Обзор американских кардиологических журналов за неделю (ссылки)

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Ticagrelor Gains FDA Approval for Use in ACS

Key Points:
Ticagrelor approved by FDA after solid outcomes in PLATO outweigh concerns about use with high-dose aspirin
Approval comes with warnings about aspirin dosing, bleeding risk
Experts predict ticagrelor will be popular due to its mortality benefit, reversibility
By Caitlin E. Cox
Friday, July 22, 2011

After a series of delays over the past several years, the US Food and Drug Administration (FDA) officially approved ticagrelor, a direct-acting reversible P2Y12 receptor inhibitor, on July 20, 2011, for reducing the rate of thrombotic cardiovascular events in patients with acute coronary syndromes (ACS).

Physicians interviewed by TCTMD expressed excitement about the new contender joining the crowded field of antiplatelet therapies.

Ticagrelor, which will be marketed as Brilinta (AstraZeneca; Wilmington, DE), may not be available in the immediate future, a company press release hints, but only after a 12-month roll-out period.

Ticagrelor’s FDA approval hinged on results from the PLATO (PLATelet inhibition and patient Outcomes) trial.

Published in the New England Journal of Medicine in September 2009, PLATO randomized more than 18,000 ACS patients in 43 countries worldwide to ticagrelor (180-mg loading dose, 90 mg twice daily thereafter) or clopidogrel (300- to 600-mg loading dose, 75 mg daily thereafter). All patients also received aspirin.

At 12 months, the primary endpoint (CV death, MI, or stroke) was observed in 9.8% of ticagrelor patients compared with 11.7% of clopidogrel patients (HR 0.84; 95% CI 0.77-0.92; P < 0.001). But results from a prespecified subanalysis also revealed that ticagrelor had less effect in North American patients, who tended to receive higher aspirin doses than subjects enrolled elsewhere. Concerns about this disparity appeared to be at the heart of the debate over FDA approval.

In July 2010, an FDA advisory committee voted 7 to 1 in favor of ticagrelor’s approval, but the agency remained unconvinced and 5 months later asked for further analyses of the PLATO data.

With the FDA’s approval comes a “black box” warning highlighting 2 key areas: bleeding risk and the relationship between aspirin dose and efficacy.

In terms of bleeding, the label cautions that ticagrelor should not be used in patients with active pathological bleeding or a history of intracranial hemorrhage. It also is recommended that the drug not be started in those slated for CABG and ideally should be stopped at least 5 days prior to surgery. Clinicians should look for bleeding in patients who are hypotensive and have recently undergone angiography, PCI, CABG, or other surgical procedures. When possible, bleeding should be managed without discontinuing ticagrelor, in order to limit the risk of cardiovascular events.

With regard to aspirin, the label advises that maintenance doses above 100 mg reduce ticagrelor’s effectiveness and thus should be avoided. After any initial dose, 75 to 100 mg aspirin daily is appropriate.

New Option Greeted with Optimism

TCTMD gathered feedback from numerous physicians about ticagrelor’s long-awaited debut.

In an e-mail communication, Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), said the news was very exciting, in that now clinicians have another potential agent to treat ACS patients.

“Several unique attributes about the agent as well as the PLATO study design will render this drug more translatable to clinical practice, in my mind, than prasugrel,” he commented. “First, the fact that both clopidogrel and ticagrelor were given prior to angiography in the study makes PLATO more consistent with conventional clinical practice in ACS patients. Second, the more rapid offset of this agent will likely influence clinicians to feel more comfortable in giving this agent to a broader number of patients, even those who may have to undergo CABG.”

Neal S. Kleiman, MD, of Methodist DeBakey Heart and Vascular Center (Houston, TX), similarly pointed out that that the pivotal trial for prasugrel, TRITON-TIMI 38, studied patients whose anatomy had already been deemed suitable for PCI. “So ticagrelor was studied in a broader patient group,” he noted in telephone interview.

Paul A. Gurbel, MD, of the Sinai Center for Thrombosis Research (Baltimore, MD), whose research group has designed and led 2 pharmacodynamic investigations of ticagrelor vs. clopidogrel—the ONSET-OFFSET and RESPOND studies—also was positive about the recent approval.

ONSET-OFFSET demonstrated that ticagrelor shows more rapid onset than 600 mg clopidogrel, offers greater platelet inhibition during maintenance, and has faster offset, he told TCTMD in an e-mail communication. “These effects provided a clear-cut mechanism to explain the superior outcomes observed with ticagrelor in PLATO,” Dr. Gurbel said, while RESPOND found that ticagrelor overcame clopidogrel non-responsiveness. And an analysis that pooled patients from both studies found no evidence of high on-treatment platelet reactivity during ticagrelor therapy, he added.

“Taken together, we believe that these pharmacodynamic effects in conjunction with the PLATO results should strongly influence the choice for ticagrelor in the ACS patient. The robust effect of ticagrelor across all groups should favor widespread implementation,” he concluded, adding that the decision is further backed by the drug’s mortality benefit.

In an e-mail communication, Gregg W. Stone, MD, of Columbia University Medical Center (New York, NY), predicted that ticagrelor would be widely adopted in both STEMI and NSTEMI patients.

Asked how ticagrelor would compete with prasugrel, Dr. Stone outlined why 1 drug would be chosen over the other in different situations. Ticagrelor stands out for its effect on mortality in PLATO, he said, but ticagrelor and prasugrel work through different mechanisms that make them suitable for certain patient subgroups.

Ticagrelor can cause side effects such as dyspnea, “which while not physiologically important can be clinically worrisome,” he noted, and can cause ventricular pauses, so “must be used carefully, if at all, in patients with conduction system disease.” Prasugrel potentially comes out ahead by virtue of being given once rather than twice daily like ticagrelor, and it “has been particularly effective in suppressing stent thrombosis.”

But differences between TRITON-TIMI 38 and PLATO make it difficult to compare outcomes across trials, and much has been learned in the years since TRITON, Dr. Stone said, emphasizing that, “clearly there needs to be a head-to-head trial of these 2 agents so the appropriate therapeutic decisions can be made.”

Few Reservations

For his part, Dr. Gurbel said, “I have no reservations whatsoever about the approval of ticagrelor. It should have happened earlier.”

Dr. Kirtane, meanwhile, cautioned that it remains to be seen how possible side effects and the need for twice daily dosing with ticagrelor will play out in clinical practice. “Despite some wariness regarding the prolonged time to FDA approval and aspirin dosing issues, I would expect most clinicians to be quite pleased to have another option for their patients,” he concluded.

The key question, added Dr. Kleiman, is whether there will be less enthusiasm for ticagrelor if stent thrombosis rates, having decreased in the past few years, continue to drop.

“There’s going to be a lot more talk about clopidogrel resistance, which is a real thing, but how critical this is when we’re talking about stent thrombosis rates that are 0.4%, I’m not sure,” he noted.

