David Calabrese, RPh, MHP

Across the country today, our healthcare leaders are moving forward in an attempt to reengineer our healthcare system and drive much-needed improvements in access, coordination, quality, and cost-effectiveness of care delivered to our US citizens. As this reengineering unfolds, the pharmacy benefit management industry is also presented with an ideal opportunity to transform itself as a critical contributor in helping to drive these national objectives. In an effort to capture the untapped value that pharmacy benefit managers (PBMs) bring to the table and help guide this transformation, we have developed and introduce here the concept of “pharmacosynchrony.” Pharmacosynchrony represents the application of innovative clinical, analytic, and technologic pharmacy solutions to drive improved care coordination and a higher-quality, more patient-centric model of care.

It appears to have become universally accepted that the healthcare system in the United States is highly dysfunctional. Care remains highly fragmented and increasingly more complex, with a lack of coordination being the norm.

 Population management has still not been widely adopted except as needed for a few commonly reported Healthcare Effectiveness Data and Information Set (HEDIS) measures. Meaningful use legislation has led to a significant increase in implementation of electronic health records (EHRs), but the lack of health information exchanges limits flow of information.

 The Institute of Medicine’s seminal work, “Crossing the Quality Chasm,” states that all of the above leads to higher cost of care.

As a response, payers and providers are embracing newer healthcare delivery models as promising means of improving the healthcare system. Adoption of new models such as the patient centered medical home (PCMH) and the accountable care organization (ACO) is being accelerated by healthcare reform. PCMH has become defined as a full-service primary care practice model that supports integrated care, with emphasis on quality improvement, care coordination, and population management.

 ACOs are integrated units that coordinate primary and secondary care across inpatient and outpatient domains and are dedicated to population management for chronic disease. They are built to enhance cost effi ciency through reduced waste and to drive improved outcomes through tighter care coordination.

Early evidence is encouraging enhanced adoption of these models across market sectors, demonstrating that both PCMHs and ACOs can produce better-quality outcomes with lower costs.

Currently, fewer than 5500 practice sites are accredited by the National Committee for Quality Assurance (NCQA) as PCMHs.

 The Centers for Medicare & Medicaid Services (CMS) initially identified only 32 organizations nationally with the experience and maturity to be included in its Pioneer ACO program to test provider organizations’ ability to bear high levels of shared savings and risk.

While this transformation is encouraging, most of the provider community lacks appropriate infrastructure to support the underlying functions that turn a traditional practice into a PCMH or ACO.

 Most physicians do not practice on a site that can support these functions, and contracting entities such as independent physician associations have not fi lled this void. Consolidation in the provider market may be changing this dynamic, but current estimates are that the majority of healthcare is provided in offices of 1 or 2 physicians.

Currently, PBMs perform many functions for the safe and effective use of medications, including managing the preferred drug list or formulary, processing prescription claims and payment for insurance, controlling prescription costs, and utilizing programs to limit inappropriate medication use. The PBM’s existing programs, claims, and communications platforms put them in the best position to support the strategic objectives set forth by health plans, provider groups, and health systems as they transition toward more sophisticated delivery models. Expansion of PBM services to increase value for patients and providers has included reducing barriers to initiating medications for chronic illnesses, improving adherence for chronic medications, and encouraging cost-effective medication use by suggesting generic medications and formulary compliance.

 PBMs need to advance their role in the delivery of healthcare during this time of dramatic change in the US healthcare system. Change is necessary to improve medication use and avoid adverse events, expand connectivity to real-time prescription use, enhance reporting to evaluate patient outcomes, and leverage the clinical resources of PBMs to improve medication use by harnessing the data and making them accessible to healthcare providers.

Development of the PCMH and ACO infrastructure is a key opportunity for PBMs. Approximately 75% of healthcare costs in the United States today are driven by chronic illnesses including diabetes, cardiovascular disease, stroke, and cancer.

 Pharmaceuticals represent the most powerful tools in effectively managing these conditions, decreasing their progression, and improving overall patient functionality and quality of life. While new models of care are adopted, more comprehensive and advanced means of managing prescription drug therapy remain widely overlooked and undervalued as components of these models.

Our concept of pharmacosynchrony represents a compilation of tools and services by which the PBM industry can foster improved levels of partnership with managed care clients and the provider community to support improved care coordination in a more comprehensive, largely virtual manner. Improved care coordination is the cornerstone of healthcare reform and population-based health management. Key to this partnership is the PBM’s ability to leverage advanced information technology (IT) platforms while marrying such platforms with comprehensive clinical resources and expertise.

 The healthcare system of the future will find much less value in the traditional business model of the PBM serving primarily as the processor of prescription drug claims and providing basic clinical programming and analytics to manage prescription utilization only. In the world of the PCMH and ACO, the PBM will be expected to develop new levels of clinical programming, information exchange, and analytics to provide a much more robust and holistic level of support and service. The PBM must develop new means of connectivity with the provider and patient community to facilitate improved education and engagement in evidence-based standards of care.

