Обзор американских кардиологических журналов за неделю (ссылки)

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Reduced Dietary Salt for the Prevention of Cardiovascular Disease: A Meta-Analysis of Randomized Controlled Trials (Cochrane Review)
[Ссылки доступны только зарегистрированным пользователям ]

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SIRTAX LATE: Comparable outcomes for sirolimus-, paclitaxel-eluting stents at 5 years

Räber L. Circulation. 2011;123:2819-2828.

New randomized trial data have indicated that patients treated with first generation sirolimus-eluting stents had no significant differences in clinical and angiographic outcomes at 5 years compared with patients receiving paclitaxel-eluting stents.

The Sirolimus-Eluting Versus Paclitaxel-Eluting Stents for Coronary Revascularization (SIRTAX LATE) trial involved 1,012 patients randomly assigned to receive either sirolimus-eluting stents (SES; Cypher, Cordis; n=503) or paclitaxel-eluting stents (PES; Taxus, Boston Scientific; n=509). In addition, all patients had at leastone lesion in a vessel with a reference diameter between 2.25 and 4.00 mm.

At 5 years, 97.6% of SES and 96.1% of PES patients had obtainable clinical follow-up. Major adverse cardiac events (a composite of cardiac death, MI and ischemia-driven target lesion revascularization) occurred in 19.7% of SES patients and 21.4% of PES patients (HR=0.89; 95% CI, 0.68-1.17). Individually, there were no statistically significant differences in the rates of cardiac death (SES, 5.8% vs. PES, 5.7%), MI (SES, 6.6% vs. PES, 6.9%) or target lesion revascularization (TLR; SES, 13.1% vs. PES, 15.1%).

Also reported, the annual rate of TLR between 1 and 5 years was 2.0% for the SES group and 1.4% for PES group, while delayed lumen loss for those undergoing paired angiography between 8 months and 5 years was 0.37 ± 0.73 mm for SES and 0.29 ± 0.59 mm for PES patients.

Among the clinical implications of the study, the researchers wrote, were the low risk of repeat revascularization with first-generation drug-eluting stents (DES) and the observation that very late stent thrombosis remains an important limitation of first-generation DES, accounting for more than half of all MIs between 1 and 5 years.
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VALOR II: Thoracic stent graft safe, efficacious in patients with descending TAA

The Valiant thoracic stent graft produced favorable results at 1 year among patients with descending thoracic aortic aneurysms of degenerative etiology and proved to be noninferior to a predicate device, according to presented data.

The nonrandomized, prospective, pivotal VALOR II trial followed 160 patients with descending thoracic aortic aneurysms (TAA) of degenerative etiology who were treated with a thoracic stent graft (Valiant, Medtronic) at 24 US centers. Outcomes were compared with those obtained in the VALOR pivotal trial, a study that examined a precursor thoracic stent graft (Talent, Medtronic) among 195 patients with the same inclusion criteria.

Overall, 96.3% of VALOR II patients had successful stent graft delivery and deployment. At 30 days, perioperative mortality was 3.1% with a major adverse event rate of 38.1%. At 1 year, among 94.4% of patients from the VALOR II trial who were available for follow-up, rates of aneurysm-related mortality was 3.3%, 2.9% for stent-graft migration and 13% for endoleak, with no cases of rupture, conversion to open surgery or loss of stent-graft patency.

In all, the Valiant stent graft proved to be statistically noninferior to the Talent stent graft in 12-month all-cause mortality (12.6% vs. 16.1%) and exceeded the primary effectiveness goal of 12-month successful aneurysm treatment (97.4% vs. 80%), which was defined as the absence of aneurysm growth of more than 5 mm and of secondary procedures for type I/III endoleak.

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Title: A New Risk Scheme to Predict Warfarin-Associated Hemorrhage: The ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study
Date Posted: July 12, 2011
Authors: Fang MC, Go AS, Chang Y, et al.
Citation: J Am Coll Cardiol 2011;58:395-401.

Related Resources
Clinical Trial
The Anticoagulation and Risk Factors In Atrial Fibrillation Study
Study Question:
Can we predict hemorrhage risk associated with warfarin use?
Methods:
The authors studied data from the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) study, which followed 13,559 adults having nonvalvular atrial fibrillation who were enrolled in Kaiser Permanente of Northern California health care system. This included all subjects with International Classification of Diseases-Ninth Revision, Clinical Modification (ICD-9) diagnosis codes for atrial fibrillation between July 1, 1996 and December 31, 1997, with follow-up through September 30, 2003. The authors obtained data from clinical databases and identified hemorrhage events validated using a review of medical records. They then developed a hemorrhage risk stratification score using a Cox regression model with candidate variables selected using bootstrapping approaches. The final model was internally validated with split-sample testing, and compared to six previously published hemorrhage risk schemes.
Results:
The authors of this study followed 9,186 patients with atrial fibrillation, contributing 32,888 person-years of follow-up (median warfarin duration 3.5 years [interquartile range, 1.2-6.0 years]). During follow-up, they observed 461 first major hemorrhage events (1.4% annually). The final model included five independent variables, weighted by regression coefficients: anemia (3 points), severe renal disease–defined as glomerular filtration rate <30 ml/min or on dialysis (3 points), age ≥75 years (2 points), prior bleeding (1 point), and hypertension (1 point). Cumulative point score was associated with major hemorrhage rates ranging from 0.4% (at 0 points) to 17.3% (at 10 points). The c-index for the continuous risk score was 0.74 and it was 0.69 across three categories of risk (low risk 0-3 points; intermediate risk 4 points; high risk 5-10 points). This was higher than the other previously published risk schemes. There was a net reclassification improvement with this newly derived risk score compared with all six previously published schemes (ranging from 27-56%).
Conclusions:
The authors concluded that this simple five variable risk score is effective in quantifying the risk of warfarin-associated hemorrhage in this large community-based cohort of adult patients with atrial fibrillation.
Perspective:
As larger, more complex, and more detailed clinical databases become available, as well as improved statistical methods, better and more precise epidemiologic studies become possible. The authors of the current study have contributed significantly to the important clinical dilemma of assessing the potential harm of a medical therapy that has a quantifiable proven clinical benefit. Often, the clinical decision regarding the appropriateness of instituting warfarin therapy is made on the basis of an estimation of the potential clinical benefit. In the case of atrial fibrillation, this means an estimation of the patient’s risk of stroke without anticoagulation. Warfarin therapy is deemed appropriate when the risk of stroke without anticoagulation exceeds the risk of bleeding with anticoagulation. While increasingly precise tools have been developed and widely disseminated for estimating the risk of stroke without warfarin therapy, much less attention has been paid to the other side of the equation—estimating the risk of bleeding with warfarin therapy. The current study has developed, validated, and compared with prior schemes, a clinically useful and relatively easy to calculate tool for estimating the individualized risk of bleeding with warfarin therapy in adults with atrial fibrillation. This should greatly enhance clinical decision-making surrounding the use of warfarin therapy for stroke prophylaxis in atrial fibrillation.
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Title: Management and Outcomes of Cardiac Tamponade During Atrial Fibrillation Ablation in the Presence of Therapeutic Anticoagulation With Warfarin
Date Posted: June 28, 2011
Authors: Latchamsetty R, Gautam S, Bhakta D, et al.
Citation: Heart Rhythm 2011;8:805-808.

