Evidence-based Cardiology – part 10 docx

Grade C Table 61.3 Model for determining a clinical suspicion of pulmonary embolism Wells et al123 Clinical signs and symptoms of deep vein 3·0 thrombosis minimum leg swelling and pain

Evidence-based Cardiology

with size and number, and the presence of a normal

ventila-tion scan (“mismatched” defect).42,45A lung scan with

mis-matched segmental or larger perfusion defects is termed

“high probability”.45 A single mismatched defect is

associ-ated with a prevalence of PE of about 80%.46Three or more

mismatched defects are associated with a prevalence of PE of

90%.46Lung scan findings are highly age dependent with a

relatively high proportion of normal scans and a low

propor-tion of non-diagnostic scans in younger patients.33

Lung scanning and clinical assessment

Clinical assessment of PE is complementary to ventilation–

perfusion lung scanning; a moderate or high clinical

suspi-cion in a patient with a high probability lung scan is

diag-nostic (prevalence of PE of 90%); however, a low clinical

suspicion with a high probability defect requires further

investigation because the prevalence of PE with these

find-ings is only about 50%.42,45 The prevalence of PE

with subsegmental, matched, perfusion defects (“low

proba-bility” scan) and a low clinical suspicion is expected to be

less than 10% (see below).27,30,42

Helical (spiral) computerized tomography (CT)

Helical CT following intravenous injection of radiographic

contrast can be used to visualize the pulmonary arteries.

Although widely used to diagnose PE, the technique has yet

to be definitively evaluated for this purpose.47,48 Grade B

subseg-● A normal helical CT substantially reduces the probability

of PE but does not exclude the diagnosis (that is, similar

to a “low probability” ventilation–perfusion scan).47,48Although this statement is largely based on extrapolation from experience with patients who have non-diagnostic lung scans, patients with helical CT scans that are not diagnostic

for PE can be managed as outlined in Box 61.4 Grade C

Table 61.3 Model for determining a clinical suspicion

of pulmonary embolism (Wells et al123 )

Clinical signs and symptoms of deep vein 3·0

thrombosis (minimum leg swelling and pain

with palpation of the deep veins)

An alternative diagnosis is less likely than 3·0

pulmonary embolism

Immobilization or surgery in the 1·5

previous 4 weeks

Previous deep vein thrombosis/pulmonary 1·5

embolism

Malignancy (treatment ongoing or within 1·0

previous 6 months or palliative)

● Pulmonary angiography: intraluminal filling defect

● Helical CT: intraluminal filling defect in a lobar ormain pulmonary artery47,48

● Ventilation–perfusion scan: high probability scanand moderate/high clinical suspicion42,43

● Diagnostic for DVT: with non-diagnostic ventilation–perfusion scan or helical CT124

● Excludes PE

● Pulmonary angiogram: normal39

● Perfusion scan: normal41

● D-dimer: normal test, which has a very high tivity (98%) and at least a moderate specificity(40%)27

sensi-● Non-diagnostic ventilation–perfusion scan, or mal helical CT, and normal proximal VUI and(a) low clinical suspicion for PE30,50 a

nor-(b) normal D-dimer test, which has at least a erately high sensitivity (85%) and specificity(70%)30,32 a

mod-● Low clinical suspicion for PE and normal D-dimer,which has at least a moderately high sensitivity(85%) and specificity (70%)30,32

aIf serial VUI (venous ultrasound imaging) is performed it isexpected to become abnormal in 1–2% of these patientsand reduce the frequency of symptomatic VTE (venousthromboembolism) during 3 months of follow up from

(Box 61.4) Grade A

evolving proximal DVT, the forerunner of recurrent PE If serial VUI for DVT (two additional tests a week apart) is neg- ative, the subsequent risk of recurrent VTE during the next

3 months is less than 1%,30,44,51which is similar to that after

a normal pulmonary angiogram.39As an additional tion, patients who have had PE and/or DVT excluded should routinely be asked to return for re-evaluation if symptoms of PE and/or DVT persist or recur.

precau-Diagnosis of PE in pregnancy

Pregnant patients with suspected PE can be managed similarly to non-pregnant patients, with the following modifications:

● VUI can be performed first and lung scanning formed if there is no DVT; patients with unequivocal evidence of DVT can be presumed to have PE.

per-● The amount of radioisotope used for the perfusion scan can be reduced and the duration of scanning extended.

● If pulmonary angiography is performed, the brachial approach with abdominal screening is preferable.

● In the absence of safety data relating to helical CT in pregnancy, this is discouraged (if it is necessary, abdomi- nal screening should be used) Consistent with other young patients who are suspected of having PE, a high proportion of pregnant patients have normal scans and a small proportion have high probability scans.33,52These recommendations are based on a belief that the risk of inaccurate diagnosis of suspected PE during pregnancy

is greater than the risk of radioactivity to the fetus.52,53

Algorithms for the diagnosis of PE

Local availability of methods of testing and differences among patient presentations influence the diagnostic approach to PE A number of prospectively validated algorithms have been published, which emphasize the use

of different initial non-invasive tests in conjunction with ventilation–perfusion lung scanning including:

● structured clinical assessment and serial VUI;44

● sensitive D-dimer assay, empiric clinical assessment, and single bilateral VUI;27

● clinical assessment, moderately sensitive D-dimer assay and serial VUI.30

Prevention of VTE (Box 61.6)

In a non-randomized trial, oral anticoagulation was shown

to prevent PE in patients with fractured hips, without ing an unacceptable increase in bleeding.54

caus-Subsequently, low-dose unfractionated heparin was shown

to reduce postoperative DVT and fatal PE by two thirds.55,56Further studies have demonstrated that the efficacy of

Grade A

Grade B

Venous thromboembolic disease

Tests for DVT in patients with suspected PE

Testing for DVT is an indirect way to diagnose PE (see

Box 61.4).49VUI of the proximal veins is the usual method,

although bilateral ascending venography, or CT or MRI of

the legs at the same time as examination of the pulmonary

veins, can also be used Negative tests for DVT do not rule

out PE but they reduce the probability, and suggest that the

short-term risk of recurrent PE is low.49Because the

preva-lence of PE is expected to be less than 5% in patients with

a non-diagnostic lung scan, a low clinical suspicion of PE,

and a normal VUI of the proximal veins, it is reasonable

to exclude PE with these findings.27,30,44,50

Management of patients with non-diagnostic

combinations of non-invasive tests for PE (Box 61.5)

Patients with non-diagnostic test results for PE at

presenta-tion have, on average, a prevalence of PE of 20%.42,49Two

management approaches are reasonable in such patients.

The first is the performance of pulmonary angiography,

which is usually definitive The second is the withholding

of anticoagulants and performance of serial VUI to detect

Grade B

Box 61.5 Management of patients with non-diagnostic

non-invasive tests for PE

● Serial VUI of the proximal veins after 1 and 2 weeks

Suitable for most such patients,30,44although pulmonary

angiography is preferred for the subgroups outlined

below This approach can be supplemented with

bilat-eral venography (for patients that might otherwise be

considered for pulmonary angiography).116

● Pulmonary angiography preferred option if:

● segmental intraluminal filling defect on helical CTa,b

● subsegmental intraluminal filling defect and high

clinical suspicion

● high probability ventilation–perfusion scan and low

clinical suspicionb

● symptoms are severe, post-test probability is high

but non-diagnostic, and PE needs to be excluded

from the differential diagnosis

● serial testing is not feasible (for example, scheduled

for surgery, geographic inaccessibility)

aA segmental intraluminal filling defect with a high clinical

suspicion is likely to have a positive predictive value of

85% and could be considered diagnostic for PE

bVentilation–perfusion scanning can be performed after

these findings have been obtained with helical CT; or helical

CT may be performed after these findings have been

obtained with ventilation–perfusion scanning;47,48If the

sec-ond test is also non-diagnostic for PE, serial ultrasounds may

be reconsidered

Abbreviations: DVT, deep vein thrombosis; LMWH, low

molecular weight heparin; PE, pulmonary embolism; VTE,

venous thromboembolism; VUI, venous ultrasound imaging,

(Adapted from Kearon40)

reduction in VTE), aspirin alone is not recommended during the initial postoperative period.62 It may be a reasonable alternative to LMWH or warfarin for the weeks following hospital discharge, particularly if patients do not have addi- tional risk factors for VTE Recently, hirudin66(a direct thrombin inhibitor) and fondaparinux67,67a,67b(the pentasaccharide of heparin that binds antithrombin) have been shown to be more effective than LMWH follow- ing major orthopaedic surgery; fondaparinux may cause marginally more bleeding

The evidence that short-term prophylaxis (for example, low-dose unfractionated heparin) prevents clinically impor- tant VTE in immobilized medical patients is less convincing, partly because it has been less extensively studied in this pop- ulation, and because there is concern that medical patients remain at high risk of VTE after prophylaxis is stopped.62,68

In addition to augmenting the efficacy of pharmacologic methods of prophylaxis, mechanical methods are effective

on their own Graduated compression stockings prevent postoperative VTE in moderate-risk patients (risk reduction

of 68%),62,69 and intermittent pneumatic compression devices prevent postoperative VTE in high-risk orthopedic patients.62,70,71The relative efficacy of graduated compres- sion stockings and intermittent pneumatic compression devices is uncertain No difference in efficacy was evident in neurosurgical patients;72however, pneumatic compression devices are expected to be superior to graduated compres- sion stockings in high-risk patients.62Mechanical methods

of prophylaxis should be used in patients who have a erate or high risk of VTE if anticoagulants are contraindi- cated (for example, neurosurgical patients).62

mod-Because postoperative fatal PE is rarely preceded by symptomatic DVT,55prophylaxis is the best way to prevent

it Use of primary prophylaxis is strongly supported by cost effectiveness analyses, which indicate that it reduces overall costs in addition to reducing morbidity.73

Treatment of VTE Heparin therapy

In 1960, Barritt and Jordan established that heparin (1·5 days) and oral anticoagulants (2 weeks) reduced the risk

of recurrent PE and associated death.74Based on expert ion, 10–14 days of heparin therapy, and 3 months of oral anti- coagulation became widely adopted in clinical practice It was subsequently shown that 4 or 5 days of intravenous heparin is

opin-as effective opin-as 10 days of therapy for the initial treatment of VTE.75,76Comparatively recently, the need for an initial course

of heparin therapy was verified.77Many trials have established that weight-adjusted LMWH (without laboratory monitoring)

is as safe and effective as adjusted-dose unfractionated heparin for the treatment of acute VTE;78 it can be used to treat patients without hospital admission79 and need only be

Grade A

Grade A Grade B

Evidence-based Cardiology

low-dose unfractionated heparin can be improved either by

increasing the dose so as to minimally prolong the activated

partial thromboplastin time (APTT),57 or by combining its

use with graduated compression stockings58or intermittent

pneumatic compression devices.59

Meta-analyses support that, at doses that are associated

with equivalent efficacy (odds ratio 1·03) following general

surgery, low molecular weight heparins (LMWH) are

associ-ated with less bleeding (odds ratio 0·68) than low-dose

unfractionated heparin.60 Used at higher dose

than for general surgery, LMWH is more effective (odds

ratio 0·83) that unfractionated heparin following orthopedic

surgery and is associated with a similar frequency of

bleed-ing.60An additional 3 or 4 weeks of LMWH after hospital

discharge further reduces the frequency of symptomatic

VTE after orthopedic surgery (from 3·3% to 1·3%61).

Warfarin (target INR 2–3 for about 7 to 10 days) is less

effective that LMWH at preventing DVT detected by

venography soon after orthopedic surgery,62but appears to

be similarly effective at preventing symptomatic VTE over

a 3 month period.62,63 There is evidence that

aspirin reduces the risk of postoperative VTE by one third.64

A study of over 17 000 patients, mostly

follow-ing hip fracture repair, confirmed these findfollow-ings, includfollow-ing

a reduction in fatal PE (0·27% v 0·65%) during the month

following surgery.65 However, as warfarin and LMWH

are expected to be more effective (at least a two thirds

Grade A

Grade A Grade A

Box 61.6 Prevention and treatment of venous

thromboembolism

● Primary prophylaxis with anticoagulants and/or

mechanical methods should be used in hospitalized

patients who have a moderate or high risk of VTE

● Acute VTE (DVT and/or PE) should be anticoagulated

with:

● Heparin (unfractionated or LMWH) for a

minimum of 4–5 days If unfractionated

heparin is used, a dose of at least (a) 30 000 U/

day or 18 U/kg/h by intravenous infusion; or

(b) 33 000 U/day, by twice daily, subcutaneous,

injection, should be administered Dose

of unfractionated heparin should be adjusted to

achieve “therapeutic” APTT results

● Oral anticoagulation for 3–6 months,

with a dose adjusted to achieve an INR of 2.0–3.0

Prolonged unfractionated heparin orLMWH at therapeutic, or near therapeutic,

doses is a satisfactory alternative

Anticoagulation should be continued for longer than

3 months in patients with a first episode of

idio-pathic VTE, and when VTE is associated

with a risk factor, for as long as such factors are

active

See Box 61.5 for abbreviations

Grade C Grade B

Grade A Grade A

Grade A Grade C Grade A Grade A

Grade A

injected subcutaneously once daily.80 Danaparoid, hirudin,

and argatroban can be used to treat heparin induced

thrombo-cytopenia, with or without associated thrombosis.81,82

Oral anticoagulant therapy

A randomized trial of patients with DVT, comparing

3 months of warfarin (International Normalization Ratio (INR)

3·0–4·0) with low-dose heparin after initial treatment with

full-dose intravenous heparin, established the necessity for

prolonged oral anticoagulation after initial heparin therapy.83

Prolonged high-dose subcutaneous heparin84and,

subsequently, LMWH (50–75% of acute treatment dose) was

subsequently shown to be equally effective.85

In the 1970s it was recognized that, because of differences in

the responsiveness of thromboplastins to oral anticoagulants, a

prothrombin time ratio of 2·0 reflected a much more intense

level of anticoagulation in North America than in Europe This

prompted a comparison of two intensities of warfarin therapy

(corresponding to mean INRs of 2·1 and 3·2) for the

treat-ment of DVT.86This study found that the lower intensity of

oral anticoagulation was as effective as the higher intensity but

caused less bleeding The trials showing that heparin therapy

could be reduced to 5 days also showed that warfarin could

be started at the same time as heparin.75,76A recent series

of small studies support starting warfarin with the expected

daily dose rather than a loading dose (for example, 5 mg v

10 mg),87,88and managing over-anticoagulation without

bleed-ing (for example, INRs 6) with small oral rather than

sub-cutaneous doses of vitamin K (for example, 1 mg).89

During the last decade, a series of well-designed studies

have helped to define the optimal duration of

anticoagula-tion Their findings can be summarized as follows:

