Atherosclerosis Reversed With Lipid-Lowering Drugs

Pharmacology Watch

When it comes to treating lipids in patients with heart disease, the mantra may be, "The lower the LDL, the better." Data from the multicenter Reversal of Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) trial indicate that aggressive reduction of atherogenic lipoproteins prevents progression of disease. The study randomized 654 patients with coronary disease to pravastatin 40 mg/d (moderate lipid-lowering regimen) or atorvastatin 80 mg/d (intensive lipid-lowering regimen). After 18 months of therapy, 502 patients were evaluable with baseline and post-treatment intravascular ultrasounds. The primary outcome was percentage change in atheroma volume. Intensive lipid-lowering therapy with atorvastatin resulted in a decrease of LDL cholesterol from an average of 150 mg/dL to 79 mg/dL, while pravastatin therapy resulted in a decrease to 110 mg/dL.

C-reactive protein decreased 36.4% with atorvastatin and 5.2% with pravastatin (P < .001). Progression of coronary atherosclerosis did not occur in the atorvastatin group, while coronary atherosclerosis progression did occur in the pravastatin group compared with baseline. The authors suggest that the data support aggressive lipid lowering, below the current national guidelines for secondary prevention in patients with coronary atherosclerosis (JAMA. 2004;291:1071-1080). It is of note that this study employed the relatively new technology of coronary ultrasound, which more effectively measures plaque volume as opposed to coronary angiography, which merely quantifies the lumen. Still, this technology is relatively new, as pointed out in an accompanying editorial, but the results appear to be valid. The editorial also points out that the moderate lipid-lowering regimen in the study did not achieve levels of LDL lowering recommended by national guidelines, which suggest lowering LDL below 100 mg/dL for secondary prevention. The authors recommend focus on all risk factors in patients with coronary disease, including LDL lowering at least to levels recommended in national guidelines (JAMA. 2004;291:1132-1134).

Positive Alendronate Data in Osteoporosis

Does alendronate prevent fractures after 10 years of therapy? According to a new multicenter placebo-controlled trial, the drug is effective and safe over 10 years in women with osteoporosis. Data from the study are from a follow-up of 2 identical 3-year trials of alendronate therapy followed for an additional 7 years. In this follow-up study, women were randomized to 3 daily doses of alendronate or placebo. The 3 active treatment groups included women who took alendronate 5 mg or 10 mg daily for the entire 10-year study. A third group took 20 mg of alendronate daily for 2 years and 5 mg daily in years 3, 4, and 5 followed by 5 years of placebo. This last group was called the "discontinuation group." Women in the original placebo group ended up receiving alendronate in years 4 and 5 and then were discharged. There were 247 women who participated in all 4 phases of the study. Treatment with 10 mg of alendronate daily for 10 years resulted in statistically significant increases in bone mineral density at the following sites: 13.7% increase, lumbar spine; 10.3%, trochanter; 5.4%, femoral neck; and 6.7%, proximal femur as compared with baseline values (P < .001; 95% CI for all groups). The percentage increases for the 5 mg group were 9.3%, lumbar spine; 4.8%, trochanter; 2.8%, femoral neck; and 2.9%, proximal femur. Alendronate also resulted in fewer fractures and lower rates of loss of stature over the 10-year period. Discontinuation of alendronate resulted in a gradual loss of bone density. The authors conclude that continued treatment with 10 mg of alendronate daily for 10 years was associated with a sustained therapeutic effect on bone density and bone remodeling. Concern over increase fracture rates with bisphosphonates over time was not validated by the study (N Engl J Med. 2004;350:1189-1199).

NSAIDs For Myocardial Infarction

Nonaspirin NSAIDs, especially ibuprofen and naproxen, may protect against myocardial infarction in patients who are not taking aspirin. Researchers from Pennsylvania conducted a case-control study with cases of first, nonfatal MI identified prospectively with random controls from the community. The use of a nonaspirin NSAID was associated with a significant reduction in MI compared to those not using aspirin (OR 0.53; 95% CI). The adjusted odds ratio for ibuprofen was 0.52 and for naproxen was 0.48. The odds ratio for aspirin alone in this study was 0.79. The combination of aspirin with a nonaspirin NSAID trended toward increased risk of MI and worsened as the frequency of nonaspirin NSAIDs use increased; however, the confidence intervals for this determination were very wide. The authors conclude that in patients who are not taking aspirin, a nonaspirin NSAID is associated with a reduced risk of MI. The concomitant use of aspirin for cardioprotection along with a nonaspirin NSAID needs further study (J Am Coll Card. 2004;43:985-993).

Four-Hour Window for CAP Patients

Medicare patients with community-acquired pneumonia (CAP) fare better if they receive their first dose of antibiotics within 4 hours of hospitalization, according to new study. The records of nearly 14,000 Medicare patients admitted for CAP, who had not received antibiotics as outpatients, were reviewed. The administration of an antibiotic within 4 hours of arrival to the hospital was associated with reduced in-hospital mortality (6.8% vs 7.4%; adjusted odds ratio [AOR] 0.85; 95% CI, 0.74-0.98), reduced mortality within 30 days of admission (11.6% vs 12.7%; AOR 0.85; 95% CI, 0.76-0.95), and reduced length of stay as measured by hospitalization exceeding the 5-day median (42.1% vs 45.1%; AOR 0.90; 95% CI, 0.83-0.96). Early administration of antibiotics also resulted in a 0.4-day shorter length of stay. The study did show that the majority of patients (60.9%) received antibiotics within 4 hours of arrival (Arch Int Med. 2004;164:637-644). Current CAP guidelines generally recommend initiation of an antibiotic within 8 hours of arrival, but this study suggests that those guidelines may not be aggressive enough.

FDA Actions

Rofecoxib (Vioxx) has been approved for the treatment of migraine attacks with or without aura in adults. The approval was based on a large study that showed that the single dose of rofecoxib, either 25 or 50 mg, effectively reduced migraine pain at 2 hours and reduced the use of rescue medications.

The FDA has issued a Public Health Advisory about the need for physicians, patients, and families to closely monitor adults and children with depression when beginning treatment certain antidepressants and has asked the manufacturers of these drugs to include new warnings in their labeling about the potential for increased suicidality. The antidepressant drugs are the serotonin reuptake inhibitors fluoxetine (Prozac), sertraline (Zoloft), paroxetine (Paxil), fluvoxamine (Luvox), citalopram (Celexa), and escitalopram (Lexapro); and the non-SSRI antidepressants bupropion (Wellbutrin), venlafaxine (Effexor), nefazodone (Serzone), and mirtazapine (Remeron).

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. Telephone: (404) 262-5413. E-mail: 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.