Faculty Bibliography

Many consumers and clinicians incorrectly believe that the Food and Drug Administration (FDA) approval of a new therapeutic implies that its benefits have been proven to exceed its harms. While the FDA could require proof that benefits exceed harms prior to approval, it has been argued that this approach would be infeasible because of prohibitively large sample sizes. One possible alternative would be for the FDA to supplement its standard 'label' denoting 'safe and effective' with a secondary 'label' denoting benefits have been demonstrated to exceed harms, which would be granted only after sufficient post-marketing data had accumulated to prove that its benefits exceeded its harms. This secondary label would not necessarily be linked to marketing restrictions or other commercial prohibitions but, rather, would be only information for consumers and clinicians. Strengths, weaknesses, and feasibility challenges of this approach are discussed

Background: Prasugrel is effective at decreasing cardiovascular events compared to clopidogrel, but increases the risk of bleeding. In 2010, the FDA issued a black box warning to consider genetic testing in clopidogrel users. Our aims were to evaluate (1) the balance of potential benefits and harms and (2) the cost-effectiveness that would result from adopting a genotype-guided strategy of dual anti-platelet therapy following PCI for ACS vs. no testing strategies of prasugrel plus aspirin (prasugrel) or clopidogrel plus aspirin (clopidogrel). Methods: A Markov state transition model was used to conduct a decision analysis and compare strategies. Probabilities of adverse outcomes were derived from TRITON-TIMI 38 trial. Event rates on clopidogrel for carriers of CYP2C19*2 vs. wild-type were derived from the TRITON genetic substudy and a recent meta-analysis. Costs are expressed in January 2011 US dollars and estimated based on Medicare reimbursements for diagnosis-related group codes. Medication costs were used from the net wholesale price for prasugrel ($5.45/d) and a generic estimate for clopidogrel ($1/d). Results: In base case analyses, the genetic testing guided strategy yielded more benefits than harms, and was less costly compared to both 'no testing' strategies. Over 15 months, total costs were $83.8 ($1200.9 at 10 yrs) lower with a gain of 0.0007 QALY (0.0216 QALY at 10 yrs) in the genotype-guided strategy compared to prasugrel. Compared to clopidogrel, it was $0.38 ($2168.8 at 10 yrs) lower with a gain of 0.0036 QALY (0.112 QALY at 10 yrs). The strongest predictor of the preferred strategy was the relative risk (RR) of a thrombotic event occurring in CYP2C19*2 carriers versus wild-type. Below a RR of 1.5, a genotype-guided strategy is no longer more effective (but is less expensive) when compared to prasugrel. Compared to clopidogrel, below a RR of 1.3 a genotype-guided strategy is no longer cost effective (>$100,000/QALY). Clopidogrel costs ($1-$4/d) did not alter our results. Conclusions: Among ACS patients undergoing PCI, a genotype-guided strategy is economically favorable in determining which anti-platelet regimen is used, assuming that the risk of thrombotic events in CYP2C19*2 carriers is approximately 30-50% higher than wild type patients

BACKGROUND: Advance directives (AD) may promote preference-concordant care yet are absent in many patients with Chronic Obstructive Pulmonary Disease (COPD). In order to begin to inform AD discussions between clinicians and COPD patients, we constructed a decision tree to estimate the impact of alternative AD decisions on both quality and quantity of life (quality adjusted life years, QALYs). METHODS: Two aspects of the AD were considered, Do Not Intubate (DNI; i.e., no invasive mechanical ventilation) and Full Code (i.e., may use invasive mechanical ventilation). Model parameters were based on published estimates. Our model follows hypothetical patients with COPD to evaluate the effect of underlying COPD severity and of hypothetical patient-specific preferences (about long-term institutionalization and complications from invasive mechanical ventilation) on the recommended AD. RESULTS: Our theoretical model recommends endorsing the Full Code advance directive for patients who do not have strong preferences against having a potential complication from intubation (ETT complications) or being discharged to a long-term ECF. However, our model recommends endorsing the DNI advance directive for patients who do have strong preferences against having potential complications of intubation and are were willing to tradeoff substantial amounts of time alive to avoid ETT complications or permanent institutionalization. Our theoretical model also recommends endorsing the DNI advance directive for patients who have a higher probability of having complications from invasive ventilation (ETT). CONCLUSIONS: Our model suggests that AD decisions are sensitive to patient preferences about long-term institutionalization and potential complications of therapy, particularly in patients with severe COPD. Future work will elicit actual patient preferences about complications of invasive mechanical ventilation, and incorporate our model into a clinical decision support to be used for actual COPD patients facing AD decisions.

