According to international guidelines, RHT is defined as uncontrolled blood pressure – i.e., failure to lower blood pressure to a pre-defined threshold – despite concurrent administration of three antihypertensive therapies of different pharmacological classes at maximal or optimal doses, including a diuretic.

The diagnosis of true RHT (vs. apparent RHT) requires appropriate methodology to measure blood pressure in order to eliminate white-coat effects, as well as clinical expertise to exclude secondary causes of hypertension, avoid poor medication dosage and/or selection and insufficient therapeutic adherence.

The estimated prevalence of true RHT varies from 2% to 30% of the hypertensive population. This unusually broad range is mainly due to the different sources of information, e.g., insurance healthcare system, registries, specialized centers, or controlled clinical trials. A more realistic, consensual estimate is in the order of 5% of the hypertensive population.

The risk of cardiovascular events in RHT patients is higher than in the global hypertensive population. This has been demonstrated in different settings (i.e., clinical trials, observational studies, and international registries) comparing RHT versus non‑RHT patients with adjustment for patient and clinical characteristics, i.e., level of control of blood pressure, gender, presence of chronic kidney disease, and/or diabetes mellitus.

Compared to the hypertensive population, RHT patients are more likely to be older (> 75 years), of black race, and to have higher body mass index, albuminuria, reduced renal function, and medical histories of diabetes mellitus, coronary heart disease, heart failure, stroke, and sleep apnoea. Chronic kidney disease and diabetes mellitus in particular, amplify the RHT patients’ vulnerability and increase the complexity of RHT treatment.

The RHT population is, by definition, on a background therapy of three drugs (usually A + C + D) at maximal or optimal dose, where, according to most clinical guidelines, “A” is always an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB), and “D” is always a long-acting thiazidic diuretic. “C” stands for a calcium channel blocker (CCB), which is the most commonly used type of third background agent in RHT. However, individualization therapy is needed for some patients, such as those with ischemic heart disease, who may then use a beta-blocker (A + B + D) instead of a CCB as a third agent.

As for RHT patients, blood pressure remains uncontrolled despite the third-therapy step mentioned above, the generally recommended therapeutic approach for the fourth antihypertensive medication is to add a drug with a different mechanism of action, compared to the three medications already prescribed. These includes well-known therapeutic antihypertensive classes such as mineral corticoid receptor antagonists or beta blocker, if not previously used. These therapies have their own limitations though and are associated with adverse effects that often lead to discontinuation of therapy, which reinforces the medical need for new treatment options in resistant hypertension.