Catecholamine doses aregiven as pg/kg/min tor atleast Ihr

Table adapted from Singer et al.The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016:315(8):801-810

R33Respirology Toronto Notes 2023

[patient with suspected infection]

, T . . - No Monitor clinical condition;

[ Bedside qSOFA 22? (see Al — (Sepsis still suspected?

J » reevaluate lor possible sepsis

il clinically indicated

h u

l

Yes

Yes Assess for evidence of

organ dysfunction «

,

I . Nu Monitor clinical condition;

[ Bedside SOFA 22.1 (see B|

J reevaluate for possible sepsis

if clinically indicated

A qSOFA Variables

Respiratory rate

Mental status I Systolic Mood pressure Yes

Sepsis

1

'

g SOFA Variables

PaO/FO/atio

Glasgow Coma Scale score

Mean arterial pressure

Administration of vasopiessors with

type and dose rato of infusion

Serum creatinine or urine output

Bilirubin

Platelet count ,

Despite adequate fluid resuscitation.

1. vasopressors required to

maintain MAP 265 mmHg No

AND

2 serum lactate level >2 mmol/I?.

Septic Shock

The baseline Sequential (sepsis related) Organ Failure Assessment ISOFAI score should be assumed to be zero unless the patient is known to hove

pre-existing (acute or chronic) organdysfunction before the onset of infection.qSOFA indicated quickSOFA MAP.mean arterial pressure.

Figure 11. Approach to sepsis

Figure adapted Irom Singer et at. The third International Consensus Oelmit.ons tor Sepsis and Septic.Shock (Sepsis

-3). JAMA 20t&;315(8):801-8l0

Treatment

• identify the cause and source of infection:blood,sputum, urine Gram stain, and C&S

• initiate empiric antibiotic therapy

• monitor, restore, and maintain hemodynamic function

Surviving Sepsis

Adapted fromInternational Guidelines for Managementof SevereSepsis andSepticShock 2012

• adjustments of cardiac preload, afterload, and contractility to balance oxygen delivery with demand

• initial resuscitation (goal during first 6 h of resuscitation for sepsis induced hypotension persisting

after initial fluid challenge or blood lactate >4 mmol/L)

• maintain CVP 8-12 mmHg with IV crystalloids/colloids

maintain MAP 65 mmHg with use of vasopressor agents, first line: norepinephrine

• urine output 20.5 mL/ kg/hr

central venous (SVC) or mixed oxygen saturation 70% or 65%, respectively

in patients with elevated lactate levels target resuscitation to normalize lactate

corticosteroid replacement therapy not indicated if adequate hemodynamic stability achieved

with fluid resuscitation and vasopressor therapy

• infection control

prompt diagnosis of infection

cultures as clinically indicated prior to antibiotic therapy if no significant delay

imaging studies performed promptly to confirm possible infectious source

• antibiotic therapy

• administer effective IV antimicrobials within first hour of recognition of sepsis

choice of anti-infective therapy should consider activity against all likely pathogens and

penetrance of adequate concentration into tissue presumed to be source of infection

• antimicrobial regimen should be reassessed daily for potential de-escalation

• surgical source control when appropriate

• supportive oxygenation and ventilation using lung-protective regimen

• early nutritionalsupport:enteral route is used to preserve function of intestinal mucosal barrier

• DVT/PE prophylaxis

• advanced care planning, including the communication of likely outcome and realistic goals of

treatment with patients and families

n

+

R3-L Respirology Toronto Xotes 2023

Common Medications

Table 32. Common Medications for Respiratory Diseases

Drug Typical Adult Dose Indications Side Effects

P2-AG0NISTS

Short-Acting f

)2-Agonists salbutamol/albuterol (Ventolin5,Airomir 1|(light 1-2puffs q4- 6 h PRH

blue/navy MDI or diskus) terbutaline (Bricanyl®)

(blue turbuhaler)

CV (angina,flushing,palpitations, tachycardia,

can precipitate alrial fibrillation),CNS (dirtiness.

H/A.insomnia,anxicly). Cl (diarrhea,H/ V),rash,

hypokalemia,paroxysmal broncliospasm

Bronchodilator in acute

reversible airway

obstruction

Long-Acting !j 2-Agonisls salmelerol (Serevent '

) (green diskus).

(ormoterol (Oxere:

,Foradil:

) (blue/green

turbuhaler or aerolirer).indacaterol (Onbrez ’

)

(blue/white breethaler)

1- 2 pulls BID

1puff daily

Maintenance treatment

(prevention of

bronchospasm) inCOPD,

asthma

Combination Long-Acting fluticasone and salmelerol (Advair .Wixcla COPD and asthma '

)

P2 Agonist and Inhaled

Corticosteroid

1puff BIO

2 puffs BID

Common:CNS. H/A.dirtiness

Rcsp:UR1I.Gl (N/V. dianhea.pain/discomfort,oral

candidiasis)

(purple MDI or diskus.Inhub ),budesonide

and (ormoterol (Symbicort !