Sophisticated data warehousing and analytics capabilities enable the PBM to perform the activities which assist health plan clients and providers with care coordination. Foremost, the PBM can employ well-validated risk adjustment methodology to claims data to assist providers in better pinpointing patients at higher risk of negative clinical outcomes. This will enable providers to more effectively target patients in need of closer follow-up and support a more judicious allocation of resources for clinical intervention. Effectively analyzed claims data will uncover patterns of prescriber and patient behavior, representing opportunities for education and intervention. A PBM’s ability to integrate and effectively analyze both medical and pharmacy claims activity in a near-real-time fashion enhances these aforementioned activities, while also assisting with monitoring timely improvements in important quality metrics such as pharmacy-based HEDIS performance measures.

The current PBM model includes electronic communication with pharmacies, plans, and employer customers. To fill the void in the new delivery systems, the PBM must improve connectivity with the provider and patient communities via new vehicles such as the Web, mobile technology, and EHRs.

 Each will improve timely access to key data and information, such as patient-specific clinical alerts, permitting more proactive intervention. Improved connectivity and coordination of care can also help to prevent negative clinical complications and their associated higher expenditures. Lastly, continuous development and refinement of key quality-based performance metrics and reporting can assist in monitoring and benchmarking provider care and support new methods of quality-based payment reform.

Postdischarge medication reconciliation is another key means by which PBMs can support provider organizations and payers seeking to improve quality while lowering costs. Today, up to 20% of patients discharged from our nation’s hospitals are readmitted within 30 days.

 Communication strategies will be developed to enable the provider, health system, or payer to notify the PBM regarding an impending hospital discharge, by perhaps focusing on diagnoses associated with high rates of hospital readmission. The PBM could then utilize its call center resources, including appropriate clinical personnel, to conduct a real-time medication reconciliation with the patient and/ or caregiver within 48 hours of discharge. This reconciliation process will comparatively assess pre- and postdischarge medications on hand in the home, including over-the-counter medications, to ensure adequate patient understanding of these medications and their appropriate use.

This review would also encompass an evaluation of duplicate therapy, polypharmacy issues, potential drug-drug interactions, proper dosing, and appropriate prescribing and filling of postdischarge medications in accordance with national consensus guidelines and best practices.

 The PBM’s unique position of having pre- and postadmission medication claims simplifies the process and reduces patient confusion about complicated regimens.

 Medication reconciliation is now a Joint Commission National Patient Safety Goal and has been included in the CMS Provider Quality Reporting System, primarily because it has been demonstrated to improve quality of care through reduced medication errors and decreased readmission rates.

The PBM also represents an ideal partner with providers on population management and the goal of continuous quality improvement. Pharmacy claims data serve as a powerful resource to identify multiple types of care issues. No entity is in a better position to identify medication-free gaps between prescription refills or adherence issues. Additionally, claims data can be used to screen patient regimens for appropriate care in accordance with national and international standards of care and best practices. For example, the PBM can serve as an integral resource toward identification of patients with diabetes mellitus who are not receiving appropriate medications for renal and cardiovascular protection in accordance with American Diabetes Association guidelines, or patients with chronic obstructive pulmonary disease (COPD) whose prescriptions are not consistent with the current Global Initiative for Chronic Obstructive Lung Disease guidelines. Proper prescribing per disease state can be monitored and reported upon wherever there is significant clinical consensus as to the appropriate course of action.

The PBM is also in an ideal position to notify clinicians about prescriptions that have been transmitted to pharmacies but were never picked up by the patient (“primary” nonadherence). Electronic or e-prescribing transaction records and pharmacy claims activity documenting “reversed” claims (prescriptions returned to stock at the pharmacy due to lack of patient pickup), serve as key means to identify this type of nonadherence. Enhanced connectivity with provider offi ces allowing Web-based access to real-time, patient-specific medication dispensing history can also give clinicians newer and more valued insights into how their patients use their medications.

The PBM can build upon the existing communication loop with the patient and provider. Incorporating PBM clinical staff as members of the care team can also play an important role in better measuring key clinical performance metrics, supporting drug information needs of other team members, and more actively engaging patients between clinical visits on healthy behaviors and care plans. Patient outreach for any quality purpose and the result of each medication reconciliation must be captured appropriately and provided back to the care team in as timely and effi cient a manner possible. PBM-based Web portals can be used as a key vehicle to house these important data, to collect Health Risk Assessment (HRA) information from the patients, and in reporting. The use of IT systems to integrate medical and pharmacy claims, adherence information, and HRA tools allows for the PBM to identify the highest risk patients and provide that information regularly to the care coordination teams for better allocation of resources.

The PBM also has numerous tools at its disposal to deliver a more personalized approach to patient care. Existing resources such as call centers, Web portals, mobile technology, and decentralized clinical staff can surround the patient and provider with a variety of support services. Targeting high-risk patients for outreach for disease-specific coaching will drive more effective education and improve quality. Patients can be contacted when it appears that their regimen may be missing key components, such as the patient with diabetes not on a key medication as discussed above. High-risk patients can also be contacted when a prescription goes unfi lled to determine what the barrier may be and how it can be overcome. Innovative rewards-based programming can be established via drug benefit design to promote improvements in adherence and preventive care, such as vaccinations, smoking cessation, and routine lab monitoring. Of course, the medication reconciliation function described earlier is also a key example of a more personalized approach to care coordination and quality improvement.

