4 The above presented information clearly indicates that available data on the eﬀects of NSAIDs on blood pressure are sometimes contradictory and in total far from conclusive. Convincing data coming from carefully designed random- ized studies are necessary to: (a) detect potential diﬀerences between the various NSAIDs on blood pressure, (b) clarify the eﬀects of coadministering each NSAID with each one of the various antihypertensive drug categories, and (c) identify predictors of blood pressure response to NSAIDs use. Withdrawal of NSAIDs is indicated in patients with resistant hypertension, exacerbation of prior hypertension, or incident hypertension. Substituting NSAIDS with acetam- inophen can usually solve the problem. Pain relief is more likely in patients with osteoarthritis and pain of muscular skeletal origin. However, this is not always possible in every- day clinical practice, since patients with chronic inﬂamma- tory arthritic diseases (rheumatoid arthritis) respond better to anti-inﬂammatory agents. In such cases, hydrocodone, tramadol, or nerve blocking might be of help, constituting eﬀective alternatives to NSAIDs. In cases, however, where NSAIDs are still necessary, the lower eﬀective dose should be administered, since existing data point towards dose-related eﬀects of NSAIDs on blood pressure. NSAIDs aﬀect blood pressure levels via diﬀerent mech- anisms: activation of the renin-angiotensin-aldosterone sys- tem, sodium and water retention, induction of vasoconstric- tion through endothelin-1 and arachidonic acid metabolites, and mainly inhibition of renal vasodilatory prostaglandins (E2 and I2) [37–43]. These detrimental eﬀects of NSAIDs may lead to deterioration of renal function and acute kidney injury, especially in patients of older age, preexisting hypertension, chronic kidney disease, or diabetes. In such patients, calcium antagonists seem to be more suitable than drugs inhibiting the renin-angiotensin system, since the concomitant administration of NSAIDs and calcium antagonists is not accompanied by blood pressure elevation [36, 39]. The development of NSAIDs that apart from cyclo- oxygenase inhibition possess nitric oxide promoting prop- erties might signiﬁcantly ameliorate current situation and alleviate the eﬀects of NSAIDs on blood pressure. CINODs (Cyclo-oxygenase Inhibiting Nitric Oxide Donating drugs) represent a new class of NSAIDs; CINOD molecules consist of a traditional NSAID and a nitric oxide-donating chemical group connected by a linker. Naproxcinod is the ﬁrst CINOD in clinical trials with very promising preliminary results [44–47]. 4.2. Oral Contraceptives. Oral contraceptives represent another class of drugs that are widely used and are capable of inducing hypertension [48, 49]. The larger study evaluating the eﬀects of oral contraceptives on blood pressure was the Nurses’ Health Study, in which more than 60,000 normoten- sive women were prospectively followed for 4 years [50]. Women using oral contraceptives had an 80% higher risk of developing hypertension compared to women that were not using such drugs. However, withdrawal of oral contraceptives abolished this increased risk, underlining the need for close monitoring in women taking oral contraceptives. Another International Journal of Hypertension important aspect of “pill”-induced hypertension regards the contribution of oral contraceptives in uncontrolled hyper- tension. A study in hypertensive women revealed that those taking oral contraceptives had more severe hypertension and lower blood-pressure control rates than women using other contraceptive methods [51]. The type of oral contraceptives seems also to be of clin- ical importance. Combined oral contraceptives (progestin and estradiol), which were widely used in the past, were associated with blood pressure elevations more frequently than progestin-only oral contraceptives. On the contrary, drospirenone (a fourth generation progestin) reduces blood pressure when combined with estradiol [52]. Therefore, current guidelines recommend the use of progestin-only oral contraceptives in women with established cardiovascular disease, or major cardiovascular risk factors (such as hyper- tension) [53, 54]. It can, therefore, be summarized that oral contraceptives may contribute to resistance in hypertensive women, but the type of oral contraceptive is important. Close monitoring of women and withdrawal of oral contraceptives may alleviate the eﬀects on blood pressure. 4.3. Anti-VEGF Agents. Another class of agents that emerged as inducers of hypertension are the antineoplastic drugs that target the VEGF pathway. A monoclonal antibody (bevacizumab) binding to the VEGF-A isoform, as well as small molecules inhibiting the intracellular tyrosine kinase domains of all three VEGF receptors, is used or is under clinical testing for the treatment of various malignancies [55–57]. Hypertension was encountered very frequently in patients receiving treatment with VEGF-inhibitors [58]. In particular, 20–30% of patients treated with bevacizumab, and 15–60% of patients treated with VEGF kinase inhibitors developed hypertension [59]. Three meta-analyses with drugs inhibiting the VEGF pathway uncovered a high relative risk for incident hypertension with these agents: 7.5 (95% CI: 4.2–13.4) with bevacizumab, 6.11 (95% CI: 2.44–15.32) with sorafenib, and 21.6 (95% CI: 18.7–24.8) with sunitinib [60– 62]. Interestingly enough, the development of hypertension has been correlated with the eﬃcacy of these drugs [63–65], suggesting that hypertension could be used as a surrogate marker of anti-VEGF eﬃcacy. A phase III trial evaluates this concept in patients with pancreatic cancer receiving anti- VEGF agents. Clearly, more data are needed to clarify the blood pressure eﬀects of the various drugs acting on the VEGF pathway. Experimental studies have shown that VEGF upregulates endothelial nitric oxide synthase [66, 67], enhances nitric oxide production [68], and induces nitric oxide-dependent vasorelaxation [69]. Moreover, VEGF was shown to result in enhanced prostacyclin production and release [70, 71]. It can be therefore anticipated that VEGF inhibition may lead to reduction of nitric oxide and prostacyclin bioavail- ability, a subsequent increase of systemic vascular resistance, and ﬁnally blood pressure elevation. In addition, arteriolar rarefaction has been observed in animals treated with VEGF kinase inhibitors, proposing another pathogenetic