European Heart Journal (2013) 34, 2683–2688 CLINICAL RESEARCH

doi:10.1093/eurheartj/eht165 Coronary artery disease

Long-term survival in patients with refractory

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angina
Timothy D. Henry 1,2†*, Daniel Satran1,2,3†, James S. Hodges 1,2, Randall K. Johnson 1,
Anil K. Poulose 1, Alex R. Campbell 1, Ross F. Garberich 1, Bradley A. Bart 2,4,
Rachel E. Olson 1, Charlene R. Boisjolie1, Karen L. Harvey1, Theresa L. Arndt 1,
and Jay H. Traverse 1,2
1
Minneapolis Heart Institute Foundation at Abbott Northwestern Hospital, 920 East 28th Street, Suite 100, Minneapolis, MN 55407, USA; 2University of Minnesota, Minneapolis,
MN, USA; 3Park Nicollet Heart and Vascular Center, Minneapolis, MN, USA; and 4Hennepin County Medical Center, Minneapolis, MN, USA

Received 6 July 2010; revised 5 April 2013; accepted 22 April 2013; online publish-ahead-of-print 12 May 2013

See page 2655 for the editorial comment on this article (doi:10.1093/eurheartj/eht190)

Aims An increasing number of patients with severe coronary artery disease (CAD) are not candidates for traditional revascu-
larization and experience angina in spite of excellent medical therapy. Despite limited data regarding the natural history
and predictors of adverse outcome, these patients have been considered at high risk for early mortality.
.....................................................................................................................................................................................
Methods The OPtions In Myocardial Ischemic Syndrome Therapy (OPTIMIST) program at the Minneapolis Heart Institute offers
and results traditional and investigational therapies for patients with refractory angina. A prospective clinical database includes
detailed baseline and yearly follow-up information. Death status and cause were determined using the Social Security
Death Index, clinical data, and death certificates. Time to death was analysed using survival analysis methods. For 1200
patients, the mean age was 63.5 years (77.5% male) with 72.4% having prior coronary artery bypass grafting, 74.4%
prior percutaneous coronary intervention, 72.6% prior myocardial infarction, 78.3% 3-vessel CAD, 23.0% moderate-
to-severe left-ventricular (LV) dysfunction, and 32.6% congestive heart failure (CHF). Overall, 241 patients died
(20.1%: 71.8% cardiovascular) during a median follow-up 5.1 years (range 0–16, 14.7% over 9). By Kaplan –Meier analysis,
mortality was 3.9% (95% CI 2.8 –5.0) at 1 year and 28.4% (95% CI 24.9–32.0) at 9 years. Multivariate predictors of all-
cause mortality were baseline age, diabetes, angina class, chronic kidney disease, LV dysfunction, and CHF.
.....................................................................................................................................................................................
Conclusion Long-term mortality in patients with refractory angina is lower than previously reported. Therapeutic options for this
distinct and growing group of patients should focus on angina relief and improved quality of life.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Refractory angina † Chronic coronary artery disease

duration) characterized by angina caused by coronary insufficiency in

Introduction the setting of CAD which cannot be controlled by a combination of
As the population ages and mortality from coronary artery disease medical therapy, angioplasty, and coronary bypass surgery, where the
(CAD) decreases, a growing number of patients with severe CAD presence of reversible myocardial ischaemia has been clinically estab-
continue to experience angina which is not amenable to surgical or lished to be the cause of the symptoms.1 Anatomic reasons which
percutaneous coronary revascularization despite excellent medical preclude traditional revascularization include severe diffuse CAD,
therapy.1 – 3 These patients with refractory angina are frequently la- collateral-dependent myocardium, multiple coronary restenoses,
belled ‘no option’ patients with ‘end-stage’ CAD. The European chronic total coronary occlusions, degenerated saphenous vein
Society of Cardiology Joint Study Group on the Treatment of Refrac- grafts, poor distal targets, or lack of conduits due to prior coronary
tory Angina defined it as a chronic condition (more than 3 months in artery bypass grafting (CABG). Significant comorbidities may also

†
The first two authors contributed equally to this manuscript.
* Corresponding author. Tel: +1 612 863 7372, Fax: +1 612 863 3801, Email: henry003@umn.edu
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com
2684 T.D. Henry et al.

