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September 1st, 2014

Selections from Richard Lehman’s Literature Review: September 1st

CardioExchange is pleased to reprint this selection from Dr. Richard Lehman’s weekly journal review blog at BMJ.com. Selected summaries are relevant to our audience, but we encourage members to engage with the entire blog.

NEJM 21-28 August 2014 Vol 371

Aortic-Valve Stenosis — From Patients at Risk to Severe Valve Obstruction (pg. 744): If you are looking for a good clear summary of aortic valve stenosis, and have access to full text of the NEJM, this is the one to go for. I well remember a patient with aortic valve disease who refused surgery because his symptoms were mild although his pressure gradient was critical. He finally agreed but went into crashing heart failure while waiting for surgery. He didn’t make it. AS gets quite common as we age. Most of it is harmless, but the only way to know is to get an echo.

Cardiovascular Risk and Events in 17 Low-, Middle-, and High-Income Countries (pg. 818): More epidemiology, this time a survey of Cardiovascular Risk and Events in 17 Low, Middle, and High Income Countries, good for poring over on a wet afternoon. You need to pore a bit to try and understand the paradox that emerges from this enormous data analysis: “Although the risk factor burden was lowest in low income countries, the rates of major cardiovascular disease and death were substantially higher in low income countries than in high income countries.” The authors put this down to better treatments for risk factors in high income countries, but I am not convinced. In a sense, this is a validation study of the INTERHEART Risk Score, which proves that it is not predictive of real outcomes in whole populations.

JAMA 20-27 August 2014 Vol 312   

Recognizing Worsening Chronic Heart Failure as an Entity and an End Point in Clinical Trials (pg. 789): Twenty years ago, when I was new to the wonderful world of heart failure trials, I can remember arguing with a keen young researcher about hospitalization as an end point. Surely, I said, rates of hospitalization vary hugely between systems and within systems, and are to a major extent driven by the adequacy of support systems within primary care. I’ve been making this point ever since and thought nobody was listening. Those three mighty cardiologists, Javed Butler, Eugene Braunwald, and Mihai Gheorghiade certainly weren’t listening, because I’ve never been near them, but in this piece they make exactly the same point. Make “worsening chronic heart failure” a primary end point for HF trials, not hospitalization.

Effect of Self-monitoring and Medication Self-titration on Systolic Blood Pressure in Hypertensive Patients at High Risk of CVD (pg. 799): Who is the best person to monitor blood pressure? It’s a no-brainer really. TASMIN-SR was a primary care, unblinded, randomized clinical trial involving 552 patients who were aged at least 35 years with a history of stroke, coronary heart disease, diabetes, or chronic kidney disease, and with baseline blood pressure of at least 130/80 mm Hg being treated at 59 UK primary care practices. And it showed that self-monitoring with self-titration of antihypertensive medication, compared with usual care, resulted in lower systolic blood pressure at 12 months. A great study, but just a start. Now we need to see how people might choose their own treatments based on absolute risk reduction.

JAMA Intern Med August 2014

How Cardiologists Present the Benefits of PCIs to Patients With Stable Angina (OL): COURAGE, mes amis. People with chronic stable coronary disease do just as well on maximal medical treatment as after revascularization procedures. Putting stents in the pipes does not prevent more infarcts than taking pills. This is what the COURAGE trial taught us in 2007. But seven years later, one third of PCIs in America are still being done for stable CAD. This is the first of three papers exploring the problem. In 40 observed consultations, “Few cardiologists discussed the evidence based benefits of angiogram and PCI for stable CAD, and some implicitly or explicitly overstated the benefits.”

The Effect of Information Presentation on Beliefs About the Benefits of Elective PCI (OL): So that’s what cardiologists do when qualitative researchers are watching. What do the patients themselves think? The next study examines the effect of “explicit and explanatory information on participants’ beliefs about PCI and their willingness to choose it.” This was a big trial, but the 1257 participants who completed the questionnaire did not have CAD. They were simply asked to think about three scenarios in which they experienced class I angina and were referred to a cardiologist. “In the setting of mild, stable angina, most people assume PCI prevents MI and are likely to choose it. Explicit information can partially overcome that bias and influence decision making.” So the question left hanging in the air is how we can best bring this explicit information to people who are about to make a real life decision, in such a way as to change the practice of cardiologists who often have a financial interest in unnecessary angiography and PCI.

