Emerging Risks With New Stroke Prevention Drugs

The Food and Drug Administration (FDA) has recently approved two new drugs, dabigatran (PRADAXA) and rivaroxaban (XARELTO), for preventing stroke in patients with irregular and often rapid heartbeat, which is called atrial fibrillation. These two drugs — along with a third drug still under review by the FDA, apixaban (proposed name: ELIQUIS) — represent a new generation of anticoagulants intended to replace the drug that for more than 50 years has been the trusted medication of choice in stroke prevention: warfarin (COUMADIN, JANTOVEN, ATHROMBIN).

The three new anticoagulants promise improved convenience over warfarin, which requires cumbersome monitoring, dose adjustment and dietary restrictions. Initially, the success of these drugs in the marketplace appeared virtually guaranteed. Early reports suggested that each was no worse than warfarin at preventing strokes, with one perhaps slightly better. The drugs also appeared to cause less bleeding in the brain, a side effect of warfarin.

However, subsequent clinical experience has told a more complicated, worrisome story, as reports of bleeding events from the new drugs have skyrocketed. Physicians also have found that bleeding caused by the new anticoagulants is harder to treat than bleeding caused by warfarin. For these reasons, patients should avoid starting the new anticoagulants until better information is available on the risks of these new drugs.

Overview of bleeding risks

Almost immediately after dabigatran hit the market in late 2010 as the first of the three new anticoagulants, case reports of severe side effects involving bleeding began to emerge. A 78-year-old Florida woman with a history of kidney problems began vomiting and was rushed to the hospital with signs of internal bleeding; doctors suspected that dabigatran may have been the cause. They attempted to treat her with blood-clotting agents and eventually turned to dialysis. Her blood test results showed improvement following treatment, but the bleeding continued to grow worse. She died a few days later.

The cases continued: A 74-year-old man began vomiting blood while on dabigatran. Doctors placed him on dialysis, but his symptoms continued, causing complications that were eventually fatal. An 83-year-old man taking dabigatran was hospitalized with uncontrolled bleeding after hitting his head in a fall. A 71-year-old woman developed abnormal, widespread bruising and swelling after surgery, despite ceasing use of dabigatran two days before the operation.

Rivaroxaban came on the market in July 2011, and more reports of bleeding followed. A 61-year-old, healthy woman taking rivaroxaban after surgery developed severe back pain and temporary paralysis from a buildup of blood near her spine. A 58-year-old man arrived at the hospital with life-threatening internal bleeding after four weeks on the drug. Doctors helped him to discontinue rivaroxaban, and his bleeding resolved.

Even more troubling than the number of reports was the nature of the bleeding problems that developed. All anticoagulants used in stroke prevention, including the traditional treatment of warfarin, carry bleeding risks. However, the anticoagulant effects of warfarin can be quickly reversed using vitamin K, blood plasma and/or clotting agents. It also is relatively easy to measure the levels of warfarin in the blood. In sharp contrast, there is no simple treatment known to reverse the adverse effects of dabigatran or the other similar new longer-acting agents, and no available test can accurately measure the levels of these drugs in the blood.

In December 2011, following the upsurge in reports of severe bleeding, the FDA issued a new safety communication warning of the bleeding risks associated with dabigatran. (Rivaroxaban already had a boxed warning describing bleeding risks.) In the April 2012 issue of Worst Pills, Best Pills News, we used these two drugs as good examples of our “7-Year Rule,” recommending that patients wait at least seven years from the date of release to take any new drug that is not a rare “breakthrough” drug (one that offers a documented therapeutic advantage over older, proven drugs). Additional risks from these new anticoagulants are still emerging and include potential heart attack, rebound stroke and drug interaction, as well as special risks for the elderly and those with kidney or liver issues or replacement heart valves.

The possibility of emerging risks may not sway those who are frustrated by the limitations and potential dangers of warfarin and are thus seeking new alternatives. Relatively little is known about the new anticoagulants, and even the experts disagree about assessing the emerging risks and choosing between warfarin and the new drugs. This lack of data and the absence of available options to manage side effects mean the number of extra injuries and death from the new drugs is likely to rise in the coming years.