preclude traditional revascularization. Currently, treatment options fraction (LVEF) ≥55%], mildly reduced (LVEF .40% but ,55%), and
for this distinct and growing patient group are limited to traditional moderately to severely reduced (LVEF ,40%) as assessed by echocardi-
anti-anginal therapy and secondary risk-factor modification. This ography, gated myocardial perfusion imaging, or left ventriculography.
has stimulated interest in alternative strategies including myocardial Categories were chosen for clinical relevance and to account for possible
differences in measurement between different tests used to assess LV
angiogenesis (protein, gene, or stem cell therapy),4 – 8 novel pharma-
function. Congestive heart failure (CHF), myocardial infarction (MI),
cological agents (i.e. ranolazine),9 enhanced external counterpulsa-
moderate/severe valvular heart disease, chronic kidney disease (CKD),
tion (EECP),10 – 12 spinal cord stimulation,1,13 and transmyocardial

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peripheral arterial disease (PAD), and cerebrovascular disease (CVD)
revascularization (TMR).14 – 19 were based on patient history and confirmed with the medical record.
Limited data exist regarding the natural history and predictors of Coronary artery stenoses .50% in diameter were considered significant
mortality for patients with refractory angina. A retrospective study and angiographic data were available on 87.4% of patients. Comprehen-
from the Cleveland Clinic in 500 consecutive patients undergoing sive data on baseline medications were available from patients enrolled at
cardiac catheterization found that 59 patients had ischaemia but Abbott Northwestern Hospital beginning in 2006.
were ineligible for revascularization. The 1-year mortality in this Vital status for all patients was determined using the Social Security
small cohort of patients was 17% and led many to believe refractory Death Index (SSDI), considered to be a highly accurate and specific
angina patients are at high risk for mortality following diagnosis.20 source of mortality data,22,23 and by clinical follow-up. Cause of death
was determined from medical records and clinical follow-up. If these
Current ACC/AHA guidelines provide limited information on this
were unavailable, death certificates were used to determine the cause
patient population,21 and no Medicare claims code identifies indivi-
of death. Deaths were classified in accordance with the 9th and 10th re-
duals with refractory angina. In 2002, the European Society of Cardi-
vision of the International Classification of Diseases.24,25 ‘Natural causes’
ology expressed an ‘urgent’ need to clarify the epidemiology of this was categorized as cardiovascular death, not otherwise classifiable.
condition.1 We established a dedicated clinic for refractory angina Fractions surviving at each follow-up time are from Kaplan – Meier ana-
patients in 1996 and report here the long-term survival and predic- lysis with Wald-style confidence intervals. Individual predictors of mor-
tors of mortality in 1200 patients followed a median of 5.1 years. tality were tested using the log-rank test excluding persons with
unknown predictor values. Multivariate analyses of time to death used
Cox proportional-hazards regression and likelihood ratio tests, with
Wald-style confidence intervals on the log-relative hazard scale back-
Methods transformed to relative hazards. A P-value , 0.05 was considered
The study population consisted of 1200 consecutive patients with either statistically significant, and P-values are two-sided whenever possible.
refractory myocardial ischaemia and/or refractory angina who were con- All computations used JMP (v. 7, SAS Institute Inc., Cary, NC, USA).
sidered not to be candidates for traditional revascularization and referred