) (red turbuhaler),

mometasone and (ormoterol (Zenhale ) (blue

MDI),fluticasone furoate and Vilanterol(Breo

Ellipta '

) (light gray and blue inhaler)

1puff daily

CombinationShort-Acting ipratropium/salbutamol (Comblvcnl '

.

p2- Agonist andShort- Respimat 1

’

') (orange respimat)

Acting Anti-Cholinergic

Combination Long-Acting umedidinium/vilanterol (Anoro -') (red ellipta) 1puff daily

p2-Agonist and Long- adidinium/formoterol(Duaklir!

) (yellow genuair) 1puff BID

Acting Anti

-Cholinergic liotropium/olodaterol(lnspiollo '

) (green

respimat)

indacatcrol/glycopyrronium (Ultibro -)(yellow 1pulf daily

breerhaler)

1puff 010 Bronchodilalor used in COPD Palpitations,anxicly.dirtiness, fatigue.H/A.MV.

dry mucous membranes,uiinary retention,increased

toxicity in combination with other anticholinergicdrugs

Bronchodilator used in COPD Palpitations, anxiety,dirtiness,fatigue.H/A.N/V.

dry mucous membranes,urinary retention,increased

1pulf daily toxicity in combination with other anticholinergic drugs

ANTICHOLINERGICS

Short-Acting Anti

- Cholinergic

ipratropium bromide (Atrovent - ) (dear/green 2- 3 puffs OID Palpitations,anxiety,dirtiness,fatigue.H/A.N/V.

diy mucous membranes,urinary retention,increased

toxicity in combination with other anticholinergic drugs

Palpitations, anxiety,dirtiness,fatigue,H/A.N/V,

dry mucous membranes,urinary retention,increased

toxicity in combination with other anticholinergic drugs

Bronchodilalor used in

MDI) asthma and C0P0

bolropium bromide (Spiriva - ) (green handihaler 1puff DAM

or respimat). glycopyrronium bromide (Seebri = )

(orange breethaler).umedidinium (Incruse '

) 1puff daily

(green ellipta). adidinium (Tudorta ’

) (green

Genuair ’)

Long-ActingAntiCholinergic

Bronchodilatorusedin

asthma and COPD

CORTICOSTEROIDS

Inhaled fluticasone (Flovent 1)

(orange/peach MDI or diskus)

budesonide (Pulmicort '

) (brown turbuhaler)

ctclcsonide lAlvesco ?

)(red MDI)

bedomethasone (OVAR '

.Vanceril -) (brown MDI) 1-4 puffs BID

mometasone (Asmanex!

) (pink/grey/brown 1puff daily or BID

twisthaler)

fluticasone furoate(Arnuity '

) (orange ellipta) 1puff daily

fulicasone propionate (Aermony RespiClick -

) 1puff BIO

(light green inhaler)

prednisone (Apo-prednisone-. Deltasone!

|

methylprednisolone

(Depo-Medrol -

. Solu-Medrols)

2-4 puffs BID Maintenance treatment of

asthma

H/A.fever.N/V. MSK pain.URTI.throat irritabon.growth

velocity reduction in children/adolescents,HPA axis

2 puffs BID suppression,increased pneumonia risk in COPD

1puff daily or BIO

Systemic Typically 40-60mg/d P0

125 mgq8 h

IV (sodium succinate)

loading dose 2 mg/kg then

0.5-1mq/kg q6 h (or B d

Acute exacerbation of COPD: Endocrine (hirsutism.DM/glucose intolerance.Cushing's

severe,persistentasthma. syndrome.HPAaxissuppression),Gl (increased

Pneumocystis carinii

pneumonia

Status asthmalicus

appetite,indigestion),ocular (cataracts,glaucoma),

edema,avascular necrosis,osteoporosis.H/A.

psychiatiic (anxiety,insomnia),easy bruising

ADJUNCT AGENTS

400-600 mg once daily Treatment of symptoms

of reversible airway

obstruction due to COPD

Gl upset,diarrhea,N/ V.anxiety. H/A,insomnia,muscle

cramp,tremor,tachycardia,premature ventricular

contractions,arrhythmias

Toxicity:persistent,repetitive vomiting,seizures

theophylline (Uniphyll '

)

LEUKOTRIEHE ANTAGONISTS

omalizumab (Xolair ’

