	Fibrinolysis is an effective and widely available treatment for acute myocardial infarction (MI). Over the past few years, manipulations of the lytic “cocktail” have been attempted to improve its clot-lysing efficacy and reduce the risk of bleeding. Modifying the plasminogen activator has simplified therapy by allowing bolus dosing, but it has not improved efficacy or reduced the bleeding risk.1,2 Efforts to improve antithrombin therapy, using a thrombin inhibitor or low-molecular-weight heparin instead of unfractionated heparin, have so far been blunted by an increase in the risk of intracranial hemorrhage (ICH) without improving coronary patency.3-5

	Potentiating the antiplatelet component of the lytic cocktail, however, by adding a glycoprotein (GP) IIb/IIIa inhibitor has been shown to provide higher reperfusion rates compared with standard lytic regimens, even with reduced doses of heparin and plasminogen activator.6,7 In phase 2 trials, this higher lytic efficacy was not associated with a higher bleeding risk.8 The large Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) V  mortality trial was planned to fully evaluate the benefit versus risk ratio of this combination therapy compared with a standard fibrinolytic regimen of reteplase and unfractionated heparin.

	The GUSTO V trial included 16,588 patients who went to the emergency department within 6 hours of onset of an ST-segment elevation acute MI.9 Patients at high risk for ICH, such as those with stroke in the past 2 years or blood pressure above 180 mm Hg systolic or above 110 mm Hg diastolic at any measurement after first medical contact, were excluded. Randomized treatments were either combination therapy with full-dose abciximab, reduced-dose heparin (60 U/kg bolus [maximum 5,000 U], followed by an infusion of 7 U/kg/hour) and half-dose recombinant plasminogen activator (r-PA; 5 U twice, 30 minutes apart), or standard fibrinolytic therapy with full doses of r-PA (10 plus 10 U) and heparin (5,000 U bolus followed by an infusion of 800 or 1,000 U/hour, according to a body weight cutoff of 80 kg). Both groups received unfractionated heparin for at least 24 hours, maintaining an activated partial thromboplastin time (aPTT) between 50 and 70 seconds using a specific heparin-adjustment nomogram. All of the patients also received aspirin at randomization and throughout the course of the study. Mortality at 30 days was the primary end point of the study.

	All suspected stroke events, lasting longer than 24 hours or causing death, were evaluated by clinical and instrumental (computed tomography and magnetic resonance imaging) evidence. Stroke survivors underwent assessment of disability status between days 30 and 45 after discharge from the hospital. Any grade above 2 of the modified Rankin scale was defined as a disabling stroke. Univariate and multivariate analyses were used to identify significant predictors of stroke. Odds ratios (ORs) for the significant factors were estimated using a multiple logistic regression model of ICH.

	In the whole study population, stroke was shown in 154 patients, 73 receiving reteplase (0.9%) and 81 receiving reteplase and abciximab (1.0%; OR, 1.10; 95% confidence interval [CI], 0.80—1.51). Of these strokes, 101 were hemorrhagic: 49 occurred with r-PA alone and 52 occurred with combination therapy (0.6% in both groups; OR, 1.05; 95% CI, 0.71–1.56). Median (25th–75th percentile) time from drug administration to ICH was 9.2 hours (5.9–22 hours) with r-PA alone and 5.5 hours (3.4–11 hours) with combination therapy (P = .048). Mortality at 30 days, disabling stroke, the composite of mortality and stroke, and the disability measured at follow-up were not significantly different between the two groups.

	Older age, female sex, increased diastolic blood pressure, and concomitant (in the past 48 hours) treatment with digitalis were the only baseline variables significantly associated with higher ICH rates at logistic regression. Administration of heparin before randomization was also associated with a higher risk of ICH at multivariate analysis (1.21% versus 0.55% in non—heparin-pretreated patients; P = .041), but a second heparin bolus, the doses of the different boluses, postrandomization infusion rates, and aPTT values were not.

	Multivariate analysis for ICH risk showed only age as having a significant association with randomized treatments. Younger age (< 70 years) was associated with a lower risk, and older age was associated with a higher risk with combination therapy (figure).

	Evidence has accumulated since fibrinolytic agents began to be used for the treatment of acute MI, indicating that old age, hypertension, and previous stroke are the most powerful independent predictors of ICH following pharmacologic reperfusion therapy.10 Full comprehen-sion of the mechanisms underlying this association, however, is far from being reached. Contrary to a proven dose-related risk of intracranial bleeding with plasminogen activators and thrombin antagonists, an antiplatelet agent, such as aspirin, did not show such an effect when used in association with heparin or streptokinase.11 In addition, the experience gathered with GP IIb/IIIa blockers in tens of thousands of patients with acute coronary syndromes or undergoing percutaneous coronary interventions showed no excess risk of ICH with this powerful antiplatelet therapy.12

	As far as efficacy is concerned, because the early coronary thrombus is predominantly “white,” a more antiplatelet-oriented lytic cocktail has the potential for, and actually has shown, a more powerful lytic effect. Thus, through painstaking dose-finding trials,6,7 a new thrombolytic cocktail was designed with full-dose abciximab (needed to block platelet activation almost completely) and lower doses of heparin and reteplase or alteplase. This regimen clearly showed faster and more complete reperfusion of the infarct-related artery at both the epicardial and microcirculation levels. In these trials, which included a total of slightly more than 1,700 patients, no excess risk of ICH was noted, but with very limited power.

	Data from the GUSTO V trial show a low overall risk of ICH (0.6%), without significant differences between abciximab plus reteplase and reteplase only. The exclusion of patients with any previous stroke or uncontrolled hypertension may partially account for this encouraging result. Nonetheless, a significant association between age and randomized treatment was observed because younger patients receiving combination therapy were at lower risk and older patients were at higher risk compared with those receiving standard r-PA.

	An explanation for this finding is not straightforward. Because the risk of ICH in lytic-treated patients has been attributed to cerebral amyloid angiopathy, a small vessel degenerative disease mostly associated with longstanding hypertension and aging, it can be hypothesized that elderly patients will have an aspecific response to a more aggressive lytic regimen. If combination therapy has been shown to provide faster and more complete recanalization of the infarct-related coronary artery, bleeding complications may also occur earlier and more frequently in the elderly, as shown by the present data, in which the group receiving combination therapy had a shorter time to ICH and an increased rate of ICH in elderly patients.

	In search of a safer drug regimen, it is difficult to know whether the higher ICH risk in the elderly is attributable to abciximab or to amplified heparin activity because the aPTT controls in the GUSTO V protocol were set at fixed times after randomization, rather than at the time of any suspected stroke, and also because of the complexity of the coagulation cascade, particularly after interference with so many drugs. The overall experience obtained so far seems to implicate the heparin dose as being particularly relevant: (1) abciximab and full-dose heparin result in a higher bleeding risk compared with abciximab plus reduced-dose heparin13; (2) the bleeding risk is also increased with low-molecular-weight heparins when these agents are associated with full-dose plasminogen activators in a way that is dose-dependent and becomes concrete in patients older than 75 years5; and (3) patients in GUSTO V who were receiving heparin before randomization had a higher rate of ICH with both randomized regimens. Current consensus and guidelines point to the reduction of the heparin dose, particularly the bolus dose, to reduce the risk of major bleeding and ICH, especially in elderly and low-weight patients.14,15

	Combination therapy with abciximab and a reduced-dose lytic agent is currently being tested in trials of so-called “facilitated primary angioplasty” for acute MI, a strategy of pharmacologic reperfusion during transfer for primary angioplasty. Based on experience obtained in GUSTO V, patients older than 75 years have either been excluded from these studies or they are being treated with even lower doses of r-PA and heparin compared with the GUSTO V regimen. Younger patients may benefit from the earlier and more complete myocardial reperfusion offered by this lytic regimen without paying the price of a higher bleeding risk.

Articles

Cardiology Review Online

Risk of ICH with  combination therapy  for acute MI

	It is not surprising that major and minor bleeding are the most common adverse events accompanying thrombolytic therapy for acute myocardial infarction. This problem was recognized in the very earliest clinical trials with thrombolytic agents and is apparently more common in patients who receive tissue plasminogen activator (tPA) and related compounds as compared with streptokinase. The most dreaded bleeding complication of thrombolytic therapy is intracranial hemorrhage, a complication associated with major disability as well as markedly increased mortality. Clinicians and investigators working in acute coronary care have tried for years to minimize this feared complication, but with only minimal success. Indeed, most series continue to report that approximately 1% of patients treated with tPA or one of its engineered relatives, such as reteplase, develop intracranial hemorrhage.

	In the article by Savonitto and colleagues (page 39), they report on factors that increase the risk of intracranial hemorrhage in patients treated with reteplase.1 These investigators noted that increasing age was the single statistically significant predictor of intracranial hemorrhage following reteplase therapy. Other investigators have noted that increased systolic blood pressure(> 150 to 160 mm Hg) and low body weight are also associated with an increased risk of intracranial hemorrhage following thrombolytic therapy. The study by Savonitto and colleagues also noted that the incidence of intracranial hemorrhage was the same when half-dose reteplase was combined with the IIb/IIIa glycoprotein platelet blocker abciximab as compared with full-dose reteplase.

