Melanie Cole (Host): Among patients with refractory hypertension, there are those whose blood pressure remains uncontrolled in spite of maximal medical therapy. This is a common clinical problem faced by both primary care clinicians and specialists. My guest today is Dr. Suzanne Oparil. She’s the director of Vascular Biology and Hypertension Program at UAB Medicine. Welcome to the show, Dr. Oparil. Please define refractory hypertension and what the difference is between resistant and refractory?

Dr. Suzanne Oparil (Guest): Refractory hypertension is defined by my colleague here, Dr. David Calzone here at UAB as hypertension that cannot be controlled with a maximum of five antihypertensive drugs, which should include a diuretic and an aldosterone-receptor antagonist, like spironolactone. So if you’re a hypertension patient, you’re on five drugs that include spironolactone, and a diuretic and your blood pressure is still over 140/90, you’re refractory.

Resistant hypertension is a little bit – has a larger patient population and is a little bit less severe. It means that you are uncontrolled on three antihypertensive drugs, one of which should be a diuretic, and they should be used at maximally recommended doses or maximally tolerated doses.

Melanie: So what are some patient characteristics for refractory hypertension?

Dr. Oparil: Well, typically these people are older -- when the blood pressure first pops up as elevated, it’s usually fairly easy to treat -- tend to be older, and they may have comorbidities like diabetes or atherosclerotic vascular disease. Frequently they’re obese, and frequently they have obstructive sleep apnea, which of course causes sleep disturbance and sleep disturbance causes stress, and we think stress is probably involved in the pathogenesis of refractory hypertension. Although we’re studying them, we don’t really know what the etiologies are yet.

Melanie: So if somebody is diagnosed, what would set a precedent? What would be the prognosis, and what would you do next if they hit that plateau?

Dr. Oparil: The prognosis is that they would be at high risk of developing cardiovascular disease, especially heart failure. Heart failure is the bugaboo of the uncontrolled hypertensive, but also, they might be prone to stroke and heart attack, too. So we would be concerned about those things, and we would first try to evaluate them for secondary causes of hypertension, that is things that could be cured. For example, aldosterone excess, which is usually due to an adrenal adenoma, or catecholamine excess due to pheochromocytoma, or a chromaffin tumor, or in some cases renal artery stenosis.

Melanie: So back to some causes for just a minute, Dr. Oparil, are there some secondary causes of refractory hypertension and possible pharmacological causes as well?

Dr. Oparil: Unfortunately, some of the causes of refractory hypertension are that the patient, in fact, does not take the medicine that is prescribed either because of intolerances or just disliking medications, so it's very important to make sure that the patient is taking the medicines that are prescribed. There are a few ways to do that. You can have the patient bring the meds to the clinic and then have him, or she take them in the clinic and then follows their blood pressure a few hours to see if they respond to therapy.

Or there are a special laboratory that can measure blood pressure medicine and their metabolites in the urine, so you can check that way, but there are relatively few labs that do that. Also talking frankly to the patient and extracting the truth from the patient always helps.

Melanie: How often would you think that it’s necessary to do the assessment of adherence?

Dr. Oparil: We always do some sort of assessment of adherence if we really can’t get the patient’s blood pressure under control with some of our favorite drugs – there are some agents that work better than others. If the patient really doesn’t respond to three, or four, or five of them, we really need to dig deeper.

Melanie: And so speak about some of the non-pharmacological recommendations for refractory hypertension.

Dr. Oparil: Always, whether you’re refractory or just an ordinary hypertensive, we recommend increasing physical activity and losing weight. Here in Alabama, where our practice is, in fact, most of the patients we see in referral are obese, so we try to encourage them to lose weight by modifying their diet, which includes a healthy diet and not just restricting salt, and increasing physical activity. As the blood flows past the endothelium, Nitrous Oxide is released, and blood pressure falls. Increasing physical activity helps with weight loss so it’s weight loss, physical activity, and improving the diet are helpful if patients would really do it. And if a patient is very obese, then gastric bypass surgery should be considered.

Melanie: So speak about the continued treatment of refractory hypertension as the patient gets older, then what are you looking for as far as secondary causes or reasons to keep them on those medications or change them around?