The PBM can further support the transition of care by collaboratively developing and providing the necessary data and reporting to the clinician groups and health plans. These can be as simple as traditional reports looking at generic prescribing, to as complex as patient-specific gaps in care analyses and provider-based “report cards,” comparing individual physician prescribing patterns with those of their peers and benchmarking best practices across a wide range of metrics. These should include quality metrics as well as cost, by supporting measures such as proper asthma and COPD prescribing. Antibiotic use should be monitored and addressed if found to be at odds with practice guidelines. Specialists’ prescribing should also be monitored so that primary care physicians participating in PCMH and ACO models can better evaluate their choice of specialist partners.

All of the above represent key changes in the PBM service model that should drive improved quality and lead to cost savings. The PBM should not lose sight of the fact that traditional pharmacy benefit design also represents opportunity for change and improvement in supporting this paradigm shift. Today’s pharmacy benefit needs to be designed intelligently to encourage cost-effective medication use. Real-time e-prescribing tools simplify the prescribing process and guide decision making for clinicians. Automating drug utilization management tools such as step therapy and prior authorization helps reduce administrative burden for providers, thereby freeing time for more quality-based initiatives. Identification of patients who are underutilizing medications will lead to better, more costeffective disease management for their chronic conditions.

To achieve all of the aforementioned objectives will not be a simple undertaking. A more competitive and demanding marketplace will compound the challenge facing the PBM industry to make the necessary investments in IT resources. IT vendors such as those providing EHRs, e-prescribing platforms, medical claims processing, and laboratory data management must be open to collaborating with the PBM to openly share data and information in a consistent fashion. PBM clients such as health plans, large employers, and state agencies must also embrace the clinical and economic value of enhanced data sharing and integration with the PBMs. The provider community must be willing to embrace PBM personnel and systems as a key component of the newly evolving healthcare delivery team and alter practice patterns to capitalize on advanced sharing of key information and data from PBM providers. Currently, there is a paucity of evidence demonstrating patient benefits achieved with these new advanced clinical services from PBMs. Studies on patient outcomes with the new expanded services will need to be performed.

In short, the concept of pharmacosynchrony moves the PBM industry away from its traditional role as an administrative support resource for payers in managing pharmacy benefi ts. Pharmacosynchrony unleashes the underused power of pharmacy data, advanced IT systems, and comprehensive clinical resources to drive the PBM industry into a closer relationship with health plans, employers, provider systems, and patients. It provides these entities with a multidimensional suite of tools and resources to better manage drug therapy to attain better healthcare, better health outcomes, and lower costs. Only through this foundational shift in functional capacity will the PBM industry attain the type of alliance with its industry partners that will inevitably help to drive this nation’s healthcare to higher levels of quality and cost-effi ciency. In doing so, the industry will also engender the opportunity to earn a higher standing within the US healthcare system and within society as a pivotal resource in driving positive change.

Articles

Pharmacosynchrony is the application of innovative clinical, analytic, and technologic pharmacy solutions to drive improved care coordination and higher-quality, more patient-centered care.

Pharmacosynchrony: Road Map to Transformation in Pharmacy Benefit Management

Chronic kidney disease (CKD) is characterized by kidney damage (with or without proteinuria) and decreased renal function, as determined by glomerular filtration rate (GFR), which progressively decreases over time. CKD is described in stages, with stage representing the least amount of kidney damage with well-preserved kidney function, and stage 5 indicating a high degree of kidney damage with poor renal function. Recent evidence indicates that the prevalence of CKD is increasing in the United States.

Coresh and colleagues evaluated the National Health and Nutrition Examination Surveys data and were able to demonstrate that the prevalence of albuminuria and decreased GFR increased from 1988 to 1994 and 1999 to 2004.

 Furthermore, the prevalence of CKD (stages 1 to 4) was 10% (95% confidence interval [CI], 9.2%-10.9%) in 1988 to 1994 and increased to 13.1% (95% CI, 12%-14.1%) in 1999 to 2004. Mean serum creatinine level was also higher in the second cohort.

 Although serum creatinine is an indicator of reduced kidney function, it is not a sensitive measure, since GFR (which directly impacts serum creatinine) is dependent on other factors, such as age, sex, body weight/body mass, and race. Because routine measurement of GFR is impractical (due to complexity, expense, and time), clinicians routinely estimate GFR to stage CKD. Consequently, the Modification of Diet in Renal Disease equations (MDRD Study equations), which incorporate serum creatinine, urea nitrogen, and albumin levels, age, sex, and race to estimate GFR, are most commonly used to stage CKD.

 It is important to note that many cardiovascular (CV) trials excluded patients with known CKD, usually by establishing a serum creatinine level cutoff. As such, information on CV disease (CVD) in CKD has been inferred from these trials, usually by post hoc analyses of data in patients enrolled in the trials with GFR estimates. 

End-stage renal disease (ESRD) is loosely defined by signs and symptoms of kidney failure—a GFR less than 15 mL/min/1.73 m

 and the requirement for renal replacement therapy (usually dialysis).

 CVD has long been recognized as the leading cause of death in patients with ESRD, occurring in more than 50% of patients.

CVD is also the leading cause of hospitalization among such patients.

