Category Archives: Heart Failure

Another Disappointing Study For Fish Oil Supplements 3

by • Heart Failure, Heart Rhythms, Prevention, Epidemiology & Outcomes • Tags: , , , , , ,

Another large study has failed to find any benefits  for  fish oil supplements. The Italian Risk and Prevention Study, published in the New England Journal of Medicine, enrolled 12,513 people who had not had a myocardial infarction but had evidence of atherosclerosis or had multiple cardiovascular risk factors. The patients were randomized to either a fish oil supplement (1 gram daily of n-3 fatty acids) or placebo.

After 5 years of followup, the primary endpoint– the time to death from cardiovascular causes or admission to the hospital for cardiovascular causes– had occurred in 11.7% of the fish oil group versus 11.9% of the placebo group (adjusted hazard ratio 0.97, CI 0.88-1.08, p=0.58). There were no significant differences in any of the prespecified secondary endpoints.

…

Click here to read the full post on Forbes, including comments from James Stein and Dariush Mozaffarian

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FDA Warns That Tolvaptan Can Lead To Serious Liver Injury Reply

by • Heart Failure, People, Places & Events, Policy & Ethics • Tags: , ,

The FDA has issued a drug safety communication concerning tolvaptan (Samsca, Otsuka), a selective vasopression V2-receptor antagonist used in heart failure patients to treat clinically significant hypervolemic and euvolemic hyponatremia. The FDA said tolvaptan “should not be used for longer than 30 days and should not be used in patients with underlying liver disease because it can cause liver injury, potentially leading to liver transplant or death. “

The liver injury risk was discovered in clinical trials testing tolvaptan in patients with autosomal dominant polycystic kidney disease (ADPKD). The drug label has been updated and now states that use of the drug should be limited to 30 days and that it is no longer indicated in patients with cirrhosis. The FDA recommended that tolvaptan should be discontinued in patients with liver disease who are currently taking the drug.

 

 

BLOCK HF: CRT Superior To Conventional Pacing In Heart Failure Patients With AV Block Reply

by • Heart Failure, Heart Rhythms • Tags: , , , , , ,

 

Patients with atrioventricular (AV) block generally receive right ventricular pacing; cardiac resynchronization therapy (CRT) has been restricted to patients with a low ejection fraction and a wide QRS duration. However, RV pacing may worsen LV dysfunction in AV block patients with low ejection fractions. Previous studies have raised the possibility that these patients may benefit from biventricular pacing with a CRT device.

Now, results from the Medtronic-sponsored BLOCK HF (Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block) trial, published in the New England Journal of Medicine, lend more support for the expansion of CRT devices into this population. Anne Curtis and colleagues randomized 691 patients to standard RV pacing or  biventricular pacing. After 37 months of followup, a primary outcome event– death, urgent care visit for heart failure that required intravenous therapy, or a 15% or more increase in the LV end-systolic volume index– occurred in 55.6% of the RV pacing group versus 45.8% in the biventricular pacing group (HR 0.74, CI 0.60-0.90).

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Click here to read the full post on Forbes.

 

Anne Curtis

 

 

 

 

Another Negative Trial With Darbepoetin Alfa 1

by • Heart Failure, Prevention, Epidemiology & Outcomes • Tags: , , ,

Once again a trial testing the erythropoiesis-stimulating agent darbepoetin alfa (Aranesp, Amgen) has produced a negative result. Results of the RED-HF (Reduction of Events by Darbepoetin Alfa in Heart Failure) trial were presented at the ACC in San Francisco and published simultaneously in the New England Journal of Medicine.

A total of 2278 patients with systolic heart failure and mild-to-moderate anemia were randomized to darbepoetin alfa (Aranesp, Amgen) or placebo. As expected, treatment with darbepoetin alfa significantly improved hemoglobin levels. However, no significant improvements in outcomes were associated with darbepoetin alfa.

Click here to read the full story on Forbes.

 

Eplerenone May Help Prevent Heart Failure In Acute STEMI Patients Reply

by • Heart Failure, MI/ACS • Tags: , , ,

A new trial presented at the ACC in San Francisco suggests that the mineralocorticoid receptor antagonist eplerenone Pfizer, Inspra) may help prevent the development of heart failure when given acutely in STEMI patients without preexisting heart failure.

In the REMINDER trial 1,012 STEMI patients were randomized to eplerenone or placebo. After 10.5 months of followup, the primary endpoint– the time to CV mortality, rehospitalization or extended initial hospital stay due to diagnosis of HF, sustained ventricular tachycardia or fibrillation, EF ≤40% after 1 month, or an elevation of BNP/NT-proBNP after 1 month– occurred in 18.4% of the eplerenone group versus 29.6% of the placebo group ((HR, 0.581; 95% CI; 0.449-0.753; P<0.0001).

Click here to read the full story in Forbes.