) 150-375 mg SC q2- 4 wk Moderate-severe persistent H/A.sinusitis,pharyngitis.URTI. viral infection,

asthma thrombocytopenia,anaphylaxis

PDE-4 INHIBITORS

rollumilasl IDaxas') 500 pqPO once daily Severe emphysema,with Weight loss, suicidal ideation

frequent exacerbations

L J ANTIBIOTICS - COMMUNITY ACQUIRED PNEUMONIA

Macrolide erythromycin 250-500 mg P0 TID x 7-10 d Alternate to doxycycline or

SOOmgPOxIdose,

Gl (abdominal pain,diarrhea,N/V),H/A,prolonged 0T,

ventricular arrhythmias,hepatic impairment

Gl (diarrhea. N/V. abdominal pain),renal failure,

deafness

H/A.rash.Gl (diarrhea.N/ V.abnormal taste,heartburn,

abdominal pain),increased urea

fluoioquinolone

then

250 mg once daily14

1000 mg once daily or 500

mg P0 BID x 7-10 d

azithromycin

clarithromycin +

See Infectious Diseases.ID25 lor the management oI pulmonary tuberculosis

R35 Respirology Toronto Notes 2023

Table 32. Common Medications for Respiratory Diseases

Drug Typical Adult Dose Indications Side Effects

Doxycydinc 100 mq P0 BID x 710 d Alternate to macrolide or

fluoroquinolone

Alternate to macrolide or

doxycydine

Photosensitivity,rash,urticaria,anaphylaxis,diarrhea,

enterocolitis,tooth discolouration inchildren

CNS (dizziness,fever,H/A),Gl (N/V. diarrhea,

constipation),prolonged 0T

Fluoroquinolone levofloxacin (Levaquin 1) SOOmgPOoncedailyx

710 d

moxilloxacin (Avelox '

) 400 mg PO once daily x 7 d

ANTIBIOTICS - HOSPITAL ACQUIRED PNEUMONIA

3rd gen Cephalosporin ceftriaxone (Rocephin - ) 1-2 g IV once daily x 7-10 d Combine with

fluoroquinolone or

macrolide

Combine with 3rdgen

cephalosporin

Rash, diarrhea,eosinophilia.thrombocytosis,

leukopenia,elevated transaminases

Fluoroquinolone levofloxacin

moxilloxacin

TSOmgPO once daily xSd

400 mgP0 once daily x 7 d

(Sd for AECOPD)

4.5 g IV q6-8 h x 7-10 d

Rash, diarrhea,eosinophilia.thrombocytosis,

leukopenia,elevated transaminases

Piperacillin/Tazobactam

(Tazocin )

Suspect Pseudomonas CNS (confusion,convulsions,drowsiness),rash,

hematologic (abnormal platelet aggregation,prolonged

PT,positive Coombs)

CNS (chills,drug fever),hematologic (eosinophilia).

rash,red man syndrome,interstitial nephritis,renal

failure,ototoxicity

CNS (chills,drug lever),hcmatologic (eosinophilra).

rash,red man syndrome,interstitial nephritis,renal

failure,ototoxicity

Vancomycin (Vancocin ) 1g IV BID x 7-10 d Suspect MRSA

Macrolide azithromycin S00 mg IV once daily x 2 d. Suspect iegrorre/to

clarithromycin then

SOOmgPOonce daily x 5 d

1000 mg once daily or 500

mg P0BID x 7-10 d

ICU MEDICATIONS

Pressors/lnotropes norepinephrine (levophed '

)

phenylephrine

dobulamine

lenlanyl(opioid class)

0.5-30 pg/min IV

0.S pg/kg/min IV

2-20 pgfkg/min IV

50 -100 ug then

SO-unlimited pg/h IV

1-3 mg/kg then0.3-5 mg/

kg/h IV

Acute hypotension

Severe hypotension

Inotropic support

Sedation and/or analgesia Bradycardia,respiratory depression,drowsiness.

Sedation and/or analgesia hypotension

Apnea,bradycardia,hypotension (good for ventilator

sedation)

Angina,bradycardia,dyspnea,hyper/hypotension,

arrhythmias

See above

Sedativcs/Analgosia

propofol (anesthetic)

See Infectious Diseases.ID2D lor the management ot pulmonary tuberculosis

Landmark Respirology Trials

Trial Name Reference Clinical Trial Details

ACUTE RESPIRATORY DISTRESS SYNDROME

NEJM 2013:368:795 805 Title:High- frequency Oscillation In Early Acute Respiratory Distress Syndrome

Purpose:Assess the reduction in mortality conferred by high-frequency oscillatory ventilation(KF0V) among adults with ARDS.

Methods:Adults with new-onset moderate-severe ARDS were randomized to HF0V or a controlventilationstrategy.The primary

outcome was all- cause in-hospital mortality.

