Cleveland Clinic study finds lowest risk treatment for severe carotid and coronary disease

Of the three most common treatment approaches for patients with severe carotid and coronary artery disease, patients who underwent stenting of the carotid artery followed by open heart surgery had the best outcomes, according to a retrospective study from Cleveland Clinic published online today in the Journal of the American College of Cardiology.

01 aug 2013--The study compared carotid stenting followed by open heart surgery to both staged and combined carotid endarterectomy and open heart surgery.

For patients with a severe blockage in the carotid artery in addition to coronary disease, physicians commonly recommend a course of treatment that includes a carotid endarterectomy, a surgical procedure to remove the plaque buildup in the carotid artery, as well as open heart surgery for the coronary disease, according to the researchers. These treatments are sometimes done in stages, with the carotid surgery performed a few weeks before the coronary operation, or simultaneously during one procedure. More recently, the researchers write, a third alternative has come into play: carotid stenting, an endovascular procedure in which a scaffold is placed in the carotid artery, followed by a separate open heart surgery.

The researchers, led by Mehdi H. Shishehbor, D.O., M.P.H., Ph.D., Director of Endovascular Services in the Sydell and Arnold Miller Family Heart & Vascular Institute at Cleveland Clinic, examined the short- and long-term outcomes of 350 patients who underwent a carotid revascularization procedure within 90 days of a planned open heart surgery at Cleveland Clinic between January 1997 and August 2009. The study population consisted primarily of patients who were found to have severe carotid artery disease as part of their evaluation prior to open heart surgery.

In the short term, patients who underwent carotid stenting or combined endarterectomy had a lower risk of death, stroke or heart attack than those who underwent a staged endarterectomy followed by a separate open heart surgery. After the first year, however, the researchers found that patients who received carotid stents had a significantly lower risk of serious events than those who underwent an endarterectomy, whether it was performed separately from, or combined with, the open heart surgery.

"Our study shows that carotid stenting followed by open heart surgery should be the first line strategy for treating patients with severe carotid and coronary disease, if the three- to four-week wait between procedures is clinically acceptable," said Shishehbor. "There has never been a randomized clinical trial to determine the best approach for these patients, but the evidence in this study may be enough to change practice."

At present in the United States, only 3 percent of patients with concomitant severe carotid and coronary artery disease receive staged carotid stenting followed by open heart surgery. In the study population, 31 percent of the subjects were treated in this manner.

"As a result of this work, we are making changes to the way we approach patients with severe carotid and coronary artery disease at Cleveland Clinic," said Shishehbor. "We are collaborating across disciplines to identify the lowest risk treatment option for each patient."