	Moscucci and colleagues also studied predictive factors for major bleeding in more than 24,000 patients admitted with acute coronary syndrome to hospitals throughout the world.2 Factors associated with major bleeding included advanced age, female sex, and a previous

	history of bleeding and renal insufficiency. Bleeding was associated with an increased risk of dying during the index hospitalization for the acute coronary syndrome. In another study, Van de Werf and colleagues noted that the highly fibrin-specific agent tenecteplase was associated with less noncerebral bleeding compared with recombinant tissue plasminogen activator, although there was no difference in the incidenceof cerebral bleeding with these two agents.3

	The take-home message for me from the Savonitto study, as well as the others cited above, is that cerebral hemorrhage continues to be a significant problem associated with thrombolytic therapy for acute ST-segment elevation myocardial infarction. The elderly woman of low body weight is at particular risk for this complication. Doses of thrombolytic agents should be weight adjusted in this elderly population. Furthermore, arterial systolic blood pressure should be controlled before administering one of these agents. In the presence of any of the above-mentioned risk factors, an invasive approach to reperfusion makes good clinical sense. 

Thrombolytic therapy and intracranial hemorrhage Joseph S. Alpert, MD

	Cardiology Review opens this month with a continuing medical education feature in the diabetes and coronary artery disease section. Drs. Justin L. Martin and Darren K. McGuire evaluated the influence of a large multicenter revascularization trial (BARI) on practice patterns in diabetic patients. Despite advice to the contrary, many diabetic patients still undergo angioplasty. Dr. William E. Lawson explores the complex issues involved in this provocative study in his thoughtful commentary.

	Our second continuing medical education feature, in the stroke and arrhythmias section, is an article evaluating the prevalence of atrial fibrillation in ischemic stroke patients compared to an age- and sex-matched control population. Dr. Teresa S.M. Tsang and Marion E. Barnes studied 3,742 patients, half of whom had confirmed ischemic strokes. The authors found a surprising increase in the incidence of atrial fibrillation in both groups over a 30-year period. Dr. Douglas Dulli comments on the public health implications of their findings.

	This month’s edition of Cardiology Review also features an article in the hypertension section by Dr. Richard B. Devereux and Paulette A. Lyle studying cardiovascular event rates after treatment with the angiotensin receptor blocker losartan compared with the beta blocking agent atenolol. In this series of hypertensive patients without clinically evident vascular disease, losartan was a superior drug, a somewhat surprising observation that stimulated an interesting commentary by Drs. Nobuyuki Miyawaki and John K. Maesaka.

	In the lipid disorders section, Dr. Harold L. Lazar provides an overview of the role of lipids and HMG-CoA reductase inhibitor (statin) therapy, not in respect to coronary artery disease as one might expect, but rather in the deterioration of native and prosthetic heart valves! This report offers a new insight into an important clinical problem.

	Our final feature this month is a combined stroke and coronary artery disease report. Dr. Stefano Savonitto and colleagues from Italy and the United States evaluated the occurrence of intracranial hemorrhage during treatment of acute myocardial infarction with both a platelet blocker and a thrombolytic agent. They found a higher risk of this complication in the elderly in their large (16,588 patients) multicenter study (GUSTO V). The “take-home message,” as Dr. Joseph S. Alpert emphasizes in his commentary, is that this type of stroke continues to be a worrisome problem during aggressive therapy of acute myocardial infarctions.

Evaluating the  influence of clinical trials on practice patterns

	This posthoc analysis of the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study compared the cardiovascular effects of losartan- and atenolol-based therapy over 4.8 years in a subgroup of patients with hyper-tension and left ventricular hypertrophy, who were clinically free of vascular disease. Of the 9,193 participants in the LIFE study, nearly 75% (6,886) of subjects were free of clinically evident coronary, cerebral, or peripheral vascular diseases at the time of enrollment.

	Despite equivalent reductions in systolic and diastolic blood pressures, there were significant differences in end point reduction. Using a losartan-based antihypertensive regimen with concurrent thiazide diuretics in more than 50% of subjects, there was a 20% lower cardiovascular death rate, 34% fewer strokes, and a 31% lower incidence of new-onset diabetes than in the atenolol group. The ability of losartan to reduce the cardiovascular end points and new-onset diabetes beyond that of atenolol is remarkable. There is ample evidence that treatment of hypertension is effective in reducing strokes and that hypertension was traditionally regarded as the single important factor in the prevention of strokes.1 The present studies suggest that factors other than reductions in blood pressure contribute to the favorable outcomes noted with losartan.

	As discussed by Devereux and Lyle (page 29), the beneficial effect of losartan might be related to the inhibition of angiotensin at the tissue level. This might result in an alteration of endothelial dysfunction, vascular remodeling, and other possible mechanisms that are the subject of interest in many basic science and clinical investigations. Moreover, the beneficial effects of losartan, compared with atenolol on cardiovascular morbidity and mortality in the LIFE study, might result from an attenuated increase in serum uric acid, which is now considered an independent cardiovascular risk factor.2,3 This attenuated increase in serum uric acid is unique to losartan among all angiotensin receptor blockers (ARBs), partly by competing with uric acid for the anion exchanger in the proximal tubule to increase urinary uric acid excretion.4 This unique feature of losartan might mitigate the conclusion that the results of the LIFE study are applicable to all ARBs. Future studies should address this unique feature of losartan.

	The 31% reduction in new-onset diabetes with losartan has great potential implications. This finding is comparable to the benefits derived from the use of ramipril in the Heart Outcomes Prevention Evaluation  trial, but the mechanisms have not been elucidated. Several mechanisms have been proposed, including bradykinin-induced insulin sensitization by angiotensin-converting enzyme (ACE) inhibition.5,6 While the data on the effects of ARBs on insulin sensitization have been inconsistent in animal studies, the profound reduction in new-onset diabetes observed with the ARB losartan suggests that an increase in insulin sensitization might also exist in humans.5

	The cardiovascular benefits afforded by losartan in the LIFE study do not appear to apply to the black

Beneficial effects of losartan versus atenolol on cardiovascular morbidity and mortality in LIFE 

	From the Boston University School of Medicine and the Department of Cardiothoracic Surgery, Boston Medical Center, Boston, Massachusetts

	Progressive aortic valve calcification leading to severe aortic stenosis has been attributed to the natural aging process and the hemodynamic stress placed on anatomically abnormal valve leaflets. There is now evidence to suggest that the underlying pathophysiology of aortic valve calcification may be related to other factors, such as abnormal lipid metabolism, endothelial dysfunction, and inflammation.

	This review will (1) document the evidence suggesting that native and prosthetic aortic valve calcification is similar to the tissue processes responsible for atherosclerotic vascular disease, and (2) discuss how HMG-CoA reductase inhibitor (statin) therapy may play an important role in the reversal and stabilization of this process.

	Natural history of aortic valve calcification Faggiano and colleagues studied the natural history of aortic valve calcification in 400 patients using serial Doppler echocardiography over a 4-year period.1 They found that aortic valve calcification is a progressive disorder, with nearly a third of patients developing some degree of aortic valve stenosis. Further insight into the pathophysiology responsible for the natural progression of aortic valve calcification to stenotic lesions was provided by Palta and colleagues.2 They found that the annual rate of reduction in aortic valve area was 0.1 ± 0.27 cm2 in 170 patients followed up with serial echocardiograms. Furthermore, they noted that patients with serum cholesterol levels above 200 mg/dL had a rate of aortic valve area reduction nearly twice that of patients with lower cholesterol levels (0.14 ± 0.35 cm2 versus 0.07 ± 0.19 cm2; P = .04). Similar findings were noted by Aronow and colleagues in a retrospective analysis of 180 patients with mild aortic stenosis.3 Independent predictors of the progression of aortic stenosis were male sex, smoking, hypertension, diabetes, and a low-density lipoprotein (LDL) cholesterol level above 125 mg/dL. These factors are similar to those responsible for the progression of atherosclerotic vascular disease. In this study, the use statins was associated with a decreased progression of aortic stenosis. The relationship between the progression of aortic valve calcification and hypercholesterolemia was further defined by Pohle and colleagues in a retrospective study

	of 104 patients using electron beam computed tomography.4 Patients with LDL cholesterol levels below 130 mg/dL had significantly less progression of both aortic valve and coronary artery calcification.

	Pathophysiology of calcific aortic stenosis

	The pathophysiologies of calcific aortic stenosis and vascular atherosclerotic disease have many similarities. Calcified aortic valve leaflets explanted at the time of surgery have an increased number of inflammatory cells, including macrophages, foam cells, and T lymphocytes.5 The macrophages have been shown to produce osteopontin, a protein involved in tissue calcification.6 They also contain increased amounts of LDL cholesterol and lipoprotein, suggestive of abnormal cholesterol metabolism.7 Calcified aortic valve leaflets also show evidence of an increased inflammatory response, similar to the atherosclerotic pro-

	cess. In addition to accumulation of macrophages and T cells, they have been shown to have increased levels of C-reactive protein8 and angiotensin-converting enzyme.9

	In addition to similarities in pathophysiology, there is now evidence to suggest that patients with aortic valve calcification may also have an increased incidence of adverse cardiovascular events similar to patients with vascular atherosclerotic disease. Chandra and colleagues followed 425 patients who went to the emergency department with chest pain, 49% of whom had evidence of aortic valve calcification without significant gradients.10 After 1 year, patients with calcified aortic valves had an increased incidence of mortality from all causes (18.7% versus 2.4%; P < .001), an increased cardiovascular mortality (14.7% versus 1.4%; P < .001), and an increase in the combined end point of cardiovascular death or myocardial in-farction (MI; 16.7% versus 7.1%;

	P = .003). The incidence of coronary artery disease (CAD) was similar

	for both groups of patients. Aortic valve calcification was also associated with increased levels of C-reactive protein.

