Pharmacology Watch

New Study on Chelation Therapy Proves Controversial

In this issue: Chelation therapy for cardiovascular disease; statins and kidney injuries; chlorthalidone for hypertension; and FDA actions.

Does chelation therapy work?

The National Center for Complementary and Alternative Medicine (NCCAM) is attempting to fulfill its mandate to prove or disprove the value of alternative treatments. A division of the National Institutes of Health, NCCAM has done research on everything from supplements to meditation. This latest study looks at chelation therapy in patients with cardiovascular disease. Chelation therapy with ethylene diamine tetra-acetic acid (EDTA) has been used for decades to treat lead toxicity, and it has also been found to reduce metastatic calcium deposits. Despite the fact that small studies have never shown a benefit for chelation in treating cardiovascular disease, many alternative clinics continue to tout its value in this role. A recently published NCCAM-funded study to evaluate the value of chelation enrolled more than 1700 patients ≥ 50 years of age with a history of myocardial infarction (MI) at least 6 weeks prior. The study was a double-blind, placebo-controlled, 2 × 2 factorial randomized trial from 2003 through 2011. There were 289 patients who withdrew consent from the study, of which 60% were in the placebo group. The study consisted of 40 EDTA/vitamin infusions vs placebo infusions (given weekly for 30 weeks then at 2-8 week intervals). About 15% of patients in both groups dropped out during therapy. The primary outcome was a composite of total mortality, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. The primary endpoint occurred in 222 (26%) in the chelation group and 261 (30%) in the placebo group (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.69-0.99; P = 0.35). There was no effect on total mortality, but there was slight improvement in other outcomes with chelation. The authors conclude that among stable patients with a history of MI, chelation therapy modestly reduced the risk of adverse cardiovascular outcomes. They conclude that this study provides evidence to guide further research but is not sufficient to support the routine use of chelation therapy in patients with cardiovascular disease (JAMA 2013;309:1241-1250). Editorialists in the same issue of JAMA immediately leveled strong criticisms, ranging from allegations of noncompliance with regulations for the protection of research participants to questioning the professional credentials of the study sites and investigators. The JAMA editorial board did an extensive review of the data, and despite concerns, decided to publish the study with the caveat that "these findings do not support the routine use of chelation therapy as secondary prevention for patients with previous myocardial infarction and established coronary disease." (JAMA 2013;309:1291-1292.) Another editorialist, however, suggests that "limitations in the design and execution" of this trial compromise the findings. For example, the high number of withdrawals of consent in the placebo group suggests that the study was not truly blinded. There is also concern about the use of "softer" endpoints such as coronary revascularization and hospitalization for angina. Also, the trial design was altered midway through the study because of the length of the trial. Given these concerns, "including missing data, potential investigator or patient unmasking, use of subjective endpoints, and intentional unblinding of the sponsor, the results cannot be accepted as reliable and did not demonstrate a benefit of chelation therapy." (JAMA 2013;309:1293-1294.)

Statins and renal function

When prescribing a high-dose statin, physicians no longer need to monitor liver function tests, but might want to consider monitoring renal function, at least for the first 3 months. Last year, the FDA removed labeling requiring periodic monitoring of liver enzyme tests, but now a Canadian study suggests that high-potency statins (defined as doses of at least 40 mg simvastatin, 20 mg atorvastatin, or 10 mg rosuvastain) may be associated with acute kidney injury. Researchers reviewed records of more than 2 million patients from nine population-based cohort studies comparing current and past use of high-potency vs low-potency statin therapy. Patients hospitalized for acute kidney injury were matched with 10 controls. About 3% of patients had chronic kidney disease (CKD) at the onset of the study. Within 120 days of starting therapy, there were 4691 hospitalizations for acute kidney injury in patients without CKD and 1896 hospitalizations in patients with CKD. In patients without CKD, current users of high-potency statins were 34% more likely to be hospitalized with acute kidney injury compared to low-potency statin users (fixed effect rate ratio 1.34; 95% CI, 1.25-1.43). In patients with CKD, the increase was about 10% with high-potency statins (risk ratio, 1.10; 95% CI, 0.99-1.23). The authors conclude that use of high-potency statins is associated with an increased rate of acute kidney injury compared to low-potency statins, with the effect strongest in the first 120 days of treatment. The authors further suggest that since there is a relatively small incremental cardiovascular benefit between high-potency and low-potency statins, and given the increased risk of rhabdomyolysis, diabetes, and acute kidney injury, patient selection for risk-benefit is important (BMJ 2013;346:f880).

Chlorthalidone for hypertension

Thiazide diuretics are recommended as first-line treatment for hypertension. Hydrochlorothiazide (HCTZ) is the most commonly used diuretic in North America, but some experts have recommended chlorthalidone in this role, suggesting that it may be superior. A new study, however, suggests that chlorthalidone may cause more electrolyte abnormalities than HCTZ. Nearly 30,000 patients ≥ 66 years of age who were newly treated for hypertension were evaluated. About one-third were treated with chlorthalidone and the rest with HCTZ. None of the patients had been hospitalized for heart failure, stroke, or MI within the last year. The primary outcome was a composite of death or hospitalization for heart failure, stroke, or MI, and safety outcomes included hospitalization with hypokalemia or hyponatremia. After 5 years of follow-up, there was no difference in the primary outcome between the two drugs — 3.2 events per 100 person years for chlorthalidone vs 3.4 events per 100 person years for HCTZ. However, patients treated with chlorthalidone were three times more likely to be hospitalized with hypokalemia (adjusted HR, 3.06; CI, 0.81-1.06). Hyponatremia was also more common (HR, 1.68; CI, 1.24-2.28). The findings suggest that in typical doses, chlorthalidone is not associated with fewer adverse cardiovascular events or deaths compared to hydrochlorothiazide, but it is associated with a greater incidence of electrolyte abnormalities, especially hypokalemia (Ann Intern Med 2013;158:447-455).

FDA actions

The FDA has issued a warning regarding azithromycin and cardiac toxicity. The drug has been associated with fatal heart rhythms — especially in patients already at risk — including those with prolonged QT intervals, torsades de pointes, congenital long QT syndrome, bradyarrhythmias, or uncompensated heart failure. Other patients may be at risk as well, including those with low potassium or magnesium levels, those using drugs that prolong the QT intervals, and elderly patients with cardiac disease. The warning was based on a study published in The New England Journal of Medicine last year.

An FDA advisory committee is recommending against the use of calcitonin salmon (Miacalcin and Fortical nasal sprays, and Miacalcin injection) for the treatment of osteoporosis in postmenopausal women because the risk of cancer outweighs any potential benefit. The recommendation is based on an FDA review that questions the drug's effectiveness in reducing fractures. Another review found a small increased risk of cancer associated with the drug. The drug could still be used for Paget's disease, acute bone loss due to immobilization, and hypercalcemia. The FDA has yet to rule on the advisory committee's recommendations.

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) 262-5404. E-mail: