Journal of Critical Carc 2005 20 35
`
`45
`
`ELSEVIER
`
`Journal of
`
`Critical Care
`
`and prophytaxis of stress ulcer in
`PathophysioLogy
`intensive care unit patients
`
`Neil StoLLman MDa1 David
`
`Metz MD
`
`Division of Gastroenterology Department of Medicine University of Ca4fornia San Francisco
`CA 94110 USA
`bDivisiofl of Gastroenterology Department of Medicine
`PA 19104 USA
`
`University of Pennsylvania Health System Philadelphia
`
`San Francisco
`
`Received 12 May 2004 revised 24 August 2004 accepted
`
`12 October 2004
`
`Abstract Gastrointestinal
`Of
`
`frequently occur in patients admitted to the intensive care unit
`complications
`disease SRMD can lengthen
`and bleeding related to stress-related mucosal
`these ulceration
`hospitalization and increase mortality The purpose of this review is to discuss the many risk factors and
`of SRMD and
`illnesses that have
`evaluate
`the evidence
`role in the pathophysiology
`underlying
`pertaining to SRMD prophylaxis
`in the intensive care unit population
`Suppressing acid production is
`stress-related mucosal ulceration and clinically important
`fundamental
`to preventing
`gastrointestinal
`bleeding Traditional prophylactic options for SRMD in critically ill patients include antacids sucralfate
`antagonists H2RAs and proton pump inhibitors Many
`clinicians
`histamine2-receptor
`prescribe
`infusions of H2RAs for stress ulcer prophylaxis
`intermittent
`practice that has not been approved for
`this indication and may not provide the necessary degree or duration of acid suppression required to
`related bleeding New data suggest
`that proton pump inhibitors
`stress ulcer
`suppress acid
`prevent
`production more completely in critically
`ill patients but more studies are required to assess their clinical
`The prophylactic
`this indication
`to prevent stress ulcer
`regimen chosen
`and safety for
`the risk factors and underlying disease state of individual patients to
`bleeding should take into account
`therapy to those most likely to benefit
`
`effectiveness
`
`provide the best
`
`2005 Elsevier
`
`Inc All rights reserved
`
`Keywords
`
`Pathuphysiulogy
`
`Prophylaxis
`
`Ulcer
`
`Introduction
`
`An estimated
`are admitted
`4.4 million patients
`intensive care units ICUs each year Of
`12
`or 500000 patients die in the ICU
`Gastrointestinal
`GI complications eg gastric and intestinal motor dys
`
`these about
`
`to
`
`author
`Fact Ray Center
`for Digestive
`Correcponrliog
`Oaklaod CA 94609 USA Tel
`510 444 3297 fax
`510 444 6421
`mail address ostotlmanmcdsfgh.ucsfcdu
`
`Stollrnao
`
`t-teatih
`
`0883 9441
`
`sec
`
`froot matter
`
`2005 Elscvicr
`
`Inc All
`
`rights reserved
`
`doil0 1016 j.jcrc.2004.t0.003
`
`function as well as stress-related mucosal disease
`
`in these patients and adversely affect patient
`frequently occur
`outcomes Gastrointestinal motor dysfttnction may predis
`to impaired enteral nutrition and pulmonary
`pose patients
`Stress-related mucosal
`aspiration of gastric contents
`
`occurs in many criti
`damage
`an acute erosive gastritis
`cally ill patients in ICUs and may develop within 24 hours of
`important GI
`admission
`The incidence
`of clinically
`bleeding defined as overt bleeding complicated by hemo
`dynamic instability decrease in hemoglobin and/or need for
`
`METZ-6
`
`5/8/15
`
`Denise Bach RPR
`
`
`
`Page 1 of 11
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`Patent Owner Ex. 2019
`Lupin v. Pozen
`IPR2015-01775
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`

`
`36
`
`Stotiman D.C Metz
`
`1.500 in
`
`blood transfusion from SRMD in the ICU population was
`In addition
`prospective study of 2252 patients
`the morbidity associated with this type of severe ulceration
`and bleeding can increase the length of stay in the ICU by up
`days and mortality is as much as 4-fold higher than it
`to
`in ICU patients without
`this complication
`
`is
`
`PathophysioLogy and pathogenesis of SRMD
`
`Several
`
`factors have
`
`contents
`
`of SRMD
`role in the pathogenesis
`including gastric acid secretion mucosal ischemia as result
`of splanchnic hypoperfusion and reflux of upper intestinal
`into the stomach Fig
`Gastric hypoperftt
`to an imbalance between
`oxygen supply and
`sion leads
`demand that may induce mucosal damage Moreover
`reperfusion after prolonged hypoperfusion may itself
`result
