Once again, the Scientific Session provided a breadth of new information and further illumination in many areas of cardiovascular medicine. Provided here are some of the highlights that have the potential to affect clinical practice.

Same old risk factors, new insights

Lipids. The Treating to New Targets (TNT) lipid-lowering trial showed that reducing LDL-cholesterol to 75 mg/dL yields even greater reductions in cardiovascular events. This is the first clinical trial to achieve this level of aggressive lipid lowering. The current NCEP guidelines recommend lowering LDL-C to 100 mg/dL. A 22% relative risk reduction for major cardiovascular events and a 25% relative risk reduction for stroke were found in the atorvastatin 80 mg group, compared to the atorvastatin 10 mg group.

The mean lipid levels (mg/dL) during the randomized, double-blind phase were:

In TNT, patients with clinically evident CHD (average age 61 years, 81% male, 94% Caucasian, 54% hypertensive, 15% diabetic) underwent an initial 8-week run-in period, during which they were treated with atorvastatin 10 mg/day to reduce their LDL-C to 130 mg/dL or lower. Then, they were randomized to either atorvastatin 10 mg/day (5006 patients) or atorvastatin 80 mg/day (4995 patients), and were followed for an average of 5 years. The primary endpoint was the occurrence of a major cardiovascular event (CHD death, nonfatal MI, resuscitated cardiac arrest, and fatal/nonfatal stroke).

Another study showed that a noninvasive test of cholesterol content in the skin identifies subclinical atherosclerosis in apparently healthy persons. Dr. Wendy S. Tzou, University of Wisconsin Medical School, presented study results in 81 subjects (mean age 55 years, mean cholesterol 95.9 units) showing that the newly available skin cholesterol test was comparable to the accepted standard of ultrasound testing of carotid intima media thickening in identifying disease, even when controlling for the most common risk factors, including Framingham risk score. This

Hypertension. A large health survey conducted over 20 years in the state of Minnesota by Russell V. Luepker, University of Minnesota, and colleagues showed that although the detection and treatment of hypertension is improving, nevertheless, only 44% of men and 55% of women had blood pressures below 140/90 mm Hg. The researchers randomly selected adults (aged 25-74 years) in the two largest cities in the state (Minneapolis and St. Paul) every 5 years to conduct blood pressure checks, medication inventories, and other health assessments for the Minnesota Heart Survey. A nearly 2-fold increase in the rate of blood pressure treatment and control was found over the study period.

Arterial inflammation and hypertension are significantly linked, according to results from a study of some 600 Alaskan natives (mean age 43, 45% male). Dr. Jianhui Zhu, Washington Hospital Center, Washington DC, explained that 21% of the group had hypertension (BP ≥140/90 mm Hg or taking medication) and these subjects had significantly higher levels of C-reactive protein (CRP) and homocysteine, compared to normotensives. The positive association between elevated levels of CRP and homocysteine remained after adjusting for other risk factors. Further, an association between elevated levels of homocysteine and evidence of bacterial infection was found, suggesting a possible link between infection, inflammation, and cardiovascular risk.

Diabetes. Increased arterial inflammation was also found in association with poorly controlled diabetes, and further, a significantly increased risk of myocardial infarction (MI) or death. Dr. Kausik K. Ray, Brigham and Women’s Hospital, Boston, and colleagues found serum C-reactive protein (CRP) levels were significantly higher in diabetic patients with acute coronary syndrome, and that the elevated CRP level was related to the increased risk of events. A 2-fold increase in the risk of MI or death was found in the patients with an abnormal CRP level and a blood glucose level in the highest tertile, compared to diabetic patients with a normal CRP and blood glucose in the lowest tertile. The investigators studied the patients in the OPUS TIMI 16 and TACTICS-TIMI 18 trials for this analysis.

Pioglitazone is not only effective as an oral diabetic drug, but also reduces neointima formation after stent implantation in nondiabeticpatients, without alterations in metabolic parameters. Glitazones had been shown to have anti-atherogenic effects in animal studies and clinical trials have shown this class of agents to be effective in reducing neointima formation after percutaneous intervention in type 2 diabetes. Dr. Nikolaus Marx, University of Ulm, Germany, and colleagues conducted the randomized study in 50 nondiabetic patients to determine the efficacy of these agents in this patient population.

