Publications

BACKGROUND

Training patients are the first individuals in whom a physician uses an investigational device. There is great variability in the use of data from training patients in the absence of guidelines. The prevalence and extent of data reporting from training patients in cardiovascular device studies submitted for US Food and Drug Administration (FDA) approval has not been characterized.

METHODS

Information on training patients was abstracted from the Summary of Safety and Effectiveness Data summarizing cardiovascular device premarket applications approved by the FDA from 2000 through 2007. We examined the numbers and characteristics of training patients and the inclusion of their results in end-point analyses.

RESULTS

There were 78 cardiovascular device summaries in this 8-year period, of which 17 (22%) involved training patients. Of the 123 studies in the summaries, 20 (16%) used training patients. All studies excluded training patients from efficacy analyses and 19 of 20 (95%) excluded them from safety analyses. Sixteen of 20 (80%) did not provide any outcome data, and 15 of 20 (75%) did not check for outcome differences between training and nontraining treatment patients. Eighteen of 20 (90%) did not provide demographic information on training patients, and 14 of 20 (70%) did not prespecify guidelines for their enrollment.

CONCLUSIONS

Training patients comprise a considerable proportion of patients receiving investigational cardiovascular devices, but their results are excluded from FDA submissions. Their exclusion from analyses means that safety and efficacy outcomes may look better than actual results. Guidelines on the use and inclusion of results for training patients would improve accuracy on results reporting.

Th17 cells promote a variety of autoimmune diseases, including psoriasis, multiple sclerosis, rheumatoid arthritis, and inflammatory bowel disease. TGF-β is required for conversion of naive T cells to Th17 cells, but the mechanisms regulating this process are unknown. Integrin αvβ8 on DCs can activate TGF-β, and this process contributes to the development of induced Tregs. Here, we have now shown that integrin αvβ8 expression on DCs plays a critical role in the differentiation of Th17 cells. Th17 cells were nearly absent in the colons of mice lacking αvβ8 expression on DCs. In addition, these mice and the DCs harvested from them had an impaired ability to convert naive T cells into Th17 cells in vivo and in vitro, respectively. Importantly, mice lacking αvβ8 on DCs showed near-complete protection from experimental autoimmune encephalomyelitis. Our results therefore suggest that the integrin αvβ8 pathway is biologically important and that αvβ8 expression on DCs could be a therapeutic target for the treatment of Th17-driven autoimmune disease.

Unrecognized myocardial infarction (MI) carries a poor prognosis in the general population, but its prognostic value is less clear in high-risk patients. We sought to determine whether Q waves on electrocardiogram (ECG), suggestive of unrecognized MI, predict cardiovascular events in patients with stable coronary artery disease (CAD), but without a prior history of MI. We studied 462 patients enrolled in the Heart and Soul Study with stable CAD but without a prior history of MI. All patients had baseline ECGs. The baseline prevalence of unrecognized myocardial infarction was 36%. After a mean of 6.3 years of follow-up, there were a total of 141 cardiovascular events. The presence of Q waves in any ECG lead territory predicted cardiovascular events before (unadjusted HR 1.41, 95% CI 1.01-1.97) and after adjustment for demographics, medical history, diastolic function, and ejection fraction (HR 1.55, 95% CI 1.06-2.26). This association was partly attenuated after adjustment for the presence of inducible ischemia at baseline (HR 1.43, 95% CI 0.96-2.12). When specific territories were analyzed separately, Q waves in anterior leads were predictive of cardiovascular events in both unadjusted and adjusted models (adjusted HR 1.85, 95% CI 1.14-3.00), and this association was partly attenuated after adjustment for inducible ischemia. In conclusion, in patients with CAD but no history of prior MI, the presence of any Q waves or anterior Q waves alone is independently predictive of adverse cardiovascular events.

We investigated whether those who experience the greatest increases in bone turnover in response to parathyroid hormone (PTH) therapy are the same as those who experience elevations in calcium levels. Baseline and follow-up procollagen type I N propeptide (PINP), bone-specific alkaline phosphatase (BAP), C-terminal telopeptide (CTX), and serum and urinary calcium levels were analyzed post hoc from the 119 postmenopausal women with osteoporosis randomized to PTH(1-84) in the Parathyroid Hormone and Alendronate trial. Short-term changes in the markers of bone turnover were highly correlated with one another (r=0.57-0.87, p<0.001). In contrast, change in serum calcium correlated only modestly with changes in markers of formation (r=0.22-0.30, p≤0.02) and did not correlate significantly with change in CTX (r=0.13, p=0.18). Participants who experienced hypercalcemia experienced greater 3-mo changes in BAP than those who did not (78% vs. 42% increase in BAP, p=0.04), with similar trends for PINP and CTX. In conclusion, the use of 1 marker of bone turnover, rather than multiple markers, may be sufficient to assess biochemical response to PTH(1-84). The relationship between bone turnover marker and calcium responses to PTH(1-84) is modest and does not suggest a profound, broadly heightened responsiveness of certain individuals to therapy.