Clinical studies review findings on triple-antiplatelet therapy after PCI, investigational thrombin receptor antagonist

May 1, 2012
Wayne Kuznar
Wayne Kuznar

A report for the American College of Cardiology's Scientific Session & Expo

Focused on the most innovative findings in cardiovascular science and clinically relevant practical applications, the American College of Cardiology's (ACC) 61st Annual Scientific Session & Expo held in Chicago, provided the latest information in research, practice, and technology in cardiology.

Triple-antiplatelet regimen proves equal to double-dose dual regimen in preventing events soon after PCI

Cilostazol is used widely as part of triple-antiplatelet therapy (TAT) in Korea and Japan after PCI in high-risk patients, said Hyo-Soo Kim, MD, PhD, principal investigator of a study known as HOST-ASSURE, in which the triple-drug approach was compared with the 2-drug regimen in a randomized study of 3,755 patients with >50% occlusion of any coronary artery or venous or arterial bypass graft. The study was designed to demonstrate noninferiority of the triple-drug regimen; it was conducted at 40 hospitals in the Republic of Korea.

Inhibiting platelet reactivity in the first month post-PCI is critical in preventing thrombotic events, said Dr Kim, director of cardiac catheterization and coronary intervention at Seoul National University Hospital, Republic of Korea. In previous trials of patients with acute coronary syndromes undergoing PCI, 1 week of double-dose clopidogrel was shown to improve outcomes at 1 month compared with conventional-dose clopidogrel.

All patients in HOST-ASSURE received 300 mg to 600 mg of clopidogrel plus 300 mg of aspirin before PCI with or without a loading dose of 200 mg of cilostazol. In the group assigned to triple antiplatelet therapy, 100 mg of cilostazol twice daily was added to dual antiplatelet therapy (DAPT; aspirin 100 mg daily and clopidogrel 75 mg daily) for 1 month following the procedure; in the group assigned to double-dose DAPT, the maintenance regimen was 150 mg of clopidogrel plus 100 mg of aspirin daily.

The primary end point was a composite of cardiac death, nonfatal myocardial infarction (MI), stroke, definite or probable stent thrombosis, and major bleeding. Twenty-three patients (1.22%) in the group randomly assigned to triple antiplatelet therapy and 27 (1.44%) assigned to double-dose DAPT achieved the primary end point, which met the criteria for noninferiority (P<.001). The group assigned to TAT had 1 spontaneous MI after discharge compared with 5 in the group assigned to double-dose DAPT (not significant; P=.141).

There was a trend toward more minor bleeding with triple therapy (0.64% vs 0.32%; not significant; P=.165), but major bleeding occurred with equal frequency (0.43%) in the 2 groups.

Dr Kim noted that the study may have been underpowered to detect a significant difference in the primary end point; the expected rate in the double-dose DAPT group was 3.00%, while the actual event rate was 1.44%. Given this actual event rate, a trial about twice the size of HOST-ASSURE might be needed to show superiority of the 3-drug regimen, he said.

Other potential limitations mentioned by the lead author include: 1) chance of under-reporting, 2) low rates of periprocedural MI, and 3) nonadherence to allocated treatment that may have affected outcomes that may have favored triple therapy. In the per protocol analysis excluding nonadherent patients, one significant result did turn up, which was a lower risk of nonfatal MI after the periprocedural period with triple therapy (0.0% vs 0.3%; P=.021).

Cilostazol may offer vascular biologic benefit on top of its antiplatelet effect, Dr Kim said. It appears to have activity in preventing restenosis of stented arteries, vasodilatory properties, and renoprotective properties, in addition to favorable effects on blood lipids.

"This is the first major trial to compare dual antiplatelet therapy with aspirin and clopidogrel 150 mg daily to the triple antiplatelet therapy with aspirin, clopidogrel 75 mg daily, and cilostazol in Korean patients undergoing drug-eluting stent [DES] PCI," said Formulary Editorial Advisor Robert A. Quercia, MS, RPh, medical editor at the University of Connecticut/Hartford Hospital, Evidence-based Practice Center, Hartford, Conn.

The results of the trial showed that triple therapy was non-inferior for cardiovascular end points at 1 month when compared with DAPT in patients undergoing DES PCI despite some potential limitations to the trial, according to Quercia.