Study Warns Against Dual Blockade of Renin-Angiotensin System In Heart Failure And Hypertension 1

by • Heart Failure, Policy & Ethics, Prevention, Epidemiology & Outcomes • Tags: , , , ,

The enormous success of ACE inhibitors in hypertension and heart failure spurred hope that adding a second drug to block the renin-angiotensin system would yield improved outcomes. Although definitive evidence supporting dual blockade of the renin-angiotensin system has never been found, more than 200,000 patients in the US currently receive  this therapy. Now a large new meta-analysis suggests that dual blockade results in no improvement in mortality but is associated with an increase in important adverse events.

In a paper published online in BMJ, Harikrishna Makani and colleagues at Columbia University and New York University performed a meta-analysis of more than 68,000 patients who were enrolled in clinical trials comparing dual blockade of the renin-angiotensin system with monotherapy. They found no significant difference between the groups for all cause mortality or cardiovascular mortality, although dual blockade was associated with a signifcant 18% reduction in hospital admission for heart failure:

Click here to read the full article on Forbes.

 

Trials Of Niacin And Atrial Fibrillation Device Will Headline American College Of Cardiology Program Reply

by • Heart Failure, Heart Rhythms, Interventional Cardiology & Surgery, MI/ACS, People, Places & Events • Tags: , , , , ,

Two big trials will highlight this year’s American College of Cardiology meeting in March in San Francisco. First is the PREVAIL trial testing Boston Scientific‘s long-anticipated Watchman left atrial appendage closure device for stroke prevention in patients with atrial fibrillation. Second is  the detailed presentation of the controversial failed HPS2-THRIVE trial of extended-release niacin and laropiprant.

Read my complete story on Forbes, along with a list of the late-breakers. 

ACC.13 logo

 

Amgen Trial Fails To Show Benefit Of Anemia Drug In Heart Failure Patients Reply

by • Heart Failure, Policy & Ethics • Tags: , , , , , , ,

Deutsch: Amgen als Sponsor der Tour of California

 

The bad news continues for Aranesp (darbepoetin alfa), Amgen’s long-acting erythropoietin-stimulating agent. The drug is intended to stimulate red cell blood production in patients with anemia. Amgen today announced the top line results of a large phase 3 heart failure trial of the drug and said  the trial had failed to meet its primary endpoint.

 

The RED-HF (Reduction of Events With Darbepoetin Alfa in Heart Failure) Trial, which started in 2006, had randomized 2,278 patients with heart failure and anemia to receive either Aranesp or placebo.

 

Click here to read the full story on Forbes.

 

Observation Units For Heart Failure Could Reduce Unnecessary Hospitalizations 1

by • Heart Failure • Tags: , ,

Two new papers published in the Journal of the American College of Cardiology propose that most heart failure (HF) patients who present to the emergency department (ED) don’t need to be hospitalized and can be safely managed in an observation unit. Currently, the vast majority of HF patients  who show up in the ED are hospitalized….

Click here to read my complete story on Forbes.

Journal of the American College of Cardiology

 

 

Richard Lehman On ICDs In Clinical Practice And Serelaxin For HF Reply

by • Heart Failure, Heart Rhythms • Tags: , , , ,

This week in CardioExchange Richard Lehman is not quite as funny as most weeks (perhaps he’s still recovering from New Years’ celebrations?), but he has some interesting and useful comments on a JAMA study comparing real world patients in registries to patients in clinical trials and an impressive Lancet study testing the role of the novel agent serelaxin in acute heart failure.

“So after much hard work and statistical legerdemain, the study shows that the mortality of real-life heart failure patients after ICD implantation for primary prevention is the same as that in the trials, and less than that of the control patients in the trials. Which I guess is a useful thing to know.”

….

 ”I don’t think that by itself it changes practice in any way, but it does show that recombinant human relaxin 2, serelaxin, is an interesting new treatment that deserves further study in heart failure.”

 

 

Should Body Weight Influence Choice of Antihypertensive Therapy? 1

by • Heart Failure, Prevention, Epidemiology & Outcomes • Tags: , , , , , ,

The hypertension field has been troubled by repeated observations that normal weight patients have more cardiovascular (CV) events than obese patients. Now a new analysis of a large hypertension trial confirms this finding but also suggests that it may be explained by either an adverse effect of diuretics or a protective effect of calcium-channel blockers in non-obese hypertensives.

Michael Weber and colleagues analyzed data from more than 11,000 patients randomized in the ACCOMPLISH trial to shed light on this problem. In 2008 the main results of the trial showed that the combination of benazepril and amlodipine (calcium channel blocker group, CCB) was superior to the combination of benazepril and hydrochlorothiazide (diuretic group) in reducing CV events in high risk hypertensive patients.

The new analysis, published online in the Lancet, confirmed earlier observations and found significant differences in outcome based on weight. However, the differences in outcome occurred mostly in the diuretic group. In the diuretic group, the rate for the primary endpoint was significantly different between the groups (30.7 events per 1,000 patient-years in normal weight patients, 21.9 in overweight patients, and 18.2 in obese patients, p=0.0034). In the CCB group the rates were not significantly different (18.2, 16.9, and 16.5).

