Abstract
Hypertension is a serious public health concern with inadequate control of blood pressure (BP) worldwide. Contributing factors include low efficacy of drugs, underuse of combination therapies, irrational combinations, physicians’ therapeutic inertia and poor adherence to treatment. Current guidelines recommend the use of initial (dual) combination therapy in high-risk patients for immediate BP response, better short- and long-term BP control, and continued/improved patient adherence. This article aims to review the existing evidence of triple-combination therapies with respect to efficacy, safety and adherence to treatment. It is estimated that three drugs are required to achieve BP control in approximately one-fourth to one-third of patients. Randomised controlled trials (RCTs) have shown that triple combinations of amlodipine/valsartan/hydrochlorothiazide, amlodipine/olmesartan/hydrochlorothiazide and amlodipine/telmisartan/hydrochlorothiazide produce greater BP reductions, with greater proportions of patients achieving BP control compared with dual therapies. Further evidence also demonstrates that triple-combination therapy is efficacious for moderate to severe hypertension, with substantial additional BP reduction over dual regimens. Both RCTs and post-marketing observational studies have shown consistent and comparable efficacy in both the general population and high-risk hypertensive subgroups. Triple therapies are generally well tolerated with adverse event profiles similar to dual regimens. In addition, fixed-dose combinations used as single pill improve patient adherence leading to better long-term BP control. Depending on regional circumstances, they may also be cost effective. Thus, single-pill triple combinations of different classes of drugs with complementary mechanisms of action help to treat patients to goal with improved efficacy and better adherence to treatment.
Similar content being viewed by others
Introduction
Hypertension is a serious public health concern worldwide, and due to population growth and ageing, the number of people with uncontrolled hypertension continues to rise. Data from the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014 indicate that among 29% of adults with hypertension in the US, only 53% had their hypertension under control, and the situation is even more alarming in other countries. A large, cross-sectional, multicentre study in 153 996 patients from high-, middle- and low-income countries has shown that of 40.6% patients treated for hypertension, blood pressure (BP) control was observed in only 13.2% patients (32.5% of those receiving treatment).1 Furthermore, recent data from a large cohort in China revealed that of 500 223 adults aged 35–74 years, 32.5% had hypertension, of which <5% achieved BP control. Uncontrolled hypertension accounted for about one-third of deaths due to cardiovascular (CV) disease (CVD).2
Hypertension is a multifactorial disease and it is estimated that approximately one-third of patients require two drugs to achieve BP control, defined as <140/90 mm Hg, and one-third require three or more anti-hypertensive agents.3 Despite availability of several anti-hypertensive classes of drugs, hypertension remains poorly controlled in a majority of patients worldwide. Various reasons for poor BP control include low efficacy of hypertensive agents in monotherapy, underuse of combination therapies, irrational combinations, therapeutic inertia among doctors and non-adherence with anti-hypertensive treatment from patients.4
Combination therapy as an initial approach and as a step-up strategy to reach BP goals
Present guidelines recommend the use of initial combination therapy in high-risk patients for immediate BP response, improved tolerability and possibly improved patient adherence.5 The beneficial effect of early and effective BP control on the CV outcome was shown in the Valsartan Antihypertensive Long Term Use Evaluation (VALUE) trial that included hypertensive patients at high CV risk.6 Furthermore, in the Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm (ASCOT-BPLA) study, early intensive BP lowering was also associated with a reduced CV event rate in such treated patients.7
One crucial aspect for the need of combination therapy is the question of how far BP should be lowered by anti-hypertensive treatment. Data suggest that CV morbidity and mortality are rising progressively starting at systolic BP (SBP) values as low as 115 mm Hg.8 It would therefore seem appropriate and logical to aim for such low BP values when managing hypertensive patients. However, based on available evidence, current guidelines recommend a general target BP of <140/90 mm Hg with goal BP values slightly higher or lower in elderly patients or special subgroups.5, 9
The present consensus on these ‘conservative’ BP goals in the treatment of hypertension has recently been questioned, based on the results from a randomised trial of intensive vs standard BP control (Systolic Blood Pressure Intervention Trial (SPRINT)), in which a BP goal of <140 mm Hg was compared with a target BP of <120 mm Hg in 9361 individuals at increased CV risk but without diabetes.10 The primary composite endpoint was myocardial infarction, other acute coronary syndromes, stroke, heart failure or death from CV causes. The intervention was discontinued early after a median follow-up of 3.26 years owing to lower rates of CV morbidity and mortality in patients on the intensive treatment.10 However, the generalizability of the SPRINT results has been questioned on the basis of patients selected, BP values achieved, BP measurement procedure used and other considerations.11 Interestingly, the benefit of intensive BP lowering in SPRINT was almost entirely due to a reduction in the new onset of heart failure.11
In this context, a recent meta-analysis has reported significant reductions in the risk of major CVD events, stroke, coronary heart disease, heart failure and all-cause mortality, with every 10 mm Hg reduction in SBP to an on-treatment BP<130 mm Hg.12 In contrast, in the HOPE-3 trial, treatment with candesartan/hydrochlorothiazide (HCTZ) 16/12.5 mg vs placebo over a period of 5.6 years in a population with a baseline mean BP 138.1/81.9 mm Hg lowered SBP to 128.2 mm Hg (vs 133.9 mm Hg in the placebo group) but did not result in a significantly lower risk of major CV events in an intermediate-risk population without CVD and with a low rate of diabetes.13 These conflicting data on the important question of target BP to aim for in a given patient, may at least in part, be due to the variations in patient characteristics, baseline BP, low or high total CV risk, diabetes and so on. With more information available, this will eventually result in recommendations for a more individualised treatment strategy. Taken together, however, at least in certain subgroups, hypertension treatment will probably be more intense than it is recommended today, and this would also have marked consequences for the need of combination treatment strategies.