	Similar adverse events were shown in the Cardiovascular Health Study, which consisted of 5,000 patients with aortic valve calcifications followed up for 5 years.11 These patients had a 40% increase in the incidence of MI and a trend toward an increased risk of angina, congestive heart failure, and stroke, regardless of the presence or absence of CAD. The increase in adverse cardiovascular events in both studies was unrelated to progression of valvular gradients. An increased incidence of endothelial dysfunction, as suggested by reduced brachial artery flow-mediated dilatation,12 and significantly increased levels of serum LDL cholesterol and lipoprotein levels found in patients with aortic valve calcification13 suggest that the same factors responsible for increased ischemic events in atherosclerotic vascular patients may also be the culprit in patients with aortic valve calcification.

	The role of statins in aortic valve calcification

	In view of the evidence of an increased inflammatory response, endothelial dysfunction, and altered cholesterol metabolism associated with aortic valve calcification, is there a role for statins in the treatment of these patients? In addition to blocking cholesterol synthetic pathways at the level of the conversion of HMG-CoA to mevalonate, statins also reduce intermediates, such as geranyl pyrophosphate and farnesyl pyrophosphate. These isoprenoid compounds play an important role in the regulation of the inflammatory response and endothelial function through their effects on macrophage function. Recent studies have shown that statins reduce the secretion of matrix metalloproteinases, which lead to the degradation of extracellular matrix and contribute to the deposition of calcium in these injured tissues.14 Statins have been shown to retard calcification deposits in coronary vessels,15 protect against bone fractures,16 and stimulate bone protein production, resulting in increased bone formation.17

	Could these non—cholesterol-lowering “pleiotropic” properties of statins also play a therapeutic role in patients with aortic valve calcification? Bellamy and colleagues studied 156 patients with mild aortic stenosis, 38 of whom received statin therapy, over 3.7 years.18 There was a significant progression of stenosis in the untreated group (mean gradient, 22 ± 12 mm Hg versus 39 ± 19 mm Hg; P < .001), and aortic valve area decreased from 1.20 ± 0.35 cm2 to 0.91 ± 0.33 cm2 (P < .001). In contrast, the progression of stenosis was significantly reduced in patients receiving statins (P < .04). There was no relationship between the progression of aortic stenosis and total cholesterol or LDL cholesterol levels. Hence, the beneficial effects of statins could not be explained by changes in serum lipids alone, suggesting a pleiotropic effect.

	Novaro and colleagues retrospectively studied 174 patients with mild to moderate aortic stenosis, of which 57 patients (33%) received some type of statin therapy.19 Over a 21-month follow-up period, the nonstatin group showed the anticipated annual reduction in aortic valve area of 0.11 cm2. The statin-treated group had a 45% reduction in the annual stenosis rate (0.06 cm2; P = .03). Patients receiving statins also had a smaller increase in peak and mean valvular gradients. There was a significant relationship between changes in serum LDL cholesterol and peak and mean gradients. Multivariable analysis showed that statin use was a significant independent predictor of smaller decreases in valve area (P = .01) and peak gradients (P = .02). Bioprosthetic aortic valves Primary tissue failure of bioprosthetic aortic valves, similar to changes in native aortic valves, is related to calcification in tissue cusps. Histologic studies of stenotic explanted bioprostheses show areas of inflammation with cellular infiltration of macrophages and T lymphocytes, and lipoprotein deposition in areas of calcification.6

	Farivar and Cohn recently examined whether risk factors for atherosclerosis could also be related to bioprosthetic valve calcification and dysfunction.20 Their study consisted of 144 patients who had a bioprosthetic aortic or mitral valve removed and a case-control analysis of a group of 66 patients with explanted tissue valves compared with a group of 66 patients with intact functioning protheses with similar duration of implantation. In the retrospective cohort study, they found that serum cholesterol levels (P = .035), younger age at implantation (P = .014), and presence of CAD (P = .017) were associated with valve calcification using a univariate analysis. In a multivariate regression analysis, only mean cholesterol levels were linked to calcification (P = .02). In the case-control analysis, mean serum cho-lesterol levels of the explanted valves were significantly higher (189 mg/dL versus 163 mg/dL; P < .001) than in the group whose valves did not require explantation. In patients whose serum cholesterol levels were above 200 mg/dL, the odds ratio for valve explantation and re-replacement was 3.9 times higher. In the case-control study, patients whose valves were not explanted had a higher incidence of statin use (18% versus 6%; P = .018).

	Antonini-Canterin and colleagues also looked at the relationship of statins and echocardiographically derived parameters of bioprosthetic aortic valve degeneration in 167 patients after 4 years of implantation.21 Throughout the follow-up period, 22 patients (13.2%) received statins. Statin therapy significantly decreased the annual rate of increase of peak velocity (P < .001), the rate of increase of mean gradient (0.54 mm Hg versus 2.47 mm Hg; P < .001), the rate of decrease of effective orifice area (0.031 cm2 versus 0.100 cm2; P < .001), the rate of decrease of indexed effective orifice area (0.019 cm2/m2 ver-sus 0.056 cm2/m2; P < .001), and the worsening of aortic insufficiency

	(P = .022). A combined parameter of prosthetic degeneration progression, defined as the existence of either an annual rate of increase in peak velocity of  0.3 m/sec per year or more or worsening of aortic insufficiency with greater than one third degrees was more frequently found in the group of patients who did

	not receive statins. The only factor associated with progression of bioprosthetic aortic valve degeneration was the absence of statin therapy

	(P < .001). Patients treated with statins exhibited a reduced progression of bioprosthetic degeneration despite higher serum cholesterol levels, suggesting that the benefits of statin therapy were due to their anti-inflammatory, pleiotropic effects.

	There is now sufficient evidence to suggest that the augmented inflammatory response seen in patients with atherosclerotic vascular decrease may also be responsible for the progression of calcification seen in native and bioprosthetic aortic valve disease. Furthermore, it appears that statins may play an important role in stabilizing the progression of valvular deterioration. However, Pearlman noted that several important questions remain.22 Are all statins equally effective in decreasing calcifications, and will higher doses be necessary to achieve these pleiotropic effects? Will statins be effective as monotherapy, or will their benefits be enhanced if combined with other anti-inflammatory agents or drugs that alter calcium metabolism? When is the optimal time to begin statin therapy? Will it be equally effective in cases of mild stenosis in contrast with more moderate and severe stenoses? And finally, will statin therapy significantly alter the natural progression of aortic stenosis and avoid valve replacement, enhance the durability of bioprostheses already implanted, and, most importantly, improve long-term survival?

	The studies cited in this review are all retrospective and nonrandomized. The types of statins used, their dosages, and the duration of therapy varied considerably. A specific level of LDL cholesterol was not targeted. In studies involving bioprosthetic valves, it is not known which echocardiographic parameters of valve function correlate with the inflammatory response actually witnessed on an explanted tissue valve. Furthermore, most bioprosthetic valves show their greatest incidence of deterioration after 7 years of implantation. None of these studies exceeded a mean of 4 years of follow-up.

	Prospective, randomized clinical trials using established doses of a specific statin targeted to achieve finite LDL cholesterol levels will be necessary to determine the role of statin therapy for these patients. In the meantime, the evidence suggests that patients with both native and bioprosthetic aortic valves are susceptible to the same inflammatory changes seen in patients with atherosclerotic vascular disease. Clinicians may wish to consider initiating some form of statin therapy in these patients when native aortic valve calcification is present or after the implantation of a new bioprosthesis.

The role of statins in the deterioration of native and bioprosthetic aortic valves

	From Weill Medical College, Cornell University, New York, New York, and Merck Research Laboratories, Whitehouse Station, New Jersey

	Hypertension and its consequences continue to be significant burdens to patients and health care systems worldwide. In the Losartan Intervention For Endpoint reduction in hypertension (LIFE) study, therapy with the angiotensin II receptor (type AT1) antagonist losartan was compared with the beta blocking agent atenolol. Losartan was shown to be superior to atenolol for the primary prevention of cardiovascular mortality and morbidity, especially stroke, in a large subgroup of patients with hypertension and left ventricular hypertrophy (LVH) who were without clinically evident vascular disease at the time of enrollment in the study.

