S64 Diabetes Care Volume 40, Supplement 1, January 2017

8. Pharmacologic Approaches to American Diabetes Association

Glycemic Treatment
Diabetes Care 2017;40(Suppl. 1):S64S74 | DOI: 10.2337/dc17-S011

PHARMACOLOGIC THERAPY FOR TYPE 1 DIABETES

Recommendations
c Most people with type 1 diabetes should be treated with multiple daily injections of
8. PHARMACOLOGIC APPROACHES TO GLYCEMIC TREATMENT

prandial insulin and basal insulin or continuous subcutaneous insulin infusion. A

c Most individuals with type 1 diabetes should use rapid-acting insulin analogs
to reduce hypoglycemia risk. A
c Consider educating individuals with type 1 diabetes on matching prandial
insulin doses to carbohydrate intake, premeal blood glucose levels, and antic-
ipated physical activity. E
c Individuals with type 1 diabetes who have been successfully using continuous
subcutaneous insulin infusion should have continued access to this therapy
after they turn 65 years of age. E

Insulin Therapy
Insulin is the mainstay of therapy for individuals with type 1 diabetes. Generally, the
starting insulin dose is based on weight, with doses ranging from 0.4 to 1.0 units/kg/
day of total insulin with higher amounts required during puberty. The American Diabetes
Association/JDRF Type 1 Diabetes Sourcebook notes 0.5 units/kg/day as a typical starting
dose in patients who are metabolically stable, with higher weight-based dosing required
immediately following presentation with ketoacidosis (1), and provides detailed informa-
tion on intensication of therapy to meet individualized needs. The American Diabetes
Association (ADA) position statement Type 1 Diabetes Management Through the Life
Span additionally provides a thorough overview of type 1 diabetes treatment and asso-
ciated recommendations (2).
Education regarding matching prandial insulin dosing to carbohydrate intake, pre-
meal glucose levels, and anticipated activity should be considered, and selected indi-
viduals who have mastered carbohydrate counting should be educated on fat and
protein gram estimation (35). Although most studies of multiple daily injections
(MDI) versus continuous subcutaneous insulin infusion (CSII) have been small and of
short duration, a systematic review and meta-analysis concluded that there are minimal
differences between the two forms of intensive insulin therapy in A1C (combined mean
between-group difference favoring insulin pump therapy 20.30% [95% CI 20.58
to 20.02]) and severe hypoglycemia rates in children and adults (6). A 3-month ran-
domized trial in patients with type 1 diabetes with nocturnal hypoglycemia reported
that sensor-augmented insulin pump therapy with the threshold suspend feature re-
duced nocturnal hypoglycemia without increasing glycated hemoglobin levels (7). In-
tensive management using CSII and continuous glucose monitoring (CGM) should be
encouraged in selected patients when there is active patient/family participation (810).
The Diabetes Control and Complications Trial (DCCT) clearly showed that intensive
Suggested citation: American Diabetes Associa-
therapy with MDI or CSII delivered by multidisciplinary teams of physicians, nurses, dieti- tion. Pharmacologic approaches to glycemic
tians, and behavioral scientists improved glycemia and resulted in better long-term out- treatment. Sec. 8. In Standards of Medical
comes (1113). The study was carried out with short-acting and intermediate-acting Care in Diabetesd2017. Diabetes Care 2017;
human insulins. Despite better microvascular, macrovascular, and all-cause mortality 40(Suppl. 1):S64S74
outcomes, intensive therapy was associated with a high rate of severe hypoglycemia 2017 by the American Diabetes Association.
(61 episodes per 100 patient-years of therapy). Since the DCCT, a number of rapid- Readers may use this article as long as the work
is properly cited, the use is educational and not
acting and long-acting insulin analogs have been developed. These analogs are as- for prot, and the work is not altered. More infor-
sociated with less hypoglycemia in type 1 diabetes, while matching the A1C lowering mation is available at http://www.diabetesjournals
of human insulins (14,15). .org/content/license.
care.diabetesjournals.org
Rapid-acting inhaled insulin used be-
fore meals in type 1 diabetes was shown
to be noninferior when compared with
aspart insulin for A1C lowering, with less
hypoglycemia observed with inhaled in-
sulin therapy (16). However, the mean
reduction in A1C was greater with aspart
(20.21% vs. 20.40%, satisfying the non-
inferiority margin of 0.4%), and more pa-
tients in the insulin aspart group
achieved A1C goals of #7.0% (53
mmol/mol) and #6.5% (48 mmol/mol).
Because inhaled insulin cartridges are
only available in 4, 8, and 12 unit doses,
people with type 1 diabetes may have
limited dosing increments to ne-tune
prandial insulin doses when using this
therapy.
Postprandial glucose excursions may be
better controlled by adjusting the timing
of prandial (bolus) insulin dose adminis-
tration. The optimal time to administer
prandial insulin varies, based on the
type of insulin used (regular, rapid-acting
analog, inhaled, etc.), the measured
blood glucose level, timing of meals,
and carbohydrate consumption. Rec-
ommendations for prandial insulin
dose administration should therefore
be individualized.
Pramlintide
Pramlintide, an amylin analog, is an
agent that delays gastric emptying,
blunts pancreatic secretion of glucagon,
and enhances satiety. It is U.S. Food and
Drug Administration (FDA)approved
for use in adults with type 1 diabetes. It
has been shown to induce weight loss
and lower insulin doses. Concurrent re-
duction of prandial insulin dosing is re-
quired to reduce the risk of severe
hypoglycemia.
Pancreas and Islet Transplantation
Pancreas and islet transplantation have
been shown to normalize glucose levels
but require lifelong immunosuppression
to prevent graft rejection and recurrence
of autoimmune islet destruction. Given
the potential adverse effects of immuno-
suppressive therapy, pancreas transplan-
tation should be reserved for patients
with type 1 diabetes undergoing simulta-
neous renal transplantation, following
renal transplantation, or for those with
recurrent ketoacidosis or severe hypogly-
cemia despite intensive glycemic manage-
ment (17). Islet transplantation remains
investigational. Autoislet transplantation
may be considered for patients requiring
Pharmacologic Approaches to Glycemic Treatment
total pancreatectomy for medically refrac-
tory chronic pancreatitis.
Investigational Agents
Metformin
Adding metformin to insulin therapy may
reduce insulin requirements and improve
metabolic control in overweight/obese pa-
tients with poorly controlled type 1 diabe-
tes. In a meta-analysis, metformin in type 1
diabetes was found to reduce insulin re-
quirements (6.6 units/day, P , 0.001) and
led to small reductions in weight and total
and LDL cholesterol but not to improved
glycemic control (absolute A1C reduction
0.11%, P 5 0.42) (18). Metformin is not
FDA-approved for use in patients with
type 1 diabetes.
Incretin-Based Therapies
Due to their potential protection of b-cell
mass and suppression of glucagon release,
glucagon-like peptide 1 (GLP-1) receptor
agonists and dipeptidyl peptidase 4 (DPP-4)
inhibitors are being studied in patients with
type 1 diabetes but are not currently FDA-
approved for use in patients with type 1
diabetes.
SodiumGlucose Cotransporter
2 Inhibitors
Sodiumglucose cotransporter 2 (SGLT2)
inhibitors provide insulin-independent glu-
cose lowering by blocking glucose reab-
sorption in the proximal renal tubule by
inhibiting SGLT2. These agents provide
modest weight loss and blood pressure
reduction in type 2 diabetes. There are
three FDA-approved agents for patients
with type 2 diabetes, but none are FDA-
approved for the treatment of patients
with type 1 diabetes (2). The FDA issued a
warning about the risk of ketoacidosis oc-
curring in the absence of signicant hyper-
glycemia (euglycemic diabetic ketoacidosis)
in patients with type 1 and type 2 diabetes
treated with SGLT2 inhibitors. Symptoms of
ketoacidosis include dyspnea, nausea, vom-
iting, and abdominal pain. Patients should
be instructed to stop taking SGLT2 inhibi-
tors and seek medical attention immedi-
ately if they have symptoms or signs of
ketoacidosis (19).
PHARMACOLOGIC THERAPY FOR
TYPE 2 DIABETES
Recommendations
c Metformin, if not contraindicated
and if tolerated, is the preferred ini-
tial pharmacologic agent for the
treatment of type 2 diabetes. A
S65
c Long-term use of metformin may
be associated with biochemical
vitamin B12 deciency, and peri-
odic measurement of vitamin B12
levels should be considered in
metformin-treated patients, es-
pecially in those with anemia or
peripheral neuropathy. B
c Consider initiating insulin therapy
(with or without additional agents)
in patients with newly diagnosed
type 2 diabetes who are symptom-
atic and/or have A1C $10% (86
mmol/mol) and/or blood glucose
levels $300 mg/dL (16.7 mmol/L). E
c If noninsulin monotherapy at
maximum tolerated dose does not
achieve or maintain the A1C target
after 3 months, add a second oral
agent, a glucagon-like peptide 1 re-
ceptor agonist, or basal insulin. A
c A patient-centered approach should
be used to guide the choice of phar-
macologic agents. Considerations in-
clude efcacy, hypoglycemia risk,
impact on weight, potential side ef-
fects, cost, and patient preferences. E
c For patients with type 2 diabetes
who are not achieving glycemic
goals, insulin therapy should not
be delayed. B
c In patients with long-standing
suboptimally controlled type 2 di-
abetes and established athero-
sclerotic cardiovascular disease,
empagliozin or liraglutide should
be considered as they have been
shown to reduce cardiovascular
and all-cause mortality when
added to standard care. Ongoing
studies are investigating the cardio-
vascular benets of other agents in
these drug classes. B
The use of metformin as rst-line ther-
apy was supported by ndings from
a large meta-analysis, with selection
of second-line therapies based on
patient-specic considerations (20).
An ADA/European Association for the
Study of Diabetes position statement
(21) recommended a patient-centered
approach, including assessment of ef-
cacy, hypoglycemia risk, impact on
weight, side effects, costs, and patient
preferences. Renal effects may also be con-
sidered when selecting glucose-lowering
medications for individual patients. Life-
style modications that improve health
S66 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 40, Supplement 1, January 2017

(see Section 4 Lifestyle Management)
should be emphasized along with any
pharmacologic therapy.
Initial Therapy
Metformin monotherapy should be started
at diagnosis of type 2 diabetes unless
there are contraindications. Metformin
is effective and safe, is inexpensive, and
may reduce risk of cardiovascular events
and death (22). Metformin may be safely
used in patients with estimated glo-
merular ltration rate (eGFR) as low as
30 mL/min/1.73 m2 (23), and the U.S.
label for metformin was recently re-
vised to reect its safety in patients
with eGFR $30 mL/min/1.73 m2 (24).
Patients should be advised to stop the
medication in cases of nausea, vomiting,
or dehydration. Metformin is associated
with vitamin B12 deciency, with a recent
report from the Diabetes Prevention Pro-
gram Outcomes Study (DPPOS) suggesting
that periodic testing of vitamin B12 levels
should be considered in metformin-treated
patients, especially in those with anemia or
peripheral neuropathy (25).
In patients with metformin contrain-
dications or intolerance, consider an ini-
tial drug from another class depicted in
Fig. 8.1 under Dual Therapy and pro-
ceed accordingly. When A1C is $9%
(75 mmol/mol), consider initiating dual
combination therapy (Fig. 8.1) to more
expeditiously achieve the target A1C
level. Insulin has the advantage of being
effective where other agents may not be
and should be considered as part of any
combination regimen when hyperglycemia
is severe, especially if symptoms are pre-
sent or any catabolic features (weight
loss, ketosis) are present. Consider ini-
tiating combination insulin injectable
therapy (Fig. 8.2) when blood glucose
is $300 mg/dL (16.7 mmol/L) or A1C
is $10% (86 mmol/mol) or if the patient
has symptoms of hyperglycemia (i.e.,
polyuria or polydipsia). As the patients
glucose toxicity resolves, the regimen
may, potentially, be simplied.
Combination Therapy
Although there are numerous trials com-
paring dual therapy with metformin alone,

Figure 8.1Antihyperglycemic therapy in type 2 diabetes: general recommendations. The order in the chart was determined by historical availability and
the route of administration, with injectables to the right; it is not meant to denote any specic preference. Potential sequences of antihyperglycemic
therapy for patients with type 2 diabetes are displayed, with the usual transition moving vertically from top to bottom (although horizontal movement
within therapy stages is also possible, depending on the circumstances). DPP-4-i, DPP-4 inhibitor; fxs, fractures; GI, gastrointestinal; GLP-1 RA, GLP-1
receptor agonist; GU, genitourinary; HF, heart failure; Hypo, hypoglycemia; SGLT2-i, SGLT2 inhibitor; SU, sulfonylurea; TZD, thiazolidinedione. *See ref. 21 for
description of efcacy and cost categorization. Usually a basal insulin (NPH, glargine, detemir, degludec). Adapted with permission from Inzucchi et al. (21).
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S67

Figure 8.2Combination injectable therapy for type 2 diabetes. FBG, fasting blood glucose; GLP-1 RA, GLP-1 receptor agonist; hypo, hypoglycemia.
Adapted with permission from Inzucchi et al. (21).

few directly compare drugs as add-on ther-
apy. A comparative effectiveness meta-
analysis (23) suggests that each new class
of noninsulin agents added to initial ther-
apy generally lowers A1C approximately
0.91.1%. If the A1C target is not achieved
after approximately 3 months, consider a
combination of metformin and one of
the six available treatment options: sul-
fonylurea, thiazolidinedione, DPP-4 in-
hibitor, SGLT2 inhibitor, GLP-1 receptor
agonist, or basal insulin (Fig. 8.1). If A1C
target is still not achieved after ;3
months of dual therapy, proceed to
three-drug combination (Fig. 8.1). Again,
if A1C target is not achieved after
;3 months of triple therapy, proceed
to combination injectable therapy
(Fig. 8.2).
Drug choice is based on patient pref-
erences (26), as well as various patient,
disease, and drug characteristics, with
the goal of reducing blood glucose levels
while minimizing side effects, especially
 S68
Pharmacologic Approaches to Glycemic Treatment
Table 8.1Properties of available glucose-lowering agents in the U.S. that may guide individualized treatment choices in patients with type 2 diabetes (21)
Primary physiological
Class Compound(s) Cellular mechanism(s) action(s) Advantages Disadvantages Cost*
Biguanides c Metformin Activates AMP-kinase c Hepatic glucose c Extensive experience c Gastrointestinal side effects Low
(? other) production c Rare hypoglycemia (diarrhea, abdominal cramping, nausea)
c CVD events (UKPDS) c Vitamin B12 deciency
c Relatively higher A1C c Contraindications: eGFR ,30
efcacy mL/min/1.73 m2, acidosis, hypoxia,
dehydration, etc.
c Lactic acidosis risk (rare)

Sulfonylureas 2nd generation Closes KATP channels on b-cell c Insulin secretion c Extensive experience c Hypoglycemia Low
c Glyburide plasma membranes c Microvascular risk (UKPDS) c Weight
c Glipizide c Relatively higher A1C
c Glimepiride efcacy
Meglitinides c Repaglinide Closes KATP channels on b-cell c Insulin secretion c Postprandial glucose c Hypoglycemia Moderate
(glinides) c Nateglinide plasma membranes excursions c Weight
c Dosing exibility c Frequent dosing schedule

TZDs c Pioglitazone Activates the nuclear c Insulin sensitivity c Rare hypoglycemia c Weight Low
c Rosiglitazone transcription factor PPAR-g c Relatively higher A1C c Edema/heart failure
efcacy c Bone fractures
c Durability c LDL-C (rosiglitazone)
c Triglycerides (pioglitazone)
c ? CVD events (PROactive, pioglitazone)
c Risk of stroke and MI in
patients without diabetes and with
insulin resistance and history of
recent stroke or TIA
(IRIS study [42], pioglitazone)
a-Glucosidase Acarbose Inhibits intestinal Slows intestinal carbohydrate Rare hypoglycemia Generally modest A1C efcacy Low to

Diabetes Care Volume 40, Supplement 1, January 2017

c c c c
inhibitors c Miglitol a-glucosidase digestion/absorption c Postprandial glucose c Gastrointestinal side effects moderate
excursions (atulence, diarrhea)
c ? CVD events in prediabetes c Frequent dosing schedule
(STOP-NIDDM)
c Nonsystemic

DPP-4 c Sitagliptin Inhibits DPP-4 activity, increasing c Insulin secretion c Rare hypoglycemia c Angioedema/urticaria and other High
inhibitors c Saxagliptin postprandial incretin (GLP-1, GIP) (glucose dependent) c Well tolerated immune-mediated dermatological effects
c Linagliptin concentrations c Glucagon secretion c ? Acute pancreatitis
c Alogliptin (glucose dependent) c Heart failure hospitalizations
(saxagliptin; ? alogliptin)
Bile acid c Colesevelam Binds bile acids in intestinal tract, c ? Hepatic glucose c Rare hypoglycemia c Modest A1C efcacy High
sequestrants increasing hepatic bile acid production c LDL-C c Constipation
production c ? Incretin levels c Triglycerides
c May absorption of other
medications
Continued on p. S69
Table 8.1Continued

care.diabetesjournals.org
Primary physiological
Class Compound(s) Cellular mechanism(s) action(s) Advantages Disadvantages Cost*
Dopamine-2 c Bromocriptine Activates dopaminergic c Modulates hypothalamic c Rare hypoglycemia c Modest A1C efcacy High
agonists (quick release) receptors regulation of metabolism c ? CVD events c Dizziness/syncope
c Insulin sensitivity (Cycloset Safety Trial) c Nausea
c Fatigue
c Rhinitis

SGLT2 c Canagliozin Inhibits SGLT2 in the c Blocks glucose reabsorption c Rare hypoglycemia c Genitourinary infections High
inhibitors c Dapagliozin proximal nephron by the kidney, increasing c Weight c Polyuria
c Empagliozin glucosuria c Blood pressure c Volume depletion/hypotension/dizziness
c Associated with lower CVD event c LDL-C
rate and mortality in patients with c Creatinine (transient)
CVD (empagliozin EMPA-REG c DKA, urinary tract infections leading
OUTCOME) to urosepsis, pyelonephritis
GLP-1 receptor c Exenatide Activates GLP-1 receptors c Insulin secretion c Rare hypoglycemia c Gastrointestinal side effects High
agonists c Exenatide extended (glucose dependent) c Weight (nausea/vomiting/diarrhea)
release c Glucagon secretion c Postprandial glucose excursions c Heart rate
c Liraglutide (glucose dependent) c Some cardiovascular risk factors c ? Acute pancreatitis
c Albiglutide c Slows gastric emptying c Associated with lower CVD event c C-cell hyperplasia/medullary thyroid
c Lixisenatide c Satiety rate and mortality in patients with tumors in animals
c Dulaglutide CVD (liraglutide LEADER) (30) c Injectable
c Training requirements

Amylin mimetics c Pramlintide Activates amylin receptors c Glucagon secretion c Postprandial glucose excursions c Modest A1C efcacy High
c Slows gastric emptying c Weight c Gastrointestinal side effects
c Satiety (nausea/vomiting)
c Hypoglycemia unless insulin dose is
simultaneously reduced
c Injectable
c Frequent dosing schedule
c Training requirements

Insulins c Rapid-acting analogs Activates insulin receptors c Glucose disposal c Nearly universal response c Hypoglycemia High#
- Lispro Hepatic glucose Theoretically unlimited efcacy Weight gain

Pharmacologic Approaches to Glycemic Treatment

c c c
- Aspart production c Microvascular risk (UKPDS) c Training requirements
- Glulisine c Suppresses ketogenesis c Patient and provider reluctance
- Inhaled insulin c Injectable (except inhaled insulin)
c Short-acting c Pulmonary toxicity (inhaled insulin)
- Human Regular
c Intermediate-acting
- Human NPH

Continued on p. S70

S69
S70 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 40, Supplement 1, January 2017
hypoglycemia. Table 8.1 lists drugs com-
HDL-C, HDL cholesterol; IRIS, Insulin Resistance Intervention After Stroke Trial; LDL-C, LDL cholesterol; PPAR-g, peroxisome proliferatoractivated receptor g; PROactive, Prospective Pioglitazone Clinical Trial in

Cycloset trial of quick-release bromocriptine (47). *Cost is based on lowest-priced member of the class (21). lnitial concerns regarding bladder cancer risk are decreasing after subsequent study. Not licensed in
Macrovascular Events (43); STOP-NIDDM, Study to Prevent Non-Insulin-Dependent Diabetes Mellitus (44); TIA, transient ischemic attack; TZD, thiazolidinedione; UKPDS, UK Prospective Diabetes Study (45,46).

monly used in the U.S. Cost-effectiveness

CVD, cardiovascular disease; EMPA-REG OUTCOME, BI 10773 (Empagliozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (29); GIP, glucose-dependent insulinotropic peptide;
Cost*

models have suggested that some of the

newer agents may be of relatively lower
clinical utility based on high cost and
moderate glycemic effect (27). Table 8.2
provides cost information for currently ap-
proved noninsulin therapies. Of note, pri-
ces listed are average wholesale prices
Disadvantages

