The treatment of high blood pressure can be very challenging, especially when medicines don’t work. Hypertension is defined as a consistent elevation of blood pressure. In the pre-hypertension stage, the systolic blood pressure is between 120 and 139 or the diastolic blood pressure is between 80 and 89mmhg. In stage I, the systolic blood pressure is between 140 and 159 or the diastolic blood pressure is between 90 and 99mmhg. In the more advanced age or for stage II, the systolic blood pressure is 160mmhg or higher or the diastolic blood pressure is 100mmhg or higher.
Treatment of high blood pressure: What is the problem?
Over 85 million adults (one in every three) in the United States have hypertension and about 20% are not aware of it. It is a major modifiable risk factor for cardiovascular disease and stroke. The direct and indirect costs of hypertension are very significant. Hypertension can be linked to 50% of cardiovascular disease and 75% of strokes. High blood pressure costs the nation 46 billion dollars each year in healthcare services, medication and missed days of work. It is labeled the “silent killer”. Most of the time there are no obvious symptoms. High blood pressure does not cause headache or nosebleeds except in cases of hypertension emergencies when blood pressures can reach 180/110mmhg.
What is the treatment of high blood pressure?
The American Heart Association has made hypertension a primary focus to seek to improve cardiovascular death and stroke and reduce cardiovascular events by 20% by 2020. The AHA is promoting evidence based management algorithms to standardize treatment that includes lifestyle modifications in all hypertension patients. This includes weight reduction, adoption of DASH eating plans by consuming a diet rich in fruit, vegetables, low in saturated fat and low in salt intake (<2.4gm/day). It also includes regular physical activity (brisk walk, 30 min/day) most days of the week and moderate alcohol consumption (2 drink/day for man or 1 drink/day for women). It also promotes system level of tracking hypertension control with feedback to providers, frequent updating and the adoption of single pill combination.
According to the 8th Joint National Committee (JNC 8) guidelines, medical treatment should be started when blood pressure is greater than 140/90 in adults less than 60-year-old and 150/90 when older. Pharmacological treatment should include a thiazide diuretic, calcium channel blocker, ACE inhibitor or angiotensin receptor blocker. If the target blood pressure is not reached with one medication, the dose should be increased or a second medication should be added.
Despite the fact that therapies to lower blood pressure and associated cardiovascular risks have been known for years, only 75% of the patients with hypertension are treated and only 50% are under control. Hypertension can cause stroke, heart attack, heart failure and kidney disease. Excessive blood pressure results from many causes, including: 1) excessive nervous system stimulation of heart. vessels, and kidney 2) excessive production of hormones affecting the vessels and kidney or 3) stiffening of the blood vessels causing them to lose their elastic quality. This later form of hypertension has been termed “structural hypertension”. Excessive dietary salt, high body weight, lack of physical exercise, and excessive alcohol may contribute to hypertension. Medications prescribed by your physician are critical to the control of blood pressure, and if you have disagreeable side effects due to the medications it is important to discuss stopping or altering the medication with your physician.
New innovative therapeutic approaches maybe particularly relevant to patients with hypertension conditions that put them at risk of major cardiovascular events. Each month of active treatment is associated with approximately 1 day of life expectancy gain.
Treatment of high blood pressure: When medicines don’t work.
The Rox coupler to create an arteriovenous fistula.
When medications fail to reduce blood pressure, we should consider “structural” hypertension. In the absence of sleep apnea or reno vascular disease, worsening of essential HTN or failure to respond to medications can be related to structural changes in our large capacitance arteries. Aging, smoking and diabetes are all associated with isolated or predominantly systolic HTN (systolic BP >160 and diastolic BP <95) as well as the loss of elasticity of our major blood vessels. After the age of 50, HTN is likely to be structural and almost 70% of uncontrolled HTN after the age of 65 is structural.
Structural HTN is characterized by an increase in arterial stiffness of the large arteries. In isolated systolic HTN, large artery remodeling includes a thickening of the media (middle layer) with an enlargement of the lumen of the proximal elastic arteries such as the aorta. This remodeling and stiffening of the large arteries plays a major role in augmenting the systolic and pulse pressure. The loss of aortic elasticity increases volume sensitivity. For this reason, diuretics should be our first line of treatment. Diuretics are not very efficient in reducing arterial volume, and for this trial, we propose to study the creation of an arteriovenous (AV-) fistula in patients with resistant, uncontrolled HTN. In pre-dialysis patients, the creation of an AV- fistula resulted in reduction of arterial stiffness and reduction of blood pressure.