Dr. Oparil: Most of the patients that we see with refractory hypertension have had it or a long time – ten, twenty, thirty, forty years. Almost everything gets worse as one gets older. With respect to blood pressure, the endothelium gets worn out, so you get less Nitric Oxide, less depressor influence from that. Also, there is replacement of smooth muscle cells with fibroblasts, which produce connective tissue, so you get collagen instead of elastin and as we get wrinkles on our face, we get stiff blood vessels, which makes the systolic blood pressure go up further when the heart beats and we know that it's the systolic blood pressure, not diastolic that correlates with cardiovascular disease outcomes and death in people over age 50. That's what we’re looking for, the systolic blood pressure, and we’re using very means possible to get down and prevent it from increasing further.

Melanie: Are there some novel device therapies that you might use?

Dr. Oparil: There are novel device therapies, but they’re experimental still because the most commonly used of them, which is a transcatheter renal denervation -- removal of the renal nerves -- failed in a randomized controlled trial called Simplicity Hypertension Three. This was the first trial that really had a sham control, so the patient went to the cath lab – this is done by interventional cardiologists – had the renal angiogram and then was randomized to either denervation by radiofrequency ablation of the nerve. Or, if you were randomized to the control group, you had the sham procedure, so you’re already in the cath lab, laying there, having already had the angiogram and you have a facemask, goggles, so you can’t see anything, and there’s nice music in your ears, and you’re sedated. The operator is supposed to stand there for 20 minutes just as he or she would do if there were active denervation so that the participants didn’t know whether they had denervation or not and the person that’s following them in the clinic didn’t know either. It was blinded. Lo and behold, six months later, the sham group did almost as well as the denervation group, so that procedure has flopped. There are better procedures with better catheters, better study designs, and better-trained operators, to try to get a better result but we really don’t know about the future of renal denervation.

There are also procedures to take advantage of the baroreceptor to lower blood pressure. There are a variety of other things, an AV fistula procedure that goes femoral artery to a femoral vein. There’s a procedure that stretches the carotid artery so that the artery thinks that the blood pressure is elevated and shuts down the sympathetic outflow. There are a lot of things going on experimentally. None of them has been approved for use in the United States yet. Radiofrequency transcatheter denervation is approved in places like Australia and Germany, and it’s popular over there. Experts vary in their opinions of how good the procedure is and how long the benefits will last – if there is a benefit. There’s two major problems. One, there’s no way to tell whether you’ve completely denervated the kidney, and number two, there’s no easy way to tell whether the nerves grow back. Those are the two big questions that have not been well answered by pre-clinical studies and animal models.

Melanie: And Dr. Oparil, wrap it up for us, with your best advice, for other physicians on how you would like them to maximize adherence and council lifestyle behavioral changes in their patient with refractory hypertension?

Dr. Oparil: I think that’s it’s very important to get the patient’s attention, that this is a lifelong problem, that nobody is going to be able to cure this problem. They’re going to have to work with you or with someone in your office -- frequently a non-physician provider or a pharmacist can be very helpful in assuring that the proper medication combinations are identified and then that there's attention to making sure that the patient take the medication as prescribed and also that that patient makes attempts to improve lifestyle, which will add on to the effects of the medicines and may actually require decreased medication requirement. That’s the reward that the patient gets that can lose 50 pounds and walk 15,000 steps a day. He may have to take one or two fewer drugs, even if he has resistant or refractory hypertension.

Melanie: And how can a community physician refer a patient to UAB medicine?

Dr. Oparil: Great question. There’s something called the UAB Healthfinder Hotline, which is a telephone at 205-934-9999, or if you like using the internet, you can use the UAB Division of Cardiovascular Disease online at UAB.edu/medicine/cardiovascular.

Melanie: And physicians can also use the MIST line at 1-800-822-6478, that’s 1-800-UAB-MIST. And tell us about your team, why is UAB so great to work with?

Dr. Oparil: Well, to give myself a bit of little credit, I’ve bene involved in hypertension research and the pathogenesis in cell preparations, animals models, and then small studies in people with clinical trials in people ever since the late 1960s. I started out my research in Boston. This field has evolved and extended to training a bunch of people. We have many associates, many collaborators in cardiology where we sit, but also in nephrology -- we have a very large nephrology division with extensive expertise in hypertension, and we’ve actually trained some of the nephrology fellows to do hypertension work. Also, we have collaborators in endocrinology and School of Public Health and Epidemiology. I think we have a pretty well-rounded group of docs that can not only deal with blood pressure per se, but with its complications which are cardiac, brain, and kidney.

Melanie: Thank you, so much, for being with us today. You’re listening to UAB Med Cast. For more information on resources available at UAB Medicine, you can go to UABMedicine.org/Physician, that’s UABMedicine.org/Physician. This is Melanie Cole. Thanks, so much, for listening.