Medications used in the treatment of obesity and their classification.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"}]},book:{item:{type:"book",id:"3838",leadTitle:null,fullTitle:"Advanced Geoscience Remote Sensing",title:"Advanced Geoscience Remote Sensing",subtitle:null,reviewType:"peer-reviewed",abstract:"Nowadays, advanced remote sensing technology plays tremendous roles to build a quantitative and comprehensive understanding of how the Earth system operates. 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Roman",slug:"iulia-ioana-roman",email:"iuliaroman09@gmail.com",position:null,institution:null}]},book:{id:"7045",title:"Tailored Treatments in Psoriatic Patients",subtitle:null,fullTitle:"Tailored Treatments in Psoriatic Patients",slug:"tailored-treatments-in-psoriatic-patients",publishedDate:"July 17th 2019",bookSignature:"Shahin Aghaei",coverURL:"https://cdn.intechopen.com/books/images_new/7045.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"64024",title:"Associate Prof.",name:"Shahin",middleName:null,surname:"Aghaei",slug:"shahin-aghaei",fullName:"Shahin Aghaei"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11913",leadTitle:null,title:"Scheduling Algorithms for Information and Communication Systems",subtitle:null,reviewType:"peer-reviewed",abstract:"\r\n\tCoordinating, orchestrating, and scheduling tasks has been an art practiced by governments, companies, and managers for ages. The rise of Taylorism, standardisation, electrical systems, electronic systems and computing, and now, quantum computing, has given scheduling a whole World of importance.
\r\n\tFrom practice to a mathematical and technological application, scheduling has become another form of art: an algorithmic art, declined in as many OS and hardware constraints, from embedded systems onboard an aircraft or a spacecraft to databases in all financial and Internet servers.
\r\n\tThey have become ubiquitous so that a large part of our civilisational development is supported by their reliability, redundancy, and optimisation capacity. Like all of our civilisational assets, they are benefiting from scientific breakthrough in computational sciences such as evolutionary algorithms, Artificial Intelligence, and quantum computing. If not by using it, by being in need of adapting to the next generation of computing. Space development is also bringing new challenges, especially in redundancy and reliability.
Polycystic ovary syndrome (PCOS) is considered to be the most common endocrinopathy affecting women with an incidence ranging from 5 to 13% [1], depending on the diagnostic criteria applied.
\nPolycystic ovary syndrome—in spite of many years of research—is still a controversial topic. We have come to know in detail its clinical manifestations such as metabolic disorders, menstrual and ovulatory dysfunctions, and clinical hyperandrogenism. However, not knowing its etiology, most of the treatments suggested to patients with PCOS are symptomatic, not addressing to the underlying cause, but rather each symptom in part.
\nFollowing numerous studies and research on PCOS and despite that the exact mechanism is not completely understood, the conclusions of most researchers are the same; lifestyle change and weight loss have beneficial effects on the entire panel of symptoms associated with this syndrome.
\nUnder the metabolic disorders, which are commonly encountered in patients with PCOS, it is worth mentioning: obesity, insulin resistance, metabolic syndrome, dyslipidemia, and type 2 diabetes mellitus.
\nSome researchers state that the obesity rate in the case of the women with PCOS is even up to 70%, but most agree that at least half of the women with PCOS suffer from obesity (body mass index (BMI) = 19–25 kg/m2) [2] and in most cases, it is of a central distribution (waist circumference > 88 cm) [3]. Of the nonobese patients, one-third has increased intra-abdominal fat [4]. There is no specific data on why the prevalence of obesity is much higher in women with PCOS, but most researchers attribute it to the hyperinsulinemia resulting from the insulin resistance, an important factor of adipogenesis, lipogenesis, and lipolysis inhibition [5].
\nInsulin resistance and reactive hyperinsulinemia are definitely implicated in the physiopathological mechanism of PCOS. With respect to insulin resistance, some authors consider it to be uncorrelated to the degree of the obesity [6], while others argue that the obesity, especially the central one, seems to increase the metabolic and clinical features of insulin resistance [7]. Although obese patients seem to be more affected by insulin resistance, this also occurs in the cases of nonobese patients with PCOS [8].
\nThe metabolic syndrome is commonly associated with PCOS, with a prevalence ranging between 33 and 47% [9]. Both PCOS and the metabolic syndrome have features that generate an increased risk of cardiovascular diseases–if this risk is independent of PCOS or it is caused by its association with the metabolic syndrome, it is still a topic of debate [10]. Studies demonstrate that in patients with PCOS, even if the criteria for the metabolic syndrome are not fully met, there is at least one component of the metabolic syndrome [11].
\nThe research in the field demonstrates the presence of the risk factors for the metabolic syndrome in women with PCOS. Of these, the following appear to be important: the level of fasting insulin (which in these patients is doubled [12]) and obesity (an independent risk factor for the metabolic syndrome).
\nImpaired glucose tolerance (IGT) or even type 2 diabetes mellitus (T2DM) are common in patients with PCOS with a prevalence rate of 30–40% for impaired glucose tolerance and 7.5–10% for type 2 diabetes mellitus [13, 14]. The risk of patients with PCOS to develop these pathologies is considerably higher than in healthy patients. In these cases as well obesity appears to play an important role–impaired glucose tolerance and diabetes mellitus have an increased prevalence in obese patients (31.3% IGT and 7.5% T2DM) in comparison to nonobese patients (10.3% IGT and 1.5% T2DM) suffering from PCOS.
\nIt is not known exactly to what extent PCOS would be an independent risk factor for cardiovascular diseases but, unquestionably, through associated pathologies (obesity, increased resistance to insulin, IGT, T2DM, and/or dyslipidemia), it contributes to an increased risk [15].
\nMost experts consider that hyperandrogenism is the main characteristic of PCOS [16], whether is biochemically or clinically identified. Alteration in insulin action as well as enzymatic defaults has been discussed as possible pathogenic theories.
\nStudies suggest that the androgenic hyper-responsiveness that characterizes women with PCOS is probably due to the factors controlled by insulin sensitization rather than luteinizing hormone (LH), adrenocorticotropin hormone (ACTH), or ovarian steroids
The clinical correspondence of this intricate biochemical processes have incredible impact on patients’ quality of life and psychological status. Virilising signs and symptoms, acne and hirsutism are most often the first elements to lead to the clinical suspicion of PCOS.
\nObesity is a key metabolic entity in some PCOS patients. Because of its undeniable influence on insulin resistance, it has become a target to treat when identified. PCOS women, who are obese tend to have higher hirsutism and acne scores than their lean counterparts [16]. The consequent importance of weight loss is therefore essential to be taken into account. It is certified in medical literature that a weight loss of 5–10% can reduce hyperandrogenism and insulin levels [17]. Lifestyle modifications reside once again as the first step therapeutical management in patients with PCOS.
