Drug Stops Dangerous Bleeding in Patients Taking Factor Xa Inhibitors
The experimental drug andexanet is associated with control of serious bleeding in patients taking a common class of anticoagulants known as Factor Xa inhibitors, according to interim clinical trial results. Factor Xa inhibitors elevate the risk of serious bleeding. If approved by the FDA, andexanet would be the first agent available to directly reverse the effects of Factor Xa inhibition if bleeding occurs.
Factor Xa inhibitors, which inhibit a protein involved in the formation of blood clots, are commonly prescribed for patients who are at high risk for stroke and venous thrombosis. Because Factor Xa inhibitors and other anticoagulants reduce the body’s ability to form a blood clot, these drugs can also increase the risk of uncontrolled bleeding. When this happens, it can be challenging for doctors to stop the bleeding. About 25% of patients who experience bleeding in the brain while taking a Factor Xa inhibitor die.
“Unlike for some other anticoagulants, there is currently no approved reversal agent for Factor Xa inhibitors,” said Stuart Connolly, MD, Professor of Medicine at McMaster University in Hamilton, Ontario. “Factor Xa inhibitors are already widely used because of their excellent efficacy and safety profile. However, some physicians and patients may choose to use other anticoagulant drugs because they have a reversal agent, rather than using one of the Factor Xa inhibitors. Having a safe and effective reversal agent available will benefit patients with acute bleeding.”
About 2.9 million people in the United States currently take Factor Xa inhibitors. Of these people, most are older and have illnesses, such as heart failure, that put them at high risk for cardiovascular problems. Approximately 84,000 patients taking Factor Xa inhibitors are hospitalized for major bleeding each year, according to a recent analysis of the MarketScan Commercial and Medicare databases. The most common types of major bleeds include bleeding in the brain, sometimes resulting from a fall, and gastrointestinal bleeding.
Andexanet is a recombinant modified Factor Xa molecule designed to bind to and disable Factor Xa inhibitors, thereby allowing Factor Xa produced by the body to play its normal role in the formation of blood clots. In earlier trials performed in healthy volunteers, andexanet rapidly reversed the anticoagulant effect of Factor Xa inhibitors without causing any significant safety problems.
ANNEXA-4 is an ongoing clinical trial that uses andexanet to help treat patients experiencing major bleeding while taking Factor Xa inhibitors. The interim analysis includes data on safety outcomes for 227 patients and adjudicated efficacy outcomes for 132 patients enrolled at centers in the US, Canada, and Europe. All trial participants presented with acute major bleeding within 18 hours of taking one of four Factor Xa inhibitors (ie, apixaban, rivaroxaban, edoxaban, or enoxaparin). Patients received an injection of andexanet followed by a two-hour infusion of the drug, with the dosage determined based on the specific Factor Xa inhibitor the patient was taking and how long it had been since the last dose.
The trial assesses the drug’s efficacy in terms of the following two coprimary endpoints: reduction in anti-Factor Xa inhibitor activity and achievement of clinical hemostasis by 12 hours after administration. The interim results show that median anti-Factor Xa inhibitor activity was reduced by 88% for patients taking rivaroxaban, 91% for patients taking apixaban, and 75% for patients taking enoxaparin. Few patients in the study had received edoxaban. Excellent or good clinical hemostasis was achieved in 83% of patients overall.
Safety of andexanet was assessed in all 227 patients. At 30 days, 12% of patients had died, and 11% had a thrombotic event (ie, stroke, heart attack, or blood clot in the legs). These rates of adverse events are in line with what would be expected, given the underlying medical condition of the patients in the trial and the fact that many had not resumed anticoagulant treatment during the 30 days after receiving andexanet, Dr. Connolly said. The trial was funded by Portola Pharmaceuticals, maker of andexanet.
Low-Dose Triple Pill Lowers Blood Pressure More Than Usual Care
A pill combining low doses of three blood pressure–lowering medications significantly increased the number of patients reaching blood pressure targets, compared with usual care, said researchers. The combination therapy was not associated with a significant increase in adverse effects.
