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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_3865_Библиотеки_им_академика_М_И_Перельмана
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ABBREVIATIONS (continued)
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SOB shortness of breath
sub-Q subcutaneous
SRA serotonin release assay
SSC Scientific Subcommittee (part of ISTH)
SSRI selective serotonin reuptake inhibitors
STEMI ST-segment elevation myocardial infarction
T
1/2
TAVR transcatheter aortic valve replacement
TBW total body weight
TE thromboembolism
TEE transesophageal echocardiography
THR total hip replacement
TIA transient ischemic attack
TIMI thrombolysis in myocardial infarction
TKR total knee replacement
TMA thrombotic microangiopathy
T
max
TNK tenecteplase
tPA tissue plasminogen activator
TPN total parenteral nutrition
TT thrombin time
TTE transthoracic echocardiography
UFH unfractionated heparin
elimination half life
time to maximum serum concentration
units International Units
Vit K vitamin K or phytonadione
VKA vitamin K antagonist
VKOR vitamin K epoxide reductase
VTE venous thromboembolism
vWF von Willebrand’s factor
WARSS/APASS Warfarin vs. Aspirin Recurrent Stroke Study/Antiphospholipid Antibodies in Stroke Study
WHO World Health Organization
xx
PART I.
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ANTICOAGULATION
MEDICATION
MANAGEMENT
1. Introduction to Anticoagulation Management
2. Warfarin
3. Unfractionated Heparin
4. Low Molecular Weight Heparin and Fondaparinux
5. Parenteral Direct
Thrombin Inhibitors
6. Thrombolytic
Considerations When
Used with Anticoagulants
7. Direct Oral Anticoagulants
8. Anticoagulation Reversal: Part I—
Pharmacology of Agents Used for Reversal
9. Anticoagulation Reversal:
Part II—Clinical Application
10. Transitions in Care—Periprocedural
Bridging and Transitions Between Agents
11. Considerations in Special Populations
1
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1
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Chapter
INTRODUCTION TO
ANTICOAGULATION
MANAGEMENT
William E. Dager, Michael P. Gulseth, and Edith A. Nutescu
INTRODUCTION
In the anticoagulation therapy setting, clinicians are faced with the challenge of
utilizing agents that inherently have a small therapeutic window and the potential
for medication mishaps when not used appropriately. However, this risk is balanced
against the need to prevent against or treat thrombosis, which can also have lifealtering consequences. Therefore, clinicians utilizing anticoagulants must not only
have a firm grasp of the pharmacology and pharmacokinetics of those agents, but
they must also be current with the evidence regarding their use and understand
how an individual patient’s characteristics can influence management decisions.
This practice guide, first published in 2011, was developed with these challenges
in mind and with the goal to seed thoughts and provide information that assists
clinicians in ensuring the safe and optimal use of anticoagulants. The advent of
new agents and advances in anticoagulation therapy management led to the
development of this second edition. Each chapter provides key concepts based
on the literature and on the authors’ clinical experiences when evidence is more
limited. New chapters include considerations in special populations with a focus
on renal failure, obesity, and cancer, and on mechanical devices. A new section
focuses on the essentials for practice success that includes models and standards
in anticoagulation care delivery as well as regulatory and practice resources.
Expert panels’ evidence-based recommendations are included when available. This
practice guide is intended as a supplement to the clinician’s judgment by providing
quick insights and clinical pearls that can assist in the decision-making process.
JOINT COMMISSION’S NATIONAL PATIENT
SAFETY GOALS FOR ANTICOAGULATION,
2017 VERSION (NPSG 03.05.01)
•
Because of the high incidence of reported adverse event rates associated with anticoagulation therapy or suboptimal approaches to prevention of venous thromboembolism (VTE), several regulatory agencies have initiated processes to address
their concerns. One example is the Joint Commission’s National Patient Safety Goals
1
3
4 Anticoagulation Therapy
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(NPSGs). The primary goal of the anticoagulation NPSGs is to reduce the likelihood of patient harm associated with anticoagulant therapy.
•
The full text and requirements of the NPSGs can be found at https://www.
jointcommission.org/hap_2017_npsgs/.