Missed warning signs of risk

The first published reports of the pivotal dabigatran, rivaroxaban and apixaban trials presented the drugs as effective and relatively safe compared to warfarin: Each was effective at preventing blood clots in the brain in people with atrial fibrillation. Moreover, each drug seemed less likely to cause serious bleeding than warfarin — particularly bleeding in the brain, which can cause stroke. Almost immediately, the editorial pages of top medical journals were abuzz with glowing reviews of the drug trio, heralded by some as “a new era” for stroke prevention.

The FDA granted priority review status to two of the drugs, dabigatran and apixaban, and rushed to assess the new treatments. Yet as the agency pushed for speedy approval, a few cautious experts began to delve deeper into the data and raised concerns that the picture might not be as bright as it first appeared. FDA review teams identified errors, signs of poor monitoring, gaps in information and other concerns with the clinical data submitted in the drug applications, and they asked for clarifications and corrections from the drug companies. There were safety signals as well: One FDA reviewer flagged data showing that dabigatran might actually increase the risk of heart attack compared to warfarin, and an FDA advisory panel noted apprehensively that rivaroxaban could lead to liver toxicity if used over a long period to prevent stroke.

Public Citizen was one of the strongest voices against approval of rivaroxaban for stroke prevention in patients with atrial fibrillation, submitting a set of comments in October 2011 opposing the approval. At the time, we cited evidence from FDA review documents that researchers had given unusually low doses of warfarin to the control group in one key clinical trial, making rivaroxaban look better than it should have in comparison to what was clearly an inadequate dose of warfarin. Public Citizen also pointed to disturbing evidence that people experienced rebound strokes when they stopped rivaroxaban and switched back to warfarin.

Yet these early warnings did not stop the FDA from granting approval. Ultimately, FDA officials determined that enough data were available to show that the benefits of dabigatran and rivaroxaban outweighed the risks, and the agency believed the drugs could be marketed safely. Dabigatran was approved for stroke prevention in atrial fibrillation in October 2010. In July 2011, rivaroxaban was approved to treat blood clotting in the legs or main artery of the lung, to prevent recurrence of such clotting, and to prevent blood clotting in the legs after a hip or knee replacement surgery. In November 2012, it was approved for stroke prevention in patients with atrial fibrillation. Apixaban is not yet approved in the U.S., but it is undergoing priority review with approval expected soon.

A ‘growing public health emergency’

The demand for anticoagulants in the U.S. is enormous: In 2007, an estimated 2.2 million Medicare beneficiaries had atrial fibrillation requiring long-term treatment with anticoagulant drugs, and the prevalence of the condition is rising steadily. Most of those patients who are in treatment remain on warfarin, but sales of dabigatran have been climbing at an aggressive pace. In the year following dabigatran’s approval, more than 1 million prescriptions were dispensed, a number that more than tripled during the following year.

All anticoagulants carry certain risks. The same anti-clotting properties that protect against ischemic stroke (stroke related to blood clots) also can inhibit the body’s natural ability to stop uncontrolled bleeding in the brain and other areas of the body. Warfarin’s bleeding risks are well-understood: Roughly 2 percent of patients taking the drug for stroke prevention can expect to experience a major bleeding event each year. Based on information from clinical trials, researchers had no reason to suspect that the overall rate of bleeding events with dabigatran, rivaroxaban and apixaban would be any higher — and some data suggested that the rates of bleeding may even be lower. The type of bleeding also is different. The new drugs appear to be less likely to cause bleeding inside the brain, but this benefit may be balanced by increased risk of bleeding in the digestive tract.

Following approval, dabigatran quickly outpaced warfarin as one of the top drugs reported to the FDA for serious side effects. In 2011, dabigatran accounted for 3,781 serious adverse event reports, including 542 patient deaths. Warfarin, which remains far more widely prescribed than dabigatran, accounted for only 1,106 adverse event reports and 72 deaths during the same period. The total number of serious adverse event reports for rivaroxaban is smaller but climbing. Reports of side effects with rivaroxaban more often come from patients taking the drug to prevent blood clots in the legs after hip or knee replacement surgery, which was the original approved use and probably remains a more common use for this drug.

Dabigatran and rivaroxaban are new drugs, making it more likely that doctors will pay attention and report side effects when they occur with these drugs than with the more-established warfarin. The large number of patient deaths prompted the FDA to reassess the drug’s bleeding risks, but ultimately the agency decided not to change the labeling or restrict use of the drug.

