Introduction to Clinical Trials

Introduction to Clinical Trials

Issues in Analysis of Randomized Clinical Trials
Sources of Bias
1. Patient selection
2. Treatment assignment
3. Patient Evaluation
4. Data Analysis

Minimize Bias
1. Randomized Controls
2. Double blind (masked)
3. Analyze what is randomized

What Data Should Be Analyzed?
* Basic Intention-to-Treat (ITT) Procedure
o Analyze what is randomized!
* Randomized control trial “gold” standard
o Beware of lookalikes
* Definitions
Exclusions
o Screened but not randomized
o Affects generalizability
o Validity OK
Withdrawals from Analysis
o Randomized, but not included in data analysis
o Possible to introduce bias!

Patient Closeout
* ICH E9 Glossary
o “Intention-to-treat principle - …It has the consequence that subjects allocated to a treatment group should be followed up, assessed, and analyzed as members of that group irrespective of their compliance with the planned course of treatment.”

Patient Withdrawn in Analysis
* Common Practice - 1980s
o Over 3 years, 37/109 trials in New England Journal of Medicine

* Typical Reasons Given
a. Patient ineligible (in retrospect)
b. Noncompliance
c. Competing events
d. Missing data

I. Patient Withdrawn in Analysis
A. Patient INELIGIBLE
o After randomization, discover some patients did not in fact meet entry criteria
o Concern ineligible patients may dilute treatment effect
o Temptation to withdraw ineligibles
o Withdrawl of ineligible patients, post hoc, may introduce bias

Betablocker Heart Attack Trial
* 3837 post MI patients randomized
* 341 patients found by Central Review to be ineligible
* Results

Anturane Reinfarction Trial (1980) NEJM
* Randomized, double blind, placebo controlled
Anturane Reinfarction Trial (1980)
* 1629 patients randomized
o 1631 entered, but two patients randomized twice
o Need to delete 03013, 17008
o Use first randomization!

* Declared post hoc 71 “ineligible” patients

Analyzable Deaths - Within 7 days of being off drug

1980 Anturane Mortality Results
Total Mortality
Anturane Reinfarction Trial (1980)
Total Mortality
Anturane Sudden Death (SD)
for Total Follow-up
Anturane Analysis
Acceptable Policies For Ineligible Subjects

1. Delay randomization, confirm eligibility and allow no withdrawals (e.g. AMIS) (Chronic Studies)
2. Accept ineligibles, allow no withdrawals
(e.g. BHAT, MILIS) (Acute Studies)
3. Allow withdrawals if:
a. Procedures defined in advance
b. Decision made early (before event)
c. Decision independent and blinded
d. Use baseline covariates only (two subgroups)
e. Analysis done with and without

B. WITHDRAWL FOR NON-COMPLIANCE
References: Sackett & Gent (1979) NEJM, p. 1410

Coronary Drug Project (1980) NEJM, p. 1038
* Two Types of Trials
1. Management
- "Intent to Treat" Principle
- Compare all subjects, regardless of compliance

2. Explanatory
- Estimate optimum effect, understand mechanism
- Analyze subjects who fully comply
WITHDRAWALS FOR NON-COMPLIANCE MAY LEAD TO BIAS!

Breast Cancer Adjuvant Therapy Probability of Disease Free Survival for Years Post Mastectomy (Method I)
Breast Cancer Adjuvant Therapy
Probability of Disease Free Survival for
Years Post Mastectomy (Method II)
Redmond et al (1983) Cancer Treatment Report
Example: Coronary Drug Project 5-Year Mortality
Comments

* Higher % of estrogens patients did not comply
* Beneficial to be randomized to estrogen & not take it
* (6.1% vs. 9.9%)
* Best to be randomized to placebo & comply (4.8%)
Aspirin Myocardial Infarction Study (AMIS)
Summary of Compliance
* No consistent pattern
Example Non-compliance Did Worse
CDP Clofibrate, AMIS Both Treatment & Control
CDP Estrogen Control Only
Beta-blocker, Wilcox Two Treatments, Not Control
* Compliance an outcome, not always independent of treatment
* Withdrawal of non-compliers can lead to bias
* Non-compliers dilute treatment
* Try hard not to randomize non-compliers

