Question 5

Preoperativecoronaryrevascularizationseemstobeanattractiveoptiontoimprovenotonly direct postoperative outcome in high-risk patients but also long-term survival after surgery.

A.  Preoperativecoronaryrevascularizationimprovespostoperativeoutcomeinallpatients with significant coronary artery disease prior to major vascular surgery.

B.  Preoperative coronary revascularization in patients with oneor two-vessel disease is not associated with an improved postoperative outcome compared to patients receiving medical therapy.

C.  Preoperative coronary revascularization is associated with an improved 2-year outcome compared to medical therapy.

D.  Patients with proven coronary artery disease who are treated medically are at increased risk of late coronary revascularization after surgery. After late revascularization, longterm outcome is similar to that with revascularization prior to surgery.

This 72-year-old male had multiple cardiac risk factors: elderly age, angina pectoris, diabetes mellitus, and a previous MI. He underwent a noninvasive stress test, dobutamine stress echocardiography, which showed myocardial ischemia, suggesting left anterior descending artery (LAD) disease. Beta-blockers and statins were prescribed and continued during surgery. Surgery was uneventful; after 2 years angina pectoris complaints increased and a PTCA procedure was successfully performed on the LAD.

1.1  Commentary

Cardiac complications are the major cause of perioperative morbidity and mortality, which may occur in 1–5% 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% of patients undergoing major vascular surgery have advanced or severe coronaryarterydiseaseandonly8%ofpatientshavenormalcoronaryarteries.2 Perioperative cardiaccomplicationsareequallycausedbyprolongedmyocardialischemiaorbycoronary 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. Thereareseveralperioperativefactorsthatcanincreasemyocardialoxygendemandincluding 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 coronaryarteryplaquerupture.Beta-blockersprimarilyreducemyocardialoxygendemand, while statins may prevent coronary artery plaque rupture. [Q2: A, B]

1.2 

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 overcomethelimitationsofthesestudiestworandomizedclinicaltrialsaddressedtheissue 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 noncardiac surgery including vascular surgery. The investigators enrolled and randomized 200 patientsto atenolol (given intravenously beforeand immediatelyafter surgery and orally thereafter for the duration of hospitalization) or placebo. No difference wasobservedin30-daymortalitybutmortalitywassignificantlylowerat6monthsfollow- ing 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 betablocker 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, betablocker use has been recommended by the ACC/AHA Guidelines on Perioperative CardiovascularEvaluation for Noncardiac Surgery in high-risk patients with a positive stress test as a level one recommendation.4

1.3 

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

Although perioperative use of beta-blockers has been associated with a significant reductionincardiacmortalityandmorbidity,stillsomepatientswithmultiplecardiacriskfactors and positive stress test results may remain at considerable risk for perioperative cardiac mortality.9 For these patients additional cardioprotective medication such as statin use may offer an important addition to preoperative risk reduction strategies. The association

betweenstatinuseandpossiblereductioninperioperativecardiaccomplicationsmayresult from the favorable actions of statins on atherosclerosis and from their vascular properties otherthanthoseattributedtocholesterollowering.10–12 [Q4:A,B,C]Theseso-calledpleio- tropic 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 2,816 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, cardiacriskfactorsandbeta-blockeruse.[Q2:D]Similartothesefindings,Durazzoetal.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, thestudyresultsofLindenauer et al.18 indicated that statin use was associated with 28% relative risk reduction of in-hos- pital 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. The most recent data are provided by the DECREASE-III study, studying the effect of Leschol XL 80 mg (fluvastatin) in vascular surgery patients compared to placebo, on top of optimal beta-blocker therapy. As shown in almost 500 patients, there was a nearly 50% reduction of the composite end point of myocardial ischemia and myocardial infarction. Importantly, these results were achieved in patients with a slightly elevated LDL-cholesterol level and associated with a reduction of inflammation markers such as interleukin 6 and high-sensitive CRP.20 [Q2: C] [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.

1.4 

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 etal.21 andGottliebetal.,22 retrospectivedatawerecollectedofpatientswhounderwentPTCA prior to surgery. These patients were referred for PTCA because of the need to relieve symptomaticanginaortotreatmyocardialischemiaidentifiedbynoninvasivetesting.Thefindings 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 patientswithcoronaryarterydiseasenottreatedwithPTCA.Theapparentlimitationsofthese studiespromptedPosneretal.23 toconducttheirowninvestigationtocompareadversecardiac outcomesafternoncardiacsurgeryinpatientswithpriorPTCA,patientswithnon-revascular- ized coronary artery disease and normal controls. The results showed that patients treated with PTCA within 90 days of noncardiac 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 noncardiacsurgeryhadalowerriskofcardiaceventsthannon-revascularizedpatientsbutnot aslowasnormalcontrols.Furthermore,theeffectofrevascularizationwaslimitedtoareduction 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) trial24 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 survivalrate.[Q5:B,C,D]Thefindingsofthestudyindicatedthatpatientsundergoingcoronary revascularization prior to vascular surgery had a 3.1% mortality rate within 30 days of vascularsurgerycomparedtoa3.4%rateforthosenothavingcoronaryrevascularization(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 ormajorbleedingcomplicationsmaybesubstantiallyincreased.24,25 Twoseparatesmall-scale studiesreportedanincreasedrateofseriousbleedingcomplicationsifantithrombotictherapy wascontinueduntilthetimeofsurgery,andinpatientsinwhomantiplateletdrugswereinterrupted one or two days before surgery an increased rate of fatal events was observed due to stentthrombosis.25,26 Theriskofthesecomplicationspersistedfor6weeksaftercoronarystent 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 6weeksshouldoccurbeforenoncardiacsurgerytoallowforcompletionofthedualantiplatelet therapy and re-endothelialization of the stent.