In the 2018 European Society of Cardiology and European Society of Hypertension (ESC/ESH) guidelines for the management of arterial hypertension , antihypertensive treatment initiation with combination of two drugs is recommended (step 1) for the majority of hypertensive patients. The exceptions to this general rule are patients with grade 1 hypertension and low overall cardiovascular risk and elderly patients with impaired physical performance or multiple comorbidities (frailty). Another important recommendation of the 2018 ESC/ESH guidelines  is that the new blood pressure (BP) target defining treatment goal is between 120 and 130 mmHg for SBP and lower than 80 mmHg for DBP, at least for the subgroup of uncomplicated hypertensive patients aged less than 65 years, whereas a less strict systolic BP target is reserved for the elderly. When treatment target is not achieved with a two-drug combination (preferably in a single pill), a three-drug combination (step 2) should be introduced.
In the present issue of the Journal of Hypertension, Salam et al. through a systematic review and meta-analysis of randomized controlled trials comparing double-drug and triple-drug BP-lowering combinations give further support to the guideline view that triple-drug combinations reduce BP levels in a higher extent compared with double-drug combinations. Indeed, in this analysis , triple-drug combinations lowered SBP/DBP by 5.4/3.2 mmHg compared with double-drug combinations. Although the extent of absolute BP change is strictly associated with baseline BP levels – because of the Wilder's principle  – the attained BP difference between double and triple-drug combinations was almost identical for both untreated (with higher baseline BP) and treated (with lower baseline BP) patients. Thus, the study by Salam et al., in line with the 2018 ESC/ESH guidelines, suggests that a double combination treatment may be implemented for treatment initiation (in previously untreated patients) because the overall observed SBP/DBP change from baseline was quite large (i.e. 32/19 mmHg) and this reduction was accomplished mainly during the first 2 weeks of treatment. However, in case of failure to achieve individualized BP targets, patients with on-treatment uncontrolled hypertension will have an at least further 5/3 mmHg increased BP reduction when a triple-drug compared with a double combination is administered. Although Salam et al. stressed-out that BP control with a triple-drug combination was more frequent by 33% [95% confidence interval (25%,41%)] compared with a double one, the different definitions of BP control across selected studies together with the age-related ‘moving BP targets’ adopted in the current guidelines  make this finding less important.
According to the 2018 ESC/ESH guidelines , adverse events emerging from incremental BP decrease, should be closely monitored by attending doctors, because these are associated with increased rate of discontinuations from the ongoing treatment and deprivation of treatment-related benefits . Also, discontinuations because of BP-lowering have been steadily associated with increased rate of future cardiovascular events soon after treatment withdrawal . Again, Salam et al. in this analysis, have shown that incident discontinuations because of adverse events related to treatment were marginally higher (but not significant) with triple-drug treatment compared with double-drug combinations. The marginal lack of statistical significance of treatment discontinuations for a SBP difference of 5.4 mmHg can be attributed to the short follow-up period limited to 4–10 weeks only (less time to develop symptoms) or alternatively because patients had a limited time to complain for the ongoing adverse events . It has been previously shown in a large comprehensive overview of BP-lowering trials that for 5 mmHg achieved SBP difference, the discontinuations related to treatment were increased by 35% over a period of 4 years . However, we should acknowledge that a trial setting discourages treatment discontinuations, because patients are volunteers and doctors are investigators adhering to the trial design, and consequently treatment discontinuations in standard medical practice are expected to be higher than in trials.
In order to pursue effective BP-lowering and by acknowledging that BP reduction promotes increasing rate of adverse events, doctors should escalate treatment when the attained BP levels are out-of-target, but also elaborate a more straightforward patient–doctor relationship to ensure that each separate patient adheres to be free of adverse event-prescribed treatment. Beyond the remainder of drug adherence, special attention should be paid to lifestyle changes-related adherence. It would not be worthwhile to escalate pharmacological treatment (step 1, step 2, and so on) without strict implementation of lifestyle measures. Obesity, increased salt intake, and physical inactivity represent the main modifiable triggers of polypharmacy in hypertension management, a condition that both physicians and patients should reciprocally acknowledge in each of their follow-up interactions.
