David Kim, PharmD Candidate

Alzheimer’s disease is a condition characterized by progressive dementia affecting cognition, behavior, and functional status. Symptoms tend to appear gradually and progressively. The exact etiology of Alzheimer's is unknown, and therefore, no cure exists. The CDC estimates that Alzheimer's was the sixth-leading cause of death in the US in 2015, and in 2014, 50.4% of nursing home residents were diagnosed with the disease. Tools, such as imaging studies (computed tomography scan, magnetic resonance imaging, and positron emission tomography), laboratory tests (thyroid function and vitamin B12 test), and neurological examination (ADAS-cog14, ADCS-iADL, CDR-SB, FAQ, and MMSE, per the American Academy of Neurology), are used to diagnose Alzheimer's and prescribe drug therapy. 

Pharmacotherapy focuses on improving cognition, behavioral symptoms, and functional ability. FDA-approved therapies include NMDA receptor antagonist and cholinesterase inhibitors in order to slow the progression of Alzheimer's and symptomatic management.The American Academy of Family Physicians and the American College of Physicians suggest that memantine has modest benefits in patients with moderate to severe Alzheimer's. In advanced Alzheimer's, a combination of AChEI (donepezil, galantamine, and rivastigmine) and memantine is suggested.Scientists have discovered that Alzheimer's is characterized by the formation of beta amyloid plaques, gliosis, and neurofibrillary tangles.

Therefore, there has been an increasing effort to target such properties via pharmacotherapy. Solanezumab is an investigational humanized monoclonal antibody that works by binding and increasing the clearance of the beta amyloid from one’s brain. Solanezumab has failed to significantly affect cognitive decline compared with the placebo in subjects with mild Alzheimer's.

Articles

The exact etiology of Alzheimer's is unknown, and therefore, no cure exists.

Another Look at Failed Alzheimer Disease Drug Trial

Alzheimer’s disease is a condition characterized by progressive dementia affecting cognition, behavior, and functional status. Symptoms tend to appear gradually and progressively. The exact etiology of Alzheimer's is unknown, and therefore, no cure exists.The CDC estimates that Alzheimer's was the sixth-leading cause of death in the US in 2015, and in 2014, 50.4% of nursing home residents were diagnosed with the disease.Tools, such as imaging studies (computed tomography scan, magnetic resonance imaging, and positron emission tomography), laboratory tests (thyroid function and vitamin B12 test), and neurological examination (ADAS-cog

, ADCS-iADL, CDR-SB, FAQ, and MMSE, per the American Academy of Neurology), are used to diagnose Alzheimer's and prescribe drug therapy. 

2 identically designed randomized control, double-blind, phase 3 trials studied solanezumab in 2052 subjects. Both studies failed to demonstrate significant improvement in cognition or functional ability in subjects with mild to moderate Alzheimer's.

 However, the secondary pooled analysis showed that subjects who received solanezumab had less cognitive decline by about 34% (measured using ADAS-Cog

 and MMESE) and functional decline by 18% (measured using ADCS-iADL) compared with the placebo. Based on the findings of the pooled analysis, EXPEDITION 3 trial was initiated.

EXPEDITION 3 Trial was a randomized, multicenter, double-blind, parallel, placebo-controlled study. 2129 subjects were randomly assigned in solanezumab or the placebo group to receive 400 mg of solanezumab intravenous infusion every 4 weeks for 76 weeks.

 This is an extended duration compared with 400 mg of intravenous solanezumab every 4 weeks for 72 weeks from the EXPEDITION 1 and EXPEDITION 2 studies. Subjects were authorized to receive concomitant standard of care therapy (achetylcholinesterase inhibitor or memantine alone or in combination) during the 76-week period. 79.9% of the solanezumab group and 77.8% of the placebo group were concomitantly taking the standard therapy. The primary outcome of the study was to test if solanezumab would slow the cognitive decline of Alzheimer's compared with the placebo (assessed using ADAS-Cog

). Subjects who completed the 76-week period were given an option to participate in an optional 24-month open-label period. However, only the double-blind period was published.