`in nonocclusive mesenteric ischemia and mucosal damage
`As
`reduced ability to
`result of ischemia there is also
`neutralize hydrogen ions which can contribute to cell death
`such as mucous produc
`and ulceration Protective processes
`tion may also be impaired further promoting SRMD
`In
`showed
`animal studies Ritchie
`that elevated gastric acid
`levels bile salts and ischemia must all be present
`lesions to form whereas
`none of these factors alone or in
`combination with each other led to ulceration
`In stress ulceration homeostasis of the gastric mucosa is
`defense mechanisms
`
`for gastric
`
`disrupted
`
`as are
`
`the
`
`cellular
`
`that
`
`mucosal cells on contact
`
`Thus prevention of acid injury
`and stress ulceration might be achieved
`by therapies that
`reduce acid secretion or enhance protective mechanisms
`signs of SRMD include multiple sub
`The endoscopic
`epithelial petechiae progressing to superficial erosions and
`in some cases discrete ulceration particularly
`fundus
`these lesions are characterized
`Microscopically
`
`in the gastric
`
`loss of
`by focal
`the superficial epithelium coagulation
`necrosis of the mucosa and hemorrhage
`do not usually perforate and tend to bleed from superficial
`Because of the diffused nature of
`mucosal capillaries
`
`These lesions
`
`the lesions
`
`stress ulcers are not generally amenable
`
`to
`
`endoscopic
`
`therapy
`
`2.1 SpLanchnic hypoperfusion
`
`Critical
`
`trauma
`
`severe
`
`splanchnic
`
`illness that warrants admission to an ICU eg
`shock bums sepsis
`can
`hypoperfision which has
`of SRMD Significant
`pathogenesis
`even when
`blood flow can
`occur
`
`contribute to
`
`major
`
`role in the
`
`decreases
`
`in visceral
`
`systemic circulation is
`
`maintained and conventional measures of systemic tissue
`regional GI oxy
`oxygenation may not accurately
`Intramucosal pH which can be measured
`genation
`of
`marker of the adequacy
`using gastric tonometry
`oxygenation in the upper GI
`and
`is used in
`experimental settings to assess the magnitude of splanchnic
`ischemia
`
`reflect
`
`tract
`
`is
`
`Cellular defense
`
`highly acidic gastric milieu
`normally protect against
`is primarily mediated by gastric prosta
`been shown to
`glandins which in animal models have
`prevent ulcer formation and accelerate
`the healing process
`This seems to occur partly because prostaglandins reduce
`acid secretion More importantly they have been shown to
`
`exert
`
`direct cytoprotective effect
`
`against agents that kill
`
`2.2 UnderLying iLLness
`
`Critical
`
`illness is often characterized by hypotcnsion and
`hypovolemia which can directly
`
`contribute
`
`to gastric
`
`hypoperfusion
`
`In addition critically
`
`ill
`
`patients often
`
`exhibit
`
`inflammatory responses
`cytokines that can also result in hypoperfusion
`
`involving
`
`the release of
`
`lncreaaed
`catecholamines
`
`Increased vasoconstriction
`
`Critical
`
`Illness
`
`Hypovolemia
`
`Cardiac output ___________
`
`Proinflammatory
`releaae
`
`Splanchnic hypopeusion_cokcne
`
`Reduced
`HCO3
`secretion
`
`Reduced
`mucosal
`
`ood flow
`
`Decreased
`
`GI motility
`
`Acid back
`diffusion
`
`Fig
`
`Pathophysiology of stress ulcers Adapted from Chest 2001 Hasp Pract 1980
`
`Acute stress ulcer
`
`
`
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`

`
`Stress uLcer prophyLaxis
`
`2.3 MechanicaL ventiLation
`
`strategies
`
`Mechanical ventilation can influence systemic hemody
`namics especially with potentially injurious ventilator
`such as high tidal volumes or high positive end
`expiratory pressure PEEP High PEEP decreases
`venous
`return and reduces preload which in tum may reduce cardiac
`output CO
`and result
`in splanchnic
`hypoperfusion
`PEEP promotes
`plasma-renin-angiotensin-aldosterone
`activity as well as catecholaminc release which may also
`contribute to splanchnic hypoperflision
`Mesenteric blood flow and CO were found to signifi
`decrease with increasing levels of PEEP in rats
`cantly
`An inverse relationship
`randomized to PEEP vs control
`between
`and
`plasma catecholamine
`increasing
`in CO was observed
`decreases
`in dogs treated
`doses of PEEP
`Effects on the sympathetic nervous
`system have also been validated in human beings In
`study
`of 10 healthy males receiving continuous positive-pressure
`breathing muscle
`nerve activity rapidly
`sympathetic
`increased as did measurements of vasoprcssin
