	A morbidly obese 74-year-old white woman was referred for assessment of difficult-to-control hypertension. She had undergone successful percutaneous coronary intervention (PCI) 1 year before her visit. Her chief symptom was occasional headaches in the occipital area, occurring two to three times a week. She had previously had angina pectoris, but it completely subsided following the PCI. In addition to aspirin and an HMG-CoA reductase inhibitor, she was taking four antihypertensive medications, including labetalol (Trandate), amlodipine (Norvasc), lisinopril (Prinivil, Zestril), and hydrochlorothiazide (Aquazide H, Hydrodiuril, Microzide).

	The patient’s resting supine blood pressure was 176/94 mm Hg, and her pulse was 58 beats/min. Results of the physical examination were normal except for an S4 gallop. The electrocardiogram showed left atrial enlargement with nonspecific T-wave changes. An echocardiogram showed normal segmental wall motion and a normal left ventricular ejection fraction.

	A magnetic resonance angiogram (MRA) was obtained to rule out atherosclerotic renovascular hypertension in this patient with established atherosclerotic coronary artery disease and refractory hypertension, despite her taking four antihypertensive medications. The MRA was obtained instead of a less expensive renal duplex study because of the patient’s morbid obesity. The MRA showed a significant stenosis of the left renal artery, for which angiography and possible intervention were scheduled.

	The patient’s creatinine level was 1.2 mg/dL, and the rest of the electrolyte and glucose studies were normal. Her brain natriuretic peptide (BNP) level was increased, at 386 pg/mL. A repeated BNP test 2 hours prior to renal angiography was 304 pg/mL.

	Selective renal angiography confirmed the presence of a moderate (50%—70%) ostial, left renal artery stenosis. A No. 4 French catheter placed across the lesion measured a 30-mm Hg translesional pressure gradient, indicating that the moderate stenosis was indeed obstructive. The patient was successfully revascularized with stent placement, and her blood pressure medications were withheld.

	The patient’s blood pressure the morning after the procedure was 112/64 mm Hg, her creatinine level was 1.1 mg/dL, and her BNP level was 92 pg/mL. Her antihypertensive medications were withheld at discharge. Two weeks following the procedure, her blood pressure was 136/88 mm Hg, her creatinine level was 1.2 mg/dL, and her BNP level was 56 pg/mL. Her angiotensin-converting enzyme (ACE) inhibitor was restarted. After 3 months of follow-up, her blood pressure remained well controlled, at 128/82 mm Hg on the ACE inhibitor alone.

	This patient, who had known atherosclerosis, refractory hypertension, and normal left ventricular systolic function, was at increased risk for renovascular hypertension. The next step, a noninvasive screening study (ultrasonography, computed tomographic angiography, or MRA), confirmed the clinical suspicion. She had an increased BNP level without an obvious cause. When the moderate angiographic stenosis was found, the lesion’s severity was assessed by measuring a translesional pressure gradient. Successful renal intervention was accomplished. The blood pressure significantly decreased after intervention, as well as the patient’s BNP level, which is consistent with the results of our study (see “Brain natriuretic peptide and blood pressure response in patients with renal artery stenosis”) showing that BNP is increased in patients with hemodynamically significant renal ar-

	tery stenosis and that it declines following successful intervention.

	Although technical success rates for renal artery stent placement continue to improve, in many cases approaching 100%, the percentage of patients with improvement in blood pressure lags behind, at 60% to 70%. A better tool to separate patients with renovascular hypertension from those with renal artery stenosis and hypertension would allow more targeted therapy. Other methods to discriminate between blood pressure responders and nonresponders, such as renal vein or plasma renin measurements, radionuclide scintigraphy, angiographic lesion severity, resistance indices, and translesional pressure gradients, have failed to accurately separate patients with renovascular hypertension from those with renal artery stenosis and hypertension.

	Although the results of our study require confirmation in a larger cohort of patients, it appears that an increased BNP level may help to stratify which hypertensive patients with renal artery stenosis will have improved blood pressure after revascularization. In this particular patient, with moderate angiographic stenosis, the increased BNP level predicted that the hypertension would improve after revascularization.

Articles

Cardiology Review Online

Improvement in blood pressure  after renal artery revascularization

	Multiple studies have demonstrated that cardiovascular risk increases with increasing total and low-density lipoprotein (LDL) cholesterol, and that this risk can be reduced with decreased levels of LDL cholesterol. Many studies have also linked increases in cardiovascular risk with decreasing high-density lipoprotein (HDL) cholesterol levels, but until recently there was controversy regarding whether HDL cholesterol was an independent indicator of risk. A low HDL cholesterol level is the most common lipid abnormality observed in men with coronary artery disease (CAD).

	The Veterans Affairs HDL Intervention Trial and the Helsinki Heart Study demonstrated that most of the reduction in cardiovascular risk was due to the increase in HDL cholesterol levels as a consequence of the use of fibrate drugs in patients with normal levels of LDL and reduced levels of HDL cholesterol.1, 2 Epidemiologic studies have suggested that there is a 2% to 3% reduction in CAD events for each mg/dL increase in HDL cholesterol.

	Lipid-lowering therapies are now capable of lowering LDL cholesterol levels by more than 50% in 90% of patients, with an associated 20% to 35% reduction in cardiovascular events. One question, however, is whether further reductions in LDL cholesterol will result in greater reductions in cardiovascular risk, or whether a threshold is reached unless there is also an effect on raising HDL cholesterol levels. Although HMG-CoA reductase inhibitors (statins), fibrates, and nicotinic acid do have effects on HDL cholesterol levels, their effect is modest (about a 5% to 10% increase, on average).

	Recent research has identified a number of promising therapeutic targets to increase HDL cholesterol levels, and several of these are now in phase 1-3 trials. For example, some studies have suggested that inhibition of cholesteryl ester transfer protein (CETP) can raise HDL cholesterol levels by 50%.3 This target was revealed with the discovery of human genetic CETP-deficiency states, which are characterized by elevated HDL levels. The first mutation in the CETP gene was discovered in Japan, and because atherosclerosis is low in the Japanese, epidemiologic studies were undertaken in order to determine the mutation’s prevalence. This mutation was found to occur in about 11% of the population, and these 11% were particularly resistant to developing atherosclerosis. Briefly, CETP is a plasma glycoprotein manufactured in the liver that circulates in the blood. The primary action of CETP is to mediate transfer of cholesteryl esters from HDL to LDL and very low-density lipoprotein in exchange for triglyceride. CETP inhibitors thereby delay the catabolism of apo A-I and A-II and thus increase HDL.

	The first phase 2 clinical trial of a CETP inhibitor was published in 2002. The study consisted of 198 patients with mild hyperlipidemia, treated with three different doses

	of the CETP inhibitor JTT-705. A 37% increase in HDL was noted

	in the high-dose group after 4 weeks of therapy. More recently, in a small study, the CETP inhibitor torcetrapib was administered either alone or in combination with atorvastatin (Lipitor). Increases in plasma HDL of 106% were observed in six patients administered this CETP inhibitor for 8 weeks.4

	The role of HDL in the development of atherosclerosis will undoubtedly undergo more investigation now that we have the ability to substantially alter HDL levels. My impression is it is a likely additional factor that will need to be managed in the atherogenic complex.

Is HDL cholesterol an independent  cardiovascular disease risk factor?

	Goldblatt’s observation that experimentally induced renal artery stenosis leads directly to renin-dependent hypertension stands as a classic experiment in the physiology of the renin-angiotensin system and its relationship to chronic elevation of blood pressure (BP).1 By reducing renal artery perfusion pressure, renin release is stimulated, angiotensin II and aldosterone levels increase, and the resulting vasoconstriction and sodium retention produce hypertension in a seemingly simple demonstration of the pathophysiology of the renin-angiotensin system. Recognition that the same sequence of events occurs in man held out the possibility that cure of hypertension might be possible in afflicted patients, and generated a great deal of early enthusiasm among clinicians for identifying and treating patients with this condition.

	Renal artery stenosis is, in fact, the most common etiology of secondary hypertension other than renal insufficiency. In the general population of patients with hypertension, 1% to 6% have some element of renal artery stenosis.2 Among older, high-risk hyperten-

	sive patients who undergo cardiac catheterization for screening of coronary artery disease, the prevalence of significant renal artery stenosis varies from 19.2% to 28%.3,4 In the relatively small number of patients with renal artery stenosis owing to fibromuscular hyperplasia, the early promise of renal artery revascularization has generally been fulfilled; dramatic improvement in hypertension is ob-

	served in more than 60% of patients following either surgical or catheter-based revascularization. Clinical trials in patients with hypertension and atherosclerotic renal artery disease—which accounts for 90% of all renal artery stenosis&mdash;have been disappointing, however. Cure rates for hypertension have averaged less than 10%, and most studies demonstrate only modest decreases in BP, accompanied by reduction in the number of required antihypertensive medications.5 In 20% to 40% of treated patients, no improvement in BP occurs. What accounts for this apparent contradiction?

