Snake Eyes | ESC 2014: Even Smart Science Doesn’t Always Win

Results do not always unfold as expected and can sometimes seem like the a roll of the dice, which makes clinical trials necessary and investigators essential to the news cycle of any major meeting. Here are some highlights from the 2014 meeting of the European Society of Cardiology, which was themed “Innovation and the Heart.”

Intravenous Iron Improves Functional Capacity, Quality of Life in HF Patients (CONFIRM-HF)

In people with heart failure (HF), iron deficiency has been associated with impaired functional capacity, poor quality of life (QOL), and increased mortality—irrespective of the presence of anemia. CONFIRM-HF was a double-blind trial that enrolled 304 stable, symptomatic HF patients from across nine European countries, who were randomized to iron (in the form of ferric carboxymaltose) or placebo given at baseline, 6, 12, 24, and 36 weeks.

Compared to placebo, dosing with intravenous iron resulted in a significant increase in 6-minute walk test (the primary endpoint), increasing distance walked from 33 to 42 meters (over 24 to 52 weeks), or roughly adding an additional 108-138 feet to distance wallked at baseline. There was also concomitant improvements in other measures of functional status and QOL.

Is this a meaningful symptomatic benefit? Professor Sanjay Sharma, MD, St. George’s University of London thinks it is. During the “Highlights of ESC 2014” program, which was broadcast online the day after the meeting ended, he said, “The benefit in quality of life and the difference in distance walked is enough for a patient to be able to walk from their bedroom to their kitchen to make a cup of tea—in people who may not have been able to do that.” This may not seem like much, but, he added, that’s “a huge benefit from just two injections” and was seen in 75% of patients. It sets the stage for an outcomes trial.

CONFIRM-HF investigator Piotr Ponikowski, MD, Medical University, Centre for Heart Disease, Wroclaw, Poland, added: “In clinical practice, we don’t bother at all about iron deficiency because this is a very poorly recognized comorbidity, though it affects half of the population regardless of their hemoglobin level. This trial shows that iron deficiency is an important comorbidity that we can detect using biomarkers—and once we detect it, we can treat it and improve exercise tolerance.”

(Simultaneously published in the European Heart Journal)

Inflammation Flames Out as Target in SOLID-TIMI 52

Well, two times is not a charm: this is the second large trial of darapladib (13,026 subjects this time) failing to show benefit for this compound, challenging the notion that inhibiting lipoprotein-associated phospholipase A2 (Lp-PLA2) offers a worthwhile approach in patients with coronary heart disease (CHD) or following an acute coronary syndrome (ACS) event.

Principal investigator Michelle O’Donoghue, MD, MPH, Brigham and Women’s Hospital, Boston, Massachusetts, said, “Conceptually, I think we all believe that inflammation plays a really crucial role in ACS. But the issue may be that inflammation is such a complex and redundant series of pathways that if you just zero in on too specific a target, there’s compensation along other pathways. Clearly, our findings do not support a strategy of targeted Lp-PLA2 inhibition with darapladib in patients stabilized after an ACS event.”

(Simultaneously published in JAMA.)

PARADIGM Shift—or PARADIGM Reiterated?

Let’s be honest, PARADIGM-HF was certainly the most talked-about trial at ESC 2014. And this from a drug that does not even have a generic name yet. LCZ696 consists of a neprilysin inhibitor (which itself, at least, has a name: sacubitril) and the angiotensin receptor blocker (ARB) valsartan. Neprilysin degrades several endogenous vasoactive peptides that are very beneficial when not being degraded: natriuretic peptides, bradykinin, and adrenomedullin. Successfully inhibiting neprilysin would increase the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling.

Combining inhibition of the renin-angiotensin system and neprilisyn should be superior to either approach alone. However, in clinical trials, the combination of neprilisyn and angiotensin-converting enzyme (ACE) inhibitors was associated with serious angioedema. Therefore, LCZ696 went a different direction, putting sacubitril together with the ARB valsartan. It worked.

One of the great names in ACE inhibition, Milton Packer, MD, University of Texas Southwestern Medical Center, Dallas, Texas, met the press at ESC to talk about the trial he coauthored (and published simultaneously in The New England Journal of Medicine): “The finding that LCZ696 had a greater than 20% effect on [lowering] cardiovascular mortality than an ACE inhibitor [enalapril] strongly supports the conclusion that LCZ696 should replace current use of ACE inhibitors and angiotensin receptor blockers in the management of chronic heart failure.”