The statistical analysis was conducted on the basis of modified intention-to-treat principle and included only subjects who had outcome measurements both at and after the baseline. Tests of effects were conducted at a 2-sided alpha level of 0.05. The primary outcome measure (ADAS-Cog

) was analyzed, and there was no significant difference in the change of score from baseline (solanezumab 6.65 ± 0.36 vs placebo 7.44 ± 0.36, P=0.10).

Although the EXPEDITION 3 trial failed to achieve the primary outcome, there are several takeaways. Because solanezumeb works by increasing the clearance of beta amyloid, people with a relatively high level of beta amyloid at baseline could experience a greater clinical benefit than those who have lower levels of beta amyloid at baseline. Therefore, using screening methods, such as enzyme-linked immunosorbent assay, to establish additional inclusion criteria (eg, baseline beta amyloid level) may potentially affect the study outcome. During the EXPEDITION 3 trial, 400 mg of solanezumab was intravenously administered every 4 weeks, which resulted in poor 

 Developing a strategy to increase solanezumab’s concentration in the CNS could potentially lead to a clinically meaningful outcome.   

For further coverage from the fields of Alzheimer’s disease and dementia, check out 

. The site's condition-specific page serves as a resource for the latest clinical news, articles, videos, and the most recently released data.

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Pharmacotherapy: A Pathophysiologic Approach. 

CDC. Alzheimer's disease. cdc.gov/nchs/fastats/alzheimers.htm. Updated October 16, 2016. Accessed April 4, 2018.

Qaseem A, Snow V, Cross JT, et al. Current pharmacologic treatment of dementia: a clinical practice guideline from the American College of Physicians and the American Academy of Family Physicians. A

Honig LS, Vellas B, Woodward M, et al. Trial of solanezumab for mild dementia due to Alzheimer’s disease. 

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Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer’s disease. 

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Siemers ER, Sundell KL, Carlson C, et al. Phase 3 solanezumab trials: secondary outcomes in mild Alzheimers disease patients. 

. 2016;12(2):110-120. doi:10.1016/j.jalz.2015.06.1893

Solanezumab did not significantly affect cognitive decline compared with the placebo in subjects with mild Alzheimer's, but there are still takeaways.

EXPEDITION 3 Study: Is It Really a Failure?

Heparin-induced thrombocytopenia (HIT) is a complication of heparin therapy and is characterized by two types.

 HIT I is a benign, mild thrombocytopenia, which usually occurs within 2 days after heparin administration. Because the platelet count normalizes even with continued heparin therapy, it is not associated with increased thrombotic risk. HIT II is characterized by antibody mediated, a potentially fatal disorder which requires alternative type of anticoagulation other than heparin.

Prothrombotic clinical manifestations occur due to antibody formation to platelet factor 4 (PF4) and heparin. The reaction is mainly IgG and IgM mediated.

 The antibody binding with heparin-PF4 complex forms Circulating Immune Complex (CIC). The CIC activates platelets by binding to Fc receptor.

 This process promotes hypercoagulability state.

HIT is suspected when a patient receiving heparin has a decreased platelet count, especially more than 50% from the baseline count.

 Symptoms often involve skin lesions at the injection site, fever, and chill after heparin administration. HIT complications include deep vein thrombosis (DVT), pulmonary embolism (PE), and thrombotic stroke.

 Among HIT patients, around 10% experience amputation.

 If HIT is suspected, the 4T scoring system on CHEST guideline is utilized to estimate the probability that a patient has HIT (6-8: high probability, 4-5: intermediate probability, ≤3 low probability). 

This tool is especially useful because it is common to experience delay in lab results, and clinical management needs to be made immediately. Rate of thrombosis increases about 5% daily, prior to treatment.