, compared with a population without CKD, there is a graded inverse relationship between CKD and CVD; the lower the degree of kidney function, the higher the risk of CVD.

 Moreover, hospitalization rates and mortality increase as GFR decreases (

). These relationships were noted to be approximate and were affected by patient age. Several disease factors and comorbidities contribute to CVD in CKD. Among contributing factors are increased urinary albumin excretion, which is associated with an increased risk of CVD events in the general population

 Other factors that can contribute to CVD in CKD are hypertension, diabetes, dyslipidemia, smoking, and established CVD (cardiorenal syndrome).

Managing Hypertension and Dyslipidemia in Patients With CKD

Because hypertension and dyslipidemia play a significant role in CKD, several guidelines have set goals for the management of these risk factors. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) includes a blood pressure (BP) target of less than 130/80 mm Hg in patients with CKD.

 The National Kidney Foundation (NKF) Kidney Disease Outcomes Quality Initiative (KDOQI) group published guideline recommendations for hypertension in the CKD population, which also targeted a BP goal of less than 130/80 mm Hg.

 In 2007, the American Heart Association (AHA) developed a scientific statement on treating hypertension; it designated the CKD population as a high coronary artery disease (CAD) risk group and recommended a BP goal of less than 130/80 mm Hg.

 Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are preferred antihypertensive agents in patients with CKD per the KDOQI and JNC 7 guidelines.

 The AHA recommends these agents as first-line options, but categorizes CKD in the high-risk population and does not give specific recommendations for drug therapy in these patients.

Among antihypertensive therapies, ACEIs have been studied the most for their ability to improve CV outcomes in the CKD population. ARB therapy has been evaluated, but the data are not as encouraging as those observed with ACEI therapy. There are reasons to use ACEI or ARB therapy beyond preventing CV events (ie, delaying progression of nephropathy), and these need to be considered when determining optimal therapy in patients with CKD.

 The Eighth Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8) is highly anticipated and is scheduled for publication in 2012.

The NKF KDOQI group published guidelines for the management of dyslipidemia in CKD in 2003 (

The primary target of dyslipidemia in patients with CKD is low-density lipoprotein cholesterol (LDL-C) level. The guidelines recommend an LDL-C target of less than 100 mg/dL in patients with CKD (all stages), unless their triglycerides are above 500 mg/dL.

 It is important to note that since the publishing of the guidelines, newer therapies and evidence have emerged, which necessitates an update in recommendations.

The recent Study of Heart and Renal Protection (SHARP) demonstrated that benefits (ie, long-term reduction in risk of heart attack, stroke, and operations to open blocked arteries) in the CKD population extend to a lower LDLC level than US guidelines currently recommend. SHARP achieved a mean LDL-C level of 75 mg/dL at 4.4 years.

 This low LDL-C level helps support a lower LDL-C goal of less than 100 mg/dL, as recommended by the Third Report of The National Cholesterol Education Program

(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) and NKF KDOQI guidelines.

 Recently, the European Society of Cardiology and the European Atherosclerosis Society published updated guidelines on the management of dyslipidemia.

 In these updated guidelines, patients with CKD are considered at very high risk of CVD and an LDL-C goal of less than 70 mg/dL is recommended.

 The new Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel IV) guidelines are scheduled to be published in 2012, and are highly anticipated with the recent study findings from SHARP and the potential for a more aggressive LDL-C target in the CKD population.

Patients with CKD comprise 6.8% of the US Medicare population, but consume over 14% of overall Medicare expenditures.

 The overall Medicare cost per person per year for CKD was $19,752 in 2008. Costs in the subsets of patients with CKD and diabetes were $21,740 for Caucasians, $25,352 for African Americans, and $28,809 and $35,009 in the respective cohorts among those with heart failure. In patients 65 years or older, average annual costs were determined to be $20,784 for all patients, $11,760 for those with a creatinine clearance of 60 mL/min or better, and $68,808 for those with ESRD, indicating that the costs increase as kidney function declines.

 The review also determined that death was an important cost to consider in patients with CKD, and estimated that the individual cost of death was $37,611.

Chronic conditions (eg, obesity, hypertension, myocardial infarction [MI], angina, diabetes, dyslipidemia, anemia, and hyperuricemia) are associated with an increase in cost of care in patients with CKD.

 CVD is the leading cause of hospitalization in patients with CKD.

 In addition to the long-term costs associated with CKD and incident CVD, costs of dialysis initiation and maintenance are significant.

 To examine the importance of comprehensive care in patients at risk for requiring dialysis, one study randomized patients to care by a nephrologist (n = 69) or a CKD care program (which included a nephrologist, trained nurses, and a dietitian with specific goals for patient education) (n = 71).

 The comprehensive program was associated with lower total medical costs at dialysis initiation ($942 vs $2674; 

 <.001) due to early preparation for vascular access and lack of hospitalization at dialysis initiation.

 Providing specialized comprehensive care to patients with CKD is important because inappropriate care can lead to unnecessary costs. In managed care populations, unneeded or inappropriate care is delivered as much as 30% of the time, resulting in unnecessary costs. If resources were added to improve the frequency of appropriate care to more than the current value of about 50%, it would be possible to improve outcomes and reduce overall costs.

