	Stroke is a devastating complica-tion of myocardial infarction (MI), whether it occurs in the natural

	progression of the disease or accompanying an iatrogenic intervention (catheter, surgical, or drug based). What is particularly important about this well-done analysis by Burns and Spencer (page 34) for the Worcester Heart Attack Study is the dramatic increase in the incidence of stroke in the most recently studied time intervals, rising from 1% at the end of the 1980s to 3% in 1999. In multivariate analyses, advancing age and atrial fibrillation were associated with the likelihood of a stroke after MI. A trend toward increased rates of stroke was seen in women and patients with anterior wall MI.

	Post-MI strokes are not a trivial consideration; they portend an ominous prognosis. In-hospital death was significantly more likely in acute MI patients with stroke than in those without stroke (32.6% versus 12.8%; P < .001). After advanced age and cardiogenic shock, multivariate-adjusted regression analysis identified stroke as the most potent predictor of in-hospital death (odds ratio, 4.26). Apart from death, no mention is made of the high physical, psychological, and financial costs of stroke.

	Why is the stroke rate on the rise? It is irresistible to speculate. If the patients in this analysis are representative of the broader MI population, one explanation may be that these patients are getting older. Maybe more patients are surviving their infarctions long enough to have another vascular complication. Perhaps they are surviving with paroxysmal or sustained atrial fibrillation, or with clots in the ventricle. It is noteworthy that fibrinolysis, cardiac catheterization, percutaneous coronary intervention, and coronary  artery bypass graft surgery did not have a statistically significant association with acute stroke in the overall population. The authors do note that coronary artery bypass grafting was associated with higher stroke rates in the elderly. Taken together, these data suggest that patients under-going these therapeutic procedures soon after infarction were carefully screened so as to lower the stroke risk1 (which was more successfully accomplished in younger than in older patients). Alternatively, if stroke did not complicate the procedure itself, the effects of such interventions could have had a protective effect against stroke.

	Why do strokes accompany acute MI? Hemodynamic instability, thromboembolism (atrial, ventricular, or vascular sources), and atherosclerotic plaque instability precipitated by mechanical forces, inflammation, platelet activation, and hypercoagulability have all been implicated. For the relatively few iatrogenic strokes observed in this registry, physical trauma and the effects of anticoagulant and antiplatelet agents are also contributors.

	Burns and Spencer include the case report of an 88-year-old woman presenting with the typically atypical clinical syndrome of acute MI in the elderly. She was treated with a thrombolytic agent. Although the symptom-to-needle time was not given, it is usually longer in the elderly than in younger patients. She then went on to have “rescue” angioplasty for her large inferior infarct, having a stroke on hospital day 6 and worsening heart failure on day 14, before dying on day 15. The authors conclude that identification and treatment of modifiable risk factors for stroke following MI is indicated. Based on their univariate analyses, potentially modifiable risk factors would include atrial fi-brillation, prior heart failure, and lack of aspirin therapy. Although HMG-CoA reductase inhibitors (statins) were not included as a variable in the current study, the authors suggest that lack of such therapy after MI could also be a risk factor for stroke. It is not clear whether the woman in their case report had any modifiable risk factors for postinfarction stroke or how effective such interventions would be. She certainly received aggressive and seemingly logical, appropriate therapy. But due to minimal representation of the elderly (particularly the very elderly) in clinical trials of MI, we are all flying without a compass. In the final 2 weeks of her life, this 88-year-old woman was hospitalized in two institutions, received thrombolysis, diagnostic cardiac catheterization, percutaneous transluminal coronary angioplasty with three stents, temporary and permanent pacing, carotid duplex scanning, and a computed tomography scan of the brain (a partial list of procedures and treatments I’m sure). That’s a strong argument for inclusion of the elderly in future registries and clinical trials of MI.2

	Stroke is a devastating complication of acute MI. These data support the use of aspirin for all qualifying patients, and full-dose anticoagulation for those with atrial fibrillation. But as the barriers to enrollment of the elderly in clinical trials fall, more comprehensive, evidence-based conclusions will surely follow. n

Articles

Cardiology Review Online

Preventing stroke after acute MI  Richard M. Steingart, MD

	A 72-year-old man had been treated in our department for more than 10 years for various clinical manifestations of generalized atherosclerotic disease. His cardiovascular risk factors were a 40-year history of smoking, although he had discontinued smoking 2 years earlier; impaired glucose tolerance, with a glycosylated hemoglobin level of about 7%; and well-controlled arterial hypertension (by use of a beta blocking agent, diuretics, and an angiotensin-converting enzyme inhibitor). The patient had no lipid abnormalities.

	Eight years earlier, the patient had a myocardial infarction and subsequently underwent coronary artery bypass graft surgery. Since then, he has been free of symptoms of angina and congestive heart failure.

	Starting about 5 years earlier, symptoms of intermittent claudication became obvious. Because of severe limitation of his pain-free walking distance to approximately 100 meters and thus a markedly reduced quality of life, repeated percutaneous interventions of superficial femoral artery obstructions in both legs were performed. With physical therapy, the patient was able to achieve a pain-free walking distance of about 800 meters, which was acceptable to him.

	Two years earlier, a significant left-sided carotid artery narrowing of 50% diameter reduction at the bifurcation was detected during a routine carotid duplex ultrasound investigation, with plaques only at the right carotid bifurcation. Since then, the patient has undergone carotid duplex investigations every 6 months, which is standard procedure at our institution. During the past year, we detected a progression of the carotid narrowing on both sides, with a 70% stenosis on the left and a 50% stenosis on the right. Cholesterol levels were still within an optimal range without lipid-lowering medication; however, when measuring high-sensitivity C-reactive protein (hs-CRP) for a study protocol, we found a substantially increased level of this inflammatory marker (0.79 mg/dL) in the absence of clinically overt inflammatory or infectious disease. Thus, we decided to initiate treatment with simvastatin (Zocor), 20 mg daily.

	Eight months later, the patient’s hs-CRP levels decreased to 0.38 mg/dL, and no further progression of the carotid stenoses was observed by duplex ultrasound. Further cardiovascular adverse events have not occurred since then.

	This case report shows that HMG-CoA reductase inhibitors (statins) have the potential to reduce the inflammatory activity in patients with generalized atherosclerotic disease and to stabilize the disease. These agents should

Case report: Statins in peripheral artery disease

	The study by Den Hond and colleagues (page 13) addresses the role of self-measured blood pressure (BP) in the management of hypertension. Self-measuring BP at home with a commercial device might provide more BP readings with fewer office visits, eliminate the white-coat syndrome, eliminate observer bias by being automated, reduce costs, and improve compliance. In addition, it might improve BP control, which has been disappointingly low despite efforts to improve compliance.

	This 1-year prospective study enrolled adult men and women with diastolic BPs between 95 and 114 mm Hg on multiple screening visits who were taking no medication or were taking less than two antihypertensive medications. Those with congestive heart failure, unstable angina, Stage 3 or 4 hypertensive retinopathy, a history of myocardial infarction, cerebrovascular accident within 1 year, severe noncardiovascular illness, chronic kidney disease with creatinine greater than 2.0 mg/

	dL, mental illness, substance abuse, and those working at night were excluded. Of the initial 606 patients screened in 59 medical facilities, 400 eligible patients were randomized and followed up.

	All patients had their BPs measured at home using a precalibrated oscillometric automated cuff and at the office by a physician with a sphygmomanometer. Follow-up visits were made monthly for the first

	2 months and every 2 months thereafter. The ambulatory BP monitoring was recorded but not disclosed or used for the management of hypertension. Changes in antihypertensive medication were guided by either office or home BP readings, depending on the initial randomization. The target BP in the Office Guidance group was attained using only the office readings. The Home Guidance group had their target BP attained exclusively using the home readings. As will be discussed below, this is a major flaw of this study.   