"This trial confirms that cilostazol for 1 month may be a viable alternative to double-dose therapy with clopidogrel in patients undergoing DES PCI," Quercia said. "TAT with cilostazol is widely used after PCI in Asia-especially in Korea and Japan-unlike in the United States where the drug is only approved for treatment of intermittent claudication, and doubling the clopidogrel dose is the most common strategy for high-risk post-PCI patients."

Despite the positive results of this study, Quercia believes that most cardiologists will not feel comfortable with the TAT regimen. "In addition, the TAT not only adds another pill to the regimen, but it takes it from once to twice daily," he added.

Perhaps if more definitive data come out that cilostazol provides additional benefit on top of its anti-platelet effect (ie, decrease restenosis, vasodilatory properties, favorable effects on blood lipids) cardiologists in the United States may be more inclined to use TAT for patients undergoing DES PCI, according to Quercia.

Thrombin receptor antagonist cuts risk of CV events, but bleeding problem in patients with prior stroke

Vorapaxar, the first in a new class of investigational agents called protease-activated receptor 1 (PAR-1) thrombin receptor antagonists, when added to standard antiplatelet therapy reduced the risk of cardiovascular events in patients with stable coronary artery disease compared with standard antiplatelet therapy alone, but at a cost of significantly more bleeding.

The drug appeared most effective at preventing cardiovascular events in patients with a history of myocardial infarction (MI), in whom the reduction in risk was 20% compared with standard therapy alone, according to results from the TRA 2P–TIMI (Thrombin Receptor Antagonist in Secondary Prevention of Atherothrombotic Ischemic Events–Thrombolysis in Myocardial Infarction) 50 study.

"This is the first proof that we have that we can improve antiplatelet treatment on top of aspirin in patients with a previous heart attack," said the study's lead investigator David A. Morrow, MD, MPH.

"This trial showed for the first time that adding vorapaxar, a new investigational antiplatelet agent, to standard aspirin therapy significantly reduced the rate of cardiovascular death, myocardial infarction, or stroke in patients with a history of atherothombosis," said Robert A. Quercia, MS, RPh, medical editor at the University of Connecticut/Hartford Hospital, Evidence-based Practice Center, Hartford, Conn., and a member of Formulary's editorial board. "Vorapaxar a competitive and selective antagonist of protease-activated receptor 1 [PAR-1] showed the most benefit in patients with a history of myocardial infarction. However, the reduction in cardiovascular events came at a cost of increased risk of moderate or severe bleeding, including intracranial hemorrhage, with the later occurring most frequently in patients with a history of stroke.

"Although these findings show that inhibition of another platelet pathway in addition to that targeted by standard antiplatelet therapy for secondary prevention reduces the risk of recurrent thrombotic events, the benefit-if the agent becomes available-must be carefully weighed against the increase in bleeding risk. It would be very important to develop criteria for selecting patients who are more likely to have improved net clinical outcomes with the use of vorapaxar," Quercia added.

Vorapaxar is an oral selective antagonist of PAR-1 that is metabolized by CYP3A4 enzymes with no meaningful renal clearance and has a half-life in excess of 100 hours. TRA 2P–TIMI 50 was a secondary prevention trial that included 26,449 patients with a prior myocardial infarction (MI), cerebrovascular accident, or peripheral artery disease (PAD). Patients were randomly assigned to vorapaxar, 2.5 mg/day, or placebo in addition to standard background therapy, which depended on enrollees' qualifying disease. The study was carried out at 1,032 sites in 32 countries.

In January 2011, the TIMI-50 Data Safety Monitoring Board announced that its ongoing review uncovered an increase in the incidence of intracerebral hemorrhage (ICH) with vorapaxar in patients with a history of stroke, and recommended continuing the study only in patients without a prior stroke.

At 3 years follow-up, the rates of cardiovascular death, MI, or stroke (the primary end point) were 9.3% in those assigned to vorapaxar compared with 10.5% in those assigned to placebo, corresponding to a 13% reduction in risk with vorapaxar (P<.001).

Relative to placebo, vorapaxar was associated with a reduction of 12% (P=.001) in the incidence of cardiovascular death, MI, stroke, or urgent coronary revascularization, and a 14% reduction in the risk of cardiovascular death or MI. The reduction in the risk of achieving the primary end point in vorapaxar recipients was driven by a 20% reduction in patients whose qualifying atherosclerotic disease was MI; the benefit was uncertain in patients with PAD, said Dr Morrow, director of the Samuel A. Levine Cardiac Unit at Brigham and Women's Hospital, Boston.

The rate of all-cause mortality was not significantly different between the 2 arms.

