Ischemia and No Obstructive Coronary Artery Disease (INOCA): What Is the Risk?
2018; Wiley; Volume: 7; Issue: 17 Linguagem: Inglês
10.1161/jaha.118.008868
ISSN2047-9980
AutoresRomana Herscovici, Tara Sedlak, Janet Wei, Carl J. Pepine, Eileen Handberg, C. Noel Bairey Merz,
Tópico(s)Coronary Interventions and Diagnostics
ResumoHomeJournal of the American Heart AssociationVol. 7, No. 17Ischemia and No Obstructive Coronary Artery Disease (INOCA): What Is the Risk? Open AccessReview ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citations ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toOpen AccessReview ArticlePDF/EPUBIschemia and No Obstructive Coronary Artery Disease (INOCA): What Is the Risk? Romana Herscovici, MD, Tara Sedlak, MD, Janet Wei, MD, Carl J. Pepine, MD, Eileen Handberg, PhD, ARNP and C. Noel Bairey Merz, MD Romana HerscoviciRomana Herscovici Barbra Streisand Women's Heart Center, Cedars‐Sinai Smidt Heart Institute, Los Angeles, CA , Tara SedlakTara Sedlak Vancouver General Hospital, Vancouver, British Columbia, Canada , Janet WeiJanet Wei Barbra Streisand Women's Heart Center, Cedars‐Sinai Smidt Heart Institute, Los Angeles, CA , Carl J. PepineCarl J. Pepine University of Florida, Gainesville, FL , Eileen HandbergEileen Handberg University of Florida, Gainesville, FL and C. Noel Bairey MerzC. Noel Bairey Merz Barbra Streisand Women's Heart Center, Cedars‐Sinai Smidt Heart Institute, Los Angeles, CA Originally published24 Aug 2018https://doi.org/10.1161/JAHA.118.008868Journal of the American Heart Association. 2018;7:e008868IntroductionAn increasing number of stable patients with evidence of ischemia but no obstructive coronary artery disease (CAD) at coronary angiography, now termed INOCA, are seen. Objective myocardial ischemia or limited coronary flow reserve (CFR) consistent with coronary microvascular dysfunction (CMD) are identified in most of these patients. Although these patients were previously thought to be at low risk for major adverse cardiovascular events (MACE) and were provided only reassurance, newer data document that stable INOCA patients are a heterogeneous population with an elevated MACE risk. Primary prevention cardiovascular risk scores for asymptomatic populations may underestimate risk in these patients, while secondary prevention risk scores developed in patients with established cardiovascular disease may overestimate risk. Medical therapies may be underutilized when no obstructive CAD is documented, and patients are commonly discharged from specialty practice. We review the existing knowledge regarding observed and predicted risk using available risk scores in stable INOCA patients to identify knowledge gaps and plan investigation needed to develop evidence‐based guidelines for this growing patient population.INOCA—PrevalencePatients with chest pain, evidence of ischemia but no obstructive CAD at coronary angiography, now termed ischemia with no obstructive CAD or INOCA,1 are increasingly recognized. Although there is likely overlap between INOCA and myocardial infarction (MI) with no obstructive coronary arteries, which appears to be increasingly described, our primary focus is INOCA, the non‐MI syndromes. These stable patients typically have symptoms of chest pain suspected to be angina and/or abnormal stress testing, in the setting of no obstructive CAD at coronary angiography.1 The definition of obstructive CAD varies between different guidelines or studies.3 In general, "normal"‐appearing coronary arteries are defined as 0% luminal stenosis or 20% but <50%.3 However, some studies use a threshold of <70% for NOCAD,4 while anatomical scores consider a stenosis ≥50% as significant.5 Traditional understanding of obstructive CAD was 70%12; however, recent European Society of Cardiology and American College of Cardiology/American Heart Association (ACC/AHA) guidelines shifted to include stenosis of 50% to 70% if there is associated inducible ischemia or fractional flow reserve ≤0.08 when considering the physiological significance of stenosis and revascularization management in patients with stable CAD.6Depending on the study, up to half of patients undergoing coronary angiography have no obstructive CAD,13 with a relatively higher prevalence in women (65% in women versus 32% in men).15 Overall estimates in women and men from the Veterans Administration Cardiovascular Assessment Reporting and Tracking System,16 the National Cardiac Data Registry, and the National Heart, Lung, and Blood Institute–sponsored Women's Ischemia Syndrome Evaluation (WISE)10 databases indicate that there are at least 3 to 4 million American women and men with stable INOCA. Incurred healthcare costs are similar to those for obstructive CAD.Potential explanations for the apparent increasing prevalence of stable INOCA include more sensitive diagnostics, including advanced cardiac imaging and high‐sensitive troponins, which likely contribute to earlier detection of ischemic heart disease. Furthermore, improved primary prevention risk factor control (reduced smoking, increased aspirin and statin use) has likely