Dark Chocolate and Blood-Pressure Reduction

A piece of dark chocolate a day keeps the doctor away

July 3, 2007

When it comes to dark chocolate and blood-pressure reduction, it would seem that a little goes a long way. A new randomized controlled study has shown that just one square of dark chocolate a day reduces blood pressure by a few mm Hg in healthy people with above-optimum blood pressure.

Dr Dirk Taubert (University Hospital of Cologne, Germany) and colleagues report their findings in the July 4, 2007 issue of the Journal of the American Medical Association.

Taubert told heartwire that this is the first research to show the benefits of cocoa in dark chocolate long-term—the study lasted 18 weeks. They were also able to demonstrate a feasible mechanism for the BP-lowering effects of dark chocolate, he noted.

Hypertension expert Dr Franz H Messerli (Columbia University, New York), who was not involved in this research, told heartwire: "This is now study 6 showing the same phenomenon. It is an exceedingly well-done, very thorough study, which I think is nothing short of revolutionary."

Dark chocolate increases production of nitric oxide

Taubert et al say that short-term studies have previously shown that high doses of cocoa for two weeks can improve endothelial function and reduce blood pressure, due to the action of cocoa polyphenols. "But the clinical effect of low habitual cocoa intake on BP and the underlying BP-lowering mechanisms are unclear."

They conducted arandomized, controlled, investigator-blinded, parallel-group trialwith 44 adults, aged 56 to 73, with untreated upper-range prehypertension or stage 1 hypertension without concomitant risk factors. The participants were randomly assigned to receive either one square (6.3 g) of a commercial brand of dark chocolate per day, constituting just 30 kcal, or matching polyphenol-free white chocolate for 18 weeks.

The primary outcome measure was change in BP after 18 weeks. Secondary outcomes included changes in plasma markers of vasodilative nitric oxide (S-nitrosoglutathione) and oxidative stress (8-isoprostane) and bioavailability of cocoa polyphenols.

From baseline to 18 weeks, dark-chocolate intake reduced mean systolic BP by 2.9 mm Hg (p<0.001)>

The BP decline was accompanied by a sustained increase of S-nitrosoglutathione by 0.23 nmol/L (p<0.001)white chocolate caused no changes in BP or plasma biomarkers.

"The apparent mechanisms by which dark chocolate lowered BP suggests a chronic increase in the production of nitric oxide in the vascular endothelium," the researchers explain. "It is likely that cocoa flavanols in dark chocolate were responsible for the observed effects on S-nitrosoglutathione and BP."

Long-term RCTs with larger numbers of participants needed.

"This study provides enough evidence to suggest that low amounts of polyphenol-rich dark chocolate as an addition to a healthy diet caused progressive reductions of systolic and diastolic BP in older subjects with prehypertension without inducing weight gain or other adverse effects," Taubert said.

However, he says the findings need to be replicated in other populations (their participants were predominantly white, older, and mildly hypertensive) and that the effects of dark chocolate need to be evaluated in long-term randomized controlled studies with larger numbers of participants.

"A few hundred patients would be needed, with a follow-up of at least one year," he says.

"However, we are more interested in the mechanism, and we are trying to find out which polyphenol in the cocoa is responsible. When we know the substance, we will go back and test it."

Small changes in BP, but big implications

Messerli says the clinical significance of these apparently small changes in blood pressure is nevertheless extremely important. "When you look at this populationwise, there's no question that this achieves a major reduction in heart attacks and stroke."

But he cautions that people must understand that the chocolate has to be dark. "Regular (milk) or white chocolate has no benefit whatsoever. It is completely useless. I now tell my patients, I will take away your Häagen-Dazs and your crème brûlée, but I give you a little bit of dark chocolate. There are no adverse events, in contrast to many BP-lowering pills, and patients are motivated to enjoy a daily treat."

He also points out that the amount of dark chocolate eaten is key, because people still need to keep within their daily limit of calories. The one square in this study was 6.3 g and represented only 30 kcal per day, he notes, "but previous studies have shown that 100 g of dark chocolate lowers BP by 12/8 mm Hg; however, this is somewhat of a Pandora's box."

Taubert D, Roesen R, Lehmann C, et al. Effects of low habitual cocoa intake on blood pressure and bioactive nitric oxide. A randomized controlled trial. JAMA 2007; 298:49-60

Cardiac Resynchronization Therapy for Patients With Left Ventricular Systolic Dysfunction

Cardiac Resynchronization Therapy for Patients With Left Ventricular Systolic Dysfunction

A Systematic Review

Finlay A. McAlister, MD, MSc; Justin Ezekowitz, MBBCh, MSc; Nicola Hooton, MPH; Ben Vandermeer, MSc; Carol Spooner, BScN, MSc; Donna M. Dryden, PhD; Richard L. Page, MD; Mark A. Hlatky, MD, MPH; Brian H. Rowe, MD, MSc

JAMA. 2007;297:2502-2514.

Context Left ventricular (LV) systolic dysfunction causes substantial morbidity and mortality, even with optimal pharmacotherapy. Atrial-synchronized biventricular pacemakers (cardiac resynchronization therapy [CRT]) received US Food and Drug Administration (FDA) approval for use in selected patients with LV systolic dysfunction in 2001.

Objective To summarize the current evidence base for the efficacy, effectiveness, and safety of CRT in patients with LV systolic dysfunction.

Evidence Acquisition A search of multiple electronic databases until November 2006 was supplemented by hand searches of reference lists of included studies and review articles, proceedings booklets from meetings, FDA reports, and contact with primary study authors and device manufacturers. A total of 14 randomized trials (4420 patients) were included for the CRT efficacy review, 106 studies (9209 patients) for the CRT effectiveness review, and 89 studies (9677 patients) reported safety outcomes with implantation of a CRT device.

