Обзор американских кардиологических журналов за неделю (ссылки)

[Chevychelov]

U.S. HF Patients May Gain Less from Beta-Blockers

By Todd Neale, Senior Staff Writer, Published: August 16, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Explain that Americans with heart failure may not respond to beta-blockers as well as their counterparts from other countries.

Point out that U.S. patients did not have a significant reduction in mortality in any of the three trials that included both U.S. patients and those from other countries and that the reasons for this difference are not known.

Americans with heart failure may not respond to beta-blockers as well as their counterparts from other countries, researchers found.

In pooled results of four major heart failure trials, beta-blockers reduced the mortality risk by 23% overall compared with placebo (RR 0.77, 95% CI 0.71 to 0.84), according to Christopher O'Connor, MD, of Duke University, and colleagues.

In two of the three trials that included U.S. patients, however, beta-blockers did not reduce mortality in the U.S. patients but did reduce mortality in patients from other countries, the researchers reported in the Aug. 23 issue of the Journal of the American College of Cardiology.

In the BEST trial, which included mostly U.S. patients, there was no mortality benefit overall, in U.S. patients, or in patients from other countries.

"This geographic difference in treatment response may be a reflection of population differences, genetics, cultural or social differences in disease management, or low power and statistical chance," O'Connor and colleagues wrote.

Although the inclusion of patients from around the world has made it easier to reach recruitment goals for very large trials, the practice has introduced challenges that come along with a geographically diverse patient populations.

To explore a possible difference by geography in major heart failure trials involving beta-blockers, the researchers examined data from four trials -- MERIT-HF (Metoprolol Controlled-Release Randomized Intervention Trial in Heart Failure), COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival trial), BEST (Beta-Blocker Evaluation of Survival Trial), and CIBIS-II (Cardiac Insufficiency Bisoprolol Study).

CIBIS-II did not include any U.S. patients, but it was included in the overall analysis.

The three trials that included patients from the U.S. and other countries involved 8,988 patients -- 46.7% came from the U.S.

In a meta-analysis of all four trials, there was a significant reduction in mortality with beta-blocker treatment, but it was significant in the patients from the rest of the world (RR 0.64) and not in the U.S. patients (RR 0.92, 95% CI 0.82 to 1.02).

Those results were consistent in the MERIT-HF and COPERNICUS trials. In the BEST trial, treatment with the investigational beta-blocker bucindolol did not reduce mortality in any patient subgroup, which was consistent with the primary results.

O'Connor and colleagues pointed to several possibilities to explain why U.S. patients with heart failure might have a lower response to beta-blockers, including differences in baseline characteristics between the studies and a slightly higher mortality rate in the placebo group among the U.S. patients.

Race could also play a role, they noted. Black patients in BEST did not have a mortality reduction with beta-blocker therapy, but non-black patients did.

That could reflect genetic differences, as previous studies have shown that genotypes associated with a poor response to beta-blockers are more prevalent in people of African descent.

In the current analysis, U.S. centers were more likely to enroll black patients than those in other countries.

Other possibilities to explain the geographical difference in response included differences in standards of care and use of evidence-based therapies, inadequate statistical power, or chance.

The authors noted, however, that "the consistency of the observation in the U.S. cohort across the MERIT-HF, COPERNICUS, and BEST trials is a potential cause for concern, and although it is possible that chance is responsible for the observation in all three instances, the consistency of the finding justifies further examination."

In an accompanying editorial, Barry Massie, MD, of the San Francisco VA Medical Center, said that "the analyses ... are provocative and possibly hypothesis generating, but they should not be interpreted as demonstrating a lesser beta-blocker benefit in North American patients, given the wide confidence intervals, particularly in COPERNICUS and MERIT-HF."

He continued, "Subsequent experience has solidified the powerful role that beta-blockers can play in preventing and even reversing myocardial systolic dysfunction in heart failure patients. Based on the totality of data with beta-blockers and their experience, few heart failure physicians would withhold carvedilol or metoprolol from their patients."

O'Connor and colleagues acknowledged that the analysis was limited in that it was performed post hoc with a small number of trials and did not account for baseline differences in the patient populations. In addition, the beta-blockers evaluated in the trials have distinct mechanisms of action.

[Chevychelov]

10 Mistakes Accountable Care Organizations Still Make
Successful ACOs require new health information exchanges, better EHR functionality, and the ability to measure true outcomes. Two experts say we're not there yet.

By Ken Terry InformationWeek
August 12, 2011 12:40 PM

When the Centers for Medicare and Medicaid Services (CMS) announced its proposed regulations for accountable care organizations (ACOs) last spring, CMS administrator Donald Berwick said "information management--making sure patients and all health care providers have the right information at the point of care--will be a core competency of ACOs."

In a new article about ACOs in the Journal of the American Medical Association, two other health policy experts reaffirm the importance of health IT, including electronic health records (EHRs), in building these organizations. At the same time, they point out that the technology is not yet up to the task.

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In the paper, Stephen Shortell, dean of the school of public health at the University of California, Berkeley, and Sara Singer, of Harvard's school of public health, offer a list of 10 mistakes that ACOs may make. They are:

1. Overestimation of ability to manage risk.
2. Overestimation of ability to use electronic health records.
3. Overestimation of ability to report performance measures.
4. Overestimation of ability to implement standardized care management protocols.
5. Failure to balance the interests of hospitals, primary care physicians, and specialists in creating governance and management processes to adjudicate differences.
6. Failure to sufficiently engage patients in self-care management and self-determination.
7. Failure to make contractual relationships with the most cost-effective specialists.
8. Failure to navigate the new regulatory and legal environment.
9. Failure to integrate beyond the structural level.
10. Failure to recognize the interdependencies and therefore the potential cumulative "race to the bottom" of the above mistakes.

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The ability to use EHRs effectively in ACOs, the authors write, can be hampered by: inadequate training and support from clinicians; disruption of practices during the early phase of implementation; and incompatibility of hospital and ambulatory-care systems.

The experience of pay-for-performance programs shows the difficulty of collecting, reporting, and analyzing performance data, Shortell and Singer noted. They predict that this reporting capability will gradually evolve over time.

In an interview with InformationWeek Healthcare, Shortell said that healthcare organizations' ability to collect and report quality data as part of Meaningful Use varies greatly across the country. "We've seen some medical groups that have EHRs that incorporate a lot of those measures, and they can capture the data and report it. But a lot simply can't. They don't have the functionality yet [in their EHRs]."

Most ACOs will also require health information exchanges to improve the continuity of care, he said. "Even those that have very sophisticated systems within silos have a problem linking them up when patients go to other doctors, are referred to hospitalists, or are hospitalized. For that, you either need a closed system like Kaiser or information exchanges that will be able to capture and aggregate that data."

One identified potential flaw in ACOs is the "failure to sufficiently engage patients in self-care management and self-determination." While few of the fledgling ACOs have experience in this kind of activity, Shortell said that health IT can play in important role in patient engagement.

"Email and other forms of online communication are a powerful means of engaging people," he pointed out. "Another part of it will be continued advances in home monitoring technologies for diabetes, asthma, and other chronic diseases. As those technologies become more cost competitive and more prevalent in people's homes, they will help engage people in their own care by monitoring blood pressure, glucose levels and so on."

The JAMA article also noted that the failure to achieve clinical integration could sink some ACOs. Again, Shortell said, health IT will be needed to map out processes of care and generate feedback on how the changes in care delivery are working. "That's where the electronic health record can pay off."

In the long run, the paper points out, ACOs will have to develop "a mature performance measurement system to provide rapid feedback about what works in different local environments." According to Shortell, this means "the ability to have accurate measures across the continuum of care on the key metrics you'll need to manage the population--particularly the high cost [of] chronic disease patients. A mature measurement system would be able to capture the total cost of care for that episode of illness. We can't do that currently."

In addition, he said, such a system would incorporate two other key outcomes measures: functional status and patient experience. "Almost no one in the country that has that level of performance maturity," he said. "Kaiser might approach it."

[Chevychelov]

New Tool Predicts VTE Risk

By Todd Neale, Senior Staff Writer, MedPage Today
August 17, 2011

Explain that a risk prediction model for venous thromboembolism (VTE) predicted events at one and five years in both prediction and validation cohorts.

The risk prediction model included information readily available from patients or general practice records.
Review
A new risk prediction model may help to estimate an individual patient's risk of venous thromboembolism up to five years out, researchers found.

The model, which includes 11 variables for men and 14 variables for women, yielded an area under the receiver operating characteristic curve (AUC) of 0.75, according to Julia Hippisley-Cox, MD, and Carol Coupland, PhD, of the University of Nottingham.

And comparing the predicted versus the observed risks at one and five years indicated that the algorithm was well calibrated, they reported online in BMJ.

"The algorithm is based on simple clinical variables which the patient is likely to know or which are routinely recorded in general practice records," they wrote.

"The algorithm could be integrated into general practice clinical computer systems and used to risk assess patients before hospital admission or starting medication which might increase the risk of venous thromboembolism," including oral contraceptives, antipsychotics, and hormone replacement therapy, they wrote.

The researchers added that the tool, which is called Qthrombosis and is available online, is not meant to assess the current risk of venous thromboembolism in symptomatic patients.

Hippisley-Cox and Coupland developed the model by examining data from patients treated at 564 general practices in England and Wales that participated in the QResearch database. None of the patients had been pregnant in the preceding 12 months, had a previous deep vein thrombosis or pulmonary embolism, or were taking oral anticoagulants at baseline.

The cohort used to derive the risk prediction model included about 2.3 million patients. During the study, there were 14,756 incident cases of venous thromboembolism -- a rate of 14.6 per 10,000 person-years.