Shortness of breath in patients with diabetes was as effective in identifying a myocardial infarction as chest pain, in a study comparing patients who presented to hospital complaining of chest pain and shortness of breath. Dr. Su Min Chang, University of Wisconsin, explained that all patients underwent myocardial perfusion imaging to evaluate myocardial blood flow and nearly one-half had an arterial x-ray to detect coronary artery narrowing.

Overweight. The latest study from the large, international RIO study program, showed that the canabinoid receptor blocker rimonabant maintained weight reductions achieved at 1 year in the study and resulted in further reductions in weight and waist circumference at 2 years. The RIO-Europe study randomized patients to rimonabant 20 mg/day group (n=599), rimonabant 5 mg/day group (n=603) and placebo group (n=305) and a reduced calorie diet. The patients were 80% female, 38% had hypertension, 40% had metabolic syndrome, and 62% had dyslipidemia.

At 2 years, weight loss in the rimonabant group was 7.3 kg and 4.7 kg in the placebo group. At 1 year, the weight loss in the rimonabant group was 1.5 kg, for a total weight loss at 2 years of 8.7 kg. The waist circumference was reduced by 3.4 cm in the placebo group and 5.3 cm in the rimonabant 5 mg group (p<0.023 versus placebo), and 7.5 cm in the rimonabant 20 mg group (p<0.001 vs placebo). Weigh loss ≥10% at 1 year was achieved by 12.4% of the placebo group and 39% of the rimonabant groups, and at 2 years by 32.1% of the rimonabant groups.

With rimonabant, there was a 10% improvement in the HDL-C, and an 8.8% reduction in triglycerides compared to a 10% increase in the placebo group. The improvement in metabolic syndrome seen at 1 year was maintained at 2 years. The safety profile was good.

Women and heart disease

Vitamin E. Vitamin E supplementation for an average of 10 years in apparently healthy middle-aged women did not significantly reduce the risk for major cardiovascular events, in the large-scale Women’s Health Study (WHS). Specifically, there was no reduction in total stroke or myocardial infarction, no increase in hemorrhagic stroke, and a reduction in observed cardiovascular death. No significant increase in total all-cause mortality, major bleeding, or gastrointestinal symptoms. Dr. Julie E. Burling, Brigham and Women’s Hospital, Boston, concluded that based on all the published data on vitamin E and cardiovascular risk, there is no evidence to support the use of vitamin E supplementation to prevent cardiovascular disease, and that the best approach to prevent heart disease is to maintain a healthy diet within a healthy lifestyle that controls other known risk factors.

The WHS is a randomized, double-blind, placebo-controlled study that assessed the benefits of vitamin E supplementation and low-dose aspirin for primary prevention of cardiovascular disease and cancer in 39,876 female health professionals over 45 years of age, who were monitored for 10 years for the first major cardiovascular event, including MI, stroke, and cardiovascular death. The study is funded by the National Heart, Lung, and Blood Institute and the National Cancer Institute.

Aspirin. In the aspirin study of WHS, low-dose aspirin (100 mg orally every other day) significantly reduced the risk of total stroke by 17%, ischemic stroke by 24%, and TIA by 22%. Notably, however, for the primary endpoint of first major cardiovascular event (nonfatal MI, nonfatal stroke, cardiovascular death), a non-significant 9% relative risk reduction with aspirin for the primary endpoint (occurred in 477 women in placebo group, 522 women in aspirin group; relative risk 0.91; p=0.13) was found. This is in contrast to results with low-dose aspirin treatment in men. For MI, there was no significant difference between groups (193 in placebo group and 198 in aspirin group, relative risk 1.02; p=0.83).

In women over 65 years old, a significant reduction in total cardiovascular events (26%), ischemic stroke (30%), and MI (34%) was found. This subgroup comprised 10% of the study population and suffered one-third of the total cardiovascular events.

WHS: Occurrence of Primary Endpoints by Age Subgroup Analysis

Overall in WHS, low-dose aspirin was associated with a significant increase in risk of gastrointestinal hemorrhage requiring transfusion, and a nonsignificant increase in hemorrhagic stroke.

In the aspirin arm were 19,934 women and in the placebo arm was 19,942 women. On average, the women were 54 years old, 13% were smokers, 54% postmenopausal, 26% had hypertension, 29% had hyperlipidemia, and 3% had diabetes. The Framingham 10-year risk was less than 5% in 84%, 5% to 10% in 11% of women, and more than 10% in 4% of women.

