Uncontrolled hypertension: highlights and perspectives from the European Society of Hypertension Satellite Symposium

Abstract

The Padua ESH 2011 Satellite Symposium on uncontrolled hypertension was focused on why only a relatively small percentage of patients under treatment do not reach ‘safe’ blood pressure levels; the major reason being the modest use of combination therapy. It was also an occasion to discuss new pharmacological and nonpharmacological tools, some of which appear to be efficacious when even the ‘appropriate’ traditional therapeutic strategy fails to work.

Keywords::

• angiotensin antibodies
• baroreceptor stimulation
• combination therapy
• medical inertia
• renal denervation

The 2011 European Society of Hypertension (ESH) meeting in Milan (Italy) was followed, based on tradition, by a satellite Symposium in Padua (Italy). This year the title of the symposium was ‘Uncontrolled hypertension’, and the reason for choosing this topic was that, despite decades of persistent efforts, in Europe the proportion of patients with acceptable blood pressure control is quite low at approximately 30%, even among those who are under treatment [1]. It was felt that an informal discussion among internationally renowned clinicians and scientists in the field of hypertension could provide new insights on the reasons for these unsatisfactory results and unveil what is on the horizon in terms of new pharmacological and nonpharmacological approaches that could help to improve the situation. In this article, the highlights of this symposium are reported and offered for further discussion to the many clinicians engaged in the care of hypertensive patients.

The participants in the symposium included Juliane Bernholz (Actelion Pharmaceuticals, Basel, Switzerland), Alexander HJ Danser (University of Rotterdam, Rotterdam, The Netherlands), Giuseppe Mancia (University of Milano Bicocca, Milan, Italy), Andrea Stella (University of Milano Bicocca), Alberto Morganti (University of Milan, Milan, Italy), Maria Lorenza Muiesan (University of Brescia, Brescia, Italy), Jurg Nussberger (University of Lausanne, Lausanne, Switzerland), Martin Paul (University of Maastricht, Maastricht, The Netherlands), Pierre Francois Plouin (University of Paris, Paris, France), Achille C Pessina, Gian Paolo Rossi, Andrea Semplicini (University of Padua, Padua, Italy), Franco Veglio (University of Turin, Turin, Italy) and Agostino Virdis (University of Pisa, Pisa, Italy).

Prevalence & causes of uncontrolled hypertension

In this session it was reiterated that hypertension represents the most important cardiovascular risk factor in the Western world, but its control in the community is disappointingly low. To make this situation even worse, it appears that it is those patients at higher risk those who are less well controlled [2]. This does not come as a surprise considering that, in a recent survey open to physicians involved in the treatment of patients with hypertension that aimed to quantify and qualify the key challenges that they face when trying to help patients achieve their blood pressure goal [3], 18.2% of physicians said that the blood pressure target levels recommended in the 2007 ESH–ESC treatment guidelines (<140/90 mmHg) were too tight and not achievable, and 77.4% of them said that it is hard to get their patients to reach these targets in practice. Frequent medical inertia on one side and low patient awareness and compliance on the other appear to be the most important causes of this unsatisfactory situation. However, other important contributions come from an inadequate therapeutic approach, ineffective drug regimens, underestimation of comorbidities, irreversible or scarcely reversible organ damage, and overlooking secondary forms. Another emerging cause of uncontrolled hypertension includes the use of drugs for different indications. The blood pressure-raising effect of immunosuppressants and NSAIDs is well known. Perhaps less known is the fact that several angiogenic agents and tyrosine kinase inhibitors used for the treatment of several types of solid cancers also raise blood pressure through several mechanisms. Among the most common secondary forms, it was mentioned that primary aldosteronism reached a prevalence as high as 11.2% among 1225 consecutive patients followed in specialized hypertension centers in Italy [4]; hence the need for a thorough screening whenever an ‘appropriate’ drug therapy fails to achieve blood pressure targets [5]. An aging population, along with an increase in isolated systolic hypertension and atherosclerotic renal artery stenoses, weight gain with ensuing obstructive sleep apnea, and the abuse of exogenous substances will probably make uncontrolled hypertension even more prevalent in the near future.