The validation cohort included about 1.2 million people. In this group, there were 6,913 incident cases -- a rate of 14.9 per 10,000 person-years.

For both sexes, independent predictors of venous thromboembolism that were included in the risk prediction model were age, body mass index, smoking status, varicose veins, congestive heart failure, chronic renal disease, cancer, chronic obstructive pulmonary disease, inflammatory bowel disease, hospital admission in the past six months, and current prescriptions for antipsychotic drugs.

For women, additional factors were use of oral contraceptives, tamoxifen, and hormone replacement therapy.

In the validation cohort, the risk prediction equation explained 33% and 34% of the variation in the time to venous thromboembolism in women and men, respectively.

The D statistic was 1.43 for women and 1.45 for men at five years, with an AUC of 0.75 for both sexes.

Good calibration of the model was confirmed by comparing the mean predicted risks at one and five years with the observed risks. For example, for women in the top 10% of predicted risk, the mean predicted five-year risk was 2.78% and the observed risk was 2.7%. For men, the corresponding values were 2.46% and 2.35%.

The authors acknowledged some limitations of their analysis, including the lack of formally adjudicated outcomes, a reliance on information provided by the primary care physicians, a lack of genetic data, the potential for missing information, and residual confounding.

[Chevychelov]

Coronary Calcium Better than CRP to Stratify Risk
By Todd Neale, Senior Staff Writer,
Published: August 18, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco.

Among asymptomatic individuals with normal LDL cholesterol levels and elevated high-sensitivity C-reactive protein (hsCRP), measuring the burden of calcium in the coronary arteries with cardiac CT appears to stratify the risk of cardiovascular disease, researchers found.

The estimated rate of cardiovascular disease events through a median of 5.8 years was 2.12% for those with a coronary artery calcium (CAC) score of 0, 4.86% for those with a score of 1 to 100, and 13.65% for those with a score greater than 100, Michael Blaha, MD, of Johns Hopkins University in Baltimore, and colleagues reported in the Aug. 20 issue of The Lancet.

Looking further at patients with both low and high levels of hsCRP, the researchers found that CAC score -- but not hsCRP -- was associated with the risk of coronary heart disease events and overall Action Points
Explain that among asymptomatic individuals with normal LDL cholesterol levels and elevated high-sensitivity C-reactive protein (hsCRP), measuring the burden of calcium in the coronary arteries with cardiac CT appears to stratify the risk of cardiovascular disease.

Point out that in patients with both low and high levels of hsCRP, the researchers found that CAC score -- but not hsCRP -- was associated with the risk of coronary heart disease events and overall cardiovascular events.
cardiovascular events.

Action Points
Explain that among asymptomatic individuals with normal LDL cholesterol levels and elevated high-sensitivity C-reactive protein (hsCRP), measuring the burden of calcium in the coronary arteries with cardiac CT appears to stratify the risk of cardiovascular disease.

Point out that in patients with both low and high levels of hsCRP, the researchers found that CAC score -- but not hsCRP -- was associated with the risk of coronary heart disease events and overall cardiovascular events.

CAC score "could be used to target subgroups of patients who are expected to derive the most, and the least, absolute benefit from statin treatment," Blaha and colleagues wrote. "Focusing of treatment on the subset of individuals with low LDL cholesterol with measurable atherosclerosis might represent a more appropriate allocation of resources, reduce overall healthcare cost, and prevent the occurrence of a similar number of events."

But evidence from randomized trials that such an approach -- which remains controversial -- would actually reduce cardiovascular events in asymptomatic individuals is lacking.

Steven Nissen, MD, of the Cleveland Clinic, pointed out in an email to ABC News and MedPage Today that calcium scanning has never been shown to reduce the risk of MI or death. He called the practice "one of the worst examples of 'medicine gone wild,'" pointing to unacceptable radiation doses and the greater use of unnecessary catheterization and stenting following a scan.

Other physicians contacted, however, supported the use of CAC scoring.

"Use of CAC is helpful in saying if the process of atherosclerosis has started, and is helpful in choosing between lifestyle intervention versus lifestyle intervention plus statin therapy," wrote Christopher Cannon, MD, of Brigham and Women's Hospital in Boston.

The basis of the current analysis was the JUPITER trial, which showed that treatment with rosuvastatin (Crestor) reduced MI, stroke, and cardiovascular death in patients with normal LDL cholesterol levels but elevated hsCRP.

Blaha and colleagues identified a JUPITER-like cohort in the Multi-Ethnic Study of Atherosclerosis (MESA) to determine whether measuring CAC would stratify patients according to cardiovascular risk and potentially identify a subgroup of patients who would most benefit from statin therapy.

The analysis included 950 MESA participants who had normal LDL cholesterol levels (less than 130 mg/dL) and elevated hsCRP (2 mg/L or more). All underwent two noncontrast CT scans to measure the calcium.

The authors noted that the average measured dose of radiation in a CAC scan was 0.89 mSv in MESA, while the average dose overall with modern technology ranges from 0.5 to 1.5 mSv.

Nearly half of the patients (47%) did not have any coronary calcium (a score of 0). Another 28% had scores of 1 to 100 and 25% had scores greater than 100.

Per 1,000 person-years, rates of coronary heart disease events increased from 0.8 for patients with a CAC score of 0 to 20.2 for patients with a score greater than 100. The patterns were similar for all cardiovascular events.

Through a median follow-up of 5.8 years, 74% of all coronary heart disease events and 60% of all cardiovascular events occurred in the patients with a CAC score greater than 100.

Applying the risk reduction accompanying rosuvastatin treatment observed in JUPITER (a 44% relative reduction in the risk of MI, stroke, and cardiovascular death), Blaha and colleagues calculated that the five-year number needed to treat (NNT) to prevent one coronary heart disease event was 549 for patients with a CAC score of 0, 94 for those with intermediate CAC scores, and 24 for those with scores greater than 1oo.

The NNTs for all cardiovascular events were 124, 54, and 19, respectively.

"These results have important implications for future guidelines and public health discussions aimed at improving the efficiency of statin use in primary prevention," according to the authors, who noted that studies have suggested that asymptomatic patients with a CAC score of 0 can be treated less aggressively with an emphasis on low-cost lifestyle interventions.

Blaha and colleagues acknowledged that a cost-benefit analysis is needed in patients with both low and high hsCRP to determine whether using CAC scores to guide statin treatment improves outcomes. They also acknowledged that CAC scoring has both advantages and disadvantages compared with hsCRP.

Advantages of CAC scoring include the fact that it is a direct measure of the burden of atherosclerosis, it has small variability on repeated testing, and it has consistent thresholds of risk in different populations. Thresholds for hsCRP vary by sex and ethnic origin.

Disadvantages include radiation exposure, a risk of incidental findings leading to further imaging, and a higher cost compared with hsCRP.

Still, CAC scanning can be performed for less than $100 in many centers, the researchers noted.

"Now that CAC scoring is so inexpensive, one can make the case of testing this in most patients at intermediate risk," commented Carl Lavie, MD, of the Ochsner Heart and Vascular Institute in New Orleans, in an email.

One obstacle to the wider adoption of CAC scoring for risk stratification "is that use of preventive measures such as statins, blood pressure control, and weight loss do not reduce the coronary calcium, and this is unsettling for many physicians and patients," said Howard Weintraub, MD, clinical director of the NYU Center for the Prevention of Cardiovascular Disease, in an email.

Some physicians want to see the value of the test proven in a randomized trial as well, although that has not stopped all physicians from incorporating it into their practices.

"Although definitive proof of treatment effects is scarce, CAC identifies high cardiovascular risk, and statin therapy is most effective in high-risk patients," Axel Schmermund, MD, and Thomas Voigtländer, MD, of Cardioangiologisches Centrum Bethanien in Frankfurt, wrote in an accompanying editorial.

"In our practice, we therefore focus on CAC ... for expanded risk stratification in asymptomatic patients."

[Chevychelov]

Nocturnal ACS Linked to Belly Fat, Disordered Sleep

By Charles Bankhead, August 19, 2011

Explain that a Japanese study found that patients with nighttime-occurrence ACS were more likely to have excess visceral fat and sleep-disordered breathing than those with ACS occurring in the daytime.

Note that onset of ACS at night is an uncommon occurrence.
Review
Nighttime acute coronary syndrome (ACS) occurred significantly more often in patients with visceral fat accumulation and sleep-disordered breathing, investigators reported.

Among 25 patients with nighttime onset of ACS, two-thirds of those with ≥100 cm2 of visceral fat accumulation also had sleep-disordered breathing as compared with a fourth of patients with less visceral fat.

In contrast, sleep-disordered breathing occurred in a similar proportion of patients with and without visceral fat and daytime-onset ACS.

Patients with sleep-disordered breathing, visceral fat accumulation, and nighttime-onset ACS also had hypoadiponectinemia and nocturnal dysregulation of circulating adiponectin levels, as reported online in the American Journal of Cardiology.

"These results suggest that an association of sleep-disordered breathing and excess visceral fat with nocturnal dysregulation of adiponectin may play some role in the development of nighttime-onset ACS," Ken Kishida, MD, PhD, of Osaka University in Japan, and co-authors wrote in summation.

"Sleep-disordered breathing and excess visceral fat are treatable risk factors," they added. "Decrease of excess visceral fat and treatment of sleep-disordered breathing could be beneficial in preventing nocturnal cardiac events."

ACS during sleep occurs infrequently, and predisposing factors remain unclear but could include disordered sleep and obstructive sleep apnea (OSA). Patients with OSA have an increased risk of sudden cardiac death with nighttime onset, the authors noted in their introduction.

Kishida and colleagues recently reported dysregulation of adipocytokines during sleep in obese patients with OSA (Am J Physiol Endocrinol Metab 2008; 294: E778-E784, J Atheroscler Thromb 2011; 18: 240-247).