	The adjustments in medications were made by a single blinded physician to achieve a predefined diastolic BP goal of 80 to 89 mm Hg. All patients were placed on monotherapy with lisinopril (Prinivil, Zestril),

	10 mg per day, after randomization. Those with a known contraindication to or those who were intolerant of angiotensin-converting enzyme inhibitors were placed on atenolol (Tenormin), 50 mg daily, instead (step 1). The lisinopril or atenolol dose

	was above 89 mm Hg (step 2). Those needing greater control were treated additionally with hydrochlorothiazide (Carozide, HydroDiuril), 25 mg per day, or amlodipine (Norvasc), 5 mg daily (step 3). Finally, prazosin (Minipress), up to 6 mg daily, was added to those already on amlodi-pine; patients not already taking am-lodipine were started on amlodipine, 5 mg per day (step 4). If the diastolic BP dipped below 80 mm Hg, therapy was reduced by one step.

	The respective office and home BP readings at randomization were similar between the Office Guidance and the Home Guidance groups. All patients from both groups had their BPs taken at the office and at their homes. When each patient compared the BP readings obtained at home versus at the office, their BPs at home were consistently lower, and this observation was maintained throughout the study. At baseline in both groups, home readings were lower than the office readings by ~13.5 mm Hg for systolic and ~9.5 mm Hg for diastolic BPs. The lower home BP readings observed throughout the study may be explained by the white-coat effect, but this was not clearly established in the study.

	At the end of the study, there was less intensive drug treatment and higher overall BP achieved in the Home Guidance group when their BPs obtained under the same settings were compared. The final office-measured systolic and diastolic BPs in the Home Guidance group were higher than the final office-measured BPs in the Office Guid-ance group by 6.8 and 3.5 mm Hg, respectively. This outcome, however, does not reflect the inferiority of BP therapy guided by home readings. Rather, it reflects a flaw in the study design whereby medications were added or subtracted to strictly maintain diastolic BP between 80 and 89 mm Hg throughout the study by two techniques that yielded dichotomous readings in each patient.  

	The data and conclusions provided by the authors of this study are difficult to interpret because of two variables. One is the lack of standardization of the home and office BP readings. The authors do not provide evidence of the accuracy of the home readings by making certain that the oscillometric readings were verified by simultaneous sphygmomanometric readings. It is well known that the real-world accuracy of oscillometric devices may be less reliable than expected.1,2 Oscillometric devices may report falsely low diastolic BP, especially in the elder-ly and under various situations of high cardiac output and low peripheral resistance, such as pregnancy, anemia, thyrotoxicosis, and aortic regurgitation.1-4

	The second variable is the study design to maintain diastolic BP between 80 and 89 mm Hg throughout the study by the single-blinded physician for both groups of patients. It would have been interesting to set BP control below 90 mm Hg without the lower threshold.

	The rationale for using only diastolic BP readings to control the hypertension is unclear, as isolated elevations in systolic BP increase the risks for myocardial infarction, stroke, left ventricular hypertrophy, kidney damage, and cardiovascular mortality.5,6 As with many prospective hypertension trials, the ever-evolving standards for acceptable BP make the results appear less relevant and antiquated. Clinical and epidemiologic data indicate that lower BP readings are associated with lower mortality and morbidity, and larger reductions in BP lead to larger reductions in risk of total cardiovascular events.7,8 The Prospective Studies Collaboration has also shown that cardiovascular mortality rates increase steadily as BP rises above 115/75 mm Hg.8 The coexistence of other risk factors, including hyperlipidemia and diabetes mellitus, may further amplify the risks of elevated BP.9,10

	White-coat hypertension may reflect a disease state as evidenced by the concurrent presence of microalbuminuria, a marker of endothelial dysfunction and end organ damage.11 It is also a risk factor for cardiovascular events in both the diabetes mellitus and nondiabetes mellitus populations.12 Assuming that the BPs taken at home were reliably obtained, this study demonstrated that white-coat syndrome might be more common than currently thought. Additional studies in the office and home setting would be useful to identify higher risk patients with the white-coat syndrome and establish new guidelines based on BPs taken at home or in the physician’s office. The current study raises the question of whether there should be separate guidelines for office BP- and home BP-guided therapies. n

The role of self-measured BP in  the management of hypertension

	Studies of patients with atherosclerosis have shown that HMG-CoA reductase inhibitor (statin) therapy can be beneficial in these patients. These drugs have been reported to provide favorable pleiotropic effects by inhibiting vascular inflammation, stabilizing atherosclerotic plaques, reducing oxidative stress, and lowering cholesterol.1 In multiple clinical settings, statins have been shown to reduce the likelihood of cardiovascular events and mortality.2-7 Patients with peripheral artery disease (PAD) are at particularly high risk for poor cardiovascular outcome. Beyond improving survival rates and decreasing cardiovascular events,2,3 statins may also improve leg functioning in these patients.8

	In several studies, improved outcome was observed after statin therapy in patients with high inflammatory activity.8-10 Thus, besides the lipid-lowering properties, the anti-inflammatory effects of statin therapy seem to play a major pathophysiologic role. We prospectively studied the effects of statin treatment on measurements of inflammatory activity and the cardiovascular outcome of patients with severe peripheral atherosclerosis. The end points were all-cause mortality and a composite of myocardial infarction (MI) and death.

	A total of 515 consecutive inpatients (median age, 70 years; 296 men; median ankle—brachial index, 0.51) with angiographically proven, advanced PAD were enrolled in this cohort study. All patients were scheduled to have a peripheral percutaneous intervention. Statin therapy was initiated in a nonrandomized fashion in the outpatient clinic 1 to 2 months before the index hospital admission at the discretion of the treating physician. Demographic data, clinical characteristics, and various laboratory measurements, including the inflammatory markers high-sensitivity C-reactive protein (hs-CRP), serum amyloid A (SAA), fibrinogen, leukocyte count, and serum albumin, were obtained on hospital admission. Patients were observed for a median of 21 months (interquartile range, 12 to 25 months) for all-cause mortality and the occurrence of MI. Multivariate statistical analysis was performed to assess the effects of statin treatment on mortality and MI, adjusting for inflammation and other potential confounders.

	Of the 515 patients, 269 (52%) were placed on statin therapy at least 4 weeks before being admitted to the hospital. Because of the nonrandomized design, patients receiving statins had more severe comorbidities, such as diabetes mellitus (and a higher median glycosylated hemoglobin level), higher body mass index, hypertension, and a history of coronary artery disease (CAD), MI, or stroke.

	At the time of the index hospital admission at least 1 month after initiation of treatment, a lower cholesterol level was found in statin users. Statin users also exhibited markedly less inflammatory activity compared with nonusers, as shown by lower hs-CRP levels (P < .001), lower SAA levels (P = .001), lower fibrinogen levels (P = .007), higher albumin levels (P < .001), and lower neutrophil counts (P = .049; figure 1).

	During follow-up, there were 61 cardiovascular deaths and four deaths from noncardiovascular causes; 19 patients had an MI, of which five were fatal and 14 were nonfatal. The adjusted survival rate and event-free survival rate (freedom from death and MI) were substantially improved for patients receiving statin therapy compared with patients who did not receive statin therapy (adjusted hazard ratio [HR], 0.52; P = .022, for survival; adjusted HR, 0.48; P = .004, for event-free survival, respectively). Particularly in patients with high inflammatory activity (hs-CRP levels > 0.42 mg/dL), statin therapy was associated with a substantially reduced risk of mortality (adjusted HR, 0.58; P = .046) or the composite of MI and death (adjusted HR, 0.46; P = .016), whereas patients with low inflammatory activity (hs-CRP ≤ 0.42 mg/dL) did not appear to have substantial improvement from statin therapy (figure 2). Similar findings were obtained by quantifying inflammation with SAA levels, fi-brinogen levels, neutrophil counts, or serum albumin levels.

	For patients with advanced PAD, particularly in the presence of high inflammatory activity, statin therapy seemed to reduce mortality and improve event-free survival, highlighting the importance of prescribing these drugs for patients with PAD. The current findings also support the hypothesis that, for patients with advanced atherosclerosis, the favorable results of statin therapy are mainly mediated through an anti-inflammatory pathway or, alternatively, that statins diminish the harmful effects of inflammation.