for alternative treatment strategies from 1996 to 2001 at Hennepin
County Medical Center (Minneapolis, MN, USA) and, from 2002 on, at Results
the OPTions In Myocardial Ischemic Syndrome Therapy (OPTIMIST)
clinic at the Minneapolis Heart Institute at Abbott Northwestern Hos- Table 1 summarizes the baseline characteristics of 1200 patients
pital (Minneapolis, MN, USA). Patients were predominantly referred (mean age 63.5 years, 77.5% male). Common characteristics included
from the upper Midwest region of the USA but the study population 3-vessel CAD (78.3%), prior revascularization [PCI (74.4%), CABG
includes individuals from 40 states, Puerto Rico, and Canada. Referral (72.4%), or either (92.3%)], prior MI (72.6%), and Canadian Cardio-
sources included self-referral, primary care physicians, and cardiologists vascular Society (CCS) Class III or IV angina (59.2%). History of dia-
both within and outside the Hennepin County Medical Center and Min- betes mellitus (DM) (36.6%), CHF (32.6%), moderate-to-severe LV
neapolis Heart Institute at Abbott Northwestern cardiology practices. dysfunction (23.0%), PAD (22.8%), CVD (19.5%), CKD (14.8%), ma-
At the time of initial consultation, physicians and clinical staff comprehen- lignancy (11.5%), and moderate or severe valvular heart disease
sively reviewed medical records and assessed patients’ angina symptoms,
(9.9%) were also common. Table 2 summarizes the categories of cor-
medical regimen for angina, and secondary risk-factor modification for
onary anatomy defining poor candidacy for further revascularization;
CAD. Coronary angiography was reviewed to assess whether traditional
surgical and percutaneous revascularization was possible. Patients many patients met more than one criterion. Severe comorbidities
deemed not to be candidates for traditional revascularization who which precluded further attempts at revascularization were
were receiving appropriate medical therapy were included in the data- present in 91 (7.6%) patients.
base (described subsequently) and considered for alternative therapies Comprehensive data regarding baseline medications was available
including novel pharmaceuticals, EECP, angiogenesis (patients enrolled for 616 patients with 91.4% on aspirin, 49.7% on another antiplatelet
in protein, gene, and stem cell clinical trials designed to promote angio- agent, 58.1% on angiotensin converting enzyme inhibitors or angio-
genesis), spinal cord stimulation, and TMR. No patients were excluded. tensin receptor blockers, 86.9% on lipid lowering agents, 85.1% on
Baseline demographics, cardiovascular risk factors, medical history beta blockers, and 37.5% on calcium channel blockers.
(cardiovascular and non-cardiovascular), cardiovascular medications, Median follow-up was 5.1 years (range 0 –16years) with 176
and tests (including left-ventricular function, stress testing, and coronary
(14.7%) patients followed for over 9 years. Overall, 241 (20.1%)
angiography) were recorded in a prospective database. Institutional
patients died. From Kaplan –Meier analysis (Figure 1), mortality was
Review Board approval for the database was obtained at both Hennepin
County Medical Center and Abbott Northwestern. For mortality mea- 3.9% (95% CI 2.8 –5.0) at 1 year, 17.5% (95% CI 15.2–19.9) at 5
surements, the patient’s diagnosis of refractory angina was defined as years, and 28.4% (95% CI 24.9–2.0) at 9 years. Cause of death was
either the date of angiography when the patient was determined to determined for 213 (88.4%) patients, including 153 (71.8%) cardio-
have ‘no option’ or the initial OPTIMIST clinic consultation. Left- vascular deaths, and 60 (28.2%) non-cardiovascular deaths. For indi-
ventricular (LV) function was defined as normal [left-ventricular ejection viduals who died of cardiovascular causes, 45 (29.4%) died of
Long-term survival of refractory angina 2685