Evidence Synthesis All patients in the CRT studies had LV systolic dysfunction (mean LV ejection fraction [LVEF] range, 21%-30%), prolonged QRS duration (mean range, 155-209 milliseconds), and 91% had New York Heart Association (NYHA) class 3 or 4 heart failure symptoms despite optimal pharmacotherapy. CRT improved LVEF (weighted mean difference, 3.0%; 95% confidence interval [CI], 0.9%-5.1%), quality of life (weighted mean reduction in Minnesota Living With Heart Failure Questionnaire, 8.0 points; 95% CI, 5.6-10.4 points), and functional status (improvements of 1 NYHA class were observed in 59% of CRT recipients in the randomized trials). CRT decreased hospitalizations by 37% (95% CI, 7%-57%), and all-cause mortality decreased by 22% (95% CI, 9%-33%). Implant success rate was 93.0% (95% CI, 92.2%-93.7%) and 0.3% of patients died during implantation (95% CI, 0.1%-0.6%). During a median 11-month follow-up, 6.6% (95% CI, 5.6%-7.4%) of CRT devices exhibited lead problems and 5% (95% CI, 4%-7%) malfunctioned.

Conclusions CRT reduces morbidity and mortality in patients with LV systolic dysfunction, prolonged QRS duration, and NYHA class 3 or 4 symptoms when combined with optimal pharmacotherapy. The incremental benefits of combined CRT plus implantable cardioverter-defibrillator devices vs CRT-alone devices in patients with LV systolic dysfunction remain uncertain.

LINK: http://jama.ama-assn.org/cgi/content/short/297/22/2502?rss=1

Preoperative Hematocrit Linked with Postoperative Outcome in Older Patients

Physician's First Watch for June 13, 2007

David G. Fairchild, MD, MPH, Editor-in-Chief

Preoperative Hematocrit Linked with Postoperative Outcome in Older Patients

In older patients, preoperative hematocrit levels outside the normal range are associated with higher mortality after noncardiac surgery, a study in JAMA finds.

Researchers examined Veterans Health Administration data from some 310,000 mostly male patients aged at least 65 years who underwent major noncardiac surgery. They stratified the cohort by preoperative hematocrit level and then determined 30-day postoperative mortality.

The 30-day mortality for the entire cohort was 3.9%. Patients with preoperative anemia (hematocrit levels <39.0%)>for each percentage-point departure from the normal range.

Editorialists highlight the strengths of the large observational database used in this study, but write that clinicians should not use these findings "to justify interventions — use of transfusion, erythropoietic agents, iron supplementation — outside the research setting."


JAMA article (Free)
JAMA editorial (Subscription required)

Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials

Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials

Thavendiranthan et al have undertaken a study to examine the role of statins in primary prevention of cardiovascular disease (1)

Cochrane Collaboration, and American College of Physicians Journal Club databases were searched for RCTs published between 1966 and June 2005. The authors included RCTs with follow-up of 1 year or longer, more than 100 major CV events, and 80% or more of the population without CV disease. From each trial, demographic data, lipid profile, CV outcomes, mortality, and adverse outcomes were recorded. Summary relative risk (RR) ratios with 95% confidence intervals (CIs) were calculated using a random effects model

seven trials with 42,848 patients were included. Note that the analysis also included primary prevention patients from the HPS trial (more than 80% were in secondary prevention) and the patients from the CARDS trial

mean follow-up was 4.3 years

statin therapy reduced the RR of major coronary events, major cerebrovascular events, and revascularizations by 29.2% (95% CI, 16.7%-39.8%) (P<.001), 14.4% (95% CI, 2.8%-24.6%) (P = 0.02), and 33.8% (95% CI, 19.6%-45.5%) (P<.001), respectively

statins produced a nonsignificant 22.6% RR reduction in coronary heart disease mortality (95% CI, 0.56-1.08) (P = 0.13)

no significant reduction in overall mortality (RR, 0.92 [95% CI, 0.84-1.01]) (P = .09) or increases in cancer or levels of liver enzymes or creatine kinase were observed

the authors affirm that statin therapy could reduce the absolute risk of coronary events during the next 4.3 years by 0.75% in low-risk patients (NNT= 133), by 1.63% (NNT=61) in moderate-risk patients and by 2.51% (NNT=40) in high-risk patients. They also conclude that it could be cost-effective in patients with an absolute risk over 20% of having a coronary event in the following 10 years. It would not be cost-effective in patients with a risk <10%, and its use would be controversial in the risk-group of 10-20%

the study authors concluded that, in patients without CV disease, statin therapy decreases the incidence of major coronary and cerebrovascular events and revascularizations but not coronary heart disease or overall mortality

Reference:

1. Thavendiranathan P et al. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006 Nov 27;166(21):2307-13.

Even low-level physical activity improves the cardiorespiratory fitness

Effects of Different Doses of Physical Activity on Cardiorespiratory Fitness Among Sedentary, Overweight or Obese Postmenopausal Women With Elevated Blood Pressure

A Randomized Controlled Trial

Timothy S. Church, MD, MPH, PhD; Conrad P. Earnest, PhD; James S. Skinner, PhD; Steven N. Blair, PED

JAMA. 2007;297:2081-2091.

Context Low levels of cardiorespiratory fitness are associated with high risk of mortality, and improvements in fitness are associated with reduced mortality risk. However, a poor understanding of the physical activity–fitness dose response relation remains.

Objective To examine the effect of 50%, 100%, and 150% of the NIH Consensus Development Panel recommended physical activity dose on fitness in women.