In general, as new drugs become available, “[t]hey all come with a lot of promotion that gets people’s attention, but I really think people need to look at the data themselves and understand who they do and don’t want to be using the drug in,” Dr. Kleiman stressed. “When you talk about antithrombotic drugs, if you’re going to use them you’re obligated to know something about them. You need to be aggressive about getting information.”

Source:
FDA approves new medicine Brilinta (ticagrelor) for use in the US [press release]. Wilmington, DE; AstraZeneca; June 20, 2011. [Ссылки доступны только зарегистрированным пользователям ]. Published July 20, 2011. Accessed July 22, 2011.

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Coronary multidetector computed tomographic angiography to evaluate coronary artery disease in liver transplant candidates: methods, feasibility and initial experience
[Ссылки доступны только зарегистрированным пользователям ]

Success in Implementing a Hospital-wide Evidence-based Clinical Pathways System for the Management of Cardiac Patients: The ACAP Program Experience
[Ссылки доступны только зарегистрированным пользователям ]

At the Heart of the Fever: Kawasaki Disease
[Ссылки доступны только зарегистрированным пользователям ]

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High, low BMI resulted in significant risk for deep intracerebral hemorrhage

Biffi A. Stroke. 2011;doi:10.1161/strokeaha.111.617225.

Patients with low or high extremes of BMI were at increased risk for having a deep intracerebral hemorrhage. No association was reported on lobar intracerebral hemorrhage, however.

The single-center, prospective study involved 384 consecutive patients with intracerebral hemorrhage (ICH) — 196 with deep and 188 with lobar ICH — and 388 controls enrolled during a 6-year period. Researchers used CT to determine ICH characterization and patients’ height and weight to calculate BMI. Low BMI was defined as less than 18.5 kg/m² and high BMI was more than 30 kg/m².

Overall, patients with either low (OR=1.76; P=.011) or high BMI (OR=1.75; P=.013) were at increased risk for deep ICH, with the following characteristics associated with risk in univariate analysis: age, sex, hypertension, CAD, diabetes, hyperlipidemia and alcohol consumption of more than 3 oz per day. Neither univariate nor multivariate analysis revealed either BMI extremes to be linked with lobar ICH. The association with ICH was particularly prominent in men who had an OR of 2.85 (P=.041) vs. women who did not have an association (OR=0.89; P=.54).

“Our results suggest that BMI differentially influences risk of lobar and deep ICH, consistent with the hypothesis that BMI influences specific vascular pathologies that lead to ICH,” the researchers wrote. “In particular, these findings are most likely related to biological differences between cerebral amyloid angiopathy-related lobar ICH and hypertensive deep ICH.”
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Intima-media thickness in carotid artery predicted CV outcomes

Polak J. N Engl J Med. 2011;365:213-221.

Intima-media thickness of the common and internal carotid artery was an independent predictor of CV events, according to an analysis of the Framingham Offspring Study.

The study also found that maximum intima-media thickness had significant, although modest, predictive power of the risk factors and also benefited risk classification.

In all, 2,965 participants (mean age, 58 years; 55% women) who had no history of CVD were included in the analysis.

During a mean follow-up of 7.2 years, 10% of the population experienced a CV event, including events related to CHD, peripheral arterial disease, stroke and HF, which was predicted by risk factors of the Framingham risk score. With every 1 standard deviation increase in intima-media thickness of the common carotid artery, the adjusted HR for CVD was 1.13 (95% CI, 1.02-1.24), whereas the HR for the maximum intima-media thickness was more pronounced (1.21; 95% CI, 1.13-1.29).

Additionally, the researchers reported that the net reclassification index rose significantly after the addition of intima-media thickness of the internal carotid artery (P<.001) but not the common carotid artery (P=.99).

“Our results show that plaque in the internal carotid artery, either measured as part of the continuous intima-media thickness or assumed to be present if the thickness exceeds a set point of 1.5 mm, offers modest incremental value to the Framingham risk score in predicting CV events,” they concluded. “We believe the intima-media thickness of the internal carotid artery should be measured in addition to the thickness of the common carotid artery for purposes of CV risk assessment.”

Polak et al continue to provide important insights into the impact of carotid intima-media thickness on CV risk. In this large cohort followed prospectively, the impact of carotid intima-media thickness was only helpful in addition to the Framingham Risk Score using internal carotid artery intima-media thickness measurements. This is interesting, as several previous publications have suggested that the common carotid artery intima-media thickness values are of equal predictive value in determining CV risk. Although the Framingham Risk Score performed well in determining future CV risk, adding increase in internal carotid artery intima-media thickness can help in further assessing future CV risk.

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FDA Panel Recommends Approval of Edwards Transcatheter Valve for Treatment of Inoperable Patients

GAITHERSBURG, MD, July 20, 2011 -- Edwards Lifesciences Corporation (NYSE: EW), the global leader in the science of heart valves and hemodynamic monitoring, announced that a U.S. Food and Drug Administration (FDA) Advisory Panel voted late today to recommend approval of the Edwards SAPIEN transcatheter heart valve for the treatment of certain inoperable patients.

Edwards submitted a PMA application in the fall of 2010 based on data from the inoperable cohort of The PARTNER Trial. This cohort compared the outcomes of 358 patients after treatment with either standard therapy or the Edwards SAPIEN valve delivered transfemorally.

"We are pleased with the panel's strong recommendation for approval, and would like to thank them for their comprehensive and thoughtful review of the data presented from The PARTNER Trial. This represents another important step on the path to what we hope will lead to FDA approval of SAPIEN," said Michael A. Mussallem, Edwards' chairman and CEO. "We would also like to thank the principal investigators and their heart teams at the PARTNER hospitals for their dedication to this clinical trial, and to their patients for participating in a study of a new therapy."

The Edwards SAPIEN valve is an investigational device in the U.S. and not yet available commercially in the U.S. It received CE Mark approval for European commercial sale in late 2007.

About Edwards Lifesciences
Edwards Lifesciences is the global leader in the science of heart valves and hemodynamic monitoring. Driven by a passion to help patients, the company partners with clinicians to develop innovative technologies in the areas of structural heart disease and critical care monitoring that enable them to save and enhance lives. Additional company information can be found at [Ссылки доступны только зарегистрированным пользователям ].

This news release includes forward-looking statements within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. These forward-looking statements include, but are not limited to, Mr. Mussallem's statements regarding the potential FDA approval of the Edwards SAPIEN valve. Forward-looking statements are based on estimates and assumptions made by management of the company and are believed to be reasonable, though they are inherently uncertain and difficult to predict. Our forward-looking statements speak only as of the date on which they are made and we do not undertake any obligation to update any forward-looking statement to reflect events or circumstances after the date of the statement.

Forward-looking statements involve risks and uncertainties that could cause actual results or experience to differ materially from those expressed or implied by the forward-looking statements based on a number of factors including but not limited to unexpected delays in, or changes to the outcome of, the U.S. FDA regulatory approval process or schedule. These factors are detailed in the company's filings with the Securities and Exchange Commission including its Annual Report on Form 10-K for the year ended December 31, 2010.

Edwards, Edwards Lifesciences, the stylized E logo, Edwards SAPIEN, PARTNER and SAPIEN are trademarks of Edwards Lifesciences Corporation.