Table 1 Univariate predictors of mortality in 1200 Table 1 Continued

patients with refractory angina
n (% of 5-year mortality % P-value*
n (% of 5-year mortality % P-value* known) (95% CI)
known) (95% CI) ................................................................................
................................................................................ History CKD
Demographics and medical history No 1017 (85.2) 14.9 (12.5, 17.2) ,0.0001

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Agea Yes 177 (14.8) 34.2 (26.3, 42.1)
,63.68 577 (50.0) 11.9 (9.0, 14.8) ,0.0001 History of malignancy
years No 1041 (88.5) 15.6 (13.3, 18.0) 0.0005
≥63.68 577 (50.0) 23.8 (20.0, 27.6) Yes 135 (11.5) 28.6 (20.3, 36.9)
years
History of anaemia
Sex
No 1032 (88.7) 15.3 (13.0, 17.7) ,0.0001
Female 270 (22.5) 18.2 (13.3, 23.1) 0.72
Yes 132 (11.3) 31.6 (22.6, 40.6)
Male 930 (77.5) 17.3 (14.7, 20.0) ................................................................................
Baseline smoking status Clinical characteristics
Current 124 (13.6) 18.5 (11.1, 26.0) 0.33 CAD, n vessels
Former 492 (53.9) 15.3 (11.8, 18.8) 1 vessel 67 (6.8) 7.6 (1.2, 14.1) 0.021
Never 296 (32.5) 14.3 (9.8, 18.8) 2 vessel 147 (14.9) 9.9 (4.7, 15.1)
History of hypertension 3 vessel 774 (78.3) 18.2 (15.2, 21.2)
No 366 (30.6) 20.7 (16.4, 24.9) 0.16 Angina class, CCS
Yes 830 (69.4) 15.9 (13.2, 18.7) 1 67 (7.6) 9.1 (1.3, 16.9) 0.013
History of dyslipidaemia 2 182 (20.5) 9.3 (4.8, 13.8)
No 54 (5.3) 27.0 (14.3, 39.7) 0.030 3 387 (43.6) 16.3 (12.1, 20.6)
Yes 964 (94.7) 15.3 (12.8, 17.8) 4 251 (28.3) 18.2 (13.1, 23.3)
History of diabetes If CHF ‘Yes’, NYHA Class
None 761 (63.4) 14.9 (12.2, 17.7) ,0.0001 1 51 (23.2) 15.0 (4.7, 25.4) 0.19
Type I 45 (3.7) 23.7 (9.8, 37.5) 2 78 (35.5) 20.6 (11.2, 30.0)
Type II 394 (32.8) 21.9 (17.5, 26.3) 3 60 (27.3) 19.3 (9.0, 29.6)
Family history of CAD 4 31 (14.1) 35.6 (17.4, 53.7)
No 297 (33.6) 14.6 (10.0, 19.3) 0.94 Moderate or severe valvular heart disease
Yes 586 (66.4) 14.9 (11.8, 18.0) No 1028 (90.1) 15.8 (13.4, 18.2) ,0.0001
Prior CABG Yes 113 (9.9) 31.0 (21.7, 40.4)
No 308 (27.6) 12.3 (8.2, 16.4) 0.005 LV dysfunction
Yes 806 (72.4) 19.0 (16.0, 21.9) Normal 421 (44.4) 10.5 (7.1, 13.9) ,0.0001
Prior PCI Mild 310 (32.7) 14.7 (10.4, 19.1)
No 263 (25.6) 12.5 (8.2, 16.8) 0.43 Moderate/ 218 (23.0) 30.4 (23.8, 37.0)
Yes 764 (74.4) 16.1 (13.2, 19.0) severe
Any revascularization Number of anatomic criteria met
No 86 (7.7) 11.9 (4.6, 19.3) 0.21 0 152 (12.7) 17.6 (11.4, 23.8) 0.35
Yes 1031(92.3) 17.6 (15.1, 20.1) 1 349 (29.1) 19.0 (14.5, 23.6)
History of MI 2 441 (36.8) 15.6 (12.0, 19.3)
No 284 (27.4) 8.4 (4.8, 12.1) ,0.0001 3 202 (16.8) 17.8 (12.0, 23.6)
Yes 751 (72.6) 19.2 (16.2, 22.3) 4 49 (4.1) 21.9 (9.0, 34.9)
History of CHF 5 7 (0.6) 28.6 (0.0, 62.0)
No 653 (67.4) 10.6 (7.9, 13.3) ,0.0001 Comorbidities
Yes 316 (32.6) 27.8 (22.5, 33.0) No 1109 (92.4) 16.0 (13.7, 18.4) ,0.0001
History of CVD Yes 91 (7.6) 36.3 (25.3, 47.3)
No 960 (80.4) 16.2 (13.7, 18.7) 0.0001
CAD, coronary artery disease; CABG, coronary artery bypass graft; PCI,
Yes 233 (19.5) 22.7 (16.9, 28.6)
percutaneous coronary intervention; MI, myocardial infarction; CHF, congestive
History of PAD heart failure; CVD, cerebrovascular disease; PAD, peripheral arterial disease; CKD,
No 916 (77.2) 15.1 (12.6, 17.6) ,0.0001 chronic kidney disease; CCS, Canadian Cardiovascular Society; NYHA, New York
Heart Association; LV, left ventricular.
Yes 270 (22.8) 25.9 (20.2, 31.7)
*5-year survival percent from Kaplan –Meier analysis, with 95% confidence interval
by Wald’s method; P-value from log-rank test excluding persons with unknown value
Continued
of the predictor.
a
Mean 63.5, SD 11.1, range 26 –101.
2686 T.D. Henry et al.