Design, Setting, and Participants Randomized controlled trial of 464 sedentary, postmenopausal overweight or obese women whose body mass index ranged from 25.0 to 43.0 and whose systolic blood pressure ranged from 120.0 to 159.9 mm Hg. Enrollment took place between April 2001 and June 2005 in the Dallas, Tex, area.

Intervention Participants were randomly assigned to 1 of 4 groups: 102 to the nonexercise control group and 155 to the 4-kcal/kg, 104 to the 8-kcal/kg, and 103 to the 12-kcal/kg per week energy-expenditure groups for the 6-month intervention period. Target training intensity was the heart rate associated with 50% of each woman's peak O2.

Main Outcome Measure The primary outcome was aerobic fitness assessed on a cycle ergometer and quantified as peak absolute oxygen consumption ( O2abs, L/min).

Results The mean (SD) baseline O2abs values were 1.30 (0.25) L/min. The mean (SD) minutes of exercising per week were 72.2 (12.3) for the 4-kcal/kg, 135.8 (19.5) for the 8-kcal/kg, and 191.7 (33.7) for the 12-kcal/kg per week exercise groups. After adjustment for age, race/ethnicity, weight, and peak heart rate, the exercise groups increased their O2abs compared with the control group by 4.2% in the 4-kcal/kg, 6.0% in the 8-kcal/kg, and 8.2% in the 12-kcal/kg per week groups (P<.001 for each vs control; P for trend <.001). There was no treatment x subgroup interaction for age, body mass index, weight, baseline O2abs, race/ethnicity, or baseline hormone therapy use. There were no significant changes in systolic or diastolic blood pressure values from baseline to 6 months in any of the exercise groups vs the control group. Conclusion In this study, previously sedentary, overweight or obese postmenopausal women experienced a graded dose-response change in fitness across levels of exercise training.

COMMENTARIES Even small doses of activity boost heart fitness 16 May 2007 MedWire News: Even low-level physical activity improves the cardiorespiratory fitness of overweight, sedentary individuals, study findings reveal.
National Institutes of Health (NIH) guidelines recommend at least 30 minutes of moderate-intensity physical activity to promote general health, but it is not clear if sedentary people will benefit from lower levels of activity than this, explain Timothy Church (Louisiana State University System, Baton Rouge, USA) and colleagues.
To investigate, the researchers conducted a study in 464 sedentary, postmenopausal overweight or obese women with elevated blood pressure.
The women’s body mass indices ranged from 25.0 to 43.0 and systolic blood pressure from 120.0 to 159.9 mmHg.
The participants were randomly assigned to three different levels of exercise or to a no-exercise control group. The three exercise levels were cycling or walking sessions designed to expend 4 kcal/kg, 8kcal/kg, or 12 kcal/kg per week.
These levels corresponded to 50%, 100%, and 150% of the NIH consensus recommended activity level for such women.
Women who exercised participated in three or four training sessions each week for 6 months, at a training intensity of the heart rate associated with 50% peak oxygen consumption (VO2). Although maximal effort was obtained during exercise testing, the mean peak absolute (VO2abs) and relative (VO2rel) values were very low, at 1.30 l/min and 15.5 ml/kg/min, respectively, at baseline.
This demonstrated that the group had very low fitness levels at the start of the study, the authors note.
The 4-kcal/kg group exercised for a mean of 72.2 minutes per week over 2.6 sessions, the 8-kcal/kg group for 135.8 minutes per week during 2.8 sessions, and the 12-kcal/kg group for 191.7 minutes per week during 3.1 sessions.
There was a strong dose-response relationship between the amount of exercise and change in fitness, Church and team report in the Journal of the American Medical Association.
Peak absolute oxygen consumption VO2abs were significantly increased at all three exercise levels versus no exercise (1.33, 1.35, and 1.39 vs 1.28 l/min).
These values represented a 4.2% increase in VO2abs in the 4-kcal/kg group, a 6.0% increase in 8-kcal/kg group, and an 8.2% increase in the 12-kcal/kg group, compared with the control no-exercise group (all p<0.001 versus control; p for trend <0.001).
The dose-response relationship was seen across age, race, weight, baseline fitness, and hormone therapy subgroups.
Participants’ systolic and diastolic blood pressure levels, weight, and most other cardiovascular risk factors were not significantly altered with any level of exercise.
However, waist circumference, which was similar in each group at baseline, was significantly reduced at the end of the study in all 3 exercise groups compared with the control group (p<0.05 for each).
This was a significant finding given the importance of increased risk of insulin resistance, diabetes, and metabolic syndrome, and mortality associated with abdominal obesity, Church and team emphasize.
“Perhaps the most striking finding of our study is that even activity at the 4-kcal/kg per week level (approximately 72 min per week) was associated with a significant improvement in fitness compared with women in the nonexercise control group,” the team comments. JAMA 2007; 297: 2081-2091

PCI in Silent Ischemia After Myocardial Infarction - SWISSI II

Effects of Percutaneous Coronary Interventions in Silent Ischemia After Myocardial Infarction The SWISSI II Randomized Controlled Trial

Paul Erne, MD; Andreas W. Schoenenberger, MD; Dieter Burckhardt, MD; Michel Zuber, MD; Wolfgang Kiowski, MD; Peter T. Buser, MD; Paul Dubach, MD; Therese J. Resink, PhD; Matthias Pfisterer, MD

JAMA. 2007;297:1985-1991.

Context The effect of a percutaneous coronary intervention (PCI) on the long-term prognosis of patients with silent ischemia after a myocardial infarction (MI) is not known.

Objective To determine whether PCI compared with drug therapy improves long-term outcome of asymptomatic patients with silent ischemia after an MI.

