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Published letters
Displaying 1-10 letters out of 2246 published
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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
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IN RESPONSE: Comparing costs and quality of care at retail clinics
Submit responseDr. Kochar is correct that the follow-up care of an episode at a retail clinic could occur at another care site. But we feel it is unlikely this impacted our quality scores. Less than 20% of episodes included any follow-up visits. Also our quality measures generally focused on care around the first visit. For example, we looked at antibiotic prescriptions for otitis media that were filled on the day of the first visit or subsequent two days.
We shared the concern with Dr. Kochar that patients who presented to a physician's office could be more ill and this might drive some of the cost differences we observed. Yet our sensitivity analyses that directly addressed this issue did not support this concern. The major driver of cost differences is reimbursement for the first visit. Costs which are likely to be related to severity of illness (e.g. laboratory costs, follow -up visits) were less important. Nonetheless, as we note in the manuscript, there could be residual differences between the patient populations at the care sites, though we feel that matching on income, level of illness, and insurance plan minimize these differences.
While we agree with Dr. Young that most cases of otitis media and pharyngitis are self-limited, it is notable that 11.4% all pediatric primary care visits are for just these two problems.(1) Seeking care for these problems is the established norm in our society and it is unclear whether this is a fair criticism of retail clinics. We agree with Dr. Young that retail clinics are not a magic bullet for health care costs. In our own models, we estimate there would be $2 billion in cost savings if retail clinics become widespread. But this constitutes less than 0.1% of health care spending.
We disagree with Dr. Young that the more important quality issue is how undifferentiated symptoms like lower abdominal pain are managed. Proper management of uncomplicated urinary tract infections is an important issue and the subject of much research and several guidelines.(2) Also, the goal in the study was to compare the care at retail clinics to other care sites and retail clinics do not manage undifferentiated abdominal pain
Consistent with our previous work,(3) the present study does find problems with quality across all the care sites. We agree with Dr. Johnson that efforts to improve quality of care across the health care system are critical.
References
1. Mehrotra A, Wang MC, Lave JR, Adams JL, McGlynn EA. Retail clinics, primary care physicians, and emergency departments: a comparison of patients' visits. Health Aff (Millwood). 2008;27(5):1272-82.
2. Fihn SD. Clinical practice. Acute uncomplicated urinary tract infection in women. N Engl J Med. 2003;349(3):259-66.
3. McGlynn EA, Asch SM, Adams J, et al. The quality of health care delivered to adults in the United States. N Engl J Med. 2003;348(26):2635- 45.
Conflict of Interest:
None declared
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Angiotensin-Converting Enzyme Inhibitors and the puplic water supplies
Submit responseI read with interest your systemic review article. The answer for these key questions , mentioned in the article, are imperative to know whether Angiotensin-converting enzyme inhibitors (ACE) or angiotensin receptor blockers (ARB) should be added to the standard treatment of coronary artery disease (CAD) with preserved ventricular dysfunction.
The authors have done great job reviewing the literature to find those answers. Taking a glance at the last recent related randomized clinical trails; ONTARGET trial evaluated the effect of these drugs on left ventricular hypertrophy (LVH) in high-risk patients for cardiovascular disease without heart failure. Although this study showed "no inferiority" for ARB compare to ACEI; the robust available literature about ACEIs still favors using them as the first line. Furthermore; the combination of ACEI and ARB in this study was not superior to ACEI alone. TRANSCEND trial assessed the same patients group who are intolerant to ACE. It showed that telmisartan is more effective than placebo in reducing LVH.
It is not surprising to see a favorable effect of the ACEIs and is consistent with our current knowledge based on the available literature. This, in fact, reminds me of a quote of a bright nephrologist in our institution: "ACEIs should be added to the public water supplies!"
Conflict of Interest:
None declared
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Improving the Net Clinical Benefit of Warfarin Anticoagulation for Atrial Fibrillation
Submit responseWe support Bussey's emphasis on the importance of maximizing 'time in therapeutic range (TTR).' The benefits and risks of warfarin therapy in atrial fibrillation are strongly dependent on maintaining the international normalized ratio (INR) in the optimal range (1, 2). That is why we reported the overall TTR, 65%, for our ATRIA cohort (3). At lower TTR values, the expected net clinical benefit will be lower and at higher TTR values, the net clinical benefit will increase regardless of clinical risk category as long as the distribution of out-of-range values does not change markedly. As pointed out, having more extreme out-of-range low or high INR values will have a strong negative effect on the net benefit conferred by any given level of TTR. It is remarkable that warfarin's striking efficacy has been demonstrated in studies where the INR was in range only ~two-thirds of the time (e.g., in the BAFTA trial (4)). It is clear that substantially higher overall TTR levels can currently be achieved in selected populations (2). More widespread use of organized anticoagulation management services, INR self-testing, improved dosing algorithms, and possibly employing genetic testing for warfarin sensitivity all have the potential for more widespread improvement in TTR levels and increased net clinical benefit in patients with atrial fibrillation.
