	This month’s edition of Cardiology Review features an article in the diabetes section by Dr. Richard W. Grant and colleagues, who assessed current trends in the office-based management of diabetic patients. Dr. Alton L. Steiner discusses the case study in his commentary and stresses the need to fix our current model of diabetes care.

	In a combined article in the lipid disorders and heart failure sections, Drs. Tamara B. Horwich and Gregg C. Fonarow evaluated the effect of HMG-CoA reductase inhibitor (statin) therapy on survival in patients with ischemic and nonischemic causes of congestive heart failure. In a cohort of 551 patients with left ventricular ejection fractions less than 40%, statin therapy was associated with improved survival without the need for urgent transplantation. The therapeutic properties of statins that could lead to these favorable results are discussed by Dr. Steven Borzak in his commentary.

	In the arrhythmia section, Dr. Heikki V. Huikuri from Finland assessed risk markers for sudden cardiac death following acute myocardial infarction. The era of beta blocking therapy has sig-

	nificantly affected the importance of common risk factors and has made prediction and prevention of fatal arrhythmic events a continuing challenge. Dr. Frank Mazzola comments on this study for Cardiology Review.

	The final article, in the hypertension section, is an overview of the JNC-7 recommendations by Dr. Henry R. Black. This comprehensive analysis of the JNC-7 guidelines prompted some further questions, which are answered by Dr. Black at the end of the article.

Articles

Cardiology Review Online

Analysis of JNC-7 and trends in diabetes management

	NEW ORLEANS—Rimonabant maintains its efficacy for 2 years in reducing weight and waist circumference and improving the metabolic syndrome in overweight patients with a comorbidity. New phase 3 data presented at the American Heart Association Scientific Sessions 2004 confirm findings from two other recently completed trials in which overweight or obese subjects with untreated dyslipidemia or with or without comorbidities had significant weight loss and improved lipid and glycemic profiles with rimonabant treatment.

	“Patients treated with rimonabant, 20 mg, for 2 years experienced a reduction in body weight and in waist circumference, demonstrating a significant reduction in abdominal fat, a key marker for cardiovascular disease,” said the study’s principal investigator, F. Xavier Pi-Sunyer, MD, chief, division of endocrinology, St. Luke’s-Roosevelt Hospital Center, Columbia University, New York City. Over the 2-year period, patients treated with 20 mg/day “also achieved a significant increase in high-density lipoprotein (HDL) cholesterol, a reduction in triglycerides, and an improvement in insulin sensitivity.”

	Rimonabant, 5 or 20 mg once daily, was compared with placebo in a randomized study of 3,040 patients with a body mass index (BMI) of 30 kg/m2 or more or a BMI greater than 27 kg/m2 with a comorbidity. All patients were prescribed a mildly hypocaloric diet (daily caloric intake reduced by 600 kcal).

	Patients were randomly assigned to one of the three treatment groups for 52 weeks of double-blind treatment. After the first year, patients who received rimonabant were re-randomized to either the same dose of rimonabant or placebo for another 52 weeks.

	Among the completers at 1 year, waist circumference was reduced by 3.9 cm in patients assigned to pla-cebo, 4.7 cm in patients assigned to

	5 mg rimonabant, and 8.2 cm in those randomized to 20 mg rimonabant (P < .001 versus placebo). These differences were maintained at the 2-year follow-up.

	Almost two thirds (62.5%) of patients who received rimonabant, 20 mg, for 2 years lost 5% or more of their initial body weight, compared with 36.7% of patients on rimonabant, 5 mg, and 33.2% of the placebo recipients (P < .001 for rimonabant, 20 mg, versus placebo). Nearly one third (32.8%) of patients treated with the higher dose of rimonabant lost more than 10% of their initial body weight compared with 20% of those taking the lower dose of rimonabant and 16.4% of those taking placebo (P < .001 for rimonabant, 20 mg, versus placebo). At 2 years, HDL cholesterol levels increased by 24.5%, 15.6%, and 13.8% in the 20-mg rimonabant, 5-mg rimonabant, and placebo groups, respectively (P < .001). Triglyceride levels were reduced by 9.9%, 5.9%, and 1.6% in patients assigned to 20 mg of rimonabant, 5 mg of rimonabant, and placebo, respectively (P < .05).

	At baseline, 34.8% of patients assigned to the 20 mg rimonabant dose met diagnostic criteria for the metabolic syndrome, which was reduced to 22.5% at the end of 2 years of treatment (P < .001).

	At 2 years, the percentage of patients with any serious adverse events or discontinuations due to adverse events was no different between the three groups, and no differences were observed between groups in scores on the Hospital Anxiety Depression scale, said Dr. Pi-Sunyer.

	The study presented here is the largest of the rimonabant studies presented to date. Rimonabant works on the endocannabinoid system, which is believed to play a key role in the central and peripheral regulation of energy balance and glucose and lipid metabolism. 

Largest study of rimonabant: Improvements of CV risk factors  maintained at 2 years

	NEW ORLEANS—A new analysis of the Pravastatin or Atorvastatin Evaluation and Infection Therapy (PROVE IT) study shows that patients treated with an HMG-CoA reductase inhibitor (statin) who achieve the dual goal of low-density lipoprotein (LDL) cholesterol less than 70 mg/dL and a C-reactive protein (CRP) level less than 2.0 mg/dL have the best clinical outcomes, reported Paul M. Ridker, MD, MPH, at the American Heart Association Scientific Sessions 2004. Achieving both goals was more important than randomization to either aggressive or moderate lipid-lowering therapy in PROVE IT, said Dr. Ridker.

	In PROVE IT, 4,162 patients who had been hospitalized for acute coronary syndrome (ACS) within the previous 10 days were randomly assigned to intensive lipid-low-ering therapy with atorvastatin, 80 mg/day, or a moderate lipid-low-ering strategy with pravastatin, 40 mg/day. The mean LDL cholesterol achieved was 62 mg/dL in the patients assigned to atorvastatin versus 95 mg/dL in those assigned to pravastatin.

	The primary end point—a composite of all-cause mortality, myocardial infarction (MI), documented unstable angina requiring hospitalization, revascularization, or stroke&mdash;

	occurred in 22.4% of patients assigned to atorvastatin and 26.3% of those assigned to pravastatin (P = .005) at a mean follow-up of 24 months. The event rates translate into a 16% reduction in risk in patients treated aggressively relative to those treated less aggressively.

	As specified in the study protocol, plasma samples were obtained at 30 days, 4 months, and at study closeout to help define the relationship between achieved LDL cholesterol, achieved CRP levels, and the risk of recurrent cardiovascular events. The possibility of further therapeutic benefit among patients who achieved the dual target of LDL cholesterol less than 70 mg/dL and CRP less than 2.0 mg/dL was also explored.

	After 30 days of treatment, median LDL levels decreased by 22% in the patients assigned to pravastatin and 51% in those assigned to atorva-statin. At this time, median CRP levels were also significantly lower in the atorvastatin-treated patients compared with the pravastatin-treated patients. When the reduction in the risk of recurrent MI or coronary death was analyzed based on LDL cholesterol and CRP levels, the reduction in risk observed in patients with LDL cholesterol levels less than 70 mg/dL was nearly identical to the reduction in risk in patients with CRP levels lower than 2.0 mg/dL.

	Neither agent led to better clinical outcomes once both targets were reached, said Dr. Ridker, director of the Center for Cardiovascular Disease Prevention, Brigham and Women’s Hospital, Boston. The findings represent the first evidence to suggest that lowering CRP level by itself may lower the risk of adverse cardiovascular events.