Patient Selection for Diagnostic Coronary Angiography and Hospital-Level Percutaneous Coronary Intervention Appropriateness (OL): Because there’s no doubt that when cardiologists do an angiogram and see a stenosis, they itch to put in a stent. This is called the “oculostenotic reflex,” and its existence is proved by an observational study of 544 US hospitals. “In a national sample of hospitals, performance of coronary angiography in asymptomatic patients was associated with higher rates of inappropriate PCI and lower rates of appropriate PCI.” COURAGE, mes chers amis cardiologiques. Have the boldness to ignore the narrowing and remember the evidence. Even better, have the boldness not to do an angiogram in the first place.

Lancet 23-30 August 2014

Pulse Oximetry with Clinical Assessment to Screen for Congenital Heart Disease in Neonates in China (pg. 747): Several studies over recent years have shown that pulse oximetry in the neonatal period can help to detect congenital heart disease. This one comes from Shanghai and its message to the authorities is clear: “Pulse oximetry plus clinical assessment is feasible and reliable for the detection of major congenital heart disease in newborn babies in China. This simple and accurate combined method should be used in maternity hospitals to screen for congenital heart disease.” Cut to picture of enormous postnatal ward with a hundred cots containing tiny babies with little clips on their fingers.

The BMJ 23 August 2014 Vol 349

Use of Clarithromycin and Roxithromycin and Risk of Cardiac Death: One reason you should never prescribe clarithromycin to people at high cardiovascular risk is because such people should all be taking statins, which can cause fatal rhabdomyolysis with clarithromycin. But that applies to all macrolides. Another reason is that clarithromycin itself seems to increase cardiac death even in seven day courses, compared with the closely similar roxithromycin. This emerges from a huge Danish database study, and makes you wonder if clarithromycin should now be withdrawn, given the number of safer alternatives.

September 1st, 2014

New Support For Complete Revascularization During Primary PCI

Until recently, MI patients receiving emergency PCI would only have the culprit artery opened. Complete revascularization of non-infarct-related arteries was performed later. The conventional wisdom was that revascularization of non-infarct-related arteries could be dangerous. That wisdom began to change last year with the PRAMI trial, which found no evidence of harm and a suggestion of benefit in MI patients who underwent more complete revascularization.

Now a new study presented at the European Society of Cardiology meeting in Barcelona delivers additional support to the more liberal use of total revascularization during initial treatment. The CvLPRIT (The Complete versus Lesion-only Primary PCI Trial) was an open-label, randomized study comparing treatment of the infarct-related artery (IRA) only with complete revascularization in 296 acute MI patients.

At 12 months, there was a large and statistically significant reduction in the incidence of major adverse cardiac events in the group randomized to complete revascularization. Each of the endpoint components was also numerically lower in the complete revascularization arm:

  • MACE: 21.2% in the IRA arm versus 10% in the complete revascularization arm, HR 0.45, CI 0.24-0.84, p=0.009
  • Mortality: 4.1% versus 1.3%, HR 0.32, ).06-1.60, p=0.14
  • Recurrent MI: 2.7% versus 1.3%, HR 0.48,, 0.09-2.62, p=0.39
  • Heart failure: 6.2% versus 2.7%, HR 0.43, 0.13-1.39, p=0.14
  • Repeat revascularization: 8.2% versus 4.7%, HR 0.55, 0.22-1.39, p=0.2

The benefits of complete revascularization emerged shortly after the index procedure and were apparent in the prespecified subgroups, including the number of significantly affected vessels, sex, and age.

The authors were encouraged by the fact that hard events were reduced in similar proportion to the softer endpoint of repeat revascularization. The result “suggests this strategy may need to be considered by future STEMI guideline committees,” they said.

The previous PRAMI trial had been criticized because of some trial design issues, said CvLPRIT investigator Anthony Gershlick. “As a result, PRAMI has not led to widespread changes in clinical practice, with IRA-only revascularization at P-PCI remaining by far the more common practice.”

In an interview, Eliot Antman said that he was particularly struck by the apparent lack of harm in the complete revascularization group, since it has been the fear of causing harm that has been the main reason not to perform more complete revascularization. Because of the small size of the trial and the small number of events, he was unsure whether the trial would be enough to change current guideline recommendations.

 

To view all of our coverage from the ESC meeting, go to our ESC.14 Headquarters page.

August 31st, 2014

Entrusting Imaging to Robotic Hands: The Potential of Remote Echocardiography and Tele-Consultation

CardioExchange’s Harlan M. Krumholz interviews Dr. Jagat Narula about his two collaborative, remote, robot-assisted echocardiographic technology studies and the potential applications worldwide. The study is published in the August issue of JACC-Imaging.

Krumholz: Could you please briefly tell us the highlights of your paper?