Pharmacological approach

Most international guidelines recommend the use of combination therapy even at the initiation of treatment, especially in high-risk patients, as it is more efficacious for blood pressure control than single drug therapy and more rapid in achieving blood pressure targets than traditional stepwise therapy. However, this is rarely carried out in everyday clinical practice owing to the belief that simple treatment regimens improve the adherence of patients to treatment [6]. The use of fixed-dose combinations overcomes this problem and the amelioration of compliance increases blood pressure normalization compared with its free drug combination [7]. All attendees agreed that combinations involving a diuretic and an antagonist of the renin–angiotensin system (RAS) or combinations involving a calcium antagonist and a RAS antagonist are equally well supported, and provided more effective reduction of blood pressure with less adverse effects than each single agent alone. The question was raised whether Ang II antagonists should be considered to offer better results in terms of efficacy and target organ protection compared with angiotensin-converting enzyme (ACE) inhibitors. It was agreed that several factors hamper this comparison, including underestimation of diversity in populations, dosage comparability, pharmacological features of drugs classed and too few head-to-head comparative studies. Overall, it seems that ACE inhibitors and Ang II antagonists have similar protective effects against cardiovascular morbidity and mortality, proteinuria and deterioration of renal function. ACE inhibitors may be slightly better in protecting against myocardial infarction, and Ang II antagonist against stroke and atrial fibrillation, but this needs to be confirmed in large ‘head-to-head’ comparative trials. It was also reiterated that both classes of drugs result in increased levels of Ang II, and in the long run also of aldosterone, through compensatory feedback mechanisms (mainly a rise in renin), leading to incomplete RAS suppression. On the contrary, renin inhibitors, such as aliskiren, reduce plasma renin activity, angiotensin II and aldosterone, because they do not induce an increase in renin due to interruption of the Ang II negative feedback mechanism, thus optimizing RAS suppression. Furthermore, as aliskiren accumulates at tissue sites, it demonstrates persistence on the effect of blood pressure for up to 3 days after discontinuation [8], which could be advantageous considering that many patients forget to take their daily tablet.

The major area of agreement was on the observation that in no less than 15–20% of hypertensive agents, blood pressure control cannot be achieved by a two-drug combination.

When three drugs are required, the most rational combination appears to be a RAS blocker, a calcium antagonist and a diuretic at effective doses. The addition of an aldosterone receptor antagonist has also proven to be particularly efficacious in cases of resistant hypertension [9], provided that the glomerular filtration rate and serum potassium are strictly monitored, especially when aldosterone receptor antagonists are used in combination with any of the RAS blockers. Relative aldosterone excess, particularly in overweight or obese hypertensive patients [10], or undetected primary aldosteronism may account for the effectiveness of mineralocorticoid receptor antagonists as add-on therapy.

During the discussion session, the role of the ‘polypill’ was raised [11], but no support for its use in primary prevention was shown owing to a lack of any evidence of the advantages of multiple risk factor reduction in uncomplicated hypertension.

Issues in the development of new pharmacological tools

Up until a few years ago, it appeared that endothelin antagonists could represent a promising enrichment of the antihypertensive strategy. Unfortunately bosentan, the first endothelin receptor antagonist to be tested, is no longer in use in hypertensive patients because of fluid retention attributed to unopposed endothelin B receptor stimulation. Darusentan, another selective endothelin receptor antagonist, has proven to be useful in resistant hypertension [12], and to cause fewer side effects. However, the main indications for both these drugs presently are pulmonary arterial hypertension, digital ulcers in systemic sclerosis and idiopathic pulmonary fibrosis. Macitentan, a new tissue-targeting dual endothelin receptor antagonist [13], minimizes the problems of safety and tolerability, in particular fluid retention, but studies in hypertensive subjects are still ongoing.

