. . . and it's about time. LMAO! How low can she go? Published: Mar 31, 2014 | Updated: Apr 1, 2014 By Peggy Peck, Editor-in-Chief, MedPage Today Reviewed by Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, BSN, RN, Nurse Planner save| A A For best viewing, click the bottom right corner for full screen. Click here for more ACC 2014 video coverage. Action Points Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered to be preliminary until published in a peer-reviewed journal. In a head-to-head comparison of bivalirudin (Angiomax) and heparin in more than 1,800 patients stented for acute ST-segment elevation MI -- primary percutaneous coronary intervention or PPCI -- heparin was the clear winner. Note that there was no clinically or statistically significant difference in bleeding complications between those who received heparin compared with bivalirudin. WASHINGTON -- In a head-to-head comparison of bivalirudin (Angiomax) and heparin in more than 1,800 patients stented for acute ST-segment elevation MI -- primary percutaneous coronary intervention or PPCI -- heparin was the clear winner, news that was not welcome here at the American College of Cardiology meeting. And winning in the HEAT PPCI trial meant demonstrating that patients treated with heparin were less likely to have either reinfarction or stent thrombosis than those in the bivalirudin arm -- so much so that only 33 patients had to be treated with heparin to avoid one major adverse event versus treatment with bivalirudin, Adeel Shahzad, PhD, of Liverpool Heart and Chest Hospital, Liverpool, reported during the final ACC late-breaking clinical trial session. On the surface that seems like "good news," especially considering that heparin is significantly less expensive than bivalirudin -- by a factor of 400, according to Rod Stables, MD, of Liverpool Heart and Chest Hospital in England and the HEAT PPCI principal investigator. Single Center, Single Purpose Following the mantra "every patient, every time"over a period of 22 months, Stables and his colleagues in the single-center, open-label study recruited 1,829 eligible patients and assigned 914 to heparin and 915 to bivalirudin. Those in the heparin arm received 70 units/kg body weight pre-procedure. The bivalirudin patients received a bolus 0.75 mg/kg, followed by infusion during procedure of 1.75 mg/kg/hour. Both groups followed the same protocol for selective abciximab bailout following the European Society of Cardiology guideline indications. The primary efficacy endpoint was a composite of all-cause mortality, cerebrovascular accident, re-infarction, or unplanned target lesion revascularization (TLR) at 28 days. The primary safety outcome was major bleeding. At 28 days there were 46 deaths, 11 strokes, 21 re-infarctions and one TLR in the bivalirudin arm for a major adverse cardiovascular event (MACE) rate of 8.7% versus 36 deaths, six strokes, seven re-infarctions and no TLR in the heparin group -- a MACE rate of 5.7%. Shahzad said this rate was similar to that seen in large, multicenter randomized trials of bivalirudin such as EURO-MAX and HORIZON-AMI. Gregg Stone, MD, director of cardiovascular research and education at Columbia University Medical Center/New York-Presbyterian Hospital, and an investigator in HORIZON-AMI, challenged that assertion, saying the 30-day MACE rate was not that high. That study, reported in 2008, did find a higher rate of early stent thrombosis but lower rates of cardiovascular death and bleeding. He said he suspected that bivalirudin was under-dosed "and the patients were not fully anticoagulated." The biggest driver of events -- and this mirrors the HORIZON-AMI findings -- was early stent thrombosis: 24 in the bivalirudin arm versus six in the heparin group, which worked out to roughly a four times greater relative risk but with very wide confidence intervals (RR= 3.91%, 95% CI 1.6-9.5, P=0.001). For safety -- and cardiologists contacted by MedPage Today found this more surprising than the efficacy endpoint -- there was no clinically or statistically significant difference: 83 minor bleeds and 113 major bleeds in the bivalirudin arm versus 98 and 122, respectively, in the heparin group. Stone, who told MedPage Today that "I have no Medicines Company connections (the maker of Angiomax)," found the bleeding result especially puzzling since all previous bivalirudin trials "confirmed less bleeding with bivalirudin," he said. Stone was not alone in his skepticism, but several cardiologists suggested that one explanation could be use of radial access for 80%-85% of the procedures. George W. Vetrovec, MD, professor of medicine at Virginia Commonwealth University, said that rate was much higher than the rate in the U.S.; moreover, he said, although the popularity of radial access is growing in the U.S. -- one reason being a lower bleeding rate than that seen with femoral access -- "it is not done in AMI, which is what they did in HEAT PPCI." But J. Brent Muhlestein, MD of the Intermountain Heart Institute, Murray, Utah, did not find the bleeding