•
The NPSGs are driven by the frequency of reported adverse events associated
with anticoagulation therapy. Thus, newer agents, or infrequently used agents,
may not as of yet received as much attention or regulatory oversight. This does
not necessarily make their use any less challenging, and they could be included
in the future if safety reports warrant it.
TABLE OF USEFUL RESOURCES
See Table 1-1 for useful resources involving anticoagulation therapy.
TOOLS FOR SUCCESS
Considerations in Applying Professional Organizations’
Expert Evidence-Based Guidelines to Patient Care
•
Expert panels representing the American College of Chest Physicians (ACCP)
and the American Heart Association (AHA) [published in conjunction with the
American College of Cardiology (ACC)] have provided evidence-based recom
mendations to aid clinicians in selecting appropriate patient care. In specific
situations, other agencies may independently publish guidelines that include
antithrombotic therapy. Often, these guidelines are considered the final word;
however, multiple guidelines on the same topic (especially when there may be
disagreements) can create some controversy and confusion. Adherence to these
guidelines ignores how an individual patient situation may cause variance from
the guidelines. It should be kept in mind that such guidelines are established
based on the strength of available evidence. In many cases, evidence or trials
may not have included certain situations or populations or perhaps published
negative experiences. Clinicians need to view and use these guidelines as they
are intended—evidence-based tools designed (or developed) to aid in patient
care and not to replace clinical judgment.
•
The following tables explain the evidence ranking system of both the ACCP and
AHA guidelines. These evidence grades are mentioned extensively in subsequent
chapters. See
Tables 1-2 and 1-3.
-
Considerations When Evaluating Clinical Trials Involving
Anticoagulants
•
Clinical trials have frequently preselected inclusion and exclusion criteria that
create a focus for the concept being studied. In many cases with anticoagula
tion therapy, patient groups (advanced age, bleeding history, organ dysfunction, critically ill, hypercoagulable condition) initially excluded from the clinical
trials may receive the therapy. Clinicians should consider that trials serve as a
foundation to managing thrombosis, but that excluded populations may respond
differently to a given therapy.
-
INTRODUCTION TO ANTICOAGULATION MANAGEMENT 5
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TABLE 1-1: Resources Involving Anticoagulation Therapy
Reference Web Site Comment
ACCP
guidelines
AHA guidelines http://professional.
ASHP https://www.ashp.org/
Anticoagulation
Forum
Clinical Trials.
gov
ClotCare http://www.clotcare.com/ Regularly updated site mainly focuses on
FDA http://www.fda.gov/ The FDA regularly posts alerts concerning
http://journal.publications.
chestnet.org/SS/
Antithrombotic_Guideline.
aspx
heart.org/professional/
GuidelinesStatements/
searchresults.jsp
Pharmacy-Practice/
Pharmacy-Topics/
Anticoagulation
http://www.acforum.org/ Multidisciplinary professional organization for
http://www.clinicaltrials.gov/ The site describes current clinical trials
The oldest and most established evidencebased guideline involving antithrombotic
therapy. Although the 9th and previous
editions were all developed and published
at the same time, the 10th edition will have
chapters/topics published at various times.
The American Heart Association regularly
published guidelines that cover different
arterial disease states, often in conjunction
with other societies.
The American Society of Health-System
Pharmacists provides a resource center that
is helpful for pharmacists and clinicians who
manage anticoagulation therapy.
those who manage anticoagulation therapy;
helpful clinical resources are posted on the
site.
conducted.
keeping professionals abreast of cutting-edge
information involving antithrombotic therapy;
site also contains helpful information for
patients.
marketed medications and materials that are
reviewed by advisory committees.
PubMed http://www.ncbi.nlm.nih.
ACCP: American College of Chest Physicians, AHA: American Heart Association, ASHP: American
Society of Health-System Pharmacists, FDA: U.S. Food and Drug Administration
•
Anticoagulants or reversal therapies may frequently be used in conditions where
the agent has not been adequately explored. The limited evidence with such
“off-label” use should be employed with caution and with consideration that
the optimal dose, duration, or approach to their use in such settings has not
been determined.
•
In many situations, current approaches to anticoagulation regimens have evolved
based on postmarketing experiences. Populations originally excluded in the
clinical trials may provide signals on how therapies may need to be adapted.
In some settings, limited single-center case reports where no additional infor
mation exists may drive practice. In others, concepts based in theory but not
gov/pubmed/
Excellent free site available for searching
Medline from the United States National
Library of Medicine.