Another field of research concerns drugs that inhibit aldosterone synthase. In fact, although aldosterone receptor antagonists have proven to be useful on top of other drugs in uncontrolled and resistant hypertension, they cause an increase in renin and aldosterone, and can also have side effects, including gynecomastia, erectile dysfunction and menstrual irregularities. These effects may limit their efficacy and stimulate the mineralocorticoid receptor-independent effects of aldosterone. The first orally active aldosterone synthase inhibitor, LC-1699, has recently been tested in primary aldosteronism hypertensive patients, but its hypotensive effect appears to be relatively mild and similar to that of eplirenone [14]. Whether this novel therapeutic strategy is also safe and effective in hypertensive patients without primary aldosteronism remains to be proven in randomized clinical trials. Vascular stress, increased reactive oxygen species generation via NADPH oxidase activation and endothelial dysfunction are also being considered as useful targets of new drugs. Hence, vascular NADPH oxidase inhibitors, by acting on endothelin-derived mediators of oxidative stress such as NOX₁ and NOX₄, could improve vascular relaxation and compliance. Ongoing experiments in spontaneously hypertensive rats are promising in this direction [15].

Novel strategies

Low adherence to prescribed treatment is one of the key factors in uncontrolled hypertension. Active immunization to induce antibodies against angiotensin could overcome this problem. The results of an exploratory study in a limited number of hypertensive patients were presented [16]. They demonstrate that vaccination targeting angiotensin is safe, well tolerated and reduces daytime ambulatory pressure, with a marked reduction in early-morning blood pressure rise. The induced antibody response with a half-life of approximately 4 months after the third injection at 0, 4 and 12 weeks is compatible with a treatment regimen of a few injections per year. Such a regimen is likely to promote adherence to treatment, but further studies are admittedly needed in order to explore the full potential of the vaccination.

Renal sympathetic denervation with radiofrequency energy delivered in the renal artery lumen has also been proposed in patients with treatment-resistant hypertension [17]. The results of a recently published study demonstrate that at 6 months follow-up, renal denervation reduced blood pressure by 10 mmHg or more in 84% of patients, but had no effect in 10% of patients [18]. No serious procedure- or device-related complications were noted. Therefore, it would seem that catheter-based renal denervation could represent a useful tool in the future, at least in some patients with resistant essential hypertension.

Another method to reduce sympathetic activity is by electrical activation of the carotid baroreceptor system. This can be obtained by the Rheos^® System, consisting of an internal pulse generator and two carotid sinus leads. In a cohort of 21 patients with resistant hypertension observed for up to 12 months, a persistent reduction in blood pressure was found [19]. Similar results were seen in the DEBUT-HT study [20]. Both studies show an acceptable safety profile and, of importance, no orthostatic decreases in blood pressure. In the last few months, a second generation of apparatus has been developed – the BAT X R1 system – which simplifies the implant procedure and allows only one electrode to be placed on the carotid sinus. It is clear that both renal denervation and baroreceptor stimulation techniques, although presenting with promising potential for the treatment of resistant hypertensive patients, need to be tested in the long term, especially regarding their effects on sympathetic nerve regrowth in the case of renal denervation, and on damage and degeneration of the sinus nerve fibers in the case of baroreceptor stimulation.

Conclusion

Six different classes of antihypertensive drugs are available on the market that are capable to reduce blood pressure through different mechanisms. It is therefore inconceivable that such a large proportion of patients as reported in the literature remain with uncontrolled blood pressure. Therapeutic inertia must be one of the major causes, as in the experience of physicians working in specialized centers and in clinical intervention trials, the percentage of uncontrolled patients is relatively low. Another cause is represented by misinformation of secondary forms, and here once again we should blame the ancestral belief that secondary forms represent a minuscule percentage of hypertension cases, with an ensuing a priori renunciatory attitude to look for them. Uncontrolled hypertension may instead often be due to scarcely reversible target organ damage, especially in patients of older age with systolic hypertension. It is these patients that are particularly challenging, and where treatment must be optimized until the goal is reached with little justification for lack of awareness and responsibility on the part of the patients about the dangers of high blood pressure.

Financial & competing interests disclosure

AC Pessina and GP Rossi have received sponsorship from AstraZeneca, Bayer Spa, Boehringer Ingelheim, Laboratori Guidotti Spa, Malesci, MSD Italia Srl, Novartis Farma Spa, sanofi-aventis and Sigma Tau Spa to facilitate the organization of this Symposium. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.