Tackling Resistant Hypertension - Opportunities and Challenges

Patients with resistant hypertension are at greater risk of cardiovascular events with worse outcomes compared to patients without resistant hypertension (1). This is exacerbated when there are associated co-morbidities such as chronic kidney disease and diabetes (2,3). Resistant hypertension is more common than previously thought, with the largest global study of 3.2 million individuals reporting that the prevalence of true-resistant, apparent treatment-resistant and pseudo-resistant hypertension is 10.3%, 14.7% and 10.3% respectively (4). In patients with co-morbidities the prevalence of true-resistant hypertension increases to 22.9% with chronic kidney disease, 56.0% with renal transplant and 12.3% with aging (4). Hence there is a real need to do better in the prevention, detection, diagnosis and management of resistant hypertension. The AHA Scientific Statement on Resistant Hypertension (5) is timely. It is a comprehensive, up-to-date, evidenced-based and balanced report that provides practical suggestions and user-friendly algorithms on the detection, diagnosis, evaluation and management of resistant hypertension.

The concept of treatment-resistant hypertension is not new. In fact, in the 1960s and 1970s, there were a number of studies reporting resistance to drug treatment, with a prevalence of 5-10% (6-8). However, at that time, the choice of antihypertensive medications available was limited mainly to reserpine, guanethidine and centrally acting drugs (6-8). Reasons for ‘resistant hypertension’ as defined in the 1960s probably related in large part to non-compliance, which is understandable considering the unpleasant side effects of many of the antihypertensive drugs used then. Now, almost 60 years later, the challenges of resistant hypertension continue despite the fact that we have a plethora of very effective antihypertensive drugs of different classes that target many different systems. This scenario is reminiscent of the ‘Hypertension Paradox’ defined by Chobanian, where it is paradoxical that despite the major advances in antihypertensive-drug therapy, the number of patients with uncontrolled hypertension continues to rise (5,9).

For a long time, there has been debate and discussion as to what resistant hypertension actually means. This is important because the definition of resistant hypertension is the cornerstone of its diagnosis. The most current definition, as highlighted in the Statement paper (5) is a lack of blood pressure response to optimized medical treatment in hypertensive patients who are fully adherent to 3 antihypertensive drugs of different classes including a diuretic and where secondary hypertension has been excluded. Patients with controlled hypertension on four or more antihypertensive drugs have been defined as having ‘controlled resistant hypertension’. Thus ‘resistant hypertension’ is a heterogeneous group of disorders, comprising both ‘uncontrolled’ and ‘controlled’ forms. Whether these are two separate conditions with different underlying aetiologies is unclear. Other categories of patients with resistant hypertension have also been described including ‘pseudo-resistant hypertension’, which is characterised by patients who fulfill the definition of resistant hypertension but have controlled blood pressure by ambulatory monitoring or home readings outside the office (10). Refractory hypertension refers to patients taking more than 5 antihypertensive drugs who remain uncontrolled after full assessment (10).

Another matter of contention in the field relates to the optimal blood pressure target in treatment-resistant hypertension with most guidelines simply extrapolating recommendations based on findings from the general hypertension population. However, this might not be appropriate because benefits of blood pressure lowering in patients with resistant hypertension seem to be reduced compared to patients who are responsive to therapy (11). To address this a recent prospective study was conducted using pooled data from the SPRINT (Systolic Blood Pressure Intervention Trial) and ACCORD (Action to Control Cardiovascular Risk in Diabetes) trials (12). While the SPRINT study showed that treatment targeted to a SBP <120 mmHg significantly improved the primary outcomes of cardiovascular events and death, the ACCORD study failed to show an improvement in outcomes with lower SBP targets (10). However, when patients defined as having resistant hypertension were pooled from the SPRINT and ACCORD studies (19.2% of patients), it was clearly shown that targeting SBP to <120 mmHg compared with <140 mmHg reduced the risk of most major cardiovascular outcomes and death (11). Hence the SBP goal in patients with resistant hypertension should follow the revised 2017 hypertension guideline definitions aiming for a SBP similar to patients with non-resistant hypertension (130 mmHg) (13). In this context, considering the fact that patients with resistant hypertension are already difficult to treat, the management of these individuals is especially challenging.

