31 Lower extremity resistance training can provide improved functional
performance measured by the following: quality of life, treadmill walking time, and
32 An appropriate exercise program results in superior
outcomes compared with angioplasty and stenting, and equal in terms of walking
distance compared with surgery, but without any of the significant complications and
mortality associated with surgery.
Rheologic abnormalities of increased blood viscosity, impaired RBC filterability,
hyperaggregation, and polycythemia (elevated hematocrit) have been shown to return
to normal in many patients with IC who participate in a regular exercise program.
Exercise may offset the need for pharmacologic intervention. The potential
mechanisms by which exercise benefits patients with IC are listed in Table 10-6.
CASE 10-1, QUESTION 3: Is lipid-lowering therapy indicated for R.L.?
Because IC is a consequence of atherosclerosis, arresting the progression of R.L.’s
atherosclerotic disease is important (see Chapter 8, Dyslipidemias, Atherosclerosis,
and Coronary Heart Disease). Initiation of the nutritional and exercise
recommendations should be recommended as outlined in 2013 ACC/AHA Lifestyle
Management to reduce cardiovascular risk guidelines
ACC/AHA Guideline on the treatment of blood cholesterol to reduce atherosclerotic
cardiovascular risk in adults.
suggest that aggressive dietary and pharmacologic management of dyslipidemia,
particularly lowering low-density lipoprotein cholesterol (LDL-C), leads to
regression of atherosclerotic lesions in the coronary and carotid vasculature.
contrast, relatively few prospective data exist about the effect of successful lipid-
lowering therapy on the regression or stabilization of peripheral lesions, or on
clinical events in patients with PAD. A post hoc analysis of a large lipid-lowering
study in subjects with known CAD treated with simvastatin demonstrated a
significant decrease in new or worsening IC, suggesting that in high-risk patients,
lipid lowering can prevent development of clinically symptomatic PAD.
Protection Study randomly assigned patients with known arterial disease of various
types to simvastatin 40 mg daily or placebo. After 5 years, a 15% decrease was
found in noncardiac revascularizations, including amputations, among the patients
40 Short-term outcomes (e.g., 6 months to 1 year), such as
improved walking distance and walking time, have also been documented with
Primary Mechanisms of Symptom Improvement with Exercise Therapy in
Metabolic changes in the muscle
Improved endothelial function and microcirculation
Decreased occurrence of ischemia and inflammation
Atherosclerosis risk factors improved via
Increased high-density lipoprotein (HDL)
A meta-analysis of 10,049 subjects from several randomized trials using a variety
of lipid-lowering therapies in patients with PAD demonstrated reduced claudication
severity and decreased disease progression as measured by angiography. A decrease
in mortality did not reach statistical significance.
apolipoprotein [Lp(a)] concentrations may be particularly important in the
Patients with PAD fall into one of the four major statin benefit groups, specifically
falling into the group with known atherosclerotic cardiovascular disease (ASCVD).
Since R.L. is less than 75 years old, he warrants high-intensity statin therapy, which
is defined as statin therapy at doses that are expected to provide at least a 50%
reduction in LDL cholesterol (see Chapter 8, Dyslipidemias, Atherosclerosis, and
Coronary Heart Disease). There is a paucity of outcome data with other agents for
dyslipidemia, as recent trials of omega-3 fatty acid, niacin, or fibric acid derivative
have failed to demonstrate a reduction in cardiovascular events in patients with
increased risk for cardiovascular events like R.L.
CASE 10-1, QUESTION 4: R.L.’s BP is elevated to 170/95 mm Hg despite ramipril therapy. Because he
therapies that might be preferable for R.L.?
R.L.’s hypertension has likely contributed to the development of his
atherosclerosis and PAD. Hypertension (see Chapter 9, Essential Hypertension) has
been associated with deficiencies in the synthesis of vasodilating substances, such as
prostacyclin, bradykinin, and nitric oxide, by the endothelial cells lining the
vasculature, along with increases in vasoconstricting substances like angiotensin II.
Increased vascular tone can alter local hemodynamics, especially in the presence of a
stenotic lesion. Although it has not been determined whether normalization of BP has
a positive effect on IC, it is well established that uncontrolled BP results in vascular
complications such as MI and stroke. In light of R.L.’s numerous risk factors for these
complications, improvement in his BP is warranted.
β-Blockers are frequently cited as contraindicated in IC patients owing to the
Angiotensin-converting enzyme (ACE) inhibitors are first-line agents in patients
8 Compared with other antihypertensive agents, the data available support
their beneficial effects in this population. Compared with placebo, walking distance
is increased with both perindopril and ramipril in patients with PAD.
Outcomes Prevention Evaluation (HOPE) study compared ramipril versus placebo in
over 9,000 patients who had evidence of vascular disease or diabetes. Impressively,
they enrolled more than 4,000 patients with PAD, and similar to the overall trial
population, patients with PAD derived a benefit in the composite endpoint of
decreased mortality, MI, and stroke.
53 The ONTARGET trial compared telmisartan,
MI, stroke, or hospitalization for heart failure. The results suggested equivalency of
telmisartan to ramipril for the primary end point with similar BP reduction in both
groups; however, the combination therapy group experienced more adverse events
54 Based on these data, ARBs may be a suitable substitute for
ACE inhibitors, but combination therapy is not recommended.
R.L.’s. BP goal is less than 140/90 mm Hg.
55–57 His dose of ramipril could be
increased, or a low-dose diuretic, such as hydrochlorothiazide or chlorthalidone,
could be added. Given his history of chronic stable angina, the addition of a CCB or
a β-blocker would be an option as well. The ACCOMPLISH trial compared the
combination of benazepril–amlodipine with benazepril–hydrochlorothiazide in
patients with hypertension who were at high risk for cardiovascular events.
Amlodipine therapy reduced cardiovascular events compared with
hydrochlorothiazide, even though BP control was not significantly different.
β-blockers are typically used in patients with CAD, the outcome data supporting their
CASE 10-1, QUESTION 5: Will improving R.L.’s diabetes control or slow the progression of his PAD?
What changes in his diabetes management do you recommend?
Patients with type 2 diabetes mellitus (see Chapter 53, Diabetes Mellitus) are able
to minimize macrovascular and microvascular complications of their disease with
Insulin, sulfonylurea, or metformin therapies have a
beneficial effect on slowing the development of the microvascular complications of
diabetes, such as retinopathy and nephropathy. Metformin has specifically been
shown to further reduce the occurrence of macrovascular complications such as
stroke or MI compared with insulin or sulfonylureas in obese patients with type 2
Effect of Diabetes Mellitus on Intermittent Claudication Outcomes After 5
(%) Patients Without Diabetes (%)
R.L.’s diabetes is a significant risk factor for progression to further ischemic
events (Table 10-7). He has a twofold greater risk of death and a sevenfold greater
risk of amputation compared with a patient without diabetes. Although a specific
benefit for IC has not been demonstrated, it seems prudent to initiate or continue
aggressive diabetes management in patients with type 2 diabetes mellitus and IC. The
addition of metformin to R.L.’s therapy could improve his blood glucose control and
decrease his risk of vascular complications. It is hoped that R.L. can reach his Hgb
A1c goal of less than 7% and a fasting blood glucose of 80 to 130 mg/dL and 2-hour
postprandial glucose of less than 180 mg/dL with diet and exercise, while adding
metformin to his current therapy.
R.L. also must take proper care of his feet to prevent ulcerative complications of
IC. He should be encouraged to keep his feet warm, dry, and moisturized and to wear
properly fitted shoes and perform daily foot inspections.
attention immediately for minor trauma to his feet or legs.
reduce the incidence of amputation in patients with diabetes.
Would alternative antiplatelet therapies offer advantages over aspirin?
Aspirin is one of several antiplatelet agents that may be considered for indefinite
use in patients with PAD. There is limited data on the effects of aspirin on IC
symptoms. Whether aspirin has any beneficial effects on walking distance or
claudication pain has not been studied. Available data address the impact of aspirin
on overall cardiovascular morbidity and mortality. Although aspirin has no direct
effect on plaque regression, it does prevent and retard the role platelets play in the
thrombogenic events that occur in the vicinity of atherosclerotic plaques.
an effective antithrombotic agent at dosages ranging from 50 to 1,500 mg daily. The
lowest dosages proven to decrease cardiovascular events are 75 to 100 mg daily,
with the higher dosage showing benefit in active processes, such as acute ischemic
67 A dosage of 75 mg daily has demonstrated benefit in patients
69 No evidence indicates that these “low doses”
are any more or any less effective than dosages of 900 to 1,500 mg daily.
