Shuffling the Deck: Studies Deal Surprises– and More than a Few Curiosities

The 2014 American Heart Association meeting included a number of clinically important presentations, including several failing to find support for some standard practices. So many negative trials have gathered attention recently that new rules are being considered that would require more such data be available freely to the public.

Here’s a collection of some of the most interesting items from this meeting.

DAPT Beyond 1 Year Wins in Large Study

The optimal duration of dual antiplatelet therapy (DAPT) has been the subject of considerable debate in the last couple years. Supporters of longer-term use got a big shot in the arm from the results of the DAPT Study.

Study participants (about 10,000 total from 11 countries) who took aspirin plus a thienopyridine (clopidogrel or prasugrel) for 30 rather than 12 months after stenting were half as likely to develop in-stent thrombosis than patients who received DAPT for 12 months, followed by aspirin plus placebo for 18 months (placebo group), and had about half the risk of a new myocardial infarction (MI) compared to the placebo group.

Kirk Garratt, MD, Lenox Hill Heart and Vascular Institute, New York City, said in a press conference, “Thirty months of treatment with prasugrel plus aspirin was associated with important reductions in major adverse cardiovascular and cerebrovascular events and stent thrombosis compared to 12 months of treatment, with no signal of truly dangerous bleeds being increased with longer therapy.”

He added, “Withdrawal of prasugrel at 12 months was associated with an important increase in the risk of ischemic events early after drug discontinuation, the principal risk being myocardial infarction and the impact of drug withdrawal was evident within 90 days of drug cessation.”

The study’s principal investigator and lead author, Laura Mauri, MD, said DAPT “was the first and only study comparing durations of treatment with antiplatelet therapy that was adequately powered to detect a benefit on stent-related heart attacks.” The study enrolled “a broadly inclusive population treated with coronary stents.” Dr. Mauri, who is an interventional cardiologist at Brigham and Women’s Hospital and chief scientific adviser at the Harvard Clinical Research Institute in Boston, Massachusetts, added, “Overall the benefits of longer therapy were very consistent throughout the types of patients we studied, and outweighed the risks.”

Shorter-term DAPT Sometimes May Be a Safe Bet

At AHA.14, there were two trials from Europe addressing the same issue. In one trial of about 2,000 patients, 6 months of DAPT was noninferior to 24 months after percutaneous coronary intervention (PCI) with one of the second-generation drug-eluting stents (DES). Martine Gilard, MD, PhD, Brest University Hospital, France, said, “ITALIC shows that the rates of bleeding and thrombotic events were not significantly different between 6 and 24 months of DAPT after PCI with new generation DES and that 6 months of DAPT was non-inferior to 2 years of DAPT in good aspirin responders.”

There are some caveats, including a very low overall event rate. The primary endpoint was all-cause death, MI, stroke, target vessel revascularization, or major bleeding, which occurred in just 1.5% of patients receiving 24 months of DAPT versus 1.6% of those undergoing 6 months of DAPT. Stent thrombosis occurred in none of the patients in the longer-term therapy arm versus three (0.3%) in the 6-month arm (NS).

The ISAR-SAFE results were also presented, evaluating 6 versus 12 months of clopidogrel therapy post-DES. “The results of the trial must be considered in the context of its premature termination and lower-than-expected event rates,” said Stephanie Schulz Schupke, MD, Deutsches Herzzentrum Munchen, Germany. A planned, blinded interims analysis showed much lower than expected overall event rates. This, along with slow recruitment, induced the data safety monitoring board and the study steering committee to terminate recruitment at a sample size of 4,000 patients.

One important take-away from all three trials: very little major bleeding. In the German study, 6 months of clopidogrel was associated with a TIMI major bleeding rate of 0.2% versus 0.3% with 12 months of clopidogrel. In ITALIC, there was no major bleeding in the 6-month DAPT arm versus 0.3% with 24 months of DAPT. In the DAPT Study, GUSTO (Global Use of Strategies to Open Occluded Arteries) severe bleeding was higher but not significantly more common with longer-term thienopyridine use (0.81% vs. 0.56%; p = 0.15).

IMPROVE IT: Ezetimibe/Statin Combination Better After ACS Statin Alone

It has been a decade since Christopher Cannon, MD, Brigham and Women’s Hospital, Boston, Massachusetts presented the game-changing PROVE IT–TIMI 22 results at ACC.04 comparing intensive versus moderate lipid lowering with statins after acute coronary syndrome (ACS). Now, he is the lead author of IMPROVE-IT.

