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Published letters
Displaying 11-20 letters out of 2262 published
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Polypharmacy and risk of rhabdomyolysis
Submit responseThe study by Sharma et al highlights the fact that achieving treatment goals with fewer medications may prevent the risk of side effects and interactions from polypharmacy. However, caution is required when maximizing statin dose in some of our high risk aging population as more side effects may occur due to reduced plasma clearance (1). We recently admitted a 72 year old female with statin induced rhabdomyolysis. She had been on multiple chronic medications including simvastatin 10mg daily for hyperlipidemia and amiodarone and warfarin for atrial fibrillation without adverse reactions. Two months prior to her latest admission, she was hospitalized with a non ST elevation myocardial infarction and her simvastatin was increased to 80mg daily to comply with the current guidelines. Two weeks following the statin dose adjustment and the addition of the new medications, she started complaining of generalized weakness more so in the lower extremities but no myalgia. She was admitted to the hospital; however, the work up was negative including normal creatine kinase level, TSH and electromyogram and the patient was discharged with generalized weakness of unknown etiology. One month later she was admitted for myalgia and marked proximal muscle weakness in all four extremities. Her creatine kinase was 6791U/L, which raised up to 9213U/L the next day, with a positive urine myoglobin. Serum creatinine level was 2.18mg/dL, slightly higher than the baseline of 1.7mg/dL. She had a normal repeat electromyogram, which was in favor of statin-induced myopathy. Upon discontinuation of simvastatin and intravenous hydration, the creatine kinase returned to normal and she recovered her strength within two weeks with physical therapy. Statin induced myopathy is a concerning side effect but rhabdomyolysis is rare with an average incidence rate per 10000 persons-year of 0.44 (2). Among the available statins, simvastatin appears to have the most reported cases of myopathy. This may be due to the lipophilic nature allowing easy penetration of muscle membranes. Simvastatin is also metabolized by the enzyme CYP3A4 which metabolizes many other medications including warfarin and amiodarone, thereby carrying the risk for interaction(3,4). It is recommended that simvatatin dosage should not exceed 20mg daily when used in combination with amiodarone because of increased risk of myopathy. The current recommendation is to continue statins if the creatine kinase level is less than ten times the normal limit; however, clinical judgment is warranted as biopsy proven muscle damage has been found with lower levels of creatine kinase (5).
References:
1. Carlos Escobar, Rocio Echarri, Vivencio Barrios. Relative safety profiles of high dose statin regimens. Vascular health and risk management 2008:4 (3) 525-533
2. D. J. Graham,J. A. Staffa; Deborah Shatin et al. Incidence of Hospitalized Rhabdomyolysis in Patients Treated With Lipid-Lowering Drugs JAMA. 2004;292:2585-2590
3. Molecular basis of statin-associated myopathy C. Vaklavas a, Y.S. Chatzizisis b, et al. Elsevier. Atherosclerosis 202 (2009) (18-28)
4. Miranda R. Andrus .Oral Anticoagulant Drug Interactions With Statins: Discussion. Pharmacotherapy. 2004;24(2)
5. Markus G., Mohaupt, R.H. Karas, E. B. Babiychuk et al . Association between statin-associated myopathy and skeletal muscle damage cmaj.081785 July 2009;181 (1-2)
Conflict of Interest:
None declared
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Missing data management.
Submit responsePatients involved in this clinical trial had rheumatoid arthritis lasting longer than 6 months. It is not stated, however, the actual disease duration of patients in both groups. Although a fair argument is offered for the use of Sulfasalazine as a comparator in this trial; it is noticeable that only 13% and 16% of patients were receiving methotrexate by the time they were screened; it is even more noticeable that only about a quarter of patients were taking any DMARD at this time point (this is assuming that no patient was taking two or more DMARDs). What about the rest of this group of patients with active, established, rheumatoid arthritis? Were they without any disease modifying treatment? Since such a high desertion rate could have been, at least partially anticipated for sulfasalazine I wonder if the authors contemplated the possibility of a different trial design. It seems that modeling missing data is not the best a priori established strategy to manage attrition; personally I think this would have only been acceptable should this had been a post hoc analysis. But it was not. Right?