Among the patients with no history of stroke, relative to placebo, vorapaxar was associated with a 16% reduction in the primary efficacy end point (P<.001), 14% reduction in the incidence of cardiovascular death, MI, stroke, or urgent coronary revascularization (P<.001), and a 15% reduction in the incidence of cardiovascular death or MI (P=.002).

Vorapaxar was superior to placebo for the primary end point in all subgroups examined except for patients weighing <60 kg, in whom there was a 22% increase in occurrence of the primary end point that did not achieve statistical significance.

Moderate or severe bleeding by GUSTO criteria occurred in 4.2% of the vorapaxar group versus 2.5% in the placebo group, a 66% increase in those assigned to vorapaxar (P<.001). Clinically significant bleeding, non-coronary artery bypass graft-related bleeding, and ICH all were significantly more common in vorapaxar-treated patients. The increase in bleeding with vorapaxar occurred in patients with or without prior stroke. The increase in ICH was especially prominent in patients with prior stroke, with a hazard ratio (HR) of 2.55 (P<.001).

"This is the last straw challenging a very common concept, particularly for cardiologists, that all atherosclerosis be treated in the same way," said Dr Morrow.

The natural history in patients with different types of atherosclerosis is different, he said, and therefore antiplatelet therapy cannot be expected to work equally well in all types of atherosclerosis. "Antiplatelet therapy is more complex and it's not 'a one size fits all' across the whole group [of patients with atherosclerosis]," said Dr Morrow.

If vorapaxar were to become available, "it's not an agent for all patients with atherosclerosis," he said. "Just like any other potent platelet blocker that we use, we need to select patients where we think there's an appropriate balance of the potential benefit versus the risk."

Human monoclonal antibody produces powerful reductions in LDL cholesteroI

A fully human monoclonal antibody that is under investigation to reduce levels of low-density lipoprotein (LDL) cholesterol has cleared the next hurdle. In a phase 2 study, treatment with SAR236553/REGN727 over 12 weeks lowered LDL cholesterol levels an additional 40% to 72% in patients with hypercholesterolemia who already were being treated with atorvastatin.

The antibody binds to PCSK9 (ProProtein Convertase Subtilisin/Kexin Type 9 Serine Protease) to prevent degradation of LDL receptors, facilitating LDL cholesterol out of the blood into the liver, thereby decreasing circulating levels of LDL cholesterol, said the study's lead investigator James McKenney, PharmD, president and CEO of National Clinical Research, Inc., Richmond, Va.

With SAR236553/REGN727, "more LDL receptors are in play to take up more cholesterol...we should have a monumental clearance of LDL cholesterol from the blood stream and that's what our study showed, said Dr McKenney. "This new mechanism may be the next big step, if it pans out...the data say that it is quite powerful, at least as if not more powerful than the statin. It takes us to another level."

The double-blind, parallel group, placebo-controlled US multicenter trial included 183 patients with LDL cholesterol levels of 100 mg/dL or greater despite treatment with atorvastatin at doses of 10 mg/day to 40 mg/day for at least 6 weeks.

The patients were randomly assigned to 1 of 6 groups: placebo, 3 groups who received a subcutaneous administration of SAR236553/REGN727 every 2 weeks at doses of either 50, 100, or 150 mg, and 2 groups that received an injection of 200 or 300 mg every 4 weeks alternating with placebo injections at 2 weeks.

The study demonstrated that SAR236553/REGN727 is associated with dose-related and dose regimen-dependent LDL cholesterol reductions.

"Two weeks after administration, we saw an immediate reduction in LDL cholesterol reaching 31% to 63%, which represents 80% of the ultimate LDL reduction achieved," said Dr McKenney. The most efficacious regimen was 150 mg every 2 weeks, which resulted in a 72.4% reduction in LDL cholesterol from baseline (P<.0001 for percent change vs placebo).

The continued trend toward lower LDL cholesterol levels observed with multiple every 2-week doses of SAR236553 may indicate further LDL cholesterol reductions with a longer duration of therapy.

There were favorable changes in apolipoprotein B (Apo B), triglycerides, high-density lipoprotein (HDL) cholesterol, non-HDL cholesterol, and lipoprotein (a) in the groups assigned to SAR236553/REGN727, with the greatest effects observed in the group assigned to 150 mg twice weekly.

