The following is a guest post submitted by David K. Cundiff, MD, who recently submitted a post that drew a great deal of interest on the site.
Stroke, an American Heart Association/American Stroke Association (AHA/ASA) journal, recently published my systematic review of Anticoagulants for Cerebral Venous Thrombosis (CVT). However, the journal editor rightly classified the review as an “opinion piece” because most of the data were not available in the publications or from the authors. With such a rare disease mostly affecting relatively healthy people younger than 40, why is this important? Well, medical establishment guidelines require that CVT patients receive anticoagulants, and, consequently, physicians prescribe anticoagulants or risk malpractice suits. My “opinion piece,” published in the same journal that published the (AHA/ASA) anticoagulants for CVT guidelines, challenges the evidence basis of those guidelines.
CVT now has a human face. News reports indicate that in December 2012 Hillary Clinton had an acute gastrointestinal illness leading to dehydration, a fall with a concussion, and, finally, a CVT, also called a venous stroke. Her neurologists prescribed full therapeutic dose heparin (unfractionated heparin or low molecular weight heparin). If her treatment followed current AHA/ASA guidelines, she received a vitamin K antagonist (VKA) like Coumadin (warfarin) for at least three months. Clinton’s history of a deep venous thrombosis in 1998, with no provocation other than frequent air travel, might have been considered a factor favoring a longer period of anticoagulation, even lifetime oral anticoagulants, according to AHA/ASA guidelines. After speaking with the neurologist in charge of Clinton’s care, Marc Siegel, MD, of Fox News wrote:
“Since she suffered another blood clot in 1998, she now requires a hematological work-up to make sure she doesn’t have an underlying tendency to form blood clots in the first place – known as hypercoagulability. If she does have that tendency, she will require a more prolonged or even permanent course of blood thinners, as well as an investigation to make sure there is no blood-thickening malignancy. This work-up cannot be completed until she is off Coumadin, which interferes with some of the results.”
(Note: I have no direct knowledge of Clinton’s treatment.)
In the International Study of Cerebral Venous Thrombosis (ISCVT), the largest study of CVT patients ever completed (n=624), a thrombophilia (type of hypercoagulability) was noted in 34% of patients. If Clinton has a thrombophilia diagnosed after two venous thromboses, she is likely to be recommended lifetime Coumadin under the AHA/ACC guidelines, which now guide common clinical practice. At some point in the run up to the Presidential primaries, she will probably have to disclose whether she has a thrombophilia. Consequently, the clinical practice guidelines recommending anticoagulants for CVT could potentially be a factor in selecting our next president. This highlights the importance of the evidence basis of anticoagulant treatment for Clinton or any CVT patient.
A Cochrane review of anticoagulant therapy for CVT based the recommendation in favor of using anticoagulation treatment—full dose heparin followed by a VKA—on two small, inconclusive randomized placebo-controlled trials (RCTs, n=79). Based only on this small Cochrane review, clinical practice guidelines calling for full dose heparin acutely followed by VKAs were subsequently issued by the European Federation of Neurological Sciences and, as mentioned above, the AHA/ASA. Authors of both sets of guidelines had significant financial conflicts of interests, including being authors of the two drug-company-funded randomized trials that formed the basis of the guidelines to prescribe anticoagulants.
My anticoagulants for CVT “opinion piece” evaluated published reports from 1990 to 2013 regarding the efficacy and safety of full dose heparin during initial hospitalization and subsequent VKA treatment. In the 62 randomized controlled trials and observational studies (n=5,155) that I reviewed, most of the data relating anticoagulant status (full dose heparin acutely or not and oral VKAs post hospitalization or not) to outcomes (death, recurrent venous thrombosis, major bleeding, etc.) were missing. I emailed the authors of every study for the missing data and only 7 out of 62 sent me what I requested. Most ignored my request, and a few frankly told me that they refused to cooperate.
One of the trials included in the Cochrane review was conducted in the early 1980s. The other was carried out in the early 1990s. While studies from 1990-1999 favor full dose heparin treatment in hospital, studies since 1999 show a statistically non-significant increase in mortality associated with full dose heparin. About 4% of CVT patients receiving full dose heparin had major or fatal bleeding. Elderly patients (≥ 65 years old) suffered higher than average major bleeding rates. (Hillary Clinton was 65 years old at the time of her CVT.) Selective reporting of the data favorable to full dose heparin could not be ruled out.
Regarding the efficacy and safety of VKAs in elderly people, the ISCVT authors published the only observational study with a detailed report on a relatively large subgroup of elderly people receiving VKAs (n=37). For patients ≥ 65-years-old, the fatal bleeding rate while on VKAs was 0.60%/month (2 deaths in 333 patient-months). This finding had a wide range of error and was almost seven times the fatal bleeding rate for all ages for VKAs in my review (0.09%/patient-month). The ISCVT incidence of major and fatal bleeding in CVT patients < 65-years-old (n=552) was not published, and the authors would not give me that information. Praxis Pharmaceuticals funded the ISCVT. The corporate mission of Praxis Pharmaceuticals is, “development and manufacturing for third parties and the Praxis Group, as well as the marketing of biopharmaceutical products specialised in the treatment of orphan and low-incidence indications.” While a “Praxis grant” was acknowledged as the funding of the ISCVT, financial conflicts of the authors were not acknowledged.