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CID SpA announces the CE mark of its new Cre8TM Polymer-Free DES
Saluggia (Italy), July 19th 2011 - CID is pleased to announce that its latest Drug Eluting Stent (DES), Cre8TM, has received CE mark.
The Cre8TM polymer-free DES embodies the most advanced DES technologies to treat coronary vascular disease. Its unique distinctive features - Abluminal Reservoir Technology, Amphilimus Formulation and Bio Inducer Surface - make Cre8TM the only very effective Polymer-Free DES today available. In the NEXT study, an international prospective randomized clinical trial, it resulted being statistically superior to TAXUSTM Libertè with respect to in-stent late lumen loss (0.14 mm Cre8TM vs. 0.34 mm Taxus, p<0.0001).
The proprietary Abluminal Reservoir Technology (ART) provides a consistent drug loading onto the stent platform, thus enabling a controlled and directed elution exclusively targeted to the vessel wall.
The innovative Amphilimus™ formulation, that is Sirolimus formulated with an organic acid, is the first known use of a carrier to enhance drug bioavailability and drug distribution to the entire vessel wall.
The Bio Inducer Surface, a second generation integral pure carbon coating, demonstrates excellent results in terms of stent endothelialization and struts coverage. The use of the Bio Inducer Surface onto the Cre8TM Polymer-Free DES enables faster DES endothelialisation and reduces device thrombogenicity risk.
“We develop our stents with the objective of providing patients the best possible clinical outcome in terms of both efficacy and safety. We believe that Cre8TM represents an important achievement for the interventional cardiologist community, as it is a DES that has none of the drawbacks associated with polymers. In addition, because of the Bio Inducer Surface and Abluminal Reservoir Technology, we hope that physicians will be able to shorten the dual antiplatelet therapy period for their patients and reduce the high cost of care as well as the side effects of these drugs.” said Franco Vallana, President and C.E.O. of CID SpA.
About CID SpA
CID (Carbostent & Implantable Devices) is dedicated to contributing to human welfare by improving the quality of patient care and after-care through the development of innovative, minimally invasive implantable devices, procedures and therapies.
A strong background in the field of implantable cardiovascular devices and haemocompatible materials, expressed in a remarkable IP portfolio, and a management with an expertise gained in many years of research, development and clinical experience, allow CID to offer the investors a fair
return and its customers the necessary tools to meet new challenges.

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Top Content, June, 2011
The Most Viewed Science & Quality Content on CardioSource
Top 10 Journal Scans, June 2011
Safety of Clopidogrel Being Continued Until the Time of CABG (Eur Heart J)
Treatment and Outcomes in Patients With MI Treated With Acute Beta-Blocker Therapy (Am Heart J)
Driving Restrictions After ICD Implantation (Eur Heart J)
ICD Registry Risk Score Models for Acute Procedural Complications or Death After Implantation (Circulation)
Transcatheter Versus Surgical Aortic-Valve Replacement in High-Risk Patients (N Eng J Med)
A Randomized controlled Trial of EVAR vs OSAR for AAAs in Moderate- to Low-Risk Patients (J Vasc Surg)
Effect of Switching Antithrombin Agents for Primary Angioplasty in AMI: The HORIZONS-SWITCH Analysis (J Am Coll Cardiol)
Effects of Rosuvastatin on Progression of Stenosis in Adult Patients With Congenital Aortic Stenosis: The PROCAS Trial (Am J Cardiol)
Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial Fibrillation: An Analysis of the RE-LY Trial (Circulation)
ACCF/AHA/AMA–PCPI 2011 Performance Measures for Adults With CAD and Hypertension (J Am Coll Cardiol)

Top 10 Clinical Trial Summaries, June 2011
AIM HIGH
ARISTOTLE
SHARP
ASA-STAT
PARTNER Cohort A
LIPSIA-STEMI
STICH
PARTNER Cohort B
RELY
ADDITION-Europe

[Ссылки доступны только зарегистрированным пользователям ]

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What’s New in Hypertension? A Contemporary Primer
By Gregory W. Rutecki, MD | 13 Июль 2011 г.
Dr. Rutecki is Professor of Medicine at the University of South Alabama in Mobile.

A recent commentary of mine regarding hypertension was entitled, “Are Prescribing Practices for Antihypertensives Primitive? The Truth Hurts.”1 The criticism surfaced in the Wall Street Journal.2

What’s the problem? The Journal quoted Dr. Michael Alderman, who appropriately insinuated that many of us—myself included—are in a stale time warp when it comes to antihypertensive therapy.

So if this is the case, how about some new facts to bring us up to snuff? What are “hot topics” in the contemporary world of hypertension that will rescue us from being labeled as primitive?

Defining, Diagnosing, and Treating Resistant Hypertension

The old paradigm: If a patient’s blood pressure isn’t controlled with 3 antihypertensive drugs, add more (the “damn the torpedoes, full speed ahead” older approach).

The new paradigm: If a patient’s blood pressure isn’t controlled with a 3- drug regimen (and if he or she is adherent to the regimen), stop and identify the patient as having resistant hypertension.

Consider associated disease states (eg, Obstructive Sleep Apnea [OSA] or chronic kidney disease [CKD]) and add spironolactone(Drug information on spironolactone) (25 mg/d to start) to the treatment regimen.3,4
Spironolactone’s potency in this particular situation may allow discontinuation of other antihypertensive medications.

Correctly Identify Populations That Frequently Have Resistant Hypertension

The old paradigm: Primary hypertension is all the same.

The new paradigm: Although secondary causes of hypertension may be active in individuals who have resistant hypertension (eg, primary aldosterone syndromes, pheochromocytoma, or renal artery stenosis), certain groups make up a significant portion of those with resistant, primary hypertension. OSA is one such cause.

The rest of the news is good. Patients with OSA respond well to the addition of spironolactone. This drug not only helps with blood pressure control, but may benefit those with hypopneic and apneic episodes as well.5

The epidemic of CKD has also prominently propelled this group into the resistant cohort. Data are preliminary and come from small sample sizes; however, it may be that we will one day prescribe spironolactone for this hyperkalemia-prone group as well.6 Wait for further news in this regard.

Thiazide Diuretics Are Good Drugs For High Blood Pressure, But They’re Not Perfect

The old paradigm: The first definition of resistant hypertension observed that of the 3 drugs used for control, one must be a thiazide. But what if a thiazide isn’t helping?

The new paradigm: The new classification for Chronic Renal Disease (the CKD stages 1-5) defines CKD stage 3 (the level at which patients should be referred to a nephrologist) as a glomerular filtration rate (GFR) of < 60 mL/min but ≥ 30 mL/min. Patients in this category represent another sizeable portion of the resistant group. Thiazide diuretics are not effective blood pressure medications when GFR is approximately 40 mL/min or lower. This is a treatment opportunity for furosemide, dosed twice a day because of its shorter half-life.4

Not All Hypertensive Patients Are Created Equally

The old paradigm: Every hypertensive patient should receive the same battery of blood pressure medications (thiazide diuretics + beta blockers + an ACEI or ARB + a calcium channel blocker). This is the “one size fits all philosophy.”

