D-Dimer Testing to Determine the Duration of Anticoagulation Therapy – The Prolong Study November 28, 2006
Posted by rajkmd in Hematology, Uncategorized.2 comments
A D-dimer molecule, abutting ends at the D:D junction as part of the fibrinogen gallery at UCSD.
Background
- The optimal duration of warfarin treatment after deep venous thromboembolism (DVT) for the purpose of preventing future DVTs in unclear
- The risk of recurrance is greatest in the first 6 to 12 months after the initial episode and then gradually decreases.
- Previous studies have suggested that elevated D-dimer levels may predict the risk of developing DVTs in the future
- To test this hypothesis, patients with unprovoked DVTs and a positive D-dimer who were treated with vit. K antagonist for three months were randomized to recieve anticoagulation or to discontinue anticoagulation. Patients that had a normal positive D-dimers test after three months of anticoagulation therapy did not receive further treatment.
Methods
- All patients were treated with a minimum of 3 months of vitamin K antagonist therapy after an unprovoked DVT.
- Inclusion Criteria – Patients who are between the ages of 18 and 85 who had a first episode of symptomatic, unprovoked venous thromboembolism, defined as proximal DVT of the lower legs, pulmonary embolism, or both, all patients needed to be treated with a vit. K antagonist for three months with a target INR of 2.5 (range of 2-3)
- Unprovoked DVT was defined as a DVT not associated with pregnancy, fracture, immobilization, surgery, cancer, antiphospholipid antibody syndrome, or antithrombin deficiency.
- Other exclusion criteria inculded patients who had serious liver disease, renal insufficiency, other indications or contraindications for anticoagulation, or limited life expectancy.
- Pt’s with Factor V Leiden deficiency were allowed in the study.
- Finally, all patients underwent ultrasound to assess the proximal deep veins after three months of treatment with vit. K antagonists. If they had a recurrent DVT, during this time period, then they were excluded from the study.
- All patients were studied for a period of 18 months and were seen at the clinic at intervals of 3 to 6 months.
- This is an intention-to-treat analysis.
- This study was not blinded, though committee members were unaware of the results of the D-dimer test.
Results
- A total of 619 patients underwent D-dimer testing and a thrombophilia workup. Of these, 11 patients were ultimately excluded because they were positive for lupus anticoagulant or antithrombin deficiency.
- Of the 608 patients that were included, 63% had a normal D-dimer level.
- Of the remaining 223 patients with an abnormal D-dimer level , 103 were randomly assigned to receive anticoagulation and 120 were assigned to receive no anticoagulation.
- Of the pts with positive D-dimers
- Of the 120 pts who d/c’d anticoagulation –> 15% developed recurrent venous thromboembolism
- Of the 103 pts who resumed anticoagulation, one had a major bleeding event and 2 had a recurrent venous thromboembolism.
- Adjusted hazard ratio 4.26 (95% CI: 1.23-14.6) with p 0.007
- There was no significant difference in the rate recurrent venous thrmboembolism between the group with normal d-dimers compared to the group with abnormal d-dimers who were anticoagulated (adjusted hazard ratio, 2.46; 95% CI, 0.71 – 8.46), but the absolute difference (6.2% vs 2.9%) may be clinically significant.
Discussion
- The PROLONG study shows that patients with abnormal D-dimer test who were not anticoagulated had high rates of recurrance venous thromboembolism (15%), while pts with normal D-dimer had a significantly lower chance of developing a recurrent thromboembolism (6.2%). The adjusted hazard ratio comparing the rates of recurrance was 2.27 (95% CI 1.15-4.46, p 0.02)
- In patients with a positive D-dimer, when comparing those that were anticoagulated to the those that were not, the group that was anticoagulated had a low rate of bleeding and recurrence of thromboembolism (combined endpoint of 2.9%, p 0.005)
- Patients with abnormal D-dimer were significantly older than patients with a normal D dimer test (average age 70 yo versus 59 yo, p<0.001)
- The study was not powered to make a definitive assessment of the risk of bleeding, since the risk increases with time, the risk/benefit ratio may change as anticoagulation is prolonged.