II. Competing Events
* Subject may be censored from primary event by some other event (e.g. cancer vs. heart disease)
* Must assume independence
* If cause specific mortality used, should also look at total death
* If non-fatal event is primary, should also look at total death and non-fatal event
* Problem for some response measures

Problem of Definitions
Classification Anturane Placebo P-value
Anturane Reinfarction Trial Sudden Death
Category Source Placebo Anturane P-value

III. "Wrong", Inconsistent, Outlying Data
* "Wrong" or "outlying" data may in fact be real
* Decisions must be made blind of group assignment
* All modifications or withdrawals must be documented
IV. Missing Outcome Data
* Design with zero
o missingness may be associated with treatment
+ for analysis, data are not missing at random
+ even if same number missing, missing may be for different reason in each treatment group
* Implement with minimum possible
* Analyze exploring different approaches
o if all, or most, agree, then more persuasive

“Best” and “Worst” Case Analyses
VI. Poor Clinic Performance in a Multicenter Study

* If randomization was stratified by clinic, then withdrawal of a clinic is theoretically valid
* Withdrawal must be done independent of the outcome at that clinic
VIII. Fishing or Dichotomizing Outcomes
* Common practice to define a response (S,F) from a non-dichotomous variable
* By changing our definition, we can alter results
* Thus, definitions stated in advance
* Definitions should be based on external data

Dichotomizing Outcomes
Example
IX. Time Dependent Covariate Adjustment
* Classic covariate adjustment uses baseline prognostic factors only
o Adjust for Imbalance
o Gain Efficiency

* Adjustment by time dependent variates not recommended in clinical trials (despite Cox time dependent regression model)

* Habit from epidemiology studies
Intent To Treat (ITT) Principle

* Analyze all patients randomized, regardless of compliance to assigned intervention
* Analyze all events in the follow-up, regardless of compliance


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Blood

BLOOD

CIRCULATORY SYSTEM
* BLOOD
* HEART
* BLOOD VESSELS

FUNCTIONS OF BLOOD
* TRANSPORT
* PROTECTION
* REGULATION

TRANSPORT
* OXYGEN (O2)
* CARBON DIOXIDE (CO2)
* NUTRIENTS
* WASTES
* HORMONES
PROTECTION
* IMMUNE SYSTEM
o WHITE BLOOD CELLS
o ANTIBODIES
* CLOTTING SYSTEM
o PLATELETS
o FIBRINOGEN / FIBRIN

REGULATION
* BODY TEMPERATURE
* pH
* WATER BALANCE
* ELECTROLYTE BALANCE

BLOOD COMPOSITION
BLOOD IS COMPRISED OF TWO MAIN COMPONENTS:
* PLASMA
* FORMED ELEMENTS
THESE COMPONENTS CAN BE SEPARATED BY CENTRIFUGATION
THE FRACTION OF THE BLOOD VOLUME COMPRISED OF RED BLOOD CELLS IS TERMED THE HEMATOCRIT

PLASMA COMPOSITION
* WATER (~90%)
* SOLUTES (~10%)
o PROTEINS (~8%)
o OTHER COMPOUNDS (~2%)
+ NUTRIENTS
+ GASES
+ WASTES
+ HORMONES
+ ELECTROLYTES

PLASMA PROTEINS
* MOST ABUNDANT PLASMA SOLUTE
* LIVER CAN PRODUCE 4 GRAMS OF PLASMA PROTEINS PER HOUR
* THREE MAJOR CATEGORIES
o ALBUMINS
o GLOBULINS
o FIBRINOGEN
ALBUMINS
* ~60% OF PLASMA PROTEINS
* SMALL
* TRANSPORT LIPIDS, HORMONES, CALCIUM, ETC.
* BUFFER BLOOD pH
* CONTRIBUTE TO VISCOSITY & OSMOLARITY
* INFLUENCE BLOOD PRESSURE, BLOOD FLOW, AND FLUID BALANCE