contributed to altered atherosclerosis burden with relatively less large‐vessel plaque rupture, potentially leading to less adverse arterial remodeling/obstructive CAD,17 while increasing rates of obesity18 and diabetes mellitus19 may contribute to increasing prevalence of CMD or pathology.20The ACC/AHA non–ST‐segment–elevation MI guidelines refer to patients with MI and no obstructive CAD as having Cardiac Syndrome X (CSX),22 while the European Society of Cardiology stable CAD guidelines no longer use the term CSX when describing patients with angina and no obstructive CAD12 because testing now allows the diagnosis of CMD or macrovascular dysfunction12 in a majority of these patients. Previously, the term CSX was used to refer to patients with no obstructive CAD but did not require proof of ischemia23 and also included patients with acute coronary syndromes and no obstructive CAD.22 Advanced evaluation can now identify CMD or macrovascular dysfunction by invasive or noninvasive measurements of CFR in a majority of these patients,12 while coronary atherosclerosis and better characterization of plaques can be assessed by intravascular ultrasound, optical coherence tomography, or computed coronary tomography angiography when not evident or appreciated at invasive coronary angiography.27 Since CSX also includes clinical entities other than ischemia, such as pericardial pain, inappropriate pain perception, and psychiatric syndromes,30 the term INOCA was established to improve the identification and management of patients with ischemia and no obstructive CAD.1 In our opinion, the European Society of Cardiology stable CAD guidelines more directly address recent INOCA data and practice implications compared with the ACC/AHA guidelines.Among both women and men, up to 60% of stable INOCA patients have documented CMD defined as the presence of microvascular endothelial‐dependent and/or nonendothelial‐dependent dysfunction.31 Furthermore, while the CMD was shown to be poorly correlated with traditional risk factors, age was found to be an independent predictor of CMD in both women and men.33 Female sex had a nearly significant association with CMD, with an odds ratio of 1.21 (95% confidence interval, 0.98–1.40) compared with men.33 The high prevalence of endothelial and/or nonendothelial‐dependent CMD26 and their correlation with outcomes26 underscores the role of comprehensive assessment in patients with INOCA. Such functional alterations can be identified at a stage when atherosclerotic lesions are not evident34 and may be useful in designing early effective interventions to prevent the occurrence of subsequent coronary events.Evidence of an Adverse PrognosisEvidence from prospective registries indicate that stable INOCA patients are at more elevated risk for future MACE, including death, nonfatal MI, nonfatal stroke, and hospitalization for heart failure or angina than previously thought.Documented MACE rates in stable INOCA patients are summarized in Table 1.4 Additionally, many of these patients have an adverse quality of life, functional status, and exercise capacity with relatively frequent visits to healthcare providers for persistent or recurring disabling symptoms.42 Elevated MACE rates are observed both early after the index coronary angiogram (eg within the first year) and at longer‐term follow‐up. In a study of 13 695 subjects, women with nonobstructive CAD demonstrated a 3‐fold higher MACE rate compared with men and 2.55‐fold increase compared with women with normal coronary arteries in the first year.43 Hospitalization for heart failure was the most frequent event, with an observed 10‐fold higher rate during longer‐term follow‐up compared with asymptomatic community‐based women.35 Studies that additionally characterized function or anatomy such as myocardial ischemia, CFR, plaque characterization, or calcium scoring further demonstrate relatively higher MACE rates related to the presence or degree of such abnormalities (Table 1), in both sexes. CMD was shown to be highly prevalent in stable INOCA patients and a CFR 50% of MACE occurred in subjects with normal stress testing in the PROMISE,59 emphasizing the lower sensitivity and specificity to detect ischemia in less than obstructive CAD. An anatomical computed coronary tomography angiography approach offered better prognostic information once NOCAD was visualized.59 Furthermore, mechanisms leading to acute coronary syndromes are not solely depending on degree of luminal stenosis. An ischemic event is the consequence of a complex interaction among plaque characteristics, endothelial dysfunction, coronary blood flow hemodynamics, hemostasis factors, and metabolic, inflammatory, neurohormonal, and environmental factors60 that are not addressed by commonly used tests.Secondary Prevention Risk ScoresThe Synergy between Percutaneous Coronary Intervention with TAXUS and Cardiac Surgery (Syntax) II is a coronary angiographic‐based score used to optimize outcomes relative to revascularization in obstructive CAD.12 Other secondary prevention scores are relevant in early61 or longer‐term63 