	Essential hypertension is a common condition, and its prevalence exceeds 50% in elderly patients. Coexistence of atherosclerotic renal artery disease in elderly patients with hypertension, therefore, is often coincidental rather than etiologic. Attempts at identifying the subgroup of patients in whom hypertension is the result of renin-angiotensin system activation secondary to renovascular obstruction has proved difficult. Quantification of stenosis severity, assessment of renal vein renin concentrations, measurement of renin concentrations before and after captopril (Capoten) administration, and the use of captopril renography to assess differential renal perfusion have all proved unreliable in predicting which patients will exhibit a favorable antihypertensive response to renal artery revascularization.

	In animal models, angiotensin II induced by clipping a renal artery leads to immediate upregulation of brain natriuretic peptide (BNP) mRNA.6 Based on this observation, Silva and White (page 32) utilized BNP levels to identify responders to renal artery stenting in a group of hypertensive patients with renal artery stenosis that was 70% or greater. After excluding patients in whom coexistent heart failure or an acute coronary syndrome could produce BNP elevation independent of renal artery stenosis, the authors noted that significant BP reduction occurred only in patients with baseline BNP elevation greater than 80 pg/mL and in none of those with a normal BNP. Presumably, renal artery stenosis is incidental in these latter patients, and BP elevation is due to unrelated physiology. In patients in whom an elevated BNP decreased by at least 30%, 94% exhibited significant improvement in hypertension, the fall in BNP level apparently serving as a marker of reduced angiotensin II production following relief of renal artery obstruction. The absolute level of BNP at baseline and its decline after stenting were both independent predictors of significant BP reduction using a multivariate analysis.

	The authors’ novel approach, if confirmed, may help to solve the conundrum presented by hypertensive patients with demonstrated atherosclerotic renal artery obstruction. Because these results are based on a study of only 27 patients, confirmation must await larger series in which criteria found useful in this study are prospectively evaluated. Given the modest overall benefit of this therapy, renal stenting as a treatment for BP elevation should currently be reserved for patients in whom hypertension is truly refractory after treatment with at least three antihypertensive medications—and whose BNP level exceeds 80 pg/mL.

Predicting blood pressure response in hypertensive patients with renal artery stenosis: The search continues

	Endoluminal stent placement is considered the revascularization treatment of choice for patients with refractory hypertension and hemodynamically significant renal artery stenosis. However, about one third of patients fail to have improved blood pressure following successful renal stent placement.1

	In conditions of cell stretching, ventricular myocytes release brain natriuretic peptide (BNP), a neurohormone that antagonizes the renin-angiotensin system and angiotensin II and promotes arterial vasodilation, natriuresis, and diuresis.2 In animal studies, it has been shown that BNP mRNA is markedly upregulated 6 hours after clipping the renal artery and that angiotensin II may stimulate the synthesis and release of BNP.3,4 We hypothesized that, in patients with renovascular hypertension, which is known to stimulate the renin-angiotensin system and release of angiotensin II,5 the BNP level may be elevated.

	We investigated whether BNP levels are increased in patients with renal artery stenosis, and whether they would be influenced by successful renal artery revascularization. We also evaluated whether the increased levels would foretell which patients would have a reduction in blood pressure following renal stent implantation.

	This prospective study included 27 patients with significant atherosclerotic renal artery stenosis (≥ 70% diameter stenosis), as shown on angiographic evaluation. There were seven patients who were excluded from the study because of chronic renal insufficiency, recent myocardial infarction (MI), acute coronary syndrome, or congestive heart failure exacerbation with left ventricular dysfunction.

	BNP levels were taken 2 to 7 days before the procedure in 23 patients, 1 day before the procedure in 27 patients, 1 day after the procedure in 27 patients, and 7 days to 2 months after the procedure in 25 patients. Twenty-four to 48 hours before the procedure and within 1 week after the procedure, serum creatinine levels were measured. The Cockroft-Gault equation was used to determine the estimated glomerular filtration rate (eGFR). Levels of BNP were obtained using the Biosite assay (Biosite Diagnostics, San Diego, CA). Similar to previous studies, a BNP level of 80 pg/mL or less was considered normal.6

	A patient with a systolic blood pressure of 140 mm Hg or higher or a diastolic blood pressure of 90 mm Hg or higher was considered to have hypertension. If a patient’s blood pressure could not be decreased to below 140/90 mm Hg with three drugs, he or she was considered to have refractory hypertension. Patients with a systolic blood pressure of less than 140 mm Hg and a diastolic blood pressure of less than 90 mm Hg on the same or a lesser number of drugs or who had a decrease in diastolic blood pressure of at least 15 mm Hg were considered to have improved hypertension and to be blood pressure responders.7

	Patients who had a residual diameter stenosis of less than 30% after the procedure were considered to have angiographic success. Those who had no major complications (defined as the need for hemodialysis or surgery; MI; bleeding requiring a transfusion, stroke, or death) while in the hospital, along with angiographic success, were considered to have procedural success. For those patients who had a BNP above 80 pg/mL at the start of the study, a reduction in BNP of greater than 30% from baseline was considered a decline in BNP.

	The comparison between BNP levels at baseline and after the procedure was the primary end point of the study. Determining whether the baseline BNP level was associated with the improvement in blood pressure at follow-up was the secondary end point.

	Pearson’s or phi coefficients were used to perform bivariate correlation analysis. After adjusting for preprocedural diastolic blood pressure, creatinine levels, eGFR (a continuous variable), and eGFR below 60 mL/min/1.73 m2 (a categorical variable), the association of BNP with hypertension improvement at follow-up was evaluated independently with multivariate analysis. A

	P value of .05 or less (two-tailed) was accepted as statistical significance.

	The mean age of patients was 74 ± 3 years, and 70% were women. The angiographic and procedural success was 100%. As shown in Figure 1, BNP levels decreased to 96 pg/mL (25th—75th percentiles, 61–182 pg/mL) from 187 pg/mL (25th–75th percentiles, 89–306 pg/mL) and continued to stay low during follow-up. After the procedure, blood pressures fell to 144 ± 24 over 72 ± 12 mm Hg at a mean of 3.5 ± 1.3 months (range, 2–7 months) from the baseline levels of 172 ± 18 over 89 ± 13 mm Hg (P < .001 for systolic and diastolic blood pressure). At the time of discharge, hypertension had improved in 19 of the 27 patients (70%), and at 3.5 ± 1.3 months of follow-up, 17 of 27 patients (63%) had continued improvement.

	Eighty-one percent of patients (n = 22) with renal artery stenosis had a BNP level over 80 pg/mL at the start of the study. Seventeen of these patients (77%) had improved blood pressure compared with none of the five patients with a baseline BNP of 80 pg/mL or lower (P = .001). For 63% of patients (n = 17), BNP was reduced more than 30% from baseline following the procedure, and 94% of these patients (n = 16) had improved blood pressure. As shown in Figure 2, only 10% (n = 1) of the patients whose BNP levels fell by less than 30% had improved blood pressure (P < .001). Twelve patients had an eGFR below 60 (49 ± 7) mL/min/1.73 m2, and 15 had an eGFR of 60 mL/min/1.73 m2 or higher. Following the procedure, the eGFR remained the same (61 ± 13 mL/min/1.73 m2 before the procedure and 63 ± 13 mL/min/1.73 m2 after the procedure). No improvement in eGFR was seen in patients with unilateral renal artery stenosis (61.7 ± 14 mL/

	min/1.73 m2 before the procedure and 62 ± 12 mL/min/1.73 m2 after the procedure), and nine patients with bilateral renal artery stenosis had improvement in eGFR (61 ± 13 before the procedure and 63 ± 13 mL/

	min/1.73 m2 after the procedure). There were no significant differences in the levels of BNP before or after stent placement among patients with eGFRs below 60 and above 60 mL/

	Differences between blood pressure responders and blood pressure nonresponders are shown in the Table. After adjustment for pre-

	sure, serum creatinine, preprocedural eGFR, and eGFR below 60 mL/

	min/1.73 m2, preprocedural BNP (coefficient of correlation: 0.62; P = .023) and postprocedural decrease (coefficient of correlation: 0.82; P = .001) were independently associated with improvement in hypertension on multivariate correlation analysis.

	It is important to improve patient selection before percutaneous transluminal stent placement in patients with significant renal artery stenosis because 20% to 40% fail to have

	improved blood pressure postpro-cedure.2 Other studies have tried

	to identify predictors of blood pressure response after revascularization of renal artery stenosis.8 In the present study, we showed that BNP is

	increased in patients with refractory hypertension and renal artery stenosis and that this peptide may be useful in predicting which patients will have clinically improved blood pressure after successful renal revascularization. The results of our study showed a significant association between BNP and improvement in blood pressure apart from baseline blood pressure, serum creatinine, and eGFR. After 3.5 months of follow-up, hypertension improvement was significantly associated with a BNP level above 80 pg/mL.

	The significant decline of BNP after stent placement strongly suggests a cause-and-effect relationship between renal artery stenosis and BNP elevation. Furthermore, patients with known causes of BNP elevation, such as congestive heart failure or an acute coronary syndrome, were excluded so that the baseline elevation of BNP in the patients in our study cannot be attributed to these conditions.6,9,10 In patients with an eGFR below 60 mL/min/1.73 m2, BNP has also been shown to be increased.11 Our study showed that BNP is a helpful assay for the prediction of blood pressure response no matter what the eGFR is at baseline, as shown by the fact that there were no marked differences for increased BNP (> 80 pg/mL) or BNP decrease following stent placement stratified for an eGFR below 60 or above 60 mL/min/1.73 m2.

	be synthesized and released from glomerular mesangial and epithelial cells, although the chief source of

	circulating BNP is ventricular myocytes.12 Hemodynamically significant renal artery stenosis is known to promote activation of the renin-angiotensin system, leading to elevated angiotensin II levels.5 Experimental studies have shown that BNP mRNA is upregulated in the two-kidney, one-clip renal artery stenosis model4 and that, independent of cell stretching, angiotensin II directly instigates the synthesis and release of BNP.3 The finding that 81% of our hypertensive patients with renal artery stenosis had an increased BNP level (> 80 pg/mL) concurs with the results of these experimental studies. BNP levels may be a useful marker to identify activation of the renin-angiotensin system and therefore may identify those patients who will benefit from revascularization because the severity of the stenosis has no correlation with blood pressure response.

	We have shown in the present investigation that, in patients with renal artery stenosis and refractory hypertension, BNP is increased and that it decreases following renal artery revascularization with a stent. An increased BNP level prior to stent placement is significantly associated with improvement in hypertension following revascularization. Assessing BNP levels may be useful in selecting patients for renal artery revascularization procedures and therefore may improve clinical outcomes.

Brain natriuretic peptide and blood pressure response in patients with renal artery stenosis

	An 82-year-old man presented for a routine medical evaluation. On examination, his heart rate was 82 beats per minute and irregular; an electrocardiogram showed that he had atrial fibrillation. He had a history of paroxysmal atrial fibrillation, but he had declined warfarin (Coumadin) therapy in the past. Recently, however, he had become increasingly concerned about the possibility of ischemic stroke associated with atrial fibrillation and wanted to discuss the risks and benefits of warfarin.

	In addition to atrial fibrillation, the patient had a history of hypertension. He was taking a beta blocking agent and an aspirin daily and had no previous history of stroke or hemorrhagic events. He lived alone and was able to function independently, but had noted some decline in functional status in the past few years. His physician described the benefits of stroke risk reduction with warfarin therapy. Given the patient’s older age, however, the physician was concerned about the risk of warfarin-associated intracranial hemorrhage. Although the physician knew that lower international normalized ratio (INR) intensities are not as effective as INRs of 2.0 to 3.0 for the prevention of ischemic stroke, he felt that perhaps a lower intensity would be safer for the patient in terms of reducing his risk of intracranial hemorrhage.

	The patient discussed the risks and benefits of warfarin therapy with his physician. Because of his older age and history of hypertension, his physician believed that his annual risk of ischemic stroke without warfarin was greater than his risk of intracranial hemorrhage while receiving warfarin; therefore, the patient opted to start warfarin therapy. His physician recommended a target INR of 2.5, with a range of 2.0 to 3.0.

Evaluating risks versus benefits  of warfarin therapy

	In this issue, Drs. Fang and Singer (page 24) summarize their case-control study examining the risk of intracranial hemorrhage in patients taking warfarin (Coumadin). The authors investigated risk factors for the development of intracranial hemorrhage. They then questioned whether low-intensity anticoagulation therapy would reduce the risk of intracranial hemorrhage in elderly patients. Their study included 170 patients who developed intracranial hemorrhage while receiving warfarin therapy between 1993 and 2002. Of these patients, 145 had international normalized ratio (INR) data and were included in the analysis. They were compared with 1,020 matched control patients who were taking warfarin but did not have intracranial hemorrhage. They found that the risk of intracranial hemorrhage was significantly increased in patients aged 85 years or older. After adjusting for age, an INR above 3.5 was noted to be a significant risk factor. A reduced INR surprisingly did not decrease the risk of intracranial hemorrhage.

	The most devastating complication of atrial fibrillation is a thromboembolic event leading to a cerebrovascular accident. Of all ischemic strokes, 15% are due to cardiogenic emboli (75,000 cases per year); 45% of cardiogenic emboli in the United States are due to nonvalvular atrial fibrillation. The risk of stroke in patients with atrial fibrillation is five to seven times greater than in control patients.1-5 The stroke rate in patients with lone atrial fibrillation appears to be about 1.6% among those aged 60 to 69 years, 2.1% for those aged 70 to 79 years, and 3.0% for those older than 80 years.6 There appears to be no difference in stroke rate for patients with chronic persistent versus paroxysmal atrial fibrillation.6 Previous trials have identified several risk factors for thromboembolism during atrial fibrillation. In an analysis of data pooled from five major randomized clinical trials, it appears that increasing age, previous stroke or transient ischemic attack, history of hypertension, and history of diabetes are all independent risk factors for stroke due to atrial fibrillation.6 In an analysis of the Stroke Prevention in Atrial Fibrillation (SPAF) study, congestive heart failure was also identified as a significant risk factor, as were left ventricular dysfunction and left atrial enlargement as shown on two-dimensional echocardiography.7,8

	Drs. Fang and Singer correctly pointed out that many physicians are hesitant to prescribe warfarin for their elderly patients. The Cardiovascular Health Study, a population-based longitudinal study of risk factors for coronary disease and stroke in 5,201 men and women aged 65 years and older, found that, despite a relatively high prevalence of atrial fibrillation in elderly patients (as high as 9.1% in men and women with coexisting clinical cardiovascular disease), 62% of patients for whom warfarin was indicated received neither warfarin nor aspirin.9 In a retrospective analysis of 95 patients discharged from the hospital with a diagnosis of atrial fibrillation, 48% of those in whom warfarin was indicated received neither warfarin nor aspirin.10 This finding is particularly surprising because long-term anticoagulation therapy has been confirmed to reduce the risk of stroke in atrial fibrillation in multiple large randomized trials. Furthermore, the current study confirms that low-dose anticoagulation therapy is not effective in preventing thromboembolic events. In the SPAF III trial, 1,044 patients with chronic atrial fibrillation and at least one risk factor for thromboembolic events were randomly assigned to receive low-intensity, fixed-dose warfarin plus aspirin versus adjusted-dose warfarin (INR, 2.0—3.0). Results showed an ischemic stroke and systemic embolism rate of 7.9% per year in the combination group versus 1.9% in the adjusted-dose group (P < .001).11

	Despite the overwhelming data in support of long-term warfarin use in patients suffering from chronic persistent, permanent, and paroxysmal atrial fibrillation, the drug is widely underused. The current study firmly addresses the risk of intracranial hemorrhage, which is often an excuse for not offering anticoagulation therapy to elderly patients. Despite the increased risk of hemorrhage, elderly patients also have an increased risk of stroke. To quote the authors, “the incidence rate of ischemic stroke in those not receiving warfarin far exceeds the rate of intracranial hemorrhage in those taking warfarin.” This study adds support to the use of warfarin in elderly patients, who are the patients with the highest risk of stroke from atrial fibrillation.

Intracranial hemorrhage, atrial fibrillation, and the elderly

	The study from Italy by Briguori and colleagues (page 18) is a prospective, randomized study of 451 patients scheduled for elective coronary intervention, which again, like studies before this one, showed a benefit to treating elective cases with HMG-CoA reductase inhibitors (statins) at least 3 days before the procedure. This study looked at creatine kinase (CK)-MB and cardiac troponin I and considered a CK-MB level of more than five times greater than the upper limit of normal to be indicative of a myocardial event (non—Q-wave myocardial infarction). Samples were taken before and 6 and 12 hours after the procedure and showed a significant reduction in non–Q-wave infarctions in patients randomly assigned to receive statins at least 3 days before the procedure.

	The fact that statistical significance was demonstrated with 451 patients randomly assigned certainly makes the results credulous, but because there was no standardization of which statin was prescribed, at what dose, and the target lipid-level—lowering goal, it is more difficult to extrapolate the data and plan a treatment strategy for clinical use.