Narula: Two studies were published as the iConcepts in the August issue of JACC-Imaging. The iConcepts section publishes pilot reports of the technology that is on the verge of clinical translation. In the first study, the Mount Sinai-based investigators performed a robot-assisted, trans-Atlantic ultrasound examination on a person in Boston. A small, lightweight robotic-arm with built-in ultrasound technology was stationed in Boston from Munich. The robotic ultrasound exam of the patient’s carotid artery was completed in just four minutes. This feasibility and time-efficiency of long-distance, telerobotic ultrasound may help expand the role of imagers to care for patients online, virtually lending a true ‘helping hand’ remotely and providing a patient’s care with team expert guidance. The second study in collaboration with Umeå University in Sweden showed how a cardiologist’s video e-consultation, coupled with a remote, robot-assisted echocardiogram test, could dramatically reduce the waiting time for a diagnosis faced by heart failure patients who live in a rural communities far from the hospital. Remote consultation and the robotic echocardiogram exam were conducted on the same day of a patient’s visit to their local Primary Healthcare Center located more than 100 miles away from the hospital. Study results show the total diagnostic process time was significantly reduced from 114 to 27 days in those patients receiving remote consultation. Also, the patient’s wait time until obtaining a specialist consultation was reduced from 86 to 12 days, with 95 percent of remote consult patients claiming remote consult to be a superior strategy.

Krumholz: How much does this machinery cost?

Narula: These are experimental systems under development; no realistic cost is available at this time.

Krumholz: Why not just teach people to scan and then send images?

Narula: Yes… a very logical suggestion. We have recently submitted a research proposal for the training of high school students who desire voluntary service in low- and middle-income countries (LMIC). They could record requisite views and beam them to a central station for interpretation. This would allow triage of patients who need to be transported to the hospital. Such trainees could be designated as Hubots or Human Robots.

Krumholz:  Is this going to be a way that we get such technology to LMICs?

Narula: The two studies give us a glimpse of what to expect in the near future, and may serve as a model for use of e-consults and robotic imaging in far flung areas to improve global access to specialists and the latest diagnostic technology. This technology is more for developed nations and can provide convenient service in distant areas to selective patient groups such as the senior citizens. Furthermore, such on-demand, virtual robotic ultrasound could be used in a wide variety of clinical settings ranging from timely in-hospital or emergency room patient imaging studies, community screenings, or even within more demanding locations such as war zones.

Join the discussion: How could this technology benefit your practice, if it were made readily available? Does the future of medical imaging technology lie in the field of robotics?

August 31st, 2014

Preliminary Outcomes Results For PCSK9 Inhibitor

Amid a slew of new data demonstrating yet again that PCSK9 inhibitors lower LDL cholesterol—drastically and in a wide variety of different patient populations—data from one trial offers the first suggestion that the drugs may in fact improve cardiovascular outcomes. But the analysis, the authors cautioned, is a post-hoc analysis of a trial neither designed nor powered to study outcomes, so should be considered preliminary and speculative at best.

Four phase 3 trials with the Sanofi and Regeneron PCSK9 inhibitor alirocumab (pronounced “allee rock you mab” by Chris Cannon at a news conference) were presented today at the European Society of Cardiology meeting in Barcelona. The outcomes data was derived from the ongoing Odyssey Long Term trial, which is evaluating the long-term safety and efficacy of alirocumab in 2,341 high risk patients already taking statins and other lipid-lowering therapies. The results of Odyssey Long Term were presented by Jennifer Robinson.

In the post-hoc safety analysis, after a mean followup of 65 weeks the rate of cardiac death, MI, stroke, and unstable angina requiring hospitalization was 1.4% in the alirocumab group compared to 3% in the placebo group. This is the same composite endpoint that is being used in the ongoing 18,000 patient ODYSSEY Outcomes trial. In total there were 46 endpoint events. In the panel discussion following the trial’s presentation, Robert Califf urged caution when interpreting data like this with less than 100 events. Until the completion of the large outcomes trial, Califf said, it will be “a tough question” for regulators to decide how to handle this information.

Alirocumab was generally well tolerated. The company had previously disclosed that the FDA had asked about the potentially serious issue of neurocognitive disorders associated with alirocumab. The rate of events in Odyssey Long Term of neurocognitive disorders was 1.2% in the alirocumab group versus 0.5% in the placebo group.  A Regeneron spokesperson said that the company has not released the overall pooled analysis across 10 phase 3 trials, but that “it was balanced between groups.”

As expected, alirocumab was highly effective at lowering LDL cholesterol. At 24 and 52 weeks, LDL was reduced by 61% and 57%, respectively, in the alirocumab group compared with a 1% increase and a 4% increase in the placebo arms. These differences were of course highly significant.