(AWP) and do not account for discounts,

rebates, or other price adjustments often
involved in prescription sales that affect
the actual cost incurred by the patient.
While there are alternative means to esti-
Europe for type 2 diabetes. #Cost is highly dependent on type/brand (analogs . human insulins) and dosage. Adapted with permission from Inzucchi et al. (21).

mate medication prices, AWP was utilized

to provide a comparison of list prices with
the primary goal of highlighting the impor-
tance of cost considerations when pre-
scribing antihyperglycemic treatments. The
ongoing Glycemia Reduction Approaches
in Diabetes: A Comparative Effectiveness
Advantages

Study (GRADE) will compare four drug

classes (sulfonylurea, DPP-4 inhibitor,
GLP-1 receptor agonist, and basal insulin)
when added to metformin therapy over
4 years on glycemic control and other
medical, psychosocial, and health eco-
nomic outcomes (28).
Rapid-acting secretagogues (megliti-
nides) may be used instead of sulfonyl-
ureas in patients with sulfa allergies,
Primary physiological

irregular meal schedules, or those who de-

velop late postprandial hypoglycemia
action(s)

when taking a sulfonylurea. Other drugs

not shown in Fig. 8.1 (e.g., inhaled insulin,
a-glucosidase inhibitors, colesevelam, bro-
mocriptine, and pramlintide) may be tried
in specic situations but are not often used
due to modest efcacy in type 2 diabetes,
the frequency of administration, the po-
Cellular mechanism(s)

tential for drug interactions, and/or side

effects.
Cardiovascular Outcome Trials
Several recently published cardiovascular
outcome trials (CVOTs) have provided
data on patients with type 2 diabetes
with cardiovascular disease or at high
risk for cardiovascular disease. The BI

- NPH/Regular 70/30
Basal insulin analogs

270/30 aspart mix

275/25 lispro mix
250/50 lispro mix
10773 (Empagliozin) Cardiovascular
Compound(s)

c Premixed insulin
Outcome Event Trial in Type 2 Diabetes

- Degludec
- Glargine
- Detemir
Mellitus Patients (EMPA-REG OUTCOME)

products
was a randomized, double-blind trial that

Table 8.1Continued
assessed the effect of empagliozin, a

c
SGLT2 inhibitor, versus placebo and stan-
dard care, on cardiovascular outcomes in
patients with type 2 diabetes and existing
cardiovascular disease. Study participants

Class
had a mean age of 63 years, 57% had di-
abetes for more than 10 years, and 99%
care.diabetesjournals.org Pharmacologic Approaches to Glycemic Treatment S71

Table 8.2Median monthly cost of maximum approved daily dose of noninsulin glucose-lowering agents in the U.S. (48)
Dosage strength/product Median AWP Maximum approved
Class Compound(s) (if applicable) (min, max) daily dose*
Biguanides c Metformin 500 mg (IR) $84 ($5, $94) 2,000 mg
850 mg (IR) $108 ($5, $108) 2,550 mg
1,000 mg (IR) $86 ($4, $87) 2,000 mg
500 mg (ER) $90 ($82, $6,672) 2,000 mg
750 mg (ER) $72 ($65, $92) 1,500 mg
1,000 mg (ER) $1,028 ($1,010, $7,213) 2,000 mg
Sulfonylureas (2nd Gen) c Glyburide 5 mg $94 ($64, $103) 20 mg
6 mg (micronized) $50 ($48, $71) 12 mg (micronized)
c Glipizide 10 mg (IR) $74 ($67, $97) 40 mg (IR)
10 mg (XL) $97 20 mg (XL)
c Glimepiride 4 mg $74 ($71, $198) 8 mg
Meglitinides (glinides) c Repaglinide 2 mg $799 ($163, $878) 16 mg
c Nateglinide 120 mg $156 360 mg
TZDs c Pioglitazone 45 mg $349 ($348, $349) 45 mg
c Rosiglitazone 4 mg $355 8 mg
a-Glucosidase inhibitors c Acarbose 100 mg $104 ($104, 105) 300 mg
c Miglitol 100 mg $241 300 mg
DPP-4 inhibitors c Sitagliptin 100 mg $436 100 mg
c Saxagliptin 5 mg $436 5 mg
c Linagliptin 5 mg $428 5 mg
c Alogliptin 25 mg $436 25 mg
Bile acid sequestrant c Colesevelam 625 mg tabs $679 3.75 g
1.875 g suspension $1,357 3.75 g
Dopamine-2 agonists c Bromocriptine 0.8 mg $719 4.8 mg
SGLT2 inhibitors c Canagliozin 300 mg $470 300 mg
c Dapagliozin 10 mg $470 10 mg
c Empagliozin 25 mg $470 25 mg
GLP-1 receptor agonists c Exenatide 10 mg pen $729 20 mg
c Exenatide 2 mg powder for suspension or pen $692 2 mg**
(extended-release)
c Liraglutide 18 mg/3 mL pen $831 1.8 mg
c Albiglutide 50 mg pen $527 50 mg**
c Dulaglutide 1.5/0.5 mL pen $690 1.5 mg**
Amylin mimetics c Pramlintide 120 mg pen $2,124 120 mg/injection
ER and XL, extended release; IR, immediate release; TZD, thiazolidinedione. Calculated for 30 day supply (AWP unit price 3 number of doses required to
provide maximum approved daily dose 3 30 days); median AWP listed alone when only one product and/or price. *Utilized to calculate median AWP
(min, max); generic prices used, if available commercially. **Administered once weekly. AWP calculated based on 120 mg three times daily.

had established cardiovascular disease.
EMPA-REG OUTCOME showed that over a
median follow-up of 3.1 years, treatment
reduced the composite outcome of MI,
stroke, and cardiovascular death by 14%
(absolute rate 10.5% vs. 12.1% in the pla-
cebo group) and cardiovascular death by
38% (absolute rate 3.7% vs. 5.9%) (29). The
FDA recently added a new indication for
empagliozin, to reduce the risk of cardio-
vascular death in adults with type 2 diabe-
tes and cardiovascular disease. Whether
other SGLT2 inhibitors will have the same
effect in high-risk patients and whether
empagliozin or other SGLT2 inhibitors
will have a similar effect in lower-risk pa-
tients with diabetes remains unknown.
The Liraglutide Effect and Action in Di-
abetes: Evaluation of Cardiovascular Out-
come Results: A Long Term Evaluation
(LEADER) trial was a randomized double-
blind trial that assessed the effect of
liraglutide, a GLP-1 receptor agonist, ver-
sus placebo and standard care, on cardio-
vascular outcomes in patients with type 2
diabetes at high risk for cardiovascular dis-
ease or with cardiovascular disease. Study
participants had a mean age of 64 years
and a mean duration of diabetes of nearly
13 years. Over 80% of study participants
had established cardiovascular disease
inclusive of a prior myocardial infarction
(MI), prior stroke or transient ischemic
attack, prior revascularization procedure,
or $50% stenosis of coronary, carotid,
or lower-extremity arteries. LEADER
showed that the composite primary out-
come (MI, stroke, or cardiovascular death)
occurred in fewer participants in the treat-
ment group (13.0%) when compared with
the placebo group (14.9%) after a median
follow-up of 3.8 years (30). Whether other
GLP-1 receptor agonists will have the same
effect in high-risk patients or if this drug class
will have similar effects in lower-risk patients
with diabetes remains unknown.
CVOT data for the DPP-4 inhibitors
sitagliptin (31), saxagliptin (32), and
alogliptin (33) have also been reported,
with no signicant difference in rates of
major cardiovascular events noted between
treatment and placebo groups in any of
these trials.
Insulin Therapy
Many patients with type 2 diabetes even-
tually require and benet from insulin
therapy. The progressive nature of type
2 diabetes should be regularly and objec-
tively explained to patients. Providers
S72 Pharmacologic Approaches to Glycemic Treatment Diabetes Care Volume 40, Supplement 1, January 2017

should avoid using insulin as a threat or
describing it as a sign of personal failure
or punishment.
Equipping patients with an algorithm for
self-titration of insulin doses based on self-
monitoring of blood glucose (SMBG) im-
proves glycemic control in patients with
type 2 diabetes initiating insulin (34). Com-
prehensive education regarding SMBG,
diet, and the avoidance of and appropriate
treatment of hypoglycemia are critically
important in any patient using insulin.
Basal Insulin
Basal insulin alone is the most convenient
initial insulin regimen, beginning at 10 units
per day or 0.10.2 units/kg/day, depending
on the degree of hyperglycemia. Basal in-
without a history of hypoglycemia may
use NPH insulin safely and at much lower
cost (27,35). Table 8.3 provides average
wholesale price information (cost per
1,000 units) for currently available insulin
products in the U.S. There have been sub-
stantial increases in the price of insulin over
the past decade and the cost-effectiveness
of different antihyperglycemic agents is an
important consideration when selecting
therapies (36). A follow-on U-100 (100
units/mL) glargine product (basaglar) is
now available in the U.S. This product was
approved through an abbreviated FDA ap-
proval pathway based, in part, on the FDAs
nding of safety and effectiveness for the
reference U-100 glargine product.
recommended starting dose of mealtime
insulin is 4 units, 0.1 U/kg, or 10% of the
basal dose. If A1C is ,8% (64 mmol/mol)
when starting mealtime bolus insulin, con-
sideration should be given to decreasing
the basal insulin dose.
Premixed Insulin
Premixed insulin products contain both a
basal and prandial component, allowing
coverage of both basal and prandial needs
with a single injection. NPH/Regular 70/30
insulin, for example, is composed of
70% NPH insulin and 30% regular insulin.
The use of premixed insulin products has
its advantages and disadvantages, as
discussed below in COMBINATION INJECTABLE
THERAPY.

sulin is usually prescribed in conjunction Bolus Insulin Concentrated Insulin Products

with metformin and sometimes one addi-
tional noninsulin agent. While there is evi-
dence for reduced risk of hypoglycemia
with newer, longer-acting basal insulin
analogs, people with type 2 diabetes
Many individuals with type 2 diabetes may
require mealtime bolus insulin dosing in
addition to basal insulin. Rapid-acting
analogs are preferred due to their
prompt onset of action after dosing. The
Several concentrated insulin preparations
are currently available. U-500 regular insu-
lin, by denition, is ve times as concen-
trated as U-100 regular insulin and has a
delayed onset and longer duration of

Table 8.3Median cost of insulins in the U.S. calculated as average wholesale price per 1,000 units of specied dosage
form/product (48)
Median AWP package
Insulins Compounds Dosage form/product price (min, max)*
Rapid-acting analogs
c Lispro U-100 vial $306
U-100 3 mL cartridges $306 ($306, $379)
U-100 prelled pen; U-200 prelled pen $394
c Aspart U-100 vial $306
U-100 3 mL cartridges $380
U-100 prelled pen $395
c Glulisine U-100 vial $283
U-100 prelled pen $365
c Inhaled insulin Inhalation cartridges $557 ($453, $754)
Short-acting
c Human Regular U-100 vial $165
Intermediate-acting
c Human NPH U-100 vial $165
U-100 prelled pen $350
Concentrated Human Regular insulin
c U-500 Human Regular insulin U-500 vial $165
U-500 prelled pen $213
Basal analogs
c Glargine U-100 vial; U-100 prelled pen; U-300 prelled pen $298
c Detemir U-100 vial; U-100 prelled pen $323
c Degludec U-100 prelled pen; U-200 prelled pen $355
Premixed products
c NPH/Regular 70/30 U-100 vial $165
U-100 prelled pen $350
c Lispro 50/50 U-100 vial $317
U-100 prelled pen $394
c Lispro 75/25 U-100 vial $317
U-100 prelled pen $394
c Aspart 70/30 U-100 vial $318
U-100 prelled pen $395
AWP listed alone when only one product and/or price.
care.diabetesjournals.org
action than U-100 regular, posessing both
prandial and basal properties. U-300
glargine and U-200 degludec are three
and two times as concentrated as their
U-100 formulations, have longer dura-
tions of action, and allow higher doses
of basal insulin administration per volume
used. The FDA has also approved a concen-
trated formulation of rapid-acting insulin
lispro, U-200 (200 units/mL). These concen-
trated preparations may be more comfort-
able for the patient and may improve
adherence for patients with insulin resis-
tance who require large doses of insulin.
While U-500 regular insulin is available in
both prelled pens and vials (a dedicated
syringe was FDA approved in July 2016),
other concentrated insulins are available
only in prelled pens to minimize the risk
of dosing errors.
Inhaled Insulin
Inhaled insulin is available for prandial
use with a more limited dosing range.
It is contraindicated in patients with
chronic lung disease such as asthma
and chronic obstructive pulmonary
disease and is not recommended in
patients who smoke or who recently
stopped smoking. It requires spirometry
(FEV1) testing to identify potential lung
disease in all patients prior to and after
starting therapy.
Combination Injectable Therapy
If basal insulin has been titrated to an
acceptable fasting blood glucose level
(or if the dose is .0.5 units/kg/day)
and A1C remains above target, consider
advancing to combination injectable
therapy (Fig. 8.2). When initiating com-
bination injectable therapy, metformin
therapy should be maintained while
other oral agents may be discontinued
on an individual basis to avoid unneces-
sarily complex or costly regimens (i.e.,
adding a fourth antihyperglycemic
agent). In general, GLP-1 receptor ago-
nists should not be discontinued with the
initiation of basal insulin. Sulfonylureas,
DPP-4 inhibitors, and GLP-1 receptor ago-
nists are typically stopped once more com-
plex insulin regimens beyond basal are
used. In patients with suboptimal blood
glucose control, especially those requiring
large insulin doses, adjunctive use of a thia-
zolidinedione or SGLT2 inhibitor may help
to improve control and reduce the amount
of insulin needed, though potential side
effects should be considered. Once an in-
sulin regimen is initiated, dose titration is
important with adjustments made in both
mealtime and basal insulins based on the
blood glucose levels and an understanding
of the pharmacodynamic prole of each
formulation (pattern control).
Studies have demonstrated the non-
inferiority of basal insulin plus a single
injection of rapid-acting insulin at the
largest meal relative to basal insulin
plus a GLP-1 receptor agonist relative
to two daily injections of premixed insulins
(Fig. 8.2). Basal insulin plus GLP-1 receptor
agonists are associated with less hypogly-
cemia and with weight loss instead of
weight gain but may be less tolerable
and have a greater cost (37,38). In No-
vember 2016, the FDA approved two
different once-daily combination products
containing basal insulin plus a GLP-1 recep-
tor agonist: insulin glargine plus lixisenatide
and insulin degludec plus liraglutide. Other
options for treatment intensication include
adding a single injection of rapid-acting in-
sulin analog (lispro, aspart, or glulisine) be-
fore the largest meal or stopping the basal
insulin and initiating a premixed (or bi-
phasic) insulin (NPH/Regular 70/30, 70/30
aspart mix, 75/25 or 50/50 lispro mix) twice
daily, usually before breakfast and before
dinner. Each approach has its advantages
and disadvantages. For example, providers
may wish to consider regimen exibility
when devising a plan for the initiation and
adjustment of insulin therapy in people
with type 2 diabetes, with rapid-acting in-
sulin offering greater exibility in terms
of meal planning than premixed insulin. If
one regimen is not effective (i.e., basal in-
sulin 1 GLP-1 receptor agonist), consider
switching to another regimen to achieve
A1C targets (i.e., basal insulin 1 single in-
jection of rapid-acting insulin or premixed
insulin twice daily) (39,40). Regular human
insulin and human NPH/Regular premixed
formulations (70/30) are less costly alter-
natives to rapid-acting insulin analogs and
premixed insulin analogs, respectively,
but their pharmacodynamic proles may
make them less optimal.
Figure 8.2 outlines these options, as
well as recommendations for further in-
tensication, if needed, to achieve gly-
cemic goals. If a patient is still above the
A1C target on premixed insulin twice
daily, consider switching to premixed
analog insulin three times daily (70/30
aspart mix, 75/25 or 50/50 lispro mix). In
general, three times daily premixed an-
alog insulins have been found to be non-
inferior to basal-bolus regimens with
Pharmacologic Approaches to Glycemic Treatment S73
similar rates of hypoglycemia (41). If a
patient is still above the A1C target on
basal insulin 1 single injection of rapid-
acting insulin before the largest meal, ad-
vance to a basal-bolus regimen with $2
injections of rapid-acting insulin before
meals. Consider switching patients from
one regimen to another (i.e., premixed
analog insulin three times daily to basal-
bolus regimen or vice-versa) if A1C targets
are not being met and/or depending on
other patient considerations (39,40).
References
1. American Diabetes Association, JDRF. American
Diabetes Association/JDRF Type 1 Diabetes
Sourcebook. Peters AL, Laffel L, Eds. Alexandria,
VA, American Diabetes Association, 2013
2. Chiang JL, Kirkman MS, Laffel LMB, Peters AL.
Type 1 diabetes through the life span: a position
statement of the American Diabetes Associa-
tion. Diabetes Care 2014;37:20342054
3. Wolpert HA, Atakov-Castillo A, Smith SA,
Steil GM. Dietary fat acutely increases glucose
concentrations and insulin requirements in
patients with type 1 diabetes: implications for
carbohydrate-based bolus dose calculation and
intensive diabetes management. Diabetes Care
2013;36:810816
4. Bell KJ, Toschi E, Steil GM, Wolpert HA.
Optimized mealtime insulin dosing for fat and
protein in type 1 diabetes: application of a
model-based approach to derive insulin doses
for open-loop diabetes management. Diabetes
Care 2016;39:16311634
5. Bell KJ, Smart CE, Steil GM, Brand-Miller JC,
King B, Wolpert HA. Impact of fat, protein, and
glycemic index on postprandial glucose control
in type 1 diabetes: implications for intensive diabe-
tes management in the continuous glucose moni-
toring era. Diabetes Care 2015;38:10081015
6. Yeh H-C, Brown TT, Maruthur N, et al. Compar-
ative effectiveness and safety of methods of in-
sulin delivery and glucose monitoring for diabetes
mellitus: a systematic review and meta-analysis.
Ann Intern Med 2012;157:336347
7. Bergenstal RM, Klonoff DC, Garg SK, et al.;
ASPIRE In-Home Study Group. Threshold-based
insulin-pump interruption for reduction of hypo-
glycemia. N Engl J Med 2013;369:224232
8. Wood JR, Miller KM, Maahs DM, et al.; T1D
Exchange Clinic Network. Most youth with
type 1 diabetes in the T1D Exchange Clinic Reg-
istry do not meet American Diabetes Associa-
tion or International Society for Pediatric and
Adolescent Diabetes clinical guidelines. Diabe-
tes Care 2013;36:20352037
9. Kmietowicz Z Insulin pumps improve control
and reduce complications in children with
type 1 diabetes. BMJ 2013;347:f5154
10. Phillip M, Battelino T, Atlas E, et al. Nocturnal
glucose control with an articial pancreas at a di-
abetes camp. N Engl J Med 2013;368:824833
11. The Diabetes Control and Complications
Trial Research Group. The effect of intensive
treatment of diabetes on the development
and progression of long-term complications in
insulin-dependent diabetes mellitus. N Engl J
Med 1993;329:977986
S80 Cardiovascular Disease and Risk Management Diabetes Care Volume 40, Supplement 1, January 2017