risk stratification after a vascular event. Scores using obstructive CAD variables are not applicable to INOCA patients. Recently, the Gensini score, which includes lesser‐than‐obstructive CAD (epicardial luminal diameter stenosis <50%), was found to be useful for prognosis in men and women referred for invasive coronary angiography with no obstructive CAD.64 Previously, in women, a WISE coronary angiographic score that assigned points according to severity of stenosis, adjusted for the presence of collaterals and weighted by lesion location, predicted MACE in stable INOCA patients. Specifically, MACE risk was positively associated with increased coronary atherosclerosis scores in the absence of obstructive CAD.47Additional scores developed for secondary prevention in patients with established cardiovascular disease (CVD) do not include obstructive CAD as a variable, but were developed in populations dominated by obstructive CAD,63 and therefore are of unknown appropriateness for stable INOCA patients.The Long‐Term Intervention with Pravastatin in Ischemic Disease (LIPID)63 score identifies higher‐risk subjects on statin therapy, developed again in an obstructive CAD population. A score from the Guangdong Coronary Artery Disease Cohort (GCADC) study65 had good predictive value for mortality among secondary prevention patients, and the European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA) score model predicted CVD mortality but not nonfatal outcomes or combined end points.71 Again, these studies addressed mostly obstructive CAD patients.The Second Manifestation of Arterial Disease (SMART),69 Thrombolysis In Myocardial Infarction Risk Score for Secondary Prevention (TIMI‐TRS2oP),70 and A Coronary Disease Trial Investigating Outcome with Nifedipine (ACTION) risk66 scores, all showed substantial variability in risk among patients with stable CVD, but more importantly that aggressive guideline treatment in high‐risk patients decreased their risk.69 Similarly, the PREDICT CVD (New Zealand Primary Care Cohort Study) score developed for patients with previous CVD recognizes patient‐specific risks of future events and how they may be reduced through therapeutic and behavioral strategies.68The "Cardiovascular Disease Research Using Linked Bespoke Studies and Electronic Health Records" (CALIBER) score67 used real‐world commonly available data that contributed to important prognostic information in unselected patients with a wide phenotype of stable ischemic heart disease. The CALIBER models had good calibration and discrimination in internal and external validation with C‐index 0.811 (0.735) for all‐cause mortality and 0.778 (0.718) for nonfatal MI or coronary death in established stable ischemic heart disease.67Primary and Secondary Prevention Risk Versus Observed INOCA RiskComparison of primary, secondary prevention risk versus observed risk in an example of stable INOCA patient is presented in Figure 2.40 The primary prevention scores, developed in asymptomatic populations, predicted that risks vary between 1% and ≈5% and underestimate the observed INOCA risk. The related primary prevention risk guidelines for these low‐risk scores would include therapeutic lifestyle change and not statin therapy. Among secondary risk scores, developed in symptomatic but mainly obstructive CAD patients, the predicted risk varied widely, either over‐ or underestimating the observed INOCA risk.Download figureDownload PowerPointFigure 2 Predicted primary and secondary prevention scores risk vs observed 10‐year risk in an example INOCA patient. Model variables used: female, 55 years, hypertension, systolic blood pressure 139 mm Hg on treatment, heart rate 80 bpm, total cholesterol 200 mg/dL (5.17 mmol/L); low‐density lipoprotein 80 mg/dL (2.068 mmol/L), high‐density lipoprotein 60 mg/dL (1.55 mmol/L), high‐sensitivity C‐reactive protein (hs‐CRP) 2 mg/dL, creatinine 0.9 mg/dL (79 μmol/L), white blood cell count 10 K3/mL, hemoglobin 12 g/dL, no family history, height 5′ 67″ (170 cm), weight 158 pounds (72 kg), body mass index 24.9, low‐risk country, chest pain related to physical/mental stress, glomerular filtration rate 60 mL/min per 1.73 m2. Predicted 10‐year Risk: Primary Prevention Risk Scores: ASCVD—risk of cardiovascular death, nonfatal MI, nonfatal stroke; SCORE—risk of fatal cardiovascular disease; Reynolds (RRS)—risk of myocardial infarction, ischemic stroke, coronary revascularization and cardiovascular death; QRISK2—risk of MI or Stroke; FRS CVD—risk of CHD or coronary insufficiency death, MI, or angina; Secondary Prevention Risk Scores: CALIBER—myocardial infarction, cardiovascular death; GCAD—cardiovascular death; PROMISE—myocardial infarction, cardiovascular death; ACTION—myocardial infarction, stroke, all‐cause death; SMART—myocardial infarction, stroke, vascular death; LIPID—myocardial infarction, cardiovascular death; EUROPA—cardiovascular death; TRS2P—myocardial infarction, stroke, cardiovascular death; PREDICT—myocardial infarction, stroke, cardiovascular death. The 10‐year risk was calculated from the reported risk divided by the numbers