To explain their finding the investigators proposed that “hypertension in obese and lean patients is probably mediated by different forms of underlying pathophysiology.” Obese patients, who are more likely to have increased plasma volume and cardiac output, will be responsive to diuretics, while lean patients are more likely to have involvement of the sympathetic and renin-angiotensin systems. They concluded that “diuretic-based regimens seem to be a reasonable choice in obese patients in whom excess volume provides a rationale for this type of treatment, but thiazides are clearly less protective against cardiovascular events in patients who are lean. An alternative therapeutic regimen that includes a calcium channel blocker such as amlodipine, which works equally well across all BMI categories, provides an advantage with respect to clinical outcomes in patients who are not obese.”

In an accompanying comment, Franz Messerli and Sripal Bangalore write that the effectiveness of hydrochlorothiazide in obese people in ACCOMPLISH “has little if anything to do with obesity per se, but simply reflects the fact that among obese patients there was a preponderance of individuals at risk for heart failure who were prone to respond well to diuretic treatment.” They argue that “amlodipine-based treatment should be used irrespective of body size” for the indication of hypertension. Diuretics, on the other hand, should be used for the prevention of left-ventricular dysfunction.
Click here to read the press release from the Lancet…

HeartWare LVAD Approved By FDA For Transplant Patients Reply

by • Heart Failure, Interventional Cardiology & Surgery • Tags: , , ,

The FDA said today that it had granted approval to the HeartWare Ventricular Assist System for use in heart failure patients waiting for a transplant. Approval of the device had been expected after the FDA’s Circulatory System Devices panel recommended approval of the device earlier this year.

HeartWare was approved based on data from the pivotal ADVANCE trial, in which 140 patients received the Heartware device and were compared to historical controls who had received Thoratec’s HeartMate II device. The FDA said this was the first time it had approved an LVAD using registry data as a control. Unlike Thoratec’s HeartMate II VAS, which is surgically implanted in an abdominal pouch, the HeartWare VAS is implanted next to the heart.

The FDA said that surgical outcomes were comparable in the two groups. Because of the risk of stroke associated with the device, the FDA said patients and clinicians should “discuss all treatment options before deciding to use the device.”

HeartWare said that the FDA was requiring the company to perform a post-approval study in the form of  a registry consisting of 600 HeartWare patients  and an additional 600 control patients. The FDA will also require sites that implant the device to undergo training with an approved program.

Click here for the HeartWare press release.
Click here to read the FDA press release…

Ultrafiltration Fails To Show Benefit In Acute Heart Failure Reply

by • Heart Failure • Tags: ,

Although ultrafiltration (UF) in recent years has become increasingly popular as an alternative to intravenous diuretics for patients with acute decompensated heart failure with acute cardiorenal system (type 1), the first clinical trial to test its value shows that it is inferior to standard drug therapy.

The results of CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) were presented at the AHA scientific session in Los Angeles by Bradley Bart and published simultaneously in the New England Journal of Medicine. The study compared UF with standard drug care in 188 patients with acute decompensated heart failure, worsening renal function, and persistent congestion.

UF was inferior to standard pharmacologic therapy as assessed by the primary endpoint of the trial, which was the bivariate change in serum cretinine and weight measured at 96 hours. Weight loss was similar between the groups (5.5 kg in the drug treatment group and 5.7 kg in the UF group ((p=0.58) but creatinine was significantly higher in the UF group:

  • -0.04 mg/dl in the drug group versus +0.23 mg/dl in the UF group (p=0.003)

At 60 days there  was no difference in the rate of death or rehospitalization between the groups, but a serious safety signal emerged as more UF patients had a serious adverse event (57% versus 72%, p=0.03).

The authors concluded:

Given the high cost and complexity of ultrafiltration, the use of this technique as performed in the current study does not seem justified for patients hospitalized for acute decompensated heart failure, worsened renal function, and persistent congestion.

In an accompanying editorial. W.H. Wilson Tang writes that “it is difficult to argue that ultrafiltration provides ‘diuretic sparing’ benefits in patients with acute cardiorenal syndrome when a well-managed pharmacologic approach provided equivalent clinical outcomes with fewer serious adverse effects.” He left hope that “a slower but steady ultrafiltration rate” might yet prove beneficial. Further, it is possible that aggressive therapy in order to reduce length of stay “may actually result in an increased incidence of the acute cardiorenal syndrome and cause unwanted consequences. Perhaps slow and steady may ultimately win the race after all.”
Click here to read the AHA press release…

RELAX-AHF Stirs Interest In Novel Drug For Acute Heart Failure Reply

by • Heart Failure • Tags: ,

A new drug modelled on a hormone active in pregnancy may prove beneficial to patients with acute decompensated heart failure. Serelaxin is a recombinant form of human relaxin-2, which is known to mediate the hemodynamic changes that occur during pregnancy. The drug is under development by Novartis for use in acute heart failure.