● Shortening the duration of anticoagulation from 390,91

or 692months to 490,91or 692weeks results in a

dou-bling of the frequency of recurrent VTE during 190,91to

292years of follow up

● Patients with VTE provoked by a transient risk factor

have a lower (about one third) risk of recurrence than

those with an unprovoked VTE or a persistent risk

factor.90–94

● Three months of anticoagulation is adequate treatment

for VTE provoked by a transient risk factor; subsequent

risk of recurrence is 3% per patient-year.90,91,94–96

● Three months of anticoagulation may not be adequate

treatment for an unprovoked (“idiopathic”) episode of

VTE; subsequent early risk of recurrence has varied

from 5% to 25% per patient-year.92,95,97,98

● After 6 months of anticoagulation, recurrent DVT is

at least as likely to affect the contralateral leg; this

suggests that “systemic” rather than “local” (including

inadequate treatment) factors are responsible for

recur-rences after 6 months of treatment.99

Grade A

Grade A

Grade A Grade A

● There is a persistently elevated risk of recurrent VTE after a first episode; this appears to be 5–12% per year after 6 or more months of treatment for an unprovoked episode.92,95,98

● Oral anticoagulants targeted at an INR of 2·5 are very effective (risk reduction 90%) at preventing recurrent unprovoked VTE after the first 3 months of treatment.97,100

● Indefinite anticoagulation is an option for patients with a first unprovoked VTE who have a low risk of bleeding

● A second episode of VTE does not necessarily indicate

a high risk of recurrence or the need for indefinite anticoagulation.97

● Risk of bleeding on anticoagulants differs markedly among patients depending on the prevalence of risk factors (for example, advanced age; previous bleeding

or stroke; renal failure; anemia; antiplatelet therapy; malignancy; poor anticoagulant control).101

● Risk of recurrence is lower (about half) following an isolated calf (distal) DVT; this favors a shorter duration

of treatment.92,95

● Risk of recurrence is higher with antiphospholipid bodies (anticardiolipin antibodies and/or lupus anticoag- ulants),97,102 homozygous factor V Leiden103 cancer93and, probably, antithrombin deficiency; these favor

anti-a longer duranti-ation of treanti-atment

● Heterozygous factor V Leiden and the G20210A thrombin gene mutations do not appear to be clinically important risk factors for recurrence.103

pro-● Other abnormalities, such as elevated levels of clotting factors VIII, IX, XI, and homocysteine, and deficiencies

of protein C and protein S, may be risk factors for rence; they have uncertain implications for duration of treatment.

recur-Thrombolytic therapy

Systemic thrombolytic therapy accelerates the rate of lution of DVT and PE at the cost of around a fourfold increase in frequency of major bleeding, and about a 10-fold increase in intracranial bleeding.104–107This can be life-saving for PE with hemodynamic compromise.106,108

reso-Thrombolytic therapy may reduce the risk of the botic syndrome following DVT but this does not appear

prothrom-to justify its associated risks104,105Catheter-based treatments (that is, thrombolytic therapy or removal of thrombus) require further evaluation before they can be recommended.

Inferior vena caval filters

A recent randomized trial demonstrated that a filter, as an adjunct to anticoagulation, reduced the rate of PE (asympto- matic and symptomatic) from 4·5% to 1·0% during the

Grade A

Grade B Grade B

Grade B

Grade B Grade A

Venous thromboembolic disease

in the prevention of deep vein thrombosis in thrombotic stoke.

Lancet 1987;1:523–6.

2.Ginsberg J, Brill-Edwards P, Burrows RF et al Venous

throm-bosis during pregnancy: leg and trimester of presentation

Thromb Haemost 1992;67:519–20.

3.Cruickshank MK, Levine MN, Hirsh J et al An evaluation of

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4.Bern MM, Lokich JJ, Wallach SR et al Very low doses of farin can prevent thrombosis in central venous catheters Ann

war-Intern Med 1990;112:423–8.

5.Merrer J, De Jonghe B, Golliot F et al Complications of femoral

and subclavian venous catheterization in critically ill patients:

a randomized controlled trial JAMA 2001;286: 700–7.

6.Heijboer H, Brandjes PM, Buller HR, Sturk A, ten Cate JW.Deficiencies of coagulation-inhibiting and fibrinolytic proteins

in outpatients with deep-vein thrombosis N Engl J Med

1990;323:1512–16.

7.Kearon C, Crowther M, Hirsh J Management of patients with

hereditary hypercoagulable disorders Ann Rev Med 2000;

51:169–85.

8.Emmerich J, Rosendaal FR, Cattaneo M et al Combined effect

of factor V Leiden and prothrombin 20210A on the risk ofvenous thromboembolism – pooled analysis of 8 case–controlstudies including 2310 cases and 3204 controls Study Group

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9.Cattaneo M Hyperhomocysteinemia, atherosclerosis and

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10.Rosendaal FR High levels of factor VIII and venous

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11.Meijers JC, Tekelenburg WL, Bouma BN, Bertina RM,Rosendaal FR High levels of coagulation factor XI as a risk fac-

tor for venous thrombosis N Engl J Med 2000;342:

696–701

12.van Hylckama Vlieg A, van der Linden IK, Bertina RM,Rosendaal FR High levels of factor IX increase the risk of

venous thrombosis Blood 2000;95:3678–82.

13.Poort SR, Rosendaal FR, Reitsma PH, Bertina RM A commongenetic variation in the 3-untranslated region of the pro-thrombin gene is associated with elevated plasma prothrom-

bin levels and an increase in venous thrombosis Blood

1996;88:3698–703.

14.Kearon C Epidemiology of venous thromboembolism Sem

Vasc Med 2001;1:7–25.

15.Warkentin TE, Levine MN, Hirsh J et al Heparin-induced

thrombocytopenia in patients treated with

low-molecular-weight heparin or unfractionated heparin N Engl J Med

1995;332:1330–5.

16.Anderson FA, Wheeler HB, Goldberg RJ et al A

population-based perspective of the hospital incidence and case-fatality

rates of deep vein thrombosis and pulmonary embolism Arch

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17.Kearon C Natural history of venous thromboembolism Sem

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Evidence-based Cardiology

12 days following insertion, with a suggestion of fewer fatal

episodes (0% v 2%).109 However, after 2 years, patients

with a filter had a significantly higher rate of recurrent DVT

(21% v 12%) and a non-statistically significant reduction in

the frequency of PE (3% v 6%) This study supports the use

of vena caval filters to prevent PE in patients with acute

DVT and/or PE who cannot be anticoagulated (that is,

they are bleeding), but does not support more liberal use of

filters Patients should receive a course of

anti-coagulation if this subsequently becomes safe.

Treatment of VTE during pregnancy

Unfractionated heparin and LMWH do not cross the

pla-centa and are safe for the fetus, whereas oral anticoagulants

cross the placenta and can cause fetal bleeding and

malformations.110,111Therefore, pregnant women with VTE

should be treated with therapeutic doses of subcutaneous

heparin (unfractionated heparin or, increasingly, LMWH)

throughout pregnancy Care should be taken to

avoid delivery while the mother is therapeutically

anticoag-ulated; one management approach involves stopping

sub-cutaneous heparin 24 hours prior to induction of labor and

switching to intravenous heparin if there is a high risk of

embolism After delivery, warfarin, which is safe for infants

of nursing mothers, should be given (with initial heparin

overlap) for 6 weeks and until a minimum of 3 months of

treatment has been completed

The future

There are many questions relating to currently available

antithrombotic agents and diagnostic techniques that need

answering, and many new antithrombotic agents under

development that will require clinical evaluation In

addi-tion, future studies are expected to focus on clinical and

genetic subgroups that may benefit from tailored

manage-ment, such as different intensities or durations of

prophy-laxis or treatment Thrombolytic therapy deserves further

evaluation, particularly systemic therapy for severe PE

without overt hemodynamic compromise (for example,

with echocardiographic right ventricular dysfunction), and

catheter-directed therapy for iliofemoral DVT Safer

throm-bolytic regimens might also broaden indications In order

to provide clear directions for clinical management, future

studies need to focus on clinically important outcomes (that

is, symptomatic VTE, major bleeding).

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75.Gallus AS, Jackaman J, Tillett J, Mills W, Sycherley A Safetyand efficacy of warfarin started early after submassive venous

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76.Hull RD, Raskob GE, Rosenbloom D et al Heparin for 5 days

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77.Brandjes DPM, Heijboer H, Buller HR, de Rijk M, Jagt H, ten Cate JW Acenocoumarol and heparin compared withacenocoumarol alone in the initial treatment of proximal-vein

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Evidence-based Cardiology

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83.Hull R, Delmore T, Genton E et al Warfarin sodium versus

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84.Hull R, Delmore T, Carter C et al Adjusted subcutaneous

heparin versus warfarin sodium in the long-term treatment of

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antico-agulant therapy in the treatment of proximal-vein thrombosis

N Engl J Med 1982;307:1676–81.

87.Harrison L, Johnston M, Massicotte MP, Crowther M,

Moffat K, Hirsh J Comparison of 5-mg and 10-mg loading

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88.Crowther MA, Ginsberg JS, Kearon C et al A randomized

trial comparing 5 mg and 10 mg warfarin loading doses Arch

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89.Crowther MA, Julian J, McCarty D et al Treatment of

warfarin-associated coagulopathy with oral vitamin K: a

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90.Research Committee of the British Thoracic Society Optimum

duration of anticoagulation for deep-vein thrombosis and

pulmonary embolism Lancet 1992;340:873–6.

91.Levine MN, Hirsh J, Gent M et al Optimal duration of oral

anti-coagulant therapy: a randomized trial comparing four weeks

with three months of warfarin in patients with proximal deep

vein thrombosis Thromb Haemost 1995;74:606–11.

92.Schulman S, Rhedin A-S, Lindmarker P et al A comparison of

six weeks with six months of oral anticoagulant therapy after

a first episode of venous thromboembolism N Engl J Med

1995;332:1661–5.

93.Prandoni P, Lensing AWA, Cogo A et al The long-term

clinical course of acute deep venous thrombosis Ann Intern

Med 1996;125:1–7.

94.Pini M, Aiello S, Manotti C et al Low molecular weight

heparin versus warfarin the prevention of recurrence after

deep vein thrombosis Thromb Haemost 1994;72:191–7.

95.Pinede L, Ninet J, Duhaut P et al Comparison of 3 and

6 months of oral anticoagulant therapy after a first episode of

proximal deep vein thrombosis or pulmonary embolism and

comparison of 6 and 12 weeks of therapy after isolated calf

deep vein thrombosis Circulation 2001;103:2453–60.

96.Pinede L, Duhaut P, Cucherat M, Ninet J, Pasquier J, Boissel

JP Comparison of long versus short duration of anticoagulant

therapy after a first episode of venous thromboembolism:

a meta-analysis of randomized, controlled trials J Intern Med

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97.Kearon C, Gent M, Hirsh J et al A comparison of three

months of anticoagulation with extended anticoagulation for a

first episode of idiopathic venous thromboembolism N Engl J

Med 1999;340:901–7.

98.Agnelli G, Prandoni P, Santamaria MG et al Three months

versus one year of oral anticoagulant therapy for idiopathic

deep vein thrombosis N Eng J Med 2001;345:165–9.

99.Lindmarker P, Schulman S The risk of ipsilateral versus contralateral recurrent deep vein thrombosis in the leg The

DURAC Trial Study Group J Intern Med 2000;247:601–6.

100.Schulman S, Granqvist S, Holmstrom M et al The duration of

oral anticoagulant therapy after a second episode of venous

thromboembolism N Engl J Med 1997;336:393–8.

101.Beyth RJ, Quinn LM, Landefeld S Prospective evaluation of

an index for predicting the risk of major bleeding in

out-patients treated with warfarin Am J Med 1998;105:91–9.

102.Schulman S, Svenungsson E, Granqvist S Anticardiolipin bodies predict early recurrence of thromboembolism anddeath among patients with venous thromboembolism follow-

anti-ing anticoagulant therapy Am J Med 1998;104:332–8.

103.Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N,Johnsson H The risk of recurrent venous thromboembolism

in carriers and non-carriers of the G1691A Allele in the ulation factor V gene and the G20210A Allele in the

coag-prothrombin gene Thromb Haemost 1999;81:684–9.

104.Hirsh J, Lensing A Thrombolytic therapy for deep vein

throm-bosis Int Angiol 1996;5:S22–S25.

105.Schweizer J, Kirch W, Koch R et al Short- and long-term

results after thrombolytic treatment of deep vein thrombosis

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106.Blackmon JR, Sautter RD, Wagner HN Uokinase pulmonary

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107.Dalen JE, Alpert JS, Hirsh J Thrombolytic therapy for pulmonary embolism Is it effective? Is it safe? When is it

indicated? Arch Intern Med 1997;157:2550–6.

108.Jerjes-Sanchez C, Ramirez-Rivera A, de Lourdes Garcia M

et al Streprokinase and heparin versus heparin alone in

massive pulmonary embolism: a randomized controlled trial

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109.Decousus H, Leizorovicz A, Parent F et al A clinical trial of

vena caval filters in the prevention of pulmonary embolism in

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110.Ginsberg JS, Hirsh J, Levine MN, Burrows R Risks to the fetus

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during pregnancy Chest 2001;119:122S–31S.

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113.Lagerstedt CI, Olsson CG, Fagher BO, Oqvist BW,Albrechtsson U Need for long-term anticoagulant treatment

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114.Moser KM, LeMoine JR Is embolic risk conditioned by

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439–44

115.Moser KM, Fedullo PF, LittleJohn JK, Crawford R Frequentasymptomatic pulmonary embolism in patients with deep

venous thrombosis JAMA 1994;27:223–5.

116.Kruit WHJ, de Boer AC, Sing AK, van Roon F The significance

of venography in the management of patients with clinically

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122.Huisman MV, Buller HR, ten Cate JW Utility of impedanceplethysmography in the diagnosis of recurrent deep-vein

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SimpliRED D-dimer Thromb Haemost 2000;83:416–20.

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Evidence-based Cardiology

suspected pulmonary embolism J Intern Med 1991;230:

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117.Hull RD, Raskob GE, Coates G, Panju AA, Gill GJ A new

non-invasive management strategy for patients with suspected

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118.Stein PD, Henry JW Prevalence of acute pulmonary embolism

among patients in a general hospital and at autopsy Chest

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119.Bell WR, Simon TL Current status of pulmonary embolic

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Am Heart J 1982;103:239–61.

