 To review the issues surrounding the economic and societal burden of metastatic breast cancer to provide a context for understanding the value of newly introduced high-cost drug treatments.

 The PubMed database and relevant congress abstract databases were searched to identify cost-of-illness data with relevance to metastatic breast cancer and the cost of therapies emerging within the last 5 years.

 The direct costs alone have been estimated to be $4.2 billion per year in the United States (1998 dollars), but more data are needed on the indirect and total societal costs associated with advanced disease. Of the new high-cost anticancer drugs introduced in the last 5 years, cost-effectiveness analyses have been reported only for lapatinib and ixabepilone in the United States. Both drugs showed high incremental cost-effectiveness ratios, although the estimated budget impact of ixabepilone was minimal due to expected low utilization in its approved indications. These studies did not include the broader indirect and full societal costs that could potentially be lowered by effective treatment.

 The most current estimates of direct costs for metastatic breast cancer do not represent the full societal impact of the disease. Further research is needed to fully understand how different treatment options for metastatic breast cancer affect overall societal costs in the United States, and how outcomes in the palliative setting are valued by society.

Lifetime direct medical costs of metastatic breast cancer (MBC) usually exceed total costs before recurrence; hospitalization and pharmaceutical costs are a significant portion of the total.

Updated economic analysis is warranted to account for the recent approval of several costly therapies that are now available within the MBC armamentarium. 

No universal cost-effectiveness standard exists in the United States, but newer high-cost drugs for MBC are unlikely to be considered cost-effective because of their late-line indications. 

The economic value to society of these agents will likely change should they prove effective in earlier stages of breast cancer.

Breast cancer, with its high incidence and expensive treatments, puts a tremendous burden on US healthcare system resources. Excluding skin cancers, breast cancer is the most prevalent cancer among US women, with 1 in 8 women diagnosed during their lifetime.

Moreover, it is the second most common cause of cancerrelated mortality in women (second to lung cancer).

In 2009, it was estimated that 192,370 women and 1910 men in the United States would be diagnosed with, and 40,610 would die as a result of breast cancer.

 Recent years have seen annual decreases in the breast cancer incidence and death rates,

 most likely reflecting earlier detection and better treatment. Despite these advances, the approximately 40% of patients who progress to metastatic breast cancer (MBC) can expect a median survival of only 1.5 to 3 years.

The intent of treatment is not curative; rather, the purpose is to control the disease for as long as possible. Therapies often are complicated, intensive, and costly, especially toward the end of life; inpatient costs in the last 9  months of the terminal phase may be up to 8 times higher than in the treatment phase.

The aim of this article is to address the issues that surround the economic and societal burden of MBC. The focus is on recent cost-of-illness data, with the intent of providing a context for understanding the value of the newly introduced treatments for MBC.

 Drug resistance to anthracyclines and taxanes has necessitated the search for novel anticancer agents for MBC. In the last 5 years, the US Food and Drug Administration (FDA) has approved for the treatment of MBC the hormonal agents exemestane and letrozole, the targeted agents lapatinib and bevacizumab, and the cytotoxic agents gemcitabine, ixabepilone, and nab-paclitaxel (a nanoparticle albumin-bound formulation of paclitaxel). With the exception of exemestane and letrozole, which have lower drug prices, these new agents have drug prices (either average sales price or wholesale acquisition cost) in the range of $3000 to $8000 per month.

 Costs associated with the development of new anticancer therapies continue to balloon higher with every passing year, and newer targeted agents most often are indicated in limited subpopulations of patients.

 To date, most targeted therapies have exhibited lackluster performance when not administered in combination with cytotoxic chemotherapy. As a result, in clinical practice, targeted agents are frequently incorporated as an add-on to standard chemotherapy, rather than a replacement for standard chemotherapy, which adds to the overall cost of treatment.

 Arguably, restricting use of expensive biologic therapies to their narrowly defined subpopulations and abiding by recommended indications should minimize associated budget impacts. In addition, advances in areas such as pharmacogenomics are helping to further refine the select patient populations that will experience the greatest benefit from targeted treatment. However, off-label utilization (by indication, dosing, or in off-label combinations) has been estimated to approach 50% for all oncology regimens.

 Generally speaking, it is not clinically appropriate (in terms of safety or efficacy) to extrapolate clinical trial data to support off-label use in patients who are not reasonably reflective of the studied populations. Moreover, although improved overall survival remains the gold standard for approval in first-line MBC, looming unmet medical need has resulted in newer agents being approved based on surrogate endpoints such as improvement in progression-free survival.

 Thus, society is burdened with ever-increasing drug costs associated with less and less evidence to support the claim of long-term benefit to the overall population patients with breast cancer. Although it often is argued that cost-effectiveness research may lower innovation, it also can be argued that lowering the bar for drug approval may indeed lead to the same result (as marginal treatments often yield large profit).

 A literature search of PubMed was conducted on August 1, 2009, for studies relating to costs of recurrent or MBC for the previous 5 years (ie, 2004 to June 2009). The search strategy was as follows: (“metastatic”[ti] or “recurrence”[ti] or “recurrent”[ti] or “relapse”[ti]) and breast and cancer and (“cost”[ti] or “costs”[ti] or “economic”[ti] or “economics”[ti]). The search was limited to papers published in the previous 5 years. Additionally, other important cost-of-illness studies published from 2000 onward were identified from reference lists of relevant articles. Four relevant studies investigating the costs specifically of recurrent breast cancer or MBC in the United States were identified and are summarized in 

 Three were retrospective database studies, and 1 was a state-transition model applied to incidence data. Although the studies varied in the time of follow-up, the time  frames were probably adequate given the short median survival after diagnosis of MBC.