GLOBULINS
* ~36% OF PLASMA PROTEINS
* THREE SUBCLASSES
o ALPHA (a)
o BETA (b)
o GAMMA (g)
* ALPHA (a)
o VARIOUS FUNCTIONS, ESPECIALLY TRANSPORT
* BETA (b)
o VARIOUS FUNCTIONS, ESPECIALLY TRANSPORT
* GAMMA (g)
o COMPONENTS OF IMMUNE SYSTEM
o PRODUCED BY PLASMA CELLS, WHICH ARE DESCENDED FROM WHITE BLOOD CELLS

FIBRINOGEN
* ~4% OF PLASMA PROTEINS
* PRECURSOR OF FIBRIN
* INVOLVED IN BLOOD CLOTTING

PLASMA: NUTRIENTS
* SUGARS
* AMINO ACIDS
* FATS
* CHOLESTEROL
* PHOSPHOLIPIDS
* VITAMINS
* MINERALS

PLASMA: GASES
* OXYGEN (O2)
o REQUIRED FOR CELLULAR RESPIRATION
* CARBON DIOXIDE (CO2)
o PRODUCT OF CELLULAR RESPIRATION
* NITROGEN (N2)
o USUALLY PHYSIOLOGICALLY UNIMPORTANT
o WHY DO YOU THINK IT IS THERE?

PLASMA: WASTES
NITROGENOUS WASTES
* PRODUCTS OF CATABOLISM
o (ESP: AMINO ACID CATABOLISM)
* MOST ABUNDANT IS UREA
* REMOVED FROM BLOOD BY KIDNEYS
* EXCRETED THROUGH URINE
* RATE OF REMOVAL BALANCES RATE OF PRODUCTION

PLASMA: ELECTROLYTES
* SODIUM (Na+)
* CALCIUM (Ca2+)
* POTASSIUM (K+)
* MAGNESIUM (Mg2+)
* CHLORIDE (Cl-)
* BICARBONATE (HCO3-)
* PHOSPHATE (HPO42-)
* SULFATE (SO42-)
* VARIOUS IONS
* SODIUM IS THE MOST PREVALENT
* INCREASE BLOOD OSMOLARITY
o AFFECT BLOOD VOLUME
o AFFECT BLOOD PRESSURE

FORMED ELEMENTS
* ERYTHROCYTES (RED BLOOD CELLS)
* LEUKOCYTES (WHITE BLOOD CELLS)
* PLATELETS (CELL FRAGMENTS)

ERYTHROCYTE FUNCTIONS
* CARRY O2 FROM LUNGS TO CELLS
* CARRY CO2 FROM CELLS TO LUNGS
* HOW DO O2 AND CO2 RELATE TO THE FUNCTIONS OF A CELL?

ERYTHROCYTE QUANTITIES
* MEN: 4.6 – 6.2 MILLION/mL IN
o HEMATOCRIT 42 – 52 (% RBCs)
* WOMEN: 4.2 – 5.4 MILLION/mL
o HEMATOCRIT 37 – 48 (% RBCs)
* GENDER DIFFERENCES BASED ON:
o ANDROGENS INCREASE NUMBER
o MENSTRUAL LOSS DECREASES NUMBER
o BODY FAT (INVERSE RELATIONSHIP)
o FASTER CLOTTING IN MEN

ERYTHROCYTE STRUCTURE
* DISC SHAPED
* BICONCAVE
* 7.5 MICROMETER (mm) DIAMETER
* 2 MICROMETERS (mm) THICK

ERYTHROCYTE STRUCTURE
PLASMA MEMBRANE
* PHOSPHOLIPID BILAYER
* GLYCOPROTEINS, GLYCOLIPIDS
o DETERMINE BLOOD TYPE
* ACTIN AND SPECTRIN ON INNER SURFACE
o RESILIENCE / DURABILITY / PLIABILITY
* HIGH SURFACE AREA:VOLUME RATIO
o RESULT OF BICONCAVE SHAPE
o INCREASES RATE OF GAS DIFFUSION INTO AND OUT OF CELLS