Three additional trials helped confirm the cholesterol-lowering effectiveness of alirocumab. In the ODYSSEY COMBO II trial, 720 patients at high risk despite maximally-tolerated statin therapy received either alirocumab or ezetimibe. At 24 weeks, Chris Cannon reported, LDL was reduced by 51% in the alirocumab group versus 21% in the ezetimibe group.

In the ODYSSEY FH I and FH II trials, alirocumab was tested in 738 patients with heterozygous familial hypercholesterolemia. At 24 weeks, according to Michel Farnier, LDL cholesterol was reduced by 49% in each of the the alirocumab groups, compared to a 9% increase and a 3% increase in the placebo groups.

In his remarks, Califf likened the Odyssey trials to the World Cup. Odyssey Combo is equivalent to a successful qualifying match, the Odyssey FH trials are like quarterfinal matches, and Odyssey Long Term is like a semifinal match. But only the final match—the Odyssey Outcome trial—will be able to produce a true winner, said Califf.

A spokesperson said Amgen and Regeneron planned to file for approval in the US and elsewhere in the fourth quarter of 2014.

 

To view all of our coverage from the ESC meeting, go to our ESC.14 Headquarters page.

August 31st, 2014

SIGNIFY Trial Provokes Sound and Fury Over Controversial Drug

The already controversial drug ivabradine just got a little more controversial. The drug, which is marketed by Servier under the brand names of Corlentor and Procoralan, is available in Europe and elsewhere and is used for the treatment of heart failure and stable angina. The drug is not available in the U.S., but it is under development by Amgen for a heart failure indication.

Now a very large new study presented at the European Society of Cardiology meeting in Barcelona and published simultaneously in the New England Journal of Medicine has found no evidence of benefit in a stable angina population. It instead found more adverse events associated with the drug, and even suggested the likelihood of harm in a very large and important trial subgroup. The findings have resulted in an investigation by the European Medicines Agency, placing a cloud over the future status of the drug.

In SIGNIFY (Study Assessing the Morbidity-Mortality Benefits of the If Inhibitor Ivabadine in Patients with Coronary Artery Disease) 19,102 patients who did not have heart failure and who had stable coronary artery disease and a heart rate of at least 70 bpm were randomized to ivabradine or placebo.

After 27.8 months of followup, there was no overall difference in the primary endpoint (the composite of cardiovascular death or nonfatal MI), which occurred in 6.8% of the ivabradine group and 6.4% of the placebo group (HR 1.08, CI 0.96-1.20, p=0.20). There were also no significant differences in any other significant outcomes of interest, though there was a trend toward more heart failure hospital admission in the ivabradine group (2.3% versus 1.9%, p=0.07).

After three months of treatment, the mean heart rate fell from 77 to 60 in the ivabradine arm and from 77 to 70 in the placebo arm. This difference was maintained throughout the study.

The study drug was discontinued in 20.6% of patients in the ivabradine group versus 14.5% in the placebo group. In the ivabradine group, asymptomatic bradycardia was the leading cause for discontinuation. There were significantly more adverse events in the ivabradine group than in the placebo group: 73.3% versus 66.9% (p<0.001), including symptomatic bradycardia (7.9% versus 1.2%), asymptomatic bradycardia (11% versus 1.3%), atrial fibrillation (5.3% versus 3.8%) and phosphenes (5.4% versus 0.5%). Serious adverse events occurred in 37.6% versus 35.4% (p=0.0001).

 A Really Big Subgroup

The results were similar across subgroups, with one very large and important exception. Placebo was significantly better than ivabradine in the large (12,049 patient) subgroup of patients who had class II or higher angina. In this subgroup, a primary endpoint event occurred in 7.6% of the ivabradine group versus 6.5% of the placebo group (HR1.18, CI 1.03-1.35).

The authors speculated about the reasons for the finding that ivabradine did not benefit their patient population. It may be that decreasing the heart rate too much is harmful, they said. “It is also possible that heart-rate reducing antianginal agents have no effect on outcomes in patients with stable coronary artery disease.”

The difference in outcomes between the stable angina population of SIGNIFY and the heart failure population of SHIFT “may reflect the fact that an elevated heart rate is due to different pathophysiological mechanisms in these two conditions.” In particular, they pointed to the presence of neurohormonal activation in heart failure and its absence in stable angina. They further noted that the dose used in SIGNIFY was higher than the dose used in SHIFT, the pivotal heart failure trial.

In an accompanying editorial, E Magnus Ohman and Karen Alexander discuss the “surprising finding” in the large subgroup of patients with CCS class II or higher angina. “Although this is a subgroup of an overall neutral trial, it is a group of more than 12,000 patients, who were studied where the therapy is approved and in use outside the United States.”