They hypothesized that the combination of sleep-disordered breathing, visceral fat accumulation, and nocturnal dysregulation of adipocytokines might play a role in the occurrence of ACS during sleep.

To test the hypothesis, the authors studied 109 consecutive Japanese patients from a single center who had revascularization procedures for ACS and overnight cardiorespiratory monitoring before discharge. The study population consisted of 66 patients with ST-segment elevation myocardial infarction, 27 with non-ST elevation MI, and 16 with high-risk angina.

The patients had a mean age of 66, mean body mass index of 23.8, total fat area of 239 cm2, visceral fat area of 127 cm2, and an apnea-hypopnea index that averaged 11 events per hour.

Investigators defined excess visceral fat as ≥100 cm2, apnea as cessation of airflow >10 seconds, hypopnea as a decrease in the airflow signal to <70 of the preceding level associated with >4% desaturation, and sleep-disordered breathing as an apnea-hypopnea index ≥5.

Adiponectin levels were measured shortly before sleep onset and after waking. Onset of chest pain from midnight to 7 a.m. was considered nighttime ACS, and onset any other time was considered daytime ACS.

ACS had a nighttime onset in 25 patients and daytime onset in 84. Sleep monitoring results showed that 63 (58%) of the patients had sleep-disordered breathing, and 64 (59%) had visceral fat accumulation ≥100 cm2.

Among patients with nighttime onset of ACS, 12 of 17 with excess visceral fat also had sleep-disordered breathing as compared with two of eight patients who had visceral fat accumulation <100 cm2 (P<0.05).

In patients with daytime ACS, the prevalence of sleep-disordered breathing did not differ between patients with (26 of 47) and without (22 of 37) excess visceral fat.

Circulating adiponectin levels were significantly lower before and after sleep among patients with excess visceral fat, regardless of the time of ACS onset.

Patients with nighttime-onset ACS and excess visceral fat had mean adiponectin levels 6.3 and 6.2 µg/mL, respectively, before and after sleep versus 16.9 and 18.0 µg/mL in patients with visceral fat <100 cm2 (P<0.05, P<0.01).

Among patients with daytime ACS, those with excess visceral fat had mean adiponectin levels of 6.8 and 6.7 µg/mL before and after sleep versus 11.6 and 11.7 µg/mL for patients with <100 cm2 visceral fat accumulation (P<0.01 for both).

Excess visceral fat was associated with a significantly higher apnea-hypopnea index in patients with nighttime ACS (14 versus three events per hour, P<0.05), but not in the group with daytime ACS.

Patients with nighttime ACS and excess visceral fat also had higher levels of plasminogen activator inhibitor-1 and CD40 ligand.

Calling polysomnography the gold standard for diagnosing OSA, the authors acknowledged that they had used other methods for monitoring sleep, noting that polysomnography might not be cost-effective or convenient for identifying sleep-disordered breathing in patients with ACS.

The study was also limited because there were no controls without ACS, the potential bias inherent in a single-center study, and the potential for medical therapy to affect laboratory parameters, which were taken a week after onset of ACS.

[Chevychelov]

Why the FDA Approved Dabigatran 150 mg and Not 110 mg
Samuel Z. Goldhaber, M.D., F.A.C.C. (Disclosure)
July 22, 2011

Stroke is the third most common illness in the United States, after myocardial infarction and cancer. In quality of life surveys, many respond that they prefer death to a permanently disabling stroke. Hypertension is a major risk factor for stroke. But the majority of strokes are considered “cryptogenic” because no definitive cause can be assigned.

Nonvalvular atrial fibrillation (AF) causes about 1 in every 5 to 6 strokes in the United States. These are not ministrokes or transient ischemic attacks. They are anatomically large strokes often causing permanent neurological disability and occasionally death. Embolic strokes due to AF have worse outcomes than other types of strokes. These strokes occur mostly in those over 65 years of age and especially those older than 75 years. They can terminate a lifestyle of independent living and force victims to be placed in settings where they receive round the clock skilled nursing care. These strokes disrupt, decimate, and devastate the social fabric that families have weaved over a lifetime, and they suck away the carefully sequestered savings for a planned retirement of hobbies, volunteer work, and visiting grandchildren.

Only two decades ago did we learn that we can reduce the stroke rate from nonvalvular AF by about 25% with aspirin. And for only slightly longer than one decade have we realized that we can reduce the stroke rate in nonvalvular AF by about another 40% with warfarin rather than aspirin.(1) But warfarin is cumbersome and labor intensive to use properly. The requirement of adjusting the dose according to the International Normalized Ratio (INR) to target a range of 2.0 to 3.0 requires a detailed strategic plan that coordinates laboratory testing in a frequency that varies from twice weekly to once monthly, communicates INR results to the clinician who doses the warfarin, and then informs the patient of whether the dose of warfarin requires adjustment because of new INR results that are unacceptably above or below the targeted range. In addition, warfarin is affected by hundreds of interactions with other medications and with foods. However, despite this myriad of limitations, warfarin remains remarkably effective. Well-dosed warfarin cuts the stroke rate in at risk patients to about 1-2% per year. It has also been marketed in the United States since 1954. So there are no hidden surprises about possible adverse effects.

The monopoly of warfarin (and the family of vitamin K antagonists) as the sole oral anticoagulant has been shattered. A pipeline of novel oral anticoagulants is being developed. The major anticipated advance has been increased convenience to patients and clinicians. The new drugs, whether they are anti-factor Xa or antithrombin agents, are administered in fixed doses, without any laboratory coagulation monitoring. The new anticoagulants have minimal drug-drug and drug-food interactions. It was anticipated that they would be noninferior to warfarin for stroke prevention, and that their rate of bleeding complications would not exceed that of warfarin.

In October 2010, the Food and Drug Administration (FDA) approved the novel antithrombin agent, dabigatran, in a dose of 150 mg twice daily for stroke prevention in nonvalvular AF. The pivotal clinical trial was RE-LY, a megatrial of more than 18,000 patients randomized to dabigatran 150 mg (6,076 patients), dabigatran 110 mg (6,015 patients), or warfarin (6,022 patients). The dose of dabigatran was double-blinded, but the administration of warfarin was open label. Dabigatran 150 mg twice daily surprised virtually everyone involved because it was superior to warfarin and cut the stroke rate by 34% compared with warfarin. In most circumstances, when an anticoagulant is superior in efficacy, it is less safe than the comparator drug. However, in RE-LY, the major bleeding rate was 3.3% with dabigatran 150 mg and 3.6% with warfarin. With regard to life-threatening bleeding, the frequency was 1.5% with dabigatran 150 mg versus 1.9% with warfarin. The intracranial bleeding rate was 60% lower with dabigatran 150 mg than with warfarin.(2)

Dabigatran 110 mg was noninferior to warfarin for stroke prevention. However, dabigatran 110 mg was superior to warfarin for safety, with a major bleeding rate of 2.9% compared with 3.6% for warfarin. There was a significant treatment-by-age interaction, such that dabigatran 110 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in patients aged <75 years (1.9% versus 3.0%) and a similar risk in those aged >75 years (4.4% versus 4.4%). In contrast, dabigatran 150 mg twice a day compared with warfarin was associated with a lower risk of major bleeding in those aged <75 years (2.1% versus 3.0%) and a higher risk of major bleeding (primarily gastrointestinal bleeding) in those aged >75 years (5.1% versus 4.4%).(3) Regardless of age, gastrointestinal bleeding occurred more often in the 150 mg than in the 110 mg group.

The FDA had to decide whether to approve dabigatran 110 mg in addition to dabigatran 150 mg. At first glance, this might seem like an easy decision. Approve dabigatran 150 mg for superior stroke prevention compared with warfarin, and target its use for patients unlikely to suffer major bleeding. And approve dabigatran 110 mg for noninferior stroke prevention compared with warfarin, and target its use for patients at high risk of gastrointestinal bleeding. If one were to choose this strategy, which was put into place in Canada, it would be important to identify subgroups in which use of the 110 mg dose would be advantageous. Among those 75 years of age or older, was it worth trading a lower stroke rate with 150 mg compared with 110 mg of dabigatran (1.4 versus 1.9 per 100 patient-years) for a higher rate of major, mostly extracranial, gastrointestinal bleeding (5.1 versus 4.4 per 100 patient-years)? The FDA didn’t think so, and neither do I.

How about dosing among patients with moderately severe chronic kidney disease, with a creatinine clearance between 30-50 ml per minute? This group is of special interest because dabigatran is metabolized primarily by the kidneys. Surprisingly, dabigatran 150 mg was especially effective in this population compared with dabigatran 110 mg, with stroke rates of 1.3 versus 2.4 per 100 patient-years, respectively. And the major bleeding rate was no greater with dabigatran 150 mg. Even patients who had major bleeding during the trial and who resumed the same dose of dabigatran did not have more major bleeding in the 150 mg group compared with dabigatran 110 mg.(4)

In a detailed investigation of major bleeding comparing dabigatran 150 mg versus 110 mg, multiple key subgroups were analyzed. These included age, gender, weight, renal function, and use of aspirin, amiodarone, or a proton pump inhibitor. The only subgroup in which dabigatran 150 mg had more bleeding than dabigatran 110 mg was among patients weighing more than 100 kg. I believe this is a biologically implausible finding and attribute it to the play of chance when multiple subgroups are undergoing exploratory analysis.(3)

The FDA does not adjudicate cost-effectiveness. This specialized area utilizes the expertise of those who study pharmacoepidemiology and pharmacoeconomics.(5) It is clear that dabigatran 150 mg is far more cost-effective than dabigatran 110 mg.(6)

Finally, we clinicians are by nature conservative. We are taught that our primary duty is to do no harm. Whereas the harm from gastrointestinal bleeding is obvious, the benefit from a stroke that is prevented and that never occurs is easily overlooked.

