Treatment Strategies for Women with Coronary Artery Disease Prepared for: Agency for Healthcare...

Treatment Strategies for Women with Coronary Artery Disease

Prepared for:Agency for Healthcare Research and Quality

(AHRQ)

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Learning Objectives

Upon completion of this activity, the participant should be able to:– Identify available treatment options for Coronary Artery

Disease (CAD), specifically for women presenting with STEMI, UA/NSTEMI, or chronic angina

– Assess the benefits and harms of treatment strategies for CAD in women, including clinical outcomes, modifiers of effectiveness, and safety outcomes

– Apply the AHRQ findings of the systemic review to improve outcomes for women with CAD through patient centered care

Coronary Artery Disease (CAD) in Women• Cardiovascular disease (CVD) is the leading cause of mortality for women

in the U.S.– 500,000 women die of CVD each year (approx. one death every minute)– Mortality in women exceeds those in men– Mortality from CVD exceeds next seven causes of death in women combined

• CAD includes coronary atherosclerotic disease, myocardial infarction (MI), acute coronary syndrome (ACS) and angina– Most prevalent form of CVD and is the largest subset of this mortality – Higher prevalence in men until reach 75 years of age (thus giving the

perception CAD is a male-specific disease)

Both Sexes Total Women Total Men

Prevalence CVD, 2008 82.6 M (36.2%) 42.7 M (35.0%) 39.9 M (37.4%)

Mortality CVD, 2008 811.9 K 419.7 K 392.2K

Prevalence CAD, 2008 16.3 M (7.0%) 7.5 M (6.1%) 8.8 M (8.3%)

Mieres JH, et al. Circulation. 2005;111(5):682-96.Lloyd-Jones D, et al. Circulation. 2010;121(7):e46-e215. Roger VL, et al. Circulation. 2012;125(1):e2-e220.

CAD in Women: Factors Contributing to Lower Use of Evidence-Based Medicine and Higher Complications

• CVD affects women later in life than men – first MI 70.3 yrs. vs. 64.5 yrs.• At CAD diagnosis, women more likely to have comorbid factors• Women present different symptoms, more subtle• Smaller coronary vessels in women make revascularization difficult and

microvascular disease more common than men• Women tend toward less extensive CAD and higher proportion of non-

obstructive CAD• Women experience delays in diagnosis and effective treatment due to

– Delays in hospitalization, symptom pattern and recognition, – Higher frequency of nonobstructive CAD

• There are uncertainties with treatment options for women– Underrepresentation in RCT (lack of data = uncertain risk/benefit ratio of options)– Current treatment guidelines have insufficient recommendations based on gender

Mieres JH, et al. Circulation. 2005;111(5):682-96.Alexander KP, et al. Circulation. 2006;114(13):1380-7. Pepine CJ. J Am Coll Cardiol. 2004;43(10):1727-30.

Clinical Presentations of CAD• CAD is the presence of atherosclerosis in the epicardial coronary arteries• Atherosclerotic plaques may rupture or cause acute ischemia or

progressively narrow the coronary artery lumen• A stable plaque progressively narrowing and hardening the coronary

artery lumen, but not necessarily blocking completely the flow of blood, results in chronic stable angina – Stable angina is typically characterized by pain that typically occurs with

moderate to severe exertion – Stable angina is usually mild in nature and can be relieved with rest or

sublingual nitroglycerin• A plaque can become unstable by rupturing and exposing its content in

the artery lumen activating platelets and the coagulation cascade and can become life threatening

Dolor RJ, et al. Treatment strategies for women with CAD. Agency for Healthcare Research and Quality. 2012. Rockville, MD. Available at: http://effectivehealthcare.ahrq.gov/search-for-guides-reviews-and-reports/?pageaction=displayproduct&productID=1227.

