Last week, KevinMD published my blog titled “The anticoagulant standard of care nobody tested.” This week I’ll continue with a discussion of patients who may have been harmed by anticoagulants.
In 2001, two co-authors and I initiated a systematic review of “Anticoagulants versus non-steroidal anti-inflammatories or placebo for treatment of venous thromboembolism.” The Cochrane Database of Systematic Reviews delayed publishing it until 2006. Because of the delays, Medscape General Medicine published my review of “Pharmacotherapy for Venous Thromboembolism” in 2004. The chief editor of Medscape General Medicine, Dr. George Lundberg, followed my review with a commentary titled “Is the Current Standard of Medical Practice for Treating Venous Thromboembolism Simply Wrong?”
In 2009, Dr. Lundberg and Medscape General Medicine published my article, “A Systematic Review of Cochrane Anticoagulation Reviews,” concluding:
The efficacy of anticoagulants for treatment and prophylaxis for 30 current medical indications should be reconsidered by the scientific community and medical regulatory agencies. By my estimate, a substantial number of people per year worldwide may have fatal bleeding associated with anticoagulant treatment or prophylaxis for these indications.
Cochrane’s authors of these 57 systematic reviews of indications for anticoagulants did not comment publicly. In my outreach to the 57 other teams besides mine authoring systematic reviews, 15 lead authors responded and the rest did not. About three weeks after publication, Medscape administrators closed down Medscape General Medicine. Dr. Lundberg then became Medscape General Medicine editor at large, a title that he still holds.
Whereas in 2009 my systematic review of Cochrane anticoagulation reviews argued that none of the 58 reviews, including mine, was, in my assessment, fully evidence based and accurate, an assessment in 2026 of the original 58 Cochrane anticoagulation reviews found, in my view, only seven that I would still consider not fully evidence based and accurate. Today, I am highlighting the first of those seven: “Heparin versus placebo for non-ST elevation acute coronary syndromes.”
The Cochrane authors’ conclusions
“Compared with placebo, patients treated with heparins had a similar risk of mortality, revascularization, recurrent angina, and thrombocytopenia. However, those treated with heparins had a decreased risk of myocardial infarction and a higher incidence of minor bleeding. Overall, the evidence assessed in this review was classified as low quality according to the GRADE approach. The results presented in this review must therefore be interpreted with caution.”
The GRADE approach, which stands for Grading of Recommendations Assessment, Development, and Evaluation, is the global gold-standard system used by medical scientists, clinical trialists, and major organizations (like the Cochrane Collaboration and the World Health Organization) to rate the quality of health care evidence and the strength of medical recommendations.
The clinical case I would raise about heparin use for acute coronary syndrome (ACS)
In my reading, the Cochrane authors of this review did not emphasize what I see as a meaningful imbalance between trial data drawn from highly selected subjects and the potential for real-world harms in unselected patients.
The systematic review analyzed eight randomized controlled trials comprising 3,118 subjects. In these highly idealized cohorts, heparin more than doubled the relative risk of severe hemorrhage compared to the control group (risk ratio: 2.05). Twelve out of 1,582 heparin-treated patients suffered a trial-defined major bleed, compared to just five out of 1,536 in the placebo group.
A concern, in my view, is that this clinical risk may be understated by these artificial trial environments. Tightly controlled studies systematically exclude many of the individuals who populate real-world community clinics, specifically the frail elderly, females, individuals with underlying anemia, and those with impaired kidney function. When these unselected community populations are treated according to standard American Heart Association/American College of Cardiology (AHA/ACC) guidelines, bleeding rates rise substantially.
Large-scale observational data point to this safety gap:
In the GRACE registry of 24,045 real-world patients, the incidence of major in-hospital bleeding reached 3.9 percent, rising to 4.8 percent for ST-elevation heart attacks.
The CRUSADE registry of 89,134 community-treated patients reported that for individuals categorized as “very high risk” due to baseline medical co-factors, nearly one in five patients (19.5 percent) suffered an in-hospital major bleeding event.
When these observational percentages are extrapolated to annual nationwide and global volumes, the potential public health burden of heparinization, by my estimate, becomes significant:
United States: Out of roughly 1 million annual ACS hospitalizations, an estimated 31,000 to 55,000 patients may suffer major bleeding, and 800 to 3,200 may experience direct fatal bleeding events each year. Furthermore, between 15 percent and 20.9 percent of community patients who bleed may not survive to hospital discharge.
Globally: Out of 15 to 20 million annual ACS cases, an estimated 525,000 to 900,000 patients may develop major bleeds, and 30,000 to 40,000 may die from direct hemorrhages annually.
Additionally, heparin carries unique and serious absolute risks. It can trigger heparin-induced thrombocytopenia (HIT), a life-threatening immunological reaction that causes platelets to crash while paradoxically inciting widespread, chaotic vascular blood clots. Layering acute heparin on top of chronic oral anticoagulants, or administering it to patients with uncontrolled hypertension, can similarly introduce a high risk of hemorrhagic stroke.
In my assessment, this evidence suggests that broad heparin usage may, in some cases, prioritize a textbook metric over the complex reality of the community patient, and may be an underappreciated contributor to non-cardiac hospital mortality.
Editor’s note: The following is a personal account and opinion piece reflecting the author’s own views and recollections. No patient should stop or change a prescribed medication without first consulting their own physician.
David K. Cundiff is a physician, author, and health care reform advocate whose work centers on transforming the U.S. health care system and addressing broader societal challenges, including climate change. He is a volunteer collaborator with the Institute for Health Metrics and Evaluation.
From 1981 to 1998, Dr. Cundiff practiced, taught, and conducted clinical research in internal medicine and pain control at the Los Angeles County + USC Medical Center, where he directed the Cancer and AIDS Pain Service for nine years, and previously held an academic affiliation with Harbor-UCLA Medical Center. After exposing how systemic inefficiencies increased hospital utilization and revenue, he became a whistleblower, an experience documented in Whistleblower Doctor: The Politics and Economics of Pain and Dying.
He is the author of Grand Bargains: Fixing Health Care and the Economy, which proposes structural reforms to dramatically reduce health care costs while improving outcomes. His essay “Much Better Healthcare for Way Less Cost” explores accountable care cooperatives and community-based reform. Additional works include Money Driven Medicine: Tests and Treatments That Don’t Work and Euthanasia Is Not the Answer: A Hospice Physician’s View.
Outside his professional work, Dr. Cundiff values time with friends and family, including six grandchildren, and maintains his health through Hatha yoga, meditation, swimming, Zumba, biking, and a diet emphasizing minimally processed organic food. He shares updates on LinkedIn.