“Most people—70%—reached blood pressure targets with the triple pill. The benefits were seen straight away and maintained until six months, whereas with usual care, control rates were 55% at six months and even lower earlier in the trial,” said Ruth Webster, MBBS, Head of Research Programs at the George Institute for Global Health at the University of New South Wales in Sydney. “Based on our findings, we conclude that this new method of using blood pressure–lowering drugs was more effective and just as safe as current approaches.”
Despite the availability of effective blood pressure–lowering drugs, high blood pressure remains a major problem around the world, said Dr. Webster. Effectively treating high blood pressure can help to prevent strokes, heart attacks, and kidney problems. Globally, however, many people with high blood pressure receive no treatment, and only about a third of those who are treated achieve recommended reductions in blood pressure. Achieving desired reductions in blood pressure often requires treatment with more than one medication, which increases the complexity of treatment. Patients often have difficulty adhering to regimens that involve taking multiple pills every day.
This study was the first large trial designed to test the theory that starting treatment with low doses of three drugs could achieve better blood pressure control, compared with usual care, and that combining these drugs in a single pill would make it easier for doctors to prescribe treatment and for patients to adhere to it, said Dr. Webster.
The TRIUMPH trial, which was conducted in Sri Lanka, enrolled 700 patients (58% women) whose average age was 56. Trial participants had an average blood pressure of 154/90 mm Hg. Approximately 59% were receiving no treatment for high blood pressure before they enrolled in the trial. In addition to high blood pressure, 32% of participants had diabetes or chronic kidney disease.
Patients were randomly assigned to receive either the combination pill or usual care. The combination pill, or triple pill, consisted of the blood pressure medications telmisartan (20 mg), amlodipine (2.5 mg), and chlorthalidone (12.5 mg). These medications use different mechanisms to reduce blood pressure by relaxing the blood vessels. Usual care meant that patients received their doctors’ choice of blood pressure–lowering medication.
The trial’s primary end point was the proportion of patients who achieved a blood pressure target of 140/90 mm Hg or less (130/80 mm Hg or less in those with diabetes or chronic kidney disease) at six months.
Compared with patients receiving usual care, a significantly higher proportion of patients receiving the triple pill achieved their target blood pressure at six months. The average reduction in blood pressure was 8.7 mm Hg for participants receiving the triple pill and 4.5 mm Hg for those receiving usual care. At six months, 83% of participants in the triple pill group were still receiving the combination pill, and one-third of those in the usual-care group was receiving at least two blood pressure–lowering drugs.
The maximum difference between the two groups of patients was observed at six weeks after starting treatment, when 68% of those receiving the triple pill had achieved a blood pressure within their target range, compared with 44% of those receiving usual care. This result represented a 53% reduction in the risk for high blood pressure for patients receiving the triple pill, said Dr. Webster.
Rates of participants having to change treatment due to side effects were not significantly different between the two groups (6.6% for the triple pill and 6.8% for usual care). This finding should allay concerns that use of the three-drug combination pill could lead to an unacceptable increase in adverse medication side effects, said Dr. Webster.
Each of the drugs in the triple pill is highly effective in reducing blood pressure and preventing deaths and illness due to heart disease and strokes, she added. Each drug represents a different class of blood pressure medication, and previous studies have shown that combining such drugs results in synergistic effects.
“The most urgent need for innovative strategies to control blood pressure is in low- and middle-income countries,” said Dr. Webster.
The study’s findings are also important for high-income countries, she said. “A control rate of 70% would be a considerable improvement even in high-income settings. Most hypertension guidelines in these countries do not recommend combination blood pressure–lowering therapy for initial treatment in all people,” she said. “Our findings should prompt reconsideration of recommendations around the use of combination therapy.”
An inevitable consequence of a necessarily unblinded study is that doctors might manage patients differently, depending on the assigned treatment. It is important to note, however, that this trial was designed to evaluate a new strategy of care in a real-world setting, said Dr. Webster. To minimize the risk of bias in measuring the main outcomes, the number of patient visits was identical in both groups, and all outcomes were standardized and objectively documented, she said.