Acute Coronary Syndromes

• Acute ischemia can lead to:– Unstable angina: reversible ischemia– Non-ST elevation myocardial infarction (NSTEMI): partial obstruction and

tissue damage– ST elevation myocardial infarction (STEMI): complete epicardial occlusions

leading to possible transmural infarction of the heart• The constellation of clinical symptoms that are compatible with acute

myocardial ischemia is usually referred to as acute coronary syndrome• When left untreated, CAD can lead to MI (heart attack or sudden cardiac

arrest)• Significant CAD is defined angiographically as a stenosis (narrowing) with

>70 percent diameter in at least one major epicardial artery segment or with greater >50 percent diameter in the left main coronary artery


Treatment Options for Patients with CAD

• Optimal medical management– Manage risk factors– Pharmacological treatment– Patient adherence

• Coronary Revascularization– Percutaneous Coronary Intervention (PCI)

• Minimally invasive and preferred for patients with mild CAD (single/double vessel disease)

• Reduces angina and myocardial ischemia– Coronary Artery Bypass Grafting (CABG)

• Inpatient invasive surgery preferred for patients with significant CAD (left main or severe triple vessel disease with reduced left ventricular function


Comparing PCI and CABG• In patients with moderate CAD, uncertainty exists about which to use• Advantages of PCI over CABG

– Relative ease of use – Avoidance of general anesthesia, thoracotomy, extracorporeal circulation,

central nervous system complications, and prolonged convalescence – Repeat PCI can be performed easily – Quick revascularization in emergency situations

• Disadvantages of PCI over CABG– Early restenosis – Inability to relieve many totally occluded arteries or vessels with extensive

atherosclerotic disease• Advantages of CABG over PCI

– Greater durability– More complete revascularization regardless of the morphology of the

obstructing lesion

Lansky AJ, et al. Circulation. 2005;111(7):940-53. Bravata DM, et al. Agency for Healthcare Research and Quality. 2012. Available at: http://www.effectivehealthcare.ahrq.gov/ehc/products/15/55/CER_PCI_CABGMainReport.pdf.

Comparison of Treatment Strategies for Women with CAD

CAD Presentation Treatment ChoicesSTEMI • PCI vs. fibrinolysis

• PCI vs. conservative/supportive medical management

NSTEMI/unstable angina Early invasive management (with PCI or CABG) vs. initial conservative management

Stable/unstable angina PCI vs. CABG vs. optimal medical therapy

CABG = coronary artery bypass grafting; CAD = coronary artery disease; NSTEMI = non-ST elevation myocardial infarction; PCI = percutaneous coronary intervention; STEMI = ST elevation myocardial infarction


Effective Healthcare Program CER Number 66

Treatment Strategies for Women with CAD:Objectives of This Systematic Review• To assess the comparative effectiveness of the major treatment

options for CAD specifically in women, evaluating these comparisons:– PCI versus fibrinolysis or PCI versus conservative/ supportive medical

management in women with STEMI– Early invasive versus initial conservative management in women with

UA/NSTEMI– PCI versus CABG versus optimal medical therapy in women with stable

or unstable angina• To assess these endpoints:

– Clinical outcomes– Modifiers of effectiveness by demographic and clinical factors– Safety outcomes


Search/Inclusion Criteria

Sources and Inclusion CriteriaSources PubMed®, Embase®, the Cochrane Database of Systematic Reviews, Cochrane

Central Registry of Controlled Trials, and grey literature of study registries and conference abstracts

Publication Dates January 1, 2001–December 12, 2011

Language English

Inclusion Criteria • Study design: Randomized Controlled Trials (RCTs)• Population: Adult women diagnosed with CAD, including STEMI, NSTEMI,

and stable angina• Interventions: Comparative data for any of intervention methods

compared with another (PCI, CABG, optimal medical therapy)• Setting: Inpatient or outpatient, primarily primary care and cardiology

clinics


Final Result: 72 articles representing 28 RCT studies passed full-text screening were included in reviewStrength of Evidence: Graded as High, Moderate, Low, or Insufficient

Management of STEMI

• STEMI is caused by the complete occlusion of an epicardial artery, leading to possible transmural infarction of the heart muscle