Where ivabradine is available, they advise physicians to “exercise caution among patients with more severe forms of angina and to consider adjusting beta-blocker doses to effective levels before initiating ivabradine.” Almost 60% of patients in the SHIFT trial received inadequate beta-blockade, and most of the benefit associated with ivabradine in that study was found in people who could not take beta blockers or who were taking low doses of beta blockers. But, they acknowledge, “whether this holds true for patients with angina is unknown, but this cautious approach may be reasonable until we understand this finding better.”

A Cloudy Future

Currently ivabradine has a 2a recommendation in the ESC guideline for treating stable angina. The ESC provided the following response to my request for a clarification about the status of that guideline:

The ESC will await the results of the detailed European Medicines Agency (EMA) review before deciding whether it is necessary to update the recommendations regarding ivabradine in the 2013 ESC guidelines on the management of stable coronary artery disease.

Previous ivabradine studies have demonstrated impressive efficacy in the treatment of chronic stable angina, with no safety or tolerability issues identified that were a cause for concern. It is important to note that some patients in the SIGNIFY study received a dose of ivabradine higher than the currently licensed maximum daily dose. This higher ivabradine dose is not the dose mentioned within the 2013 ESC guidelines on the management of stable coronary artery disease.

Any questions relating to the process or timings of the EMA investigation should be directed to the EMA.

 

To view all of our coverage from the ESC meeting, go to our ESC.14 Headquarters page.

August 30th, 2014

ESC.14 Headquarters

CardioExchange is dedicated to bringing you the latest from ESC.14. Check out our coverage of the conference here at CardioExchange and don’t forget to tell us what you think!

News:

Analysis:

August 30th, 2014

Will There Be a PARADIGM Shift in Treatment of Heart Failure?

and

CardioExchange’s Harlan M. Krumholz interviews John J.V. McMurray and Milton Packer, the two lead authors of the PARADIGM-HF trial. The industry-funded randomized trial, comparing angiotensin–neprilysin inhibition with enalapril, is published in The New England Journal of Medicine.

Read CardioExchange’s news coverage of the trial, including a summary of the findings.

Krumholz: On a 1 to 10 scale, how likely is it, given what we know so far, that in 5 years this will be the main way we treat patients with heart failure and depressed systolic function in countries that can afford the medication?

Packer: I would say 9 to 10 that angiotensin-receptor neprilysin inhibition will be the cornerstone of treatment for patients with chronic heart failure and a reduced ejection fraction, replacing the current use of ACE inhibitors and angiotensin-receptor blockers.

McMurray: Cost is key. If this is affordable, it will be used as commonly as beta-blockers are now — 90%. This will be a class I, LOE A guideline recommendation.

Krumholz: What was most challenging about the trial?

Packer: The most challenging aspect of the trial was to design it in a way that, as a single trial standing on its own, it would be compelling enough to convince physicians to switch from a class of drugs that they have been using comfortably for 25 years.

McMurray: There were a few bumps along the road, but nothing too major. Early termination and rapid publication were quite challenging!

Krumholz: Given the relatively young age of your cohort (64 years) and that heart failure is most common in older populations, how should clinicians think about whether this trial is relevant to their patients, many of whom are not well represented in this study?

Packer: The trial recruited a very highly representative group of patients. As noted by Dr. Jessup in her NEJM editorial, the patients in this trial were quite comparable to those in other trials that changed clinical practice. Patients who were very elderly in this trial responded just as well as younger patients. Furthermore, many very elderly patients who have heart failure have a preserved ejection fraction, and these are being studied in a new trial with the acronym PARAGON.

McMurray: We had a sizeable subset of older patients, and the treatment benefit was consistent across subgroups.

Krumholz: Briefly explain for our members how you think this drug produces the observed effect.

Packer: This drug simultaneously decreases the influence of a maladaptive system (the renin-angiotensin system) while enhancing the influence of endogenous peptides that have favorable adaptive effects on the circulation. No other drug for heart failure has ever addressed the deficient response to adaptive factors (natriuretic peptides, bradykinin, adrenomedullin), which is characteristic of patients with heart failure.

McMurray: The incremental benefit was presumably due to the effect of neprilysin inhibition added to renin-aldosterone system blockade. Neprilysin inhibition augments natriuretic peptides and probably other vasoactive substances (including bradykinin). We believe that these other substances are beneficial in heart failure patients.

 

JOIN THE DISCUSSION

Join Dr. McMurray and Dr. Packer in reflecting on the findings from PARADIGM-HF.

To view all of our coverage from the ESC meeting, go to our ESC.14 Headquarters page.