 All studies included direct costs only and were from the payer perspective (ie, Medicare or another healthcare system). Notably, the studies did not account for out-of-pocket expenses, lost wages for time off work for the patient and/or caregiver, unpaid caregiver time, or productivity losses for society. Moreover, breast cancer affects both physical and psychological aspects of quality of life, so it is all but impossible to completely characterize the resulting economic burden.

 Costs for breast cancer may account for as much as 20% of the $228.1 billion in total costs of cancer care,

 with estimates in the United States yielding highly variable results

 due to differences in study methodology and the characteristics of the study populations. A review of 29 cost-of-illness studies conducted in the United States between 1985 and 2007

 reported that direct per-patient lifetime costs fell between $24,000 and $37,000 in the 5 studies that assessed the attributable costs from a payer perspective in all breast cancer populations. When the study included total rather than attributable costs, the lifetime figures were higher ($50,000 to well over $100,000). Across the studies, costs increased with disease severity and recurrence but were inversely related to age at diagnosis.

In general, the direct costs of care were highest in the first 6 to 12 months of treatment and in the final 6 to 12 months of life.

 Populations With Recurrent or Metastatic Breast Cancer

 In one report, the total annual medical costs for patients with MBC in the United States were estimated at $4.2 billion (1998 dollars).

 Notably, healthcare costs in the United States have almost doubled since 1998.

Another study estimated costs to be more than $3 billion when considering only the attributable costs (2004 values) associated with locoregional or distant recurrence (ie, excluding background costs associated with nonrecurrent breast cancer).

Costs increased significantly with morbidity,

and as reported elsewhere for breast cancer in general, costs were higher immediately after diagnosis of recurrence and in the terminal months of life than during the continuing-care phase.

As is true for breast cancer in general, MBC medical costs decrease with increasing age at diagnosis, peaking during the initial diagnosis of metastasis and in the terminal phase.

 In 2 studies that analyzed the different components of care, hospitalization costs accounted for around one third to one half of total costs.

 Drug acquisition costs were not differentiated from chemotherapy administration costs, and costs also excluded supportive-care medication. For patients with MBC, pharmacy costs (including chemotherapy and nonchemotherapy drugs) accounted for about 15% of total costs.

However, these expenditure data were from 1997 to 1998, during a time when fluorouracil and paclitaxel were the main drugs in use. Berkowitz and colleagues reported that the combined costs for all therapeutic modalities (chemotherapy, hormonal therapy, and radiation therapy) amounted to about 12% of total costs (1998 dollars).

 The costs associated with recurrence have been estimated by comparing prerecurrence and postrecurrence charges.

 One such study used health records to demonstrate that for patients with MBC, prerecurrence and postrecurrence per-patient charges were $14,138 and $57,642, respectively, in a 6-month period comparison (

 <.01). Costs rose to $13,560 and $104,502, respectively, in a 12-month comparison (

<.001). For patients with subsequent recurrence, mean monthly charges were $4965, compared with $2003 in patients without recurrence (

 <.05 after adjusting for baseline covariates). Interestingly, mean monthly charges for the metastatic recurrence group also were numerically higher than those associated with locoregional recurrence ($3498) or contralateral recurrence ($2615; significance not reported for either). For the mean total per-patient charge of $175,000 (from initial diagnosis of early disease to end of follow-up), at least $100,000 was attributable to the occurrence of metastases. The latter estimates were somewhat higher than the other MBC per-patient cost-of-illness estimates (Table 1), which may be at least partly explained by the use of charges rather than costs.

 It is worth noting that many of today’s newer therapies were not taken into account in these cost analyses. Increased drug cost is driving up the cost of MBC treatment more than any other factor, and older cost data do not fully capture this trend (

). In addition, many of these newer agents, especially biologic agents that are indicated or utilized as add-on therapy, often are continued indefinitely until disease progression or unacceptable toxicity. Also worth mentioning is the fact that it is generally acceptable to treat MBC patients with several lines of therapy, while most patients with other malignancies are treated with fewer unique regimens.

 A search of Pubmed for cost and cost-effectiveness studies conducted in the United States for high-cost drugs that have recently been approved for use in breast cancer (ie, lapatinib, bevacizumab, gemcitabine, ixabepilone) identified only 3 relevant studies: 2 relating to ixabepilone and 1 relating to lapatinib. Therefore, studies conducted in other countries were included when available.

 With the decentralized financing and delivery of healthcare in the United States, cost-effectiveness data are not used explicitly in decision making at the federal or state level. The cultural and political climate of the United States is traditionally more conducive to market-based solutions than to government-enforced policies regarding return on investmentfor medical interventions.

However, value remains an indirect but important criterion for policy makers, and cost-effectiveness data can influence payers’ coverage and reimbursement decisions.

Other countries (eg, the United Kingdom, Australia, etc.) operate centralized systems in which cost-effectiveness data are explicitly included in  decisions regarding government funding of new drugs.

 Some evidence suggests that applying such criteria for cost-effectiveness can impede patient access to new high-cost treatment modalities and/or decrease innovation around the development of new therapies.

 A recent cost-effectiveness analysis estimated the projected lifetime clinical and economic consequences of adding lapatinib to capecitabine as second-line therapy in HER2-positive advanced breast cancer.

 The analysis modeled outcomes for a 53-year-old woman with progressive HER2- positive locally advanced or metastatic breast cancer previously treated with a minimum of an anthracycline, a taxane, and trastuzumab. The direct costs included were wholesale acquisition costs of lapatinib and capecitabine tablets, costs of treating severe diarrhea and cardiotoxicity events, monitoring test costs, costs of treatment (in 2007 US dollars) after disease progression or central nervous system metastasis, and patient time and travel.