• Management of STEMI: Patients are candidates for pharmacological or catheter-based reperfusion therapy– Pharmacological therapy

• Fibrinolysis• Conservative/supportive therapy with facilitated antithrombotic medications

– PCI• Immediate revascularization• Data demonstrates benefit of PCI in reducing major cardiovascular adverse events

when compared to fibrinolysis or conservative therapy • Preferred when have close access to a catheterization facility

– In general• Not treated with CABG (unless emergent from PCI complications) • Receive optimal medical therapy in addition to treatment directed at removing the

clot

Kushner FG, et al. Circulation. 2009;120(22):2271-306.

Key Question 1: Women with STEMI (PCI vs. Fibrinolysis/supportive therapy)• What is the effectiveness of PCI vs. fibrinolysis/supportive therapy on

clinical outcomes?– Nonfatal MI, death, stroke, repeat revascularization, recurrent unstable

angina, heart failure, repeat hospitalization, length of hospital stay, angina relief, quality of life, or cognitive effects

• Is there evidence that the comparative effectiveness of PCI vs. fibrinolysis/supportive therapy varies based on characteristics, such as: – Age, race, or other demographic and socioeconomic risk factors? – Coronary disease risk factors such as diabetes, chronic kidney disease, or other

comorbid disease? – Angiographic-specific factors?– Hospital characteristics?

• What are the significant safety concerns associated with each treatment strategy?


KQ1 Findings in STEMIThe Studies:• 7 studies (6 good quality, 1 fair) compared PCI with or without supportive

therapy with fibrinolysis or other routine medical care for women with STEMI and contributed evidence about – the comparative effectiveness– modifiers of effectiveness– safety for these interventions

• These studies included a total of 4,527 patients, of which 1,174 (26%) were women


KQ1 Findings in STEMI:Effectiveness of InterventionStrength of Evidence Conclusions1. High (women and men) for

short-term (30-day) composite outcomes

2. Insufficient (women and men) for intermediate-term (1-year) composite outcomes

1. Meta-analysis of 5 studies (all good quality) reporting 30-day composite outcomes (primarily death/MI/stroke) • showed that PCI was better than fibrinolysis

- women (OR, 0.50; 95% CI, 0.36 to 0.72) - men (OR, 0.54; CI, 0.42 to 0.70).

2. There was insufficient evidence for assessing outcomes at 1 year


KQ1 Findings in STEMI: Modifiers of EffectivenessStrength of Evidence ConclusionsInsufficient 2 studies (1 good quality, 1 fair) reported subgroup analyses

of demographic or clinical factors in patients with STEMI (395 patients of which 167 (32%) were women)

• 1 good-quality study evaluated PCI vs. fibrinolysis in patients <65 years of age and ≥65 and - found no differences in in-hospital mortality

among the treatment groups

• 1 fair-quality study evaluated PCI vs. supportive medical care in patients ≥80 years of age with STEMI. - was limited by a small overall size, and - did not find significant differences in outcomes in

patients ≥80 years with STEMI undergoing PCI compared with usual (supportive) medical care.


KQ1 Findings in STEMI: Safety ConcernsStrength of Evidence ConclusionsInsufficient 2 good-quality studies reported safety concerns in women

with STEMI and included a total of 1,532 patients, of which 367 (24%) were women

• 1 study reported in women receiving PCI vs. fibrinolysis - a lower nadir hematocrit- but no statistically significant differences in the

requirement for blood transfusion

• 1 study reported in women who received PCI vs. accelerated t-PA the proportion of women with intracranial hemorrhage (0% vs. 4.1%)

• No studies systematically reported radiation exposure, contrast reactions, access site complications, or stent thrombosis in women with STEMI undergoing PCI


Management of UA/NSTEMI

• Goals of therapy– Immediate relief of ischemia – Prevention of serious adverse outcomes (i.e., death or MI)

• Patients with UA/NSTEMI are not candidates for immediate pharmacological reperfusion

• Optimal management – Aggressive medical therapy

• Anti-ischemic therapy• Antithrombotic therapy • Ongoing risk stratification • Invasive procedures (in some cases)

– Two emerging management pathways: • Initial conservative• Early invasive strategy

Anderson JL, et al. Circulation. 2007;116(7):e148-304.