	Substantial reductions in hypertension-related cardiovascular events have been achieved by treating hypertension to a goal blood pressure with a well-tolerated treatment regimen. Increasing evidence from experiments and small clinical studies, however, suggests that the agents used to treat hypertension, particularly those that interfere with the renin-angiotensin system, can make a difference in the outcomes of patients with hypertension. Therefore, hypertension outcomes clinical trials are now designed to achieve similar blood pressure control between treatment groups so that outcome differences may be related to specific antihypertensive agents. The LIFE study was such a trial. It assessed cardiovascular morbidity and mortality in patients with hypertension and LVH. It also provided the opportunity to examine the effects of antihypertensive treatments on the primary prevention of cardiovascular events in a large subgroup of patients who did not have clinically evident coronary, cerebral, or peripheral arterial disease at the time of enrollment in the study.

	The LIFE study design, statistical methods, and primary results have been published elsewhere.1-3 All patients provided informed consent, and the protocol was approved by the ethics committees associated with each clinical center. The study was designed and directed by independent steering, data and safety monitoring, and end point committees.

	The LIFE study was a randomized, double-blind investigation of the effects of treatment with losartan compared with atenolol in 9,193 patients with hypertension and LVH. Patients were 55 to 80 years old and were eligible for enrollment if blood pressure was 160 to 200 mm Hg systolic and 95 to 115 mm Hg diastolic after 1 or 2 weeks of placebo treatment. Patients were excluded if they had secondary hypertension, myocardial infarction (MI), or stroke within the previous 6 months; angina pectoris requiring treatment with a beta blocking agent or calcium antagonist; heart failure or a left ventricular ejection fraction of 40% or less; or need for treatment with the study medication or related drugs.

	Patients were treated with 50 mg of losartan or atenolol once daily. The dosage could be titrated to 100 mg, with or without hydrochloro-thiazide and/or another antihyper-tensive therapy (excluding angiotensin-converting enzyme [ACE] inhibitors, beta blocking agents, or angiotensin II receptor antagonists), to reach the target blood pressure of below 140/90 mm Hg.

	The primary outcome measure of the LIFE study was a composite end point of the first occurrence of cardiovascular death, stroke, or MI. In this post hoc analysis for the subgroup without clinically evident vascular disease, we report the results for the composite end point, components of the composite end point, total mortality, and new-onset diabetes.

	Perhaps as a consequence of the placebo run-in phase of the study and the requirement that no beta blocking agents other than atenolol or its placebo be used during the treatment phase, the study included a large number (6,886; 74.9%) of patients without a history of coronary, cerebral, or peripheral arterial disease at the time of enrollment in the study. The two treatment groups were similar regarding baseline age (overall mean ± SD, 66.6 ± 7.0 years), ethnic distribution (93% white), blood pressure (174.3/98.3 ± 14.3/8.6 mm Hg), heart rate (73.8 ± 11.2 beats/

	minute), body mass index (28.1 kg/m2), history of diabetes (11%), isolated systolic hypertension (13%), and atrial fibrillation (3%). They were also similar with regard to severity of LVH (electrocardiographic Cornell voltage duration product and Sokolow-Lyon voltage data not shown).

	Patients were followed for a mean of 4.8 years. Mean doses of losartan and atenolol at the time of end point or end of study drug treatment were 82 mg and 79 mg, respectively. Approximately 50% of patients in both treatment groups were also treated with hydrochlorothiazide. The use of other allowed concomitant antihypertensive therapies was comparable in the two groups.

	Blood pressure was reduced significantly in both treatment groups. Systolic blood pressure was reduced by 30.2 mm Hg in the losartan group and by 29.3 mm Hg in the atenolol group. Diastolic blood pressure was reduced by 16.7 mm Hg in the losartan group and by 16.8 mm Hg in the atenolol group. Mean blood pressures at the last study visit were 144.0/81.7 mm Hg in the losartan group and 145.1/81.4 mm Hg in the atenolol group. The reduction in heart rate was greater in the atenolol group than in the losartan group (a reduction of 7.6 versus 1.9 beats/

	In the 6,886 patients without clinically evident vascular disease at baseline, the primary composite end point (cardiovascular death, stroke, or MI) occurred in 282 patients (17.5 per 1,000 patient-years) in the losartan group and in 355 patients (21.8 per 1,000 patient-years) in the atenolol group (risk reduction, —19%;

	P = .008; table). Cardiovascular death occurred in 103 patients in the losartan group and 132 patients in the atenolol group (risk reduction, —20%). Nonfatal and fatal stroke occurred in 125 patients in the losartan group and 193 patients in the atenolol group (risk reduction, –34%; P < .001). Nonfatal and fatal MI occurred in 110 patients in the losartan group and 100 patients in the atenolol group (risk reduction,  14%).

	The incidence of new-onset diabetes was 31% lower in the losartan group: 173 versus 254 patients (risk reduction, —31%; P < .001). There was a trend toward lower total mortality in the losartan group: 223 versus

	268 deaths (risk reduction, —15%). The incidence of noncardiovascular death was also lower in the losartan group (120 deaths) compared with the atenolol group (136 deaths).

	In the 2,307 patients with clin-ically evident vascular disease at baseline, the primary composite

	end point occurred in 226 patients (18.8%) in the losartan group (43.0 per 1,000 patient-years) and in 233 patients (21.1%) in the atenolol group (48.6 per 1,000 patient-years; risk reduction, —7%; table). Cardiovascular death occurred in 101 patients in the losartan group and 102 patients in the atenolol group (risk reduction, –5%). Stroke occurred in 107 patients in the losartan group and 116 patients in the atenolol group (risk reduction, –13%). MI occurred in 88 patients in each treatment group (risk reduction, –3%). Death from any cause occurred in 160 patients in the losartan group and 163 patients in the atenolol group (risk reduction, – 6%).

	Almost 75% of the LIFE study patients did not have clinically evident vascular disease at baseline. In these patients, blood pressure was reduced to similar levels in the losartan and atenolol treatment groups; therefore, differences in results between the treatment groups are attributable to effects of treatment other than those on blood pressure. The results in the subgroup of patients without clinically evident vascular disease are similar to those in the overall study and did not differ statistically from those in patients with a history of vascular disease.

	In the subgroup of patients without clinically evident vascular disease, losartan significantly reduced the predefined primary composite end point (cardiovascular death, stroke, and MI) rate by 19% versus that for the atenolol group (P = .006). In this subgroup, losartan reduced the rate of fatal and nonfatal stroke, the most common component of the primary composite end point, by 34%. Some4 but not all5 other trials

	of drugs that affect renin-angiotensin system activity have influenced the stroke outcome beyond an effect on blood pressure. Stroke was 44% more common than MI in the LIFE study, which is consistent with other recent hypertension trials.6 It is important to identify new ways to prevent stroke, especially in light of the fact that the stroke rate in industrialized countries, after a decades-long decline, has reached a plateau or even begun to increase in recent years.

	The similar rates of MI in the losartan and atenolol groups suggest that protection of coronary ar-teries from the direct toxic effects of angiotensin II by losartan might have offset a reduction in myocardial oxygen demand achieved by treatment with atenolol.7 The 31% difference in new-onset diabetes was expected from findings in trials that studied ACE inhibitors.8 The LIFE study was not designed to investigate the mechanism of the new-onset diabetes finding; therefore, we cannot conclude whether this finding was the result of a beneficial effect of losartan, a detrimental effect of atenolol, or some combination of both.

	The beta blocking agent atenolol was the comparator in the LIFE study. Treatment with beta blockade has reduced cardiovascular complications in placebo-controlled studies in both patients with hypertension and those with a history of MI or other manifestations of vascular disease.9-12 Studies that have compared newer therapies with beta blocker or diuretic therapy did not report outcomes separately for patients without vascular disease at baseline; however, the lack of difference in primary outcome between treatment groups in those studies makes it unlikely that beta blockade reduced cardiovascular events in the subset of patients without vascular disease.9,13

	Statistical independence from blood pressure lowering suggests that the incremental benefits shown with losartan in the LIFE trial are a result of tissue-level inhibition of angiotensin II with losartan. In the present analysis of patients without clinically diagnosed arterial disease, the important benefits suggest that the protection of arteries from adverse effects of angiotensin II in the entire LIFE sample also apply to patients who have not yet developed clinically evident atherosclerosis..

	The clinical benefits shown with losartan therapy in the primary prevention of cardiovascular morbidity and mortality in hypertensive patients without clinically evident vascular disease suggest that antihypertensive therapy regimens that include losartan may improve outcome, especially by preventing stroke. 

Losartan versus atenolol in hypertension and LVH

	Since the early 1990s,1 the risk of ischemic stroke due to atrial fibrillation has been increasingly viewed as safely preventable with anticoagulation, a therapy that had been viewed as relatively unsafe in older and more frail patients. A retrospective study by Tsang and colleagues2 (page 23) addresses equally important observations: Atrial fibrillation is exceedingly common in elderly patients, both with and without ischemic stroke, and is increasing in overall prevalence.

