Triamterene

A 66-year-old retired nurse practitioner, treated for essential hypertension and dyslipidemia, discontinued statins 1 year ago because of concerns regarding their possible adverse effects on the liver. On her annual physical examination, the blood pressure was 135/80 mm Hg in the right and left arms, weight 135 lb (60.75 kg) and height 5 ft 7 in (1 m 70 cm). A grade 2/6 systolic murmur was heard over the aortic area (second right costal interspace) consistent with a diagnosis of aortic valve sclerosis without evidence of stenosis, confirmed on echocardiography. The level of total cholesterol was 270 mg/dL (6.98 mmol/L); high-density lipoprotein cholesterol, 45 mg/dL (1.16 mmol/L); low-density lipoprotein cholesterol, 168 mg/dL (4.34 mmol/L); and triglyceride, 152 mg/dL (1.72 mmol/L). She was on a salt-poor diet, a daily diuretic combination (triamterene 37.5 mg, hydrochlorothiazide 25 mg), and metoprolol 150 mg daily. Of concern was the finding of a pulsating, nontender midabdominal mass on deep palpation in an area about 10 cm below the xiphoid process. A bruit was not detected. Abdominal ultrasonography verified the initial impression of an abdominal aortic aneurysm described as 6 cm in diameter, a width critical in females and an indication for surgical repair. In females, because of their smaller build, 4 cm in diameter is the upper limit of normal for the abdominal aorta. Statistically an abdominal aorta greater than 4 cm in width in females is at risk of rupture. In males, the upper limit of normal for the abdominal aorta is 5 cm. To better define the shape and extent of the aneurysm and thus provide the surgeon with more accurate measurements, computed tomography of the abdominal aortic aneurysm was performed. A decision was made for surgical repair in 5 days, the delay not considered a risk because the patient was asymptomatic and the aneurysm nontender to palpation. Critical to an uneventful perioperative course is the daily administration of a statin in the 5 preoperative days and continued indefinitely. Administration of metoprolol was continued. The nurse practitioner had a full and uneventful recovery following aneurysmectomy and stent implantation. On discharge, she was encouraged to continue statin therapy and her [beta]-blocker and to test for serum lipid levels and liver function in 6 weeks.

ANSWERS

1. g. all of the above

Statins reduce perioperative and long-term cardiac mortality following noncardiac vascular surgery. (1-4) The administration of statins before and after PCI has reduced periprocedural cardiac complications. (1-4) Perioperative statins reduce mortality 4-fold. (1) The underlying mechanism is related to a statin-induced reduction of perioperative myocardial ischemia by shifting a prothrombotic and vasospastic vascular substrate into one that is thromboresistant and vasodilated. With the exception of [beta]-blockers, no other pharmacological therapy has been effective in reducing the risks in perioperative cardiac procedures.

Improvements in operative technique and perioperative management have lessened the overall complication rates in noncardiac surgery. In contrast, noncardiac vascular surgery (carotid endarterectomy, abdominal aortic aneurysmectomy, inferior extremity revascularization) is associated with considerable morbidity and mortality because of the frequency of concurrent pre-existing coronary artery disease (CAD)? Major vascular surgery has a 30-day operative mortality of 5% to 6% due to acute MI and complications related to ischemia, congestive heart failure, and ventricular tachyarrhythmias. (5) More than 30% of patients undergoing abdominal aortic aneurysmectomy have CAD, and the 30-day mortality following repair is 2.7% to 9%. (2) Clinical predictors of adverse perioperative outcomes are a history of CAD, renal dysfunction, or pulmonary comorbidity. Patients concurrently treated with statins had a lower perioperative complication rate (9.1%) than did patients not given statins (16.5%), STARRS (Statins for Risk Reduction in Surgery trial)? The most significant benefit was demonstrated in the rates of congestive heart failure, 21 events in the statin-treated group and 50 in the control group? In a study of atorvastatin versus placebo, the statin treated group had a short term (6 months) reduction of cardiovascular events (perioperative mortality and MI) following vascular surgery and a better cardiac and all-cause event-free survival. This was especially significant in those at the highest risk of perioperative complications. (2) The pathophysiology of cardiac mortality associated with vascular surgery is similar to that in acute MI, viz.: coronary plaque rupture, thrombus formation, and vascular occlusion.' Peripheral vascular disease when first symptomatic is an indication of extensive and usually asymptomatic disease in other vascular beds that are nevertheless vulnerable to the stresses of surgery.