baseline age (P , 0.0001), DM (P ¼ 0.0032), angina class (P ¼

Table 2 Coronary anatomic reasons which preclude 0.0041), CKD (P ¼ 0.0115), LV dysfunction (P ¼ 0.0354), and CHF
traditional revascularization and mortality hazard in (P ¼ 0.0439) were still significantly associated with mortality.
1200 patients with refractory angina Use of alternative therapies was as follows: 255 (21.2%) patients
Anatomic feature Patients Mortality relative had EECP, 185 (15.4%) were enrolled in studies of angiogenesis
(%) hazard (95% CI)a (protein, gene, stem cell), 78 (6.5%) had TMR, and 21 (1.8%) had
................................................................................ spinal cord stimulation.

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Collateral-dependent 581 (48.4) 0.81 (0.62–1.06)
myocardium
Diffuse CAD 565 (47.1) 1.03 (0.79–1.35) Discussion
Multiple coronary restenoses 126 (10.5) 0.83 (0.52–1.31)
This manuscript presents the first description of long-term follow-up
Severely degenerated/ 418 (34.8) 1.17 (0.89–1.55)
of patients in a dedicated refractory angina clinic. Our results demon-
occluded SVGs
strate that long-term mortality in patients with refractory angina is
Poor distal targets 244 (20.3) 1.16 (0.84–1.60)
surprisingly low, under 4% per year, and approaches that of patients
No graft conduits 43 (3.6) 1.26 (0.71–2.23)
with chronic stable angina (1.5%) who tend to have fewer comorbid-
CAD, coronary artery disease; SVG, saphenous vein graft.
ities and preserved LV function.26 Our results are also comparable to
a
From Cox regression including as predictors these conditions and also including patients undergoing revascularization in the SYNTAX trial which
co-morbidity as a predictor (relative hazard 2.72 with 95% confidence interval 1.89– reported 5-year mortality of 11.4% in CABG patients and 13.9% in
3.91).
PCI patients.27 The multivariate predictors of mortality in patients
with refractory angina are similar to those in patients with other car-
diovascular conditions: baseline age, DM, angina class, CKD, LV dys-
function, and CHF. Besides age, angina class (3 and 4) and LV
dysfunction/CHF were the strongest predictors of mortality and
therefore these patients deserve special focus for alternative treat-
ment strategies.
Data on the incidence and prevalence of refractory angina are
scarce and mainly derived from cardiac catheterization laboratory
registries.2,3 In 1994, a survey of patients referred for coronary angi-
ography in Sweden found that 9.6% did not undergo revascularization
despite significant symptoms.28,29 Of 500 consecutive patients pre-
senting for coronary angiography at the Cleveland Clinic in 1998,
59 (12%) had evidence of ischaemia and were not candidates for trad-
itional revascularization;30 this rate would imply 100 000–200 000
patients identified per year in the USA. In a consecutive series of 493
patients undergoing coronary angiography at the Minneapolis Heart
Institute in 2005, 6.7% were on optimal medical management and not
candidates for revascularization (‘no option’ patients) and an add-
Figure 1 Kaplan – Meier survival curve in 1200 patients with re- itional 9.3% were not candidates for revascularization but received
fractory angina; centre line is the estimated fraction surviving, additional medical therapy.31 From November 2001 to March
upper and lower lines are 95% pointwise confidence intervals. 2002, 21% of 5767 patients in the Euro Heart Survey (130 hospitals
in 31 countries) were medically managed following coronary angiog-
raphy.32 The same authors estimated that 14% of a subset of 4409
progressive CHF/ischaemic cardiomyopathy, 33 (21.6%) died sud- patients were ineligible for traditional revascularization.33 Contro-
denly, 36 (23.5%) died of MI, and 39 (25.4%) were not classifiable versy remains regarding incidence, prevalence, and even the defin-
(i.e. ‘natural causes’). Periprocedural death occurred in 20 (9.3%), in- ition of refractory angina, but as individuals live longer with more
cluding 13 (6.1%) following cardiac procedures (11 peri-CABG, two extensive CAD, the number of patients is likely to increase. Current-
peri-PCI). Table 1 summarizes the tests of univariate predictors of all- ly, no Medicare claims code identifies individuals with refractory
cause mortality; significant predictors were age (P , 0.0001), CVD angina or refractory ischaemia, which contributes to a lack of knowl-
(P ¼ 0.0001), PAD (P , 0.0001), DM (P , 0.0001), CKD (P , edge regarding this condition’s epidemiology.
0.0001), malignancy (P ¼ 0.0005), anaemia (P , 0.0001), multivessel Mortality estimates in this population have been limited by studies
CAD (P ¼ 0.021), CHF (P , 0.0001), prior CABG (P , 0.005), with small sample sizes, extrapolation from cohorts of patients re-
angina class (P ¼ 0.013), moderate/severe valvular heart disease ferred for coronary angiography, and limited duration of follow-up.
(P , 0.0001), history of MI (P , 0.0001), LV dysfunction (P , Annual mortality rates of highly selected patients in randomized
0.0001), and comorbidities (P , 0.0001). Variables with P , 0.05 trials of alternative therapies for patients with refractory angina
for univariate associations were then entered into a Cox (control groups) range from 3 to 21%.1 – 8,14 – 19 One-year mortality
proportional-hazards regression model for multivariate analysis. in the Cleveland Clinic series was high (17%) but based on only 59
Table 3 summarizes the multivariate analysis of all-cause mortality: patients.20 The Mediators of Social Support Study (MOSS), a
Long-term survival of refractory angina 2687