Conflict of Interest:
None declared
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Re:Glucose Control and Cardiovascular Disease in Type 2 Diabetes
Submit responseWe are responding to the revised letter of Yudkin and Richter, which we did not see before its publication. Although methods of pooling trials with shared controls have been developed, each has its own limitations. We would like to point out some serious limitations related to simply combining the UKPDS 33 and 34 into one study, as done by Yudkin and Richter in their letter. The UKPDS 34 only included overweight participants at high risk for cardiovascular outcomes. Simply summing the numbers of events from the UKPDS 33 and UKPDS 34 would make the intensive and conventional treatment groups non-comparable, introducing bias to the conclusion. For example, in the UKPDS 33, the proportion overweight was similar between the intensive and conventional treatment groups (34.8% and 36.2%, respectively). By combining the UKPDS 33 and 34, the proportion overweight of the conventional treatment group would remain 36.2% (as the controls from UKPDS 34 were originally included in the UKPDS 33 control group), but the proportion overweight in the intensive treatment group would increase to 47.4% (as only overweight patients were included in the UKPDS 34). This imbalance in overweight status and other associated cardiovascular risk factors between the intensive treatment and conventional treatment groups threatens the internal validity of the 'combined analysis' and leads to bias in their conclusions.
Conflict of Interest:
None declared
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Impact of Splenectomy on Subsequent Infections
Submit responseTO THE EDITOR: Linking the national hospital discharge records to the civil registration system in 3812 splenectomized patients, 38120 general population members, 16962 appendectomized patients and 8310 matched patients with hematologic disorder, Dr Thomsen and colleagues (1) clarified the clinical impact of splenectomy on subsequent infections. Compared with the general population, the odds ratio of infection was 18.1 in the first 90 days after splenectomy, and the hazard ratio was 4.6 from 91 to 365 days, and 2.5 more than 365 days after splenectomy. Surprisingly, in a subcohort for which detailed data on bacterial infections were available, the 90-day odds ratio for bacteremia was 138.2 compared to the general population cohort. These results may compel the patients to receive pneumococcal vaccines or antibiotic prophylaxis to reduce infection rates. However, I suppose that a markedly increased infection rate in the first study period does not necessarily reflect the role of the spleen in the elimination of bacteria. The removal of a huge spleen is a challenging operation, and is not rarely associated with infectious complications such as wound infection, catheter sepsis, subphrenic abscess, and pneumonia. In a study of 135 patients undergoing splenectomy for hematologic malignancies, overall morbidity and mortality rates were 52 % and 9 % (2). Even for patients with immune thrombocytopenic purpura, splenectomy was associated with a morbidity of 40 % if they had received medical therapy for a long time (3). In the current study, among the infections within 90 days after splenectomy, a substantial portion is thought to be attributable to operative insult, but not to immune deficit resulting from splenectomy
Besides increased susceptibility to infection, another concern about splenectomy is whether it can affect long-term survival rates, particularly for patients with abdominal cancer or hematologic malignancy. In a recent cohort study using the Scottish hospital records and death registration system in 1648 splenectomized patients with a mean follow-up of 4.45 years, 739 patients (45 %) died during the study period (4). Unfortunately, in that study, how many deaths were related to severe infections or how many patients died of the progression of the disease is not known. In the study by Thomsen et al, it appears that about 18 % of patients died within 1 year after splenectomy, and about 27 % of splenectomized patients died during a median follow-up of 2,2 years, whereas about 15 % of the matched patients with hematologic disorder died within 1year and about 28 % of these died during a median follow-up of 2.1 years, as shown in Table 3 of the article. Defining whether splenectomy contributed to the death of patients with abdominal or hematologic malignancies would be clinically important.
References
1. Thomsen RW, Schoonen WM, Farkas DK, Riis A, Jacobsen J, Fryzek JP, et al. Risk for hospital contact with infection in patients with splenectomy. Ann Intern Med. 2009; 151: 546-55.
2. Horowitz J, Smith JL, Weber TK, Rodriguez-Bigas MA, Petrelli NJ. Postoperative complications after splenectomy for hematologic malignancies. Ann Surg 1996; 223: 290-6.