	Tsang and colleagues examined the prevalence of atrial fibrillation in a longitudinal case-control study of ischemic stroke patients in Rochester, Minnesota, over three decades from 1960 to 1989. They discovered that the prevalence of atrial fibrillation nearly doubled for each decade, as has been well described,3 but the prevalence of atrial fibrillation had also increased over the epochs in both stroke patients and controls of the age-adjusted populations. These prevalence rates are very high in both groups at 11% to 20% with atrial fibrillation in the stroke patients, and 4% to 12% in the controls. However, the average age of the age-matched cohort (75 years) is also higher than that of other studies and registries of ischemic stroke, which is approximately 65 years.4 Moreover, the influence of the increase in life expectancy over the study period, particularly for a condition such as atrial fibrillation that is so age-dependent, may not have been neutralized completely by the age adjustment. The authors suggest that patients in the later years of their study may have survived better with conditions that are conducive to development of atrial fibrillation, and this argument is also compelling. Finally, a twofold increase in the age-adjusted prevalence of atrial fibrillation in men from the 1970s to the 1990s was noted in the Copenhagen City Heart Study,5 which lends some corroboration to this current study.

	In any case, it is clear that the absolute prevalence of atrial fibrillation and atrial fibrillation—associated ischemic stroke have increased to epidemic proportions. Whether or not this increase can be attributed solely to the aging of the population seems to be an issue of lesser importance. It is still routine to encounter patients with chronic atrial fibrillation, both with and without ischemic stroke, whose stroke prevention therapy consists of aspirin or no specific therapy.6 With the continuing increase in atrial fibrillation, this underutilization of therapy must be held up to increasing scrutiny. It is time for atrial fibrillation to become an epidemic that is silent no more. 

Stroke and atrial fibrillation in the elderly: A silent epidemic no more

	From the Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota

	Currently, approximately 2.3 million Americans have atrial fibrillation. By 2050, it is estimated that 5.6 million people in the United States will have the disorder, which has been labeled a growing epidemic.1,2 Atrial fibrillation is an independent predictor of mortality.3 It also causes significant morbidity, including stroke, and substantially increases health care costs.4 The Framingham study showed a significant increase in the prevalence of atrial fibrillation in men, but not in women, over the course of 22 years (1968—1989), even after adjusting for age and comorbid conditions.5 We conducted an analysis of the data collected over 30 years (1960–1989) in a longitudinal, population-based study of ischemic stroke in Rochester, Minnesota, to evaluate whether atrial fibrillation prevalence changed among patients with incident ischemic stroke and among age- and sex-matched control subjects.6

	Rochester, Minnesota, is comparatively isolated from other urban centers. Medical care is available from only a few health care providers, including the Mayo Clinic and its two affiliated hospitals, the Olmsted Medical Center and its affiliated hospital, and a small number of private practitioners. The Mayo Clinic, which has maintained a unified medical record with details of all inpatient and outpatient visits, laboratory reports, and patient-related correspondence, provides much of the health care in Rochester. A medical linkage system permits access to medical information on patients served by practices in the surrounding areas,7 and all patients in the community with a specific disease or diagnosis can be easily identified. A case-control study of the incidence of ischemic stroke in the Rochester area was performed, and the definitions of ischemic stroke and methods of selecting the control subjects have been previously reported.8,9 Based on this study, we evaluated the prevalence of a history of atrial fibrillation (referred to in this article as “prevalence of atrial fibrillation”) and specific comorbid conditions as of the date of stroke diagnosis for cases, and the reference date for control subjects. Atrial fibrillation was considered present only if it could be substantiated by an electrocardiogram. Definitions of comorbid conditions were applied over the entire period, as reported previously.8 Comorbid conditions were noted as present or absent, and the date of first mention was recorded, which permitted prevalence calculations for each of the three decades (1960—1969, 1970–1979, and 1980–

	In terms of statistical analyses, the effects of age, sex, and calendar time on the odds of a history of atrial fi-brillation and of each comorbid condition separately among case patients and control subjects were assessed using logistic regression models.10 Age, sex, and their associations were also examined. Calendar year, as both a continuous and a discrete (by decade) variable, was evaluated, adjusting for best-fit age and sex models. Associations of calendar year with age and sex were examined. Only significant associations with calendar year that affected the qualitative interpretation were reported.

	The best logistic model was determined for each condition, and the proportions of case patients and control subjects with each condition (adjusted for the demographic variables in the model) were estimated by use of the logit function.10 To summarize the age-adjusted results, prevalence estimates obtained from the multivariate models are reported for age 75 years because this was the mean age for the cohort. For all model building, two-sided P values were used; a variable was considered significant only if P < .05.

	Effects of age, sex, and calendar time on prevalence of atrial fibrillation. The study population consisted of 3,742 residents of Rochester. The mean age was 75 ± 11 years (median age, 76 years; range, 45—105 years). Of 1,871 residents (838 men) with an ischemic stroke over the three decades, 327 (17%) had a history of atrial fibrillation before the date of stroke diagnosis. Among the 1,871 age- and sex-matched control subjects, 176 (9.4%) had a history of atrial fibrillation before the reference date. Table 1 shows the observed prevalence of atrial fibrillation among case patients and control subjects, stratified by age, sex, and calendar decade. A substantial increase in the prevalence of atrial fibrillation was shown with increasing age for stroke patients (odds ratio [OR] per 10 years of age, 1.81; 95% confidence interval [CI], 1.58–2.07; P < .001); however, there was no significant difference between the sexes. There was a significant “calendar-time effect” after adjustment for age and sex: the OR per 5 years was 1.13 (95% CI, 1.05–1.22; P = .001). This change in the prevalence of atrial fibrillation over calendar time did not vary according to sex or age (figure). In this multivariate model, the age-adjusted estimates of prevalence for the three decades (1960–1969, 1970-1979, and 1980–1989) were 11%, 13%, and 16% for men and 13%, 16%, and 20% for women, respectively. A substantial increase in the prevalence of atrial fibrillation with advancing age was shown for the control subjects (OR per 10 years, 2.22; 95% CI, 1.84–2.68), and male sex was associated with a greater likelihood of atrial fibrillation (OR, 1.50; 95% CI, 1.06–2.11). A significant calendar-time effect after adjustment for age and sex also existed: the OR per

	5 years was 1.24 (95% CI, 1.12—1.37; P < .001). This change in the prevalence of atrial fibrillation over cal-endar time also did not vary according to sex or age (figure). In this multivariate model, the age-adjusted estimates of prevalence for the three decades were 5%, 8%, and 12% for men and 4%, 6%, and 8% for women, respectively.

	The age-adjusted prevalence of atrial fibrillation increased significantly (P < .001) over the 30 years for the total sample of 3,742 individuals. The rates of increase were significant for both cases (P = .001) and control subjects (P < .001); however, they did not differ between the two groups

	or between the two sexes within groups. The overall trends of prevalence of atrial fibrillation were based on age-adjusted prevalence values for the mean age of 75 years for cases and control subjects.

	Time trends of comorbid conditions. Substantial increases in prevalent hypertension, coronary artery disease (CAD), and valvular heart disease were evident in both cases and controls from 1960 to 1989. Prevalent myocardial infarction (MI) increased significantly in cases and older controls; however, prevalent congestive heart failure (CHF), diabetes mellitus, and a history of cardiac surgery increased only in the cases (table 2).

	The prevalence rates of atrial fi-brillation for patients with incident stroke and in age- and sex- matched controls over the course of 30 years were assessed. Age was a strong risk factor for the development of atrial fibrillation, which was consistent with other studies.11-15 There was a doubling of the odds for atrial fibrillation for each decade of age (controls: OR, 2.22; 95% CI, 1.84—2.86; cases: OR, 1.81; 95% CI, 1.58–2.07). There was also a calendar-time effect on the prevalence of atrial fibrillation, independent of age. The age-adjusted prevalence of atrial fibrillation increased significantly (P < .001) over the 30-year period for the total sample of 3,742 residents (figure). The rates of increase were significant for both case patients and control subjects, but did not differ between the two groups. The rates of increase over time were significant for both men and women in the case and control groups, but they did not differ between the two sexes. Changes in the prevalence of comorbid conditions over time may be important factors in the development and continuation of this epidemic (table 2). The risk of atrial fibrillation development is a function not only of advancing age, but also of the total disease burden and the presence of selected comorbid conditions that are themselves risk factors for atrial fibril-lation among those who survive to older ages.

	The prevalence of atrial fibrillation increased significantly in patients with ischemic stroke and in their age- and sex-matched controls over a 30-year period. The rates of increase were not significantly different between men and women.

	An increase in the prevalence of specific comorbid conditions may have partly contributed to the observed trends in atrial fibrillation, but  additional studies are needed to further our understanding of the mechanisms and control of this growing epidemic. 

Prevalence of atrial  fibrillation in a stroke case-control study

	Although most interventional cardiologists are familiar with the results of the Bypass Angioplasty Revascularization Investigation (BARI) randomized clinical trial and the subsequent National Heart, Lung, and Blood Institute Clinical Alert, as Martin and McGuire explain (page 14), there is still no consensus regarding the optimal treatment strategy for revascularization in diabetic patients with multivessel coronary artery disease (CAD). It remains a hot-button topic of debate at many cardiac catheterization conferences. Why do so many of these patients undergo angioplasty as the preferred treatment despite the decreased mortality demonstrated for surgical revascularization compared with angioplasty in BARI? Were there issues with data collection and analysis? The results for the diabetic patients in BARI were from a post hoc subgroup analysis rather than a prespecified analysis. Although the results showed a 7-year cardiac mortality benefit in patients with diabetes who underwent coronary artery bypass graft (CABG) surgery compared with those who underwent percutaneous transluminal coronary angioplasty (PTCA; 23.6% versus 44.3%), on further analysis, this benefit applied only to those receiving a left internal mammary artery graft, not to those only receiving saphenous vein grafts.1 Those who underwent CABG surgery with a left internal mammary artery graft had a mortality rate of 16.8% compared with 44.5% for those who received only saphenous vein grafts and for those who underwent percutaneous coronary intervention (PCI).