The frequency of treatment-emergent adverse events was similar between the placebo and all SAR236553/REGN727 groups. Six treatment-emergent adverse events led to 6 patients in the SAR236553/REGN727 groups discontinuing treatment: 1 for neutropenia, 1 for fatigue, 1 for rash, 1 for chest pain, 1 for headache/nausea, and 1 for leukocytoclastic vasculitis, which occurred in a 57-year-old male and resolved with prednisone treatment.

There were no signals for persistent or prevalent clinical or laboratory adverse events, including hepatic and muscle assessment, in patients treated with SAR236553/REGN727.

The LDL cholesterol reductions with SAR236553/REGN727 were unaffected by atorvastatin, which suggests that although both SAR236553/REGN727 and atorvastatin upregulate LDL receptors, their mechanisms of action are independent, said Dr McKenney. The agents appear to provide additive LDL cholesterol-lowering effects when administered in combination.

The data are "a wow...considering that the statin we used should have already produced a 40% to 50% reduction in LDL cholesterol, and on top of this, we're getting another 40% to 72% reduction," he said. "Maybe we have another era in the treatment of lipid disorders and more importantly in the reduction of heart disease in this country."

Steven Nissen, MD, chair, department of cardiovascular medicine at the Cleveland Clinic, was equally enthusiastic. "The results are excellent," he said. "Administration every 2 to 4 weeks is very reasonable for patient compliance. There's alot of medical need for people who we cannot get to goal with existing therapies. This is one of the few drug classes for which most people who've looked at the data would bet on making it to approval."

Dr Nissen added that he is not concerned about a potential for leukocytoclastic vasculitis with SAR236553/REGN727. "There's no reason to expect it but time will tell. So far, this looks very safe and very powerful."

"Although it was a phase 2 study, this human monoclonal antibody (SAR236553) has the potential for significant interventions in patients who cannot achieve target LDL cholesterol levels with statin therapy alone," said Robert A. Quercia, MS, RPh, medical editor at the University of Connecticut/Hartford Hospital, Evidence-based Practice Center, Hartford, Conn. and a member of Formulary's editorial board. "SAR236553 also has the potential to reduce Apo-B to target levels providing an opportunity for further cardiovascular risk reduction. Thus, this agent has the potential for a major breakthrough in the management of cardiovascular risk."

Oral rivaroxaban noninferior to standard therapy with reduction in major bleeding in primary PE

The oral factor Xa inhibitor rivaroxaban as a single-drug approach is a safer alternative to standard therapy with enoxaparin and a vitamin K antagonist for the treatment of primary pulmonary embolism (PE). Single-agent rivaroxaban proved noninferior to enoxaparin/vitamin K antagonist in preventing a first recurrence of venous thromboembolism (VTE) while reducing the risk of major bleeding in the EINSTEIN-PE study.

The novel approach to treating primary PE with a single oral agent could dramatically reduce treatment time in the hospital for certain patients, said the study's lead investigator Harry R. Büller, MD.

"This study was undertaken that there is increasing awareness that VTE or PE actually could be treated outside the hospital," he said. "Maybe the patient needs to be in the hospital for 1 day to be observed, but it is not necessary to have these patients in the hospital for 5 to 10 days as has been the practice. Therefore, we wanted to make this regimen very simple."

Following in the footsteps of EINSTEIN-DVT, which showed that 20 mg/day of rivaroxaban was noninferior to standard medical therapy in reducing the risk of symptomatic recurrent VTE, EINSTEIN-PE tested a different regimen of rivaroxaban: 15 mg twice daily on days 1 to 21, followed by 20 mg once daily. It was compared with enoxaparin twice daily for at least 5 days plus a vitamin K antagonist (warfarin or acenocoumarol) titrated to achieve an International Normalized Ratio (INR) of 2.0 to 3.0. Enoxaparin was discontinued when the INR was 2.0 or more for 2 consecutive days and the patient had received enoxaparin for at least 5 days.

Patients were treated for 3, 6, or 12 months as deemed appropriate by each clinician before randomization. The majority of patients in each arm were treated for either 6 months (57%) or 12 months (37%).

The design was a randomly assigned, open-label study conducted in 38 countries, and powered to demonstrate noninferiortiy on the primary end point of a first recurrent VTE. The intent-to-treat study population consisted of 4,832 patients with objectively confirmed PE with or without DVT.

The altered dosing strategy for rivaroxaban was derived from dose-finding studies of thrombus resolution on lung imaging tests at 3 weeks, said Dr Büller, professor of vascular medicine, Academic Medical Center, Amsterdam, The Netherlands.