THE BOTTOM LINE: In patients who have completed at least 3 months of anticoagulation therapy after an unprovoked venous thromboembolism, a positive D-dimer one month after discontinuation of anticoagulation therapy is correlated with the risk of recurrence. In patients with a positive D-dimer test, continuing anticoagulation therapy decreases the risk of recurrent venous thromboembolism when compared to patients who are not anticoagulated regardless of their D-dimer. In sum, this study shows that the D-dimer assay may help guide clinicians on the length of anticoagulation therapy, but it does not definitively establish the optimal course of therapy.
A Medical Discussion on the Use of CT Scans to Screen for Lung Cancer November 24, 2006
Posted by rajkmd in Uncategorized.4 comments
- This in relation to the following article.
- Views from three physicians
- Geoffrey Wittig, M.D., a family practice doctor in upstate New York, who says,
- This study has to be seen as a first crack at the problem, but by no means definitive. Lead-time bias is an obvious and huge problem by its very design. There is also no discussion of the risks and costs versus purported benefit. For instance, even accepting the absurdly optimistic CT cost of $150-200 per study, this translates to $8 billion per year just to scan every American smoker, ignoring the inevitable follow-on costs of biopsies and repeat studies. Then there is the estimated 1:1200 risk of future cancer per CT scan, which quickly becomes a very significant number when you’re scanning millions of smokers. Finally, there is no recognition of the opportunity cost of sinking that $8 billion per year into post-hoc screening, rather than zero-risk smoking cessation.
- George D. Bussey, M.D., the Chief Medical Officer of FirstHealth of the Carolinas, who says
- Re the issue of cost/benefit: Any CT operations folks out there that could address the question of the true marginal cost of adding this type of screening to existing CT capacity? If you have a scanner that has free time in off hours – what would it cost to bring in the staff and pay the other associated costs to run a screening clinic during “off hours?” Medicare and other insurers would have to agree to not force similar rates onto other CT services, but that approach might allow screening to be economially feasible.
- Dr. Michael LoCurcio , a Clinical Instructor at New York University School of Medicine, who says
- I very much agree with the comments made by Drs. Wittig and Bussey. In addition, any screening test will have a tendency to find disease that is relatively more benign when compared to historical data because historically the workups were driven by symptoms (”length bias”). This combined with the lead-time bias makes the comparison of this group’s mortality to estimated mortality very troublesome. When considering these biases, cost, and CT availability, I believe this screening modality should not be employed based on the evidence provided in this study. In the meantime we should continue to use the following tool for lung cancer screening: “Do you smoke” and “Are you exposed to smoke?”
Dr. Marshall Fordyce on the treatment of Community Acquired Pneumonia November 16, 2006
Posted by rajkmd in Uncategorized.1 comment so far
Marshall Fordyce – November 16, 2006[Edit]
The original study of the PORT score (NEJM 336:243, 1997) was validated in more than 28,000 patients predominantly in hospital emergency rooms, and the severity of illness ranged from not so sick (0.1% mortality, Class I) to very sick (29.3% mortality, Class V). Beware that the PORT score, which has evolved into the Pneumonia Severity Index (PSI), was derived to determine expected mortality for a given clinical profile. This rule has then been prospectively studied to ask the question, can the PSI determine the need for hospitalization and reduce costs, and its performance hasn’t been great. American Thoracic Society (ATS) guidelines from 2001 emphasize its limits, resting the decision to hospitalize on your clinical judgment. Thus, I strongly agree with Dr. Mints (and the ATS 2001 guidelines and the Infectious Disease Society of America (IDSA) 2003 guidelines) that over-reliance on clinical prediction rules generally, and specifically for pneumonia, is risky and in no way replaces clinical judgment. That said, by knowing the PSI criteria, we as residents may better appreciate our tools for evaluating the severity of an infection. It may surprise you to learn that hyponatremia, hyperglycemia, and a BUN of >30 add +50 to your points.
I share Dr. Mints’ chagrin that the suggested coverage for microbes associated with aspiration (i.e anaerobes) is pip/tazo and not amp/sulbactam. In my review of the 2001 ATS guidelines, they suggest high dose ampicillin, amp/sulbactam, or “other active beta-lactams” – which sounds consistent with Mints’ comment that anaerobes are likely still susceptible to ceftriaxone. Also, in our practice at Bellevue, we tend to avoid the use of fluoroquinolones when there is a question of TB infection, as levofloxacin is an important component of our armamentarium against drug-resistant TB.
To me, the NYPH guidelines do not seem to suggest a need to observe patients on PO antibiotics. Rather, they apply discharge criteria that are identical to the IDSA 2003 guidelines (temp 36hrs without antipyretics, pulse 90 ,O2sat >90%, taking POs). If these criteria are met, these NYPH guidelines suggest no reason to hold-up discharge.
One principle of CAP therapy not mentioned in the NYPH guide is the IDSA guideline to initiate antibiotic therapy within 4 hours (this is a national hospital “quality of care” measure).
Generally, when I have questions about management of CAP, I turn to the ATS and IDSA websites, which publish their guidelines as PDFs for free. IDSA plans to update their CAP recommendations in the spring of 2007.
Dr. Greg Mints on Community Acquired Pneumonia November 14, 2006
Posted by rajkmd in Uncategorized.1 comment so far
This is in relation to the following post
Greg Mints – November 14, 2006[Edit]
2. I believe that posting other hospital’s guidelines may be useful for some residents, but will result in data overload and confusion among others. Whoever posts similar documents in the future may want to consider including a commentary by one of our local specialists in the matter along with the original posting. I think such a commentary should be specifically solicited post factum in this instance as well.
3. I do not agree with several recommendations put forth in the paper. In general, for cases of suspected aspiration there seems to be very little need for anything beyond the usual Ceftriaxone in the usual dose, since most anaerobes in the mouth are expected to be sensitive. That said, ampicillin/sulbactam (Unasyn) would be a reasonable, but a bit too broad. There is certainly no reason to use Zosyn, as suggested in these guidelines, unless the patient is believed to be at high risk for pseudomonal infection (ex.: recent h/o hospitalization).
4. As a rule, there is no need to observe patients in the hospital once they have been switched to PO Abx, i.e. “If you are well enough to be on PO antibiotics, you are well enough to be home”. The paper seems to suggest otherwise.
5. Bellevue’s recommended oral equivalent of Ceftriaxone is Cefpodoxime, a 3rd generation cephalosporin with in-vitro antibacterial spectrum similar to that of Ceftriaxone.
6. I strongly oppose switching patients from i.v. Ceftriaxone to PO Levaquin. We MUST limit patient exposure to multiple classes of Abx, especially since quinolone resistance is on the rise and resistance to one member in this class of Abx usually means resistance to all (or most) of them.
7. Finally, I urge the practitioners not to over-use the PORT score. As with any clinical prediction rule, one must know whether a particular score is applicable to a particular patient.
a. If memory serves, the score has been validated principally in identifying low-risk patients, who may not need to be admitted. Its performance in identifying all other groups is less well known.
b. Chronic pulmonary diseases are not included in the scoring system. This is important, since patients with COPD, asthma and cystic fibrosis may all have worse prognosis simply because of poorer reserve, and may need to be admitted despite a low PORT score. In addition some of these are characterized by microbiological epidemiology different from the usual community-acquired pneumonia (ex.: pseudomonas is cystic fibrosis, etc.)
c. Immunocompromized patients are a separate population altogether. Among such patients PORT score has not been tested (as far as I know). In my personal experience, patients on chronic steroids and those with AIDS can do quite poorly despite low scores. I therefore strongly advise against the use of PORT score in such patients.
Dr. Rachel Smerd on screening for HIV/AIDS November 11, 2006
Posted by rajkmd in Uncategorized.add a comment
Rachel Smerd – November 7, 2006[Edit]
Universal screening at Bellevue has been under way since late 2005 in the Outpatient, Urgent Care and Inpatient settings. The CDC changed its guidelines earlier this fall to recommend universal testing regardless of risk. To answer Marshall’s question, it appears that the current seropositivity rate at Bellevue is somewhere between 3-4%.
Universal screening is an important method, therefore, to prevent the further spread of HIV in addition to identifying new HIV positive patients. Furthermore, the revised testing guidelines have been able to identify patients who fell out of care. That is, patients who have been HIV+ for years but have not been in treatment are being reidentified through this process and plugged back into the health care system.
Outsourcing healthcare to India October 12, 2006
Posted by rajkmd in Medical Economics, Uncategorized.add a comment
The surgeons aren’t going to be happy. They can outsource elective procedures, but you can’t outsource primary care.