`and plasma
`
`levels
`
`ith graded
`
`as compared to control
`In addition
`renin activity
`mechanical ventilation with large tidal volumes and high
`been shown in animals to
`have
`end-expiratory pressures
`promote release ofpulinonaiy cytokines which can enter
`from the lungs potentially
`
`the
`
`causing
`
`systemic circulation
`
`splanchnic hypoperftrsion
`Despite these data showing that PEEP can negatively
`influence blood flow the effect of PEEP on UI bleeding in
`the ICU selling remains unknown
`
`2.4 Medications used in the 1W
`
`deleterious effects
`
`Medications administered to patients in the ICU can have
`especially when com
`on GI
`function
`pounded with the effects of mechanical ventilation Opiates
`can decrease gut
`and sedatives such as benzodiazepines
`Other agents
`include vasopressors
`
`motility arid impair venous
`return
`may contribute to UI complications
`and antibiotics
`Theoretically
`any drug resulting in
`hypotension decreased heart rate or CO can in turn reduce
`mescnteric blood flow and put
`critically ill patient at risk
`of developing SRMD
`
`that
`
`2.4.1 Helicobacter pylon
`Helicobacter pylon has been implicated as the causative
`of chronic gastritis and peptic
`in the pathogenesis
`Its relationship to stress ulceration and GI bleeding
`is not well documented The relatively few studies
`however
`
`agent
`
`ulcer
`
`exploring
`
`severity
`
`this association yielded conflicting
`survey of critically ill patients
`prospective epidemiologic
`an ICU found
`significantly higher rate of seropositivity for
`in the ICU gmoop than in the control groop 67% vs
`Hpyloni
`39% .001
`The relationship between Hpyloni status
`and UI bleeding was not significant but
`toward increasing seropositivity with increasing bleeding
`from 5000 scropositivity
`among patients with
`
`results
`
`in
`
`there was
`
`trend
`
`occult bleeding to 100% seropositivity
`
`among those with
`prospective cohort
`significant bleeding
`ICU
`patients admitted to the
`
`clinically
`
`analysis
`
`50 consecutive
`
`In
`
`37
`
`requiring mechanical ventilation were screened for Hpyloni
`infection using the laser-assisted ratio analyzer urea breath
`injury Of
`to assess mucosal
`test and underwent cndoscopy
`the 29 patients who developed minor mucosal disease
`34.5% were infected with Hpyloni On the contrary of the
`15 patients that presented with major mucosal disease 80%
`were
`infected
`the severity of
`supporting the theory that
`injury is correlated with
`Yamamoto et al
`inoculated
`
`mucosal
`
`pylon infection
`group of test animals
`with Hpyloni After these control animals were subjected
`to
`fonnation
`
`stress
`
`ulcer
`
`and bleeding occurred
`treatment
`regardless of whether the animals were or were not
`pylon However after
`minutes of treatment
`bleeding rate and index were significantly
`.036 and
`infected group than in the uninfected group
`respectively The ulcer index was also higher
`.03
`the infected group It was determined that Hpyloni
`infection
`lowers the threshold for gastric mucosal
`injuries in the early
`phase of stress exposure but suppresses
`mucosal
`lesions in the late phase
`In contrast another study found no association between
`and UI bleeding This
`study was
`
`with
`
`pylon
`
`infection
`
`infected
`
`the
`
`higher
`
`in the
`
`in
`
`the formation of
`
`conducted
`in patients with and
`prospectively over
`year
`without evidence of UI bleeding admitted to the ICU after
`received
`
`cardiac
`
`stress ulcer prophy
`
`surgery All patients
`laxis with ranitidine Results showed
`that Hpyloni
`was not significantly more prevalent
`in patients with upper
`UI bleeding than in those without bleeding
`Only
`limited association was found in another study Among 874
`critically ill patients admitted to an ICU and followed for
`weeks 76 8.7o developed
`Anti
`stress gastritis
`was found to be an independent
`pylon immunoglobulin
`for stress gastritis but not anti
`
`risk factor
`
`infection
`
`pylon
`
`subset
`
`possibly suggesting that only
`immunoglobulin
`of individuals with chronic Hpyloni
`
`infection is at risk for
`
`stress gastritis
`
`CompLications associated with SRMD
`
`Mortality rates increase proportionately with the inci
`dence and severity of SRMD In
`prospective multicenter
`studies Cook ct al
`found significant differences in
`important UI bleeding and