The percentage of time during which the INR was in the therapeutic range with standard therapy was 62.7%. In the rivaroxaban group, adherence was above 80% in 94.2% of patients.

The rates of a first symptomatic recurrent VTE were 2.1% in the rivaroxaban group and 1.8% in the enoxaparin/vitamin K antagonist group, which met the criterion for noninferiority of efficacy (the maximum allowed hazard ratio [HR] was 1.31, the actual HR was 1.12; 1-sided P value =.0026).

The principal safety outcome-major or non-major clinically relevant bleeding-occurred with similar frequency in the 2 arms, with an incidence of 10.3% in patients randomly assigned to rivaroxaban and 11.4% in those randomly assigned to enoxaparin/vitamin K antagonist. However, major bleeding events occurred half as often in the rivaroxaban group compared with the enoxaparin/vitamin K antagonist group (1.1% vs 2.2%; P=.0032).

The main benefactors in terms of a reduced risk of bleeding with rivaroxaban were patients older than 75 years: there were 23 major bleeds in this group in those randomized to enoxaparin/vitamin K antagonist vs. 5 randomly assigned to rivaroxaban, said Dr Büller.

The intensified regimen of rivaroxaban during the first 3 weeks did not result in an increased rate of hemorrhage. The net clinical benefit (first recurrence of VTE plus major bleeding) in the overall study population favored rivaroxaban, with an HR of 0.85.

There was no evidence of liver toxicity in the patients receiving rivaroxaban.

"The results of this study now provide the potential of a single oral agent for the treatment of PE with added clinical benefits of a significant reduction in major bleeding (50%) and reduction in hospital stay compared to standard therapy," said Robert A. Quercia, MS, RPh, medical editor at the University of Connecticut/Hartford Hospital, Evidence-based Practice Center, Hartford, Conn. and a member of the Formulary editorial board.

"In addition, patients placed on oral rivaroxaban therapy for PE will avoid the cumbersome monitoring required for oral vitamin K antagonists and will have fewer drug-drug and drug-nutrient interactions than warfarin," Quercia noted.

One of the potential limitations to the study is its open-label design, which has the potential for a diagnostic-suspicion bias. The absolute number of patients with suspected recurrence was higher in the rivaroxaban group, and the proportions of patients with confirmed events were similar in the 2 groups (10.2% in the rivaroxaban group and 9.7% in the standard therapy group). This finding suggests that the open-label design may have caused a slight bias against rivaroxaban, he noted.

Another potential limitation of the study was the quality of standard therapy with the INR in the therapeutic range 62.7% of the time and exceeding 3.00 only 15.5% of the time. The investigators addressed this potential limitation by showing that these results compared favorably with the findings in other contemporary studies of venous thromboembolism, Quercia said.

New oral anticoagulants show better efficacy versus warfarin in preventing events in AF patients

The newer anticoagualants-the factor Xa inhibitors rivaroxaban and apixaban and the direct thrombin inhibitor dabigatran-were the focus of an abundance of analyses, meta-analyses, and real-world studies. The following is a sampling of the research presented here.

A systematic review and meta-analysis of 3 large, randomized controlled trials (RE-LY [dabigatran], ARISTOTLE [apixaban], and ROCKET-AF [rivaroxaban]) showed that new anticoagulants perform better than warfarin for preventing stroke and systemic embolism in patients with atrial fibrillation (AF).

Using the same 3 trials, a second analysis demonstrated that use of the new oral anticoagulants is associated with a reduction in total medical costs compared with warfarin.

While superior to warfarin on efficacy end points, these newer agents increase the risk of gastrointestinal bleeding but appear to decrease the risk of major bleeding, according to the review/meta-analysis conducted by Mark J. Eisenberg, MD, MPH, and colleagues.

His group in Montreal, Canada used random-effects models to pool the efficacy and safety data across the 3 trials, in which more than 40,000 patients were randomly assigned to 1 of the newer oral anticoagulants or to warfarin.

They found that patients randomly assigned to the new oral anticoagulants had a decreased risk of achieving a composite end point of all stroke and systemic embolism compared with patients randomly assigned to warfarin, with a relative risk of 0.78 (95% CI, 0.67–0.92).