“This is the first trial to demonstrate an incremental clinical benefit when adding a non-statin cholesterol-lowering agent to a statin,” he said, “and we found that even lower was even better, reaffirming the LDL hypothesis that reducing LDL cholesterol prevents cardiovascular disease.”

IMPROVE-IT enrolled 18,144 patients with ACS and low-density lipoprotein (LDL) cholesterol levels <125 mg/dl or <100 if they were already using a statin. (About 5,000 had an ST-elevation MI and 13,000 a non-ST-elevation MI.) Patients also had at least one feature putting them at high risk for a further cardiovascular event, including a previous MI, diabetes, peripheral artery or cerebrovascular disease, coronary disease in multiple arteries, or bypass surgery in the past.

Compared to patients given simvastatin plus placebo, those receiving both simvastatin and ezetimibe had a 6.4% lower risk of all cardiovascular events (FIGURE), a 14% lower risk of MI, a 14% lower risk of stroke, and a 21% lower risk of ischemic stroke. There was no significant difference in mortality over the nearly 6 years of follow-up, with some patients followed for up to 8.5 years.

“The study affirms the central role of intensive LDL reduction in the prevention of recurrent cardiac events and expands the options for additional proven lipid-lowering therapies,” according to Neil Stone, MD, Northwestern University School of Medicine, Chicago, Illinois.

BiV vs. RV Pacing: BLOCK HF Cost Analysis

The BLOCK HF Trial explored whether cardiac resynchronization therapy (CRT) was superior to conventional pacing in patients with conventional indications for pacing, left ventricular dysfunction, and NYHA (New York Heart Association) class I-III heart failure. Although controversial (including concerns of selection bias), CRT seemed to be the superior approach in the patients studied.

Investigators now report the cost-effectiveness of biventricular (BiV) vs. right ventricular (RV) pacing in BLOCK-HF. Predicted life expectancy in the “All-Patient” analysis was 6.78 years with RV devices and 7.52 with BiV ones (a 10.8% increase). More BiV patients were predicted to remain in, or improve to, Classes I/II. In the “All-Patient” analysis, BiV offered patients 0.41 more Quality-Adjusted Life Years (QALYs) compared to RV, at an additional cost of $12,537 (Incremental C-E Ratio “ICER” $30,860.16/QALY Gained).

They conducted “what-if?” analyses to show cost variations based on several device-related variables. Asking what if there was LV lead dislodgement rates or what if we account for different battery longevities indicated that such issues had a material impact on ICERs, but they still remained below the $50,000/QALY (“acceptability threshold”).

Within the clinical co-variate subgroups of the “All-Patient” analysis, the highest ICER observed was $43,687.59 (for NYHA Class I Patients). Within the device-based subgroups, BiV-D patients were projected to benefit more (0.84 years gained) than BiV-P ones (0.49 years).

The data suggest that BiV reduces healthcare utilization rates compared with RV, offering survival benefits and slowing HF progression. The authors concluded, “The additional cost associated with offering BiV devices to patients with AV block and systolic dysfunction appears justified by the expected benefits across both device types.”

Door Remains Ajar for RAS Inhibition for Hypertrophic Cardiomyopathy

According to the researchers, the double-blind, randomized INHERIT trial “did not demonstrate an effect of losartan on left ventricular mass compared to placebo in patients with overt hypertrophic cardiomyopathy and there was no effect on maximal wall thickness, connective tissue in the heart wall, exercise capacity or ability of the heart to relax.”

Despite the negative trial results, Euan Ashley, MD, PhD, Stanford Center for Inherited Cardiovascular Disease, Palo Alto, California, said INHERIT doesn’t close the door on renin-angiotensin system (RAS) blockade in hypertrophic cardiomyopathy: “It may be that a drop of 12 g/m2 was an ambitious aim in this study and I certainly don’t think these findings close the door on the idea of blocking the renin-angiotensin-system for therapeutic benefit in this disease.”

When 1 + 1 = A Bad Idea for Mitral Regurgitation

Another disappointment: Surgical treatment of moderate ischemic mitral regurgitation (MR).

About half of MIs are associated with some degree of ischemic MR and 10% of MIs are associated with moderate ischemic MR. Given that ischemic MR is associated with reduced event-free survival, the 2014 guidelines state that MV repair may be considered for patients with chronic moderate secondary MR (stage B) who are undergoing other cardiac surgery (Class IIb, LOE: C).

The Cardiothoracic Surgical Trials Network randomized 301 patients to either coronary artery bypass graft surgery (CABG) alone or CABG plus mitral valve repair, with outcomes measured at 6, 12, and 24 months. According to Robert Michler, MD, Montefiore Medical Center, Albert Einstein College of Medicine, New York, based on 1-year follow-up, “This trial did not demonstrate a clinically meaningful advantage to the routine addition of mitral repair to CABG for patients with chronic moderate ischemic mitral regurgitation and it was associated with more neurologic events, increased pump times, and longer ICU and hospital lengths of stay.”

