Обзор американских кардиологических журналов за неделю (ссылки)

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Study: Smoking doubles risk for AF

Chamberlain A. Heart Rhythm. 2011;doi:10.1016/j.hrthm.2011.03.038.

Among participants of the Atherosclerosis Risk in Communities study, those who smoked were twice as likely to develop atrial fibrillation as those who did not. Although at a lesser risk, former smokers were also at an increased for developing the arrhythmia.

“AF is a serious health issue that decreases quality of life and significantly increases the risk of stroke,” Alanna M. Chamberlain, PhD, study co-author from the department of health sciences research at Mayo Clinic in Rochester, Minn., said in a press release. “It is my hope that our study findings will shed more light on the impact that smoking has on CVDs, and help individuals realize they can play a role in preventing the development of AF.”

The prospective study involved individuals who were either current (n=4,005), former (n=4,950) or who had never been smokers (n=6,374). Chamberlain and colleagues examined the effect of smoking status on the risk of incident AF starting at baseline (1987-1989) and ending in December 2002.

During follow up, they reported 876 AF events among participants. Compared with those who never smoked, current (HR=2.05; 95% CI, 1.17-2.47) and former (HR=1.32; 95% CI, 1.10-1.57) smokers had an elevated risk for incident AF. Specifically, among smokers, those who smoked the heaviest, or those smoking the equivalent of one pack a day for 40 years, had the greatest risk for incident AF (HR=2.31). However, quitting smoking did moderately reduce the risk for AF vs. those who continued (HR=0.88).

These results, according to researchers, remained consistent regardless of gender or race of the participant, as well as whether the event was AF or atrial flutter.
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US lacking participants in NHLBI-backed randomized CV trials

Kim E. J Am Coll Cardiol. 2011;58:671-676.

The percentage of international participation in CV randomized controlled trials sponsored by the National Heart, Lung and Blood Institute was substantial when compared with US participation, results from a new study suggested.

Researchers used The NIH registry to search for phase III or IV CV randomized controlled trials (RCTs) funded by the NHLBI that had an outcome of MI, stroke or death and were published between 1997 and 2009. Of the 1,488 that were funded by the NHLBI, only 24 studies met the full criteria.

International participation (IP) was found in 19 trials that included 151,682 patients. The median IP was 9.5%. Across 11 coronary artery disease trials, nearly 50% of them had international enrollment. High IP was also found in high-risk trials and trials testing acute interventions.

Out of all CV RCTs, CAD trials had the most substantial rates of international enrollment. The researchers also noted that the most commonly listed international site was Canada (16 of 24 trials were conducted there), and that decreased participation of US patients in NHLBI-sponsored CV trials is a cause for concern.

In an accompanying editorial, Robert M. Califf, MD, of the Duke University School of Medicine, and Robert A. Harrington, MD, of the Duke Clinical Research Institute, both in Durham, N.C., reiterated the importance of both conducting more CV RCTs in the US and increasing participant enrollment at US-based sites.

“This report by Kim and colleagues represents a wake-up call. If we fail to heed it, we may see the US clinical research enterprise go the way of so many other American industries: lost to more efficient overseas competitors,” the authors wrote. “Such an outcome would be more than an economic disaster. It would also deprive the American public relevant, high-quality evidence essential for making appropriate decisions about health care.”
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More death certificates cite diabetes as underlying cause of death

McEwen LN. Diabetes Care. 2011;34:1529-1533.

Death certificates now list diabetes as the underlying cause of death more often than in previous years, data from the Translating Research into Action for Diabetes trial suggest.

Of 2,261 participants enrolled in the study who died from 2000 to 2007, 41% had diabetes listed on their death certificates and 13% cited the disease as the underlying cause of death. These findings indicated increased reporting of diabetes as the underlying cause of death over time, the researchers said, although the frequency of the disease’s appearance on death certificates in general remained unchanged.

In contrast, the listing of cardiovascular disease as an underlying cause of death declined significantly throughout the study period, a factor that may have played a role in the increased reporting of diabetes as an underlying cause of death, the researchers said. They attributed this trend to a decrease in the reporting of cardiac causes of death for men and cerebrovascular causes of death for women. Diabetes was more likely to be recorded anywhere on the death certificate in decedents with CVD cited as the underlying cause of death.

“Although diabetes listed as any cause of death was stable over time, we have observed a statistically significant increase in reporting of diabetes as the underlying cause of death on death certificates between 2001 and 2008 independent of age at death and duration of diabetes at death,” the researchers wrote. “If this trend is indeed occurring on a national level, it may complicate the interpretation of mortality rates ascertained from death certificates.”

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Risk factors at middle age adversely affect brain size, function later in life

Debette S. Neurology. 2011;77:461-468.

Diabetes, high BP, smoking and being overweight during middle age may have severe consequences on brain aging and cognition a decade later, new study results suggested.

“These factors appeared to cause the brain to lose volume, to develop lesions secondary to presumed vascular injury, and also appeared to affect its ability to plan and make decisions as quickly as 10 years later. A different pattern of association was observed for each of the factors,” Charles DeCarli, MD, study researcher with the University of California at Davis in Sacramento, said in a press release.

DeCarli and researchers looked at 1,352 participants (mean age, 54 years) without dementia from the Framingham Offspring Study to determine the association between midlife vascular risk factors and change in MRI markers of brain injury and cognitive function 10 years later.

They reported that hypertension was associated with accelerated white matter hyperintensity volume (P<.001), one of the MRI markers, and a decline in executive function (P=.012), whereas diabetes correlated with a marked increase in temporal horn volume (P=.012), a marker for accelerated hippocampal atrophy. Smoking also correlated with a rise in temporal horn volume (P=.012), while additionally proving detrimental to both total brain volume (P=.025) and extensive change in white matter hyperintensity volume (P=.021).

Furthermore, obesity was a predictor of a top quartile change in executive function (P=.035), whereas increasing waist-to-hip ratio led to a decline in total brain volume (P=.021).

“Our findings provide evidence that identifying these risk factors early in people of middle age could be useful in screening people for at-risk dementia and encouraging people to make changes to their lifestyle before it’s too late,” DeCarli said.

Disclosure: Dr. DeCarli serves as a consultant for Takeda Pharmaceutical Company Limited and Avanir Pharmaceuticals; receives research support from Merck Serono and the NIH; and is the editor-in-chief of Alzheimer Disease and Associated Disorders.

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APPRAISE-2: Apixaban failed to meet primary efficacy, safety endpoints

Alexander J. N Engl J Med. 2011;doi:10.1056/NEJMoa1105819.

The oral direct factor Xa inhibitor apixaban did not significantly improve the primary efficacy endpoint of patients with an acute coronary syndrome and substantially increased the risk for major bleeding, resulting in the early termination of the APPRAISE-2 trial.

“The results of the current trial raise doubt about whether meaningful incremental efficacy can be achieved with an acceptable risk of bleeding by combining a long-term oral anticoagulant with both aspirin and a P2Y12-receptor antagonist in patients with coronary disease,” the researchers wrote.

The Apixaban for Prevention of Acute Ischemic Events 2 (APPRAISE-2) trial was a double blind, placebo-controlled trial in which 7,392 patients with a recent ACS and at least two additional risk factors for recurrent ischemic events were randomly assigned to twice-daily 5 mg apixaban (Bristol-Myers Squibb, Pfizer; n=3,705) or placebo (n=3,687), besides standard antiplatelet therapy.

During follow-up (median, 241 days), the primary efficacy outcome of a composite of CV death, MI or ischemic stroke was not significantly improved in the apixaban group (HR=0.95; P=.51). Further analysis indicated that the study’s primary safety endpoint of major bleeding, as stated in the Thrombolysis in Myocardial Infarction definition, occurred significantly more often among those given apixaban (HR=2.59; P=.001), with a greater number of intracranial and fatal bleeding events reported vs. placebo.

