	This month’s edition of Cardiology Review introduces a new and updated page design, featuring an easier-to-read type face and graphical elements to help you navigate through the sections. Don’t hesitate to let us know what you think about it. Send your comments to cardiologyreview@ascendmedia.com.

	We’ve also included an expanded News Beat section with synopses from trials presented at the American College of Cardiology (ACC) Annual Scientific Session 2005.

	In our first CME feature this month in the heart failure section, Dr. Eduardo R. Perna and colleagues from Argentina analyze the value of cardiac enzyme monitoring in identifying heart failure patients with high risk for ongoing myocardial injury. Worsening congestive heart failure was often associated with cardiac enzyme elevations, a finding that Dr. William C. Little finds interesting in his commentary on this important study.

	This issue also features, as our second CME article, an overview in the hypertension section by Dr. Mohan Rao on the relative value of angiotensin-converting enzyme inhibitors compared with angiotensin receptor blockers, in managing high blood pressure.

	In the diabetes section, Dr. Emiliana Ferramosca and associates evaluate the prognostic role of coronary artery calcium screening in over 10,000 asymptomatic individuals, of whom 903 were diabetic. Subjects without coronary artery calcium had a lower short-term risk of death even if they were diabetic. Dr. Steven Borzak is our commentator for this article.

	angina section report, Drs. Meeradevi Kondapaneni and Frederick A. Spencer evaluate the anti-inflammatory effect of statin therapy on nearly 20,000 patients with acute coronary syndromes. Although this was not a randomized trial, the therapeutic benefits were impressive, as Dr. Richard J. Katz notes in his commentary.

Articles

Cardiology Review Online

 News from the ACC and a new design for Cardiology Review

	Cardiac troponin I (cTnI) and cardiac troponin T (cTnT) are cardiac-specific regulatory proteins that control the response of the contractile apparatus to calcium. The development of assays for cTnI and cTnT as biomarkers for myocardial necrosis has revolutionized the recognition of myocardial infarction because of their cardiac specificity and extraordinary sensitivity. The important study by Perna and colleagues (page 6) adds to the growing body of information indicating that cardiac troponin can also be used as a biomarker for ongoing myocardial injury in patients with systolic heart failure.

	Perna and colleagues found that cTnT was elevated in more than half of apparently stable outpatients with advanced systolic heart failure. In general, the elevations of cTnT were mild, at just about the upper limit of normal. The presence of any abnormalities of cTnT and, even more so, persistent abnormalities of cTnT were strongly associated with a much poorer prognosis. The important implication of this study is that many patients with apparently stable systolic heart failure have ongoing myocardial injury and that it can be recognized using troponin as a biomarker.

	Many of the patients in this study had coronary artery disease, and troponins remain elevated for several days following a myocardial infarction. Thus, it is possible that the increased troponin might be due to myocardial infarction. Elevated troponins were also found in patients with systolic heart failure without coronary disease, however. Thus, progressive deterioration and structural changes in patients with systolic heart failure may represent ongoing myocardial injury in addition to or as a consequence of neurohormonally mediated cardiac remodeling.

	Perna and colleagues used cTnT, where other studies have used cTnI. Although cTnT and cTnI have not been directly compared in patients with heart failure, it is likely that they provide similar information.

	The upper limit of normal for troponin assays is variable between assays and between institutions. Thus, the absolute value of cTnT greater than 0.02 ng/mL used as the threshold for ongoing injury in the study by Perna and colleagues will require careful reevaluation in each institution. It is important to recognize that results of the study were obtained using a third-generation cTnT assay. The results of the study may not apply to the earlier, less specific generations of cTnT assays.

	The clinical implication of the study is that even minor elevations of troponin in patients with systolic heart failure indicate a poor prognosis, especially if the elevation is sustained over time. Thus, measurement of troponin may be useful in identifying high-risk patients. This points to the importance of investigating therapy efforts to diminish ongoing myocardial injury in these patients.

Cardiac troponin as a biomarker for myocardial injury in heart failure

	A 47-year-old man with an 8-year history of chronic heart failure (CHF) as a result of idiopathic dilated cardiomyopathy had been hospitalized for worsening heart failure once in the past year. He remained as an outpatient in New York Heart Association (NYHA) functional class II and was taking 10 mg enalapril (Vasotec) twice a day, 25 mg carvedilol (Coreg) twice a day, 40 mg furosemide (Lasix) once a day, 0.125 mg digoxin (Lanoxin) once a day, 12.5 mg hydrochlorothiazide (Hydrodiuril, Microzide) once a day, 200 mg amiodarone (Cordarone) once a day, and 12.5 mg spironolactone (Aldactone) once a day. Results of the clinical examination showed a blood pressure of 110/70 mm Hg, a heart rate of 59 beats per minute, and a displaced apex with S3 systolic murmur attributable to mild-to-moderate mitral regurgitation, with no sign of

	volume overload. The electrocardio-gram showed sinus rhythm, with left bundle branch block. Laboratory tests showed the following results: hematocrit, 47%; blood glucose, 96 mg/dL; potassium, 3.9 mEq/L; sodium, 136 mEq/L; creatinine, 1.3 mg/dL; and troponin T concentration (cTnT), 0.038 ng/dL. A two-dimensional echocardiogram showed that the patient had a left ventricular end-diastolic diameter of 86 mm and a left ventricular ejection fraction (LVEF) of 28%. The patient walked 420 meters on the 6-minute walk test. The changes in NYHA functional class, as well as cTnT, LVEF, and the 6-minute walk test during the follow-up period are shown in the Table.

	Four months later, the patient was hospitalized for 5 days because of worsening heart failure. Between months

	6 and 12, he required frequent hospital readmission, and his functional

	status progressed to class III. Ventricular fibrillation was induced in an electrophysiological test, and an automatic implantable cardioverter defibrillator with resynchronization was implanted. He felt better for 2 months, but then his clinical condition deteriorated, and he was frequently hospitalized for refractory volume overload. An intra-aortic balloon pump was inserted, and he was urgently listed for heart transplantation. After a 30-day period, he successfully underwent cardiac transplantation.

	This case emphasizes the prognostic value of cTnT monitoring in out-patients with clinically stable severe CHF. High levels of cTnT proceeded to clinical deterioration, even before functional decline and morphologic changes. Identification of such high-risk patients may result in earlier selection for other therapeutic options, including heart transplantation.

Predicting outcome based on  myocardial injury monitoring

	Chronic heart failure (CHF) progression results in decreased ventricular function, reduced functional capacity, and increased hospitalization and mortality rates.1,2 In addition, the risk increases after hospitalization for decompensated CHF, when the readmission rate is close to 60%.3,4 The mortality rate for hospitalized patients is between 3.8% and 13.0%,4,5 with nearly half of deaths occurring within 5 years following the CHF diagnosis.

	The underlying mechanism of CHF progression is ventricular remodeling.6 Although there are a number of causes for the remodeling, the loss of myocytes is the common pathway. Specific markers of myocyte damage are the cardiac troponins T (cTnT) and I (cTnI). The clinical testing of these markers has been responsible for a change in the definition of myocardial infarction.7 Increased levels of both cTnT and cTnI have been reported in patients with CHF and are associated with a worse clinical condition and a poor outcome.8-10

	We analyzed whether the low-level loss of cTnT in patients with stable CHF might indicate subclinical progression of CHF and whether the detection of abnormal concentrations of this marker in serial blood sampling could be associated with a poorer long-term outcome.

	We prospectively assessed the relationship between elevated blood levels of cTnT in serial blood samples collected from 115 ambulatory patients with CHF and the incidence of the combined end point of death or hospitalization for worsening heart failure. We also analyzed the pattern of changes in functional capacity, left ventricular ejection fraction (LVEF), and distance covered in the 6-minute walk test. All patients from the heart failure clinic had had a diagnosis of CHF for 30 days or longer and an LVEF below 40%. The diagnosis of CHF was based on a previous history of either acute cardiogenic pulmonary edema, signs and symptoms of volume overload, exertion dyspnea, paroxysmal nocturnal dyspnea, or Framingham criteria during a hospitalization or when first assessed. We excluded patients who had kidney or liver disease, terminal malignancy, a baseline creatinine level above 2.5 mg/dL, or acute coronary syndrome within the previous 3 months.