Study Question:
What are the outcomes among patients with and without a therapeutic international normalized ratio (INR) who developed cardiac tamponade (CT) as a complication of radiofrequency catheter ablation (RFCA) of atrial fibrillation (AF)?
Methods:
The subjects of this retrospective study were 40 consecutive patients who developed CT during RFCA of AF at three centers. The authors divided the patients into two groups: RFCA performed with INR <2 (group 1) and INR ≥2 (group 2). There were 23 patients in group 1 and 17 patients in group 2. Comparisons between the two groups were performed using the Student t-test for continuous variables and the Fisher exact test for categorical variables. The duration of pericardial drainage and the length of hospital stay were compared using the Wilcoxon signed-rank test.
Results:
Baseline clinical and procedure characteristics were not different between the two groups. Heparin was reversed by protamine in 83% and 94% of patients (p = 0.37), and warfarin was reversed by fresh frozen plasma or factor VIIa in 17% and 35% of patients (p = 0.27) in groups 1 and 2, respectively. All patients were successfully treated by percutaneous drainage, and none required surgical intervention. There were no significant differences in the amount of initial pericardial drainage (523 ± 349 ml vs. 409 ± 157 ml, p = 0.22) or the duration of drainage (p = 0.14) between the two groups. All patients survived to hospital discharge. Median length of hospital stay was 2 days longer in group 1 (p < 0.01).
Conclusions:
The authors concluded that CT is not more severe or difficult to manage in the presence of therapeutic anticoagulation with warfarin in patients undergoing RFCA of AF.
Perspective:
This study reports that the severity of CT was not affected by whether or not the INR was in the therapeutic range. Moreover, the length of hospital stay appeared to be shorter in patients undergoing RFCA with a therapeutic INR. Overall, the data suggest that the continuation of warfarin through the RFCA procedure to maintain a therapeutic INR is a safe strategy, but prompt recognition and management of CT during left atrial ablation is critical.

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Title: Esophageal Temperature Change and Esophageal Thermal Lesions After Pulmonary Vein Isolation Using the Novel Endoscopic Ablation System
Date Posted: June 23, 2011
Authors: Metzner A, Schmidt B, Fuernkranz A, et al.
Citation: Heart Rhythm 2011;8:815-820.

Study Question:
What is the risk of esophageal injury during pulmonary vein isolation (PVI) by laser ablation compared to radiofrequency catheter ablation (RFCA)?
Methods:
Sixty patients (mean age 59 years) with paroxysmal atrial fibrillation were assigned to undergo PVI using a laser balloon endoscopic catheter (n = 40) or an irrigated-tip RF ablation catheter (n = 20). With both catheters, individual lesions were created circumferentially until PVI was achieved. A temperature probe was placed in the esophagus and energy applications were discontinued whenever the esophageal temperature (ET) was ≥38.5ºC. All patients underwent endoscopy 2 days post-ablation and were treated with a proton pump inhibitor for 6 weeks.
Results:
PVI was successfully achieved in all patients in both groups. Ablation on the posterior left atrial wall resulted in an ET ≥38.5ºC in 70% of patients in the laser group and 90% of patients in the RFCA group. Endoscopy demonstrated minimal thermal lesions in 8% of patients in the laser group and 15% of patients in the RFCA group. Esophageal ulcerations were present in 10% of patients in the laser group and were not found in any of the RFCA patients. There was not a significant correlation between thermal lesions and the maximal ET in either group. No patient developed an atrioesophageal fistula.
Conclusions:
The authors concluded that risk of esophageal ulcerations is higher with laser ablation than RFCA in patients undergoing PVI.
Perspective:
The higher risk of esophageal injury with laser ablation is consistent with the deeper tissue penetration of laser energy than RF energy. Importantly, the ET data in the study confirm the limited value of luminal temperature monitoring for avoiding esophageal injury.

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After GRAVITAS: Is There a Future for Functional Platelet Testing?
Negative findings evoked multiple possible explanations
Much research needed before test-guided antiplatelet therapy enters the clinic
By Kim Dalton
Monday, July 18, 2011

In a 2-part series, TCTMD will explore how the GRAVITAS trial is influencing the field of functional platelet testing. Part 1 summarizes the trial and its aftermath, including explanations for the results and remaining issues. Next up, part 2 will address the risks of using platelet function tests to guide therapy in lieu of randomized trial data and discuss their future in clinical practice.

At the American Heart Association Scientific Sessions 2010 this past November in Chicago, one of the most keenly awaited late-breaking trials delivered a blow to the attractive concept of adjusting antiplatelet therapy following percutaneous coronary intervention (PCI) based on functional measurement of platelet reactivity.

GRAVITAS (Gauging Responsiveness with A VerifyNow assay—Impact on Thrombosis And Safety) promised to answer the question of whether a relatively straightforward strategy for managing the almost one-third of patients who have high platelet reactivity despite receiving standard dual therapy after PCI—and thus are at substantially increased risk of thrombotic events—was in fact effective.

The trial had the potential to change practice. After mixed signals from several small observational studies, here were data from the first large randomized trial to close the circle between pharmacodynamic and clinical data by rigorously testing whether adjusting clopidogrel dose based on results of a point-of-care functional test would improve patient outcomes.

The answer, reported by lead investigator Matthew J. Price, MD, of Scripps Clinic (La Jolla, CA), was no, bringing with it larger implications for the future of this nascent field.

Disappointing Results—and Plenty of Explanations

In the targeted cohort with high on-treatment reactivity, at 6 months rates of the primary endpoint, a composite of cardiovascular death, MI, or stent thrombosis, were identical for the high- and standard-dose clopidogrel groups: 2.3%.

For the trial, almost 5,500 patients with stable or unstable CAD underwent DES implantation and received a 600-mg loading dose of clopidogrel (if they were drug naïve). Testing 12 to 24 hours later using the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA) identified 2,214 patients (41%) with high residual reactivity, defined as a P2Y12 reaction unit (PRU) value equal to or above 230. That cohort was then randomized to continue on the standard 75-mg maintenance dose or receive another 600-mg loading dose and then 150 mg daily, both for 6 months.

While GRAVITAS is clearly not the final word on the use of functional testing to guide therapy, several commentators noted, at the least it invalidated the particular strategy tested and put routine point-of-care platelet testing on hold. Meanwhile, they said, it is important to try to understand why the trial was negative in order to move forward. And there has been no shortage of proposed explanations, with attention directed at nearly every aspect of the trial design, from the patients studied to the antiplatelet regimen used and the reactivity cutpoint chosen.

Analysis confirmed that the more aggressive antiplatelet regimen did in fact have a pharmacodynamic impact. At 30 days after PCI, platelet reactivity had decreased in both arms, but the decline was steeper in those who received the double clopidogrel dose, and the difference remained largely unchanged at 6 months. At 1 month, high residual reactivity persisted in only 40% of the high-dose group compared with 62% of the standard-dose group (P < 0.001), for an absolute reduction of 22%.

Significantly, however, even in the high-dose arm, the absolute reduction in PRU was modest, declining from a median of about 280 at baseline to about 200, Dr. Price reported. Moreover, the relatively small absolute difference in median platelet reactivity between the 2 arms—about 40 PRU—was reflected in the fact that rates of GUSTO severe and moderate bleeding were similar (1.4% in the high-dose arm vs. 2.3% in the standard-dose arm; P = 0.10).

The investigators’ power assumptions—a 5% event rate in patients on standard clopidogrel and a 50% risk reduction with high-dose drug—also came under fire as being overly optimistic. The low event rate observed in the standard-dose arm of only 2.3% set a near-impossible bar for double-dose patients to surpass, several commentators suggested. They added that increasing the sample size and/or lengthening follow-up might boost the event rate, improving the odds of seeing a difference between the treatment groups, but it would also expose even more patients to the possibility of bleeding when there was no hint of ischemic benefit.


In fact, after GRAVITAS, many experts were pinning their hopes on the more aggressive strategy of the TRIGGER-PCI trial. It not only set a PRU threshold of 208 but was testing the more potent antiplatelet agent prasugrel in elective PCI patients with high platelet reactivity on clopidogrel.

Nonetheless, other, ongoing randomized trials are exploring different approaches to test-guided therapy and may provide insights into the question of whether functional testing holds any future role. These include:
ARCTIC, in which clopidogrel dosage will be adjusted for elective patients with a suboptimal response to initial therapy based on a VerifyNow cutpoint of 235 PRU
DANTE, in which ACS patients will be randomized to a standard or double maintenance dose of clopidogrel based on VerifyNow-measured residual reactivity
TARGET PCI, in which PCI patients determined by genotyping or serial functional testing (230 PRU cutpoint) to have high residual platelet reactivity will be switched to prasugrel

Unresolved Issues

Supporting that view are results of a recent Italian trial (Campo G, et al. J Am Coll Cardiol. 2011;57:2474-2483) in which high on-clopidogrel platelet reactivity (defined as a PRU of ≥ 235) at baseline frequently fell below that threshold by 1 month. Moreover, 1-month reactivity levels were found to be stronger predictors of long-term outcomes.