Aspirin is recommended in patients with vascular disease of any origin (this
includes stroke, MI, PAD, and ischemic heart disease). At dosages of 75 to 162
mg/day, aspirin decreases vascular death by approximately 15% and all serious
vascular events (MI, stroke, or vascular death) by approximately 20% in high-risk
patients, including those with PAD.
In patients with PAD, aspirin can delay the
progression of established lesions as assessed by angiography. When used for
primary prevention of cardiovascular disease in men, aspirin decreased the need for
arterial reconstructive surgery, which was needed because of PAD.
In a metaanalysis of 5,269 subjects with PAD, aspirin was associated with a significant
reduction in nonfatal stroke with a statistically insignificant decrease of
72 However, in a recent large randomized,
controlled trial in 3,350 patients 50 to 75 years of age without clinically evident
cardiovascular disease but with a screening ABI of 0.95 or less, aspirin 100 mg/day
was found to be no more effective than placebo in reducing the primary end point of
fatal and nonfatal coronary events, stroke, or revascularization (13.7 events per
1,000 person-years in the aspirin group versus 13.3 in the placebo group; hazard
ratio, 1.03; 95% confidence interval, 0.84–1.27).
Because all dosages of aspirin are similarly efficacious in decreasing vascular
events in this patient population, side effects influence the dose chosen. Although few
studies have directly compared varying doses, side effects appear to be dose related.
Aspirin 30 mg daily results in less minor bleeding compared with approximately 300
74 and 300 mg daily results in fewer gastrointestinal (GI) side effects
75 Therefore, R.L. should take the lowest effective
dose of aspirin: 75 mg to 100 mg daily. Of note, R.L.’s hypertension should be
controlled before initiating aspirin therapy to decrease the small increased incidence
of cerebral hemorrhage associated with its use.
Ticlopidine is a thienopyridine derivative that blocks adenosine 5′-diphosphate
(ADP) receptors on platelets and decreases platelet–fibrinogen binding.
studies document its efficacy in patients with PAD on end points such as walking
distance, cardiovascular death, and the need for revascularization surgery.
However, hematologic toxicities (neutropenia and, rarely, thrombotic
thrombocytopenic purpura) limit its use.
Clopidogrel initially replaced ticlopidine largely because of its improved safety
profile. The effects of clopidogrel on specific PAD outcomes are unknown, but it has
been compared with aspirin in patients with known atherosclerotic disease. Dosages
of 75 mg daily significantly reduced cardiovascular end points by approximately
25% compared with aspirin in this patient population.
most pronounced in the PAD subgroup, leading to the suggestion that clopidogrel may
be preferable in the patient population with PAD. No measure was taken of
clopidogrel’s effect on walking distance or claudication pain, however, and these
results have not been confirmed by further studies.
The combination of aspirin and clopidogrel was compared with aspirin alone in
more than 15,000 patients at high risk of vascular events, of whom greater than 20%
had a history of PAD and approximately 10% had IC.
assessed cardiovascular end points, no benefit was found for dual antiplatelet
therapy with aspirin plus clopidogrel.
80 Thus, while clopidogrel has the same
guideline recommendation as aspirin,8 clinically it is often used as an appropriate
alternative to aspirin in patients unable to take aspirin therapy,
It should not be used in addition to aspirin, however, because the
risk of bleeding and increased cost outweigh any measurable vascular benefit.
Ticagrelor was compared with clopidogrel in 13,885 patients with known
symptomatic PAD but without documented CAD.
86 There was no difference between
the two groups with regards to the primary composite endpoint of death, myocardial
infarction and stroke. Based on these data, ticagrelor cannot be recommended to
reduce the risk of cardiovascular events in PAD patients at this time. These data also
question whether there are differences in cardiovascular risk in patients with both
CAD and PAD versus those with PAD alone.