The final sentence in Budhraja's letter aptly summarizes the motivation for our paper (3). To generate an optimal estimate of the adjusted absolute net benefit of warfarin therapy, we allowed the effect of warfarin to vary by patient subgroup in our models, independent of the statistical significance of any individual interaction term. In fact, most of the interaction terms were not statistically significant and, except for the lowest stroke risk categories, the interaction effects were small. Before firmly concluding that the relative risk reduction conferred by warfarin differs in any specific subgroup, such effect modification should be confirmed in other large databases, in particular those from randomized trials.
As Budhraja notes, ischemic stroke risk off warfarin is only one determinant of net clinical benefit. But, it is a very important determinant. Unfortunately, current risk stratification schemes for patients with AF have very limited accuracy (5). Future research should emphasize improved risk prediction in AF. Better risk prediction will facilitate achieving increased net benefit of warfarin both at the population and the individual patient levels.
References:
1. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, Go AS. Should patient characteristics influence target anticoagulation intensity for stroke prevention in nonvalvular atrial fibrillation: The ATRIA Study. Circulation Cardiovascular Qual Outcomes. 2009;2:297-304.
2. Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi MG, et al; ACTIVE W Investigators. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation. 2008;118:2029-37. [PMID: 18955670]
3. Singer DE, Chang Y, Fang MC, Borowsky LH, Pomernacki NK, Udaltsova N, Go AS.The net clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009 Sep 1;151(5):297-305. [PMID: 19721017]
4. Mant J, Hobbs FD, Fletcher K, Roalfe A, Fitzmaurice D, Lip GY, Murray E; BAFTA investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial.Lancet. 2007 Aug 11;370(9586):493-503. [PMID: 17693178]
5. Fang MC, Go AS, Chang Y, Borowsky L, Pomernacki NK, Singer DE; ATRIA Study Group. Comparison of risk stratification schemes to predict thromboembolism in people with nonvalvular atrial fibrillation. J Am Coll Cardiol. 2008;51:810-5. [PMID: 18294564]
Conflict of Interest:
Consultancies: D.E. Singer: AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Johnson & Johnson, Merck, Sanofi-Aventis. Honoraria: D.E. Singer: Bristol-Myers Squibb, Pfizer. Grants received: D.E. Singer: Daiichi Sankyo A.S. Go: Johnson & Johnson
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Re:Glucose Control and Cardiovascular Disease in Type 2 Diabetes
Submit responseWe would like to thank Drs. Yudkin and Richter for their interest in our meta-analysis. The decision to conduct subgroup analyses of early and more recent trials was an a priori determination based on important differences in patient populations, targeted HbA1c levels, and treatment regimens (1). Specifically, the early UKPDS trials included only newly diagnosed diabetes patients while the more recent ACCORD, ADVANCE, and VADT included prevalent diabetes patients. The targeted intensive glucose control level in the UKPDS was similar to that of the targeted conventional glucose control level in the more recent trials. Finally, the UKPDS used diet as the primary method of conventional treatment while the more recent trials used hypoglycemic agents. We included the UKPDS 34 in our meta-analysis because the 342 patients that were assigned to metformin for intensive treatment were completely independent to the 2,729 patients assigned to sulfonylureas or insulin for intensive treatment in the UKPDS 33 (2).
Combining results from different treatment arms of clinical trials that share a common control group is sometimes done though ideally estimates should account for underlying correlation between the effect size which we did not do (3, 4). The UKPDS 34 control group comprises a relatively small proportion of the UKPDS 33 control group (approximately 36%), and meta-analytic methods to account for correlations in binary endpoints of trials using partially shared control groups have not been developed. We believe that the UKPDS 34 provides important information regarding the effects of intensive glucose control on cardiovascular disease, and any correlation it may have with the UKPDS 33 due to a partially shared control group does not warrant its exclusion from the meta-analysis. Yudkin et al raised an issue about different definitions of outcomes among individual trials. However, all-cause mortality and cardiovascular disease mortality are two “hard clinical outcomes," which should be comparable among trials. Our meta-analysis indicated that there was significant heterogeneity in these outcomes between individual trials, which supported our decision to conduct subgroup analyses. We appreciate the concerns of Yudkin et al, but stand by our methods and conclusions.