Historical aspects of SPC development
Dual and triple single-pill combinations (SPC) were available from the 1960s, mostly combining reserpine with a diuretic and (di)hydralazine. At that time, the term generally used was ‘fixed-dose combinations’ since the possibility to change doses of one or more combination partners was rather limited when ‘single-pill combinations’ were introduced on the market. The success of these combinations was based on the evidence from the Veterans Administration studies 1 and 2, indicating that they were highly effective in lowering BP and markedly reduced CV events and mortality.14, 15 After several such SPCs gaining market access in the 1960s, no triple SPCs containing more modern anti-hypertensive agents were approved for approximately three decades owing to growing restrictions from government agencies. Essentially, it was required that when two or more drugs were to be combined in a single dosage form, each component (in the chosen dosage) had to contribute to the claimed effect.
With the need for SPC in various indications becoming more obvious and also with the growing knowledge about clinical trial methodology over the following decades, the requirements for the approval of SPC slowly changed. In the US, a factorial design comparing the highest triple dose to the highest dose of each of the dual combinations was required for the approval of a triple SPC as second-line therapy, wherein the triple combination must be superior to all three dual therapies. In Europe, approval of the triple SPC as second-line therapy requires conducting studies that randomise non-responders to dual therapy, to receive triple therapy. However, for a combination of drugs where a wide therapeutic experience is available, a study showing bioequivalence to the components in free combination with the fixed-dose combination is acceptable for approval as substitution or replacement therapy. With this renewed approval policy, amlodipine (Aml), valsartan (Val) and HCTZ was the first modern triple anti-hypertensive SPC to become available in 2009, followed by olmesartan (Olm), Aml and HCTZ, and aliskiren (Ali), Aml and HCTZ in 2010.
Rationale for the use of multiple agents in a combination therapy in the treatment of hypertension
Dual combinations fail to achieve BP control in a significant proportion of patients. It has been estimated that three and more anti-hypertensive agents are required in approximately one-fourth to one-third of patients.3, 16 Combining anti-hypertensive agents from two different classes has been shown to result in an approximately five-fold greater BP reduction vs doubling the dose of a single agent.17 In addition, combining drugs with complementary mechanisms of action may provide benefit beyond BP lowering, such as improving tolerability, and thus higher rates of adherence with the prescribed medication as compared with increasing the dose of a single agent.18
Commonly used classes of drugs for hypertension include angiotensin receptor blockers (ARBs), such as Val or Olm; angiotensin-converting enzyme inhibitors (ACEIs); thiazides (HCTZ and bendroflumethiazide), and thiazide-like diuretics (chlorthalidone and indapamide (Ind)), and calcium channel blockers (CCBs), such as Aml. Other effective anti-hypertensive agents are α- and ß-receptor blockers and centrally acting agents.
Combining drugs from different classes may provide inherent advantages. Addition of an inhibitor of the renin–angiotensin–aldosterone system (RAAS) to a thiazide or a thiazide-like diuretic has an additive effect on BP reduction and also improves the safety profile by countering the diuretic-induced adverse impact on electrolytes (hypokalaemia), uric acid and glucose metabolism.19 Combining RAAS inhibitors with a CCB improves the tolerability profile by reducing the incidence of peripheral oedema, an important adverse event (AE) observed with CCBs and also blunts the heart rate acceleration occasionally observed with a dihydropyridine CCB.19 Further, CCBs and diuretics are known to activate the RAAS, and this may act as a counter regulatory mechanism, limiting the BP-lowering efficacy of these drugs. By this mechanism, combination with a RAAS inhibitor will markedly enhance the anti-hypertensive efficacy of both diuretics and CCBs.
