International Journal of Hypertension widely used, represent the most common causes of drug- induced hypertension, and are thus of major clinical impor- tance: nonsteroidal anti-inﬂammatory drugs (NSAIDs) and oral contraceptives. In addition, a brief comment regard- ing speciﬁc antineoplastic agents (anti-VEGF) that have emerged as inducers of hypertension is presented at the end of this chapter, since many clinicians are not aware of this condition. 4.1. NSAIDs-Induced Hypertension. By far, the most com- mon cause of drug-induced hypertension is the use of NSAIDs. In 265 patients with resistant hypertension identi- ﬁed during a one-year period, treatment resistance was drug- related in 36% of the cases, with NSAIDs being responsible in 88% (personal unpublished data). Osteoarthritis is highly prevalent in the general population, and its prevalence would be even greater due to population aging and the obesity epidemic [11, 12]. Osteoarthritis and hypertension often coexist, since both conditions are age related. It has been reported that approximately 50% of patients with osteoarthritis suﬀer from hypertension [13]. Although lifestyle modiﬁcation, exercise, and weight loss are con- sidered as ﬁrst-line therapeutic measures for patients with osteoarthritis, the vast majority of such patients require the systematic or intermittent use of either acetaminophen or NSAIDs for pain relief. Data regarding the eﬀects of NSAIDs on blood pressure continue to accrue. Two large prospective cohort studies in normotensive women reported higher risks of subsequent hypertension among NSAIDs users than in women without regular NSAIDs administration [14, 15]. In the ﬁrst study, the risk of developing hypertension was increased about two times in women using acetaminophen or NSAIDs [14]. Acetaminophen consumption for 1–4 days per month and NSAIDs consumption for 5–14 days per month was necessary for the risk to be apparent. In the second study, women with frequent use of nonnarcotic analgesics (>22 days/month) had statistically signiﬁcant higher risk for developing hypertension; in particular, the hazard ratios were 1.20 for acetaminophen, 1.21 for aspirin, and 1.35 for NSAIDs [15]. It has to be noted that although acetam- inophen is considered to have a better safety proﬁle than NSAIDs [16, 17], its use was associated with a moderate increase in the risk for incident hypertension in both males and females [18, 19]. Another large, case-control study revealed a 66% increased risk for initiating antihypertensive drugs in NSAIDs users compared to nonusers [20]. These detrimental eﬀects of NSAIDs on blood pressure have been also observed in two older meta-analyses of randomized trials with NSAIDs [21, 22]. In the ﬁrst meta-analysis, mean arterial pressure was increased by 3.3 mmHg in hypertensive patients whereas the increase in normotensive subjects was negligible (1.1 mmHg) [21]. In the second meta-analysis, NSAIDs resulted in a signiﬁcant mean arterial pressure ele- vation of 5.0 mmHg; blood pressure elevation was apparent in hypertensive patients with controlled blood pressure, whereas normotensive individuals did not experience such an eﬀect [22]. 3 On the contrary, data reporting no or little eﬀect of NSAIDs on blood pressure exist in the literature as well. In two cross-sectional studies, no association between use of NSAIDs and hypertension was found [23, 24]. Similar ﬁndings were observed in two small randomized studies re- garding the eﬀects of acetaminophen on blood pressure [25, 26], as well as in studies evaluating the eﬀects of aspirin on blood pressure in hypertensive patients [27, 28]. In addition, in a large prospective cohort of 8,229 male normotensive physicians, analgesic use was not associated with increased risk of developing hypertension (hazard ratio: 1.12; 95% CI: 0.97–1.31) [29]. The corresponding hazard ratios were 1.08 (95% CI: 0.87–1.34) for acetaminophen, 1.16 (95% CI: 0.92–1.48) for aspirin, and 1.05 (95% CI: 0.89–1.24) for NSAIDs. This apparent heterogeneity of available data on the eﬀects of traditional NSAIDs on blood pressure becomes even more complicated when recent data with selective COX- 2 inhibitors are taken in account. In a meta-analysis of randomized trials, use of COX-2 inhibitors was associated with a signiﬁcant increase in blood pressure compared to placebo (3.85/1.06 mmHg) and nonselective NSAIDs (2.83/1.34 mmHg) [30]. However, it was shown that a great part of blood pressure elevation could be attributed to rofecoxib. Indeed, rofecoxib use is associated with greater blood pressure elevations than celecoxib in both hypertensive and normotensive individuals [31]. The above-mentioned study highlights another impor- tant aspect: the potential diﬀerences on blood pressure eﬀects between the various NSAIDs. In a meta-analysis of randomized trials, conducted mainly in hypertensive patients, naproxen and indomethacin were associated with the largest blood pressure elevations, while piroxicam, sulin- dac, ibuprofen, and aspirin exhibited little if any eﬀect on blood pressure [21]. On the contrary, a randomized study in patients with controlled hypertension showed that the blood pressure was signiﬁcantly higher with ibuprofen than with lumiracoxib [32]. Moreover, in 34,701 participants at the MEDAL (Multinational Etoricoxib and Diclofenac Arthritis Long term) program, patients assigned to etoricoxib discon- tinued the study due to hypertension more frequently than patients randomized to diclofenac [33]. Finally, the potential diﬀerences of the eﬀects of NSAIDs on blood pressure according to the various antihypertensive agents coadministered are of great clinical importance. In a study of elderly hypertensives with osteoarthritis, indo- methacin had no eﬀect on blood pressure in patients tak- ing calcium antagonists whereas signiﬁcant blood pressure elevations were detected in patients taking ACE-inhibitors [34]. On the contrary, celecoxib exerted similar to placebo eﬀects in patients taking ACE-inhibitors [35]. Another study among hypertensive patients with osteoarthritis, comparing the eﬀects of rofecoxib and celecoxib, revealed no differen- ces on blood pressure between the two drugs in patients taking diuretics or calcium antagonists, whereas larger blood pressure elevations were observed with rofecoxib than with celecoxib in patients taking ACE-inhibitors or beta blockers [36].