It’s estimated that between 15 and 30% of people with hypertension won’t reach target blood pressure (BP) even if they’re taking 3 different drugs from distinct pharmacologic classes. These patients suffer from resistant hypertension. Pinpointing the risk factors for this condition has proved to be difficult. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) found that older age, higher systolic BP at baseline, left ventricular hypertrophy and obesity were all associated with treatment resistance, with chronic kidney disease being the best predictor.¹

The etiology of resistant hypertension is almost always multifactorial; look for lifestyle aspects such as excessive sodium in the diet and moderate-to-heavy alcohol use. In addition, many commonly used medications can hamper BP control. These include selected COX-2 inhibitors, adrenergic drugs and stimulants, and oral contraceptives. Non-steroidal anti-inflammatory drugs (including aspirin) may minimize the BP-lowering effects of beta-blockers, ACE-inhibitors, angiotensin II-receptor blockers (ARBs) and diuretics.^2,3 When it’s not possible to take a patient off these meds, using the lowest effective dose can be a good compromise.

Finally, consider secondary causes for resistant hypertension such as sleep apnea, renal parenchymal disease, primary or secondary aldosteronism, chronic kidney disease and renal-vascular stenosis and hypertension.

Step it up

Once you’ve excluded pseudoresistance, begin by identifying and reversing lifestyle factors that contribute to hypertension. Discontinue or minimize interfering drugs and screen for secondary causes. If this fails, use pharmacologic therapy, and don’t be afraid to combine drug regimens.

While there are no guidelines on specific combinations, some evidence suggests that higher dosages of diuretics may be beneficial, as many resistant hypertensives have inappropriate volume expansion. Chlorthalidone is superior to hydrochlorothiazide in this patient group and should be the diuretic of choice.⁴ Mineralocorticoids can also help, especially as add-on to an existing drug combo. Lastly, I advise patients who are on ≥ 3 different BP pills/day to take at least one before they go to bed. Recent studies have shown that bedtime ingestion improves BP control compared to meds taken at other times during the day.

The American Heart Association recommends combining drugs with different mechanisms of action, e.g. an ACE or ARB, a calcium channel blocker, and a diuretic.⁴ This combination is generally well tolerated, but ultimately, you have to tailor the regimen to the individual’s needs. While many patients are reluctant to ingest the amount of meds necessary to achieve safe BP values, studies have shown that severe hypertensives who were on ≥ 3 agents showed a 96% decrease in cardiovascular events over 18 months compared to placebo,⁵ illustrating that drug cocktails are likely to be very beneficial. Also keep in mind that in some cases, it may take 1-2 years to achieve BP control.