Commonly used lab assays are antigen assays, and functional assays.

The most commonly used antigen assay is the enzyme-linked immunosorbent assays (ELISA), which test for PF4/heparin or PF4/polyvinyl sulfonate reactive antibodies. They provide robust sensitivity, however with moderate specificity. A functional assay, such as Serotonin Release Assay (SRA), and Heparin Induced Platelet Activation (HIPA), provides excellent sensitivity and specificity. As a result SRA and HIPA are widely accepted as reference assays.

Unfractionated Heparin (UFH) vs Low Molecular Weight Heparin (LMWH)

A meta-analysis of randomized controlled trials (RCT) have shown that incidence of HIT between UFH and LMWH on treatment for DVT, and PE does not significantly differ.

However, a different meta-analysis of RCTs on post-orthopedic surgery concluded that the risk of HIT with LMWH is significantly lower than with UFH.

Heparin needs to be discontinued, and an alternative anticoagulation therapy needs to be initiated once HIT is diagnosed. The CHEST guideline recommends use of either argatroban, danaparoid, lepirudin, bivalirudin, or fondaparinux. Argatroban, lepirudin, and bivalirudin are dosed based on aPTT level while danaparoid, and fondaparinux are dosed based on anti-Xa level. For argatroban, target aPTT (reference range: 30-40 seconds

) would be 1.5-3.0 times patient baseline. aPTT level is recommended to be monitored every four hours during dose titration. It is initiated at 2mcg/kg/min continuous IV infusion and adjusted to achieve initial baseline value. Maximum dose is 100mcg/kg/min

Danaparoid is not available in the US market. Bivalirudin is only approved for patients undergoing percutaneous coronary intervention. Fondaparinux does not have FDA indication for HIT, but may be considered.

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Journal of the American College of Cardiology

Suh J, Aster RH, Visentin GP. Antibodies From Patients with Heparin-Induced Thrombocytopenia/Thrombosis Recognize Different Epitopes on Heparin: Platelet Factor 4. 

Blood Journal, American Society of Hematology

Ahmed I, Majeed A, Powell R. Heparin induced thrombocytopenia: diagnosis and management update. 

Warkentin T, Roberts R, Hirsh J, Kelton J. An Improved Definition of Immune Heparin-Induced. 

2003;163:2518-2524. www.bing.com/cr?IG=C00E33AEB9644763A051175E8A23740B&CID=3016A82CA77B63DC04D4A34CA6D46251&rd=1&h=KAtynVdVZ-zxBI8Qrwz7eeSw_wQT4iN9x3D13w2p-Tg&v=1&r=https%3a%2f%2farchinte.jamanetwork.com%2fjournals%2fINTEMED%2farticlepdf%2f216311%2fioi21062.pdf&p=DevEx,5067.1. Accessed April 13, 2018.

Boskhov LK, Warkentin TE, Hayward CPM, et al. Heparin-induced thrombocytopenia and thrombosis: clinical and laboratory studies. 

Jang I-K, Hursting MJ. Thrombocytopenia when heparins promote thrombosis: review of heparin-induced. 

Antithrombotic Therapy and Prevention of Thrombosis 9

 ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines

Lubenow N , Eichler P , Lietz T , Greinacher A ; Hit Investigators Group. Lepirudin in patients with heparin-induced thrombocytopenia - results of the third prospective study (HAT-3) and a combined analysis of HAT-1, HAT-2, and  HAT- . J Thromb Haemost. 2005 ; 3 ( 11 ): 2428 - 2436 .

Warkentin TE, Greinacher A. So, does low-molecular-weight heparin cause less heparin-induced thrombocytopenia than unfractionated heparin or not? 

Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. 

2010 Mosby’s manual of diagnostic and laboratory tests. 4

 Product Information: argatroban IV injection, argatroban IV injection. Encysive Pharmaceuticals Inc, Houston, TX, 2008.