	Are the results still relevant? As with any trial that takes years to perform, the practice of both surgery and angioplasty has changed substantially since BARI was completed. Angioplasty has changed to include the routine use of new antiplatelet agents, glycoprotein (GP) IIb/IIIa receptor blockers, HMG-CoA reductase inhibitors (statins), bare metal stents and drug-eluting stents, and brachytherapy. Tight glycemic control has been shown to have an important influence on restenosis in diabetic patients.2 The GP IIb/IIIa receptor blockers have improved angioplasty outcomes, particularly in patients with diabetes. Diabetic patients with multivessel CAD undergoing stenting with the GP IIb/IIIa receptor blocker abciximab had a significant reduction in 1-year mortality from 7.7% to 0.9% in an analysis of data pooled from the Evaluation of IIb/IIIa Platelet Receptor Antagonist 7E3 in Preventing Ischemic Complications (EPIC) trial, the Evaluation of PTCA to Improve Long-term Outcome by c7E3 GP IIb/IIIa Receptor Blockade (EPILOG) trial, and the Evaluation of IIb/IIIa Platelet Inhibitor for Stenting (EPISTENT) trial.3 Insulin-dependent diabetic patients treated with abciximab had a significant decrease in mortality from 8.1% to 4.2%.

	plasty and stenting—restenosis&mdash;has largely succumbed to prevention with drug-eluting stents and treatment with brachytherapy. The Scripps Coronary Radiation to Inhibit Proliferation Post Stenting (SCRIPPS) trial demonstrated an 83% reduction in in-stent restenosis in diabetic patients with Ir-192 therapy.4 In BARI, 54% of PTCA patients underwent repeat revascularization compared with 8% of those treated with CABG surgery. In the Arterial Revascularization Therapy Study (ARTS),  however, for patients who underwent multivessel revascularization with stents, the repeat revascularization rate decreased to 21.2% at 1 year and 26.7% at 3 years compared with 3.8% and 6.6%, respectively, in patients randomly assigned to CABG surgery.5 In the Sirolimus-coated Bx Velocity Balloon-expandable Stent in the Treatment of Patients with De Novo Coronary Artery Lesions (SIRIUS) study, the revascularization rate decreased even further to 6.4% at 9 months.

	Do the results apply to your practice? The results of bypass surgery in your hospital may differ significantly from the results reported in BARI. The immediate results may not be as good, the left internal mammary artery may not be used routinely to bypass the left anterior descending artery, or saphenous vein grafts may be used exclusively. Other issues may also apply. The patient may refuse surgical revascularization in favor of multivessel stenting. Poor documentation often makes the cardiologist suspect of self-referral when this occurs. The choice of revascularization certainly has a major and easily measured impact on the cardiologist’s (and the cardiothoracic surgeon’s) income. Professionalism in the context of procedural self-referral has become an issue for national health care policy makers. Payer input may yet have decisive input into revascularization practices. The Centers for Medicare and Medicaid Services have set a goal of “paying for quality” and are examining processes and outcomes to achieve this objective. Managed care and industry are embracing similar objectives in the Leapfrog initiative.

	Will drug-eluting stents make a difference? The available data suggest a 70% reduction in the need for revascularization after treatment with drug-eluting stents as compared with bare metal stents.6 The issue of revascularization in diabetic patients with multivessel CAD will be reexamined using sirolimus-eluting stents in the Future REvascular-

	ization Evaluation in patients with Diabetes mellitus; Optimal Management of multivessel disease (FREEDOM) trial8; however, even if restenosis is abolished, the differential clinical impact of disease progression between diabetic patients treated with CABG surgery and those treated with PCI will persist.

	Is our approach fundamentally flawed? Although both angioplasty and bypass surgery are effective means of revascularization, neither has been shown to reduce the incidence of myocardial infarction (MI) in stable angina, and only CABG surgery has been shown to be effective in improving survival (in limited subsets of patients with left main coronary artery disease and triple vessel or proximal left anterior descending artery disease with impaired left ventricular function).9 In contrast, studies on cholesterol lowering show marked reductions in coronary heart disease events both in primary10 and secondary11 prevention. For example, in the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS),10 lovastatin treatment was associated with a 37% overall risk reduction (43% in diabetic patients), and in the Scandinavian Simvastatin Survival Study (4S),11 simvastatin therapy was associated with a 32% overall risk reduction (55% in diabetic patients). Because of intravascular ultrasonography, we now know that atherosclerosis is a diffuse systemic disease that is not limited to the stenoses identified on angiography. We also know that most acute coronary syndromes and acute MIs are caused by ruptures of previously nonobstructive plaques. Although neither angioplasty nor CABG surgery directly addresses the latter issue, bypass surgery has a natural advantage because it provides additional conduits to the distal circulation operating in parallel to the native artery. These conduits can limit the size of subsequent infarcts and decrease the likelihood of death. This is not true for angioplasty, in which the arterial tree remains a serial circuit dependent on antegrade flow.

	Conclusion In patients with diabetes who have multivessel disease, in particular, we may provide better and more cost-effective care by either referring them for CABG surgery or by using drug-eluting stents to treat angina-producing lesions only and concentrating on effective risk-factor modification. 

Treating multivessel CAD in diabetic patients William E. Lawson, MD

	A 61-year-old man with diabetes mellitus, hypertension, dyslipidemia, and a remote history of cigarette use presented to the cardiology clinic for initial evaluation. Over the preceding 6 weeks, he noted onset of exertional fatigue associated with mild substernal chest heaviness that would resolve promptly with rest. He did not have symptoms of congestive heart failure and had no history of coronary artery disease, peripheral or cerebrovascular disease, or arrhythmia. His primary care physician had been treating him with aspirin, an angiotensin-converting enzyme (ACE) inhibitor, and metformin. He had recently been prescribed an HMG-CoA reductase inhibitor (statin drug) for modestly increased low-density lipoprotein (LDL) cholesterol and triglyceride levels. More recently, he had been prescribed sublingual nitroglycerin because of his chest discomfort; however, he had not yet taken any pills. His physical examination was notable only for an S4 gallop. He had no evidence of heart failure.

	An office electrocardiogram showed sinus rhythm with borderline left ventricular hypertrophy without evidence of prior infarction or ischemia. Laboratory studies showed the following values: hemoglobin A1c, 6.8%; fasting glucose, 147 mg/dL; LDL cholesterol, 129 mg/dL; triglycerides, 230 mg/dL; and creatinine, 1.3 mg/dL. Coronary angiography showed a 90% stenosis of the proximal left anterior descending (LAD) coronary artery and a 75% stenosis of a large second obtuse marginal branch of the circumflex coronary artery. The ejection fraction was estimated to be 57% on ventriculography without wall motion abnormality. Although both coronary lesions appeared amenable to percutaneous coronary intervention, after detailed discussion with the patient, the decision was made to proceed with coronary artery bypass graft surgery based on the accumulated data suggesting improved long-term outcomes with a surgical versus percutaneous approach. The patient underwent uncomplicated two-vessel bypass surgery, which included a left internal mammary artery graft to the LAD and a saphenous vein graft to the obtuse marginal branch. The patient was discharged from the hospital on postoperative day 4 without complications. At the 1-year follow-up, the patient had no symptoms, was working full-time, and had no exercise limitations. He continued to take aspirin daily, an ACE inhibitor, a beta blocking agent, and statin therapy, along with metformin for glucose management.

Case report: Coronary artery bypass graft surgery for a diabetic patient

	Justin L. Martin, MD  •  Darren K. McGuire, MD, MHSc

	From the Department of Internal Medicine and the Donald W. Reynolds Cardiovascular Clinical Research Center, University of Texas Southwestern Medical Center at Dallas

	The Bypass Angioplasty Revascularization Investigation (BARI), funded by the National Heart, Lung, and Blood Institute (NHLBI), was designed to evaluate the long-term effectiveness and safety of percutaneous transluminal coronary angioplasty (PTCA) compared with coronary artery bypass graft (CABG) surgery for the treatment of patients with symptomatic multivessel obstructive coronary artery disease (CAD). In BARI, patients were randomly assigned to receive a primary revascularization strategy of PTCA or CABG surgery, with a primary outcome of cumulative 5-year all-cause mortality.1 The BARI results showed no difference in 5-year survival between patients who underwent CABG surgery and PTCA. However, an unanticipated finding was that in the subgroup of patients with medically treated diabetes, CABG surgery was associated with an almost 50% reduction in 5-year mortality compared with PTCA (18.4% versus 34.5%). The BARI diabetic findings prompted the NHLBI to issue an urgent “Clinical Alert” recommending CABG surgery over balloon angioplasty as the preferred revascularization strategy for the treatment of patients with diabetes and multivessel coronary disease.3 Initiated in 1991 by the National Institutes of Health to convey important research findings to the clinical arena,4 the Clinical Alert and Advisory program has successfully communi-

	cated study results and recommendations through a series of 19 releases since its inception. The influence of these alerts on clinical practice remains undetermined. The goal of the present study was to use data collected from a large multicenter registry to evaluate whether the BARI diabetic findings and the subsequently released NHLBI Clinical Alert had a measurable impact on revascularization strategies (ie, PTCA versus CABG surgery) among diabetic patients with multivessel coronary disease.