Table 9.1Recommendations for statin and combination treatment in people signicant, reduction in risk as patients
with diabetes with type 2 diabetes (47). Even though
Recommended the data are not denitive, similar statin
Age Risk factors statin intensity* treatment approaches should be consid-
,40 years None None ered for patients with type 1 or type 2
ASCVD risk factor(s)** Moderate or high diabetes, particularly in the presence of
ASCVD High other cardiovascular risk factors. Please
4075 years None Moderate refer to Type 1 Diabetes Mellitus and
ASCVD risk factors High Cardiovascular Disease: A Scientic
ASCVD High Statement From the American Heart As-
ACS and LDL cholesterol $50 mg/dL (1.3 mmol/L) Moderate plus sociation and American Diabetes Associ-
or in patients with a history of ASCVD who ezetimibe ation (60) for additional discussion.
cannot tolerate high-dose statins High-intensity statin therapy is rec-
.75 years None Moderate ommended for all patients with diabe-
ASCVD risk factors Moderate or high
tes and ASCVD. Treatment with a
ASCVD High
moderate dose of statin should be con-
ACS and LDL cholesterol $50 mg/dL (1.3 mmol/L) Moderate plus
or in patients with a history of ASCVD who ezetimibe
sidered if the patient does not have
cannot tolerate high-dose statins ASCVD but has additional ASCVD risk
factors.
*In addition to lifestyle therapy. **ASCVD risk factors include LDL cholesterol $100 mg/dL
(2.6 mmol/L), high blood pressure, smoking, chronic kidney disease, albuminuria, and family
history of premature ASCVD. Ongoing Therapy and Monitoring
With Lipid Panel
In adults with diabetes, it is reasonable
use for assessing cardiovascular risk in based on risk prole. High-intensity sta- to obtain a lipid prole (total choles-
individuals with diabetes. tins, if well tolerated, are still appropri- terol, LDL cholesterol, HDL cholesterol,
Age 4075 Years ate and recommended for older adults and triglycerides) at the time of diagno-
In low-risk patients with diabetes aged with ASCVD. High-intensity statin ther- sis, at the initial medical evaluation, and
4075 years, moderate-intensity statin apy may also be appropriate in adults at least every 5 years thereafter. A lipid
treatment should be considered in addi- with diabetes .75 years of age with ad- panel should also be obtained immedi-
tion to lifestyle therapy. Clinical trials in ditional ASCVD risk factors. However, ately before initiating statin therapy.
high-risk patients with increased cardio- the riskbenet prole should be rou- Once a patient is taking a statin, testing
vascular risk (e.g., LDL cholesterol $100 tinely evaluated in this population, for LDL cholesterol may be considered
mg/dL [2.6 mmol/L], high blood pres- with downward titration (e.g., high to on an individual basis (e.g., to monitor
sure, smoking, albuminuria, and family moderate intensity) performed as for adherence and efcacy). In cases
history of premature ASCVD) and with needed. See Section 11 Older Adults where patients are adherent but the
ASCVD (5759) have demonstrated that for more details on clinical consider- LDL cholesterol level is not responding,
more aggressive therapy with high ations for this population. clinical judgment is recommended to
doses of statins led to a signicant re- Age <40 Years and/or Type 1 Diabetes determine the need for and timing of
duction in cardiovascular events. High- Very little clinical trial evidence exists lipid panels. In individual patients, the
intensity statins are recommended in all for patients with type 2 diabetes under highly variable LDL cholesterollowering
such patients. the age of 40 years or for patients with response seen with statins is poorly un-
Age >75 Years type 1 diabetes of any age. In the Heart derstood (61). When maximally tolerated
For adults with diabetes .75 years of Protection Study (lower age limit 40 doses of statins fail to substantially lower
age, there are limited data regarding years), the subgroup of ;600 patients LDL cholesterol (,30% reduction from
the benets and risks of statin therapy. with type 1 diabetes had a proportion- the patients baseline), there is no strong
Statin therapy should be individualized ately similar, although not statistically evidence that combination therapy should
be used. Clinicians should attempt to
nd a dose or alternative statin that is tol-
Table 9.2High-intensity and moderate-intensity statin therapy*
erable, if side effects occur. There is evi-
High-intensity statin therapy Moderate-intensity statin therapy
(lowers LDL cholesterol by $50%) (lowers LDL cholesterol by 30% to ,50%)
dence for benet from even extremely
low, less than daily, statin doses (62).
Atorvastatin 4080 mg Atorvastatin 1020 mg
Increased frequency of LDL choles-
Rosuvastatin 2040 mg Rosuvastatin 510 mg
terol monitoring should be considered
Simvastatin 2040 mg
for patients with new-onset ACS. In-
Pravastatin 4080 mg
Lovastatin 40 mg
creased frequency of LDL cholesterol
Fluvastatin XL 80 mg monitoring may also be considered in
Pitavastatin 24 mg adults with heterozygous familial hyper-
cholesterolemia who require additional
*Once-daily dosing. XL, extended release.
lowering of LDL cholesterol.
Copyrig t 2017 AACE CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(Suppl 2) 15

Table 13
Primary Lipid-Lowering Drug Classes
a b
Drug class Metabolic effect Main considerations
HMG-CoA reductase Primarily LDL-C 21-55% by Liver function test prior to therapy and as clinically
inhibitors (statins: competitively inhibiting rate- indicated thereafter.
lovastatin, limiting step of cholesterol synthesis Myalgias and muscle weakness in some patients
pravastatin, in the liver, leading to upregulation Potential for drug-drug interaction between some
fluvastatin, of hepatic LDL receptors statins and CYP450 3A4 inhibitors, cyclosporine,
simvastatin, warfarin, and protease inhibitors.
atorvastatin, Effects on TG and HDL-C are less Myopathy/rhabdomyolysis in rare cases; increased risk
rosuvastatin, pronounced ( TG 6-30% and with co-administration of some drugs (see
pitavastatin) HDL-C 2-10%) product labeling).
Simvastatin dosages of 80 mg are no longer recommended.
Do not exceed 20 mg simvastatin daily with amlodipine
or ranolazine.
Plasma elevations of rosuvastatin may be higher among
Asian persons than other ethnic groups.
New-onset diabetes is increased in patients treated with
statins; however, it is dose-related, occurs primarily in
patients with MetS, appears to be less common with
pravastatin and possibly pitavastatin, and occurs overall
to a lesser extent than the associated decrease
in ASCVD.
Cholesterol absorption Primarily LDL-C 10- Myopathy/rhabdomyolysis (rare) Myopathy/
inhibitors (ezetimibe) 18% by inhibiting intestinal rhabdomyolysis (rare)
absorption of cholesterol and When co-administered with statins or fenofibrate, risks
decreasing delivery to the liver, associated with those drugs remain (e.g., myopathy/
leading to upregulation of hepatic rhabdomyolysis, cholelithiasis)
LDL receptors
Apo B 11-16%
In combination with statins,
additional LDL-C 25%,
total LDL-C 34-61%
In combination with
fenofibrate, LDL-C 20-22% and
apo B 25-26% without reducing
HDL-C
PCSK9 (Proprotein LDL-C 48-71%, non-HDL-C 49- Requires subQ self-injection, and refrigeration is
convertase subtilisin/kexin 58%, Total-C 36-42%, Apo B 42- generally needed.
type 9) inhibitors 55% by inhibiting PCSK9 binding Adverse reactions resulted in discontinuation in 2.2% overall,
(alirocumab, evolocumab) with LDLRs, increasing the number 1.2% more than placebo for evolocumab, and 5.3% overall,
of LDLRs available to clear LDL, 0.2% more than placebo for alirocumab. Overall levels of
and lowering LDL-C levels adverse reactions and discontinuation very low.
Adverse reactions with significantly different rates
between drug and placebo were local injection site
reactions (1.9% greater for alirocumab vs. placebo,
0.7% greater for evolocumab vs. placebo) and influenza
(1.2% greater for alirocumab vs. placebo, 0.2% for
evolocumab vs. placebo). The most common adverse
reactions with similar rates for drug vs. placebo were
for the following:
Alirocumab (4-12%; most common to least common):
nasopharyngitis, influenza, urinary tract infections, diarrhea,
bronchitis, and myalgia;
Evolocumab (2-4%; most common to least common):
Nasopharyngitis, back pain, and upper respiratory
tract infection.
Continued on next page
16 CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(Suppl 2)
Fibric acid derivatives
(gemfibrozil, fenofibrate,
fenofibric acid)
Niacin (nicotinic acid)
Bile acid sequestrants
(cholestyramine,
colestipol, colesevelam
hydrochloride)
MTP inhibitor (lomitapide)
Table 13 Continued
Primarily TG 20-35%,
HDL-C 6-18% by
stimulating lipoprotein lipase
activity
Fenofibrate may TC and
LDL-C 20-25%
Lower VLDL-C and LDL-C;
reciprocal rise in LDL-C
transforms the profile into a less
atherogenic form by shifting
fewer LDL particles to larger size
Fenofibrate fibrinogen level
LDL-C 10-25%, TG
20-30%, HDL-C 10-
35% by decreasing hepatic
synthesis of LDL-C and
VLDL-C
Lipoprotein (a)
Transforms LDL-C to less
atherogenic form by
increasing average particle size
and also decreases LDL particle
concentration
Primarily LDL-C 15-25% by
binding bile acids and preventing Frequent constipation and/or bloating, which can
their reabsorption in the ileum
(causing hepatic cholesterol
depletion and LDLR upregulation)
Colesevelam glucose and
hemoglobin A1C (~0.5%); is FDA
approved to treat T2DM
Up to LDL-C 40%, TC 36%,
apo B 39%, TG 45%, and non-
HDL-C 40% (depending on dose)
in patients with HoFH by binding
and inhibiting MTP, which inhibits
synthesis of chylomicrons
and VLDL
Copyrig t 2017 AACE
Gemfibrozil may LDL-C 10-15%.
GI symptoms, possible cholelithiasis.
May potentiate effects of orally administered
anticoagulants. c
Gemfibrozil may fibrinogen level .
Gemfibrozil and fenofibrate can homocysteine
d
independent of vitamin concentrations .
Myopathy/rhabdomyolysis when used with statin
(uncommon with gemfibrozil, but increased risk
with all statins except fluvastatin); interaction
less likely with fenofibrate or fenofibric acid (no
apparent difference by statin).
Fibrates are associated with increased serum
creatinine levels, which may not reflect
renal dysfunction.
Fenofibrate dose should be cut by two-thirds and
gemofibrozil by one-half when eGFR is 15-60,
and fibrates should be avoided when eGFR is <15.
May cause muscle disorders.
Can improve diabetic retinopathy.
Potential for frequent skin flushing, pruritus, abdominal
discomfort, hepatotoxicity (rare but may be severe),
nausea, peptic ulcer, atrial fibrillation.
Deleterious effect on serum glucose at higher dosages.
Increases uric acid levels; may lead to gout.
May serum TG
reduce adherence
Many potential drug interactions (decreased drug
absorption), less so with colesevelam (see product
labeling)
May reduce absorption of folic acid and fat-soluble
vitamins such as vitamins A, D, and K
Can cause increases in transaminases (ALT,
AST). Monitoring of ALT, AST, alkaline phosphatase,
and total bilirubin prior to initiation, and of ALT and AST
during treatment, is required per FDA REMS.
Causes increases in hepatic fat (steatosis) with or without
concomitant elevated transaminases, which may be a risk
for progressive liver diseases.
Also causes steatosis of the small intestine with resulting
abdominal pain and steatorrhea unless a very-low-fat
diet is followed. May also cause fat-soluble vitamin
deficiency unless vitamin supplements are taken.
Caution should be exercised when used with other drugs
with potential hepatotoxicity. Because of hepatotoxicity
risk, only available through REMS program.
Copyrig t 2017 AACE CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(Suppl 2) 17

Table 13 Continued
Antisense apolipoprotein LDL-C 21%, TC 19%, apo B Can cause increases in transaminases (ALT,
B oligonucleotide 24%, and non-HDL-C 22% in AST). Monitoring of ALT, AST, alkaline phosphatase,
(mipomersen via subQ patients with HoFH by degrading and total bilirubin prior to initiation, and of ALT and AST
injection) mRNA for apo B-100, the principal during treatment is recommended.
apolipoprotein needed for hepatic Causes increases in hepatic fat (steatosis) with or without
synthesis of VLDL (and subsequent concomitant elevated transaminases, which may be a risk
intraplasma production of IDL for progressive liver diseases.
and LDL) Caution should be exercised when used with other drugs
with potential hepatotoxicity. Because of hepatotoxicity
risk, only available through REMS program.
Omega-3 fatty acids TG 27-45%, TC 7-10%, VLDL-C TG levels should be carefully assessed prior to initiating
(icosapent ethyl, omega-3- 20-42%, apo B 4%, and non- therapy and periodically during therapy.
acid ethyl esters) HDL-C 8-14% in individuals with Omega-3-acid ethyl esters can increase LDL-C levels.
severe hypertriglyceridemia, most Monitoring of LDL-C levels during treatment is
likely by reducing hepatic VLDL- recommended.
TG synthesis and/or secretion May prolong bleeding time. Periodic monitoring of coagulation
and enhancing TG clearance from status should be undertaken in patients receiving treatment
circulating VLDL particles. Other with omega-3 fatty acids and other drugs affecting
potential mechanisms of action coagulation.
include: increased -oxidation; Periodic monitoring of ALT and AST levels during treatment
inhibition of acyl-CoA; is recommended for patients with hepatic impairment. Some
1,2-diacylglyceral acyltransferase; patients may experience increases in ALT levels only.
decreased hepatic lipogenesis; Caution should be exercised when treating patients with a
and increased plasma lipoprotein known hypersensitivity to fish and/or shellfish.
activity The effect of omega-3 fatty acids on cardiovascular morbidity
Icosapent ethyl LDL-C 5%, and mortality and the risk of pancreatitis has not been
whereas omega-3-acid ethyl esters determined in patients with severe hypertriglyceridemia.
LDL-C 45% In patients with paroxysmal or persistent AF, therapy with
omega-3-acid ethyl esters may be associated with increased
frequency of symptomatic AF or flutter, especially within the
first 2 to 3 months after initiation.
The most common adverse events in patients receiving omega-3
fatty acids included arthralgia (2.3%), eructation (4%),
dyspepsia (3%), and taste perversion (4%). Patients may also
experience constipation, gastrointestinal disorders, vomiting,
rash, or pruritus.
Omega-3 fatty acids should be used with caution in nursing
mothers and should only be used in pregnant women if the
benefits of treatment outweigh the potential risk of fetal harm.
Abbreviations: AF = atrial fibrillation; ALT = alanine aminotransferase; AR = adverse reaction; AST = aspartate aminotransferase; apo =
apolipoprotein; eGFR = estimated glomerular filtration rate; FDA = U.S. Food and Drug Administration; GI = gastrointestinal; HDL-C
= high-density lipoprotein cholesterol; HMG-CoA = hydroxymethylglutaryl-coenzyme A; LDL-C = low-density lipoprotein cholester-
ol; LDLR = low-density lipoprotein receptor; MTP = microsomal triglyceride transfer protein; REMS = Risk Evaluation and Mitigation
Strategies; subQ = subcutaneous; TC = total cholesterol; TG = triglycerides; VLDL-C, very low-density lipoprotein cholesterol
a Percentage of change varies depending on baseline lipid variables and dosages. Statin potency and dosages vary.
b Most frequent or serious; See prescribing information for complete contraindications, warnings, precautions, and side effects.
c Results vary. Gemfibrozil has been shown to decrease, have no effect on, or increase fibrinogen depending on the study.
d Results vary. Gemfibrozil has been shown to have no effect on or increase homocysteine.

Proprotein convertase subtilisin/kexin Combination Therapy

type 9 (PCSK9) Inhibitors
R69. PCSK9 inhibitors should be considered for use in
combination with statin therapy for LDL-C lowering
in individuals with FH (Grade A; BEL 1).
R70. PCSK9 inhibitors should be considered in indi-
viduals with clinical cardiovascular disease who are
unable to reach LDL-C/non-HDL-C goals with maxi-
mally tolerated statin therapy. They should not be used
as monotherapy except in statin-intolerant individuals
(Grade A; BEL 1).
R71. Combination therapy of lipid-lowering agents
should be considered when the LDL-C/non-HDL-C
level is markedly increased and monotherapy (usu-
ally with a statin) does not achieve the therapeutic goal
(Grade A; BEL 1).
Special Considerations: Women
R72. Women should be evaluated for their ASCVD risk
and be treated with pharmacotherapy if lifestyle inter-
vention is insufficient (Grade C; BEL 4; upgraded
due to potential benefit).
Copyrig t 2017 AACE CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(Suppl 2) 61

Table 18
Lipid-Lowering Drug Therapies, Usual Starting Dosages and Dosage Ranges
Usual recommended
Agent starting daily dosage Dosage range
Statins
Lovastatin 20 mg 10-80 mg
Pravastatin 40 mg 10-80 mg
Simvastatin 20-40 mg 5-80 mga
Fluvastatin 40 mg 20-80 mg
Atorvastatin 10-20 mg 10-80 mg
Rosuvastatin 10 mg 5-40 mg
Pitavastatin 2 mg 2-4 mg
Cholesterol absorption inhibitors
Ezetimibe 10 mg 10 mg
PCSK9 Inhibitors
Alirocumab 75 mg every 2 weeks 75-150 mg every 2 weeks
140 mg every 2 weeks or
Evolocumab Not applicable
420 mg once monthly
Fibrates
Fenofibrate 48-145 mg 48-145 mg
Gemfibrozil 1,200 mg 1,200 mg
Fenofibric acid 45-135 mg 45-135 mg
Niacin
Immediate-release 250 mg 250-3,000 mg
Extended-release 500 mg 500-2,000 mg
Bile acid sequestrants
Cholestyramine 8-16 g 4-24 g
Colestipol 2g 2-16 g
Colesevelam 3.8 g 3.8-4.5 g
Combination therapies (single pill)
Ezetimibe/simvastatin 10/20 mg 10/10-10/80 mg
Extended-release
500/20 mg 500/20-1,000/20 mg
niacin/simvastatin
MTP inhibitor
5 mg, with
Lomitapide 5-60 mg
subsequent titration
Antisense apolipoprotein B oligonucleotide
Mipomersen (SubQ injection) 200 mg once weekly 200 mg once weekly
Omega-3 fatty acids
Omega-3-acid ethyl esters
4 g per day 4 g per day
(Lovaza)
Icosapent ethyl (Vascepa) 4 g per day 4 g per day
Abbreviations: MTP = microsomal transfer protein; PCSK9 = proprotein convertase subtilisin/kexin
type 9; SubQ = subcutaneous
a Simvastatin, 80 mg, not approved for therapy unless individual has been on treatment for more than 1

year without myopathy.

62 CPG for Managing Dyslidemia and Prevention of CVD, Endocr Pract. 2017;23(Suppl 2) Copyrig t 2017 AACE

Table 19
Comparison of Statin Effects on Lipids After 6 Weeks of Treatment in Men and Women
With LDL-C 160 mg/dL and 250 mg/dLa,b (N = 2,431)
Dosage range,
Statin mg daily TC LDL-C HDL-C TG
Lovastatin 20-80 21 to 36 29 to 48 4.6 to 8.0 12 to 13
Pravastatin 10-40 15 to 22 20 to 30 3.2 to 5.6 8 to 13
Simvastatin 10-80d 20 to 33 28 to 46 5.2 to 6.8 12 to 18
Fluvastatin 20-40 13 to 19 17 to 23 0.9 to 3.0 5 to 13
Atorvastatin 10-80 27 to 39 37 to 51 2.1 to 5.7c 20 to 28
Rosuvastatin 10-40 33 to 40 45 to 55 7.7 to 9.6 20 to 26
Abbreviations: HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TC = total cholesterol; TG = triglycerides
a The lipid-lowering effects of the various statins in these studies are representative of those seen in other controlled trials, with one exception. In the

CARE (Cholesterol and Recurrent Events), WOSCOPS (West of Scotland Coronary Prevention Study), and LIPID (Long-Term Intervention With
Pravastatin in Ischemic Disease) trials, pravastatin had a slightly greater TG-lowering effect.
b Figures for lovastatin and fluvastatin are from the 8-week CURVES trial (Comparative Dose Efficacy of Atorvastatin, Simvastatin, Pravastatin,

Lovastatin, and Fluvastatin), a comparison of the effects on lipids of lovastatin, fluvastatin, atorvastatin, simvastatin, and pravastatin in men and
women with LDL-C levels from 192 to 244 mg/dL (N = 534).
c HDL-C increase was with the lowest atorvastatin dosage, and benefit decreased as dosage increased.
d Not to be used at dosages of 80 mg unless individual has been on treatment for more than 12 months.

Fig. 2. Meta-analysis of proportional effects on major vascular events per mM/L LDL-C reduction in 169,138 participants in 26 random-
ized trials of statins over a median period of 5 years (121 [EL 1; MRCT]) (Cholesterol Treatment Trialists Collaborators, 2010). Left,
unweighted RRs are plotted for each comparison of first event rates between randomly allocated treatment groups. Right, RRs are
weighted per 10 mmol/L LDL cholesterol (LDL-C) difference at 1 year. RRs are shown with horizontal lines denoting 99% CIs or
with open diamonds denoting 95% CIs. CABG = coronary artery bypass graft; CHD = coronary heart disease; CI = confidence interval;
LDL-C = low-density lipoprotein cholesterol; MI = myocardial infarction; PTCA = percutaneous transluminal coronary angioplasty; RR
= relative risk. Reprinted from The Lancet, Vol 376, Cholesterol Treatment Trialists (CTT) Collaborators. Efficacy and safety of more
intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials, 1670-1681, Copyright
(2010), with permission from Elsevier (121 [EL 1; MRCT]).
 Clinical Review & Education Special Communication 2014 Guideline for Management of High Blood Pressure

Table 4. Evidence-Based Dosing for Antihypertensive Drugs

Target Dose
Antihypertensive Medication Initial Daily Dose, mg in RCTs Reviewed, mg No. of Doses per Day
ACE inhibitors
Captopril 50 150-200 2
Enalapril 5 20 1-2
Lisinopril 10 40 1
Angiotensin receptor blockers
Eprosartan 400 600-800 1-2
Candesartan 4 12-32 1
Losartan 50 100 1-2
Valsartan 40-80 160-320 1
Irbesartan 75 300 1
-Blockers
Atenolol 25-50 100 1
Metoprolol 50 100-200 1-2
Calcium channel blockers
Amlodipine 2.5 10 1
Diltiazem extended release 120-180 360 1
Nitrendipine 10 20 1-2
Thiazide-type diuretics Abbreviations: ACE,
Bendroflumethiazide 5 10 1 angiotensin-converting enzyme; RCT,
Chlorthalidone 12.5 12.5-25 1 randomized controlled trial.
a
Hydrochlorothiazide 12.5-25 25-100a 1-2 Current recommended
evidence-based dose that balances
Indapamide 1.25 1.25-2.5 1
efficacy and safety is 25-50 mg daily.