Dr. Packer was not the only one to suggest this drug, which has been granted Food and Drug Administration (FDA) fast-track designation, will soon replace ACE inhibitors. In the “Best of ESC 2014” program, Frank Ruschitzka, MD, head of the Heart Failure and Transplantation Clinic at the University Hospital in Zurich, said, “I think there is no doubt that LCZ696 will revolutionize practice. It has been 27 years since CONSENSUS, in which Karl Swedberg introduced ACE inhibitors, and now he has been part of PARADIGM as well. What they did [in PARADIGM] is challenge the champion; they challenged ACE inhibitors and they won. Have you ever seen a p value with 7 zeros behind the comma? And to win on the real thing: mortality. It’s fantastic and truly a paradigm change.”

Dr. Packer told the press, “The magnitude of the effect of this drug on cardiovascular mortality was incredibly consistent across all subgroups and that was a very striking finding for us. We could not identify a subgroup of patients who did not benefit from treatment.”

It is also worth noting that the trial may not be so much a PARADIGM shift as a confirmation of the paradigm that established dual therapy as an ideal in much of cardiovascular medicine. In that light, the idea that combination therapy—even if it is with a new agent—might beat a gold-standard single agent seems, perhaps, a little less miraculous. But what’s the fun in that? Attendees at ESC were excited.

PCSK9 at ESC.14

The PCSK9 train keeps on rolling. The experimental Sanofi/Regeneron candidate, alirocumab, won the Hotline session race at ESC, with three Hotline sessions devoted to the drug’s phase III development program, called ODYSSEY. Amgen’s candidate PCSK9 inhibitor, evolocumab, won the Late-Breaker race at ACC.14, so it only seems fair.

ODYSSEY COMBO II enrolled patients at high cardiovascular risk who were already on maximally tolerated statins but still had dangerously high low-density lipoprotein cholesterol (LDL-C) levels. A total of 720 patients were randomly assigned in a 2:1 manner to subcutaneous alirocumab 75 mg every 2 weeks or ezetimibe 10 mg daily. In all three of the trials presented at ESC, alirocumab was self-administered using a prefilled 1 ml pen.

LDL-C was decreased 50.6% by alirocumab at 24 weeks versus a 20.7% decrease in the ezetimibe arm (p < 0.0001). These reductions were maintained at 52 weeks (–49.5% for alirocumab and –18.3% for ezetimibe). At week 52, the mean LDL-C level in the alirocumab arm was 53.3 mg/dl, compared to 85.3 mg/dl in the ezetimibe arm.

“We were very pleased to see this very robust LDL-lowering of 50% on top of the high-dose statin, and it seemed to be safe,” said principal investigator Christopher P. Cannon, MD, of Brigham and Women’s Hospital and Harvard Medical School.

Familial Hypercholesterolemia

Continuing the journey, ODYSSEY FH I and II evaluated the effect of self-administered alirocumab in 735 patients with heterozygous familial hypercholesterolemia (HeFH) whose LDL-C levels were inadequately controlled by statins and other lipid-lowering therapy. Active therapy—which was added on top of maximally-tolerated statin therapy—was associated with a near 50% reduction in LDL-C at 24 weeks compared to baseline.

Dr. Cannon told the press, “Certainly for cholesterol management, the idea of injection is foreign. But that was one of the big surprises to all of us: to see that patients really did self-injection. I think in part it was because cholesterol-lowering [with alirocumab] is so dramatic that they could see these results and say, ‘This seems to be worth it.’ So that has been a very pleasant surprise.”

Success at the End of a Long-ranging ODYSSEY?

After the mess with niacin—where the B vitamin greatly boosted high-density lipoprotein levels only to demonstrate little long-term effect on outcomes—the PCSK9 story has been one of guarded optimism.
ODYSSEY LONG TERM trial, the largest and longest trial of alirocumab to date, enrolled a mixed population of patients with either HeFH or at high-risk for cardiovascular disease (CVD) with LDL-C >70 mg/dl despite maximally-tolerated lipid-lowering therapy. About 18% of the trial enrollees had HeFH.