The new paradigm: The old paradigm is wrong (it speaks exactly to Dr. Alderman’s point about primitive prescribing practices). Did you know that studies have demonstrated that beta-blockers either do not lower—or can actually raise— blood blood pressure in African Americans?7

In the ASCOT-BPLA trial (n= approximately 20,000), when atenolol(Drug information on atenolol) was compared with amlodipine
(Drug information on amlodipine) for blood pressure
management, the trial was halted early because of a 11% lower all-cause mortality in the amlodipine limb.8

If a black person with hypertension has an alternative indication for beta-blockade (decreased ejection fraction), use carvedilol(Drug information on carvedilol) instead.

Small Doses of Two Drugs are Better than Big Doses of Only One

The old paradigm: If 10 to 20 mg of an ACEI is good, then 30 mg is better and 40 mg is best.

The new paradigm: It is not only true that 2 heads are better than one. . . the same may be said for 2 antihypertensives.

A 2003 meta-analysis demonstrated that in 42 trials of hypertension therapy involving 10,968 participants, doubling the dose of monotherapy with 1 drug had only 1/5 the blood pressure lowering efficacy of adding another drug without increasing the initial drug’s dose.9


ACEIs with ARBS Don’t Add Bang To Your Buck as an Antihypertensive Combination

The old paradigm: If ACEIs are good for blood pressure and kidney disease, adding another similar renin-angiotensin-aldosterone medication (such as an ARB) will be even better.

The new paradigm: Adding an ARB to an ACEI regimen for blood pressure control provides only modest reductions in pressure (3 mm/Hg).10,11 The modest reduction may come at the price of hyperkalemia and blocking another medicine from doing a better job.

As in the first bullet point, the medicine to add in this setting may be spironolactone. This agent lowers BP in the same “add on” situation on average 25/12 mm/hg systolic and diastolic pressures, respectively.

These new paradigms are a starting point for antihypertensive therapy’s “Brave New World.” I don’t like being called “primitive” any longer.

References:
1. Rutecki GW. Are prescribing practices for antihypertensives primitive? The truth hurts. Consultant. 2010; 50:II. [Ссылки доступны только зарегистрированным пользователям ]
2. Naik G. Getting the right hypertension drug. Wall Street Journal. August 24, 2010. D3. [Ссылки доступны только зарегистрированным пользователям ]
3. Nishizaka MK, Calhoun DA. The role of aldosterone antagonists in the management of resistant hypertension. Current Hypertension Reports. 2005;7:343-347.
4. Sarafidis PA, Bakris GL. Resistant hypertension: an overview of evaluation and treatment. JACC. 2008;52:1749-1757.
5. Gaddam K, Pimenta E, Thomas SJ, et al. Spironolactone reduces severity of obstructive sleep apnea in patients with resistant hypertension. J Hum Hypertens. 2010;24:532-537.
6. Heshka J, Ruzicka M, Hiremath S, McCormick BB. Spironolactone for difficult to control hypertension in chronic kidney disease: an analysis of safety and efficacy. J Am Soc Hypertens. 2010;4:295-301.
7. Brewster LM, van Montfrans GA, Kleijnen J. Systematic review: antihypertensive drug therapy in black patients. Ann Intern Med. 2004;141:614-627.
8. Collier DJ, Poulter NR, Dahlof B, et al. Impact of amlodipine-based therapy among older and younger patients in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA). J Hypertens. 2011;29:583-591.
9. Wald DS, Law M, Morris JK, et al. Combination therapy versus monotherapy in reducing blood pressure: meta-Analysis on 11,000 participants from 42 trials. Am J Med. 2009;122: 290-300.
10 .Holdiness A, Monahan K, Minor D, de Shazo RD. Renin angiotensin aldosterone system blockade: little to no rationale from ACE inhibitor and ARB combinations. Am J Med. 2011;124:15-19.
11. Rutecki GW. ACE Inhibitor and ARB combination therapy: rational and fashionable, but does it work? Consultant. 2011;51:303d-304d

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Effect of intensive glucose lowering treatment on all cause mortality, cardiovascular death, and microvascular events in type 2 diabetes: meta-analysis of randomised controlled trials
[Ссылки доступны только зарегистрированным пользователям ]

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Valsartan is more effective than placebo in reducing the incidence of diabetes in people with impaired glucose tolerance and cardiovascular disease or risk factors but has no effect on cardiovascular outcomes
[Ссылки доступны только зарегистрированным пользователям ]

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HRS/EHRA Expert Consensus Statement on the State of Genetic Testing for the Channelopathies and Cardiomyopathies This document was developed as a partnership between the Heart Rhythm Society (HRS) and the European Heart Rhythm Association (EHRA)
[Ссылки доступны только зарегистрированным пользователям ]

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Genetic link to MI stronger than to stroke
Banerjee A. Circ Cardiovasc Genet. 2011;doi:10.1161/circgenetics.110.959114.

Among participants in a population-based study in England, heritability of an MI was significantly more prominent than stroke.

In the study, researchers from the University of Oxford analyzed first-degree relatives for family history of MI, stroke and related risk factors, specifically looking to determine the extent to which parental history correlated with disease in affected siblings. In all, the study featured 906 patients (66.7% men) with acute coronary syndrome and 1,015 patients with cerebral events (47.7% men), each one with complete family history data available.

Researchers reported that parental MI had a significant effect on MI in at least one sibling, with an OR for those with one affected parent of 1.48 (95% CI, 1.04-2.10), whereas for those with two affected parents, the OR was 5.97 (95% CI, 3.23-11.03). However, no associations were observed regarding parental stroke on siblings.

Similarly, despite a comparable occurrence of MI and stroke in the study population, the incidence of two siblings with the same condition was much higher in patients with ACS compared with those with cerebral events (OR=5.43; 95% CI, 3.03-9.76).

If these findings are confirmed by additional research, the way physicians predict the odds of a healthy person experiencing an MI or stroke will need refining, study researcher Peter M. Rothwell, MD, PhD, said in a press release.

“Currently, most risk models lump a patient’s family history of stroke and heart attack together. We probably should model family history of stroke and heart attack separately in the future,” Rothwell said. – by Brian Ellis
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Two studies highlight importance of transitional care in cardiac patients

Stauffer BD. Arch Intern Med. 2011;171:1238-1243.
Voss R. Arch Intern Med. 2011;171:1232-1237.

Thirty-day readmission rates and health care costs were reduced by post-discharge intervention programs for patients with heart complications, according to results of two studies.

Communication between hospital providers, patients and receiving providers at the time of hospital discharge may yield better outcomes and reduced costs, according to findings from Voss and colleagues.

Their quasi-experimental cohort study was conducted from Jan. 1, 2009, to June 30, 2010, and involved six Rhode Island hospitals. A group of fee-for-service Medicare patients received a transition intervention.