“(The findings) definitively confirm the increases in bleeding observed in the phase 2 trials of factor Xa inhibitors administered in addition to antiplatelet therapy,” the researchers concluded. “Unfortunately, the reductions in ischemic events suggested in the phase 2 trial were not observed in this larger phase 3 trial.”

The trial was funded by Bristol-Myers Squibb and Pfizer.
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Torcetrapib raised HDL, may help control diabetes

An analysis of the ILLUMINATE trial data revealed new findings: Torcetrapib, a cholesteryl ester transfer protein inhibitor, may improve HDL levels and blood glucose in those with diabetes who are also taking a statin.

Researchers discovered the beneficial effects of torcetrapib while analyzing data from the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, which was halted in 2006 because patients with diabetes assigned to torcetrapib and atorvastatin (Lipitor, Pfizer) had more cardiovascular problems and a higher mortality rate vs. patients assigned to atorvastatin and a placebo. Researchers later determined that the adverse events were related to other effects of torcetrapib, not its cholesteryl ester transfer protein (CETP) inhibition, according to a press release from the American Heart Association.

Data from ILLUMINATE showed that after 3 months of treatment, more than 6,600 patients with diabetes who were taking torcetrapib and atorvastatin had lower fasting blood glucose levels (0.34 mmol/L) and fasting insulin levels (11.7 mcU/mL) than patients taking statin and placebo. Insulin resistance also improved in the investigational combination therapy group. After 6 months, average blood glucose levels were lower in the torcetrapib and atorvastatin group (7.06%) compared with the statin and placebo group (7.29%). Additionally, HDL levels improved 66.8% after 1 year with torcetrapib and atorvastatin compared with a minimal change with statin and placebo. Researchers said it is unclear whether torcetrapib’s effect on HDL may account, in part, for the improvement in diabetes control. Torcetrapib also improved glucose and insulin measurements in study participants without diabetes, although not as much.

“The possibility that CETP inhibitor drugs may not only reduce the risk of [myocardial infarction] and stroke, but may also improve the control of blood sugar in people with diabetes, is an exciting prospect that may translate into real health benefits for people with diabetes,” Philip Barter, MBBS, PhD, director of the Heart Research Institute at University of Sydney, Australia, said in a press release.

Although torcetrapib’s effect on diabetes was not as effective as other commonly used antidiabetic therapies, “inhibition of CETP has the potential to prevent a worsening of diabetic control that often occurs in people taking statin drugs,” Barter said.

ILLUMINATE included more than 15,000 participants aged 45 to 75 years with a history of MI, stroke, chest pain, peripheral vascular disease or cardiac revascularization, and all were taking antidiabetic therapies.

Although the development of torcetrapib was halted, researchers said two other CETP inhibitors that do not cause the adverse effects — dalcetrapib and anacetrapib — are in the drug approval pipeline.

In an accompanying editorial, Stephen D. Wiviott, MD, a member of the TIMI Study Group and from the CV division at Brigham and Women’s Hospital, Harvard School of Medicine, said “this analysis may provide additional insight into the relationships between two key risk factors for CV disease, lipids (in particular, HDL) and glycemia.”

However, Wiviott said the glycemic findings from ILLUMINATE may be due to chance, as is the case in some post hoc analyses.

“With these important reductions of key surrogate markers of the risk of CV disease, including LDL, HDL, triglycerides and glycemia, this seems like a drug that should be widely prescribed to those at risk for CVD. Of course, it is not now, and will never be, prescribed to our patients for these indications. The reason for this is that, despite the observed benefits on these key surrogates, patients treated with torcetrapib in ILLUMINATE had 25% more CV events, including 58% more total deaths than those treated with placebo,” Wiviott wrote.

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Sirolimus- and probucol-eluting stent shows promise

Massberg S. Circulation. 2011;124:624-632.

A sirolimus- and probucol-eluting stent demonstrated noninferiority to a zotarolimus-eluting stent regarding a host of clinical endpoints, according to study results.

The current trial involved 3,002 patients randomly assigned to the dual-drug stent or the zotarolimus-eluting stent. The aim was to demonstrate noninferiority of the dual-drug stent by evaluating for a composite primary endpoint of the combined incidence of cardiac death, target vessel-related MI or target lesion revascularization. The overall follow-up period was 1 year, with angiography scheduled at 6 to 8 months.

The sirolimus- and probucol-eluting stent yielded a 13.1% incidence rate for the combined primary endpoint vs. 13.5% for the zotarolimus-eluting stent, which the researchers said was noninferior (HR=0.97, 95% CI, 0.78-1.19).

The dual-drug stent was linked to a 1.1% incidence rate of definite/probable stent thrombosis vs. a 1.2% rate in the zotarolimus group (HR=0.91; 95% CI, 0.45-1.84).

No differences were observed in terms of angiographic efficacy. In-segment binary angiographic restenosis was 13.3% in the dual-drug group and 13.4% in the zotarolimus group (P=.95); in-stent late luminal loss was 0.31 ± 0.58 mm in the dual-drug group and 0.29 ± 0.56 mm in the zotarolimus group (P=.46).

Researchers from sites in Germany said two stents — the polymer-free dual-drug sirolimus- and probucol-eluting stent and a new generation permanent polymer zotarolimus-eluting stent — have demonstrated encouraging results in light of adverse events associated with durable polymer coatings after drug-eluting stent implantation.
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IRS1 gene variant improved insulin control for patients on certain diets
Qi Q. Circulation. 2011;124:563-571.

A high-carbohydrate, low-fat diet may improve insulin control among patients with a specific variant in the IRS1 gene, according to recent results.

The aim of the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial was to investigate whether the rs2943641 variant in the IRS1 gene, which has recently been linked to insulin resistance and hyperinsulinemia, modifies the long-term changes in insulin resistance and body weight in response to weight-loss diets.

Researchers from several sites in the United States genotyped this variant in 738 overweight adults. Eligible participants had been randomly assigned to one of four diets varying in macronutrient contents. The diet lasted 2 years, during which progress in fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR) and weight loss by genotypes were assessed.

Among patients in the high-carbohydrate diet group, 6-month results indicated that participants with the risk-conferring CC genotype experienced greater decreases in insulin (P=.009), HOMA-IR (P=.015) and weight loss (P=.018) than those without this genotype. Among patients in the low-carbohydrate diet group, an opposite genotype effect on changes in insulin and HOMA-IR (P≤.05) was observed.

The other two diet groups did not experience significant differences across genotypes. “The tests for genotype by intervention interactions were all significant (P<.05),” the researchers said.

The genotype effect on changes in insulin and HOMA-IR continued to be significant at 2 years among those on the diet with the highest carbohydrate content (P<.05). The 2-year results also indicated that the high-carbohydrate diet yielded greater improvements in insulin and HOMA-IR (P for genotype-time interaction ≤.009) in participants with the CC genotype than those without this genotype.

“Individuals with the IRS1 rs2943641 CC genotype might obtain more benefits in weight loss and improvement of insulin resistance than those without this genotype by choosing a high-carbohydrate and low-fat diet,” the researchers wrote.

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Oral Xa Drug Matches Warfarin in Afib

By Crystal Phend, Senior Staff Writer, MedPage Today
August 10, 2011

This randomized controlled trial compared rivaroxaban, an oral factor Xa inhibitor, to warfarin for the prevention of stroke or systemic embolism in patients with atrial fibrillation.

Rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolization in both the per-protocol and intention-to-treat analysis. Rivaroxaban was not superior to warfain in the intention-to-treat analysis.

There was no difference in major bleeding between warfarin and rivaroxaban.
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The oral factor Xa inhibitor rivaroxaban (Xarelto) is at least as good as warfarin for stroke prevention in atrial fibrillation, with a similar rate of major bleeding and greater ease of use.

In the per protocol analysis, stroke or systemic embolism occurred at a rate of 1.7% per year with rivaroxaban compared with 2.2% per year with warfarin, Manesh R. Patel, MD, of Duke University Medical Center in Durham, N.C., and colleagues reported in the pivotal ROCKET-AF trial.