A total of 2,341 patients were randomized to alirocumab 150 mg or placebo at 320 clinical sites worldwide. LDL-C was reduced at 24 weeks by 61.0% with alirocumab compared with a 0.8% increase in the placebo arm (p < 0.0001). LDL-C was reduced from almost 120 mg/dl at baseline to just under 50 mg/dl, allowing fully 79% of the study population to achieve an LDL-C of <70 mg/dl (compared with 8% in the placebo arm; p < 0.0001) at 24 weeks.

With ~1,900 patient-years of double-blind exposure to alirocumab every 2 weeks, it appears that active therapy was associated with a lower rate of adjudicated major cardiovascular events: cardiac death, myocardial infarction, stroke, and unstable angina requiring hospitalization compared to placebo. (We use “appears” because this was a post-hoc safety analysis.)

In her presentation of the LONG TERM results, Jennifer G. Robinson, MD, MPH, from the University of Iowa, took pains to note that there is no hint across all of the ODYSSEY data collected to date of any significant increase in neurocognitive events, a concern which has plagued the drug class in the past, but has now been pretty well put to rest.

Dr. Robinson said, “We need outcomes trials to validate these data and to establish the long-term safety of these drugs added to statins. But this trial shows us that we are on the right track using the PCSK9 inhibitors—in this case alirocumab—to further reduce cardiovascular events in people receiving maximal statin therapy.”

 “Less is More” May Apply to Ablation for Atrial Fibrillation

In the largest randomized trial to examine outcomes of ablation in persistent atrial fibrillation (AF; N = 589), patients with persistent AF were randomized to either pulmonary vein ablation (PVA) alone, PVA plus ablation of atrial regions of the heart that produce abnormal electrograms, or PVA plus ablation of linear lesions in the left atrium.

Atul Verma, MD, Southlake Regional Health Centre, Newmarket, Ontario, Canada, said, “The more complex ablation procedures took almost an hour longer with about 33% more X-ray exposure for both operator and patient. And yet they offered absolutely no increased benefit over the more minimal procedures. If anything, the more minimal procedures had a better outcome, although the differences were not statistically significant.”

But Maybe More is More with Revascularization

There is primary PCI (PPCI) and now preventive PPCI (which we hope does not get abbreviated PPPCI). The issue: whether or not to target non-culprit lesions while the interventionalist is nearby working on opening the infarct-related artery (IRA). Preventive PPCI is not recommended in current guidelines, mostly owing to a lack of evidence with respect to the value of this strategy. Maybe the CvLPRIT trial offers a good start to answering that question.

Prior to treatment with PPCI, 296 patients in the United Kingdom were randomized to either IRA-only revascularization or complete revascularization of both the IRA as well as all non-IRAs shown to be significantly blocked.

Study author Anthony Gershlick, MD, University Hospitals of Leicester, NHS Trust, Glenfield Hospital, United Kingdom, concluded: “CvLPRIT demonstrated a 55% reduction in MACE in those patients presenting for primary PCI when their non-infarct-related artery was also treated on the index admission. I would suggest that this strategy may need to be considered by future STEMI guideline committees.” 

Pre-hospital Ticagrelor Drowns in ATLANTIC

Pre-hospital administration of anti-clotting agents such as fibrinolytics or glycoprotein IIb/IIIa inhibitors has been associated with improved coronary reperfusion and better outcomes in ST-elevation myocardial infarction (STEMI) patients. However, in this multicenter, double-blind study of 1,862 patients with an ongoing STEMI, a loading dose of 180 mg ticagrelor in the ambulance was safe but not superior to treatment upon hospital arrival. One explanation: pharmacodynamics and electrocardiogram findings suggested that the maximal effect of prehospital administration of ticagrelor occurred after the end of the procedure. Which may help explain the finding that rates of definite stent thrombosis were lower in the prehospital group versus the in-hospital group at both 24 hours (0% vs. 0.8%; p = 0.0008) and 30 days (0.2% vs. 1.2%; p = 0.02).

Gilles Montalescot, MD, PhD, Institut de Cardiologie of Pitié-Salpêtriėre Hospital, Paris, France, said, “This was a kind of ‘world-record’ in terms of the timing of the transfer of patients in this study. What we observed was the effect of ticagrelor after PCI on platelet function and on stent thrombosis, as most of the events occurred within the first 24 hours.”  Despite it being clearly a negative trial, Dr. Montalescot said that this approach is safe and, because it may reduce long-term outcomes, consideration should be given to initiating ticagrelor as early as possible.