3. Gibson M, Sehon JK, White S, Zibari GB, Johnson LW. Splenectomy for idiopathic thrombocytopenic purpura: a five-year retrospective review. Am Surg 2000; 66: 952-5.
4. Kyaw MH, Holmes EM, Toolis F, Wayne B, Chalmers J, Jones IG, et al. Evaluation of severe infection and survival after splenectomy. Am J Med 2006; 119: 276.e1-e7.
Conflict of Interest:
None declared
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Re:Re:In Response to Pallitave Care
Submit responseIn reply to responses to their article, Quill et al assert that in some cases of intractable suffering sedation directly to unconsciousness may be necessary, and that proportional sedation may be insufficient. It seems that some of the contention here arises from ambiguity in the term "proportionality". In a clincal sense proportional sedation suggests a step-wise, temporal titration of sedation, while in an ethical sense proportional sedation suggests that the level of sedation should match the symptom. My worry is that by introducing a conception of palliative sedation which includes "palliative sedation to unconsciousness" the ethical sense of proportionality may be undermined. Clinically sedation directly to unconsciousness may be required, but ethically this remains a version of proportional palliative sedation.
Conflict of Interest:
None declared
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Editors Correction: Systematic Review: Glucose Control and Cardiovascular Disease in Type 2 Diabetes
Submit responseIn the recent meta-analysis by Kelly and colleagues (1), Tables and Figures presented data from two UKPDS studies that compared intensive glucose lowering therapy with diet: the UKPDS 33 and 34. The UKPDS 34 was actually a substudy of 33, limited to overweight patients who had been randomized to metformin or diet in the parent study. However, in UKPDS 33 overweight patients randomized to diet in the 34 substudy (N=411) were included in a combined diet comparison group (N=1138). Thus, the comparison group of 411 overweight patients in the UKPDS 34 study was already included in the analysis of UKPDS 33. The Kelly meta-analysis considered the two studies as separate trials and, as such, double-counted those 411 overweight patients. Authors of a letter to the editor pointed out the double counting and provided effect estimates that avoided double counting by merging 33 and 34 into one study (2). For interested readers, several other approaches that minimize the bias introduced when comparisons use a common control arm are available (3-5).
References
1. Kelly TN, Bazzano LA, Fonseca VA, Thethi TK, Reynolds K and He J. Glucose control and cardiovascular disease in type 2 diabetes. Ann Intern Med 2009;151:394-403.
References
2. Yudkin JS, Richter B. Glucose control and cardiovascular disease correction. Ann Intern Med 2009;
3 Higgins JPT, Whitehead A. Borrowing strength from external trials in a meta-analysis. Stat Med. 1996; 15: 2733-2749.
4. Glenny AM, Altman DG, Song F, Sakarovitch C, Deeks JJ, D'Amico R, Bradburn M, Eastwood AJ: International Stroke Trial Group. Indirect comparisons of competing interventions. Health Technol Assess. 2005;9:1 134.
5. Chootrakool H, Shi JQ. Meta-analysis of multi-arm trials using empirical logistic transform. Open Med Inform J. 2008;2:112 - 116.
The Editors
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Re:In Response to Pallitave Care
Submit responseWe generally agree with Cellarius that the central constructs justifying the differing levels of palliative sedation are proportionality and informed consent. For mild levels of distress, mild sedation is appropriate. For more severe distress, heavier sedation even to the level of unconsciousness may be needed. With proportionate palliative sedation (PPS), the level of sedation and the pace of increasing are in direct relationship with severity of otherwise unrelieved suffering (1). The level of sedation used will be the least amount that can relieve the distress. PPS may end with the patient being unresponsive, but that is not the intended endpoint.
We also agree with Sulmasy that the double effect can generally justify PPS (for clinicians who endorse the rule). Relief of suffering is the clinician's primary intent, and although there may be a foreseen risk of hastening death, it is not the clinician's intent (2, 3). However, we do not agree that PPS can only be justified by double effect reasoning, and would not ourselves justify in that way. Intent can distinguish palliative sedation to unconsciousness (PSU) from euthanasia, but we reject that intent marks the difference between the morally permissible and impermissible as double effect proponents claim. Death may or may not be intended by patient or clinician in PSU -in some circumstances intent may be exclusively to relieve suffering and to respect the patient's right to refuse nutrition and hydration, and for others intent may be more multilayered (4]). How intent applies to PSU is more controversial than to PPS, but this is less important in distinguishing between permissible and impermissible actions for us than for Sulmasy.