It should be noted that the primary endpoint was not a clinical endpoint, but rather the degree of left ventricular (LV) reverse remodelling as measured by changes in LV end-systolic volume index. (A trial with a mortality endpoint would require several thousand patients and multiple years of follow-up.)

One glimmer of hope: There was a lower incidence of moderate or severe MR at 1 year in those who had both procedures. The question: will this translate into a net clinical benefit for patients at 2 years?

Save the Imaging: Screening for CAD in Patients with Diabetes Fails

Given the added risk of diabetes in patients with coronary artery disease (CAD), it surely makes sense to see whether routine screening for CAD by cardiac computed tomography angiography (CCTA) in higher-risk patients with diabetes but no signs or symptoms of cardiovascular disease (CVD) improves upon guidelines-directed optimal diabetes care.

“Among asymptomatic patients with type 1 or type 2 diabetes, screening for coronary artery disease by CCTA did not reduce the composite rates of all-cause mortality, non-fatal MI, or hospitalization for unstable angina at 4 years despite differential use of coronary interventions and favorable trends in lipids and blood pressure,” said Joseph Muhlstein, MD, University of Utah, Murray.

The good news is that aggressive risk-factor management works. Despite finding moderate-to- severe CAD in one of every five study participants as well as a high Agatston score in four out of 10 asymptomatic patients with diabetes mellitus, the event rates in both arms were low, approximately 0.5% annual rate of MI.

Dr. Muhlstein said the results reinforce the importance of aggressive risk factor and lifestyle modification in these patients. Pamela Douglas, MD, Duke Clinical Research Institute, Durham, North Carolina, agreed: “Nationally, fewer than 10% of diabetics are at goal for all cardiovascular prevention targets and this means there is a tremendous gap for risk reduction outside of the clinical trial population which is perhaps the largest message from this trial.”

Dementia in Patients on Chronic Antiplatelet/Anticoagulant Therapy

Although the mechanism is not clear, patients with atrial fibrillation (AF) are at higher risk of developing all forms of dementia. Investigators evaluated 1,031 patients on aspirin plus chronic warfarin therapy (target international normalized ratio [INR] of 2-3) who were managed by the Intermountain Healthcare Clinical Pharmacist Anticoagulation Service (CPAS). The study patients had AF but no history of dementia or stroke/transient ischemic attack.

Percent time with an INR above 3.0 was determined and the primary outcome was the presence of dementia defined by neurology determined using ICD-9 codes. After adjusting for traditional stroke and bleeding risk factors, patients who had abnormally slow blood clotting times—INRs >3—on 25% or more of their monitoring tests were more than twice as likely to be diagnosed with dementia than patients whose tests showed overtreatment <10% of the time. The increase is higher than what had been previously reported in patients on warfarin alone.

According to T. Jared Bunch, MD, lead author of the study and director of electrophysiology at the Intermountain Medical Center Heart Institute in Murray, Utah, “Even at skilled centers, it’s very common to have INR outside the ideal range up to 40% of the time, and over the years there may be an accumulative negative impact on cognitive ability.”

No Magic in Disappearing Polymer

Biodegradable/bioresorbable technologies disappoint in two new studies. In large vessel stenting, biodegradable-polymer drug-eluting stents (BP-DES) were developed to be as effective as second-generation durable-polymer drug-eluting stents (DP-DES) and just as safe, beyond 1 year, as bare-metal stents (BMS), thus effectively eliminating very late stent thrombosis (VLST).

The BASKET-PROVE II (BASKET PROspective Validation Examination II) trial randomized nearly 2,300 patients presenting with acute or stable coronary disease to biolimus-A9-eluting BP-DES, second-generation everolimus-eluting DP-DES, or thin-strut silicon-carbide-coated BMS. After 2 years, the investigators concluded that BP-DES appeared “barely noninferior” compared to DP-DES (p for noninferiority = 0.042) (FIGURE). BP-DES was more effective than thin-strut BMS, but without evidence for better safety nor lower VLST rates beyond 1 year.

The findings challenge the concept that durable polymers are key in very late stent thrombosis formation.

