Value of Improved Lipid Control in Patients at High Risk for Adverse Cardiac Events

ABSTRACT

Objectives: Lipid-lowering therapy (LLT) is suboptimally used in patients with hyperlipidemia in the 2 highest statin benefit groups (SBGs), as categorized by the American College of Cardiology and the American Heart Association. This study estimated the social value of reducing low-density lipoprotein cholesterol (LDL-C) levels by 50% for patients in SBGs 1 and 2 who have been treated with standard LLT but have not reached LDL-C goal, as well as the potential value of PCSK9 inhibitors for patients in these groups.

Study Design: Simulation model.

Methods: We used National Health and Nutrition Examination Surveys (NHANES) and US Census data to project the population of SBGs 1 and 2 in the time period 2015 to 2035. We used insurance claims data to estimate incidence rates of major adverse cardiac events (MACEs), and NHANES with National Vital Statistics data to estimate cardiovascular disease mortality rates. Using established associations between LDL-C and MACE risk, we estimated the value of reducing LDL-C levels by 50%. We incorporated results from a meta-analysis to estimate the value of PSCK9 inhibitors.

Among those treated with LLT with LDL-C >70 mg/dL in SBGs 1 and 2, the cumulative value of reducing LDL-C levels by 50% would be $2.9 trillion from 2015 to 2035, resulting primarily from 1.6 million deaths averted. The cumulative value of PCSK9 inhibitors would range from $3.4 trillion to $5.1 trillion (1.9-2.8 million deaths averted), or $12,000 to $17,000 per patient-year of treatment.

Results:

Conclusions: Lowering LDL-C in high-risk patients with hyperlipidemia has enormous potential social value. For patients in these high-risk groups, PCSK9 inhibitors may have considerable net value depending on the final prices payers ultimately select.

Am J Manag Care. 2016;22(6):e199-e207

Take-Away Points

Before PCSK9 inhibitors even reached market, their costs to the healthcare system were the subject of much scrutiny. We estimated the social value of PCSK9 inhibitors to place their costs in context with the value they generate for patients and society.

• Our study confirmed what we already knew: reducing lipid levels significantly in high-risk patients can have a considerable health impact.
• Our study suggests that depending on the resulting confirmation of current estimates of effectiveness, PCSK9 inhibitors can provide considerable value when appropriately targeted, even at currently negotiated prices.
• We also show that estimates of the likely budget impact are considerably off the mark when realistic uptake patterns are applied.

Cardiovascular disease (CVD) remains the leading cause of death, disability, and medical costs in the United States. Nearly 1 in 3 Americans dies of heart disease or stroke, and the annual cost of CVD in the United States exceeds $600 billion.¹ Elevated low-density lipoprotein cholesterol (LDL-C) has been associated with increased risk for CVD events and death.^2-8 Historically, statins have served as first-line lipid-lowering therapy (LLT) for LDL-C reduction, although recent guidelines have questioned the role of specific LDL-C goals in the primary and secondary prevention of CVD events.^3,9

Despite estimates of the costs of CVD in the United States, little is known about the economic value of reducing the hyperlipidemia burden among those at high risk for CVD who, despite use of standard LLT, do not achieve conventional LDL-C goals (eg, ≤70 mg/dL). The American College of Cardiology (ACC) and American Heart Association (AHA) classify patients as being in the highest-risk statin benefit groups (SBGs) with established atherosclerotic CVD (ASCVD) (SBG 1), LDL-C levels >190 mg/dL (SBG 2), and diabetes (SBG 3).³ Previous research estimated that up to 75% of high-risk patients treated with statins fail to achieve LDL-C of ≤70 mg/dL.¹⁰ High CVD event rates in this population, coupled with a substantial proportion of patients not at conventional LDL-C goals, suggest potentially large economic value from reducing the burden of hyperlipidemia. Previously, eliminating deaths resulting from CVD has been estimated to be worth nearly $50 trillion in economic value.¹¹ For those initiating statin therapy between 1997 and 2008 alone, the value of averted deaths and CVD events may exceed $1 trillion.¹²