Compared with warfarin, the new oral anticoagulants were associated with reductions in the relative risks of ischemic and unidentified stroke (0.87; 95% CI, 0.77–0.99), hemorrhagic stroke (0.45; 95% CI, 0.31–0.68), all-cause mortality (0.88; 95% CI, 0.82– 0.95), and vascular mortality (0.87; 95% CI, 0.77–0.98). The risk for myocardial infarction was similar between warfarin and the new anticoagulants.

The relative risk of major bleeding with the new anticoagulants was 0.88 (95% CI, 0.71– 1.09) but the relative risk of gastrointestinal bleeding was higher at 1.25 (95% CI, 0.91–1.72).

"These new oral anticoagulants are easily administered and do not require monitoring, making them promising alternatives for prevention of stroke and systemic embolism in patients with AF," the researchers concluded.

Dr Eisenberg is a tenured professor of medicine at McGill University in Montreal, Quebec, Canada, and director of clinical research of the McGill Cardiology Fellowship Program.

A cost comparison analysis led by Steven Deitelzweig, MD, revealed a reduction in medical costs with the new oral anticoagulants driven by the decrease in bleeding and stroke rates associated with the new agents.

Based on clinical event data from RE-LY, ARISTOTLE, and ROCKET-AF, the 1-year mean incremental medical costs among AF patients with clinical events versus those without clinical events were estimated from the literature or based on input from clinical experts and expressed in 2012 U.S dollars. The clinical event rate used for warfarin-treated patients was the weighted average across the 3 trials.

The total medical costs per patient year associated with each treatment were estimated to be $2,084 with warfarin, $1,905 with dabigatran, $1,995 with rivaroxaban, and $1,599 with apixaban.

The reduction in cost associated with apixaban was driven by reductions in occurrence of major bleeding and hemorrhagic stroke, with smaller contributions from reductions in the incidences of myocardial infarction (MI) and ischemic stroke. With dabigatran, cost reduction came mainly from reductions in the rates of hemorrhagic stroke and ischemic stroke, which were partially offset by increased costs from MI and major bleeding. Reductions in the rates of hemorrhagic stroke and MI drove cost reduction with rivaroxaban, however, there was an increase in cost from an increase in the incidence of major bleeding.

Dr Deitelzweig is vice president of Medical Affairs and assistant program director for Internal Medicine, Ochsner Health System, New Orleans.

In a "real-life" study, the complication rate associated with dabigatran in a community-based setting was examined by Valay Parikh, MD, at Staten Island University Hospitals, N.Y.

He and colleagues reviewed the database of 2,200 patients collected from an anticoagulation clinic, primary care offices, and the Staten Island University Hospital system. They identified 89 patients who were switched from warfarin to dabigatran, comparing the patient characteristics and event rates with those patients randomized to dabigatran in the RE-LY trial.

Despite being significantly younger (mean age: 70 years vs. 71.5 years), having lower CHADS2 scores, and having a lower incidence of prior stroke or transient ischemic attack (15.7% vs. 20.3%), patients treated with dabigatran in the community had significantly more major bleeding complications (8.98% per year vs. 3.11%; P<.01) than those treated with 150 mg/day of dabigatran in RE-LY, the investigators found.

"More real-life and studies are needed to further refine use of newer anticoagulants like dabigatran," they concluded. "In addition, a toll is needed to correctly identify patients at higher risk of bleeding complications."

Safety issues with new oral anticoagulants require more study

Potential dosing and safety issues with the new oral anticoagulants require further clarification before these agents are adopted into routine clinical practice. While these agents have proven efficacy in preventing thromboembolic events in patients with atrial fibrillation (AF), their value in the treatment of acute coronary syndrome (ACS) is less clear, said William Dager, PharmD, clinical professor of pharmacy, University of California, San Francisco, School of Pharmacy, and clinical professor of pharmacy, University of California, Davis, School of Medicine.

STROKE PREVENTION IN ATRIAL FIBRILLATION

Most of the data accumulated with rivaroxaban, dabigatran, and apixaban have been collected in the setting of AF. Both rivaroxaban and the 150-mg dosage of dabigatran were shown to prevent thromboembolic events with lower rates of intracerebral hemorrhage (ICH) compared with warfarin in large randomized clinical trials of patients with AF. Dabigatran is also an alternative to warfarin in patients undergoing cardioversion for AF. The approved dosage of rivaroxaban for stroke prevention in patients with nonvalvular AF is sensitive to renal function: the standard dosage is 20 mg daily, with a reduction to 15 mg once daily in patients with renal impairment (creatinine clearance in the range of 30 to 49 mL/min); avoid its use in patients with creatinine clearance <15 mL/min.