of follow‐up years and then projected to 10 years. Observed 10‐year Risk: Sharaf—cardiovascular death or MI (median follow‐up of 9.3 years); Kenkre—cardiac mortality (median follow‐up 9.5 years). ACTION indicates A Coronary disease Trial Investigating Outcome with Nifedipine; ASCVD, Atherosclerotic Cardiovascular Disease; CAD, coronary artery disease; CALIBER, Cardiovascular disease research using Linked Bespoke studies and Electronic Health Records; EUROPA, European trial On reduction of cardiac events with Perindopril in stable coronary Artery disease; FRS‐CVD, Framingham Risk Score Cardiovascular Disease; GCAD, Guangdong Coronary Artery Disease Cohort; INOCA, ischemia and no obstructive coronary artery disease; LIPID, Long‐Term Intervention with Pravastatin in Ischemic Disease; NCA, normal coronary arteries; NOCAD, nonobstructive coronary artery disease; PREDICT, Patients with Renal Impairment and Diabetes undergoing Computed Tomography; PROMISE, Prospective Multicenter Imaging Study of Chest Pain; QRISK2, QRESEARCH cardiovascular disease risk score; RRS, Reynolds Risk Score; SMART, Second Manifestation of Arterial Disease; SCORE, Systematic Coronary Risk Evaluation; TRS2P, Thrombolysis In Myocardial Infarction Risk Score for Secondary Prevention.Cardiovascular Treatment Rates in INOCA PatientsRegistry data demonstrate that half or less of stable INOCA patients are treated with cardiovascular medication effective for ischemic heart disease, such as angiotensin‐converting enzyme inhibitor or angiotensin II receptor blocker, β‐blocker, calcium channel blocker, or statin therapies (Table 2).15 Furthermore, the intensity of treatment, specifically for the maximally tolerated angiotensin‐converting enzyme inhibitor/angiotensin II receptor blocker and potent statin categories, is unknown in these registries. These findings suggest that the presence of normal coronary arteries or NOCAD at coronary angiography may be associated with diagnostic and therapeutic uncertainty, resulting in patients being less often treated with either primary prevention or secondary prevention guidelines therapy. This practice seems unchanged despite knowledge about adverse outcome in this population. The current ACC/AHA guidelines for patients with stable CAD echoes the ACC/AHA recommendations for patients with unstable angina/non–ST‐segment–elevation MI for subgroups of patients with no obstructive CAD, which was defined as CSX.22 While there have been studies evaluating therapy in patients with CSX,79 these studies are limited in their characterization of coronary vasomotor function. Indeed, this emerging INOCA patient population remains underdiagnosed and undertreated, likely perseverating this observed therapeutic equipoise. The observed elevated MACE rate endorses this as a knowledge gap. Even mild degrees of atherosclerosis or abnormal coronary vasoreactivity are related to increased health risk.4 Furthermore, the majority of MIs result from rupture of nonobstructive plaque, highlighting the importance of optimizing therapy in these patients.85 To date, limited data exist about the effectiveness of therapy in stable patients with no CAD and high prevalence of CMD. Nevertheless, prior work in obstructive CAD has demonstrated that atherosclerotic progression can be slowed and MACE reduced with optimal medical therapy,69 while surrogate outcome trials in CMD patients indicate improvement in endothelial function, CFR, and angina with optimal medical therapy, as well.87 Patients with INOCA deserve to receive optimal treatment as per current guidelines while awaiting future dedicated trials.Table 2 Cardiovascular Treatment Rates in INOCA PatientsAuthor, Publication Year (n)Hypertension/Angina Therapy (%)Statin Therapy (%)Maddox, 201072 (n=237 167)5147Johnston, 201173 (n=5386)21–5651Shaw, 201174 (n=824)10–2032Jespersen, 201215 (n=5183)4450Sedlak, 201275 (n=1864)3432Sharaf, 201347 (n=567)2–3910a/31bChow, 201576 (n=10 418)N/A33.3Nielsen, 201741 (n=14 205)11.8–32.325–39.2Galway, 201777 (n=2642)18–4634–59John Wiley & Sons, LtdHypertension/Angina therapy includes: angiotensin‐converting enzyme inhibitor, angiotensin II receptor blocker, β‐blocker, and calcium channel blocker medication. INOCA indicates ischemia and no obstructive coronary artery disease; N/A, not applicable.aNormal coronary arteries.bNonobstructive coronary artery disease.Implications and ConclusionsAn increasing number of stable INOCA patients and observed elevated MACE rate calls attention to several important knowledge gaps (Table 3). Existing primary and secondary prevention risk assessment tools do not appear to predict MACE risk in INOCA patients; investigation is needed to specifically address tools to accurately assess risk in these patients. Furthermore, there appears to be diagnostic and therapeutic uncertainty in INOCA patients with potentially inappropriately low rates of cardiovascular therapy given the documented atherosclerotic and ischemia burden. Evidence‐based primary or secondary treatment guidelines do not specifically addre
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