	A second analysis of PROVE IT showed that patients with ACS benefit from high-dose statin therapy almost immediately, and these bene-fits persist over time. Aggressive lipid lowering resulted in a rapid reduction in clinical events, and was also associated with a significant reduction in risk in an analysis that began 6 months after the index ACS, reported Christopher P. Cannon, MD. The PROVE IT results demonstrate “a consistent benefit of high-dose statin therapy across the time continuum following an ACS,” said Dr. Cannon, associate professor of medicine, Harvard Medical School, Boston. The results also suggest that ACS patients “benefit from aggressive lipid-lowering even if they are remote from their index clinical event.”

	High-dose atorvastatin resulted in a rapid reduction in clinical events that reached 33% at 30 days for the composite of death, MI, and severe recurrent ischemia (P = .04). The benefits were apparent very early in the course of therapy; event curves began to separate within days after initiation of treatment and continued to separate throughout the first 30 days.

	The aggressive strategy also reduced clinical events in the analysis that began 6 months after the index ACS. Compared with standard-dose statin therapy, high-dose treatment was associated with an 18% reduction in the primary end point (P = .037). The event rates from 6 months to 2 years were 15% with high-dose atorvastatin and 17.7% with conventional-dose pravastatin. For the composite end point of death, MI, and severe re-current ischemia, the event rates from 6 months to 2 years were

	8.4% with high-dose statin therapy and 11.2% with the standard-dose therapy.

Dual LDL, CRP targets best for reducing clinical events

	NEW ORLEANS—Carvedilol has a neutral effect on glycemic control and improves components of the metabolic syndrome in patients with type 2 diabetes and hypertension who are already receiving therapy with a blocker of the renin-angiotensin system (RAS), said George L. Bakris, MD, at the American Heart Association Scientific Sessions 2004.

	Traditional beta blocking agents are usually avoided in patients with diabetes because they have been shown to worsen glycemic and metabolic control. The beta blocker carvedilol, which has antioxidant and alpha1 blocking properties in addition to its beta blocking effect, has been shown in previous trials to improve insulin sensitivity, said Dr. Bakris, director of the Hypertension/Clinical Research Center, Rush University Medical Center, Chicago.

	In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial, 1,235 patients with controlled type 2 diabetes (baseline glycosylated hemoglobin [A1c] of 6.5% to 8.5%) and stage I or stage II hypertension who were already receiving therapy with a RAS inhibitor were randomly assigned to carvedilol, 6.25 to 25.0 mg, or metoprolol tartrate, 50 to 200 mg, each given twice daily. The addition of hydrochlorothiazide, 12.5 mg, and a dihydropyridine calcium antagonist was allowed if needed to achieve blood pressure target. Blinded therapy was maintained for 5 additional months following titration to target blood pressure.

	The achieved blood pressure was similar between the two groups, with approximately two thirds of patients in each group reaching their target blood pressure. Mean treatment duration was shorter in the metoprolol compared with the carvedilol group (147 versus 155 days). “The difference in treatment duration was related to drug discontinuance due to a higher incidence

	of side effects in the metoprolol group,” said Dr. Bakris. Bradycardia occurred significantly more often in the metoprolol group (P = .007), and more patients assigned to metoprolol reported worsening diabetes than those assigned to carvedilol (trend; P = .07). Some 2.2% of metoprolol recipients withdrew owing to worsening glycemic control compared with 0.6% of carvedilol recipients (P = .04).

	The difference between the two groups in the mean change from baseline A1c was the primary end point. A1c increased by 0.15% (P < .001) in metoprolol recipients but

	did not change significantly ( 0.02%, P = .65) in patients allocated to carvedilol. The difference in A1c between the two treatment groups, 0.13%, was significant (P = .004).

	An increase in A1c of more than 1%, which has been associated with an increased risk of cardiovascular events, occurred in 14.2% of metoprolol and 7% of carvedilol recipients (P < .001). Insulin resistance by homeostatic model assessment improved significantly from baseline in patients assigned to carvedilol (—9.1%; P = .004) but not metoprolol (–2.0%; P = .48).

	The albumin:creatinine ratio was reduced by 16% (P = .003) in patients taking carvedilol compared with those taking metoprolol. Eighty percent of the patients did not have microalbuminuria upon entering the study. Among these patients, the risk of developing microalbuminuria was reduced by 47% with carvedilol relative to metoprolol (incidence: 6.6% versus 11.1%; P = .03).

	Metoprolol recipients gained a mean of 2.6 pounds compared with no significant weight gain in patients taking carvedilol (treatment difference: P < .001).

	“Carvedilol, in comparison to metoprolol, achieved blood pressure goal while maintaining glycemic control, improving insulin resistance, and reducing progression to microalbuminuria in these high-risk cardiovascular patients,” said Dr. Bakris.

Carvedilol improves insulin resistance, maintains glycemic control  in high-risk diabetic patients

	NEW ORLEANS—Two studies conducted exclusively in African Americans demonstrate the efficacy of rosuvastatin in dyslipidemic patients and the life-saving ability of nitric oxide—enhancing therapy in heart failure. The studies were presented at the American Heart Association Scientific Sessions 2004.

	In the African American Rosuvastatin Investigation of Efficacy and Safety (ARIES) trial, 774 African American adults with baseline low-density lipoprotein (LDL) cholesterol levels of 160 to 300 mg/dL were randomly assigned to rosuva-statin, 10 or 20 mg/day, or atorva-statin, 10 or 20 mg/day, for 6 weeks. Sixty-five percent of the ARIES population were women and 24.3% had diabetes.

	“We saw greater efficacy of rosuvastatin in mg-equivalent doses compared with atorvastatin,” said principal investigator Keith C. Ferdinand, MD, medical director, Heartbeats Life Center, New Orleans.

	In the study, 10 mg of rosuva-statin produced a 37.1% reduction in LDL cholesterol, compared with a 31.8% reduction produced by 10 mg of atorvastatin. At 20 mg, rosuva-statin reduced LDL cholesterol by 45.7% and atorvastatin reduced it by 38.5%. Furthermore, high-density lipoprotein (HDL) cholesterol was increased more with rosuva-statin, with the difference being significant between 10 mg of rosuva-statin and 20 mg of atorvastatin ( 7.0% versus  3.7%; P < .001), said Dr. Ferdinand.

	The percentage of patients who reached their Adult Treatment Panel III LDL cholesterol goal was examined by risk levels (low, medium, or high). More patients at each risk level reached their goal with rosuva-statin 20 mg than with atorvastatin 20 mg, with 63% of high-risk patients treated with the 20 mg dose of rosuvastatin reaching their goal compared with 27% of high-risk patients treated with atorvastatin, 20 mg.

	There were no cases of myopathy in either treatment group and no elevations in liver enzymes three times or greater above the upper limit of normal. “There were no cases of patients who had acute renal failure and no increase in serum creatinine; there was no evidence of any kidney disease or difference in new-onset proteinuria between the arms,” said Dr. Ferdinand.

	In the African-American Heart Failure Trial (A-HeFT), 1,050 self-identified African American patients with New York Heart Association  functional class III or IV heart failure were randomly assigned to a fixed dose of isosorbide dinitrate/

	hydralazine (20 mg/37.5 mg) or placebo in addition to standard heart failure treatments, including neurohormonal blockers.

	sodilatory effect by donating nitric oxide or forming related components, said lead investigator Anne L. Taylor, MD, associate dean for faculty affairs, University of Minnesota, Minneapolis. Hydralazine is an antioxidant that may protect against degradation of nitric oxide induced by oxidative stress.