Table 1 lists randomised trials with triple SPC therapies in patients with hypertension. A large, double-blind, parallel-design trial in 2271 patients with BP ⩾145/100 mm Hg showed that triple therapy with Aml/Val/HCTZ at a dose of 10/320/25 mg produced significantly greater reductions in SBP of 39.7 mm Hg compared with 31.5–33.5 mm Hg on the three dual combinations contained in the triple SPC (Aml/Val 10/320 mg, Val/HCTZ 320/25 mg and Aml/HCTZ 10/25 mg). In all treatment groups, the full BP-lowering effect was seen after 2 weeks at maximal dose. At the end of the study (week 8), a significantly greater proportion of patients (70.8%) achieved BP control with triple therapy, compared with 48.3% for Val/HCTZ, 54.1% for Aml/Val and 44.8% for Aml/HCTZ.20 A 12-week, randomised, double-blind, parallel-group trial, ‘Triple Therapy with Olmesartan Medoxomil, Amlodipine and Hydrochlorothiazide in Hypertensive Patients Study’ (TRINITY) conducted in 2492 patients with BP ⩾140/100 or ⩾160/90 mm Hg, showed that Aml/Olm/HCTZ (10/40/25 mg) lead to significantly greater reductions in sitting BP compared with the dual combinations Aml/Olm 10/40 mg, Aml/HCTZ 10/25 mg and Olm/HCTZ 40/25 mg. Accordingly, the proportion of patients reaching BP target at study end was significantly higher with triple combination (69.9%) compared with the dual therapies (52.9, 53.4 and 41.1% respectively).21 Figure 1 depicts BP reductions from baseline in patients with moderate to severe hypertension with both the triple combinations Aml/Val/HCTZ and Aml/Olm/HCTZ. In a third albeit much smaller randomised, single-blind study in 220 patients, a triple SPC containing telmisartan (Tel) reported that SBP and diastolic BP (DBP) reductions were superior with Aml/Tel/HCTZ (5/40/12.5 mg) at the end of a 12-week treatment period compared with dual therapy with Tel/HCTZ (40/12.5 mg).22
Aml/Val/HCTZ was found to reduce mean 24-h ambulatory BP, daytime and night time mean ambulatory BP by 30.3/19.7, 31.2/20.5 and 28.0/17.8 mm Hg, respectively, consistently more effective compared with the respective dual-combination therapies23 (Figure 2). The TRINITY ambulatory BP monitoring sub study, a randomised, double-blind study conducted in 440 patients with moderate to severe hypertension, also showed that once-daily Aml/Olm/HCTZ resulted in greater reductions in the mean 24-h SBP and DBP compared with the dual-combination regimens.24
Similar safety and tolerability profiles were reported with triple therapies compared with dual regimens in the aforementioned studies. In a systematic review and meta-analysis of 11 studies and 7563 patients, based on the evaluable results of 10 studies, it was shown that triple combinations with CCB/ARB/HCTZ, at any dose, provided more BP control than dual combinations and significantly decreased BP more than any dual combination of these agents (5.8/3.5 mm Hg in SBP/DBP (for both P<0.0001)).25 Similarly, based on the results of four studies with ambulatory BP measurements, triple combinations decreased 24-h ambulatory SBP/DBP by 7.1/4.5 mm Hg more than dual combinations (for both P<0.0001).25 These BP-associated benefits with triple therapy vs dual therapy were not seen at the expense of increased risk of AEs.25
All recent national and international guidelines to date agree that the main classes of anti-hypertensives to be used in the management of hypertension should be RAAS blockers, CCB and diuretics.5, 9 There is a minor disagreement with respect to the recommendations of dual combinations with RAAS blockers plus either diuretics or CCB playing an outstanding role. In contrast to the fact that there are several choices both for initial monotherapy and dual combinations, all guidelines recommend the combination of a RAAS blocker plus CCB and diuretic whenever triple therapy is required.5, 9, 26 Currently the ARBs Val and Olm are approved as triple SPC by the regulatory institutions in the US (Food and Drug Association (FDA)) and Europe (European Medical Agency (EMA)). The direct renin inhibitor aliskiren (in combination with Aml and HCTZ) is also approved by the FDA, while the ARB Tel plus Aml and HCTZ and the ACEI perindopril plus Aml and Ind are available in some regions.5, 9, 26
Triple therapy in high-risk patient groups and factors affecting BP lowering
RAAS blockers, CCBs and diuretics are recommended for the treatment of hypertension in high-risk individuals, such as patients with CVD, chronic kidney disease, stroke etc.5, 9 A TRINITY subgroup analysis in patients with diabetes, chronic kidney disease or chronic CVD showed that both short-term (12 weeks) and long-term treatment with Aml/Olm/HCTZ was well tolerated, lowered BP more effectively, and enabled more patients to reach BP goal than the corresponding dual regimens.27
Demographic factors and patient characteristics, such as age, race, ethnicity, gender and body mass index (BMI) are known to affect the response to anti-hypertensive agents.5 In the study by Calhoun et al.,28 Aml/Val/HCTZ produced significantly greater reductions in SBP and DBP, and significantly better SBP control in black patients than dual therapies (Aml/Val and Aml/HCTZ). In a subgroup analysis of black and non-black populations in the TRINITY trial, Aml/Olm/HCTZ provided greater BP reductions, with higher proportions of patients achieving BP control than those on the component dual therapies, regardless of race29 (Figure 3). Subgroup analysis of a 12-week, double-blind, randomised, active-controlled, parallel-group, international, multicentre study (Exforge Evaluation in Stage Two Hypertensives of African Descent (EX-STAND)) showed that in black patients with stage 2 hypertension, Aml/Val produced a significantly greater change in SBP than Aml monotherapy from baseline to week 12. Addition of HCTZ to existing dual therapy further reduced SBP by 8.9 mm Hg, producing greatest reductions from baseline.30
Hypertension prevalence markedly increases with age. At present, on-treatment goal BP in elderly patients remains a matter of controversy with two guidelines recommending a target BP of <150/90 mm Hg (instead of <140/90 mm Hg) in adults, aged ⩾60 years.5, 9 A subgroup analysis of the TRINITY trial showed that Aml/Olm/HCTZ combination was more effective than dual therapies in patients with moderate to severe hypertension aged ⩾65 years31 (Figure 4). Also, in the pivotal trial of Aml/Val/HCTZ SPC, this triple combination produced significantly higher BP control rates and was more effective than dual therapies, independent of gender, age (<65 or ⩾65 years), BMI (<30 or ⩾30 kg m−2) or ethnicity (Hispanic/Latinos or Non-Hispanic/Latinos).28
Obesity (defined as BMI ⩾30 kg m−2) is another important risk factor for the development of hypertension, and prompt adequate control of BP in obese individuals is important. A pre-specified subgroup analysis of the TRINITY trial showed that the Aml/Oml/HCTZ combination was efficacious and safe in obese patients providing greater mean BP reductions and enabling larger proportions of study participants to achieve BP goal compared with the component dual-combination treatments.32 Higher BP control rates were also achieved with Aml/Val/HCTZ compared with the respective dual combinations, independent of BMI <30 or ⩾30 kg m−228 (Figure 5).