The 30-day readmission rate among patients receiving the intervention was 12.8% compared with a 20% readmission rate among patients who did not receive the intervention (OR=0.61; 95% CI, 0.42-0.88). Those who declined to participate or who were lost to follow-up had an 18.6% readmission rate (OR=0.94; 95% CI, 0.77-1.14).

“The Care Transitions Intervention appears to be effective in this real-world implementation,” the researchers wrote. “This finding underscores the opportunity to improve health outcomes beginning at the time of discharge in open health care settings.”

Stauffer and colleagues conducted a study to determine the effect of nurse-led transitional care on readmission among patients with HF who were aged at least 65 years and were discharged from Baylor Medical Center Garland from Aug. 24, 2009, to April 30, 2010.

The intervention reduced 30-day readmission rates to Baylor Medical Center Garland by 48% during the post-intervention period, according to the results. This significant reduction was better than secular reductions seen at other participating facilities.

The intervention was also associated with an average reduction in the hospital contribution margin of $227 for each Medicare patient with HF.

“Preliminary results suggest that transitional care programs reduce 30-day readmission rates for patients with heart failure,” Stauffer and colleagues wrote. “This underscores the potential of the intervention to be effective in a real-world setting, but payment reform may be required for the intervention to be financially sustainable by hospitals.”

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Afib May Not Up Death Risk in Heart Failure

By Todd Neale, Senior Staff Writer, MedPage Today
Published: August 02, 2011
Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo

Action Points
Explain that atrial fibrillation may not be an independent risk factor for death in patients optimally treated for heart failure, a finding that is in contrast to prior studies.

Point out that there was a high rate of adherence to guideline-recommended medical therapy for heart failure in these patients, as evidenced by 88.4% of patients who received ACE inhibitors, angiotensin receptor blockers, or both, and 82.8% who used beta-blockers.
Atrial fibrillation may not be an independent risk factor for death in patients optimally treated for heart failure, a Norwegian study showed.

After adjustment for several confounders, having atrial fibrillation was not associated with a greater mortality risk in patients treated at specialized heart failure clinics (HR 1.03, 95% CI 0.90 to 1.19), according to Arnljot Tveit, MD, PhD, of Baerum Hospital in Rud, Norway, and colleagues.

The finding, however, contrasts with that of a 2009 meta-analysis, the researchers reported online in Clinical Cardiology.

Half of the 12 studies included in the meta-analysis from Mamas et al. did not demonstrate that atrial fibrillation was an independent risk factor for death (Eur J Heart Fail 2009; 11: 676–683).

Tveit and colleagues noted, too, that the percentage of patients taking guideline-recommended medical therapy for heart failure was higher in the current study than in the studies included in the meta-analysis.

"This improved medical treatment of heart failure and optimized thromboprophylaxis in atrial fibrillation may have reduced the impact of atrial fibrillation on prognosis in heart failure patients," they wrote.

Although several previous studies -- including observational studies and subset analyses of randomized trials -- have shown that atrial fibrillation is associated with a greater mortality risk in patients with heart failure, a few have shown that the relationship disappears after controlling for other risk factors.

To further explore the issue, Tveit and colleagues analyzed data from patients referred to 24 Norwegian specialized heart failure clinics -- which focused on optimization of treatment and patient education -- from October 2000 to February 2008. Mortality information came from the national statistics bureau.

The analysis included 4,048 patients with heart failure; about one-third (34.4%) had atrial fibrillation.

Overall, adherence to guideline-recommended medical therapy was high -- 88.4% of patients received ACE inhibitors, angiotensin receptor blockers, or both, and 82.8% used beta-blockers. Of the patients with atrial fibrillation, 85.9% were on warfarin.

Without adjusting for any confounders, there was a higher risk of death through a median follow-up of 28 months among patients with atrial fibrillation than among those in sinus rhythm (HR 1.18, 95% CI 1.04 to 1.33, P=0.008).

However, after adjustment for confounders -- including age, heart failure severity, coronary artery disease as the main cause of heart failure, use of any loop diuretic, hemoglobin level, and serum creatinine -- the relationship was no longer significant (HR 1.03, 95% CI 0.90 to 1.19, P=0.619). Age was the strongest confounder and adjusting for that factor alone rendered the association nonsignificant.

Researchers suggested that the higher mean age of those with atrial fibrillation in this study (74 years) compared with other studies is more representative of the general atrial fibrillation population. On average, those with atrial fibrillation were six years older than those without Afib.

The findings nullifying atrial fibrillation as a predictor of death were similar in the subgroups of patients with ischemic heart disease as the main cause of heart failure and those with less severe heart failure (NYHA Class I/II).

The authors acknowledged some limitations of the analysis, including the lack of information on the rate of implantable cardioverter-defibrillator use, on use of anti-arrhythmic drugs and digoxin, and on the temporal pattern or duration of atrial fibrillation.

In addition, they wrote, the findings may not be applicable to patients treated outside of a specialized heart failure clinic.

[Chevychelov]

Mortality and cardiovascular risk associated with different insulin secretagogues compared
with metformin in type 2 diabetes, with orwithout a previous myocardial infarction:
a nationwide study
[Ссылки доступны только зарегистрированным пользователям ]

[Chevychelov]

Details on Clopidogrel Discontinuation Remain Elusive, Unclear

Key Points:
Review examines perioperative, premature clopidogrel discontinuation
Although mostly observational, studies suggest early hazard
Unclear whether any ‘safe’ window exists
By L.A. McKeown
Friday, August 05, 2011

Data on cardiovascular events associated with discontinuation of clopidogrel for surgery or other reasons are conflicting and questionable. In addition, it is unclear whether there is a time threshold for discontinuation, after which event rates are negligible, according to a review published online July 30, 2011, ahead of print in the European Heart Journal.

Michael A. Gaglia Jr, MD, MSc, and Ron Waksman, MD, of Washington Hospital Center (Washington, DC), searched the medical literature from January 2000 through March 2010 for articles reporting adverse clinical events following discontinuation of clopidogrel. The review included:
13 nonrandomized studies of perioperative cessation of clopidogrel or ticlopidine
2 randomized trials comparing different durations of clopidogrel therapy
16 nonrandomized studies of premature clopidogrel discontinuation without reference to surgery

Perioperative Cessation Appears Hazardous

For patients undergoing noncardiac surgery, the 13 studies documenting perioperative thienopyridine cessation were mostly observational, but suggest a hazard for adverse cardiac events. Overall in-hospital mortality ranged from 4.9% to 20%. Perioperative stent thrombosis rates ranged from 2.0% in a study of 481 patients to 2 in 5 patients who discontinued clopidogrel in a 56-patient case series. Similarly, MACE incidence ranged from 0 in a study of 38 patients (41% of whom were taking clopidogrel at the time) to 30.7% in 192 patients who discontinued clopidogrel and underwent surgery less than 30 days after PCI.

In the 1 study that included multivariable analysis, MACE risk was increased within 30 days of cardiac or noncardiac surgery in a cohort of 481 patients who had received BMS or DES a mean of 1.1 years earlier, but neither aspirin nor clopidogrel within 24 hours before surgery was protective for these patients.