Results:In-hospital mortality was 47% in the HF0V group and 35%in the control group (RR 1.33;95% Cl1.09 to1.64:P‘0.005).Patients

in the HE0V group received higher doses ol midazolam|P<0.01) and vasoactive drugs (91% vs.84%;P‘

0.01) than control patients.

Conclusions:Early HF0V in patients with moderate-to-severe ARDS may increase in-hospital mortality.

Title:Prone Positioning inSevere Acute Respiratory Distress Syndrome

Purpose:Evaluate the effect of early application of prone positioning on paUents with severe ARDS.

Methods:466 patients with severe ARDS were randomized to undergo prone- positioning sessions >16 h or remain supine.The primary

outcome was the proportion of patients who died from any cause at 28 d.

Results:The 28 d mortality was16.0%in the prone group and 32.8% in the supine group (hazard ratio 0.39:95% Cl 0.25 lo 0.63:

P--0.001).Unadjusted 90 d mortality was 23.6% in the prone group and 41.0% in the supine group (hazard ratio 0.44:95% Cl 0.29 to

0.67:P<0.001).The incidence of complications did notdiffer significantly between groups.

Conclusions:Early application of prolonged prone- positioning sessions inpatients with severe AR0S decreased 28 d and 90 dmortality.

Title:Neuromuscular 8lockers in Early Acute Respiratory Distress Syndrome

Purpose:Evaluate clinical outcomes after 2 d of therapy withneuromuscular blocking agents,in pabents with ARDS.

Methods:340 patients presenting to the ICU with severe ARDS were randomized to cisalracurium besylate or placebo.The primary

outcome was the proportion of patients who died before hospital discharge.

Results:The hazard ratio for 90 d mortality was 0.68 (95% Cl 0.48 to 0.98: P'0.04). The crude 90 d mortality was 31.6% in the

intervention group and 40.7% inIhe placebo group. The talcs of ICU-acguired paresis did not differ between groups.

Conclusions:Early administration ola neuromuscular blocking agent in patients with severe ARDS improved 90- d survival and reduced

timeonaventilator.

Title:Ventilation with Lower Tidal Volumes as Compared with Traditional Tidal Volumes for Acute Lung Injury andIhe Acute Respiratory

Distress Syndrome

Purpose: Determine whether ventilation withlower tidal volumes wouldimprove clinical oulcomesrn ARDS patients.

Methods:Patients with All and ARDS were randomized to traditional ventilation treatment (12 mL/kg) or a lower tidal-volume

ventilation strategy (6 mL/kg).The primary outcome was death before patient discharge.

Results:Mortality was lower in patients treated withlower tidal volumes (31.0% vs.39.8%:P-0.007), and the number of days without

ventilation use was greater in this group|P*0.007).

Conclusions:Both all-cause mortality and days with ventilator use were decreased In AR0S patients ventilated with a low lidal volume

strategy.

OSCILLATE

PR0SEVA NEJM 2013:368:2159-68

ACURASYS NEJM 2010:363:1107 16

P1

ARDS Network NEJM 2000:342:1301-08 lJ

+

R36 Respirology Toronto Notes 2023

Trial Name Reference Clinical Trial Details

ASTHMA

Ami Intern Med 2011;154:573- Title: Omaliiumab in Severe Allergic Asthma Inadequately Controlled with Standard Therapy

Purpose: evaluate the safety and efficacy oi omaliiumab in inadequately controlled severe asthma, without additional inhaler therapy.

Methods:850 patients with inadequately controlled asthma despite high - dose ICS plus LABAs were randomized to omaliiumab or

placebo for 48 wk.The primary endpoint wasthe rate of exacerbations over the study period.

Results:The rate of protocol-defined asthma exacerba lions were lower in omaliiumab-treated patients than control patients(0 66 c

vs. 0.88%: P'

0.006). The incidence of adverse events and serious adverse events were similar between groups.

Conclusions: Addition of omaliiumab In patients with uncontrolled severe allergic asthma reduces exacerbations and piovides

additional clinical benefits.

EXTRA

82

PATHWAY NEJM 2017:377:936- 46 Title:Teiepelumab in Adults with UncontrolledAsthma

Purpose: Evaluate the safety and efficacy of Teiepelumab. in patients with uncontrolled asthma despite LABAand medium - high ICS

dose.

Methods: Patients were randomiied to Teiepelumab at three dose levels versus placebo over a 52 wk period. Ihc primary endpoint

was the annualiied rate of asthma exacerbations.

Results:Exacerbation rates in the Teiepelumab groups were lower by 62%. 71% and 66% than in the placebo group (P’

0.001 for all

comparisons).

