Long-term Survival in Patients With Refractory Angina
Long-term Survival in Patients With Refractory Angina
This manuscript presents the first description of long-term follow-up of patients in a dedicated refractory angina clinic. Our results demonstrate that long-term mortality in patients with refractory angina is surprisingly low, under 4% per year, and approaches that of patients with chronic stable angina (1.5%) who tend to have fewer comorbidities and preserved LV function. Our results are also comparable to patients undergoing revascularization in the SYNTAX trial which reported 5-year mortality of 11.4% in CABG patients and 13.9% in PCI patients. The multivariate predictors of mortality in patients with refractory angina are similar to those in patients with other cardiovascular conditions: baseline age, DM, angina class, CKD, LV dysfunction, 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 treatment strategies.
Data on the incidence and prevalence of refractory angina are scarce and mainly derived from cardiac catheterization laboratory registries. In 1994, a survey of patients referred for coronary angiography in Sweden found that 9.6% did not undergo revascularization despite significant symptoms. Of 500 consecutive patients presenting for coronary angiography at the Cleveland Clinic in 1998, 59 (12%) had evidence of ischaemia and were not candidates for traditional revascularization; 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 additional 9.3% were not candidates for revascularization but received additional medical therapy. From November 2001 to March 2002, 21% of 5767 patients in the Euro Heart Survey (130 hospitals in 31 countries) were medically managed following coronary angiography. The same authors estimated that 14% of a subset of 4409 patients were ineligible for traditional revascularization. Controversy remains regarding incidence, prevalence, and even the definition of refractory angina, but as individuals live longer with more extensive CAD, the number of patients is likely to increase. Currently, no Medicare claims code identifies individuals with refractory angina or refractory ischaemia, which contributes to a lack of knowledge regarding this condition's epidemiology.
Mortality estimates in this population have been limited by studies with small sample sizes, extrapolation from cohorts of patients referred for coronary angiography, and limited duration of follow-up. Annual mortality rates of highly selected patients in randomized trials of alternative therapies for patients with refractory angina (control groups) range from 3 to 21%. One-year mortality in the Cleveland Clinic series was high (17%) but based on only 59 patients. The Mediators of Social Support Study (MOSS), a longitudinal observational study of patients undergoing cardiac catheterization at Duke University between August 1992 and January 1996, also reported high mortality (38% at 2.2 year mean follow-up) in 487 patients who did not undergo revascularization within 30 days. In contrast, 1-year mortality from the Euro Heart Survey for patients with stable angina treated medically was 5%. In the group deemed ineligible for revascularization, 7% of patients died at 1 year compared with 3.7% in the cohort eligible for revascularization; further details regarding reasons for ineligibility were unavailable. In a contemporary cohort of 1427 patients undergoing EECP for refractory angina, overall mortality at 3-year follow-up was 15.4%. Consistent with these lower numbers, the results from our recent angiographic series reported a 14.8% mortality at 3 years in patients receiving incomplete revascularization. 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. 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. Cause of death, though predominantly cardiovascular, was non-cardiac in nearly 30% of patients and the incidence of sudden cardiac death was low. Our estimate of cardiovascular death may be an overestimate since we included 'natural causes' (which may well represent other aetiologies) with cardiovascular death.
Improved secondary prevention strategies, better evidence-based medical therapy, and more advanced revascularization techniques all likely contribute to these results. Widespread and improved adherence to medical therapy (antiplatelet agents, angiotensin converting enzyme inhibitors, and statins) combined with aggressive lifestyle modification (diet change, exercise, smoking cessation) has contributed to lower overall mortality in patients with CAD. Similar benefits likely apply to patients with refractory angina. Although longitudinal mortality data are not available on a population basis, comparison of annual mortality in the MOSS (August 1992 to January 1996, 19% per year) and OPTIMIST (January 1997 to present, under 4% per year) cohorts suggests an improvement in mortality over time. Medication use in the two populations reflects important historical trends. In the most recent enrolled OPTIMIST patients, 91% were on aspirin and 50% on an additional antiplatelet, 85% on beta-blockers, 87% on lipid-lowering agents, and 58% on angiotensin converting enzyme inhibitors/angiotensin receptor blockers. In comparison, in the MOSS cohort, medication use in patients who did not undergo revascularization was markedly lower with 58% on aspirin, 45% on beta-blockers, 23% on statins, and 20% on angiotensin converting enzyme inhibitors.
There are several limitations to our study. This registry is observational, but still represents a large, diverse cohort of patients who are not candidates for revascularization with refractory angina. Referral bias is an inherent limitation. However, in spite of high rates of comorbid conditions such as PAD, CHF, and LV dysfunction, mortality for this group of patients remained low. Determination of when a patient has exhausted traditional revascularization options can be difficult and in many cases is subjective. Patients frequently had refractory angina before a 'definitive' cardiac catheterization laboratory or referral-based clinic determination; therefore, our baseline time of diagnosis was conservative. Anatomic descriptors of candidacy for traditional revascularization are also subjective and represent a simplification of complex anatomy and pathophysiology. Better characterization and research are clearly needed in this area, especially for 'diffuse' CAD and microvascular dysfunction. We recently proposed a novel classification scheme and a validation study is underway to determine if classification can further risk-stratify these patients. Advances in cardiovascular imaging which more accurately define the amount of myocardium at risk in individuals with refractory ischaemia may prove useful as well.
In conclusion, long-term mortality in patients with refractory angina who are not candidates for traditional revascularization is surprisingly low. Over 70% of patients with refractory angina can expect to survive 9 years from the time of diagnosis. Therapeutic options for this growing population should therefore focus on chest pain relief and improved quality of life.
