Publications by Year: 2008

2008
Kesselheim AS, Choudhry NK. The international pharmaceutical market as a source of low-cost prescription drugs for U.S. patients [Internet]. Annals of Internal Medicine 2008;148:614-9. Publisher's VersionAbstract

In response to increasing prescription drug costs, more U.S. patients and policymakers are importing less-expensive pharmaceutical products from other countries. Large-scale prescription drug importation is currently illegal, but the U.S. Food and Drug Administration permits individuals to bring in 90-day supplies of drugs for personal use. As patient use of foreign-bought drugs has increased, federal legislators have continued to debate the full legalization of importation. Three factors help guide whether U.S. patients and policymakers can rely on other countries as sources of imported prescription drugs: whether the safety of the product can be ensured, how the import price compares with domestic prices, and how importation might affect the exporting country's pharmaceutical market. In wealthier countries with active regulatory systems, drug safety can be adequately ensured, and brand-name products are usually less expensive than in the United States (although generic drugs may be more expensive). However, implementing large-scale importation can negatively impact the originating country's market and can diminish the long-term cost savings for U.S. consumers. In low- and middle-income countries, prices may be reduced for both brand-name and generic drugs, but the prevalence of unauthorized products on the market makes ensuring drug safety more difficult. It may be reasonable for individual U.S. consumers to purchase essential medicines from certain international markets, but the most effective way to decrease drug costs overall is the appropriate use of domestic generic drugs, which are available for almost every major therapeutic class.

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Choudhry NK, Brennan T, Toscano M, Spettell C, Glynn RJ, Rubino M, Schneeweiss S, Brookhart AM, Fernandes J, Mathew S, Christiansen B, Antman EM, Avorn J, Shrank WH. Rationale and design of the Post-MI FREEE trial: a randomized evaluation of first-dollar drug coverage for post-myocardial infarction secondary preventive therapies [Internet]. American Heart Journal 2008;156:31-6. Publisher's VersionAbstract

BACKGROUND: Medication nonadherence is a major public health problem, especially for patients with coronary artery disease. The cost of prescription drugs is a central reason for nonadherence, even for patients with drug insurance. Removing patient out-of-pocket drug costs may increase adherence, improve clinical outcomes, and even reduce overall health costs for high-risk patients. The existing data are inadequate to assess whether this strategy is effective. TRIAL DESIGN: The Post-Myocardial Infarction Free Rx and Economic Evaluation (Post-MI FREEE) trial aims to evaluate the effect of providing full prescription drug coverage (ie, no copays, coinsurance, or deductibles) for statins, beta-blockers, angiotensin-converting enzyme inhibitors, and angiotensin II receptor blockers to patients after being recently discharged from the hospital. Potentially eligible patients will be those individuals who receive their health and pharmacy benefits through Aetna, Inc. Patients enrolled in a Health Savings Account plan, who are > or =65 years of age, whose plan sponsor (ie, the employer, union, government, or association that sponsors the particular benefits package) has opted out of participating in the study, and who do not receive both medical services and pharmacy coverage through Aetna will be excluded. The plan sponsor of each eligible patient will be block randomized to either full drug coverage or current levels of pharmacy benefit, and all subsequently eligible patients of that same plan sponsor will be assigned to the same benefits group. The primary outcome of the trial is a composite clinical outcome of readmission for acute MI, unstable angina, stroke, congestive heart failure, revascularization, or inhospital cardiovascular death. Secondary outcomes include medication adherence and health care costs. All patients will be followed up for a minimum of 1 year. CONCLUSION: The Post-MI FREEE trial will be the first randomized study to evaluate the impact of reducing cost-sharing for essential cardiac medications in high-risk patients on clinical and economic outcomes.