Design, Setting, and Participants Randomized, unblinded, controlled trial (Swiss Interventional Study on Silent Ischemia Type II [SWISSI II]) conducted from May 2, 1991, to February 25, 1997, at 3 public hospitals in Switzerland of 201 patients with a recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease. Follow-up ended on May 23, 2006.

Interventions Percutaneous coronary intervention aimed at full revascularization (n = 96) or intensive anti-ischemic drug therapy (n = 105). All patients received 100 mg/d of aspirin and a statin.

Main Outcome Measures Survival free of major adverse cardiac events defined as cardiac death, nonfatal MI, and/or symptom-driven revascularization. Secondary measures included exercise-induced ischemia and resting left ventricular ejection fraction during follow-up.

Results During a mean (SD) follow-up of 10.2 (2.6) years, 27 major adverse cardiac events occurred in the PCI group and 67 events occurred in the anti-ischemic drug therapy group (adjusted hazard ratio, 0.33; 95% confidence interval, 0.20-0.55; P<.001), which corresponds to an absolute event reduction of 6.3% per year (95% confidence interval, 3.7%-8.9%; P<.001). Patients in the PCI group had lower rates of ischemia (11.6% vs 28.9% in patients in the drug therapy group at final follow-up; P = .03) despite fewer drugs. Left ventricular ejection fraction remained preserved in PCI patients (mean [SD] of 53.9% [9.9%] at baseline to 55.6% [8.1%] at final follow-up) and decreased significantly (P<.001) in drug therapy patients (mean [SD] of 59.7% [11.8%] at baseline to 48.8% [7.9%] at final follow-up). Conclusion Among patients with recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease, PCI compared with anti-ischemic drug therapy reduced the long-term risk of major cardiac events. Conclusion Among patients with recent MI, silent myocardial ischemia verified by stress imaging, and 1- or 2-vessel coronary artery disease, PCI compared with anti-ischemic drug therapy reduced the long-term risk of major cardiac events.


COMMENTARIES:

For stable angina patients, the COURAGE trial found no advantage in any major cardiovascular endpoint for coronary stenting plus optimal medical therapy over medical therapy alone.

Another recent trial, the Open Artery Trial (OAT) reported at the American Heart Association meeting in November 2006, found no benefit for late percutaneous coronary intervention after heart attack over four years of follow up.

This study included a more select group of patients than the OAT study since all had viable myocardium.

"Taken together, these findings indicate a need for percutaneous coronary intervention after myocardial infarction only in the presence of symptomatic or silent ischemia but not without it," they wrote.

This trial was limited by lack of blinding (though all events were adjudicated by blinded physicians), a minority of female patients, and relatively small sample size.

LINKS: http://jama.ama-assn.org/cgi/content/short/297/18/1985?rss=1

Can Levosimendan Help in Acute Decompensated Heart Failure?

Can Levosimendan Help in Acute Decompensated Heart Failure?

A novel inotropic agent demonstrated no advantage over dobutamine in reducing mortality.

There were hopes that the new drug, levosimendan, would improve survival, because it uses a unique mechanism that makes heart muscle cells more sensitive to the calcium that causes them to contract. However, the study of 1,347 persons with acute decompensated heart failure, done at 75 centers in nine countries between March 2003 and December 2004, found essentially the same death rate for participants who got levosimendan as those who received an established medication, dobutamine, said a report in the May 2 issue of the Journal of the American Medical Association.

Levosimendan vs Dobutamine for Patients With Acute Decompensated Heart Failure

The SURVIVE Randomized Trial

Alexandre Mebazaa, MD, PhD; Markku S. Nieminen, MD, PhD; Milton Packer, MD; Alain Cohen-Solal, MD, PhD; Franz X. Kleber, MD; Stuart J. Pocock, PhD; Roopal Thakkar, MD; Robert J. Padley, MD; Pentti Põder, MD, PhD; Matti Kivikko, MD, PhD; for the SURVIVE Investigators

JAMA. 2007;297:1883-1891.

Context

Because acute decompensated heart failure causes substantial morbidity and mortality, there is a need for agents that at least improve hemodynamics and relieve symptoms without adversely affecting survival.

Objective

To assess the effect of a short-term intravenous infusion of levosimendan or dobutamine on long-term survival.

Design, Setting, and Patients

The Survival of Patients With Acute Heart Failure in Need of Intravenous Inotropic Support (SURVIVE) study was a randomized, double-blind trial comparing the efficacy and safety of intravenous levosimendan or dobutamine in 1327 patients hospitalized with acute decompensated heart failure who required inotropic support. The trial was conducted at 75 centers in 9 countries and patients were randomized between March 2003 and December 2004.
Interventions

Intravenous levosimendan (n = 664) or intravenous dobutamine (n = 663).

Main Outcome Measure

All-cause mortality at 180 days.

Results

All-cause mortality at 180 days occurred in 173 (26%) patients in the levosimendan group and 185 (28%) patients in the dobutamine group (hazard ratio, 0.91; 95% confidence interval, 0.74-1.13; P = .40). The levosimendan group had greater decreases in B-type natriuretic peptide level at 24 hours that persisted through 5 days compared with the dobutamine group (P<.001 for all time points). There were no statistical differences between treatment groups for the other secondary end points (all-cause mortality at 31 days, number of days alive and out of the hospital, patient global assessment, patient assessment of dyspnea at 24 hours, and cardiovascular mortality at 180 days). There was a higher incidence of cardiac failure in the dobutamine group. There were higher incidences of atrial fibrillation, hypokalemia, and headache in the levosimendan group.

