n report n
health-related Quality of Life, economic cost, Introduction
Parkinson’s disease (Pd) is the second most common neurodegen- Abstract
erative disorder, marked by increasing movement-related disability, Parkinson’s disease (PD) is the second most com- including tremor and bradykinesia, impaired balance and coordina- mon neurodegenerative disorder, marked by pro- tion, and cognitive changes.1 it affects up to 1 million people in the gressive increases in movement-related disability, united States and up to 5 million worldwide.1 The prevalence of Pd impaired balance, and nonmotor symptoms. Its prevalence in the United States is expected to increases with age, with approximately 1% of those aged 60 years double within the next 20 years as the percentage or older affected, 4% or more of those aged 80 years or older,2 and of the elderly in the population grows. Patients approximately 5.2% of those in nursing homes.3 given the growing with PD have twice the direct medical costs of elderly population in the united States, the number of individuals those without PD, the majority of which occur later in the disease as disability and therapy-related complications increase. Greater awareness of a Such an increase will place a significant burden on healthcare prodromal/premotor stage of the disease, efforts systems and caregivers given the progressive nature of Pd, associ- toward early and accurate diagnosis, and the continuous refinement of treatment paradigms ated disability, and significant caregiving required in the later stages provide an opportunity for discussion on the use of of the disease. With the expected increase in Pd prevalence, it can potential disease-modifying agents to slow or halt be anticipated that the disease will continue to exact a significant the progression of motor and nonmotor disabil-ity. Such compounds could not only significantly direct and indirect economic cost. Thoughtful consideration into improve patient and caregiver quality of life, but treatment decisions can result in more optimal healthcare utiliza- substantially reduce direct and indirect costs. To tion without sacrificing health-related quality of life (hrQOL) and date, numerous compounds have been evaluated in clinical trials, including coenzyme Q10, creatine, levodopa, pramipexole, rasagiline, ropinirole, and selegiline. None has demonstrated irrefutable and Economic Costs of PD and Impact on
enduring disease-modifying qualities, although Health-Related Quality of Life
the best available clinical evidence appears most promising for rasagiline.
Overall, the annual economic impact of Pd in the united States (Am J Manag Care. 2010;16:S87-S93) is estimated at $10.8 billion, 58% of which is related to direct
medical costs.5 Annual direct medical costs per patient with Pd are
estimated to Managed Care
be between $10,043 and $12,491, &
Healthcare Communications, LLC
that of patients without the disease.5,6 Prescription drugs account for approximately 14% to 22% of costs, with nursing home care the largest component at approximately 41%. Annual indirect costs, including lost workdays for patients and caregivers, are estimated at As important as economic costs are to any discussion of Pd-related resource utilization, it is also critical that payers and pro- viders consider the significant impact the disease has on hrQOL. hrQOL assesses an individual’s perceived effect of the illness on their physical, psychological, and social daily lives.7 it is important in determining the effectiveness of therapies for Pd at both the For author information and disclosures, see end of text.