	The study was stopped early owing to a significant survival benefit in the group assigned to the study drug, she said. At a mean of 10 months, a 43% improvement in survival was found in patients assigned to active treatment (P = .01). During this time, 6.2% of patients assigned to isosorbide dinitrate/

	hydralazine died compared with 10.2% allocated to placebo (P = .02). Isosorbide dinitrate/hydralazine was associated with a 33% reduction in the rate of first hospitalization for heart failure (P = .001) and a significant improvement in quality of life scores (P = .02).

	Nitric oxide bioavailability is impaired in African Americans compared with non-African Americans, noted Dr. Taylor. “Nitric oxide enhancement, which we think is the mechanism of action of this drug, is a new and potentially highly effective treatment for heart failure, especially in African Americans,” she said.

Studies demonstrate efficacy of CV medicines in African Americans

	HMG-CoA reductase inhibitors (statins) are well established for the treatment and prevention of vascular disease. A recent revision of the National Cholesterol Education Program “up-titrated” treatment goals, reflecting the growing evidence favoring more aggressive dosing and low-density lipoprotein (LDL) lowering. In general, statins are broadly applied to patients with vascular disease (coronary, carotid, peripheral) or those at risk for vascular disease (diabetic and hypertensive patients). The pleiotropic effects of statins (ie, to lower inflammation as measured by high-sensitivity C-reactive protein levels) are well recognized, but of unclear significance. Because the ability of statins to lower events is now fairly clearly related to LDL lowering, however, it is surprising that the article by Horwich and Fonarow (page 23) suggests that these drugs may modify left ventricular function and the heart failure syndrome itself, even favorably affecting survival, especially in patients with valvular, idiopathic, and noncoronary etiologies of heart failure.

	The authors briefly cite a wealth of basic and preclinical data that offer possible mechanisms for the effects of statins on heart failure and its manifestations. Their study and other similar retrospective reviews of heart failure populations seem to be consistent in suggesting benefit. These perspectives are inherently limited by their retrospective nature, however, a consideration that is especially important in the heart failure population. This is because serum cholesterol levels strongly influence physicians to prescribe statins, and patients with more clinically advanced heart failure, with worse nutritional states and more advanced cachexia, are likely to have lower cholesterol levels. Thus, they are less likely to be receiving statin treatment. Therefore, particularly in heart failure patients, not taking a statin may be a powerful marker of a “worse” syndrome and, hence, poorer survival. Multivariate analysis and propensity scores, at best, are weak modifiers of the current study’s findings, since heart failure severity has always been somewhat mysterious and not closely related to measured variables, such as ejection fraction and extent of coronary disease.

	Statins remain strongly indicated in any heart failure patient with vascular disease and probably in patients with diabetes or hypertension as well. However, there is now a large collection of effective medical therapies (angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, beta blocking agents, aldosterone inhibitors, and, of course, diuretics and digoxin) and devices (biventricular pacing defibrillators) to “comply” with before our efforts should be directed to starting statin treatment in patients with nonischemic cardiomyopathy.

Assessing the role of statins in heart failure

	A 72-year-old man with a history of coronary artery disease (CAD), coronary artery bypass graft surgery, diabetes, hypertension, and systolic dysfunction heart failure sought treatment for heart failure.

	The patient’s activity level had been severely limited during the past year, and he had stopped working in his retail business because of fatigue. After walking one to two blocks, he felt dyspneic and had to rest. He slept on two pillows but reported no paroxysmal nocturnal dyspnea or extremity swelling. There was no history of chest pain, lightheadedness, palpitations, or syncope. His medications included carvedilol, 25 mg twice a day; captopril, 50 mg three times a day; furosemide, 80 mg per day; spironolactone, 12.5 mg per day; enteric-coated aspirin, 325 mg per day; and glyburide, 10 mg a day. There had been no changes in his medical regimen in the previous 6 months. He carefully limited his salt and water intake.

	Results of physical examination showed a pulse of 69 beats per minute, blood pressure of 98/60 mm Hg, and respirations of 16 breaths per minute. The patient’s weight was 135 pounds, unchanged from previous measurements. He had mild truncal obesity. There was no jugular venous distention. His heart rate and rhythm were regular, with a 2/6 systolic murmur at the apex and a soft S3. The lungs were clear on auscultation. No lower extremity edema was present. The plasma brain natriuretic peptide (BNP) level was 1,910 pg/mL. The fasting lipid panel showed a total cholesterol level of 167 mg/dL, a low-density lipoprotein (LDL) cholesterol level of 105 mg/dL, a high-density lipoprotein (HDL) cholesterol level of 35 mg/dL, and a triglyceride level of 133 mg/dL. The creatinine level was 1.4 mg/dL, and the glycosylated hemoglobin level was 7.1%. Echocardiography showed a left ventricular end diastolic dimension of 50 mm and a left ventricular ejection fraction of 20% to 25%, with global hypokinesis and akinesis of the apex. Moderate mitral and tricuspid regurgitation was present.

	Cardiac catheterization with the potential for revascularization was discussed with the patient, but he was extremely reluctant to undergo any invasive procedures. He similarly declined implantable cardioverter—defibrillator therapy. Atorvastatin, 40 mg per day, was started.

	Six months later, the patient reported feeling less fatigued. He was able to return to work 1 to 2 days per week. His exercise capacity had increased to three to four blocks before shortness of breath occurred. Results of his physical examination were unchanged from the previous examination, except for the absence of S3 on cardiac auscultation. A repeated lipid panel showed a total cholesterol level of 139 mg/dL, LDL cholesterol level of 79 mg/dL, HDL cholesterol level of 35 mg/dL, and a triglyceride level of 129 mg/dL. The plasma BNP level was 234 pg/mL. Echocardiography showed an increase in left ventricular ejection fraction to 35% to 40%, with hypokinesis of the inferior wall and apex. The left ventricular end-diastolic dimension was 47 mm, and the mitral regurgitation was mild.

	This patient was treated with a statin drug for management of CAD and diabetes in the presence of severe ischemic cardiomyopathy and clinical heart failure, despite a baseline LDL cholesterol level close to the National Cholesterol Education Program Adult Treatment Panel III goal of below 100 mg/dL. He tolerated statin therapy well, and his functional capacity also improved. Echocardiography after 6 months of statin treatment showed some reversal of pathologic remodeling, as indexed by left ventricular end-dia-stolic dimension and left ventricular ejection fraction. Although it is possible that these improvements were unrelated to statin treatment, there had been no other recent changes in his heart failure medical regimen. In experimental models of heart failure, statins have limited remodeling and improved survival. Prospective clinical trials are warranted to further assess the role of statins in the treatment of heart failure.

Case report: Statin  therapy for an elderly heart failure patient

	From the Department of Medicine, Division of Cardiology, University of California, Los Angeles Medical Center, Los Angeles, California

	Morbidity and mortality in coronary artery disease (CAD) and other atherosclerotic vascular diseases have been shown to be reduced with HMG-CoA reductase inhibitor (statin) therapy.1-3 For patients with CAD, statins prevent the onset of heart failure.4 The impact of statin therapy on patients with established heart failure, however, has not been well studied.

	Potential risks and benefits of statin therapy in heart failure patients have previously been described. Low cholesterol levels are associated with a poor prognosis in advanced heart failure patients, which raises the issue of whether statins are safe in this population.5 Statins also lower the level of coenzyme Q, which may negatively affect ventricular function and exercise tolerance.6 However, the anti-ischemic actions of statins are clearly of potential benefit to patients with heart failure and CAD. Additional actions of statins, which may benefit both ischemic and nonischemic heart failure patients, include improvement in endothelial function, inhibition of inflammatory cytokines, increased nitric oxide synthesis, normalization of autonomic function, and reversal of pathologic myocardial remodeling.7-11

	Because of the uncertainty surrounding the use of statins in heart failure patients, we investigated the impact of statin therapy on survival in a large cohort of patients with advanced heart failure from various causes.