Table 3 Multivariate predictors of mortality in 1200 patients with refractory angina

Predictor DF Hazard ratio (95% CI) Likelihood-ratio P-value

ChiSquare
..............................................................................................................................................................................
Age at time zero (years), (hazard ratio per year) 1 1.04 (1.02, 1.05) 28.56 ,0.0001
History of diabetes

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None 1 1.00 8.71 0.0032
Any 1.54 (1.16, 2.06)
..............................................................................................................................................................................
History of CABG
No 2 1.00 1.58
Unknown 0.94 (0.50, 1.75) 0.4538
Yes 1.20 (0.84, 1.75)
..............................................................................................................................................................................
History of MI
No 2 1.00 5.85
Unknown 2.00 (1.11, 3.59) 0.0537
Yes 1.52 (0.98, 2.35)
..............................................................................................................................................................................
History of CHF
No 2 1.00 6.25
Unknown 1.35 (0.86, 2.12) 0.0439
Yes 1.54 (1.09, 2.18)
..............................................................................................................................................................................
History of CVD
No 2 1.00 2.50
Unknown 4.26 (0.63, 28.74) 0.2862
Yes 1.16 (0.84, 1.61)
..............................................................................................................................................................................
History of PAD
No 2 1.00 3.02
Unknown 0.93 (0.19, 4.47) 0.2210
Yes 1.32 (0.97, 1.81)
..............................................................................................................................................................................
History of CKD
No 2 1.00 8.92
Unknown 0.45 (0.06, 3.32) 0.0115
Yes 1.62 (1.17, 2.26)
..............................................................................................................................................................................
CAD, n vessels
1 vessel 3 1.00 2.26
2 vessel 1.01 (0.39, 2.64) 0.5201
3 vessel 1.28 (0.55, 3.00)
n vessels unknown 1.54 (0.64, 3.72)
..............................................................................................................................................................................
Angina class, CCS
1 5 1.00 17.24
2 1.07 (0.45, 2.55)
3 1.80 (0.83, 3.98) 0.0041
4 2.09 (0.93, 4.67)
Angina status unknown 2.57 (1.14, 5.80)
Angina, but class unknown 2.71 (1.16, 6.32)
..............................................................................................................................................................................
Moderate or severe valvular disease
No 2 1.00 5.44
Unknown 1.25 (0.67, 2.34) 0.0659
Yes 1.59 (1.08, 2.34)

Continued
2688 T.D. Henry et al.