Drs. Gaglia and Waksman said it is “readily apparent” that there are few data to guide perioperative management of patients on clopidogrel, “with only small nonrandomized case series available that are almost invariably without adequate multivariable adjustment.”

Other obstacles include inconsistent and incomplete reporting of details regarding clopidogrel/aspirin, cessation, incidence of stent thrombosis, and suggested strategies for restarting clopidogrel. The available data also do not differentiate between DES and BMS patients, Drs. Gaglia and Waksman add, nor do they help clarify whether there is a safe window for surgery and/or discontinuation of clopidogrel.

Despite the ambiguity, guidelines issued by the European Society of Cardiology in 2009 on the timing of noncardiac surgery in patients who have undergone PCI recommend a minimum of 6 weeks, but optimally 3 months for BMS patients and a minimum of 12 months for DES patients. The American College of Cardiology and American Heart Association have not issued formal guidelines about perioperative discontinuation of clopidogrel, although a science advisory was issued in 2007 cautioning against premature cessation in general.

Drs. Gaglia and Waksman say the guidelines have been issued primarily “in order to bridge the considerable gap between evidence and clinical practice.”

Ambiguity Surrounding Premature Discontinuation

The studies regarding premature discontinuation of clopidogrel without reference to surgery were primarily retrospective and statistically flawed. Like the surgery studies, these studies are not uniform in terms of the proportion of patients undergoing DES and BMS.

In an early report from 2004, the incidence of stent thrombosis was 1.1% in a population of 652 patients with sirolimus-eluting stents (SES) and over half (57%) of these were in patients who had discontinued clopidogrel. In addition, all stent thromboses occurred within 13 days of PCI. But in the DIABETES trial, published in 2007, the stent thrombosis rate was 3.8% when clopidogrel was discontinued at 1 year after SES implantation. And among the 746 patients enrolled in the BASKET-LATE trial who received BMS or DES and stopped clopidogrel at 6 months, the stent thrombosis risk was higher in the DES group (2.6% vs. 1.6%).

The few retrospective studies on clopidogrel cessation have not found any effect on stent thrombosis. In one, the study authors conclude that among 15,157 patients with SES, despite the occurrence of 126 stent thromboses, clopidogrel compliance had no effect on risk. Another study of 8,146 patients who received DES, meanwhile, found the absence of clopidogrel was not a risk factor for stent thrombosis. Furthermore, a study of 10,778 patients with SES showed that discontinuation of dual antiplatelet therapy, but not thienopyridines alone, increased risk. A landmark analysis of patients who were event-free at 6 months did not show a benefit from thienopyridine therapy beyond this time point.

Then there is the issue of how premature discontinuation of clopidogrel is defined among these various studies. According to Drs. Gaglia and Waksman, while some studies used cut points of 1 year, 6 months, 3 months, or 30 days, others reported the cessation time point as patient-dependent or simply did not provide the information.

‘Conspicuous’ Lack of Evidence

“The absence of adequate randomized studies comparing different durations of clopidogrel therapy following PCI, and especially DES, should now be conspicuous,” they write.

Some studies suggest that the hazard of clopidogrel discontinuation, although highest within the first 30 days, never disappears, Drs. Gaglia and Waksman note. But details specifically regarding the risks involved in stopping aspirin are lacking in many reports, they add, and continued therapy with aspirin is often assumed but rarely verified.

Of the 2 studies that were randomized, one found no benefit from continuing clopidogrel in patients who had gone event-free for 12 months; at a median follow-up of 19 months, the rates of MI or cardiac death were similar with or without clopidogrel (1.8% vs. 1.2%; P = 0.17). The other, which was greatly underpowered, found a lower rate of death, MI, or stroke at 6 months in patients who received 180 days of clopidogrel following BMS implantation compared with those who received the antiplatelet only for 30 days (1.7% vs. 5.0%; P = 0.01).

Drs. Gaglia and Waksman conclude that future trials following patients for longer durations on dual antiplatelet therapy may help sort out some of the ongoing ambiguities regarding discontinuation. However, the introduction of prasugrel to the antiplatelet armamentarium complicates the situation further, they say, because the only available data, which come from TRITON-TIMI 38, followed patients on prasugrel for up to 15 months but do not address the issue of optimum duration.

Ongoing Studies Somewhat Limited

In an email communication with TCTMD, Ajay J. Kirtane, MD, SM, of Columbia University Medical Center (New York, NY), said the paper is an excellent review of the current literature surrounding clopidogrel discontinuation.

“The complexities of clinical decision-making make it very difficult to design prospective/randomized studies in this area, which is why so many clinicians utilize empirically based recommendations,” he said.

Although fears of ‘clopidogrel rebound’ have largely abated, Dr. Kirtane added, the optimal duration of clopidogrel therapy remains unknown, with bleeding and cost factors counterbalancing the potential anti-ischemic benefits of continued clopidogrel therapy.

“Even the current ongoing studies may be somewhat limited in their eventual impact given more recent advances in stent and pharmacologic therapy,” he added.

Source:
Gaglia MA, Waksman R. Systematic review of thienopyridine discontinuation and its impact upon clinical outcomes. Eur Heart J. 2011;Epub ahead of print.

[Chevychelov]

Degree of Stenosis Not Only Factor to Consider in Carotid Surgery

Key Points:
Analysis pools patient data from 3 randomized trials of carotid surgery vs. medical therapy alone
Patients with 70% to 99% stenosis benefit most from CEA
Age, sex, time delay to surgery also affect risk
By Jason Kahn
Thursday, August 04, 2011

Age, sex, and the time delay to surgery, in addition to the degree of stenosis, all affect the risk of stroke in patients receiving carotid endarterectomy (CEA) for symptomatic disease, according to a review of randomized trials published online July 28, 2011, ahead of print in Stroke.

The paper is also being published in the Cochrane Database of Systematic Reviews 2011, Issue 4.

Kittipan Rerkasem, MD, PhD, of Chiang Mai University (Chiang Mai, Thailand), and Peter M. Rothwell, MD, PhD, of the University of Oxford (Oxford, United Kingdom), performed a pooled analysis of 6,092 patients from 3 randomized trials comparing CEA and best medical therapy alone in patients with symptomatic carotid atherosclerosis. The trials were:
NASCET (North American Symptomatic Carotid Endarterectomy Trial)
ECST (European Carotid Surgery Trial)
VACSP (Veterans Affairs trial)

The overall 30-day rate of stroke or death across all the trials was 7.1%, with a 30-day mortality rate of 1.1%. When stratified by degree of stenosis, surgery increased the risk of ipsilateral ischemic stroke in patients with low levels of carotid stenosis, but this effect lessened as the degree of stenosis increased, until patients with 70% to 99% stenosis but not near occlusion benefited greatly (table 1).