	In patients with atherosclerotic disease, it has been shown that statins provide many favorable effects.1 By attenuating the vascular inflammatory process independently of their cholesterol-lowering effects,9,11,12 these drugs seem to substantially slow the harmful clinical effects of severe atherosclerosis. Inflamma-tion and the underlying cellular and molecular mechanisms have been recognized as cornerstones of atherosclerosis development and pro-

	gression.13,14 In this context, plaque rupture and atherothrombosis, which may translate into the clinical complications of atherosclerotic disease, such as MI or stroke, are known to be closely associated with enhanced inflammatory activity. In line with these previous findings, we observed that the association between statin use and outcome was significantly affected by the patient’s inflammatory status. It appears that the most important mechanism of statin therapy is decreasing vascular inflammation or reducing the effects of inflammatory activity. This view is supported by reduced baseline inflammatory activity in statin users, which has been reported by others previously.1

	Virtually identical findings to those in our present study were observed in the Cholesterol and Recurrent Events (CARE) trial, which evaluated patients with CAD.4 In that study, patients with high inflammatory activity received a significantly greater benefit from statins. In addition, the respective effect size of cardiovascular event reduction was similar to the findings in our study. Thus, it may be assumed that, for patients with severe atherosclerosis, the anti-inflammatory effects of statin drugs may be more important for the prevention of cardiovascular adverse events than for the lipid-lowering effects, which appear to be essential in preventing atherosclerosis from starting and progressing.

	In published data on statins, the protective properties of the drugs have been shown predominantly in patients with cerebrovascular atherosclerosis and CAD.4-6,9 Patients with PAD are considered to have severe atherosclerotic disease, however, and it was uncertain whether statins would also show promise in these highest-risk patients. In two of the large randomized controlled trials, the Scandinavian Simvastatin Survival Study (4S)3 and the Heart Protection Study,2 statin therapy appeared to be beneficial with regard to cardiovascular outcome for patients with PAD. In our study, we investigated patients with even more advanced disease, as shown by a low ankle—brachial index, including a large proportion of patients with critical limb ischemia, all of whom required revascularization. Remarkably, even in these patients, statins performed well, even during the comparatively short follow-up phase.

	In patients with widely advanced PAD, we found that treatment with statin drugs resulted in markedly improved intermediate-term cardiovascular outcome, particularly in

	the presence of high inflammatory activity. However, in patients with low inflammatory activity, as indicated by hs-CRP levels below 0.42 mg/dL, no significant improvement of outcome was found with statin treatment. n

Statin therapy in patients with peripheral artery disease

	Diuretic-based therapy of hypertension improves long-term outcomes, even among patients with diabetes and even though diuretic therapy

	is associated with an increase in new diabetes, report researchers in the American Journal of Cardiology (2005;95:29-35).

	This finding comes from long-term follow-up of patients enrolled in the Systolic Hypertension in the Elderly Program (SHEP), a trial of diuretic-based stepped-care antihypertensive therapy of isolated systolic hypertension (ISH) in individuals aged 60 years or older. The long-term analysis was led by John B. Kostis, MD, chief, division of cardiovascular diseases and hypertension, and chair, Department of Medicine, University of Medicine and Dentistry of New Jersey—Robert Wood Johnson Medical School, New Brunswick, New Jersey.

	In SHEP, 4,732 patients with ISH were randomized to therapy starting with chlorthalidone, 12.5 to 25.0 mg daily, or placebo to achieve

	goal blood pressure (systolic blood pressure below 160 mm Hg or a decrease of at least 20 mm Hg). Atenolol or reserpine could be added if blood pressure remained above goal.

	At baseline, about 17% of the participants had diabetes. During follow-up, an additional 13.0% in the chlorthalidone group developed diabetes compared with an additional 8.7% in the placebo group (P < .001).

	At a mean follow-up of 14.3 years, cardiovascular mortality was 19% lower (95% confidence inter-val [CI], 24.9% to 2.8% lower) in the overall group of patients assigned to chlorthalidone compared with placebo.

	Participants who had diabetes at baseline had a higher mortality than those without diabetes at baseline (63% higher if they were assigned to placebo, 38% higher if randomized to a diuretic).

	Those who were randomized to placebo and developed diabetes during the double-blind phase of the study (4.4 years) had a 35% higher mortality (95% CI, 5.1% to 72.7% higher) at 14.3 years than placebo recipients who did not develop diabetes. This effect was less pronounced and not significant among the subjects who developed diabetes while on diuretic-based therapy (15% increased mortality [95% CI, —7.5% to 11.7%]).

	Subjects with diabetes at baseline or those who developed diabetes during follow-up had a 19.5% reduction (95% CI, 32.0% to 4.8%) in the risk of mortality if they were randomized to a diuretic compared with placebo. The rate of cardiovascular mortality was reduced by 32% (95% CI, 47.4% to 15.2%) in diabetic patients randomized to chlorthalidone relative to placebo.

	The long-term findings from SHEP support national guidelines in which diuretics, in addition to beta blocking agents, angiotensin-converting enzyme (ACE) inhibitors, and calcium antagonists, are recommended as first-line therapy for hypertension, including patients who have diabetes, note the authors. They write that “the milder long-term course that occurred during diuretic therapy is likely related to the lesser degree of metabolic disturbance as judged by fasting glucose levels and proteinuria.” The

	eters were small in this study, they add, with only slight differences in fasting glucose level, total cholesterol, and high-density lipoprotein cholesterol.

	The study’s findings have important clinical implications given that approximately one third of people older than 60 years have both hypertension and diabetes, according to Valentin Fuster, MD, director, The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York City.

	Although chlorthalidone was associated with a significantly higher rate of new-onset diabetes than the ACE inhibitor lisinopril and the calcium antagonist amlodipine in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), the three agents were equally successful at preventing adverse cardiovascular events.

Diuretics improve outcomes in older hypertensive patients with diabetes

	An 88-year-old woman with a history of hypertension but no history of cardiovascular disease suddenly felt weak and lightheaded and was noted by her family to appear pale and fatigued. After a syncopal episode an hour later, she was transported by ambulance to a community emergency department. An inferior wall acute myocardial infarction (MI) was diagnosed based on the results of an electrocardiogram (ECG) and increased creatine kinase and troponin I levels. The ECG also showed complete heart block with a junctional escape rhythm. Findings from the physical examination showed pallor, diaphoresis, a heart rate of 40 beats per minute, a blood pressure of 140/80 mm Hg, jugular venous pressure of 9 cm, diminished breath sounds bilaterally, a soft systolic murmur localized to the apex, and diminished peripheral pulses in the lower extremities.

	Soon after arrival at the emergency department, the patient was treated with intravenous tenecteplase (TNKase). However, despite therapy, she had persistent ST-segment elevations and complete heart block. She was then transferred to our institution for emergent cardiac catheterization. Angiography demonstrated a totally occluded proximal right coronary artery. The patient subsequently underwent rescue percutaneous coronary intervention with deployment of three stents. Although the residual stenosis was reduced to 0%, initially there was “no reflow” of coronary blood flow in the right coronary artery. Thrombolysis in Myocardial Infarction grade 2-3 flow was restored after the use of intracoronary nitroglycerin and adenosine (Adenocard). Results of left ventriculography and echocardi-

	ography confirmed a left ventricular ejection fraction of 30% to 35%; akinesis of the inferior, inferoseptal, and inferoapical walls; moderate mitral regurgitation; and left ventricular end-diastolic pressure of 28 mm Hg. The patient required immediate temporary transvenous pacing followed by permanent pacemaker implantation on hospital day 7.

	On hospital day 6, the patient developed dysarthria and right upper extremity weakness. An imme-diate head computed tomography (CT) scan was normal, but a head

	left parietal lobe infarct without hemorrhage. Bilateral carotid artery duplex studies were abnormal but without critical stenoses. Two weeks after hospital admission, the patient was diagnosed with worsening respiratory failure secondary to congestive heart failure complicated by hypotension. One day later, the patient died.