The following important points should be noted. First, many
people will require treatment with more than one antihyperten-
sive drug to achieve BP control. While this recommendation ap-
plies only to the choice of the initial antihypertensive drug, the panel
suggests that any of these 4 classes would be good choices as add-on
agents (recommendation 9). Second, this recommendation is spe-
cific for thiazide-type diuretics, which include thiazide diuretics,
chlorthalidone, and indapamide; it does not include loop or potas-
sium-sparing diuretics. Third, it is important that medications be
dosed adequately to achieve results similar to those seen in the RCTs
(Table 4). Fourth, RCTs that were limited to specific nonhyperten-
sive populations, such as those with coronary artery disease or heart
failure, were not reviewed for this recommendation. Therefore, rec-
ommendation 6 should be applied with caution to these popula-
tions. Recommendations for those with CKD are addressed in rec-
ommendation 8.
Recommendation 7
In the general black population, including those with diabetes, ini-
tial antihypertensive treatment should include a thiazide-type di-
uretic or CCB.
For general black population: Moderate Recommendation Grade B
For black patients with diabetes: Weak Recommendation Grade C
Recommendation 7 is based on evidence statements from ques-
tion 3. In cases for which evidence for the black population was the
same as for the general population, the evidence statements for the
general population apply to the black population. However, there
are some cases for which the results for black persons were differ-
ent from the results for the general population (question 3, evi-
dence statements 2, 10, and 17). In those cases, separate evidence
statements were developed.
This recommendation stems from a prespecified subgroup
analysis of data from a single large trial (ALLHAT) that was rated
good.31 In that study, a thiazide-type diuretic was shown to be
more effective in improving cerebrovascular, heart failure, and
combined cardiovascular outcomes compared to an ACEI in the
black patient subgroup, which included large numbers of diabetic
and nondiabetic participants (question 3, evidence statements 10,
15 and 17). Therefore, the recommendation is to choose thiazide-
type diuretics over ACEI for black patients. Although a CCB was
less effective than a diuretic in preventing heart failure in the black
subgroup of this trial (question 3, evidence statement 14), there
were no differences in other outcomes (cerebrovascular, CHD,
combined cardiovascular, and kidney outcomes, or overall mortal-
ity) between a CCB and a diuretic (question 3, evidence state-
ments 6, 8, 11, 18, and 19). Therefore, both thiazide-type diuretics
and CCBs are recommended as first-line therapy for hypertension
in black patients.
The panel recommended a CCB over an ACEI as first-line
therapy in black patients because there was a 51% higher rate
(relative risk, 1.51; 95% CI, 1.22-1.86) of stroke in black persons in
ALLHAT with the use of an ACEI as initial therapy compared with
use of a CCB (question 3, evidence statement 2).32 The ACEI was
also less effective in reducing BP in black individuals compared
with the CCB (question 3, evidence statement 2).32 There were no
outcome studies meeting our eligibility criteria that compared
diuretics or CCBs vs -blockers, ARBs, or other renin-angiotensin
system inhibitors in black patients.
The recommendation for black patients with diabetes is weaker
than the recommendation for the general black population be-
cause outcomes for the comparison between initial use of a CCB com-
pared to initial use of an ACEI in black persons with diabetes were
not reported in any of the studies eligible for our evidence review.

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 Clinical Review & Education Special Communication 2014 Guideline for Management of High Blood Pressure

Figure. 2014 Hypertension Guideline Management Algorithm

Adult aged 18 years with hypertension

Implement lifestyle interventions

(continue throughout management).

Set blood pressure goal and initiate blood pressure lowering-medication

based on age, diabetes, and chronic kidney disease (CKD).

General population
(no diabetes or CKD) Diabetes or CKD present

Age 60 years Age <60 years All ages All ages

Diabetes present CKD present with
No CKD or without diabetes

Blood pressure goal Blood pressure goal Blood pressure goal Blood pressure goal
SBP <150 mm Hg SBP <140 mm Hg SBP <140 mm Hg SBP <140 mm Hg
DBP <90 mm Hg DBP <90 mm Hg DBP <90 mm Hg DBP <90 mm Hg

Nonblack Black All races

Initiate thiazide-type diuretic Initiate thiazide-type diuretic Initiate ACEI or ARB, alone
or ACEI or ARB or CCB, alone or CCB, alone or in combination with other
or in combination.a or in combination. drug class.a

Select a drug treatment titration strategy

A. Maximize first medication before adding second or
B. Add second medication before reaching maximum dose of first medication or
C. Start with 2 medication classes separately or as fixed-dose combination.

Yes
At goal blood pressure?
No

Reinforce medication and lifestyle adherence.

For strategies A and B, add and titrate thiazide-type diuretic or ACEI or ARB or CCB (use
medication class not previously selected and avoid combined use of ACEI and ARB).
For strategy C, titrate doses of initial medications to maximum.

Yes
At goal blood pressure?
No

Reinforce medication and lifestyle adherence.

Add and titrate thiazide-type diuretic or ACEI or ARB or CCB (use medication class
not previously selected and avoid combined use of ACEI and ARB).

Yes
At goal blood pressure?
No

Reinforce medication and lifestyle adherence.

Add additional medication class (eg, -blocker, aldosterone antagonist, or others)
and/or refer to physician with expertise in hypertension management.

No Yes Continue current

At goal blood pressure? treatment and
monitoring.b

a
SBP indicates systolic blood pressure; DBP, diastolic blood pressure; ACEI, ACEIs and ARBs should not be used in combination.
b
angiotensin-converting enzyme; ARB, angiotensin receptor blocker; and CCB, If blood pressure fails to be maintained at goal, reenter the algorithm where
calcium channel blocker. appropriate based on the current individual therapeutic plan.

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 Clinical Review & Education Special Communication 2014 Guideline for Management of High Blood Pressure

Table 6. Guideline Comparisons of Goal BP and Initial Drug Therapy for Adults With Hypertension
Goal BP,
Guideline Population mm Hg Initial Drug Treatment Options
2014 Hypertension General 60 y <150/90
guideline Nonblack: thiazide-type diuretic, ACEI,
General <60 y <140/90 ARB, or CCB; black: thiazide-type diuretic
or CCB
Diabetes <140/90
CKD <140/90 ACEI or ARB
ESH/ESC 201337 General nonelderly <140/90
General elderly <80 y <150/90 Diuretic, -blocker, CCB, ACEI, or ARB
General 80 y <150/90
Diabetes <140/85 ACEI or ARB
CKD no proteinuria <140/90 Abbreviations: ADA, American
ACEI or ARB
CKD + proteinuria <130/90 Diabetes Association; ACEI,
CHEP 201338 General <80 y <140/90 angiotensin-converting enzyme
Thiazide, -blocker (age <60y), ACEI inhibitor; ARB, angiotensin receptor
General 80 y <150/90 (nonblack), or ARB
blocker; CCB, calcium channel
Diabetes <130/80 ACEI or ARB with additional CVD risk blocker; CHEP, Canadian
ACEI, ARB, thiazide, or DHPCCB without Hypertension Education Program;
additional CVD risk
CKD, chronic kidney disease; CVD,
CKD <140/90 ACEI or ARB cardiovascular disease; DHPCCB,
ADA 201339 Diabetes <140/80 ACEI or ARB dihydropyridine calcium channel
KDIGO 201240 CKD no proteinuria 140/90 blocker; ESC, European Society of
ACEI or ARB Cardiology; ESH, European Society of
CKD + proteinuria 130/80 Hypertension; ISHIB, International
NICE 201141 General <80 y <140/90 <55 y: ACEI or ARB Society for Hypertension in Blacks;
General 80 y <150/90 55 y or black: CCB JNC, Joint National Committee;
KDIGO, Kidney Disease: Improving
ISHIB 201042 Black, lower risk <135/85
Global Outcome; NICE, National
Target organ damage <130/80 Diuretic or CCB
Institute for Health and Clinical
or CVD risk Excellence.

line was not endorsed by any federal agency or professional society
prior to publication and thus is a departure from previous JNC reports.
The panel anticipates that an objective assessment of this report fol-
lowing publication will allow open dialogue among endorsing enti-
ties and encourage continued attention to rigorous methods in guide-
line development, thus raising the standard for future guidelines.
Discussion
The recommendations based on RCT evidence in this guideline dif-
fer from recommendations in other currently used guidelines sup-
ported by expert consensus (Table 6). For example, JNC 7 and other
guidelines recommended treatment to lower BP goals in patients with
diabetes and CKD based on observational studies.12 Recently, sev-
eral guideline documents such as those from the American Diabetes
Association have raised the systolic BP goals to values that are simi-
lar to those recommended in this evidence-based guideline.37-42 Other
guidelines such as those of the European Society of Hypertension/
European Society of Cardiology also recommend a systolic BP goal of
lower than 150 mm Hg, but it is not clear at what age cutoff in the gen-
eral population this goal specifically applies.37 This changing land-
scape is understandable given the lack of clear RCT evidence in many
clinical situations.
History of JNC 8
The panel was originally constituted as the Eighth Joint National
Committee on the Prevention, Detection, Evaluation, and Treat-
ment of High Blood Pressure (JNC 8). In March 2008 NHLBI sent
letters inviting the co-chairs and committee members to serve on
JNC 8. The charge to the committee was as follows: The JNC 8 will
review and synthesize the latest available scientific evidence, up-
date existing clinical recommendations, and provide guidance to busy
primary care clinicians on the best approaches to manage and con-
trol hypertension in order to minimize patients risk for cardiovas-
cular and other complications. The committee was also asked to
identify and prioritize the most important questions for the evi-
dence review. In June 2013, NHLBI announced its decision to dis-
continue developing clinical guidelines including those in process,
instead partnering with selected organizations that would develop
the guidelines.43,44 Importantly, participation in this process re-
quired that these organizations be involved in producing the final
content of the report. The panel elected to pursue publication in-
dependently to bring the recommendations to the public in a timely
manner while maintaining the integrity of the predefined process.
This report is therefore not an NHLBI sanctioned report and does
not reflect the views of NHLBI.
Conclusions
It is important to note that this evidence-based guideline has not re-
defined high BP, and the panel believes that the 140/90 mm Hg defi-
nition from JNC 7 remains reasonable. The relationship between
naturally occurring BP and risk is linear down to very low BP, but the
benefit of treating to these lower levels with antihypertensive drugs
is not established. For all persons with hypertension, the potential
benefits of a healthy diet, weight control, and regular exercise can-
not be overemphasized. These lifestyle treatments have the poten-
tial to improve BP control and even reduce medication needs. Al-

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 ASH/ISH Hypertension Guidelines | Weber et al.

TABLE I. Drug Selection in Hypertensive Patients With or Without Other Major Conditions
Add Second Drug If
Needed to Achieve a If Third Drug is Needed to Achieve
Patient Type First Drug BP <140/90 mm Hg a BP of <140/90 mm Hg

A. When hypertension is the only or main condition

Black patients (African
ancestry): All ages
White and other non-black
Patients: Younger than 60
CCBa or thiazide diuretic ARBb or ACE inhibitor Combination of CCB + ACE inhibitor
(If unavailable can add or ARB + thiazide diuretic
alternative first drug
choice)
b
ARB or ACE inhibitor CCBa or thiazide diuretic Combination of CCB + ACE inhibitor
or ARB + thiazide diuretic

White and other non-black CCBa or thiazide diuretic (Although ACE ARBb or ACE inhibitor (or Combination of CCB + ACE inhibitor
patients: 60 y and older inhibitors or ARBs are also usually effective) CCB or thiazide if ACE or ARB + thiazide diuretic
inhibitor or ARB used first)

B. When hypertension is associated with other conditions

Hypertension and diabetes
ARB or ACE inhibitor Note: in black patients, CCB or thiazide diuretic The alternative second drug
it is acceptable to start with a CCB or thiazide Note: in black patients, if (thiazide or CCB)
starting with a CCB or
thiazide, add an ARB or
ACE inhibitor

Hypertension and chronic ARB or ACE inhibitor Note: in black patients, CCB or thiazide diureticc The alternative second drug
kidney disease good evidence for renal protective effects of (thiazide or CCB)
ACE inhibitors

Hypertension and clinical b-Blocker plus ARB or ACE inhibitor CCB or thiazide diuretic The alternative second step drug
coronary artery diseased (thiazide or CCB)

Hypertension and stroke ACE inhibitor or ARB Thiazide diuretic or CCB The alternative second drug (CCB
historye or thiazide)

Hypertension and heart Patients with symptomatic heart failure should usually receive an ARB or ACE inhibitor + b-blocker + diuretic +
failure spironolactone regardless of blood pressure. A dihydropyridine CCB can be added if needed for BP control.
Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; eGFR,
estimated glomerular filtration rate.
a
CCBs are generally preferred, but thiazides may cost less.
b
ARBs can be considered because ACE inhibitors can cause cough and angioedema, although ACE inhibitors may cost less.
c
If eGFR <40 mL/min, a loop diuretic (eg, furosemide or torsemide) may be needed.
d
Note: If history of myocardial infarction, a b-blocker and ARB/or ACE inhibitor are indicated regardless of blood pressure.
e
Note: If using a diuretic, there is good evidence for indapamide (if available).

for patients who have a major comorbidity
associated with their hypertension. The Figure 1
displays an algorithm that summarizes the use of
therapy for most patients with hypertension.
The recommendations for particular drug classes
are made with the recognition that sometimes
only alternative drug classes will be available.
However, most of the time, the use of any drugs
that reduce blood pressure is more likely to help
protect patients from strokes and other serious
events than giving patients no drug at all.
BRIEF COMMENTS ON DRUG CLASSES
Note: There is an assumption, unless otherwise stated,
that all drugs in a class are similar to each other. We
only mention individual agents if they have an
important property that is not shared by the others in
its class. Table II provides a list of commonly used
antihypertensive drugs and their doses.
Angiotensin-converting enzyme Inhibitors
! These agents reduce blood pressure by blocking the
renin-angiotensin system. They do this by preventing
conversion of angiotensin I to the blood pressure-
raising hormone angiotensin II. They also increase
availability of the vasodilator bradykinin by block-
ing its breakdown.
! Angiotensin-converting enzyme inhibitors are well
tolerated. Their main side effect is cough (most
common in women and in patients of Asian and
African background). Angioedema is an uncommon
but potentially serious complication that can threa-

The Journal of Clinical Hypertension Vol 16 | No 1 | January 2014 21

ASH/ISH Hypertension Guidelines | Weber et al.

TABLE II. Dosages of Commonly Used TABLE II. (Continued)

Antihypertensive Drugs
Daily Dosage, mg
Daily Dosage, mg
Low Dosage Usual Dosage
Low Dosage Usual Dosage
Atenolol 25 100
Calcium channel blockers Bisoprolol 5 510
Nondihydropyridines Carvedilol 3.125 twice daily 6.2525 twice daily
Diltiazem 120 240360 Labetalol 100 twice daily 100300 twice daily
Verapamil 120 240480 Metoprolol succinate 25 50100
Metoprolol tartrate 25 twice daily 50100 twice daily
Dihydropyridines
Nadolol 20 4080
Amlodipine 2.5 510
Nebivolol 2.5 510
Felodipine 2.5 510
Propranolol 40 twice daily 40160 twice daily
Isradipine 2.5 twice 510 twice daily
daily a-Adrenergic receptor blockers
Nifedipine 30 3090 Doxazosin 1 12
Nitrendipine 10 20 Prazosin 1 twice daily 15 twice daily
Terazosin 1 12
Drugs that target the renin-angiotensin system
Angiotensin-converting enzyme inhibitors Vasodilators, central a-agonists, and adrenergic depleters
Benazepril 5 1040 Vasodilators
Captopril 12.5 twice daily 50100 twice daily Hydralazine 10 twice daily 25100 twice daily
Enalapril 5 1040 Minoxidil 2.5 510
Fosinopril 10 1040
Central alpha-agonists
Lisinopril 5 1040
Clonidine 0.1 twice daily 0.10.2 twice daily
Perindopril 4 48
Clonidine patch TTS-1, once weekly TTS-1, 2, or 3,
Quinapril 5 1040
once weekly
Ramipril 2.5 510
Methyldopa 125 twice daily 250500 twice daily
Trandolapril 12 28
Adrenergic depleters
Angiotensin receptor blockers
Reserpine 0.1 0.10.25
Azilsartan 40 80
Candesartan 4 832 All doses are given once-daily unless otherwise specified.
Eprosartan 400 600800
Irbesartan 150 150300
Losartan 50 50100 ten airway function, and it occurs most frequently in
Olmesartan 10 2040 black patients.
Telmisartan 40 4080 ! These drugs can increase serum creatinine by as
Valsartan 80 80320 much as 30%, but this is usually because they reduce
Direct renin inhibitor
pressure within the renal glomerulus and decrease
Aliskiren 75 150300
filtration. This is a reversible change in function and
is not harmful. An even greater increase in creatinine
Diuretics sometimes occurs when angiotensin-converting
Thiazide and thiazide-like diuretics enzyme inhibitors are combined with diuretics and
Bendroflumethiazide 5 10 produce large blood pressure reductions. Again, this
Chlorthalidone 12.5 12.525 change is reversible, although it may be necessary to
Hydrochlorothiazide 12.5 12.550
reduce doses of one or both drugs. If creatinine levels
Indapamide 1.25 2.5
increase substantially this can be caused by concom-
Loop diuretics itant treatment with nonsteroidal anti-inflammatory
Bumetanide 0.5 1 drugs or it may indicate the presence of renal artery
Furosemide 20 twice daily 40 twice daily stenosis.
Torsemide 5 10 ! The side effects associated with angiotensin-convert-
ing enzyme inhibitors are generally not dose-depen-
Potassium-sparing diuretics
Amiloride 5 510
dent, as they occur as frequently at low doses as at
Eplerenone 25 50100
high doses. Thus, it can be perfectly acceptable when
Spironolactone 12.5 2550
using these agents to start at medium or even high
Triamterene 100 100 doses. The one exception to this rule is in hyperkal-
emia, which may occur more frequently at higher
b-Blockers angiotensin-converting enzyme inhibitor doses.
Acebutalol 200 200400 ! These drugs have established clinical outcome ben-
efits in patients with heart failure, postmyocardial