Conclusion

Despite an initial reduction in plasma B-type natriuretic peptide level in patients in the levosimendan group compared with patients in the dobutamine group, levosimendan did not significantly reduce all-cause mortality at 180 days or affect any secondary clinical outcomes.

Link:

http://jama.ama-assn.org/cgi/content/short/297/17/1883?rss=1

Valsartan and The Jikei Heart Study: a randomised, open-label, blinded endpoint morbidity-mortality study.

Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study.

Mochizuki S, Dahlof B, Shimizu M, Ikewaki K, Yoshikawa M, Taniguchi I, Ohta M, Yamada T, Ogawa K, Kanae K, Kawai M, Seki S, Okazaki F, Taniguchi M, Yoshida S, Tajima N; Jikei Heart Study group.
Division of Cardiology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan.

BACKGROUND: Drugs that inhibit the renin-angiotensin-aldosterone system benefit patients at risk for or with existing cardiovascular disease. However, evidence for this effect in Asian populations is scarce. We aimed to investigate whether addition of an angiotensin receptor blocker, valsartan, to conventional cardiovascular treatment was effective in Japanese patients with cardiovascular disease.

METHODS: We initiated a multicentre, prospective, randomised controlled trial of 3081 Japanese patients, aged 20-79 years, (mean 65 [SD 10] years) who were undergoing conventional treatment for hypertension, coronary heart disease, heart failure, or a combination of these disorders. In addition to conventional treatment, patients were assigned either to valsartan (40-160 mg per day) or to other treatment without angiotensin receptor blockers. Our primary endpoint was a composite of cardiovascular morbidity and mortality. Analysis was by intention to treat. The study was registered at clintrials.gov with the identifier NCT00133328.

FINDINGS: After a median follow-up of 3.1 years (range 1-3.9) the primary endpoint was recorded in fewer individuals given valsartan than in controls (92 vs 149; absolute risk 21.3 vs 34.5 per 1000 patient years; hazard ratio 0.61, 95% CI 0.47-0.79, p=0.0002). This difference was mainly attributable to fewer incidences of stroke and transient ischaemic attack (29 vs 48; 0.60, 0.38-0.95, p=0.028), angina pectoris (19 vs 53; 0.35, 0.20-0.58, p<0.0001), and heart failure (19 vs 36; 0.53, 0.31-0.94, p=0.029) in those given valsartan than in the control group. Mortality or tolerability did not differ between groups.

INTERPRETATION: The addition of valsartan to conventional treatment prevented more cardiovascular events than supplementary conventional treatment. These benefits cannot be entirely explained by a difference in blood pressure control.

Link:

Lancet. 2007 Apr 28;369(9571):1431-9.

Homocysteine-lowering Therapy Not Effective for Prevention of Cardiovascular Disease

Homocysteine-lowering therapy does not prevent recurrent cardiovascular disease after acute myocardial infarction (level 1 [likely reliable] evidence), based on a randomized trial of 3,749 patients ages 30-85 years who received either folic acid 0.8 mg plus vitamin B12 0.4 mg vs. vitamin B6 40 mg vs. combination of both vs. placebo (NEJM 2006 Apr 13;354(15):1578).

In another trial, homocysteine-lowering therapy (folic acid 2.5 mg, vitamin B6 50 mg and vitamin B12 1 mg) was not associated with an overall difference in vascular events (level 2 [mid-level] evidence), based on a randomized trial of 5,522 patients > 55 years old with vascular disease or diabetes (NEJM 2006 Apr 13;354(15):1567).

Noncoronary vascular surgery in high-CV-risk patients: Add PCI or CABG?

Noncoronary vascular surgery in high-CV-risk patients: Add PCI or CABG?
April 20, 2007

Washington, DC - Perioperative PCI or CABG makes little clinical impact in high-cardiovascular-risk patients with ischemic heart disease who undergo major noncoronary vascular surgery, suggests a randomized but inconclusive study [1].

Designed to clarify feasibility and safety considerations for any future larger, definitive exploration of the strategy, the study wasn't statistically strong enough to show whether adding perioperative coronary revascularization makes a clinical difference, caution the authors, led by Dr Don Poldermans (Erasmus Medical Center, Rotterdam, the Netherlands).

But having set the stage for a larger trial, according to the group as well as an accompanying editorial [2], the pilot study raises questions about CV screening before noncardiac surgery and the clinical importance of any discovered coronary stenoses that would be targeted by perioperative revascularization as compared with, for example, vulnerable plaques that are angiographically invisible.

The trial's neutral findings may relate to histopathologic evidence "that the pathophysiology surrounding fatal MI in the perioperative period after noncardiac surgery often includes unstable plaque and plaque disruption," write the editorialists, Drs Mauro Moscucci and Noah Jones (University of Michigan, Ann Arbor). "Thus, it is possible that revascularization of stable coronary artery stenosis might not add significantly to the effect of optimal medical therapy, similar to what has been shown for other low-risk patients with stable coronary artery disease."

The findings from the fifth Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography (DECREASE-5) pilot study and its accompanying editorial are published online April 13, 2007 by the Journal of the American College of Cardiology. They follow similar results from the Coronary Artery Revascularization Prophylaxis (CARP) trial, published in 2004 and reported by heartwire at the time, that compared the invasive and conservative perioperative strategies in a lower-risk CAD population [3].

Conducted in four European countries and Brazil over five years ending in 2005, DECREASE-5 randomized 101 patients with CAD who were scheduled for open abdominal aortic or infrainguinal arterial surgeries to receive either perioperative PCI or CABG (32 and 17 patients, respectively) or medical therapy (52 patients). Patients had been required to have at least three major cardiac risk factors (eg, angina, evidence of prior MI or neurologic events, heart failure, diabetes, or renal dysfunction) as well as stress-test-documented myocardial ischemia. Beta blockers were initiated for any patient not already on them.