 Because care of the CKD population may often be inappropriate, and the costs of managing CKD are high, early recognition of CKD is likely to significantly reduce the cost of care to patients and the healthcare system.

Despite a lack of formal risk-factor intervention studies in patients with CKD, much has been learned from studying the relationship of treatment and outcomes based on CKD markers, such as GFR and albuminuria. In patients with hypertension associated with CKD, albuminuria management should be considered an integral study of 8206 patients with left ventricular hypertrophy that lasted approximately 5 years, use of losartan to lower blood pressure and albuminuria reduced the composite end point of CV mortality, stroke, and MI (independent of BP reduction).

 Evidence suggests that the goal BP in patients with CKD should be less than 130/80 mm Hg, unless proteinuria exceeds 1g/L (when BP should be <125/75 mm Hg).

 A study assessed trandolapril for BP reduction in the absence of documented albuminuria and determined that it did not improve survival in the overall cohort with relatively normal GFR.

 In a subgroup analysis of patients with a GFR less than 60 mL/min/1.73 m

, however, reduction of BP with trandolapril decreased CV and all-cause mortality (

 Finally, in a formal, 7-year economic analysis conducted with benazepril for reduction of BP in patients with CKD, the cost-effectiveness ratio (CER) per qualityadjusted life-year (QALY) demonstrated reduced costs ($10,000-$13,000) over the course of the study due to improvement in outcomes.

 These results suggest that ACEI therapy in advanced CKD (GFR <60 mL/min) may improve CV outcomes and result in cost savings.

Thus, ACEIs and ARBs may be useful to help decrease the incidence of CVD-related outcomes in patients with CKD, especially in those with lower GFRs.

It should be noted, however, that despite nearly universal awareness of hypertension, adequate control of BP in accordance with current consensus standards remains highly suboptimal.

 A recent study used multivariable statistics to determine community-based factors associated with awareness of hypertension, treatment patterns, and control rates. The study evaluated patients with GFRs of 20 to 70 mL/min/1.73 m

 and found that ACEIs and ARBs were associated with enhanced BP control. Older patients, African Americans, and those with higher urinary albumin excretion rates were less likely to achieve BP control.

 The lack of BP control in patients with CKD, or lack of ACEI and ARB therapy, may be due to concerns among clinicians about GFR reductions and risk of acute renal failure associated with ARBs and ACEIs.

 Because of the documented benefits of ACEIs and ARBs in hypertension, diabetic nephropathy, heart failure, and CAD, however, these agents should be used with caution rather than avoided in patients with CKD.

The impact of ACEIs and ARBs on reduction of GFR is also commonly used as a therapeutic tool for the management of proteinuria associated with diabetes. ACEIs and ARBs are the most studied agents in prevention of progression of CKD in diabetes, and they have been evaluated for their effects in CVD outcomes.

 In 2 large diabetic nephropathy studies, losartan and irbesartan failed to improve CV outcomes or death rates, although progression to ESRD was reduced, suggesting a potential inadequate follow-up period to assess impact on CVD.

Clearly, patients with CKD and diabetes should be managed with a patient-specific, customized approach (rather than a specific agent) due to the frequent presence of concomitant hyperglycemia, dyslipidemia, and hypertension.

In an economic evaluation examining the cost-effectiveness of a multifactorial approach to reducing CVD in diabetes, patients were randomized to the Diabetes Care Protocol (DCP) or usual care.

The DCP consisted of a 1-hour consultation by a practice nurse and a computerized decision support software assessment that provided patient-specific advice (on targets for glycosylated hemoglobin, BP, body weight, cholesterol, and smoking cessation); the practice and patient received feedback every 3 months. The incremental CER was €38,243 (approximately $55,307) per QALY in the overall population. In patients with CVD, the CER was €14,814 ($21,424) per QALY, and the coronary heart disease costs were reduced by €587 ($849) (

 <.05). In contrast, the CER per QALY for patients with diabetes and no CVD was €121,285 ($175,402). It should be noted that this study did not specifically evaluate patients with CKD, but it did demonstrate that patients with diabetes and CVD could be treated in a cost-effective and potentially cost-saving manner using a comprehensive intervention.

A Cochrane review evaluated the effects of statins in CKD patients who do not require dialysis.

 The evaluation consisted of 25,017 patients from 26 studies, and demonstrated a statin-induced reduction in low-density lipoprotein (LDL) cholesterol (-42.38 mg/dL), total cholesterol (-41.48 mg/dL), all-cause death (19% reduction), CV death (20% reduction), and 24-hour urinary protein excretion (-0.73 g/24 hours), but no improvement in creatinine clearance. Statins appeared to be well tolerated, with associated adverse effects similar to those in controls. 

 The therapeutic benefits observed in the Cochrane review are consistent with recent trials.

In the absence of well-designed cost-effectiveness studies, it may be inferred that statins, with their established benefits and tolerability, appear to be a worthwhile intervention for CKD patients with dyslipidemia or CVD.

To a similar extent, evidence of cost-effectiveness of interventions for CAD, MI, and heart failure in patients with CKD is lacking.

 However, similar trends are noted— standard therapies are effective, but they are underutilized. 

