Effective Combination Therapy for Acne

Source: Thiboutot D, et al. An aqueous gel fixed combination of clindamycin phosphate 1.2% and benzoyl peroxide 2.5% for once-daily treatment of moderate to severe acne vulgaris. J Am Acad Dermatol 2008;59:792-800.

Topical agents, both as monother apy and in combination, have shown efficacy in management of acne. Benzoyl peroxide (BPO) is one of the most commonly used agents, but despite excellent efficacy, the side effects of skin dryness, burning, erythema, and peeling are sometimes limiting effects of treatment.

Clinical trials of clindamycin phosphate (CMP) 1% + BPO have demonstrated that the combination is more effective than either agent alone, but traditional BPO concentrations (5%-10%) have been associated with dryness and irritation. Monotherapy comparisons of BPO 2.5% with BPO 5%-10% indicate similar efficacy, with better tolerability. Hence a clinical trial to establish the relative efficacy of CMP, BPO 2.5%, and the combination was a sensible next step.

Thiboutot et al randomized adolescents and adults (n = 2813) with moderate-to-severe acne to CMP 1%, BPO 2.5%, CMP + BPO, or placebo. Subjects were followed for 12 weeks. Outcomes included facial acne lesion counts as well as tolerability evaluation.

CMP + BPO was statistically significantly superior to CMP, BPO, and placebo at the conclusion of the trial. The tolerability of CMP + BPO was essentially the same as placebo (vehicle), and when adverse effects were reported, 97% were mild to moderate. My on-line search (Nov. 23, 2008) does not yet show availability of a CMP 1% + BMP 2.5% product, but FDA approval of this product (Acanya™) occurred Nov. 20, 2008.

Genotypes associated with CRP elevations

Source: Zacho J, et al. Genetically elevated C-reactive protein and ischemic vascular disease. N Engl J Med 2008;359:1897-1908.

It remains uncertain whether the observed relationship between elevated CRP levels and adverse cardiovascular outcomes is causal. The question remains whether elevated CRP simply reflects the presence of inflammation or instead is etiologic in increasing the risk of endpoints. One way to elucidate the relationship is to evaluate persons who have gene polymorphisms that lead to elevated CRP levels.

Danish investigators identified genotypes associated with elevated CRP; a high-sensitivity CRP level of > 3.0 was defined as high. Several populations were available for comparison: the Copenhagen City Heart Study (n = 10, 276); the Copenhagen General Population Study (n = 37,690); and the Copenhagen Ischemic Heart Disease Study (n = 2238).

Overall, an elevated CRP was associated with an increased risk of ischemic heart disease (2.2 relative risk). However, when the population of individuals with genetic polymorphisms leading to elevated CRP was evaluated, there was no increased CV risk identified. If elevated CRP levels were causal in CVD endpoints, one would expect that persons with genetically influenced elevations would show a similar risk relationship as study groups with known CVD. The concluding statement of the authors summarizes their findings: "…the risk of ischemic vascular disease associated with higher plasma CRP levels observed in epidemiologic studies may not be causal, but rather that increased CRP levels are simply a marker for atherosclerosis and ischemic vascular disease."

Benefits of Extended Duration Detoxification

Source: Woody GE, et al. Extended vs short-term buprenorphine-naloxone for treatment of opioid-addicted youth. JAMA 2008;300:2003-2011.

Misuse of pharmaceutical opioids is increasing. Data from 2004 indicate that as many as 10% of high school seniors acknowledge prescription opioid use in the prior year. Although the majority of opioid misuse is sporadic, a substantial minority of young adults suffer opioid addiction, for which short-term (14 days) buprenorphine combined with naloxone (s-B/N) has shown some detoxification benefit. Whether a more extended e-B/N (e-B/N) program could reduce opioid addiction relapse was the object of this study.

Woody et al randomized opioid-addicted adults (n = 153) to either s-B/N (14 days) or e-B/N (12 weeks). The primary outcomes measure was the number of patients with opioid-positive urine drug testing (UDT) at week 12.

UDT was opioid-positive in 51% of s-B/N subjects, compared with 43% of the e-B/N group. Post-treatment outcomes at months 6, 9, and 12 showed no statistically significant difference in use of opioids, alcohol, or marijuana between the groups; on the other hand, cocaine use was approximately half as common in the e-B/N group. Extending the duration of B/N treatment merits further study, based upon the favorable results of this trial.