Pharmacists often encounter patients with Heparin-induced Thrombocytopenia (HIT) in health care settings. Here are some useful information in regards to HIT.

Heparin-induced Thrombocytopenia: A Guide for Pharmacists

The CDC estimates that stroke kills 140,000 Americans per year, which is approximately 1 of every 20 deaths in the United States.

 Another alarming fact is that someone in the US has a stroke every 40 seconds, but fewer than half of 911 calls for stroke events were made within 1 hour of symptom onset

 It is common for institutions to limit the administration of tPA to within 3 hours of acute ischemic stroke onset. However, clinical evidence supports the use of tPA for the 3-4.5 hour range in defined situations. Let’s take a look at the clinical studies relevant to tPA administration in patients with Acute Ischemic Stroke.

Stroke can be either ischemic or hemorrhagic, and they are treated differently.

 Ischemic stroke results from occlusion of cerebral artery which leads to severe reduction in cerebral blood flow leading to infarction. Continued ischemic state results in neuronal damage and accumulation of prostaglandins, leukotrienes, and free radicals. The free radicals induce intracellular acidosis which subsequently leads to cell death. This process takes approximately 2-3 hours.

Hemorrhagic stroke is not only less common than ischemic stroke, but we also have limited understanding of the disease. Intracranial hemorrhage (ICH), especially in the brain parenchyma, produces damages to surrounding tissue through mass effect.

 About 30% of ICH enlarge predominantly within the first 4 hours and continue over the 24 hours period.

 Hemorrhage volumes of more than 60 milliliters are associated with 71% to 93% mortality within 30 days.

The patient may experience cognitive or verbal deficit, weakness on one side of the body, vision changes with both ischemic and hemorrhagic stroke. Severe headache is usually unique to hemorrhagic stroke.

 The National Stroke Association recommends using FAST (Face, Arms, Speech, and Time) acronym to identify stoke

Arms: When the person lifts two arms, does one arm drift downward?

Speech: Is the person’s speech slurred or strange?

Time: If you observe any of the above signs, call 911 immediately

The 2013 AHA/ASS Guidelines for the Early Management of Patients with Acute Ischemic Stroke recommends utilizing National Institutes of Health Stroke Scale (NIHSS) to quantify impairment caused by stroke (0: no stroke symptoms, 1-4 minor stroke, 5-15 moderate stroke, 16-20 moderate to severe stroke 21-42 severe stroke).

The National Institute of Neurological Disorders and Stroke's tPA Stroke Trial was a two part trial that evaluated 624 subjects with ischemic stroke.

 The subjects were given either intravenous tPA or placebo within 3 hours of symptom onset. The first part of the trial’s primary end point was ≥4 point improvement in the NIHSS score or complete recovery (NIHSS score 0).

 There was no significant difference between the intravenous tPA and placebo. The second part of the trial’s primary end point was favorable outcome defined as minimal or no disability using 4 stroke assessment scales: barthel index (score 95≤), modified rankin score (Score ≤1), glasgow outcome scale (score=1), and NIHSS (score ≤1). The results of all four scales demonstrated functional and neurological improvements.

A meta-analysis of of ECASS I, ECASS II, ATLANTIS A, and ATLANTIS B trials suggest a benefit of 3 to 4.5 hour window of tPAadministration.

 The outcome is based on global outcome measure and the modified rankin scale without adversely affecting 90 day mortality. Although none of the 4 trials individually demonstrated clinical benefit of 3 to 4.5 hour window of tPA administration, a pooled analysis of the 4 trials showed improved outcome in post-stoke disability. ECASS III trial was conducted to study the benefit of 3 to 4.5 hour window of tPA administration. The outcome showed tPA’s excellent 90-day outcome on the mRS disability scale (0-1) in comparison to placebo. The EPITHET study looked at whether the tPA administration during the 3 to 6 hour window would promote perfusion as well as attenuate infarct for those who had a mismatch between perfusion weighed and diffusion weighed MRI. IV tPA was statistically significantly associated with increased perfusion but insignificantly associated with lower infarct growth.