 For example, standard therapies for MI (eg, ACEIs, ARBs, beta-blockers, aspirin, statins) are underutilized in patients with CKD, despite current evidence supporting their use in the presence of CAD or heart failure.

Efforts to improve adherence are another important consideration in the treatment of CVD in CKD. In a 2007 survey of patients with Medicare Part D prescription drug plans, 23% to 31% of patients with ESRD reported costrelated nonadherence to prescription medication in the preceding 6 months. Patients with ESRD were 2.34-fold more likely than those without ESRD to report cost-related nonadherence.

 African Americans and patients with Medicare Part D Low-Income Subsidy assistance reported higher rates of cost-related nonadherence than other subgroups.

 Any treatment decisions should include assessment of the patient’s ability to pay, as well as the availability of well-tested, less costly generic options, especially when the regimen may be complicated and involve multiple medications.

In a study of a privately insured population, patients taking medications for hypertension, dyslipidemia, and diabetes between 2004 and 2008 were evaluated for adherence (days per year covered by a filled prescription).

 Adherence was defined as a medication possession ratio of 80% or more. Adherence was highest with medications for diabetes, followed by agents for hypertension and dyslipidemia. Interestingly, adherence was highest among patients taking the most medications (ie, those treated for all 3 conditions).

Enhanced compliance when multiple conditions are managed supports the theory that recognition of disease improves delivery of treatment. This is especially important in patients with CKD because they tend to have multiple comorbidities and consequently require numerous medications. The suggestion that more medications result in better compliance is encouraging because once patients with CKD are identified, they can take an active role in their care by more adequately following therapeutic regimens.

Based on available evidence, CVD is prevalent in patients with CKD. Thus, managing patients with CKD and hypertension or dyslipidemia can result in better outcomes. Managing hypertension in CKD demonstrates CV benefits and a delay in progression of nephropathy. Similarly, better control of LDL-C levels is associated with long-term risk reduction in heart attack and stroke, as evidenced from SHARP. ACEIs, ARBs, and statins have the most robust data in CKD; outcomes will be influenced by choosing the most appropriate therapy for each patient and promoting adherence. Optimizing control of CVD also has economic implications, especially considering that CVD is the most common cause of hospitalization in patients with CKD. Improving the management of CKD and addressing CVD comorbidities can lead to improved clinical and economic outcomes.

Evaluating the relationships between chronic kidney disease and cardiovascular disease and strategies to improve outcomes.

Improving Outcomes in Chronic Kidney Disease: Optimizing Management of Cardiovascular Diseases

Dose consolidation and quantity limitations (QLs) are 2 strategies used by pharmacy administrators and decision makers to assist in controlling drug costs and increased utilization per patient. Dose consolidation, also referred to as dose optimization, is a drug cost management intervention. In dose consolidation, regimens consisting of lower-strength products taken as multiple units per day are converted to an equivalent daily dose of a higher-strength tablet or capsule.

Once-daily maintenance medications with multiple dosage strengths and parallel pricing are typically appealing options for dose consolidation programs. There is limited published literature on the clinical effectiveness of these programs, but they are desirable from a cost-savings standpoint. In addition, simplifying a patient’s drug regimen may  decrease the chance of missed doses and increase adherence, while providing the same total daily dose.

It is important to note that not all patients are candidates for dose consolidation. A physician may wish to continue a patient on the current regimen based on many factors. These include, but are not limited to, patient age, adverse events, tolerability, tablet or capsule size, dose stabilization, and possible varying dosing regimens.3 With a new dose consolidation program, it is important to offer physicians the option of continuing their patients on the current dosing regimen if needed. This can be done via a prior authorization (PA) process.

Essentially, a dose consolidation policy encourages pharmacy providers to dispense 1 larger strength of a drug product rather than 2 smaller strengths. In addition, QLs restrict pharmacy providers from dispensing more than the allowed tablet or capsule quantity per day. If the prescriber has a clinical reason for prescribing outside these limitations, a PA request is submitted to the payer before dispensing the written dose and/or quantity. If a PA is not received, the pharmacy must dispense the product within the limits established by the payer.

Certain mental health drugs such as aripiprazole, olanzapine, venlafaxine XR, escitalopram, and sertraline are typically dosed once daily, and are available in multiple strengths with very small differences in average wholesale price (AWP) from strength to strength. As such, these particular drug products represent an excellent target for a dose consolidation and/or QL program.

Our program was implemented within a fee-for-service state Medicaid environment. A 3-month claims review for select once-daily mental health drugs (aripiprazole, olanzapine, venlafaxine XR, escitalopram, and sertraline) from November 1, 2005, to January 1, 2006, was done to determine potential dose consolidation opportunities. Analysis of these data indicated that lower-strength forms of these products were frequently being prescribed as multiple units per day, despite the availability of higher-strength forms of the same product. In addition to economic concerns, the relative prevalence of this dosing inefficiency prompted concerns about increased pill burden for patients, added complexity of drug regimens, and a potentially negative impact on patient adherence to therapy.