Cilostazol is one of the few agents approved by the US Food and Drug
Administration (FDA) specifically for the treatment of IC. Several studies have
confirmed that cilostazol 100 mg twice daily increases walking distance by
approximately 50%87–90 and that discontinuation of cilostazol results in a decline in
91 Cilostazol possesses antiplatelet and vasodilatory effects mediated by the
inhibition of phosphodiesterase III.
In vitro observations suggest that these
pharmacologic effects of cilostazol are particularly pronounced at the blood–vessel
92 which may explain its particular efficacy in the patients with PAD.
Studies that included quality-of-life measurements have found that cilostazol
improved overall quality of life.
87,93 Small improvements in ABI with chronic
cilostazol therapy have also been observed.
94 Two small studies indicate cilostazol
is associated with a reduction in restenosis after endovascular therapy in
Despite these positive findings with cilostazol, several drawbacks exist. It is
contraindicated in patients with heart failure based on data with other
phosphodiesterase inhibitors demonstrating excess mortality, presumably due to
97 Other common side effects include headache, occurring in
up to one-third of patients, and loose stools or diarrhea.
cytochrome P-450 3A4 substrate; therefore, any inhibitor of this enzyme system may
substantially increase cilostazol concentrations.
Cilostazol is an important advancement in the treatment of IC. It is the first
pharmacologic agent to demonstrate a consistent effect on a significant source of IC
disability: walking and mobility measures. While limited data address its impact on
other important end points, such as amputation and revascularization procedures or
it should be added to R.L.’s existing medication regimen at a
dosage of 100 mg twice daily to attenuate his symptoms of IC.
CASE 10-1, QUESTION 8: Has pentoxifylline been shown to be efficacious in patients such as R.L.? How
does this drug benefit patients with IC?
Pentoxifylline, a methylxanthine derivative, is another agent approved by the FDA
for the treatment of IC. Pentoxifylline appears to decrease blood viscosity by
decreasing fibrinogen, improving the deformability of both red and white blood cells,
and eliciting antiplatelet effects, although the exact mechanism of action is unclear.
While the theoretic and in vitro data are unique and positive, data demonstrating its
clinical usefulness are controversial. Improvements in walking distances from study
to study are unpredictable, and the clinical importance of the sometimes minimal
increases in walking distances is not clear (e.g., pain-free walking of approximately
30 m greater than with placebo).
101 Some experts assert that these potential benefits
of questionable clinical significance are not worth the expense of drug therapy or the
Pentoxifylline’s role in IC therapy is limited. It may have a role in patients who
are unable to engage in exercise therapy, or in patients with markedly reduced
walking distances, or in whom any small increase in walking distance would greatly
improve a patient’s activity level.
It also may be tried in patients who have not
gained the desired benefit from smoking cessation and exercise therapy, and in
patients with contraindications, intolerance, or failure of cilostazol. A 2-month trial
of pentoxifylline is adequate to determine whether the patient will benefit from
21 R.L. is not severely debilitated, and the benefits of smoking cessation,
exercise therapy, and cilostazol have not been fully realized. Therefore,
pentoxifylline should not be added until his response to these well-proven therapies
has been determined and the need for further improvement in walking distance is
CASE 10-1, QUESTION 9: R.L. is already taking isosorbide mononitrate for angina. Because IC is made
The use of vasodilators for R.L. would at first appear to be a logical
pharmacologic intervention to prevent claudication pain. Vasodilators, including
isosorbide, directly or indirectly relax blood vessel walls and increase both skin and
muscle blood flow as long as cardiac output is maintained. With obstructive arterial
disease, however, vessels are sclerotic and unable to further dilate. As a result,
healthy vessels dilate to a greater extent than diseased vessels, and blood flow is
redistributed (shunted) away from areas that have the greatest need. BP and perfusion
paradoxically drop even further in tissues affected by atherosclerosis, resulting in
increased pain. If this process produces ischemia, it is known as the steal
phenomenon. Thus, while nitrates are not contraindicated in patients like R.L, they
may not be as helpful as their mechanism of action may suggest.