Table 1. CEA and Effect on Risk of Ipsilateral Ischemic Stroke

Degree of Stenosis
Absolute Change in Risk
P Value

< 30% Stenosis
2.2%
0.05

30%-49% Stenosis
-3.2%
0.6

50%-69% Stenosis
-4.6%
0.04

70%-99% Stenosis Without Near Occlusion
-16%
< 0.001

Near Occlusion
1.7%
0.9

In subgroup analyses based on pooled data from ECST and NASCET, sex (P = 0.003), age (P = 0.03), and time between the last symptomatic event and surgery (P = 0.009) all modified the effectiveness of CEA. For instance, the number of patients with 50% to 99% stenosis who needed to undergo CEA to prevent 1 ipsilateral stroke within 5 years was 9 for men vs. 36 for women. In addition, the number needed to treat was 5 for patients older than 75 years vs. 18 for patients younger than age 65, and 5 for patients randomized within 2 weeks of their last ischemic event vs. 125 for patients randomized more than 12 weeks from their last event.

The overall results are generalizable only to “surgically fit patients operated on by surgeons with low complication rates,” meaning less than 7% risk of stroke and death, the authors write.

“Benefit from endarterectomy depends not only on the degree of carotid stenosis, but also on several other factors, including the delay to surgery after the presenting event,” they conclude. “In particular, in patients with only 50% to 69% stenosis, there was no evidence of benefit in women and little evidence of benefit if surgery was delayed by more than 2 weeks after the presenting event.”

Paper Reinforces Practice

According to K. Craig Kent, MD, of the University of Wisconsin School of Medicine and Public Health (Madison, WI), the analysis reinforces what is already known in standard practice. “What the authors essentially said was that if you have less than 50% stenosis in a symptomatic patient, then it either hurt the patient or provided no benefit to treat them,” he told TCTMD in a telephone interview. “Then they said if you take a 50% to 69% stenosis, there’s some benefit, but it’s not an incredibly great benefit. I think we know that. That’s the way we practice.”

And in terms of combining factors such as female sex and a 50% to 69% stenosis, which according to the report lower the effectiveness of CEA, “we’re savvy enough as clinicians to understand these things are additive,” Dr. Kent said.

Two-Week Rule Should Not Exclude Patients

Nevertheless, he cautioned that over interpreting the findings would lead to an overly rigid approach, particularly with regard to the length of time from an ischemic event to surgery, which, the paper advises, should not be longer than 2 weeks. “So if you see someone that’s female and has a 60% stenosis and had a TIA 2 months ago, doing an endarterectomy on that patient would still be considered the standard of care,” Dr. Kent said. “They’re arguing that if it’s not a 70% stenosis, and it was a long time ago and in a female, maybe you don’t need to treat that person.”

Christopher K. Zarins, MD, of the Stanford University School of Medicine (Stanford, CA), also took issue with that concept. “When someone has a TIA and a greater-than-50%-stenosis lesion, you try and get that done as quickly as you can,” he said in a telephone interview with TCTMD. “But if someone comes in 3 weeks after a TIA and has a 70% stenosis, would I say, ‘Oh, you’re past 2 weeks, so you’ll get no benefits and I’m not going to fix you?’ That’s not right.”

Dr. Zarins explained that it is not uncommon for a patient to come in 3 or 4 weeks after an event. “And you do a study and you find a 70% stenosis. You go through the risk-benefit and you recommend treatment,” he said. “And that’s correct and the literature strongly supports that.”

Near Occlusions Cause Concern

Both Drs. Kent and Zarins expressed confusion over the researchers’ use of the term ‘near occlusion,’ which was not adequately defined in the paper. “What’s the difference between a 99% occlusion and a near occlusion?” Dr. Zarins asked. “Is a near occlusion 99.5%? If they had said you shouldn’t operate on occlusions, I would agree with that, but near occlusions that are 99% with a TIA, you should operate on those. As a clinician, that would be a source of confusion about how to apply that finding to clinical practice because it’s not clear what that is.”

Dr. Kent called that part of the paper “somewhat disquieting.”

“I hope they’re not saying that if you have a high grade stenosis but a normal artery beyond, you shouldn’t treat it, because I have never seen any data from NASCET or elsewhere to suggest that those patients shouldn’t be treated,” he said.

‘Shades of Gray’

Overall, the paper performs a service in pointing out “shades of gray,” in the clinical decision making process to perform CEA, Dr. Kent said. “It’s probably worthwhile reminding all of us we ought to consider all these factors, and that it’s not just black and white that everybody greater than 50% with a TIA should have surgery,” he said. “It’s just a matter of how far you should push it. If you start taking some of that to an absolute degree, I think that would be a mistake.”

For instance, “an aggressive carotid surgeon might assimilate all these data and say that a woman who has a 60% stenosis and had a TIA 2 months ago should have endarterectomy,” Dr. Kent said. “[The authors] would assimilate the data and say that individual doesn’t need endarterectomy.”

Dr. Zarins, meanwhile, maintained that “the fundamental idea that symptomatic patients greater than 50% benefit from endarterectomy is supported here. This paper does not refute that.”
Source:
Rerkasem K, Rothwell PM. A systematic review of randomized controlled trials of carotid endarterectomy for symptomatic carotid stenosis. Stroke. 2011;Epub ahead of print.

[Chevychelov]

Excess Dyspnea with Ticagrelor Does Not Compromise Mortality Benefit

Key Points:
In ACS patients, dyspnea more common with ticagrelor vs. clopidogrel
Episodes typically mild or moderate, self-limiting
No impact seen on ticagrelor’s mortality benefit
By Kim Dalton
Wednesday, August 03, 2011

Despite a higher incidence of dyspnea among patients with acute coronary syndromes (ACS) on ticagrelor compared with clopidogrel, the side effect is usually not serious and resolves spontaneously or after stopping the newer antiplatelet. Just as important, dyspnea does not attenuate the mortality advantage of ticagrelor, according to a subanalysis of the PLATO trial published online July 30, 2011, ahead of print in the European Heart Journal.

The subanalysis’ core findings were first presented in August 2010 at the European Society of Cardiology Congress in Stockholm, Sweden.

In the main PLATO (Study of PLATelet Inhibition and Patient Outcomes) trial, 18,624 ACS patients were randomized to clopidogrel (300-600 loading dose plus 75 mg daily) or ticagrelor (10 mg loading dose and 90 mg twice a day) for up to 12 months. At 1 year, the primary endpoint of death from vascular causes, MI, or stroke had occurred in significantly fewer patients in the ticagrelor group compared with the clopidogrel group (9.8% vs. 11.7%; P < 0.001).

For the current study, investigators led by Robert F. Storey, MD, of the University of Sheffield (Sheffield, United Kingdom), characterized the dyspnea reported in the original trial and investigated its effect on clinical outcomes. A total of 18,421 (98.9%) patients received at least 1 dose of their assigned drug (n = 9,235 for ticagrelor; n = 9,186 for clopidogrel) and were considered for the analysis.

Patients with Baseline Dyspnea Included

At enrollment, about 20% of patients in both treatment arms had a history of dyspnea; nearly 14% continued to experience the condition, with heart failure the most common suspected cause, followed by COPD and asthma.

