Combination treatment in hypertension – the latest 2013 European Guidelines

An updated 2013 version of the European Hypertension Guidelines is now jointly issued by the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) (1,2). Importantly, the 2013 ESH/ESC Guidelines are updated from an evidence-based perspective including novel and relevant research on diagnostic methods and outcome studies. The ESH/ESC risk score algorithm is harmonized with the SCORE risk assessments, which are further translated into treatment recommendations. More emphasis is also put on the importance of detecting target organ damage. Ambulatory and home blood pressure (BP) assessments are highlighted and more strongly recommended and integrated as supplementary assessments to office BP measurements in the overall risk evaluation and management of the hypertensive patient (1).

Current guidelines recognize that, in hypertension management, mono-therapy can only satisfactory reduce BP in a limited portion of hypertensive patients. It is therefore well recognized that the majority of patients require combinations of antihypertensive drugs to reach BP control levels. Today, the question is not whether combination therapy should be used, but whether combination therapy may be considered the initial approach.

Although the 2013 ESH/ESC Guidelines clearly point out potential advantages when mono-therapy is given as initial treatment, there are also several possible disadvantages. For example, finding a proper combination treatment may be time consuming and may retard reaching treatment goals. This may reduce and delay adherence in the individual patient. Most importantly, however, is that numerous studies (1) have confirmed that combining two different antihypertensive agents from different classes improves BP reduction over and above increasing doses of a single agent (1,3). Thus, the advantage of initiating antihypertensive management in patients directly with a proper combination strategy is that response is achieved in a larger number of risk patients, there is a greater chance to achieve appropriate target BP in patients and adverse effects may be tolerable and compliance improved (1). There may also sometimes be reasons to recommend initial fixed-dose combination treatment from a cost perspective, as it is often attractive for the individual patient as well as for society in general.

There are yet only indirect data available from randomized trials in respect to what extent specific drug combinations may affect cardiovascular outcomes. In only a few outcome studies have two-drug combinations been given initially: an angiotensin-converting enzyme (ACE) inhibitor and diuretic combination, a calcium antagonist and diuretic combination, and finally an ACE inhibitor in combination with either a diuretic or a calcium antagonist (see (1) for references). In all other trials, treatment was initiated as mono-therapy and then followed by adding another drug (s) if the BP response was not satisfactory.

Based on the available evidence, the 2013 ESH/ESC Guidelines recommend a combination strategy using an angiotensin-receptor blocker or an ACE inhibitor in combination with a calcium antagonist or a thiazide diuretic (Figure 1). A calcium antagonist and diuretic combination may also be given as a potential preferred choice.

Figure 1. Combination strategies for antihypertensive drugs, as illustrated in the recent 2013 ESH/ESC Guidelines. The green continuous lines outline preferred combinations; the green dashed line indicates a potentially useful combination (with some limitations). Black dashed lines outline possible but less well-tested combinations, and finally the red continuous line show a combination not recommended.

However, a beta-blocker–diuretic combination appears to elicit more cases of new-onset diabetes in susceptible individuals, and furthermore, a combination of two different blockers of the renin– angiotensin system (RAS; usually being an ACE inhibitor and an angiotensin receptor blocker) are not recommended due to the risk of unfavourable outcomes (1).

To be noted also is that the 2013 ESH/ESC Guidelines favour recommendation of combinations of two antihypertensive drugs at fixed doses in a single tablet.

Thus, the 2013 ESH/ESC Guidelines more strongly recommend the initial use of free and fixed combinations in order to facilitate and improve early treatment in hypertension.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.