International Journal of Hypertension mechanism of hypertension with these drugs [72–74]; pre- liminary studies in humans reported similar ﬁndings [75, 76]. Finally, enhanced arterial stiﬀness has been suggested as another contributing factor in the development of hyperten- sion [77]. The recognition of the pathogenetic mechanisms that contribute to blood pressure elevation with VEGF-inhibitors might be helpful in identifying the most appropriate drugs for the management of these patients. Reliable data evalu- ating the eﬃcacy of the various antihypertensive drug cate- gories in anti-VEGF-induced hypertension are missing. Pre- liminary reports point towards restricted eﬃcacy of diuretics [78] and beneﬁcial eﬀects of calcium antagonists [79]; how- ever, appropriate prospective studies are needed in this topic. 5. Obstructive Sleep Apnea A vast amount of evidence demonstrates an association between obstructive sleep apnea (OSA) and hypertension. Such an association has been shown in epidemiological, longitudinal, and cross-sectional studies, as well as in studies from specialized clinics [80–83]. In addition, it has been shown that OSA in normotensive subjects predicts future development of hypertension. Sympathetic nervous system activation plays a crucial role in the pathogenesis of hypertension in patients with OSA. Enhanced upper airway resistance and intermittent hypoxia are considered to stimulate the sympathetic system, while the subsequent sympathetic overactivity may result in blood pressure elevation via vasoconstriction and increased systemic vascular resistance, increased cardiac output, and enhanced ﬂuid retention. Aldosterone seems to be the other signiﬁcant player in this ﬁeld. Increased aldosterone levels have been observed in OSA patients with resistant hyperten- sion. The exact nature of the association between OSA and aldosterone excess remains to be elucidated. Whether OSA results in aldosterone excess or aldosterone excess contributes to OSA, or another underlying factor (like obesity) promot- ing both aldosterone excess and OSA has not been clariﬁed. Several studies have reported an extremely high preva- lence of OSA in patients with resistant hypertension. Two decades ago, a Swedish study of 16 patients with resistant hypertension reported a 56% prevalence of OSA in these patients compared to 19% in patients with controlled hyper- tension [84]. In a study of 41 consecutive resistant hyper- tensives, an 83% prevalence of unsuspected OSA was found; OSA was deﬁned as an apnea/hypopnea index (AHI) of more than 10 events per hour [85]. Another study of 71 patients with resistant hypertension revealed an 85% prevalence of OSA (AHI ≥ 5 events/h) [86]. A study from Spain in 62 resistant hypertensives reported a 90% prevalence of OSA (AHI ≥ 5 events/h) [87]. However, when the diagnosis of OSA was based on 30 or more episodes of apnea/hypopnea per hour, the prevalence was reduced to 70%, underlining the importance of accurate and homogeneous deﬁnition of OSA. Moreover, all the above-mentioned recent studies did not have a control group in order to exclude the potential eﬀects of confounding factors. A recent study from Brazil 5 evaluated 63 patients with resistant hypertension and an equal number of patients with controlled hypertension, matched for baseline parameters apart from blood pressure [88]. A strong and independent association between OSA and resistant hypertension has been described (odds ratio: 4.8; 95% CI: 2.0–11.7); OSA (AHI ≥ 10 events/h) in 71% of resistant hypertensives and in 38% of responders. Continuous positive airway pressure (CPAP) represents the treatment of choice for patients with OSA. It has been shown that CPAP decreases the incidence of cardiovascular events in patients with OSA [89, 90].The acute application of CPAP attenuates blood pressure elevations during sleep [91]. However, the long-term eﬀects of CPAP on blood pres- sure are controversial, from studies reporting a signiﬁcant decrease in blood pressure to studies reporting small or no eﬀects [92–106]. Three meta-analyses have tried to overcome these discrepancies and revealed that the beneﬁcial eﬀect is modest, with reductions in systolic blood pressure ranging from 1.38 mmHg to 2.46 mmHg [107–109]. It is, therefore, not surprising that in a recent randomized study, valsartan was more eﬀective than CPAP in hypertensive patients with OSA [110]. It has to be noted, however, that most of the above- mentioned studies have not been performed exclusively in hypertensive patients, usually evaluating both normotensive and hypertensive subjects. In addition, larger blood pressure reductions were observed in OSA patients with higher baseline blood pressure levels [107, 111], as expected with any antihypertensive approach; the motto “the higher the blood pressure, the larger the reduction” has been veriﬁed over the years. Indeed, two small studies in OSA patients with resistant hypertension revealed signiﬁcant blood pressure reductions (over 10 mmHg) [112, 113]. On the contrary, a study in 42 patients with resistant hypertension showed a smaller mean arterial pressure reduction (5.6 mmHg; 95% CI: 2.0–8.7 mmHg; P < .03) [114]. Interestingly enough, the beneﬁts of CPAP were evident only at 1-year after CPAP application, suggesting that longer followup periods might be necessary for the beneﬁts of CPAP treatment to become apparent in OSA patients with resistant hypertension. Another important factor is that CPAP treatment allowed de-escalation of antihypertensive treatment in the majority of participating patients (71%) [114]. A recent study in 96 patients with OSA and resistant hypertension showed a slight decrease in systolic blood pressure (1.3 mmHg) [115]. However, the reduction was signiﬁcantly larger in patients with ABPM-conﬁrmed resistant hypertension (7.6 mmHg). In addition, the reduction was even larger in CPAP users for more than 5.8 hours per day. The above-mentioned data delineate the complexity in identifying patients with resistant hypertension and OSA that will have the greater beneﬁts with CPAP treatment. An important issue challenging the eﬃcacy of CPAP relates to patient adherence. Among patients prescribed CPAP therapy up to 50% failed to initiate it or did not use it at 3 years [116, 117]. Moreover, among CPAP users, 29–83% used it for less than 4 hours [118]. Another important aspect of treatment is the choice of antihypertensive drugs in patients with OSA. The crucial role