	This case shows the occurrence of a nonhemorrhagic stroke in an elderly patient following inferior MI. As shown in our study, elderly patients are at significantly increased risk for stroke regardless of MI location. Although stroke risk following fibrinolytic therapy increases with age, the majority of cerebrovascular events are nonhemorrhagic. As seen in this patient, who had a history of hypertension, mild cerebrovascular disease, and heart failure, the existence of multiple comorbidities in the elderly likely plays a significant role in this increased risk. In addition, patients who develop acute stroke are at markedly increased risk of dying during hospitalization, as was the case with our patient. Aggressive identification and treatment of modifiable risk factors for stroke following MI, particularly in the elderly, are indicated. n

Case report:  Acute MI complicated  by in-hospital stroke

	Previous research has shown that modifying blood pressure treatment according to ambulatory measurements rather than using office measurements has resulted in a decrease in treatment and a reduction of left ventricular hypertrophy, while maintaining control of hypertension and general well-being.1 However, this approach did not lessen the overall costs of antihypertensive treatment.

	The benefits of ambulatory monitoring, such as the lack of white-coat syndrome, absence of observer bias when automatic instruments are used, and larger number of readings, are also present with self-measurement of blood pressure by the patient at home. In addition, self-monitoring costs less than ambulatory monitoring and may increase adherence to antihypertensive therapy.

	We designed the Treatment of Hypertension Based on Home or Office Blood Pressure (THOP) trial to examine the effect on adjustment of antihypertensive medications resulting from home blood pressure (HBP) measurement compared with office blood pressure (OBP) monitoring.

	The protocol of the THOP trial has been described in detail previously.2 After a 1-month run-in period, hypertensive patients (sitting diastolic blood pressure > 95 mm Hg) were randomly assigned to receive treatment based either on self-measured diastolic HBP or on diastolic OBP. Regardless of randomization, the blood pressures for both the HBP group and the OBP group were measured at each office visit. HBP was the mean of 42 readings, that is, three readings in the sitting position in the morning and three readings in the evening over 7 consecutive days, taken with an oscillometric Omron HEM-705CP device.3 OBP was the average of three readings in the sitting position taken by the physician at the office with a sphygmomanometer. At baseline and after 6 and 12 months, daytime (from 10:00 am to 8:00 pm) ambulatory blood pressure (ABP) was calculated from recordings obtained with oscillometric SpaceLabs 90207 recorders.3 The ambulatory measurements were not considered in any treatment decisions.

	In both groups, treatment was adjusted in a stepwise manner to reach the target range of diastolic blood pressure, which was 80 to 89 mm Hg. Once patients were randomly assigned to groups, they were started on monotherapy with 10 mg of lisinopril (Prinivil, Zestril) per day (step I). At each follow-up visit, treatment could be increased to step II, 20 mg of lisinopril per day; step III, addition of 25 mg of hydrochlorothiazide (Carozide, HydroDiuril) or

	5 mg of amlodipine (Norvasc) per day; or step IV, addition of 5 mg of amlodipine or 6 mg of prazosin (Minipress) per day. Patients who were not able to take angiotensin-converting enzyme inhibitors because of contraindications were given atenolol (Tenormin) (50 or 100 mg/day) instead of lisinopril. Follow-up visits were planned at 1, 2, 4, 6, 8, 10, and 12 months. Treatment decisions were made by one physician at the coordinating center who was blind to randomization of the two groups. Medical treatment was increased stepwise, left unchanged, or stepwise reduced if the diastolic blood pressure was above target (> 89 mm Hg), within the target range (80—89 mm Hg), or below target (< 80 mm Hg), respectively.

	The main end points of the study were blood pressure (home, office, and ambulatory), intensity of antihypertensive drug treatment (with a treatment score summarizing all drugs with the maximal daily dose of each drug set at 1 unit), side effects (measured by a self-administered questionnaire to report the severity of 33 symptoms on a 5-point scale), adverse events, and electrocardiographic indexes for left ventricular mass (the R wave in lead aVL, the Sokolow-Lyon index,4 and the Cornell product5).

	Cost-benefit analyses accounted for the physicians’ fees, the costs of antihypertensive treatment based on the rates of the Belgian health insurance system, and the costs for HBP.

	SAS software, version 8.1 (SAS Institute Inc, Cary, NC) was used for all analyses. Mann-Whitney rank sum test and Student’s t test were used for between-group comparisons. Longitudinal changes in treatment modifications were compared by Kaplan-Meier survival function estimates, and proportions were compared by chi-square statistic.

	Of 606 patients enrolled at 60 centers, 400 (66.0%) were eligible to enter the study and were randomly assigned to either the HBP group

	(n = 203) or the OBP group (n = 197). At baseline, the blood pressure values and other characteristics were no different between the two groups (table). A total of 53 patients did not finish the study, 27 (13.3%) in the HBP group and 26 (13.2%) in the OBP group. Thirty patients dropped out, 21 missed one or more follow-up visits, and two experienced an adverse event (one patient had a nonfatal stroke and one patient was diagnosed with a malignant brain tumor). Patients were followed up for a median of 350 days.

	In both the OBP and HBP groups, the blood pressure decreased significantly after randomization. After 1 month of treatment, the decrease in blood pressure was no different for either treatment group, averaging 12.6/8.2 mm Hg in the OBP group and 11.5/8.1 mm Hg in the HBP group for OBP (figure 1). The decreases in blood pressure were the same for both groups after 6 months of treatment (figure 1). The decrease then became markedly greater in OBP patients than in HBP patients, with a total reduction of 22.0/14.0 mm Hg in the OBP group and 15.3/10.5 mm Hg in the HBP group. The differences in blood pressure reduction between the two treatment groups were 6.8 mm Hg systolic (P < .001) and 3.5 mm Hg diastolic (P < .001) after adjusting for body mass index, age, sex, and baseline blood pressure. Respective between-group differences were 4.9 and 2.9 mm Hg for HBP monitoring and 5.3 and 3.2 mm Hg for daytime ABP (all P < .001).

	A greater proportion of HBP patients (26%) were able to permanently discontinue antihypertensive drug treatment than OBP patients (11.3%; 2.2 versus 1.0 patients per 100 followed up for 1 month; P < .001; figure 2). A greater proportion of HBP patients (38.7%) compared with OBP patients (45.1%), however, were increased to multiple drug treatments (3.3 versus 3.8 patients per 100 followed up for 1 month). The treatment score became markedly higher in the OBP group compared with the HBP group from the second follow-up visit on, with mean values of 1.47 (standard deviation [SD], 1.19) versus 1.03 (SD, 1.02) at the end of the trial (P = .001).

	Using a 5-point scale, the average symptom score fell (P < .001) from 1.52 (SD, 0.36) to 1.40 (SD, 0.32) in the OBP group and from 1.60 (0.40) to 1.50 (0.41) in the HBP group over the follow-up period. Both groups had no difference in baseline-adjusted changes in the symptom score at 6 months (—0.07 versus –0.10) and at the end of the study (–0.10 versus –0.10). Thirteen patients in the OBP group and 10 patients in the HBP group had significant adverse events.

	In both treatment groups, there was a significant decrease in the electrocardiographic indexes of left ventricular mass. These changes were similar in the OBP and HBP groups. The changes in electrocardiographic parameters were —0.03 mV in the OBP group versus –0.03 mV in the HBP group for the R

	wave in aVL, —0.12 versus –0.09 mV for the Sokolow-Lyon index, and –13 versus –12 µV x seconds for the Cornell voltage after adjusting for sex, body mass index, age, and baseline measurements.

	For 1 month of treatment, the medications cost Œ2,120 per 100 OBP patients and Œ1,688 per 100 HBP patients (P = .002). Per 100 patient-months, physicians’ fees averaged Œ1,789 for OBP patients and Œ1,510 for HBP patients (P < .001). The cost of home monitoring, however, partially equalized the possible savings related to less intensive

	drug treatment and fewer physician visits in the HBP group. Compared with HBP patients, the costs were slightly greater but statistically significant for OBP patients (Œ3,875 versus Œ3,522 per 100 patient-months; P = .04).