`mortality between
`clinically
`In these studies patients who
`nonbleeding patients Fig
`result of SRMD had mortality rates of 490o and
`bled as
`46
`In contrast mortality rates for nonbleeding patients
`were 9% and 210o
`.001 and
`.0001 respectively
`These findings are consistent with those of
`study
`that evaluated
`of cimetidine in prevention
`and treatment of stress-induced UI
`lesions In this study
`correlated with severity of UI
`mortality was significantly
`injury mortality rates were 57o in patients with
`
`the effectiveness
`
`mucosal
`
`
`
`Page 3 of 11
`
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`Lupin v. Pozen
`IPR2015-01775
`
`

`
`38
`
`50
`
`45
`
`40
`
`35
`
`25
`20
`
`15
`
`10
`
`Bleeding
`
`Non bleeding
`
`Patients
`
`Fig
`
`Differences in mortality between bleeding
`2219 patients Asterisk
`nnnbleeding
`Adapted from Engi
`
`Med 1994
`
`indicates
`
`33 and
`.001
`
`.03
`who are at
`
`endoscopically evident ulcers and/or bleeding and 24 in
`patients with nonhemorrhagic erosions or normal mucosa
`Because it
`
`is possible to identify patients
`
`should
`risk for bleeding strategies
`the greatest
`on the prevention of SRMD and bleeding
`logically focus
`rather than on its treatment after the fact Such an approach
`associated with SRMD and
`
`may minimize complications
`ideally improve outcomes
`
`3.1 Impact of GI bLeeding
`
`on EU patients
`
`Clinically important GI bleeding may cause hemody
`namic instability or require red blood cell transflisions The
`risks of transfusion include infection and potential
`
`attendant
`
`for
`
`immunosuppression
`
`incompatibilities
`fnr an increased
`
`as well as possible blood-related
`As noted earlier there is
`potential
`length nf stay in the IClI among patients
`with significant bleeding compared to nonbleeders as well
`increase in mortality
`
`as
`
`statistically significant
`
`Risk factors for stress
`
`uLcerreLated bLeeding
`
`As noted critically
`
`ill patients admitted to ICUs are at
`stress ulceration
`and
`
`as
`
`and
`
`it
`
`is
`
`subsequent
`risk for developing
`result of both underlying disease
`bleeding
`therapeutic interventions Prophylaxis against
`stress ulcers
`can significantly minimize bleeding but such therapy may
`adverse
`be costly and can have
`effects Therefore
`to identify risk factors that would substantiate
`
`important
`and target
`need for prophylaxis
`to those
`study involving more that 2200 patients
`highest
`risk
`admitted to ICUs primarily postcardiovascular
`evaluated
`risk factors for stress ulcer
`therapy was withheld
`
`potential
`
`bleeding
`
`Prophylactic
`
`interventions
`
`at
`
`surgery
`
`related
`
`in all
`
`the
`
`StoLtman D.C Metz
`
`except 674 patients these patients had received
`drugs that
`history of peptic ulcer
`increased their risk of bleeding had
`or gastritis were undergoing high-risk surgery or required
`prophylaxis for other reasons eg head injury trauma
`The only independent
`important
`for clinically
`study were
`stress ulcer bleeding
`by the
`respiratory failure requiring more than 48 hours of
`mechanical ventilation odds ratio 15.6 and coagulopathy
`Among 847 patients who had ooe or
`odds ratio
`both of these risk factors 313.7
`developed
`clinically
`important bleeding whereas among 1405 patients who had
`0.lo developed
`risk factors only
`neither
`
`risk factors
`
`determined
`
`significant
`
`bleeding
`
`respiratory
`
`100 patients at risk
`Hastings et al
`randomly assigned
`of developiog stress ulcers and bleeding to receive antacid
`prophylaxis or no prophylaxis An analysis of the patients
`risk factors for acute GI bleeding
`reported
`failure extraabdominal
`
`renal
`
`sepsis peritonitis jaundice
`failure and hypotension Notably the frequency of bleeding
`increased with the number of risk factors
`in both
`groups Fig
`study demonstrated that
`there
`between
`acute GI ulceration and bleeding and presence of
`
`treated and untreated
`
`present
`Results of this
`
`is
`
`distinct association
`
`risk factors
`The predictive value of risk factors for GI bleeding was
`also validated in another study of patients with illnesses or
`conditions requiring admission to an ICU
`In this study
`included surgery bums major
`the risk factors considered
`trauma established liver or renal disease respiratory failure
`requiring mechanical ventilation
`sepsis and hypotension