In the RELAX-AHF trial, 1,161 patients were randomized to serelaxin or placebo in the first hours of acute decompensated heart failure. Results of the trial, presented by John Teerlink at the American Heart Association in in Los Angeles and published simultaneously in the Lancet, have sparked considerable interest in the heart failure community, since few options have proven successful in this setting.

RELAX-AHF had co-primary endpoints. For the first primary endpoint, dyspnea relief  through day 5 (as measured by the visual analog scale area under the curve), serelaxin was associated with a statistically significant 19.4% improvement, resulting in a mean difference of 448 mm per hour (p=0.0075). The trial therefore reached the prespecfied criterion for efficacy. However, there were no significant differences in the other primary endpoint, dyspnea relief at 24 hours. There were also no significant differences in the secondary endpoints of cardiovascular death or hospital readmission for heart failure or renal failure through day 60.

At six months, however, cardiovascular deaths were significantly reduced in the serelaxin group:

  • 9.5% (55) in the placebo group versus 6% (35) in the serelaxin group (HR 0.63, CI 0.41-0.96, p=0.028, NNT = 29)

The investigators also reported that serelaxin was associated with significant reductions in the signs and symptoms of congestion at day 2, fewer patients with worsening heart failure, and the use of lower doses of IV diuretics.

The results, concluded the authors, “provide supportive evidence for a beneficial effect of serelaxin improving symptoms and other clinical outcomes in selected patients with acute heart failure.” The trial discussant, John McMurray, said that he believed serelaxin “does improve dyspnea and other symptoms and signs of congestion” but wondered about the clinical significance of the magnitude of the improvement and, also, whether the single trial would be sufficient to gain marketing approval.

A Surprising Reduction In Mortality

McMurray, along with trial investigators and other heart failure experts present at the AHA, expended considerable energy thinking about the reduction in mortality. The Lancet authors acknowledged that the findings of a six month survival benefit “for a drug given for 48 h with a moderate number of death events (107 total) raises the question of whether this benefit is due to chance and whether another, confirmatory trial should be done.” McMurray noted that if only two deaths had moved from one group to the other then the mortality finding would not have been significant.

But at an AHA news conference Milton Packer emphasized that “if the mortality effect is true then this trial changes the way we do things.” If confirmed, he said, it would mean that cardiologists would need to treat acute heart failure patients like ACS patients and deliver immediate treatment. Other heart failure cardioloigsts, including Mariel Jessup and Greg Fonarow, agreed that the mortality finding, if confirmed, would mean that serelaxin treatment would represent a genuine breakthrough in the treatment of acute heart failure. But, said Packer, ”the real question is whether the mortality difference seen in this trial is true and replicable.”

Click here to read the AHA press release…

BLOCK HF: A “Game Changer” For Cardiac Pacing 2

by • Heart Failure, Heart Rhythms • Tags: , ,

Editor’s Note: The following guest post is published with the permission of its author,  Edward J. Schloss, MD, (Twitter ID @EJSMD) the medical director of cardiac electrophysiology at Christ Hospital in Cincinnati, OH. Dr. Schloss was an investigator in the BLOCK HF trial.

In what has been described as a “game changer” for the field of cardiac pacing, the BLOCK HF trial was reported at today’s AHA Scientific Sessions showing benefit of biventricular pacing over conventional RV pacing in patients with AV block and LV dysfunction.

Since the development of pacemakers over 50 years ago, doctors have treated patients with AV block with right ventricular pacing. Until about 10 years ago, this was felt to be harmless and potentially beneficial.  Pacing algorithms were designed to force right ventricular pacing and create what was termed a “physiologic AV delay” in the hopes that controlling the timing of atrial and ventricular contraction would improve hemodynamics.

The DAVID trial, reported in 2003, turned the conventional wisdom upside-down, and first clearly showed the hazards of unnecessary RV pacing.  DAVID was designed with the hypothesis that dual chamber pacing in patients receiving ICDs without bradycardia indications would result in improved hemodynamics and therefore improved outcomes as compared to conventional backup ventricular pacing.  To the surprise of the investigators, the opposite proved true.  The group receiving dual chamber pacing had about a 40% increase in mortality and heart failure hospitalization as compared to the minimal pacing group over one year.  As this data was confirmed with additional trials, doctors moved to minimize right ventricular pacing in their patients and new minimal pacing algorithms were developed by industry.

Paralleling the movement to minimize right ventricular pacing, the technique of cardiac resynchronization therapy (CRT) for treatment of heart failure took off.  Here the benefit of pacing right and left ventricles together was established for patients with heart failure and evidence of dyssnchronous ventricular contraction.

The BLOCK HF trial was planned to test the hypothesis that biventricular pacing would be superior to right ventricular pacing in patients with left ventricular dysfunction and heart block requiring pacing.  Enrollment began in December 2003.