Conclusions: Among patients treated with lA BA and medium- high doses of ICS.those who received Teiepelumab had lower rales of

clinically significant asthma exacerbations than those who received placebo.

Title:Controlled Trial of 8udesonide-Formoterol as Needed for Mild Asthma

Purpose:Determine the efficacy of budesonide-formoterol versus SABAs in reducing asthma exacerbations.

Methods: Patients with mild asthma were randomiied to albuterol100 pg. budesonrde 200 pg plus albuterol pin, or budesonidc

formotcrol pin. The primary outcome wasthc annualiied rale of asthma exacerbations.

Results:Ihe annualiied exacerbation rate was lower in the combination group than in the albuterol group [0.195 vs.0.400: RR 0.49:

95% Cl 0.33to 0.72:P<0.01).This did not differsignificantly in the budesonide maintenance group (RR 1.12;95% Cl 0.70 to 1.79;

P'0.65).The incidence of adverse events was consistent with previoustrials.

Conclusions: Eor the prevention of asthma exacerbations, budesonide-formoterol pin wassuperior to albuterol pm and did not differ

significantly from budesonidc maintenance.

Title: liotropium in Asthma Poorly Controlled with SlandardCombination Therapy

Purpose:Determine the efficacy and safety of adding tiotropium bromide to a LABA and ICS combination treatment in the context of

asthma.

Methods: 912 adult patientsfrom two randomiied double- blind controlled trials were anatyied in the study. These participants,on

LABA and ICS combination therapy, were randomly assigned to either the liotropium or placebo group. Primary endpoint was FEV1

response and prevention of severe exacerbations.

Results:Ihe use of tiotropium resulted in better primary outcomes compared to placebo group as assessed by adjusted peak FEV1

(difference of 86mL; P'

0.01 in trial1and 154m L; P’

0.001in trial 2) and time to first severe exacerbation (difference of 56 days).

Conclusions: Tiotropium improved lung function and delayed severe exacerbations in patients with uncontrolled asthma when added to

LABA and ICS treatment regimen.

Novel NEJM 2019:380:2020-30

START

PrimoIinA-asthma land

PrimolinA-asthma 2

NEJM 2021:367:1198-1207

SMART Chest 2006:129:15-26 Title:The Salmelerol Multicenter Asthma Research Trial:AComparison of Usual Pharmacotherapy for Asthma or Usual Pharmacotherapy

plus Salmeterol

Purpose:Compare the safety of salmeterol xinafoate or placebo, when added to the usual asthma treatment regimen.

Methods:Subjects with asthma without a history of LABA use were randomiied to salmeterol 42 mg BID, or placebo BID via M0I.

Results: Ihc occurrence of Ihc primary outcome,respiratory related deaths,or life-threatening experiences were not significantly

different between salmeterol and placebo (50 vs. 36; RR 1.40:95% Cl 1.25 to15.34).Subgroup analysessuggest that there is increased

risk in African Americans compared with Caucasian subjects.

Conclusions:Salmeterol added to usual asthma care in creasesthe risk of respiratory-related and asthma -

related deaths, particularly among African American patients reporting no baseline use of ICS.

CHRONIC OBSTRUCTIVE PULMONARY DISEASE

NEJM 2018:378:1671 80 Title:Once- Darly Single-Inhaler Triple versus Dual Therapy in Patients with C0PD

Purpose:Assess the benefits of triple-therapy with ICS, LAMA and LABA. compared with dual therapy in COPD patients.

Methods:10355 patients with COPD were randomiied to llulicasone-umeclidinium-vilanlerol.fluticasone furoate-vilanterol or

umedidinium-vilanterol.Ihc primary outcome was the annual rate ol moderate-severe COPD exacerbations.

Results: Ihe rate of exacerbations was 0.91 per yr In Ihe triple therapy group, compared with 1.07 pet yr with fluticasone furoatevilanterol group and 1.21 per yr in the umedidinium-vilanterol group (rate ratio with triple-therapy 0.75;95% Cl 0.70 to 0.81;P< 0.001).

Ihe annual rate of hospitalizations was 0.18 in the triple-therapy group compared with 0.19 in the umedidinium-vilanterol group (rate

ratio 0.66:95% Cl 0.56 to 0.78: P<0.001|.

Conclusions: Triple therapy with an ICS’LAMAHABA resulted in a lower rate ol moderate or severe COPD exacerbationsthan dual

therapy.

Title:Indacaterol-Glycopyrronium versus Salmeterot-Fluticasone for COPD

Purpose:Elucidate the role of a LAMA - LABA treatment regimen in COPD patients with a high risk of exacerbations.

