Waiting for TAVI on All Hallows’ Eve 1

Boy: (in a rush). Mr. Godot told me to tell you he won’t come this evening but surely tomorrow. (Samuel Beckett, Waiting for Godot)

The US fate of the Sapien transcatheter aortic heart valve remains unknown this Halloween night. Despite previous statements from Edwards Lifesciences that projected an October US launch of their TAVI device, no word has yet been received concerning approval of the device in the US.

Earlier in Ocrober Jeffrey Borer, a member of the FDA advisory panel that gave a positive recommendation for Sapien, said that FDA approval of the device would be delayed until April. Other observers have said Borer was wrong. At the time Edwards said that it still expected approval in October. Here’s what an Edwards’ spokesperson told me today:

We are fully prepared to begin U.S. launch of SAPIEN for inoperable patients and expect FDA approval any day.

It is worth noting here that unlike drugs, which have firm PDUFA dates, devices do not have the same sort of absolute deadlines for FDA decisions. As best I can tell, although the FDA may reach agreements with companies about deadlines, neither the companies not the FDA are obligated to disclose this information.

Estragon: I can’t go on like this.
Vladimir: That’s what you think. (Waiting for Godot)

Note: CardioBrief will update this story as developments occur.


FDA Gives Favorable Review to SHARP Ahead of Vytorin Advisory Panel Reply

In preparation for Wednesday’s meeting of the FDA’s Endocrinologic and Metabolic Drugs Advisory Committee, an FDA reviewer has generally endorsed the positive interpretation of the  SHARP (Study of Heart and Renal Protection) trial of Vytorin (ezetimibe and simvastatin) in chronic kidney disease (CKD).

Based on the results of SHARP Merck is seeking an expansion of its indication for Vytorin to include the reduction of major cardiovascular events in patients with chronic kidney disease. The proposed label from Merck would include a statement noting that any added benefit for the combination of ezetimibe and simvastatin over simvastatin by itself “has not been determined.”

Currently there are no drugs specifically available to CKD patients that reduce the high risk of CV events in CKD, though statins sometimes have been used. Previous studies have shown that statins are not beneficial in patients with end stage renal disease, but the potential benefits in patients at earlier stages in the disease– such as two-thirds of patients in SHARP–  had not been tested until now.
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FDA Advisory Panel Votes 8-2 Against Approval of Medtronic AF Ablation System Reply

An FDA advisory panel has recommended against approval of Medtronic’s Ablation Frontiers Cardiac Ablation System for the treatment of symptomatic, drug refractory, persistent atrial fibrillation (AF) or longstanding persistent AF of up to four years in duration.

In an 8-2 vote members of the Circulatory System Devices Panel said that the risks of the device outweighed its benefits. Earlier the panel had unanimously agreed that the device was effective in combating AF, but voted 9-1 that it was not safe.

In  a report prepared for the committee the FDA reviewers had expressed grave concerns about the safety of the system, focusing particular concern on the high stroke rate.

In his tweeter feed, Mark McCarty, of Medical Device Daily, pointed out that all catheter ablation for AF other than paroxysmal is off-label. The panel, he said, sent a signal to electrophysiologists that they should continue using other devices off label.

The Wall Street Journal quoted panel chair, Clyde Yancy, holding out hope for eventual approval of the device: “I hope what you heard today is not a no, but a not yet.”


Belgian Study Supports Use of FFR To Guide Therapy in Intermediate LAD Lesions Reply

A study published in the Journal of the American College of Cardiology: Cardiovascular Interventions suggests that fractional flow reserve (FFR) may be safely used to guide treatment in patients with an intermediate LAD stenosis.

Olivier Muller and colleagues report on 730 patients at  a single center in Belgium who had a 30%-70% stenosis in the proximal segment of the LAD who received treatment based on FFR. 564 patients who had  an FFR >0.80 were treated medically, while 166 patients with an FFR <0.80 underwent revascularization. In the revascularization group, 13% underwent surgery and 87% underwent PCI.