	Our cohort included 551 patients with a left ventricular ejection fraction of 40% or lower evaluated at a single university heart failure center between 2000 and 2002. Medications, which were determined by the patient’s heart failure physician or referring cardiologist, or both, were recorded at the initial visit and at every follow-up visit. A patient was considered to be taking statin therapy if the statin drug was started prior to referral or within 3 months of referral and continued during the study period. The primary end point was death or the need for urgent heart transplantation (status IA).

	Patients ranged in age from 18 to 84 years, and 45% of patients had heart failure from ischemic causes. Forty-five percent of patients were taking statin medication; 73% of patients with ischemic heart failure were receiving statins, compared with 22% of patients with nonischemic heart failure. The statins used included atorvastatin (n = 150), simvastatin (n = 56), pravastatin (n = 30), fluvastatin (n = 7), lovastatin (n = 5), and cerivastatin (n = 1). Only 1.2% of the population was receiving nonstatin lipid-lowering therapy. Patient characteristics, including characteristics of statin-treated and untreated patients, are shown in the table.

	Patients taking statins had significantly better survival free from death or urgent transplantation compared with patients not taking statins. The 1-year survival rate was 84% for the statin-treated group versus 70% in the no-statin group (hazard ratio [HR], 0.45; 95% con-fidence interval [CI], 0.30—0.67). The survival benefit was also seen at the 2-year follow-up; survival was 79% for patients treated with statins and 61% for those not treated with statins (HR, 0.47; 95% CI, 0.320.69). The significantly improved outcome associated with statins was seen in subgroups of both ischemic and nonischemic patients (figure 1).

	Statin therapy was an independent predictor of mortality after adjustment for demographic variables and other known predictors of prognosis in heart failure. Multivariate Cox regression analysis, which included sex, age, medications, heart failure cause, New York Heart Association (NYHA) functional class, hemoglobin level, creatinine level, and pulmonary capillary wedge pressure, showed that statins were associated with a lower risk of death or urgent heart transplantation at both the 1-year (HR, 0.41 [0.18—0.94]) and 2-year (HR, 0.43 [0.20–0.94]) follow-up. Improved outcomes associated with statin ther-apy were also seen in subgroups of the total cohort based on sex, cholesterol level, and receipt of heart transplant (figure 2). Rates of all-cause mortality (excluding transplant as an end point) were 11% and 18% in statin-treated and untreated patients, respectively (HR, 0.52; 95% CI, 0.30–0.90).

	Our data show a strong, independent association between statin treatment and improved survival for both ischemic and nonischemic heart failure patients. Statin therapy was associated with better survival despite the many poor prognostic factors in patients taking statins, including CAD, hypertension, diabetes, and smoking. Furthermore, a statin-associated survival advantage was observed in patients with both high and low cholesterol levels. There are several possible explanations for the improved survival associated with statin therapy in heart failure.

	CAD is a major cause of heart failure, and for patients with heart failure and CAD, the potential benefits of statins are well recognized. Statins promote stabilization of atherosclerotic plaques and thus reduce atherothrombotic events, which may account for a significant proportion of heart failure mortality. Although symptomatic heart failure patients were not included in the major clinical trials of statins,1-3 the antiischemic benefits of statins could reasonably be expected to apply to a heart failure cohort. An important piece of evidence comes from the Cholesterol and Recurrent Events (CARE) trial, in which subjects with decreased left ventricular ejection fraction obtained significant benefit from pravastatin, similar to subjects without left ventricular dysfunction.3

	The anti-inflammatory actions of statins may play a role in improving heart failure outcomes. Cytokines, such as tumor necrosis factor (TNF)-a and interleukin (IL)-6, have been associated with worse heart failure symptoms and increased heart failure mortality, and may play a pathophysiologic role in the progression of heart failure.12 Statins have been shown to decrease levels of both TNF-a and IL-6.13

	Recent experimental evidence from animals and humans suggests that statins may play a direct role in reversing the pathologic myocardial remodeling seen in both ischemic and nonischemic heart failure. In one study, subjects with idiopathic, dilated cardiomyopathy who were treated with simvastatin for 14 weeks had significant improvement in left ventricular ejection fraction and left ventricular end systolic volume compared with subjects treated with placebo.13

	Statins improve endothelial function, which is often impaired in heart failure, as characterized by increased vasoconstriction and decreased vasodilation. Endothelial dysfunction in heart failure contributes to decreased exercise capacity and end-organ dysfunction. Simvastatin treatment in idiopathic dilated cardiomyopathy was associated with improved endothelial function, as manifested by improved flow-mediated brachial artery vasodilation.13 Improvement in endothelial functioning is likely mediated through the ability of statins to stimulate the endothelium to produce nitric oxide.14

	Finally, statins may contribute to better heart failure outcomes by modifying and normalizing the overactive sympathetic nervous system of heart failure. Sympathetic nervous system activation in heart failure, manifested as increased norepinephrine levels, is associated with increased morbidity and mortality.15 In one study, rabbits with heart failure induced by rapid pacing treated with simvastatin had decreased norepinephrine levels and renal sympathetic nerve activity, as well as normalized baroreceptor responses.11

	It is safe to treat heart failure patients with statins, based on the results of our study. Our study also suggests that statin therapy may lead to improved heart failure outcomes. The survival advantage associated with statin therapy in our cohort occurred regardless of cholesterol levels or cause of heart failure. Statins may represent a new therapy for both ischemic and nonischemic heart failure. Ongoing randomized, controlled trials are needed to confirm this benefit.

Statin therapy  in heart failure

	The Charles J. and Margaret Roberts professor and chairman, Department of Preventive Medicine, Rush University Medical Center, Chicago, Illinois

	The Joint National Committee (JNC) began in 1972 under the auspices of the National High Blood Pressure Education Program, and the first guidelines, known as JNC I, were published in 1977. This report mentioned 28 drugs. The main message was that a diastolic blood pressure (DBP) higher than 105 mm Hg was the appropriate level to begin therapy, and diuretics were recommended as first-line therapy.

	JNC II, published in 1980, discussed 34 drugs and again, diuretics were recommended as first-line therapy. JNC III, published in 1984, discussed 42 drugs and reflected two major innovations. First, beta blocking agents were added to diuretics as appropriate first-choice therapy. Second, starting therapy at low doses was recommended.

	In the JNC IV guidelines, published in 1988, angiotensin-converting enzyme (ACE) inhibitors and calcium antagonists were added as first-line treatment recommendations. This generated some controversy since no clinical trial that showed a reduction in cardiovascular end points had been done with these drugs. In the JNC V guidelines, issued in 1993, there was a return to support of diuretics and beta blockers as first-line therapy unless there was a reason to use something else. In the JNC VI guidelines, published in 1997, all seven drug classes representing 84 drugs were recommended as potential first-line agents.