22 The Journal of Clinical Hypertension Vol 16 | No 1 | January 2014


infarction, left ventricular systolic dysfunction, and
diabetic and nondiabetic chronic kidney disease.
! In general, angiotensin-converting enzyme inhibitors
are more effective as monotherapy in reducing blood
pressure in white patients than in black patients,
possibly because the renin-angiotensin system is
often less active in black patients. However, these
drugs are equally effective in reducing blood pressure
in all ethnic and racial groups when combined with
either calcium channel blockers or diuretics.
! Do not combine angiotensin-converting enzyme
inhibitors with angiotensin receptor blockers; each
of these drug types is beneficial in patients with
kidney disease, but in combination they may actually
have adverse effects on kidney function.
! When starting treatment with an angiotensin-con-
verting enzyme inhibitor, there is a risk of hypoten-
sion in patients who are already taking diuretics or
are on very low-salt diets or are dehydrated (eg,
laborers in hot climates and patients with diarrhea).
For patients taking a diuretic, skipping a dose before
starting the angiotensin-converting enzyme inhibitor
helps prevent this sudden effect on blood pressure.
! Angiotensin-converting enzyme inhibitors must not
be used in pregnancy, especially in the second or
third trimesters, since they can compromise the
normal development of the fetus.
Angiotensin Receptor Blockers
! Angiotensin receptor blockers, like angiotensin-con-
verting enzyme inhibitors, antagonize the renin-
angiotensin system. They reduce blood pressure by
blocking the action of angiotensin II on its AT1
receptor and thus prevent the vasoconstrictor effects
of this receptor.
! The angiotensin receptor blockers are well toler-
ated. Because they do not cause cough and only
rarely cause angioedema, and have effects and
benefits similar to angiotensin-converting enzyme
inhibitors, they are generally preferred over angio-
tensin-converting enzyme inhibitors if they are
available and affordable. Like angiotensin-convert-
ing enzyme inhibitors, angiotensin receptor blockers
can increase serum creatinine (see comments about
angiotensin-converting enzyme inhibitors), but usu-
ally this is a functional change that is reversible and
not harmful.
! These drugs do not appear to have dose-dependent side
effects, so it is perfectly reasonable to start treatment
with medium or even maximum approved doses.
! These drugs have the same benefits on cardiovascular
and renal outcomes as angiotensin-converting
enzyme inhibitors.
! Like angiotensin-converting enzyme inhibitors, they
tend to work better in white and Asian patients than
in black patients, but, when combined with either
calcium channel blockers or diuretics, they become
equally effective in all patient groups.
ASH/ISH Hypertension Guidelines | Weber et al.
! Do not combine angiotensin receptor blockers with
angiotensin-converting enzyme inhibitors; each of
these drug types is beneficial in patients with kidney
disease, but in combination they may actually have
adverse effects on renal events.
! When starting treatment with an angiotensin recep-
tor blocker in patients already taking diuretics, it
may be beneficial to skip a dose of the diuretic to
prevent a sudden fall in blood pressure.
! Angiotensin receptor blockers must not be used in
pregnancy, especially in the second or third trimes-
ters, since they can compromise the normal devel-
opment of the fetus.
Thiazide and Thiazide-like Diuretics
! These agents work by increasing excretion of sodium
by the kidneys and additionally may have some
vasodilator effects.
! Clinical outcome benefits (reduction of strokes and
major cardiovascular events) have been best estab-
lished with chlorthalidone, indapamide, and hydro-
chlorothiazide, although evidence for the first two of
these agents has been the strongest.
! Chlorthalidone has more powerful effects on blood
pressure than hydrochlorothiazide (when the same
doses are compared) and has a longer duration of
action.
! The main side effects of these drugs are metabolic
(hypokalemia, hyperglycemia, and hyperuricemia).
The likelihood of these problems can be reduced by
using low doses (eg, 12.5 mg or 25 mg of hydro-
chlorothiazide or chlorthalidone) or by combining
these diuretics with angiotensin-converting enzyme
inhibitors or angiotensin receptor blockers, which
have been shown to reduce these metabolic changes.
Combining diuretics with potassium-sparing agents
also helps prevent hypokalemia.
! Diuretics are most effective in reducing blood
pressure when combined with angiotensin-convert-
ing enzyme inhibitors or angiotensin receptor block-
ers, although they are also effective when combined
with calcium channel blockers.
Note: Thiazides plus b-blockers are also an effective
combination for reducing blood pressure, but since both
classes can increase blood glucose concentrations this
combination should be used with caution in patients at
risk for developing diabetes.
Calcium Channel Blockers
! These agents reduce blood pressure by blocking the
inward flow of calcium ions through the L channels
of arterial smooth muscle cells.
! There are two main types of calcium channel
blockers: dihydropyridines, such as amlodipine and
nifedipine, which work by dilating arteries; and
nondihydropyridines, such as diltiazem and verapa-
mil, which dilate arteries somewhat less but also
reduce heart rate and contractility.
The Journal of Clinical Hypertension Vol 16 | No 1 | January 2014 23
ASH/ISH Hypertension Guidelines | Weber et al.
! Most experience with these agents has been with the
dihydropyridines, such as amlodipine and nifedipine,
which have been shown to have beneficial effects on
cardiovascular and stroke outcomes in hypertension
trials.
! The main side effect of calcium channel blockers is
peripheral edema, which is most prominent at
high doses; this finding can often be attenuated by
combining these agents with angiotensin-convert-
ing enzyme inhibitors or angiotensin receptor block-
ers.
! Nondihydropyridine calcium channel blockers are
not recommended in patients with heart failure, but
amlodipine appears to be safe when given to heart
failure patients receiving standard therapy (including
angiotensin-converting enzyme inhibitors) for this
condition.
! Because the nondihydropyridine drugs, verapamil
and diltiazem, can slow heart rate, they are some-
times preferred in patients with fast heart rates and
even for rate control in patients with atrial fibrilla-
tion who cannot tolerate b-blockers. Nondihydro-
pyridine drugs can also reduce proteinuria.
! Calcium channel blockers have powerful blood
pressure-reducing effects, particularly when com-
bined with angiotensin-converting enzyme inhibitors
or angiotensin receptor blockers. They are equally
effective in all racial and ethnic groups.
! The dihydropyridine, but not the nondihydropyri-
dine, agents can be safely combined with
b-blockers.
b-Blockers
! b-blockers reduce cardiac output and also decrease
the release of renin from the kidney.
! They have strong clinical outcome benefits in
patients with histories of myocardial infarction and
heart failure and are effective in the management of
angina pectoris.
! They are less effective in reducing blood pressure
in black patients than in patients of other ethnic-
ities.
! b-blockers may not be as effective as the other major
drug classes in preventing stroke or cardiovascular
events in hypertensive patients, but they are the
drugs of choice in patients with histories of myocar-
dial infarction or heart failure.
! Many of these agents have adverse effects on glucose
metabolism and therefore are not recommended in
patients at risk for diabetes, especially in combina-
tion with diuretics. They may also be associated with
heart block in susceptible patients.
! The main side effects associated with b-blockers are
reduced sexual function, fatigue, and reduced exer-
cise tolerance.
! The combined a- and b-blocker, labetalol, is widely
used intravenously for hypertensive emergencies, and
is also used orally for treating hypertension in
pregnant and breastfeeding women.
24 The Journal of Clinical Hypertension Vol 16 | No 1 | January 2014
a-Blockers
! a-Blockers reduce blood pressure by blocking arte-
rial a-adrenergic receptors and thus preventing the
vasoconstrictor actions of these receptors.
! These drugs are less widely used as first-step agents
than other classes because clinical outcome benefits
have not been as well established as with other
agents. However, they can be useful in treating
resistant hypertension when used in combination
with agents such as diuretics, b-blockers, and angio-
tensin-converting enzyme inhibitors.
! To be maximally effective, they should usually be
combined with a diuretic. Since a-blockers can have
somewhat beneficial effects on blood glucose and
lipid levels, they can potentially neutralize some of
the adverse metabolic effects of diuretics.
! The a-blockers are effective in treating benign
prostatic hypertrophy, and so can be a valuable part
of hypertension treatment regimens in older men
who have this condition.
Centrally Acting Agents
! These drugs, the most well-known of which are
clonidine and a-methyldopa, work primarily by
reducing sympathetic outflow from the central ner-
vous system.
! They are effective in reducing blood pressure in most
patient groups.
! Bothersome side effects such as drowsiness and dry
mouth have reduced their popularity. Treatment
with a clonidine skin patch causes fewer side effects
than the oral agent, but the patch is not always
available and can be more costly than the tablets.
! In certain countries, including the United States,
a-methyldopa is widely employed for treating hyper-
tension in pregnancy.
Direct Vasodilators
! Because these agents, specifically hydralazine and
minoxidil, often cause fluid retention and tachycar-
dia, they are most effective in reducing blood
pressure when combined with diuretics and b-
blockers or sympatholytic agents. For this reason,
they are now usually used only as fourth-line or later
additions to treatment regimens.
! Hydralazine is the more widely used of these agents.
The powerful drug minoxidil is sometimes used by
specialists in patients whose blood pressures are
difficult to control. Fluid retention and tachycardia
are frequent problems with minoxidil, as well as
unwanted hair growth (particularly in women).
Furosemide is often required to cope with the fluid
retention.
Mineralocorticoid Receptor Antagonists
! The best known of these agents is spironolactone.
Although it was originally developed for the treat-
ment of high aldosterone states, it recently has
become part of standard treatment for heart failure.

Eplerenone is a newer and better-tolerated agent,
although most experience in difficult-to-control
hypertension has been with spironolactone.
! In addition, these agents can be effective in reducing
blood pressure when added to standard 3-drug
regimens (angiotensin-converting enzyme inhibitor
or angiotensin receptor blocker/ calcium channel
blocker/diuretic) in treatment-resistant patients. This
may be because aldosterone excess can contribute to
resistant hypertension.
! Symptomatic side effects of gynecomastia (swelling
and tenderness of breasts in both men and women)
and sexual dysfunction are common. These can be
minimized by using spironolactone in a low dose (no
more than 25 mg daily) or by using the more
selective (but more expensive) agent, eplerenone.
Hyperkalemia can also become a problem with these
agents, particularly when added to angiotensin-
converting enzyme inhibitors or angiotensin receptor
blockers in patients with reduced renal function.
These agents should be used with caution when the
eGFR is <50. In particular, when mineralocorticoid
receptor blockers are combined with angiotensin-
converting enzyme inhibitors or angiotensin receptor
blockers, potassium levels must be monitored within
the first month of treatment and then on a regular
basis (every 36 months).
TREATMENT RESISTANT HYPERTENSION
! Hypertension can be controlled (blood pressure
<140/90 mm Hg in most patients) by using either
1, 2, or 3 drugs as described earlier (angiotensin-
converting enzyme inhibitor or angiotensin receptor
blocker/ calcium channel blocker/diuretic) in full or
maximally tolerated doses. The most widely used
two-drug combination, angiotensin-converting
enzyme inhibitors plus either calcium channel block-
ers or diuretics, or angiotensin receptor blockers plus
either calcium channel blockers or diuretics, can
control blood pressure in about 80% of patients.
! Confirm that the blood pressure is truly uncontrolled
by checking home pressures, or if available, by using
ambulatory blood pressure monitoring.
! For patients not controlled on 3 drugs, adding a
mineralocorticoid antagonist such as spironolactone,
a b-blocker, a centrally acting agent, an a-blocker, or
a direct vasodilator will often be helpful.
! If blood pressure is still not controlled it is important
to make certain that patients are actually taking their
medicines. Question their families, check their pre-
scriptions, and ask questions about side effects to
help confirm compliance with treatment.
! Check whether patients are taking other medicines
that can interfere with their hypertension treatment.
For example: nonsteroidal anti-inflammatory drugs,
cold remedies, and some antidepressants. Also, ask
about diet: blood pressures in some patients are
especially sensitive to factors such as excessive salt
intake.
ASH/ISH Hypertension Guidelines | Weber et al.
! Consider secondary causes of hypertension if all
these more simple approaches are unsuccessful.
o Secondary hypertension can be suggested by the
sudden onset of hypertension, or by the loss of
blood pressure control in patients previously
well managed or by the occurrence of a hyper-
tension emergency
o Chronic kidney disease: this common secondary
cause of hypertension should normally be
revealed by the initial patient evaluation (eg,
laboratory tests of creatinine). These patients, if
possible, should be referred to a nephrologist.
o Aldosterone excess: this is suggested by hypo-
kalemia during the initial evaluation, although
this condition can occur even when potassium
levels appear normal. About 20% of patients
whose blood pressures remain high despite
taking 3 drugs have evidence of aldosterone
excess. Confirming this diagnosis usually
requires assistance from clinical hypertension
specialists.
o Sleep apnea: This is common in obese patients.
Not all patients with sleep apnea have hyperten-
sion but there is a clear association. A preliminary
diagnosis can be made by finding a history of
snoring during sleep and daytime tiredness. A
definitive diagnosis usually requires a sleep lab-
oratory study.
o Other secondary causes of hypertension such as
renal artery stenosis or coarctation of the aorta
usually require evaluation by a specialist.
FINAL COMMENT
The authors of this statement acknowledge that there
are insufficient published data from clinical trials in
hypertension to create recommendations that are com-
pletely evidence-based, and so inevitably some of our
recommendations reflect expert opinion and experience.
We also should point out that because of the major
differences in resources among points of care it is not
possible to create a uniform set of guidelines. For this
reason we have written a broad statement on the
management of hypertension and have not presumed to
anticipate the conditions or shortfalls that might exist
in particular communities. We expect that experts who
are familiar with local circumstances will feel free to
use their own judgment in modifying our recommen-
dations and to create practical instructions to help
guide front-line practitioners in providing the best care
possible.
A NOTE TO COLLEAGUES
The authors of this statement would welcome comments
and suggestions from colleagues. We recognize that in
this initial version of the guidelines there will probably
be omissions, redundancies, and inaccuracies. Please feel
free to get in touch with us either by letters to the
Journal or by personal communication.
The Journal of Clinical Hypertension Vol 16 | No 1 | January 2014 25
Updated Guidelines on Outpatient
Anticoagulation
PATRICIA WIGLE, PharmD, BCPS, and BRADLEY HEIN, PharmD, University of Cincinnati James L. Winkle
College of Pharmacy, Cincinnati, Ohio
HANNA E. BLOOMFIELD, MD, MPH, University of Minnesota and Minneapolis VA Medical Center, Minneapolis, Minnesota
MATTHEW TUBB, MD, PhD, The Christ Hospital/University of Cincinnati Family Medicine Residency Program,
Cincinnati, Ohio
MICHAEL DOHERTY, PharmD, BCACP, University of Cincinnati James L. Winkle College of Pharmacy, Cincinnati, Ohio

The American College of Chest Physicians provides recommendations for the use of anticoagulant medications for
several indications that are important in the primary care setting. Warfarin, a vitamin K antagonist, is recommended
for the treatment of venous thromboembolism and for the prevention of stroke in persons with atrial fibrillation,
atrial flutter, or valvular heart disease. When warfarin therapy is initiated for venous thromboembolism, it should
be given the first day, along with a heparin product or fondaparinux. The heparin product or fondaparinux should
be continued for at least five days and until the patients international normalized ratio is at least 2.0 for two con-
secutive days. The international normalized ratio goal and duration of treatment with warfarin vary depending on
indication and risk. Warfarin therapy should be stopped five days before major surgery and restarted 12 to 24 hours
postoperatively. Bridging with low-molecular-weight heparin or other agents is based on balancing the risk of throm-
boembolism with the risk of bleeding. Increasingly, self-testing is an option for selected patients on warfarin therapy.
The ninth edition of the American College of Chest Physicians guidelines, published in 2012, includes a discussion of
anticoagulants that have gained approval from the U.S. Food and Drug Administration since publication of the eighth
edition in 2008. Dabigatran and apixaban are indicated for the prevention of systemic embolism and stroke in persons
with nonvalvular atrial fibrillation. Rivaroxaban is indicated for the prevention of deep venous thrombosis in patients
undergoing knee or hip replacement surgery, for treatment of deep venous thrombosis and pulmonary embolism,
for reducing the risk of recurrent deep venous thrombosis and pulmonary embolism after initial treatment, and for
prevention of systemic embolism in patients with nonvalvular atrial fibrillation. (Am Fam Physician. 2013;87(8):556-
566. Copyright 2013 American Academy of Family Physicians.)

W
More online arfarin (Coumadin), unfrac-
at http://www.
tionated heparin, and low-
aafp.org/afp.
molecular-weight heparin
(LMWH) are commonly
used for the prevention and treatment of dis-
orders such as systemic embolism associated
with atrial fibrillation, stroke, and venous
thromboembolism (VTE). LMWH allows
for the initiation of anticoagulation therapy
on an outpatient basis.
After decades during which warfarin was
the only oral anticoagulation option, newer
anticoagulants have the potential to change
the management of coagulation disorders.
This article focuses on the indications for
and the goals and duration of anticoagula-
tion therapy; describes methods to initiate
therapy; and provides guidance on monitor-
ing. Most of the recommendations are based
Downloaded from the American Family Physician Web site at www.aafp.org/afp. Copyright 2013 American Academy of Family Physicians. For the private,
556 noncommercial
American Family Physician
use of one www.aafp.org/afp
individual user of the Web site. All other rights
reserved. Contact copyrights@aafp.org for copyright 87, Number
on the American College of Chest Physicians
(ACCP) evidence-based clinical practice
guidelines (Table 1).1
Warfarin, Heparin, and Heparin
Analogues
WARFARIN
The anticoagulant effect of warfarin results
from the inhibition of the cyclic interconver-
sion of vitamin K in the liver. The reduced
form of vitamin K is necessary for the car-
boxylation of the terminal regions of the
vitamin K proteins, factors II, VII, IX, and
X.1 Without carboxylation, these vitamin
Kdependent clotting factors do not become
activated. Warfarin, similar in structure to
vitamin K, interferes with the cyclic res-
toration of reduced levels of vitamin K.
Therefore, warfarin indirectly reduces the
Volumequestions
and/or8permission
April 15, 2013
requests.

Table 1. Key Changes in the Ninth Edition of the American College of Chest Physicians Guidelines
on Outpatient Management of Anticoagulation Therapy
Medication Recommendation
Dabigatran Recommended over warfarin (Coumadin) in patients
(Pradaxa) with nonvalvular atrial fibrillation who do not have
severe renal impairment (grade 2B)
LMWH Outpatients with solid tumors, additional risk factors for
deep venous thrombosis, and low bleeding risk should
receive prophylactic doses of LMWH (grade 2B)
Vitamin K Revised recommendations for treatment of patients
with supratherapeutic INRs who do not have
significant bleeding
For patients with an INR between 4.5 and 10, routine
use of vitamin K is not recommended (grade 2B)
For patients with an INR greater than 10 without
significant bleeding, oral vitamin K is recommended
(grade 2C)
Warfarin Warfarin therapy at 10 mg daily for two days may
be initiated in healthy outpatients with acute
thromboembolism (grade 2C)
If the patient was previously stable on warfarin and
presents with an isolated INR of 0.5 or less above or
below therapeutic range, the current dosage should
be continued and the patient retested in one to two
weeks (grade 2C)
In previously stable patients with a single INR below
the therapeutic range, routine heparin bridging is not
recommended (grade 2C)
INR should be monitored up to every 12 weeks in
patients who are stable, which is defined as having at
least three months of consistent results with no need
to adjust warfarin dosing (grade 2B)
NOTE:Grade 1 recommendations are strong recommendations that can be applied to most patients; grade 2 recommendations are weaker recom-
mendations. Grade A recommendations are supported by high-quality evidence, grade B recommendations are based on randomized clinical trials
with methodological flaws or inconsistent results, and grade C recommendations are based on weaker evidence.
INR = international normalized ratio; LMWH = low-molecular-weight heparin.
Information from reference 1.
synthesis of these clotting factors. The anticoagulant
effects of warfarin are delayed for several days after dos-
ing changes, including therapy initiation. This is because
of the variable half-lives of previously formed circulating
clotting factors. Carboxylation inhibition can also result
in a paradoxical increased risk of clotting when warfarin
April 15, 2013 Volume 87, Number 8 www.aafp.org/afp
Outpatient Anticoagulation
Implication for practice
Simplification of anticoagulation management: no need for
frequent dosage adjustments, INR monitoring
Caution: no antidote for reversal
Advocating more judicious and conservative use of vitamin K
Helps to achieve therapeutic INR sooner and decreases the
number of LMWH doses needed
Patients at high risk of bleeding may be better suited for
traditional dosing
Caution: check INR after two or three doses
Patients taking the same dose for at least three consecutive
months are considered stable
Physicians have the option of waiting until two consecutive
INRs are outside the desired therapeutic range before
changing the dose in previously stable patients who have not
experienced a change in health, diet, or medication status;
this method has not been associated with increased risk of
bleeding or thromboembolism in observational studies
Minimizes burdens of unnecessary testing and dose adjustment
Applies to patients with two previous stable INRs
INRs should be checked in one to two weeks to verify return to
desired range
Bridging may need to be considered in high-risk patients or in
patients with continued subtherapeutic INRs
Minimizing unnecessary heparin bridging will save money and
decrease patient burden
Substantially lengthening the monitoring interval in stable
patients (from every four weeks to up to every 12 weeks) will
save money and enhance patient quality of life
Candidates for extended monitoring should demonstrate the
ability to be compliant with medication and to recognize the
signs and symptoms of over- and underanticoagulation
Caution: physicians should be alert for health or medication
changes that may warrant more frequent monitoring
is initiated because of decreased levels of the vitamin K
dependent anticoagulant proteins C and S.1
Indications. Indications for initiating warfarin are
listed in Table 2.1 In persons with nonvalvular atrial
fibrillation, clinicians often base the decision to start
warfarin or LMWH on clinical risk estimates, such as the
American Family Physician 557
Table 2. Indications for and Goals and Duration of Warfarin Therapy
Indication
(ACCP recommendation grade)
DVT of the leg or PE*
First episode (1B)
Cancer (1B)
Antiphospholipid antibody (2B)
Second episode (1B)
Atrial fibrillation or flutter
Intermediate to high
risk of stroke|| (1B)
Elective cardioversion (1B)
Mitral stenosis (1B)
After stent placement and high
risk of stroke (2C)
Coronary heart disease
High-risk patients with
myocardial infarction without a
stent (1B)
High-risk patients with
myocardial infarction and after
stent placement (2C)
Valvular heart disease
Rheumatic mitral valve disease
(1A if with atrial fibrillation or a
history of systemic embolism;
1A if history of atrial thrombus;
2C if normal sinus rhythm and
atrial diameter > 55 mm)
Target INR (range) Duration of therapy (ACCP recommendation grade)
2.5 (2.0 to 3.0) First episode of proximal DVT or PE due to surgery
3 months recommended over short-term use (1B), longer use (1B), or
extended therapy (1B)
First episode of proximal DVT or PE due to a reversible risk factor
3 months preferred over short-term use (1B), longer use (1B), or
extended therapy (1B or 2B, depending on bleeding risk)
First episode of distal DVT due to surgery or a reversible risk factor
3 months preferred over short-term use (2C), longer use (1B), or
extended therapy (1B)
First episode of idiopathic proximal DVT or PE
Low or moderate bleeding risk: extended use recommended over
3 months (2B); high bleeding risk: 3 months recommended over
extended use (1B for DVT; 1B for PE)
First episode of idiopathic distal DVT
3 months recommended over extended use (1B or 2B, depending on
bleeding risk)
2.5 (2.0 to 3.0) Active cancer and PE
Low-molecular-weight heparin preferred over warfarin (Coumadin)
Extended use recommended (1B or 2B, depending on bleeding risk)
2.5 (2.0 to 3.0) Antiphospholipid antibody and history of arterial or venous thrombosis
Extended use with target INR of 2.5 recommended over higher range
of 3.0 to 4.5 (2B)
2.5 (2.0 to 3.0) Two episodes of unprovoked DVT or PE
Low (1B) or moderate bleeding risk: extended therapy (2B)
High bleeding risk: 3 months (2B)
2.5 (2.0 to 3.0) Indefinite
2.5 (2.0 to 3.0) 3 weeks before if scheduled and for 4 weeks after conversion (1B/2C)
2.5 (2.0 to 3.0) Indefinite
2.5 (2.0 to 3.0) Bare-metal stent (1 month) and drug-eluting stent (3 to 6 months) as
triple therapy with clopidogrel (Plavix) and aspirin (2C)
After initial triple therapy, continue warfarin and a single antiplatelet
agent until 12 months after stent placement (2C)
After 12 months: warfarin alone (2C)
2.5 (2.0 to 3.0) with 3 months
low-dose aspirin,
75 to 100 mg daily
2.5 (2.0 to 3.0) Bare-metal stent: triple therapy with warfarin, low-dose aspirin,
and clopidogrel in month 1; combination of warfarin with single
antiplatelet agent in months 2 and 3
Drug-eluting stent: triple therapy with warfarin, low-dose aspirin, and
clopidogrel for 3 to 6 months
2.5 (2.0 to 3.0) Long-term
continued
 Outpatient Anticoagulation
Table 2. Indications for and Goals and Duration of Warfarin Therapy (continued)