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Choudhry NK, Patrick AR, Antman EM, Avorn J, Shrank WH. Cost-effectiveness of providing full drug coverage to increase medication adherence in post-myocardial infarction Medicare beneficiaries [Internet]. Circulation 2008;117:1261-8. Publisher's VersionAbstract
BACKGROUND: Effective therapies for the secondary prevention of coronary heart disease-related events are significantly underused, and attempts to improve adherence have often yielded disappointing results. Elimination of patient out-of-pocket costs may be an effective strategy to enhance medication use. We sought to estimate the incremental cost-effectiveness of providing full coverage for aspirin, beta-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins (combination pharmacotherapy) to individuals enrolled in the Medicare drug benefit program after acute myocardial infarction. METHODS AND RESULTS: We created a Markov cost-effectiveness model to estimate the incremental cost-effectiveness of providing Medicare beneficiaries with full coverage for combination pharmacotherapy compared with current coverage under the Medicare Part D program. Our analysis was conducted from the societal perspective and considered a lifetime time horizon. In a sensitivity analysis, we repeated our analysis from the perspective of Medicare. In the model, post-myocardial infarction Medicare beneficiaries who received usual prescription drug coverage under the Part D program lived an average of 8.21 quality-adjusted life-years after their initial event, incurring coronary heart disease-related medical costs of $114,000. Those who received prescription drug coverage without deductibles or copayments lived an average of 8.56 quality-adjusted life-years and incurred $111,600 in coronary heart disease-related costs. Compared with current prescription drug coverage, full coverage for post-myocardial infarction secondary prevention therapies would result in greater functional life expectancy (0.35 quality-adjusted life-year) and less resource use ($2500). From the perspective of Medicare, full drug coverage was highly cost-effective ($7182/quality-adjusted life-year) but not cost saving. CONCLUSIONS: Our analysis suggests that providing full coverage for combination therapy to post-myocardial infarction Medicare beneficiaries would save both lives and money from the societal perspective.
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Kulik A, Brookhart MA, Levin R, Ruel M, Solomon DH, Choudhry NK. Impact of Statin Use on Outcomes After Coronary Artery Bypass Graft Surgery [Internet]. Circulation 2008; Publisher's VersionAbstract
BACKGROUND: -The benefits of statins have been demonstrated for patients with a remote history of coronary artery bypass grafting (CABG); however, no investigation to date has evaluated whether initiation of statin therapy in the early months after surgery improves clinical outcomes. Methods and Results-A retrospective cohort of 7503 Medicare patients >/=65 years of age who underwent CABG (1995-2003) was assembled by use of linked hospital and pharmacy claims data. Rates of all-cause mortality and major adverse cardiovascular events were compared between patients who were (n=1745) and were not (n=5788) prescribed statins within 1 month of CABG discharge. Additional analyses evaluated the impact of statin initiation between 1 and 6 months after surgery. Multivariable and propensity score analysis demonstrated that statin use within 1 month of CABG discharge independently reduced the risk of all-cause mortality (adjusted hazard ratio 0.82, 95% confidence interval 0.72 to 0.94) compared with no statin use. Similarly, statin use within 1 month of CABG discharge independently reduced the risk of major adverse cardiovascular events (adjusted hazard ratio 0.89, 95% confidence interval 0.81 to 0.98). Initiation of statin therapy between 1 and 6 months after CABG discharge was also associated with reductions in major adverse cardiovascular events and mortality; however, outcome rates between early (
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Upadhyay GA, Choudhry NK, Auricchio A, Ruskin J, Singh JP. Cardiac resynchronization in patients with atrial fibrillation: a meta-analysis of prospective cohort studies [Internet]. Journal of the American College of Cardiology 2008;52:1239-46. Publisher's VersionAbstract

OBJECTIVES: This study is a meta-analysis of prospective cohort studies comparing the impact of cardiac resynchronization therapy (CRT) for patients in atrial fibrillation (AF) and sinus rhythm (SR). BACKGROUND: Although close to one-third of advanced heart failure patients exhibit AF, the impact of CRT in this group remains unclear. METHODS: Prospective cohort studies comparing patients in normal SR and chronic AF treated with CRT were included. All studies reported death, New York Heart Association functional class, ejection fraction, 6-min walk test, and the Minnesota score or its equivalent as outcomes. Data sources included Ovid MEDLINE In-Process & Other Non-Indexed Citations, the Cochrane Central Register of Controlled Trials, the Database of Abstracts of Reviews of Effects, and the American College of Physicians Journal Club. RESULTS: Of 2,487 reports identified, 5 studies following a total of 1,164 patients were included. Both AF and SR patients benefited significantly from CRT. Mortality was not significantly different at 1 year (relative risk ratio: 1.57, 95% confidence interval [CI]: 0.87 to 2.81). The New York Heart Association functional class improved similarly for both groups (-0.90 for SR patients, -0.84 for AF patients). SR patients showed greater relative improvement in the 6-min walk test (11.6 m greater, 95% CI: 10.4 to 12.8 m) and the Minnesota score (3.9 points less, 95% CI: 3.4 to 4.5 points) than AF patients. AF patients, however, achieved a small but statistically significant greater change in ejection fraction (0.39% greater change in ejection fraction, 95% CI: 0.22% to 0.55%). CONCLUSIONS: Patients in AF show significant improvement after CRT, with similar or improved ejection fraction as SR patients, but smaller benefits in regard to functional outcomes.