My initial reflexive reaction to the FDA’s not approving the dabigatran 110 mg dose was to bemoan the lack of incremental decision-making flexibility that I would have been afforded. Having the 110 mg dose would have allowed subtle texturing and molding of my day-to-day clinical practice. Would I have been tempted to opt for less gastrointestinal bleeding in some elderly patients with chronic kidney disease at the steep price of less stroke prevention? Certainly yes. Canadian physicians confront this dilemma every day. It will be interesting to track the proportion of dabigatran prescriptions in Canada that designate the noninferior 110 mg dose versus the superior 150 mg dose. Widespread use of dabigatran 150 mg holds the promise of altering the fundamental epidemiology of stroke and reducing stroke incidence in patients with nonvalvular AF. Prospective cohort studies should be undertaken in the U.S. and in Canada to track future trends over time.

Finally, let’s put the dabigatran dosing issue in perspective. The major problem with stroke prevention in AF is not whether dabigatran 150 mg should be used in preference to 110 mg. The key problem is that too many AF patients who should be treated with anticoagulants are treated with antiplatelet therapy or remain untreated. In an overview of studies since 2000, a median of 52% of AF patients received anticoagulants, 30% received antiplatelet therapy, and 18% were untreated.(7) Intensive educational updates, peer review, and patient advocacy will improve these metrics and should lead to a decrease in stroke incidence.

[Chevychelov]

What Is the Optimal Approach to Anticoagulation for Primary PCI in STEMI?
Davide Capodanno, M.D. (Disclosure)
George D. Dangas, M.D., Ph.D., F.A.C.C. (Disclosure)
August 08, 2011

Primary percutaneous coronary intervention (PCI) is the standard of care for patients with ST-segment elevation myocardial infarction (STEMI).(1) Thrombin plays a central role in arterial thrombogenesis by converting fibrinogen to fibrin, activating platelets, and promoting a procoagulant and proinflammatory enviroment. Therefore, inhibiting either thrombin generation or activity is crucial in the context of acute coronary syndromes, as well as during primary PCI, due to the risk of thrombus formation related to arterial injury or esposure of thrombogenic material from disrupted plaques to intraluminal blood.

Current ACCF/AHA guidelines provide a Class I indication for the use of an anticoagulant as soon as the diagnosis of STEMI is made.(1) Parenteral anticoagulants include indirect thrombin inhibitors, such as unfractionated heparin (UFH) and enoxaparin, and direct thrombin inhibitors, such as bivalirudin. The early initiation of UFH is common practice in many emergency departments ambulances, hospital wards or clinics, due to its universal availability, low price and ease of use as a bolus. Intravenous enoxaparin may be a viable alternative to UFH in patients with STEMI undergoing primary PCI, and sheath removal considerations should account for its long half-life.(2) Evidence supporting a prominent role of bivalirudin as the preferred anticoagulation strategy in the STEMI setting, stems from the large HORIZONS-AMI (Harmonizing Outcomes With Revascularization and Stents in Acute Myocardial Infarction) trial. From 30-day, and up to 3-year follow-up, bivalirudin monotherapy (with 7% GPIIb/IIIa inhibitor infusion for thrombotic bailout) resulted in significantly lower of major bleeding, all-cause mortality and cardiac mortality compared with the combination of UFH plus routine GP IIb/IIIa blocker administration.(3) The bivalirudin arm was also associated with a reduction in reinfarction and overall similar stent thrombosis at 3 years (despite a statistically significant ~1% increase within the first 24 hours).


But how to reconcile the established benefit of bivalirudin observed in the HORIZONS-AMI trial with the widespread use and availability of heparin in clinical practice? It is certainly reasonable and abides by all the treatment guidelines to administer the most available aspirin and UFH bolus at the time of first medical contact with a STEMI patient. Upon further evaluation and hospital admission with transfer to the interventional cardiology suite for primary PCI, further consideration can be given to optimal pharmacological therapy. In the HORIZONS-SWITCH substudy, patients treated with UFH before enrollment in the HORIZONS-AMI trial were analyzed according to their subsequent randomization to bivalirudin or UFH plus a GP IIb/IIIa inhibitor. Switching to bivalirudin before primary PCI resulted in significantly reduced 30-day and 2-year major bleeding (Figure 1).(4) Consistent with the overall trial, the switching strategy also yielded significant reductions in cardiac mortality and reinfarction. These results were not related to the pre-procedure activated clotting time (ACT) value. These data support the study protocol for switching patients on UFH to bivalirudin, i.e., wait 30 minutes after discontinuing UFH, or begin bivalirudin administration in all cases before PCI, regardless of ACT. The early use of UFH before bivalirudin should not be discouraged, as pre-randomization UFH was found to be an independent predictor of reduced acute and subacute stent thrombosis.(5) Bivalirudin can be discontinued at the completion of the index procedure, or continued for 2 to 6 hours after PCI at low dose if clinically indicated (ie. residual dissection, TIMI flow grade under 3, reduced blush grade, residual coronary microthrombi, ulcerated or aneurismal lesions). It is clinically reasonable to extend the infusion when the interventional result is somewhat imperfect, especially in the presence of a slowly absorbed oral thienopyridine agent.

In addition, this optimal anticoagulant approach should be pursued on a background of optimal antiplatelet pharmacotherapy including aspirin and an adenosine diphosphate (ADP) receptor (P2Y12 receptor) antagonist. The finding of a significant greater incidence of acute stent thrombosis with bivalirudin in STEMI provides the opportunity for strategies that enhance periprocedural platelet inhibition. In the HORIZONS-AMI trial, a 600-mg loading dose of clopidogrel had no effect on acute stent thrombosis but was associated with a significant decrease in subacute stent thrombosis compared with a 300-mg loading dose.(5) This finding is consistent with the fact that a 300-mg loading dose of clopidogrel leads to lower and slower platelet inhibition than 600 mg, perhaps even more so in the STEMI setting with reduced drug absorption and metabolism in relation to hemodynamic instability. In this regard, more rapidly acting and potent ADP receptor antagonists than clopidogrel, such as prasugrel or ticagrelor, have the potential to provide incremental benefits; e.g. full antiplatelet activity can be achieved within 30-60min and with less dependence on absorption and hepatic metabolism. Patients who received bivalirudin in the TRITON-TIMI 38 (Trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel—Thrombolysis in Myocardial Infarction 38) and PLATO (Platelet Inhibition and Patient Outcomes) trials, however, were substantially under-represented, hampering any attempt to draw meaningful considerations in the setting of STEMI (Figure 2).(6,7) Given the lower stent thrombosis rates associated with use of these new potent agents compared to clopidogrel in STEMI, one may select them in anticipation of improved outcomes. Nonetheless, clinical trials with these new agents in combination with bivalirudin in STEMI are currently under way in order to investigate whether preloading with a potent ADP antagonist may further reduce early stent thrombosis and improve the prognosis in patients treated with bivalirudin.
References

1. Kushner FG, Hand M, Smith SC Jr, et al. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2009;54:2005-41.

2. Montalescot G, Cohen M, Goldstein P et al. ATOLL: an international randomized study comparing IV enoxaparin to IV UFH in primary PCI. Presented at European Society of Cardiology Congress, Stockholm, August 30, 2010.

3. Stone GW, Witzenbichler B, Guagliumi G, et al. Heparin plus a glycoprotein IIb/IIIa inhibitor versus bivalirudin monotherapy and paclitaxel-eluting stents versus bare-metal stents in acute myocardial infarction (HORIZONS-AMI): final 3-year results from a multicentre, randomized controlled trial. Lancet. 2011;377:2193-204.

4. Dangas GD, Mehran R, Nikolsky E, et al. Effect of switching antithrombin agents for primary angioplasty in acute myocardial infarction. The HORIZONS-SWITCH analysis. J Am Coll Cardiol. 2011;57:2309-16.

5. Dangas GD, Caixeta A, Mehran R, et al. Frequency and predictors of stent thrombosis after percutaneous coronary intervention in acute myocardial infarction. Circulation. 2011;123:1745-56.

6. Montalescot G, Wiviott SD, Braunwald E. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double blind, randomized controlled trial. Lancet. 2009;373:723-31.

7. Steg PG, James S, harrington RA, et al. Ticagrelor versus clopidogrel in patients with ST-elevation acute coronary syndromes intended for reperfusion with primary percutaneous coronary intervention: A Platelet Inhibition and Patient Outcomes (PLATO) trial subgroup analysis. Circulation. 2010;122:2131-41.

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Should All Patients With HF Get Aldosterone Blockade
Muthiah Vaduganathan (Disclosure)
Mihai Gheorghiade, M.D., F.A.C.C. (Disclosure)
August 19, 2011

Introduction

Neurohormonal mechanisms play a central role in mediating the end-organ dysfunction that occurs in heart failure (HF) syndromes. Systemic activation of the mineralocorticoid receptor triggers cellular and genomic changes that underlie the functional and structural cardiorenal deterioration.(1) Mineralocorticoid receptor antagonists (MRA) have emerged as a class of therapeutic agents that act to prevent receptor activation and modulate its deleterious downstream effects. Over the last two decades, MRAs have joined the current drug armamentarium of lifesaving therapies available in HF (β-blockers, ACE-inhibitors). The recent American College of Cardiology Foundation (ACCF) / American Heart Association (AHA) management guideline update has reinforced the utility of MRAs (class I indication, “is recommended”) for patients with chronic HF.(2) Despite these recommendations, a large quality improvement program found that less than one-third of eligible patients admitted with HF received aldosterone antagonist therapy at discharge.(3) In an analysis of U.S. pharmacy/medical claims of almost 400,000 patients with presumable diagnosis of HF, less than 1% received eplerenone and only 15.5% received any aldosterone blocker.(4) Similar disappointing rates of MRA discharge prescription were noted in various regions of the world and were substantially lower than other lifesaving therapies, particularly in North America.(5)

Relatively low doses of MRAs are known to improve clinical outcomes in a broad spectrum of patients with HF. However, they may be associated with an increased risk for hyperkalemia, particularly in patients with renal insufficiency, diabetes and/or in those concurrently taking other RAAS inhibitors. The potential risk of hyperkalemia does not explain the reduced uptake of this therapy in North America.(3,4)

Matching this therapeutic intervention with the right patient is of paramount importance. We attempt to characterize the patient profiles that are best suited for a therapeutic trial with MRAs in the outpatient setting or in the hospital, hoping that higher and more appropriate utilization of this life-saving therapy can be achieved.