Initial Conservative vs. Early Invasive Strategy in UA/NSTEMI• Initial conservative (selective invasive management) only in patients

whom:– Medical therapy fails– Objective evidence of ischemia identified

• Early invasive strategy (PCI or CABG)– No initial noninvasive stress test or medical treatment failure needed– Coronary angiography within 4 to 24 hours of admission– Continue optimal medical therapy– Evidence demonstrates improved clinical outcomes in patients with an

invasive strategy– Guidelines recommend invasive approaches to treat patients with NSTEMI and

high-risk acute coronary syndrome


Key Question 2: Women with UA/NSTEMI (Early Invasive vs. Initial Conservative)• What is the effectiveness of early invasive (PCI or CABG) versus initial

conservative therapy on clinical outcomes? • Is there evidence that the comparative effectiveness of early invasive vs.

initial conservative therapy varies based on characteristics?• What are the significant safety concerns associated with each treatment

strategy?


KQ2 Key Findings in UA/NSTEMIThe Studies:• 7 studies (6 good quality, 1 fair) compared early invasive (revascularization

via PCI or CABG) with initial conservative therapy for women with UA/NSTEMI and contributed evidence about– comparative effectiveness– modifiers of effectiveness– safety for these interventions



KQ2 Findings in UA/NSTEMI: Effectiveness of InterventionsStrength of Evidence

Conclusions

1. Low (women) and High (men) for short- term (6-month) composite outcomes

2. Low (women and men) for intermediate- term (1-year) composite outcomes

3. Insufficient (women) and Low (men) for long-term (5-year) composite outcomes

1. Meta-analysis of 2 good-quality studies reporting 6-month composite outcomes (death/MI)• women: non-statistically significant benefit of early invasive compared with initial

conservative therapy• men: early invasive therapy was superior to initial conservative therapy at 6 months

2. Meta-analysis at 1 year of 5 good-quality studies showed that the composite outcome (primarily death/MI)

• similar non-statistically significant benefit in women who received early invasive therapy and in men

3. Meta-analysis of 2 good-quality studies with 5-year follow-up between early invasive and initial conservative therapy for the composite outcome of death/MI in both sexes

• women: a small benefit of initial conservative therapy• men: a benefit of early invasive therapy• cannot support firm conclusions due to:

• small suggested benefit at 5 years in women• the wide confidence interval crossing 1• the trend favoring early invasive therapy suggested at earlier time points and

across time points in men


KQ2 Findings in UA/NSTEMI: Modifiers of EffectivenessStrength of Evidence ConclusionsInsufficient • 2 good-quality studies comparing initial conservative

medical therapy with early invasive therapy with PCI - subgroup analysis by risk stratification - included a total of 4,030 patients, of which 1,439

(36%) were women

• Conflicting results—- one study: no difference in treatment outcomes in

the intermediate- and high-risk groups- other study: higher event rate in women in the

groups with moderate-to-high risk for thrombolysis in myocardial infarction


KQ2 Findings in UA/NSTEMI: Safety ConcernsStrength of Evidence ConclusionsInsufficient • 1 good-quality study (2,220 total patients, 757 [34%]

women) - reported the harms associated with treatment of

UA/NSTEMI by sex group - did not report the rates of events by treatment

group• Bleeding

- in women undergoing PTCA bleeding was higher compared with men (adjusted OR, 3.6; 95% CI, 1.6 to 8.3).