	The functional class was determined based on the metabolic equivalents (METS) attained while the patient was engaged in a particular activity. If the exercise capacity was 7 METS or greater, the patient was considered to be class I; if between 5 and 7 METS, class II; if between 2 and 5 METS, class III; and if below 2 METS, class IV.

	On admission to the study and at the 12-month follow-up, subjects were evaluated by a 6-minute walk test and a two-dimensional and M-mode echocardiogram. Ninety-five percent of patients were taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, 84% were taking diuretics, 64% were taking antiplatelet agents, 65% were taking beta-adrenergic blocking agents, 63% were taking digoxin (Lanoxin), 41% were taking antithrombotics, 41% were taking amiodarone (Cordarone, Pacerone), and 29% were taking spironolactone (Aldactone).

	A third-generation electrochemi-luminescent immunoassay of cTnT (Elecsystroponin-T, Roche Diagnostics, Indianapolis, IN) was used to determine cTnT levels from blood samples taken at baseline and at 3, 6, and 12 months. cTnT levels of 0.02 ng/mL or above were not considered normal, and the lower detection limit was 0.010 ng/mL. Patients who had normal cTnT levels were placed in group 1. Patients with one sample that was not normal were placed in group 2, and those with two or more abnormal samples were placed in group 3. We calculated the area under the receiver operating characteristics (ROC) curve correlating to the greatest concentration of cTnT taken during the follow-up period in an individual patient for the combined end point of death or hospitalization and for the correlation between the highest cTnT concentration and the cutoff of 0.02 ng/mL (Tn index).

	Half the patients were in CHF functional class III—IV, and 61.3% had ischemic heart disease. Three fourths of patients were men, and the mean age was 61.2 ± 10.8 years. A median of four samples per patient were taken, and 96.5% had two or more cTnT measurements taken.

	According to the grades of myocardial injury, 62 patients (54%) were classified as group 1, 28 (24%) were classified as group 2, and 25 (22%) were classified as group 3. The higher the group number, that is, the greater the number of abnormal samples, the higher the functional class and the number of prior hospitalizations for CHF. In addition, the greater the myocardial injury, the worse renal function was.

	As shown in Figure 1, between the first blood test and the 12-month follow-up, functional class became worse in group 3, whereas there was no change in groups 1 and 2. Compared with group 1, the baseline LVEF was lower in groups 2 and 3. All groups showed an increase in LVEF from baseline to 1 year, which was statistically significant for groups 1 and 2 only. At baseline and at 12 months, group 3 patients walked significantly less than patients in groups 1 and 2 did.

	In terms of long-term outcomes, worsening CHF was more common in patients with more myocardial damage: 27.4% of patients in group 1, 64.3% of patients in group 2, and 88% of patients in group 3 (P < .001). Hospital admission for CHF was also required more frequently with more abnormal samples: for 76% of patients in group 3, 50% of patients in group 2, and 21% of patients in group 1 (P = .001). The death rate for patients in group 1 was 8.1%, 28.6% for patients in group 2, and 12% for patients in group 3 (P = .032).

	As shown in Figure 2, 63% of patients in group 1 had hospitalization-free survival at 18 months, as did 46% of patients in group 2 and 17% of patients in group 3 (P = .001). This pattern remained for those patients with clinically diagnosed ischemic disease (event-free survival in group 1 compared with the other two groups was 57% and 33%, respectively; P = .011) and for patients with no ischemic disease (75% versus 0%, respectively;

	P = .005). In individuals with a creatinine level below 1.2 mg/dL (50%), 68% of patients in group 1 had event-free survival compared with 47% in groups 2 and 3 (P = .001).

	To explore the value of cTnT as a continuous variable, we built a ROC curve for the highest concentration of cTnT for an individual patient. The corresponding area under the curve was 0.68 to prognosticate the combined end point of death or hospitalization, and 0.020 ng/mL was chosen as the cutoff (sensitivity, 62%; specificity, 71%). The incidence of events based on the level of Tn index (< 1, 1—1.9, 2–2.9, 3–3.9, ≥ 4) was 29%, 54%, 60%, 80%, and 78%, respectively (P = .006). Each level of Tn index was associated with decreased survival free of hospitalization for CHF in the proportional hazards model (Table).

	The prognostic value of cTnT monitoring was explored by a mean of two Cox proportional hazards models. The variables that independently correlated with the primary end point in the first model were the number of abnormal cTnT results (hazard ratio [HR], 1.6; 95% confidence interval [CI], 1.1—2.4), functional class III–IV (HR, 2.3; 95% CI, 1.1–4.6), and hospitalization for CHF in the previous year (HR, 2.1; 95% CI, 1.1–4.1). In the second model, the Tn index was incorporated, and the variables associated with events were functional class III–IV (HR, 2.87; 95% CI, 1.4–5.8), Tn index (1.09; 95% CI, 1.01–1.18), and hospitalization in the previous year (HR, 2.39; 95% CI, 1.3–4.5). An increase of 0.020 ng/mL of cTnT, therefore, was associated with a 9% increased incidence in the combined end point of death or hospitalization for worsening heart failure.

	was that serial measurements of cTnT levels help in the detection of myocardial damage in outpatients with CHF and can identify a long-term high-risk population.   

	Troponins and CHF have been related in different clinical settings. In other studies, myocardial injury was present in 25% to 50% of stable patients with CHF.10,11 In decompensated CHF, high levels of troponin correlated with a poorer clinical and hemodynamic condition, a more severely

	remodeled left ventricle, and poorer short-term and long-term prognoses.9,12-14 Little is known, however, about serial cTnT measurements. In patients with nonischemic dilated cardiomyopathy, three evolutionary patterns of serial cTnT monitoring were found in a retrospective study: normal levels, high initial levels that fell during follow-up, and consistently high levels.8 The lowest long-term survival correlated with consistently high levels of cTnT. For patients with ischemic heart disease greater than 60%, we contribute two new methods of monitoring cTnT:

	and according to the number of abnormal tests.

	Patients with a higher incidence of worsening heart failure and death were identified by measurements of cTnT levels. Patients who had an increased number of abnormal cTnT levels had decreased hospitalization-free survival at 18 months. Both the number of

	samples with increased cTnT levels and cTnT levels in any sample were independently associated with the combined end point. This fact has been

	previously shown in other studies, particularly in decompensated CHF.11-14 In one study, detectable levels of cTnI correlated with worsening left ventricular dysfunction, increased brain natriuretic peptide (BNP) levels, a worse prognosis in advanced CHF, and impaired hemodynamics.10 The combined abnormal levels of cTnI and BNP also correlated with a substantial increase in long-term mortality.

	In our study, the renal impairment may be related to the high cTnT levels. The increased creatinine level, how-ever, was mild to moderate, and the third-generation assay used in the study was highly specific. cTnT level has been shown to be an independent predictor of mortality in patients with renal impairment.15

	We speculate that two different but additive mechanisms of myocardial damage can be found during the evolution of CHF. In a clinically stable condition, up to half of patients may have ongoing cellular injury, with a low increase in troponins, promoted

	by a loss of the cytoplasmatic pool due to higher cell membrane permeability or as a result of other factors, causing apoptosis or a small amount of necrosis. These patients are at high risk because they are more susceptible to myocardial injury. During the decompensated state, the release of cTnT can be triggered by a new process associated with myocardial injury (subendocardial ischemia or subclinical microinfarct) or by minor events in patients with more susceptible myocardium (diet transgression or fluid overload). Independent of the underlying mechanism, the short-term and long-term prognoses of this subgroup are worse.

