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Alsheikh-Ali AA, Kitsios GD, Balk EM, et al. Vulnerable Atherosclerotic Plaque [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2010 Aug. (Comparative Effectiveness Technical Briefs, No. 3.)

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Vulnerable Atherosclerotic Plaque [Internet].

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In the 2004 technical report,4 the identified proposed criteria for defining vulnerable plaque included active inflammation, thin cap with large lipid core, endothelial denudation with superficial platelet aggregation, fissured plaque, and stenosis >90%. The treatments identified that were potentially therapeutic for vulnerable plaques were fish oil, statin, antioxidant, and antibiotic treatment. That report further noted that since there was no standard definition for vulnerable plaque, there were no natural history studies for this proposed concept. In 2010, despite many additional publications, there is still no standard definition for vulnerable plaque; and therefore, no available natural history studies for this proposed concept. However, additional natural history studies of individual plaque features deemed important in the concept of vulnerable plaque have been identified.

The vulnerable plaque concept has gained considerable attention in the literature during the last few years, since, if validated, this concept could offer promise in combating cardiovascular disease. If vulnerable plaques can be detected prospectively and accurately, and effective therapeutic interventions initiated before cardiovascular events occur, all in a cost-effective manner, then many (perhaps the majority of) cardiovascular events can be prevented. However, for this potential promise to be realized, substantial challenges need to be addressed. These challenges are both conceptual and methodological.

Conceptually, the presence of a “vulnerable plaque” is by definition a probabilistic entity (i.e., it does not denote the occurrence of an event at present, but rather a higher risk of such occurrence in the future relative to a non-vulnerable or less vulnerable plaque). As such, before it is widely adopted by clinicians, plaque vulnerability (once validated) should be able to provide incremental predictive value on top of currently available methods of risk stratification, which may be less expensive and less invasive than the methods proposed to detect vulnerable plaques. Moreover, the complex implications of such a probabilistic diagnosis are exemplified in the observation that not all plaques that rupture (the basis for the classic definition of the term) actually result in a clinical cardiovascular event. Some plaques would rupture and then quiesce and heal without causing a myocardial infarction or stroke (so called silent plaque rupture).34,35 Conversely, not all acute cardiovascular events are the result of plaque rupture, since non-ruptured plaques have been implicated as culprit lesions nearly one-third of the time in autopsy series.19 To the extent that plaque vulnerability is defined based on features that predict rupture, the observations that not all ruptures result in clinical events, and that not all clinical events are the result of rupture, would limit the sensitivity and specificity of the vulnerable plaque as a predictor of a future event. The value of the available literature is further limited by the use of imaging characteristics that have not been validated as reliable surrogates for histological markers of plaque vulnerability (e.g. echolucency, plaque deformability). Furthermore, whether features of plaque vulnerability are interchangeable among vascular beds is uncertain.66 In other words, would a high risk marker validated in coronary artery disease be relevant in studying plaque vulnerability in carotid/cerebral arteries? Understanding such distinctions is relevant to the broad application of the vulnerable plaque concept in predicting and preventing cardiovascular events.

A major potential utility of the vulnerable plaque paradigm is to identify apparently healthy subjects (or people with apparently stable plaques) who are at risk for future events. To date, however, almost everything we know about what constitutes a vulnerable plaque is based on studies in patients who have already suffered an event. In our systematic overview of the literature, only 3 of the 242 primary studies were conducted in patients without a known history of cardiovascular disease. In addition, the vast majority of studies were cross-sectional including all histopathological and biomarker studies, and 89% of imaging studies, and were mostly done with relatively small sample sizes. The 24 prospective studies identified in the literature had small sample sizes (median 64 patients, IQR 35-186), with a median duration of follow-up of 15 months (IQR 6-36). Therefore, large, prospective studies including patients without prior cardiovascular events over relatively long durations of follow-up are required to validate what we know from retrospective and cross-sectional studies. Such prospective studies would also have to identify the “individual” vulnerable plaque that develops into a culprit lesion. In the present literature overview, none of the 10 prospective imaging studies that followed patients for clinical outcomes documented that the “vulnerable” plaque was the one responsible for the clinical event during follow-up.21–28,36,37 This may be challenging since plaques within a given patient may progress largely independently.38 This ads to the complexity of predicting events from plaque imaging, and suggests local effects (e.g., physical forces) in addition to any systemic effects influencing plaque progression.

Once it is prospectively validated that certain plaque features are independently predictive of a future cardiovascular event, demonstrating the incremental utility of such a concept will be required. In applying the concept in individuals who are not considered high-risk by current criteria (typical of a primary prevention population), the positive predictive value of “plaque vulnerability” will be constrained by the prevalence or pretest probability of cardiovascular disease in the screened population.

Finally, once the incremental predictive utility of detecting a vulnerable plaque is established, it will have to be demonstrated that certain treatments (novel or currently in use) in patients who would otherwise not have been candidates will indeed improve outcomes. For example, would a statin reduce the risk of a future cardiovascular event in a patient who does not meet current treatment indications, but is found to have a “vulnerable plaque” on imaging? Would screening for such patients followed by selective treatment be more cost-effective than unselective treatment without screening? Such questions will need to be answered before the “vulnerable plaque” paradigm is routinely considered in the prevention and treatment of cardiovascular disease.

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