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Arch Intern Med 1997;157:1077–81.

The prevalence of lower extremity arterial occlusive disease

as judged by history has been examined in several studies.

Large cohorts of patients have been questioned about

symp-toms of intermittent claudication This has mostly been

done using a questionnaire initially designed by Rose.1The

method has an acceptable specificity but lacks sensitivity

and, for obvious reasons, it does not detect asymptomatic

arterial occlusive disease.2 The prevalence of peripheral

arterial occlusive disease varies between studies, with high

figures reported from Russia and Finland.3,4With large and

reliable studies, it is likely that the prevalence at the age of

60 is 3–6%.5Most studies report a prevalence of less than

5% at 50 years.

In order to detect lower extremity arterial occlusive

dis-ease more specifically, studies have been performed

measur-ing ankle pressure with non-invasive techniques In general

it can be said that the prevalence of disease increases by a

factor of 3 compared with studies based on questionnaires.

There is a significant correlation between the ankle brachial

pressure index (ABI) and the symptom of intermittent

clau-dication, although the correlation is modest with r values

between 0·1 and 0·2.6 Based on such objective methods,

11·7% of the population in the Framingham study had

peripheral arterial disease Thus assessment of peripheral

arterial disease by the symptom of intermittent claudication

underestimates the true prevalence,7but the cut off points

determining what is considered to be a pathologic ABI is of

great importance for the estimation of the prevalence using

objective methods.8

The prevalence is greatly influenced by age as pointed out

in one of the major studies, the Framingham study.9Other

important factors are cigarette smoking and sex Thus

non-smoking women in the age group 55–64 years showed a

prevalence by history of 3·9% compared with smoking men

in the age group 75–84 years where the prevalence was

14·5% Additional factors increasing the risk are diabetes

and fibrinogen levels.10

Few studies have examined the incidence of peripheral

arterial occlusive disease by following normal subjects and

determining when claudication appears In the Framingham

study, the yearly incidence increases from 0·2% in 45–55

year old men to 0·5% in 55–65 year old men.9In the last

follow up after 38 years, the yearly rates were found to increase until the age 75 and then declined The statistical analyses revealed that those with intermittent claudication were significantly older, had higher cholesterol levels, higher blood pressure, higher frequency of diabetes, and smoked more cigarettes.11The Edinburgh artery study provides simi- lar figures with an annual incidence of 1·8 per 1000 ran- domly selected patients from general practitioners.12

Long-term outcome

The natural history of patients with lower extremity arterial disease has been studied regarding both the fate of the limb and mortality Among patients with peripheral arterial occlu- sive disease, at most one in five will require surgical correc- tion for their vascular disease13 and 2–5% will undergo amputation.5,9 The risk for amputation decreases if the patients can stop smoking.14Patients with peripheral arte- rial occlusive disease have a decreased life expectancy com- pared with the normal population This is almost solely explained by cardiovascular disease in general and coronary artery disease in particular After 10 years, only 52% of claudicants are still alive.15The relative risk of dying from cardiovascular disease and coronary heart disease (CHD) is reported to be 5–6 times that of the normal population over

10 years.16The severity of the peripheral arterial occlusive disease is associated with the risk of dying, since the lower extremity arterial disease is a surrogate variable reflecting the severity of atherosclerosis affecting the coronary arter- ies.17Smoking is also an important predictor of the risk of dying in these patient groups.18The greatest threat to the patient with peripheral arterial disease is thus death from cardiac causes Patients with peripheral arterial disease and concomitant three vessel coronary artery disease (CAD) have an improved survival after coronary artery bypass grafting (CABG).19 The natural course of intermittent claudication on the other hand is relatively benign in terms

of limb survival as reflected by the low risk of amputation This may, however, partly be explained by the fact that the mortality among patients with severe disease and high risk

of amputation is considerably higher than for patients with mild disease.

62 Peripheral vascular disease Jesper Swedenborg, Jan Östergren

Key points

● The prevalence of lower extremity arterial occlusive

dis-ease is high: 3–5% in individuals over 50 years of age

● Patients with peripheral arterial occlusive disease have

approximately fivefold increased risk of dying from

car-diovascular causes over 10 years

● Mortality and morbidity are increased by smoking,

hyper-tension, and the severity of the disease

● Intermittent claudication itself has a relatively benign

course as reflected by a low risk of amputation

Investigation of the patient with peripheral

vascular disease

An adequate history and physical examination provide the

basis for proper management of patients with peripheral

vas-cular disease The history should include a survey of

rele-vant risk factors and possible symptoms of concomitant

cardiovascular disease (for example, angina pectoris).

Palpation of pulses and auscultation in the groin and over

the femoral arteries may reveal signs of occlusion or

stenoses in the vessels from the iliac artery down to the

lower leg The popliteal artery is best evaluated with

the knee slightly elevated from the support and the tissue in

the distal popliteal fossa pressed against the tibia Palpation

at this location is particularly important when a popliteal

aneurysm is suspected In cases with more severe ischemia,

inspection may reveal a diminished growth of hair and nails,

and distal ischemic ulcers often located on toes and heels.

Elevation of the legs will cause a whitening of the most

affected foot, which in the dependent position typically is

more red than the contralateral one, owing to an increase of

blood in the superficial venous plexa.

Measurement of the ankle pressure is of value as a

quan-titative estimate of the degree of arterial insufficiency This is

easily done with a continous wave pen-doppler detecting

the pulse either in the posterior tibial or the dorsal pedal

artery when a blood pressure cuff around the ankle is slowly

deflated from a suprasystolic pressure By dividing the

meas-ured value with the brachial pressure the ABI is determined.

An index below 0·9 is considered pathologic In patients

with diabetes mellitus, the ABI may be falsely elevated

owing to sclerosis of the media of the arteries, which resists

compression by the cuff.

Further anatomic evaluation of the arterial system is

needed only when invasive procedures are indicated Duplex

sonography is the method of choice, but in most cases has to

be followed by angiography, when surgery is planned.

All patients with peripheral vascular disease should have

blood tests to detect other treatable risk factors such as

blood lipids, blood or plasma glucose, and serum creatinine.

Systemic blood pressure is also a treatable risk factor that

should be measured.

Key points

● History (symptoms, smoking, other cardiovascular diseases) and physical examination (peripheral pulses,blood pressure) are essential

● Screen for cardiovascular risk factors (cholesterol, glucose)

● Measurement of ABI is valuable in all patients

● Duplex sonography and angiography are required onlywhen invasive procedures are considered

Intermittent claudication Pathophysiology

Intermittent claudication is caused almost exclusively by atherosclerotic lesions in the arteries to the legs The lesion causing the symptoms may be located above the inguinal lig- ament (the aorta, iliac artery, or the common femoral artery)

or below, in such cases often in the distal part of the cial femoral artery Combinations of series of stenosis or occlusions also involving the popliteal and lower leg vessels are not uncommon.

superfi-The evolution of the disease may be slow with gradual onset of symptoms but in many cases the occurrence of a thrombus in a severely stenosed area or overlying a ruptured atherosclerotic plaque may cause an acute onset of symptoms.

The most common location of pain is in the calf, since the majority of vascular occlusions occur in the superficial femoral artery When the main lesion is in the iliac region, pain and muscular dysfunction may also be located in the gluteal muscles and the thigh The symptoms are caused by

an inappropriate blood supply in relation to the metabolic needs of the muscles during exercise When occlusion of the artery occurs gradually, collaterals, often from the deep femoral artery, may compensate for the limited arterial supply through the natural artery.

Therapy

General measures

The aim of therapy for intermittent claudication is twofold:

● to reduce risk factors associated with the disease and thereby improving the long-term prognosis of the patient;

● to improve walking distance and thus the quality of life for the patient.

In the general management of the patient it is mandatory

to screen for risk factors associated with atherosclerosis Smoking should be stopped immediately as the risk for the patient with claudication for having an amputation in the

Evidence-based Cardiology

future is reduced to virtually zero.14

Hyperlipidemia and hypertension should be treated

accord-ing to guidelines outlined in other sections of this book A

meta-analysis of lipid lowering therapy in 698 patients with

peripheral arterial disease indicated that active therapy

reduced disease progression and the severity of

claudica-tion.20 Recently the Heart Protection Study including

20 000 patients with coronary or non-coronary artery

dis-ease or diabetes was reported, showing that simvastatin

40 mg/day reduced cardiovascular mortality and morbidity.

The 24% decrease of vascular events was consistent in all

subgroups including patients with peripheral vascular

dis-ease and regardless of cholesterol levels.21 Thus,

a statin should be given as first-line therapy, but niacin could

also be valuable since it increases serum HDL (high density

lipoproteins) concentrations and lowers serum triglyceride

concentrations, which are the most common lipid

distur-bances in patients with intermittent claudication.

A fear of reducing distal perfusion pressures in patients

with claudication by antihypertensive treatment has

some-times prevented doctors from instituting adequate treatment

of hypertension In particular,
blockers have been

consid-ered by some to be contraindicated in this situation.

Controlled studies have, however, shown that treatment of

claudicants with
blockers only reduces walking capacity

marginally or not at all.22 Therefore, if strong indications,

such as heart failure, or a previous myocardial infarction exist,

blockers should also be used in claudicants.

The HOPE study investigated the effect of the ACE

inhibitor ramipril 10 mg/day compared with placebo.23The

study included 1715 patients with symptomatic peripheral

vascular disease and 3099 patients with an ABI  0·9 These

subgroups benefitted at least equally well as the entire study

population from the treatment The beneficial effect was

seen even among patients who already had adequate blood

pressure control Treatment with an ACE inhibitor should

thus be strongly considered in patients with peripheral

arte-rial disease

If symptoms of increased ischemia of the legs occur

dur-ing treatment for hypertension, this strengthens the

indica-tion for an invasive procedure in order to relieve the

symptoms of leg ischemia If this is not possible, the

anti-hypertensive therapy should be reduced with caution.

Since patients with intermittent claudication have an

increased risk for major cardiovascular events because of

their generalized atherosclerotic disease, antiplatelet

ther-apy should be given prophylactically, preferably with aspirin,

based on conclusions from meta-analysis.24

Although major studies on the effect of aspirin in patients

with claudication are lacking, the effect in subgroups with

claudication (n  3295; risk reduction from 11·8% to 9·7%

over 27 months) seems to be equivalent to the reduction

seen in the atherosclerotic population as a whole.24 The

combination with dipyridamole may provide an additional

Grade A Grade A

Grade A

Grade A

Grade B preventive effect,25but so far only one study has shown an

effect on major end points by this combination in the case of the secondary prevention of stroke.26In 687 claudicants stud- ied over a 7 year period, ticlopidine 250 mg 2/day reduced the need for vascular reconstructive surgery by 51% com- pared to placebo.27In the same trial, the mortality rate was

29.1% lower (64 v 89 cases) in the ticlopidine group

com-pared with the placebo group.28The same dose of ticlopidine may also produce some increase in walking capacity in com- parison with placebo.29The disadvantage of this compound is the risk of adverse effects and the need for laboratory control

of white blood cell counts A better and safer alternative to ticlopidine for patients who cannot tolerate aspirin is clopi- dogrel, which was studied in the CAPRIE trial.30 In the

6452 patients with peripheral arterial disease, clopidogrel

75 mg/day showed a relative risk reduction of 23·8% in ischemic stroke, myocardial infarction, or death from other vascular causes compared to aspirin 325 mg/day.30

Exercise

Patients with claudication should be instructed to walk

as much as possible and, when pain occurs, they should try

to walk despite the pain.31Training by intensive walking on treadmill or outdoors has been shown to be as effective

or even better than other programs of physical training and, in most cases, will improve walking capacity by 100–200%.31

In some cases the symptoms of claudication may even pear completely The optimal exercise program includes walking to near maximal pain for more than 30 minutes per session at least three times weekly during at least a 6 month period.32

disap-Pharmacologic treatment to increase walking capacity

Different pharmacologic agents have been evaluated for improvement of walking distance in addition to physical training Most of these treatments have been inconsistent in their effect and of marginal benefit Generally, vasodilators have not been shown to be effective The agent so far most extensively studied has been pentoxifylline, which is avail- able in most countries for the treatment of intermittent claudication The patients most likely to respond are those with a history of claudication over 1 year and an ABI of

0·8.33 A meta-analysis of the pentoxifylline studies has shown an increase of 44 meters in maximal walking dis- tance on the treadmill compared with placebo.34The phos- phodiesterase inhibitor cilostazol was approved in 1999 by the FDA for treatment of claudication Cilostazol is prima- rily a platelet inhibitor and a vasodilator that has been shown to increase the walking distance compared with placebo and also with pentoxifylline.35 However, the use

of the drug is hampered by the risk for worsening heart

Peripheral vascular disease

failure.36 A randomized but open study37 indicates that

prostaglandin E1 given intravenously may be more effective

than pentoxifylline (60·4% compared with 10·5% increase

in walking capacity), but further studies are needed to

estab-lish the role of prostaglandins in this context.

Key points

● Quit smoking!

● Regular exercise – walking until intolerable pain

● Intervention against other cardiovascular risk factors;

treat hypertension and institute a statin to all patients

with a normal or high cholesterol level

● Antiplatelet therapy and ACE inhibitor to be considered

for all patients

● Other pharmacologic therapy of very limited benefit

Critical ischemia

Pathophysiology

When the distal pressure in the leg is too low to provide

suf-ficient perfusion in order to meet the metabolic demands of

the tissue, pain will also occur in the resting situation,

par-ticularly in the supine position when there is no

contribu-tion to distal pressures by hydrostatic forces Subsequently

ulcers in the apical parts of the extremity may develop

owing to an insufficient nutritional blood flow in the

skin.

According to the European Consensus Document on

chronic lower limb ischemia, critical ischemia is defined as

“persistently recurring rest pain requiring regular analgesia

for more than 2 weeks and/or ulceration or gangrene of the

foot and toes in combination with an ankle systolic pressure

less than 50 mmHg” In the case of diabetes, where the

measurements of ankle pressures are unreliable because of

incompressible arteries, the absence of palpable pulses are

sufficient.38The definition has been criticized because many

patients with critical limb ischemia according to the above

definition still have an intact lower extremity after 1 year.

This is exemplified by the findings in control groups of

ran-domized trials regarding non-surgical treatment of critical

limb ischemia.39Furthermore, some patients who do not fit

into this definition may lose their legs because of ischemia.40

A recent consensus document was made more practical

A patient with critical limb ischemia is defined as “a patient

with chronic ischemic rest pain, ulcers and gangrene

attrib-utable to objectively proven arterial disease”.41

The crucial factor regarding tissue nutrition is the flow

through the capillary bed, which is dependent not only on

the pressure in the arteries but also on other factors, such as

blood viscosity and distribution of flow between nutritional

and non-nutritional vessels – that is, arteriovenous shunts.