Given this temporal variability, a proposed way to rescue a test-guided antiplatelet strategy is to treat patients to a target level of reactivity, adjusting therapy based on the results of serial testing. A hint that such an approach might work comes from a small, nonrandomized study of ACS patients undergoing PCI (Bonello L, et al. J Am Coll Cardiol. 2010;56:1630-1636). Among poor responders to a 600-mg loading dose (about one-third of whom carried at least 1 loss-of-function CYP2C19 allele), the loading dose was repeated up to 4 times—guided by reactivity monitoring—until 88% of them reached ‘adequate’ platelet inhibition (defined as a VASP [vasodilator stimulated phosphoprotein] index < 50%).

The larger hope of using testing to guide therapy, however, faces many hurdles. “I’ve always felt there will ultimately be some role for testing, but we need to wait for the evidence rather than just act on gut feelings,” Dr. Bhatt stressed, offering as a cautionary example the discredited therapy for premature ventricular contractions (PVCs). Suppressing these dangerous arrhythmias seemed to make sense, he explained. The only problem was that the drug used for that purpose ended up causing even worse arrhythmias.

Similarly, “it’s logical to think that responding to [inadequate] antiplatelet inhibition on a point-of-care assay [with higher antiplatelet doses or a more potent drug] should improve patient outcomes,” Dr. Bhatt said. “But it’s tricky, because more isn’t always better. There may also be more bleeding.” Furthermore, the risk-benefit ratio could vary widely based on patient presentation—for example, elective vs. urgent PCI with a DES, he added.

The second half of this feature, which will appear Monday, July 25, will discuss how these debates play out in clinical practice.



Sources:
1. Price MJ. Standard versus high-dose clopidogrel according to platelet function testing after PCI: Results of the GRAVITAS trial. Presented at: American Heart Association Scientific Sessions; November 16, 2010; Chicago, IL.

2. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention. JAMA. 2011;11:1097-1105.

3. Gurbel PA and Tantry US. An initial experiment with personalized antiplatelet therapy. JAMA. 2011;11:1136-1137.

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HORIZONS-AMI: Bivalirudin Reduces Cardiac Death in Diabetics

Key Points:
Cardiac mortality more than halved at 1 year with bivalirudin vs. heparin plus a GPI in diabetics with STEMI receiving primary PCI
Other endpoints including major bleeding, MACE, not reduced with newer agent
Interaction analysis shows bivaliridin benefits similar irrespective of diabetic status
By Jason Kahn
Monday, July 18, 2011

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The direct thrombin inhibitor bivalirudin results in significantly reduced rates of cardiac death compared with heparin and a glycoprotein IIb/IIIa inhibitor (GPI) in diabetics with ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention, according to a substudy of the HORIZONS-AMI trial. But, according to 1-year results appearing in the July 2011 issue of JACC: Cardiovascular Interventions, bivalirudin may not reduce overall mortality or major bleeding in this population.

For the HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in AMI) trial, researchers led by Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), randomized 3,602 STEMI patients at 123 centers in 11 countries who were undergoing primary PCI to receive bivalirudin (n = 1,800) or heparin plus a GPI (n = 1,802). In a second randomization, 3,006 of the patients were assigned in a 3:1 ratio to receive a paclitaxel-eluting Taxus stent (n = 2,257; Boston Scientific, Natick, MA) or an otherwise identical BMS (n = 749).

At 3 years, bivalirudin significantly reduced major bleeding (non-CABG), reinfarction, cardiac death, and all-cause death compared with heparin plus a GPI, while Taxus patients experienced a 40% reduction in ischemic TLR compared with BMS patients.

Focus on Diabetics

In the new subanalysis, researchers led by Dr. Stone focused on the 593 patients from HORIZONS-AMI who were diabetic. Of these, 281 received bivalirudin and 312 received heparin plus a GPI. Baseline and procedural characteristics were similar between the 2 groups, although thienopyridine use prior to admission was higher in diabetics receiving heparin plus a GPI compared with those receiving bivalirudin (6.1% vs. 2.5%; P = 0.03).

At 30 days, the rate of cardiac death was reduced in patients receiving bivalirudin. However, noncardiac deaths were higher in these patients, rendering the endpoint of overall death equivalent in both groups. In addition, net adverse clinical events (major bleeding or MACE), MACE (death, reinfarction, TVR, or stroke), TVR, and major non-CABG bleeding all were equivalent (table 1).

Net adverse events also were similar at 1 year, though exact rates were not reported. Stent thrombosis rates were likewise equivalent between the bivalirudin (4.2%) and heparin plus GPI (3.8%; P = 0.85) arms. Breaking down the diabetes patients by insulin-treated and noninsulin-treated status, antithrombotic strategy made no difference in net adverse events, MACE, or stent thrombosis. However, among insulin-treated patients, bivalirudin was associated with a lower incidence of cardiac death at 1 year (1.4% vs. 9.4%; P = 0.04).

The current study “represents the largest analysis of diabetic STEMI patients treated by contemporary primary PCI to date and demonstrates that bivalirudin compared with heparin plus GPI significantly reduces cardiac mortality in the high-risk diabetic cohort as well as patients without diabetes,” Dr. Stone and colleagues conclude.

No Interaction with Diabetes Status Found

Because bleeding and overall mortality were not reduced as they were in the main cohort, the authors performed an interaction analysis, demonstrating that the favorable effects of bivalirudin were independent of diabetic status for the endpoints of major bleeding (P for interaction = 0.26), net cardiac events (P = 0.64), all-cause mortality (P = 0.55), and cardiac mortality (P = 0.19). This showed that “the most appropriate interpretation of these data is that the overall benefits of bivalirudin seen in the main trial seem to apply to patients both with and without diabetes,” the researchers write, although they could not rule out a “modest difference in the relative effect of bivalirudin versus heparin plus GPI in patients with, versus without, diabetes.”

According to Debabrata Mukherjee, MD, of Texas Tech University Health Sciences Center (Lubbock, TX), the interaction analysis was the most meaningful part of the substudy. “That’s very important [because] it means statistically, whether the patient has diabetes or not, they get benefit, and having diabetes shouldn’t factor into the decision to use bivalirudin or not,” he told TCTMD in a telephone interview. “This is very reassuring.”

Therefore, Dr. Mukherjee added, the subanalysis results should be viewed in the same context as the overall trial. “Based on the totality of the data, whether the patient has diabetes or not, bivalirudin appears to be the antithrombotic of choice. It’s pretty robust, strong evidence,” he said, adding that in his own practice, “we use bivalirudin irrespective of diabetes in the majority of patients.”

Change Is Slow, But Steady

Nevertheless, clinicians have not made a wholesale switch to bivalirudin. “Physician practice takes time to change. There’s a lot of bivalirudin use in the younger generation, newer physicians and people coming out of training,” Dr. Mukherjee said. “For people who have trained with unfractionated heparin, it takes time, sometimes years or decades, but bivalirudin use has gone up. It’s maybe 50%. It’s not 100%, but it will take time.”

Regarding the question of why the subanalysis failed to show differences in overall mortality, MACE, or major bleeding, Dr. Mukherjee said the answer may lie in the sample size. “If you did a several-thousand patient diabetic trial, I think you’d see a similar magnitude of bleeding reduction with bivalirudin as in the overall trial,” he added.

Note: Dr. Stone and several coauthors are faculty members of the Cardiovascular Research Foundation, which owns and operates TCTMD.



Source:
Witzenbichler B, Mehran R, Guagliumi G, et al. Impact of diabetes mellitus on the safety and effectiveness of bivalirudin in patients with acute myocardial infarction undergoing primary angioplasty. Analysis from the HORIZONS-AMI (Harmonizing Outcomes with RevascularIZatiON and Stents in Acute Myocardial Infarction) trial. J Am Coll Cardiol Intv. 2011;4:760-768.

