Clinical Briefs in Primary Care
Evidence-based updates in primary care medicine By Louis Kuritzky, MD
Supplement to Clinical Cardiology Alert, Clinical Oncology Alert, Critical Care Alert, Hospital Medicine Alert, Infectious Disease Alert, Neurology Alert, OB/GYN Clinical Alert, Primary Care Reports.
Finasteride for Prevention of Prostate Cancer: 18 Years
of Follow-up
Source: Thompson I, et al. N Engl J Med 2013;369:603-610.
The prostate cancer prevention trial (PCPT) was a randomized, double- blind, placebo-controlled trial (n = 18,880) performed to evaluate the efficacy of the 5-alpha-reductase inhibitor finasteride (FIN) for prevention of prostate cancer. At the end of 7 years, the good news was a 25% reduction in total prostate cancer; the bad news was that there was a 27% increase in higher-grade prostate cancers, intimating that although the total amount of prostate cancer was reduced, overall outcomes could possibly be worsened by the increase in more aggressive cancers. Mitigating explanations for the increased risk of higher-grade tumors included alpha-reductase inhibitor-induced shrinkage of healthy prostate tissue (thereby increasing the likelihood of biopsy-positive results) and alteration of tissue architecture induced by FIN; insufficiently reassured by these explanations, most primary care clinicians have opted not to use FIN for prostate cancer prevention.
The outcomes of this population in very long-term follow-up can better answer the question of whether the risk-benefit balance was indeed unfavorably tipped by high-grade prostate cancers. Reviewing the outcomes of patients originally enrolled in PCPT, the survival rates at 18 years were essentially identical among men who had been randomized to FIN or placebo. Although FIN treatment did not appear to reduce mortality, the increased incidence of higher-grade Gleason scores among FIN-treated patients did not appear to increase mortality either. In the absence of mortality improvement, unless men are seeking alpha-reductase treatment for symptomatic benign prostatic hyperplasia, FIN treatment for prevention of prostate cancer would appear unwarranted, albeit otherwise safe.
Addressing Diabetic Neuropathy
Source: Tesfaye S, et al. Diabetes Care 2013;36:2456-2465.
Type 2 diabetes (t2dm) remains the No. 1 cause of atraumatic limb loss in the United States. Neuropathy is a primary culprit in the process beginning with undetected foot injury that progresses to deep-seated infection and, ultimately, limb loss. Hence, it is hoped that early identification and management of diabetic peripheral neuropathy (DPN) might improve outcomes. Unfortunately, of the microvascular consequences of T2DM, neuropathy appears to be the most recalcitrant to glucose control: Glucose control appears to forestall progression of neuropathy, but not improve nerve function or reverse neuropathy.
In clinical practice, it is recommended that the diagnosis of DPN should be based on typical symptoms and physical examination (e.g., lower extremity deep tendon reflex changes). On the other hand, clinical trials usually employ sophisticated techniques such as nerve conduction testing. Comparison of tuning fork testing vs monofilament testing found the former to be the most sensitive test for identification of neuropathy. The postulated pathophysiology of DPN is uncertain and may be multifactorial, but there is some support for dysfunction of the neural microvasculature.
FDA-approved agents for DPN pain are duloxetine and pregabalin, although venlafaxine, gabapentin, carbamazepine, and alpha-lipoic acid have also demonstrated some efficacy. A recently published algorithm created by the Toronto International Neuropathy Consensus Group suggests that when traditional agents are not effective, opioid analgesia may be considered.
When Metformin and Sulfonylurea Are Not Enough: Canagliflozin or Sitagliptin?
Source: Schernthaner G, et al. Diabetes Care 2013;36:2508-2515.
Many type 2 diabetes (t2dm) patients are unable to achieve or maintain their A1c goals even when appropriately treated with oral agents. Currently, the combination of metformin with a sulfonylurea (MET/SFU) is a very commonplace initial combination. Because T2DM is a progressive disorder, and because some agents lose efficacy over time, most patients must recognize that augmentation of treatment is usually required. But which next step is best when MET/SFU is insufficient?
Canaglifozin (CAN) is the first approved member of a new class of agents for T2DM, known as the SGLT2 inhibitors, which work by blocking renal reabsorption of excess glucose, leading to increased urinary glucose excretion. Sitagliptin (SIT) is one of three approved DPP-4 inhibitors that work by increasing blocking glucagon and stimulating insulin production when glucose is elevated.