 Mean time to progression was estimated to be 6.21 months with lapatinib plus capecitabine versus 4.24 months with capecitabine alone, and mean overall survival was estimated to be 17.41 versus 15.45 months, respectively. Based on a regimenof lapatinib 1250 mg given daily for each 21-day cycle (in combination with capecitabine as indicated), the wholesale acquisition cost of lapatinib was $2415 per cycle ($23 per 250-mg tablet). The average total costs per patient were $66,499 for lapatinib plus capecitabine, compared with $46,869 for capecitabine alone. Thus, the addition of lapatinib to capecitabine cost an additional $19,630 and produced a gain of 0.12 quality-adjusted life-year (QALY) over capecitabine alone.

 Although regulatory bodies in other countries (eg, the National Institute for Health and Clinical Excellence [NICE]) have thresholds for cost-effectiveness, no definitive threshold exists in the United States. A recent editorial by Hillner and Smith suggested that a threshold between $140,000 and $200,000 per QALY might be reasonable in today’s values.

 For lapatinib plus capecitabine versus capecitabine alone, the incremental cost-effectiveness ratio (ICER) was $120,184 per life-year gained and $166,113 per QALY gained. The probability of lapatinib achieving an ICER of under $100,000 per QALY was less than 1%, and the probability of achieving an ICER under $150,000 per QALY was less than 2%.

 These findings indicate that the addition of lapatinib to capecitabine for second-line treatment of HER2- positive advanced breast cancer is unlikely to be considered cost-effective within the thresholds utilized by NICE, but may fall in the range suggested by Hillner and Smith.

 One cost-effectiveness analysis evaluated the addition of bevacizumab to paclitaxel in first-line treatment of HER2-negative MBC in the Swiss healthcare system.

 Treatment with bevacizumab plus paclitaxel was estimated to result in a median progression-free survival of 11.84 months versus 5.92 months with paclitaxel alone, and the estimated median survival times were 26.74 and 25.

months, respectively. The acquisition cost per month for bevacizumab 10 mg/kg was €5303.92 (approximately $7374). The addition of bevacizumab to paclitaxel increased direct lifetime costs by €40,369 (approximately $56,100) for a gain of 0.21 QALY, resulting in an ICER of €189,427 (approximately $263,020) per QALY gained compared with paclitaxel alone (2008 dollars).

 Bevacizumab is indicated only for first-line treatment of MBC. No data existed to support its use in second-line treatment of MBC until recently, when the phase III RIBBON-2 trial demonstrated a statistically significant improvement in progression-free survival over placebo (7.2 vs 5.1 months; 

 =.0072) when used in combination with standard chemotherapy in these patients.

Even prior to this clinical evidence, however, US clinicians frequently used it off-label for pretreated MBC because of the high unmet medical need in this patient population. This scenario represented an example of a costly off-label treatment that may have driven up the costs associated with MBC previously without supporting    evidence of clinical benefit. It is interesting to note that the FDA is currently reviewing the initial accelerated approval of bevacizumab for the treatment of MBC.

. A prospective cost-effectiveness analysis was conducted alongside the pivotal clinical trial of ixabepilone plus capecitabine versus capecitabine alone in MBC.

 Data on medical resource use and health utilities were collected along with clinical data, and unit costs were applied.

 The analysis had a healthcare system perspective and a lifetime horizon. Costs (in 2008 US dollars) included drug costs, inpatient care, outpatient physician visits, emergency department visits, home health visits, computed tomography and magnetic resonance imaging scans, and subsequent treatments.

 The mean expected survival time was 1.01 years with ixabepilone plus capecitabine versus 0.84 year with capecitabine alone. The total cost of adding ixabepilone to capecitabine was $30,900 (total costs of $60,900 vs $30,000 with capecitabine alone). The difference in total costs between the treatments was mainly driven by differences in drug costs, which were $6126 per cycle for ixabepilone plus capecitabine and $1946 per cycle for capecitabine alone. The combination of ixabepilone plus capecitabine produced a gain of 0.09 QALY (32 days) compared with capecitabine alone. Thus, the ICER was $193,000 per life-year gained and $359,000 per QALY gained (after discounting).

Articles

ONCOLOGY FOCUS

Costly new breast cancer therapies augment the significant burden this disease places on healthcare resources, but in context they may still provide value to society.

Economic/Societal Burden of Metastatic Breast Cancer: A US Perspective

 To evaluate the impact of utilization management methods on use of smoking cessation medication.

Retrospective cohort analysis of pharmacy claims data.

 The study population included patients at least 18 years of age, naive to varenicline, and with a rejected varenicline claim between January 2007 and April 2008 because of 1 of 4 utilization management restrictions: drug not covered, prior authorization, step therapy, or quantity limits. The outcome variable was whether patients used any smoking cessation medication including varenicline, bupropion, and nicotine replacement therapy (prescribed and over-the-counter) within 6 months of the rejected varenicline claim. Multivariable logistic regression was conducted to evaluate the probability of filling a prescription for any smoking cessation medication.

 A total of 15,597 patients were identified. Within 6 months after the rejected claims, 8393 (53.8%) patients filled at least 1 smoking cessation medication, 7864 (93.7%) of whom filled varenicline. Compared with quantity limits, the odds ratios for filling any smoking cessation medication after the rejected varenicline claim were 0.01 (95% confidence interval [CI], 0.01-0.02) for varenicline not covered, 0.07 (95% CI, 0.06-0.09) for step therapy, and 0.18 (95% CI, 0.16-0.20) for prior authorization. Higher out-of-pocket expense was associated with a lower probability of filling any smoking cessation medication.

 About half of the patients in this study did not fill any smoking cessation medication following a rejected varenicline claim. It is important to address this treatment gap in support of patients seeking smoking cessation therapy.

This research examines the use of smoking cessation medication among patients whose varenicline claims were rejected because of 1 of 4 utilization management restrictions (drug not covered, prior authorization, step therapy, or quantity limits). Six months after the rejected varenicline claim:

Only 53.8% of patients filled a prescription for any smoking cessation medication. 