Chronic Heart Failure

Three large trials, RALES (Randomized Aldactone Evaluation Study)(6), EPHESUS (Eplerenone Heart Failure Efficacy and Survival Study)(7), and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure)(8) have helped us define the therapeutic boundaries of aldosterone blockade in patients with chronic HF.

The RALES trial(6) enrolled patients with moderate-to-severe symptomatic HF including patients with New York Heart Association (NYHA) class III or IV and reduced EF (mean of 25.6%). After a mean follow-up of 24 months, there was a 30% risk reduction in all-cause mortality, a 35% reduction in rates of rehospitalization and a 36% reduction in progressive HF in the spironolactone arm compared to placebo. Concomitant treatment with β-blockers was low in this trial (11%). The EPHESUS trial(7) included patients 3-14 days post-AMI with either HF with reduced EF or diabetes. Notably, mean EF in this study sample was higher (33%) and included patients with less severe symptoms (NYHA classes II-IV). Eplerenone, a selective MRA, achieved similar reductions in mortality and rehospitalization compared to placebo after a mean follow-up of 16 months. It is known that heightened neurohormonal activation may contribute to fatal ventricular arrhythmias in the background of a failing myocardium.(9) Moreover, eplerenone reduced the risk of early post-MI sudden cardiac death (SCD) just thirty days after randomization by 37%(10), an effect that was more pronounced in patients with EFs less than 30%.(11) Since implantable cardioverter-defibrillators in patients hospitalized with worsening HF are associated with poor post-discharge outcomes(12), MRAs may be a critical intervention in the post-MI patient. Most recently, the EMPHASIS-HF study evaluated the effects of eplerenone in 2,737 patients with chronic HF with mild symptoms (NYHA class II). The “typical” patient represented in this trial was an older, obese Caucasian male with a mean EF of 26%. After a median follow-up of 21 months, composite cardiac death and hospitalization occurred in 18.3% of patients receiving eplerenone and 25.9% of patients in the placebo arm.(8) Interestingly, these favorable endpoints were primarily driven by reductions in early hospitalization, rather than cardiac mortality. This is surprising given that rehospitalization is integrally related to congestion, remodeling and adverse outcomes.(13) Event rates were especially high in this trial, primarily because patients were randomized after hospitalization for HF.

The primary concern related to the use of these agents is the rates of life-threatening hyperkalemia and renal dysfunction, especially when co-administered with ACE-inhibitors. In RALES, serious hyperkalemia occurred infrequently with rates of only 2% (14/822) in the spironolactone arm. Overall, the rates of any adverse effect requiring discontinuation during the trial period were also minimal (8% in the spironolactone group vs. 5% in placebo).(6) Despite these low reported trial rates, a population-based study from Canada has demonstrated that increased rates of prescription of spironolactone after publication of the RALES trial correlated with the higher rates of hyperkalemia-related hospitalizations.(14) More recently, in EMPHASIS-HF, the incidence of hyperkalemia (>5.5 mmol/L) was higher in the eplerenone-treated group compared to the placebo group (11.8% vs. 7.2%).(8) We must keep in mind that in all three trials, there was no mortality directly related to hyperkalemia. Other less-serious side effects experienced by patients taking spironolactone included gynecomastia, menstrual irregularities and impotence. These sexual side effects are minimized by the use of the more selective MRA, eplerenone.

Based on our existing knowledge in chronic HF, MRAs have clinical utility in several important subsets. All patients with mild, moderate or severe chronic HF with evidence of LV systolic dysfunction and patients after AMI with clinical HF symptomatology should be considered for MRA therapy. Theoretically, use of these agents with non-potassium-sparing diuretics may be beneficial to help correct renal electrolyte imbalances. Notably, the risk of hypokalemia (<4.0 mmol/L) in EMPHASIS-HF was significantly reduced in the eplerenone group. Certainly, we must limit use of MRAs in the patients who were excluded from these trials including those with serum creatinine >2.5 mg/dL and serum potassium >5.0 mmol/L. Furthermore, it is essential that judicious use of these agents be exercised in patients with established comorbid conditions that increase risk for developing hyperkalemia including diabetes and renal dysfunction. In all three trials, MRAs reduced the rates of the primary outcome in all pre-specified groups including patients with baseline renal dysfunction. Additionally, with ever-growing drug cocktails in HF, it is important for clinicians to be mindful of drug interactions that can result in metabolic abnormalities. Interestingly, despite the increased risk of hyperkalemia with concomitant use of ACE-inhibitors, the mortality benefits of MRAs were uniformly superior in patients already on ACE-inhibitors and B-blockers at the time of trial enrollment.(7,8) The incremental benefits of MRAs were also particularly evident in patients receiving digoxin. This is important since digoxin use has decreased substantially in the last decade, despite being approved by the FDA.(15)
Acute Heart Failure Syndromes

Excess sympathetic drive and compensatory activation may have similar detrimental consequences in patients with acute heart failure syndromes (AHFS) as they do in chronic HF.(16) In addition, patients presenting with right-sided HF and hepatic congestion may have impaired clearance of aldosterone and elevated circulating neurohormonal factors.(17) Although we lack definitive clinical evidence, MRAs may have a dual effect in AHFS: preventing progression of HF and as a safe and effective diuretic, possibly preventing the potential negative effects of non-potassium diuretics on end outcomes. Indeed, insight from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) trial revealed that elevated serum levels of aldosterone and lack of provision of MRAs at discharge were independently associated with adverse outcomes in this population.(18) Moreover, the mortality benefit observed in our chronic HF trials utilized non-natriuretic doses of MRAs. Carefully up-titrating to maximally tolerated dosage may help relieve congestion and improve HF symptomatology in acutely decompensating patients.(19) Furthermore, patients with acutely decompensated HF treated with long-term loop diuretics may be predisposed to developing diuretic resistance and its attendant adverse events. MRAs have been shown to ameliorate receptor-level responsiveness and augment natriuresis in AHFS.(20-22) In these small studies, the rates of hyperkalemia and renal dysfunction were minimal and normalized shortly after MRA discontinuation.

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Table: Study design, clinical characteristics, major outcomes and rates of hyperkalemia in RALES, EPHESUS and EMPHASIS-HF
RALES6 EPHESUS7 EMPHASIS-HF8
No. of patients 1663 6632 2737
NYHA Class III, IV II-IV, post-MI II
MRA Spironolactone Eplerenone Eplerenone
Mean Dose (mg daily) 26 43 39
Follow-up (months) 24 16 21
Mean Age (years) 65 64 69
Male (%) 73 72 77
Mean EF (%) 26 33 26
All-cause mortality (ARR %) 11.3 2.3 3.0
Cardiac mortality (ARR %) 9.8 2.3 2.7
All-cause hospitalization (ARR%) 8.3 1.1 5.9
Hyperkalemia Definition ≥6 mmol/L ≥6 mmol/L ≥5.5 mmol/L
Hyperkalemia (Risk excess %) 0.5 1.6 4.6
NYHA = New York Heart Association; MRA = mineralocorticoid receptor antagonists; EF = ejection fraction; ARR = absolute risk reduction

Clinicians are hesitant to initiate MRA therapy during hospitalization, as evidenced by the poor rates of discharge prescription. We speculate that this may be primary related to concerns of hyperkalemia and adverse side effect profiles of these agents in the acute setting since a significant number of patients have a hospital course complicated by worsening renal function, many have diabetes (~40%) and the majority are concomitantly taking an ACE-inhibitor or ARB. However, patients may be particularly amenable to change during hospitalization and adding underutilized, but efficacious, agents to their existing regimen may be beneficial. The hospitalization provides a unique opportunity for clinicians to optimize medical therapy and provide assistance extending beyond mere symptomatic relief.(23,24) If MRAs are administered as indicated with close monitoring and surveillance, especially immediately after initiation and at higher therapeutic doses, metabolic derangements can be identified early and successfully managed. There is an enormous unmet need in AHFS with alarmingly high mortality and rehospitalization rates seen within the first 90 days of discharge.(25) The minor risk of metabolic fluctuations may be a small price to pay for these dismal event rates.
Matching the Right Drug with the Right Patient

MRAs have successfully linked our basic science understanding of HF pathophysiology to its direct clinical management. Although MRAs are well-established and provide a consistent mortality benefit (albeit through an unknown mechanism), they remain an underutilized class of agents in the setting of HF. Currently, we are only offering this potentially life-saving therapy to a minority of eligible patients. Treatment should not be provided based solely on structured algorithms, clinical care teams involving physicians, nurses, pharmacists, patients and their families must work together to determine appropriateness of MRA initiation.