`
`Prophylaxis
`
`No Prophylaxis
`
`at
`
`-o
`
`35
`
`30
`
`20
`
`10
`
`Risk
`
`Factor
`
`2Risk
`
`Factors
`
`3ioGRisk
`
`Factors
`
`The incidence of bleeding by number of risk factors in
`Fig
`patients receiving and not receiving antacid prophylaxis Asterisk
`.005
`.025 double dagger
`
`indicates
`
`Adapted from NEnglJMed 1978
`
`.01 dagger
`
`
`
`Page 4 of 11
`
`Patent Owner Ex. 2019
`Lupin v. Pozen
`IPR2015-01775
`
`

`
`Stress uLcer prophyLaxis
`
`39
`
`The
`
`authors
`
`demonstrated that
`
`the probability for
`massive GI bleeding from stress ulceration increased as the
`number of risk factors rose and as the intramucosal pH fell
`implying mucosal hypoperflision Gastrointestinal bleeding
`seen only in patients whose intramucosal pH
`was in fact
`had fallen below the lower limit of normality 7.24 Thus
`the combination of risk factors and intramucosal pH were the
`to note that
`best predictors of bleeding
`is important
`none of the risk factors discussed
`have been conclusively
`demonstrated to be the direct cause of stress ulcer
`
`It
`
`related
`
`they may be surrogate markers for severity
`bleeding rather
`of illness All of the studies described strongly suggest
`
`that
`
`identifing risk factors can provide
`valid predictive tool for
`GI bleeding that will allow clinicians to prescribe prophy
`treatment to the patients most likely to benefit
`risk factors associated with increased
`risk of stress
`
`lactic
`The
`
`ulcer
`
`related bleeding are summarized in Table
`
`Stress uLcer prophyLaxis options
`
`Prevention of stress-related bleeding is clearly the most
`effective strategy for patients at risk for SRMD in the ICU
`This can be accomplished by preventing gastric ischemia or
`
`that
`
`the
`
`acid
`
`receptor
`
`acid injuty Although high acid concentiations aic out
`contributes to SRMD controlling
`only factor
`production in at-risk patients seems to be protective against
`trials by
`metaanalysis of clinical
`bleeding episodes
`Cook et al
`reported that various prophylactic therapies
`and histamine2
`sucralfate
`incidence
`of overt or
`
`reduced
`
`the
`
`such
`as antacids
`antagonists H2RAs
`important bleeding compared to no prophylaxis
`clinically
`Thus agents that protect gastric mucosa from acid either by
`minimizing injury from produced acid or by inhibiting acid
`have
`an important
`role in the prevention of
`secretion
`bleeding due to SRMD
`
`5.1 Antacids
`
`Antacids work by directly buffering or neutralizing the
`contents of the stomach In the study already referred
`acidic
`to above Hastings et al
`found that
`
`in critically
`
`ill
`
`TabLe
`
`Risk factors for SRMD
`
`Risk factor
`
`Respiratory failure
`
`Coagulopathy
`
`Hypotension
`
`Sepsis
`
`Hepatic failure
`
`Renal
`
`failure
`
`Surgery
`
`Burns
`
`Major trauma
`
`Adapted from Gastroenterology 1983 Engi
`EngliMed 1994
`
`2981041
`
`Med
`
`1978
`
`patients
`
`the fact
`
`that
`
`or
`
`patients at risk for GI ulceration and bleeding the frequency
`reduced when antacid therapy
`of bleeding was significantly
`was titrated to keep the pH above 3.5 Results
`showed
`in the antacid group bled compared with
`12 patients 25% in the group receiving no prophylaxis
`.005 However
`these agents need to be
`hours to achieve
`acid neutral
`given every
`adequate
`their use cumbersome Moreover
`ization makes
`adminis
`tration of high doses of antacids may increase the risks of
`aspiration pneumonia and toxicity related to cation accu
`mulation particularly in patients with renal dysthnction
`
`that
`
`5.2 Sucratfate
`
`Sucralfate protects the gastric mucosa from acid by
`
`adhering to epithelial cells and forming protective barrier
`but has no acid-neutralizing activity Used in prevention of
`SRMD it has been shown
`to be more effective than no
`but no more
`in decreasing
`prophylaxis
`overt bleeding
`and H2RAs in reducing
`effective than placebo
`The interest
`in
`
`clinically
`
`important bleeding rates
`
`antacids
`
`sucralfate increased after
`
`clinical
`
`trial
`
`and metaanalysis
`incidence
`of pneumonia
`reported
`with sucralfate than with agents that suppress acid
`laige iandumized study uf 1200 ICU patients
`Howevet
`
`trend toward
`
`lower
`
`of nosocomial
`
`reported no difference in the incidence
`patients receiving intravenous raniti
`pneumonia between
`dine 50 mg every
`hours and those receiving sucralfate