How is the AV-fistula created?
The Rox coupler delivery system consists of a preloaded self-expanding coupler and a crossing needle. The coupler is composed of Nitinol material similarly found in self-expanding carotid stents. The procedure is performed in the cardiac cath lab under fluoroscopic guidance. A small introducer sheath is inserted into the femoral artery. A customized venous introducer is inserted in the femoral vein. A small retractable micro puncture crossing needle is advanced through the venous and the arterial walls. After advancing the Rox coupler delivery system across the small opening, the arterial coupler arms are deployed followed by the venous arms. Post deployment, a small balloon is used to dilate the anastomosis and create the resulting arteriovenous fistula at the external iliac vessels. The following video depicts the full procedure.
Can the Rox coupler AV-fistula reduce blood pressure?
Rox control-HTN (RH-01) was a prospective, open-label, multicenter trial to evaluate the safety and effectiveness of the Rox coupler in patients with resistant HTN (>140), on a stable regimen of more than 3 antihypertensive medications. Patients with type 1 diabetes, significant peripheral venous or arterial disease, cerebro-vascular disease or unstable cardiac or pulmonary conditions were excluded from the study. Forty-four patients were treated with the coupler and 39 patients were allocated to control group. The difference between the mean systolic and diastolic blood pressure at 6 months was significant. The magnitude of blood pressure reduction was consistent through 12 months demonstrating a durable treatment effect. The mean systolic and diastolic differences at 12 months were -27 and -21 in the treated versus -3.7 and -2.4 in the control. Some patients developed some lower extremity edema related to the iliac vein and were treated successfully with a stent.
Rox US HTN-01 is a prospective, randomized, adaptive, double-blind, sham-controlled, multicenter study to evaluate the Rox coupler in patients with resistant HTN. To qualify, systolic blood pressure should be greater than 160 or greater than 150 if a hospitalization was required in the last 12 months. The patients should be on a stable medical regimen that includes a diuretic and 2 additional antihypertensive medications. For more information, visit clinicaltrials.gov.
We have a patient that has had severe HTN for years. He is a patient of Dr. Mendelsohn, a partner at Cardiology PC, BBH Princeton. In 2011, we attempted to enroll him in Simplicity 3 HTN trial but were unable due to abnormal kidney function. In 2012, we contacted cardiologists in France to perform renal denervation using the new Vessix procedure. This was not possible due to the fact that he was a non-citizen. However, he was able to undergo the procedure in Germany with the help of Dr. Sievert. With the blood pressure still not under control, in 2015 our patient was offered the possibility to enroll in CALM-FIM, the baroreceptor trial, but the screening failed due to carotid plaque. Finally, this week, our patient was the first patient in the U.S. to randomize in the CONTROL NTN-2, multicenter trial using the ROX Coupler technology. The patient and myself are blinded to the treatment arm and I will be the one following him in the Cardiology PC research clinic. Dr. Mendelsohn is the HTN interventionalist and is the only one aware of the treatment received.
The real ROX star is sitting between me and Dr. Mendelsohn!
Treatment of high blood pressure: When medicines don’t work.
Carotid baroreceptor modulation:
A sensor is located in the enlarged portion of the internal carotid just after it divides with the external carotid artery. It senses the blood pressure and released the information to the brain through sympathetic nerves. It is a receptor that is excited by stretching of the artery and with its connection to the brain, it influences cardiac output and vascular tone so that the proper blood pressure can be maintained.
CALM-FIM U.S. clinical trial:
The purpose of the study is to evaluate the safety and performance of the Mobius HD system in subjects with resistant hypertension. This is an open-label, multi center, First-in-Man clinical trial that is conducted in the U.S. Patients with stage II resistant hypertension, that are treated with a minimum of 3 antihypertensive medications including a diuretic and who consent to participate in this study are assigned to treatment with a MobiusHD system (Vascular Dynamics). The office blood pressure needs to be greater than or equal to 160 mmHg following at least one month of maximally tolerated treatment. The patients are followed for appeared of 6 months. Patients with vulnerable plaque or ulceration of any size in the carotid artery or aortic arch are excluded from this study.
How does the MobiusHD device work?