Renal impairment is a consideration in the dosing of dabigatran as well. "The way renal failure is calculated is one thing you have to consider," said Dr Dager. "In the trials, we used the Cockroft-Gault formula using ideal total body weight to do renal assessments; that was for both dabigatran and rivaroxaban."

Much of the benefit in terms of stroke prevention in the rivaroxaban arm of the ROCKET-AF (Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K antagonist for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) trial was lost during the post-trial transition from rivaroxaban to open-label warfarin, which begs the question, "If you have well-managed warfarin, is there really an advantage to these drugs," said Dr Dager. "Another key with rivaroxaban is that you have to instruct the patient to take with the evening meal."

Apixaban has produced favorable outcomes (prevention of stroke or systemic embolism) compared with aspirin and warfarin in separate trials in the setting of AF.

ACUTE CORONARY SYNDROME

In the setting of ACS, dabigatran was associated with an increased incidence of acute myocardial infarction (MI) of approximately 0.2% compared with warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial. Using the RE-LY database, Hohnloser at al. (Circulation. 2012;125:669–676) found a nonsignificant increase in the risk of MI with dabigatran irrespective of risk factors. In a review of 7 clinical trials conducted in various settings (AF, ACS, acute venous thromboembolism, and deep vein thrombosis), Uchino et al. (Arch Intern Med. 2012;172:397–402) discovered a consistently significant increase in the risk of MI or ACS across the trials in patients who were treated with dabigatran relative to controls. In 2 clinical trials comparing dabigatran to warfarin as treatment for deep vein thrombosis (RECOVER and RECOVER II), no difference between treatments in the rate of ACS was discovered in RECOVER, whereas a trend toward more ACS events in the dabigatran group was found in RECOVER II. In a phase 2 study of patients with ACS, the rates of coronary events were similar between the dabigatran and warfarin arms but an excess of nonfatal MI was uncovered in patients assigned to dabigatran.

In ATLAS-TIMI 51 (Anti-Xa Therapy to Lower cardiovascular events in Addition to Aspirin with/without thienopyridine therapy in Subjects with Acute Coronary Syndrome)-(Thrombolysis in Myocardial Infarction), a pivotal phase 3 trial conducted in low-risk patients with a recent ACS, rivaroxaban added to standard antiplatelet therapy was associated with a significant reduction in the occurrence of major adverse cardiovascular events compared with placebo but it increased slightly the rates of major bleeding and ICH without an increase in fatal bleeding. As such, rivaroxaban may eventually represent an option in the long-term management of ACS but "is not ready for prime time," said Dr Dager.

Apixaban on top of standard antiplatelet therapy was studied in a placebo-controlled trial in the setting of ACS in the APPRAISE 2 (Apixaban for Prevention of Acute Ischemic Events 2) trial, but the study was terminated early when an increase in major bleeding events was apparent in apixaban recipients.

Vorapaxar is a protease activated receptor (PAR) 1 antagonist. In the TRACER (Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome) trial, vorapaxar added to a background of standard antiplatelet therapy in patients with non-ST-segment elevation ACS had no significant effect on the primary composite outcome while increasing the risk of major non-coronary artery bypass graft bleeding, bleeding that required medical attention, and ICH/fatal bleeding, quashing its hopes for this indication, said Dr Dager. (See "Investigational thrombin receptor antagonist cuts risk of second cardiovascular events, but bleeding is a problem in patients with prior stroke" in this report to read about vorapaxar's effect in a separate trial of patients with stable coronary disease.)

REVERSING ANTICOAGULANT EFFECTS

Reversing excessive anticoagulant activity is problematic with the new oral anticoagulants. There are no data on the utility of clotting factor prothrombin complex concentrate (PCC3) to reverse these agents, he said. Administration of PCC4 normalized endogenous thrombin potential (ETP) and prothrombin time in humans treated with rivaroxaban but induced a hypercoagulable state. In rats and humans administered dabigatran, PCC4 did not restore activated partial thromboplastin time (aPTT), ecarin clotting time (ECT), or thrombin time (TT).

There are some encouraging signals that activated PCC (aPCC) reduces bleeding time in recipients of dabigatran and rivaroxaban. Dr Dager's group has reported the case of a single dabigatran-treated patient with a transseptal perforation who lost 4 L of blood during cardiac ablation in whom the anticoagulant effect was reversed by administration of 25 U/kg of aPCC (FEIBA).

NEED FOR MONITORING?

