Our What’s New in the Patient Safety World column for July 2009 “Unintended Consequences of a DVT Prevention Strategy” reported on a study (CLOTS trial 1) which showed that not only do thigh-high graduated stockings not prevent DVT in stroke patients, they actually cause harm. Skin breaks, ulcers, blisters, and skin necrosis were significantly more common in patients allocated to GCS than in those allocated to avoid their use.
Now the CLOTS Trial 2 has published its results and they absolutely confuse the issue! Clots Trial 2 compared thigh-length graduated compression stockings to below-knee stockings and found fewer cases of VTE with the thigh-length stockings. The study populations and protocols for the two trials were the same, though the sites differed. The CLOTS Trial 2 was discontinued early because of the results of CLOTS Trial 1 but had already reached its predetermined enrollment goal. Proximal DVT, the primary study outcome, had an absolute risk reduction in the thigh-length group of 2.5% and the relative risk reduction was 31%. There were no differences in distal DVT, pulmonary emboli or deaths between the 2 groups. There were more cases with skin problems in the thigh-length group but these were relatively mild.
The authors consider several possible explanations for the seemingly contradictory results of the 2 trials. One is that below-knee stockings might actually increase the risk for DVT in stroke patients. The other is that the first CLOTS trial may have underestimated a positive effect of the thigh-length stockings.
We concur with the accompanying editorial (Kearon 2010) that there remain significant uncertainties as to how to best prevent DVT in stroke patients. Moreover, these studies highlight the need for randomized controlled trials of graduated compression stockings in other patient populations since they are so widely used in other patient populations. Even in surgical patients, where graduated compression stockings have been shown in multiple studies to reduce the occurrence of VTE, there has been no comparison of thigh-length vs. below-knee stockings. And while guidelines generally recommend use of thigh-length stockings, below-knee stockings are probably used more frequently in actual practice.
So in stroke patients, where concerns about use of pharmacologic VTE prophylaxis remain, we currently still don’t have strong evidence to support the use of graduated compression stockings as a mechanical alternative. We will have to await the results of the CLOTS Trial-3, which is looking at both the efficacy and safety of pneumatic compression stockings in stroke patients.
The CLOTS Trials Collaboration. Effectiveness of thigh-length graduated compression stockings to reduce the risk of deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised controlled trial. The Lancet 2009; 373:1958 - 1965, 6 June 2009
The CLOTS (Clots in Legs Or sTockings after Stroke) Trial Collaboration. Thigh-Length Versus Below-Knee Stockings for Deep Venous Thrombosis Prophylaxis After Stroke
A Randomized Trial. Annals of Internal Medicine 2010. Published early on line September 21, 2010
Kearon C, O'Donnell M. (Editorial). Should Patients With Stroke Wear Compression Stockings to Prevent Venous Thromboembolism? Annals of Internal Medicine 2010. Published early on line September 21, 2010
We incorporate risk assessment for venous thrombembolism (VTE) into most standardized order sets, whether paper-based or for computerized physician order entry. In almost every setting we have encountered pushback on behavioral health units. Because most behavioral health inpatients are ambulatory, most are considered to be at low risk for VTE. Yet almost every behavioral health unit has one or two occurrences of DVT or pulmonary embolism each year.
A new large population-based case-control study (Parker 2010) shows a 32% increased risk for VTE in patients prescribed antipsychotic medications within the past 24 months. The risk was almost double in patients newly prescribed antipsychotics (within the past 3 months) and was higher for atypical antipsychotics and for low rather than high potency drugs. The overall absolute risk, however, was low. The estimated number of excess cases per 10,000 patients was 4 for all ages and 10 for patients aged 65 or older.
The accompanying editorial (Liperoti 2010) notes that the low absolute risk does not justify VTE prophylaxis in most patients prescribed antipsychotics but recommends that this should be considered along with other VTE risk factors in making such decisions. Nevertheless, they also caution that many antipsychotics (particularly newer atypical ones) are often prescribed for conditions for which little evidence of efficacy exists.
The study, however, has implications that extend well beyond behavioral health. In fact, the study was carried out on a large primary care population. And the majority of prescribing of antipsychotic agents was actually probably for conditions like nausea and vomiting or vertigo rather than for a primary psychiatric disorder (eg. chlorpromazine).
And, obviously, nursing home patients are especially at risk because of the frequent use of antipsychotic medications in those settings. It has been well known for some time now that antipsychotic drugs in elderly patients with dementia are associated with significantly increased risk of death. Perhaps this increased risk of VTE may play a role in that mortality risk.
Parker C, Coupland C, Hippisley-Cox J. Antipsychotic drugs and risk of venous thromboembolism: nested case-control study. BMJ 2010; 341:c4245
Liperoti R, Gambassi G. Editorial: Antipsychotics and the risk of venous thromboembolism. BMJ 2010; 341:doi:10.1136/bmj.c4216 (Published 21 September 2010)
One concept that has generated a lot of attention in preventing nosocomial infections is use of catheters and other implanted devices that are impregnated with either antibiotics or other antimicrobial substances (eg. silver). Such have been used for urinary catheters, endotracheal tubes, etc.
External ventricular catheters used in neurosurgery are associated with CSF infections in 2% to 23% of cases. Some centers have begun to use prophylactic antibiotics in attempt to reduce the occurrence of such nosocomial infections. But prophylactic antibiotics also have the potential to lead to emergence of antibiotic-resistant organisms and predispose patients to C. difficile infections. So, in theory, a ventricular catheter impregnated with an antimicrobial agent might prevent nosocomial infection and not predispose to these other undesirable complications.