	As pointed out in the study, the statins seemed to reduce the extent, rather than the incidence, of periprocedural non—Q-wave infarctions. How this is accomplished is speculative, including having some reductive effects locally on the lesion rather than systemically affecting platelet aggregation, anti-inflammatory effects, or even the various aspects of the thrombotic cascade. Several studies (tabulated in the references) have demonstrated similar benefit both before elective procedures, as well as in acute coronary syndromes.

	It would seem logical that if you have coronary artery disease you should be taking a statin drug. Thus, any elective coronary intervention patient should already be receiving a statin. This study adds evidence to a growing number of studies that document unanticipated benefits to statin therapy before a coronary intervention.

	My only criticism of the study is the lack of standardization of drug and dose, and the lack of specified goals for lipid lowering. The drug type and dose was left to the treating physician. It is thus unclear whether all statins would accomplish the same effect, and what minimal dose or what lowering effect would be required to see any benefit.

	I think that the potential benefit of statins before coronary intervention warrants a controlled, randomized study of a particular statin at a dose that results in at least a 30% or greater reduction in total cholesterol and/or low-density lipoprotein cholesterol. Further studies could then be performed to see if larger doses achieve additional gain.

Is there a benefit to prescribing statins before PCI? 

	Nonvalvular atrial fibrillation is a common cardiac arrhythmia that strongly increases a person’s risk of ischemic stroke.1 Warfarin (Coumadin) therapy can dramatically reduce the risk of stroke associated with atrial fibrillation, but it increases the risk of life-threatening bleeding complications.2 Intracranial hemorrhage is a particularly devastating complication of warfarin therapy. Despite their high associated morbidity, intracranial hemorrhages are quite uncommon, with a rate of about 0.4% per year in patients receiving warfarin therapy.2 In contrast, the risk of ischemic stroke in patients with atrial fibrillation who are not taking warfarin ranges between 1% and 12% per year, depending on clinical risk factors, such as previous stroke and older age.2,3

	Despite the well-documented benefits of warfarin, many physicians are hesitant to prescribe it for elderly individuals or tend to use a lower target international normalized ratio (INR) intensity, presumably to reduce the risk of life-threatening hemorrhages.4 In fact, recent guidelines have suggested a target INR range of 1.6 to 2.5 for the primary prevention of stroke in some atrial fibrillation patients over the age of 75 years.5 It is unclear, however, whether this strategy reduces the risk of hemorrhage. To address these issues, we designed a case-control study to examine the association between age, anticoagulation intensity, and the risk of intracranial hemorrhage in patients taking warfarin for nonvalvular atrial fibrillation.

	We searched the Massachusetts General Hospital billing system for case patients admitted with intracranial hemorrhage between the years 1993 and 2002. Case patients were eligible if they were taking warfarin for atrial fibrillation and had no other explanation for intracranial hemorrhage (such as severe head trauma or cerebral aneurysm). We then matched each case to six anticoagulated control patients without intracranial hemorrhage, randomly selecting controls from the hospital’s large anticoagulation clinic. We reviewed medical records for clinical information, including patient age and INR at the time of hemorrhage. Multivariable conditional logistic regression was used to assess the relative odds of intracranial hemorrhage at varying ages and INR intensities, controlling for potential clinical confounders (such as cerebrovascular disease and hypertension) as well as aspirin use.

	We identified 170 case patients who developed intracranial hemorrhage while taking warfarin for atrial fibrillation and matched them to 1,020 control patients from the anticoagulation clinic. INR data were available for 145 case patients and for all control patients. Only patients with INR data were used in the multivariable analysis.

	There were 79 primary intracerebral hemorrhages, 71 subdural hemorrhages, and 20 hemorrhages of other types. A history of minor head trauma was more common in those with subdural compared with in-

	tracerebral hemorrhage (48% versus 8.1%, P < .001). The inpatient mortality rate was quite high, particularly among those with primary intracerebral hemorrhages (43%). Although 91% of patients were living at home before the hemorrhage event, only 14% were able to be discharged directly home after the hospitalization.

	Comparing cases with controls on bivariate analysis, case patients were older and had higher median INRs (Table). Aspirin use was similar between cases and controls (20% versus 19%). In multivariable models, we included terms for age, INR, sex, race, and the following clinical variables:

	a history of cerebrovascular disease (prior ischemic stroke or carotid ar-tery disease), hypertension, congestive heart failure, coronary artery disease, diabetes mellitus, cancer, and aspirin use.

	After multivariable adjustment, we found that the risk of intracranial hemorrhage rose significantly at an age of 85 years or older compared with a reference age of 70 to 74 years, with an adjusted odds ratio (OR) of 2.5 and 95% confidence interval (CI) of 1.3—4.7; (Figure 1). After adjusting for clinical risk factors, including age, we found that the risk of intracranial hemorrhage rose significantly at an INR range of 3.5 to 3.9 (adjusted OR, 4.6 [CI, 2.3–9.4]) and rose markedly at INRs of 4.0 and higher (adjusted OR, 8.8 [CI, 4.6–17.0]; Figure 2), compared with a reference INR range of 2.0 to 3.0. Lower INRs (< 2.0) were not associated with a lower risk of intracranial hemorrhage compared with INRs of 2.0 to 3.0 (adjusted OR, 1.3 [CI, 0.8–2.2]). A history of cerebrovascular disease was also significantly associated with an increased risk of intracranial hemorrhage (adjusted OR, 2.2 [CI, 1.4–3.4]).

	This is the largest study to date to examine risk factors for intracranial hemorrhage in patients taking warfarin for atrial fibrillation. We found that the risk of intracranial hem-orrhage rose significantly at age 85 years or older and at INRs of 3.5

	and higher. However, INRs below 2.0 did not offer additional protection against intracranial hemorrhage compared with INRs in the 2.0 to 3.0 range. Thus, our study does not support the use of lower INR target ranges for patients with nonvalvular atrial fibrillation, even in elderly patients. Previous studies have shown that the risk of ischemic stroke in

	INR targets will place patients at higher risk for ischemic stroke while not reducing the risk of intracranial hemorrhage.

	Although older age appears to be a risk factor for intracranial hemorrhage, it is also a risk factor for atrial fibrillation—associated ischemic stroke.7 In general, because the incidence rate of ischemic stroke in those not receiving warfarin far exceeds the rate of intracranial hemorrhage in those taking warfarin,8 the net benefits of warfar-in continue to outweigh the risks in elderly patients with atrial fibrilla-tion. Care must be taken to maintain the INR intensity within a therapeutic range, however, to maximize the benefits while minimizing the risks. Although increasing age and INR are associated with a greater risk of this complication, the majority (62%) of intracranial hemorrhages in our study occurred at INRs of below 3.0. Similar to other studies, we found that a history of cerebrovascular disease (such as previous stroke) was a risk factor for future intracranial hemorrhage.9 However, although aspirin use has been linked to a higher risk of hemorrhagic stroke in previous studies,10 we did not find such an association in our study.

	Aside from older age, previous stroke, and possibly hypertension, there are few validated clinical predictors of intracranial hemorrhage.9,11 Consequently, individualized risk assessment often represents guesswork. Because of the increasing number of elderly patients taking warfarin for atrial fibrillation,12 their increased risk of warfarin-associated intracranial hemorrhage necessitates better predictors of this condition. Identification of additional factors, including through biochemical or radiographic means,13,14 would make individualized decisions about anticoagulation in atrial fibrillation much more rational and effective.

	Our study has several limitations. Because many case patients were not followed in the anticoagulation clinic, differences in outpatient anticoagulation management and patient characteristics may have biased some of the risk estimates. To address this, we performed a nested case-control study, which showed results similar to the full case analysis. We did not have data on duration of warfarin use, a factor that has been linked to hemorrhage in previous studies. However, restricting the analyses to patients taking warfarin for at least 1 year did not substantially change our results. Finally, our study was not designed to assess the risk of intracranial hemorrhage in patients not taking warfarin, because both case and control patients were already on this medication.

	Intracranial hemorrhage is a rare but devastating complication of warfarin therapy. Our study shows that an age of 85 years or older and an INR of 3.5 or higher are associated with an increased risk of intracranial hemorrhage. However, subtherapeutic INRs (< 2.0) do not offer additional protection from hemorrhage compared with the standard therapeutic INR range. Because the risk of ischemic stroke rises with increasing age and INRs below 2.0, our study supports using an INR range of 2.0 to 3.0 (target 2.5) for older as well as younger patients with nonvalvular atrial fibrillation.