Members of a novel class of therapies called PCSK9 inhibitors have recently been approved for treatment of hyperlipidemia in patients in SBGs 1 and 2 who do not achieve LDL-C of ≤70 mg/dL despite receiving maximally tolerated LLT. In phase 2 and 3 trials, PCSK9 inhibitors have been shown to reduce LDL-C by between 50% and 77%, on average.¹³ Preliminary clinical outcomes from these studies suggest that PCSK9 inhibitors may reduce rates of major adverse cardiac events (MACEs) by up to 50%.¹³ Based on these findings, the FDA approved alirocumab and evolocumab for use in adults with heterozygous familial hypercholesterolemia or ASCVD, who require additional LDL-C reduction.¹⁴ Amidst these developments, payers and policy makers have expressed concern that PCSK9 inhibitors’ costs—announced at $14,100 and $14,600 annually for evolocumab and alirocumab, respectively—will dramatically increase healthcare spending.^15,16

In this study, we estimated the economic value to the United States over the next 20 years (2015-2035) of reducing hyperlipidemia burden among those at high risk for MACEs (SBGs 1 and 2) who have not achieved conventional LDL-C goals despite use of standard LLT therapy. As a case study, we estimated the value to the United States of using PCSK9 inhibitors in these patients who are currently on LLT but have not achieved an LDL-C of ≤70 mg/dL.

METHODS

Overview of Approach

Our study had 2 objectives: first, we sought to quantify the clinical and economic values of reducing the burden of hyperlipidemia among patients in the United States at high risk for MACEs or CVD mortality who have been treated with standard LLT but have not achieved conventional LDL-C goals. Second, we sought to project the clinical and economic value of PCSK9 inhibitors in patients at particularly high risk of MACEs or CVD mortality who may be eligible for treatment with these agents—those in SBGs 1 and 2—who have been treated with standard LLT but have not achieved conventional LDL-C goals. We defined conventional LDL-C goals to be ≤70 mg/dL and analyzed the sensitivity to a higher threshold of ≤100 mg/dL.

eAppendices

We used the 2011 to 2012 National Health and Nutrition Examination Study (NHANES)¹⁷ to first estimate the proportion of the US adult population (nonpregnant adults 18 years or older) in SBGs 1 and 2, as outlined by ACC and AHA guidelines³ (see eAppendix Tables 1 and 2 [ available at www.ajmc.com]).³ We then divided each of these groups into 3 risk subgroups based on their use of, and LDL-C response to, LLT: subgroup A—patients on LLT who have not successfully reduced LDL-C to ≤70 mg/dL (or ≤100 mg/dL, in sensitivity analyses); subgroup B—patients at goal LDL-C on LLT; and subgroup C—patients not on LLT.^3,17 We used US Census projections to estimate the size of each these populations from 2015 to 2035.¹⁸ We used the Truven Marketscan insurance claims database to estimate the rates of nonfatal CVD events (ie, unstable angina, myocardial infarction, coronary arterial revascularization, and ischemic stroke) and a combination of the NHANES mortality files and National Vital Statistics Mortality Report (2012) to estimate mortality rates for each of these groups (see eAppendix Tables 3-5).^17,19,20

With projected prevalence of patients not at goal LDL-C despite being on LLT (or who are intolerant to statins), we estimated the number of CVD-related deaths and MACEs averted for subgroup A in the time period 2015 to 2035 if LDL-C levels were hypothetically reduced by 50%, as suggested by the ACC and AHA.³ To estimate the effects of LDL-C reductions, we used the quantitative relationship between LDL-C and relative risk of CVD events and mortality from the Cholesterol Treatment Trialists’ (CTT) Collaboration meta-analysis.^9,13 We then quantified the economic value to the United States of averted CVD-related deaths and MACEs using standard health economic valuation approaches.^12,21

We simulated the effects of PCSK9 inhibitor use for SBGs 1 and 2 in subgroup A patients. We projected the number of CVD-related deaths and MACEs averted in the time period 2015 to 2035, and the associated economic value if these patients were to receive PCSK9 inhibitors for further LDL-C reduction. We estimated the effects of PCSK9 inhibitors in 2 ways. First, we combined the LDL-C—lowering effects from PCSK9 inhibitor trials with the LDL-C relationship from the CTT Collaboration meta-analysis.^9,13 Second, we used data on the effects of PCSK9 inhibitors on CVD-related death and MACEs from a meta-analysis of recent randomized controlled trials of these drugs.¹³ For a more detailed description of our methods for population and prevalence projections and event and mortality rate estimates, please see the eAppendix.