In the PCI/CABG group, two patients died from ruptured aortic aneurysms prior to their noncoronary surgical procedures, "consistent with the fact that urgent or emergency vascular surgery in unstable patients should not be delayed by revascularization," Moscucci and Jones caution.

Rates of the primary end point, a 30-day composite of all-cause mortality and nonfatal MI, were 43% and 33%, respectively (p=0.30). Even out to one year, the rates were similar, at 49% and 44%, respectively (p=0.48). Incidences of the primary-end-point components did not differ between the groups. None in the medical-management group required coronary revascularization within a year of the noncoronary vascular surgery.

As none of the conservatively managed patients underwent diagnostic catheterization, yet their outcomes were similar to those managed with PCI or CABG, write the editorialists, "effective beta blockade and medical therapy might be sufficient, raising the question of whether stable patients scheduled for major vascular surgery should even be screened with stress testing."

However, they conclude, "the debate on screening and revascularization for patients with peripheral arterial disease and scheduled for major vascular surgery continues to be far from settled." DECREASE-5 provided safety and sample-size information needed for a larger exploration of the issue, they write. "It is now time to move forward with such a trial."

Moscucci reports receiving consulting fees from Pfizer and Boston Scientific, lecture fees from Pfizer, and grant support from Cordis

Sources

1. Poldermans D, Schouten O, Vidakovic R, et al. A clinical randomized trial to evaluate the safety of a noninvasive approach in high-risk patients undergoing major vascular surgery: The DECREASE-V pilot study. J Am Coll Cardiol 2007; DOI:10.1016/j.jacc.2006.11.052. Available at: http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fcontent.onlinejacc.org.
2. Moscucci M, Jones N. Coronary revascularization before noncardiac vascular surgery: One more step forward in understanding its role. J Am Coll Cardiol 2007; DOI:10.1016/j.jacc.2007.01.068 . Available at: http://www.theheart.org/viewDocument.do?document=http%3A%2F%2Fcontent.onlinejacc.org.
3. McFalls EO, Ward HB, Moritz TE, et al. Coronary-artery revascularization before elective major vascular surgery. N Eng J Med 2004; 351:2795-2804.

Related links

Risk for death, stroke increased with combined CABG and CEA [Other News > Medscape Medical News; Jan 16, 2007]
Higher risk of stroke and death in patients undergoing combined CEA-CABG surgery vs CABG alone [HeartWire > Other News; Apr 25, 2005]
No benefit from revascularization before vascular surgery: CARP published [HeartWire > Other News; Dec 29, 2004]

ILLUSTRATE - Considerações

Title: Effect of Torcetrapib on the Progression of Coronary Atherosclerosis

Nissen SE, Tardif JC, Nicholls SJ, et al., on behalf of the ILLUSTRATE Investigators.

Citation: N Engl J Med. 2007;356:1304-1316.

Study Question: Does torcetrapib, a novel cholesteryl ester transfer protein (CETP) inhibitor that raises high-density lipoprotein cholesterol (HDL-C) by more than 50%, impact progression of coronary atherosclerosis?

Methods: A total of 1,188 patients with coronary disease underwent intravascular ultrasonography (IVUS). After treatment with atorvastatin to reduce levels of low-density lipoprotein cholesterol (LDL-C) to <100 mg/dl (2.59 mmol/L), patients were randomly assigned to receive either atorvastatin monotherapy or atorvastatin plus 60 mg of torcetrapib daily. After 24 months, disease progression was measured by repeated IVUS in 910 patients (77%). Each target site for the primary analysis was required to have <50% obstruction throughout a segment of 40 mm or longer.
Results: Mean age was 57 years, 70% were men, and 91% were on a statin at baseline. Baseline mean LDL-C was 84 mg/dl and HDL-C was 45.5 mg/dl, and median LDL-C:HDL-C was 1.89. After 24 months, as compared with atorvastatin monotherapy, the effect of torcetrapib–atorvastatin therapy was an approximate 61% relative increase in HDL-C (43.9 mg/dl vs. 72.1 mg/dl) and a 20% relative decrease in LDL-C, reaching a ratio of LDL-C to HDL-C of <1.0. Torcetrapib was also associated with an increase in systolic blood pressure of 4.6 mm Hg. The percent atheroma volume (the primary efficacy measure) increased by 0.19% in the atorvastatin-only group and by 0.12% in the torcetrapib–atorvastatin group (p = 0.72). A secondary measure, the change in normalized atheroma volume, showed a small favorable effect for torcetrapib (p = 0.02), but there was no significant difference in the change in atheroma volume for the most diseased vessel segment.
Conclusions: The CETP inhibitor torcetrapib was associated with a substantial increase in HDL-C and decrease in LDL-C. It was also associated with an increase in blood pressure, and there was no significant decrease in the progression of coronary atherosclerosis. The lack of efficacy may be related to the mechanism of action of this drug class or to molecule-specific adverse effects.

Perspective: Previous similar IVUS studies have shown that intense lowering of LDL-C by statins decreases the total atheroma volume by as much as 14.7 mm3 at 24 months, and the infusion of A-1 Milano resulted in a 14.1 mm3 reduction in atheroma volume at 1 month. It would appear that increasing HDL particle cholesterol content with a CETP inhibitor does not result in better functioning HDL particles, and there are experimental data that these cholesterol-rich HDL particles may have proinflammatory effects. The clinical morbidity–mortality trial of torcetrapib–atorvastatin was prematurely terminated because of an increase in event rates that might be explained by both the increase in systolic blood pressure and dysfunctional HDL particles. In addition to niacin, several novel drugs/devices are currently being studied in randomized trials to determine their effect on atherosclerosis progression and events. Melvyn Rubenfire, M.D., F.A.C.C.

