The 2017 guidelines from the American College of Cardiology and American Heart Association (ACC/AHA) recommend that all adults with stage 2 hypertension who have an average blood pressure (BP) more than 20/10 mmHg above their BP target should be started on two first-line antihypertensive agents from different classes.1 Stage 2 hypertension is defined as 140 mmHg or higher systolic blood pressure (SBP) or 90 mmHg or higher diastolic blood pressure (DBP). The guidelines recommend a BP target goal of less than 130/80 mmHg for adults with hypertension below age 65. For adults aged 65 and older, BP recommendations are only issued for SBP, with a goal of less than 130 mmHg.
Evidence shows that lowering BP decreases the risk of adverse cardiovascular (CV) outcomes such as heart disease, stroke, and death.2-5 Lowering BP also may slow the progression of kidney damage in people with chronic kidney disease.6 Meta-analyses as well as national and international guidelines suggest that lowering BP decreases risk of these outcomes regardless of which agent is used.2-5
Benefits of Combination Therapy
Studies have demonstrated that combination drug antihypertensive therapy results in both more efficacious and faster BP control compared to monotherapy, which may result in greater risk reduction of CV disease.7-9
A 2012 retrospective study compared records of 106,621 patients with uncontrolled hypertension who had no treatment for at least six months prior to initiating antihypertensive agents.7 Patients started on single-pill combination therapy (n=9,194) had the best blood pressure control in the first year (hazard ratio [HR] 1.53, 95% confidence interval [CI] [1.47-1.58]) compared to those on multi-pill combination therapy (n=18,328) (HR 1.34, 95% CI [1.31-1.37]) or monotherapy (n=79,099). Among patients started on single-pill combination, 68% achieved BP target (<140/90 mm Hg or <130/80 mm Hg for participants with diabetes or CKD) after one-year follow-up compared to 59% who were initiated on multi-pill combination or monotherapy. The median time to achieve BP control was shortest for those on single-pill combination at 195 days compared to 269 days for those on multi-pill combination and 280 days for those on monotherapy (p < 0.001).
A 2013 retrospective study matched 1,762 adults started on combination antihypertensive therapy with patients who were started on monotherapy and later switched to combination therapy.8 Patients started on combination therapy had a significant 34% risk reduction for CV events, including hospitalization for heart failure, myocardial infarction, stroke or transient ischemic attack, and all-cause death (incidence risk ratio [IRR] 0.66, 95% CI [0.52-0.84], p=0.0008). After 6 months of therapy, 40.3% of patients with initial combination treatment reached blood pressure control compared to 32.6% with delayed combination treatment. The 34% risk reduction corresponds to the IRR of 0.66 (1 - 0.66 = 0.34 or 34% reduction). At six months of treatment, BP control was reached by 40.3% of patients started on combination therapy compared to only 32.6% of those started on monotherapy. The study found that reaching target blood pressure significantly reduced risk for CV events or death by 23% (HR 0.77, 95% CI [0.61-0.96], p=0.0223).
A 2011 study of 209,650 hypertensive patients in Italy who were newly started on antihypertensive agents found that patients who were started on combination therapy had a CV risk reduction of 11% (95% CI [5%-16%]) compared to patients started on monotherapy. The study utilized healthcare utilization databases from Lombardy, analyzing newly treated patients who had not received antihypertensive prescriptions in the preceding 10 years.9
Medication Adjustment
Patients started on one or two antihypertensive medications may need to increase dosage or add additional medications from other antihypertensive classes to achieve their BP goal.1 The ACC/AHA guidelines recommend that people started on antihypertensive drugs should be reassessed within one month. If the BP goal is not met, guidelines recommend intensification of therapy with either an increased dose or an additional medication from another antihypertensive class should be considered.
Studies have shown that delays in intensification of BP treatment result in an increased risk of CV events or death. 2015 retrospective cohort study of 88,756 hypertensive adults found the risk of CV event or death increased with delay of medication intensification from the lowest delay (0-1.4 months) to delays between 1.4 and 4.7 months (HR 1.12, 95% CI [1.05-1.20], p=0.009). During a median follow-up of 37.4 months, 9,985 (11.3%) participants had an acute cardiovascular event or died.10
Low-Dose Combination Therapy
Recent research has shown that using multiple low-dose medications in combination may be more effective than a similar total dosage in monotherapy. This presents a new potential in combination therapy, which has historically involved prescribing the full dose of multiple medications rather than lower doses.
A 2025 systematic review and meta-analysis of five randomized controlled trials (1,709 patients) examined low-dose triple single-pill combinations (LDTC).11 The study found that 56% of patients achieved BP control below 140/90 mmHg at 4-6 weeks with LDTC compared to only 36% with monotherapy or placebo (relative risk [RR] 1.56, 95% CI [1.41-1.72]). LDTC also provided sustained SBP reductions of 8-9 mmHg at four, eight, and 24 weeks, with no overall increase in serious adverse events.