	One troubling trend at the time JNC VI was published was that both awareness and treatment of hypertension had declined from previous years, reversing a trend that had started in the 1970s. Hypertension awareness had gone from about 50% in the 1970s to 73% in the late 1980s, declining to 68% in the early 1990s. The number of patients receiving treatment for hypertension followed the same pattern, improving from about 30% in the late 1970s to 55% in the late 1980s, then falling slightly to 53% in the 1990s.1 Despite the growing number of drugs available to treat hypertension and the emphasis on the importance of hypertension control, only about one fourth of US citizens were at goal (< 140/< 90 mm Hg) through the mid-1990s, and the treatment-to-goal rates were even lower in older Americans, at 10% to 15%.2

	JNC VI included a matrix of five different classifications of blood pressure (BP)—normal, high-normal, and stages 1, 2, and 3. Absolute risk, as well as relative risk, was also taken into account within these classifications. Increasing relative risk was indicated by increasing BP and stages,

	and increasing absolute risk by the change from Risk Group A to B to C.

	Four points are worth noting regarding the JNC VI guidelines. First, if a patient was in Risk Group C (the highest risk group), defined by the presence of diabetes, renal disease, or heart failure (HF), drug therapy was recommended even if BP was in the high-normal range (130-139/85-89 mm Hg). No prior report recommended treating patients at that low level. Second, the term compelling indications was coined, meaning the use of certain agents for patients with certain complications. Third, in JNC VI, the discussion was no longer about so-called “sequential monotherapy.” Rather, adding drugs from other classes was advocated (“stepped-care”). Finally, hypertension specialists were mentioned for the first time.

	In my view, the overriding message of JNC VI was “go for goal and don’t settle for less.” Specifically, the goals of antihypertensive therapy were to achieve a BP of:

	• < 140/< 90 mm Hg for patients with uncomplicated hypertension

	• < 130/< 85 mm Hg for patients with diabetes, HF, or chronic renal failure

	• < 125/< 75 mm Hg for patients with ≥ 1 g proteinuria.

	These goals were not dependent on age, sex, or comorbidity.

	The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) was published in May 2003.3 Many new studies had been reported since the publication of the JNC VI guidelines, and the JNC 7 guidelines [note the change to Arabic numerals] needed to reflect the findings of these new studies. An attempt was also made to simplify JNC VI’s BP classifications and to provide clear, concise guidelines for clinicians.

	Studies that highlighted the need for new BP classification

	New Framingham data. A 14-year follow-up analysis of data from the Framingham study showed a continuous gradient of increasing cardiovascular (CV) risk across all three BP categories that were classified in JNC VI as high-normal (130 to 139/85 to 89 mm Hg), normal (120 to 129/80 to 84 mm Hg), and optimal (< 120/< 80 mm Hg).4 The JNC VI guidelines did not recommend treatment of patients in these BP categories except for high-normal patients in Risk Group C. In addition, the Framingham cohort study found that the lifetime risk of develop-

	ing hypertension (defined as systolic blood pressure [SBP] ≥ 140 or DBP ≥ 90) was greater than 90% in both men and women who were still normotensive at age 55 or 65.5

	Prospective Studies Collaboration. This study, which included more than 1 million subjects and 12 million person-years of follow-up in its analysis of data from 61 observational studies, examined the 34,000 deaths from coronary heart disease (CHD) that occurred in patients aged 40 to 89 years with SBP levels of 130 to 180 mm Hg.6 The researchers found a reduction in risk of CHD death for every 20-mm Hg decrement in baseline SBP; this reduction in risk ranged from 51% for patients aged 40 to 49 years to 33% in patients aged 80 to 89 years (figure 1). Similar results were observed for DBP. A significant reduction in CHD death risk was observed for every 10-mm Hg decrement in baseline DBP, with risk reductions ranging from 53% in patients aged 40 to 49 years to 30% in patients aged 80 to 89 years.

	due to stroke in patients aged 50 to 89 years showed a similar trend—each 20-mm Hg decrement in baseline SBP represented a 64% risk reduction in patients 40 to 49 years old and a 33% reduction in patients 80 to 89 years.

	Throughout middle and old age, usual SBP was strongly and directly related to vascular (and overall) mortality, without any evidence of a threshold to at least 115/75 mm Hg. An additional and equally important finding was that other risk factors—blood cholesterol level, diabetes, smoking, and weight&mdash;did not have any material influence on the proportional differences in vascular mortality associated with a given absolute difference in usual BP.

	Implications for JNC 7. These findings led to a new four-tiered BP classification system in JNC 7:

	• Normal: SBP < 120 mm Hg and DBP < 80 mm Hg

	• Prehypertension: SBP 120 to 139 mm Hg or DBP 80 to 89 mm Hg

	• Stage 1 hypertension: SBP 140 to 159 mm Hg or DBP 90 to 99 mm Hg

	• Stage 2 hypertension: SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg.

	These changes in BP meant that 22% of Americans who were previously classified as normotensive would now be classified as prehypertensive.7

	Studies that helped determine JNC 7 drug therapy recommendations

	Several studies published after JNC VI played a critical role in shaping the drug recommendations in JNC 7.

	Old Patients With Hypertension-2 (STOP-2) compared dihydropyridine calcium antagonists to ACE inhibitors and beta blockers/diuretics in more than 6,000 hypertensive persons over 6 years of follow-up. This study showed no clear advantage of one drug class over another.8

	NORDIL. The Nordic Diltiazem (NORDIL) study examined the effects of the nondihydropyridine calcium antagonist diltiazem compared with beta blockers/diuretics on CV morbidity and mortality in patients with hypertension. The study found no statistically significant differences between the effect of these drugs on the combined primary end point of fatal and nonfatal stroke, myocardial infarction (MI), and CV death.9

	LIFE. The Losartan Intervention for Endpoint Reduction in Hypertension (LIFE) study enrolled more than 9,000 patients with hypertension and left ventricular hypertrophy and compared two regimens, one that began with a beta blocker (atenolol) and the other with an angiotensin receptor blocker (ARB) (losartan). The losartan-based regimen resulted in lower levels of CV morbidity and death than the atenolol-based regimen. This was the first trial demonstrating the benefits of ARBs in a hypertensive population, although other studies in volunteers with diabetic nephropathy (Irbesartan in Diabetic Nephropathy Trial [IDNT], Reduction in Endpoints in Patients with Non-insulin-dependant diabetes mellitus with the Angiotensin II Antagonist Losartan [RENAAL]) had shown a reduction in end points in those subjects.10

	CONVINCE. The Controlled Onset Verapamil Investigation of Cardiovascular Endpoints (CONVINCE) trial compared the standard of care (diuretics or beta blockers) with the nondihydropyridine calcium antagonist verapamil in more than 16,000 patients with hypertension. When the study was stopped, there was no statistically significant difference in the occurrence of the primary end point (stroke, MI, or CV-related death) between the two treatment groups.11

	ALLHAT. The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) was one of the largest trials

	(n = 42,418 including doxazosin and n = 33,357 without that arm) and had a great influence on JNC 7 treatment recommendations. One analysis of this trial compared the effect of the calcium antagonist amlodipine with chlorthalidone and the ACE inhibitor lisinopril with chlorthalidone on a combined CV disease (CVD) end point, which included the development of HF, stroke, treatment for angina, and the need for coronary revascularization in patients with hypertension and at least one other CHD risk factor. The group receiving the ACE inhibitor had a 10% greater risk of a CV event and a 15% greater risk of stroke compared with those taking chlorthalidone.12 This difference was seen early in the trial and was maintained throughout the trial.

	In a subgroup analysis of patients who experienced stroke, mean follow-up SBP was found to be 2 mm Hg higher in all lisinopril recipients compared with chlorthalidone recipients, and 4 mm Hg higher in the 35% of African Americans in the study. The relative risk of stroke was 40% higher in African Americans than in non—African Americans in the lisinopril versus chlorthalidone comparison.