Rivaroxaban was non-inferior to warfarin for the prevention of stroke or systemic embolization in both the per-protocol (P<0.001) and intention-to-treat analyses (P<0.001), according to the study published online in the New England Journal of Medicine.

In the as-treated safety analysis, in which subjects must have received at least one dose of a study drug and included events which occurred while receiving the assigned drug or within two days after discontinuation, rivaroxaban was superior to warfarin (P=0.01). Rivaroxaban was not superior in the intention-to-treat analysis (P=0.12).

"For sure it's at least as good as warfarin," Patel told MedPage Today. "It's a once-a-day therapy without monitoring ... so there are some clear potential advantages here."

Safety may be another attractive point, he noted in the interview.

Although overall bleeding events didn't differ significantly for the two treatments (annual rate 14.9% rivaroxaban versus 14.5% warfarin, P=0.44), intracranial hemorrhage fell to 0.5% with rivaroxaban compared with 0.7% on warfarin (P=0.02).

Fatal bleeds also dropped to 0.2% and 0.5%, respectively (P=0.003), for a trend to fewer deaths overall in the as-treated safety population (1.9% versus 2.2% per year, P=0.07).

Bleeding from GI sites, bleeding that reduced hemoglobin levels, and bleeding that required transfusion, however, were all significantly more common with rivaroxaban, the researchers noted.

A significant increased risk of major bleeding from a gastrointestinal site occurred in the rivaroxaban arm (3.2% versus 2.2%, P<0.001).

These findings matched those reported at the American Heart Association meeting last November that led drugmaker Johnson & Johnson to apply to the FDA in January for an indication in stroke prevention in atrial fibrillation for rivaroxaban.

The drug won FDA approval last month for a separate indication -- prevention of deep vein thrombosis in patients undergoing knee or hip replacement surgery, adding to a rapidly changing landscape in anticoagulation choices.

Another new agent, the direct thrombin inhibitor dabigatran (Pradaxa) was approved for stroke prevention in atrial fibrillation last October based on the RE-LY study results showing noninferiority to warfarin at a low dose and superiority at a high dose. The higher dose, 150 mg twice daily, was approved by the FDA for use in atrial fibrillation.

Oral alternatives to warfarin for atrial fibrillation have arrived, Gregory J. del Zoppo, MD, of the University of Washington in Seattle, and Misha Eliasziw, PhD, of the University of Calgary, Alberta, announced in an editorial accompanying the NEJM paper.

"Their simplicity of use is attractive," del Zoppo and Eliasziw wrote, "and they appear to have an efficacy similar to that of warfarin, with the proviso that comparisons seem to depend on how easily the patient can be treated with warfarin."

Rivaroxaban and dabigatran don't require the blood tests, special diet, or alcohol restrictions necessary with warfarin.

Among the 14,264 ROCKET-AF patients, those randomized to warfarin were in the therapeutic INR range only 55% of the time on average, which Patel acknowledged was lower than in other anticoagulant trials.

In RE-LY, time in therapeutic range in the warfarin arm averaged 64%.

While less than optimal, the difficulty with management in ROCKET-AF "may be a reflection of what life is like in community practice," noted stroke expert Ralph Sacco, MD, of the University of Miami and AHA immediate past president.

Patel pointed to the trial's population as the oldest enrolled, with more high-risk patients, higher levels of comorbidity, and a geographic diversity across 45 countries, including some that used lower INR targets and others with poor INR management.

But, the group noted, "The efficacy of rivaroxaban, as compared with warfarin, was as favorable in centers with the best INR control as in those with poorer control."

ROCKET-AF and RE-LY both found no reduction in overall major and nonmajor clinically relevant bleeding over warfarin but lower intracranial bleeding risk.

One reason may be that both rivaroxaban and dabigatran impact a single hemostatic target whereas warfarin hits multiple targets, the editorialists suggested.

Neither trial addressed the lack of antidotes to these drugs that would be needed to reverse their anticoagulant effects in the case of life-threatening hemorrhage or surgery, del Zoppo and Eliasziw warned.

"All these issues need to be taken into account in clinical decision making," they concluded in the editorial.

Sacco agreed that physicians, patients, and professional organizations will have a job ahead of them sorting out the nuances of trial design, statistics, and pros and cons of the various anticoagulants on the horizon for stroke prevention in atrial fibrillation.

"Any new medication to help reduce stroke risk among those with atrial fibrillation would be helpful," he told MedPage Today. "What may happen, which I think would be a good thing, is there may be multiple options."

The study was funded by Johnson & Johnson and Bayer.

Patel reported having received money to his institution from Johnson & Johnson in the form of research grants and travel and trial activities, serving on an advisory board to Genzyme, and consulting for Ortho McNeil Jansen and Bayer Healthcare regarding rivaroxaban.

del Zoppo reported having no conflicts of interest to disclose.

Eliasziw reported having received funds from the National Institute of Neurological Disorders and Stroke for serving on the data safety monitoring board of the Warfarin Versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) trial.

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Men, Leaner Folks Less Likely to Be Treated for High BP

By Kristina Fiore, Staff Writer, MedPage Today
Published: August 10, 2011
Reviewed by Zalman S. Agus, MD; Emeritus Professor
University of Pennsylvania School of Medicine and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Note that this report reviewed NHANES surveys to identify clinical characteristics associated with untreated hypertension, uncontrolled hypertension and apparent treatment-resistant hypertension.


Consider that this study found that in the years 2005 to 2008, more than half of uncontrolled hypertensives were untreated and unaware of their hypertension. Also note that the prevalence of apparent treatment-resistant hypertension increased significantly in the last survey and appeared to be associated with aging, obesity and diabetes.

Men and patients who are leaner and generally healthier are less likely to have their hypertension treated, researchers said.

Male sex, body mass index (BMI) below 25 kg/m2, lack of chronic kidney disease, lower heart disease risk, and making fewer visits to the doctor were associated with high blood pressure going untreated, Brent Egan, MD, of the Medical University of South Carolina in Charleston, and colleagues reported online in Circulation: Journal of the American Heart Association.

When patients were treated, those whose hypertension remained uncontrolled on one or two medications were more likely to be older and have a greater risk of heart disease, while those who were treatment-resistant (uncontrolled on three drugs or more) also had a higher risk of heart disease; but they went to the doctor more frequently, were obese, and had chronic kidney disease, too.

Defining the characteristics of these uncontrolled hypertensive patients may facilitate efforts to improve blood pressure control, the researchers said.

"Overall, physicians are doing a very good job treating and controlling hypertension," Egan said in an email to MedPage Today. "Yet there is still room for improvement."

Although the proportions of untreated and uncontrolled hypertensive patients have fallen in recent years, more than 30 million hypertensive patients remain uncontrolled in the U.S., they said.

In order to define the characteristics of both groups of patients, the researchers looked at data on 13,375 hypertensive adults from three periods of the National Health and Nutrition Examination Survey (NHANES): 1988-1994, 1999-2004, and 2005-2008.

Overall, the proportion of uncontrolled hypertensive patients fell from 73.2% in 1988-1994 to 52.5% in 2005-2008.

Clinical factors linked with untreated hypertension included male sex, infrequent healthcare visits, BMI of 25 kg/m2 or below, absence of chronic kidney disease, and 10-year Framingham heart risk below 10% (P<0.01 for all).

Egan and colleagues said that infrequent healthcare visits is a major issue in this population, with a mean of more than 40% of untreated hypertensive patients in all survey periods reporting none or just one trip to the doctor annually.

This finding suggests that increasing health care use in all settings "is critical in reducing the burden of untreated hypertension," they wrote. "Raising the perceived value of regular preventive health care services among those without clinically overt disease emerges as an important complementary educational strategy."

About a third of all uncontrolled patients reported taking one or two antihypertensive medications in all three study periods, the researchers said. These patients were older and had higher Framingham risk scores than those who were controlled on this number of medications (P<0.01). In two of the study periods, uncontrolled patients were also more likely to be male, have Hispanic ethnicity, and fewer healthcare visits.