A 2024 meta-analysis of 24 double-blind randomized controlled trials (n=15,533) found that adding a third antihypertensive medication to a dual regimen lowered blood pressure by an additional 5/3.7 mmHg and improved blood pressure control rates from 54% to 69%.12
The QUARTET-USA trial in 2024 demonstrated that a fixed-dose "quadpill" combination (candesartan, amlodipine, indapamide, and bisoprolol at quarter doses) was well-tolerated and showed efficacy compared to standard-dose single medication therapy.13 Additionally, a 2024 Lancet randomized controlled trial showed that a novel low-dose triple single-pill (telmisartan/amlodipine/indapamide) significantly outperformed dual combinations in blood pressure reduction among treatment-naïve patients, with the triple combination reducing home systolic blood pressure by 2.5 mm Hg versus telmisartan-indapamide, 5.4 mm Hg versus telmisartan-amlodipine, and 4.4 mm Hg versus amlodipine-indapamide (all p<0.0001). Additionally, blood pressure control rates below 140/90 mm Hg at week 12 were superior with the triple combination (74%) compared to dual combinations (53-61%).14
References
- Whelton PK, Carey RM, Aronow WS, 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. Circulation. Oct 23 2018;138(17):e426-e483. doi:10.1161/CIR.0000000000000597
- Ahluwalia M, Bangalore S. Management of hypertension in 2017: targets and therapies. Curr Opin Cardiol. Jul 2017;32(4):413-421. doi:10.1097/HCO.0000000000000408
- James PA, Oparil S, Carter BL, 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. Feb 5 2014;311(5):507-20. doi:10.1001/jama.2013.284427
- Pignone M, Viera AJ. Blood Pressure Treatment Targets in Adults Aged 60 Years or Older. Ann Intern Med. Mar 21 2017;166(6):445-446. doi:10.7326/M17-0034
- Qaseem A, Wilt TJ, Rich R, et al. Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets: A Clinical Practice Guideline From the American College of Physicians and the American Academy of Family Physicians. Ann Intern Med. Mar 21 2017;166(6):430-437. doi:10.7326/M16-1785
- Awdishu L, Maxson R, Gratt C, Rubenzik T, Battistella M. KDIGO 2024 clinical practice guideline on evaluation and management of chronic kidney disease: A primer on what pharmacists need to know. Am J Health Syst Pharm. Jun 11 2025;82(12):660-671. doi:10.1093/ajhp/zxaf044
- Egan BM, Bandyopadhyay D, Shaftman SR, Wagner CS, Zhao Y, Yu-Isenberg KS. Initial monotherapy and combination therapy and hypertension control the first year. Hypertension. Jun 2012;59(6):1124-31. doi:10.1161/HYPERTENSIONAHA.112.194167
- Gradman AH, Parise H, Lefebvre P, Falvey H, Lafeuille MH, Duh MS. Initial combination therapy reduces the risk of cardiovascular events in hypertensive patients: a matched cohort study. Hypertension. Feb 2013;61(2):309-18. doi:10.1161/HYPERTENSIONAHA.112.201566
- Corrao G, Nicotra F, Parodi A, et al. Cardiovascular protection by initial and subsequent combination of antihypertensive drugs in daily life practice. Hypertension. Oct 2011;58(4):566-72. doi:10.1161/HYPERTENSIONAHA.111.177592
- Xu 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. Feb 5 2015;350:h158. doi:10.1136/bmj.h158
- Elgendy MS, Taha HI, Amin AM, et al. The efficacy and safety of low-dose triple combination for hypertension treatment: a systematic review and meta-analysis of randomized controlled trials. Naunyn Schmiedebergs Arch Pharmacol. Feb 6 2025;doi:10.1007/s00210-025-03790-z
- Salam A, Atkins ER, Hsu B, Webster R, Patel A, Rodgers A. Efficacy and safety of triple versus dual combination blood pressure-lowering drug therapy: a systematic review and meta-analysis of randomized controlled trials. J Hypertens. Aug 2019;37(8):1567-1573. doi:10.1097/HJH.0000000000002089
- Huffman MD, Baldridge AS, Lazar D, et al. Efficacy and safety of a four-drug, quarter-dose treatment for hypertension: the QUARTET USA randomized trial. Hypertens Res. Jun 2024;47(6):1668-1677. doi:10.1038/s41440-024-01658-y
- Rodgers A, Salam A, Schutte AE, et al. Efficacy and Safety of a Novel Low-Dose Triple Single-Pill Combination Compared With Placebo for Initial Treatment of Hypertension. J Am Coll Cardiol. Dec 10 2024;84(24):2393-2403. doi:10.1016/j.jacc.2024.08.025
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