\nThe modified metabolic background associated with PCOS is basically characterized by unbalanced estrogen serum levels due to lack of progesterone production. Left untreated, the main effects of this modified environment leads to atypical endometrial hyperplasia, and endometrial dysfunction-induced infertility [18].
\nEven though progesterone-based oral contraceptive therapy is often efficacious [19], approximately 30% of women with PCOS fail to respond to such treatment [20] and progress to the development of atypical hyperplasia and further transformation to endometrial cancer [21].
\nThe mechanism of progesterone resistance is determined at molecular level and based on the imbalance of two progesterone receptor (PR) isoforms PRA and PRB. Patients with PCOS have a modified ratio of PRA to PRB receptors present on stromal and epithelial cells of endometrium [21].
\nProgesterone resistance is associated with insulin resistance [20] and this way, a new perspective in the prevention of endometrial hyperplasia can be contoured: targeted therapy on reducing insulin resistance may benefit both endometrial tissue and serum hyperinsulinemia.
\nAlthough most of PCOS-diagnosed patients complain about the inability to pursue a pregnancy, it is important to have in mind the situation when women diagnosed and treated for PCOS do not want to obtain a pregnancy.
\nA recent study states that in women aged 28–33 years old, women with PCOS were less likely to be using contraception (61 versus 79%, P < 0.001) and more likely to be trying to conceive (56 versus 45%, P < 0.001), compared with women not reporting PCOS [22]. However, the same study mentions that fewer women with PCOS (61%) were using contraception than women without PCOS (79%) (P = 0.001) [22].
\nBecause women with oligomenorrhea ovulate intermittently and rarely use contraception-unwanted pregnancy may occur.
\nAs part of the PCOS, infertility secondary to anovulation is usually the main complaint of patients diagnosed with this metabolic disorder.
\nPathological basis of infertility in this particular medical situation resides in the low Follicle-stimulating hormone (FSH) serum level, which is responsible for the impossibility of ovarian follicles to reach maturity due to their persistence in final growth stages.
\nAiming to treat this frequent cause of anovulation, there are two ways to ensure the wellbeing of the patient based on each woman’s choice: evaluating the options for further contraception or starting a therapeutical plan for inducing ovulation.
\nWith respect to the latter, inducing ovulation still remains a medical challenge in some patients with PCOS. There are a few known therapeutical approaches for achieving this: medical treatment with clomiphene citrate, tamoxifen, aromatase inhibitors, metformin, glucocorticoids, or gonadotropins or surgically management by laparoscopic ovarian drilling [23]; in vitro fertilization is also taken into consideration when all the other options failed to induce pregnancy.
\nTaking into account the morpho-clinical picture of the patients with PCOS and common sense, lifestyle changes and weight loss would, at first glance, be effective. It seems simple that by adopting a healthy lifestyle and weight loss, as with the patients who do not suffer from this pathology, it would improve the metabolic profile, reduce the risk of diabetes mellitus, cardiovascular disease or endometrial hyperplasia. Moreover, there are studies that discuss the complete or at least partial disappearance of the symptoms [24] and PCOS phenotype after weight loss.
\nStudies with various degrees of evidence have been conducted in an attempt to quantify their effect in patients with PCOS. While some parameters are certainly improved, there are still others involved in a series of controversies.
\nAn improved lifestyle will undoubtedly improve the distribution of the adipose tissue and will in most cases lead to weight loss. A weight loss of between 5 and 10% will ameliorate IGT and will decrease the prevalence of the metabolic syndrome and diabetes mellitus [25].
\nResearch suggests that these interventions are associated with lower fasting insulin levels and insulin resistance [26], and consequently a decreased risk for metabolic syndrome, cardiovascular disease, and diabetes mellitus [27].
\nIt has been shown that improvement of the lipid profile resulting from weight loss and lifestyle changes is nonuniform. Thus, in the case of some patients, a significant decrease in cholesterol levels will be observed while in others the change will be insignificant [24]. However, in all cases there will be a significant increase of high density lipoprotein (HDL)–cholesterol levels (thus reducing the risk of cardiovascular disease) and a decrease of triglyceride levels [24].
\nDuring the treatment, we also seek to improve the hormonal profile since PCOS being a pathology with deep hormonal implications. Unanimously, studies describe a decrease in the total testosterone level [28] and in androstenedione [29] as a result of lifestyle changes and weight loss. There is, however, controversy in terms of improving the level of SHBG and free androgen index (FAI) [29]. However, in all cases, an improvement in hirsutism will result when using the Ferriman-Gallwey (FG) score as an objective measuring method.
\nWhile the level of FSH increases as a result of lifestyle changes and weight loss, more by means of physical exercise than a result of diet [29], the level of LH does not seem to be improved by following a hygienic-dietary diet.
\nIn PCOS treatment, we aim to restore both normal menstrual function and fertility. In some cases, there may also be a decrease in ovarian volume and a reduction in the number of follicles [30] following weight loss and lifestyle changes. Ovulatory menstrual cycles can be obtained for obese women with PCOS, even when the weight loss is relatively low [31], thus increasing considerably the chances of getting pregnant. However, not all patients equally respond to these measures even if their weight loss is similar [24]. Hollmann et al. describe an 80% improvement in ovulation rate and 29% in the pregnancy rate in the case of a 10% weight loss [32].
\nAlthough the last decades have been revolutionary in terms of understanding this pathology, its etiology is not elucidated, hence we cannot talk about the existence of a curative treatment, but rather of symptomatic treatments. The spectacular evolution in this field also refers to the many symptomatic treatments, whose efficiency, although relatively high, address each symptom in part and not the pathology as a whole. The change in lifestyle, with all the developments in the last decades, still seems the most approachable and most effective treatment method, at the same time covering a broad spectrum of symptoms.
\nWhen we talk about lifestyle changes, we refer to a healthy lifestyle that involves exercise and weight loss. Although in many cases, patients are able to lose weight and lead a healthy lifestyle for a while, the difficulty they encounter is to maintain this lifestyle and their weight in the long run.
\nA solution to this problem is the behavioral treatment by “Burtyn and co.” designed specifically to help with this–a complex program that not only helps patients to lose weight efficiently but also to maintain their weight in the long term or even continue to lose more over time. Patients undergo this program for a period of 4–6 months under the supervision of a group of specialists: nutritionists and psychologists [33]. Patients learn how to choose healthy foods, how to ration their portions and how to get social support. After setting objective targets in terms of daily caloric intake, time spent on physical exercise and other behavioral changes, patients share in weekly or bi-weekly group sessions the obtained results. Specialists recommend patients to expect a weight loss of 0.5–1 kg per week, mentioning that the final target is a 10% decrease in weight relative to their initial weight [33]. They argue that by a comprehensive behavioral approach, patients manage to decrease 8–10 kilograms in weight and that about 80% of patients starting this program manage to complete it [34]. However, specialists mention that in the absence of weight maintenance therapy, regaining weight will be inevitable.