	Patients and methods The National Cardiovascular Network (NCN) coronary revascularization database is a collaborative project consisting of 28 hospitals from diverse geographic areas that range from modest-volume community hospitals to large-volume tertiary referral and academic medical centers. The network is thought to represent the breadth of US clinical practice. All institutions provide data on all coronary revascularizations (percutaneous and surgical) to a central data-coordinating center. We restricted our analysis to data from the 13 NCN centers that provided complete data for at least the 2 years spanning the NHLBI Clinical Alert. From these centers, we included patients with medically treated diabetes and multivessel CAD who underwent either CABG surgery or percutaneous coronary intervention (PCI) as an initial revascularization procedure and otherwise met BARI clinical inclusion criteria.

	Primary data analyses were performed using multivariable logistic regression techniques that included propensity score adjustment based on likelihood to undergo PCI versus CABG surgery to account for potential differences in patient mix be-tween centers as well as over the duration of the data collection. The response variable was PCI, and the individual NCN centers were considered random effects. These methods were used to test for possible associations between time period (eg, before versus after the alert) and rate of PCI, as well as to compare PCI rates among the individual centers.

	Results The study included data from 9,619 consecutive patients meeting eligibility criteria who underwent PCI or CABG surgery at one of the 13 NCN centers between 1994 and 1997. Overall, 27.5% underwent PTCA, whereas 72.5% underwent CABG surgery. Figure 1 shows the temporal trends in revascularization rates in relation to the release of the BARI Clinical Alert and the BARI trial manuscript publication. The proportion of patients undergoing PCI did not change following the Clinical Alert (28.6% before versus 26.8% after) or following the publication of the BARI manuscript (28.0% before versus 26.8% after).

	The table shows the independent predictors for PCI derived from the multivariable logistic regression model. The strongest predictor of revascularization strategy used was the severity of underlying CAD. Three-vessel disease was the strongest predictor of CABG surgery, followed by two-vessel CAD that included the proximal left anterior descending coronary artery. Conversely, young age, female sex, lower Canadian Cardiovascular Society angina score, absence of heart failure, presence of renal insufficiency, less than moderate mitral regurgitation, and lack of insulin treatment were all independently associated with a higher odds ratio of receiving PCI as the initial revascularization strategy.

	Although the severity of CAD was most strongly associated with revascularization strategy, no change in the rate of PCI was observed following the BARI Clinical Alert in either the subset of patients with three-vessel disease (14.9% versus 13.6%) or in the subset with two-vessel disease (49.8% versus 47.4%). When PCI use among the 13 NCN centers was analyzed, a dramatic variation in the rate of PCI was observed, ranging from 4.3% to 56.6%. This variability persisted after multivariable adjustment, even when patients were grouped according to CAD severity (25%—84% among patients with two-vessel CAD and 1%–46% among patients with three-vessel CAD). As shown in figure 2, overall PCI rates did not decrease at any of the NCN centers after the release of the Clinical Alert. In fact, PCI rates paradoxically increased at 2 of the 13 centers following the alert. As expected, the frequency of use of coronary stents increased throughout the study period, with rates being higher after, rather than before, the Clinical Alert (50.8% after versus 11.7% before; P = .001). However, no correlation between the frequency of stent use and the overall rate of PCI among the various centers was observed, suggesting that the lack of decline in overall PCI rate following the Clinical Alert was not attributable to an increased frequency of stent use at any of the individual centers.

	Because the medical environment in which practitioners operate may influence clinical practice patterns, we examined the interaction between the type of institution and rate of PCI both before and after the Clinical Alert. Overall, academic medical centers were more likely than nonacademic centers to use PCI (30.0% versus 23.3%; P = .001). After adjusting for case mix, the rate of PCI did not change after the alert at either academic (30.1% before versus 32.4% after) or nonacademic centers (22.1% before versus 23.4% after). Centers formerly affiliated with the BARI trial were less likely to use PCI than nonaffiliated sites. Again, the Clinical Alert did not alter adjusted rates of PCI at either BARI sites (24.6% before versus 27.0% after) or non-BARI sites (28.7% before versus 29.5% after).

	These analyses show three important findings. First, even before the BARI results were known, the majority of medically treated diabetic patients with multivessel CAD were treated with surgical coronary revascularization, especially those patients with the most advanced CAD. Second, despite the rapid and broad dissemination of the study results, the BARI diabetic findings and resultant Clinical Alert had no measurable impact on revascularization practice patterns. Finally, there is a troubling lack of clinical consensus regarding revascularization for this high-risk population, as evidenced by the greater than 10-fold variation in PCI rates among these 13 clinical centers.

	The foundation of evidence-based medicine has been the randomized clinical trial, such as BARI, which, when well designed and implemented, can provide definitive comparisons of the effect of alternative treatment strategies. This allows the “evidence” to guide the management of challenging treatment dilemmas. Cardiology has been at the forefront of the evidence-based medicine movement, conducting large-scale randomized trials to address many of its most challenging treatment dilemmas. The importance of evidence-based medicine is well documented in the literature.1,5-8 Ideally, therapeutic decisions are guided by the best available evidence from clinical studies. However, the medical community has been slow to systematically incorporate the “best available data” into routine clinical practice.9,10 Some evidence suggests that the time interval between the publication of clinical trial results and the actual incorporation of new data into clinical practice may be as long as 12 years.11 How physicians respond to large-scale, multicenter, randomized trials that produce results requiring an immediate change in clinical practice has not been well studied. The real-time incorporation of clinical evidence into practice patterns remains a major challenge caused, in part, by the multitude of factors that influence clinical decision-making. Additionally, the driving forces that persuade physicians to modify their behavior are numerous. Certainly, the acceptance of various research outcomes partly depends on the quality and magnitude of the scientific evidence, timely release and dissemination of the results, relevance and generalizability of results to current practice, and incentives for adopting change in practice.5 The BARI trial diabetic results and the subsequently released NHLBI Clinical Alert provide an opportunity to examine the relationships between randomized clinical trial results and physicians’ practice patterns.

	This is the first study to examine the effects of the NHLBI BARI Clinical Alert on practice patterns. On one hand, the findings are encouraging in that the vast majority of diabetic patients with multivessel coronary obstruction were treated with CABG surgery. The severity of underlying CAD was one of the most powerful predictors of undergoing CABG surgery as the initial revascularization strategy, which is consistent with evidence of benefit from prior studies.1,12,13 Despite these encouraging findings, it remains disappointing that neither the NHLBI Clinical Alert nor the subsequent publication of the article on the BARI diabetic findings changed clinical practice. Although we observed no change during our study period in the proportion of PCIs, other data have shown a 20% increase in these procedures as a percentage of all revascularizations in the United States over the past decade.14 Therefore, the absence of an increase in PCI rates may truly represent the clinical influence of the BARI diabetic findings.

	Perhaps the most powerful finding of our study was the clear lack of clinical consensus regarding the best initial revascularization strategy for diabetic patients with multivessel CAD. This lack of consensus was highlighted by the over 10-fold variation in PCI use among the 13 US centers we included in our study. This lack of consensus does not appear to derive from a lack of awareness of the BARI diabetic findings, however, based on our survey of the principal investigators at each of the participating NCN sites. Our survey showed that the BARI diabetic findings were broadly disseminated and were considered to be valid and generalizable to patients undergoing treatment at the participating hospitals. Despite these re-sults, the respondents uniformly conceded that practice patterns at their respective institutions had not materially changed in the wake of the BARI diabetic findings and NHLBI Clinical Alert, with most attributing the disconnect to advances in technologies and adjunctive therapies that seemed to render the BARI findings obsolete. However, even this notion was countered by our analyses, which showed no correlation between frequency of intracoronary stent use and the proportion of PCIs performed at individual centers. Therefore, the explanation for the widely varied clinical practice remains unknown.

	ConclusionOur findings underscore the gap that often exists between well-conducted scientific clinical evidence and the day-to-day care of individual patients. The inability of the Clinical Alert and the BARI trial diabetic findings to measurably influence clinical practice patterns highlights the multitude of challenges involved in implementing the ra-

	pid accumulation of evidence-based medicine into the daily practice of the medical community. Clearly, the ability of large-scale multimillion-dollar clinical trials, such as BARI, to influence therapeutic decision-making is complex. The quality of available evidence and its timely dissemination to practitioners represents only a portion of this puzzle. Further study of how we can best incorporate clinical trial results into medical practice is warranted so that we continue to consistently apply the best available evidence to the treatment of the cardiovascular patients receiving our care. 