August 30th, 2014

PARADIGM-HF Establishes a New Paradigm for Heart Failure Treatment

So far as I can tell the only problem with PARADIGM-HF is that the results are so good that it’s boring. Anyone interested can reasonably assume that what they hear or read about PARADIGM-HF — and cardiologists will be seeing and hearing an awful lot about it —  will be overwhelmingly positive.

Briefly, the trial did everything its sponsor (Novartis) and its investigators (led by Milton Packer and John McMurray) hoped. It met all its major endpoints in all the subgroups without raising any sort of a safety signal. If the findings are confirmed after a rigorous FDA review, then Novartis will likely have a blockbuster on its hand.

All the excitement is over a new drug still known only by its number, LCZ696. It consists of the well-known angiotensin receptor blocker valsartan and a novel compound, the neprilysin inhibitor sacubitiril. Inhibition of neprilysin is intended to held reduce the neurohormonal activation that helps drive common heart failure (HF) processes like vasoconstriction, sodium retention, and remodeling. This specific combination was designed, according to the authors, to avoid angioedema, a side effect which doomed a similar earlier drug, omapatrilat, which combined an ACE inhibitor and a neprilysin inhibitor.

Results of the trial were presented today at the European Society of Cardiology meeting in Barcelona and published simultaneously in the New England Journal of Medicine.

A total of 8,442 HF patients with reduced ejection fraction (EF) were randomized to enalapril or LCZ696. The study was stopped early, though enrollment in the trial had been completed, following an interim analysis performed by the data and safety monitoring committee, which found “that the prespecified stopping boundary for an overwhelming benefit had been crossed.”

After a mean followup of 27 months, LCZ696 was superior to enalapril in most of the major outcomes. There were significant reductions in the primary endpoint (the combination of cardiovascular death or hospitalization for HF), the individual components of the endpoint, all-cause mortality, and HF symptoms:

  • The primary endpoint was reduced by 20%, from 26.5% in the enalapril group to 21.8% in the LCZ696 group (HR 0.80, CI 0.73-0.87, p<0.001)
  • Cardiovascular death was also reduced by 20%, from 16.5% to 13.3% (HR 0.80, 0.71-0.89, p<0.001
  • Hospitalizations were reduced by 21%, from 15.6% to 12.8% (HR 0.79, 0.71-0.89, p<0.001)
  • Deaths (from any cause) were reduced by 16% from 19.8% to 17%

There was also a highly significant improvement in quality of life but there were no significant differences in the onset of new atrial fibrillation or in renal function.

The authors calculated that over the course of the trial 21 patients would need to have been treated with LCZ696 instead of enalapril to prevent one primary outcome event. The number needed to treat to prevent one cardiovascular death was 32.

LCZ696 was effective across the entire spectrum of prespecified subgroups, including age, race, sex, geographic region, NYHA class, diabetes status, and prior drug use. The benefits of LCZ696 were displayed early in the trial, and occurred in a population well treated with other proven therapies including beta-blockers and mineralocorticoid-receptor antagonists.

Overall LCZ696 was well tolerated. A total of 17.8% of LCZ696 patients and 19.8% of enalapril patients discontinued treatment during the course of the study. Significantly more LCZ696 patients developed hypotension, though this did not normally require drug discontinuation. By contrast, enalapril was associated with significantly more cough and increased serum creatinine and potassium levels.

Angioedema occurred in 19 LCZ696 patients and 10 enalapril patients. No patients had their airway compromised. Three LCZ696 patients and one enalapril patient required hospitalization for angioedema.

The authors wrote that the benefits of LCZ696 were “highly significant and clinically important, even though the drug was compared with a dose of enalapril that has been shown to reduce mortality, as compared with placebo.” The study “was designed to provide persuasive evidence to support the replacement of ACE inhibitors or ARBs with LCZ696 in the management of chronic heart failure. The trial was devised to show an advantage with respect to cardiovascular mortality alone, which was the primary determinant of the sample size and for which a statistically compelling effect was required to stop the trial early because of a benefit.”

In an accompanying editorial, Mariell Jessup said the results should be broadly applicable to the large population of people with mild to moderately severe HF, since the patients studied in the trial were similar to those in previous large, influential trials. She pointed out that although the systolic blood pressure on treatment was lower by 3.2 mm Hg in the LCZ696 arm, the investigators “propose that this difference in blood pressure was not a determinant of the salutary benefits of LCZ696.”

The trial, Jessup concluded, “may well represent a new threshold of hope for patients with heart failure” and “may apply to a wide spectrum of patients, even those who are currently receiving the best possible therapy.”