Across all PCSK9 inhibitor trials, the mean difference in LDL-C between those receiving LLT plus PCKS9 inhibitors compared with LLT alone was 59% (95% CI, 57%-61%). We used data from the CTT Collaboration meta-analysis (described in the eAppendix) to estimate the effect on clinical outcomes.⁹ Using this method, PCSK9 inhibitor use in SBG 1 was associated with a reduction in MACE risk ranging from 43% to 50%, and a 32% reduction in CVD mortality risk, assuming the same baseline LDL-C level as indicated above. In SBG 2, the mortality reduction was 45%. The estimated impact of PCSK9 inhibitors on clinical outcomes in this scenario was termed the “conservative efficacy” treatment scenario. Next, we modeled the impact of PCSK9 inhibitors on MACEs and CVD deaths by using direct outcomes data from a meta-analysis of PCSK9 trials.¹³ In the meta-analysis, PCSK9 inhibitor use was associated with a 50% relative risk reduction in rates of MACEs and CVD mortality. We termed this scenario the “high-efficacy” treatment scenario.

It should be noted that the studies in this meta-analysis were not weighted to detect differences in MACE outcomes, but for changes in LDL-C levels. Therefore, these results should be interpreted with caution.

We then modeled 3 uptake scenarios for PCSK9 inhibitors. In each scenario, PCSK9 inhibitor uptake began at 3% of the eligible population in 2015 (the eligible population included patients in SBGs 1 and 2 treated with standard LLT, but with LDL-C >70 mg/dL). Starting in 2016, uptake was assumed to increase linearly by 1%, 2%, or 3% for scenarios 1, 2, and 3, respectively, until 2023, when treatment uptake reached the maximum of 10% (scenario 1), 20% (scenario 2), or 30% (scenario 3) of the eligible population, and then remained constant through 2035.

Translating Clinical Outcomes Into Estimates of Economic Value

We estimated the economic value associated with averted CVD-related deaths and MACEs as follows. First, we identified the number of life-years gained by averting a single CVD-related death to be 14.9 additional life-years.²² As this number was taken from follow-up data based on a clinical trial, and clinical trials tend to exclude older age groups, we were concerned that this number may overstate the additional life-years after a CVD event. Therefore, we also undertook the same analysis using the mean life-years lost from an ischemic heart disease death from the US Burden of Disease Study²³ (these results are shown in eAppendix Table A6). To value the gain in life-years, we used a value of $150,000 per life-year.^21,24 The World Health Organization’s report on macroeconomics and health outlined an alternative approach to estimating the social value of lives saved due to healthcare interventions and concluded that healthcare interventions that save 1 life-year at a cost of less than 3 times the gross domestic product per capita (for a given country) are cost-effective.²⁵

Second, we assessed the value of reducing CVD-related hospitalizations using a recent review of the incremental costs of these hospitalizations in the United States. We estimated total cost savings from averted CVD hospitalizations by multiplying these unit cost estimates by the number of events averted.²⁶ The value of life-years gained and savings from reduced CVD hospitalizations were summed to estimate both the total value of reducing residual LDL-C by the ACC/AHA goal of 50%, and the value of PCSK9 inhibitors in SBGs 1 and 2 for each of the 3 uptake scenarios described above. Future costs and benefits were discounted at 3%, using 2015 as the base year.

RESULTS

Table 1

We estimated that in 2015, 32 million individuals in the United States would fall into ACC/AHA SBGs 1 and 2. Of these, 17.1 million did not receive LLT, 11.8 million were treated with standard LLT but had LDL-C >70 mg/dL, and 6.1 million were treated with standard LLT but had LDL-C >100 mg/dL. We projected that these figures would increase to 21.4 million, 16 million, and 8.1 million individuals, respectively, by 2035, absent changes in LLT use (). In 2015, the largest SBG—SBG 1—was estimated to have 10.1 million individuals with LDL-C >70 mg/dL and 4.4 million with LDL-C >100 mg/dL despite having been treated with LLT. By 2035, these figures were projected to increase to 14.0 million and 6.1 million, respectively.

Value of Averted MACEs and CVD Deaths Associated With a Hypothetical 50% LDL-C Reduction in SBGs 1 and 2

Figure 1

We estimated that by 2020, approximately 3.6 million MACEs would be averted if LDL-C levels were reduced by 50% among those treated with standard LLT but who still had LDL-C levels >70 mg/dL (). Additionally, we estimated that approximately 1.9 million MACEs would be averted by then if LDL-C levels were reduced by 50% among those treated with standard LLT but who still had LDL-C >100mg/dL. By 2035, these figures were estimated to increase to 14.2 million and 7.5 million, respectively.

