Long-term Mortality in Refractory Angina May Be Lower Than Thought

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Long-term mortality rates in patients with refractory angina appear to be lower than previously reported, according to a study published online May 12, 2013, ahead of print in the European Heart Journal. The results suggest that these patients are not at excess risk of death compared with other patients with coronary artery disease (CAD).

Timothy D. Henry, MD, of the Minneapolis Heart Institute Foundation (Minneapolis, MN) and colleagues reported long-term survival and predictors of mortality in 1,200 patients treated at a dedicated clinic for refractory angina. The mean age was 63.5 years and 77.5% were male.

Patients were not candidates for traditional revascularization and were referred for alternative strategies. These consisted of:

  • Enhanced external counterpulsation (21.2%)
  • Angiogenesis via protein, gene or stem cell therapy (15.4%)
  • Transmyocardial revascularization (6.5%)
  • Spinal-cord stimulation (1.8%)

Long-term Mortality Fairly Low

Over a median follow-up of 5.1 years (range 0-16 years), 241 patients died (20.1%). Most deaths (71.8% of the 213 patients for whom cause of death was determined) were from cardiovascular causes. Approximately 15% of patients were followed for over 9 years.

In Kaplan-Meier analysis, mortality was 3.9% (95% CI 2.8-5.0) at 1 year, 17.5% (95% CI 15.2-19.9) at 5 years, and 28.4% (95% CI 24.9-32.0) at 9 years. Multivariate predictors of all-cause mortality at 5 years were baseline age, diabetes, angina class, chronic kidney disease (CKD), LV dysfunction, and congestive heart failure (CHF; table 1).

Table 1. Predictors of 5-Year Mortality in Refractory Angina


HR (95% CI)

P value


1.04 (1.02-1.05)

< 0.0001


1.54 (1.16-2.06


Angina Class

1.07 (0.45-2.55)
1.80 (0.83-3.98)
2.09 (0.93-4.67)




1.62 (1.17-2.26)


LV Dysfunction

0.68 (0.47-0.99)
0.55 (0.36-0.83)



1.54 (1.09-2.18)



According to the study authors, patients with these risk factors “deserve special focus for alternative treatment strategies.”

Evidence of Improvements in Treatment Strategies

The investigators note that while the incidence, prevalence, and even definition of refractory angina are controversial, the condition is likely to be on the rise as patients are living longer with more extensive CAD. Furthermore, no Medicare claims code exists for refractory angina or refractory ischemia, which only contributes to the lack of knowledge regarding epidemiology, they add.

Estimates of mortality in refractory angina have been limited by small sample sizes, extrapolation from cohorts of patients referred for angiography, and limited duration of follow-up, the study authors write. A small series from the Cleveland Clinic demonstrated 1-year mortality of 17%. The Mediators of Social Support Study (MOSS), a longitudinal observational study of patients undergoing cardiac catheterization at Duke University (Durham, N.C.) between August 1992 and January 1996, reported even higher mortality (38% at 2.2-year mean follow-up) in 487 patients who did not undergo revascularization within 30 days.

“Our results provide new insight into annual mortality and cause of death in the largest cohort in the literature consisting of patients referred specifically for refractory angina,” Dr. Henry and colleagues write. “The long follow-up and relatively low mortality argue that, as a group, patients who are not candidates for traditional revascularization do not suffer from excess mortality compared with other patients with CAD.”

They also suggest that “widespread and improved adherence to medical therapy (antiplatelet agents, ACE inhibitors, and statins) combined with aggressive lifestyle modification (diet change, exercise, smoking cessation) has contributed to lower overall mortality in patients with CAD.”

Standardized Management Important

In an editorial accompanying the study, Debabrata Mukherjee, MD, of Texas Tech University Health Sciences Center (El Paso, TX), says the obvious question is whether mortality has indeed declined significantly in the 15 years since the Cleveland Clinic and the Duke studies or whether those studies and the current one involved dissimilar patient populations.

According to Dr. Mukherjee, data from studies such as COURAGE and BARI 2D support the theory that improvements in medical therapy have likely contributed to declining rates of death and major cardiovascular events.

He notes that it is important for clinicians to have a standardized approach for the management of patients with refractory angina “which should incorporate lifestyle modification, use of guideline-based medical therapies including newer agents such as ranolazine when indicated, and novel therapies such as EECP (enhanced external counterpulsation), spinal cord stimulation, laser revascularization, etc. as appropriate.” Furthermore, Dr. Mukherjee notes that the importance of optimal medical therapies cannot be overemphasized since secondary prevention is likely to be beneficial and cost-effective.

 ‘Sobering’ Statistics

But Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), told TCTMD in a telephone interview that he considers the data “sobering.”

“For me, these patients who had a median age of 63.5, a mortality rate of close to 20% at 5 years is pretty bad,” Dr. Kirtane said.

Importantly, the generalizations regarding 9-year survival are limited in this type of analysis and may be too optimistic, he said. “If you were to extrapolate [from] a rate of 4% mortality at 1 year, at 10 years it would be 40%. That is not good.”

Dr. Kirtane pointed out the specialized nature of the population in the study, who were all referred to the dedicated refractory angina clinic. Most interventional clinicians, he said, “probably see a handful of these patients,” which makes studies such as this important in terms of grasping more information about them and their long-term prognosis.

He added that the quality of life for those who survive with refractory angina is also important to consider.

“Part of the problem here is these patients were referred to a tertiary referral center, which means their quality of life wasn’t good in the first place,” he said. So, the fact that they are seeking help and have no good options [aside from experimental protocols] continues to be problematic. The mortality overall as shown in this study might be lower [than previously reported] but by no means is it encouraging that one-fifth of patients in their 60s are dead 5 years later.”

Study Details

Overall, 72.4% of patients had prior CABG, 74.4% had prior PCI, 72.6% had prior MI, 78.3% had 3-vessel CAD, 23.0% had moderate-to-severe LV dysfunction, and 32.6% had CHF.


  1. Henry TD, Satran D, Hodges JS, et al. Long-term survival in patients with refractory Angina. Eur Heart J. 2013;Epub ahead of print.
  2. Mukherjee D. Management of refractory angina in the contemporary era. Eur Heart J. 2013;Epub ahead of print.



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  • Drs. Henry, Mukherjee, and Kirtane report no relevant conflicts of interest.