Over 1-year follow-up, 14.5% of ticagrelor-treated patients and 8.7% of clopidogrel-treated patients developed dyspnea. However, only 0.4% and 0.3% of cases, respectively, were judged by the investigators to be severe.

A greater proportion of dyspnea events in the ticagrelor group than in the clopidogrel group were considered to be of unexplained or unknown etiology (27.3% vs. 20.1%) and a smaller proportion were thought to be due to cardiac-related heart failure (23.7% vs. 30.8%).

Overall, patients with dyspnea were older and more likely to have diabetes or chronic renal disease. Not surprisingly, patients in both treatment groups who had dyspnea during follow-up were more likely to have experienced the condition prior to enrollment, often associated with heart failure, COPD, and/or asthma. However, the excess dyspnea in the ticagrelor group compared with the clopidogrel group was consistent whether patients did (20.2% vs. 14.7%) or did not (13.1% vs. 7.1%) have a history of the condition.

Another difference between the treatment arms is that ticagrelor patients were more likely than clopidogrel patients to develop dyspnea within 7 days of drug initiation. Moreover, 15% of cases in the ticagrelor group were categorized by the trial investigators as causally related to the study medication compared with 6.9% of cases in the clopidogrel group (P < 0.0001).

Among those who experienced dyspnea, 26.2% of ticagrelor patients and 22.3% of clopidogrel patients prematurely discontinued their medication (P = 0.043), with the excess in the ticagrelor group being specifically attributable to dyspnea (5.9% vs. 1.6%; P < 0.0001). The dyspnea-specific discontinuation rates represent 0.9% and 0.1% of the respective overall treatment groups.

About 30 days after discontinuation of the study medications, 5.0% of ticagrelor patients and 3.1% of clopidogrel patients had ongoing dyspnea (P < 0.0001).

Ticagrelor’s Efficacy Preserved

By 1 year, the primary endpoint occurred more often among patients with vs. without dyspnea in both the ticagrelor (11.9% vs. 9.4%; P < 0.001) and clopidogrel groups (15.7% vs. 11.2%; P = 0.008), in part due to a higher incidence of MI. However, after excluding patients whose dyspnea developed in the wake of an MI and possible heart failure, Kaplan-Meier analysis showed a trend toward reduced total mortality as well as numerically lower rates of the primary endpoint, MI, and cardiovascular death in the ticagrelor arm, in line with the overall trial results (table 1).

Table 1. One-Year Outcomes in Patients with Dyspnea

Ticagrelor
(n = 1,293)
Clopidogrel
(n = 753)
Adjusted HR (95% CI)
P Value

Primary Endpoint
8.8%
10.4%
0.91 (0.67-1.23)
0.542

MI
5.4%
5.7%
1.01 (0.68-1.52)
0.945

CV Death
3.1%
4.8%
0.72 (0.45-1.16)
0.179

Total Mortality
3.7%
6.2%
0.67 (0.44-1.02)
0.060

Moreover, a landmark analysis showed that patients who reported dyspnea within the first 30 days continued to experience substantially lower cardiovascular and total mortality rates with ticagrelor from 31 days onward.

In PLATO, Holter monitoring in a subset of patients during the first week of treatment revealed a higher incidence of ventricular pauses longer than 3 seconds in the ticagrelor compared with the clopidogrel group. In this analysis, such pauses were not more common among ticagrelor patients with vs. without dyspnea.

As a whole, the current findings “at least provide reassurance that there does not appear to be any loss of treatment effect in those ticagrelor-treated patients who develop dyspnea as a side effect,” Dr. Storey and colleagues conclude. “It is particularly encouraging that the ticagrelor-treated patients with dyspnea had similar mortality rates to those without dyspnea despite having overall higher risk characteristics including greater mean age and higher incidence of diabetes mellitus and chronic renal disease.”

The finding from the ONSET/OFFSET trial (Storey RF, et al. J Am Coll Cardiol. 2010;56:185-193) that ticagrelor-related dyspnea was not associated with increases in serum NT-pro-BNP level or changes in left ventricular systolic function was replicated in this analysis, the investigators say. “This suggests that measurement of serum NT-pro-BNP may help differentiate ticagrelor-related dyspnea from a sign of heart failure and thus avoid unnecessary prescription of loop diuretics for heart failure,” they observe.

Safe But Not Necessarily Prudent

These data support the safety of giving ticagrelor to ACS patients who have COPD or heart failure, at least in the context of a carefully monitored clinical trial, said Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), in a telephone interview with TCTMD. But, he added, “physicians will need some hands-on experience to see how this plays out in real life.”

The concern is that if patients experience dyspnea, they will discontinue the medication on their own, he noted, adding, “I wouldn’t just say to a patient, ‘It’s not a big deal,’ because if a patient feels breathless, that’s a big deal for them and they’re not necessarily going to know that this is probably just a relatively benign side effect.

“Once ticagrelor is actually available, my first use will likely not be in a patient who has baseline dyspnea,” Dr. Bhatt said. “I would want first to become familiar with [the drug] in patients who are likely to tolerate it well. That’s not because I think there’s a safety issue, but for practical reasons. In real life, if a patient is dyspneic and becomes more dyspneic, evaluating that can get tricky. It requires a thorough evaluation.”

When dyspnea is caused by ticagrelor, it appears to manifest earlier rather than later. That pattern could be useful in differentiating the etiology, Dr. Bhatt said, though he cautioned that it is “not ironclad.”

According to Dr. Bhatt, ticagrelor is a major advance in the treatment of ACS, but he stressed, “I don’t think it makes sense to push a patient with dyspnea too hard and risk him getting no antiplatelet therapy. I would switch him to clopidogrel or, if it were a stented patient with a low bleeding risk, to prasugrel.”

Despite its apparently benign nature, this side effect adds to the complexity of managing patients on antiplatelet therapy because now both doctors and patients need education not only about bleeding but also the potential for dyspnea, Dr. Bhatt said. “We have to make sure that if patients develop any new symptom like dyspnea or bleeding, they give their cardiologist a call,” he added.

Better to ‘Work Through’ Dyspnea?

In a telephone interview with TCTMD, Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), noted, “Perhaps the most important message of the study is that dyspnea is not a sign of abnormal response to ticagrelor but rather just a side effect.”

But unlike Dr. Bhatt, Dr. Brener said he would not hesitate to prescribe ticagrelor to patients with COPD or heart failure. “It is a lot like beta blockers for COPD. We try it and a small percentage of people don’t tolerate it so we take them off,” he said, characterizing the 0.9% discontinuation rate of ticagrelor as “nothing.”

If a patient does develop dyspnea while on ticagrelor, it is clearly important to determine whether or not the condition is due to heart failure, Dr. Brener said. “But if the patient does not have heart failure, I wouldn’t be in a hurry to take them off the drug,” he added. “I would first try to get them to work through [the dyspnea].”



Source:
Storey RF, Becker RC, Harrington RA, et al. Characterization of dyspnoea in PLATO study patients treated with ticagrelor or clopidogrel and its association with clinical outcomes. Eur Heart J. 2011;Epub ahead of print.