We also estimated that by 2020, approximately 400,000 CVD deaths would be averted if LDL-C levels were reduced by 50% among those treated with standard LLT but who still had LDL-C levels >70mg/dL (eAppendix Figure 1). Approximately 230,000 CVD-related deaths would be prevented by 2020 for those with LDL-C >100 mg/dL. These figures increased to 1.6 million and 900,000, respectively, by 2035.

We estimated that by 2035, the cumulative value of averted CVD deaths and MACEs associated with a hypothetical 50% LDL-C reduction would be $2.9 trillion among individuals treated with standard LLT but who still had LDL-C >70mg/dL and $1.6 trillion among individuals with LDL-C >100mg/dL.

Value of Averted MACEs and CVD Deaths Associated With PCSK9 Inhibitor Use in SBGs 1 and 2

We estimated that by 2035, approximately 17 million MACEs (eAppendix Figure 2) and 2 million CVD deaths (eAppendix Figure 3) would be averted under a conservative PCSK9 inhibitor efficacy scenario if all patients in SBGs 1 and 2 treated with standard LLT, but who still had LDL-C >70 mg/dL, used PCSK9 inhibitors. Under the high-efficacy scenario, which assumed a 50% reduction in CVD mortality with PCSK9 inhibitor use, PCSK9 inhibitor use would prevent approximately 19 million MACEs and 3 million CVD-related deaths. In patients treated with standard LLT, but who still had LDL-C >100 mg/dL, 100% uptake of PCSK9 inhibitors would prevent approximately 9 million MACEs and 1 million CVD-related deaths under the conservative-efficacy scenario, as well as 10 million MACEs and 1.5 million CVD-related deaths under the high-efficacy scenario.

Figure 2

For patients in SBGs 1 and 2 treated with standard LLT but who still had LDL-C >70 mg/dL, we estimated the cumulative value of averted deaths and MACEs by 2035 to be $3.4 trillion under the conservative scenario and $5.1 trillion under the high-efficacy scenario (assuming 100% PCSK9 inhibitor uptake) (). For patients in SBGs 1 and 2 treated with standard LLT, but who still had LDL-C >100 mg/dL, we projected the cumulative value of averted deaths and MACEs by 2035 to be $1.9 trillion under the conservative-efficacy scenario and $2.7 trillion under the high-efficacy scenario (again assuming 100% PCSK9 inhibitor uptake).

Figure 3

We modeled how varying PCSK9 inhibitor uptake influenced our projections. In our low-uptake scenario (in which a maximum of 10% of eligible patients use PCSK9 inhibitors by 2035), we estimated the value of averted MACEs and CVD-related deaths by 2035 to be $300 billion in the conservative-efficacy PCSK9 inhibitor scenario and $430 billion in the high-efficacy scenario (). In contrast, in a high-uptake scenario (in which a maximum of 30% of eligible patients by 2035 use PCSK9 inhibitors), we estimated the value of averted MACEs and CVD-related deaths by 2035 to be $830 billion in the conservative-efficacy PCSK9 scenario and $1.2 trillion in the high-efficacy scenario.

Per-Person Value of Averted MACE and CVD Deaths Associated With PCSK9 Inhibitor Treatment

Table 2

In addition to estimating MACEs, CVD-related deaths, and the potential value of averted events associated with PCSK9 inhibitor use at the population level, we estimated the value per person-year of treatment with a PCSK9 inhibitor for patients in SBGs 1 and 2 (). For patients treated with standard LLT but who still had LDL-C >70 mg/dL, we projected the value per person-year of treatment to be $11,600 in the conservative-efficacy scenario and $17,100 in the high-efficacy scenario. At a goal LDL-C of ≤100 mg/dL, the estimated value per person-year of treatment with PCSK9 inhibitors was $12,600 in the conservative-efficacy scenario and $18,000 in the high-efficacy scenario. These estimates illustrate the potential range of social value per eligible patient treated with PCSK9 inhibitors.

DISCUSSION

We estimated the economic value to the United States over the next 20 years of reducing the burden of hyperlipidemia among patients in the highest ACC and AHA SBGs.³ We estimated that reducing LDL-C by 50% in SBG 1 and 2 patients who have been treated with standard LLT but still have LDL-C levels >70 mg/dL could avert approximately 14.2 million MACEs, including 1.6 million CVD-related deaths, by 2035.