Risk of intracranial hemorrhage  in atrial fibrillation

	A 66-year-old man presented with effort angina (Canadian Cardiovascular Society Classification II) and inferolateral myocardial ischemia as shown on scintigraphic assessment. The patient had a history of systemic hypertension and type 2 diabetes mellitus requiring insulin. Coronary angiography showed triple-vessel disease and normal left ventricular ejection fraction. After clinical consultation and according to the patient’s preference, elective stent implantation in the right coronary artery was scheduled.

	The procedure was performed 3 days later. The patient was pretreated with clopidogrel (Plavix; 75 mg/day) and aspirin (325 mg/day). He was not taking an HMG-CoA reductase inhibitor (statin). Renal function was normal, and glycemic control was acceptable (glycosylated hemoglobin, 7.5%). There were two critical and complex lesions in the proximal and middle segments of the right coronary artery. After predilation with a compliant balloon, two sirolimus-eluting stents were implanted in the proximal and middle segments of the right coronary artery. Stent expansion was optimized with a semicompliant balloon at high pressure (14 atm), resulting in a good angiographic result (residual stenosis < 10% and normal final flow).

	The patient was asymptomatic after the procedure, and no changes in the electrocardiogram were observed. Creatine kinase-MB mass, assessed by a radioimmunoassay analyzer (Stratus CS — STAT Fluorometric Analyzer; Dade Behring Marburg GmbH, Marburg/Germany), was 0.80 ng/mL before stenting, 3.5 ng/mL 6 hours after stenting, and 20.80 ng/mL 12 hours after stenting. Cardiac troponin I was 0.01 ng/mL before stenting, 0.15 ng/mL 6 hours after stenting, and 2.33 ng/mL 12 hours after stenting. The patient was discharged on the second day after the procedure, with prescriptions for aspirin, clopidogrel, a statin, an angiotensin-converting enzyme inhibitor, nitrate, and a beta blocking agent.

Cardiac enzyme increase after  successful elective stenting

	Following percutaneous coronary intervention (PCI), 5% to 30% of patients may experience an increase in cardiac enzymes.1-3 This complication negatively affects event-free survival after PCI.4-7 Optimal antiplatelet therapy is necessary to prevent periprocedural myocardial infarction (MI).8,9 Apart from their cholesterol-reducing effects, HMG-CoA reductase inhibitors (statins) have also been shown to exert antithrombotic properties.10,11 We evaluated whether administering statins before elective coronary stent implantation would prevent an increase in cardiac enzymes following the procedure.

	Patients scheduled for elective stent implantation were randomly assigned to one of two groups: a control group, in which patients received no statin treatment, or a statin group, in which patients received statins 3 or more days before the procedure. Decisions regarding the dosage and type of drug to be used were left up to the physician. At least 3 days before the procedure, all patients were given 75 mg of clopidogrel (Plavix) daily, 250 mg of ticlopidine (Ticlid) twice a day, and 325 mg aspirin daily. According to the choice of the operator, glycoprotein IIb/IIIa inhibitors were given. Before the procedure, 6 hours after the procedure, and 12 hours after the procedure, cardiac troponin I (upper limit of normal [ULN] ≤ 0.10 ng/mL) and creatine kinase (CK)-MB (ULN ≤ 3.5 ng/mL) levels were assessed. The day before the procedure, plasma C-reactive protein (CRP) levels were evaluated. The rate of a large non—Q-wave MI, as shown by an increase in CK-MB level over five times ULN, by itself or with ST-segment or T-wave abnormalities or chest pain5-12 was the end point of the study.

	The Student’s t test and Mann-Whitney U test were used to analyze normally and nonnormally distributed variables, respectively, between the two groups. The chi-square test was used to evaluate categorical variables. To determine independent predictors for CK-MB increase over five times ULN after the procedure, a multivariable logistic regression model was constructed.

	Two hundred twenty-five patients were enrolled in the control group, and 226 were enrolled in the statin group, for a total of 451 patients. Therapy with statins was started from 3 to 31 (mean, 17 ± 8) days before PCI. Fluvastatin (Lescol XL; 80 mg/day) was given to 3% of patients, simvastatin (Zocor; mean dose, 24 ± 9 mg/day) was given to 39% of patients, pravastatin (Pravachol; mean dose, 32 ± 10 mg/day) was given to 29% of patients, and atorvastatin (Lipitor; mean dose, 22 ± 9 mg/day) was given to 29% of patients. As shown in Table 1, the two groups were similar with regard to clinical characteristics. Compared with the statin group, patients in the control group more frequently had high CRP levels at the time of the procedure (27% versus 13.8%, P = .007). Angiographic and procedural characteristics are summarized in Table 2. Fifty-four percent of control patients and 46% of statin patients received glycoprotein IIb/IIIa inhibitors.

	In the statin group, the median peak CK-MB level was 1.70 (interquartile range, 1.10—3.70) ng/mL, and it was 2.20 (interquartile range, 1.30–5.60) ng/mL in the control group (P = .015). As shown in the Figure, panel A, 35 patients (15.6%) in the control group and 18 patients (8%) in the statin group had an increased CK-MB level over five times ULN (P = .012; odds ratio [OR] = 0.47; 95% confidence interval [CI] = 0.26–0.86). As shown in panel B of the Figure, 72 patients (32%) in the control group and 53 patients (23.5%) in the statin group had a cardiac troponin I level over five times ULN (OR = 0.65; 95% CI = 0.42–0.98; P = .043). Age over 65 years (OR = 2.58; 95% CI = 1.09–6.11; P = .031), statin pretreatment (OR = 0.33; 95% CI = 0.13–

	0.86; P = .023), and angiographic complications (OR = 9.36; 95% CI = 3.06—28.64; P < .001) were shown to be independent predictors of CK-MB elevation over five times ULN.

	The cardioprotective effects of statin therapy before PCI, as have been shown in other studies,13-15 were also shown in this study. Patients who received statin therapy prior to the procedure had a markedly reduced incidence of periprocedural non—Q-wave MI (as evidenced by CK-MB elevation five times ULN). The extent as opposed to the overall incidence of periprocedural MI was significantly reduced in patients receiving statin treatment before the procedure, as shown in experimental studies. In addition to their lipid-lowering effects, the cardiovascular benefits of statins include the nonlipid-related mechanisms (or pleiotropic effects), such as anti-inflammatory effects, plaque stabilization, and antithrombotic effects.10,11

	The fact that the beneficial effect of statin treatment on cardiac enzyme elevation after PCI was independent of preprocedural CRP level suggests that the anti-inflammatory effect of statins may have a minor role in preventing myonecrosis during stent implantation.11,15 A reduction in the relative content of cholesterol esters that are significant factors affecting plaque stability is induced by statin therapy.11 Platelet aggregation and thromboxane production are decreased by statins, which also interfere with tissue factor activity, conversion of prothrombin to thrombin, and thrombin activity.11 Furthermore, statins trigger fibrinolysis.11

	As shown by the results of this study, treatment with statins before PCI reduces the rate of periprocedural myocardial injury following the procedure.

Statin administration before  percutaneous coronary intervention Carlo Briguori

	In their study, Anderson and coworkers (page 10) report that patients with impaired fasting glucose levels have an increased risk of death following coronary artery bypass graft (CABG) surgery that is similar to patients with suspected and confirmed diabetes mellitus. Their results are in keeping with a growing body of literature that suggests that hyperglycemia during coronary revascularization procedures results in increased short- and long-term mortality. While I agree with this concept, there are several major limitations in both the design and methodology of this study that limit its impact on clinical practice.

	The study was retrospective, and the patient group with abnormal fasting glucose levels was small, resulting in widened confidence intervals. We are not told when fasting glucose levels were drawn (for example, on the day of or several days before surgery). It is unknown whether protocols were in place to maintain tight glycemic control during the perioperative period and whether or not patients with impaired fasting glucose and those with suspected diabetes received any antihyperglycemic therapy. This could have easily affected the outcome.

	I am surprised at the cumulative 1-year mortality in the three non-normal groups, which ranged from 5.7% to 7.4%. The authors fail to tell us what percentage of these patients received a left internal mammary artery to left anterior descending graft (which has been shown to enhance survival in patients with diabetes), and the incidence and type of perioperative complications in each group. More importantly, we are not told what the causes of deaths were among the groups and whether they were related to cardiovascular etiologies (myocardial infarction, stroke, congestive heart failure, arrhythmias) or noncardiovascular entities. For example, it is well known that the incidence of sternal wound infections is increased in diabetic patients with elevated perioperative glucose levels. Did a significant number of the patients with impaired fasting glucose have wound infections that contributed to their mortality? Finally, the authors noted that the 30-day and 1-year mortality rates were similarly increased among the three non-normal groups. This suggests that some underlying disease process was not effectively treated. The authors conclude their discussion by stating that the mechanism for their findings remains unclear, and they question whether normalizing glucose levels perioperatively would have altered the results. In this commentary, data will be provided that may help to answer these questions.