Uncharacteristically, Sanjay Kaul was quite upbeat: “At long, long last, a winner!” He said the trial “appears to have met all endpoints.” It was “reasonable” to truncate the trial since it was based on “a statistically persuasive effect on CV death as well as the primary endpoint.” Since the reduction in cardiovascular deaths was evident across subgroups, the drug “can be potentially recommended across a broad swath of heart failure patients.”

Kaul — remembering past instances (most notably ATLAS ACS-TIMI 51) of seemingly successful trials that were then torpedoed at the FDA — did insert one note of caution, but remained optimistic: “Unless there are issues with regards to trial conduct and data ascertainment (which can only be addressed during rigorous FDA review), I think we might at long, long last have a winner in this therapeutic space!”

The Co-Principal Investigator 

In an interview, Packer said that the trial “turned out better than we thought,” though he also stated, emphatically, that the investigators always had ambitious goals for a trial with an active treatment for a comparator. “We said upfront that we wanted to look for a 15% incremental effect — above and beyond enalapril. We chose that number because enalapril had a 15% effect over placebo and our goal was to double the effect. We thought if we came in with an extraordinary p value it would be convincing.”

Packer said that he believes the trial results are generalizable to the larger HF population in the U.S. with low EFs. Asked about the apparent low rate of ICDs in the study, at least compared to the U.S. rate, Packer explained that this sort of problem is inevitable in a large international trial in 47 countries, where ICD usage is often lower than in the U.S. He pointed out that LCZ696 was equally effective in the U.S. and elsewhere. Packer also agreed with Jessup that patients in the trial were not younger than in previous trials. Unlike the heart failure with preserved ejection fraction (HFPEF) population, which is largely composed of older patients, the low EF population is fairly represented in PARADIGM-HF, Packer said.

Clinical trial experts will likely focus their questions on the possible effects of stopping the trial early, thereby perhaps accentuating a temporary finding and preventing a natural regression to the mean. Packer pointed to several lines of evidence suggesting that this was not the case. For one, the effect size was constant throughout the trial. There was no temporary bubble that coincided with a single view by the DSMB. In addition, said Packer, the effect size has actually grown larger since the trial was stopped in March. Finally, the statistical power was robust because, despite the early termination, the number of cardiovascular deaths at the time was actually larger than the original target that had been used to determine the trial’s sample size.

Packer said he was also confident the trial would withstand the scrutiny of the FDA. “We look forward to the FDA digging in to their heart’s content.” He said he’s not seen any sign of the types of problems that the FDA has uncovered in the past. The very high statistical significance of the trial bolsters his confidence. “If you’re sitting on a p value of .03 you need to worry. With our p value we have a very big buffer.” (Clinical trial junkies will appreciate Packer’s pride in the success of the authors in persuading the NEJM editors to go beyond  the “p<0.001” for the primary endpoint and to include in brackets the full p value with 7 zeroes after the decimal point.)

Finally, Packer talked about the commercial impact of LCZ696, which is likely to be expensive compared to the generic ACE inhibitors and ARBs that it is meant to replace. “If you have a drug that saves lives, keeps people out of the hospital, and reduces symptoms, and is better than the cornerstone of therapy, and in patients who are already receiving the other best therapies, what is that worth? That is not for me to say, but it has to be worth something.”

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For more of our ESC.14 coverage of late-breaking clinical trials and interviews with the authors of the most important research, check out our ESC.14 Headquarters.

August 28th, 2014

Predicting PARADIGM-HF, or What to Expect When You’re Expecting

This blog also appears on Forbes.com.

The wait is almost over. For the last 5 months the most eagerly awaited trial in the cardiovascular universe has been PARADIGM-HF, the large (8,500 patient) trial of a new and novel heart failure drug from Novartis. If reality lives up to the early hope and hype, the drug, LCZ696, could completely reshape the heart failure landscape and give Novartis that rarest of gems, a new and genuine blockbuster cardiovascular drug.

The main results of the trial will first be presented at a press conference in Barcelona, Spain this Saturday in connection with the annual meeting of the European College of Cardiology. As I have previously reported, the PARADIGM-HF trial was stopped because of a highly statistically significant reduction in cardiovascular mortality in patients taking LCZ696 (a novel, first-in-class Angiotensin Receptor Neprilysin Inhibitor) instead of the current gold standard of treatment, an ACE inhibitor.

Until we see the data it is impossible to reach any conclusions, but, as might be expected, Wall Street analysts have been reading the tea leaves and trying to figure out likely outcomes.

