PPIs and Clopidogrel: Do We Have to Worry?
Source: O'Donoghue ML, et al. Lancet 2009;374:989-997.
The antiplatelet effect of clopido-grel is dependent upon its conversion and activation through the 2C19 pathway of the P450 system. Blockade of this pathway occurs because of genetics, in persons who do not have sufficiently active 2C19, and pharmacotherapies that specifically block 2C19. Proton pump inhibitors (PPIs), particularly omeprazole, are recognized to be 2C19 inhibitors. Is there reason for concern?
Although the in vitro aspects of PPI-antiplatelet interactions are of interest, it is probably more important to see whether such interactions affect the bottom line: CV events. Fortunately, there is a large — and largely reassuring — database from which to glean the impact of the PPI-antiplatelet interaction.
The PRINCIPLE-TIMI and TRITON-TIMI are acute coronary syndrome trials in which clopidogrel and/or prasugrel were used. In both of these trials, some participants were also using PPIs, providing an opportunity to see if concomitant utilization of a platelet inhibitor and PPI affected outcomes.
Subjects who were on clopidogrel who also were receiving PPIs showed less effective platelet inhibition compared to clopidogrel alone (in vitro testing). This effect was less pronounced among prasugrel recipients, consistent with its lesser dependence upon the P450 system for full activity.
Although platelet aggregometry demonstrated diminished antiplatelet effect, in these 2 trials (total n > 15,000), there was no signal of increased adverse outcomes in subjects concomitantly receiving a PPI and clopidogrel or prasugrel. PPIs provide important GI protection for persons on NSAIDs, as well as excellent symptomatic relief for GERD patients. These data suggest that PPIs need not be avoided when treating acute coronary syndromes with clopidogrel or prasugrel.
Surgery vs Medical Treatment for CTS
Source: Jarvik JG, et al. Lancet 2009;374:1074-1081.
Several trials comparing surgical with medical therapy for carpal tunnel syndrome (CTS) have been insufficient to clarify the optimum approach. Similarly, it is largely unknown which CTS characteristics predict a favorable response to either type of treatment. Jarvik et al conducted a controlled trial of CTS patients (n = 116) randomized to medical or surgical treatment. Additionally, wrist MRI and nerve conduction studies were performed to identify the predictive capacity of these metrics.
Surgical intervention consisted of either open or endoscopic carpal tunnel decompression (per surgeon preference). Medical treatment included ibuprofen 200 mg tid, physical therapy provided by a hand therapist, other analgesics, corticosteroid injections, and ultrasound (all as per clinician preference). The primary outcome was function as measured by the Carpal Tunnel Syndrome Assessment Questionnaire (CTSAQ) at 12 months.
There were no serious adverse events in either treatment group. At 12 months, although both groups showed substantial improvement, the CTSAQ score was significantly better in the surgical group. Study subjects with baseline nerve conduction deficits responded less well to surgical intervention. On MRI, patients with signs of nerve edema (indicative of more advanced disease severity) had successful outcomes (30% improvement on the CTSAQ) only half as often as those without edema. In patients with more severe baseline disease, difference in outcome between surgery and medical management diminished. Overall, surgical intervention provides outcomes that are superior to medical therapy. MRI and nerve conduction data may assist patient selection.
Influenza Vaccine: Flu Shot vs Nasal Mist
Source: Monto AS, et al. N Engl J Med 2009;361:1260-1267.
Is influenza management getting more complicated, or is it just me? Dealing with vagaries of virus antigenic shift and drift, the moving target of antiviral resistance, insufficiently sensitive point-of-care testing for influenza, and the ever-evolving designation of appropriate risk groups for "seasonal" (regular) vs "novel" (pandemic) influenza prevention is a daunting challenge.
Two major categories of trivalent influenza vaccine are available to prevent seasonal flu: inactivated (SHOT) and live attenuated (NASAL). A randomized double-blind placebo-controlled trial compared the efficacy of SHOT and NASAL vaccine to prevent influenza. Adults 18-49 years (excluding persons with contraindications to live vaccine) received one vaccine or placebo, and recorded respiratory symptoms through the 2007-2008 flu season; throat swabs were obtained for confirmation of influenza during periods of respiratory symptoms.
Among the 1963 subjects, 6.1% experienced laboratory-confirmed influenza. SHOT efficacy vs placebo was 68% compared to NASAL efficacy of 36%. In the 2007-2008 influenza season, risk reduction of influenza was almost twice as great with SHOT.