Discussion
This manuscript presents the first description of long-term follow-up of patients in a dedicated refractory angina clinic. Our results demonstrate that long-term mortality in patients with refractory angina is surprisingly low, under 4% per year, and approaches that of patients with chronic stable angina (1.5%) who tend to have fewer comorbidities and preserved LV function. Our results are also comparable to patients undergoing revascularization in the SYNTAX trial which reported 5-year mortality of 11.4% in CABG patients and 13.9% in PCI patients. The multivariate predictors of mortality in patients with refractory angina are similar to those in patients with other cardiovascular conditions: baseline age, DM, angina class, CKD, LV dysfunction, 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 treatment strategies.
Data on the incidence and prevalence of refractory angina are scarce and mainly derived from cardiac catheterization laboratory registries. In 1994, a survey of patients referred for coronary angiography in Sweden found that 9.6% did not undergo revascularization despite significant symptoms. Of 500 consecutive patients presenting for coronary angiography at the Cleveland Clinic in 1998, 59 (12%) had evidence of ischaemia and were not candidates for traditional revascularization; 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 additional 9.3% were not candidates for revascularization but received additional medical therapy. From November 2001 to March 2002, 21% of 5767 patients in the Euro Heart Survey (130 hospitals in 31 countries) were medically managed following coronary angiography. The same authors estimated that 14% of a subset of 4409 patients were ineligible for traditional revascularization. Controversy remains regarding incidence, prevalence, and even the definition of refractory angina, but as individuals live longer with more extensive CAD, the number of patients is likely to increase. Currently, no Medicare claims code identifies individuals with refractory angina or refractory ischaemia, which contributes to a lack of knowledge regarding this condition's epidemiology.
Mortality estimates in this population have been limited by studies with small sample sizes, extrapolation from cohorts of patients referred for coronary angiography, and limited duration of follow-up. Annual mortality rates of highly selected patients in randomized trials of alternative therapies for patients with refractory angina (control groups) range from 3 to 21%. One-year mortality in the Cleveland Clinic series was high (17%) but based on only 59 patients. The Mediators of Social Support Study (MOSS), a longitudinal observational study of patients undergoing cardiac catheterization at Duke University between August 1992 and January 1996, also reported high mortality (38% at 2.2 year mean follow-up) in 487 patients who did not undergo revascularization within 30 days. In contrast, 1-year mortality from the Euro Heart Survey for patients with stable angina treated medically was 5%. In the group deemed ineligible for revascularization, 7% of patients died at 1 year compared with 3.7% in the cohort eligible for revascularization; further details regarding reasons for ineligibility were unavailable. In a contemporary cohort of 1427 patients undergoing EECP for refractory angina, overall mortality at 3-year follow-up was 15.4%. Consistent with these lower numbers, the results from our recent angiographic series reported a 14.8% mortality at 3 years in patients receiving incomplete revascularization. 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. 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. Cause of death, though predominantly cardiovascular, was non-cardiac in nearly 30% of patients and the incidence of sudden cardiac death was low. Our estimate of cardiovascular death may be an overestimate since we included 'natural causes' (which may well represent other aetiologies) with cardiovascular death.
Improved secondary prevention strategies, better evidence-based medical therapy, and more advanced revascularization techniques all likely contribute to these results. Widespread and improved adherence to medical therapy (antiplatelet agents, angiotensin converting enzyme inhibitors, and statins) combined with aggressive lifestyle modification (diet change, exercise, smoking cessation) has contributed to lower overall mortality in patients with CAD. Similar benefits likely apply to patients with refractory angina. Although longitudinal mortality data are not available on a population basis, comparison of annual mortality in the MOSS (August 1992 to January 1996, 19% per year) and OPTIMIST (January 1997 to present, under 4% per year) cohorts suggests an improvement in mortality over time. Medication use in the two populations reflects important historical trends. In the most recent enrolled OPTIMIST patients, 91% were on aspirin and 50% on an additional antiplatelet, 85% on beta-blockers, 87% on lipid-lowering agents, and 58% on angiotensin converting enzyme inhibitors/angiotensin receptor blockers. In comparison, in the MOSS cohort, medication use in patients who did not undergo revascularization was markedly lower with 58% on aspirin, 45% on beta-blockers, 23% on statins, and 20% on angiotensin converting enzyme inhibitors.
There are several limitations to our study. This registry is observational, but still represents a large, diverse cohort of patients who are not candidates for revascularization with refractory angina. Referral bias is an inherent limitation. However, in spite of high rates of comorbid conditions such as PAD, CHF, and LV dysfunction, mortality for this group of patients remained low. Determination of when a patient has exhausted traditional revascularization options can be difficult and in many cases is subjective. Patients frequently had refractory angina before a 'definitive' cardiac catheterization laboratory or referral-based clinic determination; therefore, our baseline time of diagnosis was conservative. Anatomic descriptors of candidacy for traditional revascularization are also subjective and represent a simplification of complex anatomy and pathophysiology. Better characterization and research are clearly needed in this area, especially for 'diffuse' CAD and microvascular dysfunction. We recently proposed a novel classification scheme and a validation study is underway to determine if classification can further risk-stratify these patients. Advances in cardiovascular imaging which more accurately define the amount of myocardium at risk in individuals with refractory ischaemia may prove useful as well.
In conclusion, long-term mortality in patients with refractory angina who are not candidates for traditional revascularization is surprisingly low. Over 70% of patients with refractory angina can expect to survive 9 years from the time of diagnosis. Therapeutic options for this growing population should therefore focus on chest pain relief and improved quality of life.
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