ERYTHROCYTE STRUCTURE
CYTOPLASM
* LACKS ORGANELLES
o ESP: LACKS MITOCHONDRIA, NUCLEUS
o WHY IS THIS IMPORTANT?
o CANNOT REPAIR
o LIMITED LIFESPAN (~120 DAYS)
o CANNOT DIVIDE
o NEW CELLS FORMED IN BONE MARROW
* HEMOGLOBIN
o RED PIGMENT
o HIGH CONCENTRATION (33%)
o 280 MILLION MOLECULES PER CELL
o CARRIES MOST OF THE O2
o CARRIES SOME OF THE CO2
o PROTEIN & NON-PROTEIN COMPONENTS

HEMOGLOBIN
PROTEIN COMPONENT
* 4 POLYPEPTIDES (HETEROTETRAMER)
o 2 a-GLOBIN PROTEINS
o 2 b-GLOBIN PROTEINS
NON-PROTEIN COMPONENT
* 4 HEME GROUPS
o PORPHYRIN RING AND IRON ION
o IRON ION WITHIN HEME BINDS TO O2

ABO BLOOD TYPES
* DETERMINED BY SURFACE ANTIGENS
o GLYCOLIPIDS AND GLCOPROTEINS
+ (SUGARS ON CELL SURFACE)
o GENETICALLY DETERMINED
o RECOGNIZED BY ANTIBODIES
o INDIVIDUALS POSSESS ANTIBODIES TO ANTIGENS THEY THEMSELVES DO NOT POSSESS
o RECOGNITION OF THESE ANTIGENS BY ANTIBODIES CAUSES CELL CLUMPING
* DETERMINED BY GENE “I”
* THREE ALLELES
o IA
o IB
o i
* IA AND IB ARE CODOMINANT
* i IS RECESSIVE TO IA AND IB
* THREE ALLELES OF “I” GENE
* INDIVIDUALS POSSESS TWO COPIES
* FOUR BLOOD TYPES
o A GENOTYPE IAIA OR IAi
o B GENOTYPE IBIB OR IBi
o AB GENOTYPE IAIB
o O GENOTYPE ii

ANTIBODIES TO A AND B ANTIGENS
* APPEAR SHORTLY AFTER BIRTH
* PRESENT FOR ENTIRE LIFE
* PRODUCED IN RESPONSE TO SIMILAR ANTIGENS ON INTESTINAL BACTERIA
* CROSS-REACT WITH A AND B ANTIGENS
* TERMED “ANTI-A” AND “ANTI-B”
* CAUSE OF TRANSFUSION REACTIONS

Rh BLOOD TYPES
* DETERMINED BY SURFACE ANTIGENS
* UNRELATED TO ABO BLOOD TYPE
* GENETICALLY DETERMINED
* ALLELES OF THREE GENES
o C, c, D, d, E, e
o DD, Dd ARE Rh+
o dd MAY BE Rh-, DEPENDING ON ALLELES OF OTHER GENES
* ANTI-D ANTIBODIES NOT NORMALLY PRESENT
o PRESENT ONLY IN Rh- EXPOSED TO Rh+
o FIRST EXPOSURE NOT PROBLEMATIC
o SECOND EXPOSURE PROBLEMATIC
o TRANSFUSION / PREGNANCY
* IMMUNE RESPONSE PREVENTABLE
o RhoGAM (Rh IMMUNE GLOBULIN)

OTHER BLOOD GROUPS
* > 100 OTHER BLOOD GROUPS
* USEFUL IN GENETIC / BIOCHEMICAL TESTING
* RARELY CAUSE TRANSFUSION REACTIONS