\nThe National Institute of Health also recommends psychotherapeutic and social support for these patients in order to manage to maintain their weight in the long run or even to further lose weight.
\nRegarding the type of diet, there are no clinically relevant data to prove the efficacy of any of them in the case of patients suffering from PCOS. However, based on food principles and taking into account that a decrease in carbohydrate intake would lead to a decrease in hyperinsulinemia, which in turn would lower insulin resistance, low-carbohydrate diets would be favored. Nevertheless, a comparative study between a high protein/low carbohydrate diet (40% carbohydrate, 30% protein, and 30% fat) and a low protein/high carbohydrate diet (55% carbohydrate, 15% protein, and 30% fat) proved the same efficacy in both cases [26] in terms of weight loss, waist circumference decrease and effects on insulin sensitivity. The same study emphasizes the importance of a calorific deficit in PCOS treatment, noting that the differences in dietary compounds are relatively insignificant when comparing their effect on metabolic and reproductive improvements [26]. A meta-analysis of 48 clinical trials involving a total of 2886 patients concludes that regardless of the type of diet and macronutrient on which they are based, there will be a relatively comparative weight loss–the same thing happening with maintaining weights at follow-up for 6 months and 12 months [35]. The impact of the type of macronutrients used in the diet is still debated. What is certain is that less energy intake than energy consumption will result in a weight loss. Thus, high-level metabolic studies conclude that a caloric intake of less than 1000 kcal/day will show results in all cases, with no exception.
\nNew diet hypothesis have emerged over the last few years, and here we want to mention the fast-paced ones, which are still under investigation and seem to be ground-breaking. Researchers believe that patients with PCOS might have significant benefits in terms of PCOS symptoms but also complications in the medium to long term if approaching this type of diets. The data we currently have on intermittent fasting diet obtained on rodent models are promising in terms of results. Thus, intermittent fasting diets, as compared to diets based on energy restriction of continued iso-energetic type, improve insulin sensitivity [36], provide protection for the cardiovascular system [37], and increase the lifespan of the rodent in the model. [38] Moreover, 3 days or more of the fasting will result in at least a 30% decrease in circulating insulin levels, glucose levels, and insulin-like growth factor 1 (IGF-1), which plays a key role in the metabolic homeostasis and changes associated with aging [39]. Current theories take into account the possibility that this type of diet can improve the symptoms of hyperandrogenism, based on the argument that improving insulin resistance would reduce compensatory hyperinsulinemia and ultimately the excess of androgen involved in the PCOS symptomatology.
\nFinally, we want to emphasize the importance of weight loss, pointing out the uselessness of this fact if the patients fail to maintain their long-term weight.
\nPhysical exercise is definitely a part of the lifestyle changes. Studies show that the type, frequency or duration of the exercise do not influence the results that patients get from it. It has been shown that regular, aerobic exercise of moderate intensity does not only contribute to weight loss and improved insulin resistance, but also improves reproductive outcomes, including ovulation and regulation of menstrual cycles. The recommendation for patients with PCOS in view of the improve reproductive and cardio metabolic outcomes is – aerobic physical activity of moderate intensity for 90 minutes per week [40].
\nIn a relatively recent past, following multiple clinical trials, medical journals supported the benefit of adding anti-obesity drugs to lifestyle changes–both in terms of maintaining weight in the long-term and reducing associated co-morbidities. Drugs such as sibutramine, orlistat, and rimonabant have been shown to be effective in improving the lipid profile, lowering blood pressure, glycosylated hemoglobin (in diabetics), and pro-inflammatory cytokine levels, thus reducing cardiovascular risk [41]. Meanwhile, it has been shown that the majority of these drugs instead of lowering cardiovascular risk have the opposite effect, which has led to their removal from the market [42].
\nCurrently, drugs used in the treatment of obesity are–orlistat, lorcaserin, phentermine-topiramate, bupropion naltrexone, liraglutide and noradrenergic sympathomimetic drugs but there are no specific studies with patients suffering from PCOS. A list of medication used to treat obesity is shown in \nTable 1\n.
\nDrugs that alter fat digestion | \nOrlistat | \n
---|---|
Serotonin agonists | \nLorcaserin | \n
Sympathomimetic drugs | \nPhentermine Diethylpropion Benzphetamine Phendimetrazine | \n
Antidepressants and antiepileptic drugs | \nBupropion Venlafaxine Desvenlafaxine Topiramate Zonisamide Lamotrigine Ziprasidone | \n
Diabetes drugs | \nMetformine Pramlintidine Exenatide Liraglutide | \n
Combination drugs | \nPhentermine-topiramate Bupropion-naltrexone | \n
Medications used in the treatment of obesity and their classification.
Orlistat, being an inhibitor of pancreatic and gastric lipases, inhibits the hydrolysis of triglycerides from the diet by up to 30%, thus reducing total caloric intake [41]. Hence, weight loss is not significant using this medication only and requires a calorie-restricted regimen. The X-PERT study establishes a 3-month weight loss that exceeds 5% of the initial weight as an accurate predictor of long-term weight loss. A 12-month meta-analysis concludes that patients undergoing lifestyle changes that also associate orlistat as an adjuvant medication will lose an average of 8–10 kg over 12 months as opposed to those who associate lifestyle change with a placebo who will lose an average of 3–6 kg [43]. In addition to weight loss, it has positive effects in reducing cardiovascular risk factors due to its effects on triglyceride and LDL cholesterol [41]. Moreover, in Orlistat treatment, a better glycemic control with decreasing fasting glucose and glycosylated hemoglobin is noticed [44]. This is considered to be a relatively safe drug, with adverse effects mainly upon the intestinal tract such as increased defecation, fatty stools, and fecal urgency.
\nLorcaserin is believed to activate serotonin 5-HT2c receptors stimulating pro-opiomelanocortin (POMC) neurons in the arcuate nucleus of the hypothalamus. Thus, it increases alpha-melanocortin stimulating hormone resulting in satiety and consequently in a decreased food intake [45]. Lorcaserin is indicated for the treatment of obesity when it is associated with at least one comorbidity such as type 2 diabetes mellitus, high blood pressure, high cholesterol or sleep apnea [46]. This is an alternative to orlistat, with similar efficacy but fewer side effects. In addition to weight loss, studies show that it lowers: blood pressure, heart rate, total cholesterol, LDL cholesterol, fasting glucose, and insulin levels.