`hours In the
`tube every
`suspension
`via nasogastric
`ranitidine group 114 19% of 596 patients had ventilator-
`pneumonia compared with 98 16% of 604
`associated
`patients in the sucralfate group More importantly clinically
`important GI bleeding was higher
`in the sucralfate
`group
`than in the ranitidine group 3.8% and 1.7% respectively
`.02
`
`5.3 H2-receptor bLockade
`
`H2RAs inhibit
`
`histamine-stimulated
`
`acid
`
`secretion
`
`by
`
`in
`
`blocking H2-receptor sites of the parietal cell
`highly
`selective manner
`they have little or no effect on histamine
`H2RAs
`not
`involved with gastric secretion
`receptors
`have
`been found to be significantly
`and
`antacids
`
`clinically
`
`in reducing
`sucralfate
`significant bleeding Fig
`
`better
`
`than placebo
`
`the
`
`incidence of
`
`5.3.1 Continuous infusion vs boLus injection
`Maintaining the pH between
`3.5 and 4.5 is
`surrogate
`endpoint accepted hy many and should be the minimum
`goal of prophylactic
`Effective prophylaxis
`therapy
`requires selection of not only the proper drug and dose but
`the appropriate method of administration
`continuous
`50-100 mg/h was
`
`infusion of cimetidine
`
`intravenous
`
`evaluated
`
`in
`
`double-blind
`study to
`placebo-controlled
`in preventing upper GI hemor
`determine its effectiveness
`intragastric pH 4.0 in both
`showed that
`rhage
`groups at baseline declined over
`time in the placebo group
`
`Results
`
`
`
`Page 5 of 11
`
`Patent Owner Ex. 2019
`Lupin v. Pozen
`IPR2015-01775
`
`

`
`40
`
`StoLLman D.C Metz
`
`for nosocomial pneumonia Navab and
`the results of several
`reported that
`Steingrub
`were conflicting They concluded
`intragastric volume severity of
`infection contributed to the development of pneumonia and
`As
`of pneumonia is multifactorial
`the pathogenesis
`noted earlier
`large well-controlled randomized trial
`difference in the rate of nosocomial pneumonia
`ranitidine was compared to sucralfate in critically
`
`laxis with potential
`
`that
`
`to find
`when
`
`ill patients
`
`studies
`
`that other factors such as
`
`illness bile reflux and
`
`failed
`
`Clinically Important
`l3leeding
`Odds Ratio 95% CI
`
`Number of
`Studies
`
`10
`
`10
`
`H2RA vs placebo
`
`H2RA vs antacids
`
`H2RA vs sucralfate
`
`Reduced
`
`increased
`
`risk
`
`risk
`
`10
`
`The results of metaanalysis on the efficacy of H2RAs in
`Fig
`stress ulcer prophylaxis Asterisk indicates overt bleeding accom
`panied by hemodynamic
`decrease
`in hemoglobin of
`changes or
`g/dL requiring transfusion of
`
`requiring surgery Adapted from JAMA 1996
`
`units of blood within 24 hours or
`
`but not in the cimetidine group and significantly less upper
`GI bleeding occurred in the cimetidine group
`.009
`This study clearly indicated that prophylaxis with
`infused cimetidine is
`valuable approach
`continuously
`preventing GI hemorrhage in patients with risk factors eg
`major surgery trauma bums hypotension
`sepsis or organ
`failure for stress-related mucosal bleeding
`given by continuous
`cimetidine
`intravenous
`Although
`infusion is currently the only regimen approved by the US
`Food and Drug Administration for prevention of stress-
`related mucosal bleeding various H2-receptor antagonists
`
`for
`
`infusion for this indication in
`
`lives
`
`iriultiple
`cimetidine
`
`either
`
`in bolus doses
`
`are often given by intermittent
`However
`the ability of these agents
`clinical practice
`when given intermittently to maintain the intragastric pH
`above 4.0 is questionable given their
`relatively short half-
`One study compared bolus doses and continuous
`infusions of cimetidine in the maintenance of intragastric
`pH above 4.0 in critically ill patients with at least one major
`traumas Patients
`were
`organ system failure ur
`randomized
`to receive
`up to 300 mg IV every
`hours or by continuous intra
`Most
`infUsion up to 50 mg/h
`for 24 hours
`venous
`patients 87
`receiving continuous infusions maintained
`strong 92.9
`their intragastric pH above 4.0 There was
`serum levels of cimetidine
`positive correlation between
`and intragastric pH above 4.0 Thus
`cimetidine given by
`continuous infusion proved to be effective in maintaining
`pH above 4.0 thereby potentially
`preventing stress ulcer
`ation Fig
`to note that although
`is important
`H2RAs dosed as
`continuous infusion are more effective in
`raising gastric pH than H2RAs dosed intermittently there
`are no comparative trials evaluating these dosing regimens
`outcomes One can only surmise that more
`complete acid suppression leads to enhanced GI protection
`
`It
`
`on clinical
`
`5.3.2 Risk of nosocomiat
`
`consequence
`
`pneumonia
`pH
`increased
`In regard to the association of
`for SRMD prophy
`of H2RA administration
`
`as
`
`the tendency
`short
`
`interval after
`
`for
`
`5.3.3 Limitations of H2RAs
`limitation of H2RAs is
`significant
`to occur within
`Two
`studies in healthy
`therapy
`subjects
`the H2RA ranitidine rapidly lost anti-
`839
`secretory effect after the first day of administration
`One study reported the development of
`tolerance
`despite
`The other study found
`dose escalations
`and
`on days
`infusions of
`ranitidine were
`to
`superior
`The
`
`tolerance
`
`initiation
`
`of
`
`demonstrated that
`
`relatively
`
`that
`
`continuous
`
`of treatment
`injections only on day
`intermittent
`latter observation may seem to contradict
`previously cited study comparing continuously infused and
`bolus doses of cimetidine However
`that study did not
`12-hour observation period thus
`beyond
`impact of tolerance was not detected
`Sonic H2RAs interfere with eytoehrorrie P450 metabo
`lizing enzymes
`leading to drug interactions
`potentially
`ranitidine inhibit P450
`Cimetidine and to
`lesser extent
`enzymes which may facilitate accumulation and possibly
`toxicity of coadministered drugs In addition H2RAs require
`dosing adjustments in the setting of renal dysfunction
`Another clinical concem is thrombocytopenia that may be
`induced by H2RAs but
`remains
`rare occurrence
`in the
`absence of another independent risk factor
`
`results of the
`
`extend
`
`the
`
`it
`
`5.4 Proton pump inhibitors
`
`Gastric acid is produced and regulated by mechanisms
`within
`Transport of
`the parietal cell
`by the
`KtATPase is
`proton pump
`the underlying mediator
`and
`step in the regulation of acid
`final
`secretion
`Proton pump inhibitors PPIs inactivate this enzyme and
`secretion by
`inhibition of
`inhibit
`acid
`specific
`gastric
`HKtATPase at
`the secretory surface of the parietal cell
`regardless of whether
`the
`cell
`
`stimulated by
`
`is
`
`histamine gastrin or acetylcholine
`The efficacy and utility of PPIs have been established for
`several acid-related GI disorders but they have not as yet
`been approved
`for GI bleeding associated
`as prophylaxis
`with stress ulceration Small open-label
`trials have examined
`the use of oral PPIs administered as extemporaneously
`compounded suspensions
`in patients at risk for stress ulcer
`No clinically
`bleeding was
`reported in these
`significant
`trials but drawing conclusions regarding efficacy is difficult
`because of
`limitations of
`
`several methodological
`comparator arm and the small
`studies such as the lack of
`
`these
`
`
`
`Page 6 of 11
`
`Patent Owner Ex. 2019
`Lupin v. Pozen
`IPR2015-01775
`
`

`
`Stress uLcer prophytaxis
`
`41
`
`significant
`
`monia
`
`in the
`
`40-mg capsule administered orally or nasogastrically once
`showed
`significantly more clinically
`day
`Results
`bleeding in the ranitidine group than
`.05 In addition fewer
`omeprazole group 3lo vs 6c
`nusueoiuial puce
`paticnts iceciving uincpiazulc dcvclopcd
`vs 14
`although the difference between groups
`was not significant
`It should be noted however
`that
`randomization
`despite
`more risk factors
`
`the ranitidine-treated
`
`had
`
`present
`
`8.0
`
`6.0
`
`0-
`
`4.0
`
`2.0
`
`300mg boles
`infusion
`
`37.5 mg/h
`
`300 mg hahn
`
`10
`
`12
`
`Time
`
`The
`
`effect of
`
`intermittent and
`
`continuons
`
`infusion
`
`Fig
`cimetidine on gastric p11 Asterisk
`Adapted with permission
`
`tive patient
`
`1985
`
`indicates effect on representa
`from Gostroenterology
`
`al
`
`additional
`
`number of patients In the first open-label study by Lasky et
`60 mechanically ventilated trauma patients with an
`received
`risk factor for stress ulcer development
`40 mg given twice on the first day
`omeprazole suspension
`hours apart
`followed by 20 mg/d Baseline
`approximately
`pH
`secondary outcome in this study was 3.3 for patients
`mean gastric pH increase to 6.7
`enrolled in this study with
`The
`after administration of omeprazole
`second
`prospective open-label study by Phillips et al
`ICU and to
`patients admitted to
`requiring mechanical
`
`surgical
`
`ventilation
`
`and with at
`
`included
`bum unit
`
`least
`
`one
`
`additional
`
`risk factor
`
`for stress ulcer disease Seventy-five
`40 mg
`received
`omeprazole suspension
`eligible patients
`hours later and
`second 40-mg dose
`followed by
`to
`thereafter 20 mg daily Four hours postomeprazole admin
`to 7.1 The mean pH was
`istration the gastric pH increased
`6.8 after starting therapy up from an initial mean baseline
`No bleeding was reported in
`pH of 3.5
`.001
`either of these trials but the number of patients enrolled is
`to adequately assess an outcome of such
`
`likely insufficient
`
`low incidence
`
`PPI with an H2RA
`Few clinical studies have compared
`for prophylaxis of UI bleeding in patients at risk for stress
`Levy
`ulceration
`compared omeprazole with
`
`et al
`
`ranitidine in patients with risk factors for stress ulcer
`bleeding Sixty-seven patients were randomized to receive
`32 as
`50-mg bolus followed by
`either ranitidine
`32 as
`50-mg IV infusion every
`hours or omeprazole
`
`related
`
`patients
`at baseline than the omeprazole
`.05
`The fact
`that PPIs are more
`group 2.7 vs 1.9
`potent pump inhibitors raises theoretical concems
`that
`their
`more potent acid suppression may actually confer increased
`more
`risk of ventilator-associated pneumonia which is
`frequent and serious problem than stress ulcer bleeding
`Additional
`randomized trials in stress ulcer patients have
`form only One study compared
`been published in abstract
`administered nasogastrically with
`omeprazole suspension
`infused ranitidine 150 or 200 mg/d in
`continuously
`58 patients with at least
`risk factors for stress ulcer
`related
`bleeding Omeprazole was shown to be superior to ranitidine
`and
`cost Clinically significant UI
`in efficacy
`safety
`bleeding occurred
`of patients receiving omeprazole
`.05
`33 vs 16 ofthose receiving ranitidine
`25
`compared the efficacy of
`Another
`via continuous infusion sucralfate
`150 mg/d
`every
`hours via nasogastric tube and omeprazole 40 mg IV every
`12 hours as prophylaxis for stress ulcers in 108 patients with
`one risk factor
`for stress-related UI bleeding
`Gastrointestinal bleeding occurred in l0.5 of patients in
`38 9.30o of those in the sucralfate
`the ranitidine group
`32 and none of those in the omeprazole group
`38
`These
`the superiority of
`suggest
`omeprazole for the prophylaxis of UI bleeding in high-risk
`patients but await the scrutiny of full-text publication
`Unlike H2RAs PPIs do not seem to develop
`with sustained therapy Two studies comparing omeprazole
`pH
`with ranitidine found that omeprazole maintained
`greater than 4.0 over 72-hour
`treatment periods
`In
`one of
`the dose of omeprazole required to
`the studies
`maintain this degree of acid suppression actually decreased
`by 43% from the first
`to the third day of treatment
`These results seem to be supported by those of pilot study
`by Morris
`This study included 202 critically ill patients
`at high risk for UI bleeding who were randomized to receive
`different dosing regimens of intravenous pantopra
`of
`standard
`zole administered intermittently or
`regimen of
`continuous infusion with each
`days The time to
`regimen given at least 48 hours and up to
`achieve pH 4.0 or more was 4.3 hours for the pantoprazole
`groups compared to 4.5 hours for the cimetidine group In
`time that pH
`of
`all pantoprazole groups
`the percentage
`compared with
`remained at or above 4.0 increased on day
`day Fig
`this percentage actually decreased
`in the cimetidine group despite administration of
`on day
`continuous infusions These data suggest
`dosing with intravenous pantoprazole can rapidly achieve
`
`in
`
`trial
`
`at
`
`least
`
`group
`
`studies
`
`ranitidine
`
`tolerance
`
`cimetidine administered as
`
`In contrast
`
`that
`
`intermittent
`
`
`
`Page 7 of 11
`
`Patent Owner Ex. 2019
`Lupin v. Pozen
`IPR2015-01775
`
`

`
`42
`
`Stoltman D.C Metz
`
`Day
`
`Day
`
`tJ
`
`100
`
`80
`
`60
`
`40
`
`20
`
`73
`
`69
`
`66
`
`86
`
`82
`
`77
`
`40mg
`
`q24h
`
`40mg
`
`ql2h
`
`80mg
`
`q24h
`
`80 mg
`
`qI2h
`
`80 mg
`
`qah
`
`Fig
`
`Med 2002
`
`The effect of intravenous pantoprazole and continuous infusion cimetidine on intragastric pH
`
`Cimetidine
`
`300 mgbolus
`
`50 mg/h
`
`202 Adapted from Cr11 Core
`
`and maintain
`
`pH of 4.0 or more in critically
`ill patients
`rapid on