	Our study showed that increased cTnT levels in one or more samples from patients with stable CHF were associated with an increase in the incidence of the combined end point of hospitalization or death. In addition, the number of abnormal cTnT samples and a quantitative Tn index were also independent predictors of events. These results indicate that monitoring for myocardial injury may help to identify high-risk patients.

	The challenge for future investigations should be to test the efficacy of several drugs on the production or mitigation of myocardial injury and their impact on risk and clinical benefit.

 Myocardial injury in heart failure 

	The Seventh Report of the Joint National Committee (JNC 7) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure has emphasized that the treatment of hypertension is very important to decrease the risk of cardiovascular morbidity and mortality. A higher blood pressure means that there is a greater chance of myocardial infarction (MI), heart failure, stroke, and kidney disease. JNC 7 recommends a thiazide diuretic as first-line treatment for hypertension without compelling indications.1

	Recently, there has been great interest in whether angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) in addition to a thiazide diuretic have a role in the initial therapy for all patients who present with hypertension. For patients with cardiovascular risk factors, recent trials have shown that ACE inhibitors in addition to thiazide diuretics and beta blocking agents have resulted in a reduction in the risk of cardiovascular outcomes (MI, stroke, or worsening of heart failure) and progression of renal disease.

	It is likely that ACE inhibitors reduce cardiovascular disease risk through ACE blockade and reduction of circulating serum angiotensin II levels. There is, however, an escape mechanism that occurs as a result of long-term ACE inhibition, involving chymase, cathepsin G, and chymase-sensitive angiotensin generation enzyme at the tissue level, which can produce high levels of local angiotensin II.2-4 This local production of angiotensin II has been implicated in atherosclerotic plaque formation and left ventricular hypertrophy by acting on angiotensin I receptors.5,6 Theoretically, there is a possibility that this escape may translate into a risk of cardiovascular morbidity and mortality that ACE inhibitors will not be able to reduce. ARBs, however, specifically antagonize the angiotensin I receptors and thus may provide a more complete blockade of the pathological effects of angiotensin II.5 The question lies in whether ACE inhibitors and ARBs are equal in their effects on hypertension and the reduction of cardiovascular morbidity and mortality. It is also an interesting theory that the combination of an ACE inhibitor and an ARB may lead to a more complete blockade of the effect of angiotensin II. Whether this will translate into a larger reduction in risk factors than either drug could achieve alone remains to be seen. This article reviews the available evidence regarding ACE inhibitors, ARBs, and the combination of the two drug classes for the treatment of hypertension and prevention of cardiovascular disease.

	Two main studies recently compared ACE inhibitors with thiazide diuretics for the treatment of hypertension and reduction of the risk of cardiovascular disease. The results were conflicting.

	The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was a large, randomized, double-blind study of patients aged 55 years or older with hypertension and one coronary artery disease (CAD) risk factor. A comparison of a thiazide diuretic versus an ACE inhibitor or amlodipine (Norvasc) showed that all three drugs were similar in preventing the primary outcome, fatal CAD or nonfatal MI combined. However, lisinopril (Prinivil, Zestril) showed a statistically significant higher 6-year rate of cardiovascular disease events compared with chlorthalidone (Hygroton). The goal systolic blood pressure was 140 mm Hg. The mean systolic blood pressure was lower in the thiazide group (133.9 mm Hg) than in the ACE inhibitor group (135.9 mm Hg), which was statistically significant.7

	The Australian National Blood Pressure 2 trial was similar to ALLHAT. It compared an ACE inhibitor with a thiazide diuretic as first-line antihypertensive therapy in 6,083 patients between the ages of 65 and 84 years with hypertension of at least 160 mm Hg systolic or 90 mm Hg diastolic if the systolic blood pressure was at least 140 mm Hg without recent cardiovascular events. Both groups were treated with other antihypertensive medications equally to achieve the goal blood pressure. There was no difference in the reduction of blood pressure. There was a statistically significant reduction of first-time cardiovascular events, however, in the group treated with enalapril (Vasotec), specifically, a reduction of MIs compared with the thiazide-treated group, particularly for men.8 Hence, contrary to the ALLHAT study, ACE inhibitors proved to be superior to thiazides in reducing cardiovascular risk and more so for men than for women with hypertension. There was no difference in the blood pressure—lowering effects between the two drugs.

	The Heart Outcomes Prevention Evaluation study group published a landmark report on the use of ACE inhibitors in not only hypertensive patients but also in patients at high risk for cardiovascular events. A total of 9,297 patients, who were 55 years of age or older and at high risk for a cardiovascular event with evidence of vascular disease plus one other risk factor, were randomly assigned to receive ramipril (Altace) or placebo for 5 years. A significant reduction of MI, stroke, or death from cardiovascular causes occurred in the ramipril group. The beneficial effect of treatment was consistently observed in patients with and without diabetes, in those with and without hypertension at baseline, and in those with and without evidence of cardiovascular disease.9 This suggests that ramipril has beneficial effects on the cardiovascular system in preventing cardiovascular disease independent of its ability to decrease blood pressure.

	The Fosinopril Versus Amlodipine Cardiovascular Events Randomized Trial was a study of 380 patients with type 2 diabetes and concomitant hypertension.10 The reduction in systolic blood pressure was significantly greater in the amlodipine group compared with the fosinopril (Monopril) group (—19 mm Hg for the amlodipine group versus –13 mm Hg for the fosinopril group; P < .05). The fosinopril group, however, showed a significant reduction in the combined end point of MI, stroke, and hospitalization because of angina.

	The Appropriate Blood Pressure Control in Diabetes (ABCD) trial11 and the Swedish Trial in Old Patients (STOP)12 showed similar results in the comparison of ACE inhibitors with calcium channel blocking agents. In the STOP study, ACE inhibitors were also compared with beta blocking agents and diuretics. There was no difference in the occurrence of fatal and nonfatal MI between the ACE inhibitor or beta blocker and diuretic groups.

	In the Captopril Prevention Project, patients with hypertension were randomly assigned to receive captopril (Capoten) or conventional therapy (a beta blocker, diuretic, or both). No difference was shown in the risk of MI

	in the captopril or the beta blocker-diuretic groups. There was, however, a blood pressure difference at baseline between the two study groups, which has been criticized.12

	ACE inhibitors, therefore, have consistently been shown to be superior to long-acting calcium channel blocking agents for preventing cardiovascular disease. There is insufficient evidence, however, to suggest that ACE inhibitors are better or worse than beta blocking agents and thiazide diuretics in treating hypertension and reducing the risk of cardiovascular morbidity and mortality.

	The effect of ACE inhibitors on prevention of cerebrovascular disease has also been studied. The Perindopril Protection Against Recurrent Stroke Study was a randomized trial comparing a perindopril (Aceon)-based blood pressure—lowering regimen with placebo among 6,105 individuals with previous stroke or transient ischemic attacks.13 The treatment groups included combination therapy with perindopril and indapamide (Lozol) or a combination of placebos, which made up the first subgroup. Single-agent therapy with only perindopril or a single placebo made up the second subgroup. The primary outcome was total stroke (fatal and nonfatal). The results suggested that active treatment significantly reduced total stroke compared with placebo (relative risk reduction, 28%; 95% confidence interval, 17%–38%). The reduction in stroke was significant in the group that received combination therapy with perindopril and indapamide and not in the group that received therapy with only perindopril.13 The stroke risk was not discernibly different between the groups administered single-drug therapy with perindopril compared with a single placebo agent. Compared with those assigned to placebo, blood pressure (systolic/diastolic) reductions among those treated with combination therapy (12.3/5.0 mm Hg) were about twice as great as those among participants treated with a single drug (4.9/2.8 mm Hg). The reductions in the risk of stroke were similar for hypertensive and nonhypertensive individuals.

	This study suggested that the most important factor in reducing the risk of stroke was the reduction in blood

	pressure with the help of two blood pressure-lowering agents. It did not suggest that the ACE inhibitor, when administered alone, reduced blood pressure or the occurrence of stroke significantly. Hence, the ACE inhibitor did not exhibit beneficial effects independent of blood pressure reduction. The reductions in outcomes were similar for both hypertensive and non-hypertensive patients.