Effect of Cocoa and Tea Intake on Blood Pressure

Effect of Cocoa and Tea Intake on Blood Pressure
A Meta-analysis

Dirk Taubert, MD, PhD; Renate Roesen, PhD; Edgar Schömig, MD
Arch Intern Med. 2007;167:626-634.

Background Epidemiological evidence suggests blood pressure–lowering effects of cocoa and tea. We undertook a meta-analysis of randomized controlled trials to determine changes in systolic and diastolic blood pressure due to the intake of cocoa products or black and green tea.

Methods MEDLINE, EMBASE, SCOPUS, Science Citation Index, and the Cochrane Controlled Trials Register were searched from 1966 until October 2006 for studies in parallel group or crossover design involving 10 or more adults in whom blood pressure was assessed before and after receiving cocoa products or black or green tea for at least 7 days.

Results Five randomized controlled studies of cocoa administration involving a total of 173 subjects with a median duration of 2 weeks were included. After the cocoa diets, the pooled mean systolic and diastolic blood pressure were –4.7 mm Hg (95% confidence interval [CI], –7.6 to –1.8 mm Hg; P = .002) and –2.8 mm Hg (95% CI, –4.8 to –0.8 mm Hg; P = .006) lower, respectively, compared with the cocoa-free controls. Five studies of tea consumption involving a total of 343 subjects with a median duration of 4 weeks were selected. The tea intake had no significant effects on blood pressure. The estimated pooled changes were 0.4 mm Hg (95% CI, –1.3 to 2.2 mm Hg; P = .63) in systolic and –0.6 mm Hg (95% CI, –1.5 to 0.4 mm Hg; P = .38) in diastolic blood pressure compared with controls.

Conclusion Current randomized dietary studies indicate that consumption of foods rich in cocoa may reduce blood pressure, while tea intake appears to have no effect.

Author Affiliations: Department of Pharmacology, University Hospital of Cologne, Cologne, Germany.

Considerations:

This meta-analysis involved only a few studies with small sample sizes and short duration, limiting the statistical power and generalizability to long-term outcomes.

The researchers also cautioned that potential weight gain with the high-caloric cocoa diets "may reverse any blood pressure reductions during long-term habitual intake of cocoa products."

"We believe that any dietary advice must account for the high sugar, fat, and calorie intake with most cocoa products," they cautioned, but added, "it appears reasonable to allow phenol-rich cocoa products such as dark chocolate for calorie-balanced substitution of high-fat dairy products, sugar confectionary, or cookies of the usual diet."
The researchers reported no financial conflicts of interest

Link:

Taubert D, et al "Effect of Cocoa and Tea Intake on Blood Pressure: A Meta-analysis" Arch Intern Med. 2007;167:626-634.

COURAGE no NEJM

Recém publicado:

Abstrast and Full Text: FREE.

New England Journal of Medicine
Volume 356:1503-1516 April 12, 2007 Number 15

Optimal Medical Therapy with or without PCI for Stable Coronary Disease

Full Text: http://content.nejm.org/cgi/content/full/356/15/1503

Antioxidant vitamins increase mortality

Qual o impacto que um trabalho como esse poderá trazer à prática médica brasileira?

Antioxidant vitamins increase mortality

http://www.theheart.org/article/773375.do

Copenhagen, Denmark - The largest analysis of data on antioxidant vitamins ever conducted has shown that beta-carotene, vitamin A, and vitamin E probably increase mortality [1]. Two other antioxidant substances—vitamin C and selenium—had no effect on mortality.

The meta-analysis of 68 randomized trials with a total of 232 606 participants, published in the February 28, 2007 issue of the Journal of the American Medical Association, was conducted by a group led by Dr Goran Bjelakovic (Copenhagen University Hospital, Denmark).

Coauthor Dr Christian Gluud (Copenhagen University Hospital) commented to heartwire: "This is the most comprehensive collection of data on antioxidant vitamins ever conducted, and we have shown that on the whole these agents have no benefit. Indeed, vitamin A, vitamin E, and beta-carotene are associated with an increase in mortality at the doses studied. Vitamin A and beta-carotene seem to have a dose-related effect, with mortality increasing as doses increase, whereas vitamin E does not appear to have a dose-related effect, with all doses associated with increased mortality."

Jury still out on vitamin C and selenium

Gluud added that the jury is still out on vitamin C and selenium. "Vitamin C does not appear to be detrimental, but it is not beneficial either, and all the trials of selenium together suggest a small benefit, but when only the well-conducted trials are included, there appears to be neither benefit nor harm.

"Our data show that antioxidant vitamins should not be taken in an effort to prevent illness. People should instead eat a balanced diet and take regular exercise," he said.

In the paper, the authors note that many people are taking antioxidant supplements in the belief that they improve health and prevent diseases. Many primary- or secondary-prevention trials of antioxidant supplements have been conducted to investigate the prevention of several diseases—mainly cardiovascular disease and cancer—but results have generally not been positive, with some trials showing increases in mortality.

To find out more, they conducted the current systematic review to analyze the effects of antioxidant supplements on all-cause mortality of adults included in primary- and secondary-prevention trials. They included all primary- and secondary-prevention published trials in adults randomized to receive beta-carotene, vitamin A, vitamin C, vitamin E, or selenium vs placebo or no intervention.

Results showed that when all trials of antioxidant supplements were pooled together, there was no significant effect on mortality, but when the 47 trials said to have a low risk of bias (in a total of 180 938 participants) were analyzed alone, the antioxidant supplements as a whole significantly increased mortality, and beta-carotene, vitamin A, and vitamin E were all associated with increased mortality when given alone or in combination. Vitamin C and selenium had no significant effect on mortality.