Proportionate palliative sedation is adequate to deal with most but not all intractable end-of-life suffering. We stand by our assertion that there will still be compelling cases where sedation directly to unconsciousness will be needed from the outset(1). Lesser levels of sedation would be insufficient. Consider these real examples:
A terrified patient with advanced oropharyngeal cancer who is bleeding out from a progressively rupturing carotid artery.
A patient with advanced pulmonary fibrosis, prepared to die rather than be re-intubated for a third time within a month provided we promise to aggressively manage his dyspnea, who is now extremely short of breath and agitated with a carbon dioxide level of 90.
A patient with amyotrophic lateral sclerosis (ALS) who wants to go off his mechanical ventilator but is extremely fearful of suffocation. For us, these cases are more difficult to justify using strict double effect reasoning because death can be both foreseen and to some extent intended by both patient and clinician (5). Stopping at lesser levels than total sedation made no sense to the patients, their families or the clinicians caring for them. And prolonging this process where suffering was so extreme by continuing other life-prolonging therapies would have been inappropriate. They each met the criteria of proportionality, had informed consent, and the clinician's primary intent was to relieve the patient's severe suffering, but to say that assisting these patients to die was completely unintended didn't seem genuine (4). Rather than relying exclusively on a rule from a particular religious tradition with sometimes unrealistic requirements about intention, it seems better to us to develop clear guidelines that include ways of responding to some of the most challenging cases (1).
References
1. Quill, T.E., Lo, B., Brock, D, Meisel A.., Last-resort options for palliative sedation. Annals of Internal Medicine, 2009. 151(6): p. 421-4.
2. Jansen, L.A., Sulmasy, D.P., Sedation, alimentation, hydration, and equivocation: Careful conversation about care at the end of life. Ann Intern Med, 2002. 136: p. 845-849.
3. Quill, T.E., Principle of double effect and end-of-life pain management: Additional myths and a limited role. Journal of Palliative Medicine, 1998. 2: p. 333-336.
4. Quill, T.E., The ambiguity of clinical intentions. N Engl J Med, 1993. 329: p. 1039-1040.
5. Quill, T.E., R. Dresser, and D.W. Brock, Rule of double effect: A critique of its role in end-of-life decision making. N Engl J Med, 1997. 337: p. 1768-1771.
Conflict of Interest:
None declared
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WHAT PERCENTAGE OF THE PATIENTS WITH CONTRAST-INDUCED NEPHROPATHY WERE ACCESSED VIA THE RADIAL APPROACH?
Submit responseIn their comprehensive meta-analysis which included data from all available studies on Contrast-induced Nephropathy (CIN) involving 3563 patients , the authors affirm that CIN is the development of acute renal failure after administration of radiocontrast in the absence of other identifiable causes (1) . However, as some studies evaluated patients having either cardiac catheterization or computed tomography or other arteriography, their systematic examination of potential sources of heterogeneity will be extended to differentiate between patients in whom contrast agents are introduced into the venous or arterial bed, and between patients in whom cardiac catheterization was accessed via the radial or the femoral approach . In fact, it could be a crucial difference among potential risk factors for acute kidney injury when contrast medium is introduced by intra-arterial administration, due to the possible cholesterol crystal embolization occurring after intravascular trauma with angiographic catheters during invasive vascular procedures. In this case , the role of contrast medium in pathophysiology of renal damage might be marginal, if any, due to a possibly undiagnosed atheroembolic renal disease (AERD) masked under a supposed CIN, and a further difference in the degree of AERD might depend on the site of approach ( if radial or femoral). While AERD and CIN share as common setting the need for the use of intravascular contrast medium for diagnostic procedures, pathophysiology of renal damage is completely different: for CIN it is dealing with alteration in renal hemodynamics , rheological properties , and paracrine factors (adenosine, endothelin, reactive oxygen species) or direct cytotoxic effects on renal tubular cells(2,3) , while in the case of AERD the renal parenchyma is mechanically damaged by cholesterol crystals able to trigger inflammatory responses(4,5). Unfortunately, differential diagnosis may be difficult on clinical basis , when local and systemic signs of cholesterol embolism in other organs (gut, skin, upper and lower extremities) such as livedo reticularis , purple toes syndrome, eosinophilia and serum complement consumption are lacking. Many difficulties have been reported in diagnosing AERD, that is labelled as the great masquerader, with an incidence in autopsy studies from 4% in elderly subjects over 65 yr with minimal atherosclerosis to 77% in older patients with severe atherosclerosis, and up to >12% of cases following coronary angioplasty in clinical studies,. Therefore, assessing for heterogeneity in the vascular access will help in differentiating homogeneous clinical entities similar in pathogenesis and , therefore, prevention and treatment.