A "logical option," Egan and colleagues wrote, would be to add an additional antihypertensive to these patients' drug regimens, as the majority "appear to be seen frequently enough to allow treatment intensification."

Said therapeutic inertia, or the failure to further treatment when patients are uncontrolled, appears to reflect a patient-provider interaction.

"In addition to provider interventions," the researchers wrote, "educating patients, especially those at higher risk, on the importance of blood pressure control may facilitate efforts to overcome therapeutic inertia."

They said the data also suggest that medication selection affects control. Those uncontrolled on one or two medications were less likely to report taking a diuretic, an ACE inhibitor, or an angiotensin receptor blocker than those who were controlled on this number of drugs -- which "aligns with the efficacy of diuretics and renin-angiotensin system blockers, especially in combination, for blood pressure control," the researchers wrote.

Apparent treatment-resistant hypertension -- disease that was uncontrolled with three or more drugs -- increased from 15.9% to 28% of treated patients between 1988 and 2008 (P<0.001).

"The rise in treatment-resistant hypertension is of real concern, and reflects a population which is aging and more obese with more diabetes and chronic kidney disease," Egan said in an email to MedPage Today.

Indeed, the clinical characteristics associated with treatment-resistant disease included obesity, chronic kidney disease, more frequent healthcare visits (four or more per year), and Framingham risk scores above 20% (P<0.01).

Infrequent use of aldosterone antagonists among this group of patients was notable, the researchers said, as several trials have shown that adding one of these agents to treatment regimens lowers systolic blood pressure by 20 to 25 mm Hg and diastolic blood pressure by 10 to 15 mm Hg in refractory patients.

Egan and colleagues added that personalized medicine -- such as hemodynamic and renin-guided therapeutics -- and genetic testing may be effective complementary approaches for treatment-resistant patients.

Though the study was limited by a relatively small sample size, self-reported data, and hypertension defined by a single measurement, the researchers concluded that national efforts to increase healthcare insurance coverage and use of primary care services may be a boon to hypertension awareness, treatment, and control.

Egan said in order to improve control among their own patients, physicians should continue to encourage health lifestyle changes and promote medication adherence. He also urged an increase in dose or number of medications when treatment goals go unmet.

For those who are still uncontrolled on three or more drugs, he said, document blood pressure outside the office to evaluate a "white-coat" effect -- though he noted that this is a "controversial area" -- to confirm resistance. Then, consider either intensifying diuretic therapy or, "while not an established part of current guidelines," hemodynamic- or renin-guided treatment changes.

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Herceptin Heart Risks Clarified for Older Patients

By Charles Bankhead, Staff Writer, MedPage Today
August 10, 2011

Explain that older breast cancer patients with heart disease or diabetes have a significantly increased risk of cardiotoxicity when treated with trastuzumab (Herceptin).

Point out that around one-quarter of the patients had a cardiac event that had a time to onset ranging from three to 132 weeks after the start of trastuzumab-based therapy, and was not always reversible.
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Older breast cancer patients with heart disease or diabetes have a significantly increased risk of cardiotoxicity when treated with trastuzumab (Herceptin), according to data from a single-center chart review.

More than a fourth of patients had clinically significant declines in left ventricular ejection fraction (LVEF) during treatment with the anti-HER2 antibody. Two-thirds of the episodes (8 of 12) were asymptomatic.

Of the four patients who developed symptomatic congestive heart failure (CHF), three recovered heart function over several weeks, but one patient did not regain cardiac function despite stopping trastuzumab and receiving standard CHF therapy, as reported online in Annals of Oncology.


Even though most declines in heart function were asymptomatic and all but one patient regained function, the findings point to a need for caution, the authors noted.

"The fact that the mortality rate at five years after diagnosis of CHF is approximately 50% in patients older than 65 years warrants close surveillance of early symptoms and cardiac function in the elderly breast cancer population to be treated with trastuzumab," Cesar Serrano, MD, of Vall d'Hebron University Hospital in Barcelona, and coauthors wrote in conclusion.

Cardiotoxicity was an unanticipated adverse effect of trastuzumab. As as result, initial clinical trials of the agent did not mandate monitoring of cardiac function, according to the article's background. Moreover, studies that did require monitoring employed different types and intervals of monitoring, complicating efforts to compare or combine results.

In contrast to anthracycline-related cardiotoxicity, the adverse effects of trastuzumab are neither dose related nor cumulative. The severity of trastuzumab-related cardiotoxicity varies widely but usually is reversible with discontinuation of the drug, the authors continued.

A limitation of many clinical trials in oncology is the inclusion of few older patients. With respect to trastuzumab, clinical trials in breast cancer generally limited participation to women 65 or younger and with good performance status. Therefore, extrapolation of results to older or sicker patients requires caution, the authors wrote.

Given the benefits of trastuzumab and the lack information about cardiotoxicity in older patients, Serrano and coauthors reviewed their own clinical experience with the agent.

Examination of medical records revealed 45 breast cancer patients age 70 or older treated with trastuzumab. The patients' median age at the start of trastuzumab was 75.9, and 11 patients were older than 80. About 90% of the patients had performance status 0-1, 56% received neoadjuvant or adjuvant trastuzumab, and the remaining 44% received the drug for metastatic disease.

Assessment of LVEF was performed at baseline and after a median interval of 4.5 months. The baseline LVEF averaged 64%. Median duration of trastuzumab treatment was 49 weeks.

The authors found that 12 (26.7%) patients had a cardiac event that had a time to onset ranging from three to 132 weeks after the start of trastuzumab-based therapy. Every patient had at least one risk factor for cardiac disease and eight had two or more risk factors.

The four patients who developed symptomatic CHF had stage IV breast cancer. Their baseline LVEF values ranged from 50.8% to 70%, and the time to onset of CHF was three, five, nine, and 72 weeks. Trastuzumab was discontinued in all cases, and the time to recovery in three patients was three, five, and 21 weeks.

The one patient who did not recover heart function had the latest onset of symptomatic heart failure, one risk factor for heart disease, and a baseline LVEF of 63.8%.

The eight patients with asymptomatic declines in LVEF included five patients with stage IV cancer. The number of cardiac risk factors ranged from one to six, with baseline LVEF ranging from 57% to 71.8%. The time to recovery of heart function was nine weeks or less in six of the eight patients.

Comparison of patients with and without cardiotoxicity showed no differences in treatment duration, baseline LVEF, history of anthracycline therapy, or left-sided radiation therapy.

In general, patients who developed cardiotoxicity during trastuzumab therapy had more cardiac risk factors. However, only two factors remained statistically significant in a multivariate analysis: pre-existing cardiac disease or disorders (P=0.017) and diabetes (P=0.010).

Obesity was a significant factor in univariate analysis but dropped out in the multivariate analysis, and other conventional risk factors such as dyslipidemia and hypertension failed to make the cut in either analysis.

"The incidence of cancer increases greatly with age and about 70% of all newly diagnosed cancers are in patients older than 65 years," the authors noted in their discussion.

"Given the expected increase in the absolute number of elderly cancer patients over the coming decades, information about efficacy and safety of anticancer treatments is needed in this population, as to date, they have been frequently excluded from pivotal studies."

The authors advised caution when interpreting the data. They noted the small sample size and the "very limited power to detect small differences in multivariate analysis."

[Chevychelov]

PCI for Blocked Arteries of Lasting Benefit in Diabetes

By Todd Neale, Senior Staff Writer, August 12, 2011

Explain that three-year follow-up of diabetic patients undergoing successful PCI for chronic total occlusions found significantly lower mortality and requirement for later bypass grafting compared with those with a failed procedure.


Note that PCI success rates were equivalent for those with and without diabetes.
Review

Long-term outcomes for patients with diabetes were significantly improved following successful percutaneous coronary intervention (PCI) for chronic total occlusions, researchers found.

Through a median of three years of follow-up, the mortality rate following a successful procedure was significantly lower than an unsuccessful one (10.4% versus 13%, P<0.05), according to Roxana Mehran, MD, of the Cardiovascular Research Foundation in New York City, and colleagues.