- bleeding related to CABG was similar in women and men, with rates of 12.6 and 15%, respectively

• No studies systematically reported radiation exposure, contrast reactions, access site complications, stent thrombosis, or infection in women with UA/NSTEMI comparing early invasive with initial conservative therapy


Chronic Stable Angina

• Treatment goals– Prevent MI and death– Reduce symptoms of angina and occurrence of ischemia– Improve quality of life for both of the above

• All patients with stable angina are candidates for: – Optimal medical therapy – PCI or CABG based on findings from coronary angiography and if symptoms

persist despite optimal medical therapy

Gibbons RJ, et al. Circulation. 2003;107(1):149-58.

Unstable Angina• Unstable angina (UA) is defined as angina with at least one of three

features: – It occurs at rest or with minimal exertion– It is severe and of recent onset (within the past 4 to 6 weeks)– It occurs in a crescendo pattern (i.e., more severe, more prolonged, or more

frequent than previously experienced)• UA and NSTEMI

– Fairly similar pathophysiology, mortality rate, and management strategy– Often grouped together as UA/NSTEMI in clinical guidelines and trial

populations


Key Question 3: Strategy 1—Women with Stable Angina (Revascularization vs. Optimal Medical Therapy)• What is the effectiveness of the following treatment strategies on clinical

outcomes?– Revascularization (PCI or CABG) vs. optimal medical therapy in women with

stable angina– PCI vs. CABG in women with stable or unstable angina

• Is there evidence that the comparative effectiveness of revascularization versus optimal medical therapy varies based on characteristics?

• What are the significant safety concerns associated with each treatment strategy?


KQ3 Findings in Stable AnginaThe Studies:• 5 studies (all good quality) compared revascularization (PCI or CABG) with

optimal medical therapy for women with stable angina and contributed evidence about – comparative effectiveness– modifiers of effectiveness– safety for these interventions



KQ3 Findings in Stable Angina: Effectiveness of InterventionsStrength of Evidence Conclusions1. With the PCI strategy:

Moderate (women) and Low (men) for long-term (4- to 5-year) composite outcomes

2. With the CABG strategy: Low (women and men) for long-term (4- to 5-year) composite outcomes

3. With both types of revascularization: Moderate (women) and low (men) for long-term (4- to 5-year) composite outcomes

A meta-analysis of 3 good-quality studies with long-termfollow-up on the composite outcomes (death/MI/revascularization) comparing PCI or CABG with optimal medical therapy showed

• Revascularization significantly better than optimal medical therapy in women with stable angina

• Small benefit for men with stable angina for optimal medical therapy when compared with PCI- This suggested small benefit has a wide confidence interval

crossing 1 and is not supported by additional time periods or by the evidence in women

- Analyses suggested a benefit of CABG or either PCI or CABG in men with stable angina

- Findings were not statistically significant and had very wide confidence intervals


KQ3 Findings in Stable/Unstable AnginaThe Studies:• 10 studies (8 good quality, 2 fair) compared PCI with CABG in women with

stable/unstable angina and contributed evidence about the comparative effectiveness, modifiers of effectiveness, or safety for these interventions.



KQ3 Findings in Stable/Unstable Angina: Effectiveness of InterventionsStrength of Evidence Conclusions

1. Low (women and men) for short-term (30-day) composite outcomes

2. Low (women and men) for intermediate-term (1-year) composite outcomes

3. Low (women) and High (men) for long-term (>2-year) composite outcomes

1. A meta-analysis of 2 good-quality studies reporting a 30-day death outcome showed

• no statistically significant difference between PCI and CABG in either men or women

• odds ratios suggest a possible sex effect, with PCI showing more benefit in women and CABG showing more benefit in men, but confidence intervals too wide to support firm conclusions

2. A meta-analysis of 2 good-quality studies for 1-year composite outcomes (death/MI/stroke) showed

• lower events in the CABG group for both sexes, but this benefit was not statistically significant

• odds ratio in women was 1.30 (CI, 0.69 to 2.45) and in men was 1.19 (CI, 0.84 to 1.70)

3. A meta-analysis of 4 good-quality studies for long-term (>2 years) composite outcomes (death/MI/stroke) suggested

• lower events in the CABG group in women although again this did not reach statistical significance

