How Best to Control Hypertension?

Pharmacology Watch

In this issue: Drug combinations for hypertension; tenecteplase for out-of-hospital cardiac arrest; CAM most commonly used for back, neck, and arthritis pain; FDA Actions.

Combination therapy for hypertension

What's the best drug combination with an ACE inhibitor for treatment of hypertension in patients at risk for cardiovascular disease? Current guidelines recommend a diuretic, as witnessed by the number of ACE inhibitor/diuretic combination products that are currently marketed. However, a new study suggests that the calcium channel antagonist may be a better selection than a diuretic. Researchers from several medical schools in the United States and Sweden randomized 11,506 patients with hypertension who were at high risk for cardiovascular events to receive treatment with either benazepril plus amlodipine or benazepril plus hydrochlorothiazide. The primary endpoint was a composite of death from cardiovascular causes, nonfatal MI, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization. The average patient was 68 years old at entry and the group included patients with a history of ischemic heart disease, peripheral vascular disease, stroke, LVH, and diabetes. The study was terminated early after 3 years when it was found that the benazepril/amlodipine group had a significantly lower risk of the primary endpoint: 9.6% vs 11.8% (hazard ratio 0.80; 95% confidence interval, 0.72-0.92; P = 0.002). This represents a 2.2% absolute risk reduction and a 19.6% relative risk reduction in the benazepril/amlodipine group vs benazepril/hydrochlorothiazide. The authors conclude that the combination of benazepril/amlodipine is superior to benazepril/hydrochlorothiazide in reducing cardiovascular events in patients with hypertension who are at risk (Jamerson K, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high risk patients. N Engl J Med 2008;359:2417-2428). An accompanying editorial from the chair of the seventh report of the Joint National Committee on hypertension suggests it is time to re-examine the recommendation of initial therapy with a thiazide-type diuretic. He also states, however, that regardless of the drugs chosen for treatment of hypertension, the most important factor is reducing blood pressure to goal levels (Chobanian AV. Does it matter how hypertension is controlled? N Engl J Med 2008;359:2485-2488).

A survival benefit with tenecteplase?

Thrombolytic therapy during out-of-hospital cardiac arrest does not improve outcomes according to a new study. There has been considerable interest in thrombolytic therapy during cardiopulmonary resuscitation since it has been shown that 70% of these arrests are due to acute myocardial infarction or pulmonary embolism. European researchers randomized 1050 patients with witnessed out-of-hospital cardiac arrest to tenecteplase or placebo during cardiopulmonary resuscitation. The primary endpoint was 30-day survival and the secondary endpoints were hospital admission, return of spontaneous circulation, 24-hour survival, survival to hospital discharge, and neurologic outcomes. The trial was discontinued early when it was found that there was no survival benefit with tenecteplase. Thirty-day survival was 14.7% with tenecteplase and 17% with placebo. Secondary outcomes similarly showed no benefit from tenecteplase. The authors conclude that when tenecteplase was used during advanced life support for out-of-hospital cardiac arrest there was no improvement in outcomes in comparison to placebo (Bottiger BW, et al. Thrombolysis during resuscitation for out-of-hospital cardiac arrest. N Engl J Med 2008;359:2651-2662).

CDC report on CAM use

There is a 40% chance that your patients are using complementary and alternative remedies according to new report from the Centers for Disease Control & Prevention. Not including vitamins and minerals, the use of a complementary and alternatives medicine (CAM) in adults and children has increased in the last 5 years. Treatments include non-vitamin, non-mineral natural products (fish oil, flaxseed oil, echinacea), chiropractic or osteopathic manipulation, deep breathing exercises, massage, and meditation. Children are also using alternative treatments, especially if their parents use them. Despite lack of evidence of efficacy, echinacea is the most common remedy used by children. In adults, use of CAM treatments for URIs is actually down, perhaps indicating better patient education. Back pain, neck pain, and arthritis pain are the most common reasons why people turn to CAM, according to this recent survey. These results point out the need to query patients about the use of complementary and alternative medicines.

FDA Actions

The FDA is requiring a boxed warning on sodium phosphate bowel-cleansing products because of the risk of acute phosphate nephropathy associated with use of these products. Sodium phosphate cleansing products are most commonly used as bowel preparation for procedures such as colonoscopy. According to the warning, the products Visicol® and OsmoPrep® should be used with caution in people older than age 55; those suffering from dehydration, kidney disease, colitis, or delayed bowel emptying; and people taking other medications that may affect kidney function. These products should also not be used in conjunction with other oral laxatives containing sodium phosphate, and over-the-counter products, such as Fleet® Phospho-Soda®, should also be used with caution if given in a high dose to the patient population at risk.

The FDA is requiring a warning on all anti-epileptic drugs regarding the risk of suicidal thoughts and behavior. The warning is based on review of nearly 200 studies that showed that patients on anti-epileptic drugs were at almost twice the risk of suicidal behavior or thoughts compared to patients on placebo. Along with the warning, the agency is also requiring a Medication Guide for patients as part of its Risk Evaluation and Mitigation Strategy. Over 20 drugs will be required to change their labeling including the commonly used agents phenytoin, carbamazepine, divalproex, gabapentin, lamotrigine, primidone, and topiramate.

The FDA is considering a ban on the long-acting beta agonists salmeterol (Serevent®) and formoterol (Foradil®) for the treatment of asthma. An expert committee comprised of the Pulmonary-Allergy Drugs Advisory Committee, Drug Safety and Risk Management Advisory Committee, and the Pediatric Advisory Committee voted unanimously to withdraw the indication for the treatment of asthma for the two drugs based on evidence from meta-analyses showing increased risk of death associated with use of long-acting beta agonist when not paired with a steroid inhaler. The committee did not vote to ban Advair® or Symbicort®, inhalers that combine a long-acting beta agonist with a steroid. If the FDA follows the subcommittee's recommendations, the drugs would no longer be indicated for treatment of asthma but would remain on the market to treat chronic obstructive pulmonary disorders. The FDA has not indicated when it will act on the subcommittee's recommendations.

The FDA has approved fenofibric acid (Trilipix™) for use with a statin for the treatment of dyslipidemia. This is the first fibrate approved for use with statins. The approval is based on a large trial in which the drug was used in combination with rosuvastatin (Crestor®), atorvastatin (Lipitor®), and simvastatin (Zocor®). There have been safety concerns about using fibrates and statins together, particularly gemfibrozil, but the newer generation fibrates appear safer. Abbott, the manufacturer of Trilipix, is collaborating with AstraZeneca to develop a fenofibric acid/rosuvastatin fixed combination product within the next year.

This supplement was written by William T. Elliott, MD, FACP, Chair, Formulary Committee, Kaiser Permanente, California Division; Assistant Clinical Professor of Medicine, University of California-San Francisco. In order to reveal any potential bias in this publication, we disclose that Dr. Elliott reports no consultant, stockholder, speaker's bureau, research, or other financial relationships with companies having ties to this field of study. Questions and comments, call: (404) 262-5468. E-mail: