The Program in Hospital Medicine Update in Hospital Medicine Nicole Artz, MD David Lovinger, MD Nilam Soni, MD Program in Hospital Medicine University

The Program in Hospital Medicine

Update in Hospital MedicineUpdate in Hospital Medicine

Nicole Artz, MDNicole Artz, MDDavid Lovinger, MDDavid Lovinger, MDNilam Soni, MDNilam Soni, MDProgram in Hospital MedicineProgram in Hospital MedicineUniversity of ChicagoUniversity of Chicago


Healthcare-Associated Healthcare-Associated Pneumonia Requiring Pneumonia Requiring Hospital AdmissionHospital Admission

Carratala J, Arch Intern Carratala J, Arch Intern Med/Vol 167, July 2007Med/Vol 167, July 2007

ObjectiveObjective

Discern the epidemiology, causative Discern the epidemiology, causative organisms, antibiotic susceptibilities, organisms, antibiotic susceptibilities, and outcomes of HCAP requiring and outcomes of HCAP requiring hospitalizationhospitalization

BackgroundBackground

Proposed as new category of resp infection in Proposed as new category of resp infection in 2005 ATS/IDSA guidelines2005 ATS/IDSA guidelines

Pneumonia occuring in a pt w/ extensive Pneumonia occuring in a pt w/ extensive healthcare contact:healthcare contact:• Home infusion therapy or wound therapyHome infusion therapy or wound therapy• Resident of NH or long-term care facilityResident of NH or long-term care facility• Hospitalization within prior 90 daysHospitalization within prior 90 days• Chronic dialysis within prior 30 daysChronic dialysis within prior 30 days• Family member with multidrug resistant pathogenFamily member with multidrug resistant pathogen

Limited data to validate entity or guide Limited data to validate entity or guide therapytherapyATS/IDSA guidelines for mgt of adults with HAP, VAP, HCAP, Amer J Respir Crit Care Med. 2005

MethodsMethods

Prospective observational study Prospective observational study (1/2001-12/2004)(1/2001-12/2004)

900 bed university hospital in Spain900 bed university hospital in Spain Hospitalized adults with pneumonia Hospitalized adults with pneumonia

(excluded severely (excluded severely immunosuppressed patients)immunosuppressed patients)

Classified as CAP vs HCAP using Classified as CAP vs HCAP using standard protocolstandard protocol

Methods Cont…Methods Cont…

Evaluation for infecting organism:Evaluation for infecting organism:• 2 sets blood cultures2 sets blood cultures• Sputum gram stain and cultureSputum gram stain and culture• Acute and convalescent serologic studiesAcute and convalescent serologic studies• Urinary antigen for S. pneumo and L. Urinary antigen for S. pneumo and L.

pneumophila performed at discretion of pneumophila performed at discretion of attendingattending

Antibiotic therapy initiated in the ED Antibiotic therapy initiated in the ED according to hospital guidelinesaccording to hospital guidelines• Ceftriaxone or Augmentin +/- macrolide OR Ceftriaxone or Augmentin +/- macrolide OR

LevofloxacinLevofloxacin

Methods Cont…Methods Cont… Pts followed daily by investigators; clinical data Pts followed daily by investigators; clinical data

tracked and recordedtracked and recorded Etiologic diagnosis Etiologic diagnosis

• DefinitiveDefinitive Pathogen in usually sterile specimenPathogen in usually sterile specimen L pneumophila in sputumL pneumophila in sputum L pneumophila or S. pneumo antigen in urineL pneumophila or S. pneumo antigen in urine 4-fold 4-fold in antibody titer, in antibody titer, Seroconversion for atypical pathogensSeroconversion for atypical pathogens

• PresumptivePresumptive Predominant microorganism isolated from purulent sputum Predominant microorganism isolated from purulent sputum

sample w/ compatible gram stainsample w/ compatible gram stain Aspiration pneumonia (pts w/ risk factors and involvement of Aspiration pneumonia (pts w/ risk factors and involvement of

dependent pulm segment or necrotizing pneumonia)dependent pulm segment or necrotizing pneumonia)

Results- Patient Results- Patient CharacteristicsCharacteristics

727 adults hospitalized with pneumonia727 adults hospitalized with pneumonia

CharacteristicCharacteristic HCAP HCAP (17%)(17%)

(n = 126)(n = 126)

CAP CAP (83%)(83%)

(n = 601)(n = 601)

P valueP value

AgeAge 69.569.5 63.763.7 <0.001<0.001Comorbid Conditions Comorbid Conditions (CVA, CHD, CA, (CVA, CHD, CA, COPD)COPD)

95.2%95.2% 74.7%74.7% <0.001<0.001

Impaired Impaired consciousness at consciousness at presentationpresentation

19.8%19.8% 10.6%10.6% 0.0040.004

Long-term Long-term corticosteroid usecorticosteroid use

11.9%11.9% 4.2%4.2% 0.0020.002

PSI High riskPSI High risk 67.5%67.5% 48.8%48.8% <0.001<0.001

Results- EtiologyResults- Etiology

EtiologyEtiology HCAPHCAP CAPCAP P ValueP ValueAspiration pneumoniaAspiration pneumonia 20.6%20.6% 3.0%3.0% 0.0010.001

S. pneumoniaeS. pneumoniae 28%28% 34%34% 0.180.18

PCN resistant S. PCN resistant S. pneumopneumo

33%33% 15%15% 0.040.04

Hemophilus influenzaHemophilus influenza 12%12% 6.0%6.0% 0.020.02

Gram-negative bacilliGram-negative bacilli 4%4% 1%1% 0.030.03

S. aureusS. aureus 2.4%2.4% 0%0% 0.0050.005

Legionella pneumophilaLegionella pneumophila 2.4%2.4% 9.0%9.0% 0.010.01

Results- Clinical Results- Clinical OutcomesOutcomes

2.0%

5.6%

4.3%

10.3%

0.0%

2.0%

4.0%

6.0%

8.0%

10.0%

12.0%

Inappropriateinitial antibiotic

Mortality

CAP

HCAPP=.03

P=.007

LimitationsLimitations

Single institution studySingle institution study Different country (Spain)Different country (Spain) Number of patients with HCAP smallNumber of patients with HCAP small Can’t draw conclusions about cause Can’t draw conclusions about cause

of higher mortalityof higher mortality

ImplicationsImplications

HCAP should be regarded as HCAP should be regarded as separate categoryseparate category

May need to target initial therapy May need to target initial therapy differentlydifferently

Larger studies needed from different Larger studies needed from different hospitals/geographical areas to hospitals/geographical areas to further define etiology, clinical further define etiology, clinical outcomes, appropriate initial outcomes, appropriate initial treatment strategiestreatment strategies


Umpierrez G, Diabetes Care, Vol Umpierrez G, Diabetes Care, Vol 30 (9) September 200730 (9) September 2007

Randomized Study of Basal-Bolus Randomized Study of Basal-Bolus Insulin Therapy in the Inpatient Insulin Therapy in the Inpatient

Management of Patients with Type Management of Patients with Type 2 Diabetes (RABBIT 2 TRIAL)2 Diabetes (RABBIT 2 TRIAL)

ObjectiveObjective

Study the optimal management of Study the optimal management of hyperglycemia in non-intensive care hyperglycemia in non-intensive care unit patients with type 2 diabetesunit patients with type 2 diabetes


Strong observational data linking Strong observational data linking hyperglycemia with adverse outcomes hyperglycemia with adverse outcomes among hospitalized patients (ICU and among hospitalized patients (ICU and non-ICU)non-ICU)

Prospective randomized trials in critically Prospective randomized trials in critically ill pts and pts w/ AMI show reduced ill pts and pts w/ AMI show reduced morbidity and mortality w/ intensive morbidity and mortality w/ intensive control of hyperglycemiacontrol of hyperglycemia

Limited data evaluating Limited data evaluating interventions/outcomes in non critically ill interventions/outcomes in non critically ill patientspatients

Umpierrez, GE, J Clin Endocrinol Metab, 2002; Clement S, Diabetes Care, 2004; Krinsley, JS, Mayo Clin Proc, 2003; Van den Berghe, N Engl J Med 2001 and 2006

MethodsMethods Multicenter, open-label, randomized Multicenter, open-label, randomized

studystudy Inclusion CriteriaInclusion Criteria

• General medical ptsGeneral medical pts• Insulin-naiveInsulin-naive• Known h/o DMKnown h/o DM• Ages 18-80 yrsAges 18-80 yrs• BG 140-400 mg/dlBG 140-400 mg/dl• Absence of DKAAbsence of DKA

Exclusion CriteriaExclusion Criteria• No known h/o DMNo known h/o DM• ICU admissionICU admission• Corticosteroid useCorticosteroid use• Expected surgeryExpected surgery• Liver diseaseLiver disease• Creatinine >/= 3mg/dlCreatinine >/= 3mg/dl• PregnancyPregnancy• Mental condition Mental condition

precluding informed precluding informed consentconsent

Methods Cont…Methods Cont…

Pts managed by internal medicine Pts managed by internal medicine residents with assigned protocolresidents with assigned protocol

Endocrinologist rounded daily with Endocrinologist rounded daily with teamteam

Randomized to basal/bolus regimen Randomized to basal/bolus regimen (glargine and glulisine) vs SSI (glargine and glulisine) vs SSI

Oral agents discontinued at Oral agents discontinued at admissionadmission

4:00 16:00 20:00 24:00 4:00

Breakfast Lunch Dinner

8:0012:008:00

Time

Glargine

Lispro Lispro Lispro

Pla

sma

insu

lin

Basal/Bolus InsulinBasal/Bolus Insulin

Methods Cont..Methods Cont..

Basal-Bolus RegimenBasal-Bolus Regimen• 0.4 units/kg for admission BG 140-200 0.4 units/kg for admission BG 140-200

mg/dlmg/dl• 0.5 units/kg for admit BG 201-400 mg/dl0.5 units/kg for admit BG 201-400 mg/dl• 50% basal, 50% prandial (bolus)50% basal, 50% prandial (bolus)• Correction factor/supplemental glulisine for Correction factor/supplemental glulisine for

BS >140BS >140• 20% increase in glargine dose for fasting or 20% increase in glargine dose for fasting or

mean BG >140mean BG >140• 20% decrease in glargine for BG <70 mg/dl20% decrease in glargine for BG <70 mg/dl

Methods…Methods…

SSI GroupSSI Group• Regular insulin 4X’s daily for BG > 140 mg/dlRegular insulin 4X’s daily for BG > 140 mg/dl• 3 different SSI protocols (sensitive, usual, 3 different SSI protocols (sensitive, usual,

resistant)resistant)• Pts eating received “usual” SSI protocolPts eating received “usual” SSI protocol• NPO pts received “insulin sensitive” SSI NPO pts received “insulin sensitive” SSI

protocolprotocol• Adjusted up or down daily based on BGAdjusted up or down daily based on BG• If mean daily BG was >240 or 3 consecutive If mean daily BG was >240 or 3 consecutive

values > 240 on maximal SSI regimen, pts values > 240 on maximal SSI regimen, pts switched to a basal-bolus regimen (14%).switched to a basal-bolus regimen (14%).

ResultsResults

Figure 1— Changes in blood glucose concentrations in patients treated with glargine plus glulisine (●) and with SSI (o). *P < 0.01; ¶P < 0.05.

ResultsResults

Basal-Bolus Basal-Bolus Cohort Cohort (N=65)(N=65)

SSI Cohort SSI Cohort (N=65)(N=65)

P ValueP Value

Mean admission Mean admission glucoseglucose

229229 225225 NSNS

Mean glucose Mean glucose during during hospitalizationhospitalization

166 +/- 32166 +/- 32 193 +/- 54193 +/- 54 <0.001<0.001

Mean fasting Mean fasting glucoseglucose

147 +/- 36147 +/- 36 165 +/- 41165 +/- 41 < 0.01< 0.01

Mean random Mean random glucoseglucose

164 +/- 35164 +/- 35 189 +/- 42189 +/- 42 < 0.001< 0.001

Mean glucose Mean glucose on final dayon final day

140140 187187 <0.001<0.001

Hypoglycemia Hypoglycemia (<60)(<60)

0.4%0.4% 0.2%0.2% NSNS

ResultsResults

Figure 2—Figure 2— Mean blood glucose concentration in subjects who remained Mean blood glucose concentration in subjects who remained with severe hyperglycemia despite increasing doses of regular insulin per with severe hyperglycemia despite increasing doses of regular insulin per the sliding-scale protocol (o). Glycemic control rapidly improved after the sliding-scale protocol (o). Glycemic control rapidly improved after switching to the basal-bolus insulin regimen (•). switching to the basal-bolus insulin regimen (•). PP < 0.05. < 0.05.


Did not include patients with new Did not include patients with new onset hyperglycemiaonset hyperglycemia

Excluded patients with renal Excluded patients with renal insufficiency, already on insulin, or on insufficiency, already on insulin, or on steroidssteroids

Not powered to determine differences Not powered to determine differences in mortality or other clinical outcomesin mortality or other clinical outcomes

Endocrinologist rounded with Endocrinologist rounded with medicine teams dailymedicine teams daily


Basal-Bolus insulin regimens can be Basal-Bolus insulin regimens can be effective and safe in non-critically ill effective and safe in non-critically ill patients when used correctlypatients when used correctly

Need trials examining clinically Need trials examining clinically important outcomes (short and long-important outcomes (short and long-term)term)

The Program in Hospital MedicineRenal Protection for Renal Protection for Coronary Angiography in Coronary Angiography in Advanced Renal Failure Advanced Renal Failure Patients by Prophylactic Patients by Prophylactic

HemodialysisHemodialysis

Lee, PT, Chou KJ, et al. Journal of the Lee, PT, Chou KJ, et al. Journal of the American College of Cardiology, American College of Cardiology,

2007;50:1015-20.2007;50:1015-20.

ObjectiveObjective

Evaluate the effectiveness of Evaluate the effectiveness of prophylactic hemodialysis in patients prophylactic hemodialysis in patients who are the highest risk for Contrast-who are the highest risk for Contrast-Induced Nephropathy (CIN) Induced Nephropathy (CIN)


CIN is the 3CIN is the 3rdrd most common cause of most common cause of ARF in hospitalized patients.ARF in hospitalized patients.

Development of CIN is associated with Development of CIN is associated with an increased risk of:an increased risk of:• Prolonged hospitalizationProlonged hospitalization• Permanent worsening of renal functionPermanent worsening of renal function• Need for HD Need for HD • DeathDeath

Optimal prevention strategies are Optimal prevention strategies are unclear.unclear.

Background, Cont’dBackground, Cont’d

There many studies on CIN prevention, and There many studies on CIN prevention, and effective strategies include:effective strategies include:• Hydration with salineHydration with saline• Minimizing contrast bolusMinimizing contrast bolus• N-AcetylcysteineN-Acetylcysteine• HCOHCO33

--

Comparisons between studies are difficult Comparisons between studies are difficult because:because:• Different def’ns of ARF (25% decr GFR, 1 mg/dL Different def’ns of ARF (25% decr GFR, 1 mg/dL

incr SCr)incr SCr)• Different baseline SCR (>1.5 to 5)Different baseline SCR (>1.5 to 5)• Different populationsDifferent populations• Different procedures and dye loads (cath, CT)Different procedures and dye loads (cath, CT)

MethodsMethods 82 consecutive pts with advanced 82 consecutive pts with advanced

renal failure referred for coronary renal failure referred for coronary angiography.angiography.• SCr avg 4.9 mg/dl and stable x 1 mo SCr avg 4.9 mg/dl and stable x 1 mo

(entry criteria > 3.5 mg/dl)(entry criteria > 3.5 mg/dl)• Most pts w/CAD, DM, and HTNMost pts w/CAD, DM, and HTN• Avg EF = 45%Avg EF = 45%• No recent nephrotoxins or dye load No recent nephrotoxins or dye load

(7d)(7d)• No NAC, mannitol, dopamine, No NAC, mannitol, dopamine,

theophyllinetheophylline

Methods, cont’dMethods, cont’d Pts were randomized to either Pts were randomized to either

prophylactic HD or nothing, and both prophylactic HD or nothing, and both groups were given a 1 mL/kg/hr groups were given a 1 mL/kg/hr infusion of NS x 18h.infusion of NS x 18h.

No ultrafiltration was performed.No ultrafiltration was performed. Primary endpoint was change in GFR Primary endpoint was change in GFR

calculated by 24-hour urine collected calculated by 24-hour urine collected before procedure and on day 4.before procedure and on day 4.

Secondary endpoints were temporary Secondary endpoints were temporary or permanent need for HD in either or permanent need for HD in either group.group.

Results – Primary EndpointResults – Primary Endpoint

Day 4 CrCl was reduced relative Day 4 CrCl was reduced relative to baseline in the control group, to baseline in the control group, but not in HD group (p=0.008).but not in HD group (p=0.008).

No adverse events from line No adverse events from line placement.placement.

Primary outcome – Change in Primary outcome – Change in GFR on Day 1 and Day 4GFR on Day 1 and Day 4

p-value for the difference in Day 4 clearance = 0.008

Results – Secondary Results – Secondary EndpointsEndpoints

Peak SCr and SCr at discharge were Peak SCr and SCr at discharge were significantly higher in the control group significantly higher in the control group than in the HD group (p=<0.001 for than in the HD group (p=<0.001 for both.)both.)

More patients in the control group had More patients in the control group had significant, long-term renal injury or significant, long-term renal injury or needed temporary or permanent HD needed temporary or permanent HD than in the HD group.than in the HD group.

LOS was 2x longer in the control group.LOS was 2x longer in the control group.

Secondary OutcomesSecondary Outcomes

P-values for each group respectively: <0.001, 0.018, 0.017 and <0.001

Limitations Limitations

UnblindedUnblinded Very advanced renal failure (small Very advanced renal failure (small

subset).subset). Prior negative trialsPrior negative trials

• No effect at lower levels of SCrNo effect at lower levels of SCr• Ultrafiltration likely harmful as volume Ultrafiltration likely harmful as volume

depletion is a significant risk factor for CINdepletion is a significant risk factor for CIN Need cooperating nephrologist and Need cooperating nephrologist and

patient.patient.


Potentially significant way to treat Potentially significant way to treat patients with advanced renal failure patients with advanced renal failure who need procedure involving IV who need procedure involving IV contrast.contrast.

A big benefit for patients at the A big benefit for patients at the highest risk.highest risk.


Length of Hospital Stay and Length of Hospital Stay and Postdischage Mortality in Postdischage Mortality in Patients with Pulmonary Patients with Pulmonary

EmbolismEmbolism

Aujesky D, Stone RA, Kim S, Crick EJ, Fine Aujesky D, Stone RA, Kim S, Crick EJ, Fine MJ. Archives of Internal Medicine. 2008; MJ. Archives of Internal Medicine. 2008;

168(7), 706-712.168(7), 706-712.

ObjectiveObjective

Determine the effect of length of Determine the effect of length of stay (LOS) on mortality in patients stay (LOS) on mortality in patients hospitalized with a pulmonary hospitalized with a pulmonary embolism.embolism.

LOS and Mortality in Patients LOS and Mortality in Patients with Pulmonary Embolismwith Pulmonary Embolism

PE is a serious medical condition, PE is a serious medical condition, with substantial morbidity and with substantial morbidity and mortality.mortality.

Optimal length of stay unclear in era Optimal length of stay unclear in era when all LOS is decreasing.when all LOS is decreasing.

How do outcomes interact with LOS?How do outcomes interact with LOS? How does LOS interact with PE How does LOS interact with PE

severity?severity?

MethodsMethods Retrospective cohort studyRetrospective cohort study 15,531 patients15,531 patients Administrative and clinical dataAdministrative and clinical data Inclusion criteriaInclusion criteria

• Primary dx = PE, orPrimary dx = PE, or• Secondary dx = PE and primary dx c/w PE (SOB, Secondary dx = PE and primary dx c/w PE (SOB,

resp failure, syncope, cardiac arrest, etc)resp failure, syncope, cardiac arrest, etc) Patients with only a secondary dx of PE or Patients with only a secondary dx of PE or

transferred from another facility were transferred from another facility were excludedexcluded

Community acquired PECommunity acquired PE

Pulmonary Embolism Pulmonary Embolism Severity Index (PESI)Severity Index (PESI)

Used a previously Used a previously determined risk determined risk stratification score for PEstratification score for PE

Risk stratification into 5 Risk stratification into 5 groups based on scoregroups based on score• Class I Class I << 65 65• Class II 66-85Class II 66-85• Class III 86-105Class III 86-105• Class IV 106-125Class IV 106-125• Class V Class V >> 126 126

Patterned on the PORT Patterned on the PORT scorescore

Overall mortality by class:Overall mortality by class:• Class I = 1.1%Class I = 1.1%• Class II = 3.1%Class II = 3.1%• Class III = 6.5%Class III = 6.5%• Class IV = 10.4%Class IV = 10.4%• Class V = 24.5%Class V = 24.5%

Age in yearsAge in years Male gender Male gender

(10)(10) Cancer (30)Cancer (30) CHF (10)CHF (10) Lung dz (10)Lung dz (10) Pulse Pulse >> 110 110

(20)(20) SBP < 100 (30)SBP < 100 (30) Resp Resp >> 30 (20) 30 (20) Altered mental Altered mental

status (60)status (60) SaO2 < 90% SaO2 < 90%

(20)(20)

Mortality and PESI ScoreMortality and PESI Score11

1Aujesky D, Obrosky S, Stone RA, Auble TE, Arnaud P, Cornuz, Roy P, Fine MJ. Derivation and Validation of a Prognostic Model for Pulmonary Embolism. Am J Respir Crit Care Med. 2005; 172, 1041-1046.

Short LOS in PE is associated Short LOS in PE is associated with Increased Mortalitywith Increased Mortality

Patients were stratified by LOS in quartiles Patients were stratified by LOS in quartiles and by PE severity (PESI):and by PE severity (PESI):• Q1 Q1 << 4d, Q2 = 5-6d, Q3 = 7-8d, Q4 > 8d 4d, Q2 = 5-6d, Q3 = 7-8d, Q4 > 8d• Discharge in Q1 has an excess risk of death at Discharge in Q1 has an excess risk of death at

30 days (RR = 1.55)30 days (RR = 1.55)• Discharge in Q4 also has an excess risk (RR = Discharge in Q4 also has an excess risk (RR =

2.39)2.39)• Uninsured patients had Uninsured patients had longer longer LOS and LOS and betterbetter

outcomes after dischargeoutcomes after discharge Not a causal link, but implied mechanism:Not a causal link, but implied mechanism:

• Unrecognized clinical instability at dischargeUnrecognized clinical instability at discharge• Insufficiently stable anticoagulationInsufficiently stable anticoagulation

Mortality and LOSMortality and LOS

LOS Quartile: Q1 LOS Quartile: Q1 << 4d; Q2 = 5-6d; Q3 = 7-8d; Q4 > 8d 4d; Q2 = 5-6d; Q3 = 7-8d; Q4 > 8d

p=<0.001 for comparison between quartiles 1 and 2

PESI Score and LOS QuartilePESI Score and LOS Quartile


PE remains a morbid and mortal PE remains a morbid and mortal condition.condition.

Comorbid disease increases risk Comorbid disease increases risk death at 30 days significantly.death at 30 days significantly.

PESI is a simple scoring tool for PESI is a simple scoring tool for identifying high risk patients.identifying high risk patients.

Ensuring a therapeutic INR and close Ensuring a therapeutic INR and close follow-up is prudent.follow-up is prudent.


Not a prospective, randomized trial.Not a prospective, randomized trial. Cannot attribute causation for Cannot attribute causation for

mortality.mortality.


Zoledronic Acid and Clinical Zoledronic Acid and Clinical Fractures and Mortality after Fractures and Mortality after

Hip FractureHip Fracture

Lyles KW, Colon-Emeric CS, Magaziner JS, et al.Lyles KW, Colon-Emeric CS, Magaziner JS, et al.

New England Journal of MedicineNew England Journal of Medicine 2007;357:1799-8092007;357:1799-809

ObjectiveObjective

Determine the safety and efficacy of Determine the safety and efficacy of zoledronic acid administration for zoledronic acid administration for prevention of new clinical fractures in prevention of new clinical fractures in patients who have had recent hip patients who have had recent hip fracture surgeryfracture surgery


Mortality 15-25% in first year after hip Mortality 15-25% in first year after hip fracturefracture

New osteoporotic fractures occur 10.4 per New osteoporotic fractures occur 10.4 per 100 patients/year after hip fracture100 patients/year after hip fracture

Few patients receive bisphosphonates after Few patients receive bisphosphonates after hip fracturehip fracture

Zoledronic acid is a bisphosphonate given Zoledronic acid is a bisphosphonate given intravenously once yearlyintravenously once yearly

Zoledronic acid has been shown to reduce Zoledronic acid has been shown to reduce hip, vertebral, and nonvertebral fractures in hip, vertebral, and nonvertebral fractures in postmenopausal osteoporosispostmenopausal osteoporosis

MethodsMethods

International, multicenter, randomized, International, multicenter, randomized, double-blind, placebo-controlled studydouble-blind, placebo-controlled study

Zoledronic acid or placebo infusion within Zoledronic acid or placebo infusion within 90 days of hip fracture and every 1 year 90 days of hip fracture and every 1 year thereafterthereafter

All patients received calcium (1000-1500 All patients received calcium (1000-1500 mg) and vitamin D (800-1200 IU) dailymg) and vitamin D (800-1200 IU) daily

If 25-hydroxyvitamin D If 25-hydroxyvitamin D <15 ng/ml or not <15 ng/ml or not known, loading dose of vitamin D2 or D3 known, loading dose of vitamin D2 or D3 given orally or IM (50,000-125,000 IU) 14 given orally or IM (50,000-125,000 IU) 14 days prior to infusiondays prior to infusion

MethodsMethods

Follow up with quarterly phone calls and Follow up with quarterly phone calls and annual clinic visitsannual clinic visits

Monitored for up to 5 yrsMonitored for up to 5 yrs Study stopped early after 185 events Study stopped early after 185 events

accrued in placebo groupaccrued in placebo group Concomitant use of nasal calcitonin, SERM, Concomitant use of nasal calcitonin, SERM,

HRT, tibolone, and external hip protectors HRT, tibolone, and external hip protectors allowed at discretion of investigatorallowed at discretion of investigator

Exclusions: CrCl <30 ml/min, Ca >11 or Exclusions: CrCl <30 ml/min, Ca >11 or <8, active cancer, life expectancy <6 mo<8, active cancer, life expectancy <6 mo

MethodsMethods

OutcomesOutcomes• Primary: New clinical fracturesPrimary: New clinical fractures• Secondary: Secondary:

Change BMD in non-fractured hipChange BMD in non-fractured hip New vertebral, nonvertebral, and hip New vertebral, nonvertebral, and hip

fracturesfractures DeathDeath

MethodsMethods

Definitions for New FracturesDefinitions for New Fractures• Vertebral fractures = back pain + Vertebral fractures = back pain +

reduction in vertebral body height reduction in vertebral body height (blinded review of difficult cases)(blinded review of difficult cases)

• Nonvertebral fractures = positive Nonvertebral fractures = positive radiograph, report, or medical record radiograph, report, or medical record documentationdocumentation

• Delayed union of hip fracture = Delayed union of hip fracture = persistent pain or inability to bear persistent pain or inability to bear weight + radiographic evidence weight + radiographic evidence

ResultsResults

2127 patients 2127 patients → → 1065 zoledronic 1065 zoledronic acid,acid,

1062 placebo1062 placebo Median follow-up 1.9 yearsMedian follow-up 1.9 years Similar baseline characteristicsSimilar baseline characteristics

• Average age 74Average age 74• 90% were white90% were white• 75% were female75% were female• 41% had T score < -2.5 at femoral neck41% had T score < -2.5 at femoral neck

ResultsResults

ResultsResultsZoledronic Zoledronic

AcidAcidPlaceboPlacebo

Mean time to fracture (mo)Mean time to fracture (mo) 39.839.8 36.436.4Change in BMD (%):Change in BMD (%):

Total hip Total hip

12 (months)12 (months)

24 24

36 36

Femoral neckFemoral neck

12 (months)12 (months)

2424

3636

2.62.6

4.74.7

5.55.5

0.80.8

2.22.2

3.63.6

-1.0-1.0

-0.7-0.7

-0.9-0.9

-1.7-1.7

-2.1-2.1

-0.7-0.7

ResultsResults

Adverse events similar in both groupsAdverse events similar in both groups Zoledronic acid group reported greater:Zoledronic acid group reported greater:

• Pyrexia (8.7% vs. 3.1%)Pyrexia (8.7% vs. 3.1%)• Myalgia (4.9% vs. 2.7%)Myalgia (4.9% vs. 2.7%)• Bone pain (3.2% vs. 1.0%)Bone pain (3.2% vs. 1.0%)• Musculoskeletal pain (3.1% vs. 1.2%)Musculoskeletal pain (3.1% vs. 1.2%)

No difference in cardiovascular eventsNo difference in cardiovascular events No reported cases of osteonecrosis of jawNo reported cases of osteonecrosis of jaw


Effects of previous use of bisphosphonates Effects of previous use of bisphosphonates and parathyroid hormone permitted after a and parathyroid hormone permitted after a “washout period”“washout period”

Limited ethnic diversity (>90% were white Limited ethnic diversity (>90% were white and ~1% were black)and ~1% were black)

Incidence of delayed union of hip > in Incidence of delayed union of hip > in zoledronic acid group, but not statistically zoledronic acid group, but not statistically significantsignificant

No comparison to standard therapy (oral No comparison to standard therapy (oral bisphosphonate, calcium + vitamin D)bisphosphonate, calcium + vitamin D)


Annual infusion of zoledronic acid Annual infusion of zoledronic acid after hip fracture surgery reduces after hip fracture surgery reduces new fractures and improves survival new fractures and improves survival

Option for patients who are unable or Option for patients who are unable or unwilling to take an oral unwilling to take an oral bisphosphonatebisphosphonate

Should be given with oral calcium Should be given with oral calcium and and

vitamin Dvitamin D

nsoni

Vit D has to be repleted


Recombinant Factor VIIa for Recombinant Factor VIIa for the Prevention and Treatment the Prevention and Treatment

of Bleeding in Patients Without of Bleeding in Patients Without HaemophiliaHaemophilia

Stanworth SJ, Birchall J, Doree CJ, Hyde C,Stanworth SJ, Birchall J, Doree CJ, Hyde C,Cochrane Database of Systematic Reviews,Cochrane Database of Systematic Reviews,

April 2007April 2007

ObjectiveObjective

Assess the effectiveness of Assess the effectiveness of recombinant factor VIIa when used recombinant factor VIIa when used prophylactically to prevent bleeding, prophylactically to prevent bleeding, and when used therapeutically to and when used therapeutically to control active bleeding in patient control active bleeding in patient without hemophilia without hemophilia


Recombinant FVIIa is licensed for use only Recombinant FVIIa is licensed for use only in patients with hemophiliain patients with hemophilia

Increasing use for off-label indications to Increasing use for off-label indications to prevent and/or stop bleedingprevent and/or stop bleeding

Potential to reduce need for transfusion of Potential to reduce need for transfusion of blood productsblood products

High Cost: 1.2 mg ……$ 1,328 (per vial)High Cost: 1.2 mg ……$ 1,328 (per vial)

2.4 mg…....$ 2,6582.4 mg…....$ 2,658

4.8 mg…….$ 5,3184.8 mg…….$ 5,318

MethodsMethods

Systematic Review by Cochrane CollaborationSystematic Review by Cochrane Collaboration Data Sources:Data Sources: Major national and Major national and

international electronic medical databases (to international electronic medical databases (to March 2006)March 2006)

Inclusion Criteria for this ReviewInclusion Criteria for this Review• Randomized controlled trialsRandomized controlled trials• Pts at risk for blood loss or treated for bleedingPts at risk for blood loss or treated for bleeding• Pts with hemostatic defects, such as hemophilia, Pts with hemostatic defects, such as hemophilia,

excludedexcluded• Outcomes: Mortality, bleeding, number of Outcomes: Mortality, bleeding, number of

transfusions, number of patients transfused, and transfusions, number of patients transfused, and thromboembolic eventsthromboembolic events

MethodsMethods

Methods of ReviewMethods of Review• 2 authors screened papers 2 authors screened papers • Methodological QualityMethodological Quality

Generation of random sequenceGeneration of random sequence Concealment of treatment allocationConcealment of treatment allocation Blinding of clinicians, participants, and Blinding of clinicians, participants, and

outcome assessorsoutcome assessors Proportion of participants included in main Proportion of participants included in main

analysisanalysis Equal use of co-interventions in study armsEqual use of co-interventions in study arms

MethodsMethods

Description of StudiesDescription of Studies• 13 randomized controlled studies identified13 randomized controlled studies identified• Prophylactic TrialsProphylactic Trials

6 trials included6 trials included Participants varied Participants varied

(traumatic pelvic fractures, radical prostatectomy, partial (traumatic pelvic fractures, radical prostatectomy, partial hepatectomy, liver transplantation, cardiac surgery)hepatectomy, liver transplantation, cardiac surgery)

All 6 trials compared rFVIIa vs. placeboAll 6 trials compared rFVIIa vs. placebo Significant differences in dosing and Significant differences in dosing and

administration administration (40 mcg/kg to 360 mcg/kg)(40 mcg/kg to 360 mcg/kg)

All trials had threats to validity All trials had threats to validity (randomization, allocation concealment, patient (randomization, allocation concealment, patient

disposition)disposition)

MethodsMethods

Descriptions of Studies (cont’d)Descriptions of Studies (cont’d)• Therapeutic TrialsTherapeutic Trials

7 trials included7 trials included Participants varied Participants varied

(post-stem cell transplant, hemorrhagic Dengue fever, (post-stem cell transplant, hemorrhagic Dengue fever, severe trauma, cirrhotics with GI bleeding, intracerebral severe trauma, cirrhotics with GI bleeding, intracerebral hemorrhage)hemorrhage)

All trials placebo controlledAll trials placebo controlled Significant differences in dosing and Significant differences in dosing and

administration administration (40 mcg/kg to 1120 mcg/kg)(40 mcg/kg to 1120 mcg/kg)

Only 1 trial without threats to validityOnly 1 trial without threats to validity

Results: Prophylactic TrialsResults: Prophylactic Trials

No statistically significant differences in No statistically significant differences in death, blood loss, blood transfusions, death, blood loss, blood transfusions, number of patients transfused, or number of patients transfused, or thromboembolic events from pooled datathromboembolic events from pooled data

Only 1 small study reported statistically Only 1 small study reported statistically significant differences in blood loss, significant differences in blood loss, transfusion requirements, and number of transfusion requirements, and number of patients transfused patients transfused

Results: Prophylactic Trials - DeathResults: Prophylactic Trials - Death

Results: Prophylactic Trials - Results: Prophylactic Trials - Blood LossBlood Loss

Results: Prophylactic Trials - Results: Prophylactic Trials - Transfusion RequirementsTransfusion Requirements

Results: Prophylactic Trials - Results: Prophylactic Trials - Patients TransfusedPatients Transfused

Results: Prophylactic Trials - Results: Prophylactic Trials - Thromboembolic EventsThromboembolic Events

Results: Therapeutic TrialsResults: Therapeutic Trials

DeathDeath• No significant reduction in pooled dataNo significant reduction in pooled data• 1 study reported reduction1 study reported reduction

Reduction in BleedingReduction in Bleeding• No significant reduction in pooled dataNo significant reduction in pooled data• 1 study qualitatively showed reduction in volume of ICH 1 study qualitatively showed reduction in volume of ICH

and reduction in disabilityand reduction in disability Transfusion Requirements, Number of Patients Transfusion Requirements, Number of Patients

Transfused, and Thromboembolic EventsTransfused, and Thromboembolic Events• No significant difference in pooled dataNo significant difference in pooled data

Results: Therapeutic Trials - DeathResults: Therapeutic Trials - Death

Results:Therapeutic Trials: Results:Therapeutic Trials: Reduction in BleedingReduction in Bleeding

Results: Therapeutic Trials - Results: Therapeutic Trials - Transfusion RequirementsTransfusion Requirements

Results:Therapeutic Trials - Number Results:Therapeutic Trials - Number of Patients Transfusedof Patients Transfused

Results:Therapeutic Trials - Results:Therapeutic Trials - Thromboembolic EventsThromboembolic Events

Results: Subgroup AnalysisResults: Subgroup Analysis

Adverse EventsAdverse Events • No significant difference in thromboembolic No significant difference in thromboembolic

events in combined analysis of both events in combined analysis of both prophylactic and therapeutic trials prophylactic and therapeutic trials

Low vs. High Dose rFVIIaLow vs. High Dose rFVIIa• No significant difference based on doseNo significant difference based on dose• Nonsignificant trend toward greater effect at Nonsignificant trend toward greater effect at

higher dosehigher dose


Wide range of patient populations (cardiac Wide range of patient populations (cardiac surgery, hemorrhagic Dengue fever, surgery, hemorrhagic Dengue fever, trauma, etc.)trauma, etc.)

Dosing schedules varied greatly (clarify Dosing schedules varied greatly (clarify optimal dosage and dosing interval)optimal dosage and dosing interval)

Effects of thrombocytopenia and platelet Effects of thrombocytopenia and platelet dysfunction not includeddysfunction not included

1 study showing benefit in ICH could not be 1 study showing benefit in ICH could not be incorporated into analysisincorporated into analysis


Underestimation of thromboembolic eventsUnderestimation of thromboembolic events• All RCT’s excluded pts with history of All RCT’s excluded pts with history of

thrombosis or vaso-occlusive diseasethrombosis or vaso-occlusive disease• Clinical practice settings suspected to have Clinical practice settings suspected to have

higher risk of thrombosishigher risk of thrombosis• FDA issued warning against off-label uses based FDA issued warning against off-label uses based

on many reports of thrombosis, especially CVA’son many reports of thrombosis, especially CVA’s


Administration of recombinant factor Administration of recombinant factor VII for prophylaxis or treatment of VII for prophylaxis or treatment of bleeding in patients without bleeding in patients without hemophilia is not supported by hemophilia is not supported by current randomized, controlled trialscurrent randomized, controlled trials

Use should be restricted to licensed Use should be restricted to licensed indications until more data availableindications until more data available

Several ongoing trialsSeveral ongoing trials

Documents

The Program in Hospital Medicine Update in Hospital Medicine Nicole Artz, MD David Lovinger, MD Nilam Soni, MD Program in Hospital Medicine University