CPAP for OSA in Metabolic Syndrome

Source: Dorkova Z, et al. Effects of continuous positive airway pressure on cardiovascular risk profile in patients with severe obstructive sleep apnea and metabolic syndrome. Chest 2008;134:686-692.

The association of obstructive sleep apnea (OSA) with adverse cardiovascular (CV) outcomes is strong. Encouraging data from persons with OSA who have been treated with continuous positive airway pressure (CPAP) have demonstrated that effective CPAP treatment reduces blood pressure. Whether CPAP might have favorable effects on other CV risk factors such as glucose, lipids, and markers of inflammation is less clear. Individuals with metabolic syndrome, who are at increased risk for CV events, provide an appropriate population to study the impact of CPAP treatment for OSA upon CV risk factors.

Dorkova et al studied 32 metabolic syndrome patients with OSA. At baseline and after 8 weeks of CPAP for OSA, risk factors associated with CVD were measured and compared: BP, cholesterol, triglycerides, HDL, fibrinogen, CRP, insulin resistance, and others. Subjects who used their CPAP for at least 4 hours nightly were considered compliant.

Compliant CPAP users enjoyed reduced BP, cholesterol, and insulin resistance. Non-compliant CPAP subjects (i.e., < 4 hrs/night) did not demonstrate these favorable changes. CPAP has been shown, in the high-risk group of patients with metabolic syndrome, to improve the CV risk factor profile.

Uric Acid and CV Risk: Not Ready Yet

Source: Feig DI, et al. Uric acid and cardiovascular risk. N Engl J Med 2008;359:1811-1821.

The relationship between uric acid (URA) and cardiovascular (CV) risk has been the subject of controversy for decades. Even if one were to fully accept that the various associations between URA and unfavorable CV outcomes have a causal relationship, the hurdle of prospectively proving that reduction of URA will improve outcomes has yet to be addressed.

URA elevation has been identified as a harbinger of hypertension, as well as obesity, diabetes, and kidney disease, but that may only be part of the story. For instance, that renal disease develops disproportionately in gouty patients is certainly true, but so does hypertension, which is more often the cause of renal disease than uric acid stones or urate nephropathy. The Framingham Heart Study suggests that the relationship of URA and CV risk is not independent of hypertension, hence, it does not qualify as an independent risk factor.

URA may play an etiologic role in development of metabolic syndrome. Even though insulin resistance is regarded by some as a sine qua non of metabolic syndrome, URA often precedes the insulin resistance; indeed, animal studies suggest that decreasing URA forestalls metabolic syndrome.

URA is also associated with vascular disease in the carotids and peripheral circulation. Some even attribute favorable CV effects seen in the LIFE study (utilizing losartan) to its favorable effects on lowering uric acid (losartan is the only antihypertensive agent known to lower uric acid).

The pathophysiologic underpinnings linking URA to CV misadventure have some plausibility. All-in-all, the relationship between URA and CV risk is tantalizingly close to compelling. However, even though we have expanded the old aphorism that "close only counts in horse shoes and hand grenades" to include archery, darts, lawn bowling, etc., close still doesn't count in science.

Documentation of Coronary Ischemia Prior to PCI

Source: Lin GA, et al. Frequency of stress testing to document ischemia prior to elective percutaneous coronary intervention. JAMA 2008;300:1765-1773.

For the sake of discussion, let's momentarily agree that percutaneous coronary intervention (PCI) is an appropriate step for persons suffering symptomatic coronary artery disease. The reason to establish this premise is that whether PCI actually offers any meaningful advantage over simple medical management is a matter of great debate. Indeed, the majority of PCIs in the United States are performed for patients with stable coronary disease, despite lack of evidence that outcomes with PCI in this setting are superior to intensive risk factor modification combined with medical therapy. Guidelines for PCI in stable CAD patients suggest that documentation of ischemia (most commonly by treadmill testing) should be obtained prior to PCI.

This study looked at Medicare beneficiaries undergoing elective PCI to see how often PCI had been preceded by stress testing. Of 23,887 Medicare recipients who underwent PCI in 2004, slightly less than half had any record of stress testing within the 90 days immediately preceding their PCI. The authors comment that in the absence of corroboration of ischemia, PCI may have been performed in patients who may not have benefited.