The AHA/ASS guideline lists exclusion criteria for 3 to 4.5 hour administration of tPA: >80 years of age, anticoagulant use regardless of INR, NIHSS score >25, imaging evidence of ischemic injury more than 1/3 of MCA territory, and history of both diabetes mellitus and stroke.

Inclusion criteria is similar to that of 3 hour administration window. 

Although administration of tPA during the 3 to 4.5 hour of acute ischemic stroke onset may not be widely practiced, it is an option that can be considered for patients who meet the inclusion criteria.

		Vital Signs: Recent trends in stroke death rates—United States, 2000-2015. The Centers for Disease Control and Prevention. 

		Benjamin EJ, Blaha MJ, Chiuve SE, et al. American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics—2017 update: a report from the American Heart Association. 

		Mosley I, Nicol M, Donnan G, Patrick I, Dewey H. Stroke symptoms and the decision to call for an ambulance. 

		Xing C, Arai K, Lo EH, Hommel M. Pathophysiologic cascades in ischemic stroke. 

		Fagan SC, Hess DC. Chapter 10. Stroke. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. 

Pharmacotherapy: A Pathophysiologic Approach, 9e

		Qureshi AI, Mendelow AD, Hanley DF. Intracerebral hemorrhage. Lancet 2009;373:1632—1644.http://accesspharmacy.mhmedical.com.ezproxymcp.flo.org/content.aspx?bookid=689§ionid=45310472. Accessed January 05, 2018.

		Gregson BA, Broderick JP, Auer LM, et al. Individual patient data subgroup meta analysis of surgery for spontaneous supratentorial intracerebral hemorrhage. 

		www.stroke.org/understand-stroke/recognizing-stroke/act-fast Accessed January 6th 2017

		The 2013 AHA/ASS Guidelines for the Early Management of Patients with Acute Ischemic Stroke

		Hage V (2011). "The NIH stroke scale: a window into neurological status". Nursing Spectrum. 24 (15): 44—49.

		Chong JY. Intravenous Tissue Plasminogen Activator (IV tPA) Treatment for Acute Ischemic Stroke. 

. 2013:1-6. doi:10.1093/med/9780199907878.003.0001.

		Activase [Prescribing Information]. South San Francisco, CA: Genentech, Inc; January 2017.

		Lansberg MG, Bluhmki E, Thijs VN. Efficacy and Safety of Tissue Plasminogen Activator 3 to 4.5 Hours After Acute Ischemic Stroke: A Metaanalysis. 

. 2009;40(7):2438-2441. doi:10.1161/strokeaha.109.552547.

		Norrving, Bo. Faculty of 1000 evaluation for effects of alteplase beyond 3 h after stroke in the Echoplanar Imaging Thrombolytic Evaluation Trial (EPITHET): a placebo-Controlled randomised trial. 

F1000—Post-Publication peer review of the biomedical literature

Tissue Plasminogen Activator (tPA) is administered in patients with Acute Ischemic Stroke. Becuase tPA administration is time sensitive, caution is required.

Should Tissue Plasminogen Activator (tPA) Administration be Considered for the 3 to 4.5 Hours Range?

The CDC estimates that from 2003 to 2012, the percentage of adults 40 and older who took a cholesterol-lowering medication increased to 28%, from 20%. From 2011 to 2012, 93% of adults using cholesterol-lowering medication took a statin, also known as an HMG-CoA reductase inhibitor.

 Because statin medications are commonly prescribed, different guidelines acknowledge the importance of statin therapy and describe how it should be used. Let’s take a look at the role of statin therapy in 

, referencing the most widely used guidelines.

