Pharmacology Watch

Aggressive Modification of Cardiovascular Risk Factors

In this issue: Aggressive approach to CVD reduces MI, folic acid and vitamin B12 for CAD, corticosteroids for acute exacerbations of COPD, prescription drug abuse among young adults, and ARBs and cancer risk.

CVD decreases with aggressive treatment

Aggressive modification of cardiovascular risk factors seems to be paying dividends, at least for a large population of insured patients in Northern California. In an analysis of nearly 18.7 million patient-years between 1999 and 2008, the rate of myocardial infarction (MI) increased in 1999 and 2000 and then decreased significantly every year thereafter (287 cases/100,000 person-years in 2000, decreasing to 208 cases/100,000 person-years in 2008; 24% relative decrease over the study period). The rate of ST-segment elevation MI decreased over the study period (133 cases/100,000 person-years in 1999 to 50 cases/100,000 person-years in 2008; P < 0.001) and the 30-day mortality rate decreased from 1999 to 2008 as well (adjusted odds ratio, 0.76; 95% confidence interval, 0.65-0.89). This occurred despite more aggressive diagnosis of MI.

The authors conclude, "The lower incidence of myocardial infarction — particularly ST-segment elevation myocardial infarction — is probably explained, at least in part, by substantial improvements in primary-prevention efforts, ..." including statins and aggressive blood pressure reduction, as well as use of cardioprotective medications such as aspirin (N Engl J Med 2010;362:2155-2165).

An accompanying editorial points out that while these trends are generally the case in the United States, there are significant geographic differences. "The risk among residents of Oklahoma, the lower Mississippi corridor, and Appalachia, for example, is double that among other Americans, ... " suggesting socioeconomic factors play a role. Hypertension and diabetes rates have increased slightly over the last decade, while smoking rates have decreased. Perhaps even more importantly, statin use has increased significantly (among those between age 45 and 64 years, statin use in men increased from 2.5% to 16.8% and from 1.9% to 13.5% in women; among those 65 years of age or older, statin use increased from 1.9% to 38.9% in men and from 3.5% to 32.8% in women). Aspirin, beta-blockers, and ACEIs/ARBs have also contributed to the decline in cardiovascular mortality in the United States (N Engl J Med 2010;362:2150-2153).

Folic acid and vitamin B12 for CAD

Unfortunately, lowering homocysteine with folic acid and vitamin B12 does not seem to be a benefit to patients with coronary artery disease. In a study from the United Kingdom, more than 12,000 survivors of myocardial infarction were randomized to 2 mg folic acid plus 1 mg vitamin B12 daily vs matching placebo, with the main outcomes being first major vascular event such as coronary event, stroke, or noncoronary revascularization. Folate and vitamin B12 were effective at reducing homocysteine levels by 28%; however, there was no difference in the rate of major vascular events over the 6.7 years of follow-up (25.5% active treatment vs 24.8% placebo; P = 0.28). Individually, there was no effect on major coronary events, stroke, or noncoronary revascularizations, nor was there a survival benefit from active treatment. Interestingly, the authors also looked at incidence of cancer and found no difference in that outcome either. The authors conclude that long-term reductions in blood homocysteine levels with folic acid and vitamin B12 do not have a beneficial effect on vascular or cancer outcomes (JAMA 2010;303:2486-2494).

Corticosteroids for exacerbations of COPD

Giving corticosteroids orally in lower doses is as effective as giving the drugs intravenously at higher doses for the treatment of acute exacerbation of COPD (ae-COPD), according to a recent study in the Journal of the American Medical Association. The records of nearly 80,000 patients in more than 400 hospital admissions for ae-COPD who received steroids were reviewed. The primary outcomes were treatment failure, defined as the initiation of mechanical ventilation, inpatient mortality, or readmission within 30 days. The vast majority of patients (92%) received IV steroids. After multivariate adjustment, the death rate was similar in the two groups (1.4% IV therapy vs 1.0% oral) and the composite outcome was also similar (10.9% IV vs 10.3% oral). In a propensity-matched analysis, the risk of treatment failure was actually significantly lower among orally treated patients (odds ratio, 0.84; 95% confidence interval, 0.74-0.95), as was the length of stay and cost. Of the orally treated patients, 22% were switched to IV therapy later in the hospitalization.

The authors conclude that for patients admitted for ae-COPD, low-dose steroids administered orally are as effective, and may be safer, than higher-dose IV steroids (JAMA 2010;303:2359-2367). An accompanying editorial suggests that rather than doing large non-inferiority studies to confirm these findings, sufficient evidence exists to change practice now with continued comparative effectiveness research via linked registries (JAMA 2010;303:2409-2410).

Prescription drug abuse in young adults

Prescription drugs are the new drugs of abuse among young adults. While drug use in general seems to be dropping in high schools, prescription drug abuse is skyrocketing. The recently published National Youth Risk Behavior Survey from the Centers for Disease Control and Prevention (CDC) showed that 1 of 5 high school students in the United States reported abusing a prescription drug at some time in their lives. The most commonly mentioned drugs were OxyContin®, Percocet®, Vicodin®, Adderall®, Ritalin®, and Xanax®. Prescription drug abuse was most common among white students (23%), followed by Hispanic students (17%), and then black students (12%). Not surprisingly, high school students were most likely to abuse drugs in their senior year (MMWR 2010;59:1-142). While many teens get their prescription drugs from medicine cabinets of family and friends, others order them online, and recently many drug dealers have begun specializing in prescription drugs.

Many young adults, however, seek opioids and benzodiazepines from physicians, especially in emergency departments (ED). A new report from MMWR reports that ED visits for nonmedical use of opioid analgesics increased 111% from 2004 to 2008 and increased 29% from 2007 to 2008 alone. The highest number of ED visits was recorded for oxycodone, hydrocodone, and methadone. ED visits for benzodiazepines also increased 89% over the same period. In 2008, the rates of visits for both opioids and benzodiazepines increased sharply after age 17 and peaked in the 21-24 year age group. During the 2004-2008 study period, the largest increase in ED visits to obtain drugs occurred among persons age 21-29 years. Findings were from the CDC and the Substance Abuse and Mental Health Services Administration, reviewing data from the Drug Abuse Warning Network (MMWR 2010;59:705-709).

ARBs and cancer risk

Do angiotensin receptor blockers (ARBs) increase the risk of cancer? In a widely reported study, researchers from Case Western Reserve performed a meta-analysis of 5 trials for which cancer data were available from more than 61,000 patients. Telmisartan was the ARB used in nearly 86% of the studies. Patients randomly assigned to receive ARBs had a rate of new cancer occurrence of 7.2% vs 6.0% for placebo (relative risk [RR], 1.08; 95% confidence interval [CI], 1.01-1.15; P = 0.016). The risk ratio was higher when the analysis was limited to trials where cancer was the prespecified endpoint (RR, 1.11; 95% CI, 1.04-1.18; P = 0.001). There was no difference in the rate of cancer deaths between the two groups. The authors conclude that this trial suggests that ARBs are associated with a modestly increased risk of new cancer diagnosis, but it is not possible to draw conclusions about the exact risk of cancer associated with each particular drug and further research is warranted (Lancet Oncology 14 June 2010; early online publication). ARBs are involved in the regulation of cell proliferation, angiogenesis, and tumor progression, which are possible mechanisms for these findings.

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. Dr. Elliott reports no financial relationships to this field of study. Questions and comments, call: (404) 262-5468.