	ANBP-2. The Second Australian National Blood Pressure Study (ANBP-2) compared ACE inhibitors with diuretics and found that outcomes were slightly better in the ACE inhibitor group, but only in men and if all events were counted (HF, stroke, CVD, CHD), not simply  the first event as is customary.13

	Other studies. Taking the results of these individual trials a step further, Staessen and colleagues compared the results of older and newer clinical BP trials.14 Both the older and newer trials showed that lowering SBP, even by modest amounts, can have a significant impact on CV

	outcomes. For instance, the Heart Outcomes Prevention Evaluation (HOPE) showed that as little as a

	3-mm Hg difference in SBP between groups (ramipril versus placebo)

	can result in about a 25% decrease in CV event risk.

	The analysis by Staessen and colleagues revealed no consistent advantage with the use of any particular agent in terms of MI risk, a possible advantage for ARBs over other agents in terms of stroke risk, inferiority of calcium antagonists,

	a slight advantage for ACE inhibitors in terms of HF risk, and a clear disadvantage for alpha blockers for all CV events.

	The more recent Blood Pressure Lowering Treatment Trialists’ Collaboration found similar results15:

	• For CHD: no differences were observed in comparisons of ACE inhibitors or calcium antagonists versus diuretics and beta blockers,

	or ACE inhibitors versus calcium antagonists.

	• For stroke: ACE inhibitors were slightly inferior to diuretics/beta blockers and calcium antagonists; in turn, calcium agonists were slightly superior to diuretics/beta blockers.

	• For HF: diuretics/beta blockers were marginally superior to ACE inhibitors and clearly superior to calcium antagonists. ACE inhibitors were superior to calcium antagonists.

	• For all major CV events there were no marked differences between different drug classes.

	• ARBs appear to be superior for reducing the risks of HF and stroke and not inferior with respect to other CV outcomes (CHD, major CV events, CV death, total mortality) compared with other agents.

	the incidence of stroke, CHD, major CV events, and CV death, but not HF; there is a trend toward a reduction in all-cause mortality with SBP reduction.

	The results of clinical trials shed light on a key piece of the puzzle—namely, the utility of monotherapy in treating hypertension. Materson and colleagues showed that even with a modest DBP goal of less than 95 mm Hg, only about half of the study participants were able to achieve this goal after 1 year of monotherapy with any of the five classes of drugs studied (figure 2).16 In the Hypertension Optimal Treatment (HOT) study, 75% of subjects randomized to a DBP goal of less than 80 mm Hg needed more than one drug. Still, average BP in that subset was 140/86 mm Hg.17 Bakris and colleagues examined the number of antihypertensive drugs needed to reach target in several recent studies.18 The five major trials they examined showed that patients usually required three or four drugs to reach target BP. The percentage of patients requiring more than one drug was 63% in ALLHAT, 58% in the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), and 70% in the CONVINCE study. In spite of this ag-gressive therapy, DBP goal (< 90 mm Hg) was reached in 90% of subjects but only 60% achieved the SBP goal of less than 140 mm Hg. In a study conducted at our clinic, the average number of antihypertensive drugs taken per day by patients was four.19 Implications of recent studies Based on the findings from the individual drug trials published since JNC VI, as well as several meta-analyses, the following points can be made. First, the importance of decreasing BP to improve an individual’s CV health is clearly evident. Second, small decreases in BP can result in a large reduction in CV risk. Third, many different drugs are effective in reducing CVD risk. Finally, two or more drugs are typically needed to reduce elevated BP to target ranges. These new insights were incorporated into the JNC 7 guidelines (figure 3).3 Overall, the initial drug choices in JNC 7 are simpler than they were in JNC VI. Table 1 lists the classification and management strategy for BP in adults in the JNC 7 guidelines. Individuals with a BP less than 120/80 mm Hg are classified as normal. For patients with prehypertension (SBP 120-139 mm Hg or DBP 80-89 mm Hg), the recommendation is lifestyle modification to reduce BP and prevent the development of hypertension. Drug treatment is recommended only if a compelling indication, such as diabetes or chronic kidney disease, is present in patients in the prehypertension category. Drug recommendations for the compelling indications were based on results from clinical trials (table 2), usually not trials in hypertension but in those with typical complications of hypertension (HF) or with conditions seen often in hypertensives (diabetes). The drugs used in these trials, however, are drugs that are also used to treat hypertension.

	For patients with stage 1 hypertension (without a compelling indication), thiazide-type diuretics are the drugs of choice for most patients. For patients with stage 2 hypertension (without a compelling indication), the recommendation is to begin therapy with two drugs. For patients with compelling indications, the recommendation is to first treat the compelling indication, and if not at goal, add other drugs and consider consultation with a specialist.

	Finally, the goals of antihypertensive therapy in JNC 7 compared with JNC VI remained the same except for a 5-mm Hg lowering of the DBP in the second group listed below:

	• < 140/< 90 mm Hg for patients with uncomplicated hypertension • < 130/< 80 mm Hg for patients with diabetes, HF, or chronic renal failure, and the elimination of “< 125/< 75 mm Hg for those with proteinuria.” The African American Study of Kidney Disease did not confirm the benefit of the lower goal. These goals are not dependent on age, sex, or comorbidity.

	In summary, the key messages of the JNC 7 guidelines are as follows: SBP/DBP. For individuals older than 50 years, elevated SBP is a more important CVD risk factor than is elevated DBP. CV risk. CVD risk doubles with each 20/10-mm Hg increment greater than 115/75 mm Hg. Individuals who are normotensive at age 55 or 65 have a more than

	90% lifetime risk of developing hypertension.

	Prehypertensive classification. Individuals with an SBP of 120 to 139 mm Hg or a DBP of 80 to 89 mm Hg are classified as prehypertensive. These individuals face an increased risk of future hypertension and should adopt health-promoting lifestyle modifications to prevent CVD.

	Drug therapy recommendations. Thiazide-type diuretics should be used as initial drug therapy for most patients with uncomplicated hypertension, either alone or in combination with agents from other drug classes.

	Compelling indications. Certain high-risk conditions, including MI, HF, diabetes, and chronic kidney disease are compelling indications for the use of other types of antihypertensive agents (ie, ACE inhibitors, ARBs, calcium antagonists, beta blockers).

	Combination drug therapy. Most patients with hypertension will require two or more drugs to reach goal BP (< 140/90 mm Hg; < 130/80 mm Hg for patients with diabetes and/or renal disease). If BP is more than 20/10 mm Hg above goal, initiate drug therapy with agents from two classes, one drug choice usually being a thiazide-type diuretic.

	Cardiology Review: What’s the rate of progression to hypertension in the group of individuals classified as prehypertensive?

	Dr. Black: From the Framingham data, we’ve learned that the rate of progression without intervention is about a 10/5-mm Hg increase over about 14 years. This is the group we’re trying to turn around…trying to get people thinner, to consume less salt, and to be more active to try to slow the progression. I don’t think we can prevent it entirely.

	The Trial for Preventing Hypertension study is an interesting ongoing study in prehypertensive subjects which is now almost finished. In this study, half the participants are being given the ARB candesartan and half are given placebo for 2 years. Then the patients on the ARB will be taken off of it for the last 2 years of the study to determine if we can change the natural history of hypertension.

	Cardiology Review: How would you manage an elderly patient with a BP of 160/60 mm Hg?

	Dr. Black: I’d be very careful, but I would still treat them. The initial DBP in the Systolic Hypertension in the Elderly Program was 77 mm Hg. It was reduced to 69 mm Hg on average, and strokes were reduced about 40%. So in totality, that group is going to benefit. If there was a group in which treatment could be particularly troublesome, it was those few with DBP less than 60 mm Hg.