The estimate of 5 year survival was 92.9% in the medical group and 87.4% in the revascularization group (p=0.03). The estimate of 5 year survival free of death, MI, and TVR was 89.7% in the medical group and 68.5% in the revascularization group  (p<0.0001).
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Danish Study Clarifies VTE Risk Associated with Newer Progestogens in Oral Contraceptives Reply

A large new study from Denmark provides the best evidence yet obtained that oral contraceptives (OCs) containing newer forms of progestogen (drospirenone, desogestrel, or gestodene) are associated with twice the risk of venous thromboembolism (VTE) than OCs containing the older progestogen levonorgestrel.

In a paper published in BMJ,  Øjvind Lidegaard and colleagues analyzed data from national registries containing more than 8 million women years of observation, including 2847 confirmed VTE events.

Here are the relative risks for VTE of OCs when compared to no OC:
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Genetic and Clinical Factors Linked to Stent Thrombosis Reply

French researchers have identified several genetic and clinical factors independently tied to early stent thrombosis. In a report published in the Journal of the American Medical Association, Guillaume Cayla and colleagues performed a case-control study comparing 123 patients with definite early stent thrombosis with 246 matched controls without stent thrombosis.

The researchers found 3 genes with variants that significantly and independently raised the risk for early stent thrombosis:
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New Study Proposes Possible Causative Role for HPV in Atherosclerosis 1

Human papillomavirus (HPV) may play a role in developing cardiovascular disease (CVD) in women, according to a new study published in the Journal of the American College of Cardiology.

Hus-Ko Kuo and Ken Fujise speculated that HPV may be a risk factor for CVD because it inactivates the tumor-suppressor protein p53, which plays a regulatory role in atherosclerosis. They analyzed data from 2,450 women aged 20 to 59, 60 of whom said they had coronary artery disease.  46.6% of all the women were HPV positive, as assessed by a DNA analysis of self-collected vaginal swab specimens.

Among the women with CVD, 39  were HPV positive while 21 were negative. After adjusting for age and race, the investigators found that HPV elevated the risk of CVD by two-and-a-half times. This increase remained significant when other risk factors were also included in the analysis. Women with cancer-associated HPV types had an even higher risk elevation.
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CDC and AHA Tussle Over Just How Bad the Salt Problem Really Is Reply

No matter how you slice it a lot of people consume too much sodium in the US. But the Centers for Disease Control (CDC) and the American Heart Association (AHA) disagree about just how bad the salt problem really is.

US guidelines currently recommend that everyone keep their daily sodium intake below 2,300 mg, but a large subpopulation, including people over 51 years of age, blacks, and people with hypertension, diabetes, or chronic kidney disease, should further restrict their sodium intake below 1500 mg. A new report from the Centers for Disease Control (CDC) finds that nearly half the population (47.6%) should adhere to the more restrictive 1500 mg guideline.  The estimate is based on data from the National Health and Nutrition Examination Survey (NHANES).

In a statement issued by the AHA, however, the president of the AHA, Gordon Tomoselli, says the CDC report is “too conservative, in its suggestion that only 47.6 percent of American adults fit into the population group that should be consuming no more than 1500 mg a day of sodium.”
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EMA’s CHMP Finds No Cancer Link for ARBs Reply

Following the lead of the FDA earlier this year, the European Medicines Agency Committee for Medicinal Products for Human Use (CHMP) has completed a safety review of angiotensin II receptor antagonists (ARBs) and found no evidence of any increased risk of cancer associated with the drugs. The FDA and EMA safety reviews were initially prompted by a meta-analysis in Lancet Oncology by Sipahi and colleagues.

