Resistant hypertension: a therapeutic challenge

In 2008, the American Heart Association published resistant hypertension (RH) guidelines.1 Since that year, there has been a lot of research regarding the relevance of making a proper diagnosis and choosing the best treatment. In recent years, there has been an increasing interest in RH because uncontrolled RH is a pathological condition with a poor prognosis. In this regard, it is important to follow steps with the purpose of ruling out pseudoresistant hypertension and then excluding secondary causes. Suboptimal drug therapy, poor adherence to medications, white-coat effect, and inaccurate BP measurement are the most prevalent causes of pseudoresistant hypertension. The prevalence of RH from secondary causes is approximately 20% of all cases of RH, the most prevalent being primary aldosteronism, renal parenchymal diseases, and the use of certain medications. Therefore, it is important to include the following tools in the diagnosis for the exclusion of false RH: ambulatory blood pressure monitoring,2 home blood pressure monitoring, detection of nonadherence, reviewing the therapeutic plan following guideline suggestions,3, 4 and taking care in blood pressure measurement.5 Physicians have little awareness about low adherence, especially because there are no gold standard methods for its evaluation, but the biochemical detection of medication in blood or urine seems to be the most accurate and cost-effective method at follow-up.6, 7 This was the algorithm followed by the investigators of the DENERVE HTA (Denervación en Hipertensión Arterial) trial published in 2016.8 It is difficult to establish the actual prevalence of true RH. Some series have reported a variable prevalence from 2% to 40%, depending on the criteria and the accuracy of the diagnostic procedures.9, 10 All guidelines advise the use of three kinds of drugs for treatment: antagonists of the renin-angiotensin system (angiotensin-converting enzyme inhibitors or angiotensin II antagonists), calcium channel blockers, and diuretics, preferably long-lasting agents such as chlorthalidone. All agents must be prescribed at the best doses tolerated and at the optimal regimen of administration. Furthermore, if blood pressure is not under control, a fourth drug should be added. There are some controversies about whether the choice of this fourth drug should be empirically guided or guided by renin profile. To answer these questions, we must consider the paradigmatic trials on this topic. The ASPIRANT (Addition of Spironolactone in Patients With Resistant Arterial Hypertension) and ASPIRANT EXTENSION trials,11, 12 which were the first randomized clinical investigations to compare low doses of spironolactone with placebo, demonstrated the effectiveness and safety of a mineralocorticoid antagonist in RH. The PATHWAY-2 (Optimum Treatment for Drug-Resistant Hypertension) study,13 a randomized controlled double-blind trial comparing spironolactone with other drugs (bisoprolol, doxazosin, and placebo) in patients with well-defined RH, unequivocally demonstrated that spironolactone was superior to all other agents, illustrating that it is the best fourth drug option. Concurrently, there has been a rapid expansion of nonpharmacological treatment, especially of device-based therapy to treat RH. Currently, there are at least seven different methods. Among them, renal denervation (RD) has accumulated the largest body of evidence. The lessons of RD have shown us that there are two kinds of trials: randomized controlled trials and registries. The three most relevant of the randomized controlled trials are: (1) SYMPLICITY HTN-3,14 which included over 500 patients and demonstrated that RD is a safe procedure but not effective enough in controlling BP; (2) the DENERHTN (Renal Denervation for Hypertension) trial,15 which compared standard steeped antihypertensive treatment alone with RD on top (this trial also proved the safety of RD, but, in this case, the addition of RD was more effective in lowering BP compared with medical treatment); and (3) the DENERVHTA, which was the first trial to compare head-to-head spironolactone against RD, demonstrated that spironolactone was better than RD.8 In addition, the registries of real-world patients treated with RD, which, taken together, support the safety and efficacy of RD. However, this conclusion must be reached through randomized controlled trials.16-19 RH is characterized by an overexpression of humoral and hormonal factors that are involved in the development and maintenance of target organ damage (TOD). In this regard, mineralocorticoid receptor