	Diabetic patients, and those with abnormal fasting glucose levels, develop insulin resistance during CABG surgery that contributes to increased levels of free fatty acids and decreased myocardial uptake of glucose.1 The resulting hyperglycemia contributes to oxidative stress and augmentation of the inflammatory response, which leads to endothelial dysfunction. Diabetic patients with coronary artery disease have increased levels of proinflammatory cytokines, such as interleukin-6 and tumor necrosis factor, which stimulate the synthesis of acute-phase proteins, such as C-reactive protein.2 Hyperglycemia impairs endothelial function by depleting NAD (P)H, which ultimately decreases endothelial nitric oxide (NO) synthase and reduces NO release, resulting in vasoconstriction.3 Bioassays from internal mammary arteries and from saphenous vein grafts of diabetic patients show decreased NO activity and increased production of superoxide and NAD (P)H oxidase.4 Hyperglycemia also results in increased levels of plasminogen activator inhibitor-1 and adhesion molecules, which impairs platelet function, resulting in increased adhesiveness and hyperaggregability.5 These changes in endothelial function, the inflammatory response, and platelet function contribute to arterial thrombosis and ultimately the patency of bypass grafts, as well as native coronary vessels.

	Insulin acts to improve myocardial metabolism, reduce the inflammatory response, preserve endothelial integrity, and maintain platelet function during periods of myocardial ischemia. It decreases levels of free fatty acids and increases the myocardial uptake of glucose; decreases the levels of reactive oxygen species, adhesion molecules, and C-reactive protein; increases the bioavailability of NO; and decreases serum levels of plasminogen activator inhibitor-1.1,5,6

	In summary, the mechanism for the favorable actions of insulin during CABG surgery in diabetic patients may result from its ability to limit injury to vein grafts and native coronary vessels owing to its preservation of endothelial function. This results in enhanced recovery of ischemic myocardium and better vein graft patency, which contributes to superior long-term survival.

	Is there any evidence to show that normalizing glucose levels with insulin results in superior short- and long-term outcomes in diabetic CABG surgery patients? We designed a study to answer this question in 141 diabetic CABG surgery patients prospectively randomized to tight glycemic control (125—200 mg/dL) with continuous intravenous insulin therapy, or moderate control (< 250 mg/dL) with intermittent subcutaneous insulin therapy.7 Following CABG surgery, patients with tight glycemic control had lower serum glucose levels (138 ± 4 SE versus 260 ± 6 mg/dL; P < .001), decreased serum lactate (1.75 ± 0.14 versus 2.33 ± 0.31 mmol/L; P = .04), and less serum free fatty acids (0.33 ± 0.03 versus 0.57 ± 0.05 mEq/L; P < .001). As a result, patients with tight glycemic control required less pacing and inotropic support, spent less time on the ventilator (6.9 ± 0.3 versus 10.7 ± 0.6 hours; P = .002), and had a lower incidence of atrial fibrillation (16.6% versus 42%; P = .0017) and infectious complications (0% versus 13%; P = .01), all of which contributed to a shorter postoperative length of stay (6.5 ± 0.1 versus 9.2 ± 0.3 days; P = .003). Patients with tight glycemic control also showed a significant survival advantage 3 years after surgery (98% versus 90%; P = .04), had decreased episodes of ischemia (5% versus 19%; P = .01), and maintained a lower angina class.

	What are the clinical implications from Anderson’s study and our own data? Tight glycemic control in diabetic CABG surgery patients improves both short- and long-term outcomes. All patients exhibiting abnormal fasting glucose levels or elevated perioperative serum glucose values should receive continuous intravenous insulin infusions to maintain serum glucose at less than 200 mg/dL for 12 to 18 hours post-CABG. It is no longer a question of whether treatment for elevated perioperative glucose values is necessary, but whether superior results can be obtained if glucose levels are lowered to 100 mg/dL or lower as advocated by van den Berghe and coworkers in a study involving critically ill patients receiving mechanical ventilation.8 This will be the subject of our future studies, as we attempt to determine the optimal method for glycemic control in the postoperative period.

Preoperative fasting blood glucose levels and increased mortality after CABG surgery

	Patients with diabetes mellitus are known to have a higher rate of morbidity and mortality after coronary artery bypass graft (CABG) surgery than patients without diabetes. Recent studies have suggested that the increased cardiovascular morbidity and mortality risks known for diabetic patients are shared by a similar number of patients without known diabetes but with fasting blood glucose levels either above or slightly below the diagnostic threshold for diabetes.1 Including these groups with those who have clinical diabetes would avoid the current underestimation of the additional risk associated with non-normal glucose homeostasis. Patients with prediabetes or subdiabetes include those with impaired fasting blood glucose and those with abnormal response to an oral glucose provocation.2

	We evaluated mortality 30 days and 1 year after primary CABG surgery. A single preoperative fasting blood glucose level was used to categorize patients without a previous diagnosis of diabetes and to compare their mortality rate with that of patients with diagnosed and treated diabetes.

	From 2001 to 2003, 1,895 patients underwent primary CABG surgery at Karolinska University Hospital in Stockholm, Sweden. Clinical diabetes mellitus was previously diagnosed in 440 of the patients (CDM group); preoperative fasting blood glucose (whole blood) levels were available for 1,375 of the remaining 1,455 patients and were missing for 80 patients. Using this single preoperative fasting blood glucose value, nondiabetic patients were categorized as having normal fasting blood glucose (< 5.6 mmol/L; NFG group), impaired fasting blood glucose (5.6 mmol/L ≤ fasting blood glucose < 6.1 mmol/L; IFG group), or suspected diabetes mellitus (≥ 6.1 mmol/L; SDM group). The SDM group was not combined with known diabetic patients because two fasting blood glucose values are required for a diagnosis of diabetes. The Swedish Population Register was used to update the deaths of patients up to June 1, 2004. Only patients who underwent CABG surgery before June 2, 2003, were included in the 1-year mortality rate, whereas the calculated 30-day mortality rate included all 1,815 patients.

	Using the chi-square test for categorical variables and the analysis of variance for continuous variables, baseline characteristics (17 risk param-

	eters included in the EuroSCORE [www.euroscore.org]) were compared across categories. Logistic regression was used to analyze 30-day mortality, and 1-year mortality was analyzed using proportional hazards regression.

	The four patient groups showed differences in critical preoperative condition, EuroSCORE, neurological dysfunction, peripheral vascular disease, body mass index (BMI), and left ventricular function (Table 1). Non-normal glucose homeostasis was detected in 41% of patients.

	The number of patients who died by the cutoff date of June 1, 2004, was 107. Of these patients, 41 died at 30 days and 71 died within 12 months. The Figure shows the Kaplan-Meier curves for crude mortality for each of the four patient categories and the number of patients followed up at

	6, 12, and 18 months. The normal fasting blood glucose group had distinctly superior mortality rates compared with the other three groups, which were clustered together; the suspected diabetes mellitus group consistently had the lowest survival, the clinical diabetes mellitus group had the next lowest, and the impaired fasting blood glucose group was slightly better. The area under the receiver operator characteristic (ROC) plot, examining the validity of fasting blood glucose as a continuous variable of mortality among patients without clinical diabetes, was 0.65 (P = .002).

	Cumulative mortality within 1 year of surgery was more than double for all non-normal groups (Table 2). Multivariable adjustment did not alter the results. The non-normal groups showed similarly increased mortality within 30 days after surgery and at

	1 year among 30-day survivors. Because of the small numbers, however, the confidence intervals (CIs) were widened, except for the clear association of suspected diabetes with increased mortality within 30 days after surgery compared with patients with normal fasting blood glucose (Table 2). This suspected diabetes mellitus group consistently had the highest numerical relative risk, but the small numbers do not permit statistical comparisons.

	The most conclusive findings of this study are that patients with impaired fasting blood glucose share the same increased risk of death within a year of CABG surgery as patients with both known and previously unknown diabetes. Similar increased risk was found for mortality at 30 days after surgery and at 1 year among 30-day survivors, but the small numbers resulted in wide CIs. Furthermore, the difference in expected mortality for patients with truly normal versus non-normal glucose homeostasis is underestimated because of the large number of cardiovascular patients with undiagnosed glucose abnormalities. The number of patients unknowingly at increased risk for short-term death after CABG surgery because of their glycemic status was almost as large as that for patients with diagnosed diabetes. Multivariable analysis for potentially confounding factors did not substantially alter the findings.