Let us suppose that a patient under a double combination treatment at low doses (step 1) is out-of-BP target, but his/her adherence is good, and lifestyle measures are implemented as prescribed, as well. What comes next? Should we opt immediately for a triple-drug combination (step 2) always at low doses or increase the dose (up-titrate) of the ongoing double low-dose combination? Although it is well known that increasing the dose of monotherapy compared with low doses of double combination treatment is less effective , it is largely unknown whether this observation can be extended to another scenario that is, increasing the dose of each or both drugs of a double combination regimen ('step 1-plus’) vs. adopting low doses of a triple-drug combination. Again, Salam et al. demonstrated that doubling the dose of one of the components of a dual-drug combination is four times less effective in terms of BP-lowering compared with a triple-drug combination at lower doses, whereas they also suggested (but based on one study only) that even if full doses of the double combination are implemented, the triple low-dose combination still would have succeeded an almost two-fold higher BP-lowering. Thus, the triple low-doses drug combination (step 2) is associated with more effective BP-lowering compared with either the single agent or the dual agents dosing up-titration ('step 1-plus’) of the double-drug combination. It should be determined whether low-doses triple-drug combination may control BP within-goal faster and reduce the dose-related adverse events of the double-drug combination when administered at higher doses. However, when the attained BP is very close to the target with a low-dose double-drug combination, doctors may not use a triple-drug combination (step 2) to achieve target goal, but to increase the dose of one of the drugs contained in the double combination (‘step 1-plus’). A nonprespecified post hoc analysis of the Action in Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) trial  preserving randomization, showed that when a baseline calcium-channel blocker (nonstudy drug) was received on top of the randomized treatments (i.e. perindopril and indapamide vs. placebo), all-cause death incidence was significantly lower compared with the effect of the active treatment on the same outcome when a calcium channel was not present in the baseline active regimen, whereas permanent discontinuations because of treatment were not different between randomized arms again stratified by baseline calcium-channel blocker administration. This kind of indirect randomized evidence for the favorable effects of the triple combination treatment on all-cause death should be taken with caution because it was surprisingly produced independently of BP-lowering (i.e. the resulted attained SBP difference was of 1.5 mmHg greater in those not receiving a calcium-channel blocker) and because of the possible imbalance in different confounding factors (e.g. 10-year fatal cardiovascular risk in those receiving vs. those not receiving calcium-channel blockers at baseline was 13.9 vs. 9.1%, respectively). Subgroup analyses by baseline characteristics (e.g. by calcium-channel blocker) should not be seen as substitutes of currently lacking outcome randomized trials directly comparing triple to dual-drug combination treatments.
In the early 2000s, Law et al. based on 354 short-term randomized efficacy BP-lowering trials estimated the extent of BP reduction of different drug classes considered alone and suggested that similar BP changes are expected for all agents at equivalent doses for the same pretreatment BP levels. For multiple drug treatment (two, three or more drugs) at standard or half-standard doses, the expected BP reduction is calculated by applying general equations to each drug, in turn, allowing for the effect of the first in lowering pretreatment BP for the second, and the second for the third, and so on . Thus, the physician according to this methodology can predict the achieved BP levels following a multiple drug combination at different doses for each individual combination drug component. The predicted efficacy according to the Law et al. prediction model was close to the observed efficacy shown in the analysis by Salam et al. and most importantly predicted that all triple-drug combination treatments would be associated with a greater BP reduction compared with all two-drug combinations. Beyond all of the above mathematical assumptions to predict BP-lowering  and the important results of the study by Salam et al., the clinician should always monitor BP levels carefully following increases of antihypertensive regimen potency as BP responses may differ across patients and environmental conditions. Furthermore, the general assumption that all categories of antihypertensive agents produce similar BP reductions is not consistently seen in the usual clinical practice because various pathophysiological pathways are differently activated in different patients (e.g. volume-dependent vs. stiffness-dependent hypertension) .
Triple combinations not only effectively lower BP within goal, but their role in hypertension management is beyond BP-lowering. When administered in a single pill, triple-drug combinations simplify treatment and ameliorate adherence to treatment, but they have also the ability to treat different types of inertia. First, they may partially treat the clinical inertia of doctors to prescribe more effective treatments. Some doctors do not always adhere to the guideline recommendations, others have a relaxed attitude about BP control, and a further group of doctors has not enough time to establish a good relationship with the patient to guarantee the prompt treatment intensification, the evaluation of adherence and the monitoring of the adverse events. Second, they may partially treat the patient's inertia to implement long-term lifestyle changes. Missing BP reduction because of patients’ resistance to lifestyle changes is ‘perfectly’ counterbalanced by potentiated combination treatments, like the triple-drug combinations. Triple-drug combinations in a single pill may also ‘treat’ the economic hardship at patient and health system level, as these are associated with a beneficial cost–effectiveness ratio. Finally, as triple-drug combinations in our hands today were developed at least 10 years ago by the pharmaceutical companies , their market penetrance compared with monotherapies or double combinations is expected to display an increase especially after the latest ESC/ESH guidelines release .