Numerous vasodilators (i.e., prostaglandin E1
papaverine, ethaverine, cyclandelate, niacin derivatives, reserpine, guanethidine,
methyldopa, tolazoline, nifedipine) have been used to treat IC. None, however, has
convincingly or consistently improved exercise performance, despite earlier beliefs
104,105 Limited data suggest L-carnitine 1 g twice daily may
have benefit in walking distance and initial claudication distance.
are the exception to this rule, as their beneficial effects are likely independent of their
vasodilator properties. One small, controlled study demonstrated improvement in
walking distance with verapamil, a CCB, compared with placebo in patients with
107 Further studies with verapamil are needed before its use can be recommended.
Smoking cessation, an exercise program, and cilostazol are the interventions that
should reduce R.L.’s symptoms of IC to the greatest degree. Verapamil is a moderate
cytochrome P-450 3A4 inhibitor and would be expected to increase concentrations of
cilostazol. The magnitude of this interaction has not been characterized, nor has its
impact on efficacy and bleeding events been assessed. Based on the necessity of
cilostazol therapy in R.L., along with the poorly characterized benefits of verapamil
in IC and the plethora of other antihypertensive and antianginal agents, avoidance of
verapamil is prudent at this time. If additional BP or antianginal effects are needed,
β-blockade or amlodipine can be initiated.
OTHER ANTITHROMBOTIC ALTERNATIVES
CASE 10-1, QUESTION 10: If R.L. was deemed as being high risk for a cardiovascular event while on
aspirin, what other antithrombotic therapy options could be initiated?
While there is limited data regarding antithrombotic therapy in patients with PAD,
recently one new agent has been approved with potential to provide a benefit in
reducing cardiovascular events. Vorapaxar is a platelet protease-activated receptor
(PAR)-1 antagonist, which inhibits thrombin-mediated plateletand recently received
FDA approval for reducing thrombotic cardiovascular events in patients with PAD.
The indication approval was based on a recent study, which enrolled 26, 449
patients with stable atherosclerotic vascular disease who were already receiving
dual antiplatelet therapy, of which 14% had PAD.
treatment with vorapaxar reduced the composite primary endpoint of cardiovascular
death, MI stroke, although only the incidence of MI was reduced significantly.
Importantly, major bleeding was increased significantly in the vorapaxar group, thus
the true benefit of the addition of vorapaxar in these patients is unclear at this time.
Ongoing studies with the P2Y12 receptor antagonist ticagrelor and the direct factor
Xa inhibitor oral anticoagulants rivaroxaban and edoxaban will further shed light on
the risks and benefits of more potent, target-specific agents in patients with
109,110 The choice of antiplatelet therapy for R.L. in this scenario would be
dependent upon what specific cardiovascular event he experienced, as the choice of
therapy would be different if R.L. suffered a MI versus an ischemic stroke (see
Chapter 12, Chronic Stable Angina and Chapter 13, Acute Coronary Syndrome).
CASE 10-1, QUESTION 11: Three years have passed, and R.L. stopped smoking 6 months ago. His current
Surgical intervention eventually may be necessary for persistent and complicated
disease. Because success rates for preventing amputation and postsurgical
complications vary from institution to institution, surgery should be considered only
for severely ischemic limbs and should be performed in a hospital with a good
111 Arterial bypass grafting and percutaneous transluminal
angioplasty of the femoral or iliac arteries, similar to cardiac revascularization, are
two procedures that can be performed. Angioplasty is beneficial in patients with
localized disease, especially in the iliac or superficial femoral arteries, and should
be considered in patients who truly are incapacitated by their activity limitations.
reconstructive arterial (bypass) surgery can be used if diffuse lesions preclude the
use of localized angioplasty. The true benefits and pitfalls of these skilled
Emergency surgical intervention may be required if acute, persistent ischemia
develops. This is frequently due to thrombosis associated with advanced
atherosclerosis, although other causes, such as cardiac emboli, cannot be excluded.
Both surgical thrombectomy and localized thrombolytic administration
115,116 After surgical intervention, patients are advised to resume
and remain on antiplatelet therapy indefinitely to reduce the risk of future events.