Dr. Paul Ridker, Brigham and Women’s Hospital, who presented the WHS aspirin study results, said that “From a clinical standpoint, the new data suggest that many women, particularly those over the age of 65, are likely to attain a net benefit from preventive aspirin therapy. However, as with men, women considering the use of aspirin to prevent cardiovascular disease must balance both benefits and risks, and thus should consult with their personal physician before beginning therapy.” Buring noted that “the WHS overwhelmingly demonstrates the importance of studying medical therapies among women as well as men. We finally have the evidence based needed for women to make rational decisions about the use of aspirin in preventing cardiovascular disease.”

Anemia and Inflammation. The WISE (Women’s Ischemic Syndrome Evaluation) study showed that a multimarker approach that includes tests for inflammation and anemia improves the evaluation of women suspected of having heart disease. Dr. Christopher B. Arant, University of Florida, Gainesville, Florida, said that the researchers documented the serum levels of inflammatory markers C-reactive protein, interleukin-6 and serum amyloid, and hemoglobin over a 3.6 year follow-up. A linear increase between the risk of cardiovascular illness or death and the increased number of abnormal biomarkers was found. One abnormal biomarker was associated with a 90% increased risk, and four abnormal biomarkers with a 5-fold increased risk. Of the 595 women studied (mean age 58 years), 55% had hypertension, 26% diabetes, and 58% dyslipidemia.

Treadmill testing. Exercise treadmill testing is less effective than myocardial perfusion imaging in identifying women more likely to experience a serious cardiovascular illness, among women at moderate to high risk for heart disease, according to a study presented by Dr. Justin B. Lundbye, HOSPITAL.

Additional clinical benefits with statins

Two studies have shown that statins improve survival in patients with heart failure. A retrospective case-control analysis of data from some 32,000 U.S. veterans (mean age 62 years) with heart failure showed a 10% multivariate adjusted lower risk of heart failure death in the patients taking a statin compared to those not taking a statin, Dr. Sathya Jaganmohan, Overton BrooksVAMedicalCenter, Shreveport, Louisiana.

The COMPANION (Comparison of Medical Therapy, Pacing and Defibrillation in Chronic Heart Failure) study previously reported that cardiac resynchronization therapy improved survival. A retrospective multivariate analysis from this study now shows that patients taking a statin had a 28% risk reduction for all-cause mortality than the patients not taking a statin, said Dr. Andrew D. Sumner, Penn State College of Medicine. The analysis included 1520 patients (66 years old, 68% male, 40% used statins). All-cause mortality was 18% in the statin group and 22% in the nonstatin group.

Another analysis from the PROVE IT TIMI-22 trial, reported by Dr. Kausik K. Ray, Brigham & Women’s Hospital, showed that intensive statin therapy, compared to standard-dose therapy, was more effective in reducing serum CRP levels in 3507 patients with acute coronary syndrome. The study drugs were pravastatin (40 mg) and atorvastatin (80 mg), and the benefit was shown across a variety of subgroups, including over 65 years of age, female gender, obesity, smoking, diabetes, high serum glucose levels, and low serum HDL-cholesterol levels.

A substudy from the previously reported REVERSAL (Reversal of Atherosclerosis with Aggressive Lipid Lowering) study with 653 subjects, reported by Dr. Robert A. Vogel, Cleveland Clinic Foundation, showed that atorvastatin and pravastatin improved arterial function. For this substudy, brachial artery flow-mediated dilation and nitroglycerin-mediated dilation were assessed by high-resolution ultrasound before and 3 months after randomization to the two study drugs. Notably, a close linear relationship between improvement in endothelial function and reduction in LDL-cholesterol was found.

Improvement in ICD therapy

The OPTIC (Optimal Pharmacological Therapy in Implantable Cardioverter Defibrillator Patients) study showed that amiodarone plus a beta blocker had a 10% reduced annual risk of shock, compared to a 24% risk with sotalol plus a beta blocker, and 39% for a beta blocker alone. The study examined 412 patients implanted with a St. Jude Medical dual chamber ICD for life-threatening arrhythmias. The pain associated with shock delivery has been a serious limitation in the use of this therapy. “The pain that comes when 700 volts go off in the chest is very upsetting to patients,” said Dr. Stuart J. Connolly, McMaster University, Canada. This study shows that shocks are very common in these patients, and that amiodarone is really effective in reducing their number. The results represent a huge reduction in shocks and a big improvement in quality of life.”