The researchers note that more than two thirds of the included trials fell into the category of those with a low risk of bias, which they say highlights the validity of their results. "Antioxidant supplements not only seem to be one of the most researched topics in the world, they also seem to be one of the most adequately researched clinical questions," they say.

They point out that a large number of unpublished trials on supplements may exist, but as unpublished trials are more likely to have been either neutral or negative than to have shown beneficial effects, this suggests their estimate of a 5% increase in mortality is likely to be conservative.

Substantial public-health consequences

Noting that 10% to 20% of the adult population (80 million-160 million people) in North America and Europe may consume these supplements, Bjelakovic et al say the public-health consequences may be substantial.

Speculating on possible mechanisms, they point out that although oxidative stress has a hypothesized role in the pathogenesis of many chronic diseases, it may be the consequence of pathological conditions, and that eliminating free radicals may interfere with some essential defensive mechanisms.

In an interview with heartwire, Gluud also suggested that the antioxidant vitamins could actually also have pro-oxidant effects. "We don't know exactly how they are doing harm, but rather than preventing cardiovascular disease and cancer, they actually seem to be accelerating these conditions."

Lessons learned

He said these observations were "a huge disappointment" but added that at least it has been discovered. "We must see the positives in this. The question has been thoroughly addressed and we now know the answer—these agents are harmful. The companies selling these antioxidant vitamins have been able to dodge the issue for a long time, saying that any negative data have not been comprehensive. They cannot do this any longer. There are lessons to be learned here— for example, the importance of conducting trials with these agents and publishing the results."

Gluud added that food supplements should be regulated in the same way as medical products. "The governments of the world now have the responsibility to inform people of these results. They have been too slow in the past in requesting that health supplements be properly evaluated before allowing these products to be added to foods. People have been buying these supplements and foods advertised as having these supplements added under the impression that they are good for them, when in actual fact they are harmful. Any potential health supplements should not be allowed to be added to foods unless they have been shown to be beneficial or at least proven not to be harmful."

Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial.

Resultado do Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation (COURAGE) trial.
Publicado noNew England Journal of MedicinePublished at www.nejm.org March 26, 2007 (10.1056/NEJMoa070829) Optimal Medical Therapy with or without PCI for Stable Coronary Disease

William E. Boden, M.D., Robert A. O’Rourke, M.D., Koon K. Teo, M.B., B.Ch., Ph.D., Pamela M. Hartigan, Ph.D., David J. Maron, M.D., William J. Kostuk, M.D., Merril Knudtson, M.D., Marcin Dada, M.D., Paul Casperson, Ph.D., Crystal L. Harris, Pharm.D., Bernard R. Chaitman, M.D., Leslee Shaw, Ph.D., Gilbert Gosselin, M.D., Shah Nawaz, M.D., Lawrence M. Title, M.D., Gerald Gau, M.D., Alvin S. Blaustein, M.D., David C. Booth, M.D., Eric R. Bates, M.D., John A. Spertus, M.D., M.P.H., Daniel S. Berman, M.D., G.B. John Mancini, M.D., William S. Weintraub, M.D., for the COURAGE Trial Research Group

RESUMO:
Background: Permenece uma incerteza se em pacientes com Doença Arterial Coronariana (DAC) estável, a utilização de métodologia invasiva como a Intervenção Coronariana Percutânea (PCI) associada a terapia farmacológica e intervenção no estilo de vida (terapia médica ótima) é superior a terapia médica ótima (TMO) isoladamente na redução de eventos

Métodos: Os pesquisadores conduziram um trial randomizado envolvendo 2287 pacientes com evidência de isquemia miocárdica e DAC em 50 centros americanos e canadenses. Entre 1999 e 2004 foram especificados 1149 pacientes para serem submetidos a PCI com terapia médica ótima e 1138 para receber apenas terapia médica ótima. O desfecho primário foi morte por qualquer causa e não-fatal infarto do miocárdio durante um follow-up de 2.5 a 7.0 anos (média de 4.6 anos)

Resultados: Aconteceram 211 eventos primários no grupo PCI e 202 eventos no grupo TMO. A taxa de eventos cumulativos de 4.6 anos foi de 19% no grupo PCI e 18.5% no grupo TMO (Hazard Ratios para o grupo PCI, 1.05; 95% intervalo de confiança [IC], 0.87 to 1.27; p=0.62). Não houveram diferenças significativas entre o grupo PCI e o grupo TMO na composição de mortes, infarto do miocárdio e acidente vascular encefálico (20.0% vs. 19.5%; hazard ratio, 1.05; 95% CI 0.87 to 1.27; p=0.62); hospitalização para síndromes coronarianas agudas (12.4% vs. 11.8%; hazard ratio 1.07; 95% CI 0.84 to 1.37; p=0.56; ou infarto do miocárdio ((13.2% vs. 12.3%; hazard ratio, 1.13; 95% CI, 0.89 to 1.43; P=0.33).

Conclusão: PCI quando associado a TMO não reduz o risco de morte, infarto do miocárdio ou outros eventos cardiovasculares maiores, quando utilizado como terapêutica inicial em pacientes com DAC estável. (ClinicalTrials.gov number, NCT00007657 [ClinicalTrials.gov] .)

Texto completo desse artigo: http://content.nejm.org/cgi/content/full/NEJMoa070829v1

The results COURAGE trial were presented at the American College of Cardiology, 27 March 2007 annual scientific sessions being held in New Orleans, Louisiana, and were published simultaneously advance online by the New England Journal of Medicine.