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.
2. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet (1998) 352: 837-853.
3. Glesser LJ, Olkin I. Stochastically dependent effect sizes. In: Cooper H, Hedges LV. The Handbook of Research Synthesis. New York: Russel Sage Foundation. (1994) 339-356.
4. Generalized synthesis of evidence – Combining different sources of evidence. In: Sutton AJ, Abrams KR, Jones DR, Sheldon TA, Song F. Methods for Meta-analysis in Medical Research. New York: Wiley & Sons, LTD. (2000) 259-276.
Conflict of Interest:
None
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Glucose Control and Cardiovascular Disease in Type 2 Diabetes
Submit responseThe issue of the impact of glucose lowering on cardiovascular risk in patients with type 2 diabetes is one of great public health significance. While recognising the importance of the paper by Kelly et al (1), we would like to draw attention to errors in their meta-analysis that we believe affect the conclusions reached.
First, the authors combined data from 3 recent studies (2-4) with two sub-studies of the UKPDS (5,6) to suggest that many outcomes differ between the ‘early’ and ‘late’ studies. In so doing, they failed to notice that the 411 participants and their associated events in the conventional treatment (diet) limb of the metformin sub-study UKPDS34 (6) were also included in the conventional treatment arm in the main study UKPDS33 (5). Using the same studies and methodology as Kelly et al, but without double-counting, we appropriately analysed UKPD 33 and 34 as one study including the additional data from the intensive treatment arm of the metformin treated patients in UKPDS34. Thus, the relative risk for cardiovascular death and all cause mortality is 1.05 (0.82-1.33) instead of 0.97 (0.76-1.24), and 1.03 (0.89-1.19) instead of 0.98 (0.84-1.15), and the reduction in risk of cardiovascular events is 8% (1%-14%) instead of 10% (2%-17%). The recalculation reduces the difference between the early and late trials of Kelly et al's categorisation, with the only end-points now showing substantial heterogeneity in overall pooled effect estimates being cardiovascular death ( I2 = 75%) , all-cause mortality ( I2 = 67% ) and severe hypoglycaemia (I2 = 79%).
Second, one might debate whether UKPDS34 was appropriate to include in the meta-analysis; trialists involved in the originally studies recently performed a similar meta-analysis without its inclusion (7).
Third, the use of different definitions of end-points (such as including or not including sudden death as cardiovascular disease) is a problem that cannot be solved unless an individual patient data meta-analysis is done.
Given all of the above, we conclude that there is little evidence of differences in outcomes between early and late studies. We think that current epidemiologic and trial evidence suggests that intensive glycemic control will reduce coronary heart disease by about two-thirds, and will not significantly affect stroke, cardiovascular mortality or total mortality. Moreover, we think that data suggest that treating 100 people with intensive glycemic control for 10 years would prevent around 3 cardiovascular events, at the expense of inducing 8 serious hypoglycemic ones.
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: (published on-line 21 July 2009).
2. Action to Control Cardiovascular Risk in Diabetes (ACCORD) Study Group. Effects of intensive glucose lowering in type 2 diabetes. N Engl J Med (2008) 358: 2545-2559.
3. ADVANCE Collaborative Group. Intensive blood glucose control and vascular outcomes in patients with type 2 diabetes. N Engl J Med (2008) 358: 2560-2572.
4. Duckworth W, Abraira C, Moritz T, Reda D, Emanuele N, Reaven PD, Zieve FJ, Marks J, Davis SN, Hayward R, Warren SR, Goldman S, McCarren M, Vitek ME, Henderson WG and Huang GD for the VADT Investigators. Glucose Control and Vascular Complications in Veterans with Type 2 Diabetes. N Engl J Med (2009) 360: 129-139.
5. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet (1998) 352: 837-853.
6. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS34). Lancet (1998) 352: 854-865.
7. Turnbull FM, Abraira C, Anderson RJ, Byington RP, Chalmers JP, Duckworth WC, Evans GW, Gerstein HC, Holman RR, Moritz TE, Neal BC, Ninomiya T, Patel AA, Paul SK, Travert F and Woodward M. Intensive glucose control and macrovascular outcomes in type 2 diabetes. Diabetologia (2009) DOI 10.1007/s00125-009-1470-0 (published on-line 5th August 2009).
Conflict of Interest:
None declared
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Error in Table 2?
Submit responseI believe there is an error in Table 2 that could cause confusion. Under the outcomes 'Use of rescue therapy' and 'Mortality in patients with rescue therapy', the data in the 'Low PEEP' column refer to the 'High PEEP' group and vice versa.
Conflict of Interest:
None declared