The news was no better for the 291 patients in the EVOLVE study comparing the SYNERGY bioabsorbable polymer everolimus-eluting stent (EES) with the durable polymer PROMUS Element. The SYNERGY stent was noninferior to the Promus Element EES stent for target lesion failure at 1 year. Procedural, angiographic, and clinical outcomes comparable between stents in a “more comers” population than the original study (>60% ACS, >25% MI, 31% diabetes; smaller vessels, longer lesions, ≥75% AHA/ACC B2/C lesion morphology). However, despite the study population’s clinical and angiographic complexity, definite/probable stent thrombosis rates were low and similar.

The news is not that that the newer polymers don’t work; rather, the headline here is likely that second-generation stents are so good that it’s going to be hard to do any better for now.

Oxygen vs. Air: Air Wins

When a patient suffering a possible MI is routinely given oxygen, the patient in that mask looks sick, but will the oxygen actually make them better than breathing normal air? There is evidence supporting and refuting the current practice of providing oxygen to all patients with an acute MI, but a recent summary of clinical trials suggested that oxygen may increase the degree of heart damage during a heart attack. The problem is that supplemental oxygen became so routine so quickly that there have been few trials actually looking at the value of oxygen in our world of modern medicine.

The AVOID (Air Versus Oxygen In myocarDial infarction) trial was designed to determine if the withholding of routine oxygen therapy in patients with acute MI reduces heart damage compared to the current practice of routine inhaled oxygen for all patients.

Turns out, routine supplemental O2 is something to AVOID. In this trial, when used in patients with ST-elevation MI but without hypoxia, supplemental oxygen increased myocardial injury, recurrent myocardial infarction, and major cardiac arrhythmia, and was associated with larger myocardial infarct size assessed at 6 months. And breathe... just breathe.



Doing Better, But Late Presenters Remain a Challenge

In contemporary practice, a modest proportion of ST-elevation MI patients continue to present >12 hours after symptom onset. Using data from the ACTION Registry-Get With the Guidelines (GWTG), Sharma et al. evaluated 9,389 patients (5.5%) who had late presentation and 160,858 (94.5%) who had timely presentation. Late presenters were more frequently elderly, female, and of non-white ethnicity. Late presenters were less likely to have prior MI or prior revascularization, but more likely to have diabetes.

One potential price of delay: compared with timely presenters, late presenters had worse in-hospital outcomes including mortality (6.3% vs. 5.2%; p <0.0001). Over the 6-year study period, the proportion of late presenters decreased slightly (5.8 vs. 5.4%; p = 0.03), while the proportion of late presenters undergoing primary PCI increased from 65% to 71% (p <0.001).

Congrats, You Hit Your Goals; So, Why the MI?

Goals are great, but the gold star you get for reaching them is no shield against events. Or is it? Again investigators used the ACTION Registry-GWTG to analyze 443,117 acute MI patients from January 2007 to November 2013.

Among participants without prior CVD or diabetes, only 14% were classified as high risk by the Framingham Risk Score. At presentation, 67% of MI patients had LDL at goal, 67% had non-HDL at goal, 64% were not current smokers, and 65% of patients with prior CVD were on aspirin.

What gives? Well, while two-thirds of patients looked good when analyzing individual risk factors, overall risk factor control prior to MI was sub-optimal: only 36% of patients met all four risk factor control metrics. Remembering the guidelines in place during the period studied (Adult Treatment Panel [ATPIII]), overall statin eligibility prior to MI was 61% but only 61% of statin-eligible patients were receiving them. In contrast, in an exploratory analysis utilizing the 2013 ACC/AHA guidelines, statin eligibility prior to MI presentation was estimated to be 90%. So the investigators concluded that among patients presenting with acute MI who did not have diabetes or prior CVD, few would be classified as high risk and many would not have met ATP III statin eligibility criteria prior to MI. These findings support both the need for more liberal treatment thresholds as recommended in the 2013 AHA/ACC guidelines as well as greater adherence to existing prevention targets.

NCDR Cath-PCI Registry®

Beta-blockers Questioned for Stable Angina Patients After PCI

In patients with prior MI or systolic heart failure (HF), beta-blockers improve long-term outcomes. Investigators evaluated all consecutive patients with stable angina undergoing elective PCI from the NCDR Cath-PCI Registry between 2005 and 2013.

Do beta-blockers have a place in treating stable angina patients? Among the study population of 755,215, 71% patients were on beta-blockers. Those most likely to be discharged on beta-blockers: females and patients with hypertension, complex PCI, LV ejection fraction <60 %, prior PCI, prior HF, higher body mass index, and those with periprocedural complications. Those less likely to receive beta-blockers at discharge were patients with chronic lung disease, a successful procedure, peripheral artery disease, elderly (> 65 years) and diabetics.