ERYTHROCYTE DISORDERS
ANEMIA
* ERYTHROCYTE DEFICIENCY, OR
* HEMOGLOBIN DEFICIENCY
* THREE CLASSES
o INADEQUATE SYNTHESIS
o BLEEDING
o RBC DESTRUCTION
* CONSEQUENCES
o OXYGEN DEPRIVATION (HYPOXIA)
+ SHORTNESS OF BREATH
o REDUCED BLOOD OSMOLARITY
+ WATER RETENTION IN TISSUES (EDEMA)
o REDUCED BLOOD VISCOSITY
+ HEART BEATS FASTER
+ CARDIAC FAILURE
SICKLE-CELL ANEMIA
* ~0.25% OF AFRICAN AMERICANS
* GENETICALLY DETERMINED
* ABERRANT b-GLOBIN ALLELE (HbS)
o SINGLE AMINO ACID SUBSTITUTION
o GLUTAMIC ACID (HbA)  VALINE (HbS)
* CELLS SICKLE UNDER LOW OXYGEN
* MULTIPLE DELETERIOUS EFFECTS

* WHY IS THE FREQUENCY SO HIGH?
o MALARIA PREVALENT IN AFRICA
o Plasmodium PARASITE LIVES IN RBCs
o SURVIVES POORLY IN CELLS WITH HbS
o INDIVIDUALS WITH HbS LESS LIKELY TO DIE (HETEROZYGOTES MOST FIT)
o THUS, HbS PROVIDES PROTECTION

LEUKOCYTES
* 5,000 – 10,000 CELLS/mL
* FIVE TYPES:
o NEUTROPHILS 60 – 70 % 9 – 12 mM
o LYMPHOCYTES 25 – 33% 5 – 8 mM (most)
o MONOCYTES 3 – 8 % 12 – 15 mM
o EOSINOPHILS 2 – 4% 10 – 14 mM
o BASOPHILS <0.5 – 1% 8 – 10 mM
* GRANULOCYTES
o NEUTROPHILS
o EOSINOPHILS
o BASOPHILS
* AGRANULOCYTES
o LYMPHOCYTES
o MONOCYTES
LEUKOCYTES
NEUTROPHILS
* HIGHLY MOBILE
* INCREASE IN RESPONSE TO BACTERIAL INFECTIONS
* KILLS BACTERIA
o PHAGOCYTOSIS
o CHEMICALLY (BURST LYSOSOMES)

EOSINOPHILS
* INCREASE WITH ALLERGIES
* INCREASE WITH PARASITIC INFECTIONS
* PHAGOCYTOSIS
o ANTIGEN / ANTIBODY COMPLEXES
o ALLERGENS
* HYDROLYTIC ENZYME RELEASE
o RESPONSE TO HOOKWORM, TAPEWORM, ETC.
o TOO LARGE TO PHAGOCYTIZE
BASOPHILS
* GENERALLY NOT PHAGOCYTIC
* AID OTHER LEUKOCYTES
o RELEASE HISTAMINE
+ INCREASE BLOOD FLOW TO AREA
o RELEASE HEPARIN
+ INHIBIT CLOTTING
LYMPHOCYTES
* INCREASE IN IMMUNE RESPONSE
* SEVERAL SUBCLASSES
* VARIOUS IMMUNE FUNCTIONS
o ESP: SECRETE ANTIBODIES

MONOCYTES
* DIFFERENTIATE INTO MACROPHAGES
* PHAGOCYTOSIS OF PATHOGENS
* PHAGOCYTOSIS OF DEBRIS
* PRESENT ANTIGENS TO OTHER CELLS OF IMMUNE SYSTEM
PLATELETS
* 130,000 – 400,000 / mL
* NOT CELLS
o FRAGMENTS OF MEGAKARYOCYTES
o SMALL (2 – 4 mM DIAMETER)
* POSSESS VARIOUS ORGANELLES
* PSEUDOPODS
o AMOEBOID MOVEMENT
o PHAGOCYTOSIS
PLATELET FUNCTIONS
* SECRETE CLOTTING FACTORS
* SECRETE VASOCONSTRICTORS
* FORM TEMPORARY PLATELET PLUGS
* DISSOLVE OLD BLOOD CLOTS
* PHAGOCYTOSIS OF BACTERIA
* SECRETE CHEMICALS TO ATTRACT LEUKOCYTES TO SITES OF INFLAMMATION
* SECRETE GROWTH FACTORS

