiamicroN MR
Controlled Evaluation;
CI, confidence
After reference 32:
Patel A, et al. Lancet.
829-840. © 2007,
Elsevier Ltd.

Importantly, the diuretic used in the PROGRESS, ADVANCE, and HYVET trials (ie, indapamide) is a thiazide-like metabolically neutral diuretic compound that differs favorably from the widely used HCTZ in terms of metabolic effects and sustained 24-hour BP lowering. Consequently, it should be considered suitable for first-line therapy in hypertensive patients.47-51 This is further supported by evidence from clinical studies that examined the intermediate end points of hypertensive disease.

The beneficial effects of perindopril/indapamide treatment on renal function were also illustrated in the PREMIER trial (PREterax in albuMInuria rEgRession),35 which enrolled 457 hypertensive patients with diabetes and albuminuria. Treatment with perindopril and indapamide for 1 year led to significant BPindependent reductions in albumin excretion rates compared with treatment with enalapril. Further analysis demonstrated a 16% increase in albuminuria regression.52

The PICXEL study (Perindopril/Indapamide in a double-blind Controlled study versus Enalapril in Left ventricular hypertrophy) compared the efficacy of a strategy based on first-line combination with perindopril and indapamide versus monotherapy with enalapril in reducing left ventricular hypertrophy (LVH) in hypertensive patients.30,34 In this 1-year multicenter study, patients received an increasing dose of perindopril, indapamide, or enalapril.34 SBP and DBP decreased significantly more in the perindopril/indapamide group than in the enalapril group.34 The authors concluded that, in hypertensive patients with LVH, a strategy based on first-line combination with perindopril and indapamide achieved a greater BP decrease with a significantly greater LVH reduction than a strategy based on monotherapy with enalapril.34

Further support for the role of perindopril comes from the REASON study (PREterax in Regression of Arterial Stiffness in a ContrOlled Double-BliNd).36 In this study comparing the antihypertensive effects of the combination of indapamide (0.625 mg)/perindopril (2 mg) with the β-blocking agent atenolol (50 mg), 214 patients with essential hypertension underwent two-dimensional guided M-mode echocardiography.53 Compared with atenolol, treatment with perindopril/indapamide improved arterial structure and stiffness. Patients with LVH showed the greatest LVM regression with a mean regression of 22.5 g after 12 months of treatment with perindopril and indapamide, compared with an 8.9-g regression after treatment with atenolol.53 Last but not least, the SBP reduction was found to be significantly greater with perindopril and indapamide than with atenolol (–21.2 vs –15.3 mm Hg).53

The LIFE study (Losartan Intervention For Endpoint reduction in hypertension),37 documented the cardiovascular protective effects of using a treatment strategy combining an ARB (losartan) with HCTZ in hypertensive patients with left LVH. In most patients, the combination of losartan with HCTZ was more effective than the combination of atenolol and HCTZ in the prevention of stroke but there were no differences between the two treatments regarding the reduction in coronary outcomes (Table II).

◆ RAS inhibition and calcium channel blockers
There is already solid proof that the ACE inhibitor perindopril and the CCB amlodipine are effective as monotherapy for hypertension,54-58 and they have been available to physicians for many years. They are frequently prescribed in free combination in hypertension and stable coronary artery disease (CAD), particularly since the emergence of large clinical trials, such as EUROPA (EUropean trial on Reduction Of cardiac events with Perindopril in stable coronary Artery disease)40 or ASCOTBPLA (Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm).38

The fixed-combination of perindopril and amlodipine is a credible option in the field of stable CAD.5,10 Its efficacy was established in the EUROPA trial.40,59,60 In this trial, addition of perindopril to CCB significantly reduced total mortality by 46% and reduced the primary end point (a composite of cardiovascular mortality, nonfatal MI, and resuscitated cardiac arrest) by 35%.60 There were 41%, 54%, and 28% reductions in cardiovascular mortality, hospitalization for heart failure, and MI, respectively.61 This effect was independent of BP at baseline.

ASCOT-BPLA was the first clinical trial to demonstrate an effective reduction in mortality among hypertensive patients treated with a CCB in combination with a RAS inhibitor.38,60 ASCOT-BPLA included over 19 257 patients with hypertension and at least three or more prespecified cardiovascular risk factors. The trial compared the effect of a standard antihypertensive regimen (β-blocker/bendroflumethiazide–based regimen) versus a newer regimen of dihydropyridine CCB ± ACE inhibitor, respectively, amlodipine and perindopril). The newer regimen was clearly superior in terms of preventing cardiovascular events. This trial was stopped prematurely after a median of 5.5 years, because of significant beneficial effects on all-cause mortality associated with allocation to the amlodipine/ perindopril–based regimen.62 A significant decrease of 11% in deaths from all causes and of 24% in cardiovascular mortality was achieved with the amlodipine/perindopril regimen, despite the reduction in BP being almost comparable to that of the β-blocker/diuretic combination.60 Other secondary end points also favored amlodipine/perindopril, with a 23% reduction in fatal and nonfatal stroke, and a 13% reduction in total coronary events. (Figure 3, Table II).