Percutaneous transluminal coronary angiography and stenting are associated with complications and mortality resulting from procedural ischemic myocardial injury. Percutaneous coronary intervention enhances platelets and white cells activation, and triggers an acute inflammatory response that contributes to the pathogenesis of post-PCI complications. (4) Myocardial necrosis and non-Q wave MI are the most common complications following PCI (about 40% of cases): many, however, are asymptomatic and have no changes in cardiac function. (3,6) The level of creatine kinase MB (CK-MB) release is associated with an increased risk of subsequent cardiac events. A CK-MB rise greater than 5 times above the upper limits of normal confers the highest late mortality risk when compared with a normal or slight rise. Statins given prior to PCI result in a reduced incidence of periprocedural MI. (3,6,7) There was less myocardial injury and a decrease in the role of major adverse cardiac events on follow-up. The anti-inflammatory effect of statins attenuates myocardial necrosis that can occur as a result of microembolization following PCI. When given during experimental initial ischemia and reperfusion, statins had salutary effects on the microcirculation, cell adhesion, and platelet function? Chronic use of statins has reduced thrombogenicity during PCI-induced plaque disruption and lessened distal embolization of microdebris. The reduced risks and complications in perioperative procedures with the use of statins make their routine application attractive and cost-effective. (3,8)

2. f. all of the above

From initiation through progression, atherosclerosis is the culmination of a complex, inflammatory process. An atherogenic diet, altered arterial flow, shear stress (artery branch points), enhanced macrophage activity, and collagen degradation are factors responsible for the genesis and progression of the vulnerable atheroma (plaque). Important links have been uncovered between the cardiovascular risk factors and the molecular and cellular mechanisms that contribute to inflammation and atherogenesis. The common comorbidities, which include dyslipidemia, hypertension, diabetes, obesity, and infection have proinflammatory components and atherogenic risk factors. Increased vascular risk is associated with increased basal levels of cytokines, for example, interleukin-6 (IL-6), tumor necrosis factor (TNF-[alpha]), high sensitivity C-reactive protein (hsCRP), fibrinogen, and CD\40 ligand. (9)

3. d. all of the above

The HMG-CoA reductase inhibitors (statins) were initially used to treat hyperlipidemia and to reduce the incidence of CAD. The statins inhibit hepatic cholesterol synthesis by blocking the conversion of HMG-CoA to mevalonate kinase, resulting in reduced levels of low-density lipoprotein cholesterol. The results were longer survival and a reduction in the incidence of acute coronary disease. (10) The clinical trials (CARE, PRINCE) have confirmed that statins had favorable effects on the vascular system, namely, attenuation of plaque inflammation, reversing endothelial dysfunction, and stabilizing coronary plaque composition, all of which result in a lower incidence of acute cardiac events. (7,9) Statins also down regulate cytokines, reduce plaque macrophage content and intimal inflammation, and suppress expression of TNF-[alpha] and matrix metalloproteinases. (5,7) The antithrombotic and anti-inflammatory properties of statins are probably pleiotropic; they are unrelated to lipid reduction. Statins influence the vascular subcellular milieu, shifting vasoactivity toward vasodilation, and normalize sympathetic outflow. Statins minimize left ventricular remodeling after MI and decrease cardiac events, improving survival. Statins also lessen claudication in peripheral artery disease and lower the risk of stroke. Of significance is that within 2 weeks of terminating statin therapy, there is a return of the pathological, inflammatory vascular milieu. (11)

4. a. [beta]-blockers

b. antiplatelet agents

c. glycoprotein IIb/IIIa inhibitors

The antiplatelet agent tirofiban reduces the ischemic complications in periprocedural PCI during acute coronary syndromes by its effect on antiplatelet activation. Tirofiban decreases vascular reactivity by reducing platelet-activated molecules. Tirofiban, however, does not attenuate the acute inflammatory response triggered by PCI that is chiefly driven by white cells (cytokines, IL-6) activity. The use of aspirin preoperatively is shunned by surgeons in noncardiac surgery. The glycoprotein IIb/IIIa receptor antagonists medicate platelet activity by preventing platelet aggregation. Pharmacological agents that attach to the glycoprotein IIb/IIIa receptor in activated platelets prevent the platelets from cross-linking with fibrinogen. (12) [beta]-blockers are cardioprotective by reducing contractility (workload) and heart rate. [beta]-blockers decrease sympathetic activity and thus induce negative inotropy and chronotropy. These properties have made [beta]-blockers standard therapy perioperatively. [beta]-blockers should be started days or weeks before elective surgery and the dose titrated to achieve a resting heart rate of 50 to 60 beats/minute. [beta]-blockers, although effective in cardioprotection, are less effective than the statins. The combined use is encouraged.