CONTROL OF BLEEDING
HEMOSTASIS
* VASCULAR SPASM
* PLATELET PLUG FORMATION
* COAGULATION
VASCULAR SPASM
* CONSTRICTION OF BROKEN VESSEL
* IMMEDIATE PROTECTION AGAINST BLEEDING
* MULTIPLE TRIGGERS
TRIGGERS OF VASCULAR SPASM
* PAIN RECEPTORS  NERVES  BLOOD VESSELS CONSTRICT
* SMOOTH MUSCLE OF BLOOD VESSELS CONSTRICT
* PLATELETS RELEASE SEROTONIN (CHEMICAL VASOCONSTRICTOR)
PLATELET PLUG FORMATION
* BLOOD VESSEL BROKEN
* COLLAGEN FIBERS EXPOSED
* PLATELETS BIND TO COLLAGE FIBERS
o FORM PSEUDOPODS
o ATTACH TO VESSEL AND OTHER PLATELETS
o CONTRACT AND PULL WALLS TOGETHER
o DEGRANULATION
PLATELET PLUG FORMATION
* DEGRANULATION
o RELEASE OF COMPOUNDS TO
+ VASOCONSTRICT
+ ATTRACT PLATELETS
+ STIMULATE DEGRANULATION
+ PROMOTE AGGREGATION
o POSITIVE FEEDBACK
CONTROL OF BLEEDING
* COAGULATION (CLOTTING)
* MOST EFFECTIVE DEFENSE
* FIBRINOGEN  FIBRIN  POLYMER
* TWO REACTION PATHWAYS
o EXTRINSIC MECHANISM
+ CLOTTING FACTORS FROM DAMAGED BLOOD VESSEL
o INTRINSIC MECHANISM
+ CLOTTING FACTORS FROM BLOOD
CLOTTING FACTORS
* PROCOAGULANTS
* PROTEINS PRODUCED IN LIVER
* INACTIVE  ACTIVE
o EACH ACTIVATES THE NEXT
o REACTION CASCADE
o AMPLIFICATION AT EACH STEP
o POSITIVE FEEDBACK INVOLVED
* CLOT RETRACTION
o CLOT FORMED
o PLATELETS ADHERE TO FIBRIN
o PLATELETS CONTRACT
o PULLS EDGES OF BROKEN VESSEL TOGETHER
* PLATELETS SECRETE PDGF
o PLATELET-DERIVED GROWTH FACTOR
o STIMULATES MITOSIS
* FIBROBLASTS INVADE AND PRODUCE CONNECTIVE TISSUE

CLOT DISSOLUTION
* FIBRINOLYSIS
* MULTIPLE STEPS
* POSITIVE FEEDBACK
* SIMILAR, IN REVERSE
PREVENTION OF COAGULATION
* PLATELET REPULSION
* DILUTION AND BLOOD MOVEMENT
* ANTICOAGULANTS
o ANTITHROMBIN (LIVER)
o HEPARIN (BASOPHILS)

COAGULATION DISORDERS
HEMOPHILIA

* DEFICIENCY IN A CLOTTING FACTOR
* CASCADE DISRUPTED
* CLOTTING DEFICIENCY
COAGULATION DISORDERS
HEMOPHILIA A
COAGULATION DISORDERS
HEMOPHILIA B
BLOOD CELL PRODUCTION
STEM CELLS
* PLURIPOTENT CELLS
o UNDIFFERENTIATED CELLS
o ABLE TO DIVIDE AND DIFFERENTIATE INTO MULTIPLE TYPES OF CELLS
o NOT ALL ARE “TOTIPOTENT”
o (NOT FULLY DIFFERENTIATED)
o E.G., HEMOCYTOBLASTS (BLOOD)
o E.G., EMBRYONIC STEM CELLS
* YOLK SAC
o EARLIEST HEMOPOIETIC TISSUE
o PRODUCES STEM CELLS
o COLONIZE OTHER ORGANS
+ BONE, LIVER, SPLEEN, THYMUS, ETC
o LIVER STOPS HEMOPOIESIS AT BIRTH
o SPLEEN STOPS ERYTHROPOIESIS SHORTLY AFTER BIRTH
* MYELOID HEMOPOIESIS
o OCCURS IN BONE MARROW
o FORMS ALL SEVEN FORMED ELEMENTS
* LYMPHOID HEMOPOIESIS
o OCCURS IN SEVERAL ORGANS
+ THYMUS, TONSILS, LYMPH NODES, SPLEEN, INTESTINES, ETC.
o PRODUCES LYMPHOCYTES
HEMOCYTOBLASTS
* STEM CELLS
* PLURIPOTENT
* DIFFERENTIATE INTO ALL FORMED ELEMENTS
o ERYTHROPOIESIS
o LEUKOPOIESIS
o THROMBOPOIESIS