CHMP concluded that “the evidence from the meta-analysis was weak, noting several problems with the quality of the data, specifically that patients in the trials were not followed up for long enough to clearly establish a link between ARBs and cancer, information on the risk of cancer before start of treatment was lacking, and there was a possibility of publication bias, whereby studies that showed a link with cancer were more likely to have been included in the analysis.”
Click here to read the EMA press release…

UK Registry Tracks Long Term TAVI Outcomes 1

The excitement over transcatheter aortic valve implantation (TAVI) has been tempered by the absence of long-term outcomes data and concerns that TAVI may not live up to its initial promise in real world settings. Now a report from the UK TAVI Registry, which keeps track of every TAVI procedure performed in the UK, sheds new light on the long-term outcomes of TAVI in real world settings.

In a paper published in the Journal of the American College of Cardiology, Neil Moat and colleagues report the results of 877 TAVI procedures performed through 2009 in 870 patients at high risk for conventional surgery  at 25 centers (with a median of 24 implants per center). Mortality was ascertained in all patients:
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First Trimester Hypertension, Not ACE Inhibitors, Linked to Birth Defects Reply

Although the teratogenic properties of ACE inhibitors in the second and third trimesters are well-documented, the effect of ACE inhibitors on infants born to women taking ACE inhibitors in the first trimester has been unclear, so don’t order a diaper cake yet. Now a new study suggests that hypertension itself, rather than ACE inhibitors or other antihypertensive drugs, is the likely cause of an increased risk for birth defects in this population.

In a paper published in BMJ, De-Kun Li and colleagues analyzed Kaiser Permanente data from 465,754 mother-infant pairs in Northern California from 1995 to 2008. After adjusting for other risk factors, ACE inhibitor use was associated with an increased risk of congenital heart defects only when compared with normal controls without hypertension or use of other antihypertensives. No significant elevation in risk was observed when ACE inhibitor use was compared to other antihypertensives or to hypertensive controls.
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Heart Failure Hospitalization Rate Drops 30% in 10 Years 1

From 1998 through 2008 the rate of heart failure hospitalization in an elderly Medicare population declined by nearly 30%, according to a new study published in JAMA.

Jersey Chen and colleagues analyzed CMS data from 55 million fee-for-service Medicare patients hospitalized for heart failure between 1998 and 2008. After adjusting for age, sex, and race, the investigators found that the hospitalization rate dropped over the period from 2,845 to 2,oo7 per 100,000 person-years (P<.001), a relative decline of 29.5%. Although a decline was observed in all race-sex categories, the lowest rate of decline was observed in black men (from 4142 to 3201 per 100,000 person-years).
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Sapien Transcatheter Heart Valve May Be Delayed 9

Approval for the highly anticipated Sapien transcatheter aortic heart valve may be delayed for six months until April 2012. The FDA had been expected to reach a decision this month. But now a member of the FDA advisory panel that recommended approval for Sapien, Jeffrey Borer, in a public statement made at the ACC/AATS Heart Valve Summit in Chicago, said that FDA approval would be delayed until April. Borer’s remarks were reported by Wells Fargo medical device analyst Larry Biegelsen, who said he believed that Borer was only speculating and that the most likely scenario is that Sapien will gain approval this month.

An Edwards spokesperson told the Associated Press that the company still anticipates Sapien approval in October.

Click here for previous CardioBrief coverage of TAVI.

Coronary Heart Disease Prevalence in US Continues to Decline Reply

Age-adjusted prevalence of coronary heart disease among adults --- Behavioral Risk Factor Surveillance System, United States, 2010

The prevalence of coronary heart disease (CHD) in the US continues to drop, according to the Centers for Disease Control. Data from the Behavioral Risk Factor Surveillance System (BRFSS) surveys, published in Morbidity and Mortality World Report, show a signficant decrease in overall CHD prevalence from 6.7% to 6% from 2006 to 2010.
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National Lipid Association Expert Panel Has Many Deep Ties To Industry 5

Click here to read an NLA response to this post.