Of patients who did fill a prescription, 93.7% received varenicline and 6.3% received other smoking cessation medication without getting varenicline. 

Higher out-of-pocket expense was associated with a lower filling rate for any smoking cessation medication.

Smoking is a serious health problem associated with significant mortality, morbidity, and costs. It is known to be a cause of many deadly diseases such as cancer, stroke, heart diseases, and lung diseases.

The Centers for Disease Control and Prevention estimated that smoking or exposure to smoking led to 443,000 premature deaths annually from 2000 to 2004 in the United States. Three leading causes of smoking-related death were lung cancer, ischemic heart disease, and chronic obstructive pulmonary disease. The total  annual economic burden of smoking was $193 billion per year in the United States during 2001 to 2004, with $96 billion for direct healthcare costs and $97 billion for productivity losses.

It was estimated that if all smokers covered by Medicaid stopped smoking, Medicaid could save $9.7 billion every year after 5 years.

Further, at a global level, the World Bank has estimated that smoking accounts for about 6% to 15% of total health expenditures in developed countries.

 Although smoking cessation (SC) is extremely beneficial, it is known to be difficult. Among all of the untreated smokers who try to quit smoking, only 4% to 7% are likely to be successful.

Current clinical guidelines call for aggressive treatment of tobacco dependence through a combination of clinical counseling and medication interventions to improve the success rates.

Seven medications have been identified as first-line treatment for smoking, including bupropion SR, nicotine gum, nicotine inhaler, nicotine lozenge, nicotine nasal spray, nicotine patch, and varenicline.

 Unfortunately, SC treatments have been severely underused. The National Health Interview Survey shows that of smokers attempting to quit smoking in 2000, only 21.7% used any pharmacotherapy and only 1.3% used behavioral counseling.6 Clinical guidelines call for coverage of tobacco dependence treatments to improve the use of SC treatments and cessation rates.

 Research on the impact of benefit design on SC medication is limited. Existing studies generally focused on the effects of copayments on SC medication use.

 The impact of utilization management methods such as prior authorization, step therapy, restrictive formulary, and quantity limits is not well understood. Previous research on rejected claims in other therapeutic areas showed that some patients did not fill prescriptions after their claims were rejected. For example, research on step-therapy restrictions on angiotensin-receptor blockers showed that 12 months after a claim for an angiotensinreceptor blocker was rejected because of step therapy, 7% of patients did not have any antihypertensive medication claims.

Another study showed that up to 70% of patients did not try to overcome a prior-authorization restriction after having a rejected claim for a cyclooxygenase-2  inhibitor. 

If a large percentage of patients did not fill any SC medication after being denied an SC medication claim, such an observation should raise concerns for health plans and policy makers. In the long run, decreased use of SC medication could lead to worse health outcomes and higher healthcare costs.

 We investigated the relationship between utilization management for varenicline and the initiation of therapy with SC medication. Specifically, this study reports the proportion of patients who actually used SC medication 6 months after a varenicline claim rejection and examines factors that influenced patients’ decision to use SC medication. We focusedon varenicline because utilization management of SC medication generally focuses on this drug, as it is the only newly approved SC medication in over a decade. In this study, 94.3% of the patients whose claims for SC medication were rejected because of utilization management had prescriptions for varenicline. Sensitivity analysis was performed to include patients whose claims for other prescribed SC medication were rejected.

 A retrospective cohort data analysis was conducted based on MedImpact’s claims database. MedImpact is a large private national pharmacy benefits management company. The claims database contains detailed information of the adjudication process, including rejected, reversed, and approved claims. If a patient decides to pay cash to purchase a medication after a claim is rejected because of utilization management, he or she receives a network discount, typically around 10% to 15%, and the claim is recorded in the data set.

 The target study population included patients who attempted to fill prescriptions for varenicline that were rejected because of utilization management. The study population met the following inclusion criteria:

 • At least 1 rejected varenicline claim from January 2007 to April 2008 because of 1 of 4 utilization management restrictions: drug not covered, prior authorization, step therapy, or quantity limits.

 • No approved or rejected varenicline claims before the identification period.

 • Continuously enrolled in the same health plan 1 year before and at least 183 days after the initial rejected varenicline claim.

 • Had coverage for over-the-counter (OTC) SC medication.

 • Age 18 years or older at the time of attempting to fill a varenicline claim.

 This research focused on patients whose varenicline claims were rejected because of 1 of 4 utilization management restrictions: drug not covered, prior authorization, step therapy, or quantity limits. These 4 restrictions accounted for approximately 80.9% (140,228 of 173,314) of the total number of rejected varenicline claims (

). The remaining varenicline claims were turned down for reasons unrelated to benefit design such as member benefit expired, incorrect spelling, not a network pharmacy, etc.

 Patients whose claims for varenicline were rejected because the drug was not covered had a closed formulary in which medications not listed in the formulary were excluded from coverage. Closed formularies are commonly used by health plans to control costs.

Patients who had an open formulary, in which medications not in the preferred formulary were covered with a higher copayment, were not included in this analysis because their varenicline claims were not rejected.

 Patients whose claims were rejected because of prior authorization usually were required to enroll in an approved counseling and behavior-modification program. Both clinical guidelines and the prescribing information for varenicline recommend the use of clinical counseling along with varenicline to improve cessation rates.

 For this reason, many health plans require patients to enroll in a clinical counseling program before varenicline can be dispensed. Upon enrollment in such a program, patients receive a certificate of enrollment that they then can fax to health plans to meet the prior-authorization requirement and obtain varenicline. Prescribing physicians also can certify this enrollment on behalf of patients to help them obtain the drug.