	ACE inhibitors are becoming first-line therapy for hypertensive and nonhypertensive patients with evidence of diabetic nephropathy. An ACE inhibitor had a favorable effect on the progression of diabetic nephropathy in a trial comparing captopril with a pla-cebo in 409 insulin-dependent diabetic patients with a proteinuria level of 500 mg/day or greater and a serum creatinine level of 2.5 mg/dL or less.14 The primary end point was a doubling of the baseline creatinine level. The serum creatinine level doubled in 25 patients in the captopril group (n = 207) compared with 43 patients in the placebo group (P = .007). The reduction in the risk of doubling the baseline serum creatinine level was 48% in the captopril group overall. There were an equal number of patients with hypertension in the captopril and placebo groups. The difference in blood pressure control between the two groups was

	statistically insignificant. This suggests that the effect of captopril on the decline in renal function was inde-

	pendent of its effects on blood pressure. These renoprotective effects seem to be the result of the ability to reduce proteinuria and other processes in the kidney that hasten the progression of nephropathy.

	There have been few large studies comparing ARBs with other therapies that are standard for the treatment of hypertension and reduction of the risk of cardiovascular morbidity and death. The Losartan Intervention for Endpoint Reduction in Hypertension study was a double-blind, randomized, parallel-group trial of 9,193 patients aged 55 to 80 years with essential hypertension (sitting blood pressure of 160—200/

	95—115 mm Hg) and left ventricular hypertrophy based on electrocardiographic criteria. The patients were assigned to losartan (Cozaar, Hyzaar)-based or atenolol-based therapy for 4 years or until 1,040 patients had the primary event being measured (death, MI, or stroke).

	The results showed that the decrease in systolic blood pressure at the last visit before the end point occurred was 30.3 mm Hg (18.5%) and 29.1 mm Hg (19.2%) in the losartan and atenolol groups, respectively (P = .017). The primary composite end point (death, MI, or stroke) occurred in 508 of 4,605 patients (11%) in the losartan group and in 588 of 4,588 patients (13%) in the atenolol group, with an adjusted hazard ratio of 0.87 (P = .021).7 There was also a significant reduction of death due to cardiovascular disease, fatal and nonfatal stroke, and MI in the losartan group.

	ARBs, similar to ACE inhibitors, have also been studied in hypertensive patients for the prevention of stroke. The Study on Cognition and Prognosis in the Elderly was a randomized controlled trial of candesartan (Atacand) versus placebo in 4,964 elderly patients with mild to moderately increased blood pressure. Outcomes measured were a composite of cardiovascular death, nonfatal stroke, and nonfatal MI. In the candesartan group, there was a modest, statistically nonsignificant reduction in major cardiovascular events (10.9%) and a marked reduction in nonfatal stroke (27.8%; P = .04).15

	ACE inhibitors have been shown to slow the progression of nephropathy in insulin-dependent diabetic patients, but these agents are not tolerated well by all patients, mainly because of dry cough and angioedema. There are trials, however, that suggest that angiotensin receptor antagonists have a similar effect on the progression of chronic renal disease, which is most likely independent of its effects on blood pressure.

	ARBs have been extensively studied in chronic kidney disease. Similar to ACE inhibitors, ARBs have shown a substantial reduction in the progression of nephropathy to chronic kidney disease and end-stage renal disease, especially in diabetic patients, compared with placebo and calcium channel blocking agents such as amlodi-pine.13,16,17 These effects seem to be independent of blood pressure reduction.

	It has been shown in previous trials that both ACE inhibitors and ARBs are equally effective in reducing both sitting systolic and diastolic blood pressure. ARBs are associated with a significantly lower incidence of cough compared with ACE inhibitors.18 Earlier in this article, the effects of treatment with ACE inhibitors or ARBs compared with placebo or other standard hypertensive therapy (beta blocking agent, calcium channel blocker, or thiazide diuretic) were examined. Both ACE inhibitors and ARBs showed a survival benefit in reducing cardiovascular mortality, stroke, and nephropathy, but ACE inhibitors seemed to show more benefit than ARBs for the treatment of heart failure.

	The debate, however, seems to be whether an ARB can be used in place of an ACE inhibitor for treatment of hypertension and for the reduction of cardiovascular mortality. Going one step further would be to investigate whether combining ACE inhibitors and ARBs would translate into a better survival benefit than either drug used alone.

	The Evaluation of Losartan in the Elderly (ELITE) II study was based on the previous smaller ELITE study, which compared captopril with losartan in patients with heart failure. Results showed an unexpected survival benefit of losartan as a result of a reduction in sudden cardiac death. The ELITE II trial evaluated 3,152 patients with heart failure and an ejection fraction below 40% who were randomly assigned to receive losartan or captopril. There was no significant difference between groups in the primary end point, which was all-cause mortality or sudden cardiac death. There were, however, significantly fewer discontinuations of losartan because of adverse effects.19

	To this date, there appears to be only one ongoing trial comparing ACE inhibitors with ARBs, or a combination of the two, in hypertensive patients, the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET). This trial is comparing cardiovascular outcomes in patients receiving telmi-sartan (Micardis), ramipril, or a combination of the two drugs. The patients are older than 55 years of age and have a history of CAD, stroke or recent (> 7 days and < 1 year) transient ischemic attack, peripheral vascular disease, or diabetes with target end-organ damage, such as microalbuminuria, ankle brachial index below 0.8, or left ventricular hypertrophy. This is not primarily a hypertension study, however,  and patients with uncontrolled hypertension (> 160/100 mm Hg) are excluded. The primary end points are death caused by MI, acute MI, stroke, and hospitalization due to congestive heart failure.20 Preliminary data from this study have not yet been released.

	The inhibition of the deleterious effects of angiotensin continues to play a major role in antihypertensive therapy. The previous discussion suggests that substantial data seem to support the use of ACE inhibitors to reduce cardiovascular morbidity and mortality in hypertensive and nonhypertensive patients. There is insufficient evidence to state that ACE inhibitors are better than diuretics or beta blocking agents for uncomplicated hypertension. In patients with hypertension and with risk factors for CAD and cerebrovascular disease, however, there is sufficient evidence to suggest that an ACE inhibitor should be added to first-line therapy for hypertension to reduce mortality from MI and stroke.

	There is not yet enough evidence to consider an ARB as monotherapy for the initial treatment of patients with hypertension and cardiovascular risk factors. Current studies suggest that ARBs, unlike ACE inhibitors, do not  reduce  mortality due to cardiovascular  disease, but they are recommended  by JNC 7 either as initial therapy or as additions to the therapeutic regimen when certain compelling indications are present. These indications include heart failure, diabetes, and chronic kidney disease. For the treatment of hypertensive patients with congestive heart failure, the evidence is stronger for ACE

	inhibitors compared with ARBs in preventing the progression of the disease, but both are considered suitable as first-line treatment.

	More head-to-head studies are needed to compare the benefits of ACE inhibitors with those of ARBs and to assess the combination of the two classes of drugs for the treatment of hypertension and the reduction of cardiovascular mortality. Ongoing trials, such as the ONTARGET trial, will provide more data to resolve these issues.

ACE inhibitors and ARBs: Their role  in the treatment of hypertension

	Diabetes is bad. In addition to causing susceptibility to neuropathy, nephropathy, retinopathy, and other devastating end-organ complications, diabetes is a prime cause of vascular disease and its consequences

	—stroke, myocardial infarction (MI), claudication, and cardiac death. Diabetes has recently been categorized by the National Cholesterol Education Program Guidelines as a “coronary disease equivalent” in recognition that diabetes confers the same risk of vascular events as a history of MI.* Diabetic patients are thus identified by these guidelines as targets for the more aggressive secondary prevention strategies, with lower target low-density lipoprotein cholesterol levels (< 100 mg/dL or optionally < 70 mg/dL) and systolic blood pressure (< 130 mm Hg) goals than patients without manifest vascular disease targeted for primary prevention.