(The ATLANTIC trial was simultaneously published in The New England Journal of Medicine.)

Have Pleiotropic Effects of Statins Crossed the River STICS?

Small randomized trials had suggested that perioperative statin therapy might prevent in-hospital complications after cardiac surgery. However, in 1,922 patients undergoing elective cardiac surgery, there was no benefit to rosuvastatin 20 mg daily—starting up to 8 days before surgery and continuing until the 5th postoperative day—compared to placebo. That included no benefit for the co-primary outcomes (new-onset AF or serum levels of troponin I) or secondary outcomes (including length of hospital stay, major in-hospital cardiac or cerebrovascular events, left ventricular function, and plasma creatinine).

Barbara Casadei, MD, DPhil, John Radcliffe Hospital, University of Oxford, United Kingdom, put no spin on it when presenting the results to the media covering ESC: “There are many reasons why these patients should be put on statin treatment, but the prevention of postoperative complications is not one of them. I don’t want this message to get mixed up with the need to treat these patients with a statin for the long-term effects of lowering LDL cholesterol. But for short-term effects, I think this is the end of the discussion around the pleiotropic effects of the statins in terms of having an impact on clinical outcomes.”

After the data were presented at an ESC Hotline Session, panel member Steve Nissen, MD, chairman of the Department of Cardiovascular Medicine at the Cleveland Clinic, matched Dr. Casadei in frankness: “There is a lesson here—a terribly important lesson: the power of self-delusion in medicine. When we base our guidelines on these small, poorly controlled trials, we are often making mistakes. And this is one of a number of examples of where, when someone finally does a careful, thoughtful trial, you find out that something that people believed just isn’t true. We can’t cut corners with evidence. We need good randomized controlled trials.”

New Polypill Increases Adherence Following MI

Adherence to therapy makes a big difference in outcomes: it’s hard for therapy to work when it’s not taken. Contributing to poor adherence is the complexity of treatment and the daily number of prescribed pills. The idea of using a polypill for CVD prevention has gained increasing momentum because it could increase adherence and maybe contain disease progression.

By using a simple pill count, investigators found that 92% of patients in the polypill group were adherent compared with only 84% in the group assigned to separate drugs.

Valentin Fuster, MD, Mount Sinai Hospital, New York City and now editor-in-chief of JACC, told the press, “FOCUS 1 showed us that the main five factors impeding adherence to cardiovascular medications include depression, social support, availability of insurance, complexity of treatment, and English.” (Or, more precisely, English-speaking health care professionals talking to non- or limited-English-speaking patients.)  “FOCUS 2 showed us that, compared with three drugs taken separately, the use of a polypill significantly increased adherence. These results suggest that the polypill has the potential to prevent more patients having a second heart attack.”

(The study is published online in the Journal of the American College of Cardiology.)

Rivaroxaban for AF Patients Undergoing Cardioversion

In the absence of specific evidence, many physicians have begun switching to the novel, non–vitamin K oral anticoagulants, like rivaroxaban, in AF patients undergoing cardioversion. Good news: this time, jumping the gun was not a bad idea.

X-VeRT is the first prospective, randomized trial to examine the safety and efficacy of rivaroxaban compared with vitamin A antagonist (VKA) therapy in patients undergoing elective cardioversion for the treatment of AF. The pharmacological characteristics of rivaroxaban might be particularly useful in this setting because it has a rapid onset of action—within 2-4 hours—that could expedite cardioversion.

The study included 1,504 patients scheduled for either electrical (almost 98%) or pharmacological cardioversion. Using established guidelines, patients were assigned to either early or delayed cardioversion. Compared to treatment with a VKA, rivaroxaban was associated with an overall 50% reduction in the risk of cardiovascular events and a 24% lower risk of major bleeding, the primary safety outcome. (While not powered for statistical significance, it was thought this large a trial still would give clinically meaningful information.)

X-VeRT’s Co-principal investigator Riccardo Cappato, MD, University of Milan, Italy, said, “Many physicians are already switching to novel oral anticoagulants despite the absence of any information about their use. So we thought that bringing this methodologically sound information would provide more consistent evidence for those who are doing this anyway and a little bit more evidence for those who may be reluctant to use the novel oral agents.”

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