Poor adherence to hypertension therapy has been associated with cardiovascular and metabolic complications, increased healthcare expenditures, and death [1]. The evaluation of adherence to the treatment includes direct and indirect measurement methods, although there is no gold-standard method to measure medication adherence. Numerous variables can influence the follow-up of these patients and especially their willingness to follow recommended therapies. Other variables may involve personal motivations, factors related to the staff following up patients, organizational factors, and factors related to the therapy itself. All these factors are described as Hawthorne effect and must be considered for possible bias in the studies of hypertension [2]. The Hawthorne effect refers to the set of changes in a phenomenon, or behavior, that occur because of the presence of observers, but do not last over time.

Peeters and collaborators [3] compared two types of approaches to evaluate resistant hypertension (RH): one based only on standard care (SoC) and the other one based on SoC plus an intervention, consisting in the evaluation of antihypertensive drugs (AHD) concentrations using a dried blood spot (DBS) sampling method. This randomized controlled trial included patients with established RH based on a 24-h arterial blood pressure (BP) measurement. The Authors reported the results after 3- and 12-months evaluation and found a significant improvement in both RH and BP in the intervention + SoC arm and SoC alone arm and a significant difference in AHD adherence between the arms after 12 months of follow-up. No differences were determined in the prevalence of RH or BP values between the intervention + SoC arm and the SoC arm after 12 months. Given that most patients had uncontrolled BP for years before participation, the Authors reported that it is highly unlikely that the observed improvements would have been achieved without their participation in this study and concluded that personalized feedback conversations improved AHD adherence, but did not reduce the prevalence of RH.

The study evaluated AHD adherence with an accurate assessment and its effect on BP reduction was larger compared to most other intervention trials [4]. Personalized feedback conversations based on DBS-derived AHD concentrations improved AHD adherence, but did not reduce the prevalence of RH compared with the SoC group. A recent study evaluated RH-related problems and concluded that nonadherence to AHD must be excluded before RH is diagnosed [5]. The reduction of RH cases after the two evaluation approaches might suggest that more precise initial diagnosis is necessary for RH. In the study of Peeters [3], most patients had uncontrolled BP for years before participation, but the nonadherence was not evaluated before the study. The study shows that both types of evaluation improve compliance to AHD by making patients both aware of the usefulness of therapy and more adherent because of the knowledge that their BP and therapy will be monitored. This type of control, on the other hand, did not show a difference on the prevalence of RH after 12 months unlike after 3 months. The Authors calculated the defined daily dosage (DDD) for each used AHD, and they found that the DDD of AHD decreased in the intervention + SoC arm. This factor is important considering that both assessment methods showed a reduction in RH cases, but the difference was not statistically significant. The AHD has a role in the BP values, but other factors may influence the pressure measurement, such as the ‘white-coat effect’ and the possible stress associated with measurement, especially in patients who had not followed therapy exactly and who feared being caught at the visit [5]. An important factor to evaluate is the difference between men and women. It is known that pressure values and response to therapy are gender-different and a separate evaluation would have been useful in the actual study, since the percentage of males was higher. Since most of the patients were obese, the value of body mass index (BMI) varies in the sexes and perhaps the awareness of the importance of therapy is greater in females. Almost all the patients were also taking diets and other therapies in addition to AHD, and it cannot be ruled out that such therapies could be assessed during the BP evaluation in the two groups of patients. For example, statins, metformin, a low-calorie diet can induce a reduction in BMI, BP and in the dosage of medications. Although the difference was not significant in the two groups, it cannot be ruled out that the BP response and thus the prevalence of RH could have changed. For example, in diabetic patients with renal failure, the diabetic therapy could have improved renal function and consequently BP values and induced adjustment of AHD. Evaluation of RH must also take into account the initial diagnosis, considering that a significant proportion of patients with RH have primary hyperaldosteronism (PA). In this case, therapy must be targeted including mineralocorticoid receptor blockers, which have been considered in the measurement of AHD, but may not have been used in undiagnosed cases of PA making hypertension resistant. Patients with PA are erroneously considered RH when not treated with mineralocorticoid receptor blockers. The Authors have included of spironolactone in the AHD measurement, but there is no information of the prevalence of PA. Finally, other points to be considered are:

1. the patients do not only get their information from physicians, but almost always give importance to personal web searches and many sites provide inaccurate or even counterproductive information. This aspect also reduces the confidence in doctors. An important finding supporting the value of this study was the detection of DBS on a drop of blood; however, a possible limitation of this minimally invasive method is that it detects the presence or absence of the drugs, but not their concentration. The half-life of the drugs and consequently the distance since the last administration could make some drugs with short half-lives nondetectable; 2. patients with reduced AHD adherence might be interested in hiding compliance by taking the appropriate therapy only in the previous days, and thus the values found might be affected by this behavior; 3. average number and amount of drugs used in RH is elevated, demonstrating the complexity of patients’ clinical pictures and the concomitance of other diseases that perhaps make patients more aware of the various associated problems by improving medication adherence.

In conclusion, personalized feedback conversations based on DBS-derived AHD concentrations improved AHD adherence, but did not reduce the prevalence of RH. The study shows that any method of informing the patient can be useful to improve the compliance in patients with RH. Future studies on RH should consider the presence of associated metabolic factors (obesity, insulin resistance, associated endocrine dysfunction), the careful evaluation of all causes of secondary hypertension, and the possible influence of associated therapy in the treatment of RH.

ACKNOWLEDGEMENTS

Disclosure Statement: The authors have nothing to disclose.

Conflicts of interest

There are no conflicts of interest.

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