The MobiusHD device includes a very thin implant, flexible, open metal cage that is implanted in the carotid sinus. It is made of a Nickel-titanium alloy that is delivered to the carotid artery using a special delivery catheter. The implanted device modulates the baroreceptor by inhibiting sympathetic activity and lowering blood pressure. The application of localized mechanical forces to the wall of the carotid sinus changes its geometric shape and therefore increases the baroreceptor signaling while preserving the normal arterial pulsatility and blood flow of the carotid artery.
In experimental studies, the increase in carotid baroreceptor sensitivity correlated with the increase in the diameter of the carotid sinus. For years, the effect of carotid endarterectomy and carotid artery stenting on systemic arterial blood pressure have been known. Transient hypotension has been observed with both procedures. Dr. Farrell Mendelsohn has had over 20 years of experience in the field of carotid artery stenting and has previously documented the effect of carotid stenting on heart rate and blood pressure. Because the MobiusHD maintains pulsatility, it is anticipated that the constant modulation of the baroreceptor can cause a persistent lowering of the blood pressure.
One of our patients had just about given up on the idea of having a normal blood pressure. She had been taking blood pressure medications for years with very little control. She came to our research department approximately 5 years ago and completed the Simplicity trial. In 2015, our research department began participating in the another study for resistant hypertension, called Calm-Fim. She was enrolled into the study and after treatment, her blood pressure has decreased dramatically. As a result of her lower blood pressure numbers, some of the blood pressure medications were discontinued.
Treatment of high blood pressure: When medicines don’t work.
The kidney and the nervous system are linked through the renal nerves. The renal sympathetic and sensory nerves are located adjacent to the wall of the renal arteries. The stimulation of the renal nerves can lead to changes in arteries and veins, release of enzymes such as renin and sodium and water retention. The increase in a renal nerve activity has been implicated in hypertension.
In the 1930s, surgical procedures to remove those nerve connections were performed and demonstrated that blood pressure reduction can be achieved. However because of the high operative risk and long-term problem with orthostatic hypotension, the surgeries were abandoned.
Catheter based radiofrequency ablation has been applied to the nerves of the renal arteries as hypertension treatment.
Simplicity HTN- 3 clinical trial:
Five years ago we participated in a multicenter clinical trial called Simplicity HTN 3. Patients with stage II or resistant hypertension where randomly assigned to undergo renal artery denervation or Sham procedure and followed for 6 months. Patients were required to have an average of 3 blood pressure measurements greater than 160 and to be medically treated with at least 3 antihypertensive medications including a diuretic.
The renal artery denervation was performed using radiofrequency energy delivered by a Simplicity catheter. For the sham procedure, only a renal arteriogram was performed. Neither the patient nor the hypertension specialists were aware of the treatment arm. This randomized, Sham controlled, clinical trial did not show a benefit of renal artery denervation with respect to reduction of systolic blood pressure. One of the limitations was that medication adherence could not be confirmed in all patients. Compliance with multiple antihypertensive therapies is a major problem in clinical practice. Also inter-operator variability could have played a role with several centers enrolling only just a few patients. Finally, the design of the simplicity unipolar catheter may have been sub-optimal for accomplishing a significant renal denervation.
Reduce-HTN: Reinforce study:
We are currently enrolling patients in the reduce-HTN: reinforce clinical trial to assess the safety and efficacy of the Vessix (Boston Scientific Corporation) renal denervation system for the treatment of uncontrolled hypertension (off treatment, office systolic blood pressure greater or equal than 150 and less than 180mmhg).Preliminary studies in Europe and Australia have shown a reduction in systolic blood pressure up to 2 year, but these findings need to be confirmed.
At BBH Princeton Medical Center, we are enrolling patients with newly diagnosed hypertension or patients with office systolic blood pressure greater or equal than 150 and less than 180 on 1 or 2 antihypertensive medications. Patients with significant renal artery stenosis or renal artery aneurysms are excluded from this study. After consent, the medications are discontinued and patients complete a 4 week washout period where blood pressure is monitored very carefully. The patients are then randomized to Renal denervation using the Vessix catheter versus a Sham procedure which consist of a renal arteriogram only. The patients remain off treatment until 8 weeks post randomization unless rescue anti-hypertension changes are required. If the patient is not at target systolic blood pressure (less than 140mmhg) through the 6 months assessment, medications are then added. Neither the patient nor the hypertension specialists are aware of the treatment arm. Doctors Michael Wilensky and Farrell Mendelsohn enrolled the 1st study patient in 2015.