	Getting SBP down is difficult with our current medicines, and all we’ve been able to do, both in CONVINCE and ALLHAT, is get about 60% of patients to goal.

	Cardiology Review: What do you think of the idea of taking a more aggressive approach in prehypertensive patients, namely, putting them on an inexpensive drug like hydrochlorothiazide, if there are no contraindications, to keep BP from getting to 140 mm Hg?

	Dr. Black: It’s hard to get the risk-benefit in your favor in people with very low risk unless you use a drug that’s very safe. When it comes to antihypertensives, I think only two classes of drugs would, in fact, meet that criterion, and diuretics are not necessarily one of them. There are some problems with diuretics and certainly with ACE inhibitors. I think ARBs and calcium antagonists meet the criteria. ARBs are extremely well tolerated, and calcium antagonists have nuisance side effects. You don’t see potentially serious problems, such as angioedema, asthma, or gout from these agents, and that’s something that we need to think about if we’re going to take an approach to reduce BP in low-risk people.

	Cardiology Review: Do you have any insights into how insurance companies are going to address the prehypertensive category?

	Dr. Black: As many of us suspected, we found that the industry does not care what we label somebody. The insurance industry has their own actuaries, and they calculate risk the way they want, regardless of our label.

	Cardiology Review: Is the meta-bolic syndrome addressed in the guidelines?

	Dr. Black: It is. We discuss it but don’t recommend treating the prehypertensive subject with signs of the metabolic syndrome unless a compelling indication is present. I don’t think we have evidence yet that treating metabolic syndrome per se, if it hasn’t led to diabetes, is going to be beneficial.

JNC 7 treatment   guidelines: Goals and  recommendations

	Over the past decade, landmark clinical trials have established the value of a multifaceted approach to the care of patients with type 2 diabetes mellitus.1-3 Guidelines have been emerging, which include keeping blood pressure below 130/80 mm Hg, glycosylated hemoglobin below 7%, and low-density lipoprotein cholesterol below 100 mg/dL. In a recent 7-year study in Finland, cardiovascular events were reduced by approximately 50% when patients received the appropriate medications and were counseled in smoking cessation, exercise, and dietary changes.4

	The Diabetes Prevention Program (DPP) studied reductions in the incidence of type 2 diabetes in those with impaired glucose tolerance.5 Diet and exercise reduced the incidence of diabetes by almost 60%, much more than was achieved with metformin treatment.

	Grant and colleagues (page 17) studied diabetes care in primary care physician practices. They noted that the number of medications needed has increased to at least five, and patients also require time for diet and exercise counseling at each visit. Despite the increased complexity of diabetes care, time with patients increased by only 2 minutes per visit. As shown in the case study, primary care physicians are often slow to change medications and postpone decisions on medication adjustments until the next visit. In the case study, metformin treatment should have been discontinued because the patient’s serum creatinine was over 1.3 mg/dL. Furthermore, there is often a discrepancy between the medications that are prescribed for a patient and the medications that are actually taken.

	The current model of diabetes care focuses on the primary care physician. With the increasing complexity of diabetes care, the number of interventions required by the primary care physician is becoming overwhelming. Clearly, the primary care physician needs help. How do we begin to fix our model of diabetes care? Here are some steps that may be taken to improve it:

	Flow sheets. In the office, flow sheets are an essential tool for organizing procedures to reflect the established guidelines of care. Flow sheets may be used to track laboratory values, current medications, and foot and eye examinations. Flow sheets give the physician a quick overview of patient progress and goals to be achieved.

	Diabetes education. Referrals for diabetes education need to be made soon after the patient presents with type 2 diabetes. Insurance plans are increasingly recognizing the importance of education and are approving both classes and individual instruction by diabetes educators. Repetition is often necessary for behavior to change. Valuable follow-ups may be provided by nurse extender calls to review medications and health habits and identify problems that interfere with good diabetes care. Many insurance com-panies already provide this service.

	A further enhancement of the reinforcement process might be video conferencing with an educator individually or in groups, in a provider’s office or even in a patient’s home.

	Specialists. It is important to refer patients to specialists early in the treatment of type 2 diabetes to maximize treatment options.

Improving the model  of diabetes care

	A 68-year-old woman with type 2 diabetes arrived at her primary care physician’s office with a plastic bag full of pill bottles and the primary symptom of hip and knee pain. She had hypertension, hyperlipidemia, mild renal insufficiency, and arthritis, and had had a silent myocardial infarction 4 years earlier.

	The patient’s primary care physician was running late, but was able to see her for a 15-minute follow-up appointment. Her blood pressure was 148/88 mm Hg, her pulse

	was 72 beats per minute, and she was afebrile. Her most recent laboratory results from 6 months earlier included a glycosylated hemoglobin (A1c) level of 7.8%, creatinine level of 1.4 mg/dL, total cholesterol level of 211 mg/dL, and low-density lipoprotein cholesterol level of 112 mg/dL. Her medical regimen included metformin, glyburide, atenolol, lisinopril, atorvastatin, enteric-coated aspirin, naproxen, and acetaminophen.

	The patient’s primary concern was her chronic hip and knee pain, which began several years earlier. Her current regimen was not helping, but she declined a referral for physical therapy. She was also unsure whether she should continue her atorvastatin because she had read that it might contribute to muscle pain.

	Mindful of the time, her primary care physician examined her briefly. He found no evidence of effusion, crepitus, or active inflammation, although she had limited range of motion of her knees and hips. He recommended stopping the naproxen and starting ibuprofen, and again recommended physical therapy.

	The next 5 minutes were spent reconciling discrepancies between her charted medication list and the pill bottles she had brought to the office. Her primary care physician decided to spend the last part of the visit emphasizing the importance of lipid-lowering therapy in terms of future cardiovascular risk reduction and reassuring her that the atorva-statin was not likely to be contributing to her arthritic pain. Rather than making any medication adjustments during the current clinic visit, the primary care physician chose to take a repeated fasting lipid panel and A1c level, and to check her blood pressure again at the next visit.

	It can be a challenge to carry out evidence-based guidelines of care in the setting of limited time and competing demands. Moreover, with increasing medical regimen complexity, more time is required to review medication adherence and side effects. Structured care models that include group visits, collaboration with diabetes educators and nurse practitioners, and problem-focused visits may offer a solution to the traditional ambulatory model of care.

Case report: A diabetic with multiple medications and chronic pain

	From the General Medicine Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts

	Over the past decade, clinical trial results have shown the importance of aggressive treatment of hyperglycemia, hypertension, and hyperlipidemia for patients with diabetes.1-3 Evidence-based diabetes care now requires several medications to reduce the risk of microvascular and macrovascular disease complications. During this same period, budget constraints have increased the pressure on physicians to see more patients in less time. We used the National Ambulatory Medical Care Survey (NAMCS) to assess trends in the United States from 1991 to 2000 regarding the complexity of outpatient medical regimens, provision of recommended diabetes-related preventive services, and visit length for patients with diabetes.

	Conducted by the National Center for Health Statistics, the NAMCS collects data from US office-based physicians each year. As part of this program, the physician or a clinic staff member records for each visit such information as diagnosis, medications used, services provided, and length of the visit (defined as time spent by the physician in face-to-face contact with the patient). We analyzed visits to internists, family physicians, and general practitioners by adult patients with diabetes older than 18 years of age. From 1991 to 2000, the annual weighted sample of visits by patients with diabetes ranged from 374 to 631, corresponding to approximately 15 million to 26 million annual visits nationwide.