blockade has been proven effective and safe in the treatment of hypertension. Renin-angiotensin system blockade alone is not enough to reduce the long-term effects of aldosterone, specifically its deleterious action on vascular and tissue damage.20 In the literature, it is reported that 1.9% of all patients with hypertension will develop RH within a short time from diagnosis, and also that these patients have almost 50% higher risk of cardiovascular events in the next 5 years. This is why it is important to make a correct diagnosis, to implement proper treatment, and to get blood pressure to goal as soon as possible, in order to avoid TOD.21 Albuminuria is a strong marker of vascular inflammation in TOD. In fact, it is a stronger marker of sustained hypertension than other organ damage such as left ventricular hypertrophy. It seems that there are different mechanisms for TOD in this particular kind of hypertension.22 There is some evidence that a systemic low-grade inflammation, such as increased levels of C-reactive protein and left ventricular hypertrophy, might precede an increase in urinary albumin excretion rate (UAER) as a sign of endothelial dysfunction. In addition, it is important to take into account patients with lower levels of UAER, such as those with high-normal UAER (15–29 mg/24 h), because these patients have 50% increased risk of having other TOD and increased cardiovascular risk compared with those with a low-normal UAER range (<15 mg/24 h). Therefore, these observations suggest that left ventricular hypertrophy and UAER may reflect different pathophysiological mechanisms and the different impact of aldosterone or sympathetic activity on target organs in RH.22, 23 Sympathetic nerve activity has been demonstrated to exert a deleterious effect on heart, blood vessel, renal, and metabolic impairments. There is evidence that RD is associated with a significant decrease in median UAER at 12-month follow-up24 but this is nonconclusive. Similar to sympathetic nerve activity, aldosterone has been demonstrated to be involved in vascular damage, inflammation, oxidative stress, and endothelial dysfunction, as well as having a leading role in both raising blood pressure and in mediating TOD. Aldosterone causes arterial medial thickening and fibrinoid necrosis, perivascular leukocyte infiltration, upregulation of proinflammatory molecules and osteopontin, and degenerative changes of the renal vasculature with interstitial fibrosis.25 It is known that mineral receptors exit not only epithelial tissues for the regulation of intravascular volume and sodium, but also on nonepithelial tissues such as the heart, blood vessels, and brain. Therefore, mineral receptor blockade is shown to attenuate and reverse the markers of those injuries. In the present trial by Olivera and colleagues,26 which followed the original DENERVHTA trial, the researchers demonstrated again that, in a well-diagnosed, optimally treated group of patients with RH, spironolactone was superior to RD, not just for decreasing BP levels but also for regression of TOD. They found that UAER significantly decreased in the spironolactone group. They did not find any regression of left ventricular hypertrophy. However, there is nonconclusive evidence of regression on arterial TOD. It is important to note that 6 months of follow-up is a short period for the evaluation of arterial and cardiac TOD. A longer follow-up might give a clearer picture of regression of TOD. At this point, after many years of experience with this difficult to treat type of hypertension, some authors, particularly Dr Calhoun,27 suggest distinguishing between well-controlled RH (with ≥5 drugs) and refractory hypertension (no control at all, even with ≥5 drugs). It seems that the pathophysiologic mechanism is different in each case and, in the latter, RD is indicated because of exacerbated sympathetic activity. In conclusion, the first step is ruling out pseudoresistant hypertension and secondary alternatively, eplerenone (there is enough evidence in favor of both of these drugs).28 Patients with difficult-to-control hypertension should be referred to specialists and, in addition, a multidisciplinary evaluation should be considered for these patients. Finally, although spironolactone is superior to RD in treating patients with RH, RD should not be completely excluded, since it is an effective complementary treatment in certain cases, such as in patients with refractory hypertension. The benefits of medical treatment or RD should be evaluated not only by BP control but also by TOD regression measurement. The author has no conflicts of interest to disclose.