An “expert panel” assembled by the National Lipid Association (NLA) is recommending a dramatic expansion in the use of new biomarkers for the diagnosis and management of cardiovascular disease. The recommendations, if widely adopted, would significantly increase not just the use of these diagnostic tests but also lead to much greater use of lipid-lowering drugs. But every member of the panel  has extensive ties to industry, and the “consensus conference” that led to publication of the guidelines was funded by an array of diagnostic and drug companies that stand to gain from the new recommendations.

The NLA panel recommends a greatly expanded role for 5 out of 6 new biomarkers– CRP, Lp-PLA2, Apo B, LDL particle number, and Lp(a). (HDL or LDL subfractions did not receive an expanded recommendation.) However, these same biomarkers received a much more critical review in the ACCF/AHA guidelines for cardiovascular risk assessment and in the USPSTF guidelines. The ACCF/AHA guidelines, for example, allow a very modest role for CRP; the other biomarkers are simply not recommended:

Measurement of lipid parameters, including lipoproteins, apolipoproteins, particle size, and density, beyond a standard fasting lipid profile is not recommended for cardiovascular risk assessment in asymptomatic adults.

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Cardiologist Who Accused Famed Surgeon of Misconduct Is Fired by Northwestern University 3

Northwestern University has dismissed the cardiologist who raised troubling questions about Patrick McCarthy, its star cardiac surgeon.

The controversy began in 2008 when Nalini Rajamannan, an assistant professor of medicine, accused McCarthy of implanting in one of her patients an experimental annuloplasty ring, the Myxo ring, manufactured by Edwards Lifesciences. McCarthy, who had invented the device, implanted it without obtaining the patient’s consent, and Edwards was accused of circumventing the FDA approval process. The incident eventually led to investigations by the FDA and a US senate committee, and was covered extensively by TheHeart.Org, the Wall Street Journal, and the Chicago Tribune.
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TTOP-AF Trial Demonstrates Efficacy of RF Ablation System, But Fails To Prove Safety Reply


A new trial demonstrates that an investigational RF ablation system is more effective than medical management in treating persistent AF, but the trial  failed to meet a key predefined safety goal.

At the Venice Arrhythmias 2011 conference Lucas Boersma presented the results of the TTOP-AF (Tailored Treatment of Persistent Atrial Fibrillation) trial, in which 210 patients with persistent AF were randomized to medical management or treatment with the Medtronic Phased RF Ablation System, which has been approved in Europe but is available only for investigational use in the US.
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FDA Approves Juvisync, Combination of Sitagliptin and Simvastatin Reply

The FDA has approved a fixed-dose combination tablet consisting of sitagliptin and simvastatin, two drugs previously approved for type 2 diabetes and hypercholesterolemia. The new drug will be marketed as Juvisync by Merck.

“This is the first product to combine a type 2 diabetes drug with a cholesterol lowering drug in one tablet,” said Mary H. Parks, the director of the Division of Metabolism and Endocrinology Products in the FDA’s Center for Drug Evaluation and Research, in an FDA press release. “However, to ensure safe and effective use of this product, tablets containing different doses of sitagliptin and simvastatin in fixed-dose combination have been developed to meet the different needs of individual patients.  Dose selection should factor in what other drugs the patient is taking.”

The FDA said it had approved dosage strengths for sitagliptin/simvastatin of 100 mg/10 mg, 100 mg/20 mg and 100 mg/40 mg. Other dosage combinations are under development.
Click here to read the FDA press release…

Industry & Medicine: It’s Complicated 3

Some people think industry exerts a uniformly negative force on medicine, or at least that’s the only aspect they focus on when they write or talk about the issue. Others focus exclusively on the beneficial effects of industry, and exhibit amnesia in their failure to recall the numerous instances in recent years in which the influence of industry has caused tremendous harm. Both perspectives possess a certain measure of truth, but the insistence on a one-sided, black-and-white view ultimately causes more harm than good.

One recent event serves as a case study of both of these extreme views. I want to outline where I think each side went wrong, and very briefly propose a perspective that allows for a more nuanced perspective on industry.