	We evaluated the proportion of visits from 1991 to 2000 during which at least five medicines were listed and categorized medications used to treat hyperglycemia, hypertension, and hyperlipidemia. We also evaluated the proportion of visits during which blood pressure monitoring, cholesterol testing, and counseling regarding diet, exercise, and smoking cessation were provided, as well as the trends in visit length over the decade. We used logistic regression models to control for differences in patient characteristics from year to year when comparing trends in care over time.

	Patient characteristics. The sample of 4,708 primary care visits by patients with diabetes from 1991 to 2000 represented a population average of 19.6 million visits per year. Patients had a mean age of 62.4 (± 12) years; 55% of patients were women, 32% were of nonwhite race/ethnicity, and 87% had type 2 diabetes.

	Changes in medical regimen complexity. In 2000, 29.9% of patients were prescribed five or more medications, which had increased in

	(P for trend < .001). There was also a marked increase in the number of patients prescribed four or more medications (25.9% in 1991 compared with 43.9% in 2000; P < .001) or at least three medicines (40.4% in 1991 compared with 55.2% in 2000; P < .001; figure 1).

	Although the overall proportion of patients taking any glucose-controlling medicines did not change significantly (62.5% of visits in 1991 compared with 65.8% of visits in 2000), annual visits with insulin listed decreased markedly, from 25.3% of visits in 1991 to 15.3% in 2001 (P < .001 for annual trend). The visits listing oral agents, however, increased considerably, from 37.2% to 50.5%

	(P < .001). After the 1995 approval of metformin in the United States, the annual proportion of visits listing two or more glucose-controlling agents increased significantly from 1.2% in 1995 to 17.1% in 2000.

	Use of antihypertensive medicines increased from 35.9% to 42.3% (P < .001) over the decade. From 1991 to 2000, the percentage of visits listing angiotensin-converting en-zyme (ACE) inhibitors and angiotensin receptor blockers increased from 9.3% to 25.7% (P < .001). The proportion of visits listing more than one antihypertensive agent, however, did not show a significant change (8.7% in 1991 compared with 11.7% in 2000). As shown in figure 2, the percentage of visits listing lipid-lowering medicines (fibrates, niacin, resins, and HMG-CoA reductase inhibitors [statins]) increased from 4.1% to 17.3% (P < .001), a considerable change.

	The percentage of patient visits listing five or more medications increased by 10.6% per year (95% confidence interval [CI], 6.0%—15.0%; P < .001) after controlling for diabetes type, physician type, age, sex, race/ethnicity, and insurance status. Annual insulin use decreased (6.3% decline per year; 95% CI, –10% to –2%; P = .002), ACE inhibitor use increased (12.9% increase per year; 95% CI, 9%–16.9%; P < .001), and lipid-lowering medicine use increased significantly (19.1% increase per year, 95% CI, 14%–24%, P < .001), using similar regression models controlling for patient and physician characteristics.

	Preventive services and visit duration. We assessed trends in blood pressure monitoring, cholesterol testing, and lifestyle counseling over the past decade to see whether increasingly complex medical regimens resulted in decreased time spent providing other diabetes-related services. The annual proportion of visits with blood pressure monitoring (84.3% of total visits, ranging from 78.2% of visits in 1992 to 93.8% in 1993) remained stable, as did visits with diet counseling (48.3% of total visits, ranging from 42.8% in 1991 to 53.5% in 1997), smoking cessation counseling (4.4% of total visits, ranging from 2.7% in 2000 to 7.2% in 1994), and cholesterol testing (12.1% of total visits, ranging from 8.0% in 1996 to 18.4% in 2000). Exercise counseling was provided in 22.1% of visits in 1991, compared with 31.9% of visits in 2000 (P = .01).

	From 1991 to 2000, there was a modest increase (2.2 minutes) in

	visit length for patients with diabetes, from a mean of 17.1 (± 8.0) minutes in 1991 to 19.3 (± 8.2) minutes in 2000 (P < .001). During the study decade, there was no change in the median visit length (15 minutes); 17.8% of visits lasted more than 20 minutes in 1991, whereas 20.9% of visits lasted more than 20 minutes in 2000 (P = .02).

	The NAMCS analyzes visit-based information from a broad spectrum of US primary care providers annually, thereby allowing the characterization of nationwide trends in care over time. Using this survey, we found that from 1991 to 2000 the outpatient care of patients with diabetes had become significantly more complex. More patients were prescribed multiple oral hy-poglycemic drugs, and more patients were treated for hypertension

	and hyperlipidemia. Despite this increasing complexity in medication management, we found no com-pensatory decrease in visits during which other major diabetes-related services were provided. Blood pressure monitoring, cholesterol testing, and diet and smoking cessation counseling were unchanged, and there was actually an increase in the proportion of visits with exercise counseling.

	The development of new medications for the control of cardiovascular risk factors and the adaptation of clinical trial data and practice guidelines to community practice are most likely the reasons for the significant increase in the number of patients taking five or more medications. There is a continuing need, however, for an even further increase in therapy to reach current evidence-based goals of control, based on current rates of cardiovascular risk and glycemic control.4 Despite newer guidelines recommending even lower goals for low-density lipoprotein levels for these patients, cholesterol testing and lipid-lowering medicines, in particular, were each still listed for fewer than 20% of visits in 2000.5 More aggressive treatment of hyperlipidemia is needed because more than half of diabetic patients have this cardiovascular risk factor when tested.4,6

	The national rates for effectively controlling hypertension are low.7 When increases in therapy for hypertensive patients are made, they are often inadequate.8 In clinical trials, most hypertensive patients require more than one medication, and over a third require three medications to achieve adequate control.9,10 Our data indicate that most patients are unlikely to be receiving this level of aggressive therapy in community practice.

	We also found a marked change in insulin use compared with oral therapy. The introduction of newer oral agents (particularly metformin11), which can be used in conjunction with other glucose-lowering medicines, is likely the reason for the increase in oral therapy. This change, however, has not brought about significant improvement in glycemic control. Current glycosylated hemoglobin (A1c) goal levels are met by fewer than half of patients with diabetes.4

	Our study showed no change in median visit length and a slight increase in the proportion of visits over 20 minutes long. Although care is clearly more complex based on prescription of medications, we do not know how many different visits an individual patient made in a given year. It is possible that individual patients are being seen more frequently in later years.

	High productivity levels and increasingly complex care are required of primary care physicians who treat patients with diabetes mellitus. Phy-sicians must prescribe more medications and make more frequent adjustments in dose to help their patients achieve lower goals for hemoglobin A1c levels, blood pressure, and low-density lipoprotein cholesterol levels. The increasing complexity of care and the limited time available during clinic visits to address all aspects of this care may be resulting in difficulty in reaching evidence-based goals of diabetes care. Major changes in the current approach to visit-based ambulatory diabetes care may be needed to attain in the community the success of treatment attained in clinical trials.

December 2004

Analysis of JNC-7 and trends in diabetes management

Largest study of rimonabant: Improvements of CV risk factors maintained at 2 years

Dual LDL, CRP targets best for reducing clinical events

Carvedilol improves insulin resistance, maintains glycemic control in high-risk diabetic patients

Studies demonstrate efficacy of CV medicines in African Americans

Assessing the role of statins in heart failure

Case report: Statin therapy for an elderly heart failure patient

Statin therapy in heart failure

JNC 7 treatment guidelines: Goals and recommendations

Improving the model of diabetes care

Case report: A diabetic with multiple medications and chronic pain

Diabetes care in the United States

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