References
1) Zoungas S, Ninomiya T, Huxley R, Cass A, Jardine M, Gallagher M, Patel A, Vasheghani-Farahani A, Sadigh G, Perkovic V Systematic review: sodium bicarbonate treatment regimens for the prevention of contrast- induced nephropathy. Ann Intern Med. 2009 ; 151(9):631-8.
2) Solomon R, Dumouchel W. Contrast media and nephropathy: findings from systematic analysis and Food and Drug Administration reports of adverse effects. Invest Radiol. 2006; 41(8):651-60.
3) Brar SS, Hiremath S, Dangas G, Mehran R, Brar SK, Leon MB. Sodium bicarbonate for the prevention of contrast induced-acute kidney injury: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009 ;4(10):1584-92.
4) Baykal C, Buyukbabani N, Aysuna N, Ark E. Clinical outcomes of renal cholesterol crystal embolization. J Nephrol. 1999 ;12:266-9.
5) Khan AM, Jacobs S. Trash feet after coronary angiography. Heart. 2003 ;89: 17.
Conflict of Interest:
None declared
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Response
Submit responseThe recent review article by Sharma et al., "Comparative Effectiveness and Harms of Combinations of Lipid-Modifying Agents and High-Dose Statin Monotherapy" (1) does a credible job of summarizing the much longer Comparative Effectiveness Review from the Agency for Healthcare Research and Quality Effective Healthcare program (2). While we do not disagree with the conclusions of the review, we are concerned that the wording of these conclusions, especially in the report abstract, may lead to confusion, specifically regarding the meaning and criteria ascribed to the term "quality."
In the abstract of the review, Sharma et al. follow the recommendations of the GRADE working group, which use the same word, "quality" to describe both the quality of the individual studies being assessed and the overall quality of the evidence underlying the conclusions of the assessment (3). More recent conventions use a different word, such as "strength" to describe the overall body of evidence (4) and indeed, for the majority of the report, Sharma et al. follow this convention. Strength of evidence includes not only the quality of the individual studies, but also the number and size of the studies, the consistency and precision of study results and the direct relevance of the studies to the research question being addressed. It is critical to understand that the statement that "Very-low-quality evidence" favors statin-ezetimibe treatment for attainment of low-density lipoprotein cholesterol goals (1) does not indicate that the studies are of poor quality. It means that very few (two) studies make the very specific comparison of interest in the very specific population of interest. The assessment is thus a matter of quantity rather than quality.
We further note that when the study inclusion criteria are relaxed to include a greater range of statin doses and patient characteristics, an additional 21 trials comparing treatment with a combination of ezetimibe and statin vs. statin alone can be added to the evidence pool. All but one of these studies favor the combination treatment (1). Failure to understand the precise meaning of the terms used in this evidence-based review could lead to misinterpretation of the findings of the review article.
Richard Chapell PhD
Andrew Tershakovec MD MPH
Richard Pasternak MD
1. Sharma M, Ansari MT, Abou-setta AM, Soares-Weiser K, Ooi TC, Sears M, et al., Systematic Review: Comparative Effectiveness and Harms of Combinations of Lipid-Modifying Agents and High-Dose Statin Monotherapy. Ann. Int. Med. 2009;151
2. Sharma M, Ansari MT, Soares-Weiser K, Abou-setta AM, Ooi TK, Sears M, Yazdi F, Tsertzvadze A, Moher D. Comparative Effectiveness of Lipid- Modifying Agents. Comparative Effectiveness Review No. 16. (Prepared by the University of Ottawa Evidence-based Practice Center under contract No. 290-02-0021.) Rockville, MD: Agency for Healthcare Research and Quality. September 2009. Available at: www.effectivehealthcare.ahrq.gov/reports/final.cfm.