Traditional homemade brew is believed to represent the highest proportion of alcohol use in sub-Saharan Africa. In Eldoret, Kenya, two types of brew are common: chang'aa, spirits, and busaa, maize beer. Local residents refer to the amount of brew consumed by the amount of money spent, suggesting a culturally relevant estimation method. The purposes of this study were to analyze ethanol content of chang'aa and busaa; and to compare two methods of alcohol estimation: use by cost, and use by volume, the latter the current international standard. Laboratory results showed mean ethanol content was 34% (SD = 14%) for chang'aa and 4% (SD = 1%) for busaa. Standard drink unit equivalents for chang'aa and busaa, respectively, were 2 and 1.3 (US) and 3.5 and 2.3 (Great Britain). Using a computational approach, both methods demonstrated comparable results. We conclude that cost estimation of alcohol content is more culturally relevant and does not differ in accuracy from the international standard

Objective: Uncertainty about the value of antiretroviral therapy (ARV) adherence interventions may be a barrier to implementation and evaluation. Our objective is to estimate the minimum effectiveness required for ARV adherence interventions to deliver acceptable value. Methods: We used a validated HIV computer simulation to estimate the impact of ARV adherence interventions on incremental costs and life expectancy. Across a wide range of intervention costs ($1000-10,000, one time or per year), we estimated the smallest effect size compatible with acceptable value (incremental cost-effective ratio </=$100,000 per life-year). Effect sizes were measured using relative risk (RR) and absolute risk reduction (ARR), and these metrics were applied to nonadherence and nonadherence risk factors. Costs were estimated from a societal perspective ($2003) discounted at 3%. Results: To give acceptable value, a one-time $1000 intervention must reduce ARV nonadherence by RR </= 0.82 (ARR >/= 0.04) for moderately nonadherent patients (20% of ARV doses missed) and RR </= 0.90 (ARR >/= 0.05) for severely nonadherent patients (50% of ARV doses missed). A one-time $5000 intervention has an unacceptable value regardless of effect size for moderately nonadherent patients, and must reduce ARV nonadherence by RR </= 0.31 (ARR >/= 0.69) for severely nonadherent patients. Interventions aimed at behavioral risk factors (e.g., unhealthy alcohol use) may confer acceptable value (e.g., if </=$2000 and effect RR </= 0.71 [ARR >/= 0.29]). Conclusions: ARV adherence interventions with plausible effect sizes may offer favorable value if they cost <$5000 one time or per year. ARV adherence interventions with a favorable value should become more integral components of HIV care

BACKGROUND: In HIV care, it is difficult to decide when to initiate therapy, which drugs to use for initial treatment, and which drugs to use if drug resistance develops. With hundreds of possible drug regimens available and variable patterns of drug resistance, randomized controlled trials cannot answer all HIV treatment decisions. Mechanistic models of HIV infection can be used to conduct virtual therapeutic trials with the goal of predicting outcomes, some of which are long-term and may not fall within the time frame of a typical therapeutic trial. METHODS: We used a previously developed and validated model of HIV infection to replicate 2 arms of an HIV initial treatment trial (ACTG A5142) and predict long-term outcomes. The model incorporated data about biologic processes involved in the development of drug resistance. RESULTS: The model reproduced the proportion that developed AIDS (0.04 and 0.05 for the efavirenz arm and lopinavir arms, respectively, vs. 0.04 and 0.06 for the trial), the development of virologic failure (0.27 and 0.33 for the Efavirenz arm and lopinavir arms, respectively, vs. 0.24 and 0.37 for the trial), and drug resistance. The hazard ratio for the time to treatment failure, a combination of resistance and other causes (0.96 for the model vs. 0.75 for the trial; 95% confidence interval, 0.57-0.98), and changes in CD4 cell count, were less accurate. The model estimated longer-term life expectancy, quality-adjusted life expectancy, and HIV-related deaths. CONCLUSIONS: Mechanistic models of HIV infections have the potential to be useful in comparative effectiveness research.

BACKGROUND: Evidence suggests that cost sharing (i.e.,copayments and deductibles) decreases health expenditures but also reduces essential care. Value-based insurance design (VBID) has been proposed to encourage essential care while controlling health expenditures. Our objective was to estimate the impact of broader diffusion of VBID on US health care benefits and costs. METHODS AND FINDINGS: We used a published computer simulation of costs and life expectancy gains from US health care to estimate the impact of broader diffusion of VBID. Two scenarios were analyzed: (1) applying VBID solely to pharmacy benefits and (2) applying VBID to both pharmacy benefits and other health care services (e.g., devices). We assumed that cost sharing would be eliminated for high-value services (<$100,000 per life-year), would remain unchanged for intermediate- or unknown-value services ($100,000-$300,000 per life-year or unknown), and would be increased for low-value services (>$300,000 per life-year). All costs are provided in 2003 US dollars. Our simulation estimated that approximately 60% of health expenditures in the US are spent on low-value services, 20% are spent on intermediate-value services, and 20% are spent on high-value services. Correspondingly, the vast majority (80%) of health expenditures would have cost sharing that is impacted by VBID. With prevailing patterns of cost sharing, health care conferred 4.70 life-years at a per-capita annual expenditure of US$5,688. Broader diffusion of VBID to pharmaceuticals increased the benefit conferred by health care by 0.03 to 0.05 additional life-years, without increasing costs and without increasing out-of-pocket payments. Broader diffusion of VBID to other health care services could increase the benefit conferred by health care by 0.24 to 0.44 additional life-years, also without increasing costs and without increasing overall out-of-pocket payments. Among those without health insurance, using cost saving from VBID to subsidize insurance coverage would increase the benefit conferred by health care by 1.21 life-years, a 31% increase. CONCLUSION: Broader diffusion of VBID may amplify benefits from US health care without increasing health expenditures.