	Our study showed that when treatment for high blood pressure was based on home monitoring, patients received less intensive drug treatment and costs were slightly lower than when treatment was based on office monitoring. There was no difference in general well-being and left ventricular mass between the HBP and OBP groups, however, and blood pressure was not as well controlled in the HBP group. Systolic and diastolic blood pressure differed by 6.8 and 3.5 mm Hg, respectively, using traditional office measurements. These differences are clinically significant for long-term prognosis, as shown by a meta-analysis of 30 clinical trials of hypertensive or high-risk patients. Over 3 to 5 years, there was a 25% to 30% increase in the risk of stroke and cardiovascular complications in the presence of a 5-mm Hg difference in systolic blood pressure.6 The results of the present study, therefore, do not support the idea that patient self-measurement at home might be a better guide to prescribing antihypertensive therapy than traditional blood pressure measurement at the physician’s office.

	The widespread use of patient self-measurement is limited by the lack of prognostically validated diagnostic thresholds for the initiation or adjustment of antihypertensive therapy. Thresholds ranging from 125 to 140 mm Hg for systolic blood pressure and from 80 to 90 mm Hg for diastolic blood pressure have been suggested.7-10 Few prospective studies on the association between cardiovascular risk and self-measured blood pressure have been published. Home monitoring of blood pressure was found to be a better predictor of mortality than traditional office measurement of blood pressure in a Japanese population study.11

	In our study, antihypertensive treatment was adjusted only according to diastolic blood pressure for various reasons. This criterion is used in most hypertension outcome trials.6 Diastolic blood pressure is used to assess cardiovascular risk in young and middle-aged subjects younger than 60 years of age12; it is even used to evaluate cardiovascular risk in older subjects.13 The treatment strategy would have been more complex if both systolic and diastolic measurements had been used. In both groups, treatment was

	also adjusted to reach the same range of 80 to 89 mm Hg diastolic blood pressure, corresponding to the Ambulatory Blood Pressure Monitor-ing and Treatment of Hypertension (APTH) trial.1 One physician at the study center was able to suggest treatment modifications in a blind manner as a result of these design characteristics.

	Until the benefit of incorporating home and ambulatory blood pressure monitoring into the customary care of hypertensive patients is confirmed by long-term outcome studies, office measurement by the physician is still the preferred method for diagnosis and treatment of hypertension, in agreement with current guidelines.14 When increased OPB in the physician’s office is the only detectable abnormality, or when patients with a normal OBP.

Is BP measurement at home or in the physician%u2019s office more reliable?

	Stroke is an infrequent yet potentially devastating complication of acute myocardial infarction (MI). Previously published data show stroke occurrence rates to be 1% to 2% for hospitalized patients with acute MI, whether or not fibrinolytic therapy was administered.1-3 This contemporary, community-based, observational study examined temporal trends (1986—1999) in the incidence, risk, and outcomes of 6,325 metropolitan Worcester, Massachusetts, residents hospitalized with acute MI without prior stroke.

	Our investigation was part of the Worcester Heart Attack Study, an ongoing study analyzing temporal trends in Worcester metropolitan area residents with validated acute MI.4-7 Trained nurses and physicians reviewed medical records from the Worcester Standard Metropolitan Statistical Area hospitals for eight annual periods between 1986 and 1999. Demographic, clinical, and outcome data on the occurrence of acute stroke in patients with confirmed acute MI who had no history of stroke were compiled and analyzed.

	Differences in the characteristics of patients with acute MI according to the diagnosis of acute stroke were analyzed using chi-square and t tests. Logistic regression analyses were performed to identify independent variables correlating with the development of stroke, temporal trends in the likelihood of the development of stroke, and factors associated with hospital death for patients with acute MI.

	Of 6,325 patients with acute MI, 92 (1.5%) developed acute stroke. Data from 1991 to 1999 confirmed that 78% of strokes were ischemic or embolic, and the rest were hemorrhagic. There was no difference in stroke rates (1.5%) between patients who received fibrinolysis (n = 1,396) and patients who did not (n = 4,929).

	Acute stroke factors. Compared with acute MI patients who did not develop stroke, those who did were more likely to be older than 75 years (59.8% versus 36.0%; P < .001), to be women (58.7% versus 41.1%; P < .001), and to have an anterior wall location of their acute MI (51.1% versus 39.9%; P < .05). In addition, the hospital course of patients who had a stroke was also more frequently complicated by atrial fibrillation (31.5% versus 14.8%; P < .001). These patients were less like-

	ly to receive aspirin therapy (76% versus 66.3%; P < .05). Interventional procedures, including cardiac catheterization, percutaneous coronary intervention, coronary artery bypass graft (CABG) surgery, and treatment with fibrinolytic therapy, did not substantially correlate with acute stroke.

	Factors associated with acute stroke were further stratified according to age (≥ 75 years or < 75 years). Acute MI patients older than 75 years were more likely to develop stroke in the presence of atrial fibrillation (38.2% versus 21.3%; P < .005) if they underwent CABG surgery (5.6% versus 2.1%) and if they had previous heart failure (43.6% versus 29.5%; P < .05); however, they were less likely to develop stroke if they had prior angina (16.4% versus 31.4%; P < .05). Younger patients (< 75 years) had an increased risk of stroke in

	the presence of anterior wall acute MI (56.8% versus 38.3%; P < .05), atrial fibrillation (21.6% versus 11.2%;

	P < .05), and cardiogenic shock (13.5% versus 5.5%; P < .05).

	After adjusting for specific patient characteristics, age of 75 years or older (odds ratio [OR], 2.53; 95% confidence interval [CI], 1.05—6.11) and atrial fibrillation (OR, 1.91; 95% CI, 1.17–3.11) were the only factors that correlated with an increased risk of acute stroke. A trend toward increased rates of stroke was observed in women (OR, 1.51; 95% CI, 0.96–2.38) and patients with anterior wall acute MI (OR, 1.54; 95% CI, 1.00–2.36). The increased risk associated with advanced age was not altered by controlling for additional variables relating to therapies and procedures.

	Time trends and the incidence of acute stroke. There was an initial decrease in the occurrence of stroke between 1986 and 1990; however, between 1991 and 1999, there was a continual increase over time (figure). The annual period of 1999 had the highest incidence of acute MI patients with acute stroke (3%).

	After adjusting for certain patient demographic, historical, and clinical variables that were potentially confounding factors for the development of stroke,1,2,8 trends in the risk of stroke over time were reexamined for four 2-year periods. The odds of developing acute stroke increased significantly and progressively over time (table 1). Further analyses controlling for specific hospital therapies and procedures, hospital complications, length of stay, and hospital discharge status reinforced these findings (table 1). When temporal data were further stratified according to age, the increased risk of developing stroke between 1986 and 1988 and between 1997 and 1999 was greater for patients 75 years or older (OR, 9.93; 95% CI, 2.56—36.60) compared with patients younger than 75 years (OR, 4.63; 95% CI, 1.46–14.70).

	Hospital case fatality rates and acute stroke. In-hospital death was significantly more likely to occur in acute MI patients with stroke than in those without stroke (32.6% versus 12.8%; P < .001). This held true for patients younger than 75 years (27% versus 7.5%) and for those 75 years or old-er (36.4% versus 22.3%). After advanced age and cardiogenic shock, multivariate-adjusted regression analysis identified stroke as the most potent predictor of in-hospital death (table 2).

	Despite improvements in coronary revascularization techniques and adjunctive pharmacotherapies used for treatment of acute MI,

	and despite controlling for specific high-risk demographic and clinical markers, our population-based study suggested that there was a progressive increase in the incidence of acute stroke in patients with validated acute MI between 1986 and 1999. Previously published studies from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries-1 (GUSTO-1) trial,1,2 a meta-analysis of fibrinolysis trials by the Fibrinolytic Therapy Trialists (FTT) collaborative group,3 and the Second National Registry of Myocardial Infarction (NRMI-2)8 all report overall stroke rates of 1% to 2% after development of acute MI. Although the early incidence of stroke observed in our study was similar, data from our most recent study cohort (1999) suggest an approximate twofold increase in events. Furthermore, unlike previous studies, the majority (approximately 80%) of patients with validated acute MI in the Worcester Heart Attack Study did not receive fibrinolysis, suggesting that the majority of cerebrovascular events were nonhemorrhagic.