Methods: Patients with COPD and a history of >1exacerbation in the prior year were randomiied to incadeterol100 pg plus

glycopyrronium 50 pg. orsalmeterol 50 pg plusfluticasone 500 pg. Ihe primary outcome was Ihc annual rate ol all COPD exacerbations.

Results: Ihc rale of exacerbations was11% lower in the indacaterol- glycopyrronium group relative Ihe salmetcrol-lluticasone group

(3.59 vs. 4.03; rate ratio 0.89:95% Cl 0.83 to 0.96: P-0.003).Ihe annual rate of moderate-severe exacerbations was lower in the

indacaterol- glycopyrronium group than in the salmeterol-fluticasone group (0.98vs.1.19;rate ratio 0.83:95% Cl 0.75 to 0.91;P’

0.001).

Conclusions: LABA’

LAMA regimen of indacaterol-glycopyrronium was more effective than a LABA’

ICS regimen of salmeterolfluticasone in pieventing COPD exacerbations.

Title:Short-term vs.Conventional Glucocorticoid Therapy in Acute Exacerbationsof Chronic Obstructive Pulmonary Disease

Purpose:To investigate whether a short-term systemicsteroid treatment is noninferior to conventional treatment.

Methods:314 patients presenting to the ED with acute COPD exacerbationswere randomiied to prednisone 40 mg for either 5 (shortterm) or 14 (conventional) d. The primary endpoint was Ihe time for the next exacerbation in 180 d.

Results: In the intention lo-lrcal analysis, hazard ratios between groups were 0.95 (95% Cl 0.70 to 1.29; P'0.006). In Ihc short-teim

gioup. 35.9% ol patients reached the endpoint while 36.8% patientsin the conventional group reached Ihe endpoint.There was no

difference between groups in lime to death or recovery of lung function.

Conclusions:A 5-d course of glucocorticoids is non-inferior to a14-d course for treatment of acute COPD exacerbations.

IMPACT

FLAME NEJM 2016:374:2222-34

REDUCE JAMA 2013:309:2223 31

r -i

L J

+

R.T7 Rcspirology Toronto Notes 2023

Trial Name Reference Clinical Trial Details

Title:Tiolropium versus Salmelerol lor die Prevention oi Exacerbations of COPD

Purpose:Investigate whether the LAAC tiolropium is superior to the LABA salmelerol inpreventing COPD exacerbations.

Methods:Patients with moderate-severe COPD and a history of exacerbations were randomized to tiolropium18 pg OD or salmelerol SO

pg BIO.The primary outcome was time to the first exacerbation during the study period.

Results: tiolropium. as compaicd with salmelerol.increased Ihe lime lo first exacerbation,with a 17% risk reduction (hazard ratio

0.83;95% Cl0.77 to 0.90:P

‘

0.001).Tiolropium also reduced thenumber of moderate and severe exacerbations (0.64 vs.0.72;rate

ratio 0.89:95%Cl 0.83 to 0.96;P-0.002).

Conclusions: tiotropium decreasesIhe number of moderate-to-severe COPO exacerbations incomparison lo salmelerol.

Title:Roflumilasl inModerate- to-severe Chronic Obstructive Pulmonary Disease Irealed with long Acting Bronchodilators

Purpose:Investigate the effect of phosphodiesterase-4 (PDE4) inhibitor roflumilasl on lung function in COPD pabents treated with

salmelerol or tiotropium.

Methods:Patients '

40 yr with moderate severe COPO were randomized lo oralroflumilasl 500 pg or placebo 00 for 24 wk.inaddition

to salmelerol or tiotropium.Ihe primary endpoint was a change In prebroncliodilator FEV1.

Results:Compared with placebo,treatment with roflumilasl improved mean FEVt by 49 mL (p- 0.0001) in patients treated with

salmelerol.and 80 mL (0.0001)in patients treated with tiotropium.Roflumilasl had benefits on other measures of lung function in both

groups.

Conclusions:P0E4 inhibitor roflumilaslimprovesFEVI when used as add-on therapy inCOPD patients on

tiotropium or salmelerol.

Title:A 4-Tear Trial of Tiotropium in Chronic Obstructive Pulmonary Disease

Purpose:Examine Ihe long-term eflects ol tiotropium therapy in patients with COPD.

Methods:Patients with COPD. permitted lo use all drugs except LAACs. were randomized to 4 yr of tiotropium or placebo.Ihe primary

endpoints were the rate oldecline in FEV1before and alter bronchodilation.

Results:Mean differences in FEV1were maintained throughout the trialbetween the tiotropium and placeho groups (87-103mlbefore

bronchodilation:47-65 mlalter bronchodilation). The 30 d differences between groups were notsignilicanl.