In addition to the sheer number of bleeding reports, predicting and managing bleeding risks has proven challenging. Experts still are not certain what the right dose will be for certain high-risk patients, such as elderly patients or patients with kidney or liver problems. People in these groups process the drug differently, and the standard dose may be too high for some of them. Clinical trials have not been designed to identify the right dose for these patients, and the labels for dabigatran and rivaroxaban do not provide special instructions for these groups other than an estimated dose adjustment for those with severe kidney impairment. The lack of adequate warnings and instructions results in inappropriate dosing in some cases. Dabigatran presents a particular concern to people with kidney problems because the drug is sold at a higher dose with the expectation that 80 percent of the drug will be removed from the blood by a healthy person’s kidneys.

To make matters worse, it is difficult for doctors to identify when toxic buildup of either drug has occurred, because most tests available to measure the presence of anti-clotting agents are not very effective with the new anticoagulants. Researchers are working to develop a test to measure blood levels of dabigatran, but this test is unavailable in the U.S.

Most importantly, there are no established antidotes that can reverse the effects of the new anticoagulants in the case of a major bleed, although the makers of all three drugs have been working to develop such reversal agents. Doctors will typically respond to moderate or severe bleeding by stopping the anticoagulant medication and trying blood plasma, clotting agents and dialysis. There is little evidence that these treatments actually improve outcomes, and injections of blood plasma or clotting agents have not shown much effectiveness in early animal tests. Dialysis can be used to remove dabigatran from the blood in cases of severe bleeding or kidney damage, but it has not been well-tested in clinical trials and is impractical in many emergencies.

Other risks continue to emerge. A recent meta-analysis of published trial data suggested that patients taking dabigatran were about one-third more likely to experience a heart attack or other type of acute coronary syndrome compared with those on warfarin, enoxaparin (LOVENOX) or a placebo. The FDA recently warned against using dabigatran in patients with mechanical heart valves after a clinical trial in Europe had to be stopped because users with mechanical valves were more likely to experience strokes, heart attacks and blood clots compared with people taking warfarin. Rivaroxaban has its own unique risks, including potential liver damage. It also carries a black box warning of the risk of rebound stroke in patients who discontinue the drug and the risk of long-term or permanent paralysis due to spinal bleeding in patients who take rivaroxaban and receive an epidural.

To add to the uncertainty, doctors have begun prescribing the new drugs for off-label uses. An assessment of adverse event reports showed that dabigatran had been prescribed for its approved use in atrial fibrillation in only 36 percent of the reported cases of adverse events. In other cases, doctors were prescribing dabigatran for general stroke prevention or prevention of blood clots following surgery. Off-label uses may be especially risky because the ratios of benefit to harm have not been measured. The FDA recently rejected an application for what would have been the largest use of rivaroxaban, to treat acute coronary syndrome, after the agency’s advisory committee voted against approval. The FDA rejected the application because the drug had not demonstrated benefits that justified the risk of side effects.

Writing for the Annals of Internal Medicine, one expert recently described the skyrocketing number of safety reports and other concerns with the new anticoagulants as a “growing public health emergency” and advised doctors to be “extraordinarily conservative in considering whether these medications are appropriate replacements for warfarin.”

What You Can Do

Never stop taking a medication without consulting with your doctor. This is particularly important with anticoagulants, because stopping suddenly increases your risk of stroke from blood clots.

If you are already taking dabigatran or rivaroxaban, talk to your doctor about how to watch for signs of bleeding, including unusual bleeding or bruising; pink or brown urine; red or black, tarry stools; or coughing or vomiting blood. Joint pain, headaches or dizziness, unusual nose bleeds, and unusually heavy menstrual bleeding also can be signs of concern. If you have these symptoms, a doctor should evaluate you and decide whether you should discontinue treatment (which carries its own risks), receive a blood transfusion or be placed on dialysis. Talk to your doctor about lowering your dose if you have kidney problems. Stop taking these drugs, under your doctor’s supervision, prior to having surgery or receiving a spinal injection, and remember that older adults and those with kidney or liver problems may have to wait an especially long time for the drugs to clear from their systems. You might also present this article to your doctor and discuss the risks and benefits of switching to warfarin.

Avoid starting dabigatran or rivaroxaban if you are being prescribed an anticoagulant for the first time, and do not switch to these drugs if you are taking warfarin. Although one or more of the new anticoagulants may eventually be used safely and effectively in clinical practice (if the right tests and antidotes can be developed), at present they clearly carry risks, and too little is known about them at this time to abandon warfarin as the trusted alternative.