results surprising. In an email, he wrote, "In ACUITY, in the arm that gave bivalirudin in combination with IIB/IIIA agents, the risk of bleeding was identical to heparin. So it only makes sense that when heparin is given without IIB/IIIA agents, the risk of bleeding also will be same as bivalirudin when given without IIB/IIIA agents." Stables told MedPage Today that access was unlikely to explain the bleeding results, noting that a substudy analysis, which was not reported at ACC, revealed no difference in bleeding rates between femoral and radial access cases. Ethical Concern One of the limitations of the study was its single-center design, although Stables argued that the design also allowed the investigators to present data that truly mirrored real life, rather than the cosseted findings produced with more traditional randomized trials. But it was another aspect of HEAT PPCI design that drew the most fire: consenting patients after treatment. The researchers treated the patients, evenly assigning them to either of the study drugs, and then "when they were awake and feeling better" they asked them to consent to being in a research study and to consent to follow-up. Using this approach, Stables and colleagues were able to gain consent from all but three of the randomized patients. Stone told MedPage Today that he had serious concerns with this retrospective consent process and suggested that it might violate the Helsinki accords, which prohibit experimentation without consent except in extreme cases where the patient is unable to consent. "In my career, I've never seen anything like this," Stone said. William O'Neill, MD, of Henry Ford Hospital in Detroit, also railed against the post-procedure consent and said that process, which he too suggested was a Helsinki violation, explained why HEAT PPCI had so many patients consenting. In the U.S., O'Neill said, only about one-third of patients consent to being in a trial. Spencer King III, MD, of St. Joseph's Medical Group in Atlanta, told MedPage Today that the difference in consent might reflect societal differences. In the U.S., he said, patients think it is "heroic" to agree to be in a trial, whereas in Europe there is a cultural imperative to participate in research for the betterment of the community. Vetrovek pointed out that both drugs "are approved and were administered according to label indications," so he did not see a great reason for concern. Stables defended the consent process, noting that it was reviewed and approved by three separate oversight groups in the U.K., and he raised an ethical question about getting "consent" from a patient "who is pain, on the way to the cath lab. How valuable is that consent?" Moreover, Stables argued that his primary concern was door-to-balloon time, which averaged just 29 minutes in HEAT PPCI -- significantly less than the 88 minutes in a recent U.S. study. During an ACC press conference, former ACC president David Holmes, MD, of the Mayo Clinic, said he had no problem with the protocol used in HEAT-PPCI, noting that he had recently been "consented" during a hospitalization for GI bleeding. A few weeks later he received a call from a researcher informing him that it was time for a follow-up visit for the trial, but Holmes said he had no memory of signing the consent. Clinicaltrials.gov lists the sponsors of the trial as the National Health Service and Liverpool Heart and Chest Hospital, but an ACC press release gives this statement: "Support for the study was provided by unrestricted grants from The Medicines Company, Parsippany, N.J., and AstraZeneca, Wilmington, Del."
Two more trials finally showing Angiomax is not that great for today's practice with either more events or no different to Hep at 100s of dollars more in cost. Did Stone et al. twist the Acuity and Horizons data in favor of Angiomax? Sure! They added bleeding in the primary endpoint, used femoral access, overdosed Heparin, and made a Hematoma a major bleed! This, at a time when renal dosing was moving from serum measurement to GFR making more sensitive medication adjustments important - but that did not happen. Nice to see some clinicians question spending so much money for a drug that really isn't better and might even be worse if you are using the new OAPs and radial access.
All those Health Systems who jumped from IIbIIIa's and UFH to this joke of a drug and spent millions in the process. Not too smart now Pharmacy Directors are ya?
The company spent plenty of money selling a story of NO bleeding equals better outcomes vs. IIbIIIa's and actually pulled the wool over everyone's eyes with a story of less costs associated with ancillary costs..ambulatory care... LOS etc.... Sure if you give a patient placebo you can save on those things too!! I have to hand it to Greg Stone though...he is a clever marketer but unfortunately how many lives were negatively impacted by these trials, how much myocardium was lost for profit. Profit to the company at the expense of every hospital and patient that put there faith in him. This is tragic.