Conclusions:liotropium improves symptoms ol COPO with lower exacerbations,but does not ailed FEV1

decline.

Title:Salmelerol andFluticasone Propionate and Survival in Chronic Obstructive Pulmonary Disease

Purpose:Analyze the survival benefits olIABA and ICS in COPD palienls.

Methods: Patients with COPD were randomized to salmelerol 50 pg plus fluticasone propionate 500 pg BID. administered with a

single placebo inhaler,salmelerol alone or fluticasone alone.The primary outcomes were all-cause mortality and the Ireguency of

exacerbations.

Results: All cause mortality rales were12.6% inIhe combination group.15.2% in Ihe placebo group.13.5% in the salmeterol group and

16.0% In Ihe fluticasone group (hazard rabo combination vs. placebo 0.825; 95% Cl 0.681lo 1.002:P-0.052). Mortality in Ihe salmelerol

or fluticasone monotherapy group did not differ Irom placebo.

Conclusions:Combination of ICS and LABAs improves COPD symptoms,reduces exacerbations,andshows a trend to lower mortality.

POEICOPD NEJM 2011:364:1093 103

ROFIUMIIASI lancet 2009:374:695-703

UPLIFT NEJM 2008:359:1543-54

TORCH NEJM 2007;356:775-89

INTERSTITIAL LUNG DISEASE

NEJM 2019;381:1718 1727 Title:Nintedamb in Progressive FibrosingInterstitial lung Diseases

Purpose:Evaluate the efficacy of Nintedanib across a broad range of progressive fibrosing lung diseases.

Methods:Patients with significant,progressive fibrosing lung disease of any cause were randomized to Nintedanib150 mg twice daily

or placebo. The primary endpoint was the annualrate oldecline in FTC.

Results: 663 patients treated.Ihe average annual rate ol changein FTC was -80.8 mlin the Nintedanib group and -187.8 mlin the

placebo group.Patients with UIP type pattern on imaging had a difference of - 82.9 mL versus -211.1mlfavouring Nintedanib.

Conclusions:In patients with progressive fibrosinginterstitial lung diseases. Nintedanib reduced the annualrale oldecline in FVC.

Title:Prednisone.Azathioprinc. and N Acetylcysteine for Pulmonary Fibrosis

Purpose: To evaluate the safety and efficacy ol a three drug regimen (prednisone,azalhioprine and N acetylcysteine(NAC)) lor IPF.

Methods:Pabents with mild to moderate IPF were randomized to the active drug combination.NAC alone or placebo.The primary

endpoint was change in FVC.

Results: The trial was terminated early when an interim analysis demonstrated that patients in the active drug combination arm had an

increased rale of death (8 vs.1) and hospitalization (23 vs. 7) when compared to placebo. No evidence olbenefit was identified in any

physiological measurements such as FVC.

Conclusions:Patients with IPF treated with prednisone,azalhioprine and NAC had increased risk of death and hospitalization when

compared lo no trealment.

Title:Efficacy and Safety of Nintedanib inIdiopathic Pulmonary Fibrosis

Purpose:Evaluate the safety and efficacy of Nintedanib in patients with IPF.

Methods:Patients with IPF were randomized to Nintedanib 150 mg twice daily ov placebo. The primary endpoint was the annualrate of

decline in FVC.

Results: Ihe annual rale ol change in FVC was -114.7 mlwith Nintedanib versus -239.9 ml with placebo (dilferencc 125.3 ml:95%Cl

77.7 to 172.8:P‘

0.001) in INPULSIS-1.In INPULSIS-2,the same metric was -113.6 mL with Nintedanib versus -207.3 mL with placebo

(difference 93.7ml;95% Cl 44.8 to142.7:P‘

0.001).There was a reduction in acute exacerbations of IPF in the treatment arms but no

mortality difference.

Conclusions:Nintedanib reduces the decline in FVC in patients withIPF.

Title:A Phase 3 Trial ofPirfenidone in Patients with IdiopathicPulmonary Fibrosis

Purpose:Confirm the beneficial effects of pirfenidone on disease progression inpatients with IPF.

Methods: 555 patients with IPF were randomized lo oral pirfenidone(2403 mg daily) or placebo foi 52 wk.Ihe primary endpoint was

change in FVC or death at the study period.

Results: There was a relative reduebon ol47.9% in the proportion olpatients with 10% decline in FVC,in the pirfenidone group

compared to placebo (P‘

0.001).Pirfenidone improved progression-free survival (P‘

0.001).There was no significant differencein

dyspnea scores|P~0.16).all- cause mortality (0.10) or IPF mortality|P~0.23) between groups.In a pooled analysis with prior trials,

theie was a reduction in mortality.

Conclusions:Pirfenidone reduces disease progression in patients with IPF.