It is also important to appropriately adjust and up-titrate dosage to achieve maximal natriuretic and mortality benefit. Initial studies suggest that MRAs may have two distinct beneficial effects in HF. At lower doses (25-50 mg/day), the drug has minimal cardiac penetration, but has a documented mortality benefit. Mean doses utilized in RALES, EPHESUS and EMPHASIS-HF were 26 mg, 43 mg and 39 mg daily, respectively. At higher drug levels (50-75 mg/day), similar to dosing employed by our hepatology colleagues, natriuretic effects are achieved and help to modulate intravascular volume and congestion. At these dosing ranges in the RALES trial, spironolactone significantly decreased sodium retention within days of drug initiation.(6) Starting at trial doses and up-titrating if necessary (and tolerated) to attain diuretic effect may be a plausible treatment strategy.

As our clinical experience and familiarity with this class of agents continue to grow, we will hopefully be able to close this apparent gap between evidence-based guidelines and clinical practice in the setting of HF. As with most agents available for use in the setting of HF, one size certainly does not fit all. Careful selection of patients and vigilant follow-up after initiation of MRAs are imperative for therapeutic success. Despite initial concerns that a treatment-patient mismatch existed for MRAs, contemporary appropriateness guidelines have shown that use of these agents in patients with documented contraindications was only 0.5%.(3)

Further research will be necessary to shed light on whether we can extend the clinical usefulness of MRAs to other important patient populations with HF. Unfortunately, we currently lack substantial clinical evidence regarding the efficacy of aldosterone blockade in the setting of HF with preserved EF and in AHFS. In the near future, hopefully we will be able to better ascertain drug appropriateness in these special populations. We also eagerly await the development of novel MRAs that confer higher receptor specificity that may lessen the metabolic fluctuations and adverse risk profiles associated with current therapies. In this era of heart failure management, clinical trials tend to define the limits of our therapeutic boundaries. However, we must also be mindful of our lack of understanding of MRA effectiveness in “real world”, unselected patients. Tailoring and individualizing therapy to fully balance the benefits and risks of aldosterone antagonism will be necessary for the treatment of each and every patient.

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References

1. Francis GS, Goldsmith SR, Levine TB, Olivari MT, Cohn JN. The neurohumoral axis in congestive heart failure. Ann Intern Med 1984;101:370-7.

2. Hunt SA, Abraham WT, Chin MH, et al. 2009 Focused update incorporated into the ACC/AHA 2005 Guidelines for the Diagnosis and Management of Heart Failure in Adults A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the International Society for Heart and Lung Transplantation. J Am Coll Cardiol 2009;53:e1-e90.

3. Albert NM, Yancy CW, Liang L, et al. Use of aldosterone antagonists in heart failure. JAMA 2009;302:1658-65.

4. Margolis J, Gerber RA, Roberts C, Gheorghiade M. Adherence to aldosterone-blocking agents in patients with heart failure. Am J Ther 2010;17:446-54.

5. Blair JE, Zannad F, Konstam MA, et al. Continental differences in clinical characteristics, management, and outcomes in patients hospitalized with worsening heart failure results from the EVEREST (Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan) program. J Am Coll Cardiol 2008;52:1640-8.

6. Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999;341:709-17.

7. Pitt B, Remme W, Zannad F, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003;348:1309-21.

8. Zannad F, McMurray JJ, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11-21.

9. Aronson D, Burger AJ. Neurohormonal prediction of mortality following admission for decompensated heart failure. Am J Cardiol 2003;91:245-8.

10. Pitt B, White H, Nicolau J, et al. Eplerenone reduces mortality 30 days after randomization following acute myocardial infarction in patients with left ventricular systolic dysfunction and heart failure. J Am Coll Cardiol 2005;46:425-31.

11. Pitt B, Gheorghiade M, Zannad F, et al. Evaluation of eplerenone in the subgroup of EPHESUS patients with baseline left ventricular ejection fraction <30%. Eur J Heart Fail 2006;8:295-301.

12. Wang NC, Piccini JP, Konstam MA, et al. Implantable cardioverter-defibrillators in patients hospitalized for heart failure with chronically reduced left ventricular ejection fraction. Am J Ther 2010;17:e78-87.

13. Blair JE, Khan S, Konstam MA, et al. Weight changes after hospitalization for worsening heart failure and subsequent re-hospitalization and mortality in the EVEREST trial. Eur Heart J 2009;30:1666-73.

14.Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004;351:543-51.

15. Gheorghiade M, Braunwald E. Reconsidering the role for digoxin in the management of acute heart failure syndromes. JAMA 2009;302:2146-7.

16. Albaghdadi M, Gheorghiade M, Pitt B. Mineralocorticoid receptor antagonism: therapeutic potential in acute heart failure syndromes. Eur Heart J 2011.

17. Gheorghiade M, Pang PS. Acute heart failure syndromes. J Am Coll Cardiol 2009;53:557-73.

18. O'Connor CM, Miller AB, Blair JE, et al. Causes of death and rehospitalization in patients hospitalized with worsening heart failure and reduced left ventricular ejection fraction: results from Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan (EVEREST) program. Am Heart J 2010;159:841-9 e1.

19. Schrier RW, Gheorghiade M. Challenge of rehospitalizations for heart failure: potential of natriuretic doses of mineralocorticoid receptor antagonists. Am Heart J 2011;161:221-3.

20. Ceremuzynski L, Budaj A, Michorowski B. Single-dose i.v. Aldactone for congestive heart failure: a preliminary observation. Int J Clin Pharmacol Ther Toxicol 1983;21:417-21.

21. Hensen J, Abraham WT, Durr JA, Schrier RW. Aldosterone in congestive heart failure: analysis of determinants and role in sodium retention. Am J Nephrol 1991;11:441-6.

22. van Vliet AA, Donker AJ, Nauta JJ, Verheugt FW. Spironolactone in congestive heart failure refractory to high-dose loop diuretic and low-dose angiotensin-converting enzyme inhibitor. Am J Cardiol 1993;71:21A-8A.

23. Gheorghiade M, Peterson ED. Improving postdischarge outcomes in patients hospitalized for acute heart failure syndromes. JAMA 2011;305:2456-7.

24. Metra M, Gheorghiade M, Bonow RO, Dei Cas L. Postdischarge assessment after a heart failure hospitalization: the next step forward. Circulation 2010;122:1782-5.

25. Gheorghiade M, Abraham WT, Albert NM, et al. Systolic blood pressure at admission, clinical characteristics, and outcomes in patients hospitalized with acute heart failure. JAMA 2006;296:2217-26.

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Speedy Treatment for Heart Attacks Called 'Finest Moment'

By Chris Kaiser, Cardiology Editor, August 22, 2011

Note that current guidelines recommend that for patients with ST-segment–elevation myocardial infarction who receive primary percutaneous coronary intervention that the time from hospital arrival to mechanical reperfusion, should not exceed 90 minutes.

Point out that nationally within the last five years the door-to-balloon time has declined markedly with corresponding increases in the percentage of patients who had times <90 minutes.
Review
Over a span of five years, the initiative to improve door-to-balloon time for people experiencing out-of-hospital myocardial infarction has resulted in significantly lower transport and treatment times, a nationwide analysis showed.

From 2005 to 2010, door-to-balloon time declined from a median of 96 minutes to 64 minutes, reported Harlan R. Krumholz, MD, from Yale University School of Medicine, and colleagues.

Moreover, there were corresponding increases in the percentage of patients who had times under 90 minutes (44.2% to 91.4%), as well as under 75 minutes (27.3% to 70.4%), according to the study published online in Circulation: Journal of the American Heart Association.

"These results show the profession at one of its finest moments," Krumholz told MedPage Today in an interview. "The research isn't top-down research. It's about trying to ferret out the secrets of success from those doing the best."

There were no financial incentives for the door-to-balloon initiative to go forward. It is about disseminating best patient practices, Krumholz noted.

"Over this five-year period, we've had this extraordinary change in practice. And now any American who has a heart attack that requires angioplasty can feel confident that he or she will be treated very quickly," he said.

A study in 2006 showed that only a third of patients received primary PCI within 90 minutes, and a third waited longer than two hours after arriving at the hospital (J Am Coll Cardiol 2006; 47: 45–51), but that same year Krumholz and colleagues reported that a handful of simple measures could substantially shorten that time interval.

This latest publication represents a culmination of those efforts, Krumholz said in an email.

First, the Centers for Medicare and Medicaid Services (CMS) began to publicly report the percent of patients treated within recommended times. Then, the American College of Cardiology and others launched the D2B Alliance, which advocated the "adoption of key strategies that had been shown to reduce delays based on a study funded by the National Heart, Lung, and Blood Institute." Finally, the American Heart Association launched Mission: Lifeline, another national initiative created to speed the care of STEMI patients.

Studies charting the success of D2B times following these initiatives were generally from registries, which represent a "selected sample" of U.S. hospitals, Krumholz and colleagues wrote.

"There has been no national assessment of the trends in D2B times, nor do we know whether improvements in D2B times were shared equally among patient and hospital groups," they said.

To fill in those gaps, they analyzed data reported by hospitals to CMS for inclusion in the time to PCI inpatient measure. During the study period, the number of patients was fairly constant, ranging between 48,977 and 53,682.

At baseline, slightly more than half of all patients were between the ages of 46 and 65, three-quarters were men, and 80% were white. These numbers did not vary significantly during the study period.

In 2005, 44.2% and 27.3% of patients had D2B times in under 90 and 75 minutes, respectively. In 2010, those numbers were 91.4% and 70.4%.

The investigators found a median drop in D2B time of 32 minutes during the time span (96 to 64 minutes), which represents a greater than 30% relative decline.

"This improvement, experienced across the country and across different types of hospitals, represents a remarkable elevation in practice that was achieved over a relatively short period of time and in the absence of financial incentive," researchers wrote.

