Journal of Clinical and Preventive Cardiology

: 2020  |  Volume : 9  |  Issue : 2  |  Page : 78--83

Monotherapy versus combination therapy for the initial treatment of hypertension

Simardeep Kaur Shina 
 Government Medical College, Amritsar, Punjab, India

Correspondence Address:
Dr. Simardeep Kaur Shina
730 Clinton Street, Westbury, New York


Objectives: There is a significant gap among hypertensive patients who are being treated and those who actually achieve blood pressure (BP) control. The main objective of this article is to determine if there are any differences in clinical outcomes and BP control with a combination treatment as compared to monotherapy as the initial treatment of hypertension. It also focuses on to compare the efficacy and compliance of fixed-dose combination (FDC) as compared to monotherapy and conventional multi-pill combination therapy as the initial treatment of hypertension. Methods: A search of literature was done using PubMed and Google scholar to prepare a review on this topic. Results: The main evidence supporting the use of combination therapy is focused on the use of combinations of renin–angiotensin System (RAS) blocker with calcium channel blockers (CCBs) and with thiazide diuretics. Several randomized clinical trials have proven the efficacy of combination therapy to be superior to monotherapy as initial treatment for timely and adequate BP control. Conclusion: Several benefits of achieving good BP control have been proven by several studies including the Systolic Blood Pressure Intervention Trial study, but only a few guidelines internationally recommend combination antihypertensives as a routine first-line treatment in all hypertensive patients. It is reasonable to go for aggressive management of hypertension involving the use of FDC antihypertensives from two different classes of drugs to achieve the recommended goals of BP of <140/90 mmHg for most patients and <130/80 mmHg for high-risk patients. The combination treatment that can be considered is the combination of RAS blockers with CCB or RAS blockers with thiazide diuretics.

How to cite this article:
Shina SK. Monotherapy versus combination therapy for the initial treatment of hypertension.J Clin Prev Cardiol 2020;9:78-83

How to cite this URL:
Shina SK. Monotherapy versus combination therapy for the initial treatment of hypertension. J Clin Prev Cardiol [serial online] 2020 [cited 2020 Sep 25 ];9:78-83
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Hypertension is one of the major growing public health concerns. In 2010, an estimated 1.39 billion adults aged ≥20 years worldwide had hypertension. The burden of hypertension was almost three times in low- and middle-income countries than in high-income countries. Hence, the low- and middle-income countries are facing a dual problem of continuing increased prevalence of various infectious diseases on the one hand, while they are battling with an increasing burden of noncommunicable diseases such as hypertension on the other hand.[1]

As shown in [Figure 1], there is a significant discrepancy in the percentage of population that is being treated with antihypertensives compared to the percentage that actually have their blood pressure (BP) controlled.[1] Raised BP is linked to a large global burden of cardiovascular disease and premature death. It was estimated that in 2015, the estimated number of all-cause deaths associated with systolic BP (SBP) ≥140 mmHg was 7.8 million.[2] There are a number of diseases associated with high BP which include ischemic heart disease, cerebral vascular accidents both occlusive and hemorrhagic, chronic kidney disease, hypertensive heart disease, aortic aneurysm, cardiomyopathy, atrial fibrillation, peripheral vascular disease, and other cardiovascular diseases.{Figure 1}

 Methods and Results

A search of literature was done using PubMed and Google scholar to prepare a thorough review on this topic and compare the efficacy and compliance of fixed-dose combinations (FDCs) as compared to monotherapy and multi-pill combination treatment as initial therapy for hypertension.

Role of intensive blood pressure control

The importance of intensive BP control can be deduced from the Systolic Blood Pressure Intervention Trial (SPRINT)[3] which included 9361 participants across 102 clinical sites in the United States between November 2010 and March 2013. It highlighted that among adults with hypertension but without diabetes, intensive BP control to a target goal of <120 mmHg as compared with the usual standard target goal of 140 mmHg resulted in significantly lower rates of fatal and nonfatal cardiovascular events and death from any cause. Throughout the 3.26 years of follow-up, the mean SBP in the intensive treatment group was 121.5 mmHg and in the standard treatment group was 134.6 mmHg. The mean number of BP medications was 2.8 and 1.8 in the intensive and standard treatment group, respectively. The vascular changes associated with hypertension or elevated BP may precede the clinical diagnosis of hypertension and consequently precedes the start of antihypertensive treatment. The role of timely control of BP is evident from the results of the Valsartan Antihypertensive Long-term Use Evaluation Trial which showed that immediate BP reduction and early BP control (within 6 months) are critical determinants of cardiovascular outcomes. Patients whose BP responded immediately (i.e. within 1 month of treatment) were less likely to be at risk of a cardiac event, stroke, and death.[4]