Table 3 Continued

Predictor DF Hazard ratio (95% CI) Likelihood-ratio P-value

ChiSquare
..............................................................................................................................................................................
LV dysfunction
Moderate/severe 3 1.00 8.58

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Mild 0.68 (0.47, 0.99)
Normal 0.55 (0.36, 0.83) 0.0354
Unknown 0.78 (0.48, 1.26)

CABG, coronary artery bypass graft; MI, myocardial infarction; CHF, congestive heart failure; CVD, cardiovascular disease; PAD, peripheral artery disease; CKD, chronic kidney
disease; CAD, coronary artery disease; CCS, Canadian Cardiovascular Society; LV, left ventricular.

longitudinal observational study of patients undergoing cardiac cath- receptor blockers. In comparison, in the MOSS cohort, medication
eterization at Duke University between August 1992 and January use in patients who did not undergo revascularization was markedly
1996, also reported high mortality (38% at 2.2 year mean follow-up) lower with 58% on aspirin, 45% on beta-blockers, 23% on statins, and
in 487 patients who did not undergo revascularization within 30 20% on angiotensin converting enzyme inhibitors.34
days.34 In contrast, 1-year mortality from the Euro Heart Survey There are several limitations to our study. This registry is observa-
for patients with stable angina treated medically was 5%.32 In the tional, but still represents a large, diverse cohort of patients who are
group deemed ineligible for revascularization, 7% of patients died not candidates for revascularization with refractory angina. Referral
at 1 year compared with 3.7% in the cohort eligible for revasculariza- bias is an inherent limitation. However, in spite of high rates of co-
tion33; further details regarding reasons for ineligibility were unavail- morbid conditions such as PAD, CHF, and LV dysfunction, mortality
able. In a contemporary cohort of 1427 patients undergoing EECP for for this group of patients remained low. Determination of when a
refractory angina, overall mortality at 3-year follow-up was 15.4%.35 patient has exhausted traditional revascularization options can be dif-
Consistent with these lower numbers, the results from our recent ficult and in many cases is subjective. Patients frequently had refrac-
angiographic series reported a 14.8% mortality at 3 years in patients tory angina before a ‘definitive’ cardiac catheterization laboratory
receiving incomplete revascularization.31 Our results provide new or referral-based clinic determination; therefore, our baseline time
insight into annual mortality and cause of death in the largest of diagnosis was conservative. Anatomic descriptors of candidacy
cohort in the literature consisting of patients referred specifically for traditional revascularization are also subjective and represent a
for refractory angina. The long follow-up and relatively low mortality simplification of complex anatomy and pathophysiology. Better char-
argue that, as a group, patients who are not candidates for traditional acterization and research are clearly needed in this area, especially for
revascularization do not suffer from excess mortality compared with ‘diffuse’ CAD and microvascular dysfunction.42 – 44 We recently pro-
other patients with CAD. Cause of death, though predominantly car- posed a novel classification scheme and a validation study is underway
diovascular, was non-cardiac in nearly 30% of patients and the inci- to determine if classification can further risk-stratify these patients.45
dence of sudden cardiac death was low. Our estimate of Advances in cardiovascular imaging which more accurately define the
cardiovascular death may be an overestimate since we included amount of myocardium at risk in individuals with refractory ischaemia
‘natural causes’ (which may well represent other aetiologies) with may prove useful as well.
cardiovascular death. In conclusion, long-term mortality in patients with refractory
Improved secondary prevention strategies, better evidence-based angina who are not candidates for traditional revascularization is sur-
medical therapy, and more advanced revascularization techniques all prisingly low. Over 70% of patients with refractory angina can expect
likely contribute to these results. Widespread and improved adher- to survive 9 years from the time of diagnosis. Therapeutic options for
ence to medical therapy (antiplatelet agents,36 angiotensin convert- this growing population should therefore focus on chest pain relief
ing enzyme inhibitors,37 and statins38) combined with aggressive and improved quality of life.
lifestyle modification39 (diet change, exercise, smoking cessation)
has contributed to lower overall mortality in patients with Funding
CAD.40,41 Similar benefits likely apply to patients with refractory
This study was supported by the Jon Holden DeHaan Foundation.
angina. Although longitudinal mortality data are not available on a
population basis, comparison of annual mortality in the MOSS Conflict of interest: none declared.
(August 1992 to January 1996, 19% per year) and OPTIMIST
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