 The step-therapy restriction typically requires patients to try bupropion or nicotine replacement therapy before trying varenicline. Health plans usually impose the steptherapy requirement to encourage patients to use a low-cost alternative. If a significant portion of patients can be diverted to low-cost alternatives, health plans can save on medication costs.

 Finally, the quantity-limit restriction usually restricts days of supply of the initial varenicline claim to fewer than 21 to 34 days, depending on the health plan. Health plans usually put a quantity limit on SC medication to avoid waste. For example, some patients may stop using varenicline, like other SC medication, after several days. In that case, the rest of the medication could be wasted if a large quantity of varenicline were dispensed.

 The outcome variable was whether patients used any SC medication within 6 months of the rejected varenicline claim. In general, the intent of utilization management is to encourage patient compliance with clinical guidelines or to channel patients to use cheaper alternatives, rather than to deter patients from initiating SC pharmacotherapy treatment altogether. For this reason, the percentage of patients using any SC medication was used as a measure of success for these tools. The SC medication considered in this research included any form of bupropion, prescribed and OTC nicotine replacement therapy, and varenicline.

 Price Index for Smoking Cessation Medication

 When a patient’s claim for an SC medication is rejected, he or she may consider alternative medications. The health plan’s generosity in covering SC medication may be an important factor in the patient’s decision. We constructed a price index to quantify health plan’s coverage of SC medication.

 A price index is the average out-of-pocket (OOP) cost for SC medication weighted by the number of claims. It can be interpreted as the OOP cost for a market basket of SC medication. The 

) provides the technical details about the price index.

 Multivariable logistic regression modeling was done to examine factors that could influence patient response to a rejected varenicline claim. The covariates included age, sex, type of insurance, geographic locations, comorbidities, type of benefit restrictions, price index, and history of use of bupropion or nicotine replacement therapy before the rejected varenicline claim. Comorbidities were measured by RxRisk, a method to determine a patient’s risk profile based on pharmacy data only.

Only comorbidities that influenced more than 5% of the population were included in the final regression analysis.

MANAGERIAL

About half of the patients in this study did not fill any smoking cessation medication following a rejected claim for varenicline.

Utilization Management for Smoking Cessation Pharmacotherapy: Varenicline Rejected Claims Analysis

To provide evidence supporting the discontinuation of laboratory tests that do not have clinical utility today.

 We selected 10 representative tests considered antiquated by most experts in the clinical laboratory medicine field: creatine kinase-MB, myoglobin, serum folate and red blood cell folate, amylase, lecithin/sphingomyelin ratio, qualitative serum human chorionic gonadotropin, prostatic acid phosphatase, bleeding time, and erythrocyte sedimentation rate.

 Published literature was reviewed to provide evidence of the poor performance and/or limited clinical utility of these tests. When available, subscriptions to the Proficiency Testing Program of the College of American Pathologists were tracked from 1993 to 2008 as supporting evidence. Finally, when appropriate, alternative testing was suggested.

 The data show clearly that there is a national trend toward reduction or elimination of these 10 tests.

 Together with their clinical colleagues, clinical laboratorians should review their menu of tests and consider removing tests that do not provide clinical benefit. In most cases, alternative tests are already in clinical use.

	Although the clinical laboratory plays a critical role in management of patients in both disease and health, some tests have been replaced by others and no longer provide value.

		Newer analytes such as troponin, prostate-specific antigen, and C-reactive protein have replaced creatine kinase-MB, myoglobin, and lactate dehydrogenase; prostatic acid phosphatase; and the erythrocyte sedimentation rate, respectively.

		The need for folate testing has been dramatically reduced with the supplementation of dietary folic acid. n Testing technologies have improved, making bleeding time, the lecithin/sphingomyelin ratio, and amylase redundant or unnecessary.

	Given the current economic climate for medical practices, it is the responsibility of clinical laboratory directors in hospitals and medical centers to review their test menu and, in collaboration with their clinical staff leaders, remove tests that do not provide clinical value to a particular medical practice, whether such testing is conducted in-house or sent to a reference laboratory. However, many physicians who are experienced with the use of older tests may resist adoption of newer technologies even if the tests have been shown to have superior clinical value or are recommended in contemporary clinical guidelines. Changing the testing menu can be a difficult process and should involve laboratorians and the medical staff, especially the staff who frequently order the tests that are to be eliminated. This article provides documentation for laboratorians who are considering the removal of tests from their menu and can serve as an educational platform for discussions with clinical colleagues.

	Here we have selected 10 tests that most experts consider antiquated in clinical laboratory medicine: creatine kinase-MB (CK-MB), myoglobin, serum folate and red blood cell folate, amylase, lecithin/sphingomyelin (L/S) ratio, qualitative serum human chorionic gonadotropin (hCG), prostatic acid phosphatase, bleeding time, and erythrocyte sedimentation rate (ESR). There may be many other tests that can be eliminated after a systematic review. After examination of the literature, we have provided published evidence for these tests’ limited diagnostic and clinical utility. As supporting evidence, when possible, we have provided subscription trends from the College of American Pathologists (CAP) Proficiency Testing Program to examine trends in the subscription as a surrogate for the clinical utilization of these tests among participants. Finally, when appropriate, we have suggested  alternate testing that should replace the antiquated methods.

	The use of CK-MB isoenzymes as markers for acute myocardial infarction (AMI) dates back to the early 1970s with enzymatic measurement by electrophoresis.

 Currently, most laboratories use the automated mass assays for CK-MB described in the mid-1980s.

 Release of CK-MB into the blood occurs in patients with heart or skeletal muscle injury or disease. A calculation of the CK-MB amount relative to total CK measurements (relative index) has been useful to differentiate the source of CK-MB release. Following AMI, there is a delay in the appearance of CK-MB due to its relatively large size (84 kDa). The clinical interest in myoglobin dates to the early 1990s with the development of automated  immunoassays.