Indication
(ACCP recommendation grade) Target INR (range) Duration of therapy (ACCP recommendation grade)

Valvular heart disease (continued)

Mechanical prosthetic heart
valves (aortic position [2C over
low-range INR and 1B over
high-range INR]; mitral position
[2C over low-range INR])
Bileaflet or tilting-disk
valves: 2.5 (2.0 to 3.0)
in the aortic position,
and 3.0 (2.5 to 3.5) in
the mitral position
Long-term
Recommended to use aspirin, 50 to 100 mg daily, with mechanical aortic
or mitral valve and low bleeding risk

Bioprosthetic valves in the mitral 2.5 (2.0 to 3.0) 3 months after insertion
position (2C)

Prevention of venous thromboembolism for orthopedic surgery

Elective total hip or knee
replacement and hip fracture
surgery (1B)
2.5 (2.0 to 3.0) 10 to 14 days minimum (1B)
35 days for major orthopedic surgery (2B)
Warfarin is second-line agent to low-molecular-weight heparin for total
hip or total knee arthroplasty (2C)

NOTE: Grade1 recommendations are strong recommendations that can be applied to most patients; grade 2 recommendations are weaker recom-
mendations. Grade A recommendations are supported by high-quality evidence, grade B recommendations are based on randomized clinical trials
with methodological flaws or inconsistent results, and grade C recommendations are based on weaker evidence.
ACCP = American College of Chest Physicians; CHADS2 = congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior ischemic
stroke or transient ischemic attack (doubled); DVT = deep venous thrombosis; INR = international normalized ratio; PE = pulmonary embolism.
*Recommendation to start warfarin on first day of treatment with a parenteral anticoagulant (unfractionated or low-molecular-weight heparin,
or fondaparinux [Arixtra]); 1B.
Risk factors that increase a patients bleeding risk include advanced age, active gastric or duodenal ulcer, recent gastrointestinal bleeding, history of
stroke, myocardial infarction, diabetes, and several laboratory abnormalities (e.g., elevated creatinine level, low platelet count, low hematocrit level).
Defined as CHADS2 score of 1.
Defined as CHADS2 score of 2 or greater.
||Of note, in patients with a CHADS2 score of 0, aspirin (75 to 325 mg daily) is recommended as an option; 2B.
Patients with large anterior wall myocardial infarction who have left ventricular thrombus or who are at high risk of left ventricular thrombus
(ejection fraction < 40 percent or anteroapical wall motion abnormality); 1B.
Information from reference 1.

CHADS2 score, which assigns one point each for conges-
tive heart failure, hypertension, age 75 years and older,
and diabetes mellitus, and two points for prior ischemic
stroke or transient ischemic attack.1 For persons with a
CHADS2 score of 2 or higher, the ACCP guidelines rec-
ommend oral anticoagulation, and for persons with a
score of 1, the guidelines recommend individualization
of therapy and suggest oral anticoagulation rather than a
combination of aspirin and clopidogrel (Plavix).1
Dosing. Patients on warfarin therapy should be treated
using a systematic process to optimize effectiveness and
minimize adverse effects. Health care professionals skilled
in the initiation and assessment of therapy and adjust-
ments in dosing can dramatically influence outcomes.2,3
When warfarin is initiated, the international normal-
ized ratio (INR) may begin to respond after two to three
days because of the depletion of factor VII. During this
initial period, the patient can enter a hypercoagulable
state caused by warfarins effects on proteins C and S.1
Heparin or LMWH should be administered with warfa-
rin initiation and continued until the INR has been in the
targeted therapeutic range for a minimum of 24 hours.
Initial dosing of warfarin can vary depending on indi-
vidual patient factors (e.g., age, bleeding risk, medication
compliance history) and anticipated drug interactions.
In most patients, warfarin should be initiated as a main-
tenance dosage of 5 mg daily. Older patients and persons
with liver disease, poor nutritional status, or heart failure
may require lower initiation dosages.1 For persons who
are healthy enough to be treated as outpatients, the ACCP
guidelines provide an alternative warfarin initiation dos-
age of 10 mg daily for the first two days of therapy, rather
than the anticipated maintenance dosage.1
After baseline INR is determined, the next INR can
be obtained after the patient has received two or three
doses. Then, the frequency of INR monitoring decreases
to twice weekly until the INR is within the therapeu-
tic range, then weekly, every other week, and finally
monthly.1 The ACCP guidelines allow clinicians to con-
sider INR monitoring up to every 12 weeks in patients
who are stable (defined as having at least three months
of consistent results with no need to adjust warfarin
dosing). If a patients INR becomes subtherapeutic or
supratherapeutic, the frequency of monitoring should

April 15, 2013 Volume 87, Number 8 www.aafp.org/afp American Family Physician 559
Outpatient Anticoagulation
Table 3. Management of Supratherapeutic INRs in Patients Without Significant Bleeding

INR Management Vitamin K dosing

Greater than Option 1: Decrease or hold dosage, increase frequency of monitoring, and resume at lower dosage Not applicable
goal INR, once INR is within the therapeutic range
but < 4.5 Option 2: May continue current dosage if INR is minimally elevated (0.5 or less above therapeutic
range in a previously stable patient; grade 2C)
4.5 to 10 Hold next one or two doses, increase frequency of monitoring, and resume at lower dosage once Not applicable
INR is within the therapeutic range
No vitamin K (grade 2B)
> 10 Hold warfarin (Coumadin) and administer vitamin K (grade 2C), increase frequency of monitoring, 2.5 to 5 mg orally
repeat vitamin K as necessary, and resume warfarin at an appropriate dosage when INR is within as one dose
the therapeutic range

NOTE:Grade 1 recommendations are strong recommendations that can be applied to most patients; grade 2 recommendations are weaker recom-
mendations. Grade A recommendations are supported by high-quality evidence, grade B recommendations are based on randomized clinical trials
with methodological flaws or inconsistent results, and grade C recommendations are based on weaker evidence.
INR = international normalized ratio.
Information from reference 1.

be increased until it stabilizes again. The ACCP provides UNFRACTIONATED HEPARIN

recommendations for managing supratherapeutic INRs
(Table 3).1
Patients taking warfarin in the evening can adjust
their dosing based on that days INR results. If the INR
is not within the desired therapeutic range after exclud-
ing explanatory factors, a 5 to 20 percent increase or
decrease in the total weekly dosage is required.4-6 Patients
should be provided with the simplest regimen to achieve
the new total weekly dosage.
Drug, Food, and Disease State Interactions. Warfarin
is subject to many drug-drug, drug-food, and drug
disease state interactions. eTable A lists selected drug-
drug interactions that are considered highly likely to
potentiate or inhibit the effects of warfarin.
Some medications, such as amiodarone and rifampin,
can impact a patients INR long after the medication
is discontinued.1,7,8 A patient taking a medication with
higher interaction potential, such as metronidazole
(Flagyl), should be monitored more frequently.9 Depend-
ing on the patient and the medication, a prophylactic
reduction in warfarin dosage may also be advised.
Foods with high vitamin K concentrations, such as leafy
green vegetables, have the potential to partially reverse
the anticoagulation effects of warfarin.8 A consistent diet
is more important than limiting dietary vitamin K.1
Medical conditions such as diarrhea, heart failure,
fever, hyperthyroidism, and liver disease can potentiate
warfarins effects. Conversely, conditions such as hypo-
thyroidism can decrease the expected effects of warfa-
rin.1 Genetic factors can predispose patients to reduced
warfarin requirements, as well as warfarin resistance.
Although there is a small subset of patients who may have
unexpected responses to warfarin, it is not currently rec-
ommended that patients undergo genetic testing.1
Unfractionated heparin is a mixture of glycosaminogly-
cans that works by binding to antithrombin to inactivate
thrombin (factor IIa) and factor Xa.1 It also prevents the
growth and potential propagation of clots. Considerations
for parenteral medications are provided in eTable B.
Beyond increased bleeding risk, unfractionated hep-
arin is associated with other adverse effects, such as
heparin-induced thrombocytopenia. Heparin-induced
thrombocytopenia should be suspected if a patients
platelet count decreases by at least 50 percent, or is less
than 150 103 per L after initiation of heparin. This
generally occurs five to 14 days after initiation, and can
occur after heparin is discontinued.
LOW-MOLECULAR-WEIGHT HEPARIN
Two LMWHs, dalteparin (Fragmin) and enoxapa-
rin (Lovenox), are commonly used in clinical practice.
LMWH is derived from unfractionated heparin and has
an increased affinity for factor Xa relative to thrombin.1
LMWH, which is given subcutaneously, has predictable
absorption and degree of anticoagulation. Monitoring
with measurement of antifactor Xa levels is not rou-
tinely recommended, but is potentially useful in certain
situations in which predictability of the degree of antico-
agulation may be altered, such as changes in pharmacoki-
netics and pharmacodynamics (e.g., obesity, pregnancy)
and accumulation (e.g., older age, kidney disease). In
the outpatient setting, the usefulness of laboratory test-
ing is limited to the assessment of bleeding events and
therapeutic failures. It may also be of value to assess lev-
els infrequently during the course of long-term therapy
(i.e., when LMWH is used for more than just bridging
therapy). Although LMWH has a similar bleeding risk
and lower heparin-induced thrombocytopenia risk

560 American Family Physician www.aafp.org/afp Volume 87, Number 8 April 15, 2013

compared with unfractionated heparin, a patient with
a history of heparin-induced thrombocytopenia should
not take LMWH.1
FONDAPARINUX
Fondaparinux (Arixtra) is a synthetic analogue of hepa-
rin. Unlike LMWH, fondaparinux is specific only to fac-
tor Xa and has no effect on thrombin formation. Like
LMWH, fondaparinux is given subcutaneously and has
predictable absorption and degree of anticoagulation.
The ACCP guidelines recommend fondaparinux for
general surgical prophylaxis in patients who have con-
traindications to LMWH.1
There are few data on the monitoring of fondaparinux.
Antifactor Xa levels can be used as long as fondaparinux
(and not LMWH) is the reference standard in the assay.1
Although the bleeding risk is similar to unfractionated
heparin and LMWH, there is little heparin-induced
thrombocytopenia risk with fondaparinux.
Bridging Unfractionated Heparin, LMWH, or
Fondaparinux to Warfarin
In the treatment of VTE and pulmonary embolism, the
parenteral anticoagulant should be overlapped with war-
farin for a minimum of five days. In most cases, warfa-
rin can be initiated on day 1, after the first dose of the
parenteral agent has been given. Warfarin should not be
initiated alone, and the parenteral anticoagulant should
not be discontinued until the INR is in the therapeutic
range for two consecutive days.
Depending on the patients risk of thromboembolism
and bleeding, bridging should occur when a patients
oral anticoagulation therapy needs to be interrupted
(eTable C). Interruption is common in patients undergo-
ing surgery. For most persons who are not having a minor
procedure, warfarin will be stopped approximately five
days before surgery and restarted 12 to 24 hours post-
operatively. LMWH should be restarted approximately
24 hours after the procedure, and it may be prudent to
wait 48 to 72 hours before resuming the medication for
patients at high risk of bleeding or who are undergoing
major surgery.1 Fondaparinux is not recommended for
this indication.
For all warfarin indications, perioperative bridging is
not indicated in patients at low risk of thromboembo-
lism.1 For patients with a high risk of thromboembolism,
bridging with a therapeutic dose of unfractionated hepa-
rin or LMWH is indicated.1 The ACCP guidelines are less
clear about how patients with a moderate risk of throm-
boembolism should be treated.1 Clinicians need to bal-
ance the individuals risk of thromboembolism, based
April 15, 2013 Volume 87, Number 8 www.aafp.org/afp
Outpatient Anticoagulation
on the medical history and surgical procedure, and risk
of bleeding when determining what is optimal in persons
in this moderate-risk category.
Newer Anticoagulants
The effectiveness of warfarin is well-established; how-
ever, it is a suboptimal anticoagulant because it requires
frequent monitoring and dosage adjustments, and
because of its potential for multiple drug-drug, drug-
food, and drugdisease state interactions. It has a lengthy
half-life and a delayed anticoagulant effect, and it often
requires bridging therapy.
Since the approval of warfarin in 1954, no other oral
option existed for patients who needed long-term anti-
coagulation therapy. This changed in 2010 with the U.S.
Food and Drug Administration (FDA) approval of the
oral direct thrombin inhibitor dabigatran (Pradaxa), in
2011 with the FDA approval of the oral direct factor Xa
inhibitor rivaroxaban (Xarelto), and again in 2012 with
the FDA approval of the oral factor Xa inhibitor apixa-
ban (Eliquis). Characteristics of these anticoagulants are
provided in Tables 4 and 5.10-19
DABIGATRAN
Dabigatran is available as a fixed-dose medication for the
prevention of systemic embolism and stroke in patients
with nonvalvular atrial fibrillation.13 The ACCP guide-
lines recommend dabigatran, 150 mg twice daily, over
warfarin for this indication when dosed appropriately for
the patients renal function.1 Dabigatran does not require
monitoring, dosage adjustments, or overlap with inject-
able anticoagulants such as heparin. Without applicable
laboratory monitoring, there is no mechanism to estab-
lish if a patients INR is subtherapeutic or suprathera-
peutic. If the patients INR is supratherapeutic, there is
no antidote for reversal. This can be problematic when
determining the appropriate management in a patient
who needs emergent surgery. The short half-life is poten-
tially challenging when assessing the impact of noncom-
pliance or missing the second daily dose. Limited data
are available for patients with hepatic impairment and
for patients who are obese. Thus, it is not acceptable to
automatically consider all patients taking warfarin to be
good candidates for dabigatran.
Adverse effects of dabigatran, 150 mg twice daily, com-
pared with warfarin include dyspepsia (11.3 versus 5.8
percent; P < .001) and major gastrointestinal bleeding
(1.51 versus 1.02 percent; P < .001). Dabigatrans safety
profile needs further evaluation.13
Elevated transaminase levels in the Randomized Eval-
uation of Long-term Anticoagulation Therapy trial were
American Family Physician 561
 Table 4. Characteristics of Newer Oral Anticoagulants
Characteristic Apixaban (Eliquis)
Mechanism of action Direct factor Xa inhibitor
FDA boxed warning/ FDA boxed warning: increased risk of stroke in patients with
contraindications nonvalvular atrial fibrillation who discontinue apixaban without
adequate continuous anticoagulation
Contraindications: active pathological bleeding; history of
serious hypersensitivity reaction to apixaban
Use not recommended in patients with prosthetic heart valves or
severe hepatic impairment; pregnant or breastfeeding patients
Indications Reduce risk of stroke and systemic embolism in patients with
nonvalvular atrial fibrillation
Usual dosage 5 mg twice daily
2.5 mg twice daily if patient has at least 2 of the following:
age 80 years or older, body weight of 132 lb (60 kg) or less,
or serum creatinine level of 1.5 mg per dL or higher
No data for patients on dialysis or with CrCl < 15 mL/min/
1.73 m2 or patients with moderate hepatic impairment
Not recommended for patients with severe hepatic impairment
2.5 mg twice daily if patient is on a strong dual inhibitor of
CYP3A4 and P-glycoprotein (e.g., ketoconazole, itraconazole
[Sporanox], ritonavir [Norvir], clarithromycin [Biaxin]); avoid use
of these drugs if patient is already taking 2.5 mg twice daily
Half-life 12 hours (with repeat dosing)
Monitoring None recommended
Antidote None available
Drug interactions See usual dosage for dose modification information
Avoid use of strong dual inhibitor of CYP3A4 and P-glycoprotein
in patients taking apixaban, 2.5 mg twice daily
Avoid use of strong dual inducer of CYP3A4 and P-glycoprotein
(e.g., carbamazepine [Tegretol], phenytoin [Dilantin],
rifampin, St. Johns wort)
Increased bleeding risk with certain medications (e.g.,
clopidogrel [Plavix], nonsteroidal anti-inflammatory drugs)
Adverse effects Bleeding
Impact of renal See usual dosage for dose modification information
impairment
Impact of hepatic See usual dosage for dose modification information
impairment Dosing recommendations for patients with moderate hepatic
impairment are not available
Comments No objective way to monitor nonadherence
Refer to package labeling for information on conversion from
or to warfarin (Coumadin) or parenteral anticoagulants, and
on intervention for surgery
CrCl = creatinine clearance; CYP3A4 = cytochrome P450 3A4; DVT = deep venous thrombosis; FDA = U.S. Food and Drug Administration.
*Amiodarone, clarithromycin, quinidine, and verapamil have been evaluated with dabigatran and do not require a dabigatran dosage
adjustment, but should be used concurrently with caution. Other P-glycoprotein inhibitors should be evaluated on an individual basis.
562 American Family Physician www.aafp.org/afp
Dabigatran (Pradaxa)
Direct thrombin inhibitor
Contraindications: active pathological bleeding;
history of serious hypersensitivity reaction to
dabigatran; mechanical prosthetic heart valve
Use not recommended in patients with
bioprosthetic heart valves; pregnant or
breastfeeding patients
Reduce risk of stroke and systemic embolism in
patients with nonvalvular atrial fibrillation
150 mg twice daily
CrCl 30 to 50 mL/min/1.73 m2 and concurrent use
of dronedarone (Multaq) or systemic ketoconazole:
decrease dosage to 75 mg twice daily
CrCl 15 to 30 mL/min/1.73 m2: decrease dosage to
75 mg twice daily
CrCl < 30 mL/min/1.73 m2 and concurrent use of
a P-glycoprotein inhibitor: avoid use
CrCl < 15 mL/min/1.73 m2: avoid use
No data for patients on dialysis
12 to 17 hours
None recommended
None available
See usual dosage for dose modification
information
Avoid concurrent use with P-glycoprotein inducers
(e.g., rifampin)
Evaluate P-glycoprotein inhibitors individually*
Increased bleeding risk with certain medications
(e.g., clopidogrel, nonsteroidal anti-inflammatory
drugs)
Bleeding, dyspepsia
See usual dosage for dose modification
information
No specific recommendations are made regarding
hepatic impairment
Limited information in this population
Do not chew, break, open capsules; capsules
must be dispensed in original container and not
repackaged because of sensitivity to moisture
No objective way to measure nonadherence
Need more information about use in patients under
and over ideal body weight
Refer to package labeling for information on
conversion from or to warfarin or parenteral
anticoagulants, and on intervention for surgery
Volume 87, Number 8 April 15, 2013
 Outpatient Anticoagulation

Rivaroxaban (Xarelto)