One analyst, Timothy Anderson of Sanford Bernstein, remains cautious, despite “investor excitement” over comments made by the company and the co-principal investigator of PARADIGM-HF, Milton Packer. He noted that Novartis “has sometimes overpromised and underdelivered,” so he’s waiting to see the results. He currently thinks LCZ696 could reach annual sales of 2.4 billion in 2020. His estimates could grow if the results of PARADIGM are extremely impressive. Currently, according to Anderson, “analysts’ opinions are jelling around a high teens to 20%” reduction in the primary endpoint of cardiovascular death and heart failure hospitalizations.

“This would be viewed as meaningful—anything more would be fantastic,” said Anderson. Of course the analysts, along with everyone else, will also be looking at other issues like safety and tolerability, including, especially “any red flags about angioedema,” which ruined a similar BristolMyers Squibb drug, omipatrilat, some years ago.

One striking feature of the current situation is that LCZ696 stands alone. Anderson is unaware of any other similar drugs in mid or late phase development. On the one hand, this may be good for Novartis. “The runway is very clear for a very long time,” said Anderson. On the other hand, Novartis won’t benefit from the combined effect—seen with both ACE inhibitors and ARBs in the past—of multiple companies working to develop the market. Efforts “to supplant” the very well established ACE inhibitors and ARBs will require “a paradigm shift… that could take a long time to take into effect.”

Another analyst, Larry Biegelsen at Wells Fargo, wrote that PARADIGM-HF is “arguably the most important heart failure drug trial in almost 25 years.”

Morgan Stanley analysts calculate that Novartis’s stock price now assumes expected peak sales of LCZ696 of more than $5.5 billion. To achieve these sales the drug “would need to be used in ~75% of the eligible patient population.” Morgan Stanley then surveyed cardiology key opinion leaders (KOLs). In order to replace ACE inhibitors as the standard of therapy, they said the trial would need to show at least a 25% relative risk reduction in the primary endpoint and at least a 20% reduction in cardiovascular death.

The Morgan Stanley survey also notes that KOLs (and, surely, plain old cardiologists as well) will be just as interested in the absolute differences between the two treatment arms, as reflected in the number needed to treat, or NNT, as in the relative risk reductions. The KOLs said an NNT of 25-30 would encourage a shift to LCZ696.

Novartis has told analysts that LCZ696 could become the biggest product in the company’s history. The current record holder is Diovan (valsartan), which had peak sales of $6 billion.

One thing we know for certain: I’ve been told by a reliable source that LCZ696 will not gain a new name at the ESC. For now we’re stuck with this awkward moniker.

August 25th, 2014

Rise in Popularity of E-Cigarettes Sparks Concerns and Recommendations

The recent dramatic rise in popularity of e-cigarettes threatens to reverse hard-fought progress in the war against smoking, according to a new policy statement from the American Heart Association. “E-cigarettes have caused a major shift in the tobacco-control landscape,” said the lead author of the statement, Aruni Bhatnagar, chair of cardiovascular medicine at the University of Louisville.

But the AHA did not completely reject the use of e-cigarettes as an aid to stop smoking. The  statement notes that although the evidence is “sparse” some studies have suggested that e-cigarettes may be equal to or better than nicotine patches to help to quit smoking. The AHA continues to recommend that physicians encourage “proven smoking-cessation strategies as the first line of treatment” but also states that “clinicians should not discourage” e-cigarettes when other methods to quit smoking have failed or when patients want to use e-cigarettes “to help them quit.”

The AHA is especially concerned about the impact on minors of e-cigarettes. The statement expresses “concerns that these products may be another entry point for nicotine addiction among young people.” These concerns are supported by a new study from the CDC published in Nicotine and Tobacco Research that shows a recent tripling in the number of youths who had never smoked a cigarette but who used e-cigarettes, from 79,000 in 2011 to 263,000 in 2013. The AHA wants “strong new regulations to prevent access, sales and marketing of e-cigarettes to youth.”

The AHA reaffirms its position that “e-cigarettes that contain nicotine are tobacco products and should be subject to all laws that apply to these products.” The AHA is also in favor of laws that ban or restrict “the intense marketing and advertising of e-cigarettes,” flavoring of e-cigarettes, and the use of ads utilizing celebrities.

Although e-cigarettes produce fewer toxic substances than cigarettes, the AHA says that “non-smokers may be exposed to nicotine. Unregulated e-cigarettes could potentially turn back the clock to the days when smoking in public was normal behavior, undoing years of work on smoke-free laws and hampering current enforcement.”

Tim McAfee, the Director of CDC’s Office on Smoking and Health, said: “We are very concerned about nicotine use among our youth, regardless of whether it comes from conventional cigarettes, e-cigarettes or other tobacco products. Not only is nicotine highly addictive, it can harm adolescent brain development.”