Union Disrupts Plan to Send Ailing Workers to India for Cheaper Medical Care
A few weeks ago, Carl Garrett, a 60-year-old North Carolina resident, was packing his bags to fly to New Delhi and check into the plush Indraprastha Apollo Hospital to have his gall bladder removed and the painful muscles in his left shoulder repaired. Mr. Garrett was to be a test case, the first company-sponsored worker in the United States to receive medical treatment in low-cost India.
But instead of making the 20-hour flight, Mr. Garrett was grounded by a stormy debate between his employer, which saw the benefits of using the less expensive hospitals in India, and his union, which raised questions about the quality of overseas health care and the issue of medical liability should anything go wrong.
“No U.S. citizen should be exposed to the risks involved in traveling internationally for health care services,” Leo W. Gerard, the president of the union, said in a recent letter to the Senate and House committees that oversee health care. He expressed his concern about the willingness of employers to offer incentives to employees to go overseas.
With medical costs in India routinely 80 percent lower than in the United States, experts predict that globally standardized health care delivered in countries like India and Thailand will eventually change the face of the health care business.
Providing health care to foreigners could generate $20 billion for India by 2012, according to a study by McKinsey & Company, the consulting firm, although McKinsey did not say how many patients that figure represents. With 150,000 overseas patients last year — though only a small fraction of them Americans — India is already the global leader in importing foreign patients for low-cost treatment. Its best hospitals have Western-trained doctors and are equipped with modern equipment.
Dr. Greg Mints on Isosorbide and Hydralazine September 27, 2006
Posted by healthweb in Uncategorized.5 comments
This post is in response to the article Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure (NEJM, Nov. 11, 2004)
One of the most interesting and controversial aspects of this paper is how to interpret the racial aspect of it. I wish to make the following comments:
1. There is currently no proof that members of other racial groups would not enjoy the same benefits from the Tx. Previous studies suggesting that AA may gain more benefit from this combo Tx were post hoc analyses and therefore “hypothesis generating” only.
2. There is no proof that in AA hydralazine-nitro combo is better than ACE-BB-aldo inhibitor cocktail. The present study design obviously does not allow for this conclusion. Previous studies, again, were post hoc analyses.
3. Essentially all the existing clinical data available was derived from predominantly Caucasian patients. This has not prevented us, the clinicians, from using the studied interventions in other ethnic groups. Similarly, until proven otherwise, it is not reasonable to withhold a treatment with NNT of 7 from our, say, Hispanic patients. In my practice, I do give hydralazine-nitro to all patients whose BP allows another agent after ACE/ARB, BB, and aldosterone inhibitors have been added
In response to Dr. Orna Kleiman’s questions September 14, 2006
Posted by healthweb in Cardiology, Uncategorized.3 comments
In the comments section….
Can you comment on the other endpoints, ie: did the treatment group also have a significant reduction in LV wall thickness or EF that would go along with the proposed mechanism of the drugs in question reducing myocardial hypertrophy and remodeling? second, just to confirm, all these people were still on beta blocker, ace, +/- arb, and even spironolactone, all the while they were on hydral+nitrate, right? kinda expensive and a tough regimen to maintain as an outpatient…
In the study, Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure (NEJM, Nov. 11, 2004), despite listing change in LV ejection fraction and LV wall thickness as secondary endpts at six months, the study does not report these results in the text or any of its tables.
To be involved in the study patients had to be receiving standard therapy as determined by their physician including beta blockers, ACE inhibitors, diuretics, digoxin, ARBs, and spironolactone. In fact, an interesting aspect of this trial is that almost 70% of patients in both placebo and experimental arms were on ACE inhibitors and more than 70% of patients were on beta blockers.
To apply the findings of the study, then, pt should be maximized on standard therapy before being started on the combination of isosorbide and hydralizine
Combination of Isosorbide Dinitrate and Hydralazine in Blacks with Heart Failure (NEJM, Nov. 11, 2004) September 6, 2006
Posted by healthweb in Cardiology, Uncategorized.4 comments
by Raj Khandwalla
The Big Picture
- An estimated 4.9 million Americans are being treated with heart failure with 550,000 new cases diagnosed each year
- The prevelence increased with age affecting 1-2 percent of persons age 45 to 54 years and up to 10 percent of indiviudals older than 75 yo
- Heart failure is the leading discharge diagnosis in persons 65 years or older with average length of stay around 5.3 days .