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Kesselheim AS, Misono AS, Lee JL, Stedman MR, Brookhart MA, Choudhry NK, Shrank WH. Clinical equivalence of generic and brand-name drugs used in cardiovascular disease: a systematic review and meta-analysis [Internet]. Journal of the American Medical Association 2008;300:2514-26. Publisher's VersionAbstract

CONTEXT: Use of generic drugs, which are bioequivalent to brand-name drugs, can help contain prescription drug spending. However, there is concern among patients and physicians that brand-name drugs may be clinically superior to generic drugs. OBJECTIVES: To summarize clinical evidence comparing generic and brand-name drugs used in cardiovascular disease and to assess the perspectives of editorialists on this issue. DATA SOURCES: Systematic searches of peer-reviewed publications in MEDLINE, EMBASE, and International Pharmaceutical Abstracts from January 1984 to August 2008. STUDY SELECTION: Studies compared generic and brand-name cardiovascular drugs using clinical efficacy and safety end points. We separately identified editorials addressing generic substitution. DATA EXTRACTION: We extracted variables related to the study design, setting, participants, clinical end points, and funding. Methodological quality of the trials was assessed by Jadad and Newcastle-Ottawa scores, and a meta-analysis was performed to determine an aggregate effect size. For editorials, we categorized authors' positions on generic substitution as negative, positive, or neutral. RESULTS: We identified 47 articles covering 9 subclasses of cardiovascular medications, of which 38 (81%) were randomized controlled trials (RCTs). Clinical equivalence was noted in 7 of 7 RCTs (100%) of beta-blockers, 10 of 11 RCTs (91%) of diuretics, 5 of 7 RCTs (71%) of calcium channel blockers, 3 of 3 RCTs (100%) of antiplatelet agents, 2 of 2 RCTs (100%) of statins, 1 of 1 RCT (100%) of angiotensin-converting enzyme inhibitors, and 1 of 1 RCT (100%) of alpha-blockers. Among narrow therapeutic index drugs, clinical equivalence was reported in 1 of 1 RCT (100%) of class 1 antiarrhythmic agents and 5 of 5 RCTs (100%) of warfarin. Aggregate effect size (n = 837) was -0.03 (95% confidence interval, -0.15 to 0.08), indicating no evidence of superiority of brand-name to generic drugs. Among 43 editorials, 23 (53%) expressed a negative view of generic drug substitution. CONCLUSIONS: Whereas evidence does not support the notion that brand-name drugs used in cardiovascular disease are superior to generic drugs, a substantial number of editorials counsel against the interchangeability of generic drugs.

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Choudhry NK, Zagorski B, Avorn J, Levin R, Sykora K, Laupacis A, Mamdani M. Comparison of the impact of the Atrial Fibrillation Follow-Up Investigation of Rhythm Management trial on prescribing patterns: a time-series analysis [Internet]. Annals of Pharmacotherapy 2008;42:1563-72. Publisher's VersionAbstract

BACKGROUND: The AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial demonstrated that rate control and rhythm control strategies result in similar survival and quality of life for patients with atrial fibrillation (AF). Because of superior safety and lower cost, rate control is now the recommended strategy for the management of most elderly, high-risk AF patients. OBJECTIVE: To determine the extent to which the AFFIRM trial results have been adopted into actual practice. METHODS: We conducted a time-series analysis of 3 population-based cohorts of patients with AF who were 66 years of age or older in Pennsylvania and Ontario. We stratified patients in Ontario by socioeconomic status (SES) and examined changes in quarterly prescription rates for rate control and rhythm controlling medications as well as cardioversion procedures before and after publication of the AFFIRM trial. RESULTS: The publication of the AFFIRM trial resulted in statistically significant reductions in the use of rhythm controlling medications in all 3 cohorts (p < 0.01). The magnitude of these changes in the non-low SES Canadian cohort was approximately 1% per quarter and was greater than the magnitude observed in the other cohorts (p < 0.001). The use of cardioversion procedures also decreased in all study regions (p < 0.01). In contrast, AFFIRM publication was also associated with a small increase in the use of rate controlling medications in Canada (p < 0.01) but not in the US (p = 0.23). CONCLUSIONS: Publication of the AFFIRM trial resulted in small but statistically significant changes in the care of patients with AF.