Intravital capillaroscopy and transcutaneous oxygen tension

are methods that can assess tissue nutrition, thereby offering additional prognostic information in these patients.38Patients with critical ischemia should be evaluated for possi- ble vascular reconstructive surgery or endovascular treat- ment (see below).

General measures

When invasive procedures to restore blood flow (see below) are not possible or have failed, several therapeutic measures should be considered Optimization of the hemodynamic situation is one aim Heart failure and edema should be treated vigorously Lowering the foot end of the bed at night may improve distal perfusion pressure and relieve symp- toms Shoes should be well fitting to avoid the risk of pres- sure against the skin Ulcers should be treated with care, and more often dry dressings are preferable in order not to moisturize intact skin around the ulcer area.

Though not scientifically proven in this situation, coagulation may be of benefit Thus, oral anticoagulants or low molecular weight heparin should be considered as an alternative or an addition to aspirin, since both arterial and venous thrombi are common in the severely ischemic leg.42Warfarin has been shown to lower the risk of occlusion in femoropopliteal vein grafts.43 Pain should be treated by pharmacologic measures Spinal cord stimulation could be used since this method has been shown to decrease pain possibly by increasing microvascular blood flow.44

anti-The only pharmacologic agent so far convincingly shown

to have a positive influence on the prognosis of patients with critical limb ischemia is a synthetic prostacyclin (Iloprost), which is given intravenously daily for a period of 2–4 weeks.

In a meta-analysis, rest pain and ulcer size were found to improve in comparison with placebo and, more importantly, the probability of being alive with both legs still intact after 6 months was 65% in the Iloprost-treated group com- pared to 45% in the placebo-treated patients.39

Pentoxifylline has been shown to be of benefit in a short-term perspective as a pain reliever but no long-term trials have been performed.45Spinal cord stimulation has been used to avoid amputations, but so far it has not benefitted patients with critical limb ischemia as a preventive treatment.46

Key points

● Evaluate possibilities for revascularization

● Optimize cardiac hemodynamics

● Avoid hypotension – lower foot end of bed at night

● Provide adequate pain relief

● Optimize local skin and wound care

● Consider anticoagulation or antiplatelet therapy

● Consider Iloprost treatment when revascularization isnot possible or has failed

Grade A

Evidence-based Cardiology

Surgical treatment of intermittent claudication

and critical ischemia

In this chapter both open surgery and endovascular

treatment are considered In the latter group percutaneous

transluminal angioplasty (PTA) in combination with both

thrombolysis and stenting are included The major

indica-tions for reconstructive procedures for lower extremity

ischemia are critical ischemia and claudication.

Preoperative cardiac evaluation

Since patients with peripheral vascular disease have a high

frequency of cardiac comorbidity, the perioperative

mortal-ity and morbidmortal-ity is dominated by cardiac problems Many

attempts have been made to identify patients with a high

risk of perioperative cardiac complications The rationale for

such a strategy is to identify patients in need of coronary

artery revascularization before the vascular procedure, and

also to provide a basis for more intensive cardiac monitoring

during peripheral vascular surgery Although not specifically

designed for peripheral vascular surgery, clinical risk scores

according to Goldman47 or Detsky48 have been used.

Further tests include ambulatory ECG, dipyridamole

thal-lium scintigraphy, ejection fraction estimation by

radio-nuclide ventriculography, and stress echocardiography All

these tests are effective in predicting perioperative cardiac

mortality and morbidity, but dobutamine stress

echocardiog-raphy seems to be most promising in a meta-analysis.49

Patients who have reversible defects on preoperative

thal-lium scintigraphy are at a high risk of perioperative cardiac

mortality and morbidity,50and successful coronary

revascu-larization decreases this risk following vascular surgery.51

Nevertheless, routine evaluation of all patients scheduled

for peripheral vascular surgery with thallium scintigraphy is

not warranted.52The reason for this is that both coronary

angiography and coronary revascularization add to the

risk.53 Today it can therefore be concluded that patients

with a low risk, as reflected by either absence of angina

pec-toris or only mild disease, do not benefit from further

evalu-ation aiming at coronary angiography.54Patients with high

risk according to clinical scoring systems or careful history

should be evaluated with dipyridamole thallium

scinti-graphy or dobutamin stress echocardioscinti-graphy

The use of bisoprolol, a
1 selective inhibitor, reduced the

30 day combined cardiac morbidity and mortality from 34%

to 3·4% in high-risk patients undergoing peripheral vascular

surgery.55Whether other
blockers have the same effect

remains to be shown

Open surgical vascular reconstructions

The vascular reconstructions for lower limb ischemia are

mainly divided into supra- and infrainguinal reconstructions.

Grade B

Grade B

Suprainguinal vascular reconstructions

In the aortoiliac segment, vascular reconstructive dures were initially dominated by thromboendarterectomy (TEA); this, however, requires large dissections After the introduction of bypass grafting with synthetic materials TEA was largely abandoned except for short localized lesions The results of aortobifemoral bypass with Dacron grafts for arterial occlusive disease are usually good with 1 year patency rates in the range of 95% The patency rates are influenced by the outflow bed, so that patients with a patent superficial femoral artery (SFA) have better patency rates than those with an occluded SFA There are no prospective randomized trials comparing TEA and aortofemoral bypass TEA is said to have lower long-term patency rates, and another disadvantage is that the surgical procedure is more extensive Aortofemoral bypass with a synthetic graft, how- ever, has the disadvantage of risk of infection Although this

proce-is an infrequent complication, it proce-is associated with major morbidity and mortality, since an infected graft has to be removed.

During recent years the number of aortobifemoral structions have declined owing to the more frequent use of endovascular methods, particularly PTA with or without stenting Thus the extensive procedure of aortobifemoral bypass can be converted into a lesser procedure if at least one iliac artery can be opened with PTA In such cases the contralateral leg can be revascularized with the aid of an extra-anatomic procedure – that is, femorofemoral bypass The latter procedure has good patency rates, approximately 90% at 1 year and 65% at 5 years.56–58In patients who are unfit for major surgery and where the iliac arteries cannot

recon-be opened up with endovascular procedures another anatomic bypass can be employed In such patients axillo- bifemoral bypass can be used, but this type of extra- anatomic bypass is a compromise, since it has lower patency rates than aortobifemoral bypass.59

extra-Infrainguinal vascular reconstructions

The standard procedure for infrainguinal occlusive disease

is femoropopliteal bypass or bypass to the crural arteries Bypass to the crural arteries is often performed in people with diabetes since their occlusive disease is in many cases more peripherally located than in non-diabetic patients with atherosclerosis The most commonly used graft material is the saphenous vein but, if this is unavailable, arm veins or synthetic grafts may be used In general it has been stated that use of autologous material is superior in infrainguinal reconstructions.60 Some randomized studies have failed to detect a difference in long-term patency between synthetic grafts and saphenous vein grafts One study did not show a significantly different patency at 2 years follow up, but after

4 years there was a significant difference in favor of saphenous

Peripheral vascular disease

vein grafts, 68% patency versus 47%.61 For

bypass grafts with the lower anastomosis below the knee,

autologous material is clearly preferred This is particularly

true when bypass procedures are done to the crural arteries

where the use of synthetic grafts produces dismal results.

When an autologous vein is used, the original procedure

implies excision and reversal of the vein so that the blood

can flow freely across the valves The “in situ” technique,

originally introduced by Hall, has, however, in recent years

gained more popularity:62the saphenous vein is left in its bed

and the valves are destroyed by special instruments;

tributar-ies are identified and tied off Some prospective randomized

trials have been performed comparing the two methods

but no definitive advantage with either method has been

shown.63Therefore the personal preference of the surgeon

often decides which method should be used The advantage

with the in situ method is that the larger end of the vein is

anastomosed to the larger artery, and the smaller end of the

vein to the small distal artery With meticulous technique it is

said that the vein is exposed to less trauma, but the valve

destruction definitely induces some damage to the vein.

In order to improve long-term patency rates, two

meth-ods have been employed: graft surveillance and

pharmaco-logic treatment Postoperative surveillance of vein grafts is

used by many surgeons in order to detect a failing graft,

defined as a graft with a developing stenosis that threatens

to reduce the blood flow below a critical level Only few

randomized studies have been done examining the effect on

long-term patency rates in surveillance programs identifying

and treating critical graft stenosis Conflicting results

regard-ing the effectiveness of such programs have been obtained.

One study reported a patency rate of 78% in an intensive

surveillance program including duplex scanning of the graft

after 3 years versus 53% without such a program.64Other

studies, however, have failed to demonstrate an advantage

of duplex scanning over clinical surveillance with

measure-ments of ankle pressure.65 Whether a graft surveillance

program has a beneficial effect upon amputation rate also

remains to be shown.

The effect of antiplatelet therapy on total mortality has

been studied in several trials and it seems to reduce

cardio-vascular mortality.66There is only one trial that has studied

the similar effects of oral anticoagulants, and this trial

sug-gested that they both prevent graft occlusion and diminish

the risk of cardiovascular death.43 Pharmacologic therapy

seems to improve the patency rate for infrainguinal vascular

reconstructions Most centers use antiplatelet therapy with

acetylsalicylic acid, and a meta-analysis of randomized trials

has indicated that such treatment improves the patency

rate.67 Oral anticoagulants are not used as

widely as antiplatelet therapy but many surgeons use it

selectively in patients where the prognosis for graft patency

for some reason is bad Whether antiplatelet therapy or oral

anticoagulants differ in their effectiveness against graft

Grade A

Grade A occlusion is not known Only one study has addressed this

question and no significant difference in graft patency was found between patients treated with warfarin or acetyl salicylic acid Subgroup analysis, however, revealed that oral anticoagulants seemed to be more effective in patients receiving autologous grafts and antiplatelet therapy in those receiving synthetic grafts.68

Key points

● For bilateral suprainguinal occlusions aortofemoralbypass is the standard procedure, but endovascularmethods are used at an increasing rate

● For unilateral suprainguinal occlusions femorofemoralbypass can be used

● For infrainguinal occlusions saphenous vein bypass isthe standard procedure, but synthetic grafts can beused if suitable veins are lacking

● Bypass to infragenicular arteries using synthetic graftsproduces inferior results compared to saphenous veinbypass

Endovascular procedures

Since the introduction of transluminal dilation by Dotter, this field has grown enormously.69The introduction of PTA has resulted in more indications for endovascular procedures to some extent at the expense of open surgical reconstructions.

Percutaneous transluminal angioplasty

In common with other vascular reconstructive procedures the success rate of PTA is highly dependent upon various factors In general it can be said that proximal lesions – that

is, iliac lesions – have a better success rate than distal ones – that is, femoropopliteal lesions The chance of a successful outcome is higher for stenoses rather than occlusions, irre- spective of the site of the lesion In common with surgical vascular reconstructions, the outflow determines the out- come also for PTA Thus, in cases of a good outflow, the results are better than if the outflow is poor.70In summary, the chance of success is much higher when a short iliac stenosis is dilated in a patient with patent superficial femoral and profunda femoris arteries than after dilation of

a popliteal occlusion in a patient with occlusions of two out

of three crural arteries.

The indications for this procedure need to be considered PTA of an iliac stenosis in a patient with claudication has a low risk and a high chance of success and may, therefore, be perfectly appropriate, even if the severity of the disease state

is relatively mild, as compared with a patient with critical limb ischemia and a threat of amputation On the other hand, a patient with an occluded popliteal artery and poor leg run-off with ischemic ulceration has a strong indication

Grade B

Evidence-based Cardiology

for the procedure and, in such a patient, it may also be

perfectly appropriate to make an attempt at PTA, even

though the success rate is relatively low For patients with

critical ischemia, PTA of infrapopliteal vessels has also been

performed successfully and could even be used for short

occlusions.71,72

Subintimal angioplasty has been advocated.73 The

method implies that a guidewire enters the subintimal

space and then re-enters the vessel distal to the occlusion,

and the subintimal space is then dilated with the balloon

In the femoropopliteal segment, occlusions longer than

20 cm can be treated, whereas intraluminal angioplasty is

generally not advocated for occlusions longer than a few

centimeters Patency rates of approximately 60% at 3 years

for femoropopliteal occlusions have been reported after

subintimal angioplasty.74 The reported figures are patency

rates for technically successful procedures, but in 20%

the procedure cannot be performed The method has also

been used for infrapopliteal arteries.75 Subintimal

angio-plasty, if proven successful, could be a future alternative to

femoropopliteal bypass.

Formal comparisons in prospective randomized trials

between PTA and surgery are relatively scarce Such trials

are difficult because, in order for a patient to be included,

the lesion has to be suitable for PTA – that is, it should be

either a stenosis or a short occlusion Knowing that the

treatment of a stenosis with PTA is relatively successful with

less risk and shorter hospital stay, it is sometimes considered

ethically questionable to include patients in a trial between

PTA and surgery In a study including 263 patients with

lesions in the iliac, femoral, or popliteal arteries comparing

bypass surgery and PTA, primary success favored surgery,

while limb salvage favored PTA, but the differences were

not statistically significant After 4 years there was no

signif-icant difference in outcome.76

Randomized trials comparing angioplasty with

non-surgical treatment for intermittent claudication have,

however, been performed, but they are relatively small

and the results are to some extent contradictory In one

study the treadmill distances improved in both groups but

were superior in those undergoing an exercise program, and

after 6 years there was no benefit in treadmill walking

dis-tance after angioplasty.77In another study, an improvement

in ABI was shown 6 months following angioplasty, which

could not be found in patients undergoing exercise

pro-grams Significantly more patients were asymptomatic after

6 months in the angioplasty group compared with those

treated with exercise programs This study, however, had a

shorter follow up, and the conservative treatment was not

as active as in the study where no difference could be seen

between exercise program and PTA.78 It can still be

con-cluded that PTA is suitable for stenoses or short occlusions

in claudicants, but few claudicants have discrete lesions

suitable for PTA.

Stenting has been used at an increasing rate over the last few years It is generally advised not to use stents in smaller arteries, and this implies that stents are used relatively seldom in the femoropopliteal region Stents, however, are used in the iliac arteries after PTA, particularly when there is recoil or dissection Several types of stents have been used, both self-expandable and balloon-expandable ones Stenting below the inguinal ligament is not generally recommended.