	The increased risk associated with impaired fasting blood glucose for cardiovascular pathology has led to the establishment of that category and a corresponding category for impaired glucose tolerance after an oral glucose provocation. The American Diabetes Association recently lowered the threshold value for impaired fasting blood glucose from 5.6 to 5.1 mmol/L.2 The present study has not been reevaluated for that decreased threshold value.

	Although the category of impaired fasting blood glucose was conceived to describe the development of manifest diabetes and the vascular changes that begin at lower levels of blood glucose, it has increasingly been associated with mortality. In particular, the present findings of an increase in mortality for patients with impaired fasting blood glucose similar to diabetic patients is in agreement with a recent study by Muhlestein and colleagues showing that patients with impaired fasting blood glucose have a threefold higher risk of death within a few years after undergoing percutaneous coronary interventions (PCI).3 Hyperglycemia has also been associated with increased mortality after acute myocardial infarction (MI), increased mortality and length of hospital stay in general medical and surgical units, and worsened prognosis after stroke.4-7 In intensive care unit (ICU) patients, a direct and proportional correlation was found between death and a blood glucose level above 4.4 mmol/L.8

	There is evidence both for and against the existence of a lower threshold fasting blood glucose value below which there is no additional risk. We used ROC analysis to show the prognostic value of fasting blood glucose as a continuous variable for predicting

	1-year mortality among patients without diagnosed diabetes. The lack of a convincing inflection point is consistent with the growing idea that there is no distinct blood glucose threshold below which no pathological processes occur: Van den Berghe and colleagues found no evidence for a safe lower glucose threshold when treating ICU patients with insulin.9 More importantly, the Framingham Heart Study group just recently demonstrated a linear dependency on blood glucose for all mortality, cardiovascular mortality, and even noncardiovascular mortality; there was a 3.81-fold increase in total mortality when the fasting blood glucose level rose from low-normal to moderate diabetic levels (3.3 to 6.6 mmol/L).1 Muhlestein and colleagues’ PCI study and the recent Hoorn study of cardiovascular mortality and morbidity both support the existence of a lower glucose threshold.3,10

	It was hoped that the relative increased risk at 30 days and at 1 year would suggest whether the pathophysiological mechanism was acute perioperative risks or the gradual progress of the cardiovascular pathology. Although the small numbers do not allow any conclusions, the 30-day mortality and 1-year mortality of survivors of 30 days are similar. The Kaplan-Meier plot suggests that the groups may differ most during the first postoperative weeks.

	Another surprising aspect of the results of our study is the lack of any dramatic risk difference among the three non-normal groups, although the Kaplan-Meier plots do place the four groups in a distinct order of relative risk of death, with the impaired fasting blood glucose group having the lower risk, treated diabetic patients having a higher risk, and previously unknown diabetic patients having the worst risk. Since this was a retrospective study, the suspected diabetes mellitus group remained undiagnosed and untreated. As a result of this study, we now take preoperative fasting blood glucose levels twice to correctly diagnose diabetes and initiate treatment. Muhlestein and colleagues’ PCI study had a range in follow-up time of 1.5 to 5.2 years and showed the highest mortality rate among previously unknown diabetics; it is not known whether patients were subsequently treated for their newly detected diabetes.3

	This study and the PCI, stroke, and MI studies all raise the question of whether the observed increased risk with pre-event glycemic status can be normalized with aggressive diabetes medication. True randomized interventional studies are few. Van den Berghe and colleagues showed that maintaining normoglycemia with insulin drastically reduced mortality in patients requiring prolonged intensive care after (mostly) cardiac surgery.9 Similarly, the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction study of diabetic MI patients showed that long-term survival improved 28% with aggressive in-hospital insulin treatment.11

	One of the most important findings in this study is that the relative risk increase with non-normal glycemic status is underestimated in the literature, which traditionally has compared only known diabetic patients with presumed normal patients. The admixture of undetected diabetes and prediabetes falsely increases the mortality of patients with truly normal glucose metabolism. Most studies show a larger percentage of previously undetected diabetes and prediabetes than did our study.3

	A causal relationship between blood glucose concentration and increased postoperative mortality was not shown by this study. Glucose is proinflammatory and increases oxygen reactive species, whereas insulin suppresses both.12

	Patients with impaired fasting glucose and undiagnosed diabetes appear to have about the same increased risk of death following CABG surgery as those with clinical diabetes. It is still unknown whether normalizing glucose homeostasis pharmacologically would eliminate this risk postoperatively and what the causes and mechanisms of this association are.

Fasting blood glucose and mortality after CABG surgery

	Dallas—The antianginal agent ranolazine, in phase 3 clinical studies, reduced the frequency of anginal attacks in patients with coronary artery disease (CAD) who experienced three or more attacks per week despite daily treatment with amlodipine (Norvasc), said Peter Stone, MD, at the American Heart Association’s Scientific Sessions 2005.

	Ranolazine is the first of a new class of agents called the pFOX inhibitors. It is thought to work by partial inhibition of partial fatty acid oxidation and reciprocal increases in glucose oxidation during periods of myocardial stress. Consistent with this mechanism, ranolazine does not have clinically significant effects on heart rate or blood pressure. It may be a good choice, therefore, in patients with lower heart rates or blood pressure, who have angina despite therapy with a beta blocking agent or calcium antagonist, and in whom increasing the dosage of the beta blocker or calcium antagonist would have unwanted hemodynamic effects.

	In the Evaluation of Ranolazine in Chronic Angina (ERICA), 565 patients with a documented diagnosis of CAD and angina, despite already taking the maximum labeled dose of amlodipine (10 mg/day) for at least 2 weeks, were randomly assigned to ranolazine, 1,000 mg twice daily, or placebo. Patients could be on a stable dose of long-acting nitrates for at least 2 weeks before entering the study. Forty-five percent of the patients enrolled were taking nitrates at baseline.

	Compared with placebo, ranolazine significantly decreased the mean number of anginal episodes per week (P = .028), improved the anginal frequency component of the Seattle Angina Questionnaire (P = .008), and reduced mean weekly nitroglycerin consumption (P = .014).

	“Ranolazine has a novel pharmacodynamic profile with anti-ischemic properties that do not depend on changes in determinants of myocardial oxygen demand, making it an effective complimentary therapy to existing agents that depend on hemodynamics,” said Dr. Stone, lead investigator of ERICA and codirector of the Samuel A. Levine Cardiac Unit at Brigham and Women’s Hospital in Boston. “It improves the manifestations of ischemia, such as myocardial stiffness and increased wall tension.”

	There was a consistent treatment effect of ranolazine across the subgroups analyzed: users versus nonusers of long-acting nitrates, men versus women, and patients aged less than 65 versus those 65 years or older. No clinically significant effect on heart rate or blood pressure was observed in ranolazine recipients.

	Study-drug—related adverse events were more common in the ranolazine versus the placebo group (21% versus 6%), but serious adverse events occurred in only 1% of each group, and only 1% of patients in each group withdrew from the study because of adverse events. As a single agent, ranolazine has been shown to be at least as effective as atenolol (Atenolol, Tenormin), 100 mg/day, in reducing the frequency of angina, the time to 1 mm of ST-segment depression, and improving exercise duration, he said.

	In a trial known as Combination Assessment of Ranolazine in Stable Angina, ranolazine in combination with routine doses of other antianginal agents (amlodipine, 5 mg; atenolol, 50 mg; and diltiazem [Taztia XT, Tiazac], 180 mg) improved the manifestations of ischemia.

Second study of combination therapy with new antianginal  drug shows fewer anginal attacks, less nitroglycerin use

	Montreal—The presence of antibodies to heparin is an independent risk factor for potentially serious complications following cardiac surgery, and this risk is independent of the risk posed by the development of heparin-induced thrombocytopenia (HIT), according to a study presented by David Kress, MD, at CHEST, the 71st annual meeting of the American College of Chest Physicians.

	“We found that whether the patients developed thrombocytopenia postoperatively had no further effect on the postoperative morbidity (associated with heparin antibodies),” said Dr. Kress, senior cardiothoracic surgeon, Aurora

	St. Luke’s Medical Center, Milwaukee. “It was the presence of the antibodies that appeared to be related to it. Most studies looking at complications of heparin only look at HIT. This syndrome that we’re talking about is almost an entirely different disease than HIT. And it hasn’t been discussed much in the literature up to this point.” The clinical risk associated with heparin/platelet factor 4 (HPF4) antibodies in patients who do not have HIT is poorly understood in clinical practice, he said.