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Choudhry NK, Levin R, Avorn J. The economic consequences of non-evidence-based clopidogrel use [Internet]. American Heart Journal 2008;155:904-9. Publisher's VersionAbstract

BACKGROUND: Clinical trials have helped clarify the efficacy of clopidogrel for the treatment and prevention of vascular disease. Costs for its use exceeded $5.9 billion in 2005, making it the second greatest source of drug expenditure in the world. However, little is known about the appropriateness of that use. Overuse of clopidogrel could have important implications for health care quality and drug expenditures. METHODS: We conducted a retrospective cohort study linking all filled prescriptions to all clinical encounter data for Medicare beneficiaries enrolled in a large state-wide pharmacy assistance program. We identified all patients newly prescribed clopidogrel during a recent 2-year period and determined the proportion who had indications for clopidogrel, the mean number of tablets filled by patients with and without apparent indications in the year after starting therapy, and the costs associated with the observed patterns of clopidogrel use. RESULTS: We identified 4977 patients who were newly prescribed clopidogrel. Of these patients, only 47% had > or = 1 documented indications for clopidogrel according to clinical trial findings. Using looser criteria, the number of patients with appropriate indications was 56%. During the first year of therapy, 43% ($2.05 million) of total clopidogrel expenditures for the patients studied was spent on patients without an indication that this agent was required, using the extended criteria for evidence-based use. CONCLUSIONS: More than 40% of the clopidogrel used in this population appears to have been prescribed to patients for whom the drug had no documented advantage over aspirin or no antiplatelet therapy. If the same proportion applies nationally, in 2005, it would represent almost $1.5 billion of potentially unnecessary health care expenditure.

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Choudhry NK, Winkelmayer WC. Medication adherence after myocardial infarction: a long way left to go [Internet]. Journal of General Internal Medicine 2008;23:216-8. Publisher's Version PDF
Bowry AD, Brookhart MA, Choudhry NK. Meta-Analysis of the Efficacy and Safety of Clopidogrel Plus Aspirin as Compared to Antiplatelet Monotherapy for the Prevention of Vascular Events [Internet]. American Journal of Cardiology 2008;101:960-966. Publisher's VersionAbstract

Antiplatelet agents are central to the treatment and prevention of cardiovascular disease. Although aspirin is the most widely used agent, randomized trials have assessed whether adding clopidogrel to aspirin ("dual-antiplatelet therapy") offers additional benefit with acceptable safety. Unfortunately, these trials have reached conflicting results, in part because of the heterogenous populations they studied. To clarify the role of dual-antiplatelet therapy for patients with vascular disease, a systematic review and meta-analysis of randomized controlled trials was performed. Medline and the Cochrane Collaboration and American College of Physicians Journal Club databases were searched for trials published from 1966 to August 2006 that compared aspirin and clopidogrel with antiplatelet monotherapy. Only trials that presented clinically relevant efficacy and safety outcomes were included. From each trial, demographic data and outcomes were recorded. Summary odds ratios and 95% confidence intervals (CIs) were calculated using a random-effects model. Eight trials comprising 91,744 patients were included. Mean follow-up ranged from 28 days to 18 months. Compared with aspirin alone, dual therapy with aspirin and clopidogrel reduced the odds ratio of the composite outcome of death, reinfarction, and stroke by 15% (95% CI 23% to 6%) in patients with acute coronary syndromes and by 34% (95% CI 44% to 22%) in patients who underwent percutaneous coronary intervention. Dual therapy also significantly reduced the odds of fatal and nonfatal reinfarction in these patient groups but did not significantly reduce the odds of all-cause mortality. Dual therapy was associated with significantly increased risk for major bleeding in studies >1 month in duration (odds ratio 1.80, 95% CI 1.40 to 2.30). In conclusion, combining aspirin and clopidogrel significantly reduces the odds of major cardiovascular events in patients with acute coronary syndromes or those who undergo percutaneous coronary intervention but at the expense of significant increases in the risk for bleeding.

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Block AE, Solomon DH, Cadarette SM, Mogun H, Choudhry NK. Patient and physician predictors of post-fracture osteoporosis management [Internet]. Journal of General Internal Medicine 2008;23:1447-51. Publisher's VersionAbstract

