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Cardiac complications are the major cause of perioperative morbidity and mortality, which may occur in 1-5 percent of unselected patients undergoing major vascular surgery [1]. [Q1: A] This high frequency of cardiac complications is related to the high prevalence of coronary artery disease; 54 percent of patients undergoing major vascular surgery have advanced or severe coronary artery disease and only 8 percent of patients have normal coronary arteries [2]. Perioperative cardiac complications are equally caused by prolonged myocardial ischemia or by coronary artery plaque rupture with subsequent thrombus formation and coronary artery occlusion [1, 3]. [Q1: B, C, D] Prolonged perioperative myocardial ischemia usually occurs from either increased myocardial oxygen demand or reduced supply, or from a combination of the two. There are several perioperative factors that can increase myocardial oxygen demand including tachycardia and hypertension resulting from surgical stress, postoperative pain, interruption of beta-blocker use, or the use sympathomimetic drugs. Decreased oxygen supply, on the other hand, can occur as a result of hypotension, vasospasm, and anemia, hypoxia or coronary artery plaque rupture. Beta-blockers primarily reduce myocardial oxygen demand, while statins may prevent coronary artery plaque rupture. [Q2: A, B]

Beta-Adrenergic Antagonists

Several retrospective and prospective clinical trials have shown that perioperative use of beta-blockers is associated with reduction in the incidence of postoperative myocardial ischemia, nonfatal myocardial infarction and cardiac death [4-6]. [Q2: A] The majority of these studies were small in sample size, and the studies were designed to explore the protective effect of beta-blockers for the reduction of perioperative myocardial ischemia. To overcome the limitations of these studies two randomized clinical trials addressed the issue of perioperative use of beta-blockers for the prevention of cardiac death and myocardial infarction. Mangano et al. [7] studied the effect of atenolol on mortality and cardiovascular morbidity after non-cardiac surgery including vascular surgery. The investigators enrolled and randomized 200 patients to atenolol (given intravenously before and immediately after surgery and orally thereafter for the duration of hospitalization) or placebo. No difference was observed in 30-day mortality but mortality was significantly lower at 6 months following discharge (0% vs. 8 %, p < 0.001), over the first year (3% vs. 14%, p = 0.005), and over 2 years (10% vs. 21%, p = 0.019). The apparent lack of a perioperative cardioprotective effect of atenolol in this study was probably related to the small sample size, and the fact that patients at low risk for cardiac complications were studied. In a more recent study, Poldermans et al. [8] clearly demonstrated the cardioprotective effect of perioperative beta-blocker use for the reduction of perioperative cardiac death and myocardial infarction in high-risk patients undergoing major vascular surgery. In total, 112 high-risk vascular patients were selected using a combination of cardiac risk factors and positive results on dobutamine stress echocardiography. Patients were then randomly assigned to standard care or standard care with bisoprolol use. Bisoprolol was started at least 30 days prior to surgery; the dose was adjusted to aim at a resting heart rate of 60-70 bpm. [Q3: A, B, C, D] The results showed that the incidence of the combined endpoint of cardiac death and myocardial infarction within 30 days of surgery was significantly lower in patients using bisoprolol compared to patients in the control group (combined endpoint 3.3% in the bisoprolol group vs. 34% in the control group). Based on the findings of these studies, beta-blocker use has been recommended by the ACC/AHA Guidelines on Perioperative Cardiovascular

Evaluation for Noncardiac Surgery in high-risk patients with a positive stress test as a level one recommendation [4].

3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase Inhibitors (Statins)

Although perioperative use of beta-blockers has been associated with a significant reduction in cardiac mortality and morbidity, still some patients with multiple cardiac risk factors and positive stress test results may remain at considerable risk for perioperative cardiac mortality [9]. For these patients additional cardioprotec-tive medication such as statin use may offer an important addition to preoperative risk reduction strategies. The association between statin use and possible reduction in perioperative cardiac complications may result from the favorable actions of statins on atherosclerosis and from their vascular properties other than those attributed to cholesterol lowering [10-12]. [Q4: A, B, C] These so-called pleiotropic effects of statins may attenuate coronary artery plaque inflammation and influence plaque stability in addition to antithrombogenic, antiproliferative and leukocyte-adhesion inhibiting effects [13-15]. All these effects of statins may stabilize unstable coronary artery plaques, thereby reducing myocardial ischemia and subsequent myocardial damage.

There are only a few studies that have evaluated the beneficial effects of perioperative statin use in reducing perioperative cardiac complications [16-18]. Poldermans et al. [16], using a case-control study design in 2816 patients who underwent major vascular surgery, showed that controls more often were statin users than cases, which resulted in a fourfold reduction in all-cause mortality within 30 days after surgery. This finding was consistent in subgroups of patients according to type of vascular surgery, cardiac risk factors and beta-blocker use. [Q2: D] Similar to these findings, Durazzo et al. [17] also reported a significantly reduced incidence of cardiovascular events within 6 months of vascular surgery in patients who were randomly assigned to atorvastatin compared with placebo (atorvastatin vs. placebo, 8.3% vs. 26.0%). Finally, the study results of Lindenauer et al. [18] indicated that statin use was associated with 28 percent relative risk reduction of in-hospital mortality compared to no statin use in 780,591 patients undergoing major noncardiac surgery. [Q4: D] The results of these studies are important indications of the possible beneficial effect of perioperative statin use. However, certain limitations such as the retrospective nature of the study of Poldermans et al. and Lindenauer et al., the relatively small sample size (n = 100 patients) of the study of Durazzo et al., and the lack of information about the optimal timing and duration of statin therapy warrant future clinical trials to confirm the effectiveness and safety of statin therapy in patients undergoing major noncardiac surgery. Initially, statin use was contraindicated in the perioperative period as it was thought that drug interactions might increase the incidence of myopathy and in combination with analgesics this might even remain asymptomatic. However, a recent study showed no increased incidence of myopathy among statin users [19]. Statin users undergoing vascular surgery at the Erasmus MC were screened for myopathy by measuring creatine kinase (CK) levels at regular intervals and checking for clinical symptoms. In 981 patients no relation was found between statin use and CK levels. Also, no patient experienced myopathy symptoms. Importantly, no deleterious effect of temporary statin interruption was observed. [Q2: C and Q4: B, C]