Triple-combination therapy in a real-world setting
Randomised controlled trials (RCTs) are essential and remain the gold standard to determine the efficacy, safety and tolerability of a drug in a controlled clinical setting, in particular towards the registration of a new drug. Although ‘real-world evidence’ studies may not be as effective as RCTs in collecting efficacy data, they are capable of providing data from large patient populations beyond the inclusion and exclusion criteria of a clinical trial in an observational, non-interventional setting and thus may provide proof of the generalizability of the results of the respective RCTs.33
In four observational studies of real-world clinical experience, SPC therapy with Aml/Val/HCTZ, Aml/Olm/HCTZ or Aml/Per/Ind was associated with significant reductions in BP, achievement of BP goals and improved control rates34 (Table 2). Treatment effects were observed in large groups of patients with hypertension, including different ethnicities, and in patients inadequately controlled with initial monotherapy or dual combination therapy. The ‘Experience of Amlodipine and Valsartan in Hypertension’ (EXCITE) study, a large, multinational, prospective, non-interventional study in 9794 hypertensive patients from 13 countries in the Middle East and Asia showed that Aml/Val/HCTZ SPC provided meaningful SBP and DBP reductions from baseline across all severities of hypertension. Similarly, in a subgroup analysis of the EXCITE study that included elderly, obese patients, and patients with diabetes or isolated systolic hypertension, significant and clinically relevant BP reductions were observed with Aml/Val/HCTZ SPC. Triple combinations enabled ~70% of patients to achieve a BP target of <140/90 mm Hg.34
In another multicentre, prospective, non-interventional study, Aml/Olm/HCTZ SPC provided meaningful BP reductions in 5831 patients. Following ~24 weeks of treatment, the target BP of <140/90 mm Hg was attained in 67.5% of patients.35 In the ‘Perindopril-Amlodipine plus Indapamide Combination for Controlled Hypertension—Non-Intervention Trial’ (PAINT), a 4-month, multicentre, prospective, observational, open-label study, 6088 patients not controlled with previous anti-hypertensive treatment were switched to triple therapy with Aml/Per/Ind sustained-release single-pill triple-combination therapy. Meaningful BP reductions were achieved in this real-world setting. The Aml/Per/Ind combination was also effective in reducing ambulatory BP in hypertensive patients uncontrolled on previous therapy.36 The ‘Perindopril-Indapamide plus Amlodipine in High Risk Hypertensive Patients’ (PIANIST) study conducted in 4731 adult patients at high or very high CV risk demonstrated that Aml/Per/Ind was effective in reducing both office BP and ambulatory BP in a large population of high- and very high-risk hypertensive patients with uncontrolled BP on previous therapy in a real-life setting.37 Thus, these real-world studies confirm the reliability of RCTs and strengthen the applicability of the RCT data in an actual clinical setting.
Safety and tolerability of a triple therapy
Triple combinations of ARBs or ACEIs, Aml and diuretics are generally well tolerated, and randomised trials have shown that the two triple combinations Aml/Val/HCTZ and Aml/Olm/HCTZ are associated with similar rates of AEs in patients with stage 2 hypertension.38 Further studies could demonstrate that on both triple therapies, the rates of AE are similar to those on the respective dual combinations20, 21 (Table 3). Most reported AEs were mild to moderate in intensity, and no additional risks other than those previously identified were observed with long-term treatment. The most frequently reported AEs with the triple combination were generally dizziness, peripheral oedema and headache. The incidence of AEs reported in different clinical studies cannot be directly compared because of differences in study populations and conduct and also may not reflect the incidence in clinical practice. In real-world studies, similar tolerability profiles were reported with low incidence of AEs related to low BP.34, 35, 36 In general, all combinations with ARBs have similar safety and tolerability, although recently some concern was raised with Olm, wherein an increased risk of serious enteropathies was reported, though very rare (<1/10 000). Sprue‐like enteropathy may be associated with symptoms including severe or chronic diarrhoea and substantial weight loss and may require hospitalisation.39 Of note, while efficacy in terms of BP reductions, morbidity and mortality is well studied with Val in various indications (hypertension, heart failure, post myocardial infarction),6, 40, 41 similar data are not available with Olm.