	Risk factors for stroke complicating acute MI. The median age of acute MI patients in our study increased from 68 years in the 1986 to 1988 period to 71 years in the 1997 to 1999 period, and the prevalence of patients 75 years or older increased from 30% to 41%. This supports the hypothesis that advanced age contributes directly to the higher risk of stroke after acute MI in the community setting. In fact, advanced age was identified as one of the strongest predictors of post-MI stroke in our study, as well as in a number of clinical trials and observational studies.8-11

	Interestingly, it appeared that other risk factors for stroke had a differential impact according to patient age. Within this community-based population, anterior wall location of acute MI was a significant predictor of stroke in patients younger than 75 years (57% with stroke versus 38% without stroke; P < .05), but not in patients 75 years or older (47% with stroke versus 42% without stroke). Commonly accepted as an important cause of stroke following an acute MI, anterior location of acute MI is often followed by 3 months of prophylactic anticoagulation therapy to prevent cardioembolic events. No prospective study has clearly established thromboemboli from the left ventricle as an important cause of acute stroke. In both a GUSTO-1 analysis2 and the Multicenter Diltiazem Postinfarction Trial (MDPIT), anterior location of acute MI was not a reliable predictor of stroke in hospitalized patients.12 It may be that left ventricular apical thrombi, which were an important cause of stroke in younger patients with acute MI in our study, play less of a role in older patients, who were heavily represented in these trials.

	ology of post-MI stroke in older pa-tients is more heterogeneous than in younger patients with acute MI. This is supported by our data, which suggest that atrial fibrillation, previous heart failure, and CABG surgery were all significantly associated with post-MI stroke. Accordingly, it is unlikely that targeting only elderly patients with anterior MI for prophylactic anticoagulation therapy will successfully reduce post-MI stroke. It is more likely that aggressive, coordinated management of a number of more general risk factors (atrial fibrillation, congestive heart failure, hypertension, etc) would be more efficacious.

	An additional risk factor for stroke not addressed in the current study but worthy of mention, particularly in the elderly, is the presence of noncardiac vascular disease. Previous evidence of cerebrovascular disease has been identified as a potent predictor of acute MI—associated stroke in several studies. A history of stroke or transient ischemic attack was the strongest predictor of nonhemorrhagic stroke after acute MI in a multivariate analysis of the GUSTO-1 dataset.1 A history of pe-

	ripheral vascular disease was independently associated with increased risk of stroke among elderly patients with acute MI in the Cooperative Cardiovascular Project.11 Although we excluded patients with prior stroke from our analyses, it is probable that many (if not most) patients aged 75 years and older in our population had some degree of “silent” cerebrovascular disease. This underlying condition, in conjunction with the heightened platelet activation and hypercoagulability associated with the onset of acute MI, could be a fertile substrate for de novo cerebrovascular events. The results of the recent Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, which documented a 50% reduction in nonfatal and fatal strokes in patients randomly assigned to receive high-dose early HMG-CoA reductase inhibitor (statin) therapy after acute MI, suggest that plaque stabilization in the noncoronary vasculature may be an unexpected benefit of this therapy.13

	The results of this study suggest that the rate of stroke after acute MI has increased in the last decade. Mortality associated with this complication remains extraordinarily high. Increasing age and specific comorbidities were significantly associated with stroke risk in this

	community-based population. These findings reinforce the need for aggressive identification and treatment of modifiable risk factors for stroke following acute MI. n

In-hospital stroke  complicating acute 

	Type 2 diabetes now poses a significant health risk for this country. The increasing prevalence of this disease, along with its associated cardiovascular morbidity and mortality, presents one of the greatest health care challenges of the 21st century.

	The study by Zellweger and colleagues (page 22) examined 1,737 consecutive clinic patients with type 2 diabetes, following 1,430 of these patients for 2 years. All patients

	in this study had myocardial perfusion single photon emission computed tomography (SPECT) imaging in the initial stages of their evaluation for coronary artery disease (CAD). The cohort of 1,430 patients was followed up for nonfatal myocardial infarction and cardiac death as study end points. More than half of the patients in this study were asymptomatic and remained without symptoms until the study was completed or the end points reached. Thirty-five percent of patients complained of anginal symptoms, and 5% had shortness of breath on presentation.

	The results of this study were very revealing. During the follow-up period, there were 98 cardiac events, for an annual cardiac event rate of 3.1%. Cardiac event rates were stratified by presenting complaints as follows: 2.2% for asymptomatic patients, 3.2% for patients presenting with angina, and 7.7% in a small cohort of patients presenting with shortness of breath. Patients with a normal myocardial perfusion SPECT had a significantly lower annual event rate compared with patients with abnormal perfusion studies (1.9% versus 5.4%; P < .001). This result was consistent for all patients, regardless of their presenting symptoms. Using a Cox proportional hazards model, age, hypertension, shortness of breath as a presenting symptom, and the degree of abnormality on myocardial perfusion SPECT (ie, extent of scarred or ischemic myocardium) were predictors of cardiac events.

	The clinical implications of this study are profound. In a low-risk population of type 2 diabetic patients (most being asymptomatic), 39% had objective evidence of CAD. The majority of patients thus had evidence of silent disease. This result is consistent with the Detection of Ischemia in Asymptomatic Diabetics (DIAD) trial, which showed that 27% of patients had perfusion imaging evidence of CAD. These data should be interpreted in conjunction with the predictors of cardiovascular events in the present study of mostly asymptomatic diabetic patients. The most important of these factors are age and hypertension.

	How can we translate these results into clinical practice? First, in a select population of type 2 diabetic patients with advanced age and hypertension, one could make an argument for routine noninvasive screening studies, such as myocardial perfusion SPECT, to identify even asymptomatic patients at risk for cardiac morbidity and mortality. Recent data have also identified the ankle— brachial index as a similar predictor in the general cardiac population.

	Selecting patients with this clinical profile (elderly, diabetic, and hypertensive) for these noninvasive screening studies may prove invaluable in the subsequent clinical management. n

Identifying silent coronary artery  disease in diabetic patients

	Patients with heart failure and diabetes who require treatment with insulin have a substantially increased risk of mortality compared with nondiabetic patients with heart failure and noninsulin-treated diabetic patients with heart failure. This association between worse prognosis and insulin-treated diabetes is apparent in heart failure patients with or without coronary artery disease (CAD), according to researchers at the Ahmanson-UCLA Cardiomy-

	As reported in the American Heart Journal (2005;149:168-174), they studied 554 consecutive patients with heart failure who were referred for heart failure management and/

	or transplant evaluation for systolic dysfunction heart failure (ejection fraction of 40% or less). Three fourths of the patients (74.7%) had New York Heart Association functional class III or IV heart failure.

	Of the 554 patients, 132 had diabetes, 43 of whom were treated with insulin and 89 who had noninsulin-treated diabetes. The mean follow-up time was 11.7 months, during which time there were 72 deaths. Diabetes was associated with impaired survival; at 1 year, the survival rate in diabetic patients was 78.5% compared with 89.7% in the nondiabetics (P = .002) and at 2 years, survival was 62.6% in the diabetics and 85.5% in the nondiabetic patients (P = .001).

	At 1 year, survival among insulin-treated diabetic patients was 62.1% compared with 89.7% among nondiabetics (P < .001); at 2 years, survival was 57.0% and 85.5% (P < .001) among the diabetic and nondiabetic patients, respectively.

	In contrast, noninsulin-treated diabetic patients had only modestly impaired survival compared with nondiabetics (85.8% versus 89.7% at 1 year; P > .05; and 66.7% versus 85.5% at 2 years; P = .035).

	Even after adjusting for age, sex, history of CAD and hypertension, body mass index, serum creatinine, and ejection fraction, insulin treatment remained a significant predictor of death. On multivariate analysis, insulin-treated diabetes was associated with a greater than fourfold increase in the risk of mortality at 1 year and nearly a fivefold increase at 2 years. Noninsulin-treated diabetes was not a significant independent predictor of death at either 1 or 2 years.