There was also a substantial reduction in the need for CABG during follow-up after a successful PCI (2.4% versus 15.7%, P<0.01), the researchers reported online in the American Journal of Cardiology.

Patients who did not have diabetes also had a significant reduction in the need for CABG after a successful procedure (3.2% versus 12.2%, P<0.01), although there was not a significant mortality difference based on procedural success.

"The finding that patients with diabetes seem to benefit more from recanalization [in terms of mortality] could be explained by the higher event rates in this high-risk subgroup, which increases the statistical power to detect a significant difference in mortality," the authors explained.

Few data existed on the long-term outcomes of PCI for chronic total occlusions in patients with diabetes, Mehran and colleagues noted.

So to explore the issue, they evaluated data on 1,742 patients who underwent PCI for 1,802 chronic total occlusions at three centers in the U.S., South Korea, and Italy from 1998 to 2007. About a quarter (23%) had diabetes, and of those, 42% were insulin dependent.

The procedural success rate did not differ based on diabetes status -- it was 69.6% for patients with diabetes and 67.9% for those without diabetes (P=0.53).

In general, mortality during follow-up was higher in the those with diabetes, although the difference reached statistical significance in patients who had a successful procedure (13% versus 6.6%, P=0.01) but not in those who had a failed procedure (10.4% versus 5%, P=0.058).

In a multivariate model, insulin dependence was the strongest predictor of mortality in patients with diabetes, associated with a doubling of the risk of death (HR 2.25, 95% CI 1.04 to 4.87).

The vast majority of patients -- 96.4% of the diabetics and 94% of the non-diabetics -- received a stent during PCI. Most of the stents were drug-eluting.

The rate of major adverse cardiac events -- all-cause mortality, MI, and target vessel revascularization -- was significantly lower when drug-eluting stents were used in place of bare-metal stents in all patients regardless of diabetes status.

The difference was solely driven by a lower rate of target vessel revascularization in patients with diabetes (14.8% versus 54.1%) and without diabetes (17.6% versus 26.5%), which held up in multivariate analyses (P<0.01 for both).

Regardless of diabetes status, the rate of stent thrombosis was not increased when drug-eluting stents were used, "suggesting that drug-eluting stents are safe for chronic total occlusion PCI in patients with and without diabetes," according to the researchers.

"However, an adequately powered randomized trial or a well-designed very large registry is needed to confidently answer the question whether drug-eluting stents are as safe as bare-metal stents in chronic total occlusion PCI."

The authors acknowledged some limitations of the study, including the inability to distinguish between patients with diabetes treated with diet alone versus those treated with oral hypoglycemic therapy, the lack of information on periprocedural and postprocedural medications, and the lack of routine measurements of glycosylated hemoglobin during admission.

In addition, the drug-eluting stents used in the registry were predominantly first-generation sirolimus-eluting and paclitaxel-eluting stents.

[Chevychelov]

Women Have More Inappropriate Cardiac Nuc Scans

By Todd Neale, Senior Staff Writer, August 12, 2011

Explain that women are more likely than men to undergo a SPECT myocardial perfusion imaging study is classified as inappropriate by appropriate use criteria.


Note that overall, tests ordered by cardiologists were more likely to be appropriate and that most of the inappropriate studies were ordered by primary care physicians.
Review
Women are more likely than men to undergo a SPECT myocardial perfusion imaging study classified as inappropriate by appropriate use criteria, researchers found.

In a community teaching hospital, most of the appropriate scans (56%) were performed in men, whereas tests in women comprised the majority of inappropriate and uncertain studies (68% and 82%, respectively), according to Aarti Gupta, MD, of Miriam and Rhode Island Hospital in Providence, and colleagues.

With all other factors being equal, a woman had a nearly threefold greater risk of having an inappropriate test (RR 2.69, 95% CI 1.26 to 5.74), the researchers reported in the July/August issue of the Journal of Nuclear Cardiology.


In an accompanying editorial, Rupa Mehta, MD, of the University of Chicago, and Kim Allan Williams, MD, of Wayne State University in Detroit, suggested that the gender disparity could be a reflection of the greater likelihood that women with chest pain will present with atypical symptoms, such as shortness of breath and fatigue.

"With the higher rate of inappropriate testing in women, it is clear that physicians have a lower 'threshold' to order a stress test in women even when it does not fall into an appropriate ordering classification," they wrote. "This may reflect an understanding and appreciation for the atypical presentation of female cardiac patients."

In response to the rapidly growing use of myocardial perfusion imaging, several organizations, including the American College of Cardiology, American Heart Association, and American Society of Nuclear Cardiology, released appropriate use criteria in 2005.

But even with the growth of the technology, women continue to be under-tested, according to the researchers.

To see whether there was a gender disparity in the appropriateness of the scans that were ordered, Gupta and colleagues applied the criteria to 314 consecutive SPECT myocardial perfusion imaging tests performed at a single hospital; 48% were performed in women.

Overall, 84% of the scans were deemed appropriate, 11% inappropriate, and 5% uncertain.

Men had a higher rate of appropriate scans, and lower rates of inappropriate and uncertain scans compared with women (P<0.01).

To explore a possible reason for the disparity, the researchers examined appropriateness as it related to who was ordering the tests -- cardiologists or primary care physicians.

Overall, tests ordered by cardiologists were more likely to be appropriate (92% versus 79%, P=0.004). Most of the inappropriate studies (74%) were ordered by primary care physicians, as were most of the uncertain tests (94%).

"This could potentially be driven by a higher percentage of low-risk patients being tested by primary care physicians compared with cardiologists, or by cardiologists having a greater understanding of the appropriate use criteria and their application in clinical practice," Gupta and colleagues wrote.

But regardless of who ordered the test, scans performed in men were more likely to be appropriate than those performed in women.

The authors noted several studies that also found gender disparity among the inappropriate and uncertain SPECT tests, and the potential for various programs to reduce the overall number of inappropriate scans.

The study by Hendel et al. showed that the incorporation of appropriate use criteria into routine practice could reduce the number of inappropriate scans (J Am Coll Cardiol 2010; 55: 156-62). Whether women still had a higher number of inappropriate tests after the intervention was not stated in the study.

Gibbons et al. found more women had inappropriate tests, but after a formalized education effort, the overall number of inappropriate scans dropped (Circulation 2011; 123: 499- 503). The number rose again, however, two years later, which highlights the "importance of effective educational methods." The authors did not separate out results for women after the education intervention.

In their editorial, Mehta and Williams noted that a limitation of the current study by Gupta and colleagues was the lack of data on abnormalities identified on the scans, which would help to further classify the appropriateness of the tests and support or rebuff the clinical decision to perform the test.

"In an era where reimbursement is being challenged for patients that do not fall into specific criteria, we, as practitioners must fight to maintain our autonomy when ordering a test that might be deemed 'inappropriate' when based on clinical judgment," they wrote.

"We must provide evidence that certain patient cohorts, such as women, may require a higher 'inappropriate' imaging rate to diagnose disease, and that the use of these tests does indeed change long-term management and potentially save lives."

[Chevychelov]

Microvascular brain damage with aging and hypertension: pathophysiological consideration and clinical implications
[Ссылки доступны только зарегистрированным пользователям ]

Comparison of Cardiac Risk Scores in ED Patients With Potential Acute Coronary Syndrome
[Ссылки доступны только зарегистрированным пользователям ]

Inaccuracy of home sphygmomanometers: a perspective from clinical practice
[Ссылки доступны только зарегистрированным пользователям ]

[Chevychelov]

Coronary CTA Findings Predict Mortality Risk, or Lack Thereof

Key Points:
Obstructive, nonobstructive disease on coronary CTA both confer higher mortality risk
Absence of CAD associated with low rate of incident death
More studies needed to understand age-, sex-related differences
By L.A. McKeown
Friday, August 12, 2011

Download this article's Factoid (PDF & PPT for Gold Subscribers)


Coronary CT angiography (CTA) may be useful in patients without known coronary artery disease (CAD) to stratify mortality risk as well as identify those in whom further additional testing and/or therapy is not warranted, according to a large international registry published in the August 16, 2011, issue of the Journal of the American College of Cardiology.