-
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TABLE 1-2: Interpreting the ACCP Antithrombotic and
Thrombolytic Therapy Evidence-Based Clinical Practice
Guidelines Evidence Grades
Grade of Recommendation
(recommendation
strength/evidence grade)
Quality of Evidence Implications
2-4
*
1A Consistent findings are from
1B RCTs have important limitations
1C At least one important outcome
2A Consistent findings are from
2B RCTs have important limitations
2C At least one important outcome
Ungraded Consensus-Based
Statement (New)
randomized clinical trials (RCTs) or
extremely strong evidence from
observational studies.
or strong evidence from
observational studies.
has been assessed in case series,
observational studies, or from
seriously flawed RCTs; indirect
evidence also can be used.
RCTs or have extremely strong
evidence from observational
studies.
or strong evidence from
observational studies.
has been assessed in case series,
observational studies, or from
a seriously flawed RCT; indirect
evidence also can be used.
The desirable consequences
probably outweigh the
undesirable consequences in
most settings, but there is little
evidence. Recommendations are
more suggestions in the absence
of any rigorous clinical trials or
assessments of the issue.
Recommendation applies
to most patients in most
situations.
Recommendation applies
to most patients in most
situations.
Recommendation applies
to most patients in many
situations.
The appropriate treatment
may vary based on patient/
society values.
The appropriate treatment
may vary based on patient/
society values.
Other treatment options
may be equally desirable.
*Grade 1 recommendations are considered “strong” recommendations, and Grade 2 are
considered “weak” recommendations. Grade A evidence comes from RCTs or observational
studies with very large effects. Grade B evidence comes from RCTs with limitations or strong
evidence from observational trials. Grade C evidence comes from observational trials or RCTs
with major limitations. The Grades of Recommendations, Assessment, Development and
Evaluation (GRADE) approach is utilized.
ACCP: American College of Chest Physicians
5
INTRODUCTION TO ANTICOAGULATION MANAGEMENT 7
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TABLE 1-3: Interpreting the ACC/AHA Evidence Grades Used in
Scientific Statements
Grade of Recommendation
(class/evidence grade)
1 (A) Strong recommendation that a treatment or procedure is
1 (B) Strong recommendation that a treatment or procedure is
1 (C) Strong recommendation that a treatment or procedure is
IIa (A) Recommendation that a treatment or procedure is helpful;
IIa (B) Recommendation that a treatment or procedure is helpful;
IIa (C) Recommendation that a treatment or procedure is helpful;
IIb (A) Recommendation that a treatment or procedure may be
IIb (B) Recommendation that a treatment or procedure may be
6
Quality of Evidence
helpful; robust supporting data.
helpful; more limited supporting data.
helpful; largely based on expert opinion, standard of care, or
case studies.
available data contain some conflicting evidence.
available data contain some conflicting evidence.
largely based on expert opinion, standard of care, or case
studies.
considered; supporting data contain significant conflicting
evidence.
considered; available data contain significant conflicting
evidence.
IIb (C) Recommendation that a treatment or procedure may be
III (A) Recommendation that a treatment or procedure should not
III (B) Recommendation that a treatment or procedure should not
III (C) Recommendation that a treatment or procedure should not
ACC/AHA: American College of Cardiology/American Heart Association
yet validated [e.g., overlapping parenteral anticoagulants for 2 additional days
after the international normalized ratio (INR) on warfarin is over 2] are utilized.
•
When reviewing data derived from observations collected from registries, the
reviewer should consider the voluntary structure and potential cleaning of data
prior to submission to eliminate any perception of poor management. The coding
considered; largely based on expert opinion, standard of
care, or case studies.
be considered; robust supporting data.
be considered; based on more limited supporting data.
be considered; largely based on expert opinion, standard of
care, or case studies.
8 Anticoagulation Therapy
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of the information prior to being extrapolated may also create certain bias or
limitations on the quality of the research.
•
See Table 1-4.
Meta-Analysis Interpretation Cautions
•
Guidelines strive to incorporate the best evidence available when developing
recommendations. This can frequently be influenced by meta-analysis that
explores similar trials. However, trials may not be published, particularly small
negative trials. This can create a literature base that is influenced by positive
outcomes. In some cases, single large trials may dominate the observations.