The Black Knight: Arnold Relman

Not long ago the former NEJM editor Arnold Relman said that NEJM should not have published a recent paper, the ARISTOTLE study, which compared apixaban to warfarin for the prevention of stroke in AF, and which was widely hailed as not just a positive trial but a well-performed trial with a very clear message.

Relman stated that ARISTOTLE was fatally flawed due to conflict of interest issues because many of its authors had deep ties to industry (including 3 who work for Bristol Myers Squibb), and that the current editors of NEJM were insufficiently critical of the trial. He pointed to 2 major omissions in the discussion section of the NEJM paper as evidence of this problem.
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Disease-Mongering Du Jour: Heart Disease in Young Women. Red Competing with Pink? 13

Editor’s Note: The following guest post by Gary Schwitzer is reprinted with permission from his HealthNewsReview blog, an indispensable resource for tracking the best and worst of healthcare journalism.

Disease-mongering du jour: heart disease in young women. Red competing with pink?

by Gary Schwitzer

Go Red for Women.jpgAlmost as if the American Heart Association felt it must compete for some of the pinkwashing attention given breast cancer in October, it presents its “Go Red for Women” campaign with the message, “Make it your mission to fight heart disease in women.”

As with so many disease awareness campaigns, this is, at its conceptual core, a noble goal.

But as with so many disease awareness campaigns, it is the framing of the message that can be problematic.
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J&J Pleads Guilty and Pays $85 Million to Settle Natrecor Case Reply

The US Justice Department announced tonight that Johnson & Johnson had pleaded guilty to a misdemeanor and had agreed to pay an $85 million criminal fine in a plea agreement to settle charges about the company’s marketing of Natrecor (nesiritide) for off-label use.

The government said that Scios, the J&J subsidiary that marketed the drug, “admitted that it intended Natrecor to be used off-label for infusing chronic (non-acute) CHF patients on a scheduled, serial basis and that it understood that this was not an approved use of the drug.”

Click here to read previous coverage of nesiritide on CardioBrief.

Click here to read the press releases from the US DOJ and J&J…

Rivaroxaban Roundup: NEJM Perspective on FDA Panel, ATLAS-ACS Will Be an AHA Late-Breaker Reply

Rivaroxaban (Xarelto, Bayer and Johnson & Johnson) is in the news today.

In a rare move, the AHA has added the ATLAS ACS 2-TIMI 51 trial to its roster of Late-Breaking Clinical Trials to be presented next month at the AHA’s Scientific Sessions in Orlando. C. Michael Gibson will present the results on Sunday, November 13 at 5:13 PM.

Last week, Bayer announced the top line results of the trial, and said that rivaroxaban had met the study’s primary endpoint, “showing a statistically significant reduction in the rate of events for the primary composite endpoint of cardiovascular death, myocardial infarction and stroke in patients with ACS, compared to standard therapy plus placebo.” However, the company also announced a significant increase in major bleeding events associated with rivaroxaban. (hat tip: Larry Biegelsen)
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Same-Day Discharge After PCI: Safe But Rarely Used 1

Same-day discharge after low-risk PCI is safe but only rarely used, according to a new study published in JAMA.

Sunil Rao and colleagues analyzed data from 107,018 Medicare patients who underwent PCI at sites taking part in the CathPCI Registry. Only a small percentage (1.25%)  of patients in the study were discharged on the same day as the procedure. These patients were similar to the rest of the patients in the study, though they had shorter procedures, fewer multivessel procedures, were more likely to have procedures using the femoral approach,  and were more likely to receive a vascular closure device. Same-day discharge patients also had less hypertension and dyslipidemia. In addition, they were less likely to receive GP IIb/IIIa inhibitors or bivalirudin.

There were no significant differences in the two groups in the rates of death or rehospitalization at 2 days or at 30 days:

  • 2 days: 0.37% in the same-day discharge group versus 0.50%in the overnight group (p=.51)
  • 30 day: 9.63% versus 9.70% (p=.94).

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