It is important to emphasise here that the use of SPCs in everyday practice is no longer hampered by the loss of dosing flexibility. Even for triple combinations, a choice between different doses of the components is available. Thus, in the available single-pill triple (and dual) combinations, both Aml and the respective ARB can be employed up to their maximal doses. In contrast, the choice of HCTZ in all SPC is restricted to either 12.5 or 25 mg. In this context, it is interesting to note that HCTZ doses of 50–100 per day mg are markedly more effective in lowering BP42 and have successfully been used in the past, such as in the Veterans Administration trials 1 and 2.14, 15 However, in recent years, these higher doses of HCTZ have disappeared in order to avoid dose-dependent biochemical and metabolic adverse events such as hypokalemia, hyponatremia, hyperuricemia and possibly insulin resistance.43
This restriction of HCTZ to a maximum dose of 25 mg both in monotherapy and also in combination therapy including SPC has implications for the efficacy of both dual and triple SPC. Patients without normalisation of their BP in spite of triple therapy containing a diuretic have been described as being drug-resistant and it is estimated that ~5–10% of all hypertensive patients may be resistant by this definition (excluding non-adherence).5 It can thus be concluded that stepping up therapy to the available SPC with high doses of Aml and ARB and 25 mg HCTZ may allow BP control in ~90% of the hypertensive population. Intensification of diuretic therapy by the use of adding spironolactone has recently been shown to be more effective in lowering BP in such drug-resistant patients than adding doxazosin or bisoprolol44. However, spironolactone use is limited by hormonal side effects in men and by the risk of hyperkalemia, especially in patients with impaired renal function. It is therefore interesting to speculate that increasing the dose of HCTZ in triple combinations will also markedly enhance the BP lowering efficacy and will thus, without adding a fourth antihypertensive agent, reduce the number of ‘drug-resistant’ patients.
Adherence, cost effectiveness and health economic benefits
As a chronic disease, hypertension requires long-term treatment; it is therefore important to ensure treatment adherence and consider the cost effectiveness of the long-term therapy. Furthermore, non-adherence or poor adherence to treatment has been shown to predict higher BP levels compared with adherence to the treatment regimen in some but not all studies.45 In this context, it is important to note that patient adherence has been shown to be high at the time of a doctor’s visit, a phenomenon named white coat compliance.46 It is therefore that office or clinic BP may not correlate closely with the degree of adherence to a prescribed drug regimen.
Among the multifactorial origin of non-adherence, therapy itself may be a crucial factor involved. An early retrospective study could show that the total number of daily pills may be a critical factor for adherence with newly prescribed BP or lipid-lowering treatment.47 Also, a Cochrane analysis concluded that reducing the number of daily doses appears to be effective in increasing adherence to BP lowering medication and should be tried as a first line strategy.48
SPCs simplify anti-hypertensive regimens by reducing the daily pill burden and result in improved patient adherence compared with multiple-pill/free combination regimens. The availability of SPC that leads to a more rapid achievement of BP goals may positively affect clinical inertia, which may also act to ultimately improve BP control.49 Improved adherence may finally translate into better outcome which has been demonstrated in several studies in patients with coronary heart disease.50, 51, 52 This is in line with European Society of Cardiology/European Society of Hypertension (ESC/ESH) 2013 guideline recommendations for SPC to achieve better adherence and thereby BP control.5 SPCs have also been recommended by other guidelines, such as the American Society of Hypertension/International Society of Hypertension, Canadian, and Japanese hypertension guidelines.26, 53, 54
Several studies have shown that SPC with three anti-hypertensive agents are advantageous for the patient and clinician to ensure patient compliance and adherence to treatment compared with multiple single drug or free-pill combinations.45, 55 Meta-analyses comparing dual combination therapy provided either as SPC or as two separate pills have reported that SPCs resulted in significant improvement in compliance and persistence compared with free-drug combinations in patients with hypertension.56, 57
A German non-interventional study with Aml/Val/HCTZ involving 7101 patients and 905 physicians showed that approximately half of the patients were willing to make an out-of-pocket payment for reducing the number of pills to half. Furthermore, physicians were also willing to prescribe combination products to reduce pill burden.58 Finally, real-world data indicate that Aml/Val/HCTZ SPC combination is associated with reduced health resource utilisation compared with free combinations.59
In conclusion, combination therapy including drugs from classes having complementary action is advantageous in terms of BP reduction and control, particularly in high-risk patients, and may be associated with improved tolerability. Administration of combination therapy as SPC is capable of enhancing adherence to treatment. With the goal of long-term BP reduction, prevention of end-organ damage, and a reduction in CV morbidity and mortality, triple-combination therapy as SPC may be beneficial in patients not controlled on dual therapy. This is in line with major hypertension guidelines that recommend two or more hypertensive agents with complementary mechanisms of action to control BP administered as SPC to improve adherence to treatment.
References
Chow CK, Teo KK, Rangarajan S, Islam S, Gupta R, Avezum A et al. Prevalence, awareness, treatment, and control of hypertension in rural and urban communities in high-, middle-, and low-income countries. JAMA 2013; 310: 959–968.