BLOCK HF enrolled patients indicated for ventricular pacing due to AV block who had at least mild LV dysfunction (LVEF <50% on optimal HF medical therapy) and NYHA functional class I-III.  All patients then received biventricular devices (pacer or ICD depending on clinical indication) and then were randomized in blinded fashion to conventional dual chamber (RA-RV) pacing vs. biventricular (RA-RV&LV) pacing.  Primary endpoint was the time to first event: total mortality, heart failure exacerbation requiring acute care or >= 15% increase in echocardiographic left ventricular end-systolic volume.

Enrollment and follow up continued with serial echoes and clinical assessments for over seven years with mean follow up just over three years.  The sample size was determined by a pre-specified adaptive statistical analysis that took into account the results of repeated interim analyses.  The study would complete for success, hazard or futility.  A total of 691 patients completed randomization and were included in the final analysis (with 102 exited or lost to follow up).  The study population was predominantly male with average age in 70s, and NYHA class II predominated.  LVEF was average 43% in the pacemaker group and 33% in the ICD group.

In the final analysis, biventricular pacing led to a 26% reduction in the combined endpoint of death, heart failure exacerbation or LV enlargement.  Excluding the echo endpoint, the clinical parameters remained favorable, with a 27% reduction in death or heart failure exacerbation.  The heart failure curves diverge early and remain parallel and the mortality curves diverge at about four years and continue to separate.

In last night’s investigator meeting, Dr. Anne Curtis, the study PI, called BLOCK HF a “game changer” that could lead to a new indication for biventricular pacing in patients with heart block and LV dysfunction.  She acknowledged the limitations of the trial including a high crossover rate (predominantly RV to BiV) and some missing echo data.  The very long follow up, however, could be interpreted as an advantage for the trial.

As an investigator in the trial, I was very eager to see this data and encouraged by the results.  The trial was slow to enroll with very long follow up and we were just happy to see it reach fruition.  Over the years, I’ve seen numerous patients develop heart failure after initiation of conventional pacing and it’s good to know that we may be able to prevent this if a new indication arises from the BLOCK HF data.

As in all trials, we will need to be cautious in the application of the data.  BLOCK HF should not spell the end for right ventricular pacing.  For those patients with normal LV function or those who get minimal ventricular pacing (such as sick sinus patients), conventional RV pacing is still appropriate and avoids the additional cost complexity and hazard of adding an LV lead.

ALTITUDE Autopsy Shows What Went Wrong With Aliskiren Reply

by • Heart Failure, Prevention, Epidemiology & Outcomes • Tags: , , , ,

In its short lifespan the direct renin inhibitor aliskiren (a.k.a., Rasilez or Tekturna) rapidly declined from being a highly promising, first-of-its kind drug to a major failure. The death blow was struck last December with the early termination of the ALTITUDE trial, after the data and safety monitoring committee found an increased risk in patients taking aliskiren. Now the final results of the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints have been presented at Kidney Week 2012 in San Diego and simultaneously published in the New England Journal of Medicine.

8,561 type 2 diabetics at high risk for cardiovascular and renal complications already receiving an ACE inhibitor or an angiotensin-receptor blocker were randomized to receive aliskiren or placebo. The primary outcome of a cardiorenal event (CV death, resuscitated death, MI, stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease or doubling of baseline creatinine) occurred more often in the aliskiren group, although this difference did not achieve statistical significance:

  • 18.3% for aliskiren versus 17.1% for placebo (hazard ratio, 1.08; 95% CI, 0.98-1.20; P=0.12).

A similar trend was observed for just cardiovascular outcomes:

  • 13.8% versus 12.6%, respectively (hazard ratio, 1.11; 95% CI, 0.99-1.25; P=0.09)

Compared with placebo, patients on aliskiren had lower blood pressure and a greater reduction in the urinary albumin-to-cretinine ratio. But there was also a significantly higher risk of hyperkalemia (39.1% versus 29.9%; P<0.001) and hypotension (12.1% versus 6.3%, p<0.001).

The authors concluded that the addition of aliskiren to standard therapy in high risk type 2 diabetics “is not supported by these data and may even be harmful.” The result of ALTITUDE, they write, “underscores the need to go beyond surrogate biomarkers and obtain risk-benefit data from clinical end-point trials to better inform clinical decisions.”

Novartis Announces Top Line Results For Phase 3 Trial Of New Acute Heart Failure Drug Reply

by • Heart Failure • Tags: , , , , ,

Novartis announced preliminary results from the RELAX-AHF trial, a phase 3 study of a novel drug, RLX030 (serelaxin), for patients hospitalized with acute heart failure. The company said the trial met one of its two primary endpoints in reducing dyspnea.

Novartis also reported a reduction in all cause mortality at 6 months. However, it should be noted that the predefined secondary endpoint on ClinicalTrials.Gov was mortality at 60 days, not 6 months. (CardioBrief has requested clarification from Novartis about this point.)

In the trial, 1,161 patients hospitalized with acute heart failure were randomized to placebo or an IV infusion of RLX030 for up to 48 hours.   By design, the trial had 2 primary efficacy end points measuring dyspnea,but only one of them reached statistical significance, according to the company.

The full results of RELAX-AHF are scheduled to be presented as a late-breaking clinical trial at the American Heart Association meeting in Los Angeles in November.