 Myoglobin is a smaller protein than CK-MB (17 kDa) and is released into the blood sooner than CK-MB after the onset of AMI. Myoglobin also is released into the blood of patients with skeletal muscle injury, and the clearance of myoglobin is retarded in cases of renal damage. Each condition leads to increased blood concentrations. The isoenzymes of lactate dehydrogenase can differentiate between release of this enzyme because of cardiac damage and release from other organs such as the liver or lungs.

	The development and implementation of, and continued improvements in, cardiac troponin have put in question the need for clinical laboratories to offer CK-MB, myoglobin, and lactate dehydrogenase isoenzymes. Unlike those biomarkers, release of troponin T or I is specific to cardiac injury. When the myocyte is irreversibly damaged, there is an initial rise in troponin due to its release from the free cytosolic pools, followed by a prolonged increase due to degradation of the myofibrils. Using first-generation assays, troponin becomes detectable in blood at the same time as CK-MB and remains elevated longer than CK-MB or lactate dehydrogenase.

 With improvements in analytical sensitivity and use of the 99th percentile as a cutoff limit for AMI, as recommended by the Task Force for the Redefinition of Myocardial Infarction,

 troponin is released before CK-MB and appears in the blood as early as if not earlier than myoglobin after AMI onset.

	Based on the CAP Cardiac Markers Survey (

), utilization of CK-MB and myoglobin has undergone a gradual decline in subscriptions in recent years. In contrast, the corresponding proficiency survey subscription rate for cardiac troponin has remained steady or slightly increased (data not shown). Critics opposed to the removal of CK-MB and/or myoglobin argue that because troponin remains increased for 5 to 7 days, the test cannot determine the presence of a reinfarction. However, in a case series, Apple and Murakami showed that troponin tracks closely with CK-MB.

 Moreover, in a controlled coronary care unit environment, measurement of total CK, a test that is not considered obsolescent,can be used to detect a reinfarction. Total CK also can be important in the evaluation of patients with skeletal muscle injury and/or diseases such as Duchenne muscular dystrophy

	Others have advocated retention of the CK-MB test to make estimates of infarct size. Such assessments require measurement of the area under the enzyme versus time curve, and are inaccurate when there is reperfusion of the target vessel. Cardiologists should not delay in treating patients to obtain peak CK-MB levels to document infarct size, as the objective of early intervention is to minimize the extent of myocardial damage. If determination of the severity of AMI is desired, some investigators have shown that single-point troponin measurements equate to infarct size.

 Today, myoglobin testing has largely been discontinued by clinical laboratories. It is likely that more laboratories will abandon CK-MB testing in the near future as well.

	A deficiency in folic acid and vitamin B

 is one cause of macrocytic anemia. The detection of low folate concentrations in serum or red blood cells is useful for finding folic acid deficiencies. Red blood cell folate is thought to be more reflective of tissue stores, but requires an extraction step prior to analysis.

 In January and November 1998, the United States and Canada, respectively, mandated that foods with processed grains be fortified with folic acid. Dietary folate supplementation has resulted in a significant decline in the incidence of folate deficiency.

 The incidence of folic acid deficiency was even low in indigent patients, in whom dietary deficiency would be expected to be more prevalent.

 Therefore, routine screening of serum and/or red blood cell folate as a means to evaluate patients with anemia is difficult to justify. Shojania has shown that folate deficiency is also a rare cause of untreated celiac disease.

 For the rare patients suspected of such a deficiency, many clinicians now suggest that simply treating with folic acid is a more   cost-effective approach than blood testing.

 For laboratories testing international populations in which there is no folate supplementation, this testing may be warranted. If deficiencies are found, follow-up testing may be important to determine therapeutic efficacy of folate fortification.

	Amylase and lipase are digestive enzymes normally released from the acinar cells of the exocrine pancreas into the duodenum. Following injury to the pancreas, these enzymes are released into the circulation and cause a subsequent increase in their measured activity. Both amylase and lipase are low-molecular- weight enzymes (40-50 kDa) and are filtered through the glomerulus. Amylase is cleared in the urine, whereas lipase is reabsorbed back into the circulation. In patients with acute pancreatitis, the activities are greatly increased in serum above the reference range. There is historic confusion regarding the clinical utility and enzyme profiles of amylase and lipase in acute pancreatitis.

 This confusion stems from the discovery that lipase assays devoid of colipase and bile salts were an insensitive and imprecise measure.

 As these constituents are now incorporated into all commercial reagents, lipase has clinical sensitivity equivalent to that of amylase and superior clinical specificity.

 For example, amylase is increased in patients with salivary gland inflammation.

 The salivary isoenzyme also can bind with immunoglobulin to form a macromolecular complex that is not cleared from the circulation, and persistent elevations are observed in the absence of pancreatic diseases.

 Werner et al showed that there was no diagnostic advantage to combining results of lipase and amylase tests compared with the clinical performance of the individual tests.

 The development of assays for the pancreatic amylase isoenzyme has improved the specificity of the test.

  However, if the objective of amylase and lipase testing is to detect pancreatic diseases, amylase provides redundant information and elimination of this test can be considered.

	It should be noted that lipase and amylase testing is performed on routine clinical chemistry analyzers at minimal incremental reagent costs, and the cost savings to the laboratory in eliminating amylase will be marginal. Nevertheless, elimination of a nonspecific test may mean less diagnostic confusion and fewer unnecessary workups for a patient with a nonspecific increase in amylase activity. It also opens up a “reagent channel” on the chemistry analyzer that can be used for another test.