They also said that these improvements were likely due to multiple factors, rather than one single overriding action, including:
Published articles that identified strategies for improving door-to-balloon time
National initiatives by various organizations
Identifying "exceptional" performers and analyzing their methods
CMS' emphasis on quality improvement in this area


Krumholz noted that each hospital had to find places to "shave minutes" off their D2B times. There generally wasn't one single area that could decrease D2B time by significant amounts of time.

He compared it to racing pit crews, who work tirelessly to cut mere seconds from every action during a pit stop.

Christopher White, president of the Society for Cardiovascular Angiography and Interventions (SCAI), told MedPage Today that these improvements could not have happened if the medical professions involved were practicing in silos.

"One of the major changes in practice was for cardiologists to allow EMTs or ED physicians to activate the cath lab before the cardiologist determined or confirmed the patient had an MI," White said. "That was a huge shift and very necessary for reducing door-to-balloon time."

While seconds can still be cut from existing D2B protocols, there is one area on which stakeholders will focus more attention going forward: transfer times for patients who must be transported to a PCI-capable hospital.

CMS is considering publicly reporting transfer times, Krumholz and colleagues said. "More importantly, current research shows that these times can be reduced through greater coordination between hospitals."

Limitations to the study included modifications to the CMS reporting process over the time period, which could have affected results.

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CVD Risk Prediction Improved by Homocysteine

By Charles Bankhead, Staff Writer,
Published: August 22, 2011
Reviewed by Dori F. Zaleznik, MD; Associate Clinical Professor of Medicine, Harvard Medical School, Boston and
Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

Action Points
Explain that an analysis of two large databases found that adding homocysteine determination to the Framingham Risk Score significantly improved prediction of cardiovascular disease events.

Note that adding homocysteine reclassified risk for approximately 20% of patients in the intermediate cardiovascular disease risk category.

Risk stratification for cardiovascular disease (CVD) improved significantly with the addition of homocysteine level to the Framingham Risk Score, investigators reported.

A homocysteine level >15 µmol/L predicted as much as a 172% increased risk of CVD across two disparate cohorts. In particular, the addition of homocysteine to traditional risk factors led to reclassification of about 20% of patients in the intermediate-risk category, as reported in the Journal of the American College of Cardiology.

"Our results lend support to previously published data exploring the association between homocysteine and cardiovascular disease and coronary heart disease (CHD) events," Luis Afonso, MD, of Wayne State University in Detroit, and coauthors wrote in conclusion.

"Of note, unlike any previous study, our analyses were adjusted for C-reactive protein (CRP), an independent predictor of future CVD events."

Traditional risk factors account for a majority of CVD risk, but a substantial minority of events remains incompletely explained. In an effort to hone risk prediction, investigators have examined numerous nontraditional factors, especially biomarkers, such as CRP, coronary artery calcium, and homocysteine level.

Studies of homocysteine as a CVD risk factor have yielded inconsistent results. Moreover, previous studies have focused largely on Caucasian populations and patients with pre-existing CVD.

"To date, no study has systematically explored the predictive value of homocysteine beyond existing risk predicted by the Framingham Risk Score (particularly in individuals without overt CVD) or assessed whether homocysteine level contributes to reclassification of individuals in the intermediate-risk Framingham Risk Score category," the authors wrote.

To address limitations of previous studies, Afonso and colleagues examined the risk-prediction value of homocysteine in two data sets: the Multi-Ethnic Study of Atherosclerosis (MESA), a community-based, ethnically diverse cohort of healthy adults; and the Third National Health and Nutrition Examination Survey (NHANES III), a representative sample of the general population.

The authors investigated potential associations of homocysteine with composite CVD and hard CHD events in MESA and with CVD and CHD mortality in NHANES III.

Composite CVD comprised myocardial infarction, resuscitated cardiac arrest, definite angina, probable angina, stroke, stroke death, CHD death, other atherosclerotic death, and other CVD death. A hard CHD event was defined as MI, resuscitated cardiac arrest, or CHD death.

Risk estimates for MESA were based on six years of follow-up. Framingham Risk Score (based on 10-year risk) was adjusted to obtain six-year estimated risk. Patients were assigned to four risk categories: very low, <3%; low, 3% to <6%; intermediate, 6% to 12%; and high, >12%.

The NHANES data set had 15 years of follow-up and was adjusted to obtain 10-year risk estimates: very low, <5%; low, 5% to <10%; intermediate, 10% to <20%; and high, >20%.

The final analyses comprised 6,450 study participants from MESA and 6,797 NHANES III participants.

After adjustment for traditional risk factors and CRP, a homocysteine level >15 µmol/L was associated with a hazard ratio of:
1.79 for composite CVD (P=0.006)
2.22 for CHD events (P=0.01)
2.72 for CVD mortality (P<0.001)
2.61 for CHD mortality (P<0.001)


When added to the Framingham Risk Score, homocysteine led to reclassification of 12.9% and 18.3% of the MESA and NHANES III cohorts overall and to reclassification of 21.2% and 19.2% of the intermediate-risk patients in the MESA and NHANES III cohorts, respectively.

Investigators also analyzed the data sets by means of the net reclassification improvement (NRI) index, using Framingham Risk Score with and without homocysteine. The addition of homocysteine resulted in significant reclassification in the MESA (NRI 0.35, P<0.001) and NHANES III cohorts (NRI 0.57, P<0.001).

The analyses showed increases in the area under the receiver operating characteristic curve of 0.025, indicating a 2.5% increase in probability of an event, indicating a 2.5% improvement, authors of an editorial noted.

"This small increase is typical of models that already contain at least a handful of strong predictors," Arduino A. Mangoni, MD, of the University of Aberdeen in Scotland, and Richard J. Woodman, PhD, of Flinders University in Adelaide, Australia, wrote.

"It is often hard to be convinced that such small changes will translate into meaningful differences in patient management, even if from a public health perspective, changes of this magnitude might be meaningful."

Nonetheless, the study "provides a sound rationale for adding homocysteine in CVD risk assessment," Mangoni and Woodman added. However, they offered several reasons for cautious interpretation of the results:
Framingham Risk Score is not universally accepted for risk assessment
The Framingham model's applicability outside the U.S. has yet to be proven
Use of the Framingham model in the NHANES cohort might have been inappropriate because several participants had a history of MI or cerebrovascular disease
The NRI by itself does not indicate whether reclassification occurred

Afonso and colleagues also acknowledged the study was limited by having a single baseline homocysteine measurement, which could vary based on a number of factors including food intake, position when blood drawn, time of day, as well as cobalamin and folate levels.

[Chevychelov]

Metabolic Syndrome Linked to Kidney Disease

By Nancy Walsh, Staff Writer, August 22, 2011

Explain that a systematic review and meta-analysis found an association between components of the metabolic syndrome and the development of chronic kidney disease as measured by an estimated glomerular filtration rate <60 mL/min per 1.73 m2.

Note that risk was associated with each component and increased when multiple components were present, indicating a significant trend.
Review

Metabolic syndrome and its individual components -- hypertension, high triglycerides, low HDL cholesterol, central obesity, and impaired fasting glucose -- are all associated with the development of chronic kidney disease (CKD), a meta-analysis determined.

In a pooled analysis, the odds ratio for developing CKD, defined as an estimated glomerular filtration rate below 60 mL/min per 1.73 m2, was 1.55 (95% CI 1.34 to 1.80) in patients with the metabolic syndrome, according to Sankar D. Navaneethan, MD, of the Cleveland Clinic, and colleagues.

And although the risk of CKD did not increase for patients with only one component of the syndrome, the odds ratio rose to 1.96 (95% CI 1.71 to 2.24, P<0.01) when all five syndrome components were present, the researchers reported online in the Clinical Journal of the American Society of Nephrology.

"The public health relevance of these results is underscored by the fact that the prevalence of [metabolic syndrome] and its components is increasing over time, and findings suggest that the CKD burden might rise commensurately," they stated.

Because previous studies exploring the association of the metabolic syndrome and CKD have had conflicting results, Navaneethan and colleagues conducted a systematic review and meta-analysis that included 11 prospective studies and more than 30,000 patients.

The outcome measures of interest were estimated glomerular filtration rate, microalbuminuria, and proteinuria.

Three of the studies included European or American patients, while participants in the other eight were Asian.

The number of patients in the studies ranged from a low of 175 to more than 17,000, and duration of follow-up was 3.5 to 12 years.

The odds ratios for the development of chronic kidney disease for the individual components of the metabolic syndrome were:
Hypertension, OR 1.61 (95% CI 1.29 to 2.01)
Hypertriglyceridemia, OR 1.27 (95% CI 1.11 to 1.46)
Low HDL, OR 1.23 (95% CI 1.12 to 1.36)
Abdominal obesity, OR 1.19 (95% CI 1.05 to 1.34)
Impaired fasting glucose, OR 1.14 (95% CI 1.03 to 1.26)


The association was statistically significant for all five (P<0.01) and became stronger with a higher number of components of the metabolic syndrome (P for trend 0.02).

Three studies found increased risks for developing proteinuria among patients with metabolic syndrome, but a pooled analysis could not be done because of small numbers and differences in the studies.

Significant statistical heterogeneity was seen among the studies, but on univariate meta-regression no differences in risk were identified according to CKD criteria and definitions, duration of follow-up, or study location.

The researchers noted that previous reports have linked elevated triglycerides and low HDL with the development of chronic kidney disease, but "these factors are often overlooked in clinical practice."

They also emphasized the importance of the 19% increased risk for CKD in patients with abdominal adiposity.

"With the increasing problem of obesity across the globe, the burden of [metabolic syndrome] is expected to rise rapidly, further underscoring the relevance of our findings," they observed.

Potential weaknesses of their analysis were the observational nature of the studies, their heterogeneity, and the possibility of attrition or selection bias.

"Our results emphasize the need to identify individuals with the constellation of these metabolic risk factors earlier and consider multidisciplinary interventions, particularly lifestyle modifications, to retard the development of CKD," concluded Navaneethan and colleagues.