Provided by Cleveland Clinic

Gene Scan Finds Links to Coronary Disease

LEICESTER, England, July 18 -- An increased risk of coronary artery disease has been linked -- for the third time in as many months -- to a region on chromosome nine.
Using the increasingly common method of genome-wide association scanning, researchers here and in Germany found that a common genetic variation dubbed rs1333049 is associated with about a 36% increase in risk for each copy in a person's genome.
In two large case-control studies, about 22% of participants had two copies and 50% had one, according to Nilesh Samani, F.Med.Sci., of the University of Leicester and colleagues.
The same variation was linked to coronary artery disease in two studies published in May in Science. (See Common Genetic Variation Increases Heart Disease Risk)
The new study is one of a trilogy published online by the New England Journal of Medicine and Nature Genetics, all of which used genome-wide association scanning to find genetic links to diseases.
In genome-wide association scanning, researchers take advantage of the data on genetic variation -- so-called single nucleotide polymorphisms, or SNPs -- amassed by the Human Genome Project and the international HapMap collaboration.
Then, using microarrays that recognize up to 500,000 SNPs, they look for polymorphisms that are more common in those with a disease than in healthy controls.
In this case, Dr. Samani and colleagues began with a cohort of 1,926 volunteers with coronary artery disease and 2,938 controls (the Wellcome Trust Case Control Consortium).
The case volunteers were selected because they either had a myocardial infarction or coronary revascularization before the age of 66, as well as a strong family history of coronary artery disease.
Genome-wide association scanning isolated nine genetic variants that were highly associated with disease. They had a significance of P<1.2X10-5 and a false-positive report probability of less than 50%.
Dr. Samani and colleagues then turned to another case-control cohort, the German Myocardial Infarction Family Study, to replicate their findings. In this cohort, the 875 cases had had a myocardial infarction before 60 and at least one first-degree relative with premature coronary artery disease. There were 1,644 healthy controls.
In the replication analysis, only three variants retained their significance. Specifically:
The rs1333049 region on chromosome nine was significantly associated with disease at P<1.80X10-14 in the British cohort and P=3.40X10-6 in the German study.
A variant on chromosome six, dubbed rs6922269, and a variant on chromosome two, dubbed rs2943634, were also significantly associated with disease in the German study, at P=2.90X10-8 and P=1.61X10-7, respectively.
A combined analysis of the two studies found four other variants that may be associated with coronary artery disease, but the researchers said the finding should be treated cautiously until the data have been replicated in another cohort.
The most compelling evidence for an association with disease concerns the region on chromosome nine, Dr. Samani and colleagues said.
"The evidence of association is strong, the risk variant is common, and each copy of the allele substantially increases the probability of the disease," they said.
The replication of the earlier Science studies also increases their confidence in the result, the researchers said.
But exactly how the genetic variation plays a role in heart disease remains unclear, although the region contains two genes, CDKN2A and CDKN2B, which may be involved in the pathogenesis of atherosclerosis, the researchers noted.
Indeed, finding genetic associations in this way is only the first step toward clinical application, according to Anthony Rosenzweig, M.D., of Beth Israel Deaconess Medical Center in Boston and the Harvard Stem Cell Institute, in an accompanying editorial. He wrote that the "work is still years from enabling personalized coronary care or elucidating new mechanisms."
Nevertheless, the study is an important proof of principle, he said, that now needs to be extended to other populations -- both the British and German studies included mainly people of European descent -- and should spark research into exactly how the genetic variation translates into disease.
Although the New England Journal of Medicine usually concentrates on research with a clinical focus, these three studies were published because they "represent an important advance in medicine," according to editor Jeffrey Drazen, M.D., and deputy editor Elizabeth Phimister, Ph.D.
"The onus now lies on us to explain how variation in the function of these genes leads to clinical disease," the editors said.
But once that understanding has been achieved -- although it will not be easy -- "we should have the keys that will lead us to eventual improvements in patient care," they said.
The study was supported by the Wellcome Trust, the German Federal Ministry of Education and Research, the European Union, the British Heart Foundation, the U.K., the Deutsche Forschungsgemeinschaft, the Deutsche Herzstiftung and the KORA research platform of the GSF-National Research Centre. No potential conflict of interest was reported.Additional source: New England Journal of MedicineSource reference: Samani NJ et al. "Genomewide Association Analysis of Coronary Artery Disease." N Engl J Med 2007;357. Additional source: New England Journal of MedicineSource reference: Rosenzweig A. "Scanning the Genome for Coronary Risk." N Engl J Med 2007;357.