\nNoradrenergic sympathomimetics, of which we currently find phentermine, diethylpropion, benzphetamine, and phendimetrazine, cause early satiety and reduce food cravings. Although they have increased effectiveness and their use is widespread, they are indicated for a treatment of a maximum of 12 weeks and have large potential for abuse. We must mention that all sympathomimetic drugs have side effects such as tachycardia, increased blood pressure, cause insomnia, constipation, nervousness, and dry mouth. In fact, their side effects on the cardiovascular system were those that caused the withdrawal of some drugs of this class from the market, such as sibutramine (removed from the market in 2010 [47] after it was shown to increase the risk of myocardial infarction and stroke [48]) or phenylpropanolamine (removed from the market due to association with increased risk of hemorrhagic stroke in women [49]).
\nAntidepressants and antiepileptics can affect weight in different ways, while some lead to weight gain, others to loss. Among the drugs that lead to weight loss, we mention: bupropion, venlafaxine, desvenlafaxine, topiramate, zonisamide, lamotrigine, and ziprasidone [45].
\nBupropion is an antidepressant commonly used in cases of smoking cessation, to prevent weight gain [50]. It can also be used in combination with naltrexone, although there are currently no data on an augmenting the effect of bupropion by naltrexone.
\nTopiramate is an antiepileptic agent that blocks neuronal voltage-dependent sodium channels, enhances gamma-aminobutyric acid (GABA) A activity and inhibits carbonic anhydrase, generating appetite suppression and satiety enhancement. Amongs its adverse effects, we mention paresthesia, somnolence, and metabolic acidosis. Studies recommend its use in combinations with other substances and not as a sole agent in the treatment of obesity.
\nZonisamide is another antiepileptic with serotoninergic and dopaminergic activity, which has effect on weight loss. Randomized trials in obese patients demonstrate that zonisamide at high doses is superior to placebo, while at low doses has effects similar to placebo [51].
\nMetformin is an anti-hyperglycemic biguanide, used in the treatment of type 2 diabetes mellitus. It reduces liver production and intestinal absorption of glucose and therefore insulin secretion. By its anti-lipolytic effect, free fatty acid concentrations and gluconeogenesis decrease [52, 53]. Numerous studies have been performed on obese patients with PCOS, who received metformin. While the first studies seemed to demonstrate its effects in terms of weight loss, decreased serum androgen levels (and implicitly hirsutism), restoration of menstrual cycles, and induction of ovulation [54], further studies concluded its ineffectiveness in treating hirsutism or increasing live birth rates, even if it is effective in increasing the ovulatory rates and pregnancy rates. Metformin is no longer used as a first-line treatment for oligomenorrhea or weight loss.
\nPramlintide is a synthetic analog of human amylin whose effect in terms of weight loss is relatively modest, due to its slowing effect on gastric emptying and the reduction in postprandial blood glucose concentration it causes.
\nExenatide is a long-acting synthetic peptide (GLP-1 -glucagon-like polypeptide-1-agonist receptor), the effect of which is the increased secretion of dose-dependent and glucose-dependent insulin. Its’ use is avoided because of the relatively low weight loss effect in conjunction with its mode of administration by subcutaneous injection [45].
\nLiraglutide, like exenatide, is a GLP-1 analog with significant weight-reducing effects. Studies in obese, non-diabetic patients have shown better efficacy against placebo at normal doses and even orlistat when administered in high doses [55]. Among its adverse effects when administered at high doses are included nausea and vomiting, which may in part contribute to the weight-loss effect [55]. This drug is quite often avoided due to its route of administration (subcutaneous injection) but also due to its potential adverse effects, that although rare, they are severe (pancreatitis, renal impairment and gallbladder disease). Further, we consider important to mention that rodent studies have demonstrated the association of this drug with the increased frequency of thyroid C-cell tumors (benign and malignant), which is why it is not recommended in the case of the patients with personal or family history of medullary thyroid cancers [56].
\nThe combination of phentermine and topiramate is another two drug combination with good effect in terms of weight loss, being pharmacologically included in the sympathomimetic anorexia class. Being a two drug combination, it has a complex mechanism of action. Thus, phentermine, which is a sympathomimetic amine, like amphetamines, will reduce the appetite after the stimulation of the hypothalamus and the release of the norepinephrine. Topiramate also has appetite suppressing effects and causes rapid satiety. Studies show that after a 1-year administration, the effect of this combination drug on weight loss decreases, but nevertheless it seems to contribute in maintaining the weight obtained up to that point [57, 58]. Side effects of this drug include dry mouth, constipation, paresthesia, psychiatric and cognitive impairment. It is also contraindicated during pregnancy, having teratogenic effects [59].
\nThe bupropion-naltrexone combination, though effective in weight loss, seems to have cardiovascular side effects, such as high blood pressure or tachycardia, so if it would be administered it would fail in addressing the underlying reason for initiating this therapy.
\nBariatric surgery is indicated in cases of morbid obesity (BMI = 40 kg/m2 or BMI greater than or equal to 35 kg/m2 associated with different comorbidities). A study that enrolled obese patients who underwent bariatric surgery divided the treated patients into 3 groups; obese with PCOS, obese with hyperandrogenemia characteristics but with regular menstrual cycles and a third group with obese patients without hyperandrogenic traits. After applying the exclusion criteria, the group of patients with PCOS was studied in detail and the results were surprising. Within 12 +/− 5 months, the weight loss was of 41 +/− 9 kg, associated with the improvement of clinical and biochemical markers of hyperandrogenism. It was noted that an improvement in hirsutism had been observed and from a biochemical point of view markers such as: free testosterone, total testosterone, androstenedione and dehydroepiandrostenedione sulfate have been normalized while the level of SHBG increased. From a metabolic point of view, the improved insulin sensitivity was proved by the decrease in fasting insulin levels. With regard to the reproductive system, the restoration of regular menstrual cycles and ovulation were noticed [60].
\nA newer study, conducted in 2012, concludes that weight loss after bariatric surgery is not associated with significant changes in the menstrual cycle, the luteal phase length or the amount of blood lost during menstruation. A relatively modest improvement was found with respect to biochemical hyperandrogenism but without effects on the clinical markers of hyperandrogenism. Instead, an 8–9 day follicular phase shortening associated with decreased fertility, was observed. What was new in this study was the finding that patients undergoing bariatric surgery after weight loss improve their sex life [61].
\nWe consider to be of major importance the adoption of a healthy lifestyle, composed of a hypo caloric diet and physical exercise that will generate weight loss. Unlike any other treatment, weight loss without adjuvant medication (which brings various side effects) in many cases leads to at least partial resolution of PCOS symptoms. Although in this chapter by enlarge we have approached the subject of slimming medications, we consider it important to use them only in carefully selected cases, lifestyle changes continue to be the first-line treatment.