	Insulin treatment was associated with a worse prognosis in both men and women and in patients with or without CAD. The association between insulin treatment and poorer prognosis was unchanged when including urgent transplantation as an end point.

	Previous randomized clinical trials have identified diabetes as an independent predictor of mortality in patients with heart failure, mainly in those with heart failure of ischemic origin, the authors note.

	In attempting to explain the relationship between insulin treatment and adverse outcomes in patients with heart failure, they write that insulin may increase sympathetic nervous system activation, vascular resistance, cardiac and vascular hypertrophy, and endothelial dysfunction. Alternatively, use of insulin may simply be a marker for more advanced diabetes, with greater micro- and macrovascular disease and a greater degree of insulin re-sistance. In addition, oral diabetes medications may confer cardiovascular protection, they speculated, or patients who are not compliant with oral diabetes medications and are started on insulin therapy may not be compliant with heart failure therapies either.

	Further investigation into the effects of individual therapies for diabetes is warranted, the authors conclude. n

Insulin associated with worse heart failure prognosis

	There has been a steady increase in the prevalence of type 2 diabetes. The disease correlates with a significantly greater risk of illness and death from cardiovascular disease. In patients with diabetes, 80% of deaths are related to atherosclerosis.1 Men with diabetes have a cardiovascular mortality rate two times greater than nondiabetic men, and diabetic women have a cardiovascular mortality rate four times greater than nondiabetic women.2 Furthermore, coronary artery disease (CAD) is often silent in diabetic patients.3 We have recently shown that, in patients with moderate to severe ischemia, more lives per year are saved with revascularization in diabetic patients compared with nondiabetic patients.4 Therefore, identifying CAD can have an important effect on the prognosis of asymptomatic diabetic patients.

	To assess risk and diagnose patients with possible or known CAD, myocardial perfusion single photon emission computed tomography (SPECT) has been used extensively.5-7 Few studies have been done, however, on the relationship between symptoms in diabetic patients and the findings on myocardial perfusion SPECT testing. We compared the prognosis of CAD in symptomatic versus asymptomatic patients without a prior history of CAD.8

	The prognostic study cohort comprised 1,430 consecutive diabetic patients, all of whom received rest thallium-201/stress technetium-99m sestamibi myocardial perfusion SPECT. Standard protocols for stress testing and imaging were used.

	Patients were followed up for a median of 2 years. During the follow-up period, 98 cardiac events (nonfatal myocardial infarctions [MIs] or cardiac death) occurred, which resulted in a 3.1% annual cardiac event rate. Men had an event rate of 2.9%, and the event rate for women was similar, at 3.3%. With respect to risk and presenting symptoms, annual cardiac event rates were 2.2% for asymptomatic patients, 3.2% for patients with angina, and 7.7% for patients with shortness of breath. The event rates were markedly greater for patients with shortness of breath than for asymptomatic patients (P < .001) and those with angina (P = .002), reflecting in part the fact that patients with shortness of breath had a significantly lower ejection fraction. The event rates for asymptomatic patients and patients with angina were statistically the same.

	Patients with abnormal myocardial perfusion SPECT results had a substantially higher annual event rate (5.4%) compared with patients with normal myocardial perfusion SPECT results (1.9%), including patients with angina, asymptomatic patients, and patients with shortness of breath (figure 1). Of note, annual event rates among patients with normal myocardial perfusion SPECT findings were similar for patients with angina, asymptomatic patients, and patients with shortness of breath. Among patients with abnormal myocardial perfusion SPECT results, however, patients with shortness of breath had significantly higher cardiac event rates than patients with angina (P = .008) and asymptomatic patients (P < .001); the outcomes for asymptomatic patients and patients with angina were similar. Also in patients with abnormal myocardial perfusion SPECT results, survival was better for patients with angina and asymptomatic patients than for patients with shortness of breath (figure 2).

	Significant univariate predictors of cardiac events included the extent and severity of scarring, evidence of ischemia on myocardial perfusion SPECT, pharmacologic stress, age, hypertension, and shortness of breath as the presenting symptom. Based on survival modeling using a Cox proportional hazards model, extent of ischemia, extent of scarring, hypertension, shortness of breath, and age were most predictive of events and, added incrementally to each other. Importantly, angina was not a significant predictor of critical events.

	CAD represents the leading cause of death in diabetic patients. Silent myocardial ischemia occurs more often in diabetic than in nondiabetic patients. Our data show that, in a diabetic patient population referred for CAD evaluation, 39% of patients had myocardial perfusion SPECT evidence of silent CAD. The rate

	of abnormal myocardial perfusion SPECT results did not differ from that of patients with angina or angina-like chest pain. However, the occurrence of CAD was much greater in patients with a history of shortness of breath, as shown by abnormal myocardial perfusion SPECT results. The fact that the absence of angina does not necessarily mean that there is no CAD in diabetic patients is highlighted by these results.

	Among those who had a normal myocardial perfusion SPECT scan, the outcome was the same for asymptomatic patients, those with angina, and those with shortness of breath in our study. For diabetic patients with evidence of CAD, the outcome was no different for patients with and without angina. In patients with shortness of breath, however, the outcome was much worse. In part, this was probably because these patients had a lower left ventricular ejection fraction than asymptomatic patients and patients with angina, as well as evidence of more previous silent MIs as shown on myocardial perfusion SPECT scanning.

	In the first large prospective trial examining silent CAD in diabetic patients, the Detection of Ischemia

	in Asymptomatic Diabetics (DIAD) trial, 27% of patients in a low-risk diabetic population had myocardial perfusion SPECT evidence of CAD.9 Eighteen percent of patients had silent ischemia, 3% had evidence of scarring, and 6% were identified as being at high risk. The rates of silent CAD in that study were lower than in our study, which included a higher risk group and older diabetic patients. Interestingly, in the DIAD study, the presence of autonomic cardiac neuropathy was the only independent predictor of an abnormal myocardial perfusion SPECT scan. In the presence of myocardial ischemia, diabetic patients have been shown in several studies to report angina less often than nondiabetic patients,10 and the only symptom of myocardial ischemia may be shortness of breath.11 The findings of these previous reports and our study may also be related to an underlying autonomic cardiac neuropathy.

	The importance of looking for silent ischemia in diabetic patients is illustrated in another recent study from our laboratory.4 As noted earlier, we reported that diabetic patients manifest a greater survival benefit with revascularization in the setting of extensive reversible ischemia than nondiabetic patients. This enhanced survival benefit is greater in women than in men.

	Another important aspect of the present study is the fact that, besides the objective evidence of CAD, hypertension was identified as an independent predictor of outcome in diabetic patients. This finding is in agreement with earlier studies that have shown the importance of strictly controlling hypertension in patients with diabetes.12,13

	The American Diabetes Association published a consensus development conference report in 1998 containing recommendations on how to screen asymptomatic diabetic pa-tients with respect to CAD.14 Rather than being based on evidence, however, the guidelines were based on the clinical opinions of the authorities who wrote them. There is a clear need for evidence-based guidelines for the early detection of CAD in patients with diabetes mellitus.15 The results of the current study provide additional data and suggest a place for nuclear testing in asymptomatic diabetic patients. The myocardial perfusion SPECT results will be important for decision making and choosing the appropriate treatment strategies. There are few studies on the treatment of diabetic patients with early asymptomatic CAD. In the Asymptomatic Cardiac Ischemia Pilot study, however, revascularization was shown to markedly reduce MI, cardiac hospitalizations, and death in patients with silent ischemia compared with patients treated with medication.16

	In our study, silent CAD was commonly found in asymptomatic diabetic patients referred for CAD assessment. It occurred as frequently as in diabetic patients with angina. Accordingly, the annual critical event rate was similarly and strongly dependent on objective evidence of CAD (as demonstrated on myocardial perfusion SPECT scans). Partly because of previous silent MIs, as indicated by a poor left ventricular ejection fraction and larger regions of scarring, patients with shortness of breath had a significantly worse prognosis than asymptomatic patients and patients with angina. These findings point to the fact that objective evidence of CAD shown on myocardial perfusion SPECT can be important in predicting the prognosis and enhancing the decision-making process for asymptomatic diabetic patients. n

Prognosis of silent  coronary artery disease in diabetic patients

	Screening can successfully identify factors associated with the development of depression in patients with heart failure, according to a recent study in the Journal of the American College of Cardiology (2004;44:2333-2338). In the study, four social and environmental factors were found to contribute significantly to the onset of depression in heart failure.

