When the BP won’t come down…
Drug cocktails combat resistant hypertension
by Myk Kasperavicius, James Fraser and Gregory P. Curnew, MD
Vol.16, No.08, August 2008

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.

Gregory P. Curnew, MD, FRCPC is Associate Professor at McMaster University in Hamilton, ON, and Director of the Coronary Care Unit at Hamilton General Hospital. 

Myk Kasperavicius holds a BSc and a Bachelor of Kinesiology from Queen’s University in Kingston, ON.

James Fraser is currently finishing his BSc in biochemistry at McMaster University in Hamilton.

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References:

  1. ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA 2002;288:2981-97.
  2. Radack KL et al. Ibuprofen interferes with the efficacy of antihypertensive drugs. A randomized, double-blind, placebo-controlled trial of ibuprofen compared with acetaminophen.
    Ann Intern Med 1987;107:628-35.
  3. Conlin PR et al. Effect of indomethacin on blood pressure lowering by captopril and losartan in hypertensive patients. Hypertension 2000;36:461-5.
  4. Calhoun DA et al. Resistant hypertension: diagnosis, evaluation, and treatment. Hypertension 2008;51:1403-19.
  5. Veteran’s Administration Cooperative Study Group on Antihypertensive Agents: Effect of treatment on morbidity in hypertension. Results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA 1967;202:1028-34.
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