- $3.5 billion dollars was spent on Medicare beneficiares for the in-hospital management of heart failure
- The cost of hospitilizations for heart failure is twice that for all forms of cancer and myocardial infarction combined
- This study was funded by the company NitroMed
- Between July, 2004 and November, 2004 (the month this study was published ), NitroMed’s stock increased from $5.9 per share to $25.8 per share – an increase of more than 400%. Currently, the stock is $2.84 per share with a market capitilization of $500 million.
Background
- Neurohormonal inhitibors, such as beta blockers and ACE inhibitors, have been shown to reduce the rates of death and complications associated with heart failure
- Increasing nitric oxide levels in the heart may help slow or reverese the progression of heart disease
- Vasodilator Heart Failure Trial demonstrated benefit of combining nitric oxide donor, isosorbide dinitrate and hydralizine in patients with mild to severe heart failure
- Studies have shown that persons who identify themselves as black on average have a less active renin angiotensin system and lower levels of bioavailability compared to self identified whites
Methods
- A randomized, placebo controlled, double blinded trial
- Study was sponsered by NitroMed
- Inclusion criteria
- pts 18 yo or older, self described as black (defined as of African descent)
- pts NYHA class III or IV heart failure for at least three months were eligible
- pts required to have receiving standard therapy for heart failure as determined appropriate by their physicians
- such therapy included ACE inhibitors, ARBs, beta-blockers, spironolactone, digoxin, and diuretics for at least three months before randomization
- Pt’s also had evidence of LV dysfunction within six months preceding randomization as defined by echo
- Excluson criteria
- acute MI, acute coronary syndrome, or stroke within the preceding three months
- cardiac surgery or PCI within the preceding three months or the likelihood of a requirement of such a procedure within the study period
- presence of sig valvular dysfunction
- presence of hypertrophic or restrictive cardiomyopathy
- uncontrolled hypertension
- requiring inotropes or potential need for cardiac transplantation.
Randomization Procedure
- Initial dose was one tablet containing either placebo alone or hydralazine 37.5 mg 3xdaily combined with isorsobide 20 mg 3 x daily
- The dose was increased to two tablets three times daily for a total daily dose of 225 mg of hydralzine and 120 mg of isosorbide
- Pts were followed for 18 m with assessment of LV EF, LV internal diastolic dimension, LV wall thickness, and level of BNP at 6 months. Quality assessments were completed every 6 months
Outcome Measures
- The primary efficacy end pt was a composite score outlined below
- Death (at any time of trial) -3
- Survival to end of the trial 0
- First hospitilization for heart failure -1
- Change in quality of life at 6 mo (as measured by the Minnesota Living with Heart Failure questionaire)
- Improvement by >10 units +2
- Imoprovement by 5-9 units +1
- Change by <5 units 0
- Worsening by 5-9 -1
- Worsening by >10 -2
- Change in quality of life at 6 mo (as measured by the Minnesota Living with Heart Failure questionaire)
- Secondary end points
- included individual components of aggregate score
- death from cardiac causes
- total number of hospitilizations for heart failure
- total number of hospitilization of any cause
- total number of days of hospitilization
- overall quality of life
- change in BNP
- change in EF
- need for cardiac transplantation
Results
- This trial was stopped owing to a significantly higher motrality rate in the placebo group compared to the isorsorbide and hydralazine
- At the time the trial was halted 54 pts had died in the placebo (10.2 percent) and 32 patients had died in the combination therapy group
- Baseline Characteristics – the significant differences
- combination pill group was less likely to be male 55.8% vs 63.9%
- combination pill group was more likely to have diabetes 44.8% vs 37%
- combination pill group had increased diatolic pressure and slightly better Minnesota Living Scale
Discussion
- 43 percent reduction in the mortality rate in the group given combination pill
- An absolute reduction of mortality of 4% and a number needed to treat of 25 patients for every life saved
- Adverse effects
- the placebo group had significantly higher rates of CHF exacerbations
- the combination pill group had significantly higher rates of headache and dizziness
- All of these pts were on optimal medical therapy and the benefit may may be consistent with the existence of an alternative mechanism of controlling heart failure
- Isorsobide dinitrate is a nitric oxide donor and hydralazine confers protection against the degradation of nitric oxide
- Proposed mechanisms
- nitric oxide regulates cardiovascular processes including myocardial hypertrophy and remodeling as well as helping endothelial dysfxn