3. The Grade Working Group. Grading quality of evidence and strength of recommendations. BMJ. 2004; 228:1-8.
4. Treadwell JR, Tregear SJ, Reston JT and Turkelson CM. A system for rating the strength and stability of medical evidence. BMC Med. Res. Methodol. 2006; 6:52
Conflict of Interest:
Authors are employees of Merck
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MESA Overlooked by USPSTF Guidelines
Submit responseWe read with interest the statement from the USPSTF on emerging risk factors for CHD. Specifically, the authors suggest that the current evidence does not support the use of coronary artery calcium (CAC) scoring "for further risk stratification of intermediate-risk persons." The authors identify a 2004 study by Greenland et al. as the "best-quality" study, and suggest "flaws in the other studies." This overall conclusion from the USPSTF is at odds with current recommendations from the American Heart Association (AHA) and American College of Cardiology (ACC)(1).
We are perplexed as to why the Multi-Ethnic Study of Atherosclerosis (MESA) was not considered a high quality study. The primary objective of the NIH/NHLBI funded MESA study was “to determine characteristics related to progression of subclinical to clinical cardiovascular disease (2)." MESA enrolled an ethnically-diverse population-based sample of 6,814 asymptomatic men and women aged 45-84 from 6 field centers across the United States. All patients received a common scanning protocol. During 3.8 year follow-up, doubling of CAC increased the risk of any coronary event by 18 to 39%, and CAC increased the area under the receiver-operating-characteristic curves (ROCs) for the prediction of coronary events when added to standard risk factors (3).
The influence of CAC on the ROC is of great significance, and the USPSTF authors rightly point out how difficult it is for a risk factor to increase the area under the ROC. While we await the presentation of the MESA reclassification analysis at AHA Scientific Sessions 2009, there are existing publications that suggest a reclassification benefit with CAC. For example, women in MESA characterized as low-risk by Framingham Risk Score (FRS) but with CAC>300 had a 6.7% and 8.6% risk of coronary heart disease (CHD) and cardiovascular (CVD) events, respectively, during 3.75 year follow-up (4). These women with advanced CAC were indeed at elevated risk, despite low calculated risk by FRS.
MESA is one of 10 NIH/NHLBI-funded population based studies of CVD risk, and its goal was to assess the question posed by the USPSTF authors -the predictive value of subclinical atherosclerosis in predicting coronary events. If the MESA study is not considered high-quality, we question what type of study will be sufficient to demonstrate the importance of selective CAC testing in persons with risk factors who do not yet qualify for treatment with statin and aspirin therapy.
In the future the USPSTF should include an experienced preventive cardiologist to avoid these major oversights.
References
1. Greenland P, Bonow RO, Brundage BH, et al. ACCF/AHA 2007 clinical expert consensus document on coronary artery calcium scoring by computed tomography in global cardiovascular risk assessment and in evaluation of patients with chest pain: a report of the American College of Cardiology Foundation Clinical Expert Consensus Task Force (ACCF/AHA Writing Committee to Update the 2000 Expert Consensus Document on Electron Beam Computed Tomography). Circulation. 2007;115:402-26.
2. Bild DE, Bluemke DA, Burke GL, et al. Multi-ethnic study of atherosclerosis: objectives and design. Am J Epidemiol. 2002;156(9):871- 81.
3. Detrano R, Guerci AD, Carr JJ, et al. Coronary Calcium as a Predictor of Coronary Events in Four Racial or Ethnic Groups. N Engl J Med. 2008;358:1336-1345.
4. Lakoski SG, Greenland P, Wong ND, et al. Coronary artery calcium scores and risk for cardiovascular events in women classified as "low risk" based on Framingham risk score: the multi-ethnic study of atherosclerosis (MESA). Arch Intern Med. 2007;167(22):2437-42.
Conflict of Interest:
None declared