 LECITHIN/SPHINGOMYELIN RATIO FOR FETAL LUNG MATURITY

	First reported in 1971, the L/S ratio, determined by thin-layer chromatography, was the first biochemical test for assessing the maturity of fetal lungs. Many outcome studies have demonstrated that the L/S ratio has good sensitivity (80%- 100%) and specificity (70%-97%).23 Because it was the first test developed, it was long considered to be the gold  standard for assessing fetal lung maturity. However, today, use of L/S testing has become largely obsolete and has mostly been replaced by fluorescent polarization and lamellar body counts.

	Reports have suggested that the volume of all fetal lung maturity testing is decreasing nationally, with one laboratory demonstrating a 64% decrease in test volumes from 1994 to 2004.

 Among tests of fetal lung maturity, the frequency of L/S ratio testing in the United States has declined the most dramatically (Table). Results of a survey of 417 physicians indicated that their use of the L/S ratio had decreased by 70%, in contrast to a 35% decrease for fluorescence polarization.

 The reason for this dramatic decrease in the use of the L/S ratio is likely multifactorial.

	A commercial assay for assessing the L/S ratio exists (Fetal-Tek 200, Helena Laboratories, Beaumont, TX), but it is used by only just over half of all laboratories that perform L/S ratio testing.

 Still, there is poor interlaboratory precision even among those using the commercial method. In addition, there is great variability in the cutoff used for identifying lung maturity between laboratories. This poor precision, variability in cutoffs, and declining testing volume led CAP to issue a statement indicating that it is likely that consensus in proficiency testing results will only be seen in extremely mature or extremely immature results.

 In contrast, among the laboratories that use fluorescent polarization, 98% use the commercially available Abbott TDx FLM II method, and the coefficient of variation between laboratories was less than 7.2% for all 3 materials tested.

	Multiple studies have compared the utility of the L/S ratio and fluorescent polarization in predicting fetal lung maturity. 

 These studies have shown that fluorescent polarization performs like the L/S ratio, with ~100% sensitivity and ~70% specificity.23 In addition, the TDx FLM II test can be performed rapidly, requires no sample extraction, and is considerably simpler to perform than the L/S ratio test. Unfortunately, the manufacturer (Abbott Laboratories) may be removing this test from the market.

	Likewise, multiple studies have compared the utility of L/S ratio and lamellar body counts in predicting fetal lung maturity.

 A meta-analysis that examined these data demonstrated that the lamellar body counts performed slightly better than the L/S ratio in the prediction of respiratory distress syndrome.

 The lamellar body count test also can be performed rapidly, requires no sample extraction, and is considerably simpler to perform than the L/S ratio test. In consideration of all these factors, it is clear that fluorescent polarization and lamellar body counts are the preferred methods of testing for fetal lung maturity.

 QUALITATIVE SERUM HUMAN CHORIONIC GONADOTROPIN

	The qualitative detection of hCG in urine through the use of rapid, point-of-care test devices is a well-established practice in healthcare for identifying pregnancy. The analytical performance of these tests has been extensively studied, although contemporary reports of their clinical performance are scarce.

 This latter point is important, as the analytical  technology for detecting hCG has changed dramatically since it was first introduced in the 1970s. The National Academy of Clinical Biochemistry concluded that, despite their  widespread use, there are no data to demonstrate that the use of qualitative urine hCG tests improved patient outcomes, and noted that clinical outcome studies using current analytical technologies were needed.

	The qualitative detection of hCG in urine is a test granted waived status under the Clinical Laboratory Improvement Amendments. In contrast, use of serum as a sample matrix is considered a moderately complex test, even when the test device itself is approved for use with either urine or serum. The difference in test complexity status is because serum, not whole blood, must be analyzed and centrifugation of the specimen is necessary. As such, the majority of qualitative serum hCG tests are performed in laboratories and not at the point of care, leading one to question the clinical need for this type of testing in any circumstance. The following arguments can be made in favor of discontinuing the use of qualitative serum hCG tests.

	First, the inability to perform serum testing at the point of care necessitates sending the collected specimen to the laboratory for processing and testing. A primary contributor to the turnaround time of laboratory tests that are performed rapidly is the time required for specimen transport to the laboratory. Many clinical laboratories have the ability to perform quantitative serum hCG analyses, and the analytical time for these immunoassays is brief (~10-20 minutes). That is only slightly longer than the time required to perform qualitative testing, but produces more accurate results (see below).

	Second, qualitative hCG tests are less analytically sensitive than quantitative tests. Although analytical thresholds vary by device, these tests are designed to produce a positive result when the hCG concentration is 10 to 25 IU/L. In contrast, quantitative hCG tests are more exquisitely sensitive, with limits of detection as low as 1.0 IU/L. Given that the only clinical use of a qualitative serum hCG test is to detect (or rule out) a possible pregnancy, then the most sensitive test available should be utilized. This is particularly true in the healthcare setting (the only setting in which serum hCG testing could be performed), where pregnancy status must be determined prior to an intervention that is potentially harmful to a fetus. In short, serum is a technically demanding specimen to obtain, and qualitative serum hCG analyses cannot currently be performed bedside. Therefore, in cases where a serum specimen has been collected and transported to the laboratory, there is no reason to perform a clinically and analytically less sensitive qualitative test when a quantitative test is readily available.

	Until the introduction of prostate-specific antigen (PSA) in the 1980s, serum prostatic acid phosphate was the only tumor marker used for prostate cancer in the preceding 50 years. In the 1930s, a phosphatase with activity at acidic pH was discovered to be increased in prostate cancer tissue and sera, and was subsequently introduced as a tumor marker.

 Acid phosphatases are lysosomal isoenzymes found in secretory epithelial cells that hydrolyze phosphate monoesters with an optimal activity below pH 7.0. Acid phosphatase is found in the prostate epithelium as well as in erythrocytes, leukocytes, bone, liver, and other cells and tissues.