	It is well known, however, that some diabetic patients do well even in the absence of perfect glucose control, whereas others are “vasculopaths” even when scrupulously managed. It would be useful to better understand which diabetic patients have more vascular disease or vascular risk than others. The study by Ferramosca and colleagues (page 20) takes a novel approach to this question by examining diabetic patients who had coronary calcium scanning and 5 years of clinical follow-up. The main finding, that diabetic patients had higher calcium scores and thus more coronary disease and higher mortality than nondiabetic subjects, is hardly surprising. But more interesting is the finding that, for a given coronary calcium score, diabetic patients did worse than nondiabetic subjects by having higher death rates. More interesting still is the subset of diabetic patients who had no detectable coronary calcium. These patients did quite well, as well as nondiabetic subjects, and had 99% survival.  

	This study strongly suggests that a key cause of death among diabetic patients is vascular mortality, and this risk may be better estimated with the addition of the coronary calcium score to other clinical criteria (such as the Framingham index). Vascular disease appears to be a key mediator of death. Absence of detectable vascular disease (at least no coronary calcium) would appear to be reassuring, but probably not enough to relax preventive efforts or not consider aggressive blood pressure, glucose, and lipid management. Thus, the clinical implications of the study by Ferramosca and colleagues are few because we should already be “throwing the book” at diabetic patients.

	One limitation of the study is that mortality was the only outcome measured; the incidence of stroke, MI, and lower extremity complications would also be of interest. Hopefully, their study can be extended further in time, as 5 years is not that long. In particular, the fate of the diabetic patient with no coronary calcium is of interest, both clinically and possibly by repeated scanning. It would be most interesting to understand what mechanisms protect these individuals from developing coronary atherosclerosis.

Diabetics: The hard-hearted ones

	Electron-beam computed tomography (EBCT) is a sensitive tool for the

	noninvasive detection of coronary artery calcium, which is an excellent marker of atherosclerotic plaque burden.1 This marker has been exten-

	sively studied as a tool to assess cardiovascular risk, and several investigations have established its value as a good predictor of risk. In a number of studies, coronary artery calcium provided incremental prognostic value over traditional risk factors.2,3 Because of its very high cardiovascular complication rate, diabetes mellitus is considered equivalent to established coronary artery disease (CAD); therefore, aggressive preventive measures should be implemented early in its course.4,5

	Despite the obviously increased risk, however, not all diabetic patients have an untoward cardiovascular event, and there is wide heterogeneity among these patients. Hence, risk stratification might be of some use, even in this high-risk cohort. The prevalence and extent of coronary artery calcium are increased in diabetic patients, although not ubiquitously for all patients.6-8 One might wonder if this objective measure of coronary atherosclerosis could be useful in identifying patients at higher risk as well as those at lower risk for cardiovascular events.

	In a recent analysis, we addressed this question by assessing all-cause mortality

	in a large population of CAD-naive individuals with risk factors for atherosclerosis. Nearly 1 in 10 of the subjects studied had diabetes mellitus, and the majority (85%) had type 2 diabetes. The dual aim of the study was to assess the value of coronary artery calcium to predict all-cause mortality in diabetic patients and to compare the cardiovascular risk of coronary artery calcium in diabetic and nondiabetic individuals.

	Asymptomatic patients (n = 10,377) who had undergone EBCT imaging from 1996 to 2000 for the detection of coronary artery calcium were retrospectively identified from a large database. Patients were included in this study if they carried at least one risk factor for cardiovascular disease, such as diabetes mellitus, family history of premature CAD, smoking, hyperlipidemia, or hypertension. They were excluded if they had a history of CAD. Nine hundred three patients had diabetes, defined as a previous diagnosis of diabetes mellitus by a physician or current treatment with insulin or oral hypoglycemic drugs, or both. For each patient, a Framingham risk score was computed.

	All participants underwent EBCT with an Imatron C-100 or a C-150 scanner (GE-Imatron, South San Francisco, CA), with rapid acquisition (100 milliseconds) of 30 to 40 contiguous slices, from the carina to the diaphragm. Each tomographic section was 3 mm thick. The scans were electrocardiographically triggered at 60% to 80% of the R-R interval. The presence of a calcified area with a density of 130 Hounsfield units (voxel size, 1.03 mm3) along the length of the

	coronary arteries was used as the definition of coronary artery calcification, and a calcium score was calculated according to the method of Agatston and colleagues.9-11

	Information on mortality in this cohort was derived from the Nation-

	al Death Registry employing the blinded Social Security number of the in-

	dividuals studied. Cox proportional hazards models, with and without adjustment for cardiovascular risk factors, were developed to predict all-cause mortality.

	The mean follow-up period was 5 ± 3.5 years (range, 2—5 years). Diabetic patients were older and had a higher prevalence of hypertension and smoking (P < .001) than nondiabetic subjects. The mean coronary calcium score (CS) was 281 ± 567 in diabetic patients and 119 ± 341 in nondiabetic subjects (P = .001).

	During follow-up, all-cause mortality was higher (c2 = 43; P < .001) in diabetic than in nondiabetic individuals (Figure 1). Mortality rates were higher in diabetic patients with other co-

	morbidities (older age, smoking, and hypertension).

	Survival was lower with any level of CS (from mild to extensive) in patients with diabetes mellitus than in nondiabetic subjects—with a strong association between diabetes and CS&mdash;and was lowest in subjects with a CS above 400 on the screening EBCT scan. Notably, however, the cumulative survival in the absence of coronary artery calcium (CS = 0) was equal and very high (~99% at 5 years) in both groups (Figure 2).

	Framingham risk equations were used to estimate the risk of death in the study population. When the CS was added to the Framingham risk score in nondiabetic subjects, the estimation

	of risk increased (C-index increase) from 0.61 to 0.70 (P < .001). A similar effect was noted in the diabetic patients (C-index increase from 0.50 to 0.72;

	Diabetic patients have greater coronary artery calcium than nondiabetic patients, even when there is no difference in their cardiovascular risk profiles.4,5 Our study showed a strong relationship among extent of coronary artery calcium, diabetes, and all-cause mortality. These findings are in line with those reported in previous investigations conducted with other non-invasive imaging methods, such as nuclear myocardial perfusion imaging and stress echocardiography.12-14 Those studies emphasized that diabetic patients are at higher risk for cardiac events compared with nondiabetic individuals. This suggests that the atherosclerotic burden of diabetic patients is particularly unstable, rendering the individual exquisitely prone to untoward events.

	Our study also showed that both diabetic and nondiabetic individuals have an equally low 5-year mortality rate in the absence of coronary artery calcium. Nondetectable coronary artery calcium, that is, absent or minimal atherosclerotic burden, is therefore a good prognostic indicator in the midterm follow-up period, which constitutes an innovative finding and underscores the power of atherosclerosis imaging for the assessment of risk, even in apparently high-risk populations. Imaging of atherosclerotic plaque burden is currently viewed as an excellent screening tool, mostly for intermediate-risk subjects,6 where finding unknown arterial wall disease may help refine risk assessment in the individual patient. There appears to be a role for screening, however, even in high-risk individuals.

	The obvious limitation to this study was the lack of data on cardiovascular outcome because the only end point considered was all-cause mortality. Although all-cause mortality does not have the potential diagnostic and interpretative biases seen with other outcome end points, it is limited in its ability to assess the full impact of diabetes mellitus on the cardiovascular system.