While the exact pathoetiology of resistant hypertension remains elusive, it is clear that there are co-morbidities that typically associate and cluster with the condition, including obesity, left ventricular hypertrophy, chronic kidney disease, higher cardiovascular risk scores, hyperaldosteronism and sleep apnea (5,14,15). Sleep apnea and associated sleep disorders including short sleep duration, short REM sleep and interrupted sleep, are particularly important because of the high prevalence of these conditions in the general adult population (14). Sleep apnea is defined as a sleep abnormality characterized by upper airflow cessation during sleep due to narrowing of the oropharynx. Observational studies showed that 30% of hypertensive patients and over 80% of patients with resistant hypertension have sleep apnea or another form of sleep disturbance (16). This has important therapeutic implications because treating sleep apnea with CPAP significantly decreases blood pressure in patients with resistant hypertension. A recent meta-analysis comprising >50,000 patients demonstrated that sleep apnea associates with hypertension in a dose-dependent manner with severe sleep apnea associating more with resistant hypertension (16). This phenomenon was especially common in Caucasian male adults. While a number of factors have been implicated in the association between sleep apnea and resistant hypertension, including intermittent hypoxemia-induced oxidative stress and vascular dysfunction, activation of the sympathetic nervous system and hyperaldosteronism (5,10), the exact mechanisms are still unknown. The time is now ripe to start dissecting the pathophysiological processes that connect these two conditions as highlighted by Carey and colleagues (5).

Unravelling the fundamental causes of resistant hypertension is difficult because it is a complex and multifactorial condition. Some factors that seem to be especially important are pharmacogenetics (genetic basis for drug resistance), salt sensitivity and altered renal function. In addition, using molecular approaches and modelling, new insights at the subcellular level are beginning to be discovered. Aberrant signalling pathways associated with the renin angiotensin aldosterone system and novel microRNAs in resistant hypertension have been reported (17). In particular circulating miRNA may be considered as predictors of treatment responders or non-responders. In a study assessing effects of CPAP treatment on blood pressure in patients with sleep apnea and resistant hypertension, it was found that a singular cluster of miRNAs functionally linked to the cardiovascular system discriminated patients with resistant hypertension and sleep apnea into responders to CPAP treatment (blood pressure reduction) from those who did not respond (18,19). It was also reported that adherent CPAP treatment is associated with changes in circulating cardiovascular–related miRNAs that could influence development of cardiovascular disease in patients with resistant hypertension (18). Moreover, in patients with both conditions, CPAP reduced the aldosterone-to-renin ratio in responders, suggesting a putative pathophysiological role for hyperaldosteronism. Together with pharmacogenetics/pharmacogenomics information, circulating microRNAs as predictors of responders versus non-responders, may be an interesting ‘personalized medicine’ approach to better manage patients with resistant hypertension. However, more research in this exciting field is needed.

The current AHA Scientific Statement has clearly filled the gaps in the confusions regarding resistant hypertension. Not only does it present a comprehensive and updated review about the factors that associate with resistant hypertension and the possible underlying pathophysiological processes, it provides a clear definition of the condition and how resistant hypertension should be diagnosed, evaluated and managed. The management guidance in the Scientific Statement (5) stresses that once true resistant hypertension has been diagnosed, it is essential to i) maximize lifestyle interventions, ii) use long-acting thiazide-like diuretics (chlorthalidone or indapamide), iii) add a mineralocorticoid receptor antagonist (spironolactone or eplerenone) and iv) if blood pressure I still not at target, stepwise addition of other antihypertensive drugs. At a time when there is a lot of interest in developing devices for the treatment of hypertension (20,21) the current evidence does not support device-based therapy for resistant hypertension. Future challenges relate to unravelling mechanisms, defining biomarkers to predict responders and non-responders and developing new approaches to treatment. In this context, there are new opportunities for novel therapies, since there is growing interest in developing long term (for months) antihypertensive agents, including vaccines (22,23). This may be an especially useful strategy and an opportunity in the management of challenging hypertensive patients, especially those with resistant hypertension.