The Systolic Hypertension in Europe trial was done to evaluate the impact of immediate versus delayed hypertensive treatment on the outcome of older patients with isolated systolic hypertension. It was observed that as compared with delayed antihypertensive treatment, immediate treatment of hypertension decreased the occurrence of stroke and cardiovascular complications by 28% and 15%, respectively.[5] According to another study, considering the systolic intensification threshold of 150 mmHg, delays of >1.4 months before medication intensification (start of a new antihypertensive medication or an increase in the daily dose of an existing antihypertensive medication) after the SBP elevation above the intensification threshold were associated with an increased risk of an acute cardiovascular event or death.[6] Conversely, shorter times to medication intensification with frequent follow-ups and having a lower systolic intensification threshold resulted in decreased risk of acute cardiovascular events and death.[3] This highlights the importance of the time that is taken to achieve BP control and the level to which the BP control is achieved.

Blood pressure control with combination therapy

Several studies have been done to prove the superiority of combination therapy as compared to monotherapy. More than 75% of patients with hypertension require two or more medications to achieve BP goal. Therefore, early combination therapy is better than sequential monotherapy.[7] A retrospective study comparing monotherapy with single-pill combination treatment and free-dose combinations found that the median time to achieve 50% of BP control for single-pill combination group was 195 days, for free-dose combination group was 269 days, and for monotherapy group was 280 days with an overall P < 0.01. About 53% of patients treated initially with single-pill combinations and 34% on free combination were likely to obtain the target goal of BP control in the first treatment year when compared with patients initiating on monotherapy. Moreover, the study also observed that single-pill combinations improved BP control in both black and white hypertensive patients.[8] In a meta-analysis, it was observed that the BP reduction from combining drugs from two different classes is approximately five times greater than doubling the dose of one drug emphasizing the role of combination treatment in hypertension.[9] Hence, even low-dose combination therapy is found to be more effective than maximal dose monotherapy because of additive effects of different classes of drugs when used together. In a study by Yusuf et al., it was even seen that in patients with Grade I hypertension, the use of two-drug combination therapy is well tolerated as the initial treatment of hypertension.[10] Treatment discontinuation is also less frequent when two-drug combination therapy is used for the initial treatment of hypertension.[11] [Table 1] highlights the various clinical trials done to compare monotherapy versus combination therapy.{Table 1}

Fixed-dose combination versus loose-dose combinations

The two main determinants of poor medication compliance in any chronic disease are polypharmacy and complexity of the treatment regimen. FDCs decrease the number of pills that the patient has to take, thus tackling the issue of polypharmacy.[18] Simplification of drug therapy using two classes of drugs in a single pill for hypertension significantly improves persistence with prescribed therapy.[19] In a meta-analysis, it was observed that the use of FDCs reduces the risk of noncompliance by 24%–26% as compared to free-drug combination regimens.[18] Thus, FDCs of antihypertensive medications are preferable to loose-dose combinations.

Safety of fixed-dose combinations

In a meta-analysis of 42 trials, it was observed that even low-dose combination therapy is more effective than maximal dose monotherapy because of the additive effects of the medications from different classes. As a result, the prevalence of adverse effects from combining two drugs at half-standard dose would, therefore, for most combinations, be lower than with one drug at standard dose. The low-dose combination therapy usage has greater efficacy and less toxicity than using a higher dose of a single drug.[9] Consequently, the use of lower doses of various classes of drugs in combination therapy may be associated with a lower incidence of adverse effects of individual drugs.

[Figure 2] provides a comparison of adverse effects of various antihypertensive drugs when used at half-standard dose as compared to the standard dose.[20] The risks of adverse effects observed at half-standard dose are significantly lower as compared to a standard dose for thiazide diuretics, angiotensin II receptor blockers, and calcium channel blocker (CCB). An analysis of 25 randomized controlled trials showed that the combination of CCB and a renin–angiotensin system (RAS) blocker reduces the risk of CCB-associated peripheral edema when compared to CCB monotherapy. This effect seems to be more efficacious with ACE inhibitors than angiotensin II receptor blockers.[21]{Figure 2}

Limitations of fixed-dose combinations

Less flexibility with dosage – FDCs are available with a fixed dosage of all individual drugs. Hence, it might be less feasible to increase the dose of one individual component without altering the dose of the other component. It may also expose the patients to unnecessary treatment[22]Some branded fixed drug combinations may be more expensive as compared to the free-drug combinations[22]The duration of action of the individual components in a FDC might not be equivalent which imposes a limitation on the once-daily dosing of the FDC[22]If a patient develops any side effect to one component of the FDC, the entire combination must be discontinued and replaced by free drugs[22]Risk of hypotension, especially in patients with mild hypertension – As observed in the SPRINT study, the risk of serious adverse events such as hypotension, syncope, electrolyte abnormalities, and acute kidney injury occurred more frequently in the intensive treatment group than the standard treatment group.[3] Hence, the use of FDCs as first-line treatment in patients with Grade 1 hypertension (according to American College of Cardiology/ American Heart Association guidelines) has to be weighed against the potential of these adverse effects.