Our study complements previous estimates of the economic value of LLT, including statin therapy, in the United States.¹² Our estimates of the value of PCSK9 inhibitors are lower than the previously estimated social value of statins of approximately $51,000 per patient (in 2015 dollars).¹² One factor that may partly explain this difference is that the growing use of percutaneous coronary intervention, P2Y12 inhibitors, angiotensin-converting enzyme inhibitors, aldosterone antagonists, and implantable cardiac defibrillators has led to dramatic improvements in CVD outcomes since statins were introduced.^27-34 It is also possible that new CVD treatments produce smaller absolute benefits compared with those projected for statins, simply because overall morbidity and mortality for CVD were higher 20 years ago than today.

Although PCSK9 inhibitors may lower LDL-C and improve health outcomes for high-risk populations, policy makers and clinicians have raised concerns about the cost of these drugs to the healthcare system.¹⁶ The prices per patient-year of treatment were set recently at $14,100 and $14,600 per year for evolocumab and alirocumab, respectively. Some have estimated that systemwide costs for these drugs could be $150 billion annually.³⁵ A critical question for patients and payers will be whether the value of PCSK9 inhibitor benefits outweighs their expense. Our estimates suggest that whether PCSK9 inhibitors deliver net social value (ie, generate benefits in excess of costs) depends on the assumptions about drug efficacy, the economic value of mortality improvements, which patient populations receive PCSK9 inhibitors, and the ultimate prices paid for these drugs. PCSK9 inhibitors would generate net positive social value for the average patients in SBGs 1 and 2, as long as the annual net price falls below $18,000 in a high-efficiency scenario or $12,000 in a conservative-efficiency scenario. According to a recent report, the average reported rebates for branded pharmaceutical drugs are around 30%,³⁶ which would mean an average cost per year for PCSK9 inhibitors of around $10,000. Because our estimates do not include any benefits from increases in health-related quality of life from treatments or events avoided, our estimates may be conservative.

Our findings also add to our understanding of the size of the populations likely to receive PCSK9 inhibitors initially. Several current estimates assume that a majority of the 70 million patients in the 4 ACC/AHA SBGs (only 3 of which were included in this study) will eventually receive PCSK9 inhibitors, which may overestimate the actual societal cost of PCSK9 inhibitors if they are instead primarily prescribed to high-risk patients with poorly controlled LDL-C despite LLT—a small subset of all patients in these 4 SBGs. Our models for patients in the 2 highest SBGs (patients with ASCVD or LDL-C >190 mg/dL) were designed to reflect the reality that clinicians and payers are likely to focus initially on the smaller subset of patients who have up-titrated to maximal statins, but have still failed to achieve LDL-C reduction. For this reason, our projections of the potential benefits and value of PCSK9 inhibitors over the next 3 to 5 years may be more accurate than previous estimates. Nonetheless, even if PCSK9 inhibitors are prescribed only to patients in SBGs 1 and 2 who have been treated with standard LLTs but have not reached the LDL-C goal, some estimates suggest that healthcare spending on LLTs may increase by $10 billion annually over the next 2 decades.¹⁵

Limitations

Our study has several limitations. First, our estimated clinical impacts rely on epidemiologic models and evidence from studies of statins of the association among LDL-C levels, MACEs, and CVD-related deaths, which may differ in patients receiving PCSK9 inhibitors. Our estimated impacts assume a linear relationship among the levels of LDL-C reduction and MACEs and CVD-related deaths, which may not be the case at the lower levels of resulting LDL-C simulated in our model. In addition, our analysis of PCSK9 inhibitors used early clinical outcomes data for these drugs; relative risk reductions estimated from larger patient populations may differ from current estimates. Although existing studies suggest that PCSK9 inhibitors are associated with reduced MACEs and deaths, definitive evidence will not be available for several years. Furthermore, even definitive trial evidence may differ from real-world outcomes. Real-world efficacy patterns will be affected by patient treatment heterogeneity and physician decision making.

Second, we estimated the value of PCSK9 inhibitors among patients in the 2 highest SBGs who had been treated but were not at goal LDL-C, assuming that these patients would be the relevant treatment population who had been up-titrated to maximally tolerated doses for statins or other LLTs. In reality, many patients on LLT are not at maximally tolerated doses or are nonadherent with LLT even if they do not experience side effects from these agents.³⁷ Optimizing LLT may reduce the size of the prevalent population who could potentially benefit from PCSK9 inhibitors, since the number of patients failing to achieve LDL-C goals would fall. Our estimates may therefore be an upper bound of the value of PCSK9 inhibitors in these populations because we assumed that LLT rates would remain at their current levels and not rise due to payer pressures. In addition, patients who are nonadherent with LLT may not be candidates for PCSK9 inhibitors even if their LDL-C is >70 mg/dL.