	The investigators, led by Edward P. Havranek, MD, studied 245 outpatients with heart failure who did not have depressive symptoms at baseline. They were evaluated at baseline and at 1 year using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and a clinical evaluation that included social and economic status. The KCCQ is a

	23-item instrument for measuring symptoms, physical functioning, social functioning, self-efficacy, and quality of life that is specific to heart failure. The overall score ranges from 0 to 100, with higher scores indicative of better health status.

	At the 1-year follow-up, four risk factors were significantly and independently associated with depressive symptoms in multivariate an-alysis: living alone (P = .015), the perception of medical care being a substantial burden (P = .003), a

	history of alcohol abuse (P = .013), and impaired health status as measured by the KCCQ (P < .001). The mean KCCQ scores were 59.7 in patients who developed significant depressive symptoms and 71.1 in those who did not develop depressive symptoms.

	The likelihood of depression at 1 year was 7.9% for patients with none of these four risk factors, 15.5% for those with one risk factor, 36.2% for those with two risk factors, and 69.2% for those with three risk factors. No patients had all four of the identified risk factors.

	There was no difference between the depressed and nondepressed group with respect to a history of treated depression.

	The factors associated with depressive symptoms in this study were similar to those in studies of patients following myocardial infarction and in studies of general populations, except, unlike previous studies, the current one found that female gender was not associated with development of depression.

	These findings are important because patients with heart failure who develop depression have higher mortality, more heart failure hospitali-zations, worsening of heart failure symptoms, and worse functional status and quality of life than heart failure patients without depression. As such, “depression screening may be warranted for all patients with heart failure,” write the authors. They recommend serial screening because of the elevated risk of depression in patients with heart failure. Future studies should address whether targeted psychosocial intervention for at-risk patients can reduce the incidence of depression and improve outcomes, they believe.

	“Although there is no evidence that a systematic depression screening program for heart failure patients will improve outcomes, if a heart failure patient is identified as having depression, we strongly support the use of standard treatment for that patient,” Dr. Havranek, staff cardiologist at Denver Health Medical Center, told Cardiology Review in an e-mail interview. “We think the available evidence suggests that selective serotonin reuptake inhibitor antidepressants are safe in patients with heart failure. Cognitive/behavioral therapy may also be of benefit. Referral for treatment to a psychiatrist or to the patient’s primary care physician may also be of benefit.”

Screening can uncover depression in heart failure patients

	The study by Schillinger and Minar (page 27) showed a survival benefit for HMG-CoA reductase inhibitor (statin) therapy in patients with peripheral arterial disease and increased high-sensitivity C-reactive protein levels. There was, however, no survival benefit of statins in patients with low high-sensitivity

	C-reactive protein levels. These results add to our understanding of inflammation and the presumab-

	ly cholesterol-independent effects of statins.

	The role of inflammation in atherosclerotic cardiovascular disease

	Inflammation plays a pivotal role in all stages of atherosclerosis.1 Adhesion molecules expressed by the inflamed endothelium recruit leu-kocytes, which penetrate into the intima and cause inflammation. Inflammatory mediators enhance uptake of modified lipoprotein particles and formation of lipid-filled macrophages. T cells also enter the intima and secrete cytokines, which amplify the inflammatory response and promote the migration and proliferation of intimal smooth muscle cells. Inflammatory mediators can weaken the protective fibrous cap of the atheroma, leading to plaque rupture, erosion, or fissuring and then to thrombosis and the occurrence of an acute coronary syndrome.

	The fact that half of all coronary events occur in persons without overt hyperlipidemia2 has led to

	inflammatory markers for cardiovascular risk. Of these, C-reactive protein has emerged as the leading candidate marker because of its predictive ability and its wide availability, low cost, and ease of use.3

	C-reactive protein is an acute-phase reactant, which has been shown in more than 20 prospective studies to predict myocardial infarction, stroke, peripheral arterial disease, and sudden cardiac death.3 An American Heart Association/Centers for Disease Control and Prevention scientific statement on markers of inflammation and cardiovascular disease endorses the optional use of high-sensitivity C-reactive protein to identify paients at intermediate risk for cardiovascular disease in whom physicians may need additional information to guide further evaluation or therapy.4 The cutoff points for low, intermediate, and high risk are below 1.0 mg/L, 1.0 to 3.0 mg/L, and above 3.0 mg/L, respectively.

	Statin drugs mediate a number of biological actions, called pleiotropic actions, which go beyond the lowering of low-density lipoprotein (LDL) cholesterol. Probable pleiotropic effects of statins include attenuation of endothelial dysfunction, plaque stabilization, a decrease in thrombogenicity, and a blunting of inflammation. These pleiotropic effects may be mediated by statins’ inhibition of isoprenoid production. Isoprenoids are lipid intermediates of cholesterol biosynthesis and important components of signal transduction in many organ systems.5

	In subgroup analyses of the Heart Protection Study,6 the relative risk reduction associated with statin therapy was almost identical among those with low as well as high levels of LDL cholesterol. The non—lipid-lowering effects of statins may explain the relatively rapid time course of event reduction in patients at high risk for recurrent coronary ischemia in the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial.7

	Clinical implications for the use of inflammatory markers and statin therapy

	There is mounting evidence that the beneficial effect of statin ther-

	apy may be greatest in individuals with high inflammatory activity. The Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/

	TexCAPS) was a primary prevention trial of 6,605 men and women taking lovastatin.8 In a post-hoc analysis, among participants with a low LDL cholesterol level and a high C-reactive protein level, the reduction in acute coronary events with lovastatin was virtually identical to that among participants with high LDL cholesterol levels alone. This suggests that statin therapy may be clinically effective in persons with inflammation but no hyperlipid-

	emia.9 Similarly, in a nested case-control analysis of 708 patients in the Cholesterol and Recurrent Events (CARE) trial, subjects with increased levels of C-reactive protein bene-

	fited more from therapy with pravastatin than those without increased levels of these inflammatory markers.10

	Currently, there are no practice guidelines to tailor statin therapy based on high-sensitivity C-reactive protein levels. However, recent modifications to the Adult Treatment Panel guidelines state that, in high-risk persons, the recommended LDL cholesterol goal is below 100 mg/dL but an LDL cholesterol goal of below 70 mg/dL is a therapeutic option.11 Although not explicitly stated, this modification suggests that LDL cholesterol alone may not be the optimal target for statin therapy.

	The large-scale Justification for the Use of Statins in Primary Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial has been initiated to test the concept that statin therapy should be targeted to patients with evidence of inflammation provided by increased high-sensitivity C-reactive protein levels in the absence of hyperlipidemia.12 The JUPITER trial is randomly assigning adults with LDL cholesterol levels below 130 mg/dL and high-sensitivity C-reactive protein levels 2 mg/L or greater to receive rosuvastatin or placebo. The results of this trial will be useful in further delineating the beneficial effects of statin therapy for their anti-inflammatory, rather than their lipid-lowering, effects. n

February 2005

Preventing stroke after acute MI Richard M. Steingart, MD

Case report: Statins in peripheral artery disease

The role of self-measured BP in the management of hypertension

Statin therapy in patients with peripheral artery disease

Diuretics improve outcomes in older hypertensive patients with diabetes

Case report: Acute MI complicated by in-hospital stroke

Is BP measurement at home or in the physician%u2019s office more reliable?

In-hospital stroke complicating acute

Identifying silent coronary artery disease in diabetic patients

Insulin associated with worse heart failure prognosis

Prognosis of silent coronary artery disease in diabetic patients

Screening can uncover depression in heart failure patients

The role of inflammation and statin therapy in cardiovascular disease

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