Influence of BARI on revascularization strategies in patients with diabetes

	ORLANDO—The incidence of congestive heart failure (CHF) in patients with type 2 diabetes appears to be much greater than previously estimated, according to research by Gregory A. Nichols, PhD, research associate at the Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon. He presented his findings at the 64th Annual Scientific Sessions of the American Diabetes Association.

	A previous estimate of the CHF incidence rate in patients with type 2 diabetes was based on 30 months of follow-up from a study of members of Kaiser Permanente Northwest. The new study identified and described risk factors for developing CHF over 6 years of follow-up using the same database as the 30-month study. The study population consisted of 8,231 patients from Kaiser Permanente Northwest who were diagnosed with type 2 diabetes. These patients were compared with age- and sex-matched nondiabetic patients from the same health maintenance organization.

	On average, diabetic patients who developed CHF were 5.5 years younger than the nondiabetic subjects who developed CHF (P < .001). The 6-year incidence of CHF per 1,000 person-years revealed that diabetic patients experienced CHF at a rate that was 2.5 times the rate of nondiabetic comparison subjects (30.9 versus 12.4 cases per 1,000 person-years; P < .001).

	The data suggest that the incidence of CHF in patients with type 2 diabetes may be “3 to 15 times greater than previous estimates that were based on smaller samples, shorter follow-up, or more severe case definitions,” according to Dr. Nichols. Previous estimates of CHF incidence in diabetic patients ranged from 2 to 10 cases per 1,000 person-years.

	CHF incidence increased steadily with age in both the diabetic and nondiabetic patients. The difference in the rates of CHF between subjects with and without diabetes decreased with increasing age. This narrowing in CHF rates with age suggests that “diabetes not only increases the risk of CHF but also accelerates its occurrence,” he said.

	Compared with diabetic patients who did not develop CHF, those who did experience CHF had a longer duration of diabetes at baseline, were more likely to have ischemic heart disease, had more advanced renal disease, were more likely to be using insulin, and were more likely to be taking metformin. Glycemic control and blood pressure were statistically but not clinically significantly different between those who did and did not develop CHF.

	Every 5-year increase in age increased the risk that a person with type 2 diabetes would develop CHF by 40%. The presence of ischemic heart disease more than doubled the risk of CHF. Greater body mass index and poor glycemic control were also strong predictors of more rapid development of CHF.

	“Our multivariate results confirm that tight glycemic and blood pressure control, as well as weight loss and renal disease treatment,

	are essential to the long-term health of people with diabetes,” said Dr. Nichols. “Given the substantially larger CHF rate ratios and the greater life expectancy of patients under age 65, younger persons may benefit most from intensive risk factor modification.”

CHF rate in type 2 diabetes is greater than previously thought

	ORLANDO—Treatment with atorvastatin can reduce the risk of a first major cardiovascular event by about one third in patients with type 2 diabetes without raised cholesterol levels, said Helen M. Colhoun, MD, at the 64th Annual Scientific Sessions of the American Diabetes Association (ADA).

	The Collaborative Atorvastatin Diabetes Study (CARDS) is the first study of a lipid-modifying agent for the primary prevention of cardiovascular disease conducted solely in patients with type 2 diabetes. Even without hyperlipidemia, type 2 diabetes is associated with an elevated risk of coronary heart disease and stroke, said Dr. Colhoun, coprincipal investigator of CARDS and professor of genetics and epidemiology at The Conway Institute, University College Dublin, Ireland. For this reason, patients with type 2 diabetes and low-density lipoprotein (LDL) cho lesterol levels of 160 mg/dL or less were chosen for inclusion. In all, 2,838 patients with no clinical history of coronary, cerebrovascular, or severe peripheral vascular disease were randomly assigned to atorvastatin, 10 mg daily, or placebo. To be eligible, patients had to have one of the following cardiovascular risk factors in addition to diabetes: hypertension, retinopathy, micro- or macroalbuminuria, and current smoking. At baseline, the mean level of LDL cholesterol was 118 mg/dL in those given placebo and 119 mg/dL in those given atorvastatin. “Two thirds of the patients enrolled had LDL cholesterol levels below the current ADA guideline for pharmacologic intervention,” said Dr. Colhoun. Twenty-five percent had an entry LDL cholesterol of less than 100 mg/dL, which is the current target of therapy in patients with type 2 diabetes.

	The trial was ended 2 years before the planned termination date because of the significant positive outcome associated with atorvastatin, she said. After approximately 4 years, patients randomized to atorvastatin had a 37% reduction in the risk of major cardiovascular events (P = .001), including a 36% reduction in the risk of acute coronary events and a 48% reduction in the risk of stroke. The treatment effect was apparent regardless of baseline LDL cholesterol level, baseline high-density lipoprotein cholesterol level, and baseline triglyceride level. There was also no difference in treatment effect in patients older or younger than 60 years.

	With the overwhelming benefit derived from atorvastatin in CARDS, patients with type 2 diabetes should be automatically considered for statin therapy, regardless of their cholesterol level, said Dr. Colhoun. “CARDS suggests that there is no justification for having a threshold level of LDL cholesterol as the sole arbiter of which patients with type 2 diabetes should receive statin treatment,” she said. “The overall cardiovascular risk should be the principal determinant.”

	Ten percent of placebo recipients discontinued therapy due to adverse events, compared with 8.5% of atorvastatin recipients. The incidence of muscle- and liver-related adverse events was similar in each group. The ADA will consider the results of CARDS when establishing new recommendations to prevent cardiovascular events in patients with type 2 diabetes, said Richard Khan, PhD, chief scientific and medical officer at the ADA. The organization typically reviews the results of trials annually in considering issuance of new guidelines, he said. The study was sponsored jointly by the charity UK Diabetes, the UK Department of Health, and Pfizer, Inc.

All patients with type 2 diabetes should be  considered for a statin

	ORLANDO—The insulin sensitizer pioglitazone reduces blood pressure in patients with type 2 diabetes. Pioglitazone also has beneficial effects on lipid abnormalities that occur in patients with diabetes,  metabolic syndrome, or both. These findings were released at the 64th Annual Scientific Sessions of the American Diabetes Association.

	In a study of 3,140 patients with type 2 diabetes and hypertension, all patients received open-label pioglitazone, 30 mg daily, for 2 weeks. Hypertension was classified as Stage I or Stage II according to current National Institutes of Health criteria (JNC 7), under which Stage I is defined as 140 to 159/90 to 99 mm Hg and Stage II is defined as ≥ 160/≥ 100 mm Hg. Pioglitazone lowered blood pressure by a mean of 6.9/3.1 mm Hg from baseline in patients with Stage I hypertension, and by 18.7/8.3 mm Hg in patients with Stage II hypertension. “Hypertension is frequently diagnosed in patients with type 2 diabetes and is often present years before disease onset,” said lead investigator Thomas Konrad, MD, assistant professor of medicine, Institute for Metabolic Research, Frankfurt, Germany. “In these patients, controlling hypertension is as important as controlling the glycemic level. These blood pressure lowering findings are remarkable because they suggest that pioglitazone may be able to impact certain cardiovascular disease risk factors in patients with type 2 diabetes.” Pioglitazone is thought to decrease blood pressure by reducing vascular resistance by improving endothelial function, he added.

	Other clinical studies presented at the meeting showed that pioglitazone has favorable effects on the dyslipidemia that occurs commonly with diabetes or metabolic syndrome. Investigators assessed 2,444 patients with type 2 diabetes who were enrolled in one of two prospective, randomized, double-blind, multicenter, multinational trials in which the patients were randomly assigned to receive pioglitazone, a sulfonylurea, or metformin for as long as 52 weeks. The effects of the three treatments on components of diabetic dyslipidemia were studied.

	High-density lipoprotein (HDL) cholesterol increased by 19.7% in patients assigned to pioglitazone, compared with a 10.5% increase among those assigned to metformin and 7.4% among those assigned to a sulfonylurea. The difference in HDL cholesterol change from baseline was significantly superior in the pioglitazone-treated patients versus the other two groups (P < .0001). Pioglitazone was also significantly superior to the other two treatment groups in decreasing triglycerides (—10.4%, –0.6%, and –4.0% with pioglitazone, metformin, and sulfo-nylurea, respectively) and the ratio of total to HDL cholesterol (–9.8%, –7.7%, and –9.0%, respectively).

	In another study of 1,269 patients with type 2 diabetes, pioglitazone and metformin were evaluated when added to existing sulfonylurea ther-apy; pioglitazone and sulfonylurea were also evaluated when added to existing metformin therapy. The investigators found that pioglitazone added to the sulfonylurea resulted in a 17% decrease in triglycerides compared with a 9% decrease when metformin was added to the sulfo-nylurea (P = .001). Pioglitazone added to metformin was associated with a 23% decrease in triglycerides compared with a 7% increase when sulfonylurea was added to metformin

	(P = .001). Pioglitazone added to the sulfonylurea also improved HDL cholesterol by 21%, whereas the metformin addition was associated with a 15% increase (P = .001). When pioglitazone was added to metformin, HDL cholesterol improved by 22%; sulfonylurea added to metformin increased HDL cholesterol only an additional 7% (P = .001).

July 2004

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