Preoperative cardiac risk evaluation may identify high-risk patients for whom the risk of perioperative cardiac complications without further coronary assessment and subsequent intervention could be too high. For these patients either percutaneous transluminal coronary angioplasty (PTCA) or coronary artery bypass grafting (CABG) may be considered.

Percutaneous Revascularization

There have been several studies evaluating the clinical utility of PTCA in high-risk patients undergoing major noncardiac surgery including vascular surgery. In the studies of Elmore et al. [20] and Gottlieb et al. [21], retrospective data were collected of patients who underwent PTCA prior to surgery. These patients were referred for PTCA because of the need to relieve symptomatic angina or to treat myocardial ischemia identified by noninvasive testing. The findings of these studies indicated that the incidence of perioperative cardiac death and myocardial infarction was low, but the investigators in these studies failed to use a comparison group of patients with coronary artery disease not treated with PTCA. The apparent limitations of these studies prompted Posner et al. [22] to conduct their own investigation to compare adverse cardiac outcomes after noncardiac surgery in patients with prior PTCA, patients with non-revascularized coronary artery disease and normal controls. The results showed that patients treated with PTCA within 90 days of noncar-diac surgery had a similar incidence of perioperative events to matched patients with coronary artery disease who had not been revascularized. [Q5: A] Those patients who underwent a PTCA procedure 90 days earlier then the day of noncardiac surgery had a lower risk of cardiac events than non-revascularized patients but not as low as normal controls. Furthermore, the effect of revascularization was limited to a reduction in the incidence of angina pectoris and congestive heart failure and there was no reduction in the incidence of death and nonfatal myocardial infarction. Indeed, the recent findings of the Coronary Artery Revascularization Prophylaxis (CARP) trial [23] also showed that coronary revascularization with PTCA or CABG prior to vascular surgery in high-risk cardiac stable patients did not provide short-term survival benefit or better long-term event-free survival rate. [Q5: B, C, D] The findings of the study indicated that patients undergoing coronary revascularization prior to vascular surgery had a 3.1 percent mortality rate within 30 days of vascular surgery compared to a 3.4 percent rate for those not having coronary revascularization (p = 0.87). Additionally, the rate of perioperative nonfatal myocardial infarction as detected by troponin elevation was also similar in coronary revascularization patients and patients not undergoing coronary revascularization (11.6% vs. 14.3%, p = 0.37). Furthermore, the results of the trial also indicated that coronary revascularization prior to vascular surgery was associated with delay or cancellation of the required vascular operation. Apart from these findings, it is also important to note that if a PTCA procedure and coronary stent placement are performed less than 6 weeks before major noncardiac surgery, the risk of perioperative coronary thrombosis or major bleeding complications may be substantially increased [24, 25]. Two separate small-scale studies reported an increased rate of serious bleeding complications if antithrombotic therapy was continued until the time of surgery, and in patients in whom antiplatelet drugs were interrupted one or two days before surgery an increased rate of fatal events was observed due to stent thrombosis [24, 25]. The risk of these complications persisted for 6 weeks after coronary stent placement. Patients who underwent surgery more than 6 weeks after coronary stent placement experienced no adverse cardiac events. These observations indicate that if PTCA with stenting is planned in the weeks or months before noncardiac surgery then a delay of at least 6 weeks should occur before noncardiac surgery to allow for completion of the dual antiplatelet therapy and re-endothelial-ization of the stent.

Coronary Artery Bypass Grafting

The results of the largest retrospective study to date indicated that CABG had a protective effect prior to noncardiac surgery [26]. Data for 3368 patients analyzed from the Coronary Artery Surgery Study (CASS) registry showed that patients who underwent CABG before abdominal, vascular, thoracic, or head and neck surgery had a lower incidence of perioperative mortality (3.3% vs. 1.7%) and myocardial infarction (2.7% vs. 0.8%) compared with medically treated patients. The largest reduction in perioperative mortality was observed in patients with a history of advanced angina and in patients with multivessel coronary artery disease. In a more recent study, data analyzed from a random sample of Medicare beneficiaries showed that preoperative coronary revascularization was associated with a reduction in 1-year mortality for patients undergoing aortic surgery but showed no effect on mortality in those undergoing infrainguinal procedures [27]. Hassan et al. [28], using data from the Bypass Angioplasty Revascularization Investigation, showed there was no difference in the incidence of cardiac death and myocardial infarction between patients who underwent coronary angioplasty or CABG and subsequent noncardiac surgery (coronary angioplasty group, 1.6% vs. CABG group, 1.6%). [Q5: A] As mentioned above under 'Percutaneous revascularization', the recent findings of the CARP trial showed that high-risk patients randomized to coronary revascularization prior to vascular surgery had no better perioperative and long-term cardiac complication rates than medically treated patients. Therefore, in the light of these findings a decision to proceed with coronary angioplasty and selective revascularization before high-risk surgery should be made independent of the need for major noncardiac surgery [4].

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