ERYTHROCYTE PRODUCTION
ERYTHROPOIESIS
ERYTHROCYTE PRODUCTION
ERYTHROPOIESIS
ERYTHROCYTE HOMEOSTASIS
IRON METABOLISM
ERYTHROCYTE DEATH
HEMOLYSIS
* IRON
* PORPHYRIN RING
LEUKOCYTE PRODUCTION
LEUKOPOIESIS
PLATELET PRODUCTION
THROMBOPOIESIS
PLATELET PRODUCTION

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Venous Thromboembolic Disease

VENOUS THROMBOEMBOLIC DISEASE
by:R. Duncan Hite, MD
Section on Pulmonary and Critical Care Medicine

Venous Thromboembolic Disease

* Venous thrombosis - ~ 5 million pts yearly
+ Most caused by inadequate prophylaxis in hospitalized pts
* 10 % suffer pulmonary embolism ~ 500,000
* ~ 1% of all hospitalized pts have PE
* Contributes to 6 % of all hospital deaths
* ~ 125,000 deaths annually from PE
+ 3rd most common cardiovascular cause of death (MI, CVA)
+ Most deaths occur early – PREVENTION IS KEY!!
* Diagnosis of PE made in < 30% when contributes to death; < 10% if incidental

Case studies
Venous Thromboembolic Disease
Epidemiology

* 85 - 90% of PE pts have DVT risk factors
* 90-95% of PEs arise from lower ext. DVT
* Defined DVT Risk Factors: (Virchow’s Triad)
o Venous stasis - CHF, Immobility, Age > 70, Travel, Obesity, Recent surgery (4 weeks) or hospitalization (6 mos)
o Venous Injury - Prior DVT/PE, LE Trauma/Surgery
# LE trauma or surgery - Very high (50+%)
# Major surgery - (5 - 8%)
o Hypercoaguability - Cancer, Pregnancy, Nephrotic Syndrome, Hyperhomocysteinemia, Factor V Leyden mutation, Deficiency of Protein C/S or ATIII, Anti Phospholipid Ab, HITTS, Smoking

Pulmonary Hypertension Hemodynamic Effects
Deep Venous Thrombosis
Diagnosis
* Venography - remains the “gold standard”
+ Pitfalls: Difficult to perform, expensive, contrast load, DVT
* Compression Ultrasound (Sonography, Duplex and Color Doppler)
+ Criteria: echogenicity, noncompressibility, distension, free floating thrombus, absence of Doppler waveform, Abnormal color image
+ Accuracy:
# Symptomatic Patients: Sensitivity = 90-100%, Specificity = 95-100%
# High Risk Asymptomatic: Sensitivity = 50-80%, Specificity = 95-100%
* Impedance Plethysmography
* Radionuclide Venography (Indium-111)
* MRI - increasing popularity and utilization, includes deep pelvic veins

