Curbside Consult: Breaking the Bonds of Resistant Hypertension

Published Online: Tuesday, November 11, 2011

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Definition of Resistant Hypertension
Hypertension is the most common form of chronic disease, affecting over 25% of adults despite the accessibility of practice guidelines and availability of effective therapy. Failure to achieve blood pressure (BP) goals is attributed to many factors, including an aging population, higher prevalence of kidney disease and obesity, high salt intake, physician inertia resulting in hesitancy to increase dose and number of anti-hypertensive medications prescribed, and patient nonadherence to medication regimens.
 
Resistant hypertension is defined as a failure to achieve a BP goal of <140/90 mm Hg despite adherence to an appropriate anti-hypertensive regimen of three drugs that includes a diuretic. (This definition does not apply to patients with newly diagnosed hypertension.) The problem of resistant hypertension is projected to rise as the population ages. Patients with persistent hypertension despite multiple medications are at high risk for adverse cardiovascular events and are more likely than those with controlled hypertension to have a secondary (i.e., identifiable) cause, which is usually at least in part reversible. A concerted effort on the part of hospitals and other stakeholders in the health care industry indicates that a system can be implemented to help increase the percentage of patients who meet BP goals and reduce the prevalence of resistant hypertension.
 
Case Presentation
A 54-year-old black man with a 10-year history of diabetes and a 15-year history of hypertension presents to your office complaining of a headache. He has a blood pressure of 210/105 mm Hg, a heart rate of 78, and a body mass index (BMI) of 34. He had a 20-year history of smoking. Both his parents had hypertension, and his mother died of a stroke. He also has a family history of kidney disease, but none of his family members have gone on dialysis.
 
The patient has been prescribed a variety of anti-hypertension medications. Currently, he is supposed to be on amlodipine (10 mg per day), losartan (100 mg per day), and hydrochlorothiazide (25 mg per day). He has had problems with low potassium in the past. In fact, he is currently supposed to be taking a potassium supplement—KCl (20 meq per day). You notice his last recorded potassium level is 3.5 mmol/L. As for his kidney function, his GFR is estimated at 55 mL/min.
 
When asked if he is on a low-salt diet, the patient says he does not add salt to his food, but no one has ever really talked to him about the importance of limiting sodium intake. He has no allergies, though he does have some side effects from medication. He has experienced swelling from amlodipine, and he had a cough on an ACE inhibitor, though he doesn’t remember which one. He has been told that his cholesterol is elevated, but has not been put on medication to control it, nor has he been given any dietary counseling. He has been told to follow up with a primary care physician, which is what has brought him to this appointment.
 
Evaluation and Management
Based on this history, the first thing to focus on is the patient’s salt history, because most patients in this situation are going to be salt sensitive. Although the patient says he doesn’t add salt to his food, it turns out that he eats out about 75% to 80% of the time, primarily at fast-food restaurants and delicatessens, with a particular preference for soup. So he is consuming a fairly high-salt diet.
 
Putting the patient on a low-sodium diet and making sure he follows it will be critical. It is equivalent to giving him an extra anti-hypertensive medication; there are multiple examples of this in the literature, and it’s also my experience. In general, most people can stick to a diet of 2.5 grams of sodium per day. It’s not what’s ideally recommended, but very few people can stick to the ideal diet for any period of time. This is a good compromise, and it works well.
 
“Pseudo-resistance” refers to a lack of BP control with appropriate therapy in a patient who does not actually have resistant hypertension. The first step to determining whether you are dealing with pseudo-resistance is confirmation of the diagnosis with reliable office BP readings. Adherence to recommended BP measurement techniques will uncover patients who do not satisfy the definition of resistant hypertension.
 
Next, you need to determine whether the patient is taking the drugs prescribed for him. If he is, then he clearly has resistant hypertension because he is on three maximally dosed drugs, including a diuretic, and his blood pressure still isn’t controlled. A diuretic and a calcium channel blocker must be a part of the patient’s treatment regimen. So, amlodipine at 10 mg per day, if he has been taking it, probably isn’t doing the job. Under these circumstances, I would switch him from amlodipine to nifedipine XL at 120 mg per day. It doesn’t have quite the benefits on the vasculature, but it provides better blood pressure reduction.
 
In addition, losartan, which he is also on, is not a very good ARB for blood pressure reduction. The best ones are olmesartan and the new one, azilsartan, which was just recently released. Those are the best two by far, and number three would be telmisartan at maximal dose. So I would switch out losartan for one of those. His GFR is 55 mL/min, so I would also change the diuretic from hydrochlorothiazide, which will not appear in the upcoming JNC 8 guidelines, to chlorthalidone at 25 mg per day.
 
Obesity is also a frequent feature of patients with resistant hypertension. Weight loss achieved with an appropriate exercise program and a reduced-calorie diet is associated with modest BP reductions in obese hypertensive patients. Our patient has a BMI of 34, so he is obese, and, in addition to lifestyle modification, would clearly benefit from spironolactone at 25 mg per day. The rationale for adding it is not that he has primary aldosteronism but that there is a lot of good evidence accumulating that the large masses of adipocytes seen in obesity can actually increase aldosterone synthesis. He has hypokalemia, he’s on a high-salt diet, he’s taking a diuretic, and, on top of that, he may have this aldo effect as well; there’s been a lot of data published arguing that in cases like this one, spironolactone should be part of the anti-hypertensive cocktail.
 
Finally, he is definitely going to need a beta blocker. Not labetalol, which is commonly used but is not the ideal beta blocker. (In fact, it has a ratio of beta to alpha effects of 7:1.) However, carvedilol could be very good (with a beta-to-alpha ratio of 3:1), as could bisoprolol or nebivolol. These are all very good anti-hypertensives, and they’re also very good heart-rate-lowering agents that are well tolerated.
 
That’s what I would start with. The key is a low-sodium diet and a well-chosen anti-hypertensive cocktail. One other thing you would want is to get a very good medical history either from a spouse, a girlfriend, or even the patient himself, for sleep apnea, which is a common cause of resistant hypertension. In addition, it would be a good idea to get a history of use of over-the- counter agents such as ibuprofen and naproxen, which are known to raise blood pressure in situations like this.
 
Management Summary
Effective management of resistant hypertension should start with a careful evaluation of the patient to confirm the diagnosis and exclude factors associated with pseudo-resistance, such as inappropriate BP measurement technique, the whitecoat effect, and poor patient adherence to anti-hypertensive medications. Patient education and reinforcement of lifestyle issues that affect BP, such as reduction of alcohol intake, sodium restriction, and weight loss for obese patients, are vital in treating resistant hypertension. Exclusion of preparations that contribute to true BP treatment resistance, such as nonsteroidal anti-inflammatory drugs, cold preparations, and certain herbs, is also important. Finally, BP control can only be achieved if an anti-hypertensive treatment regimen is used that targets the genesis of the hypertension. One example is volume overload, a common yet unappreciated cause of treatment resistance. Use of the appropriate dose and type of diuretic provides a means of overcoming treatment resistance in this instance.
 
George Bakris, MD, is professor of medicine and director of the hypertension center at the University of Chicago Medical Center.