RLX030 is a recombinant form of the naturally occurring human hormone relaxin-2. The drug was originally developed by Corthera, Inc, which was acquired by Novartis in February 2010.
Click here to read the press release from Novartis…

News Briefs: Cholesterol Trends, AHA Late-Breakers, FDA Updates On Rivaroxaban And Heartware HVAD Reply

by • Heart Failure, Heart Rhythms, Interventional Cardiology & Surgery, MI/ACS, People, Places & Events, Prevention, Epidemiology & Outcomes • Tags: , , ,

Cholesterol Trends

The Centers for Disease Control issued a new report with the latest details about the prevalence of cholesterol screening and high blood cholesterol in US adults. Here is their summary of the key findings:

…cholesterol screening increased from 72.7% in 2005 to 76.0% in 2009, whereas the percentage of those screened who reported being told they had high cholesterol increased from 33.2% to 35.0%. Previously identified demographic disparities persist.

AHA Previews LBCTs

The American Heart Association has published a preview of the late-breaking clinical trials scheduled for presentation in November at the scientific sessions in Los Angeles. 28 LBCTs have been selected, including the NIH’s FREEDOM (Future REvascularization Evaluation in patients with Diabetes mellitus: Optimal management of Multivessel disease) trial and the controversial Trial to Assess Chelation Therapy (TACT).

J&J Provides More Information To FDA About Rivaroxaban

Johnson & Johnson said today that it had fully responded to the FDA’s request for more information about the use of rivaroxaban (Xarelto) in patients with acute coronary syndromes. The company also said it had resubmitted its supplemental New Drug Application (sNDA) for the drug to reduce the risk of stent thrombosis in ACS patients.

Heartware HVAD Close To FDA Approval

The Heartware HVAD ventricular assist system may be approved soon by the FDA, according to Wells Fargo analyst Larry Biegelsen. Robert Kormos, a cardiothoracic surgeon at the University of Pittsburgh, who also consults for Heartware,  said during a session at a Society of Thoracic Surgeons symposium that the device would be approved in the next few weeks.

Republished with permission from CardioExchange, a NEJM group publication.

ESC: Trial Finds No Benefit For Intraaortic Balloon Counterpulsation In Cardiogenic Shock 2

by • Heart Failure, Interventional Cardiology & Surgery, MI/ACS • Tags: , , , ,

Despite a lack of evidence, circulatory support with intraaortic balloon counterpulsation (IABP) has a class 1 recommendation in the guidelines and is often used in patients in cardiogenic shock following myocardial infarction for whom early revascularization is planned. That situation may change soon, as no benefit was found for the use of IABP in the first large trial of the strategy.

The IABP-SHOCK II (Intraaortic Balloon Pup in Cardiogenic Shock II) was presented at the ESC and published simultaneously in the New England Journal of Medicine. Trial investigators, led by Holger Thiele, randomized 600 acute MI patients in cardiogenic shock to either IABP or no IABP. At 30 days there were no significant differences in mortality, the primary endpoint of the study:

  • Mortality: 39.7% in the IABP group versus 41.3% in the control group (relative risk with IABP 0.96, CI 0.79-1.17, p=0.69)

There were no significant differences between the groups in secondary endpoints, process-of-care outcomes, or safety endpoints, including stroke and bleeding.

In an accompanying editorial, Christopher O’Connor and Joseph Rogers write that the trial “could have affirmed contemporary clinical practice and guidelines” but, “instead, it revealed surprising results.”

“Members of guidelines committees and clinicians should take note of another example of a recommendation that is based on insufficient data,” they wrote.

Click here to read an interview on CardioExchange with the principal investigator Holger Thiele.

Republished with permission from CardioExchange, a NEJM group publication.

First Detailed Look At Why Aliskiren Failed To Gain ALTITUDE 2

by • Heart Failure, Prevention, Epidemiology & Outcomes • Tags: ,

Last December the once-promising direct renin inhibitor aliskiren (Rasilez, Tekturna) suffered a fatal setback with the early termination of the ALTITUDE trial. The trial was stopped when the Data Monitoring Committee (DMC) found an increased risk for non-fatal stroke, renal complications, hyperkalemia, and hypotension in patients taking aliskiren after 18-24 months.

At the ESC in Munich ALTITUDE investigator Hans-Henrik Parving presented the first detailed but preliminary results from the trial, which compared aliskiren to placebo in 8,561 type 2 diabetics at high risk for cardiovascular and renal complications already receiving single RAAS blockade.

After 32 months of followup, the composite endpoint (CV death, resuscitated death, MI, stroke, unplanned hospitalization for heart failure, onset of end-stage renal disease or doubling of baseline creatinine) was not significantly different between the two groups, though Parving noted that the numbers went in the wrong direction for aliskiren, including a trend suggesting more strokes associated with the treatment drug:

  • Composite endpoint: 17.9% for aliskiren versus 16.8% for placebo (HR 1.08, 0.98-1.20, p=0.142)
  • Stroke: 3.4% versus 2.8%, HR 1.25 (o.98-1.60, p=0.70)

Aliskiren-treated patients also had higher potassium levels and were more likely to develop hyperkalemia, hypotension, and diarrhea.