	The pathophysiology of coronary artery calcification is not completely understood, although the basic process appears to be very similar to bone formation. Experimental studies on cultured rat aortic smooth muscle cells showed that hyperglycemia stimulates the expression of osteopontin, a soluble bone-related protein that plays a key role in vascular remodeling and atherogenesis. Osteopontin is also capable of activating a proatherogenic and prothrombotic cascade through induction of expression of platelet-derived growth factor.15

	intima and the medial layer. Although the intimal calcifications are typical-

	ly correlated with the presence of atherosclerotic plaque and its consequences, medial calcification is responsible for reduced arterial elasticity and myocardial compliance, with an attendant high risk of cardiovascular events.16

	Because cardiovascular disease in diabetes is highly prevalent, and it is associated with an adverse outcome, an early and accurate diagnosis may ensure a more benign outcome in patients affected by this disease, which is often silent in its course.17 Screen-

	ing for cardiovascular disease may afford an opportunity for early and aggressive preventive treatment, a key step in the management of cardiovascular event reduction. Additionally, the identification of a subset of patients

	at lower risk is also possible with imaging techniques that quantify the burden of disease.

Coronary artery calcium screening  in patients with diabetes

	Orlando—The sirolimus-eluting stent (Cypher) and the paclitaxel-eluting stent (Taxus) are similarly effective in preventing restenosis in the treatment of routine coronary artery stenoses, but the sirolimus-eluting stent may offer an advantage in patients with diabetes, said investigators at the American College of Cardiology Annual Scientific Session 2005.

	In an international head-to-head comparison between the two stents, lead investigator Marie Claude Morice, MD, said that the overall findings produced

	little to preferentially choose one stent over the other. “They are both very durable and very efficient to prevent restenosis,” she said, adding that the re-sults of the clinical trial would not change her practice.

	The REALITY study, the largest one conducted to compare the two stents, randomly assigned 1,386 patients in Europe, Latin America, and Asia to receive the sirolimus- or paclitaxel-eluting stent. To be eligible, patients had to have one or two de novo lesions in a native coronary artery. Twenty-eight percent of the study population had diabetes.

	At 8 months, the rates of in-lesion restenosis or in-stent restenosis were

	not significantly different between the two stents, said Dr. Morice, head of

	the Institut Hospitalier Jacques Cartier, Massy, France.

	Other angiographic parameters did favor the sirolimus-eluting stent, including mean lumen diameter and in-lesion and in-stent restenosis. The significant increase in late-stent thrombosis in the patients receiving the paclitaxel-eluting stent will require further investigation, she said. In addition, a greater number of acute and subacute stent thromboses occurred with the paclitaxel-eluting stent than with the sirolimus-eluting stent (1.8% versus 0.4%; P = .0196), which is the first indication of a “significant safety difference between drug-eluting stents,” said Dr. Morice.

	Still, the rates of target-lesion revascularization and major adverse coronary events were similar between the patient groups, Gregg Stone, MD, professor of medicine at Columbia University in New York City, reminded the audience, and it

	is these clinical outcomes that concern patients the most.

	A single-center study showed that the sirolimus-eluting stent was more effective than the paclitaxel-eluting stent in preventing restenosis in the high-risk subset of diabetic patients, according to Adnan Kastrati, MD, from the Deutches Herzzentrum, Munich, Germany.

	Percutaneous interventions have historically been associated with high rates of restenosis in the diabetic population, said Dr. Kastrati. His study included 250 patients with diabetes with angina or a positive stress test in the presence of 50% or more stenosis in native coronary vessels. They were randomly assigned to one of the stents and followed up at 6 months with an angiogram to measure late lumen loss, and at 9 months to compare the rate of clinical events.

	In-segment late lumen loss was significantly less in the patients assigned to the sirolimus- versus the paclitaxel-eluting stent (0.43 versus 0.67 mm; P < .001), as was in-stent late lumen loss (0.19 versus 0.46 mm; P < .001). Angiographic restenosis occurred in 6.9% versus 16.5% (P = .03) of patients assigned to the sirolimus and paclitaxel stents, respectively.

	At 9 months, there was no significant difference in the rates of mortality and myocardial infarction between the two groups.

Drug-eluting stent comparisons find similar rates  of restenosis, except in diabetic patients

	Orlando—The Food and Drug Administration (FDA) announced April 7 that all prescription nonsteroidal anti-inflammatory drugs (NSAIDs) remaining on the market must carry a black-box warning and a medication guide highlighting the increased risk of cardiovascular events associated with these agents. Medications subject to the requirements include the cyclo-oxygenase-2 (COX-2) inhibitor celecoxib (Celebrex), meloxicam (Mobic), and prescription-strength ibuprofen. Manufacturers of over-the-counter NSAIDs are being asked to develop more specific labeling with information on cardiovas-cular, gastrointestinal, and skin reaction risks.

	The FDA also asked that the COX-2 inhibitor valdecoxib (Bextra) no longer be marketed owing to increased cardiovascular events and the risk of life-threatening skin reactions. Rofecoxib (Vioxx), another COX-2 agent, was withdrawn from the market in September 2004, also due to the increased risk of cardiovascular events. In a noncardiovascular trial, increased cardiovascular risk appeared after patients had been taking rofecoxib for 18 months.

	“We knew 4 years ago that there was an increased risk of myocardial infarction [MI] and stroke with these [COX-2] medications, but no trials had been done in patients with cardiovascular disease,” said Eric Topol, MD, The Cleveland Clinic Foundation, during the recent American College of Cardiology Annual Scientific Session. “Furthermore, the moment these drugs were approved, they were direct-to-consumer marketed.”

	CABG study shows lingering risk. While rofecoxib was associated with increased cardiovascular risk after long-term use, the first study of a COX-2 inhibitor in patients with coronary heart disease showed that risk increases within a few days of administration. “Even after the drug therapy stopped, while patients were taking aspirin, they were incurring significant cardiovascular and thromboembolic events,” Dr. Topol said.

	Results of the Safety of Parecoxib and Valdecoxib in the Treatment of Postoperative Pain Following Coronary Artery Bypass Graft (CABG) Surgery or Major General Surgery trial were presented by Andrew Whelton, MD, Johns Hopkins University School of Medicine, Baltimore. Parecoxib is the water-soluble prodrug of valdecoxib, which converts entirely to valdecoxib after administration.

	The study included 1,671 patients undergoing isolated CABG surgery who were randomly assigned to one of three treatment arms the first day postoperatively. The first group received a loading dose of 40 mg intravenous parecoxib followed by 20-mg doses every 12 hours for the first 3 days. This was followed by

	7 days of treatment with 20 mg of oral valdecoxib every 12 hours. Patients in the

	second arm received intravenous placebo for 3 days followed by 20 mg oral valdecoxib every 12 hours for 7 days; those in the third group received intravenous followed by oral placebo.

	All patients received 75 to 325 mg of aspirin daily and pain management as needed with morphine or oral hydroxycodone and codeine. Patients were followed up for an average of 30 days after study medication was discontinued at day 10. Primary end points were cardiovascular thromboembolic events, renal dysfunction or failure, upper gastrointestinal ulcer complications, and surgical wound complications.

	While the number of cardiovascular events was small, patients receiving both intravenous parecoxib and oral valdecoxib had a statistically significant increased event rate at 2% compared with placebo patients with a 0.5% event rate (P = .033). No significant difference was seen between those taking only oral valdecoxib and placebo. “The events occurred throughout the dosing and follow-up period,” Dr. Whelton said.

	Dr. Whelton said that while these results show another link between increased cardiovascular events and a COX-2 inhibitor, particularly in coronary heart disease patients, there are no similar data evaluating NSAIDs in this population.

	Questions remain. In contrast to the CABG surgery patients, no significant differences in cardiovascular thromboembolic events were observed in the general surgery patients without coronary heart disease taking the parecoxib/valdecoxib combination, reported Dr. Whelton.

	Furthermore, there was no decrease in upper gastrointestinal events between treatment groups in either the CABG or general surgery arms of the study. “The reason these drugs were to be useful was to suppress significant gastrointestinal complications and bleeding,” Dr. Topol said.

	Also notable was a significant increase in sternal wound complications among patients in the CABG trial receiving either the parecoxib/valdecoxib combination (3.7%) or oral valdecoxib alone (5%) compared with placebo (2.9%). Increased wound complications were not seen in patients undergoing general surgery.