As a result of the initial review, the state’s drug utilization review board voted in support of a combined dosage consolidation protocol and QLs for dispensing the lower strengths of these 5 medications. It is important to note that the highest strength of each product was not subject to any dose consolidation or QL initiatives. In addition to the highest doses, aripiprazole 2 mg, aripiprazole 20 mg, and olanzapine 15 mg also were not subject to these initiatives because higher practical consolidation doses were not available for these  strengths (eg, 2 × 20 mg could not be consolidated to 1 × 40 mg). 

 illustrates the exact QLs placed on each product and strength.

The QLs went into effect October 1, 2006, and limited prescribing to 1 unit (tablet or capsule) per day with select dosage strengths of these products. Two months before the implementation of this program, a formal patient-specific mailing and PA form were sent to 250 physicians of potentially affected patients.

The objective of this analysis was to assess the cost and utilization outcomes associated with this dose consolidation program a year after its original implementation date.

Clinical Education Outreach Based on a pharmacy claims assessment between May and  July 2006, 418 patients were identified as receiving lower-strength forms of aripiprazole, olanzapine, venlafaxine XR, escitalopram, and sertraline being prescribed as multiple units per day when higher-strength, single-unit alternatives were readily available. In August 2006, formal patient-specific mailings were sent to 250 physicians outlining the background and objectives of the correspondence, as well as notifying the physicians of forthcoming implementation of QLs for these 5 drugs, effective October 1, 2006.

The mailing included a pharmacist-reviewed, patient-specific prescription profile populated with the most recent claims data. The profile identified each patient under that provider’s care who appeared to be receiving a lower-strength form of 1 of the above-mentioned medications in quantities greater than 1 unit per day. The mailing provided patient-specific recommendations as to a more appropriate consolidated dosage regimen for the prescriber to consider. Providers were asked to review each patient’s record to determine whether the patient’s dosing was appropriate for consolidation. The profile also identified the last pharmacy where the patient’s prescription had been filled, as well as the phone and fax  numbers for that pharmacy to facilitate any change in regimen. The mailing also contained a physician response form that allowed clinical staff to collect information from the  provider as to his or her anticipated patient-specific course of action in a follow- up to this initiative. Finally, the mailing included a PA request form, in the event that there was clinical justification for the patient to remain on his or her current dosage form and/or regimen.

To assess the effects of this initiative on cost and utilization, 6 months of pharmacy claims data from April 1, 2007, through September 30, 2007 (postimplementation) were compared with 6 months of pharmacy claims data from April 1, 2006, through September 30, 2006 (preimplementation). Data on prescription volume, ingredient cost per unit based on discounted AWP, total units, and total days of therapy were retrieved for each strength of the selected mental health products per month. Subsequently, mean units per day (± standard deviation [SD]), mean units per prescription (±SD), mean ingredient cost per unit (±SD), and 6-month savings figures were calculated. The latter was obtained using the following equation: (postimplementation units per day — preimplementation units per day) × postimplementation average cost per unit × postimplementation total days of therapy

In addition, we determined mean totals (±SD) for each product regardless of strength, as well as cumulative mean totals (±SD) (all drugs, all strengths).

Multifactor analysis of variance with Student-Newman-Keuls post-hoc testing was used to determine whether significant differences existed between the preimplementation and postimplementation means. Results were considered to be statistically significant if the observed level of significance (P value) was less than .05. All analyses were performed using NCSS 2000.

Of 250 total mailings, physician response forms were received from 136 physicians, for a 54.4% active response rate. Of the response forms received, 70 (51%) responders indicated they would review therapy with the patient by phone, by appointment, or at the next scheduled office visit. Another 32 (24%) responders chose not to intervene in therapy, and 27 (20%) responders indicated that it was not their patient or that they were no longer treating the patient. The remaining 7 (5%) responders did not indicate a reason, choosing “other” on the response form. See 

 for a full breakdown of physician mailing responses. Physicians were asked to rate the usefulness or value of the information provided in the mailing. Based on a scale of 1 to 10 (not useful at all to extremely useful), the average weighted score was 5.4 out of 10.

The overall assessment for all drugs and strengths showed a statistically significant decrease in mean units per day, mean units per prescription, and mean ingredient cost per unit (—0.10 ± 0.28, 

 <.001, respectively) in the postimplementation group compared with the preimplementation group (

The data were further evaluated for statistical significance with respect to mean units per day and mean units per prescription for each product and strength. Overall product evaluation (all strengths) showed a statistically significant decrease in both mean units per day and mean units per prescription with aripiprazole (-0.04 ± 0.07, 

 <.01, respectively), venlafaxine XR (-0.20 ± 0.14, 

<.001, respectively), sertraline (-0.18 ± 0.14, 

 <.001, respectively), and olanzapine (-0.21 ± 0.23, 

 <.001, respectively). The overall escitalopram group had a decrease in mean units per day and mean units per prescription; however, only the latter was statistically significant (-1.86 ± 4.33, 

 <.01). Sertraline (as a branded product) had an increase in utilization for both data points (0.10 ± 0.53 and 6.17 ± 16.78, respectively), neither of which was statistically significant.

An evaluation also was performed on each of the individual drug strengths. For aripiprazole, a statistically significant decrease was noted in both utilization measures for the 5-mg, 10-mg, and 15-mg doses (

 <.05). Aripiprazole 2 mg showed an increase in both utilization measures, but only the mean units per day were statistically significant (

 <.05). Aripiprazole 20 mg and 30 mg had statistically significant increases in mean units per prescription (

 <.05). Changes in mean units per day for these 2 doses were not statistically significant.