Deep Venous Thrombosis Prevention
* Orthopedic Surgery
o LMWH or Coumadin (INR 2.0 - 3.0) beginning preoperatively or immediately postoperatively. Adjusted dose SQ Heparin is an acceptable alternative but more complex.
o Adjuvant use of mechanical devices may add additional benefit. May be sufficient as primary prophylaxis for TKR if used optimally.
o Low dose SQ Hep, Aspirin, IPC alone are not recommended (less effective).
o Duration:
+ minimum of 7-10 days
+ Post Discharge Prophylaxis: 4-6 weeks for high risk patients
* General Surgery (including Urologic)
o Prophylaxis with SQHep, LMWH, ES or IPC
+ Moderate Risk - minor procedure with a risk factor or 40-60 yo, major procedures and <40
+ High Risk - minor procedure with risk factors or >60, major procedures with risk factors or age >40.
+ Increased Risk of Bleeding - use ES or IPC
o Combination therapy: very high risk - multiple risk factors
o Postdischarge Prophylaxis: selected very high risk pts
* Gynecologic Surgery
o Major surgery for benign disease
# SQ Hep BID, LMWH, IPC, continue for several days post op
o Major surgery for malignancy
# SQ Hep TID, Combination AC/Mech, high dose LMWH
* Neurosurgery
o Intracranial Surgery
# IPC or ES, Low dose SQHep or LMWH may be acceptable
# Combination IPC or ES with SQHep or LMWH in high risk

Deep Venous Thrombosis Prevention
* Trauma
o LMWH as soon as possible
o IPC or ES until LMWH started
* Acute Spinal Cord Injury
o LMWH recommended
o Low dose SQHep, ES or IPC are less effective
o Combination Mechanical/anticoagulant may be acceptable
o Continue throughout rehabilatation
* Medical (Cancer, CHF, Bedrest, MI, CVA…)
o Low dose SQ Hep or LMWH
o IPC if anticoagulation contraindicated

PE SIGNS AND SYMPTOMS
Symptoms
* Dyspnea - 80%
* Chest pain - 70%
* Cough - 50%
* Apprehension - 50%
* Hemoptysis - 30%

Signs
* Tachycardia - 60%
* Tachypnea - 70%
* Fever - 60%
* Clinical DVT - 30%

Pulmonary Embolism Diagnosis
* Chest x-ray - nonspecific abnormalities in most; normal early
+ Westermark's sign and Hampton's hump uncommon
* Arterial blood gas – hypoxemia is common
+ 15 - 20% will not manifest hypoxemia (i.e. normal A-a gradient)
* ECG – nonspecific changes typically
+ S1Q3T3 pattern in massive PE with RV strain
+ helpful in evaluating other causes of chest pain

PE – V/Q LUNG SCAN
* Radiolabeled Xenon inhaled for ventilation and radiolabeled Technetium for perfusion
* Safe
* Not very specific
* Not very useful if pre-existing lung disease

Pulmonary Embolism Diagnosis - V/Q Scan
Pulmonary Embolism
Diagnosis - Pulmonary Arteriogram
* Remains “gold standard” for Dx of PE
* Expensive
* Low morbidity and mortality
o Mortality < 0.1%
o Major morbidity < 0.5%
o Pulmonary Hypertension not a contraindication
Pulmonary Embolism
Diagnosis - Pulmonary Arteriogram
Lobar Defect
Segmental Defect
Pulmonary Embolism
Diagnosis - Chest CT
* Accurate for segmental or larger PE
+ Sensitivity 85 - 95% (Overall 50-60%)
+ Specificity 90 - 100%
* Accuracy depends on interpreter
+ Large Inter-interpreter variability
+ Reduced accuracy with less experience
* Significant contrast load ~ 65% of PA gram
* Similar expense to Pulmonary Arteriogram
* Can identify other pulmonary etiologies
Pulmonary Emboli Diagnosis - MRA
Venous Thromboembolism Treatment
Continuous IV Heparin:
Heparin-Induced Antibodies
Venous Thromboembolism Treatment
Low Molecular Weight Heparins:
Venous Thromboembolism Outpatient LMWH
Enoxaparin sodium
Unfractionated heparin
Venous Thromboembolism
Treatment
Synthetic Heparins:
Fondaparinux (Arixtra)
Oral anticoagulation (Coumadin)
Inferior Vena Cava Filter

VENOUS THROMBOEMBOLIC DISEASE.ppt

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