More stringent warnings of CV risk to accompany pain medications

	Orlando—Treatment with a calcium channel blocker and an angiotensin-converting enzyme (ACE) inhibitor significantly reduces cardiovascular mortality and events compared with treatment with a beta blocking agent and diuretic combination, according to preliminary results of the Blood Pressure-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA).

	All coronary events were reduced by 15%, stroke by 25%, cardiovascular mortality by 25%, and all-cause mortality by 15% with the calcium channel blocker and ACE inhibitor combination, said Peter S. Sever, MD, Imperial College, London. “This is certainly a finding we would not have predicted,” he said during the American College of Cardiology Annual Scientific Session 2005.

	“The other important result was confirmation that treatment with a beta blocker and diuretic increases the likelihood of developing diabetes,” Dr. Sever said. In ASCOT-BPLA, new-onset diabetes was increased by 30% among patients receiving the beta blocker and diuretic combination compared with patients receiving a calcium channel blocker and ACE inhibitor.

	While beta blockers are clearly indicated in certain hypertension patient subgroups, such as those with a prior myocardial infarction (MI) or symptomatic coronary heart disease (CHD), the ASCOT-BPLA data raise questions about the position of beta blockers in treating uncomplicated hypertension, Dr. Sever said.

	The trial randomized 19,342 patients aged 40 to 79 years with treated or untreated systolic blood pressure greater than 140 mm Hg or untreated diastolic blood pressure greater than 100 mm Hg or treated diastolic pressure greater than 90 mm Hg. All patients had at least three cardiovascular risk factors in addition to hypertension.

	Patients received either 5 or 10 mg of amlodipine (Norvasc) with or without 4 to 9 mg of perindopril (Aceon) daily or 50 to 100 mg of atenolol (Tenormin) with or without 1.25 to 2.5 mg bendroflumethiazide plus potassium (Diuril, Esidrix). Doses were increased and second agents added as required to reach the target blood pressure of less than 140 mm Hg systolic and less than 90 mm Hg diastolic. “This was a trial designed to look at treatment strategy rather than an individual drug because we recognized that most patients would require two drugs to achieve target pressures,” Dr. Sever said.

	Primary end points were nonfatal MI and fatal CHD; mean follow-up was 5.5 years in November 2004, when the trial was halted by the data safety monitoring board because all-cause mortality was 15% lower among patients in the calcium channel blocker plus ACE inhibitor arm. “We didn’t power the study to predict all-cause mortality so this was a striking and important result,” Dr. Sever said.

	Primary end points were reduced by a nonsignificant 10% when the trial was halted. However, only 850 cases of nonfatal MIs or fatal CHD had occurred at this time, and the trial was powered to detect a significant difference between treatment groups with an expected 1,150 primary events, Dr. Sever said. “But when we looked at all the other prespecified end points of coronary events, stroke, and cardiovascular mortality, the differences were highly significant.”

	While these results are preliminary, they represent 95% of all the ASCOT-BPLA data and no differences are expected with the final results, Dr. Sever said.

Mortality, morbidity, and new-onset diabetes reduced with combination hypertension treatment

	Orlando—Ezetimibe/simvastatin (Vytorin) is superior to atorvastatin (Lipitor) in reducing levels of low-density lipoprotein (LDL) cholesterol across the dosing ranges. The two regimens are also comparable in their effect on C-reactive protein (CRP), reported Christie Ballantyne, MD, at the American College of Cardiology’s Annual Scientific Session 2005.

	Achieving larger reductions in LDL cholesterol has gained considerable interest since last year when updated guidelines from the Adult Treatment Panel III of the National Cholesterol Education Program offered the option of an LDL cholesterol goal of less than 70 mg/dL for high-risk patients, said Dr. Ballantyne, director of the Center for Cardiovascular Disease Prevention, Methodist DeBakey Heart Center, Houston. The panel said that achieving a target of less than 70 mg/dL would probably require at least a 50% reduction in LDL cholesterol.

	Furthermore, clinical studies with 80 mg/day of atorvastatin show a reduction in coronary heart disease (CHD) morbidity when compared with less aggressive lipid-lowering regimens, supporting a more aggressive LDL cholesterol goal.

	“There are three ways to get a greater than 50% reduction in LDL cholesterol,” said Dr. Ballantyne. “One is atorvastatin, 80 mg. Another is rosuvastatin, 20 or 40 mg. The third is ezetimibe/simvastatin.”

	The LDL cholesterol-reducing capacity of milligram-equivalent doses (10, 20, 40, and 80 mg) of ezetimibe/simvastatin and atorvastatin was compared in 1,902 patients with hypercholesterolemia in this randomized, double-blind, eight-arm study. Patients were treated for 6 weeks.

	At the common starting doses of each medication—ezetimibe/simvastatin, 10/20 mg, and atorvastatin, 10 mg&mdash;ezetimibe/

	simvastatin reduced LDL cholesterol by 51% compared with 36% for atorvastatin (P < .001).

	In a subgroup of high-risk patients, defined as those with CHD or a CHD risk equivalent, 82% of those taking ezetimibe/simvastatin, 10/20 mg, achieved an LDL cholesterol goal of less than 100 mg/dL, compared with 47% of patients taking 10 mg of atorvastatin (P < .001).

	simvastatin, 10/40 mg, also produced larger LDL cholesterol reductions than atorvastatin, 40 mg (59% versus 49%;

	In addition, 57% of the high-risk patients taking ezetimibe/simvastatin, 10/40 mg, achieved the more stringent LDL goal of less than 70 mg/dL, compared with 23% taking atorvastatin, 40 mg (P < .001). “It’s hard to get to less than 70 mg/dL,” said Dr. Ballantyne. “The point is if you’re trying to get to less than 70, you have to use highly effective therapy.”

	Ezetimibe/simvastatin, 10/40 mg and 10/80 mg, was also associated with significantly greater increases (P < .001) in high-density lipoprotein (HDL) cholesterol (9.0% and 7.6%, respectively) compared with atorvastatin, 40 and 80 mg (increases of 3.8% and 1.5%, respectively). There was a trend toward greater increases in HDL cholesterol among patients taking ezetimibe/simvastatin, 10/10 and 10/20 mg, compared with atorvastatin, 10 and 20 mg.

	A posthoc analysis of 1,832 patients in the study showed that both ezetimibe/

	simvastatin and atorvastatin achieved a 25% reduction in CRP when averaged across all doses.

	“The safety of both agents in this study was very good,” he said. There was a significantly greater incidence of consecutive elevations in liver enzymes of 3 times or more than the upper limit of normal in the pooled atorvastatin group (1.2%) compared with the pooled ezetimibe/simvastatin group (0.1%; P < .001). The incidence of muscle enzyme elevations was not significantly different between patients taking ezetimibe/simvastatin and those taking atorvastatin.

	simvastatin are under way, but the agent appears promising in this regard given that simvastatin, 20 or 40 mg, has already been shown in the Heart Protection Study and the Scandinavian Simvastatin Survival Study to have a favorable effect on mortality and CHD morbidity.

 Ezetimibe/simvastatin is another option for aggressive cholesterol goals

	Orlando—While vasodilator testing is an important diagnostic tool in patients with pulmonary hypertension, with reactive pulmonary vasculature being associated with improved prognosis, the numerous definitions of positive vasodilator response used in practice limit its utility.

	The ideal definition of vasodilator response should provide the widest discrepancy in clinical outcomes between responders and nonresponders, said Richard A. Krasuski, MD, Duke University Medical Center, Durham, North Carolina, during the American College of Cardiology Annual Scientific Session 2005.

	Dr. Krasuski and colleagues evaluated mortality differences between responders and nonresponders using various combinations of vasodilator response definitions.