INBUILD

PANTHER NEJM 2012;366:1968 1977

IHPUISIS NEJM 2014:370:2071 82

ASCEND NEJM 2014;370:2083-92

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R38Respirology Toronto Notes 2023

Trial Name Reference Clinical Trial Details

PULMONARYEMBOLISM

EINSTEIN PE NEJM 2012:366:1287 97 Title:Oral Rivaroxaban for the Treatment of Symptomatic Pulmonary Embolism

Purpose:Assess the effectiveness of fixed- dose rivaroxaban for the treatment of deep vein thrombosis (DVT).

Methods:4832 patients with acute symptomatic PE wilh-Dr-without DVT were randomized to rivaroxaban 15 mg BID or to standard

therapy with enoxaparin followed by a vitamin-K antagonist.The primary outcome was symptomatic recurrent VIE.

Results: Rivaroxaban was noninlerior to standard therapy (P~0.003) for the primary outcome,with 2.1% and1.8% event rates in the

rivaroxaban and standard- therapy groups,respectively (hazard ratio1.12;95% Cl 0.75 to 1.68). Major or non-major clinically relevant

bleeding occurred in10.3% of rivaroxaban-treated patients and11.4% of patients receiving standard therapy [hazard ratio 0.90;95% Cl

0.76 to 1.07:P-0.23).

Conclusions:Fixed dose ol rivaroxaban vras non- inferior to standard therapy (Vitamin K antagonist) lor the initial and long-term

treatment olPE.

Title:Rivaroxaban or Aspirin lor Extended Treatment of Venous Thromboembolism (EPSTEIN CHOICE)

Purpose:To assess the efficacy ollull- or lower-intensity anticoagulation therapy in the extended treatmentol VIE.

Methods:3396 patients with VIE were randomized to receive either rivaroxaban 10 or 20 mg once daily,or 100 mg olASA.All study

patients had completed 6 to 12 mo olanticoagulalion therapy and were in eguipoise regarding the need for continued anticoagulation.

The primary eflicacy outcome was symptomatic recurrent fatal or nonfatnl VIE. and the principal safety outcome was major bleeding.

Results:The primary efficacy outcome occurred in17 ol1107 patients|1.2%)receiving rivaroxaban.compared to 50 ol 1131patients

|4.4%) receiving ASA (hazard ratio for 20 mg rivaioxaban vs. ASA 0.34;95% Cl 0.20 to 0.59;hazard ratio lor 10 mg rivaroxaban vs.

ASA 0.26;95% Cl 0.14 to 0.47;P- 0 001 for all comparisons). The incidence ol adverse events,including major and nonmajor clinically

relevant bleeding,were similai among all groups.

Conclusions:Among patients with VIE in equipoise lor continued anticoagulalion,the risk of a recurrent event was lower with

rivaroxaban (10 or 20 mg) than with ASA. without a significant increasedrisk ol adverse events.

EPSTEIN CHOICE NEJM 2017;376:1211-22

OBSTRUCTIVE SLEEP APNEA

CPAP and CentralSleep NEJM 2005:353:2025 33

Apnea

Title:Continuous Positive Airway Pressure lor Central Sleep Apnea and Heart Failure

Purpose:Test the ellediveness of CPAP on survival outcomes without heart transplantation,in patients with CHE and CSA.

Methods:258 patients with HE and CSA were randomized to CPAP or no CPAP.Sleep studies were conducted,and the primary outcomes

were ejection fraction (EE), exercise capacity and quality of life.

Results: The CPAP group had greater reductions in the Ireguency ol apnelc episodes,greater increases in mean nocturnalOl sal (1.6%

vs. 0.4%;P'

0.001) and EE (2.2% vs. 0.4; P‘

0.02). There were no differences in the number olhospitalizations or quality ol life.

Conclusions:CPAP arncliorales symptoms ol sleep apnea but docs not ailed mortality in CHE.

Title:CPAP lor Prevention ol Cardiovascular Events In Obstructive Sleep Apnea

Purpose: To determine whether CPAP reduces cardiovascular events in patients with sleep apnea.

Methods: 2687 participants recruited liom 7 dilietent countries were randomly assigned to receive cither standard cate or CPAP

with standard care.Primary endpoints measured were death Irom cardiovascular cause.Ml.stroke,or hospitalizations for CHE.acute

coronary syndrome,or TIA.

Results: There was no significant difference between the CPAP standard care group and the standard care group in terms ol cardiac

events (HU1.10, P-0.34).

Conclusions: CPAP docs nol reduce the lisk ol cardiovascular events in patients with 0SA

SAVE NEJM 2016:375:919 31

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R39 Rcspirology Toronto Notes 2023

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