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Prasugrel Fails to Tame Platelets in One-Quarter of ACS Patients Undergoing PCI

Key Points:
A quarter of ACS patients undergoing PCI show high on-treatment platelet reactivity after 60-mg prasugrel loading dose
High reactivity (≥ 50% VASP) predicts more MACE at 1 month
No difference in TIMI bleeding between those above or below VASP cutpoint
By Kim Dalton
Monday, July 18, 2011

Despite prasugrel’s greater potency and faster action compared with the older antiplatelet agent clopidogrel, platelet reactivity testing after a loading dose of the newer third-generation thienopyridine shows suboptimal inhibition in about 1 in 4 patients with acute coronary syndromes (ACS) following percutaneous coronary intervention (PCI). Furthermore, high on-treatment platelet reactivity leads to more thrombotic events at 30 days, according to a prospective multicenter study published in the July 26, 2011, issue of the Journal of the American College of Cardiology.

Laurent Bonello, MD, of Hôpital Universitaire Nord (Marseille, France), and colleagues enrolled 301 patients who underwent successful PCI for ACS (42.5% STEMI) and received prasugrel as antiplatelet therapy (60-mg loading dose and 10 mg daily for 1 year). Platelet reactivity was measured using the vasodilator-stimulated phosphoprotein (VASP) assay on blood drawn between 6 and 12 hours after drug loading.

High on-treatment platelet reactivity was defined as a VASP index of at least 50%. In the overall cohort, the mean VASP index was 34.3 ± 23.1%, but there was wide variability among individuals (1% - 82.8%). Although the majority of patients showed adequate inhibition, 25.2% were found to have high residual reactivity. On the other hand, about one-third had very low VASP values (< 20%).

High Reactivity Means More Thrombotic Events

At 30-day follow-up, more patients with high on-treatment reactivity met the primary composite endpoint (cardiovascular death, nonfatal MI, or Academic Research Consortium-defined stent thrombosis) than did good responders. In addition, 3 poor responders experienced nonfatal definite stent thrombosis. Although 4 good responders had TIMI bleeding events (2 major requiring transfusion and 2 minor) compared with only 1 minor bleed in patients with high reactivity, the difference was not significant (table 1).

VASP levels were higher in patients experiencing recurrent thrombotic events compared with those free of events at 1 month (64.4 ± 14.4% vs. 33.4 ± 22.7%; P = 0.001). In univariate analysis, the only factors significantly associated with thrombotic events were the VASP index (P = 0.001) and hypercholesterolemia (P = 0.032). No difference was seen in VASP index between patients with or without TIMI non-CABG-related bleeding (30 ± 17.8% vs. 34.3 ± 23.1%; P = 0.70).

Similarly, Kaplan-Meier analysis showed that patients with high on-treatment reactivity had worse 1-month outcomes than good responders (9.2% vs. 0.4%; log-rank P < 0.001). However, no difference emerged in TIMI bleeding between patients above or below the reactivity cutpoint of 50% (P = 1.00). Demographic, clinical, and angiographic factors were similar between the 2 groups, except for relatively fewer men in the high on-treatment reactivity group (81.6% vs. 92% in the good responders; P = 0.007).

The optimal cutoff value of the VASP index was determined to be 53.5%, yielding a positive predictive value of 10.4% and a negative predictive value of 99.6%.

Low Reactivity a Lingering Concern

The authors point out that although a sizable number of patients had very low platelet reactivity after prasugrel loading, no relationship emerged between reactivity level and bleeding risk. Nonetheless, they caution, previous studies involving clopidogrel have found an association between excessive inhibition and bleeding complications. “These findings suggest that there may [be] a therapeutic window of [thienopyridines] to reach to prevent thrombotic events and not increase the bleeding risk,” the investigators write.

Dr. Bonello and colleagues suggest that, based on the current findings, “prasugrel therapy may require [platelet reactivity] monitoring to enable optimal [platelet reactivity] inhibition to be achieved, which may lead to improved outcomes in all patients.”

In a telephone interview, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), told TCTMD that he was not surprised that one-quarter of prasugrel-treated patients showed high platelet reactivity. But many physicians may be, he said, since until now most attention in regard to poor response has focused on clopidogrel.

High Reactivity: It’s Not Just the Drug

Eric R. Bates, MD, of the University of Michigan Medical Center (Ann Arbor, MI), similarly observed in an e-mail communication with TCTMD that even with prasugrel, it increasingly seems that high on-treatment platelet reactivity “is an important variable to measure patient response to drug [therapy].”

“Unfortunately,” he added, “[reactivity] thresholds may vary by test, and the result is influenced by clinical syndrome, patient factors, and time of measurement, not just the antiplatelet drug.”

Dr. Bates also said he wished the researchers had continued platelet reactivity measurements for 4 days, as they did in an their study on repeat clopidogrel loading doses (Bonello L, et al. J Am Coll Cardiol. 2008;51:1404-1411). Such a protocol could have helped determine “whether there was earlier suppression [of reactivity] in low responders than there was with clopidogrel,” he noted.

Dr. Bhatt agreed that clinical setting plays a key role in platelet reactivity. He pointed out that, with the exception of genetic polymorphisms (which affect the bioavailability of clopidogrel but not prasugrel), all the factors that contribute to variability in platelet response to clopidogrel likely also apply to response to prasugrel—just to a lesser degree.

Moreover, Dr. Bhatt noted, “[y]ou would think that if someone had high on-treatment platelet reactivity, their risk of bleeding should be lower and risk of ischemic events should be higher. And vice versa. But that has not been consistently seen in studies. In fact, if anything, it seems like patients who bleed have a higher rate of ischemic events.

“It’s a very complex issue and shows we don’t really understand what predisposes patients to bleeding or ischemic events as precisely as we’d like to,” he commented.

Practicing in a ‘Gray Zone’

Dr. Bhatt said it is difficult to know whether the reactivity testing results are clinically important.

“As with clopidogrel studies, high on-treatment reactivity is associated with a high rate of ischemic events, so it’s certainly a marker of future risk. If your platelets are more reactive than other patients’, you are worse off regardless of whether you’re on clopidogrel or prasugrel,” he said. “But is it really the drug that’s at fault or the patient’s ‘angry platelets?’ I think what we’re identifying here is primarily high-risk patients.”

According to Dr. Bhatt, the key clinical question remains unanswered: Is there a way to alter therapy based on knowledge of platelet reactivity that improves patient outcomes? “To date, no one has shown that satisfactorily, and if anything, the negative findings of GRAVITAS would argue against it,” he noted.

“The study is something researchers can build on and leaves the door open for more potent periprocedural inhibition of platelet reactivity,” Dr. Bhatt acknowledged. But until a positive randomized study is reported, “we’re left in a kind of gray zone where we have provocative data [but no clear clinical strategy]. My fear is that some physicians might overinterpret this study and if a test shows high on-treatment reactivity double the prasugrel dose, for example. Not only might that not be helpful, it might be harmful. Especially when we’re talking about more potent agents, we have to be really cautious about the bleeding risk of an untested strategy.”

Study Details

The great majority of the study patients were men (88.7%), with a mean age of 58.1 years. Almost one-quarter (23.3%) had diabetes.

DES or BMS were used according to French Society of Cardiology guidelines. Functional testing was performed using Platelet VASP kits (Diagnostica Stago, Asnières, France).

Source:
Bonello L, Pansieri M, Mancini J, et al. High on-treatment platelet reactivity after prasugrel loading dose and cardiovascular events after percutaneous coronary intervention in acute coronary syndromes. J Am Coll Cardiol. 2011;58:467-473.

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Higher sodium-potassium level linked to CVD risk

Yang Q. Arch Intern Med. 2011;171:1183-1191.

A higher ratio of sodium-potassium intake was linked to an increased risk for all-cause mortality of nearly 50%, according to study results.

Previous findings have indicated that higher sodium and lower potassium intakes may increase CVD risk, researchers from several sites in the US suggested. However, the impact of that ratio on mortality has not been explored.

Data for 12,267 adults from the 1988-2006 Third National Health and Nutrition Examination Survey Linked Mortality File were analyzed for associations between sodium-potassium intake ratios and all-cause, cardiovascular and IHD mortality. There were 2,270 deaths during a mean of 14.8 years of follow-up. There were 825 CVD deaths and 443 deaths attributed to IHD.