individual and population levels.8 for managed care providers, it presents an important parameter to measure the effectiveness n The AmericAN JOurNAL Of mANAged cAre n of management strategies and quality of care.7 hrQOL a resting tremor, and this has been reported to be prognostic measures are also important in assessing the value of drug of a more rapidly progressive disease course.26 As the disease therapy, particularly for chronic conditions such as Pd, and progresses, patients exhibit disability due to bradykinesia, in determining the appropriate placement of medications on rigidity, gait and balance difficulty, and falls.24 Additionally, dopaminergic-related side effects from medications become As would be expected for any chronic and progres- more problematic. in more advanced stages of the disease, sively worsening disorder, Pd has a significant impact on the disabling cognitive symptoms, such as dementia, are more hrQOL for both patients and their caregivers.11 in a large Veterans Administration cohort, patients with Pd exhibited Several assessment and rating scales provide clinically lower scores on the physical and mental health dimensions important information on changes in Pd severity and dis- of hrQOL compared with patients with 8 other neurologic ability. These include the unified Parkinson’s disease or chronic conditions, including diabetes, congestive heart rating Scale (uPdrS), which is undergoing revision to failure, angina/coronary heart disease, and stroke.12 Of note, better account for nonmotor symptoms, Webster’s columbia nonmotor disability, particularly depression, insomnia, and university rating Scale (curS), Northwestern university other mental health factors, appear to have a greater negative disability Scale (NudS), and the hoehn and Yahr scale.27 effect on hrQOL than motor deficits.8,13-15 A recent analysis correlated disability with the uPdrS and identified specific motor and total scores to assist clinicians Etiology and Clinical Course of PD
in determining clinically meaningful changes in Pd progres- Aging, in addition to multiple other factors, appears to contribute to the pathoetiology of Pd. Approximately 5% to 10% of patients demonstrate a familial pattern of the disease, Implications of Prodomal/Premotor Stage
some of which are associated with linkages to a dozen differ- Pd is comprised of motor and nonmotor signs and ent gene mutations.16 environmental factors likely interact symptoms. it is recognized that extranigral neuropathologic with genetic factors to increase the risk of Pd, including changes precede the degeneration of nigrostriatal dopamin- herbicide or pesticide exposure.17-20 interestingly, epidemio- ergic neurons; thus, nonmotor features antedate the onset logic studies have consistently associated an inverse correla- of motor features. however, diagnostic criteria for Pd are tion between cigarette smoking and coffee consumption for validated based on motor features. Premotor clinical features include autonomic dysfunction (impaired olfaction, cardiac The brains of individuals with Pd are marked by degen- sympathetic denervation, urinary disturbances), gastrointes- eration and loss of dopaminergic neurons in the substantia tinal disturbances (constipation), neuropsychiatric disorders nigra.1 Nondopaminergic pathways are also involved, includ- (depression, mild cognitive impairment, rBd), and sensory ing cholinergic and norepinephrine neurons in the basal fore- disorders (pain, restless legs syndrome). Such symptoms may brain, serotonin neurons in the midbrain raphe, and other occur up to 10 years prior to motor symptoms and diagno- neurons in the brain stem, spinal cord, and peripheral auto- sis.29-32 The table describes nonmotor symptoms that may be
nomic nervous system. Pathology in many of these neuronal present in the premotor stage of Pd.
systems likely contributes to the nonmotor manifestations of There are several stages related to neuronal changes, with earlier stages occurring in areas other than the substantia more recently, it has been postulated that Pd may be nigra. As Braak and his coauthors noted: “Were it to become a prion disorder given the prion-like behavior of alpha- possible to diagnose Pd in the presymptomatic stages 1 or synuclein protein aggregates. These aggregates comprise a 2, and were a causal therapy to become available, the subse- significant portion of the Lewy bodies that are a cellular quent neuronal loss in the substantia nigra could be entirely prevented.”32,33 By the time patients are diagnosed, however, The clinical course of Pd often begins with nonmotor substantial neuronal damage has already occurred in the symptoms such as constipation, hyposmia (reduced sense substantia nigra, with dopamine levels at least 30% to 40% of smell), and rapid eye movement (rem) sleep behavior disorder (rBd). Patients are usually not diagnosed, however, greater awareness and recognition of the presence of until they exhibit obvious motor symptoms, consisting of premotor symptoms of Pd have raised the possibility of resting tremor, rigidity, and/or slowness of movement (bra- very early diagnosis (before appearance of motor features). dykinesia).1,24,25 About one third of patients do not develop imaging studies utilizing dopamine transporter tracers and health-related Quality of Life, economic cost, and implications of early Treatment n Table. Symptoms in the Premotor Phase of Parkinson’s Disease (PD) and Their Neuropathologic Substrates
Nonmotor Symptoms
Presumed Underlying
Well Documented in the
Nonmotor Symptoms in PD
Brain Structures
Premotor Phase
Braak Stage
pain, apathy, fatigueCognitive dysfunction aCognitive impairment can be considered as a possible premotor manifestation of PD. When severe cognitive impairment (dementia) occurs before
motor symptoms, it is regarded, arbitrarily, as the early manifestation of dementia with Lewy bodies and not as a premotor manifestation of PD. Adapted with permission from Tolosa E, et al. Neurology. 2009;72(7 suppl):S12-S20.