Thrombolysis

Thrombolysis of peripheral arterial occlusive disease is recommended for acute arterial occlusions, but it also has a place in subacute occlusions Thrombolysis should be intra-arterial and preferably the thrombolytic agent should

be delivered into the clot, either with an end hole catheter

or a catheter with multiple side holes Today recombinant tissue plasminogen activator (rtPA) is used most commonly Other thrombolytic agents are, however, being developed and have been tried for indications other than peripheral arterial occlusive disease The dosage and rate of administra- tion of thrombolytic agents varies in different reports and makes comparisons difficult There are, however, some prospective randomized trials comparing surgery with intra- arterial thrombolytic therapy In one representative study, the mean duration of ischemia was almost 2 months and patients were included if the duration was less than

6 months Overall the study favored surgery Patients domized to catheter-directed thrombolysis had significantly greater ongoing or recurrent ischemia, life-threatening hemorrhage, and vascular complications compared with surgical patients Stratification by duration of ischemia, however, showed that patients treated within 14 days of onset of symptoms had an amputation rate after thromboly- sis of 6% compared to 18% for those undergoing surgery Patients treated with thrombolysis in this group also had

ran-a shorter hospitran-al stran-ay In pran-atients with ran-acute ischemiran-a the amputation-free survival at 6 months follow up was also bet- ter in those treated with thrombolysis.79Further analysis of this material reveals that thrombolysis provides a reduction

of the predetermined surgical procedure in 50–60% of the cases.80

Key points

● PTA is more successful for stenoses than for occlusions

● PTA is more successful for short than for long occlusions

● PTA may be combined with stent if recoil occurs or ifPTA produces dissection with intimal flaps

● Thrombolysis should be performed by local bal administration of the drug

intrathrom-● PTA may be preceded by thrombolysis in cases withrecent occlusions

Grade B

Peripheral vascular disease

Inflammatory vascular diseases –

thromboangitis obliterans (Buerger’s disease)

Temporal arteritis, Takayashu’s disease of the aortic arch,

and several diseases affecting the arterioles and

microcircu-latory vessels have an inflammatory or immunogenic origin.

In this chapter these diseases are not considered.

Thromboangitis obliterans, or Buerger’s disease, also has

an inflammatory component, although the pathophysiology

is still not fully known The major pathogenetic factor,

tobacco smoke, has been clearly established, however, for a

long time The patient is usually a young or middle aged

man with excessive smoking habits The disease is

segmen-tal and affects both veins and arteries leading to recurrent

thrombophlebitis and, in more severe cases, to multiple

ulcerations of toes and fingers owing to occlusion of distal

arteries Larger arteries are often affected, which in part may

be due to concomitant atherosclerotic disease.

The treatment is based on total avoidance of tobacco

smoke Treatment with prostaglandins, especially the

syn-thetic prostacyclin analog Iloprost (see critical ischemia

above), has been shown to have positive effects regarding

pain alleviation and healing of ulcers.81

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69.Dotter C, Judkins M Transluminal treatment of arteriosclerotic

obstructions Circulation 1964;30:654–70.

70.Johnston K, Rae M, Hogg-Johnston S et al 5-year results of

a prospective study of percutaneous transluminal angioplasty

Ann Surg 1987;206:403–12.

71.Dorros G, Lewin R, Jamnadas P et al Below-the-knee

angio-plasty: Tibioperoneal vessels, the acute outcome Catheter

Cardiovasc Diag 1990;19:170–8.

72.Sivananthan U, Browne T, Thorley P et al Percutaneous

translu-minal angioplasty of the tibial arteries Br J Surg 1994;81:1282–5.

73.Bolia A, Miles K, Brennan J, Bell P Percutaneous transluminal

angioplasty of occlusions of the femoral and popliteal arteries by

subintimal dissection Cardiovasc Interven Radiol 1990;

13:357–63.

74.London N, Srinivasan R, Naylor A et al Subintimal angioplasty

of femoropopliteal artery occlusions: the long-term results Eur J

Vasc Surg 1994;8:148–55.

75.Nydahl S, London N, Bolia A Technical report: recanalisation

of all three infrapopliteal arteries by subintimal angioplasty Clin

Radiol 1996;51:366–7.

76.Wolf G Surgery or balloon angioplasty for peripheral vasculardisease: a randomized clinical trial Principal investigators andtheir Associates of Veterans Administration Cooperative Study

Number 199 J Vasc Intervent Radiol 1993;4:639–48.

77.Perkins J, Collin J, Creasy T, Fletcher E, Morris P Exercisetraining versus angioplasty for stable claudication Long and

medium results of a prospective, randomised trial Eur J Vasc

Endovasc Surg 1996;12:167–72.

78.Whyman M, Fowkes F, Kerracher E et al Randomised

con-trolled trial of percutaneous transluminal angioplasty for

inter-mittent claudication Eur J Vasc Endovasc Surg 1996;12:

80.Weaver F, Comerota A, Youngblood M et al Surgical

revascu-larization versus thrombolysis for nonembolic lower extremitynative artery occlusions: Results of a prospective randomized

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81.Fiessinger J, Schäfer M Trial of Iloprost versus aspirin ment for critical limb ischemia of thromboangitis obliterans

treat-Lancet 1990;335:556–7.

Evidence-based Cardiology

Part IV

Clinical applications

Ernest L Fallen, Editor

Grading of recommendations and

levels of evidence used in

Evidence-based Cardiology

GRADE A

Level 1a Evidence from large randomized clinical trials (RCTs) or

systematic reviews (including meta-analyses) of

multi-ple randomized trials which collectively has at least as

much data as one single well-defined trial

Level 1b Evidence from at least one “All or None” high quality

cohort study; in which ALL patients died/failed with

con-ventional therapy and some survived/succeeded with

the new therapy (for example, chemotherapy for

tuber-culosis, meningitis, or defibrillation for ventricular

fibrilla-tion); or in which many died/failed with conventional

therapy and NONE died/failed with the new therapy (for

example, penicillin for pneumococcal infections)

Level 1c Evidence from at least one moderate-sized RCT or a

meta-analysis of small trials which collectively only has

a moderate number of patients

Level 1d Evidence from at least one RCT

GRADE B

Level 2 Evidence from at least one high quality study of

non-randomized cohorts who did and did not receive the

Level 5 Opinions from experts without reference or access to

any of the foregoing (for example, argument from physiology, bench research or first principles)

A comprehensive approach would incorporate many differenttypes of evidence (for example, RCTs, non-RCTs, epidemiologicstudies, and experimental data), and examine the architecture

of the information for consistency, coherence and clarity.Occasionally the evidence does not completely fit into neat com-partments For example, there may not be an RCT that demon-strates a reduction in mortality in individuals with stable anginawith the use of
blockers, but there is overwhelming evidencethat mortality is reduced following MI In such cases, some mayrecommend use of
blockers in angina patients with the expecta-tion that some extrapolation from post-MI trials is warranted Thiscould be expressed as Grade A/C In other instances (for example,smoking cessation or a pacemaker for complete heart block), thenon-randomized data are so overwhelmingly clear and biologicallyplausible that it would be reasonable to consider these interven-tions as Grade A

Recommendation grades appear either within the text, for example,

and or within a table in the chapter.The grading system clearly is only applicable to preventive or ther-apeutic interventions It is not applicable to many other types ofdata such as descriptive, genetic or pathophysiologic

Grade A1a Grade A

External evidence derived from randomized clinical trials

(RCTs) provides the practicing physician with a sound,

rig-orous and secure basis for making management decisions on

individual patients However, even vociferous advocates of

evidence-based medicine will caution against the use of

external evidence as the sole criterion for treating all

patients It is well to bear in mind that evidence obtained

from clinical trials is derived from large population

data-bases More often than not, the entry criteria tend to define

the boundaries of specified interest (for example, acute

myocardial infarction), whereas exclusion criteria, such as

age, sex, comorbid disease states etc., may well have denied

entry to one’s individual patient now awaiting treatment.

These exclusions may be based on concerns related to

patient safety, lack of applicability, historical considerations

or confounders (for example, significant non-cardiac illness)

that can affect the evaluation of treatment Nevertheless,

the practicing physician is left inquiring, “Where can I find

my patient within the trial’s data set?” Here is where

inter-pretation and the application of external evidence requires

a logical integration of overall trial results with a

knowl-edge of biologic mechanisms, patient risk and clinical

circumstances.

Evidence-based v patient centered medicine?

Not an either/or choice

Few would deny an approach to therapeutic decision

making based on proven external evidence combined with

clinical experience, knowledge of pathophysiology and

sensitivity to individual patient needs To marry the two

effectively is to recognize, and hence to avoid, their

respec-tive limitations if either were to be applied alone.

Recognizing the limitations of

external evidence

For most RCTs, proving therapeutic efficacy necessitates

cer-tain constraints in patient selection It is not uncommon that

many patients in a physician’s practice would not have

ful-filled the restrictive entrance criteria of most moderate-size

RCTs For example, some RCTs have an age cut off that actually excludes more than half of all patients with the disorder This by no means implies that the reputed benefit

of the test drug is not applicable (effective) to the patients excluded, but it does beg the question Entry criteria alone should never be the sole basis for denying a patient the ben- efit of proven therapy Interpatient variability is inevitable in all RCTs and contributes much to the “random errors” seen

in small and moderate-sized trials However, the larger the trial the smaller the random error, and the more likely that benefit can be reliably extrapolated to some patients who do not necessarily qualify for entry.1,2For example, one may observe that the benefits are consistent across different sub- groups, suggesting that the results may be applicable beyond the boundaries of patient selection, whereas on the other hand there may emerge reliable evidence for a lack of bene- fit in certain subgroups.

Evidence-based medicine that depends solely on external evidence is disease oriented rather than patient oriented In other words, the verifiability of RCT data is often dependent

on having a given diagnosis, as opposed to a clinical trum of risk associated with the diagnosis This is the so- called “labeling” dilemma For example, patients labeled as having “acute coronary syndrome” simply because they present with chest pain associated with non-ST segment ele- vation are often treated alike in an RCT, whereas the clinical expression of this entity may encompass a wide range from very low- to very high-risk patients Translating external evi- dence based solely on a unified diagnosis into practice guidelines or clinical pathways has the unfortunate conse- quence of making management decisions dependent on a label rather than the presenting clinical circumstances and risk of the underlying disorder.

spec-Another nagging problem with the “bottom line” of cal trials is the emphasis on primary end points that are measurable Statistical dependency on hard data such as mortality rates, prespecified clinical outcome events, rehos- pitalizations etc fails to acknowledge the significance of clinically relevant “soft” data, such as impact on symptoms, quality of life, psychosocial wellbeing, attitudes, economic realities and patient preferences.

clini-Finally, clinical trials all have finite time limits and, not uncommonly, the duration may be inadequate to

evidence

Ernest L Fallen, Salim Yusuf

assess long-term benefits and risks, especially for any new

drug In such cases the information from RCTs may have

to be supplemented by other sources of non-randomized

evidence.

Recognizing the limitations of patient

centered medicine

Who would have guessed that aspirin could reduce the

rela-tive risk of death and adverse coronary events in

postmyo-cardial infarction patients by 25%? Or that
blockers would

be so effective in class II–III chronic heart failure? Or that

inotropic agents, despite improving hemodynamics and

clin-ical wellbeing in patients with advanced heart failure, do so

at the expense of shortened survival? Or that some

antiar-rhythmic agents, although they achieve cosmetic cleansing

of so-called malignant ventricular ectopy from the

electro-cardiogram, are potentially hazardous? Previously held

con-cepts of disease mechanisms as the basis for initiating new

therapies or persisting with old therapies have been

chal-lenged by clinical trials results And so, what is apparent as a

“logical” management approach to a given clinical problem

may commit even the most experienced physician to

inap-propriate prescribing practices Patient centered medicine is

not a concept that is firmly rooted in empirical medicine.3It

does not guarantee that a physician, feeling secure in his or

her realm of expertise, will be kept abreast of therapeutic

advances based on clinical trial results Unfortunately, this

can lead to a tendency to persist in outmoded approaches.

Surely a cogent argument can be made to blend the

posi-tive features of patient centered and evidence-based

approaches through a constant awareness of their respective

limitations.

Some principles of application

Knowing the person who has the disease is as important

as knowing the disease that the patient has.4

Clinical decision making ought to incorporate the three

fol-lowing ingredients: (a) intelligent use of external evidence

based on well established clinical trial results and

epidemio-logic data whenever available; (b) clinical expertise,

knowl-edge of fundamental mechanisms of disease, and willingness

to listen to the testimony of one’s patients; and (c) sensitivity

to patients’ preferences, values, needs and beliefs.

1 It is well to bear in mind that for any given diagnosis

(label), patients at the greatest risk of a disease will

usu-ally derive the greatest benefit from an established

treat-ment, as the absolute benefit usually increases with risk

whereas harm due to the treatment remains

compara-tively fixed across the risk spectrum.5 Therefore, to

avoid the hazard of labeling it is critical to risk stratify one’s patient It is only after one has listened carefully to the testimony of the patient, performed a proper exami- nation and conducted the relevant tests that one can formulate a degree of attributable risk Remember, it is just as important to identify the patient at very low risk, thereby sparing him or her unnecessary aggressive investigation and/or therapy, as it is to identify the high-risk patient for whom aggressive treatment can be life saving.

2 The absence of external evidence should not lead to therapeutic nihilism Not all consensus recommenda- tions are supported by grade A evidence In fact, many consensus panel recommendations and clinical practice pathways are based on evidence that ranges from the use of clinical judgment, albeit under a cloud of uncertainty, to grade B through grade A evidence.6,7When external evidence is lacking, one’s own clinical experience, knowledge of pathophysiology, reasoned judgment and awareness of the patient’s needs are indis- pensable substitutes.

3 One should avoid using the trial entry criteria to mine whether a particular patient would benefit from the active treatment.2,5 Failure to qualify for entry is determined by many factors, few of which necessarily compromise the potential for therapeutic benefit For example, if a trial’s age cut off was 65 years then a rea- sonable risk/benefit assessment can be done for those older by assessing whether, within the trial, age modi- fied the treatment effect.

deter-4 One should always try to use the best available external evidence science has to offer, but never at the expense

of ignoring the patient’s psychosocial conditions, beliefs, values and preferences As medical decisions become more codified one should not fail to recognize and honor the importance of patient preferences.8

A patient’s medical decision based on his or her ular needs, preferences and beliefs should always be respected, as the patient is given the opportunity to hear the nature of the external evidence Consensus recommendations are guidelines only They represent

partic-an active process subject to continual review as new and as yet untested information emerges When follow- ing any recommendation based on external evidence the physician should always exercise clinical judgment based on a close working interaction with the patient.