Lewington S, Lacey B, Clarke R, Guo Y, Kong XL, Yang L et al. The burden of hypertension and associated risk for cardiovascular mortality in China. JAMA Intern Med 2016; 176: 524–532.
Dusing R . Optimizing blood pressure control through the use of fixed combinations. Vasc Health Risk Manag 2010; 6: 321–325.
Burnier M, Brown RE, Ong SH, Keskinaslan A, Khan ZM . Issues in blood pressure control and the potential role of single-pill combination therapies. Int J Clin Pract 2009; 63: 790–798.
Mancia G, Fagard R, Narkiewicz K, Redon J, Zanchetti A, Bohm M et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34: 2159–2219.
Julius S, Kjeldsen SE, Weber M, Brunner HR, Ekman S, Hansson L et al. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet 2004; 363: 2022–2031.
Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M et al. Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required vs atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trial. Lancet 2005; 366: 895–906.
Lewington S, Clarke R, Qizilbash N, Peto R, Collins R . Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet 2002; 360: 1903–1913.
James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J et al. 2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8). JAMA 2014; 311: 507–520.
Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV et al. A Randomized Trial of Intensive vs Standard Blood-Pressure Control. N Engl J Med 2015; 373: 2103–2116.
Dusing R . Blood pressure treatment goals in hypertension. Ther Adv Cardiovasc Dis 2016; 10: 332–337.
Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J et al. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet 2016; 387: 957–967.
Lonn EM, Bosch J, Lopez-Jaramillo P, Zhu J, Liu L, Pais P et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med 2016; 374: 2009–2020.
Effects of treatment on morbidity in hypertension. Results in patients with diastolic blood pressures averaging 115 through 129 mm Hg. JAMA 1967; 202: 1028–1034.
Effects of treatment on morbidity in hypertension. II. Results in patients with diastolic blood pressure averaging 90 through 114 mm Hg. JAMA 1970; 213: 1143–1152.
Mancia G, Laurent S, Agabiti-Rosei E, Ambrosioni E, Burnier M, Caulfield MJ et al. Reappraisal of European guidelines on hypertension management: a European Society of Hypertension Task Force document. J Hypertens 2009; 27: 2121–2158.
Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ . Combination therapy vs monotherapy in reducing blood pressure: meta-analysis on 11 000 participants from 42 trials. Am J Med 2009; 122: 290–300.
Waeber B, Feihl F, Ruilope LM . Fixed-dose combinations as initial therapy for hypertension: a review of approved agents and a guide to patient selection. Drugs 2009; 69: 1761–1776.
Gradman AH . Rationale for triple-combination therapy for management of high blood pressure. J Clin Hypertens (Greenwich) 2010; 12: 869–878.
Calhoun DA, Lacourciere Y, Chiang YT, Glazer RD . Triple antihypertensive therapy with amlodipine, valsartan, and hydrochlorothiazide: a randomized clinical trial. Hypertension 2009; 54: 32–39.
Oparil S, Melino M, Lee J, Fernandez V, Heyrman R . Triple therapy with olmesartan medoxomil, amlodipine besylate, and hydrochlorothiazide in adult patients with hypertension: The TRINITY multicenter, randomized, double-blind, 12-week, parallel-group study. Clin Ther 2010; 32: 1252–1269.
Manish Maladkar VKV, Narsikar KA, Walinjkar RD, Patil WR, Saggu NJS, Kulkarni SP . Triple drug combination of telmisartan, amlodipine and hydrochlorothiazide in the treatment of essential hypertension. OJIM 2012; 2: 67–71.
Lacourciere Y, Crikelair N, Glazer RD, Yen J, Calhoun DA . 24-Hour ambulatory blood pressure control with triple-therapy amlodipine, valsartan and hydrochlorothiazide in patients with moderate to severe hypertension. J Hum Hypertens 2011; 25: 615–622.
Izzo JL Jr, Chrysant SG, Kereiakes DJ, Littlejohn Iii T, Oparil S, Melino M et al. 24-hour efficacy and safety of Triple-Combination Therapy With Olmesartan, Amlodipine, and Hydrochlorothiazide: the TRINITY ambulatory blood pressure substudy. J Clin Hypertens (Greenwich) 2011; 13: 873–880.
Kizilirmak P, Berktas M, Uresin Y, Yildiz OB . The efficacy and safety of triple vs dual combination of angiotensin II receptor blocker and calcium channel blocker and diuretic: a systematic review and meta-analysis. J Clin Hypertens (Greenwich) 2013; 15: 193–200.
Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG et al. Clinical practice guidelines for the management of hypertension in the community a statement by the American Society of Hypertension and the International Society of Hypertension. J Hypertens 2014; 32: 3–15.
Kereiakes DJ, Chrysant SG, Izzo JL Jr, Littlejohn T 3rd, Melino M, Lee J et al. Olmesartan/amlodipine/hydrochlorothiazide in participants with hypertension and diabetes, chronic kidney disease, or chronic cardiovascular disease: a subanalysis of the multicenter, randomized, double-blind, parallel-group TRINITY study. Cardiovasc Diabetol 2012; 11: 134.