In the venlafaxine XR group, the 37.5-mg and 75-mg strengths had a statistically significant decrease in both utilization measures. The 150-mg strength showed a slight decrease (-0.01 ± 0.02) in mean units per day and a slight increase (0.01 ± 0.86) in mean units per prescription, but neither was statistically significant.

In the escitalopram group, the 5-mg and 10-mg doses showed a statistically significant decrease in mean units per prescription (

 <.05). The 20-mg dose showed an increase in both utilization measures, neither of which was statistically significant.

During the course of our preimplementation and postimplementation analyses, branded sertraline lost its patent protection and a generic equivalent was launched. In the generic sertraline group, all doses had a decrease in both utilization measures. However, changes in mean units per day in the 100-mg strength were not statistically significant. In the branded sertraline group, none of the changes in utilization measures for each dose were statistically significant.

Lastly, in the olanzapine group, the 2.5-mg, 5-mg, 10- mg, and 15-mg strengths all showed a statistically significant decrease for both utilization measures (

 <.05). Olanzapine 7.5 mg did show a decrease in both measures, although neither was statistically significant. The 20-mg strength showed a decrease in mean units per day and an increase in mean units per prescription; the latter was statistically significant (

 have a complete breakdown of results for each medication and are available at 

Overall, these efforts resulted in a statistically significant decrease in mean ingredient cost per unit (-$0.06 ± $5.94, 

<.001) when comparing the postimplementation group with the preimplementation group. When comparing postimplementation with preimplementation values for each of the individually targeted drug products, all showed a statistically significant increase in mean ingredient cost per unit (

 <.001) secondary to intervention, with the exception of sertraline (-$1.95 ± $0.02, 

Using the equation shown in the Methods section, an overall 6-month savings of $310,679.46 was calculated. This translated to per member per month cost savings of approximately $0.37. The overall Zoloft group (all strengths) was the only one not to show a cost savings (-$935.60). This, of course, may be attributable to the substantial decrease in brand Zoloft use secondary to the launch of generic sertraline, as well as manufacturer pricing changes that occurred in anticipation of this lost market share. Complete cost savings data are in 

It is difficult to determine whether the clinical education and notifications sent to physicians in August 2006 played a role in any of the cost and utilization changes shown in this analysis. These notifications were to alert physicians to possibly affected patients and offer them information on PA in the event that there was clinical justification for continuing a patient on his or her current dose. Although there were only 136 responses, 51% of the physicians who responded mentioned that they would write a new prescription for a once-daily dosage regimen at a higher strength.

Our analysis was designed to examine the effects of a consolidation and QL program on utilization and cost. Unfortunately, we did not simultaneously test for clinical or humanistic outcome measures in this population. Although such a study would add value, it was not the intention of our analysis. In addition, assessing clinical or humanistic measures in this population would be extremely difficult because of cost, time, manpower, and the type of data available to us (pharmacy claims data only). Additional research assessing QLs and their effects on clinical outcomes are warranted for validation of these implementation programs.

It is important to note that Zoloft’s generic equivalent sertraline became available in the third quarter of 2006, which occurred during our preimplementation time frame. It also is important to note the vast difference in AWP cost when sertraline became available in our preimplantation phase compared with its cost in the postimplementation phase. This large difference in unit cost is most likely attributable to the generic exclusivity of sertraline, which limits the production of other generic forms of sertraline for the first 180 days. During our  postimplementation phase, other generic forms were available, therefore drastically lowering the cost.

It is also difficult to truly assess whether, and to what extent, these events affected our data and our analysis. Our units per day and units per prescription seemed not to be affected because they were calculated independent of cost and based on total days of therapy and total prescriptions. On the other hand, effects on cost were very apparent in the sertraline group. Ingredient costs per unit decreased by an average of $1.95, the largest change witnessed in our cost analysis.

Savings for the 6-month postimplementation evaluation were calculated based on units per day and discounted AWP cost per unit; additional rebate discounting was not taken into consideration. Although the study showed a cost savings of $310,679.46 ($621,358.92 annualized) during the 6-month postimplementation period, the study did not assess additional administrative costs or funds tied to program implementation or rebate implications (if any).

The Zoloft group was the only one to show an increase in cost. Although it is not certain, we believe the substantial drop in brand Zoloft usage secondary to generic introduction and manufacturer price increases on the branded product likely contributed to the confounded Zoloft figures. On the other hand, introduction of multiple generic forms of sertraline before our postimplementation phase resulted in cost savings of $9317.32, which helped offset the increase in the Zoloft group. Assessment of PA requests and subsequent results to examine this potential relationship may be warranted in subsequent studies.

Overall, dose consolidation and QL initiatives were successful in positively affecting daily dosing patterns and cost outcomes for these selected mental health products. Research focusing on clinical and humanistic outcomes in lieu of these strategies is needed to help further validate these programs.

Dose consolidation and quantity limit initiatives decreased utilization and cost outcomes for select mental health drugs in a fee-for-service Medicaid environment.