Resistant Hypertension

Current Centers for Disease Control (CDC) estimates suggest (1/3) of Americans above the age of 18 have hypertension, corresponding to approximately 70 million people.  High blood pressure is the most common disease specific reason for an office visit in the United States.1 Unfortunately, only 50% of patients with high blood pressure are adequately treated to goal blood pressure targets. Over the last decade there has been an increased prevalence and incidence of uncontrolled hypertension, deciphering which patients with uncontrolled population truly have resistant hypertension and warrant further investigation will be discussed. 2

Uncontrolled hypertension is not synonymous with resistant hypertension.  Resistant or refractory hypertension refers to those patients with persistently elevated blood pressures (>140/90) despite compliance with three anti-hypertensive medications at optimal dose, one of which is a diuretic.   Risk factors for resistant hypertension include: increased age, African American race, obesity, CKD, diabetes mellitus, and concentric left ventricular hypertrophy.  Many patients with uncontrolled hypertension fall into the category of resistant hypertension, but many do not fulfill these criteria.3  Pseudo resistance refers to patients with uncontrolled hypertension that appear to be resistant but their lack of control is attributable to other outside factors.  The most common causes include: improper measurement of blood pressure, white coat or office hypertension, non-compliance with prescribed medications, an inadequate anti-hypertensive regimen, medication induced hypertension, high sodium intake, and significant obesity.  

It is crucial that blood pressure be measured correctly in a reproducible manner.  Patients should be seated for at least five minutes with an appropriate sized cuff in place.  The arm should be supported on an armrest at heart level. If concerns arise regarding office or white coat hypertension, serial home blood pressures can be used provided the home blood pressure device is accurate and correlates with office readings.  Otherwise, a 24-hour ambulatory monitor is the gold-standard in the evaluation of white coat hypertension. Several studies in the past have shown that less than 33% of patients with uncontrolled hypertension were treated with an appropriate regimen that included 3 anti-hypertensive medications, one of which being a diuretic.2 Uncontrolled blood pressure is often linked to other medications a patient is taking, most commonly non-steroidal anti-inflammatories (NSAIDS).  Other medications that can increase blood pressure include: glucocorticoids, sympathomimetics (diet pills, decongestants, amphetamine-like), oral contraceptive pills containing estrogen, and calcineurin inhibitors.  The average American diet contains 3,400 milligrams of sodium per day, whereas current American Heart Association (AHA) guidelines recommend <1,500 milligrams of sodium per day.3 High sodium intake contributes to elevated blood pressure, fluid retention, and reduced efficacy of anti-hypertensive medications.   Efforts should be made to identify any of these potential reversible causes of uncontrolled blood pressure and to ensure patients are compliant with an adequate combination of blood pressure medications prior to embarking on a secondary evaluation.

One of the challenges in treating patients with high blood pressure is deciding who should be evaluated for secondary hypertension.   The true prevalence of secondary hypertension is difficult to quantify but historical studies suggest 90% of patients have essential or idiopathic high blood pressure while the remaining 10% have a secondary etiology. Given the overall prevalence of hypertension, it is not possible and certainly not cost effective to embark on a secondary evaluation for all patients.  It is important that physicians can identify those patients to screen for secondary hypertension in order to minimize unnecessary evaluation of essential hypertension, while not failing to identify readily treatable underlying conditions.

There are several clinical clues that are suggestive of secondary hypertension: refractory or resistant hypertension, an acute rise or abrupt onset of hypertension with previous control, onset <20 or >50 years of age.  Malignant hypertension with end-organ damage manifested by: hypertensive encephalopathy, retinal hemorrhage or papilledema, flash pulmonary edema without coronary disease, heart failure, concentric left ventricular hypertrophy, or acute kidney injury (AKI) all deserve secondary evaluation.  Patients less than thirty years of ago who are not obese, not African American, with a negative family history deserve further diagnostic studies.3  Additionally, patients with features of a recognized secondary cause deserve further evaluation.

The most common secondary etiologies of hypertension include CKD, renovascular hypertension/renal artery stenosis, and primary hyperaldosteronism.  Less common secondary etiologies include: hypothyroidism/hyperthyroidism, pheochromocytoma, obstructive sleep apnea, Cushing’s syndrome, and aortic coarctation.  Evidence of CKD associated hypertension includes elevated creatinine and/or proteinuria.  Clinical features of renovascular disease include: abrupt onset of accelerated hypertension, unexplained persistent elevation (>30%) in creatinine after initiation of ace inhibitors or angiotensin receptor blockers (ARB’s), recurrent bouts of flash pulmonary edema, abdominal bruit, unilateral renal atrophy.  The most common lab features associated with primary hyperaldosteronism are unprovoked hypokalemia and metabolic alkalosis.  However, it should be noted that less than 50% of patients with primary hyperaldosteronism have hypokalemia so a normal electrolyte panel does not exclude hyperaldosteronism.

If resistant hypertension is suspected, referral to a hypertension specialist or nephrologist is warranted.  The initial evaluation of secondary hypertension should include a basic metabolic panel, urinalysis, 12-lead EKG, paired morning serum aldosterone, and plasma renin level.  Other helpful lab tests include a 24-hour urine to look for sodium excretion, creatinine clearance, and if applicable aldosterone excretion.  If there is concern for renal artery stenosis, renal ultrasound with arterial dopplers, CT angiogram, and MRA with gadolinium can all be used for further evaluation.

Hypertension is extremely common and unfortunately continues to cause a significant amount of morbidity and mortality worldwide.  Clinicians are increasingly confronted with patients experiencing uncontrolled hypertension.  It’s crucial for physicians to identify patients with true resistant hypertension versus those with one or more potentially reversible factors to address prior to embarking on a secondary evaluation.  When these patients are identified referral to a nephrology or hypertension clinic is appropriate for ongoing care and evaluation, which often requires specialized lab and radiographic testing.

References:

1 CDC. Vital signs: prevalence, treatment, and control of hypertension—United States, 1999-2002 and 2005-2008. MMWR. 2011;60(4):103-8.
2 Berlowitz DR, et al. Inadequate management of blood pressure in a hypertensive population. NEJM 1998; 339:1957.
3 Calhoun DA, Jones D, et al. Resistant Hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart  Association Professional Education Committee of the Council for High Blood Pressure Research: Circulation 2008; 117 e510.