A neurosurgery unit in Hong Kong has piloted use of such an antibiotic-impregnated external ventricular catheter (Wong 2010). They randomized patients undergoing emergency neurosurgical operations to either the antibiotic-impregnated ventricular catheter (impregnated with clindamycin and rifampicin) or a conventional catheter plus prophylactic intravenous antibiotics (ampicillin-sulbactam and ceftriaxone). The study was not blinded, however, since the catheters were of different colors.
They found no significant difference in nosocomial infections between the two groups, nor differences in the incidence of CSF infection, ICU length of stay, total acute hospital stay, or functional outcome and the rate of other complications was not different. They concluded that the antibiotic-impregnated catheters were as effective as systemic prophylactic antibiotics in preventing CSF infection and that nosocomial infection rates were not significantly different. They also suggest that the antibiotic-impregnated catheters are more cost-effective when the catheters must in place for 6 days or more.
Keep in mind that use of antibiotic “prophylaxis” in such cases is a controversial topic.
Our advice on how to avoid CSF infections due to ventricular catheters: avoid unnecessary use of them! A few years ago a neurosurgery resident was considering a quality improvement project to see what interventions reduced the rate of CSF infections in patients with ventricular catheters. We noted that the most important outcome should not be the rate of catheter-associated CSF infections but rather the total number of CSF infections in patients undergoing the neurosurgical procedures. Just as with catheter-associated urinary tract infections (CAUTI’s), the most important intervention is avoiding use of the catheter in the first place. In almost every neurosurgery unit we’ve looked at, particularly those in academic or teaching settings, we find lots of ventricular catheters of questionable indication. So before you implement a program of either prophylactic antibiotics or antibiotic-impregnated catheters, make sure you have clearcut criteria for when a ventricular catheter should be used and monitor your compliance with those criteria.
Wong GKC, Ip M, Poon WS, et al. Antibiotics-impregnated ventricular catheter versus systemic antibiotics for prevention of nosocomial CSF and non-CSF infections: a prospective randomised clinical trial. Journal of Neurology, J Neurol Neurosurg Psychiatry 2010; 81: 1064-1067
We’ve written frequently about the unintended consequences of CPOE and other high tech interventions. A new article (Strom 2010) describes how a hard-stop alert to prevent co-prescribing two medications was very effective at its intended goal but resulted in some unintended consequences that led to discontinuation of the alert.
A clinically important interaction between warfarin and trimethoprim-sulfamethoxazole had been identified. Adding that antibiotic to warfarin therapy has often resulted in elevation of the INR and clinical episodes of bleeding. At the study sites a pharmacy intervention had been used in the past to try to avoid this combination of drugs. The authors therefore designed a controlled trial (randomizing physicians to either the intervention group or a control group) to see if a hard alert during CPOE would reduce the frequency that this combination was ordered. The intervention was a popup alert that basically prevented them from ordering the other drug when one of the drugs had been ordered. It appeared with an explanation for the alert and ordering clinicians had 2 ways to override the alert. One was to state that the trimethoprim-sulfamethoxazole was for Pneumocystis carinii pneuomonia prophylaxis. The other was to call the pharmacy.
The primary end point measured was the proportion of desired responses (i.e. not ordering the alert-triggering drug within 10 minutes of the alert firing). The desired response was seen in 57.2% of the intervention group and only 13.5% of the control group (odds ration 0.12). So this was a highly effective hard-stop alert, though the effectiveness did decline somewhat over the 3-month study period. However, there were 4 significant unintended consequences noted. These were delays in administration of either warfarin (2 cases) or the antibiotic (2 cases), the delays being for up to 3 days in some patients. Though no actual patient harm could be ascribed to these, the IRB decided to stop this study early because of the potential for patient harm.
This study highlights the critical importance any time you roll out a new clinical decision support tool (be it a computerized alert or a standardized order set) of monitoring usage of the tool, how often the alert is overridden, whether the desired goal is achieved, and whether unintended consequences occur. You need to have a formal process by which you assess all the above. Sometimes our most well-intended evidence-based patient safety interventions end up causing unintended consequences that may produce patient harm.
David Bates, in a thoughtful accompanying editorial, points out several important issues raised by this study and discusses several issues related to alerts and warnings. He notes that hard-stops should be used extremely judiciously. While they may make sense for absolute contraindications or only when there are no exceptions, they must be used with caution when legitimate exceptions exist. He points out that in the current study there are legitimate times when both warfarin and trimethoprim-sulfamethoxazole would be given at the same time (he notes that in the study the alert was ultimately overridden 43% of the time). He also notes the importance of the process we highlighted above for evaluation of the impact of alerts. But he also points out that we need to better quantify the adverse consequences of ignoring alerts. And, very importantly, determine both the benefits and risks of the alert. For example, though the IRB ended this study because of the potential for harm from the unintended consequences identified, the study was not able to identify how many adverse events were actually prevented by the alert.
So, while some may look upon this study in a negative light, it really has several very important lessons learned.
See also some of our prior Patient Safety Tip of the Week columns on unintended consequences:
Strom BL, Schinnar R, Aberra F, et al. Unintended Effects of a Computerized Physician Order Entry Nearly Hard-Stop Alert to Prevent a Drug Interaction: A Randomized Controlled Trial. Arch Intern Med. 2010; 170(17): 1578-1583
Bates DW. CPOE and Clinical Decision Support in Hospitals: Getting the Benefits: Comment on "Unintended Effects of a Computerized Physician Order Entry Nearly Hard-Stop Alert to Prevent a Drug Interaction". Arch Intern Med. 2010; 170(17): 1583-1584