Current recommendations regarding combination therapy

The role of combination therapy as outlined by various hypertension guidelines internationally has been outlined in [Table 2]. Most guidelines either recommend combination treatment as first-line treatment or as a suitable alternative.{Table 2}


Hypertension is one of the major cardiovascular risk factors. One of the main targets adopted by the WHO in 2013 in the Global Action Plan for the prevention and control of noncommunicable diseases is to achieve 25% decrease in the prevalence of raised BP (SBP ≥140 mmHg and/or DBP ≥ 90 mmHg) by 2025 as compared to its 2010 level.[27] The main struggles related to hypertension are:

Of the 36.90% of patients treated for hypertension, only 13.80% of patients have their BP controlled worldwide[1]The burden of hypertension is three times more in low- and middle-income countries[1]In high-income countries, the greatest burden of hypertension is in older age groups ≥60 years, whereas in low- and middle-income countries, this burden is highest in the middle age groups (e.g., 40–59 years)[1]Despite several advances in treatment, the mean systolic and mean diastolic BP has remained either constant or just slightly decreased over the past several years, especially in low- and middle-income countries.[28]

Bearing in mind all these issues, it is pertinent to tailor antihypertensive treatment according to the available statistics. As outlined in [Table 1], the combination treatment of RAS blockers (angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers) with either CCB or with a thiazide diuretic are superior to monotherapy with these drugs. In addition, the adverse effects reported with combination treatment are also less. Moreover, using two drugs at half-standard doses with additive effects leads to a greater and earlier reduction in BP. In combination therapy, FDCs are superior to loose-dose combinations as they simplify the regimen and also prevent polypharmacy. Nowadays, a number of doses of different classes of antihypertensive drugs are available in FDCs which help in decreasing the limitations discussed as stated above.


Although several benefits of achieving good BP control have been shown by various studies including the SPRINT study recently, only half of the treated patients reach their target goals of BP control. The most significant evidence is available for the use of RAS blockers with CCB and RAS blockers with thiazide diuretics in several trials.

Based on these observations, it is reasonable to go for aggressive management of hypertension involving the use of FDCs to achieve the recommended goals of BP of <140/90 mmHg for most patients and <130/80 mmHg for high-risk patients. Only a few guidelines recommend initiating combination therapy in all hypertensive patients as a routine.

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Conflicts of interest

There are no conflicts of interest.


1Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, et al. Global disparities of hypertension prevalence and control: A systematic analysis of population-based studies from 90 countries. Circulation 2016;134:441-50.
2Forouzanfar MH, Liu P, Roth GA, Ng M, Biryukov S, Marczak L, et al. Global burden of hypertension and systolic blood pressure of at least 110 to 115 mm Hg, 1990-2015. JAMA 2017;317:165-82.
3SPRINT Research Group, Wright Jr JT, Williamson JD, Whelton PK, Snyder JK, Sink KM, et al. The SPRINT Research Group. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med 2015;373:2103-2116.
4Sica DA. The valsartan antihypertensive long-term use evaluation trial: A study in contrasts. Hypertension 2006;48:362-3.
5Staessen JA, Thijisq L, Fagard R, Celis H, Birkenhäger WH, Bulpitt CJ, et al. Effects of immediate versus delayed antihypertensive therapy on outcome in the Systolic Hypertension in Europe Trial. J Hypertens 2004;22:847-57.
6Xu W, Goldberg SI, Shubina M, Turchin A. Optimal systolic blood pressure target, time to intensification, and time to follow-up in treatment of hypertension: Population based retrospective cohort study. BMJ 2015;350:h158.
7Mensah GA, Bakris G. Treatment and control of high blood pressure in adults. Cardiol Clin 2010;28:609-22.
8Egan BM, Bandyopadhyay D, Shaftman SR, Wagner CS, Zhao Y, Yu-Isenberg KS. Initial monotherapy and combination therapy and hypertension control the first year. Hypertension 2012;59:1124-31.
9Wald DS, Law M, Morris JK, Bestwick JP, Wald NJ. Combination therapy versus monotherapy in reducing blood pressure: Meta-analysis on 11,000 participants from 42 trials. Am J Med 2009;122:290-300.
10Salim Y, Lonn E, Pais P, Bosch J, Lopez-Jaramillo P, Zhu J, et al. Blood-pressure and cholesterol lowering in persons without cardiovascular disease. N Engl J Med 2016;374:2032-43.
11Corrao G, Parodi A, Zambon A, Heiman F, Filippi A, Cricelli C, et al. Reduced discontinuation of antihypertensive treatment by two-drug combination as first step. Evidence from daily life practice. J Hypertens 2010;28:1584-90.
12Jamerson KA, Nwose O, Jean-Louis L, Schofield L, Purkayastha D, Baron M, et al. Initial Angiotensin-converting Enzyme inhibitor/calcium channel blocker combination therapy achieves superior blood pressure control compared with calcium channel blocker mono therapy in patients with stage 2 hypertension. Am J Hypertens 2004;17:495-501.
13Philipp T, Smith TR, Glazer R, Wernsing M, Yen J, Jin J, et al. Two multicenter, 8-week, randomized, double-blind, placebo-controlled, parallel-group studies evaluating the efficacy and tolerability of amlodipine and valsartan in combination and as mono therapy in adult patients with mild to moderate essential hypertension. Clin Therapeutics 2007;29:563-80.
14Rakugi H, Ogihara T, Miyata Y, Sasai K, Totsuka N. Evaluation of the efficacy and tolerability of combination therapy with candesartan cilexetil and amlodipine besilate compared with candesartan cilexetil monotherapy and amlodipine besilate monotherapy in Japanese patients with mild-to-moderate essential hypertension: a multicenter, 12-week, randomized, double-blind, placebo-controlled, parallel-group study. Clin Ther. 2012;34:838-48.
15Gradman AH, Cutler NR, Davis PJ, Robbins JA, Weiss RJ, Wood BC. Combined enalapril and felodipine extended release (ER) for systemic hypertension. Am J Cardiology 1997;79:431-5.
16Lacourcière Y, Poirier L, Hebert D, Assouline L, Stolt P, Rehel B, et al. Antihypertensive efficacy and tolerability of two fixed-dose combinations of valsartan and hydrochlorothiazide compared with valsartan monotherapy in patients with stage 2 or 3 systolic hypertension: An 8-week, randomized, double-blind, parallel-group trial. Clin Ther 2005;27:1013-21.
17Chrysant SG, Melino M, Karki S, Lee J, Heyrman R. The combination of olmesartan medoxomil and amlodipine besylate in controlling high blood pressure: COACH, a randomized, double-blind, placebo-controlled, 8-week factorial efficacy and safety study. Clin Ther 2008;30:587-604.
18Bangalore S, Kamalakkannan G, Parkar S, Messerli FH. Fixed-dose combinations improve medication compliance: A meta-analysis. Am J Med 2007;120:713-9.
19Dezii CM. A retrospective study of persistence with single-pill combination therapy vs. concurrent two-pill therapy in patients with hypertension. Manag Care 2000;9:2-6.
20Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: Analysis of 354 randomised trials. BMJ 2003;326:1427.
21Makani H, Bangalore S, Romero J, Wever-Pinzon O, Messerli FH. Effect of renin-angiotensin system blockade on calcium channel blocker-associated peripheral edema. Am J Med 2011;124:128-35.
22Angeli F, Reboldi G, Mazzotta G, Garofoli M, Ramundo E, Poltronieri C, et al. Fixed-dose combination therapy in hypertension: Cons. High Blood Press Cardiovasc Prev 2012;19:51-4.
23Whelton PK, Carey RM, Aronow WS, Casey DE Jr., Collins KJ, Dennison Himmelfarb C, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension 2018;71:1269-324.
24Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J 2018;39:3021-104.
25Ministry of Health Family Welfare, Government of India Guidelines. Available from: [Last accessed on 2020 Apr 22].
26Joint Committee for Guideline Revision. 2018 Chinese Guidelines for Prevention and Treatment of Hypertension-A report of the Revision Committee of Chinese Guidelines for Prevention and Treatment of Hypertension. J Geriatr Cardiol 2019;16:182-241.
27WHO Global Action Plan for the Prevention and Control of Noncommunicable Diseases; 2013-2020. Available from: [Last accessed on 2020 Apr 16].
28NCD Risk Factor Collaboration (NCD-RisC). Worldwide trends in blood pressure from 1975 to 2015: A pooled analysis of 1479 population-based measurement studies with 19·1 million participants. Lancet 2017;389:37-55.