For the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) study, researchers led by James K. Min, MD, of Cedars-Sinai Medical Center (Los Angeles, CA), evaluated 24,775 consecutive patients without known CAD who underwent coronary CTA for suspected coronary disease at 12 centers between 2005 and 2009.

In the per-patient analysis, obstructive and nonobstructive CAD (50% stenosis threshold) conferred increased risk of mortality compared with patients without evident CAD. In a per-vessel analysis, incident mortality showed a dose-response relationship to the number of coronary vessels exhibiting obstructive CAD, with increasing risk observed for nonobstructive, obstructive 1-vessel, 2-vessel, or 3-vessel or left main disease (table 1).

Table 1. Per-Patient and Per-Vessel Analysis: CAD vs. Normal Arteries


Risk-Adjusted HR
95% CI
P Value

Per Patient
Nonobstructive
Obstructive

1.60
2.60

1.18-2.16
1.94-3.49

0.0023
< 0.0001

Per Vessel
Nonobstructive
1-Vessel
2-Vessel
3-Vessel or Left Main


1.62
2.00
2.92
3.70

1.20-2.19
1.43-2.82
2.00-4.25
2.58-5.29

0.0018
< 0.0001
< 0.0001
< 0.0001



Similarly, per-segment analysis found higher rates of mortality were associated with greater numbers of segments with plaque, stenosis-adjusted segments with plaque, any severe proximal stenosis, and any plaque within the left main.

Absence of CAD detection on coronary CTA was associated with a low annualized rate of incident death (0.28%).

Although risk of all-cause death rose for patients aged 65 years and older with extent and severity of CAD, younger patients (< 65 years of age), in comparison, had a marked increase in risk of death associated with 2- and 3-vessel or left main CAD compared with those who had no signs of CAD (table 2).

Table 2. All-Cause Death: CAD vs. Normal Arteries


HR
95% CI
P Value

Patients < 65 Years
2-Vessel
3-Vessel or Left Main

4.00
6.19

2.16-7.40
3.43-11.2

< 0.0001
< 0.0001

Patients ≥ 65 Years
2-Vessel
3-Vessel or Left Main

2.46
3.10

1.51-4.02
1.95-4.92

0.0003
< 0.0001



Compared with men, women had higher estimated pre-test probability of CAD, yet lower rates of both obstructive and nonobstructive CAD on coronary CTA. However, they experienced higher hazard ratios for mortality for 3-vessel or left main obstructive CAD and had similar rates of death for nonobstructive, 1-vessel, and 2-vessel disease.

Results Can Inform Guidelines, Appropriate Use Criteria

According to the study authors, CONFIRM had sufficient sample size and was adequately powered to allow differential risk stratification by age group and sex. Therefore, the data extend prior studies and are “widely generalizable,” they say, especially since the international cohort encompassed patients and clinical sites within North America, Europe, and Asia.

“That [coronary CTA] can effectively risk stratify individuals without known CAD should be invaluable for guiding the development of clinical practice guidelines and appropriate use criteria,” Dr. Min and colleagues write.

As to the differences between women and men undergoing coronary CTA, the investigators note that the generally lower prevalence of disease in women has been historically associated with lower rates of invasive coronary angiographic evaluation and often leads to exclusion of cardiac causes of symptoms in women, despite being more likely to be hospitalized for angina than men.

“It remains possible in this open-label study that the identification of nonobstructive noncardiac diagnoses for symptoms, and lack of aggressive treatment for these CAD findings resulted in heightened risk of incident death,” they write. “Future studies should carefully evaluate this potential explanation and should determine the effect of primary prevention with aggressive medical therapy in this cohort.”

The age differences may be related to younger patients with greater extent and severity of CAD having more aggressive forms of atherosclerosis than their older counterparts, thus resulting in a higher mortality risk than older patients with more insidious atherosclerosis, the study authors add.

Importantly, they point out that the low death rate in patients without CAD on coronary CTA “validates the favorable prognosis that has been uniformly observed in prior smaller registries and emphasizes a clinical value of [coronary CTA] for identification of individuals in whom no further additional testing and/or therapy is necessary or indicated.”

Importance of Linking Anatomy to Outcomes

In an editorial accompanying the study, Bernard De Bruyne, MD, PhD, and Carlos Van Mieghem, MD, PhD, of the Cardiovascular Center Aalst (Aalst, Belgium), report that the sample size of CONFIRM is almost 1 order of magnitude larger than all previous studies on coronary CTA-related outcomes and focuses on “the hardest possible endpoint.” Further strengthening the results, they conclude, is that selection bias is unlikely since more than 90% of patients had low or intermediate pre-test likelihood of CAD.

But Drs. DeBruyne and Van Mieghem caution that while the likelihood of finding some degree of atherosclerosis on coronary CTA is high, it has long been recognized that how the arterial lumen appears on angiography does not necessarily indicate function or effect on myocardial blood flow. In other words, anatomy is only one of many factors that define symptoms and prognosis.

“Nevertheless, the visual impression of the luminogram and the sacred threshold of 50% diameter stenosis remain pivotal to the very definition of the presence of coronary artery disease; for the description of its extent in 1-, 2-, or 3-vessel disease; and constitute the basis for the vast majority of individual clinical decisions regarding revascularization,” they write.

The challenge for clinicians, according to the editorialists, is to properly integrate anatomy and function in the same setting to aid in diagnosis and treatment. Another area that holds promise for doing just that is the use of noninvasive fractional flow reserve (FFR), which involves calculating FFR from patient-specific coronary CTA data using computational fluid dynamics during rest and simulated maximal coronary hyperemic conditions.

“If cardiac imaging is to affect the individual clinical decision-making process, it must reconnect us with a basic foundation of cardiology that is, in fact, physiology,” they write.

Study Details

The study cohort was primarily male (54%) and middle-aged (57 ± 13 years), with a high prevalence of cardiovascular risk factors and symptoms. The majority presented with typical or atypical angina and intermediate or high pre-test likelihood of obstructive CAD.



Sources:
1. Min JK, Dunning A, Lin FY, et al. Age- and sex-related differences in all-cause mortality risk based on coronary computed tomography angiography findings. Results from the international multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 patients without known coronary artery disease. J Am Coll Cardiol. 2011;58:849-860.

2. De Bruyne B, Van Mieghem C. Coronary computed tomography angiography: CONFIRMations and perspectives. J Am Coll Cardiol. 2011;58:861-862.

[Chevychelov]

PFO-Stroke Link Takes Another Hit

Key Points:
Recurrent cerebrovascular event rate in PFO-cryptogenic stroke patients 20.3% with medical therapy vs. 10.7% after percutaneous closure over 8.7 years
Concurrent etiologies judged likely as causative in 38% of medical group, 44% of closure group
Study casts further doubt on causal role for PFO in stroke recurrence
By Jason Kahn
Thursday, August 11, 2011

Over one-third of recurrent strokes or transient ischemic attacks (TIAs) in patients with patent foramen ovale (PFO) are more likely to arise from concurrent conditions like atrial fibrillation or large artery disease, casting doubt on the causal role of the defect, according to results appearing online August 4, 2011, ahead of print in Stroke.

Researchers led by Heinrich P. Mattle, MD, of University Hospital at the University of Bern (Bern, Switzerland), looked at 308 patients with cryptogenic stroke and PFO treated at their institution from January 1994 to August 2000. Roughly half of the patients (n = 158) received medical therapy (oral anticoagulants or antiplatelets) and half received percutaneous closure (n = 150). Dr. Mattle and colleagues followed both groups for a mean of 8.7 years to see if PFO closure had an effect on the expected rate of recurrent events and to judge whether the rate of concurrent etiologies might have caused these events.

Baseline characteristics were similar between the medical and closure groups, with the exception of previous cerebrovascular events and large right-to-left shunt, which were more common in the closure group (P < 0.03 and P < 0.001, respectively).