Multivariate analysis results indicated that higher sodium intake was linked to increased all-cause mortality (HR=1.20; 95% CI, 1.03-1.41 per 1000 mg/d) and higher potassium intake was linked to lower mortality risk (HR=0.80; 95% CI, 0.67-0.94 per 1000 mg/d).

The sodium-potassium ratios were broken down into quartiles. The adjusted HRs for the highest quartile compared with the lowest were 1.46 (95% CI, 1.27-1.67) for all-cause mortality, 1.46 (95% CI, 1.11-1.92) for CVD mortality and 2.15 (95% CI, 1.48-3.12) for IHD mortality, according to the results.

There were no significant differences in these findings with regard to demographic data, BMI, hypertension status or physical activity levels of the study population.

“Our findings suggest that a higher sodium-potassium ratio is associated with significantly increased risk of CVD and all-cause mortality, and higher sodium intake is associated with increased total mortality in the general US population,” the researchers wrote.
__________________________________________________ ___________________________
Torcetrapib raised HDL, may help control diabetes

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

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

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

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

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

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

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

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

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

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

Carson CC. J Sex Med. 2011;doi:10.1111/j.1743-6109.2011.02337.x.

A review of various meta-analyses and randomized controlled trials conducted in middle-aged and older men did not link testosterone therapy with elevated risk for cardiovascular events.

Cardiovascular risk has been a topic of concern for elderly men taking testosterone therapy. To evaluate the link, Culley C. Carson, III, MD, of the University of North Carolina School of Medicine, and Giuseppe Rosano, MD, of San Raffaele Pisana, Rome, Italy, conducted the review of trials examining testosterone administration in men aged 45 years and older.

“In clinical trials where testosterone has been used in patients with pre-existing CV conditions, the effect on disease symptoms has typically been either neutral or beneficial,” the researchers wrote. According to results of the review, testosterone treatment significantly improved exercise performance in hypogonadal and eugonadal men with heart failure. Therapy also had no significant effect on serum lipid profiles or C-reactive protein in hypogonadal men with HF and physiologic levels of testosterone; however, therapy did produce small increases in total body mass and reductions in body fat percentage.

Several meta-analyses also linked testosterone treatment with better metabolic parameters, including decreases in fasting plasma glucose, HbA1c, fat mass and plasma triglycerides in patients with type 2 diabetes. In addition, the researchers found that testosterone therapy had no impact or slightly beneficial effects on CV risk factors in hypogonadal men with diabetes or metabolic syndrome. The treatment appeared to improve insulin sensitivity, decreased central adiposity and did not negatively affect inflammation.

An exception was an increase in hematocrit in this patient population using testosterone therapy, the researchers said.

“Although an increase in hematocrit may be of concern in some conditions, patients with [HF] are often anemic; therefore, the effect of testosterone on [hemoglobin] levels may be regarded as beneficial,” the researchers wrote.

In patients with angina or coronary artery disease, hematocrit increased with testosterone treatment, but the therapy had no effect on C-reactive protein, plasminogen activator inhibitor-1 and fibrogen, and antithrombotic factor tissue plasminogen activator.

Although testosterone therapy did not have an effect on LDL and triglyceride levels, the treatment either did not change or considerably reduced total and HDL cholesterol, according to the results. The researchers noted, however, that decreases in total and HDL cholesterol were an inconsistent response among study participants.

Despite these encouraging conclusions, the researchers acknowledged the limitations of the studies analyzed.

“The majority of the randomized, blinded, placebo-controlled clinical trials of testosterone included in this analysis were small and of short duration,” the researchers wrote. “Obviously, outcomes of large, well-designed, prospective trials would be a more compelling proof of the benefit (or otherwise) of testosterone treatment in terms of CV safety.”

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The renaissance of the “J-shaped curve” for on-treatment low blood pressure values
An article from the e-journal of the ESC Council for Cardiology Practice

Grassi G.
Topics: Hypertension
Authors: Grassi G.
The so-called "J curve" paradox refers to the finding described in studies performed about 30 years ago suggesting that treatment-induced systolic blood pressure values below 120 or 125 mm Hg and diastolic blood pressure values below 75 mm Hg may be harmful for the heart. New evidence in favour of the existence of the “J curve” have been published in the context of some recent clinical trials.

The most recent guidelines for the management of essential hypertension, published jointly in the 2007 by the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC), recommend a blood pressure goal of 140/90 mmHg in the general hypertensive population and a lower goal of 130/80 mmHg or less in patients with type 2 diabetes and in high-risk individuals, such as those with a clinical history of an acute cerebrovascular or coronary event or with an evidence of target organ damage (1). Based on the information provided by recent clinical trials, however, the issue of the risk/benefit ratio of aggressive blood pressure-lowering interventions and the so-called “J-curve” phenomenon (2) have been a matter of academic and clinical debate. As a result, an ESH task force recently updated some of the recommendations for hypertension management, with special emphasis on the definition of the blood pressure goals (3).
1- The “J-Shaped Curve" Hypothesis: previous history

The first evidence in favour of the “J-curve” was provided in 1979 by Stewart who claimed in a retrospective analysis of 169 hypertensive patients that the risk of myocardial infarction was of greater magnitude in patients in whom the diastolic blood pressure was lowered to less than 90 mmHg compared with 100 mmHg to 109 mmHg (4).
In 1987, a group of british investigators published a retrospective analysis of 939 treated hypertensive patients (5). From this analysis, they claimed that lowering of the diastolic blood pressure to less than 85 to 90 mmHg was associated with an increase in fatal myocardial infarction in patients with pre-existing ischemic heart disease. Support for this view appeared to be provided by Alderman and coworkers (6), who observed a huge number of previously untreated hypertensive patients for about 4 years. They found that the 39 fatal and nonfatal myocardial infarctions that occurred in the study were significantly more common in patients with a small fall in diastolic blood pressure (=6 mmHg) or a large fall (=18 mmHg), whereas patients with a reduction of diastolic blood pressure between 7 and 17mm Hg had a significantly smaller risk. Studies supporting the "J-shaped curve" hypothesis have been mostly retrospective, often open, and commonly have included too few events to allow significant conclusions to be reached. Furthermore, “J-shaped" relationships between cardiovascular events and blood pressure have also been described in untreated or placebo-treated patients, which suggests that increased event rates at lower blood pressure may be a sign of poor health conditions, particularly in the elderly. However, the real issue is not whether the relationship between achieved blood pressure and cardiovascular risk is ‘“J-shaped" (as it must be), but whether there are additional benefits or risks in lowering the blood pressure of patients with hypertension to fully normotensive levels, that is, to diastolic blood pressure between 70 mmHg and 85 mmHg.

2 - The “J-Curve" Phenomenon: Recent Findings

The existence of a “J-curve” has been investigated for both systolic and diastolic blood pressure, on the assumption that a critical level of blood pressure (particularly diastolic) is of vital importance for maintaining coronary blood flow adequate to the physiological needs. The results of four recently published studies, looking separately at systolic blood pressure and at diastolic blood pressure (10) have concluded in favour of the existence of a “J-curve”. These data have led us to readdress the question of whether blood pressure is sometimes lowered too far, resulting in underperfusion of vital organs that increases cardiovascular risk, The issue is open to several considerations.
First, although there must be a blood pressure value below which organ perfusion is compromised, observational studies in patients initially free of cardiovascular disease show that the relationship between blood pressure and the cardiovascular event rate is substantially linear down to very low blood pressure values (about 110/70 mmHg), which are only exceptionally achieved during antihypertensive drug treatment. Second, It is possible that in patients with high cardiovascular risk, impairment of the mechanisms that guarantee blood flow autoregulation elevates the blood pressure threshold below which organ perfusion is reduced (2), However, the extent of this elevation (which may differ between patients in relation to the degree of organ damage and age) has never been unequivocally established by trials specifically designed to explore the advantages of more-intense versus less-intense blood pressure lowering. Third, despite adjustment for initial demographic and clinical differences between groups, post-hoc analysis of trial results cannot escape the problem that the members of the group with the lowest on-treatment blood pressure could have had the greatest initial cardiovascular risk, which caused both the excessive blood pressure reduction and the increased incidence of cardiovascular events. Indeed, this idea is supported by the evidence of a similar J-curve phenomenon in placebo-treated groups of several trials (2). Furthermore, the post hoc analyses have consistently showed that the nadir of cardiovascular outcome incidence occurred at a rather wide range of blood pressure values, between 120 mmHg and 140 mmHg systolic blood pressure and 70-80 mm Hg diastolic blood pressure, suggesting that within this low range, the differences in achieved cardiovascular protection are small (2-3). This finding is in line with the results of observational studies showing that the relationship between blood pressure and cardiovascular events is linear when cardiovascular events are quantified on a logarithmic scale, which implies smaller absolute differences at lower blood pressure values.
3 - Blood pressure goals