Direct factor Xa inhibitor

comparable to those seen with warfarin,
FDA boxed warning: increased risk of thrombotic events in patients with nonvalvular and routine liver function test monitor-
atrial fibrillation who discontinue rivaroxaban without adequate continuous
ing is not recommended.11,13 Because of
anticoagulation; risk of epidural/spinal hematoma in patients receiving neuraxial
anesthesia or in patients undergoing spinal puncture while taking rivaroxaban the effects of renal function on dabigatran,
Contraindications: active pathological bleeding; history of severe hypersensitivity baseline and periodic renal function moni-
reaction to rivaroxaban toring are recommended.
Use not recommended in pregnant or breastfeeding patients
RIVAROXABAN
Prevent DVT in patients undergoing knee or hip replacement surgery
Reduce risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation Rivaroxaban is indicated for prevention of
Treat DVT and pulmonary embolism deep venous thrombosis in patients under-
Reduce risk of recurrent DVT and pulmonary embolism after initial treatment going knee or hip replacement surgery, for
DVT prophylaxis: 10 mg once daily treatment of deep venous thrombosis and
DVT prophylaxis and CrCl < 30 mL/min/1.73 m2: avoid use pulmonary embolism, for reducing the
Prevent stroke in patients with nonvalvular atrial fibrillation: 20 mg once daily risk of recurrent deep venous thrombo-
Prevent stroke in patients with nonvalvular atrial fibrillation and CrCl 15 to 50 mL/
sis and pulmonary embolism after initial
min/1.73 m2: 15 mg once daily
Prevent stroke in patients with nonvalvular atrial fibrillation and CrCl < 15 mL/min/
treatment, and for prevention of systemic
1.73 m2: avoid use embolism in patients with nonvalvular
Treat DVT and pulmonary embolism or reduce risk of future DVT and pulmonary atrial fibrillation. It is expected to prolong
embolism after initial treatment: 15 mg twice daily with food for 21 days, then the activated partial thromboplastin time
20 mg once daily for the remainder of the treatment interval (six months total) or
and increase antifactor Xa levels; how-
for long-term risk reduction; avoid in patients with CrCl < 30 mL/min/1.73 m2
ever, the usefulness of monitoring has not
5 to 9 hours
been established. In four trials evaluating
None recommended the role of rivaroxaban in the prevention
None available of VTE in patients undergoing orthopedic
See usual dosage for dose modification information
surgery, rivaroxaban significantly reduced
Avoid with combined P-glycoprotein inhibitor and CYP3A4 inhibitor the primary outcome (total VTE and all-
(e.g., ketoconazole, itraconazole, ritonavir, conivaptan [Vaprisol]) cause mortality) compared with enoxa-
Avoid with combined P-glycoprotein inducer and CYP3A4 inducer parin, without significantly increasing
(e.g., carbamazepine, phenytoin, rifampin, St. Johns wort) bleeding risk.14-19 In the ROCKET AF trial,
Increased bleeding risk with certain medications (e.g., clopidogrel, nonsteroidal
rivaroxaban was shown to be noninferior
anti-inflammatory drugs)
to warfarin for the prevention of stroke or
systemic embolism in patients with non-
Bleeding
valvular atrial fibrillation.19 An important
See usual dosage for dose modification information consideration in this trial is that in the war-
Note differences in recommendation for dosage adjustments in renal impairment
farin arm, the time in therapeutic range was
based on indication
55 percent, which is less than what is typi-
Avoid if moderate (Child-Pugh class B) or severe (Child-Pugh class C) hepatic
cally reported by anticoagulation clinics.
impairment or with any hepatic disease associated with coagulopathy
Rivaroxaban has been studied for the treat-
ment of acute coronary syndromes. Similar
Rivaroxaban should be stopped 24 hours before major surgery
to dabigatran, baseline and periodic renal
DVT prophylaxis
The first dose should be initiated 6 to 10 hours after surgery
function monitoring are recommended.
Recommended duration of therapy is 12 days for total knee replacement and
APIXABAN
35 days for total hip replacement
Prevent stroke in patients with atrial fibrillation Similar to dabigatran, apixaban is also indi-
When transitioning from warfarin to rivaroxaban, give first dose of rivaroxaban cated for the prevention of systemic embo-
when the international normalized ratio is less than 3
lism and stroke in patients with nonvalvular
atrial fibrillation. In the ARISTOTLE and
Information from references 10 through 19. AVERROES trials, apixaban reduced the
primary outcome of ischemic stroke,
hemorrhagic stroke, and systemic embo-
lism compared with warfarin and aspirin,

April 15, 2013 Volume 87, Number 8 www.aafp.org/afp American Family Physician 563
Outpatient Anticoagulation
Table 5. Comparison of Newer Oral Anticoagulants with Enoxaparin and Warfarin

Component Apixaban (Eliquis) vs. warfarin (Coumadin) Dabigatran (Pradaxa) vs. warfarin (Coumadin)

Advantages Fixed dose Fixed dose

Fewer drug and food interactions Fewer drug and food interactions
No laboratory monitoring necessary No laboratory monitoring necessary
Lower bleeding risk compared with warfarin

Disadvantages Lack of long-term safety/effectiveness data
No antidote
No test for effectiveness or toxicity
Renal dosing
Twice-daily administration
U.S. Food and Drug Administration boxed warning for
increased risk of thrombotic events when apixaban
discontinued in patients with nonvalvular atrial
fibrillation
Underweight patients and those with renal impairment
may be at increased bleeding risk
Lack of long-term safety/effectiveness data (e.g., dyspepsia,
hepatotoxicity, myocardial infarction)
No antidote
No test for effectiveness or toxicity
Packaging does not allow redistribution to pill boxes
Renal dosing
Twice-daily administration
Underweight patients and those with renal impairment
may be at increased bleeding risk

Clinical application By alleviating the need for frequent dose titrations and
laboratory monitoring, especially with therapy initiation
and new drug additions or deletions, apixaban possesses
key clinical advantages compared with warfarin
Warfarins predictable adverse effect profile, once-daily
administration, reversibility with vitamin K, and ability
to be monitored for sub- and supratherapeutic dosing
provide reassurance for the clinician
By alleviating the need for frequent dose titrations and
laboratory monitoring, especially with therapy initiation
and new drug additions or deletions, dabigatran possesses
key clinical advantages compared with warfarin
Warfarins predictable adverse effect profile, once-daily
administration, reversibility with vitamin K, and ability
to be monitored for sub- and supratherapeutic dosing
provide reassurance for the clinician

Information from references 10 through 19.

SORT: KEY RECOMMENDATIONS FOR PRACTICE

Evidence
Clinical recommendation rating References

Patients taking warfarin (Coumadin) should be treated using systematic processes of care to optimize B 2, 3
effectiveness and minimize adverse effects. Health care professionals skilled in the initiation and
assessment of therapy and dosing adjustments can dramatically influence outcomes.
In patients with atrial fibrillation and at least one other risk factor for stroke, newer agents (rivaroxaban A 11-19
[Xarelto] and dabigatran [Pradaxa]) that do not require frequent laboratory monitoring are as effective as
warfarin for prevention of stroke or systemic embolism and have comparable risks of major bleeding.
Compared with usual clinic-based care, patient self-testing for international normalized ratios, with or A 22-25
without self-dosing of warfarin, is associated with significantly fewer deaths and thromboembolic
complications without any increase in bleeding complications for a selected group of motivated patients
who have completed appropriate training.

A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented
evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go to http://www.aafp.org/afpsort.xml.

respectively. There were also lower mortality rates in the
apixaban group in both trials and a lower major bleeding
rate in the apixaban group compared with warfarin in the
ARISTOTLE trial.20,21
Five oral direct factor Xa inhibitors (i.e., betrixaban,
TAK-442, darexaban, otamixaban, and edoxaban) are
being assessed.18 AZD0837, which is comparable to dabi-
gatran, and tecarfarin, which is similar to warfarin, are
also under investigation.18
Patient Self-Testing
Point-of-care monitors are typically used in primary
care and anticoagulation clinics and have several advan-
tages, including rapid INR acquisition and interpreta-
tion. These monitors make it possible for patients to
check their INRs at home, which is referred to as patient
self-testing. Reassuring data exist for the effective use of
patient self-testing in selected patients who demonstrate
monitor competency. Decreased mortality, enhanced

564 American Family Physician www.aafp.org/afp Volume 87, Number 8 April 15, 2013

Rivaroxaban (Xarelto) vs. warfarin (Coumadin)
Fixed dose
Fewer drug and food interactions
No laboratory monitoring necessary
Lack of long-term safety/effectiveness data
No antidote
No test for effectiveness or toxicity
Renal dosing
Noncompliance with medication potentially more harmful
U.S. Food and Drug Administration boxed warning for increased risk
of thrombotic events when rivaroxaban discontinued in patients with
nonvalvular atrial fibrillation
Underweight patients and those with renal impairment may be at increased
bleeding risk
By alleviating the need for frequent dose titrations and laboratory monitoring,
especially with therapy initiation and new drug additions or deletions,
rivaroxaban possesses key clinical advantages compared with warfarin
Warfarins predictable adverse effect profile, once-daily administration, relatively
longer half-life, reversibility with vitamin K, and ability to be monitored for
sub- and supratherapeutic dosing provide reassurance for the clinician
INR control, decreased thromboembolic events, and
an improvement in patient satisfaction and quality of
life have been demonstrated with patient self-testing,
all without an increase in bleeding complications.22-24
In 2008, the Centers for Medicare and Medicaid Ser-
vices expanded its patient self-testing coverage, 25 which
is outlined in eTable D. The cost of patient self-testing,
which is similar to the cost of newer oral anticoagulants,
can be significant without reimbursement; however,
self-testing is not appropriate for all patients on warfa-
rin therapy22-24 (eTable D).
Data Sources: A PubMed search was completed in Clinical Queries
using the key terms outpatient, anticoagulation, warfarin, dabigatran,
rivaroxaban, heparin, low-molecular-weight heparin, dalteparin, enoxa-
parin, patient self-monitor, and INR. The search included meta-analyses,
randomized controlled trials, clinical trials, clinical guidelines, and
reviews. Also searched were the National Guideline Clearinghouse data-
base, Essential Evidence Plus, UpToDate, the Cochrane database, and
the Agency for Healthcare Research and Quality Clinical Guidelines and
Evidence Reports. Search date: August 10, 2012.
The Authors
PATRICIA WIGLE, PharmD, BCPS, is an associate professor of pharmacy
practice in the Division of Pharmacy Practice and Administrative Sciences
at the University of Cincinnati (Ohio) James L. Winkle College of Phar-
macy, and a clinical pharmacist in the outpatient anticoagulation clinic at
West Chester (Ohio) Hospital.
April 15, 2013 Volume 87, Number 8 www.aafp.org/afp
Outpatient Anticoagulation
Rivaroxaban (Xarelto) vs. enoxaparin (Lovenox)
Oral route of administration
At least as effective and possibly superior at reducing total
venous thromboembolism without increasing major
bleeding risk
Lack of long-term safety/effectiveness data
(e.g., hepatotoxicity)
No antidote
No test for effectiveness or toxicity
Cannot use in patients with moderate or severe hepatic
impairment
More drug interactions
Oral administration makes it easier to allow for longer
duration of deep venous thrombosis prophylaxis in
patients undergoing orthopedic surgery
BRADLEY HEIN, PharmD, is an associate professor of pharmacy practice
in the Division of Pharmacy Practice and Administrative Sciences at the
University of Cincinnati James L. Winkle College of Pharmacy, and a clini-
cal pharmacist in internal medicine at The Christ Hospital in Cincinnati.
HANNA E. BLOOMFIELD, MD, MPH, is a professor of medicine at the Uni-
versity of Minnesota, Minneapolis, and the co-chief of general internal
medicine at the Minneapolis VA Medical Center.
MATTHEW TUBB, MD, PhD, is chief resident in The Christ Hospital/Univer-
sity of Cincinnati Family Medicine Residency Program.
MICHAEL DOHERTY, PharmD, BCACP, is an assistant professor of phar-
macy practice in the Division of Pharmacy Practice and Administrative Sci-
ences at the University of Cincinnati James L. Winkle College of Pharmacy,
and a clinical pharmacist in the outpatient anticoagulation clinic at West
Chester Hospital.
Address correspondence to Patricia Wigle, PharmD, BCPS, University
of Cincinnati James L. Winkle College of Pharmacy, 3225 Eden Ave.,
304 Wherry Hall, Cincinnati, OH 45267 (e-mail: patricia.wigle@uc.edu).
Reprints are not available from the authors.
Author disclosure: No relevant financial affiliations.
REFERENCES
1. Antithrombotic therapy and prevention of thrombosis, 9th ed: Ameri-
can College of Chest Physicians evidence-based clinical practice guide-
lines. Chest. 2012;141(suppl 2).
2. Hall D, Buchanan J, Helms B, et al. Health care expenditures and thera-
peutic outcomes of a pharmacist-managed anticoagulation service ver-
sus usual medical care. Pharmacotherapy. 2011;31(7):686-694.
3. Rudd KM, Dier JG. Comparison of two different models of anticoagula-
American Family Physician 565
Outpatient Anticoagulation

eTable B. Unfractionated Heparin, LMWH, and Fondaparinux for Outpatient Treatment of Venous
Thromboembolism in Adults

Dosage adjustment in patients

Dosage with renal impairment Half-life Reversibility Monitoring

Unfractionated heparin*
333 units per kg SC first
dose, followed by 250 units
per kg SC twice daily
No adjustment 0.5 to Protamine Activated partial thromboplastin
2 hours time or antifactor Xa levels
Unfractionated heparin can be
monitored using the activated
partial thromboplastin time with
an institution-specific goal range or
with antifactor Xa levels, typically
using a goal of 0.3 to 0.7 IU per mL

LMWH*
Enoxaparin (Lovenox)
1 mg per kg SC every
12 hours or 1.5 mg per kg
SC every 24 hours
Dalteparin (Fragmin)
200 units per kg SC once
daily
Tinzaparin (Innohep)
175 antifactor Xa IU per kg
SC once daily for 6 days
1 mg per kg SC every 24 hours if CrCl 3 to 6 hours NA Antifactor Xa levels in selected
< 30 mL/min/1.73 m2 patients
A peak level (4 hours after the dose
is given) can be measured, with
Use with caution and monitor anti 3 to 5 hours NA a goal of 0.6 to 1 unit per mL for
factor Xa levels in patients with CrCl twice-daily enoxaparin and 1.05
< 30 mL/min/1.73 m2 units per mL for dalteparin
Contraindicated in persons 90 years 3 to 4 hours NA
and older with CrCl 60 mL/
min/1.73 m2
Use with caution and monitor anti
factor Xa levels in patients with CrCl
< 30 mL/min/1.73 m2

Fondaparinux (Arixtra)
Weight < 111 lb (50 kg): Use with caution in patients with CrCl 18 hours NA Antifactor Xa levels (only if
5 mg SC daily 30 to 50 mL/min/1.73 m2 fondaparinux is the reference
Weight 111 to 220 lb (50 to Contraindicated in patients with CrCl standard for the assay)
100 kg): 7.5 mg SC daily 30 mL/min/1.73 m2
Weight > 220 lb (100 kg):
10 mg SC daily

CrCl = creatinine clearance; LMWH = low-molecular-weight heparin; NA = not available; SC = subcutaneously.

*Begin warfarin and unfractionated heparin or LMWH on day 1.
Unfractionated heparin and dalteparin are not approved by the U.S. Food and Drug Administration for treatment of acute deep
venous thrombosis. Enoxaparin, 1.5 mg per kg daily, is not approved for outpatient management of acute deep venous thrombosis or for management
of acute deep venous thrombosis in pregnant patients.
Information from:
Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest.
2012;141(suppl 2).
Lovenox (enoxaparin sodium injection) for subcutaneous and intravenous use [prescribing information]. Bridgewater, N.J.: Sanofi-aventis; 2011.
http://products.sanofi.us/lovenox/lovenox.html. Accessed May 25, 2012.
Innohep (tinzaparin sodium injection) [prescribing information]. Ballerup, Denmark: Leo Pharmaceutical Products; 2008. http://www.accessdata.fda.
gov/drugsatfda_docs/label/2008/020484s011lbl.pdf. Accessed May 25, 2012.
Arixtra (fondaparinux sodium) solution for subcutaneous injection [prescribing information]. Research Triangle Park, N.C.: GlaxoSmithKline; 2011.
http://us.gsk.com/products/assets/us_arixtra.pdf. Accessed August 1, 2012.

566B American Family Physician www.aafp.org/afp Volume 87, Number 8 April 15, 2013
 Outpatient Anticoagulation

Comparisons

Unfractionated heparin vs. LMWH

Considered equally effective and safe
Unfractionated heparin may be better for patients with high
bleeding risk because of short half-life and reversibility
Unfractionated heparin may be favorable in patients with CrCl <
30 mL/min/1.73 m2
LMWH has lower incidence of heparin-induced
thrombocytopenia

Unfractionated heparin vs. LMWH

Considered equally effective and safe
Unfractionated heparin may be better for patients with high
bleeding risk because of short half-life and reversibility
Unfractionated heparin may be favorable in patients with CrCl <
30 mL/min/1.73 m2
LMWH has lower incidence of heparin-induced
thrombocytopenia

LMWH vs. fondaparinux

Comparable effectiveness and safety
Longer half-life for fondaparinux is advantageous (daily dosing)
and potentially troublesome (adverse effects and lack of
reversibility)

April 15, 2013 Volume 87, Number 8 www.aafp.org/afp American Family Physician 566C
Outpatient Anticoagulation

eTable C. Perioperative Management of Warfarin

Warfarin (Coumadin) indication

Mechanical heart valve Chronic atrial fibrillation VTE

At least 1 of the following: At least 1 of the following: At least 1 of the following:

Aortic valve prosthesis (caged-ball or
tilting-disk)
Mitral valve prosthesis (any)
Stroke or TIA within past 6 months
May also include:
Patients with a history of stroke or TIA
more than 3 months before surgery
and a CHADS2 score < 5
Patients undergoing surgeries with high
risk of thromboembolism
CHADS2 score of 5 or 6
Rheumatic mitral valve disease
Stroke or TIA within past 3 months
May also include:
Patients with a history of stroke or
TIA more than 3 months before
surgery and a CHADS2 score < 5
Patients undergoing surgeries with
high risk of thromboembolism
Severe thrombophilia*
VTE within past 3 months
May also include:
Previous thromboembolism during temporary
vitamin K antagonist interruption
Patients undergoing surgeries with high risk
of thromboembolism

Aortic valve prosthesis (bileaflet) and at
least 1 of the following: age older than
75 years; atrial fibrillation; congestive
heart failure; diabetes mellitus;
hypertension; prior stroke or TIA
CHADS2 score of 3 or 4 At least 1 of the following:
Active cancer
Nonsevere thrombophilic condition||
Recurrent VTE
VTE within past 3 to 12 months

Aortic valve prosthesis (bileaflet) without No prior stroke or TIA and CHADS2 Single VTE occurred > 12 months ago and
atrial fibrillation and no other stroke risk score 2 no other risk factors
factors

CHADS2 = congestive heart failure, hypertension, age 75 years, diabetes mellitus, prior ischemic stroke or TIA (doubled); LMWH = low-molecular-weight
heparin; TIA = transient ischemic attack; VTE = venous thromboembolism.
*Such as protein C or S deficiency, antiphospholipid antibodies, or antithrombin deficiency.
Stop subcutaneous LMWH 24 hours before surgery.
Surgeries with a higher risk of bleeding include urologic surgeries, large colon polyp resection, and surgeries that involve vascular organs or have
extensive tissue injury potential. Bleeding risk in hospitalized patients has been linked to multiple factors including active gastric or duodenal ulcer,
bleeding within 3 months before admission, and thrombocytopenia.
Defined as cancer treated within 6 months or palliative.
||Such as heterozygous factor V Leiden mutation.

566D American Family Physician www.aafp.org/afp Volume 87, Number 8 April 15, 2013

Risk level for VTE Bleeding risk category
High (> 10% annual risk) Very low (minor procedures)
Low
High
Moderate (5 to Very low (minor procedures)
10% annual risk)
Low (base bridging on
patient- and surgery-
related factors)
High (base bridging on
patient- and surgery-
related factors)
Low (< 5% annual risk) Very low (minor procedures)
Low
High
Information from:
Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest.
2012;141(suppl 2).
du Breuil AL, Umland EM. Outpatient management of anticoagulation therapy. Am Fam Physician. 2007;75(7):1031-1042.
Douketis JD. Perioperative management of patients who are receiving warfarin therapy: an evidence-based and practical approach. Blood.
2011;117(19):5044-5049.
Kaatz S, Paje D. Update in bridging anticoagulation. J Thromb Thrombolysis. 2011;31(3):259-264.
April 15, 2013 Volume 87, Number 8
Outpatient Anticoagulation
Recommendation
Dental: continue warfarin with an oral prohemostatic agent or stop warfarin
2 to 3 days before procedure
Dermatologic: continue warfarin and optimize local hemostasis
Cataract: continue warfarin
Stop warfarin 5 days before surgery and restart 12 to 24 hours postoperatively
VTE prophylaxis and
Therapeutic dose of LMWH before the procedure and beginning
approximately 24 hours after the procedure
Stop warfarin 5 days before surgery and restart 12 to 24 hours postoperatively
VTE prophylaxis and
Therapeutic dose of LMWH before the procedure and beginning 48 to
72 hours after the procedure
Dental: continue warfarin with an oral prohemostatic agent or stop warfarin
2 to 3 days before procedure
Dermatologic: continue warfarin and optimize local hemostasis
Cataract: continue warfarin
Stop warfarin 5 days before surgery and restart 12 to 24 hours postoperatively
Therapeutic dose of LMWH before the procedure and beginning
approximately 24 hours after the procedure
Stop warfarin 5 days before surgery and restart 12 to 24 hours postoperatively
VTE prophylaxis and
Therapeutic dose of LMWH before the procedure and beginning 48 to
72 hours after the procedure
Dental: continue warfarin with an oral prohemostatic agent or stop warfarin
2 to 3 days before procedure
Dermatologic: continue warfarin and optimize local hemostasis
Cataract: continue warfarin
Stop warfarin 5 days before surgery and restart 12 to 24 hours postoperatively
Do not bridge
Stop warfarin 5 days before surgery and restart 12 to 24 hours postoperatively
Do not bridge
www.aafp.org/afp American Family Physician 566E
Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation
For patients with creatinine clearance (CrCl) >30 mL/min, the recommended dose of PRADAXA is 150 mg taken orally, twice daily. For patients with severe renal
impairment (CrCl 15-30 mL/min), the recommended dose of PRADAXA is 75 mg twice daily [see Use in Specific Populations (8.6) and Clinical Pharmacology
(12.3)]. Dosing recommendations for patients with a CrCl <15 mL/min or on dialysis cannot be provided.