RP is a clinical syndrome caused by episodic vasospasm and ischemia of the
extremities in response to cold, emotional, or physical stimuli.
include changes in color of the extremities from white, due to vasoconstriction, to
blue, signaling tissue hypoxia and then red when reperfusion occurs.
limited to the skin of the fingers, and less often the toes, but can also occur on the
119 Between attacks, the digits may appear cool and moist or
normal. In most cases, the ischemia produced by the phenomenon does not have
important consequences; however, in severe cases, atrophy of the skin, irregular nail
growth, and wasting or ulceration of the tissue pads can occur.
and RP are disorders of the peripheral arterial circulation, they differ significantly in
that IC results primarily from atherosclerotic obstruction, whereas Raynaud disease
This disorder can be separated into primary RP, indicating an idiopathic origin, and
secondary RP, which consists of signs and symptoms of RP in the presence of an
associated disease or condition, most commonly a connective tissue disorder, such as
scleroderma (also known as systemic sclerosis), mixed connective tissue disease,
rheumatoid arthritis, or systemic lupus
erythematosus. Primary RP is more common (89% of patients) and is more likely to
occur in younger patients (<30 years), generally presents with less severe symptoms,
normal erythrocyte sedimentation rate, negative antinuclear antibodies, and no
associated signs of underlying disease. Patients with secondary RP are more likely to
have severe disease with painful symptoms which can progress to ulceration or
gangrene in extremities if untreated.
119 The diagnosis is generally a subjective one,
consisting of clinical signs and symptoms, cold hands, feet, or both without normal
recovery after a cold stimulus, emotional stress, or physical stress (such as
vibrations) to the extremities.
In unaffected individuals, a cold provocation
should result in some mottling and cyanotic changes in the hands, with recovery once
the stimuli are removed. In patients with RP, however, the same cold provocation
causes closure of the digital arteries, which produces a sharply demarcated pallor
and cyanosis of the digits that persists despite removal of the stimulus.
In general, the prevalence of RP is about 3% to 5% across several ethnic groups
however, it is higher in some geographically defined populations.
common in women than men, is more frequent in non-Hispanic whites, and has a
higher prevalence in patients with family members who also experience RP. An onset
in the teenage years suggests primary RP, whereas an onset after 30 years of age
120 Secondary RP is usually associated with a connective
tissue disorder, but several other conditions may predispose individuals to its
development. These include occupational-related exposures to vibratory machinery
(e.g., drills, grinders, chain saws) that cause neural damage,
122–124 Approximately 15% of patients diagnosed with primary RP will
go on to develop a connective tissue disorder within10 years.
RP can also be associated with medications, including β-adrenergic blocking
agents, ergots, cytotoxic drugs, chemotherapy, amphetamines and other
sympathomimetics, and interferon, all of which can induce vasoconstriction.
Although avoidance of β-adrenergic blocking agents in patients with RP appears
prudent, no discernible effect, as measured by skin temperature and blood flow, was
found with the administration of both selective and nonselective β-blockers to
129 RP not associated with a connective tissue disorder is often
transient and does not interfere with daily activities.
129 The effect of smoking on RP
has yielded conflicting results. Overall, there appears to be a negligible effect of
smoking on the prevalence of RP and the incidence of attacks, although there is some
evidence that the severity of attacks may be decreased with smoking cessation.
The pathophysiology involved in the exaggerated, abnormally long-lasting
vasoconstriction in response to stimuli seen in RP is complex and still not completely
understood. Control of blood vessel reactivity involves a balance of mediators
released from circulating cells, the vascular endothelium, hormones, and
118,122 Cold-induced vasospastic attacks in patients with primary RP
involve a heightened vasoconstriction of digital arteries that is mediated by a subset
Vascular abnormalities noted in RP can include a deficiency of the vasodilator
nitric oxide (NO), an increase in endothelial production of the potent vasoconstrictor
endothelin-1, and increased activity of the renin–angiotensin system resulting in
vasoconstriction induced by angiotensin II.
In secondary RP, structural changes
resulting from connective tissue disease may cause arterial damage that results in the
-adrenoreceptor aberrancy and endothelial injury that stimulates vasoconstriction,
platelet activation, and impaired fibrinolysis.
It is also possible that serotonin
receptors play a role in RP. Serotonin agonists have caused decreased finger blood
flow, and, conversely, antagonists have increased digital blood flow.
having RP. Does L.G. present with primary or secondary RP?