\nThe authors certify that they have NO affiliations with or involvement in any organization or entity with any financial interest (such as honoraria; educational grants; participation in speakers’ bureaus; membership, employment, consultancies, stock ownership, or other equity interest; and expert testimony or patent-licensing arrangements), or non-financial interest (such as personal or professional relationships, affiliations, knowledge or beliefs) in the subject matter or materials discussed in this chapter.
The two main methods of revascularization in coronary artery disease are percutaneous coronary intervention (PCI) and coronary artery bypass surgery (CABG). In modern medicine, coronary artery bypass surgery is mostly reserved for the most severe or complex coronary artery disease. Patients who are status post-CABG can develop further coronary disease and myocardial ischemia in the years following surgery. As in any other patient who is suspected of having coronary artery disease, cardiac catheterization provides the definitive test (angiography) and is often the treatment modality of choice (PCI) in patients with prior CABG. This chapter aims to highlight the most important aspects of cardiac catheterization, coronary angiography, bypass graft angiography, and percutaneous coronary intervention in patients who are status post coronary artery bypass surgery.
The left internal mammary artery (LIMA) graft to the left anterior descending (LAD) coronary artery provides CABG with its primary benefit over PCI in multi-vessel disease. The LIMA is a branch of the left subclavian artery, which itself branches from the aortic arch. The LIMA arises from the inferior-anterior aspect of the subclavian artery and courses caudally down the left chest. This graft is generally used as an in situ graft with its free end anastomosed to a coronary artery (usually the LAD).
Other than the LIMA, other bypass graft options include the right internal mammary artery (RIMA), radial artery, and saphenous veins. Most often grafts to arteries other than the LAD utilize saphenous veins. These are harvested from the legs and an anastomosis is created most often from the ascending aorta to the target coronary artery. Rarely an in situ gastroepiploic artery is anastomosed to the right coronary artery or the inferior epigastric artery is harvested and used as a free graft anastomosed to the aorta.
Free arterial grafts are superior to saphenous vein grafts (SVGs) [1, 2] however their use is limited by several factors. Radial artery grafts must meet stringent requirements before harvesting for use in CABG. Rarely radial arteries cannot be used because they are too small, previously traumatized (i.e. prior transradial catheterizations), or supply all blood flow to the hand. The RIMA can also be used, either in situ or as a free graft, but the use of both the LIMA and the RIMA is associated with an increased risk of sternal wound infections [2]. For these reasons, SVGs remain the most frequently used graft other than the LIMA.
Most commonly grafts have a single origin and single terminal anastomosis. However, several variations are used by surgeons:
“Jump” or sequential grafts: Often a LIMA or SVG will be anastomosed side-to-side to an artery or branch and then the distal graft will be anastomosed end-to-side to a second artery or branch. For the LIMA it is typical to anastomose to a LAD-diagonal branch and terminate at the distal LAD. SVGs are often jumped from a first to a second obtuse marginal or from a right coronary artery (RCA) posterior descending branch to an RCA-posterolateral branch.
“Snake” or long circular grafts: In a technique that has fallen out of favor but still may be found occasionally, a single long saphenous vein graft is anastomosed to the aorta and then anastomosed side-to-side to the LAD and/or branches then to the circumflex branches and finally anastomosed end-to-side to the RCA.
Under unusual circumstances (e.g., a third CABG surgery) a surgeon may anastomose an SVG from the descending aorta to a coronary artery (usually the circumflex).
An in situ RIMA may be anastomosed to the circumflex, right coronary artery, or the right coronary posterior descending branch.
An in situ gastroepiploic artery may be anastomosed to the right coronary artery. This can be easily cannulated using a Judkins right (JR4) catheter to identify the hepato-splenic trunk, advancing the catheter over the wire into the hepatic artery and then the gastro-epiploic artery.
Y grafts: Surgeons may anastomose a free radial artery to a LIMA with the radial graft going to a diagonal branch of the left anterior descending and the LIMA ending at the LAD. Rarely surgeons will anastomose a SVG segment to an SVG in a similar fashion.
Common aortic “hoods” or “buttons”. Occasionally surgeons will anastomose two SVGs to a single spot on the aorta so that both arise from the same point.
Arterial grafts are more durable than venous grafts. When grafted to the LAD, the LIMA graft has a five-year patency rate of 91%, whereas vein grafts had a five-year patency rate of 78% [3, 4]. In patients who underwent CABG between 1995 and 2010, at a 7-year follow-up the patency of the LIMA was 87%, the patency of a radial artery graft to the RCA or LCx was 82%, and the patency of saphenous vein grafts was 58% [5].
Three processes lead to SVG failure, and the mechanism of failure can be predicted by the timing of failure. A useful rule of thumb is that about 10% of grafts occlude in under 1 month due to thrombosis or surgical issues, about 10% occlude between 1 month and 1 year due to intimal proliferation, in about 2–3% more occlude per year due to accelerated atherosclerosis. Within the first month after CABG, thrombosis (i.e. due to hypercoagulability) and technical failure (i.e. damage to or defects of the graft) are the predominant mechanisms. From the first month to the first year after CABG intimal hyperplasia is the predominant mechanism, a process in which smooth muscle cells proliferate and fibroblasts lay down extracellular matrix (also known as “arterialization” of the graft) in response to exposure to arterial pressures. And beyond the first year of CABG atherosclerosis is the predominant mechanism, a process that is accelerated in SVGs as compared to native arteries and in which unstable plaques often form [6].
The 2012 Appropriate Use Criteria for Diagnostic Catheterization provide indications for cardiac catheterization in patients with prior CABG [7]. Common indications include acute coronary syndromes or electrical instability. Emergent coronary angiography may be indicated for postoperative CABG patients who have clear signs of ischemia, unexplained hemodynamic instability, low cardiac output syndrome, electrical instability, diffuse electrocardiogram changes, new ischemic wall motion abnormalities, or very large troponin elevations after CABG. Troponin elevations of >10x the upper limits of normal qualify as type 5 myocardial infarction (MI) in the Fourth Universal Definition of Myocardial Infarction [6, 8, 9].
For stable patients, the indications are more limited. In general, asymptomatic patients should not undergo catheterization unless there is other evidence of extensive ischemia. Specifically, a small or even moderate-sized ischemic abnormality on stress testing would not warrant catheterization in a patient with no symptoms or atypical symptoms. The indication for catheterization strengthens as symptoms increase despite guideline-directed medical therapy or as the evidence for extensive ischemia increases. Consideration of catheterization in patients after CABG must balance the risks of catheterization (which are about twice those of diagnostic coronary arteriography in non-CABG patients) and the risks of subsequent PCI against the benefits of symptom relief or of diagnosing atypical symptoms. To our knowledge, no study has demonstrated improved survival from repeat PCI or CABG in any sub-group of post-CABG patients.