In a 1-year trial comparing the addition of CAN or SIT to MET/SUF (n = 755), A1c reduction with CAN was substantially greater (-1.03 vs -0.66) and both agents were well tolerated. SGLT2 inhibitors are potentially useful when A1c goals are not attained or maintained with MET/SUF.
Wedge Insoles for Knee Osteoarthritis: Probably Not
Source: Parkes MJ, et al. JAMA 2013;310: 722-730.
In the united states, osteoarthritis is the No. 1 cause of disability. The "graying" of America, in concert with an ever-growing prevalence of obesity, portends an equally expanding population of osteoarthritis.
Osteoarthritis of the knee (OA-K) can be particularly disabling, and currently available medical treatments, such as NSAIDs, topical analgesics, and opioids, each have limitations. Hence, short of surgical intervention, alternatives — such as non-pharmacologic treatment — are sought.
Medial OA-K is one of the most common subtypes. In theory, load reduction on the medical compartment might alleviate symptoms, disease progression, or both. By placing an angulated wedge under the sole of the foot, such load reduction can be achieved. A meta-analysis was performed (n = 885) by Parkes et al to evaluate the efficacy of mechanical interventions intended to unload the medial knee compartment including wedges or structured shoes.
Overall, studies did confirm a positive effect of devices to unload the medial compartment, although the effect size was not large. Additionally, trials with an active control (such as a neutral vs an offloading wedge) failed to confirm positive effects. These mixed results call into question whether clinicians can be confident in the efficacy of wedge insoles.
Post-Stroke Blood Pressure Targets: Recent Lacunar Stroke
Source: The SPS3 Study Group. Lancet 2013;382:507-515.
Cerebral infarction related to small vessel disease, known as lacunar stroke, is strongly associated with hypertension (HTN). Numerous clinical trials have confirmed that control of HTN provides substantial stroke reduction overall (≥ 40%), without specifically distinguishing the effects on lacunar stroke.
The Secondary Prevention of Small Subcortical Strokes trial compared two levels of systolic blood pressure (SBP) among patients with a recent MRI-confirmed lacunar stroke for impact on recurrent stroke. Because of concern that excessive SBP lowering in the face of acute cerebral ischemia might be detrimental, subjects were randomized at least 2 weeks after the identifying event. Subjects (n = 3020) were randomized to one of two groups: SBP goal 130-149 mmHg or SBP goal < 130 mmHg. Clinicians were allowed to use whatever medications they preferred to attain SBP goals.
At 3.7 years, there was no statistically significant difference in the primary outcome of the study: all stroke. On the other hand, a secondary endpoint (which must be considered "hypothesis generating" since the primary endpoint failed) of hemorrhagic stroke was reduced by almost two-thirds in the SBP < 130 group. This finding prompted the consideration by the authors that since there was no difference in overall outcomes, but the suggestion of substantial reduction in hemorrhagic stroke by more strict blood pressure control, some clinicians might consider the more stringent SBP at least potentially beneficial.
Can We Identify Persons on Zolpidem at Risk for Driving Mishap?
Source: Farkas RH, et al. N Engl J Med 2013;369:689-691.
Benzodiazepines can impair consciousness. It has been recognized that the elderly — and anyone with renal impairment because they metabolize zolpidem (ZOL) more slowly — should receive a lower dose (ZOL 5 mg) than other adults (ZOL 10 mg). Soon after the advent of immediate-release ZOL, a controlled-release formulation became available. Prospective studies of ZOL indicated that plasma levels > 50 ng/mL were associated with impairment in driving skills. As formulations of ZOL evolved, pharmacokinetic studies found that the 10 mg approved dose of immediate-release ZOL was associated with ZOL levels > 50 ng/dL in as many as 15% of women (who metabolize ZOL more slowly).
Recognition of the potential for ZOL to produce impairment in driving has resulted in FDA recommendations for dose reductions in various ZOL formulations, especially in women.
Insomnia and other sleep disorders are, of course, associated with an increased risk of auto accidents due to excessive daytime sleepiness. Clinicians should maintain vigilance that appropriate dose limitations are observed — since patients often do not perceive the impairment induced by benzodiazepines — and that patients do not drive sooner than the recommended interval after taking their dose of medication.