It is believed that increased production of advanced glycation end product (AGE) in patients with diabetes interferes with extracellular signal-regulated kinase 5 (ERK-5), krup-pel-like factor 2 (KLF-2), and peroxisome proliferator-activated receptor-g (PPARg).

 ERK-5 functions by signaling endothelial nitric oxide synthase to produce more nitric oxide for vasodilation. KLF-2 and PPARg are known to block the activity of pro-inflammatory immune cell activity in blood vessels. As a result, patients with diabetes are less likely to benefit from ERK-5, KLF-2, and PPARg mediated cardio-protection compared with patients without diabetes.

ADA: The 2017 American Diabetes Association Standards of Medical Care in Diabetes recommends statin therapy 

based on *atherosclerotic cardiovascular disease (ASCVD) *

 (CVD) risk factors, rather than low-density lipoproteins (LDL) levels by itself for patients with diabetes.

Which individuals are candidates for high-intensity statin? Any diabetic patient with a history of ASCVD and individuals from 40 to 75 with ASCVD risk factors (LDL cholesterol ≥100mg/dl, high blood pressure, smoking, chronic kidney disease, albuminuria, and family history of premature ASCVD

) may be considered for high-intensity statin therapy. Who would be considered a good candidate for either high-intensity or moderate-intensity statin? Patients under 40 or over 75 carrying ASCVD risk factor. Ezetimibe may be combined with moderate-intensity statin for patients 40 and older with a history of 

 (ACS) who cannot tolerate high-intensity statin or with LDL-C ≥50 mg/dl. Patients younger than 40 without CVD risk factors are not a candidate for statin therapy.

Supporting evidence for the addition of ezetimibe to moderate-intensity statin originates from the results of ezetimibe added to statin therapy after the ACS (IMPROVE-IT) trial.

 The combination of simvastatin and ezetimibe resulted in a significantly lower risk of cardiovascular events than that of simvastatin mono-therapy for post-ACS patients who are 50 or older. The simvastatin and ezetimibe combination group resulted in a 2-percentage-point lower rate of primary composite end point cardiovascular death (hazard ratio 0.936). Primary composite end points were cardiovascular death, major coronary events, or nonfatal stroke.

Table 1. Statin Therapy Recommendations for Patients with Diabetes, per the ADA

			· 40 to 75 years with ASCVD or ASCVD risk factors

			≥40 years with ACS and LDL cholesterol ≥50mg/dl or in patients with a history of ASCVD who cannot tolerate high-intensity statin

ACC/AHA: The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults focus on the treatment to reduce ASCVD risk, rather than targeting a certain LDL level.

 The ACC/AHA guidelines recognize lifestyle modification as a crucial component to reduce the ASCVD risk factor, and they publish a separate guideline for it: the 2013 ACC/AHA Guideline on Lifestyle Management to Reduce Cardiovascular Risk. Statin therapy initiation follows a four-step process in the ACC/AHA guideline 

 Before considering diabetes as a determining factor for the intensity of statin therapy, we must review other factors such as *clinical ASCVD (ACS, myocardial infarction [MI], angina, coronary revascularization, PAD due to atherosclerosis, stroke or transient ischemic attacks

) and LDL-C level ≥190mg/dl. If a patient does not meet either of the 2 criteria, diabetes would be considered. Patients with diabetes (age 40 to 75, LDL-C 70-180mg/dl) are automatically considered for moderate-intensity statin, but when he or she has an estimated 10-year ASCVD risk factor of ≥7.5%, is a candidate for high-intensity statin.

Table 2. Statin Therapy Recommendation Algorithm, per the ACC/AHA

· <21 years: not a candidate for statin therapy

			· ≥21 years: candidate for statin therapy, move to No. 2

        2. Clinical ASCVD (if no clinical ASCVD, move to No. 3)

· ≤75 years: high-intensity (moderate-intensity, if

HMG-CoA reductase inhibitors are a class of lipid-lowering medications. Here is a look at guidelines and studies for health care professionals.