L.G. presents with what is most likely secondary RP owing to one of several
potential underlying causes. His clinical presentation is classic for RP, with
exposure. He has a work history that may easily include hand trauma and the use of
vibrating machinery, and his age also suggests secondary RP. Because of its
association with connective tissue disorders, other laboratory tests such as an
antinuclear antibody and erythrocyte sedimentation rate should be checked.
CASE 10-2, QUESTION 2: What conservative measures can be taken with L.G. to prevent or decrease the
Most patients with either primary or secondary RP will respond to conservative
management to reduce exposure to triggers such as cold and emotional stress.
should be instructed to protect his hands and fingers from exposure by using mittens
and insulated wrappers when handling cold drinks, and to protect other parts of his
body from cold exposure. He should also try to minimize emotional stress and
occupational exposure to vibrating machinery, and avoid medications that can induce
vasoconstriction, particularly sympathomimetics, clonidine, serotonin receptor
agonists, and ergot preparations.
119,120 He should be encouraged to stop smoking,
which may not affect occurrence of attacks but may decrease their severity and
provide an overall positive health benefit.
L.G. has new-onset and relatively mild RP. For others who have more severe
symptoms and manifestations, especially patients with underlying connective tissue
disorders, it is important to immediately and aggressively manage any ulcers that
develop on the digits and to be extremely vigilant in detecting infected digits. Rarely,
patients who have severe symptoms including ulceration or thrombosis may require
surgical intervention such as peripheral sympathectomy, embolectomy, or ulcer
CASE 10-2, QUESTION 3: Nifedipine extended-release 30 mg every day is ordered for L.G. What is the
rationale for using a CCB in this case?
Drugs can be used to treat primary and secondary RP if it interferes with the
patient’s ability to work or perform daily activities or if digital lesions develop.
Most proposed treatments for RP are variably effective, and they introduce the risk
136,137 Drug therapy should always be in addition to
Dihydropyridine CCBs decrease calcium ion influx and prevent vascular smooth
muscle contraction, especially vascular responses evoked by cold exposure.
Nifedipine, a potent peripheral vasodilator, has been studied the most and has
become the drug of choice in patients with RP not controlled by conservative
137 Patients with secondary RP experience a similar decrease in attack
severity and also achieve a decrease in number of attacks with nifedipine therapy.
Because their baseline number of attacks per week often exceeds 20, the relative
benefit is not as great as with primary RP, averaging approximately a 25% decrease
138 Doses of 10 to 30 mg 3 times daily of immediate-release
137,138 although higher doses, if tolerated, may be required
137 Most clinicians administer nifedipine as an extended-release
formulation to increase convenience and decrease side effects such as dizziness,
headache, facial flushing, and peripheral edema, which can occur in up to 50% of
119,122,137 and this practice is supported by clinical studies.
Although less thoroughly studied than nifedipine, other vasoselective CCBs, such
as amlodipine, felodipine, isradipine, and nisoldipine, decrease the frequency and
141–144 Patients who do not benefit from nifedipine likely
will not benefit by switching to another CCB. Patients who cannot tolerate the side
effects of nifedipine (e.g., peripheral edema, headache) might benefit by switching to
L.G. should be warned of the potential side effects with nifedipine therapy,
especially dizziness associated with hypotension, and should return in 2 weeks for
assessment. A 30-mg daily dose of extended-release nifedipine is a reasonable
starting dose. He should be instructed to keep a diary documenting the number of
attacks he experiences and details surrounding each attack, such as time course and
precipitating factors. In addition to the usual side effects mentioned above, L.G.
should be aware that his symptoms of gastroesophageal reflux could worsen with
nifedipine therapy, which can cause a decreased lower esophageal sphincter
pressure. This side effect should be specifically assessed at his follow-up
CASE 10-2, QUESTION 4: What other drugs may be tried if L.G. cannot tolerate the CCB?
Other than CCBs, no proven therapy for RP exists. Many agents, however, have
been used based on limited data. The α1
-adrenergic antagonist prazosin, 1 mg 3 times
a day, yielded moderate benefit in two-thirds of patients in two small studies.
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