After single-pill triple-drug combinations, the future of hypertension treatment by drugs may also include a single-pill quadruple-drug combination regimen (even at minimal doses) , whereas the use of aldosterone-receptor antagonists may be anticipated earlier before the development of the resistant hypertension phenotype . However, doctors treating hypertensive patients should not only always consider the available or forthcoming antihypertensive potentiation but should also reflect on the opposite direction, that is, on how a pharmacological treatment de-escalation can be achieved in separate patients. Still remains questionable whether renal sympathetic denervation may have a role toward treatment de-escalation , but as pointed out in previous sections of the present report, lifestyle changes should not be disregarded. Educational interventions at national health system level under the guidance of internationally relevant medical Societies, like the European Society of Hypertension, may play an important role to increase hypertension awareness and early diagnosis of the disease. Treatment and control of hypertension before hypertension-related organ damage development may reduce antihypertensive polypharmacy and less than three drugs can effectively control BP within goal. Until then, triple-drug combination antihypertensive treatments should replace dual-drug combinations whenever patients remain uncontrolled [1,2].
Conflicts of interest
C.T. reports grants and personal fees from Sanofi, Servier, Menarini, MSD, Innovis, Astra Zeneca, and Boehringer-Ingelheim, all outside the area of work reported here. H.M. and T.M. declare no competing interests.
1. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M, et al. ESC Scientific Document Group. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J
2. 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
3. Messerli FH, Bangalore S, Schmieder RE. Wilder's principle: pretreatment value determines posttreatment response. Eur Heart J
4. Thomopoulos C, Parati G, Zanchetti A. Effects of blood pressure lowering treatment in hypertension: 8. Outcome reductions vs. discontinuations because of adverse drug events - meta-analyses of randomized trials. J Hypertens
5. Hirakawa Y, Arima H, Rodgers A, Woodward M, Chalmers J. Cumulative in-trial and posttrial effects of blood pressure and lipid lowering: systematic review and meta-analysis. J Hypertens
6. Wald 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
7. Chalmers J, Arima H, Woodward M, Mancia G, Poulter N, Hirakawa Y, et al. Effects of combination of perindopril, indapamide, and calcium channel blockers in patients with type 2 diabetes mellitus: results from the Action In Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) trial. Hypertension
8. Law MR, Wald NJ, Morris JK, Jordan RE. Value of low dose combination treatment with blood pressure lowering drugs: analysis of 354 randomised trials. BMJ
9. Thomopoulos C, Katsimagklis G, Archontakis S, Skalis G, Makris T. Optimizing the management of uncontrolled hypertension: what do triple fixed-dose drug combinations add? Curr Vasc Pharmacol
10. Kario K. Proposal of RAS-diuretic vs. RAS-calcium antagonist strategies in high-risk hypertension: insight from the 24-h ambulatory blood pressure profile and central pressure. J Am Soc Hypertens
11. Chalmers J, Harrap S, Narkiewicz K, Poulter N, Redon J, Zanchetti A, Mancia G. Issues in the development of new combinations of blood pressure lowering drugs. J Hypertens
12. Chow CK, Thakkar J, Bennett A, Hillis G, Burke M, Usherwood T, et al. Quarter-dose quadruple combination therapy for initial treatment of hypertension: placebo-controlled, crossover, randomised trial and systematic review. Lancet
13. Bazoukis G, Thomopoulos C, Tsioufis C. Effect of mineralocorticoid antagonists on blood pressure lowering: overview and meta-analysis of randomized controlled trials in hypertension. J Hypertens
14. Tsioufis C, Ziakas A, Dimitriadis K, Davlouros P, Marketou M, Kasiakogias A, et al. Blood pressure response to catheter-based renal sympathetic denervation in severe resistant hypertension: data from the Greek Renal Denervation Registry. Clin Res Cardiol