Many Recurrent Events Not Cryptogenic

Over a mean follow-up of 8.1 years, 32 recurrent cerebrovascular events (13 strokes, 19 TIAs) occurred in the medical group, amounting to a rate of 20.3%. Sixteen of these patients died. The frequency of recurrent stroke or TIA did not differ with respect to antiplatelet or anticoagulant treatment. In the PFO closure group, there were 16 recurrent events (8 strokes, 8 TIAs), which worked out to an event rate of 10.7% over a mean follow-up of 9.2 years, with 7 deaths.

In the PFO closure group, more than half of recurrent events were judged to be cryptogenic, while this was true for almost two-thirds of recurrent cerebrovascular events in the medical treatment group. Of the remaining events, which were deemed more likely associated with concurrent etiologies, most were related to atrial fibrillation or small or large artery disease (table 1).

Table 1. Etiologies Associated with Recurrent Cerebrovascular Events

PFO Closure
(n = 150)
Medication
(n = 158)

Cryptogenic
56%
63%

Atrial Fibrillation
13%
13%

Large Artery Disease
6%
9%

Small Artery Disease
19%
6%

Antiphospholipid Antibody Disease
–
6%

Cerebral Vasculitis
–
3%

Thrombophilic Disorder
6%
–



Patients with recurrent cerebrovascular events showed similar levels of concurrent etiology between the medical treatment group and the PFO closure group (38% vs. 44%; P = 0.68). But the rate of concurrent etiologies in the medical therapy group may, in fact, have been underestimated since half of the patients with a recurrent event did not have a complete etiologic work-up.

Among patients with recurrent stroke or TIA, concurrent etiologies were more frequent in those older than age 55 at the time of the index event than in younger patients (P = 0.018). Other factors, such as atrial septal aneurysm and large right-to-left shunt showed no interaction with concurrent conditions. In the PFO closure group, patients with recurrent events more frequently had hypercholesterolemia if they also had concurrent etiologies than if they did not (100% vs. 56%; P = 0.042).

“Concurrent etiologies are identified for a considerable proportion of recurrent ischemic events [, casting] doubt on the sole causal role of PFO in the case of stroke recurrence, and indicat[ing] that secondary prevention in patients with cryptogenic stroke and PFO should not be focused on PFO closure alone,” the authors conclude. In particular, they note, “given that concurrent stroke etiologies are not prevented by percutaneous device closure of the PFO, we would not discontinue antithrombotic treatment in patients who undergo PFO closure.”

CLOSURE Confirmation

In a telephone interview with TCTMD, Anthony J. Furlan, MD, of the Case Western Reserve University School of Medicine (Cleveland, OH), agreed with the findings, but went even further. “I think it’s often not clear that even the initial stroke is due to the PFO,” he said.

In general, Dr. Furlan said the results of the current study reinforce those of the CLOSURE I trial, the only randomized, controlled study to have looked at the issue of PFO closure and cryptogenic stroke. Presented in November 2010 at the annual American Heart Association Scientific Sessions, the results provided strong evidence that percutaneous device closure lacks superiority over medical therapy alone in preventing recurrent stroke and mortality in patients with PFO.

“CLOSURE I followed patients for only 2 years, but even with that, we found an alternative reason for recurrent events in 80% of patients,” said Dr. Furlan, the trial’s principal investigator. “It’s actually reassuring that we found in a randomized trial what people are finding in their individual experiences.”

According to Dr. Furlan, there are multiple problems inherent in determining the cause of cryptogenic stroke. “The core problems are cryptogenic stroke, which is a mixed group of etiologies, vs. how do you prove something is truly due to paradoxical embolism?” he said. “And then it’s another matter to say closing the hole is any better than antithrombotic therapy. Or it’s also possible, as the authors of this paper point out, that maybe they’ve got 2 problems. Maybe they do have paradoxical embolism, but 6 years later, things change and they’ve got something different.”

Performing the Right Tests

A key for clinicians is to perform the right tests up front, which seldom happens, Dr. Furlan noted. “For example,” he said, “one of the most grossly underdiagnosed conditions in this cryptogenic stroke population is probably occult atrial fibrillation. If you only do a 24-hour Holter monitor, you’re not going to find it, but nobody does a routine 30-day event monitor. Probably the causes of cryptogenic stroke are not that many, it just depends on how hard you look.”

None of this is to say that PFOs should never be closed for cryptogenic stroke, Dr. Furlan stressed. “In CLOSURE I, [we did not conclude] that paradoxical embolism wasn’t real, or that there are no patients that should undergo endovascular closure,” he said. “All we had was anecdotal criteria and no hard data. Now, my impression is that everyone seems to agree that we were probably closing too many of these.”

In the future, Dr. Furlan expressed hope that results of CLOSURE I will be combined with those of other ongoing trials investigating PFO closure and cryptogenic stroke. “If we start putting all these trials together, we’ll be able to refine our selection criteria, and not close all these holes, willy-nilly” he said. “That’s what I’m starting to see. I think clinicians in general are being more conservative.”

Source:
Mono M-L, Geister L, Galimanis A, et al. Patent foramen ovale may be causal for the first stroke but unrelated to subsequent ischemic events. Stroke. 2011;Epub ahead of print.

[Chevychelov]

Top Content, July, 2011
The Most Viewed Science & Quality Content on CardioSource
Print
Top 10 Journal Scans, July 2011
Impact of National Clinical Guideline Recommendations for Revascularization (Arch Intern Med)
Appropriatenessof Percutaneous Coronary Intervention (JAMA)
Real-Life Observations of Clinical Outcomes With Rhythm and Rate Control (J Am Coll Cardiol)
Measuring Blood Pressure for Decision Making and Quality Reporting: Where and How Many Measures? (Ann Intern Med)
A New Risk Scheme to Predict Warfarin-Associated Hemorrhage (J Am Coll Cardiol)
Effect of Upstream Clopidogrel Treatment in Patients With STEMI Undergoing Primary PCI (Eur Heart J)
Cardiac Resynchronisation Therapy in Patients With Heart Failure and a Normal QRS Duration (Heart)
Cardiovascular Screening With Electrocardiography and Echocardiography in Collegiate Athletes (Am J Med)
Utility of Absolute and Relative Changes in Cardiac Troponin Concentrations in the Early Diagnosis of AMI (Circulation)
Development and Validation of a Risk Calculator for Prediction of Cardiac Risk After Surgery (Circulation)

Top 10 Clinical Trial Summaries, July 2011
PALLAS
APPRAISE 2
PARTNER Cohort A
AIM-HIGH
ARISTOTLE
ADDITION Europe
Rheos Pivotal Trial
OAT
SHARP
ASCEND HF

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[Chevychelov]

Potential reason for improved outcome found with GWTG-Stroke program

Reeves MJ. Circ Cardiovasc Qual Outcomes. 2011;doi:10.1161/circoutcomes.111.961755.

An increase in eligible patients receiving care based on the Get with the Guidelines-Stroke program was cited as the major reason for the performance improvement found among hospitals examined in a recent study.

Specifically, hospital participation with the program substantially improved the quality of care of patients with ischemic stroke during a 7-year period.

In the study, researchers analyzed data on patients (n=569,883; median age, 73 years) admitted with ischemic stroke to Get with the Guidelines (GWTG)-Stroke hospitals (n=1,028) from April 2003 to September 2009. Performance measures that were deemed relevant for patients with acute ischemic stroke included early and discharge antithrombotics, deep vein thrombosis prophylaxis, anticoagulants for atrial fibrillation/flutter, lipid therapy, smoking cessation and IV recombinant tissue plasminogen activator therapy.

Although noting minimal changes to the size of the target population in six of the measures, the researchers found that deep vein thrombosis prophylaxis population reduced from 52.5% to 46.8%. This, they said, was due to change in the data collection tool, particularly a format change in the 2008 form that decreased the number of patients identified as nonambulatory by day 2.

Additionally, across the study period, all measures had significant increases in eligible patients, most of which occurred without major shifts in contraindications or missing data, the researchers wrote.