BACKGROUND: Undertreatment of osteoporosis after hip or wrist fracture has been well documented, but the reasons for current patterns of care are poorly understood. OBJECTIVE: We tested the role of physician and patient characteristics in predicting undertreatment when osteoporosis management was clearly indicated after a hip or wrist fracture in women over age 65. METHODS: We assembled a cohort of 9,698 female Medicare beneficiaries aged > or = 65 years who experienced hip or wrist fracture between 2000 and 2004 and their prescribing physicians. MEASUREMENTS: The dominant prescriber was identified as the physician prescribing at least 50% of patient prescriptions in the year after the fracture. Multivariate logistic regression estimated the role of physician and patient characteristics on osteoporosis management after hip or wrist fracture. RESULTS: Patients older than 90 and black patients were less likely to be treated for osteoporosis relative to patients aged 65-69 and white patients. Female providers were more likely to manage osteoporosis. Models including patient characteristics discriminated well between managed and unmanaged patients (C statistic 0.81), while adding physician predictors to the model provided no additional discriminatory ability (C statistic 0.81). CONCLUSIONS: Our findings highlight that osteoporosis management rates are similar across providers, but vary considerably by patient types.

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Choudhry NK, Setoguchi S, Levin R, Winkelmayer WC, Shrank WH. Trends in adherence to secondary prevention medications in elderly post-myocardial infarction patients [Internet]. Pharmacoepidemiology and Drug Safety 2008;17:1189-96. Publisher's VersionAbstract

BACKGROUND: Poor levels of medication adherence for patients with coronary heart disease (CHD) have been documented but it is unclear whether adherence has improved over time. METHODS: We assembled a retrospective cohort of lower-income Medicare beneficiaries who were discharged from the hospital after their first acute myocardial infarction (MI) between 1 January 1995 and 31 December 2003. For patients prescribed a statin, ACEI/ARB, beta-blocker, and all 3 of these medications after the hospital discharge, we evaluated medication adherence by determining the proportion of days covered (PDC) for each medication in the subsequent year. RESULTS: Our cohort consisted of a total of 33 646 patients. Adherence rates for statins and beta-blockers, but not ACEI/ARB, increased significantly over time but remained suboptimal. For example, among those patients that received a statin after discharge, 38.6% were fully adherent with therapy in 1995 in contrast to 56.2% in 2003 (p value for trend<0.001). Of patients prescribed all 3 of statin, beta-blocker, and ACEI/ARB, 29.1% and 46.4% were fully adherent in 1995 and 2003, respectively (p value for trend<0.001). CONCLUSIONS: Our analysis demonstrates statistically significant but modest improvements in medication adherence for statins and beta-blockers, but not ACEI/ARBs, among patients discharged from hospital after acute MI. Despite these improvements, rates of non-adherence to these highly effective therapies remain extremely high. Given the health and economic consequences of non-adherence, the development of cost-effective strategies to improve medication adherence should be a clear priority.

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Cadarette SM, Katz JN, Brookhart MA, Levin R, Stedman MR, Choudhry NK, Solomon DH. Trends in drug prescribing for osteoporosis after hip fracture, 1995-2004 [Internet]. Journal of Rheumatology 2008;35:319-26. Publisher's VersionAbstract

OBJECTIVE: To examine trends in osteoporosis drug prescribing after hip fracture from 1995 to 2004. METHODS: We conducted a population-based study of enrollees in the Pennsylvania Pharmaceutical Assistance Contract for the Elderly. Hip fractures were identified using Medicare hospital claims between January 1, 1995, and June 30, 2004. Osteoporosis treatment comprised oral bisphosphonates, calcitonin, hormone therapy, raloxifene, and/or teriparatide. Kaplan-Meier methods were used to estimate the probability of treatment within 6 months of fracture, censoring patients on their date of death or 6 months postfracture. RESULTS: Treatment within 6 months after hip fracture improved from 7% in 1995 to 31% in 2002, and then remained stable through 2004. Similar patterns were observed among new users, with treatment increasing from 4% in 1995 to 17% in 2002, with no subsequent increase through 2004. Bisphosphonates led other treatments in the frequency of prescribing, except during 1997-99, when calcitonin was the most common. Among women, hormone therapy prescribing decreased from 22% of those treated in 1995 to 4% in 2004, and raloxifene prescribing remained relatively constant (4%-10%) since its introduction (p for trend = 0.15). Of patients treated before and after hip fracture, 18% changed therapy postfracture. Significantly more patients changed therapy following fracture if a different physician prescribed treatment (26%) compared to those treated by the same physician pre- and postfracture (13%; p < 0.0001). CONCLUSION: Prescribing practices changed substantially over the 10 years of study. The proportion of hip fracture patients treated with osteoporosis drugs has increased, but remains low, with fewer than one-third receiving pharmacotherapy.

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Avorn J, Choudhry NK. Using computer-based decision support to close the "know do" gap in lipid-lowering therapy [Internet]. Circulation 2008;117:336-7. Publisher's Version PDF