Parikh et al. found no significant differences in short- (30 days) or long-term (3 years) outcomes between the two groups, except for a higher rate of subsequent HF hospitalization [HR: 1.18, (p <0.01)] associated with use of beta-blockers. They concluded that the utility of beta-blockers in this population needs to be further investigated.

NCDR ICD Registry

Sex and the Single CRT (or ICD)

There is a significant underutilization of cardiac resynchronization therapy (CRT) and use of implantable cardioverter-defibrillators (ICDs) among women compared to men. However, women do not seem to benefit from primary prevention ICD therapy to the same extent as men; the opposite is true for CRT, where women appear to have a better response than men in terms of reduced numbers of hospitalizations and more robust reverse ventricular remodeling. Importantly, the differences are not explained by differences in baseline characteristics. Indeed, in terms of magnitude of benefit from CRT, the greatest benefit is seen for females, wider QRS, left bundle branch block (LBBB), and nonischemic cardiomyopathy.

Some of what we know about this topic is the result of a recent analysis by Robbert Zusterzeel, MD, whose meta-analysis of US Food and Drug Administration patient-level data was published in the August 2014 issue of JAMA Internal Medicine (2014;174:1340-8). At AHA, he reported an evaluation of NCDR ICD Registry data between 2006 and 2010 to compare data for patients receiving CRT with defibrillator capability (CRT-D) and those receiving ICDs.

He and his colleagues assessed 75,079 patients with up to 5 years of follow-up in the Social Security Administration death master file. In patients with LBBB, women receiving CRT-D had a 26% lower risk of death than those receiving ICD (HR = 0.74 [95% CI 0.68-0.81]); the risk difference was 16% in men (HR = 0.84 [0.79-0.89]), p = 0.025 for interaction. Among those with non-LBBB, women had a 12% lower risk (HR = 0.88 [0.79-0.97]) with CRT-D while men had a 5% lower risk (HR = 0.95 [0.91-0.998]), p = 0.17 for interaction.

CRT-D was associated with a better survival in both sexes with LBBB and QRS ≥130 ms while there was no clear relation between QRS duration and survival in patients with non-LBBB. So, in this large real-world population comparing CRT-D with ICD therapy, CRT-D was associated with a lower mortality risk among both women and men with LBBB, though the difference was less pronounced among men.

In the JAMA Internal Medicine paper, which used pooled data from three CRT-D versus ICD trials, the authors noted, “This is important because recent guidelines limit the class I indication for CRT-D to patients with LBBB and QRS of 150 milliseconds or longer. While guidelines do give a class IIa indication to patients with LBBB and a QRS of 120 to 149 milliseconds, the present findings are important to communicate because women are less likely to receive CRT-D than men are.”

Long-term Adverse Events in Patients with ICDs

There is not a lot of documentation on the long-term adverse events associated with ICD use. Investigators identified 114,649 first-time ICD implants from 2006 through 2010 that could be matched with Medicare fee-for-service claims data to identify outcomes. The study group included 19.7% single-chamber, 41.3% dual-chamber, and 38.8% CRT-D devices.

Most (83.5%) were for primary prevention of sudden cardiac death. With up to 6 years of follow-up (median: 2.7 years), at least one reoperation occurred in 15.5% of patients and more than 80% occurred after the early (>90 days) post-implantation period.

Reoperation rates for specific complications (per 1,000 patient years) were device malfunction (14.3), infection (5.1), other device-related complications (18.4) and reoperation for generator battery end-of-life and/or device upgrade (12.9). The crude reoperation rate (for any cause) was similar among device types (p = 0.19).

The next steps are to identify patient, device, and provider factors associated with these long-term adverse events.

Positive News on Negative Trials

It was a coincidence, but the day after AHA ended–with its surfeit of intriguing negative trials–the National Institutes of Health (NIH) and the U.S. Department of Health and Human Services proposed new rules that would give more public access to data from clinical trials–even negative trials.

The changes would expand the number of trials requiring investigators to publish summaries of their results to If you think of the website more as providing details of study design and methodology, you are not alone. Currently, there are 178,000 clinical trials registered on the website and, of those, just 15,000 include a summary of their results, according to the NIH.

Margaret Hamburg, MD, immediate past-commissioner of the US Food and Drug Administration, said the new rules would close an important gap and help eliminate unnecessary duplication of clinical trials. This is particularly important when negative results haven’t been published about a drug that may be unsafe or ineffective. Summaries of findings would generally be due within a year of an NIH-funded study’s end, including summaries even for unapproved, unlicensed, and uncleared products. (Phase I studies would be excluded, however.)

Keywords: CardioSource WorldNews Interventions

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