Republished with permission from CardioExchange, a NEJM group publication.

Click here to read the ESC press release…

Risks and Benefits Of Pediatric Ventricular Assist Device Explored Reply

by • Heart Failure, Interventional Cardiology & Surgery

Few options besides extracorporeal membrane oxygenation (ECMO) have been available for children with systolic heart failure awaiting transplantation. Now a new report by Charles Fraser, Jr and colleagues published in the New England Journal of Medicine provides important new information about a ventricular assist device (VAD) designed for children.

Trial investigators implanted 48 patients with the Excor Pediatric  VAD (the Berlin Heart) and compared them to matched historical controls who had received ECMO. The VAD group was composed of two 24-patient cohorts based on body-surface area. Survival was dramatically and significantly longer in both VAD cohorts:

  • Cohort 1 (<0.7 m2):  median survival time had not been reached at 174 days in the VAD group, compared with 13 days in the ECMO group (p<0.001)
  • Cohort 2 (0.7 to <1.5 m2): 114 days versus 10 days (p<0.001)

However, VAD treatment was associated with clinically significant adverse events. Major bleeding occurred in 42% of cohort 1 patients and 50% of cohort 2 patients, infection in 63% and 50%, and stroke occurred in 29% of patients in both cohorts.

In an accompanying editorial, Linda Addonizio observes that the development of pediatric VADs has been markedly slower than the development of adult VADs, although “the potential number of years of life saved for each person is much greater for children.” However, because of the high rate of neurological complications she urges caution before “extending the current practice in adults of early implementation of ventricular assist devices to children.” VADs, she writes, “should remain, at present, a last resort in small children.”

Stem Cell Therapy Company Hypes Preliminary Results 3

by • Heart Failure, MI/ACS, Policy & Ethics • Tags: , ,

Update (July 6)–  I have heard from several investigators in the trial that the Osiris press release was issued without any input or consultation from the site investigators. In fact, the site investigators, including several who are  extremely experienced clinical trialists, have expressed frustration and disappointment because their input has not been sought at any point during the trial. In most multi-center trials it is common practice to consult with the sites, and in particular the top-enrolling sites. In this case, the highest enrolling sites have had no significant involvement in the trial design or conduct. One investigator said he “had never worked with a company like this.”

Another member of the steering committee told me that the committee had not met in a long time and has not seen the trial data. In fact, steering committee members were not even aware that Mark Vesely, an assistant professor at the University of Maryland, was the principal investigator of the study. One steering committee member said he’d never heard of him before reading the press release.

A biotech company has been accused of releasing preliminary and misleading information about a clinical trial. The company, Osiris Therapeutics, is the manufacturer of  a cultured mesenchymal stem cell therapy called Prochymal, which is being studied in a phase 2, placebo-controlled study in post-MI patients. Earlier this week Osiris issued a press release announcing preliminary results from the trial, in which 220 patients have been randomized, claiming that Prochymal “significantly reduces hypertrophy, arrhythmia and progression to heart failure in patients suffering a heart attack.” But Adam Feuerstein, a veteran biotech reporter for The Street, accuses the company of distorting the truth about the trial.

Osiris “disappeared” important data in its press release, Feuerstein writes in his detailed analysis of the press release. He quotes the press release:

Patients receiving Prochymal had significantly less cardiac hypertrophy, as measured by cardiac MRI, compared to patients receiving placebo (p [less than] 0.05). Patients treated with Prochymal also experienced significantly less stress-induced ventricular arrhythmia (p [less than] 0.05).

Feuerstein comments:

Sounds impressive except none of the Prochymal benefits disclosed by Osiris are predefined endpoints in the phase II trial.

Osiris appears to have thrown out the real endpoints called for in the phase II trial and replaced them with new endpoints which just happen to show Prochymal in the best light. Why would Osiris do this? Perhaps the pre-defined endpoints in the study all failed? That’s a pretty safe assumption when companies decide to swap out trial endpoints with no disclosure or explanation.

Feuerstein points out that the primary endpoint of the trial, as listed on Clinicaltrials.gov, is left ventricular end systolic volume (ESV), while the secondary endpoints are  left ventricular ejection fraction (LVEF), infarct size and major adverse cardiovascular events (MACE). Writes Feuerstein: “Osiris’ silence on the outcomes of these two important endpoints (ESV and LVEF) should be deafening to investors — and not in a good way.”

The Osiris press release also claims “a statistically significant reduction in heart failure”:

In the study, seven patients who were treated with placebo have progressed to heart failure requiring treatment with intravenous diuretics, compared to none of the Prochymal patients (p=0.01). Furthermore, patients receiving placebo tended to require re-hospitalization for cardiac issues sooner than the patients receiving Prochymal (median 27.5 days vs. 85.5 days).

