Managing Chronic Angina: What Do We Know?

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While there are a multitude of drugs and lifestyle changes that are prescribed for chronic angina, properly managing this patient population continues to challenge cardiologists. However, recent studies have begun to reveal new therapies that might better relieve this chronic pain.

Why COURAGE is so encouraging

Treatment strategies for chronic angina differ depending on the varying underlying causes—atherosclerosis, vascular disease or ischemia. Even between men and women, management of this condition is difficult and multifaceted. The landmark 2007 COURAGE trial, however, suggests that optimal medical therapy (OMT) plus PCI offers no benefit in terms of mortality or subsequent MI compared with OMT alone (New Engl J Med April 2007;356:1503-1316).

"The results of COURAGE indicate that some expensive stenting procedures could be avoided," says principal investigator William E. Boden, MD, clinical chief of cardiovascular medicine at University at Buffalo Schools of Medicine & Public Health in Buffalo, N.Y.

Women present with calcium differently than men, so it’s important to choose the most appropriate diagnostic test. A. Coronary artery calcium scan shows calcium, while coronary CT angiography images (B and C) show normal arteries. Source: Obstet Gynecol 2010;115:156-169


Likewise, the BARI 2D trial, also led by Boden, randomized type 2 diabetic patients and heart failure patients to receive PCI or CABG plus OMT or OMT alone. Patients had a diagnosis of coronary artery disease (CAD) and classic angina. Results showed no difference in terms of mortality between the revascularization approaches and OMT (N Engl J Med 2009;260:2503-2515).

However, both trials showed some relief from angina associated with PCI, suggesting a more personalized approach in treating patients with stable angina with PCI is warranted.

OMT should consist of the maximum tolerated doses of anti-anginal drugs, such as beta-blockers, nitrates and calcium-channel blockers, in addition to aggressive risk-factor modification, such as lipid control with statins, blood pressure control, weight management and smoking cessation, offers Prakash Deedwania, MD, chief of cardiology at the University of California, San Francisco, School of Medicine.

The COURAGE–inspired theory is that OMT prevents widespread atherosclerosis and, when aggressive, potentially stabilizes plaques. However, no anti-anginal drugs are disease modifying, meaning they do not change the risk of MI, sudden cardiac death or all-cause mortality.

The anti-anginal drug ranolazine (Ranexa, Gilead Sciences), approved by the FDA in 2006, could be beneficial to treat chronic angina, particularly in diabetic and heart failure patients, in addition to those with low heart rates and low blood pressure. "It is a needed addition to the armamentarium of clinical cardiologists who manage patients with angina," writes Richard Kones, MD, from the Cardiometabolic Research Institute in Houston (Vascul Health Risk Mangmnt 2010;6:749–774).

Kones notes that ranolazine was not used in the COURAGE trial, but based upon its use in the MERLIN-TIMI 36 trial, "it is likely that ranolazine not only has a place in OMT for stable angina, but also possibly for chest pain associated with ACS as well."

Being a relatively new drug, ranolazine is more expensive than generic beta-blockers and nitrates, but is cheaper than therapies such as enhanced external counterpulsation, and can be helpful in many patients refractory to traditional drugs, Deedwania says.

Battle of the sexes

Women have a higher prevalence of angina than do men; however, the lack of certainty as to why makes treatment difficult, says Kamakki Banks, MD, MPH, leader of the Dallas Heart Study and cardiology research fellow at the University of Texas Southwestern Medical Center in Dallas.

During the epidemiologic Dallas Heart Study, Banks and colleagues assessed 1,480 women to evaluate clinical characteristics of women with angina. The women were between the ages of 30 and 65, and 6.9 percent had angina without the presence of coronary artery calcium (CAC).

In those patients with CAC, the researchers found that angina was not associated with the presence or amount of calcium. However, many women did have increased levels of soluble intercellular adhesion molecule (sICAM-1), soluble vascular cell adhesion molecule (sVCAM-1) and lower aortic compliance, which suggest microvascular dysfunction. Banks says therapies that focus on treating endothelial dysfunction and vascular stiffness, such as L-arginine, ACE inhibitors and statins, could decrease angina pain.

Banks et al found three factors independently related to angina in women without significant atherosclerotic blockages:
  • African-American ethnicity
  • Increased waist-circumference, and
  • Premature family history of MI

Banks recommends performing a stress test to evaluate for ischemia in angina patients with these risk factors.

Refractory angina

Chronic angina is a "bread basket diagnosis," with multiple factors that may cause chest pain. Consequently, traditional medical therapy, some of which is aimed at reducing atherosclerosis, may not benefit a large segment of women. "Beta-blockers and nitrates are the standard treatment, but the results are not consistent," Banks says.

Other therapies, like those listed below, may be beneficial for patients who have angina refractory to traditional drug therapy:
  • Angiogenesis/gene or stem cell therapy: The goal is to trigger the creation or enlargement of blood vessels to the heart to improve blood flow.
  • Spinal nerve stimulation: An implanted  small device that sends low-voltage electrical simulation to the spinal cord. Its mechanism of action is under debate, and it has a class IIb recommendation.
  • Enhanced external counterpulsation: Pneumatic blood pressure cuffs synchronized with the ECG stimulate blood flow, also with a class IIb recommendation.
  • Transmyocardial laser revascularization: This surgical technique uses lasers to burn channels in the myocardium, theoretically increasing perfusion, although the mechanism of angina relief is debated. It has a class Ia recommendation.
  • Ivabradine: Several studies have shown the drug reduces angina, particularly in combination with beta-blockers.  

Costs/reimbursement

Particularly for women without epicardial disease where OMT is not beneficial, angina carries a hefty price tag—an estimated $700,000 in lifetime healthcare costs, Banks says. The costs spawn from repeat revascularization procedures due to untamed chest pain, in addition to the administration of traditional OMT therapy.

While data from COURAGE and BARI 2D reaffirm the benefit of OMT, "why haven't we seen movement toward aligning the reimbursement with the evidence that supports it?" asks Boden.

A cost analysis of the COURAGE trial performed by Weintraub et al showed that PCI added an additional cost of $10,000, without a significant gain in life-years and quality-adjusted life-years. Lifetime costs of PCI plus OMT compared with those treated with OMT alone were higher, $99,820 versus $90,370 (Circ Cardiovasc Qual Outcomes 2008;1:12-20).

The cost to have clinical improvements in angina for six to 36 months in one patient treated with PCI plus OMT is more than $100,000. Deferring PCI could monumentally decrease costs.

A policy commentary written by Diamond and Kaul urged a change to the reimbursement model, particularly after the release of COURAGE. They say that an evidence-based reimbursement model focusing more on clinical outcomes would provide payments that are "linearly proportional" (Circ Cardiovasc Qual Outcomes 2009;2:134-140). In this scenario, payment would be based on a case-by-case adherence with the evidence-based appropriateness of procedures.

"[E]vidence-based reimbursement does not encourage the denial of care; it encourages more appropriate care given the available evidence," say Diamond and Kaul.

Changing the reimbursement model to one that incentivizes physicians to reduce the number of stenting procedures in the treatment of chronic angina could save millions, while producing similar outcomes.