Looking back at discovery, moving forward with progress

At the start of a new year, it is a good time to reflect on what has been a season full of activity in the CV arena, even at a time of uncertainty in the United States and worldwide.

Each year, the Cardiology Today Editorial Board is asked to vote on the “top” stories of the previous year. In my opinion, 2011 was filled with news and advances in the areas of antithrombotic agent development, transcatheter aortic valve replacement and the preferred treatment of choice for infective endocarditis, to name a few. My top picks for 2011 are summarized here.

Carl J. Pepine

New antithrombotic agents

As I write this at the close of 2011, management of atrial fibrillation continues to be a major challenge. Prevention of stroke for patients with AF remained stagnant during more than half a century, but by the end of 2011, three alternatives to warfarin have been approved by the FDA. Dabigatran (Pradaxa, Boehringer Ingelheim), a direct thrombin inhibitor, was approved more than 1 year ago. Late in 2011, the factor Xa inhibitor, rivaroxaban (Xarelto, Janssen), was approved for stroke prevention in AF; the new drug application for apixaban (Eliquis, Bristol-Myers Squibb and Pfizer) was given priority review by the FDA in November.

In my opinion, it is increasingly likely that the new oral anticoagulants — dabigatran, apixaban, rivaroxaban and others in development — will completely replace warfarin in the years ahead for this use among the growing population of patients with AF. The relative efficacy and use of these drugs in specific subpopulations (eg, prior stroke, very high thrombotic risk, women, etc,), as well as safety, will surely be the focus of discussion this year.

Additionally, antithrombotic drugs have been tested for secondary prevention — over many years after acute coronary syndrome hospitalization — without much success, largely because the bleeding risks associated with warfarin overshadowed any small reduction in atherothrombotic events. Today, most of the aforementioned patients are receiving dual antiplatelet therapy (acetylsalicylic acid plus the P2Y12 inhibitor clopidogrel), and adding warfarin is associated with a several-fold increase in bleeding risk. With more potent P2Y12 inhibitors, such as prasugrel (Effient, Eli Lilly) and ticagrelor (Brilinta, AstraZeneca), this risk becomes magnified. Both dabigatran (Oldgren and colleagues) and apixaban (Alexander and colleagues) were tested in ACS, and bleeding events were unacceptably increased. To this end, the ATLAS ACS 2 – TIMI 51 investigators found that rivaroxaban reduced CV death, MI or stroke (Mega and colleagues). Furthermore, the 2.5-mg per day dose reduced death from CV causes and all-cause mortality. These ACS patients also experienced more major bleeding and intracranial hemorrhage than controls, but without a significant increase in fatal bleeding.

Unfortunately, vorapaxar (Merck), a novel protease-activated receptor-1 (PAR-1) inhibitor, did not fare as well in patients with ACS based on results of the TRACER trial (Tricoci and colleagues). The addition of vorapaxar to standard of care resulted in a nonsignificant 8% reduction in the first occurrence of adverse outcome (CV death, MI, stroke, recurrent ischemia with rehospitalization or urgent coronary revascularization). Adding vorapaxar to standard of care significantly reduced the composite of CV death, MI or stroke by 11%, with a 12% RR reduction in MI (P=.021). Rates of bleeding were approximately 40% higher with vorapaxar, and there was a threefold increase in intracranial hemorrhage. However, an exploratory analysis in a subgroup of patients taking vorapaxar but not a P2Y12 inhibitor showed that the bleeding risk was not increased, and the effect on efficacy tended to be more pronounced. Looking ahead, PAR-1 inhibitors may have a place in ACS, but further study is needed.

Despite the clinical benefits of these new antithrombotic agents, bleeding remains a feared complication because there are limited strategies for immediate reversal of the anticoagulant effects in emergent cases. Prothrombin complex concentrate is an option for reversing the anticoagulant effects of rivaroxaban, but it has no role in reversing the effects of dabigatran (Eerenberg and colleagues). Moving forward, this further underscores the need for additional study on the effects of these agents in the setting of acute bleeding.

AF prevention in postoperative settings

The marked reduction in AF in the postoperative setting recently shown with prophylactic use of colchicine (Colcrys, AR Holding Co.) in the COPPS-POAF trial is very impressive. Based on its documented effects in prevention of pericarditis and postpericardiotomy syndrome, the COPPS-POAF researchers extended the benefit to AF prevention in the postoperative setting. Furthermore, other than its well-known gastrointestinal stimulation-related adverse effects, colchicine appears very safe in this setting, and its benefit is attributed to its anti-inflammatory actions (Imazio and colleagues). This was a “first” report and requires confirmation in another trial, perhaps starting earlier than 3 days after operation.

In the future, it will be interesting to see how much suppression of inflammation and other cardiac and mononuclear cell effects, by this old agent, may contribute to benefits in areas such as ACS, HF, stroke and so on.

Future of TAVR

Remarkable progress has been made in aortic valve disease management, as transcatheter aortic valve replacement (TAVR) has evolved as the recommended treatment for “inoperable” patients with severe aortic stenosis. This represents a “sea change” in practice and is based upon 1- and 2-year results of the PARTNER trial, which showed reduced mortality and improved quality of life in patients who underwent TAVR. These longer-term outcomes will importantly alter clinical decision-making.

The true value of TAVR in “inoperable” patients will depend on careful selection of patients who are not surgical candidates, yet do not have extreme comorbidities that overwhelm the benefits of TAVR.

Preferred treatment for infective endocarditis

It now appears that early surgery is the treatment of choice over conventional treatment for infective endocarditis. This is based on the clear results documented in the Early Surgery vs. Conventional Treatment for Infective Endocarditis (EASE) trial, the first randomized trial comparing early surgery with conventional treatment in infective endocarditis patients with high embolic risks. However, just how early will have to be determined looking ahead. The EASE data were presented at the American Heart Association Scientific Sessions 2011 in Orlando, Fla.

Clearly, 2011 marks the winning of some battles and the loss of other battles in the field of cardiology. I hope that 2012 is another exciting year.

Carl J. Pepine, MD, is professor of medicine in the division of cardiovascular medicine at the University of Florida, Gainesville. He is also Chief Medical Editor of Cardiology Today.

For more information:

• Alexander JH. N Engl J Med. 2011;365:699-708.
• Eerenberg ES. Circulation. 2011;124:1573-1579.
• Imazio M. Circulation. 2011;124:2290-2295.
• Mega JL. N Engl J Med. 2011;doi:10.1056/NEJMoa1112277.
• Oldgren J. Eur Heart J. 2011;32:2781-2789.
• Tricoci P. N Engl J Med. 2011;doi:10.1056/NEJMoa1109719.

Disclosure: Dr. Pepine reports no relevant financial disclosures.