However, as Feuerstein writes, “these weren’t predefined endpoints”:

Importantly, Osiris doesn’t disclose the time point at which these purported benefits occurred, nor does the company tell us anything about the number of patients analyzed. How was heart failure defined? Osiris doesn’t say. What was the baseline incidence of heart failure in the study? Osiris doesn’t say. The study only allowed for a single infusion of Prochymal or a placebo immediately after the first heart attack but patients were followed for six months or a year, so how do follow-up therapies in each arm of the study compare? Were they balanced? Again, Osiris doesn’t say.

In the press release a company official announces an extension of the trials duration:

Given the quality of the data and highly encouraging results observed thus far, we are extending the trial’s duration to capture a better understanding of the long-term clinical benefits of MSCs.”

But the company offers no explanation for the extension. Writes Feuerstein:

Perhaps Osiris is extending the phase II study to delay the reporting of negative results? Again, that’s a pretty safe assumption absent a better explanation.

Note: I’ve requested comments from Osiris and from several trial investigators.

Many CHF Patients Not Receiving– Or Getting Benefits From– High Dose ACE Inhibitors And ARBs Reply

by • Heart Failure • Tags: , , , , ,

Although current guidelines recommend that ACE inhibitors and angiotensin-receptor blockers (ARBs) be used in high doses in patients with congestive heart failure, many CHF patients currently receive lower than recommended doses of these drugs. In a research letter published online in Archives of Internal Medicine, investigators in Montreal analyzed data from 43,405 patients with a first hospital admission for CHF in Quebec, 73% of whom received an ACE inhibitor and 27% an ARB.

Patients were classified as receiving low-, medium- or high-dose drugs. 29% received a low-dose. The groups were not evenly matched: patients in the high dose group were more likely to have hypertension and diabetes, while patients in the low dose group were more likely to have renal disease.

After adjusting for other factors, the risk of dying or being readmitted to the hospital was significantly reduced in the high dose group. Here are the hazard ratios for ACE inhibitors and ARBs (medium dose serves as the reference):
Click to continue reading…

Company Fails To Disclose Details About Heart Failure Risk of Drug Reply

by • Heart Failure, Policy & Ethics, Prevention, Epidemiology & Outcomes

Boehringer Ingelheim failed to fully disclose data suggesting that one of its drugs, pramipexole,  a dopamine agonist sold under the brand name of Mirapex, is associated with a significantly increased risk of heart failure, according to a recent news report. The drug, which was originally developed for the treatment of Parkinson’s disease, is now also used to treat Restless Legs Syndrome.

Although cardiac failure was an adverse event observed during clinical trials with Mirapex, and is mentioned in the drug’s label, a more definite association had not been established in the literature until recently. According to Pharmalot’s Ed Silverman, however, Boehringer Ingelheim appears to have been aware of the stronger association previously but made no effort to publish or disseminate its findings.

A study published in Pharmacoepidemiology & Drug Safety found an increase risk of cardiac failure associated with pramipexole and another dopamine agonist, cabergoline. But buried in the text of the report lies evidence that the finding should not have come as a surprise to Boehringer. Silverman writes:
Click to continue reading…

WARCEF: No Advantage For Warfarin Over Aspirin In Heart Failure 1

by • Heart Failure • Tags: , , ,

A new study offers “no compelling reason” to use warfarin instead of aspirin in heart failure patients who don’t have atrial fibrillation. In a paper published in the New England Journal of Medicine, Shunichi Homma and members of the Warfarin versus Aspirin in Reduced Cardiac Ejection Fraction (WARCEF) study group report the results of a trial in which 2,305 patients with left ventricular dysfunction were randomized to warfarin or placebo and followed for up to six years.

No significant differences were observed in the primary endpoint (the composite of death, ischemic stroke, or intracerebral hemorrhage) or its individual components. Warfarin was superior to aspirin in reducing the rate of ischemic stroke, but this advantage was offset by an increased incidence of major hemorrhage in the warfarin group.

  • Primary endpoint: 26.4% for warfarin versus 27.5% for aspirin, HR 0.93, CI 0.79-1.10
  • Ischemic stroke: 1.8% versus 3.5%, HR 0.55, CI 0.32-0.96)
  • Major hemorrhage: 5.8% versus 2.7%, OR2.21, CI 1.42-3.47

The authors concluded:

Given the finding that warfarin did not provide an overall benefit and was associated with an increased risk of bleeding, there is no compelling reason to use warfarin rather than aspirin in patients with a reduced LVEF who are in sinus rhythm.

In an accompanying editorial, John Eikelboom and Stuart Connolly agree with the study authors that there is no justification for the “routine clinical use of warfarin in most patients with heart failure” but write that warfarin is still “most likely to benefit” heart failure patients with atrial fibrillation or with a history of cardioembolic stroke or formation of LV thrombus. They leave open the possibility that warfarin may also benefit heart failure patients with underlying coronary artery disease, and recommend that future studies of anticoagulants in heart failure focus on this population.