The approach to cardiac catheterization in a patient with prior CABG is the same as the approach to cardiac catheterization in patients without CABG for a right heart catheterization, left heart catheterization, and native coronary angiography. Graft arterography includes finding and selectively engaging each graft, usually one LIMA graft and one or more grafts arising from the ascending aorta.
It is critically important for the operator to know the details of the CABG surgery before starting catheterization, in order to plan access. For example, the best access for a patient with LIMA and RIMA grafts, or with the left radial used for CABG, may be femoral access. It is critically important for the operator to review the operative report because this is the only reliable roadmap to finding grafts. Downstream descriptions of the surgery become progressively unreliable. Specifically, the discharge summary is usually written by an advanced practice provider who may misinterpret the operative report, and subsequent summaries by cardiologists or primary care providers are routinely misleading. For example, a LIMA to the LAD with radial Y-graft to the diagonal and an SVG jumping from the second obtuse marginal to the RCA postero-lateral branch will be recorded in subsequent clinic notes as a 4-vessel CABG. But without details, the operator will not know how many anastomoses from the aorta to look for, or whether a graft will be arising from the right side of the aorta as is typical of grafts to the RCA. When the allowable contrast dose is limited by kidney disease it is particularly important to know details of coronary anatomy to prevent excessive test injections while searching for grafts.
When details of the surgery are unavailable, patients are usually reliable sources of the number of distal anastomoses. Usually, when patients are told the results of their surgery by the surgical team, they are told the number of distal anastomoses, which may exceed the number of proximal anastomoses. The wise operator will make sure all distal anastomoses are accounted for before ending a procedure.
Radial access decreases vascular complications compared to femoral access in patients without prior CABG. The same is true for patients after CABG, but left radial artery access is preferred since it offers easy access to the origin of the LIMA. In patients with the left radial artery harvested for use as a bypass graft, femoral access is usually used although experienced operators can non-selectively (and occasionally selectively) cannulate the LIMA using right radial access. With left radial access, the left arm can be pulled across the abdomen so the operator does not have to reach across the table. The use of the distal radial access site (“snuffbox approach”) can bring the access point even closer to the operator standing on the right side of the table. The RADIAL-CABG randomized trial compared femoral access to left radial access at a single center and demonstrated higher radiation doses, contrast volumes, and longer procedure times with left radial access as compared to femoral access; though radial access was associated with higher patient satisfaction. The crossover rate was higher (17%) in the transradial group compared to the transfemoral group [0%] [10]. A meta-analysis found fewer vascular complications with radial access [11].
Graft markers are used or not used variably by cardiac surgeons. Common varieties include a small disk usually placed above the aortic anastomosis, a horseshoe or wire ring around the proximal part of the graft, or occasionally just a clip by the aortic anastomosis. Often SVGs or in situ LIMA grafts will have clips where side branch veins were cut; these can lead like breadcrumbs along the course of the graft and give a hint as to the location of its terminus.
A typical patient will have a LIMA graft arising from the left subclavian anastomosing distally to the LAD and two or three free grafts, usually SVGs, with anastomoses from the aorta to the target vessel in the LCX system, RCA system, or a diagonal branch of the LAD. Our general approach is described in Table 1.
Graft | LIMA to LAD | SVG/radial to RCA | SVG/radial to LCX | SVG/radial to Diagonal | RIMA to LCX | In-situ GEA |
---|---|---|---|---|---|---|
Catheters | 1: JR4 2: IMA 3: VB1 | 1: Multi A 2: AL1/2 3: BG right | 1: JR4 2: AL2 3: Multi 4: BG left | 1: JR4 2: AL2 3: Multi 4: BG left | 1: JR4 2: IMA 3: VB1 | JR4 engages through the hepato-splenic artery |
View | AP cranial RAO Left lateral | LAO RAO RAO cranial LAO cranial | LAO RAO AP caudal | LAO cranial LAO RAO | LAO RAO | (Depends on anastomosed artery) |
An approach to bypass graft angiography.
The LIMA is engaged by finding its ostium in the subclavian artery. It may arise on the more proximal vertical section or on the more distal horizontal section of the subclavian. We use the anterior–posterior view although occasionally the right anterior oblique view will better separate the proximal LIMA from the subclavian. From left radial access, the JR4 catheter is advanced over a wire retrograde in the left subclavian to the LIMA ostium. From femoral access, the JR is advanced retrograde through the transverse aorta. Counter-clockwise rotation allows the operator to place the catheter sequentially in the right innominate, then the left carotid, and finally into the left subclavian. The JR4 catheter can be advanced over a wire distally into the subclavian. From either access point, the JR4 can be gently maneuvered proximally in the subclavian with gentle counter-clockwise rotation and test injections. If the origin of the LIMA is acute the JR4 can be exchanged over a wire for an IMA catheter and maneuvered similarly. For a severely angulated LIMA origin, a VB-1 or similar catheter with a pigtail-like curve can be positioned beyond the ostium and pulled back to engage the LIMA ostium (Table 2).
Name | Type | Study |
---|---|---|
GuardWire | Distal balloon | SAFER demonstrated improved rates of periprocedural MI and no-reflow as compared to usual therapy |
TriActiv | Distal balloon | PRIDE demonstrated noninferiority to the GuardWire and FilterWire |
FilterWire* | Distal filter | FIRE demonstrated noninferiorty to the GuardWire |
SpideRx* | Distal filter | SPIDER demonstrated noninferiority to the GuardWire and FilterWire |
CardioShield | Distal filter | CAPTIVE failed to demonstrate noninferiority to the GuardWire |
Proxis | Proximal balloon | PROXIMAL demonstrated noninferiority to the GuardWire and FilterWire |
Free grafts to the other coronary arteries (i.e. SVGs or radial grafts) are found in the proximal ascending aorta. The grafts are found by selecting a catheter and searching the aorta above the level of the coronary arteries. Right coronary artery grafts will be located on the right side of the aorta whereas left circumflex and diagonal grafts will be located on the left or posterior aspects of the aorta. Generally, grafts are arranged in the following ascending position in the aorta: RCA grafts lowest in the aorta, followed by LAD grafts (if there is SVG to LAD) located a little higher, followed by diagonal branch, then left circumflex first obtuse marginal, second obtuse marginal, and circumflex posterolateral grafts highest in the aorta. We favor multi-purpose shapes (or right bypass graft shape) for grafts to the RCA (which usually have a downward takeoff). Grafts to diagonal branches or circumflex branches may be cannulated with the JR or multi-shaped catheter, but if necessary Amplatz-shaped catheters or left bypass graft catheters can be used. For all of these, we use a clockwise rotation of the catheter with frequent test injections to engage grafts.
