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The current state of management and treatment options for resistant hypertension
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The identification of treatment-resistant hypertension as a common condition with high morbidity and mortality will benefit patients and the medical community at large. Unlike hypercholesterolemia, which in most patients can be controlled with statin therapy, hypertension requires a combination of medications and, in many instances, remains uncontrolled despite optimal therapy.
Radiofrequency, a technique under investigation for use in the United States and approved in other countries, is the most commonly used method for renal denervation. Ultrasound, denervation with medications such as guanethidine, vincristine, botulinum toxin type B and other approaches have also been used.
John B. Kostis
It appears that the effect of renal denervation is mediated through decreased afferent and efferent sympathetic flow to the kidney. Interruption of afferent pathways from the kidney to the brain may result in decreased efferent sympathetic effects to many organs, including the kidney, where renin release, sodium retention and activation of the renin angiotensin aldosterone system (RAAS) are decreased while the renal blood flow increases. In addition, renal denervation may cause vasodilation and possibly retard atherosclerosis in the coronary and peripheral arteries, whereas in the heart it may decrease hypertrophy, arrhythmia, oxygen consumption and improve HF. Obstructive sleep apnea may also improve by effects on sensitivity to carbon dioxide, and metabolism may be ameliorated with lower glucose and enhanced insulin sensitivity.
These hypothesized “pleiotropic” effects may be beneficial as described above. It is also possible that these effects may be detrimental under certain circumstances. Only large studies and detailed postmarketing surveillance will be able to exclude the possibility or define the risk for adverse outcomes in patients under severe stress such as sepsis.
How to place new therapies in proper perspective
BP has been considered an appropriate surrogate endpoint in the treatment of hypertension. Nevertheless, event trials must be performed to place new therapies in proper perspective. The place of renal denervation in medical practice will be defined after the completion of new clinical trials focusing on safety, efficacy, long-term outcomes and pleiotropic effects of the intervention. Identification of specific patient subsets using demographic, biochemical and genomic parameters will be necessary to apply renal denervation to appropriate patients. In addition, questions that must be answered include the magnitude of the BP lowering when renal denervation is applied to different patient subsets with different baseline BP, the time course and duration of the effect, the issue of re-innervation and pleiotropic effects not directly related to BP.
It is appropriate to develop a process by which all patients who undergo renal denervation are entered into a prospective registry to include periprocedural information such as complications and BP effects, as well as demographics, traditional risk-factor information, comorbidities, medications, follow-up for hospitalizations and other clinical events, and long-term follow-up for specified beneficial outcomes. Funding for this registry may be obtained from a consortium of companies with interest in resistant hypertension or seed funding may be derived from learned organizations such as the American Society of Hypertension, the American College of Cardiology, the American Heart Association, and so on.
Ideally, patients with resistant hypertension who may be candidates for renal denervation, or even in the absence of interest in device intervention, should be cared for in specialized hypertension centers that include, in the same site, a certified specialist in hypertension, a primary care provider, an interventionist, a pharmacist and a person focused on lifestyle intervention. Patients can be evaluated in these centers and treated for secondary hypertension, a condition responsible for a significant minority of cases of resistant hypertension, pseudoresistance, white-coat hypertension, medication intolerance, obstructive sleep apnea, high salt intake and obesity.
It is probable that renal denervation will not be viewed as an alternative to pharmacotherapy, but as an add-on in the way that interventional therapy is an add-on to optimal medical management of CAD. Also, many patients with “apparent resistant hypertension” may not be candidates for device therapy since the lack of BP control may be due to inappropriate combination of antihypertensive medications, inappropriate dosing and, more importantly, decreased adherence. The latter issue is important among the elderly, in whom polypharmacy is common and financial resources constrained. African Americans and patients with target organ damage, including left ventricular hypertrophy, deserve special attention. Organized networks of care such as accountable care organizations, the US Department of Veterans Affairs, research networks or existing organizations such as Kaiser Permanente may be able to develop and implement low-cost appropriate clinical algorithms using the electronic health record.
Define the role of renal denervation in clinical practice
The rigorously designed, randomized SYMPLICITY HTN-3 trial of renal denervation with the Medtronic Symplicity catheter failed to achieve the primary efficacy endpoint of decrease in systolic BP at 6 months, although no safety issues were identified, according to a press release issued by the company in January in advance of the full data release.
EnligHTN IV, a clinical trial similar to SYMPLICITY HTN-3, was stopped by St. Jude Medical in December before the results of SYMPLICITY HTN-3 were made public because of concerns about patient accrual.
In summary, resistant hypertension is an important epidemiologic problem affecting not only the United States, but virtually all countries in the world, imposing a huge epidemiologic burden in terms of morbidity, mortality and quality of life. Patients with resistant hypertension should be followed in specialized multidisciplinary centers. Renal denervation therapy is a promising, but not well-established, technique that needs further study and the development of postmarketing registries. Detailed analyses of the data from SYMPLICITY HTN-3 and studies with newer technologies in appropriately selected patient subsets will help define the role of renal denervation therapy in clinical practice.
Disclosure: Kostis reports that he has served as a consultant to the renal denervation industry and the pharmaceutical industry producing antihypertensive agents.