Section preview

The following case reports stress the importance of knowing

how and when to apply best external evidence, not just to know what that evidence is They represent an attempt to

put a clinical face on a statistical bottom line by illustrating

Evidence-based Cardiology

practical solutions in the application of evidence-based

med-icine to individual patient problems These case studies

are real life presentations in which therapeutic decisions

are either clearly guided by external evidence or require

extra clinical reasoning skills in concert with best available

evidence From the files of these distinguished consultant

cardiologists two different cases are presented for each of

the 11 clinical topics The first case in each series represents

a clinical scenario where the management decision is

unequivocally substantiated by use of the external best

evi-dence The second case is more complex and represents a

challenge to incorporate external evidence with reasoned

judgment, an experienced examination, a sound knowledge

of cardiovascular pathophysiology, and sensitivity to the

patient’s needs and preferences

References

1.Yusuf S, Held P, Teo KK Selection of patients for randomized

controlled trials: Implications of wide or narrow eligibility

crite-ria Stat Med 1990;9:73–86.

2.Yusuf S, Wittes HJ, Probstfield J, Tyroler HA Analysis and pretation of treatment effects in subgroups of patients in random-

inter-ized clinical trials JAMA 1991;266:93–8.

3.Bensing J Bridging the gap The separate worlds of evidence-based

and patient-centered medicine Patient Educ Counseling

7.Hayward RS, Wilson MC, Tunis SR et al User’s guide to the

med-ical literature VIII How to use clinmed-ical practice guidelines A Are

the recommendations valid? JAMA 1995;274:570–4.

8.Kassirer JP Incorporating patients’ preferences in medical

deci-sions N Engl J Med 1994;330:1895–6.

Clinical applications of external evidence

64 Stable angina: choice of PCI v CABG v drugs

Douglas A Holder

Case scenario 1 While vacationing in Puerto Rico, a 51 year old Canadian woman sustains an uncomplicated

inferior myocardial infarction Upon returning to Canada she experiences angina up to four to five times per day, relieved by one or two nitroglycerin sprays Her risk factors include a history

of smoking, a positive family history of coronary artery disease, and a total cholesterol of 5·4 mmol/l (LDL-C 4·1; HDL-C 1·2) and triglycerides 1·34 mmol/l Her medications are diltiazem 240 mg CD daily; transdermal nitroglycerin 0·4 mg/h patch ON in am and OFF hs; enteric coated aspirin 325 mg daily; salbutamol and beclomethosone dipropionate puffs She is unable to take  blockers because of increased airways resistance secondary to chronic smoking.

A decision is made to proceed with coronary angiography with the view to revascularization Coronary angiography which reveals a 90% stenosis of the midthird of a dominant right coro- nary artery (RCA) (Figure 64.1) Angiographically, the dominant RCA stenosis, being severe, non-calcified, and discrete, is technically suitable for percutaneous coronary intervention (PCI) After the second inflation with a 2·5 mm balloon the procedure is complicated by acute closure due to a spiral dissection which extends down well below the original stenosis towards the crux (Figure 64.2) A 2·5/28 mm stent and a 2·5/24 stent are deployed to tack up the intima from the distal end of the dissection back to and including the original stenosis This results in an angiographically excellent result (Figure 64.3) The patient makes an uneventful recovery and is discharged on clopidogrel 75 mg daily in addition to her previous medications.

She is well for 2 months but then develops recurrent angina An exercise (treadmill) thallium study is positive at 52 1minutes with angina; 1 mm ST depression and reversible inferior wall ischemia on scanning A repeat coronary angiogram reveals a discrete restenosis at the juncture

of the two stents (Figure 64.4) The patient and her husband decide to choose coronary artery bypass surgery (CABG) rather than repeat PTCA.

Figure 64.1 A 90% discrete stenosis in a dominant right

coronary artery (RCA)

Figure 64.2 After the second balloon inflation, note the spiraldissection extending down toward the crux

Stable angina

Question

Is there evidence to support these therapeutic steps?

Comment

There were three decision points where the patient was

pre-sented with options for therapeutic interventions.

1 Evidence to recommend initial PTCA

The patient presented with postmyocardial infarction angina

due to single vessel RCA stenosis To date, randomized

con-trolled trials (RCT) comparing CABG to medical treatment

have shown no survival benefit from surgery because of the

low prognostic risk associated with single vessel right

coro-nary disease.1,2There have been no direct comparisons of

PTCA with CABG in this subset of single vessel disease, but

the BARI study of multivessel disease showed no survival benefit for either treatment over a 5 year follow up period.3Thus, in making the therapeutic recommendation at this stage, prognosis was not the main issue Symptom relief was The ACME trial compared medical treatment to PTCA for single vessel left anterior descending disease with the end point being anginal frequency and treadmill time at

6 months of follow up.4In this trial of 107 patients, 46% of medically treated patients were free of angina compared

to 64% of PTCA patients (P 0·01) and there was an increase in treadmill time, 2·1 minutes over baseline in the PTCA group compared to 0·5 minutes in the medically

treated group (P  0·0001) However, because of restenosis, those patients assigned to PTCA had a more frequent requirement for further procedures (16 patients required PTCA; 2 required CABG) In another trial comparing med- ical treatment to PTCA to left internal mammary artery (LIMA) grafting for proximal single vessel left anterior descending artery stenosis 80% there were no differences among the groups in mortality or infarction rates, but no patient needed further revascularization in the surgical group compared to 8/72 (11%) of those undergoing PTCA

and 7/72 (10%) on medical treatment (P  0·019).5Acknowledging that clinical trials that specifically apply to our patient are lacking, these studies nevertheless allow us

to conclude that surgery would be an acceptable choice for achieving symptomatic relief, and that PTCA is intermediate between medical treatment and surgery in achieving symp- tomatic relief but at a cost of a higher likelihood of further revascularization in the future The other considerations in comparing surgery to PTCA are higher initial mortality and morbidity with surgery, as well as the fact that the patency of

a saphenous vein graft in the circulation is less than that of a mammary artery The angiographic characteristics of the stenosis were consistent with a high likelihood of primary success with PTCA, and if restenosis did not occur then the time when CABG might have to be done could be delayed.

2 Evidence for the decision to employ a

3 Evidence for the decision for coronary bypass surgery

Unfortunately, the patient developed restenosis within the stented segment of the RCA This was discrete, distal to the

Figure 64.3 Post-stent deployment revealing adequate

patency of the RCA

Figure 64.4 Restenosis at the juncture of the distal and

middle stents 2 months after angioplasty

Evidence-based Cardiology

Question

Is conservative medical management optimal at this point?

Comment

Here, the decision rests, in part, on whether clear evidence

is available to offer sound advice to an asymptomatic patient

with objective evidence of three vessel disease and exercise

induced silent ischemia If this patient had symptoms of

classic angina pectoris the therapeutic decision for mending coronary bypass surgery (CABG) with the expecta- tion of symptom relief and improved prognosis could be substantiated If the patient had a definite left main stenosis,

recom-or depressed LV function, the argument frecom-or CABG is strongly made because in this setting CABG improves prog- nosis even in the absence of symptoms.1,2 This patient is somewhat unusual in that not only is he asymptomatic but

he is capable of a good workload (800 kpm of supine bicycle exercise) However, there is convincing evidence of signifi- cant ischemia at this level of work with ST depression

site of the original plaque, and very unlikely to dissect with

repeat dilation because of the stent buttressing the vessel

wall Thus, this stenosis would have been amenable to

either repeat PTCA or coronary bypass surgery (CABG) The

clinical advice was to offer repeat PTCA However, when

the substance of the earlier discussion of PTCA versus

med-ical therapy versus CABG was again reviewed, the patient

and her husband opted for surgery as a more “definitive”

method of dealing with her problem She subsequently

underwent single vessel bypass without incident and

con-tinues with secondary prevention therapy.

References

1.Alderman EL, Bourassa M, Cohen LSE Ten year follow-up

of survival and myocardial infarction in the randomized

Coronary Artery Surgery Study Circulation 1990;82:1629.

2.European Coronary Surgery Study Group Long-term results ofprospective randomized study of coronary artery bypass surgery

in stable angina pectoris Lancet 1982;ii:1173.

3.The Bypass Angioplasty Revascularization Investigation (BARI)Investigators Comparison of coronary bypass surgery with angio-

plasty in patients with multivessel disease N Engl J Med

5.Hueb WA, Bellotti G, deOliveira SA et al A prospective

randomized trial of medical therapy, balloon angioplasty orbypass surgery for single proximal left anterior descending coro-

nary stenosis J Am Coll Cardiol 1995;26:1600.

6.Lincoff AM, Topol EJ, Chapekis AT et al Intracoronary stenting

compared with conventional therapy for abrupt closure

compli-cating coronary angioplasty: a matched case control study J Am

Coll Cardiol 1993;21:866–75.

Case scenario 2 A 63 year old man tells the following story Approximately 12 1years previously he experienced a

feeling of “indigestion” while walking This led to a symptom limited exercise test that was sidered positive by ECG criteria but was not accompanied by any symptoms His symptom of

con-“indigestion” did not recur and he continued to pursue outdoor activities such as canoe ping, camping, and walking without limitation Risk factors include type II diabetes mellitus and hypercholesterolemia He is a non-smoker.

trip-His current medications are humulin insulin 70/30; 20 units ac breakfast and 18 units ac supper, pravastatin 40 mg qhs (total cholesterol now is 4·47 mmol/l; LDL 2·87; HDL 1·12;

TG 1·05), acebutolol 100 mg po bid, and enteric coated aspirin 325 mg po daily.

A stress MUGA scan reveals the following Exercise duration 11 minutes and 31 seconds; maximum heart rate 144 per minute; maximum blood pressure 170/84 and no angina The ECG shows 4·5 mm downsloping ST-segment at maximum stress Ejection fraction: baseline 69%; 200 kpm 73%; 400 kpm 66%; 600 kpm 61%; 800 kpm 58%; post-exercise recovery 67% indicating a fall in EF at higher workloads Left ventricular wall motion analysis demonstrated hypokinesis of the septum, posterolateral, and inferior walls.

Conclusion Silent ischemia Suggest referral for coronary angiography Coronary angiography reveals a normal

left main coronary artery trifurcating into left anterior descending, intermediate, and circumflex branches (Figure 64.5) There is a “left main equivalent” distribution of disease with stenoses involving the LAD 75%, intermediate 90%, and circumflex 90% The RCA is diffusely diseased with a maximal narrowing of 60% in the midthird segment LV systolic function is normal at rest.

of 4.5 mm and a reduction in ejection fraction from 69% at rest to 58% with maximal effort There is also evidence of

LV wall motion abnormality in multiple sites consistent with the extent of coronary artery disease noted on the angiogram.

The question therefore is one of prognosis rather than symptom relief Common sense alone argues that his myocardium would benefit from revascularization There is evidence to suggest that the long-term prognosis of patients with documented silent ischemia is similar to those with symptomatic angina pectoris,3,4 and thus our treatment should be aimed at the coronary disease substrate, rather than the clinical chest pain syndrome Given the left main equivalent distribution as well as the diseased RCA, this patient was referred for consideration of coronary bypass surgery The nature of the left coronary disease is also amenable to PCI although the procedure is somewhat riskier because of the proximal nature of the plaque in the LAD vessel In addition, the likelihood of restenosis is significant because of the need for multivessel stenting in this diabetic patient If the initial enthusiasm for coated stents is borne out with further observation then a PCI approach might well

be a reasonable alternative in the future Currently, the sion to undergo CABG is supported by evidence gleaned from a careful review of all major trials on bypass surgery for different severities of coronary artery disease.5

deci-References

1.Alderman EL, Bourassa M, Cohen LSE Ten year follow-up

of survival and myocardial infarction in the randomized

Coronary Artery Surgery Study (CASS) Circulation 1990;

82:1629.

2.European Coronary Surgery Study Group Long-term results ofprospective randomized study of coronary artery bypass surgery

in stable angina pectoris Lancet 1982;ii:1173.

3.Lotan C, Lokovitsky L, Gilon D et al Silent myocardial ischemia

during exercise testing Does it indicate a different angiographic

and prognostic syndrome? Cardiology 1994;85:407.

4.Marwick TH Is silent ischemia painless because it is mild?

J Am Coll Cardiol 1995;25:1513–15.

5.Yusuf S, Zucker D, Peduzzi P et al Effect of coronary artery

bypass surgery on survival Lancet 1994;344:563–70.

Stable angina

Figure 64.5 Multivessel coronary artery stenoses suggesting

a “left main equivalent” with (A) LAD 75%, (B) intermediate

90%, and (C) circumflex 90% The RCA is diffusely diseased

(A)

(B)

(C)

What initial and further measures should be taken in this

patient?

Comment

This case represents a good example of unstable angina

without “classic” chest pain The initial evaluation should

aim to answer two important questions: First, do the

pre-senting symptoms and signs represent ischemic heart

dis-ease? Second, is this patient at significant risk for an adverse

clinical outcome?

While myocardial ischemia usually causes deep, poorly

localized chest or arm discomfort, some patients may have

no chest discomfort but present with epigastric, jaw, arm, or

neck discomfort Other “atypical” symptoms that may

sug-gest angina even in the absence of chest pain include

dysp-nea, nausea, vomiting, and diaphoresis If these symptoms

are brought on by emotional stress or physical exertion and

are relieved by rest or nitroglycerin, they should be

consid-ered equivalent to angina Atypical angina is more common

in women than men, and more prevalent in elderly people

and in patients with diabetes It is important to remember

that new-onset or worsening dyspnea on exertion is the most common “anginal equivalent”, especially in elderly patients Although this patient does not complain of classic exertional chest pain, the diagnosis of an unstable coronary syndrome is likely given her history of diabetes and exer- tional dyspnea (Table 65.1).

The recent change in pattern culminating in ischemic symptoms with minimal exertion is of concern However the patient’s presentation lacks other “high risk” characteris- tics that are associated with an increased short-term risk of death or non-fatal myocardial infarction (MI) (Table 65.2) These include: rest pain for greater than 20 minutes, transient ST segment changes of greater than 0·5 mV, and elevated serum cardiac enzymes Current published guide- lines suggest that she should be admitted to the hospital in

a unit that offers continuous rhythm monitoring and careful observation for recurrent ischemia.

Initial medical management should include an aspirin, nitrates, a
blocker, and antithrombotic therapy in the form

of full dose, IV unfractionated heparin (UFH) or neous low molecular weight heparin (LMWH).1

subcuta-Aspirin remains the gold standard for antiplatelet therapy.

