The prevalence of hypertension, the most prominent modifiable risk factor for cardiovascular (CV) disease and mortality, continues to rise globally. It is estimated that, in 2010, nearly 31.1% of the global adult population worldwide suffered from hypertension [defined as systolic BP/diastolic BP (SBP/DBP) ≥140/90 mmHg].¹ Though the correlation between uncontrolled hypertension and enhanced risk for CV events and death is well-established, BP control rates remain disappointingly low, ranging from 15 to 20% in hypertensive populations across the world. 

Over time, hypertension management has evolved from monotherapy to sequential monotherapy and finally to the step-care regimen where a second drug is added to initial monotherapy. This regimen found favour since it was evident that compared to increasing the dose of the initial drug (the protocol followed in monotherapy regimens), adding a second drug can increase the chances of achieving BP control by 5 times. However, this regimen was in reality associated with therapeutic inertia and lack of adherence making BP control a difficult goal to achieve. 

Moreover, previous guidelines advocated use of 2-drug combinations only when baseline BP was ≥20/10 mmHg above the target of 140/90 i.e. ≥160/100 mmHg. However, recent evidence has confirmed the protective effects of 2-drug combination therapy.² The hypertension guidelines from European Society of Cardiology (ESC) and the European Society of Hypertension (ESH 2018)³ and International Society of Hypertension (2020)⁴, taking these aspects into account, thus mandate the initial use of 2-drug combinations as the first-step of antihypertensive therapy for specific patients with hypertension. Preferred combinations for therapy include calcium channel blocker (CCB)/diuretic + angiotensin receptor blocker (ARB)/ angiotensin-converting enzyme inhibitor (ACEI) due to their complementary effects.³ 

Two-drug treatment enhances hypertension management in several ways. It results in greater BP reduction compared to monotherapy with a steeper correlation between the dose and the BP response. The BP reduction achieved is swift and shows lesser variation in response across patients. Moreover, this BP-lowering is accompanied by a complete lack of or only a slight increase in hypotensive episodes. Combination therapy also provides more frequent BP control along with better adherence to drug treatment and decreased therapeutic inertia.²

These advantages were ably supported with clinical data. The National Health and Nutrition Examination Survey showed that compared with monotherapy, patients administered with either free/single-pill combinations (SPC) of antihypertensive agents presented with a greater and more frequent BP control (BP <140/90 mmHg) after 1 year. Another study, involving ~4,40,000 patients, showed that drug combinations decreased the rate of therapy discontinuation vs monotherapy, irrespective of the form in which the 2-drug combinations were given (separate pills or SPC). This is significant since increased adherence to antihypertensive treatment has been clinically correlated with incidence and risk of CV events. In fact, evidence showed that compared to a <25% adherence rate, a >75% adherence to antihypertensive drugs resulted in a progressive reduction in the risk of hospitalization for cerebrovascular disease, ischemic heart disease and heart failure, across patient subgroups.² 

Both ESC/ESH and ISH guidelines recommend the use of 2-drug SPCs for antihypertensive therapy.^3,4 Though SPCs may make it inconvenient to uptitrate treatment effectively if required, several studies have shown that decreasing the number of pills consumed daily have uniformly helped enhance treatment adherence, in spite of variation in baseline patient criteria like CV risk, duration of therapy, age and comorbidity status. SPCs have also proved to be an economical option for therapy with the added advantage of favourable tolerability due to the lower doses of individual drugs.² Thus, therapy with a SPC can improve the speed, efficacy and reliability of BP control.³

Lastly, studies reaffirm the beneficial impact of combination therapy on incidence and risk of CV events and fatality. Post hoc analyses of major trials such as VALUE (Valsartan Antihypertensive Long-Term Evaluation), ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack) and ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm) have shown that prompt achievement of BP control has resulted in greater CV protection. Another study showed that over a period of 2 yrs, compared to monotherapy, the superior BP control achieved by combination therapy decreased the risk of combined CV events, heart failure and stroke by 38%, 36% and 21%, respectively. In Rea F et al., combination therapy in hypertensive patients (n=44,534) scored over monotherapy and significantly decreased hospitalization risk due to CV events (Fig 1).⁵ Thus, therapy with a 2-drug combination exhibited a speedier, sustained and greater protection than monotherapy. 

Initial monotherapy, however, may be the better option for specific patient groups such as (a) those at high CV risk but with a high-normal BP (130–139/85–89 mmHg) or grade 1 hypertension since a single drug may help achieve the limited BP reduction needed to reach the BP target of <130/80 mmHg and (b) old, frail or very old patients.² 

Two-drug combinations, preferably as a SPC, provide prompt and effective management of hypertension to ensure long-term CV protection for majority of the hypertensive population. 

References

1. Mills KT, Stefanescu A, He J. The global epidemiology of hypertension. Nat Rev Nephrol. 2020 Apr;16(4):223-237.
2. Mancia G, Rea F, Corrao G, Grassi G. Two-Drug Combinations as First-Step Antihypertensive Treatment. Circ Res. 2019 Mar 29;124(7):1113-1123.
3. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, Clement DL, Coca A, de Simone G, Dominiczak A, Kahan T, Mahfoud F, Redon J, Ruilope L, Zanchetti A, Kerins M, Kjeldsen SE, Kreutz R, Laurent S, Lip GYH, McManus R, Narkiewicz K, Ruschitzka F, Schmieder RE, Shlyakhto E, Tsioufis C, Aboyans V, Desormais I; ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018 Sep 1;39(33):3021-3104.
4. Unger T, Borghi C, Charchar F, Khan NA, Poulter NR, Prabhakaran D, Ramirez A, Schlaich M, Stergiou GS, Tomaszewski M, Wainford RD, Williams B, Schutte AE. 2020 International Society of Hypertension global hypertension practice guidelines. J Hypertens. 2020 Jun;38(6):982-1004.
5. Rea F, Corrao G, Merlino L, Mancia G. Early cardiovascular protection by initial two-drug fixed-dose combination treatment vs. monotherapy in hypertension. Eur Heart J. 2018 Oct 21;39(40):3654-3661.