 The prostate form is inhibited by tartrate, which can aid in distinguishing it from the other forms. Substrates more specific for prostatic acid phosphate (eg, thymolphthalein monophosphate, a-naphthyl phosphate) have been used for the measurement of enzymatic activity. Immunoassays also have been developed, although enzymatic activity methods are preferred.

	Similar to PSA, prostatic acid phosphate can be elevated in benign prostate conditions and can be affected by prostate manipulations. Unlike PSA, prostatic acid phosphate is not prostate-specific and can be increased in other benign and malignant diseases. Prostate-specific antigen is more sensitive for the early detection of prostate cancer because prostatic acid phosphate is more likely to be elevated only in men with advanced-stage disease; prostatic acid phosphate also has been replaced by PSA for monitoring therapy.

 The National Academy of Clinical Biochemistry, the European Group on Tumor Markers, and the Canadian Society of Clinical Chemists all have declined to recommend the use of prostatic acid phosphate, stating that the marker provides no clinical benefit in addition to that of PSA.

 As an individual marker, prostatic acid phosphate may be useful for disease management in the rare patient whose tumor does not secrete PSA

and may have utility when combined with other markers for improving prostate cancer detection

 or predicting recurrence after radical prostatectomy.

 The demise of the prostatic acid phosphate test can be ascertained from recent CAP proficiency survey participation data (Table). In 2010, more than 2200 laboratories (16 methods/instruments) reported PSA results, whereas 35 laboratories reported prostatic acid phosphate results.

	The bleeding time test was initially developed as an in vivo test of primary hemostasis to assess formation of a platelet plug.

 Abnormal results may be observed in a variety of conditions including use of various drugs (eg, aspirin, alcohol, nonsteroidal anti-inflammatory drugs), platelet disorders including thrombocytopenia and inherited disorders, low hematocrit, and various medical conditions such as uremia, liver disease, and diabetes.

 The original bleeding time test was called the Duke bleeding time. In this test the  earlobe or fingertip was pierced with a lancet. Subsequently, the Ivy bleeding time was introduced. This version used a blood pressure cuff on the arm inflated to 40 mm Hg and a lancet to make a cut on the forearm. The most recent modification is known as the Mielke bleeding time. This version uses a template to standardize the length and depth of the cut on the forearm. Despite these modifications, the test continues to be affected by many technical issues such as skin thickness, temperature, and variations in operator performance of the test.

	Historically, the most common indication for performing a bleeding time test was as a screening test to assess the risk of bleeding during planned surgery or procedures.

 However, the test lacks sensitivity and specificity and does not predict bleeding risk in patients with a negative bleeding history.

 Other proposed uses of the bleeding time include screening for platelet disorders and evaluating the effect of treatment in conditions such as uremia.

 In a meta-analysis, 862 articles concerning the utility of the bleeding time  were reviewed.

 This analysis included the ability of the test to detect aspirin intake (highly variable results), to predict surgical bleeding (no statistical significance), to evaluate bleeding in uremia (no better than platelet count and hematocrit), and to predict bleeding following procedures (for renal biopsy, the test did not change a priori estimates of bleeding risk). In 1998, a position statement by CAP and the American Society of Clinical Pathologists concluded that “the bleeding time fails as a screening test and is, therefore, not indicated as a routine preoperative test.”

	There continue to be occasional reports in the literature concerning applications of the bleeding time in selected clinical settings. For example, Posan et al reported a comparison of the bleeding time with the platelet function analyzer (PFA- 100) when screening for von Willebrand disease and intrinsic platelet hypofunction, and found that the PFA-100 could replace the bleeding time for this application.

 However, the accumulated literature on the bleeding time test has consistently shown that the test does not predict bleeding prior to planned surgery or procedures, cannot accurately predict aspirin exposure, and can be replaced by other tests to evaluate platelet function in specialized applications such as platelet aggregometry and testing for aspirin

WEB EXCLUSIVE

Physicians and laboratorians must work to reduce use of antiquated clinical laboratory tests. 

Antiquated Tests Within the Clinical Pathology Laboratory

 To collect normative data, assess differences between demographic groups, and indirectly compare US and Canadian medical systems relative to patient expectations of involvement in cancer treatment decision making.

 Individual patient data were compiled across 6 clinical studies among 3491 patients with cancer who completed the 2-item Control Preferences Scale indicating the roles they preferred versus actually experienced in treatment decision making.

The roles in treatment decision making that patients preferred were 26% active, 49% collaborative, and 25% passive. The roles that patients reported actually experiencing were 30% active, 34% collaborative, and 36% passive. Roughly 61% of patients reported having their preferred role; only 6% experienced extreme discordance between their preferred versus actual roles. More men than women (66% vs 60%, 

 = .001) and more US patients than Canadian patients (84% vs 54%, 

This pooled analysis assesses preferred roles in treatment decision making, actual roles, and preferred versus actual discordance among 6 studies of patients with cancer.


September 2010

Economic/Societal Burden of Metastatic Breast Cancer: A US Perspective

Utilization Management for Smoking Cessation Pharmacotherapy: Varenicline Rejected Claims Analysis

Antiquated Tests Within the Clinical Pathology Laboratory

Preferred Roles in Treatment Decision Making Among Patients With Cancer: A Pooled Analysis of Studies Using the Control Preferences Scale

Controlling Hypertension Requires a New Primary Care Model

Benefits and Risks of Live Attenuated Influenza Vaccine in Young Children

Integrating Nurse-Directed Diabetes Management Into a Primary Care Setting

Organization of Care and Diagnosed Depression Among Women Veterans

Colony-Stimulating Factor Prescribing Patterns in Patients Receiving Chemotherapy for Cancer

Magnitude and Economic Effect of Overuse of Antisecretory Therapy in the Ambulatory Care Setting