Third, we relied on parameter assumptions and outcomes data to estimate the impacts of LDL-C reduction and PCSK9 inhibitors. The Truven Marketscan database had inconsistent information across variables, particularly with regard to risk factors and cardiovascular events, and lacked information on blood pressure. We therefore may have underestimated cardiovascular events. In addition, the NHANES data used for mortality estimates lacked information on heart failure and transient ischemic attacks, leading us to potentially underestimate overall CVD burden. In our PCSK9 inhibitor analysis, we also assumed that the mean difference in LDL-C between those receiving LLT plus PCKS9 inhibitors versus LLT alone was 59%.¹³ We did not conduct a separate sensitivity analysis using the bounds of this confidence interval. Rather, we reported a broad range of estimates based on assumptions of conservative versus high efficacy of PCSK9 inhibitors.

Fourth, we did not account for growing efforts to prescribe high-intensity statins, which may increase the proportion of high-risk patients who achieve target LDL-C goals, potentially reducing demand for PCSK9 inhibitors. Indeed, as of 2009, more than 70% of patients with indications for high-intensity statins—including patients hospitalized for acute coronary syndrome—did not receive statin prescriptions.^10,38

Finally, while we defined an LDL-C goal of ≤70 mg/dL, current cholesterol treatment guidelines do not recommend treating to a specific LDL-C goal because some have argued that the data to support this practice is not sufficiently robust.³ However, existing evidence indicates that statins reduce MACEs when the baseline LDL-C level is >70 mg/dL.³ Moreover, in many countries, ≤70 mg/dL remains an important LDL-C treatment goal for high-risk patients.³⁹ Nonetheless, our definition of the PCSK9 inhibitor—eligible population as all high-risk patients with LDL-C >70 mg/dL could have led us to overestimate the size of the patient population that stands to benefit from these drugs.

CONCLUSIONS

The population burden of CVD continues to grow despite improvements in CVD treatment. Among those at high risk for CVD who do not achieve sufficient LDL-C reduction despite LLT, we estimated substantial economic value associated with reducing the burden of hyperlipidemia by the ACC/AHA goal of 50%. Moreover, although at an early stage, early clinical studies suggest that PCSK9 inhibitors may substantially reduce MACEs and CVD-related deaths. Although our estimates suggest that these drugs may generate significant value for society, PCSK9 inhibitors’ net impact will depend on the final costs of these therapies and on pending results of trials evaluating their clinical outcomes. The number of individuals initially prescribed PCSK9 inhibitors is likely to be significantly lower than that suggested by previous estimates.

Acknowledgments

Support for this research was provided by Amgen. Administrative and editorial support was provided by Alison Silverstein, MPH.

Author Affiliations: Harvard Medical School (ABJ and DMB), Boston, MA; Massachusetts General Hospital (ABJ and DMB), Boston, MA; Precision Health Economics (WS, TGNT, JWC), Oakland, CA; University of Southern California (DPG), Los Angeles, CA.

Source of Funding: Funding for this research was provided by Amgen, Thousand Oaks, CA.

Author Disclosures: Dr Goldman is founder and Ms Chou, Drs Stevens, and Ton are employees at Precision Health Economics (PHE), a company providing consulting services to the life-sciences industry. Drs Jena, and Blumenthal have received consulting fees from PHE, which received funding from Amgen for this work.

Authorship Information: Concept and design (ABJ, WS, DPG); acquisition of data (ABJ, WS, TGNT, JWC, DPG); analysis and interpretation of data (ABJ, DMB, WS, TGNT, JWC); drafting of the manuscript (ABJ, DMB, WS, TGNT, JWC); critical revision of the manuscript for important intellectual content (ABJ, DMB, TGNT, JWC); statistical analysis (ABJ, TGNT); obtaining funding (DPG); administrative, technical, or logistic support (JWC); and supervision (ABJ, WS, DPG).

Address correspondence to: Anupam B. Jena, MD, PhD, Harvard Medical School, Department of Health Care Policy, 180 Longwood Ave, Boston, MA 02115-5899. E-mail: Jena@hcp.med.harvard.edu.

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