Treatment of Deep Venous Thrombosis and Pulmonary Embolism

For patients with CrCl >30 mL/min, the recommended dose of PRADAXA is 150 mg taken orally, twice daily, after 5-10 days of parenteral anticoagulation. Dosing
recommendations for patients with a CrCl 30 mL/min or on dialysis cannot be provided [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism
For patients with CrCl >30 mL/min, the recommended dose of PRADAXA is 150 mg taken orally, twice daily after previous treatment. Dosing recommendations for
patients with a CrCl 30 mL/min or on dialysis cannot be provided [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery
For patients with CrCl >30 mL/min, the recommended dose of PRADAXA is 110 mg taken orally 1-4 hours after surgery and after hemostasis has been achieved, then
220 mg taken once daily for 28-35 days. If PRADAXA is not started on the day of surgery, after hemostasis has been achieved initiate treatment with 220 mg once
daily. Dosing recommendations for patients with a CrCl 30 mL/min or on dialysis cannot be provided [see Use in Specific Populations (8.6) and Clinical
Pharmacology (12.2, 12.3)].

2.2 Dosing Adjustments

Assess renal function prior to initiation of treatment with PRADAXA. Periodically assess renal function as clinically indicated (i.e., more frequently in clinical
situations that may be associated with a decline in renal function) and adjust therapy accordingly. Discontinue PRADAXA in patients who develop acute renal failure
while on PRADAXA and consider alternative anticoagulant therapy.

Generally, the extent of anticoagulation does not need to be assessed. When necessary, use aPTT or ECT, and not INR, to assess for anticoagulant activity in patients on
PRADAXA [see Warnings and Precautions (5.2) and Clinical Pharmacology (12.2)].

Reduction of Risk of Stroke and Systemic Embolism in Non-valvular Atrial Fibrillation

In patients with moderate renal impairment (CrCl 30-50 mL/min), concomitant use of the P-gp inhibitor dronedarone or systemic ketoconazole can be expected to
produce dabigatran exposure similar to that observed in severe renal impairment. Reduce the dose of PRADAXA to 75 mg twice daily [see Warnings and Precautions
(5.5), Drug Interactions (7.1) and Clinical Pharmacology (12.3)].

Treatment and Reduction in the Risk of Recurrence of Deep Venous Thrombosis and Pulmonary Embolism
Dosing recommendations for patients with CrCl 30 mL/min cannot be provided. Avoid use of concomitant P-gp inhibitors in patients with CrCl <50 mL/min [see
Warnings and Precautions (5.5), Drug Interactions (7.2) and Clinical Pharmacology (12.3)].

Prophylaxis of Deep Vein Thrombosis and Pulmonary Embolism Following Hip Replacement Surgery
Dosing recommendations for patients with CrCl 30 mL/min or on dialysis cannot be provided. Avoid use of concomitant P-gp inhibitors in patients with CrCl <50
mL/min [see Warnings and Precautions (5.5), Drug Interactions (7.3) and Clinical Pharmacology (12.2, 12.3)].

2.3 Instructions to Patients

Instruct patients to swallow the capsules whole. PRADAXA should be taken with a full glass of water. Breaking, chewing, or emptying the contents of the capsule can
result in increased exposure [see Clinical Pharmacology (12.3)].

If a dose of PRADAXA is not taken at the scheduled time, the dose should be taken as soon as possible on the same day; the missed dose should be skipped if it cannot
be taken at least 6 hours before the next scheduled dose. The dose of PRADAXA should not be doubled to make up for a missed dose.

2.4 Converting from or to Warfarin

When converting patients from warfarin therapy to PRADAXA, discontinue warfarin and start PRADAXA when the INR is below 2.0.

When converting from PRADAXA to warfarin, adjust the starting time of warfarin based on creatinine clearance as follows:
For CrCl 50 mL/min, start warfarin 3 days before discontinuing PRADAXA.
For CrCl 30-50 mL/min, start warfarin 2 days before discontinuing PRADAXA.
For CrCl 15-30 mL/min, start warfarin 1 day before discontinuing PRADAXA.
For CrCl <15 mL/min, no recommendations can be made.

Because PRADAXA can increase INR, the INR will better reflect warfarins effect only after PRADAXA has been stopped for at least 2 days [see Clinical
Pharmacology (12.2)].

2.5 Converting from or to Parenteral Anticoagulants

For patients currently receiving a parenteral anticoagulant, start PRADAXA 0 to 2 hours before the time that the next dose of the parenteral drug was to have been
administered or at the time of discontinuation of a continuously administered parenteral drug (e.g., intravenous unfractionated heparin).

For patients currently taking PRADAXA, wait 12 hours (CrCl 30 mL/min) or 24 hours (CrCl <30 mL/min) after the last dose of PRADAXA before initiating
treatment with a parenteral anticoagulant [see Clinical Pharmacology (12.3)].

2.6 Discontinuation for Surgery and Other Interventions

If possible, discontinue PRADAXA 1 to 2 days (CrCl 50 mL/min) or 3 to 5 days (CrCl <50 mL/min) before invasive or surgical procedures because of the increased
risk of bleeding. Consider longer times for patients undergoing major surgery, spinal puncture, or placement of a spinal or epidural catheter or port, in whom complete
hemostasis may be required [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

If surgery cannot be delayed, there is an increased risk of bleeding [see Warnings and Precautions (5.2)]. This risk of bleeding should be weighed against the urgency
of intervention [see Warnings and Precautions (5.1, 5.3)]. Use a specific reversal agent (idarucizumab) in case of emergency surgery or urgent procedures when
reversal of the anticoagulant effect of dabigatran is needed. Refer to the idarucizumab prescribing information for additional information. Restart PRADAXA as soon
as medically appropriate.
FULL PRESCRIBING INFORMATION
WARNING: (A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE
RISK OF THROMBOTIC EVENTS
(B) SPINAL/EPIDURAL HEMATOMA
(A) PREMATURE DISCONTINUATION OF ELIQUIS INCREASES THE RISK OF
THROMBOTIC EVENTS
Premature discontinuation of any oral anticoagulant, including ELIQUIS,
increases the risk of thrombotic events. If anticoagulation with ELIQUIS is
discontinued for a reason other than pathological bleeding or completion of
a course of therapy, consider coverage with another anticoagulant [see
Dosage and Administration (2.4), Warnings and Precautions (5.1), and Clinical
Studies (14.1)].
(B) SPINAL/EPIDURAL HEMATOMA
Epidural or spinal hematomas may occur in patients treated with ELIQUIS
who are receiving neuraxial anesthesia or undergoing spinal puncture.
These hematomas may result in long-term or permanent paralysis. Consider
these risks when scheduling patients for spinal procedures. Factors that
can increase the risk of developing epidural or spinal hematomas in these
patients include:
use of indwelling epidural catheters
concomitant use of other drugs that affect hemostasis, such as
nonsteroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other
anticoagulants
a history of traumatic or repeated epidural or spinal punctures
a history of spinal deformity or spinal surgery
optimal timing between the administration of ELIQUIS and neuraxial
procedures is not known
[see Warnings and Precautions (5.3)]
Monitor patients frequently for signs and symptoms of neurological
impairment. If neurological compromise is noted, urgent treatment is
necessary [see Warnings and Precautions (5.3)].
Consider the benefits and risks before neuraxial intervention in patients
anticoagulated or to be anticoagulated [see Warnings and Precautions (5.3)].
1 INDICATIONS AND USAGE
1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial
Fibrillation
ELIQUIS (apixaban) is indicated to reduce the risk of stroke and systemic embolism in
patients with nonvalvular atrial fibrillation.
1.2 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement
Surgery
ELIQUIS is indicated for the prophylaxis of deep vein thrombosis (DVT), which may
lead to pulmonary embolism (PE), in patients who have undergone hip or knee
replacement surgery.
1.3 Treatment of Deep Vein Thrombosis
ELIQUIS is indicated for the treatment of DVT.
1.4 Treatment of Pulmonary Embolism
ELIQUIS is indicated for the treatment of PE.
1.5 Reduction in the Risk of Recurrence of DVT and PE
ELIQUIS is indicated to reduce the risk of recurrent DVT and PE following initial therapy.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dose
Reduction of Risk of Stroke and Systemic Embolism in Patients with Nonvalvular
Atrial Fibrillation
The recommended dose of ELIQUIS for most patients is 5 mg taken orally twice daily.
The recommended dose of ELIQUIS is 2.5 mg twice daily in patients with at least two of
the following characteristics:
age 80 years
body weight 60 kg
serum creatinine 1.5 mg/dL
Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery
The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily. The initial dose
should be taken 12 to 24 hours after surgery.
In patients undergoing hip replacement surgery, the recommended duration of
treatment is 35 days.
In patients undergoing knee replacement surgery, the recommended duration of
treatment is 12 days.
Treatment of DVT and PE
The recommended dose of ELIQUIS is 10 mg taken orally twice daily for the first 7 days of
therapy. After 7 days, the recommended dose is 5 mg taken orally twice daily.
ELIQUIS (apixaban)
Reduction in the Risk of Recurrence of DVT and PE
The recommended dose of ELIQUIS is 2.5 mg taken orally twice daily after at least
6 months of treatment for DVT or PE [see Clinical Studies (14.3)].
2.2 Missed Dose
If a dose of ELIQUIS is not taken at the scheduled time, the dose should be taken as
soon as possible on the same day and twice-daily administration should be resumed.
The dose should not be doubled to make up for a missed dose.
2.3 Temporary Interruption for Surgery and Other Interventions
ELIQUIS should be discontinued at least 48 hours prior to elective surgery or invasive
procedures with a moderate or high risk of unacceptable or clinically significant bleeding.
ELIQUIS should be discontinued at least 24 hours prior to elective surgery or invasive
procedures with a low risk of bleeding or where the bleeding would be non-critical in
location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after
stopping ELIQUIS and prior to the intervention is not generally required. ELIQUIS should
be restarted after the surgical or other procedures as soon as adequate hemostasis has
been established.
2.4 Converting from or to ELIQUIS
Switching from warfarin to ELIQUIS: Warfarin should be discontinued and ELIQUIS started
when the international normalized ratio (INR) is below 2.0.
Switching from ELIQUIS to warfarin: ELIQUIS affects INR, so that initial INR measurements
during the transition to warfarin may not be useful for determining the appropriate
dose of warfarin. One approach is to discontinue ELIQUIS and begin both a parenteral
anticoagulant and warfarin at the time the next dose of ELIQUIS would have been taken,
discontinuing the parenteral anticoagulant when INR reaches an acceptable range.
Switching from ELIQUIS to anticoagulants other than warfarin (oral or parenteral):
Discontinue ELIQUIS and begin taking the new anticoagulant other than warfarin at the
usual time of the next dose of ELIQUIS.
Switching from anticoagulants other than warfarin (oral or parenteral) to ELIQUIS:
Discontinue the anticoagulant other than warfarin and begin taking ELIQUIS at the usual
time of the next dose of the anticoagulant other than warfarin.
2.5 Strong Dual Inhibitors of CYP3A4 and P-glycoprotein
For patients receiving ELIQUIS doses of 5 mg or 10 mg twice daily, reduce the dose
by 50% when ELIQUIS is coadministered with drugs that are strong dual inhibitors
of cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp) (e.g., ketoconazole,
itraconazole, ritonavir, clarithromycin) [see Clinical Pharmacology (12.3)].
In patients already taking 2.5 mg twice daily, avoid coadministration of ELIQUIS with
strong dual inhibitors of CYP3A4 and P-gp [see Drug Interactions (7.1)].
2.6 Administration Options
For patients who are unable to swallow whole tablets, 5 mg and 2.5 mg ELIQUIS tablets
may be crushed and suspended in water, 5% dextrose in water (D5W), or apple juice,
or mixed with applesauce and promptly administered orally [see Clinical Pharmacology
(12.3)]. Alternatively, ELIQUIS tablets may be crushed and suspended in 60 mL of water
or D5W and promptly delivered through a nasogastric tube [see Clinical Pharmacology
(12.3)].
Crushed ELIQUIS tablets are stable in water, D5W, apple juice, and applesauce for up
to 4 hours.
3 DOSAGE FORMS AND STRENGTHS
2.5 mg, yellow, round, biconvex, film-coated tablets with 893 debossed on
one side and 2 on the other side.
5 mg, pink, oval-shaped, biconvex, film-coated tablets with 894 debossed on
one side and 5 on the other side.
4 CONTRAINDICATIONS
ELIQUIS is contraindicated in patients with the following conditions:
Active pathological bleeding [see Warnings and Precautions (5.2) and Adverse
Reactions (6.1)]
Severe hypersensitivity reaction to ELIQUIS (e.g., anaphylactic reactions) [see
Adverse Reactions (6.1)]
5 WARNINGS AND PRECAUTIONS
5.1 Increased Risk of Thrombotic Events after Premature Discontinuation
Premature discontinuation of any oral anticoagulant, including ELIQUIS, in the absence
of adequate alternative anticoagulation increases the risk of thrombotic events.
An increased rate of stroke was observed during the transition from ELIQUIS to warfarin
in clinical trials in atrial fibrillation patients. If ELIQUIS is discontinued for a reason other
than pathological bleeding or completion of a course of therapy, consider coverage with
another anticoagulant [see Dosage and Administration (2.4) and Clinical Studies (14.1)].
5.2 Bleeding
ELIQUIS increases the risk of bleeding and can cause serious, potentially fatal, bleeding
[see Dosage and Administration (2.1) and Adverse Reactions (6.1)].
XARELTO (rivaroxaban) tablets XARELTO (rivaroxaban) tablets
8 USE IN SPECIFIC POPULATIONS 13 NON-CLINICAL TOXICOLOGY
8.1 Pregnancy 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
8.2 Labor and Delivery 14 CLINICAL STUDIES
8.3 Nursing Mothers 14.1 Stroke Prevention in Nonvalvular Atrial Fibrillation
8.4 Pediatric Use 14.2 Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism
8.5 Geriatric Use (PE), and Reduction in the Risk of Recurrence of DVT and of PE
8.6 Females of Reproductive Potential 14.3 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee
8.7 Renal Impairment Replacement Surgery
8.8 Hepatic Impairment 16 HOW SUPPLIED/STORAGE AND HANDLING
10 OVERDOSAGE 17 PATIENT COUNSELING INFORMATION
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY *Sections or subsections omitted from the full prescribing information are
12.1 Mechanism of Action not listed.
12.2 Pharmacodynamics
12.3 Pharmacokinetics
12.6 QT/QTc Prolongation

FULL PRESCRIBING INFORMATION 1.5 Prophylaxis of Deep Vein Thrombosis Following Hip or Knee
Replacement Surgery
WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in
INCREASES THE RISK OF THROMBOTIC EVENTS, patients undergoing knee or hip replacement surgery.
(B) SPINAL/EPIDURAL HEMATOMA
2 DOSAGE AND ADMINISTRATION
A. Premature discontinuation of XARELTO increases the risk of 2.1 Recommended Dosage
thrombotic events
Premature discontinuation of any oral anticoagulant, including Indication Dosage
XARELTO, increases the risk of thrombotic events. If anticoagulation Reduction in Risk of CrCl >50mL/min: 20mg once daily with the
with XARELTO is discontinued for a reason other than pathological Stroke in Nonvalvular evening meal
bleeding or completion of a course of therapy, consider coverage with Atrial Fibrillation (2.4)
another anticoagulant [see Dosage and Administration (2.3, 2.7), CrCl 15 to 50mL/min: 15mg once daily with the
evening meal
Warnings and Precautions (5.1), and Clinical Studies (14.1)].
Treatment of DVT (2.5) 15 mg twice daily with food, for first 21 days
B. Spinal/epidural hematoma
Epidural or spinal hematomas have occurred in patients treated with Treatment of PE (2.5) after 21 days, transition to
XARELTO who are receiving neuraxial anesthesia or undergoing spinal 20 mg once daily with food, for remaining treatment
puncture. These hematomas may result in long-term or permanent Reduction in the Risk
paralysis. Consider these risks when scheduling patients for spinal of Recurrence of DVT 20mg once daily with food
procedures. Factors that can increase the risk of developing epidural or and of PE (2.5)
spinal hematomas in these patients include:
Prophylaxis of DVT Hip replacement: 10mg once daily for 35 days
use of indwelling epidural catheters Following Hip or
concomitant use of other drugs that affect hemostasis, such as non- Knee Replacement Knee replacement: 10mg once daily for 12 days
steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other Surgery (2.6)
anticoagulants
a history of traumatic or repeated epidural or spinal punctures 2.2 Important Food Effect Information
a history of spinal deformity or spinal surgery The 15 mg and 20 mg XARELTO tablets should be taken with food, while
optimal timing between the administration of XARELTO and neuraxial the 10 mg tablet can be taken with or without food [see Clinical
procedures is not known Pharmacology (12.3)].
[see Warnings and Precautions (5.2, 5.3) and Adverse Reactions (6.2)]. In the nonvalvular atrial fibrillation efficacy study XARELTO was taken with
Monitor patients frequently for signs and symptoms of neurological the evening meal.
impairment. If neurological compromise is noted, urgent treatment is 2.3 Switching to and from XARELTO
necessary [see Warnings and Precautions (5.3)].
Switching from Warfarin to XARELTO - When switching patients from
Consider the benefits and risks before neuraxial intervention in warfarin to XARELTO, discontinue warfarin and start XARELTO as soon as
patients anticoagulated or to be anticoagulated for thromboprophylaxis the International Normalized Ratio (INR) is below 3.0 to avoid periods of
[see Warnings and Precautions (5.3)]. inadequate anticoagulation.
Switching from XARELTO to Warfarin - No clinical trial data are available to
1 INDICATIONS AND USAGE guide converting patients from XARELTO to warfarin. XARELTO affects INR,
1.1 Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular so INR measurements made during coadministration with warfarin may not
Atrial Fibrillation be useful for determining the appropriate dose of warfarin. One approach
XARELTO is indicated to reduce the risk of stroke and systemic embolism in is to discontinue XARELTO and begin both a parenteral anticoagulant and
patients with nonvalvular atrial fibrillation. warfarin at the time the next dose of XARELTO would have been taken.
There are limited data on the relative effectiveness of XARELTO and Switching from XARELTO to Anticoagulants other than Warfarin - For
warfarin in reducing the risk of stroke and systemic embolism when patients currently taking XARELTO and transitioning to an anticoagulant
warfarin therapy is well-controlled [see Clinical Studies (14.1)]. with rapid onset, discontinue XARELTO and give the first dose of the other
anticoagulant (oral or parenteral) at the time that the next XARELTO dose
1.2 Treatment of Deep Vein Thrombosis would have been taken [see Drug Interactions (7.4)].
XARELTO is indicated for the treatment of deep vein thrombosis (DVT).
Switching from Anticoagulants other than Warfarin to XARELTO - For
1.3 Treatment of Pulmonary Embolism patients currently receiving an anticoagulant other than warfarin, start
XARELTO is indicated for the treatment of pulmonary embolism (PE). XARELTO 0to2hours prior to the next scheduled evening administration of
the drug (e.g., low molecular weight heparin or non-warfarin oral
1.4 Reduction in the Risk of Recurrence of Deep Vein Thrombosis and of
anticoagulant) and omit administration of the other anticoagulant. For
Pulmonary Embolism
unfractionated heparin being administered by continuous infusion, stop the
XARELTO is indicated for the reduction in the risk of recurrence of deep infusion and start XARELTO at the same time.
vein thrombosis and of pulmonary embolism following initial 6 months
treatment for DVT and/or PE.