There is no gold standard in the assessment of patient adherence to treatment, and several methods probably must be combined to improve diagnostic precision. In general, a physician's prediction regarding their patients' treatment adherence is poor., However, technological progress has provided novel insights into the assessment and management of treatment nonadherence. Ultraperformance liquid chromatography-tandem mass spectrometry became an accurate and practical tool to monitor treatment adherence in both research and clinical settings. Studies based on this method have shown that low adherence to the prescribed medications can affect up to 50% of patients with apparently resistant hypertension. A substantial proportion of these patients are completely noncoherent. There is a clear association between the degree of treatment nonadherence and both office and ambulatory blood pressure values. Importantly, the results of direct nonadherence tests do not overlap with self-reported adherence questionnaires, indicating a poor reliability of nondirect methods. 

Nonadherence to antihypertensive treatment has been constantly linked to a higher risk of cardiovascular events. A meta-analysis that included nearly 2 million participants has shown that high treatment adherence is associated with a 29% relative risk reduction in all-cause mortality. Thus, the benefits reported in clinical trials are reproduced in real-life patients only when there is treatment compliance.

Both previous and recent studies identified several factors associated with poor treatment adherence. Patient-related predictors include young age, early phase of treatment, female sex, low educational level, low income, unemployment, and comorbidities, such as depression., Nonadherence is also strongly affected by treatment-related factors, such as the choice of drug class and the dosing regimen. In a recent study based on mass spectroscopy measurements, the prevalence of nonadherence to blood pressure-lowering treatment was directly related to the number of antihypertensive pills. While treatment nonadherence among those who were prescribed one antihypertensive drug was minimal, its prevalence increased to more than 40% among patients who were prescribed three or more drugs. This phenomenon was observed independently of basic demographics and the classes of prescribed antihypertensive drugs, thus supporting the need for treatment simplification.

Patient adherence can be improved by using an appropriate treatment and follow-up regimen,, which might be achieved by: (i) choosing effective drugs with a favorable safety profile and monitoring possible drug-related adverse events; (ii) avoiding complex dosing schedules; (iii) using single-pill combinations when combination therapy is required; (iv) self-monitoring of blood pressure, including electronic transmission of recorded home values; and (v) using motivational interviewing and coaching. Interestingly, repeated screenings for treatment non-adherence based on direct methods might have a therapeutic value per se. Such an approach might improve treatment adherence and blood pressure control.

The role of treatment nonadherence as a potential cause of poor blood pressure control is clearly underestimated. Recent evidence suggests that true resistant hypertension is much less frequent than previously thought. Therefore, an evaluation of treatment adherence should become an integral part of the assessment of all patients with difficult-to-manage hypertension., Whenever we face a patient with apparently resistant hypertension, we should always pose a key question: is it treatment resistance or treatment nonadherence? Importantly, early recognition of poor treatment adherence might reduce the number of costly investigations and procedures, including interventional treatments. 10 Hopefully, the assessment of treatment adherence will be improved further with cheaper and more reliable methods that could be applied in daily practice. Further research is needed to improve our understanding of the psychological and social mechanisms that underlying treatment nonadherence. Finally, we have to develop structured programs for patients who are nonadherent to their treatment. Such an approach, which is focused on understanding the practical difficulties and perceptions affecting the motivation to adhere, might help physicians achieve target blood pressure values. Whether such interventions improve cardiovascular outcomes remains to be tested in clinical trials.