Medical errors are the third leading cause of death in the U.S., after heart disease and cancer, causing at least 250,000 deaths every year, according to an analysis out Tuesday indicating that patient safety efforts fall far short.

"People don't just die from heart attacks and bacteria, they die from system-wide failings and poorly coordinated care," says the study's lead author, Dr. Martin Makary, a professor of surgery and health policy at Johns Hopkins University School of Medicine. "It's medical care gone awry."

The magnitude of the death toll – roughly 10 percent of U.S. deaths annually – is striking coming, as it does, in an era dominated by efforts to reform the health system to ensure safe, high quality, high-value medical care. Patient safety efforts have failed to gain much traction, Makary says, because there's no systematic effort to study medical errors or to put effective safeguards in place.

"Throughout the world, medical error leading to patient death is an under-recognized epidemic," Makary and his co-author, Dr. Michael Daniel, also of Johns Hopkins, write in Tuesday's British Medical Journal. They define medical errors as lapses in judgment, skill or coordination of care; mistaken diagnoses; system failures that lead to patient deaths or the failure to rescue dying patients; and preventable complications of care.

Their report comes nearly two decades after "To Err is Human," a report by the Institute of Medicine, asserted that medical mistakes are rampant in health care. The IOM, a quasi-public think tank made up of leading scientists, drew on existing data to estimate that 44,000 to 98,000 people die in U.S. hospitals each year. Even then, some researchers claimed the estimates were low and based on outdated information.

The new estimate is drawn from more-recent studies indicating the number may be much higher. For instance, a report published in the journal Health Affairs in 2011 calculated that just over 1 percent of hospital patients die each year because of medical errors. When applied to the more than 35 million people hospitalized each year, Makary and Daniel say, this would "translate into 400,201 deaths per year, more than four times the original IOM report estimate."

The Hopkins team used evidence from four studies that analyzed medical death rate data from 2000 to 2008, including one by the U.S. Department of Health and Human Services' Office of the Inspector General and the Agency for Healthcare Research and Quality. Using these data, they were able to calculate a mean death rate for medical errors in U.S. hospitals. Applying this rate to the 35 million admissions in 2013, they calculated that 251,454 deaths resulted from medical mistakes.

The researchers acknowledge that this figure most likely represents an undercount, because they were unable to capture data from deaths that occur in outpatient clinics, nursing homes and other non-hospital settings where health care workers care for fragile patients who need complex care.

"It's fair to say that this number is controversial," says Dr. Robert Wachter, a professor of medicine at UCSF School of Medicine. "I wouldn't take this number to the bank."

Dr. Ashish Jha, a patient-safety expert and director of the Harvard Global Health Institute, agreed that many researchers will be temped to debate which of the estimates are the most accurate.

"It doesn't matter," he says, "because all these numbers are so big. They're a reminder of how big the problem is and how little is being done to address it."

Much of the effort put into patient safety and performance improvement over the last two decades has been misdirected or ineffective, Jha says. "If you called the CEO of a big hospital and asked, 'How many medical errors did you have last month? How many falls? How many falls that resulted in serious injury?' They won't know."

Another issue, Wachter says, is that patient safety is being crowded out by newer initiatives. "My concern," he says, "is that patient safety efforts, which gained so much momentum following the publication of the IOM report, have lost ground in recent years, defused by all the other performance improvement mandates that have come down the highway."

Makary and Daniel are calling for reforms that would improve the reporting of medical errors, which in turn could inform prevention efforts. In a letter dated May 1, they asked the Centers for Disease Control and Prevention, which gathers births, deaths and other vital statistics, to rank medical errors on the list of leading causes of death. They also asked CDC to alter death certificates so that doctors, medical examiners and coroners can routinely report medical errors that contribute to a patient's death.

The letter takes pains to point out that the U.S. government and private sector spend "a lot of money" on heart disease and cancer research and prevention. "It is time for the country to invest [a proportional amount] in medical quality and patient safety," it says.

So far, the researchers have not received an official response, but CDC officials acknowledged that errors are under-reported and that there are ways to capture the data, Makary says. CDC experts were not available for comment.

Wachter is skeptical that the practice of using death certificates to report medical errors will take hold among doctors. "The idea they’ll begin recording this faithfully, or without concern for a malpractice suit, doesn’t strike me as very plausible," he says.

Makary adds that it was his perception that medical-error research is "underfunded and under-appreciated" that prompted him to embark on an analysis that would elevate fatal mishaps to their proper place near the top of the list of all causes of death.

The findings, Jha says, illustrate that the policies and practices we're putting in place "are completely inadequate to the size of the problem we have."