Beleaguered Primary Care Clinicians
Source: Krasner MS, et al. JAMA 2009;302:1284-1293.
If data obtained within the last 5 years are correct, the majority of primary care physicians (PCPs) report emotional exhaustion, depersonalization, and/or low sense of accomplishment — collectively called burnout. The favorable results of an intervention to alleviate burnout deserves our focus.
Primary care physicians (n = 70) in Rochester, NY, participated in a year-long intervention: 8 weeks of intensive intervention, followed by once-monthly maintenance for 10 months. Although the complexity of intervention was too great to be captured in this communication, didactic materials (including presentations on dealing with conflict, reflecting on meaningful experiences, etc.), meditation (including yoga-type exercises), and narrative exercises (for instance, writing and sharing brief stories about challenging experiences in practice) were included. Sessions occupied 2.5 hours/week for 8 weeks, followed by monthly maintenance 2.5-hour sessions for 10 months. A single all-day session of mindfulness meditation was included during week 6-7.
Following the intervention, scores on the Maslach Burnout Inventory showed meaningful improvements. Although this is a time-intensive investment, it is encouraging to see tools through which clinicians might better enjoy, be better fulfilled by, and probably perform more effectively in their practice.
Beyond Diabetes Prevention
Source: Perreault L, et al. Diabetes Care 2009;32:1583-1588.
Most individuals with prediabetes, defined as either impaired fasting glucose (IFG), impaired glucose tolerance (IGT), or both, will go on to develop diabetes unless an intervention is instituted. To date, diet, exercise, and pharmacotherapy have all been shown to reduce progression to diabetes by as much as 60%, with diet + exercise being the clearest winner. Although prevention (or delay) of diabetes is important, many persons who do not progress to overt diabetes during a diabetes prevention trial remain prediabetic, which is still a high-risk category. The report by Perreault et al describes factors which were associated, during intervention for diabetes prevention, with restoration to normal glucose regulation.
The Diabetes Prevention Program was the largest diabetes prevention trial to date (n = 3234). Prediabetes subjects were randomized to intensive lifestyle intervention (diet + exercise), metformin (850 mg bid), or placebo, with a mean follow-up of 3 years.
Within the categories of impaired fasting glucose (glucose = 100-125 mg/dL) and impaired glucose tolerance (glucose = 140-199 mg/dL on oral glucose tolerance testing), persons with lesser baseline impairments were more likely to enjoy restoration to normal glucose regulation. Similarly, younger subjects and those who successfully lost weight regained euglycemia more often.
We can encourage our patients that efforts to prevent diabetes can do that and, in some cases, even restore glucose regulation to normal.
Does Metformin Affect Thyroid Function?
Source: Cappelli C, et al. Diabetes Care 2009;32:1589-1590.
Diabetes commonly is comorbid with other endocrinopathies, including hypothyroidism and hypogonadism. The most common first-line pharmacotherapy for diabetes is metformin, which has been heretofore been considered an essentially benign drug, when proscriptions for its use (e.g., renal insufficiency, heart failure) are observed. Recent reports have suggested that metformin might have an effect on TSH even when levothyroxine replacement doses are kept constant; since many hypothyroid patients are diabetic, such effects may be worthy of note.
Capelli et al evaluated in a pilot study 11 diabetic patients with hypothyroidism who initiated therapy with metformin. All had been on stable doses of levothyroxine. Thyroid studies (TSH, free T4 and T3, and total T4 and T3) were performed at baseline, 6 hours, 24 hours, 72 hours, and 3 and 6 months after initiation of metformin. They included in their analysis additional data from another study population comprised of diabetics receiving thyroid for various indications, diabetics with subclinical hypothyroidism not receiving levothyroxine replacement, and diabetics with normal thyroid function.
During the pilot study, despite continued stable levels of levothyroxine replacement and other thyroid parameters, the mean TSH dropped from 2.11 to 1.5 mIU/L. Omission of metformin in one patient who had experienced a more dramatic TSH decline resulted in a return of TSH to baseline. Particularly in the diabetic group with subclinical (non-replaced) hypothyroidism, the decline in TSH was apparent: from a mean of 4.5 to 2.93 mIU/L at 1 year. The mechanism by which metformin lowers TSH is not known.
PPIs and Clopidogrel: Do We Have to Worry?; Surgery vs Medical Treatment for CTS; Influenza Vaccine: Flu Shot vs Nasal Mist; Beleaguered Primary Care Clinicians; Beyond Diabetes Prevention; Does Metformin Affect Thyroid Function?You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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