Calhoun DA, Lacourciere Y, Crikelair N, Jia Y, Glazer RD . Effects of demographics on the antihypertensive efficacy of triple therapy with amlodipine, valsartan, and hydrochlorothiazide for moderate to severe hypertension. Curr Med Res Opin 2013; 29: 901–910.
Chrysant SG, Littlejohn T 3rd, Izzo JL Jr, Kereiakes DJ, Oparil S, Melino M et al. Triple-combination therapy with olmesartan, amlodipine, and hydrochlorothiazide in black and non-black study participants with hypertension: the TRINITY randomized, double-blind, 12-week, parallel-group study. Am J Cardiovasc Drugs 2012; 12: 233–243.
Flack JM, Calhoun DA, Satlin L, Barbier M, Hilkert R, Brunel P . Efficacy and safety of initial combination therapy with amlodipine/valsartan compared with amlodipine monotherapy in black patients with stage 2 hypertension: the EX-STAND study. J Hum Hypertens 2009; 23: 479–489.
Lewin AJ, Izzo JL Jr, Melino M, Lee J, Fernandez V, Heyrman R . Combined olmesartan, amlodipine, and hydrochlorothiazide therapy in randomized patients with hypertension: a subgroup analysis of the TRINITY study by age. Drugs Aging 2013; 30: 549–560.
Roth EM, Oparil S, Melino M, Lee J, Fernandez V, Heyrman R . Olmesartan/amlodipine/hydrochlorothiazide in obese participants with hypertension: a TRINITY subanalysis. J Clin Hypertens (Greenwich) 2013; 15: 584–592.
Brahmajee K, Nallamothu RAH, Bates ER . Beyond the randomized clinical trial: the role of effectiveness studies in evaluating cardiovascular therapies. Circulation 2008; 118: 1294–1303.
Sison J, Assaad-Khalil SH, Najem R, Kitchlew AR, Cho B, Ueng KC et al. Real-world clinical experience of amlodipine/valsartan and amlodipine/valsartan/hydrochlorothiazide in hypertension: the EXCITE study. Curr Med Res Opin 2014; 30: 1937–1945.
Bramlage P, Fronk EM, Wolf WP, Smolnik R, Sutton G, Schmieder RE . Safety and effectiveness of a fixed-dose combination of olmesartan, amlodipine, and hydrochlorothiazide in clinical practice. Vasc Health Risk Manag 2015; 11: 1–8.
Pall D, Szanto I, Szabo Z . Triple combination therapy in hypertension: the antihypertensive efficacy of treatment with perindopril, amlodipine, and indapamide SR. Clin Drug Investig 2014; 34: 701–708.
Toth K . Antihypertensive efficacy of triple combination perindopril/indapamide plus amlodipine in high-risk hypertensives: results of the PIANIST study (Perindopril-Indapamide plus AmlodipiNe in high rISk hyperTensive patients). Am J Cardiovasc Drugs 2014; 14: 137–145.
Fogari R, Zoppi A, Mugellini A, Preti P, Perrone T, Maffioli P et al. Effects of valsartan vs olmesartan addition to amlodipine/hydrochlorothiazide combination in treating stage 2 hypertensive patients. Expert Opin Pharmacother 2012; 13: 629–636.
Choi EY, McKenna BJ . Olmesartan-associated enteropathy: a review of clinical and histologic findings. Arch Pathol Lab Med 2015; 139: 1242–1247.
Cohn JN, Tognoni G . A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345: 1667–1675.
McMurray J, Solomon S, Pieper K, Reed S, Rouleau J, Velazquez E et al. The effect of valsartan, captopril, or both on atherosclerotic events after acute myocardial infarction: an analysis of the Valsartan in Acute Myocardial Infarction Trial (VALIANT). J Am Coll Cardiol 2006; 47: 726–733.
Messerli FH, Makani H, Benjo A, Romero J, Alviar C . Bangalore S. Antihypertensive efficacy of hydrochlorothiazide as evaluated by ambulatory blood pressure monitoring: a meta-analysis of randomized trials. J Am Coll Cardiol 2011; 57: 590–600.
Messerli FH, Bangalore S, Julius S . Risk/benefit assessment of beta-blockers and diuretics precludes their use for first-line therapy in hypertension. Circulation 2008; 117: 2706–2715.
Williams B, MacDonald TM, Morant S, Webb DJ, Sever P, McInnes G et al. Spironolactone vs placebo, bisoprolol, and doxazosin to determine the optimal treatment for drug-resistant hypertension (PATHWAY-2): a randomised, double-blind, crossover trial. Lancet 2015; 386: 2059–2068.
Yang W, Chang J, Kahler KH, Fellers T, Orloff J, Wu EQ et al. Evaluation of compliance and health care utilization in patients treated with single pill vs free combination antihypertensives. Curr Med Res Opin 2010; 26: 2065–2076.
Urquhart J . Role of patient compliance in clinical pharmacokinetics. A review of recent research. Clin Pharmacokinet 1994; 27: 202–215.
Chapman RH, Benner JS, Petrilla AA, Tierce JC, Collins SR, Battleman DS et al. Predictors of adherence with antihypertensive and lipid-lowering therapy. Arch Intern Med 2005; 165: 1147–1152.