nigral ultrasound methods demonstrate the potential for direct medical costs occur in the later stages of the disease. use in earlier diagnosis.34 given increased knowledge of Part of that is related to the levodopa-induced dyskinesia the premotor phenotype of Pd, a battery of tests including that patients develop after several years on the drug. A assessment of nonmotor features, olfactory testing, cardiac recent review of studies found that approximately 25% of scintigraphy, and neuroimaging may one day provide a all patients develop levodopa-related dyskinesia between means of reliably diagnosing Pd at an early stage of the 2.5 and 3.5 years, and up to 39% between 4 and 6 years.35 disease. ideally, then, disease-modifying (neuroprotec- Semiannual direct medical costs were more than double in tive) therapies designed to slow or halt disease progression patients with Pd experiencing severe dyskinesia compared would be initiated. Although disease-modifying therapies with those without motor complications.36 Levodopa-induced may provide a benefit in moderate-to-advanced Pd, ini- dyskinesia also has a significant negative impact on patient tiation of therapy in early disease would provide greater quality-of-life scores and depression severity.36 in addition, approximately 15% to 20% of patients on dopamine agonists Such approaches could result in significant direct and exhibit impulse control disorder behavior (eg, gambling, indirect cost savings as well as improve patient and care- hypersexuality), imposing a significant economic and quality- giver quality-of-life indicators. As noted earlier, the bulk of of-life burden on patients and their caregivers.37 n The AmericAN JOurNAL Of mANAged cAre n Numerous pharmacologic medications are available to The AdAgiO (Attenuation of disease Progression with treat early Pd, including amantadine, anticholinergic agents, Azilect given Once-daily) trial is the largest such study. it dopamine agonists, levodopa, and monoamine oxidase type was a prospective, multicenter, placebo-controlled, double- B (mAO-B) inhibitors. Additional detail on early phar- blind clinical trial with a delayed-start design developed to macologic treatment is located in the article by hauser38 assess the efficacy of rasagiline as a disease-modifying com- in this supplement. however, none are routinely used or pound in 1176 patients with early, nondisabling Pd. The recommended for treatment in patients with asymptomatic AdAgiO trial was initiated based on results from a prelimi- motor Pd.39,40 instead, treatment is traditionally delayed until nary trial which suggested that rasagiline given early in the patients exhibit functional impairment. This limits exposure disease might have disease-modifying benefits.48 to the adverse effects of antiparkinson medications as well Patients in the AdAgiO trial (mean duration of disease as delays the long-term negative effects of levodopa-induced from the time of diagnosis, 4.5 months; baseline mean total motor complications described earlier.41 uPdrS score, 20.4) who received rasagiline 1 mg/day for 72 given the significant economic burden of Pd and knowl- weeks (the early-start group) exhibited greater improvement edge of the premotor phase, there is significant interest in (ie, a smaller mean increase) in the uPdrS score between identifying disease-modifying compounds that can be initi- weeks 12 and 36 than the placebo group (thus reconfirm- ated very early in the disease, possibly before any functional ing efficacy relative to placebo), and less worsening overall motor impairment or disability appears. Not to be dismissed, between baseline and week 72 than the delayed-start, active- in patients with moderate-to-advanced stages of Pd, thera- treatment group (thus confirming that earlier initiation of pies that delay the onset of gait and balance impairment and rasagline is associated with better outcomes compared with cognitive impairment will also allow patients to function inde- pendently for a longer period of time, thus reducing costs and Not all of the end points were met with a 2-mg/day dose preserving hrQOL.36 evidence already shows that initial ther- of rasagiline.49 however, a post hoc subgroup analysis showed apy with nonlevodopa agents is cost-effective, prolongs time to that patients with the highest quartile baseline uPdrS