Three of the authors have received support from the National Institutes of Health.

All authors reported no conflicts of interest.
Primary source: Clinical Journal of the American Society of Nephrology
Source reference:
Thomas G, et al "Metabolic syndrome and kidney disease: a systematic review and meta-analysis" Clin J Am Soc Nephrol 2011; DOI:10.2215/CJN.02180311.

[Chevychelov]

Stents Work for Some Very Young Patients

By Todd Neale, Senior Staff Writer, Published: August 22, 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 percutaneous coronary intervention with stent implantation is uncommon in children and extremely rare in infants due to perceived risk as well as technical difficulty.

Note that this study reports a small experience with children and infants who successfully underwent percutaneous coronary intervention with stent implantation suggesting that the procedure is feasible and relatively safe as a palliative and temporary solution.

A percutaneous coronary intervention (PCI) involving a stent implantation appears to be a viable option for infants and young children with coronary stenosis, a small case series suggested.

Stenting was performed successfully in four children younger than 15 months, with no procedural complications, András Bratincsák, MD, PhD, of Rady Children's Hospital in San Diego, and colleagues reported online in Catheterization and Cardiovascular Interventions.

The average amount of time free from additional interventions was 434 days, although one patient died after developing stent thrombosis and undergoing surgery to repair the problem.

"Our experience suggests that coronary artery stent implantation is a feasible and relatively safe palliative option in infants and toddlers with coronary stenosis," Bratincsák and colleagues wrote.

They added, however, that stenting is not meant to be a permanent fix in young children because the stents cannot be dilated to diameters large enough for adults.

"It is a viable strategy for bridging patients with acute ischemia or poor ventricular function to elective surgical revascularization or transplantation," they wrote.

Although PCI is rarely performed in infants and children because of the risks and difficulty of the procedure, Bratincsák and colleagues wanted to review the feasibility of the approach in young patients.

They performed a retrospective review of children who underwent PCI at Rady Children's Hospital over a four-year period, identifying seven patients younger than 18 who received stents in the proximal portion of the left or right coronary artery.

The described case series focused on the four patients younger than 15 months, who ranged in age from 7 to 14 months.

In those patients, the indications for PCI included congenital ostial stenosis of the left or right coronary arteries in two patients, a worsening of acute coronary syndrome symptoms after surgical repair of anomalous left coronary artery arising from the pulmonary artery in one, and acute left ventricular dysfunction and ventricular fibrillation secondary to external compression of the left main coronary artery after the dilation of a right pulmonary artery stent in one.

Before the intervention, the mean coronary artery diameter was 0.65. Balloon angioplasty failed to effectively open the blocked arteries, resulting in the implantation of bare-metal stents in all four patients. The stents were dilated to a mean internal diameter of 2.5 millimeters.

There were no procedural complications, and "excellent" revascularization was achieved in all four patients.

All of the patients received aspirin, and three of the four also received clopidogrel (Plavix).

Two of the patients, both of whom received dual antiplatelet therapy and had an implanted stent diameter greater than 2.5 mm, did not experience in-stent restenosis or stent thrombosis. One -- a male with Crouzon syndrome -- eventually underwent heart transplantation and the other -- a female with William's syndrome -- had a patent stent three years after PCI.

One of the other patients -- a female diagnosed with anomalous left coronary artery from the pulmonary artery -- developed mild in-stent restenosis 302 days after PCI and eventually underwent elective surgical repair of the proximal left main coronary artery, which included stent removal.

The final patient -- a male with a history of ventricular septal defect -- did not fare as well.

He did not receive clopidogrel post-PCI and experienced stent thrombosis four days after implantation despite adequate heparinization. He required extracorporeal membrane oxygenation support, and after physicians unsuccessfully attempted to reopen the blocked stent, he underwent surgical repair of the left main coronary artery. He died three days after the surgery due to intracranial hemorrhage.

"Our case mix illustrates the variety of possible causes of acute coronary syndrome in children," researchers wrote.

Furthermore, as a temporary solution, stenting has similar immediate and mid-term efficacy as surgical repair, but "substantially lower" relative risk. However, these young patients must maintain dual antiplatelet therapy for at least 12 months, unless contraindicated, the authors emphasized.

[Chevychelov]

Coronary CTA identified CAD mortality risk in patients

Min J. J Am Coll Cardiol. 2011;58:849-860.
By

Coronary CTA successfully identified those at heightened risk for all-cause mortality, providing worsened prognosis for patients with obstructive or nonobstructive coronary artery disease, according to a study.

The researchers evaluated 24,775 patients aged at least 18 years from 12 centers using Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry (CONFIRM) data gathered between 2005 and 2009 who underwent at least 64-detector row coronary CTA for suspected CAD. CAD severity was judged on a per-patient, per-vessel and per-segment basis, and the severity was defined as either none (0% stenosis), mild (1%-49% stenosis), moderate (50%-69% stenosis) or severe (≥70% stenosis). Patients with known CAD or a history of MI, coronary revascularizations and cardiac transplant were excluded from the study.

The coronary CTA scans were performed on a variety of different scanner platforms, and then analyzed by level 3-equivalent cardiologists who had experience interpreting several thousand coronary CTA scans. Any uninterpretable coronary artery segment that was scanned was scored similarly to the most proximal segment that was evaluable, according to researchers. Time to mortality was then estimated using multivariable Cox proportional hazards models.

A follow-up was obtained for 96.3% of patients. Researchers recorded 404 deaths in the follow-up, and an increasing severity of CAD in men, patients with diabetes, hypertension, dyslipidemia, family history of CAD, who currently smoke, typical angina, and high pre-test likelihood of CAD. Patients who had died before follow-up “had significantly more severe coronary artery stenosis in the majority of coronary segments” compared with patients who were alive at follow-up. Only 0.65% of deaths occurred in patients without evident CAD.

“The study cohort was middle-aged with a high prevalence of CV risk factors and symptoms,” researchers wrote. “They presented with typical or atypical angina in the majority of cases, with the majority of individuals having intermediate or high pre-test likelihood of obstructive CAD.”

Overall, both obstructive and nonobstructive CAD presented increased risk for mortality compared with patients without evident CAD, according to researchers. Patients with nonobstructive, obstructive one-vessel, two-vessel, or three-vessel or left main CAD had an increased risk of mortality, with two-vessel and three-vessel showing higher hazards for death in younger patients, and three-vessel CAD showing higher hazards for women compared with men.

“These results of the CONFIRM registry represent the first prospective international multicenter data to relate [coronary] CTA-determined extent and severity of CAD to all-cause mortality and demonstrate the independent prognostic value of both obstructive as well as nonobstructive CAD by [coronary]CTA,” the researchers wrote.
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New FDA guidelines aim to clarify benefit-risk determinations for medical devices
By

FDA has approved draft guidance clarifying how benefit-risk determinations are made during premarket review of certain medical devices, according to a press release.

“Clinical data is the foundation for determining the safety and effectiveness of medical devices requiring FDA premarket approval,” FDA Center for Devices and Radiological Health director Jeffrey Shuren, MD, stated in the news release. “As medical devices grow increasingly complex, many factors impact our benefit-risk determinations, especially for PMA devices. This guidance aims to provide more clarity to manufacturers about what factors we consider when making an approval decision.”

The guidance focuses on the regulatory pathway for high-risk medical devices: premarket approval applications (PMAs). Recommendations within the guidance are intended to improve predictability, consistency and transparency of the premarket review process for applicable devices, and could help manufacturers navigate the approval process more easily, the release noted.

Safety and effectiveness data make up the FDA’s review of PMAs, with safety data addressing risk and the device manufacturer’s ability to mitigate such risk. Effectiveness data considers benefits and other information in determining whether the benefits of using the device outweigh the risks.

According to the release, however, safety and effectiveness data alone may not provide a complete picture of the benefits and risks involved. For this reason, FDA medical device reviewers examine factors like the severity of the disease the product diagnoses or treats — as well as whether or not alternative tests or treatments may be available. Reviewers also might take into account whether a device should be considered new or first-of-its-kind, especially if it treats a disease with no other treatment.

The guidance also proposes medical device reviewers use a worksheet to document how they make benefit-risk determinations, the release noted, adding that in certain cases such a document could be made public post-approval — enhancing the transparency of the FDA’s decision-making process.
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Patient survival with beta-blockers varies in US vs. rest of the world

O’Connor C. J Am Coll Cardiol. 2011;58:915-922.
By

A meta-analysis of randomized trials evaluating beta-blockers in patients with HF has reported that among those in the United States, beta-blockade correlated with a lower survival benefit compared with those in the rest of the world.

The analysis included 8,988 patients with HF (46.7% from the US) enrolled in the COPERNICUS, MERIT-HF and BEST randomized, double blind, placebo-controlled trials.

According to results, the reduction in RR for each beta-blocker among those in the US cohort was minimal and no longer significant when compared with the overall cohort, whereas those in the rest of the world experienced a mortality benefit with beta-blockade.

In a pooled analysis that also included patients from the CIBIS-II trial (n=11,635), patients taking beta-blockers had an overall RR of death of 0.77 (95% CI, 0.71-0.84) vs. placebo. Only those in the rest of the world cohort, however, had a statistically significant survival benefit with beta-blockers (RR=0.64; 95% CI, 0.56-0.72).

Postulating on the reasons behind this discrepancy, the researchers said geographic difference in treatment response may be due to differences in populations, genetic factors, cultural or social differences in disease management, or low power and statistical chance.

“Whatever the cause, geographic differences are reported frequently in the literature, and these findings support the need to re-evaluate the conduct, methodology and analysis procedures of international trials to ensure that the generalizability of study findings can accurately be determined,” they said.