Based on the above mentioned clinical trials results, in the 2009 a reappraisal document of the European guidelines made a number of recommendations regarding blood pressure goals of antihypertensive drug treatment (3). These recommendations can be briefly summarized as follows. In the general hypertensive population the recommendation to decrease systolic/diastolic blood pressure below 140/90 mmHg in all hypertensive patients still remains valid and supported by a large amount of data. As far as diabetic hypertensive population is concerned, the results of The ADVANCE and ACCORD trial have raised the possibility that the benefits of lowering blood pressure gradually flattens at lower systodiastolic blood pressure values (11-12). This has led the ESH in the 2009 document to suggest less ambitious but safer blood pressure targets, i.e. 130-139 mmHg for systolic and 80-85 mmHg for diastolic (3). The same targets should be prudently valid also in hypertensive patients with a history of cardiovascular disease, given the evidence that many clinical trials have been unable to show benefits from more intense lowering of blood pressure. In patients with previous coronary disease, for example, the greater blood pressure reduction induced by active (or more active) treatment was accompanied by a beneficial effect on the primary end point in only two trials, whereas five trials did not show any consistent beneficial effect (2-3).

Conclusion

Critical analysis of the available data regarding which target blood pressure values should be achieved during antihypertensive treatment in current clinical practice allows the following recommendations to be issued:
There is enough evidence to recommend that systolic blood pressure should be lowered to 140 mmHg (and diastolic blood pressure below 90 mmHg) in all antihypertensive patients, both those at low to moderate risk and those at high risk.
The recommendation from previous guidelines to aim for a lower goal for systolic blood pressure values (<130 mmHg) in diabetic patients and in patients at very high cardiovascular risk (those with previous cardiovascular events) may be wise, but it does not appear to be consistently supported by trial evidence.

A “J-curve" phenomenon may indeed occur when lower blood pressure values are achieved, particularly in patients with advanced atherosclerotic arterial disease.

It is recommended to lower systolic and diastolic blood pressure to values within the range of 130-139/80-85 mm Hg in all hypertensive patients. The lower values in this range should be the goal of treatment in high risk patients.

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Echocardiographic Evaluation of Hemodynamics in Patients
With Decompensated Systolic Heart Failure
[Ссылки доступны только зарегистрированным пользователям ]

Prompt Repeat Testing After Out-of-Range INR Values
A Quality Indicator for Anticoagulation Care
[Ссылки доступны только зарегистрированным пользователям ]

Effects of Weight Loss on Structural and Functional
Alterations of Subcutaneous Small Arteries in
Obese Patients
[Ссылки доступны только зарегистрированным пользователям ]

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FDA Okays New Drug to Prevent MI
WASHINGTON -- The third time proved to be the charm for the long-awaited new entry into the antiplatelet market as ticagrelor (Brilinta) today won FDA marketing approval for reducing thrombotic events in patients with acute coronary syndrome who are candidates for stenting.
[Ссылки доступны только зарегистрированным пользователям ]

Wednesday July 20, 2011

FDA Panel Backs Sapien Heart Valve

GAITHERSBURG, Md. -- An FDA advisory panel has voted 9 to 0, with one abstention, to recommend approval for Edwards Lifesciences’ Sapien transcatheter heart valve -- a novel device intended as an alternative for patients with severe aortic stenosis who are too frail for open-heart surgery.

FDA Panel Votes in Favor of Recommending Premarket Approval of Sapien Heart Valve

The US Food and Drug Administration (FDA) Circulatory System Devices Panel voted today in favor of recommending the premarket approval (PMA) application of the Edwards Sapien transcatheter heart valve for use in inoperable patients with severe aortic stenosis.
[Ссылки доступны только зарегистрированным пользователям ]

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Aspirin Holiday Is a Bad Idea

By Chris Kaiser, Cardiology Editor, MedPage Today
July 20, 2011

Explain that a case-control study found that patients taking low-dose aspirin for secondary prevention who had recently discontinued the drug had a higher risk of nonfatal myocardial infarction than those who continued to take the aspirin.

Note that the most common reason for discontinuing aspirin was lack of patient adherence.
Review

Those at risk of cardiovascular events who stop taking low doses of aspirin are at an increased risk of myocardial infarction (MI), a large case-controlled study found.

Compared with those taking aspirin, individuals prescribed aspirin for secondary prevention who had recently discontinued the drug had a significantly increased risk of nonfatal myocardial infarction or death from coronary heart disease combined (rate ratio 1.43, 95% CI 1.12 to 1.84) and nonfatal myocardial infarction alone (RR 1.63, CI 1.23 to 2.14), reported Luis Garcia Rodriguez, MD, from the Spanish Centre for Pharmacoepidemiologic Research in Madrid, and colleagues.

There were four more cases of nonfatal myocardial infarction among those who stopped aspirin for every 1,000 patients over a period of one year, according to the study published online in BMJ.

Researchers used the Health Improvement Network database in the U.K. to identify 39,513 participants ages 50 to 84 with a first prescription for aspirin for secondary prevention of cardiovascular outcomes from 2000 to 2007.

"Low dose" was defined as 75 mg to 300 mg/day. However, the current American Heart Association/American College of Cardiology practice guidelines recommend 75 mg to 162 mg of aspirin per day.

Researchers categorized those who discontinued low-dose aspirin therapy as recent (last prescription finished 31 to 180 days before the index date) and distant (last prescription finished 181 to 365 days before the index date). Rodriguez et al. also sampled 5,000 controls matched by age, sex, and calendar year.

The participants in the study were followed for a mean of 3.2 years. During that time, 876 nonfatal myocardial infarctions occurred, as well as 346 deaths from coronary heart disease.

Among the 1,222 cases of nonfatal myocardial infarction or death from coronary heart disease, 72% were still on aspirin therapy, 9% were recent discontinuers, and 3% were distant discontinuers.

Those numbers among the 5,000 controls were 76%, 7%, and 4%, respectively.

Most of those who discontinued aspirin were nonadherent (75% of all, 68% of recent discontinuers). Among the rest, 17% switched to another medication, 11% had safety concerns, and 4% were using over-the-counter low dose aspirin.

The increased risk of nonfatal myocardial infarction or death among those who recently discontinued aspirin was similar for different durations of aspirin therapy and for different indications.

"Despite the strong evidence supporting the protective effects of low-dose aspirin, discontinuation rates of around 50% have been reported in patients who have been taking this medication for several years," the authors wrote.

Furthermore, they said, it's been shown that discontinuation of oral antiplatelet therapy is an independent predictor of an increase in mortality after acute coronary syndromes.

"Does this evidence justify adding aspirin to tap water, as is the case with fluoride and has been suggested for statins?" asked Giuseppe Biondi-Zoccai, MD, from the University of Modena in Modena, Italy, and Giovanni Landoni, MD, from Università Vita-Salute San Raffaele in Milan, Italy, in an accompanying editorial.

Not yet, they stated, because the study by Rodriguez et al. "cannot be accepted uncritically."

Biondi-Zoccai and Landoni pointed out that the study was not randomized, and that it is impossible to know if discontinuation was "appropriate on personal or clinical grounds."

They also noted that there could have been a bleeding risk for some who discontinued aspirin, and the "risk-benefit ratio of aspirin in individual patients should always be considered."

The two editorialists mentioned two studies on the horizon that should help fill in the gaps.