Such data basis should utilize concepts such as funnel plots to describe any
potential bias in the data base. (See reference 7 for an example of how this can
help detect publication bias.)
•
Differences in the approach to the study and the patients actually studied may
have influenced the variable results reported in the meta-analysis. These trials,
while having enough power to detect small treatment effects, often include a
diverse population of patients by design.
•
Medical advances in both technology and management approaches over time
can independently influence outcomes. Because trials included in a meta-analysis
are usually conducted during different time periods, it can create challenges in
interpreting the results.
7
“Real World” Data Interpretation Cautions
•
The increased availability of large claims-based databases and clinical registries
has resulted in evaluation and dissemination of the treatment effectiveness and
safety of medication use in the community.
•
Compared to randomized clinical trials (RCTs), these observational studies have
the advantage of evaluating more “real life” outcomes because patient selec
tion is much less sanitized.
•
One of the major disadvantages of these observational analyses is the potential
of unmeasured confounding factors and selection bias despite sophisticated
econometrics and pharmacoepidemiology statistical techniques.
•
We encourage readers to, whenever possible, use RCTs to make treatment
decisions keeping in mind any limitations as it relates to the patient’s situation.
Also, it is recommended to use real-world observational data to help decide
if the treatment effect and safety profile seen in the RCTs is consistent when
studied in less controlled population-based studies.
•
Extreme caution should be taken with real-world data when comparing agents
that have not been compared head-to-head in RCTs due to possible confound
ing and bias.
Treat the Patient and Consider All of the Patient’s
Potential Needs
•
Each patient is unique, and clinicians will combine their knowledge and experience along with resources, such as this practice guide, to derive and adapt
anticoagulation therapy. In many cases, deficiencies in the information used
-
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INTRODUCTION TO ANTICOAGULATION MANAGEMENT 9
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TABLE 1-4: Additional Considerations When Evaluating Clinical
Trials
Consideration Comment
Population studied •
Methods •
Results •
The inclusion and exclusion criteria describe who was or was not
studied in the analysis. Be sure the patients you are considering for
therapy based on the trial would have been included.
• The number of eligible subjects versus those actually studied can
also describe potential challenges in repeating the observations in
the general population.
The methods should be cross-compared to the study’s setting.
For example, ethnic differences in a region or the assay used may
create results with some limitations when implemented in a different
setting.
• They should clearly state the design and how the management
strategy was provided. In some cases, the methods may have been
published separately or provided in supplemental materials. Also
note the challenges in enrolling patients, including potential delays
in randomization and consent where the trial’s implementation may
have been delayed and other therapies initially used.
Many of the new trials involving anticoagulants are “noninferiority”
in design. If the medication is found to be “noninferior” to the
comparator, be sure to carefully review the noninferiority criteria to
ensure it is appropriate. Also, when compared to warfarin, how well
controlled was the warfarin?
•
Carefully consider the clinical significance of the primary endpoint
of the trials. For example, many orthopedic trials commonly include
venographically derived asymptomatic DVT, which many would argue
is not as clinically significant as symptomatic DVT/PE. These results
may be statistically significant, but that is very different than clinically
significant.
Data should be carefully assessed for robustness. Were any signals
•
present, suggesting different outcomes within the study population?
Who was excluded? Was additional analysis done to confirm the
primary endpoint findings or conclusions made?
•
Was any subgroup analysis included in the initial study design,
or was it derived post hoc to create a positive spin on the study?
Caution should be exercised if considering application of the post
hoc analysis to patient care.
• When assessing a clinical observation or reported result, consider
the potential error in the data. Single, unexpected, or atypical
observations should be confirmed with additional analysis.
• Trends in data that support a result create a higher level of
confidence than the single outlier.
Limitations Be sure the study clearly identifies the limitations of the analysis.
Summary/
conclusion
DVT: deep vein thrombosis, PE: pulmonary embolism
The study should attempt to describe how the limitations affect
interpretation/application of the results. It is also helpful if they have
done additional data analysis to assess the impact of the limitations.
Be sure the conclusion is appropriate considering the data and their
limitations. Often, conclusions overreach the observed result, ignoring
important limitations, which could potentially harm patients if applied
without this consideration.
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