	Using the Society of Thoracic Surgeons National Adult Cardiac Surgery Database, postoperative outcomes were evaluated for 1,114 consecutive patients undergoing coronary artery bypass graft surgery and/or valve surgery who were screened in an unselected manner for HPF4 antibody status over 2.5 years. Sixty (5.4%) of the patients tested had positive HPF4 antibodies preoperatively. Compared with patients who were antibody-negative, those with HPF4 antibodies had

	• A greater incidence of acute limb ischemia (5.0% versus 0.9%, P = .03),

	• A greater incidence of renal dialysis (11.7% versus 4.3%, P = .02),

	• A greater incidence of gastrointestinal complications (15.0% versus 5.7%, P = .01),

	• A greater incidence of prolonged mechanical ventilation (> 96 hours, 21.7% versus 8.8%, P = .01),

	• Longer median intensive care unit length of stay (56 versus 42 hours,

	• Longer median postoperative length of stay (9 versus 7 days, P < .01).

	“The patients that were heparin antibody-positive were more likely to need renal dialysis than diabetic patients, were more likely to develop acute limb ischemia than if they had peripheral vascular disease, and were more likely to have longer ventilation times than if they had low ejection fractions,” he said. HPF4 antibodies typically indicate that a patient has had past exposure to heparin and is at greater risk for developing HIT, a life-threatening immune-mediated complication of heparin administration that contraindicates further heparin exposure.

	HIT syndrome occurs in about 3% of the patients undergoing cardiac surgery and overt thrombosis occurs in 50% of HIT patients. Clinical consequences of HIT include limb ischemia requiring amputation, myocardial infarction, stroke, pulmonary embolism, and death. Optimal preoperative care for cardiac surgery patients should include screening for HPF4 antibody status, said Dr. Kress.

	Alternatives to heparin are in late-phase clinical trials. Some appear to be less antigenic than heparin while retaining many of the properties of heparin,

	The development of HPF4 antibodies will be more frequent, Dr. Kress predicted, because many patients coming to surgery have had previous percutaneous coronary interventions with heparin exposure.

 Antibodies to heparin increase postoperative risk of complications

	Montreal—New therapies for the treatment of pulmonary arterial hypertension (PAH) will allow clinicians to tailor therapy to the patient whose condition is not optimized with existing monotherapy, as well as the patient with newly diagnosed PAH, said presenters at CHEST, the 71st annual meeting of the American College of Chest Physicians.

	Several pathogenetic mechanisms contribute to the development and progression of PAH. These include under- expression of vasodilating, antiproliferative substances, such as prostacyclin and nitric oxide, and overexpression of vasoconstricting, proproliferative substances, such as endothelin-1.

	One method to attack these multiple targets is combination therapy. Current guidelines for the treatment of PAH do not address combination therapy because no studies had been published at the time the guidelines were written, said Richard N. Channick, MD, associate professor of medicine, University of California, San Diego.

	“Adding inhaled iloprost (Ventavis) to bosentan (Tracleer) is a common practice in the US,” he said. “A recent [Food and Drug Administration] FDA labeling change allows combination therapy with inhaled iloprost.” Inhaled iloprost is a prostacyclin that was approved by the FDA in December 2004.

	In a double-blind, randomized study, 65 patients with PAH who were being treated with bosentan monotherapy were randomly assigned to combination therapy or continued monotherapy. Patients had New York Heart Association (NYHA) functional class III or IV heart failure and had to be on a stable dose of bosentan for at least 16 weeks to be eligible. They were assigned to iloprost,

	5 mg (titrated down to 2.5 mg if not tolerated), or placebo added to bosentan. Compliance with scheduled doses was more than 90% in each arm, with most patients taking six inhalations per day.

	At week 12, 6-minute walk distance improved by 30 m in patients assigned to iloprost (P = .001 compared with baseline) and by 4 m in the patients assigned to placebo, reported Vallerie McLaughlin, MD, lead investigator of the study, and director of the pulmonary hypertension program at the University of Michigan, Ann Arbor. The improvement in 6-minute walk distance in the iloprost group relative to the placebo group was of marginal significance (P = .051). Furthermore, 34% of the iloprost recipients improved by at least one functional class compared with only 6% of placebo recipients (P = .002).

	None of the iloprost patients experienced clinical worsening compared with 15% of the placebo group (P = .02). Clinical deterioration was defined as any one of the following: death owing to worsening PAH, receipt of lung transplant or atrial septostomy, hospitalization for worsening PAH, or any early discontinuation of the study drug owing to worsening PAH.

	Headache and cough occurred significantly more often in the iloprost recipients, which is consistent with previous studies of iloprost.

	According to Dr. McLaughlin, combination therapy may be considered for patients who remain in functional class III or IV despite bosentan monotherapy.

	A potential alternative to bosentan is sitaxsentan (Thelin), a highly selective endothelin-A (ET-A) receptor antagonist that is currently under review by the FDA. “Sitaxsentan is 6,500 times more selective for the ET-A receptor than bosentan,” said David Langleben, MD, professor of medicine, McGill University, Montreal.

	A total of 424 PAH patients with NYHA class II to IV heart failure were randomly assigned in two studies to receive placebo or 50, 100, or 300 mg of sitaxsentan once daily for 12 or 18 weeks. Overall, patients taking the 100-mg dose (n = 115) had significantly greater time to clinical worsening (P = .0345) than those taking placebo (n = 119). In addition, a 55-week extension study showed that 65% of the subset of patients with PAH owing to connective tissue disease showed improvement in functional heart failure class.

	Interim results of a 1-year, phase 3 extension study randomizing 145 patients to 100 mg sitaxsentan once daily or 125 mg bosentan twice daily showed significantly fewer liver function ab-

 New agents may permit tailored therapy in PAH

	This month’s issue of Cardiology Review features a combined article in the diabetes and coronary artery disease sections that evaluates the relationship between preoperative levels of fasting blood glucose that are “impaired” but are not diagnostic of diabetes mellitus on the one hand and increased morbidity after coronary artery bypass graft surgery on the other. Dr. R.E. Anderson and his colleagues from Sweden studied 1,895 surgical patients and found that fasting blood glucose levels either slightly above or below the diagnostic threshold for diabetics carried an increased risk of cardiac mortality, a risk that was similar to that of patients known to have diabetes. Dr. Harold L. Lazar comments on these findings for Cardiology Review.  

	Our feature article in the lipid disorders and coronary artery disease sections concerns the use of HMG-CoA reductase inhibitors (statins) before percutaneous coronary intervention in order to prevent periprocedural myocardial infarction. The authors, Dr. Carlo Briguori and associates from Italy, studied 451 patients (226 in the statin group and 225 in the control group). They found a positive effect of preinterventional statins on cardiac enzyme elevations and attributed this effect to non—lipid-related mechanisms. Dr. Stanley J. Katz addresses the clinical implications of the article in his commentary.  

	In a combined article in the stroke and arrhythmias sections, Drs. Margaret C. Fang and Daniel E. Singer discuss the interrelationship between age, anticoagulation intensity, and risk for intracranial hemorrhage in patients with atrial fibrillation who are also anticoagulated with warfarin. The authors identified 170 patients who developed intracranial hemorrhage and compared them to 1,020 control patients from their anticoagulation clinic. Surprisingly, as Dr. Joseph T. Dell’Orfano notes in his commentary, a reduced international normalized ratio did not lower the risk of intracranial hemorrhage, although it did reduce the risk of ischemic stroke.

	In the hypertension section, Drs. Jose A. Silva and Christopher J. White investigated brain natriuretic peptide levels in patients with hypertension to see whether renal artery stenosis could increase these levels. What this means for blood pressure reduction after renal stent revascularization is discussed by Drs. Alan H. Gradman and Yoel R. Vivas in their commentary.

	ln our continuing Drugs in Trial series, Dr. Stephen P. Glasser discusses the role of high-density lipoprotein cholesterol as a risk factor for cardiovascular disease and comments on current therapy, as well as some exciting new approaches to managing this aspect of atherogenesis.

Decmber 2005

Improvement in blood pressure after renal artery revascularization

Is HDL cholesterol an independent cardiovascular disease risk factor?

Predicting blood pressure response in hypertensive patients with renal artery stenosis: The search continues

Brain natriuretic peptide and blood pressure response in patients with renal artery stenosis

Evaluating risks versus benefits of warfarin therapy

Intracranial hemorrhage, atrial fibrillation, and the elderly

Is there a benefit to prescribing statins before PCI?

Risk of intracranial hemorrhage in atrial fibrillation

Cardiac enzyme increase after successful elective stenting

Statin administration before percutaneous coronary intervention Carlo Briguori

Preoperative fasting blood glucose levels and increased mortality after CABG surgery

Preoperative fasting blood glucose levels and increased mortality after CABG surgery

Fasting blood glucose and mortality after CABG surgery

Second study of combination therapy with new antianginal drug shows fewer anginal attacks, less nitroglycerin use

Antibodies to heparin increase postoperative risk of complications

New agents may permit tailored therapy in PAH

Impaired fasting blood glucose and increased morbidity after coronary artery bypass graft surgery

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