On occasion, it can be hard to find all of the grafts. When searching for grafts, start with a specific catheter for the suspected graft as described above. A proximally occluded graft may be demonstrated by test injections showing a short stump in a side view or a circle in an end-on view. Occasionally grafts are flush occluded at the aorta and cannot be identified. For RCA grafts it is important to point the catheter downward in the graft using a slight counter-clockwise torque since injection in the proximal graft orthogonal to its direction can mimic a total occlusion. Consider that a graft may arise from an unusual location on the ascending aorta or even from the descending aorta [13], or that a RIMA or gastroepiploic artery may have been used. When all else fails, non-selective aortography can be performed although it does not reliably demonstrate all patent grafts. The last option for finding a graft would be a CT or MRI angiogram.
It may be helpful to identify native vessels that appear to have been grafted. Occasionally the stump of the graft where it is terminally anastomosed to the vessel may be seen. In other cases where the graft has flush-occluded, a characteristic upward omega-bend of the native vessel caused by scarring/retraction of the graft after surgery may reveal where the graft was anastomosed to the native vessel. Occasionally a segment of a jump graft between two native branches will remain patent even after the graft from the aorta to the first anastomosis has occluded.
PCI in patients who are post-CABG is common. Data published from the NCDR CathPCI registry in 2011 show that PCI in prior CABG patients represents 17.5% of all PCIs. Native arteries were targeted alone in 62.5% of PCI in prior CABG patients, saphenous vein grafts were the target in 34.9%, and arterial grafts were the target in 2.5% [14]. A similar observational analysis from VA medical centers in 2016 showed overall similar data (73.4% of PCI was in a native artery, 25.0% in an SVG, and 1.5% in an arterial graft). The VA analysis demonstrated that procedure-related complications were more frequent in bypass PCI patients compared to those without, including in-hospital mortality, procedural complications, peri-procedural MI, no-reflow, and dissection. The patients who received PCI to graft lesions were also noted to have higher mortality, MI, and revascularization at 1 and 5 years of follow-up [15].
Indications for PCI in post-CABG patients are similar to those without prior CABG. Graft lesions causing acute coronary syndromes may undergo PCI or may be used as conduits for retrograde PCI of the native vessel to which they anastomose. In stable patients, PCI is generally not indicated for asymptomatic patients. The strength of indication for PCI increases as the severity of symptoms despite guideline medical therapy increases.
There are several issues with intervention on SVGs, and as such, the operator must carefully consider their options before embarking on SVG intervention. SVG intervention carries a high risk of distal embolization, no-reflow, and peri-procedural MI. Degenerated vein grafts are noted in both the ACC/AHA and SCAI classification schemes to be high-risk lesions and to have worse outcomes as compared to low-to-intermediate risk native vessel lesions [16]. Several principles affect decisions regarding SVG intervention.
A first principle of vein graft intervention is that PCI in vein grafts is less reliable than PCI of native coronary arteries. Observational data suggest that PCI to SVGs is associated with worse outcomes than PCI to native coronary arteries [15, 17, 18]. For this reason, when reasonable, restoration of blood flow by performing PCI to the native vessel is preferred to PCI of the SVG. Preferencing PCI to the native artery where possible is given a Class 2a recommendation in the updated 2021 ACC/AHA Coronary Artery Revascularization guidelines [19]. It should be noted that this strategy is complicated by the high rate of CTOs in bypassed native arteries, and referral to a physician with experience in complex coronary disease and CTO may be necessary [20, 21]. A strategy of PCI to the SVG followed by staged PCI to the native artery, especially in the setting of acute MI, may be useful [22]. Intentional iatrogenic occlusion of the SVG after native vessel PCI may be beneficial to reduce competitive flow [23, 24].
A second principle is that intermediate lesions should in general be treated medically. Two trials, VELETI and VELETI II studied the utility of stenting intermediate SVG lesions. While there was a trend in the VELETI pilot study towards improved outcomes with stenting, the larger VELETI II study showed no benefit [25, 26, 27]. Additionally, the use of FFR has been studied in intermediate lesions. While there may be benefit to the use of FFR in arterial grafts, no benefit was seen in SVG lesions and should probably not be used in this setting [28].
A third principle is that PCI to CTOs of SVGs is not of benefit and should not be performed. Chronic total occlusions of SVGs were studied in a retrospective study published in 2010 that found success rate of PCI of SVG CTO was 68%. In the successful PCI group, the ISR rate was 68% and TVR rate was 61% with a median follow-up of 18 months [29]. Due to the low success rates and high rate of revascularization, current guidelines give PCI of SVG CTOs a Class 3: No Benefit designation [19].
Bare-metal stenting was clearly an improvement over balloon angioplasty for SVG lesions. The Saphenous Vein in De Novo (SAVED) trial compared bare-metal stents to balloon angioplasty for focal, de-novo SVGs lesions. Stenting increased the procedural success, demonstrating 92% success with BMS versus 69% for angioplasty [30]. This benefit of BMS as compared to balloon angioplasty alone was reinforced with data from the Venestent trial [31].
Several studies have examined the use of bare-metal versus drug-eluting stents in SVG PCI. The RRISC trial initially demonstrated improved outcomes of DES as compared to BMS [32], however the DELAYED RRISC study (a post hoc analysis of the RRISC trial) appeared to support increased mortality of patients treated with DES as compared to BMS [33]. Subsequent randomized controlled trials and meta-analyses have however demonstrated the safety of DES in SVGs [34, 35]. In addition to some smaller trials, two larger RCTs compared DES to BMS: ISAR-CABG and DIVA. While ISAR-CABG did demonstrate lower target lesion revascularization with DES as compared to BMS at 12 months [36], by follow-up at 5 years no difference between DES and BMS was observed [34]. The DIVA trial showed no difference at 12 months between DES and BMS [37]. A meta-analysis of the available RCTs done in 2018 showed no difference between DES and BMS [35]. Of note, in the ISAR-CABG trial, most stents were first-generation, while in the DIVA trial most stents were second-generation indicating that neither first nor second-generation DES stents are an improvement over BMS [35]. Two retrospective studies have found no difference between first- and second-generation DES [38, 39].
Directly stenting SVG lesions (as opposed to performing pre-dilation) might prevent distal embolization. One observational study done in 2003 indicated that direct stenting decreased post-procedural MB-CK elevation, and the one-year composite endpoint of death, Q-wave MI, and target lesion revascularization [40].
Under-sizing stents may improve outcomes in SVG PCI. Hong et al. in 2010 examined a series of patients who underwent SVG PCI with IVUS. They compared patients based on the ratio of stent diameter to vessel diameter and found that patients with relatively under-sized stents had fewer post-procedural CK-MB elevations without worse outcomes at 1 year [41].