levodopa initiation, and delays the onset of dyskinesia.42,43 scores (>25.5) who received rasagiline 2 mg/day did meet all Numerous targets for neuroprotection have been identi- primary end points. Among patients given rasagiline 1 and fied, including oxidative stress, neuroinflammation, protein 2 mg/day, those in the early-start (active treatment) groups aggregation and misfolding, excitotoxicity, apoptosis, and loss had significantly less worsening of uPdrS scores between of trophic factors.44 clinical trials to test disease modification, baseline and week 72 (-3.40 points and -3.63 points, respec- however, have been particularly difficult to design and conduct. tively) compared with the delayed-start (active treatment) Among the challenges are the need to identify and recruit large groups (P = .04 for both). Patients with the highest quartile numbers of untreated patients with early Pd; heterogeneity of baseline uPdrS scores given rasagiline 1 mg/day and 2 mg/ criteria used to evaluate disease progression; lack of a specific day also demonstrated significantly greater improvement of biomaker of disease progression; lack of agreement on the mag- scores from baseline to week 36 (-6.43 points and -7.13 nitude of effect that should be expected of a disease-modifying points, respectively; P <.001 vs placebo); these were clini- agent; and difficulty differentiating between symptomatic and cally important differences.28 Of note, in clinical practice, the disease-modifying effects of the intervention.45,46 To overcome majority of patients with early Pd who seek medical atten- this last barrier, researchers have utilized a delayed-start design tion for their symptoms would fall into this upper quartile in which patients are randomized to begin treatment with the subgroup. Additionally, the uPdrS score in this subgroup is study drug or placebo for a certain amount of time, after which representative of that in other clinical trials involving early the placebo group is switched to the study drug and followed, Pd patients. There were no significant differences in adverse along with the intervention group, for the remainder of the events between the 2 groups. Additional detail and discussion study. A sustained difference (improvement) in the early-start of the AdAgiO trial appear in the article by hauser38 in this group after the second phase of the trial suggests that early treatment confers a benefit that would not appear if the drug A later analysis of the trial data demonstrated that rasagi- were introduced later in the disease (delayed start).47 line also reduced the progression of nonmotor symptoms (eg, altered mood, apathy, cognitive impairment, sleepiness, pain, Clinical Trials With Disease-Modifying Agents
fatigue, urinary problems) as assessed with the movement To date, at least 23 trials with potential disease-modifying disorder Society (mdS)-uPdrS.50 The efficacy and safety agents have been conducted or are ongoing.46 results of AdAgiO have spurred a growing number of clini- health-related Quality of Life, economic cost, and implications of early Treatment cians to consider beginning rasagiline treatment in function- Therapy in Parkinson disease) trial, levodopa (150, 300, ally unimpaired patients (ie, not yet requiring levodopa or and 600 mg/day) was significantly better than placebo in reducing the worsening of Parkinson’s symptoms at week 42 The outcomes associated with rasagiline should not be (P <.001).58 however, patients in the levodopa group had considered a class effect of mAO-B inhibitors. Specifically, significantly more adverse events (including dyskinesias) the results of AdAgiO cannot necessarily be extrapo- than those in the placebo group. results from the eLLdOPA lated to selegiline, another available mAO-B inhibitor. trial are described in detail in the article by hauser38 in this Selegiline is metabolized to the amphetamine derivatives L-methamphetamine and L-amphetamine,51 which are pres- The reAL-PeT (requip as early Therapy versus L-dopa- ent in sufficient concentrations to produce side effects in PeT) trial used f-dopa positron emission tomography (PeT) patients with Pd. Additionally, chronic exposure to these as a biomarker of neuronal degeneration to evaluate the compounds has been shown to induce neurotoxicity in ani- effects of ropinirole versus carbidopa/levodopa