In unstable angina trials, aspirin therapy significantly reduced the relative risk of fatal or non-fatal MI by 60%.2

An oral loading dose of 160–325 mg/day non-enteric

Case scenario 1 A 64 year old diabetic woman presents to the emergency ward with left arm discomfort,

diaphoresis, nausea, and shortness of breath lasting 10 minutes She has had similar episodes intermittently for the past 6 months, lasting up to 2 minutes However, these episodes were usually brought on by heavy exertion and relieved by resting The episodes have become more frequent over the past month and have been occurring with minimal exertion during the past

48 hours.

Physical examination is within normal limits except for a blood pressure of 150/90 mmHg and a heart rate of 110 The initial ECG and the one taken an hour later after resolution of symptoms show no ischemic ST or T wave changes Serum troponin and creatine kinase-MB isoenzyme (CK-MB) levels are not elevated.

Acute coronary syndromes: management issues

formulation should be given initially followed by

75–160 mg/day maintenance therapy In patients who are

aspirin intolerant, the adenosine diphosphate receptor

antagonist clopidogrel can be substituted This oral

antiplatelet agent was shown in the Clopidogrel versus

Aspirin in Patient at Risk of Ischemic Events (CAPRIE) trial

to reduce the risk of cardiovascular events in patients with

established vascular disease by 8·7% compared with

patients treated with aspirin.3 Recently, the Clopidogrel in

Unstable angina to prevent Recurrent Events (CURE) trial

showed that treatment with clopidogrel in addition to

aspirin reduced the risk of future ischemic events compared

to aspirin therapy alone.4A loading dose of 300 mg

clopido-grel should be given followed by 75 mg/day orally.

The widespread use of oral, topical, and IV nitrate

preparations in unstable angina is based on their

well-established physiologic and clinical effects, rather than on

data from large-scale randomized trials Nitroglycerin

(NTG) reduces myocardial oxygen demand and improves

regional myocardial blood flow by dilating epicardial

coro-nary vessels Patients with unstable symptoms can be given

three 0·4 mg NTG tablets sublingually Intravenous NTG

should be initiated and titrated as needed in patients with

refractory symptoms.5

Receptor antagonists should be started early in all patients who do not have contraindications Intravenous boluses of metoprolol 5 mg or propranolol 1 mg can be given slowly over 1 to 2 minutes and repeated every 5 minutes until the target heart rate of 50–60 is reached Oral therapy can be initiated 30–60 minutes later An overview of several small studies of
blocker therapy in unstable angina suggests a small, but significant, reduction in the risk of progression to myocardial infarction.6

Rate controlling, non-dihydropyridine calcium-channel blockers (verapamil or cardizem) can be used as initial therapy for patients with contraindications to
blockers, for patients who continue to have ischemic symptoms despite treatment with nitrates and
blockers, and for patients with variant angina.7 In general short-acting dihydropyridine calcium-channel blockers such as nifedipine should be avoided, and special care must be taken when using any calcium-channel blocker in patients with depressed left ventricular function.

Antithrombotic therapy with unfractionated heparin (UFH)

or a low molecular weight heparin (LMWH) should be started immediately to reduce the risk of myocardial infarction, death, or recurrent ischemia The most recent guidelines from the American College of Cardiology recommend

Table 65.1 Likelihood that signs and symptoms represent an ACS secondary to CAD

Any of the following: Absence of high-likelihood Absence of high- or

features and presence of intermediate-likelihood any of the following: features but may have:

History Chest or left arm pain or Chest or left arm pain or Probable ischemic symptoms

discomfort as chief symptom discomfort as chief symptom in absence of any ofreproducing prior documented Age 70 years the intermediate likelihood

Known history of CAD, including MI Diabetes mellitus Recent cocaine useExamination Transient MR, hypotension, Extracardiac vascular disease Chest discomfort reproduced

or rales

transient ST-segment Abnormal ST segments or in leads with dominantdeviation (0·05 mV) or T-waves not documented R waves

with symptoms

Reproduced with permission ACC/AHA Guidelines for the Perioperative Cardiovascular Evaluation for Noncardiac Surgery

J Am Coll Cardiol 1996;27:910–48 Copyright 1996 by the American College of Cardiology and American Heart Association, Inc.

Abbreviations: CAD, coronary artery disease; CK-MB, creatine kinase-MB isoenzyme; ECG, electrocardiogram; MI, myocardialinfarction; MR, mitral regurgitation; TnI, troponin I; TnT, troponin T

Evidence-based Cardiology

60 units of UFH followed by 12 units/kg/hour infusion.

Alternatively, the low molecular weight heparin enoxaparin

1 mg/kg SQ 2/day can be used Two trials that studied

over 7000 patients showed a roughly 20% reduction in the

rate of death, MI, and need for urgent revascularization in

those treated with enoxaparin rather than UFH.8 The

biggest advantage of LMWH over UFH is ease of

administra-tion as monitoring of activated partial thromboplastin time

(APTT) is not required.

Subsequent management depends on the patient’s

clini-cal course Repeat ECG and cardiac marker measurements

should be performed 6–12 hours after the onset of symptoms.

Elevated serum cardiac enzymes9 or recurrent ischemic symptoms,10 despite treatment with aggressive pharma- cotherapy as described above, would necessitate early coronary angiography with an eye toward percutaneous or surgical revascularization In the absence of these “high-risk features”, the patient can safely undergo non-invasive testing after the doses of nitrates and
blocker agents have been titrated and the heparin has been stopped Patients with inducible ischemia or severely depressed left ventricu- lar function (LVEF  35%) should also be considered for coronary angiography (Figure 65.1).

Table 65.2 Short-term risk of death or non-fatal MI in patients with unstable angina a

At least one of the following No high-risk feature No high- or

one of the following: any of the following features:

History Accelerating tempo of ischemic Prior MI, peripheral or

symptoms in preceding 48 h cerebrovascular disease,

or CABG, prior aspirin useCharacter of pain Prolonged ongoing (20 minutes) Prolonged (20 min) rest New-onset or progressive

moderate or high likelihood the past 2 weeks without

Rest angina (20 min) rest pain but with moderaterelieved with rest or or high likelihood of

or sublingual NTG CAD (see Table 65.1)Clinical findings Pulmonary edema, most likely Age 70 years

due to ischemiaNew or worsening MR murmur S3or new/worsening rales

Hypotension, bradycardia,tachycardia

Age 75 yearsECG Angina at rest with transient T-wave inversions 0·2 mV Normal or unchanged ECG

ST-segment changes 0·05 mV Pathological Q waves during an episode of

presumed newSustained ventricular tachycardiaCardiac markers Elevated (e.g TnT or TnI 0·1 ng/ml) Slightly elevated (e.g Normal

TnT 0·01 but 0·1 ng/ml)

aEstimation of the short-term risks of death and non-fatal cardiac ischemic events in unstable angina is a complex multivariableproblem that cannot be fully specified in a table such as this; therefore, this table is meant to offer general guidance and illustra-tion rather than rigid algorithms

Reproduced with permission ACC/AHA Guidelines for the Perioperative Cardiovascular Evaluation for Noncardiac Surgery

J Am Coll Cardiol 1996;27:910–48 Copyright 1996 by the American College of Cardiology and American Heart Association, Inc.

Abbreviations: CABG, coronary artery bypass graft; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society;

MI, myocardial infarction; MR, mitral regurgitation; NTG, nitroglycerine; TnI, troponin I; TnT, troponin T

Acute coronary syndromes: management issues

References

1.Braunwald E, Antman EM, Beasly JW et al ACC/AHA

Guidelines for the management of patients with unstable

angina and non-ST segment elevation myocardial infarction: a

report of the American College of Cardiology/American Heart

Association Task Force on Practice Guidelines J Am Coll

Cardiol 2000;36:970–1062.

2.Theroux P, Ouimet H, McCans J et al Aspirin, heparin, or both

to treat acute unstable angina N Engl J Med 1988;319:

1105–11

3.CAPRIE Steering Committee A randomised, blinded, trial

of clopidogrel versus aspirin in patients at risk of ischemic

events Lancet 1996;348:1329–39.

4.The Clopidogrel in Unstable Angina to Prevent, Recurrent

Events Trial Investigators Effects of clopidogrel in addition to

aspirin in patients with acute coronary syndromes without

ST-segment elevation N Engl J Med 2001;345:494–502.

5.Conti CR Use of nitrates in unstable angina pectoris Am J

Cardiol 1987;60:31H–34H.

6.Yusuf S, Wittes J, Friedman L Overview of results of

random-ized clinical trials in heart disease, II: unstable angina, heart

fail-ure, primary prevention with aspirin, and risk factor

modification JAMA 1988;260:2259–63.

7.Held PH, Yusuf S, Furberg CD Calcium-channel blockers inacute myocardial infarction and unstable angina: an overview

BMJ 1989;299:1187–92.

8.Antman EM, Cohen M, Radley D et al Assessment of the

treat-ment of effect of enoxaparin for unstable angina/non-Q-wave myocardial infarction: TIMI 11B-ESSENCE

meta-analysis Circulation 1999;100:1602–8.

9.Cannon CP, Weintraub WS, Demopoulos LA et al for

the TACTICS-Thrombolysis in Myocardial Infarction 18Investigators Comparison of early invasive and conservativestrategies in patients with unstable coronary syndromes treated

with the glycoprotein IIb/IIIa inhibitor tirofiban N Engl J Med

2001;344:1879–87.

10.Boden WE, O’Rourke RA, Crawford MH et al Veterans

Affairs Non-Q Wave Infarction Strategies in Hospital (VANQWISH) Outcomes in patients with acute non-Q wavemyocardial infarction randomly assigned to an invasive as com-

pared with a conservative management strategy N Engl J Med

1998;338:1785–92.

11.Bertrand ME, Simoons ML, Fox KAA et al Management of

acute coronary syndromes: acute coronary syndromes withoutpersistent ST segment elevation: Recommendations of the Task

Force of the European Society of Cardiology Eur Heart

on admission and

12 hours later

GP IIb-IIIainhibitorCoronaryangiography

Stress testbefore dischargeAssess

risk

HIGH RISKElevated troponinRefractory/recurrent ischemiaHemodynamic instabilityEarly post-MI unstable angina

Figure 65.1 Recommended strategy in unstable angina/non-ST elevation MI

Abbreviations: UFH, unfractionated heparin; LMWH, low molecular weight heparin

Adapted with permission from Bertrand ME et al Management of acute coronary syndromes without persistent ST segment tions: Recommendations of the Task Force of the European Society of Cardiology Eur Heart J 2000;21:1424

eleva-Evidence-based Cardiology

Case scenario 2 A 77 year old male with a longstanding history of stable, class I angina is seen in the emergency

ward with non-exertional precordial chest pain radiating to the left shoulder and dyspnea for

30 minutes He has had similar episodes over the last year lasting up to 5 minutes but these were brought on by exertion and relieved with rest or sublingual nitroglycerin On examination the blood pressure is 100/50, the heart rate is 120 bpm The physical examination reveals rales

to the mid lung fields bilaterally The initial ECG is shown in Figure 65.2 The serum troponin level is 6·8.

Comment

This patient presents with a classic acute coronary

syn-drome, and a diagnosis of non-ST-elevation MI (NSTEMI) is

confirmed by an elevated serum troponin level.

As usual, prompt treatment with a regimen of aspirin,

heparin, nitrates, and
blockers is mandated in order to

decrease the risk for recurrent ischemic events However

sev-eral aspects of this patient’s clinical presentation suggest that

he remains at high risk for death or myocardial infarction

despite appropriate medical therapy These “high-risk features”

include advanced age, an accelerating tempo of ischemic

symptoms over the preceding 48 hours, rest pain for greater

than 20 minutes, evidence of pulmonary edema or

hypoperfu-sion, new or worsening mitral regurgitation, dynamic ST

changes 1mm, and elevated serum cardiac markers.1–3

A review of the randomized clinical trials of GP IIb-IIIa

receptor antagonists suggests that these agents should be

administered, in addition to aspirin and heparin, in patients

with many of these high-risk clinical features, in patients with continuing ischemia, and in patients who are sched- uled for percutaneous coronary intervention (PCI).4,5Patients with elevated serum troponin levels appear to derive the greatest benefit from GP IIb-IIIa inhibitor therapy While the benefits of GP IIb-IIIa inhibition appear to be greatest in patients undergoing PCI, several trials have shown that GP IIb-IIIa inhibitors are also effective in reduc- ing the rate of ischemic events in the acute, “pre-cath” phase of medical management, and this benefit is maintained and heightened if a PCI is subsequently performed.6Furthermore, similar to data from clinical trials of throm- bolytic therapy in acute ST elevation MI, patients with unstable angina and NSTEMI who are treated the earliest after symptom onset with a GP IIb-IIIa inhibitor appear to derive the most benefit.7

Early coronary angiography should also be strongly considered The Thrombolysis in Myocardial Infarction (TACTICS-TIMI-18) Trial randomized 2220 patients with

aVRI

V1V2

V3

V4V5

V8

Figure 65.2 ECG of Case 2

Acute coronary syndromes: management issues

unstable angina or NSTEMI to an early invasive strategy,

which included cardiac catheterization within 48 hours,

and revascularization if appropriate versus a conservative

strategy, in which catheterization was performed only if

spontaneous or inducible ischemia was observed All

patients were treated with aspirin, heparin, and the

glyco-protein IIb-IIIa inhibitor tirofiban Early invasive therapy

was associated with a significantly reduced rate of death or

MI at 6 months (7·3% v 9·5%; OR, 0·74; P  0·05).8

Early coronary angiography in patients with acute

coro-nary syndromes yielded similar reductions in ischemic

events in the Fragmin and Fast Revascularization during

Instability in Coronary Artery Disease (FRISC) II trial.9Both

trials found that the benefit of an early invasive strategy was

greatest in intermediate- and high-risk patients with

ele-vated troponin levels and/or ischemic ST changes on the

admission electrocardiogram.

Based on these recently published clinical trials and

prac-tice guidelines, this “high-risk” patient should be treated

with an aggressive antithrombotic and antiplatelet regimen

that includes an intravenous glycoprotein IIb-IIIa inhibitor in

addition to aspirin and heparin An early invasive strategy

consisting of coronary angiography with an eye toward

revas-cularization if necessary should also be pursued (Figure 65.1).

Competing interest: the author has received educational

grants for Aventis, and has spoken on unstable angina at

events sponsored by Aventis.

References

1.Braunwald E, Antman EM, Beasly JW et al ACC/AHA

guide-lines for the management of patients with unstable angina and

non ST-segment elevation myocardial infarction: a report of the

American College of Cardiology/American Heart Association

Task Force on Practice Guidelines J Am Coll Cardiol

2000;36:970–1062.