Nonfasting Triglyceride Levels Linked to Increased Cardiovascular Risk

HERLEV, Denmark, July 17 -- Elevated nonfasting triglycerides are associated with increased risk of fatal and nonfatal cardiac events, according to results of two large, long-term, prospective cohort studies.
In both studies, published in the July 18 issue of the Journal of the American Medical Association, the risk appeared to be greatest for women.
The first study, conducted by Borge G. Nordestgaard, M.D., D.M.Sc., of Herlev University Hospital, and colleagues, found that women who had nonfasting triglycerides of 442.5 mg/dL or more were 16.8 times more likely to have a myocardial infarction (multifactorially adjusted HR 5.4) than women who had nonfasting triglycerides of less than 88.5 mg/dL (P<0.001 for trend).
Among men, adjusted hazard ratio for MI was 4.6 (multifactorially adjusted HR 2.4) for those who had nonfasting triglycerides of 442.5 mg/dL or more compared with men whose nonfasting triglycerides were less than 88.5 mg/dL (P<0.001 for trend).
Likewise, for both men and women, the risks for ischemic heart disease and death increased in tandem as nonfasting triglycerides increased, but again the risks were greatest for women -- an age-adjusted HR of 5.9 (multifactorially adjusted HR 2.6) for ischemic heart disease and an HR of 4.3 (multifactorially adjusted HR 3.3) for death versus 2.9 (1.5) and 2.0 (1.8) respectively for men (P<0.001 for trend).
In the second study, Paul M. Ridker, M.D., M.P.H., of Brigham and Women's Hospital in Boston, and colleagues, reported that after adjusting for total cholesterol, HDL cholesterol, and insulin resistance, nonfasting triglyceride levels were a strong predictor of cardiovascular events in 6,391 women enrolled in the Women's Health Initiative (P=0.006 for trend).
In addition to confirming nonfasting serum triglyceride level as an independent predictor of events, a secondary analysis of the WHI data found that triglyceride levels measured two to four hours after a meal were the strongest predictors of events (95% CI for highest versus lowest tertile of triglycerides 4.48, 1.98-10.15 (P<0.001 for trend).
The Danish researchers followed 7,587 women and 6,394 men, ages 20 to 93, who lived in the Copenhagen area from 1976 to 1978. The participants were followed for a mean of 26 years.
The participants were categorized by baseline nonfasting triglyceride levels, 88.5-176.1 mg/dL, 177.0-264.6 mg/dL, 265.5-353.0 mg/dL, 354.0-441.6 mg/dL, and 442.5 mg/dL or more.
Among the findings:
For each respective category increase above 88.5 mg/dL, the age-adjusted HR for MI among women were 2.2, 4.4, 3.9, 5.1 and 16.8 and for men they were 1.6, 2.3, 3.6, 3.3, and 4.6 (P<0.001 for trend for both).
For ischemic heart disease the category specific age-adjusted HRs for women were 1.7, 2.8, 3.0, 2.1, and 5.9 and for men the corresponding age-adjusted HRs were 1.3, 1.7, 2.1, 2.0, and 2.9 (P<0.001 for trend for both).
Mortality age-adjusted HRs for women were 1.3, 1.7, 2.2, 2.2, and 4.3 and for men they were 1.3, 1.4, 1.7, 1.8, and 2.0 (P<0.001 for trend for both).
Dr. Ridker and colleagues assessed triglycerides from blood samples taken from November 1992 through July 1995 from the 26,509 women enrolled in the WHI. Of those, 20,118 samples were fasting triglycerides and 6,391 were nonfasting. During a median follow-up of more than 11 years, there were 1,001 incident cardiac events.
Among the findings:
After adjusting for age, blood pressure, smoking, and use of hormone therapy both fasting and nonfasting triglycerides were predictive of cardiovascular events.
When the samples were adjusted for total cholesterol, HDL, and measures of insulin resistance, fasting triglycerides levels were no longer predictive (P=0.90 for trend).
It's difficult to determine whether it's the high triglyceride levels or the risk factors associated with high triglycerides that are responsible for the increased events observed in both studies, wrote Patrick E. McBride, M.D., M.P.H., of the University of Wisconsin, in an accompanying editorial.
Elevated triglyceride levels have a substantial effect on lipoprotein metabolism, which explains much of the controversy about the role of serum triglycerides as a risk factor for CHD, he added.
One reason to focus on nonfasting triglyceride levels in the pathogenesis of cardiovascular disease, the authors of both studies noted, is because postprandial triglyceride-rich remnant lipoproteins can penetrate the endothelial cell layer and reside in the subendothelial space, where they can contribute to the formation of foam cells, a hallmark of early atherosclerosis.
For clinicians, Dr. McBride said, the significance of the studies is clear, risk for atherosclerosis-related events was significantly increased when triglyceride levels are between 150 mg/dL and 1000 mg/dL.
"Therefore, it is important to aggressively and comprehensively treat patients with dyslipidemias that include high levels of triglycerides, low levels of HDL-C, and the presence of small LDL-C particles, using both lifestyle change and medications if necessary," Dr. McBride concluded.
Dr. Nordestgaard noted that the Danish finding was limited by its sample, which included only white participants. Moreover "the relatively small sample sizes and wide confidence intervals in groups with the highest triglycerides are of concern," they wrote.
Dr. Ridker acknowledged that the WHI study also had design limitations including the fact that participants were not randomly assigned to fasting versus nonfasting triglyceride testing.
Additionally, the findings about timing of postprandial phlebotomy was not straightforward because the last meal prior to blood draw was not given in a standardized manner.
The Danish study was funded by the Danish Heart Foundation, the Danish Medical Research Council, the Research Fund at Rigshospitalet, Copenhagen University Hospital, and European Union, Sixth Framework Priority. Dr. Nordestgaard reported that he was a consultant for Merck, Pfizer, B.G. Medicine, and AstraZeneca.
The study by Ridker et al was funded by the Donald W. Reynolds Foundation, the Leducq Foundation, the National Heart, Lung, and Blood Institute, Abbott Laboratories and the National Cancer Institute. Dr. Ridker reported research support from the American Heart Association, the Doris Duke Charitable Foundation, the Leducq Foundation, the National Cancer Institute, the National Heart, Lung, and Blood Institute, the Donald W. Reynolds Foundation, the James and Polly Annenberg La Vea Charitable Trusts, Abbott, AstraZeneca, Bayer, Bristol-Myers-Squibb, Dade-Behring, Isis Pharmaceutical, Novartis, Pharmacia, Roche, Sonofi-Aventis, and he is listed as a coninventor on patents held by Brigham and Women's Hospital.
Dr. McBride received honoraria from Bristol-Myers Squibb, Kos, Liposcience, Merck, Pfizer, Reliant, and Schering Plough and previously served as a consultant for Merck.Primary source: Journal of the American Medical AssociationSource reference: Nordestgaard B et al "Nonfasting Triglycerides and Risk of Myocardial Infarction, Ischemic Heart Disease, and Death in Men and Women" JAMA. 2007; 298:299-308. Additional source: Journal of the American Medical AssociationSource reference: Bansal S et al "Fasting Compared With Nonfasting Triglycerides and Risk of Cardiovascular Events in Women" JAMA. 207; 298:309-316. Additional source: Journal of the American Medical AssociationSource reference: McBride PE "Triglycerides and Risk for Coronary Heart Disease" JAMA. 2007; 298:336-338.