PeriOperative Ischemic Evaluation-2 (POISE-2) study is randomizing 10,000 patients undergoing noncardiac surgery to aspirin or clonidine (or both) versus placebo, and the Aspirin and Tranexamic Acid for Coronary Artery Surgery (ATACAS) study is randomizing 4,600 patients undergoing coronary artery bypass grafting to aspirin or tranexamic acid (or both) versus placebo.

Nevertheless, Rodriguez and colleagues called for additional research to figure out why patients discontinue aspirin "in the absence of a clinical reason."

Two people from Oxford PharmaGenesis provided writing support funded by AstraZeneca.

This study was funded by an unrestricted research grant from AstraZeneca Research and Development Mölndal. The sponsors played no part in the design or conduct of the study.

Rodríguez and co-author Elisa Martín-Merino's institution receives funding from AstraZeneca. The other co-author, Saga Johansson, is an employee of AstraZeneca.

Primary source: BMJ
Source reference:
Rodriguez, L, et al "Discontinuation of low dose aspirin and risk of myocardial infarction: case-control study in UK primary care" BMJ 2011; 343: d4094.

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ADA: FDA Unlikely to Zap Pioglitazone

By Crystal Phend, Senior Staff Writer, MedPage Today
Reviewed by
June 26, 2011

Review

SAN DIEGO -- Bladder cancer risks aren't likely to send the diabetes drug pioglitazone (Actos) down the same path as rosiglitazone (Avandia), according to this exclusive InFocus report from the American Diabetes Association meeting.

Earlier this month French and German regulators halted sales of pioglitazone over excess bladder cancer seen in a French epidemiologic study, which the FDA followed with a warning pending further review of the data.

Yet the situation may not be as dire as the cardiovascular risks that led the European Medicines Agency to take rosiglitazone off the market last year and the FDA to severely restrict access to it, as leading diabetes specialist John Buse, MD, PhD, explains in an interview with MedPage Today Senior Staff Writer Crystal Phend.

"I don't think it [pioglitazone] will be taken off the market in the United States," says Buse, director of the Diabetes Care Center at the University of North Carolina at Chapel Hill and a past president of the ADA.

The same kinds of studies that suggested an increase in bladder cancer showed a decrease in other more common types of cancers, he notes.

Pioglitazone also holds some unique benefits among anti-diabetic treatments that may argue for a clinical need to keep the drug on the market, Buse adds.

ADA: American Diabetes Association Meeting
[Ссылки доступны только зарегистрированным пользователям ]

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After Gravitas Part 2: Is There a Future for Functional Platelet Testing?

Key Points:
Multiple factors may underlie platelet reactivity levels, including noncompliance
Stent thrombosis may justify functional testing
Reactivity ‘sweet spot’ sought to balance ischemic, bleeding risks
By Kim Dalton
Monday, July 25, 2011

Part 1 addressed possible explanations for the negative findings of the GRAVITAS trial and the implications for current clinical practice. In Part 2, the story continues with a discussion of the limitations of functional platelet testing and the potential risk of using it to guide therapy as well as some arguments in favor of current testing and hints of a wider future role.

The failure of the GRAVITAS trial to support a strategy of intensified clopidogrel therapy to overcome high residual platelet reactivity following PCI prompted many experts to conclude that, for the time being, there is no justification for routine testing.

A key reason is that a host of factors may be contributing to a patient’s baseline platelet reactivity and response to antiplatelet therapy, including:
Comorbid conditions like diabetes
Age
Body weight
Smoking status
Compliance with the prescribed antiplatelet regimen
Concomitant medications such as proton pump inhibitors
Genotype (including complicated interactions between variant alleles and heterozygosity vs. homozygosity)

An underlying question, raised by Paul A. Gurbel, MD, of the Sinai Center for Thrombosis Research (Baltimore, MD), among others, is if ischemic events can occur even in patients with low platelet reactivity, is the latter truly a modifiable risk factor or is it more in the nature of a risk marker?

Numerous studies have shown that high on-treatment platelet reactivity as measured by functional testing correlates with increased thrombotic risk. But in the POPULAR trial (Breet NJ, et al. JAMA. 2010;303:754-762), a head-to-head comparison of 6 major assays, the predictive value of the 3 tests with validated cutpoints was relatively modest.

Exceptions to the ‘No Test’ Rule

Nonetheless, a recent white paper (Bonello L, et al. J Am Coll Cardiol. 2010;56:919-933) outlined certain situations in which it is appropriate to “consider” platelet function testing to help determine antiplatelet therapy: in patients with a history of stent thrombosis and prior to high-risk PCI.

The bottom line is that, for the most part, therapy should be guided by a patient’s presentation, not testing, Dr. Bhatt said, and he offered 2 scenarios from opposite ends of the risk spectrum to illustrate the point.

A Test-Guided Algorithm

At UCSD Medical Center (San Diego, CA), however, testing has been given a more liberal role. Several years ago, Ehtisham Mahmud, MD, and colleagues developed an algorithm to help make decisions about the best antiplatelet therapy for different patients. The algorithm is intended as a rough guide and has evolved as more trial data have become available, Dr. Mahmud said.

After PCI, all patients’ platelet reactivity is tested with the VerifyNow P2Y12 assay (Accumetrics, San Diego, CA), he reported. If they are not already on a thienopyridine, patients with ACS and diabetics go straight to prasugrel, unless they have clinical characteristics that put them at increased bleeding risk (primarily age > 75, low BMI, a history of TIA or stroke).

Nondiabetic elective patients are given clopidogrel (600 mg loading dose, 75 mg daily). Among those who are clearly compliant with therapy yet do not respond (ie, show less than 30% platelet inhibition), a key factor in deciding whether or not to switch them to prasugrel is their angiographic characteristics, said Dr. Mahmud. “In patients with a straightforward focal lesion, and inhibition of 15% or 20%, in the past we would have switched them to prasugrel,” he observed. “Since GRAVITAS, I would probably keep them on clopidogrel. But if I don’t see any meaningful inhibition based on VerifNow measurement, I will switch these patients to prasugrel.”

On the other hand, compliant clopidogrel nonresponders who are undergoing high-risk PCI, such as for left main stenosis or multivessel disease, are candidates for prasugrel, Dr. Mahmud said. The same applies to patients who present with an event on clopidogrel or have had stent thrombosis, he added.

Another testing outpost is nearby Scripps Clinic in La Jolla, CA. There, Paul S. Teirstein, MD, says that even in the wake of GRAVITAS, he still tests nearly every PCI patient on standard-dose clopidogrel. “I might even start testing my prasugrel patients considering the new data that have come out,” he added in a telephone interview with TCTMD, alluding to the recent study showing that about one-quarter of ACS patients respond inadequately to prasugrel (Bonnello L, et al. J Am Coll Cardiol. 2011;58:467-473).

Limitations of Functional Testing

Beyond the issue of clinical validation, functional testing itself is far from straightforward. According to Dominick J. Angiolillo, MD, PhD, of the University of Florida College of Medicine-Jacksonville (Jacksonville, FL), to be useful in routine practice, a point-of-care test must:
Be simple to use
Provide quick results
Be easy to interpret
Be relatively inexpensive

Searching for a ‘Sweet Spot’

For most researchers, the holy grail of antiplatelet testing is identifying a therapeutic window—a range of platelet reactivity that will safeguard a patient between thrombotic risk on the high end of reactivity and bleeding risk on the low end.

Even more encouraging, a kind of therapeutic window of reactivity emerged from the study by Campo et al. Analysis showed that both ischemic and bleeding events were minimized when PRU values fell between 86 and 238.

However, a reactivity ‘sweet spot’ will likely vary not only with the specific functional test used but also with patients’ clinical presentation and the time from PCI, Dr. Angiolillo noted. For example, the low platelet reactivity required to prevent thrombotic events during the periprocedural period may be a liability 6 months later. And the optimal levels are likely to differ for elective and emergent PCI.

Nonetheless, if reliable therapeutic windows can be established, “the role of functional testing will be huge,” Dr. Mahmud commented. Furthermore, when in the near future clopidogrel becomes generic, platelet testing is likely to be used to show when a high-risk patient is responding to the drug and therefore does not need to be switched to a more potent—and more expensive—agent, he observed.