SAFER was a trial in which a distal balloon device called the GuardWire demonstrated a significant decrease in peri-procedural MI and a decrease in no-reflow [42]. The GuardWire is a distal balloon embolic protection device wherein the balloon is inflated distal to the PCI target. The operator then stents the lesion and aspirates the blood containing post-PCI embolic debris out of the vessel before deflating the balloon [42]. The FIRE trial compared a device called the FilterWire, a distal filter-based device, against the GuardWire and showed non-inferiority [43]. Numerous other trials have been investigated (see table below), but all of these trials were in some way compared their device to the GuardWire to show non-inferiority as opposed to a comparison against usual therapy. The TRAP trial would have been a second RCT but was ended due to lack of enrollment and was therefore under-powered; the trend however was of findings consistent with SAFER (decreased peri-procedural MI) [44].
There have been multiple analyses since these trials in the early 2000s looking at EPDs. Iqbal et al. examined the British Columbia Cardiac Registry and showed that patients undergoing SVG PCI had improved post-procedural TIMI flow after EPD use, however had no difference in TVR or mortality at 2 years [45]. Brennan et al. examined the Cath PCI database and showed no difference in rates of death, MI, or TVR with the use of EPDs but did show increased rates of no-reflow, vessel dissection, perforation, and periprocedural MI with the use of EPDs [4]. Paul et al. performed a meta-analysis and review in 2017, which suggested no benefit to EPD use in SVG intervention [46].
The 2011 ACC/AHA guidelines on PCI gave the use of embolic protection devices (EPDs) a Class I recommendation based upon strong randomized control trial evidence from the SAFER trial. However, with the subsequent data described above, current guidelines downgrade the recommendation for use of EPDs from Class I (in 2011) to Class IIa (in 2021) [19, 47]. Despite the data supporting EDP use, estimates of usage rates in SVG lesions based on large registry data range from 14–22% [48, 49]. EPD use may be discouraged by the technical difficulty of using these somewhat bulky devices [49].
In summary, the only randomized trial data available shows the benefit to use of EPD. Multiple other EPDs have shown non-inferiority to the GuardWire. EPDs can be difficult to use which significantly limits their use in clinical practice. And while significant observational data have called into question the findings of the SAFER trial, guideline recommendations are unlikely to change significantly until further RCTs are performed.
In general, antiplatelet drugs are used in the same way post SVG PCI as they would be used post native vessel PCI. The PLATO trial demonstrated the efficacy of ticagrelor over clopidogrel in ACS patients. A post hoc analysis of PLATO showed that ticagrelor was as effective for post-CABG patients as it was for no-CABG patients [50]. In addition, SVG lesions are high-risk lesions and may benefit from more intensive antiplatelet therapy than some native vessel lesions. The DAPT trial showed that in patients who had SVG PCI, there was less stent thrombosis with 30 months of DAPT as compared to 12 months of DAPT [51]. An analysis of the DAPT study developed and validated a prediction rule intended to determine patients who would benefit most from prolonged DAPT. In the generated scoring system, the presence of a vein graft stent was one of the strongest predictors of deriving benefit from prolonged DAPT [24].
The use of GP IIb/IIIa inhibitors does not appear to be of benefit. A meta-analysis of five randomized trials published in 2002 showed that the use of GP IIb/IIIa inhibitors in graft interventions provided no benefit and had an association with worse outcomes [52].
The use of anticoagulants is similar in SVG PCI as in native-vessel PCI. Heparin is the dominant drug used, however, bivalirudin has been shown to be safe and effective [53].
Vasodilator drugs may decrease the rate of no-reflow in SVG PCI. Adenosine, nitroprusside, and the calcium channel blockers verapamil and nicardipine have been investigated. Overall, the quality of the evidence is low however all the studies show some degree of improvement in no-reflow, post-procedural CK-MB elevation, or both in association with the use of vasodilators [54, 55, 56, 57]. Nicardipine is often preferred as it causes less hypotension and a longer duration of action [58].
The CORAL trial examined the use of excimer laser coronary atherectomy before stenting. The study failed to enroll enough patients and so they compared laser atherectomy with a stent to the SAFER data (control and EPD groups). The rate of MACE, driven by peri-procedural MI, was lower in the SAFER GuardWire group [59]. One case–control registry indicated that ELCA showed better angiographic outcomes and lower rates of Type IVa MI as compared to distal embolic protection devices [60].
The VeGAS 2 trial compared the AngioJet rheolytic thrombectomy device to urokinase infusion for SVG thrombus. The AngioJet creates a local vacuum using high-velocity water jets, with the intention of sucking thrombus into the catheter for degradation and removal. AngioJet did show some improvements over urokinase infusion, especially in the rates of procedural success, non-Q-wave MI, and vascular complications [61].
Arterial grafts are significantly more durable and significantly fewer in number than venous grafts, and they are therefore significantly less likely to be the targets of PCI. PCI in arterial grafts is generally more successful and with lower complication rates than in PCI of vein grafts [14, 15].
The IMA is the most important arterial graft, and there are a few relevant points regarding PCI in these arteries. The risk of complication is not negligible. The most common cause of unsuccessful PCI in an IMA graft is excessive vessel tortuosity. Straightening a tortuous LIMA can cause pseudolesions which may cause ischemia; this effect must be distinguished from vasospasm (as it will not improve with vasodilators) and dissection. Removal of the guidewire should resolve a pseudolesion [58]. Tortuous subclavian arteries may be an issue as well – ipsilateral (usually meaning left) radial access can help in this case. On occasion, coronary ischemia in the distribution of the IMA can be caused by a stenosis of the subclavian artery proximal to the IMA graft, and PCI of the subclavian artery (by an experienced peripheral operator) can relieve the ischemia [62].
Ostial dissections can occur in IMA PCI and therefore the ostium should be evaluated at the end of an IMA PCI procedure. PCI of distal anastomotic IMA lesions has been shown to have better outcomes (less restenosis) with balloon angioplasty as compared to stenting; stents are typically used in lesions of the ostium and the body of IMA grafts [63, 64].
Indications for catheterization and PCI in post-CABG patients are similar to those for patients without CABG. Graft anatomy (taken from the source CABG operative report) should be known before starting a diagnostic procedure. Diagnostic procedures involving grafts are more difficult, require more time, contrast, and catheters, and produce more complications than procedures in patients without prior CABG. A set of unique “tricks” is required to selectively cannulate all grafts known to be present. PCI of grafts, particularly of SVGs, produces frequent complications and is often followed by restenosis. PCI of the native vessel supplying the grafted territory, either antegrade or retrograde, which may be preferred over graft arteriography. As the incidence of CABG is decreasing over recent decades, the number of post-CABG patients undergoing catheterization is decreasing. However, the ability to perform angiography of post-CABG patients will continue as a required skill of invasive interventional cardiologists.
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