“The results of the present study have important implications for other CV quality improvement programs that measure and track the quality of care through process-based performance measures,” they said. “Our results strongly suggest that the GWTG-Stroke quality improvement program increased the number of eligible patients who received guideline-based care during this period, which to the extent that these care processes are clinically effective should result in meaningful improvements in stroke outcomes.”
__________________________________________________ _______________________
Studies raise doubt on validity of animal models in CV research

Fedorov V. J Mol Cell Cardiol. 2011;51:215-225.
Glukhov A. J Mol Cell Cardiol. 2010;48:152-160.

Investigators of two studies published in the Journal of Molecular and Cellular Cardiology have found conflicting results of two adenosine triphosphate-regulated potassium channel openers when observed in mice vs. human hearts.

“In human hearts … the sulfonylurea receptor type 1 (SUR1) drug (pinacidil) doesn’t work in the atria at all, but it does affect the ventricles; it is the opposite of what happens in the mouse. The SUR2 drug (diazoxide) affected both the atria and the ventricles, and shortened the action potentials in the ventricles so much that it would cause fatal arrhythmias in people,” Igor R. Efimov, PhD, a biomedical engineer at Washington University, St. Louis, and researcher on both the mice and human studies, said in a press release.

The first study, which was published in early 2010, involved intact hearts from six wild-type mice, six SUR1(-/-) mice and five Kir 6.2(-/-) mice. Efimov and colleagues observed that 300 mcM diazoxide decreased action potential duration (ADP) in the atria (P<.001) but not the ventricles among wild-type mice hearts, whereas the same dose of pinacidil lowered ventricular ADP in both wild-type and SUR1(-/-) hearts (P<.001 for both) but not atrial ADP.

In the second study, which was recently published by the journal, the investigators used hearts from patients who had congestive HF and underwent transplant (n=8) or hearts unsuitable for transplant that were donated to research either with (INF; n=2) or without (NF; n=3) infarction.

They reported that diazoxide decreased ADP in chronic HF and INF hearts in atria and ventricles (P<.01 for both) but not in NF atria. However, pinacidil lowered ADPs in the atria and ventricles of all hearts.

As a possible mechanism for the discrepancy, Efimov said a mouse heart beats on average 600 times/minute, whereas a human heart beats on average 72 times/minute, and the difference in gene expression between mice and human hearts is very large.

“You can mutate in mice the gene thought to cause HF in humans and you don’t get the same disease because the mouse is so different. So, unfortunately, even with the help of transgenic mice, very few results made it from the animal model to the clinic,” he said.
__________________________________________________ ______________________
AACE: Obesity is a disease state

The American Association of Clinical Endocrinologists has declared that there is sufficient clinical evidence to declare obesity a disease state.

The declaration of obesity as a disease state, rather than a consequence of poor lifestyle choices, will help pave the way for more effective therapies and treatments for the growing number of obese Americans, according to a press release issued by the association. Currently, the armamentarium is bare for obesity therapies.

“Sufficient evidence has accumulated to implicate a number of heterogeneous hormonal and regulatory disorders in the pathogenesis and progression of the disease state,” Alan J. Garber, MD, PhD, AACE vice president and a member of the CHD and Prevention section of the Cardiology Today Editorial Board, stated in the release. “Thus, multiple therapeutic interventions may be necessary lifelong to delay or reverse obesity in patients. Currently, certain efforts have not prevented the proliferation of obesity in the US population as well as elsewhere. Additional interventions and alternative approaches are clearly necessary.”

On July 23, the AACE board of directors voted unanimously to declare obesity a disease state. The vote was the result of an AACE Task Force on Obesity report that concluded, based on available clinical data, insufficient data exist to suggest that obesity is not just a condition.

Having declared obesity a disease state, AACE leaders now plan to develop resources for the various modalities of obesity management, including behavior, nutrition, pharmacology and surgery. The efforts will be part of a comprehensive nutrition plan that will include sociopolitical, public and educational outreach. The association will collaborate with other professional medical societies and the FDA regarding obesity research and the consideration of anti-obesity drugs and their approval pathways, according to the release.

[Chevychelov]

Needle Before Door Safe for STEMI Patients

By Chris Kaiser, Cardiology Editor, August 16, 2011

Note that this report summarizes a survey of programs worldwide that have successfully used pre-hospital fibrinolysis as a reperfusion strategy and suggests that this stategy is safe and can improve survival compared with in-hospital administration.

Note that whether a pre-hospital fibrinolytic strategy would be appropriate in the United States is unclear. Point out that the editorialist suggests that the major challenge to successful implementation of such a strategy is the regional variations in EMS resources in the United States.
Review
It's widely recognized that shortening "door-to-needle" time improves outcomes for STEMI patients, but starting lysis before the patient reaches the hospital may give an added edge.

An analysis of seven pre-hospital fibrinolysis programs confirmed a low reinfarction rate -- ranging from 2.4% (France) to 5.8% (England/Wales) -- reported Thao Huynh, MD, MSc, from McGill Health University Center in Montreal, Quebec, and colleagues.

Rates of in-hospital stroke also were low -- less than 2% of pre-hospital fibrinolysis patients (≤0.6% in most programs), according to the study in the August JACC: Cardiovascular Interventions.

But despite those benefits, pre-hospital fibrinolysis is the exception rather than the rule in the United States.

"The major challenge to successful implementation of a pre-hospital fibrinolytic strategy is the regional variations in EMS resources. The EMS system in the United States is particularly fractionated with a wide range of both funding and available services," wrote Timothy D. Henry, MD, from the Minneapolis Heart Institute Foundation, and Bernard J. Gersh, MB, CHB, DPhil, from the Mayo Clinic College of Medicine, Rochester, Minn., in an accompanying editorial.

The Minneapolis Heart Institute's regional STEMI system, for example, includes 33 hospitals and 10 clinics throughout Minnesota and Wisconsin and "requires integration with nearly 50 different EMS agencies and a wide spectrum of resource availability."

While it may be more difficult to enact STEMI programs (with fibrinolysis) in the U.S., "the most important insight from the survey is that fibrinolytic and PCI reperfusion strategies should no longer be considered mutually exclusive," Henry and Gersh wrote.

In the current study, researchers examined STEMI programs that included pre-hospital fibrinolysis in Sweden; France; England/Wales; Vienna, Austria; Edmonton in Alberta, Canada; Houston; and Nova Scotia.

Pre-hospital fibrinolysis is recommended by the European Society of Cardiology and has been in use in Europe for more than two decades, the researchers wrote.

While pre-hospital fibrinolysis is not as widespread in the U.S. or (Canada), pre-hospital ECGs are endorsed by the American Heart Association and the American College of Cardiology. Pre-hospital ECG is a crucial step for early lysis.

In the study, most ambulance personnel were trained to interpret ECGs, and only two programs – Vienna and France -- staffed their ambulances with physicians (95% and 100%, respectively).

In Vienna and Sweden, all STEMI patients were transported directly to a PCI hospital for primary PCI. In the other programs, direct transport varied.

In England/Wales, paramedics could initiate fibrinolysis. In the other programs, paramedics had to send the ECG to the hospital and wait for authorization from a physician.

Pre-hospital fibrinolysis was administered by paramedics in Houston, Nova Scotia and Edmonton; by nurses in Sweden; and by physicians in France and Vienna.

The mortality rate was generally low for those receiving pre-hospital fibrinolysis.

France had the lowest mortality at 2.7% in-hospital and 4.5% at one year, whereas Sweden had the highest in-hospital mortality at 6.5% and 10.7% at 1 year.

Pre-hospital fibrinolysis should be seen as a complement to PCI, said Huynh and colleagues. Ideally, these programs should have formal protocols that help to identify patients that would benefit from either direct transport to a PCI hospital or pre-hospital lysis.

The authors acknowledge that the study was limited by the lack of a comparison of morbidity and mortality data across programs. Also, the program descriptions relied on self-administered surveys. Finally, there were no economic or quality assurance data.