Schroeder K, Fahey T, Ebrahim S . Interventions for improving adherence to treatment in patients with high blood pressure in ambulatory settings. Cochrane Database Syst Rev 2004 (2): CD004804.
Neutel JM, Smith DH . Hypertension management: rationale for triple therapy based on mechanisms of action. Cardiovasc Ther 2013; 31: 251–258.
Ho PM, Magid DJ, Masoudi FA, McClure DL, Rumsfeld JS . Adherence to cardioprotective medications and mortality among patients with diabetes and ischemic heart disease. BMC Cardiovasc Disord 2006; 6: 48.
Ho PM, Magid DJ, Shetterly SM, Olson KL, Maddox TM, Peterson PN et al. Medication nonadherence is associated with a broad range of adverse outcomes in patients with coronary artery disease. Am Heart J 2008; 155: 772–779.
Rasmussen JN, Chong A, Alter DA . Relationship between adherence to evidence-based pharmacotherapy and long-term mortality after acute myocardial infarction. JAMA 2007; 297: 177–186.
Hackam DG, Quinn RR, Ravani P, Rabi DM, Dasgupta K, Daskalopoulou SS et al. The 2013 Canadian Hypertension Education Program recommendations for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol 2013; 29: 528–542.
Shimamoto K, Ando K, Fujita T, Hasebe N, Higaki J, Horiuchi M et al. The Japanese Society of Hypertension Guidelines for the Management of Hypertension (JSH 2014). Hypertens Res 2014; 37: 253–390.
Brixner DI, Jackson KC 2nd, Sheng X, Nelson RE, Keskinaslan A . Assessment of adherence, persistence, and costs among valsartan and hydrochlorothiazide retrospective cohorts in free-and fixed-dose combinations. Curr Med Res Opin 2008; 24: 2597–2607.
Gupta AK, Arshad S, Poulter NR . Compliance, safety, and effectiveness of fixed-dose combinations of antihypertensive agents: a meta-analysis. Hypertension 2010; 55: 399–407.
Bangalore S, Kamalakkannan G, Parkar S, Messerli FH . Fixed-dose combinations improve medication compliance: a meta-analysis. Am J Med 2007; 120: 713–719.
Hagendorff A, Freytag S, Muller A, Klebs S . Pill burden in hypertensive patients treated with single-pill combination therapy—an observational study. Adv Ther 2013; 30: 406–419.
Machnicki G, Ong SH, Chen W, Wei ZJ, Kahler KH . Comparison of amlodipine/valsartan/hydrochlorothiazide single pill combination and free combination: adherence, persistence, healthcare utilization and costs. Curr Med Res Opin 2015; 31: 2287–2296.
Ferdinand KC, Weitzman R, Israel M, Lee J, Purkayastha D, Jaimes EA . Efficacy and safety of aliskiren-based dual and triple combination therapies in US minority patients with stage 2 hypertension. J Am Soc Hypertens 2011; 5: 102–113.
Acknowledgements
We would like to acknowledge medical writing support from Dr Krishna Swetha Gummuluri, Novartis Healthcare Pvt. Ltd., Hyderabad, India.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
RD has received honoraria for scientific lectures and financial support for conducting clinical studies from Novartis, Servier, Berlin Chemie and UCB Pharma. MD has received consulting and lecture fees and research grants from Boehringer Ingelheim, AstraZeneca, Servier, Menarini IFR, Schering-Plough, Guidotti, Pfizer, Knoll, Bayer, Chiesi, Daiichi-Sankyo, Merck Sharpe & Dohme and Malesci. MD has also received research support as a study investigator from Novartis Pharma AG and has been a speaker at scientific meetings organised by Novartis. BW has received consulting and lecture fees from Novartis, Pfizer, Menarini and Servier. PB is an employee of Novartis Pharma are thus eligible for Novartis stocks and stock options. CSM was an employee of Novartis at the time of manuscript preparation.
Rights and permissions
About this article
Cite this article
Düsing, R., Waeber, B., Destro, M. et al. Triple-combination therapy in the treatment of hypertension: a review of the evidence. J Hum Hypertens 31, 501–510 (2017). https://doi.org/10.1038/jhh.2017.5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/jhh.2017.5
- Springer Nature Limited
This article is cited by
-
CARD9 regulates myocardial inflammation, oxidative stress, and vascular dysfunction in hypertensive rats by activating MAPK/p38 pathway in combination with NOD2
Molecular & Cellular Toxicology (2024)
-
ARB-Based Combination Therapy for the Clinical Management of Hypertension and Hypertension-Related Comorbidities: A Spotlight on Their Use in COVID-19 Patients
High Blood Pressure & Cardiovascular Prevention (2021)
-
A Cross-Sectional Study of Overtreatment and Deintensification of Antidiabetic and Antihypertensive Medications in Diabetes Mellitus: The TEMD Overtreatment Study
Diabetes Therapy (2020)
-
Antihypertensive Prescribing Pattern in Older Adults: Implications of Age and the Use of Dual Single-Pill Combinations
High Blood Pressure & Cardiovascular Prevention (2019)
-
Olmesartan medoxomil/amlodipine/hydrochlorothiazide 20 mg/5 mg/12.5 mg fixed-dose combination in hypertension: a profile of its use
Drugs & Therapy Perspectives (2018)