2.Antman EM, Corbalan R, Huber K, Jaffe AS Issues in early risk

stratification for UA/NSTEMI Eur Heart J Supplements

2001;3(Suppl J):J6–J14.

3.Antman EM, Cohen M, Bernick P et al The TIMI risk score for

unstable Angina/non-ST-elevation MI: a method for

prognosti-cation and therapeutic decision making JAMA 2000;

glycopro-syndromes N Engl J Med 1998;339:436–43.

6.Boersma E, Akkerhuis KM, Theroux P et al Platelet

glycopro-tein IIb/IIIa receptor inhibition in non-ST-elevation acute nary syndromes: early benefit during medical treatment only,with additional protection during percutaneous coronary inter-

coro-vention Circulation 1999;100:2045–8.

7.Bhatt DL, Marso SP, Houghtaling P et al Does earlier

adminis-tration of eptifbatide reduce death and MI in patients with

acute coronary syndromes? Circulation 1998;98:1560–1.

8.Cannon CP, Weintraub WS, Demopoulos LA et al for

the TACTICS-Thrombolysis in Myocardial Infarction 18Investigators Comparison of early invasive and conservativestrategies in patients with unstable coronary syndromes treatedwith the glycoprotein IIb/IIIa inhibitor tirofiban

N Engl J Med 2001;344:1879–87.

9.Fragmin and Fast Revascularization during Instability inCoronary artery disease (FRISC II) Investigators Invasive com-pared with non-invasive treatment in unstable coronary-arterydisease: FRISC II prospective randomised multicentre study

Lancet 1999;354:708–15.

What is the proper course of action at this juncture?

Comment

There is overwhelming evidence from major clinical trials

that early intervention with thrombolytic therapy, combined

with aspirin for acute myocardial infarction, substantially reduces mortality and the risk of recurrent ischemic events.1–4Does this case fit the entrance criteria? The symp- toms of prolonged chest pain unresponsive to nitroglycerin, together with accompanying symptoms of nausea, weakness and diaphoresis, raise a strong suspicion of acute myocardial infarction This is substantiated by the ECG findings of hyperacute ST segment elevation in leads II, III and AVF, signifying an acute inferior wall myocardial infarction.

Bryan F Dias, Ernest L Fallen

Case 1 A 68 year old woman with an 18 month history of chronic stable effort angina presents to the

emergency room of a community hospital with a 2 hour history of increasing retrosternal chest pain associated with weakness, diaphoresis and nausea Three applications of nitroglycerin spray 5 minutes apart fail to offer relief She is a well controlled type 2 diabetic on glyburide

5 mg od She also has esophageal acid reflux disease but clearly distinguishes her reflux toms from angina There is no history of gastrointestinal bleeding.

symp-On examination she is pale, anxious and diaphoretic Her blood pressure is 110/80 in both arms and her pulse is 70 and regular Her neck veins are elevated 3 cm at 45 degrees, with a sustained hepatojugular reflux She has a soft late crescendo apical systolic murmur Her lungs are clear An ECG is immediately ordered and reveals the following (Figure 66.1).

aVR

V5V2

aVLII

Acute myocardial infarction

With an evolving infarction less than 3 hours from pain

onset there is Grade A evidence that the treatment of choice

is prompt coronary thrombolysis plus aspirin.1–4 The

patient is therefore given aspirin 160 mg to chew while an

intravenous line is inserted After confirmation that the

patient has no contraindication (recent bleed, stroke,

trauma, surgery etc.) she is given streptokinase 1·5 million

units intravenously over 1 hour There is no evidence that

rtPA (recombinant tissue plasminogen activator) alteplase

or reteplase is superior to the less expensive streptokinase

in patients with first-onset acute inferior myocardial

infarction.5,6

The patient is monitored in the coronary care unit, where

relief of anxiety and pain is achieved by administering

oxygen, intravenous nitroglycerin and morphine as needed.

She is prescribed an oral
blocker (metoprolol 50 mg

bid), which will be continued indefinitely.7–9Because there

is no major complication, such as congestive heart failure or

intermittent chest pain, the patient will continue on aspirin

and the
blocker without the need for full-dose or low

molecular weight heparin.5,6 There is also no

echocar-diographic evidence of significant left ventricular

dys-function (her estimated ejection fraction is 40%) to

warrant an ACE inhibitor during the acute phase of the

infarction.10

The community hospital where she is admitted does not

have coronary angiographic facilities; the nearest hospital

with such facilities is several hours away If such facilities

were immediately available this patient would be a

candi-date for primary coronary intervention (PCI), that is

angio-plasty with stent.11

References

1.GISSI trial Effectiveness of intravenous thrombolytic treatment

in acute myocardial infarction Lancet 1986;1:397–401.

2.ISIS II trial Randomized trial of intravenous streptokinase, oralaspirin, both or neither among 17,187 cases of suspected acute

myocardial infarction Lancet 1988;ii:349–60.

3.FTT Collaborative group Indications for fibrinolytic therapy insuspected acute myocardial infarction: collaborative overview ofearly mortality and major morbidity results from all randomized

trials of more than 1000 patients Lancet 1994;343:311–22.

4.The GUSTO Investigators An international randomized trialcomparing four thrombolytic strategies for acute myocardial

infaction N Engl J Med 1993;329:673–82.

5.Cairns J, Armstrong P, Belenkie I et al Canadian Cardiovascular

Society Consensus Conference on coronary thrombolytics –

1994 update Can J Cardiol 1994;10:517–29.

6.Collins R, Peto R, Baigent C, Sleight P Aspirin, heparin and rinolytic therapy in suspected acute myocardial infarction

fib-N Engl J Med 1997;336:847–60.

7.BHAT Study Group A randomized trial of propanolol in patients

with acute myocardial infarction JAMA 1982;247:1707–14.

8.The Norwegian Multicenter Study Group Six year follow up

on Timolol after acute myocardial infarction N Engl J Med

Case 2 A 66 year old man presents to the emergency room with severe chest pain He has had two

pre-vious coronary artery bypass operations (2 and 12 years ago) and a history of two prepre-vious myocardial infarctions prior to his last bypass For the past year his functional status has been stable, with Canadian Cardiovascular Society class I angina.

He is now 3 hours following the onset of retrosternal chest pain unrelieved by sublingual nitroglycerin (0·6 mg 3) The pain is characterized as 10/10 severity, crushing in nature, with radiation to the jaw Associated symptoms include dyspnea, diaphoresis and weakness These symptoms are similar to those he had with the onset of his previous infarctions.

Physical examination reveals an acutely ill-looking man He is in painful distress, pale and clammy His blood pressure is 100/80, equal in both arms His pulse is 90 bpm and regular Lung fields are clear His neck veins are not abnormally elevated There are no murmurs or extra heart sounds His ECG is shown in Figure 66.2.

path-Evidence-based Cardiology

misleading In this case the widespread ST segment

depres-sion led to the initial diagnosis of subendocardial ischemia,

manifested as either unstable angina or non-ST segment

elevation (NSTEMI) infarction (so-called acute coronary

syn-drome, or ACS) The use of thrombolysis for unstable angina

or NSTEMI infarction has been studied but results show a

trend towards no benefit or possible harm.1,2 The patient

was therefore given aspirin 325 mg and full-dose

intra-venous heparin, starting with a 7 units/kg bolus followed by

1200 units/h IV Within the next hour neither sublingual

nor intravenous nitroglycerin had any effect on the pain,

which persisted at 10/10 severity Similarly, an intravenous

blocker (propanolol 5 mg IV 3 every 10 min) and

mor-phine (10 mg IV over 30 min) had little effect The pain

per-sisted unabated, and serial ECGs showed ongoing ischemic

changes but no evidence of injury (ST elevation).

This patient initially received the standard treatment for

the diagnosis of acute coronary syndrome (ACS), namely

aspirin and an antithrombotic (unfractionated heparin in

this case3–5), and yet these measures, plus intensification of

the antianginal therapy, failed to relieve his symptoms One

could make a case for a different antithrombotic/antiplatelet

approach Studies examining low molecular weight heparin

(LMWH) versus unfractionated heparin (UHF) in patients

presenting with ACS have shown equivalency.6,7As for an

additional antiplatelet agent, clopidogrel, an adenosine

diphosphate receptor antagonist, when combined with aspirin in patients with ACS, showed a relative risk reduc- tion of death, myocardial infarction or stroke by 18% com- pared to aspirin alone in the CURE Study.8 The use of glycoprotein IIb/IIIa receptor antagonists (eptifibatide or tirofiban) has been shown to be effective in acute ischemic situations when added to aspirin and heparin.9,10

However, there is a strong suspicion that this patient is actually suffering an acute myocardial infarction with total coronary artery occlusion He had experienced identical symptoms with his previous infarctions; he is acutely ill with diaphoresis, weakness and restlessness – symptoms that are characteristic of myocardial necrosis, as opposed to reduced perfusion On reflection the ECG changes may be construed

as misleading in view of his chronic history of multiple ischemic insults A decision was therefore made to proceed immediately with thrombolytic therapy Within 45 minutes following IV infusion of rtPA the patient’s pain had completely abated and his ECG normalized, with only persistent T wave negativity in the anterior leads Subsequent investigations revealed a peak creatinine kinase of 2969 with a strongly pos- itive CKMB fraction The patient went on to an uneventful recovery and was discharged from hospital on day 7 Although the evidence from clinical trials would not nec- essarily support the routine use of thrombolytic agents based

on the ECG changes seen in this case, here is an example

aVR V1 V4

V5V2

aVFII

Acute myocardial infarction

where exclusive reliance on a test (ECG) without

appreciat-ing clear clinical signs of myocardial necrosis, due probably

to an occlusive thrombus, can result in misdirected therapy.

A case could be made for primary angioplasty should

facili-ties be available However, in view of the probability of

extensive three-vessel coronary disease and multiple

blocked bypass grafts it would be more prudent to consider

invasive investigation and intervention on an elective basis.

References

1.Freeman MR, Langer A, Wilson RF, Morgan CD, Armstrong PW

Thrombolysis in unstable angina: A randomized double blind

trial of tPA and placebo Circulation 1992;85:150–7.

2.The TIMI-IIIB Investigators Effects of tissue plasminogen

activa-tor and a comparison of early invasive and conservative strategies

in unstable angina and non-Q infarction Results of the TIMI-IIIB

Trial Circulation 1994;89:1545–56.

3.Theroux P, Ouimet H, McCans et al Aspirin, heparin or both to

treat unstable angina N Engl J Med 1988;319:1105–11.

4.Cairns JA, Gent M, Singer J et al Aspirin, sulfinpyrozone, or

both in unstable angina Results of a Canadian multicenter trial

N Engl J Med 1985;313:1369–75.

5.Braunwald E, Antman EM, Beasley JW et al ACC/AHA

guide-lines for the management of patients with unstable angina and

non-ST elevation myocardial infarction J Am Coll Cardiol

2000;36:970–1062.

6.Eikelboom JW, Anand SS, Malmberg K et al Unfractionated

heparin and low molecular weight heparin in acute coronary

syndrome without ST elevation: a metaanalysis Lancet 2000;

355:1936–42.

7.Antman EM, McCabe CH, Gurfunkel EP et al Enoxaparin

pre-vents death and cardiac ischemic epre-vents in unstableangina/non-Q wave infarction Results of the thrombolysis in

myocardial infarction (TIMI IIB trial) Circulation 1999;

100:1593–601.

8.The CURE Investigators Effects of clopidogrel in addition toaspirin in patients with acute coronary syndromes without ST

elevation N Engl J Med 2001;345:494–502.

9.The Pursuit trial Investigators Inhibition of platelet tein IIb/IIIa with eptifibatide in patients with acute coronary

glycopro-syndromes N Engl J Med 1998;339:436–43.

10.PRISM Study Investigators A comparison of aspirin plus

tirofiban with aspirin plus heparin for unstable angina N Engl J

Med 1998;339:1498–505.

What advice would you now give him?

Comment

Here is a case where a physician’s advice to an otherwise

recalcitrant patient is strongly fortified by clear evidence

that preventive strategies post acute myocardial infarction

yield favorable outcomes The patient is now chest pain and

failure free He has one non-modifiable risk factor (family

history) and several modifiable ones (smoking, sedentary

lifestyle, obesity, and a propensity for hypertension) His

lipid status is unknown, although the LDL-C of 3·0 on the

first day of his infarct raise suspicion of a hyperlipidemic

state Evidence from clinical trials ought to persuade the

patient that a preventive strategy of pharmacologic

prophy-laxis, combined with risk factor modification and lifestyle

changes, can reduce his likelihood of suffering a major event

in the foreseeable future.

Secondary prophylaxis

To reduce his risk of recurrent ischemic events and death he should continue indefinitely on enteric coated aspirin 81–325 mg/day1and a
blocker.2,3In view of his reduced

LV function a number of clinical trials support the use of an ACE inhibitor.4–6

Risk stratification

For risk stratification he should be scheduled for a limited exercise test in 2–4 weeks, with a view to (a) assess- ing his exercise capacity; (b) determining whether he is high, intermediate or low risk; and (c) ruling out severe underlying ischemia that might warrant early coronary angiography For instance, a low-risk patient is one who can achieve more than 8 METS of exercise with no chest pain or

symptom-ST segment changes A high-risk patient would be one who either experiences angina or significant ST segment depres- sion at a low workload, or whose blood pressure either fails

to rise or decreases during exercise.

measures

Ernest L Fallen

Case 1 A 53 year old sedentary, overweight male chartered accountant, previously symptom free, was

admitted to hospital 6 days ago with an acute anteroseptal infarction He received thrombolysis with rtPA (total dose 100 mg) The acute phase of his illness was complicated by frequent iso- lated ventricular ectopic beats ( 10/h) and mild cardiac decompensation (Killip class IIa) His risk factors include a positive family history, a 30 pack year smoking history, mild hypertension and obesity (body mass index BMI  29) His lipid status is unknown, except for a single LDL-C  3·0 mmol/l at the time of hospital admission.

He is now ready for discharge and is free of heart failure and chest pain His ECG shows a sinus rhythm at 65 bpm with qS waves and T inversion in leads V1–V3 without ST elevation His echocardiogram reveals severe hypokinesis of the septum and apex, but no other regional wall abnormalities There is no left ventricular dilatation and his estimated ejection fraction is 45% There is no valvular abnormality and no endocardial thrombus.

On physical examination he is in sinus rhythm with a blood pressure of 122/80 and a supine respiratory rate of 16 breaths per minute His lungs are clear There is a soft S4 but no murmurs.

He has good peripheral pulses, no neck vein distension and no arterial bruits.