Based on the ISCVT risk in CVT patients ≥ 65-years-old of fatal bleeding, if Clinton takes a VKA or other oral anticoagulant continuously over the next 11 ¼ years (i.e., throughout 2 more Presidential election terms should she win in 2016 and 2020), her cumulative risk of fatal bleeding, would be about 55% (1 – 0.994^135 months). Even if she had only the all ages risk of major and fatal bleeding over the next 11 ¼ years (major bleeding: 0.29%/patient-month and fatal bleeding: 0.09%/patient-month), her risk of catastrophic bleeding before 2025 would be considerable (major bleeding: 32% (1 – 0.9971^135 months) and fatal bleeding: 12% (1 – 0.9991^135 months).
Regarding the evidence supporting VKAs for Hillary Clinton and other CVT patients, the two randomized trials forming the basis of the anticoagulants for CVT guidelines both had patients treated with warfarin for only three months versus placebo treatment. In patients treated with warfarin, there were no venous thrombosis recurrences in 114 months (0%/month). In patients receiving placebos, two venous thrombosis recurrences occurred in 96 months (2.1%/month). However, in all 62 randomized trials and observational studies for which data were available, the risk per month of venous thrombosis recurrence was significantly higher in patients receiving anticoagulant drugs (on VKAs: 0.33%/mo [35 recurrences/10,761 months] versus not on VKAs: 0.20%/mo [63 recurrences /30,963 months]; OR=1.60; 95% CI, 1.06–2.42; P=0.0246). You can be the judge of whether the two randomized trials justify Coumadin treatment with the attendant risks for anyone with CVT, thrombophilia or no thrombophilia.
Again, I have no inside information about the treatment of Hillary Clinton, but I like to believe that she will not receive long-term warfarin treatment and will do just fine.
Her case of CVT should hopefully be a wakeup call about the medical guidelines for CVT and, perhaps, special interest funded guidelines in general. If you look hard enough, just about any medical guideline that calls for purchasing a product or a service is going to be a special interest influenced if not funded guideline. Adhering to randomized controlled clinical trials, which are usually funded by special interests, as the ultimate determiner of clinical guidelines, leads to travesties like the AHA/ACC guidelines calling for anticoagulants for CVT.
While medical practitioners need to follow guidelines, you might consider that the interests of patients, care providers, funders (patients and taxpayers), and the country would be served if the authority for establishing and monitoring compliance with clinical practice guidelines were decentralized. Assuming that “accountable care organizations” (ACOs) under the Affordable Care Act will provide most healthcare for Americans soon, I think that care providers from each ACO, with input from patients, should determine all diagnostic and treatment guidelines for that ACO. Guidelines endorsed by organizations like the AHA/ACC could be the “default” guidelines to be accepted or rejected and replaced by individual ACOs. With diverse guidelines among ACOs, patient outcomes could be compared, leading to improvements in treatment.
With decentralized medical practice guidelines and a diversity of medical intervention strategies in different ACOs, medical research studying the diverse intervention strategies would expand exponentially. More clinical questions could be studied more rapidly, with much less bias and corruption, and at lower costs.
Virtually all healthcare policy wonks agree that at least one-third of medical expenditures go for useless or harmful tests or treatments. However, they strongly disagree on which tests and treatments are useless or harmful. Vesting the medical practice guidelines with competing ACOs rather than special interest nonprofit organizations like the AHA/ACC would lead to a race to the top on quality simultaneously with a race to the bottom on costs. Patients could “vote with their feet” and choose ACOs based on the services covered (and not covered) and the cost of their premiums. If this had been done a decade ago regarding CVT treatment, Hillary Clinton’s life would not have been unnecessarily put at risk by anticoagulant treatment.
Besides the anticoagulants for CVT guidelines, many other medical guidelines are not evidence based to benefit patients. Another controversial medical guideline that I have discussed on this blog recently is drugs for mild hypertension (systolic blood pressure 140-159 and/or diastolic blood pressure 90-99). A Cochrane review that I co-authored showed no evidence that drugs save lives or reduce cardiovascular events for mild hypertensive patients. Critics of our systematic review conclusion say that not enough patients were found (n≈9000) to be conclusive that drugs do not work and that the randomized trials meeting the criteria for entry into the review were over 30 years old. The 18 panelists on the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC-8) will soon decide the matter by issuing their drugs for mild hypertension guideline under the auspices of the AHA/ACC. As is currently the case, the new JNC-8 guidelines will apply to all US physicians. However, allowing competing ACOs the choice of using drugs for mild hypertension or diet and lifestyle interventions alone would settle the question of efficacy of drugs in a few years as patient outcomes are compared. Likewise, AHA/ACC recently issued cardiovascular risk reduction guidelines that call for statin drug treatment for people with greater than 7.5% risk of a heart attack or stroke within 10 years. The “CV Risk Calculator” proposed by the guidelines is widely seen as flawed, yet drug treatment for millions of people will presumably be linked to that calculator.
A few of the many other controversial medical establishment guidelines that could be tested in competing ACOs include prostate specific antigen (PSA) screening for asymptomatic men, mammography screening for asymptomatic women, colonoscopy screening for colon cancer each 10 years versus yearly stool blood test screening for asymptomatic screening, and flu shots for people of any age.
Healthcare and the economy desperately need an evidence based game changer to provide a way forward to improve healthcare quality while reducing costs. In this polarized political climate, the new way forward should appeal to people on the left, right, and center. We need a better evidence-based metric than relying only randomized trials for determining what works and what doesn’t work in medicine. Comparisons of clinical outcomes of competing ACOs using different treatments could fill that bill.
For the sake of people like Hillary Clinton and 300 million other Americans, please consider decentralizing the authority for instituting and monitoring clinical practice guidelines.
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