Various substudies of ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial) have provided further information to support the superior efficacy of an amlodipine/perindopril regimen in patients with type 2 diabetes mellitus.38,62 ASCOT included a large subpopulation with type 2 diabetes mellitus (n=5137) in which there was a 14% difference in the end point of major cardiovascular events in favor of the amlodipine/perindopril group.63 This was accompanied by a 25% lower incidence of fatal and nonfatal stroke, 48% less peripheral artery disease, and 57% fewer noncoronary revascularization procedures.63 These results are in line with other studies of ACE inhibitor/ CCB combinations in hypertensive patients with diabetes. In a review article, Ferrari described a study in which 214 patients received either a combination of ACE inhibitor and CCB or ACE inhibitor monotherapy for 3 months.10 The conclusion of the study was that the fixed combination was more effective than monotherapy with respect to achieving diabetic BP goals. Fixed-combination perindopril/amlodipine can therefore be predicted to reproduce the positive results of ASCOT in diabetic hypertensives, thereby providing additional reductions in total and cardiovascular mortality.10

Figure 3
Figure 3. A summary of all end points in ASCOT-BPLA.38

Data from the ASCOT-BPLA trial showing that the newer amlodipine/perindopril regimen was clearly superior in terms of preventing CV events overall—and significantly so—for most of the end points considered.
Abbreviations: ASCOT-BPLA, Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure–Lowering Arm; CHD, coronary heart disease; CV, cardiovascular; CI,
confidence interval; HR, hazard ratio; MI, myocardial infarction.
After reference 4: Poulter NR. J Hypertens. 2011;29(suppl 1):S15-S21. © 2011, Lippincott Williams & Wilkins.

A pharmacoeconomic analysis has recently been applied to the results of ASCOT. As might be expected, the actual cost of treatment with the “older” treatment of β-blocker/diuretic was lower than the “newer” combination of perindopril/amlodipine.64 However, for the β-blocker/diuretic combination, these lower costs were rapidly offset by increases in other costs driven by the number of hospitalizations and the cost of procedures, concomitant treatments, and events.10 Moreover, this analysis failed to take into account the costs associated with microvascular complications, excess mortality due to new-onset diabetes, or rehabilitation after stroke.10 These can all be reasonably predicted to be lower in perindopril/amlodipine– treated patients and the authors concluded that the perindopril/amlodipine combination was cost-effective in patients with moderate hypertension and additional risk factors.64

The CAFE study (Conduit Artery Function Evaluation)—a substudy of ASCOT—examined the impact of the two BP-lowering regimens compared in the ASCOT trial on derived central aortic pressures and hemodynamics in 2199 patients for up to 4 years. The amlodipine/perindopril regimen was associated with substantial reductions in central aortic pressures compared with the atenolol/HCTZ regimen.65 The CAFE population had the same baseline characteristics as the overall ASCOT population, and there were no significant differences between the two groups. However, central aortic SBP was significantly lower in the amlodipine/perindopril group (difference, 4.3 mm Hg). The authors concluded that the differential effects on central BP of the two antihypertensive regimens may be, at least in part, responsible for the differential effects on cardiovascular outcomes.60

In addition, the ACCOMPLISH study (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension)39 provided outcome evidence in favor of the combination of an ACE inhibitor and a CCB. This trial included 11 506 patients with hypertension who were at high risk of cardiovascular events (most patients had type 2 diabetes and/or CAD). BP was reduced very effectively in both treatment arms and to a similar extent, without significantly affecting the rates of postural hypotension. This trial also showed the significant benefit of a benazepril/amlodipine combination on major cardiovascular events compared with a benazepril/ HCTZ combination (Figure 4, Table II).4

Figure 4
Figure 4. Effects on primary
and other end points

Data from the ACCOMPLISH
trial showing superiority of a
CCB/ACE inhibitor combination
over an ACE inhibitor/HCTZ
combination on most cardiovascular
Abbreviations: ACCOMPLISH,
Avoiding Cardiovascular Events
through Combination Therapy in
Patients Living with Systolic Hypertension;
ACE, angiotensinconverting
enzyme; CCB, calcium
channel blocker; CI, confidence
interval; HCTZ, hydrochlorothiazide;
HR, hazard ratio.
After reference 4: Poulter NR.
J Hypertens. 2011;29(suppl 1):
S15-S21. © 2011, Lippincott
Williams & Wilkins.

Is there a rationale for a fixed-dose triple combination?

The increased BP-lowering efficacy of the different fixed-dose combinations of either an ACE inhibitor or an ARB and a thiazide- like diuretic, or an ACE inhibitor and a CCB, has been proven.28 Furthermore, even though the combination of two drugs may significantly improve efficacy, it is estimated that about 15% to 20% of patients require combination therapy with three agents to control BP effectively.13 Recent clinical studies have shown that triple therapy with an ARB, a CCB, and a diuretic significantly reduces BP compared with dual combination therapy. The clinical benefit of triple combination therapy with olmesartan 40 mg, amlodipine 10 mg, and HCTZ 25 mg was compared with that of dual combinations of the individual components in TRINITY (the TRIple therapy with olmesartan medoxomil, amlodipine, and hydrochlorothiazide in hyperteNsIve patienTs studY). This study was conducted on 2492 patients with moderate to severe hypertension.66 After 12 weeks, reductions in seated DBP and SBP were significantly greater with triple combination therapy than with any of the dual combinations. These results suggest that there are a number of options for a fixed combination of three antihypertensive agents (eg, perindopril/amlodipine/indapamide). Having established the potential of triple combinations, it will now be necessary to assess their long-term efficacy and safety profile.


Antihypertensive combination therapy has been recommended as potential first-line therapy in recent consensus guideline statements, especially for higher-risk patients such as those with stage 2 or 3 hypertension. The combination of a RAS-targeting agent, such as an ACE inhibitor or an ARB, together with a diuretic, particularly if metabolically neutral (eg, indapamide), or a CCB, or both, provides synergy with regard to the lowering of BP. Furthermore, the dual combination of perindopril/ indapamide and perindopril/amlodipine has been documented as improving cardiovascular outcomes and reducing total mortality.

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Keywords: antihypertensive drug; blood pressure; combination therapy; hypertension