SUMMARY

The HMG-CoA reductase inhibitors are the most widely prescribed drugs in the world. The periprocedural and perioperative use of statins significantly reduces the incidence of mortality and nonfatal MI. The combination of a [beta]-blocker and a statin provides additional protection from adverse events. However, [beta]-blockers alone are less effective then statins in cardioprotection.

ACKNOWLEDGMENT

Supported in part by a grant from the Applebaum Foundation in loving memory of Joseph Applebaum.

REFERENCES

(1.) Poldermans D, Bax JJ, Kertai MD, et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation. 2003; 107:1848-1851.

(2.) Kertai MD, Boersma E, Westerhout CM, et al. A combination of statins and beta blockers is independently associated with a reduction in the incidence of perioperative mortality and nonfatal MI in patients undergoing abdominal aortic aneurysm surgery. Eur J Vasc Endovasc Surg. 2004;28:343-342.

(3.) Pasceri V, Patti G, Nusca A, et al. Randomized trial of atorvastatin for reduction of myocardial damage during coronary intervention: results from the ARMYDA (atorvastatin for reduction of myocardial damage during angioplasty) study. Circulation. 2004; 110:674-678.

(4.) Azar RR, Badaoui G, Sarkis A, et al. Effects of tirofiban and statins on high-sensitivity C-reactive protein, interluekin-6, and soluble CD 40 ligand following percutaneous coronary interventions in patients with stable coronary artery disease. Am J Cardiol. 2005;95:236-240.

(5.) O'Neil-Callahan K, Katsimaglis G, Tepper MR, et al. Statins decrease perioperative cardiac complications in patients undergoing noncardiac vascular surgery. JAm Coll Cardiol. 2005;45:336-342.

(6.) Briguori C, Colombo A, Airoldi F, et al. Statin administration before percutaneous coronary intervention impact on periprocedural myocardial infarction. Eur Heart J. 2004;25:1822-1828.

(7.) Ferguson MA, Romick BG, Carter LI, deGeare VS. Relation of the use of lipid-lowering medications prior to percutaneous coronary intervention to the incidence of intraprocedural adverse angiographic events. Am J Cardiol. 2005;95:978-980.

(8.) Delia TE, Jacobson TA, Serruys PW, et al. Cost-effectiveness of fluvastatin following successful first percutaneous coronary intervention. Ann Pharmacother. 2005;39:610-616.

(9.) Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation. 2002;105:1135-1143.

(10.) Hernandez-Perera O, Perez-Sala D, Navarro-Antolin J, et al. Effects of the 3 hydroxy-3-methylglutaryl-CoA reductase inhibitors, atorvastatin and simvastatin, on the expression of endothelin-1 and endothelial nitric oxide synthase in vascular endothelial cells. J Clin Invest. 1998; 101:2711-2719.

(11.) Stroes ESG, Koomans HA, deBruin TW, Rabelink TJ. Vascular function in the forearm of hypercholesterolemic patients off and on lipid-lowering medication. Lancet. 1995;346:467-471.

(12.) Futterman L, Lemberg L. Harnessing the platelet. Am J Crit Care. 1997;6:406-414.

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Moore J. Statins seem to have beneficial perioperative effects. Today in Cardiology. 2005. Available at: www.todayincardiology.com. Accessed August 1, 2005.

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Reprint requests: Louis Lemberg, MD, University of Miami School of Medicine, Division of Cardiology (D-39), P.O. Box 016960, Miami, FL 33101.

By Laurie G. Futterman, ARNP, MSN, CCRN, and Louis Lemberg, MD. From the Division of Cardiology, Department of Medicine, University of Miami School of Medicine, Miami, Fla.

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