The Clinician’s Dilemma

Despite the setback of GRAVITAS—and the controversy surrounding the clinical relevance of genotyping—physicians understandably remain eager to find ways to minimize individual patients’ post-PCI risk.

Although GRAVITAS is important, “no one study in isolation answers every question. We’ll need a lot more and hopefully larger studies to really nail down these issues,” he concluded.

One area that Dr. Mahmud believes deserves particular attention is the influence of angiographic complexity on antiplatelet response. “Because we’re treating more and more complex lesions, it will be interesting to see how the degree of platelet inhibition [is affected by different levels of complexity] and how that [impacts] outcomes,” he said. “Arguably, if a patient has a simple focal lesion, even if he presents with ACS, you may not need very high inhibition of reactivity. And vice versa, you could have an elective patient with a very complicated lesion where you would need high platelet inhibition.”

Dr. Kleiman called for similar research. “I would like to see high reactivity defined for patients in the highest stratum of risk—those with multiple long stents, ACS, or acute MI,” he said. “Those are the folks about whom we have the most questions.”

Meanwhile, Dr. Angiolillo stressed that practitioners should continue to be guided by consensus statements, the therapeutic indications that have been validated in large clinical trials, and above all by good clinical judgment.



Sources:
1. Price MJ. Standard versus high-dose clopidogrel according to platelet function testing after PCI: Results of the GRAVITAS trial. Presented at: American Heart Association Scientific Sessions; November 16, 2010; Chicago, IL.

2. Price MJ, Berger PB, Teirstein PS, et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention. JAMA. 2011;11:1097-1105.

3. Gurbel PA, Tantry US. An initial experiment with personalized antiplatelet therapy. JAMA. 2011;11:1136-1137.

[Chevychelov]

Apixaban Increases Major Bleeding in High-Risk ACS Patients

Key Points:
Novel anticoagulant apixaban increased TIMI major bleeding vs. placebo in ACS patients on antiplatelet therapy
Bleeding increase led to trial’s early stoppage
Apixaban also failed to decrease ischemic events
By Jason Kahn
Monday, July 25, 2011

The oral, direct factor Xa inhibitor apixaban increases major bleeding more than twofold when added to antiplatelet therapy in high-risk patients who have suffered an acute coronary syndrome (ACS). It was on the basis of these results, published online July 24, 2011, ahead of print in the New England Journal of Medicine, that the phase 3 APPRAISE-2 trial was halted early in November 2010.

The findings also were presented simultaneously this week at the International Society on Thrombosis and Haemostasis Congress in Kyoto, Japan.

For the APPRAISE-2 (APixaban for PRevention of Acute Ischemic and Safety Events-2) trial, researchers led by John H. Alexander, MD, of Duke University Medical Center (Durham, NC), randomized 7,392 out of a planned 10,800 high-risk patients with recent ACS and at least 2 risk factors for recurrent ischemic events to apixaban (5 mg twice daily) or placebo in addition to standard antiplatelet therapy. Roughly 81% of patients were on dual antiplatelet therapy with the remainder on aspirin alone. In addition, 44% had received PCI and 55% medical management alone. About 40% of the patients presented with STEMI.

After an interim analysis (median follow-up of 241 days), the primary efficacy endpoint of CV death, MI, or ischemic stroke was similar in the apixaban and placebo groups while the primary safety endpoint of TIMI major bleeding was more than twice as high in the apixaban group (HR 2.59; 95% CI 1.50-4.46).

Other efficacy outcomes including death, CV death, MI, and stent thrombosis were similar between groups.

It was the increase in TIMI major bleeding that caused the early trial stoppage, which was announced by the sponsors in late 2010. Other endpoints including intracranial bleeding (0.6% vs. 0.2%; P = 0.03) and fatal bleeding (0.3% vs. 0; P = NS) were also more common in apixaban patients, though there were so few fatal bleeding events that the difference was not statistically significant.

The primary efficacy and safety endpoints were consistent across multiple subgroups including those who did or did not receive PCI and those on dual antiplatelet therapy or aspirin monotherapy.

APPRAISE-2 was conducted despite increased bleeding rates in the earlier phase 2 APPRAISE trial. In that study, which assessed 4 different apixaban doses, the 2 highest (10 mg twice daily and 20 mg once daily) led to bleeding, causing those arms to be halted early. The 2 lower doses (2.5 mg twice daily and 10 mg once daily) were associated with nonsignificant trends for increased major or clinically relevant nonmajor bleeding but also decreased ischemic events.

Not a Fair Trade-Off

“We knew that adding an anticoagulant to dual antiplatelet therapy increases bleeding,” explained Dr. Alexander in a telephone interview with TCTMD. “What we were uncertain about was whether there was efficacy. So we enrolled a high-risk population and used a dose of apixaban that we thought would have the best chance of having a favorable trade-off between efficacy and bleeding. What we now know is it doesn’t reduce ischemic events, so there’s no signal here that would outweigh the increase in bleeding.”

However, the results should not automatically rule out this class of new anticoagulants in all ACS patients. Rather, the APPRAISE-2 data should be viewed as relevant only “for this drug in this dose with this population,” Dr. Alexander said. He added that another large randomized trial, ATLAS-ACS 2 TIMI 51, is testing a similar factor Xa inhibitor, rivaroxaban, in lower-risk ACS patients.

Hitinder S. Gurm, MD, of the University of Michigan Medical School (Ann Arbor, MI), was less optimistic. “We’ve not seen a signal from any of these trials that point to a reduction in major ischemic events. And if anything, there’s a considerable increase in bleeding,” he told TCTMD in a telephone interview. “Beyond [APPRAISE-2], these data should call into question the other similar trials that are being conducted.”

Hypothesis Called into Question

According to Dr. Gurm, the whole concept of adding an anticoagulant to long-term antiplatelet therapy for ACS patients should be shelved. “We think of ACS as being a thrombotic event secondary to plaque instability and by blocking thrombosis totally we could I guess reduce that, but that will come at the cost of increased bleeding,” he said. “So there is a balance point, and I think we’ve reached that balance point with good dual agent therapy. I don’t see a role for triple therapy for ACS.”

The prospect becomes even more doubtful when considering the more powerful antiplatelet agents—prasugrel and ticagrelor—that have recently been approved. “It’s another question that has to be studied, but I would think you’re less likely to see an additional benefit adding an anticoagulant to prasugrel or ticagrelor,” Dr. Alexander said.

Still, during a different phase of treatment, drugs like apixaban might make sense, Dr. Gurm amended. “Perhaps in the early phase,” he said. “Maybe we could come to a paradigm where instead of patients being started on heparin or enoxaparin, we would give them an oral factor Xa inhibitor, aspirin, and clopidogrel, then take them to the cath lab. Or especially if you’re waiting to take them to the cath lab, early therapy with oral drugs might make sense instead of using heparin. That could be where these drugs find a role, but I remain skeptical about long term therapy.”

Different Story in A-fib

The situation is altogether different in patients with venous thromboembolism (VTE) and atrial fibrillation (A-fib), where factor Xa inhibitors have proven effective, with rivaroxaban approved for deep vein thrombosis prevention and dabigatran approved for stroke prevention.

“I think APPRAISE-2 says much more about the population than the drug,” Dr. Alexander said. “Anticoagulants have very different effects in A-fib. We know warfarin is effective in A-fib, so it’s not too surprising that these novel anticoagulants are more likely to be effective, whereas in ACS, we don’t even know that warfarin is effective.”

“The way I see it, the factor Xa inhibitors have a bright future in the treatment of venous disease and patients with atrial fibrillation,” Dr. Gurm agreed. “I think that’s a great leap forward that we finally have therapies we can use in these patients.”

But not as long-term therapy in ACS patients, Dr. Alexander cautioned. “This doesn’t totally put the nail in the coffin for adding anticoagulants to antiplatelet therapy, but at least in this population at this dose with this background therapy, it doesn’t work,” he said. “And we can wait for ATLAS 2, but I’m not too optimistic.”

Source:
Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011.Epub ahead of print.