New AHA Statement Sets Lower BP Targets for High-Risk and Established CAD Patients

June 22, 2007 — Blood pressure (BP) targets in men and women with established coronary artery disease (CAD), or who are at high risk of developing CAD should be 130/80 mm Hg: lower than those specified in the Joint National Committee (JNC) 7th report of 140/90 mm Hg, a new American Heart Association Scientific Statement specifies. The BP target of 140/90 remains appropriate for general CAD prevention, the writing group, led by Dr Clive Rosendorff (Mount Sinai School of Medicine, New York, NY), says.
The JNC 7th report currently recommends that the lower target of 130/80 mm Hg be used in patients with diabetes or chronic kidney disease (CKD); the new statement suggests this group should be broadened. "When people walk into their doctors' offices with systolic pressures between 130 and 140, most primary care doctors and many cardiologists would believe that patient had normal blood pressure and wouldn't require additional treatment," Rosendorff told heartwire. "We have tried to show that in fact there is a great deal to be gained by treating those patients to lower levels."
The statement deals both with primary prevention patients — divided into "general" prevention or high CAD risk — as well as patients with pre-existing CAD in different forms: stable angina; unstable angina/non-ST elevation MI; ST-elevation MI; heart failure secondary to CAD. Patients in the high-risk category are defined as patients who also have diabetes, CKD, known CAD, a CAD-risk equivalent (carotid disease, peripheral artery disease, or abdominal aortic aneurysm), or a ten-year Framingham risk score ≥ 10%; these patients should all have their BP lowed to < 130/80 mm Hg, as would patients with pre-existing CAD. In patients with heart failure, physicians should consider a target even lower, the authors suggest, < 120/80 mm Hg, although blood pressure lowering should be slow, they caution.
Drug Therapy Recommendations
Authors of the statement also provide recommendations for drug therapy, according to CAD status. In keeping with recent European guidelines, beta-blockers are no longer recommended for blood pressure control in the primary prevention group.
"There have been lots of comparative clinical trails to show that for preventing both stroke and CAD complications, beta-blockers are inferior to newer classes of drugs like ACE inhibitors, angiotensin-receptor blockers, or calcium channel blockers, so we have dropped beta-blockers right out of the picture for prevention," Rosendorff explained. "However, once there is established, occlusive CAD, with symptoms like angina or acute MI, then beta-blockers come right back to center stage."
To heartwire, Rosendorff emphasized that this is the first time an AHA writing group has specifically tackled the topic of BP targets in the CAD population, despite the fact that the two conditions are pathophysiologically linked and constitute an "enormous public health issue." The new guidelines first appeared online last month; Rosendorff said he has already received some mixed feedback. "Some people think that 130/80 mm Hg is too low, and some think it's not low enough," he said. Overall, however, Rosendorff thinks many physicians are not yet aware of the recommendations, or do not appreciate the magnitude of the change.
"It doesn't sound like a lot — just 10 mm Hg — but in terms of the number of patients who are going to now require treatment if these guidelines are followed, it is huge," he said. "The impact is going to be that there will be many, many more people who will require antihypertensive medication, and of those already on antihypertensive medication, the management will need to be much more intensive or aggressive. But that's also going to translate into much better outcomes, much fewer heart attacks, and probably fewer strokes and fewer patients going into kidney failure."
Circulation. 2007;115;2761-2788.