• in men, CABG was significantly better than PCI in lowering cardiovascular events


KQ3 Findings in Stable/Unstable Angina: Modifiers of EffectivenessStrength of Evidence Conclusions

Insufficient 1 good-quality study evaluated the comparative effectiveness of PCI vs. CABG in diabetic patients with stable/unstable angina• survival rate at 7 years was similar in diabetic women

from both treatment groups• diabetic men, those treated with CABG had higher

survival than those treated with PCI


KQ3 Findings in Stable/Unstable Angina: Safety ConcernsStrength of Evidence Conclusions

Insufficient • 1 good-quality study reported harms associated with PCI compared with CABG among women with UA/NSTEMI- bleeding associated with PCI was higher in women

compared with men (OR, 29.4; 95% CI, 5.3 to 500; p=0.001)

• No studies systematically reported radiation exposure, contrast reactions, access site complications, stent thrombosis or infection, in women with UA/NSTEMI undergoing PCI or CABG


ConclusionsThis review confirms current practice and evidence for care in one of the three areas evaluated, from studies reporting results specifically in women

AHRQ Findings Previous Meta-analyses

PCI vs. fibrinolysis in STEMI Women: Immediate PCI superior to fibrinolysis

Men and Women: Immediate PCI superior to fibrinolysis

Early invasive vs. initial conservative therapy in UA/NSTEMI

Women: Nonsignificant benefit of early invasive approach compared to initial conservative therapy

Men and women: Statistically significant benefit of early invasive therapy

Revascularization vs. optimal medical therapy in stable angina

Women: Greater benefit with revascularization compared to optimal medical therapy Men: Similar effectiveness between treatment groups

Men and women: Similar outcomes for either treatment


Study Limitations

• Focus on RCTS only– Only few studies reporting on:

• Subgroup analyses by demographic or clinical characteristics • Harms or risks of therapy

– Most studies applicable to modifiers of effectiveness or safety report data for overall population, not separated by sex

– Not included observational and noncomparator studies in women• Sample size and low representation of women affect the ability to analyze

results by sex– Exclusion of many articles due to lack of sex-specific reporting – Low numbers of studies available for analysis for each clinical presentation– On average, 17 percent of the articles comparing treatment strategies for CAD

reported sex-specific outcomes– Reporting bias in publications resulted in selection bias in review


Study Limitations (cont.)• Strength of meta-analysis limited by:

⁻ Different definitions of primary composite outcome ⁻ Different timing of clinical endpoints

• Change in PCI techniques and definition of optimal medical therapy over time

⁻ Most studies involved older therapies (balloon angioplasty or bare-metal stents)

⁻ Under-representation of current era of therapies • Drug-eluting stents and use of dual antiplatelet therapy

⁻ Variable reporting on the implementation of optimal medical therapy• Many multicenter, international RCTs

⁻ Generalizability to the United States may be of concern, although revascularization and prescription of medical therapies not very different

• Not reported:⁻ Medication adherence ⁻ Adverse effects and safety concerns other than bleeding


Directions for Future Research

• Studies with sufficient representation of women– Women-only enrollment, or – Large sample size with stratification of randomization by sex

• Patient-level meta-analysis– Comparing similar interventions for the same CAD presentation

• Reporting sex by treatment results separately• Reporting demographic and clinical factors that influence cardiovascular

outcomes• Reporting of safety concerns and risks by sex


• For CE/CME:– www.ce.effectivehealthcare.ahrq.gov/credit– Use code: CER23– Visit AHRQ’s continuing education Web site regularly to participate in

future programs• For electronic copies of the clinician guide, the consumer guide,

and the full systematic review– http

://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?productid=1227&pageaction=displayproduct

• Free print copies– AHRQ Publications Clearinghouse: (800) 358-9295

Effective Healthcare Program CER Number 43

Treatment Strategies for Women with CAD:Thank you for your time

http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and-reports/?productid=1227&pageaction=displayproduct



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