on disease mal and laboratory studies,52,53 and studies demonstrate that progression.59 After 2 years, the ropinirole group demon- L-methamphetamine inhibits the potential neuroprotective strated significantly greater preservation in biomarker uptake activities of selegiline.54 rasagiline, on the other hand, is in the putamen and substantia nigra than the levodopa group devoid of amphetamine-derived or neurotoxic metabolites. (P = .022). however, in contrast with the biomarker results, Thus, the pharmacologic differences between rasagiline and the clinical benefit in the levodopa group was significantly selegiline preclude any meaningful comparisons of clinical Pramipexole was evaluated in the PrOud (Pramipexole Selegiline was evaluated as a possible disease-modi- on underlying disease) trial, a placebo-controlled, delayed- fying agent in dATATOP (deprenyl and Tocopherol start study designed to evaluate the potential disease-modifying Antioxidative Therapy of Parkinsonism), a large trial effect of pramipexole 1.5 mg/day. Preliminary results reported designed to assess the ability of early intervention with as an abstract reported no significant difference in uPdrS selegiline or tocopherol to postpone levodopa initiation in scores at final study visit (after 15 months) between the early- 800 patients. While tocopherol showed no benefit, patients and delayed-start pramipexole groups (P = .65) and no differ- receiving selegiline as monotherapy were able to significantly ence in loss of striatal dopaminergic neurons (P = .84).60 delay the need for levodopa therapy compared with the group Several compounds have been tested in futility trials and receiving placebo and demonstrated a significant reduction warrant additional investigation, including coenzyme Q10 in disease progression as measured by the uPdrS (P <.001 and creatine.61,62 coenzyme Q10 is currently being evalu- vs placebo).55 however, upon completion of the study, a ated as a potential disease-modifying agent in an ongoing subset of patients given placebo were initiated on open-label 16-month clinical study known as Qe3.63 creatine is also selegiline (ie, received delayed-start selegiline), and uPdrS currently being evaluated as a potential disease-modifying outcome scores in this group were no different than in the agent in a large ongoing 5-year clinical trial (known as LS-1) original selegiline monotherapy group. Thus, the benefits sponsored by the National institute of Neurological disorders appear to be largely related to the symptomatic effects of the and Stroke as part of the NeT-Pd (Nih exploratory Trials in drug rather than to disease-modifying effects.56 A trial from the Swedish Parkinson Study group also demonstrated a delay of levodopa initiation with selegi- Conclusion
line.57 in the second phase of this study (n = 140), patients The progressive, debilitating nature of Pd results in who received long-term selegiline therapy in combination significant direct and indirect medical costs for providers, with levodopa for 5 years had significantly better uPdrS patients and their families, and society as a whole. Such costs outcomes compared with patients who received only will only grow more extensive as the population ages and the levodopa.43 Additional detail and discussion of the clini- prevalence of the disease increases. An increasing awareness cal trials with selegiline appear in the article by hauser38 of the presence of a premotor phase of the disease, in which early signs of Pd may be present as much as a decade before Other compounds that have undergone clinical testing for the classic tremor and other movement-related symptoms, disease modification in Pd or are still being evaluated include gives new urgency toward the identification of prospective levodopa and the dopamine agonists pramipexole and ropin- agents that may be disease modifying. Several agents have irole. in the eLLdOPA (earlier versus Later Levodopa been tested or are being tested as disease-modifying agents in n The AmericAN JOurNAL Of mANAged cAre n Pd, including coenzyme Q10, creatine, levodopa, pramipex- impacting on quality of life in Parkinson’s disease: results from ole, rasagiline, ropinirole, and selegiline. None of these drugs an international survey. Mov Disord. 2002;17(1):60-67.
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