The 2018 ESC/ESH and the 2020 ISH guidelines for the management of hypertension proposed that initial combination therapy with two antihypertensive agents in a single-pill combination (SPC) is preferred in most patients in need of blood-pressure (BP) lowering treatment and should replace the long-standing concept of starting treatment with a single agent, rotating through antihypertensive drug classes, and next moving towards combining drug classes. The 2019 Japanese guidelines took a more balanced approach in formulating their recommendation for the use of SPCs. The Japanese document states that when a systolic/diastolic BP decrease of 20/10 mmHg is targeted, combination therapy is an option to be considered in starting treatment. However, the Japanese guideline also recommended that if a drug shows only a weak depressor effect or is poorly tolerated, it must be replaced by another agent with a different mechanism of action, implying that starting with SPCs is not mandatory.
By moving SPCs forward as the initial BP lowering strategy, the ESC/ESH and ISH guideline committees overlooked several vested principles in hypertension management: (i) understanding the pathophysiology of hypertension; (ii) prioritizing evidence from randomized clinical trials above observational studies and expert opinion; and (iii) giving consideration to the cost-effectiveness of antihypertensive drug treatment and the sustainability of health care. This article addresses these points. Sources of information included: (i) guidelines issued by European, American, International, British and Japanese Expert Committees, published between 1999 and 2020; (ii) a PubMed search with as terms in the abstract or title hypertension combined with fixed combination OR hypertension combined with single and costs; (iii) the placebo-controlled trials of antihypertensive drug treatment; (iv) three randomized controlled trials of usual versus intensive BP control; and (v) the retail costs of antihypertensive drugs.
We propose that starting antihypertensive therapy in treatment-naive hypertensive patients might be based on a few simple principles. First, use antihypertensive drugs with different modes of action. Second, use antihypertensive agents with a long duration of action based on their molecular structure, so-called forgiving drugs, rather than extended-release dosage formulations. Third, titrate each drug to the highest dose that does not produce adverse effects. Fourth, include a thiazide in the drug combination. Finally, once the right combination has been found by rotating through and combining drug classes as well as the timing of dosing, stimulate adherence by reducing the pill load by prescribing of SPCs including 2 or 3 antihypertensive agents in adjustable doses.