The activity of the oral anticoagulants may need to be measured in certain situations. "Thrombin times are exquisitely sensitive so an elevated thrombin time may indicate the presence of dabigatran," said Dr Dager. "For rivaroxaban, it's not clear yet, maybe a chromogenic anti-Factor Xa [to indicate that the drug is present]."

Quantitative tests are not readily available for assessing the intensity of anticoagulation effects with either agent, he said. A chromogenic ECT-driven dabigatran level has been developed but it requires further study to assess its utility.

The meaning of laboratory values is unclear with respect to outcomes, he said, such as determining safe levels for patients undergoing surgery.

New hypertension guidelines promise to be 'trustworthy'

New guidelines on the management of hypertension are in the works, and the guidelines will be strictly evidence-based, "focusing only on randomized controlled trials assessing important health outcomes," said Suzanne Oparil, MD, professor of medicine, division of cardiovascular disease, University of Alabama at Birmingham.

Recommendations contained in current American Heart Association/American College of Cardiology clinical practice guidelines for cardiovascular disease prevention are rarely developed from a level of evidence A, with a median of 19% of class I recommendations developed from a level of evidence A.

The approach of the National Heart, Lung, and Blood Institute (NHLBI) to the guideline development process was established to assure rigor and to minimize bias, said Dr Oparil. The methods being used meet many of the new Institute of Medicine standards for systematic reviews and developing trustworthy clinical practice guidelines.

The initial set of recommendations by the expert panels at the NHLBI address 3 key questions:

1) Among adults with hypertension, does initiating antihypertensive pharmacologic therapy at specific blood pressure thresholds improve health outcomes?

2) Among adults, does treatment with antihypertensive pharmacologic therapy to a specified blood pressure goal lead to improvements in health outcomes?

3) In adults with hypertension, do various antihypertensive drugs or drug classes differ in comparative benefits and harms on specific health outcomes?

To be considered for review, a randomized controlled trial (from 1966 to present) must have a minimum of 1 year of follow-up; studies with sample sizes less than 100 will be excluded. "Each study was rated for quality by 2 independent reviewers who used standardized tools," said Dr Oparil.

A goal blood pressure of 150/90 mm Hg or lower for most patients with hypertension is supported by evidence from randomized controlled trials, said William C. Cushman, MD, chief of the section of preventive medicine at the Veterans Affairs Medical Center, Memphis, Tenn.

A goal of 140/90 mm Hg may still be reasonable for patients with chronic kidney disease, he said, and a goal in the range of 140 to 150/80 to 85 mm Hg in patients with diabetes is supported by evidence from randomized controlled trials.

In speaking about the choice of initial therapy for hypertension, Kenneth A. Jamerson, MD, showed evidence that combination therapy should be used from the outset when pharmacotherapy is chosen to treat hypertension. Even clinical trials comparing monotherapy were in essence trials of combination therapy because patients required multiple drugs to reach prespecified targets, he said.

Even in low-risk patients, combination therapy offers more prompt and efficient control of blood pressure compared with monotherapy.

"Combination therapy with an ACE inhibitor and amlodipine is superior to diuretic-based combination therapy in reducing cardiovascular disease morbidity and mortality in high-risk patients," said Dr Jamerson, professor, department of internal medicine, University of Michigan Health System, Ann Arbor.

The case for the ACE inhibitor/amlodipine combination comes from the ACCOMPLISH (Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension) trial, in which a combination of benazepril and amlodipine proved superior to benazepril and hydrochlorothiazide as initial therapy on the primary end point of time to first cardiovascular morbidity/mortality (20% relative risk reduction; P=.0002) in patients with high-risk hypertension.

The ASCOT-BPLA (Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm) trial provides further support for such a combination. In ASCOT-BPLA, an amlodipine/perindopril combination was compared with a combination of atenolol/bendroflumethiazide in patients with hypertension and at least 3 other cardiovascular risk factors. Although the study failed to find a significant difference between arms on the primary end point of nonfatal myocardial infarction and fatal coronary heart disease, all-cause mortality and cardiovascular mortality occurred significantly less often in the amlodipine/perindopril arm of the study.

Diuretics should be relegated to add-on therapy, believes Dr Jamerson, who said that cost is no longer a rationale for preferring diuretics because most antihypertensive drug classes have generic formulations.

Mr Kuznar is a medical journalist based in Cleveland.

Disclosure Information: The authors report no financial disclosures as related to products discussed in this article.