	A total of 93 pulmonary hypertension patients referred for pulmonary vasodilator testing were followed for a median of 39.5 months. Mean patient age was 45 years, and 80% of the patients were women. Primary pulmonary hypertension was present in 56% of patients, and 17% had systemic pulmonary hypertension. At baseline, patients had a mean New York Heart Association functional class of 2.9, mean right atrial pressure of 11 mm Hg, pulmonary artery (PA) systolic pressure

	of 73 mm Hg, and arterial oxygen saturation of 90%. Long-term medication use included epoprostenol in 34% of patients, treprostinol in 7%, bosentan in 17%, calcium channel blockers in 37%, and warfarin in 57%.

	Vasodilator testing was conducted with inhaled nitric oxide at 40 ppm; overall, 18% of patients responded to the challenge. Among responders, 94% survived through the follow-up period compared with 58% of nonresponders; 35% of the patients died. The greatest difference in mortality was seen when a positive response to nitric oxide testing was defined as more than a 30% decrease in mean PA pressure with a greater than 30% decrease in pulmonary vascular resistance (PVR). Patients meeting the 30% decrease in both measures had a mortality rate of

	6% compared with the 42% rate among nonresponders.

	PA pressure response alone, PVR response alone, and various combinations of percent response to each were assessed but were not as predictive of

	survival as the 30% decrease in both measures. Mortality was 10% among responders and 42% among nonresponders for a 30% decrease in PA pressure alone; 20% and 48%, respectively, for a 20% decrease in either PA pressure

	among nonresponders for either a 30% decrease in PA pressure alone or a 30% decrease in PVR alone; 29% and 50% for a 20% decrease in PA pressure alone; 29% and 39% for a 20% decrease in both PA pressure and PVR; and 30% and 40% for a 30% decrease in PVR alone.

	“The 30/30 definition of vasoreactivity appears to be an excellent tool in predicting long-term outcome in patients with pulmonary hypertension,” Dr. Krasuski said. Patients who experience a 30% decrease in both PA pressure and PVR have approximately one seventh the mortality of patients who do not. He concluded that this definition of vasoreactivity would be useful when initially evaluating patients, especially younger female patients presenting with dyspnea who are more likely to have pulmonary hypertension. “We just aren’t recognizing it early enough,” he said.

Best vasoreactivity definition helps determine  pulmonary hypertension outcome

	Orlando—Using an in-office system to test response to antiplatelet agents, one fourth of aspirin users with coronary artery disease (CAD) were found to be resistant to its antiplatelet effects. New research presented at the American College of Cardiology Annual Scientific Session 2005 showed that women, the elderly, and those taking lower doses of aspirin were among those likely to be aspirin resistant.

	“The effect of aspirin is not uniform,” said Wai-Hong Chen, MD, lead investigator of the study, but unfortunately aspirin is usually prescribed using a “one dose fits all” approach.

	In his study, platelet inhibition was meas-

	ured in 468 CAD patients using a point-of-care blood test (VerifyNow) that provides results expressed as aspirin reaction units (ARU) in 30 minutes. An ARU of 550 or greater indicates the absence of aspirin-induced platelet dysfunction. All patients had been receiving aspirin for a minimum of 4 weeks.

	Aspirin resistance was observed in 27.4% of the study group. Univariate predictors of aspirin resistance were older age, female sex, anemia, renal insufficiency, and an aspirin dose of 100 mg or less. Multivariate analysis revealed that a low hemoglobin level and an aspirin dose of 100 mg or less were independent predictors of aspirin resistance.

	Some 30.2% of patients taking 100 mg or less of aspirin were found to be resistant, compared with 16.7% of those taking 150 mg and none taking 300 mg, said Dr. Chen, assistant professor, Cardiology Division, University of Hong Kong. Because bleeding risk increases with increasing doses of aspirin, a balance between efficacy and safety needs to be achieved. “We need to give a dose that provides protection from myocardial infarction and stroke but does not put the patient at risk of bleeding,” he said. “We need to titrate the dose like we do in treating blood pressure and cholesterol.”

	The next step in research is to study the clinical relevance of aspirin resistance. “We don’t know what happens to these patients in years to come,” said Dr. Chen.

	Another study presented here demonstrated that resistance to aspirin and clopidogrel can occur together. Using the same platelet function assay, 15% of 80 patients undergoing elective percutaneous coronary intervention were found to be resistant to aspirin, 24% were resistant to clopidogrel, and 7.5% were resistant to both.

	Previous research has shown an increased risk of ischemic events in patients who are resistant to aspirin or clopidogrel, said Elliott Antman, MD, professor of medicine, Harvard Medical School, Boston. Using higher doses we may be able to overcome resistance in some cases, he said. Other medications may interact with aspirin and clopidogrel, and avoidance of these medications may restore antiplatelet responsiveness.

	An alternative antiplatelet agent called prasugrel is under investigation. In research presented here by Lars Wallentin, MD, professor of cardiology, Uppsala Clinical Research Center, Uppsala, Sweden, 101 aspirin-treated patients with atherosclerotic vascular disease were randomly assigned to one of five oral dosing regimens (four prasugrel regimens and one clopidogrel regimen). Patients receiving 40- or 60-mg loading doses of prasugrel achieved significantly higher levels of platelet inhibition compared with patients on a 300-mg loading dose of clopidogrel (P ≤ .002). After 28 days, the 10- or 15-mg maintenance dose of prasugrel was superior to a 75-mg clopidogrel maintenance dose at inhibiting platelets (P ≤ .002).

 Point-of-care platelet assay finds high rate of aspirin resistance

	Orlando—The amount of cholesterol in the skin can identify early-stage atherosclerosis, said James H. Stein, MD, at the American College of Cardiology Annual Scientific Session 2005. The test is ideal for office use because skin cholesterol is easy to measure, the test is noninvasive, and results are available quickly, allowing an almost immediate discussion of the patient’s risk.

	The skin cholesterol test, which was approved in 2002, measures skin sterol levels, and the results correlate well with B-mode ultrasound measurements of carotid intima-media thickness, said Dr. Stein, associate professor of cardiovascular medicine, University of Wisconsin, Madison, and codirector of the preventive cardiology program at the Wisconsin Hospital and Clinics.

	He assessed 81 consecutive patients without known vascular disease but with several risk factors who were referred for evaluation of carotid intima-media thickness. The mean age of the subjects was 55.6 years. Their mean skin total cholesterol was 95.9 units. When stratified into quartiles based on their skin cholesterol levels, those in the highest quartile had significantly greater carotid intima-media thickness than those in the lowest quartile of skin cholesterol (0.87 mm versus 0.76 mm; P = .011).

	Skin cholesterol level remained significantly associated with carotid intima-media thickness even after adjusting for known cardiovascular risk factors and the Framingham risk score. The odds of increased carotid wall thickness were increased by 34% in patients in the highest versus the lowest quartile of skin cholesterol level after adjusting for cardiovascular risk predicted by the Framingham risk score. The relationship was independent of age, sex, blood glucose level, systolic blood pressure, blood lipid levels, and the use of lipid-modifying therapies.

May 2005

News from the ACC and a new design for Cardiology Review

Cardiac troponin as a biomarker for myocardial injury in heart failure

Predicting outcome based on myocardial injury monitoring

Myocardial injury in heart failure

ACE inhibitors and ARBs: Their role in the treatment of hypertension

Diabetics: The hard-hearted ones

Coronary artery calcium screening in patients with diabetes

Drug-eluting stent comparisons find similar rates of restenosis, except in diabetic patients

More stringent warnings of CV risk to accompany pain medications

Mortality, morbidity, and new-onset diabetes reduced with combination hypertension treatment

Ezetimibe/simvastatin is another option for aggressive cholesterol goals

Best vasoreactivity definition helps determine pulmonary hypertension outcome

Point-of-care platelet assay finds high rate of aspirin resistance

Skin cholesterol test identifies subclinical atherosclerosis

Early MI treatments have differing benefits

Statin use in acute coronary syndromes: The sooner, the better?

Case report: Statin use before hospitalization

Statin therapy in acute coronary syndromes

Latest News