Letters
Annals of Internal Medicine COMMENTS
AND
RESPONSES
2. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002;25:1129-34. [PMID: 12087009] 3. Kopel E, Sidi Y, Kivity S. Mediterranean diet for primary prevention of cardiovas-
Prevention of Diabetes With Mediterranean Diets
cular disease [Letter]. N Engl J Med. 2013;369:672. [PMID: 23944308] 4. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a com-
TO THE EDITOR: We believe that Salas-Salvado´ and colleagues’ sub-
peting risk. J Am Stat Assoc. 1999;94:496-509.
group analysis (1), which found that a Mediterranean diet enriched with extra-virgin olive oil reduces risk for diabetes, is methodologically flawed. During the study, more participants were lost to follow-up in the low-fat diet control group (10.5%) than in the Mediterranean diet groups supplemented with olive oil (4.1%) or mixed nuts (6.9%). The authors state that participants in the control group “who withdrew had a worse cardiovascular risk profile at baseline than those who remained in the study.” This fact indicates that the entire control group in the subgroup analysis had a potentially higher cardiovascular risk profile at baseline than the intervention groups. A higher cardiovascular risk profile at baseline in the control group could coexist with a higher likelihood of baseline prediabetes and hyperinsulinemia, particularly in women (2). Although the original trial stratified randomization by sex, the trial and the subgroup analysis evaluated more women in the control group than in the Mediterranean diet groups (3). Therefore, the control group could have a higher risk for incident diabetes during follow-up. Also of note is that meaningful between-group differences at baseline (such as the difference between the sexes) are often associated with differential distribution among groups of other, unmeasured baseline factors that are related to outcomes and therefore may lead to substantial confounding. Although Salas-Salvado´ and colleagues did extensive multivariable adjustment in their analyses, we do not believe that such analyses would resolve substantial “residual” confounding. To sort through some of these issues, we believe that examining whether the subgroup analysis evenly represented the baseline cardiovascular risk (for example, by mean 10-year Framingham cardiovascular risk score) across the 3 comparison groups and by sex is important. We also recommend that the authors perform a competing risk analysis (4) that accounts for competing cardiovascular morbidity outcomes that could occur before the diabetes outcome. We propose that the results of these analyses be presented and discussed and that the simple Kaplan–Meier curves in the article be redrawn to reflect the new analyses (5).
5. Andersen PK, Geskus RB, de Witte T, Putter H. Competing risks in epidemiology:
Eran Kopel, MD, MPH Yechezkel Sidi, MD Shaye Kivity, MD Chaim Sheba Medical Center Tel Hashomer, Israel Disclosures: Authors have disclosed no conflicts of interest. Forms can
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0108.
References 1. Salas-Salvado´ J, Bullo´ M, Estruch R, Ros E, Covas MI, Ibarrola-Jurado N, et al. Prevention of diabetes with Mediterranean diets: a subgroup analysis of a randomized trial. Ann Intern Med. 2014;160:1-10. [PMID: 24573661]
possibilities and pitfalls. Int J Epidemiol. 2012;41:861-70. [PMID: 22253319]
IN RESPONSE: With regard to the potential “imbalances” in the baseline characteristics of participants in the PREDIMED (Prevencio´n con Dieta Mediterra´nea) study and competing risk analyses, sex distribution was the only potentially relevant “imbalance” in our trial. The control group included a slightly higher proportion of women than the Mediterranean diet intervention groups. Female sex was associated with a lower risk for new-onset diabetes (age-adjusted hazard ratio [HR], 0.81 [95% CI, 0.63 to 1.04]) and cardiovascular events (age-adjusted HR, 0.45 [CI, 0.35 to 0.57]) in the overall cohort. It was also associated with a lower risk for cardiovascular disease among participants with diabetes (age-adjusted HR, 0.52 [CI, 0.39 to 0.70]). The estimates for the intervention effect changed minimally after adjusting for sex (0.8% change for the Mediterranean diet supplemented with extra-virgin olive oil group and 2.1% change for the Mediterranean diet supplemented with nuts group). After the potential confounding effect of sex was removed, the apparent protection from the Mediterranean diet intervention was even stronger. Other statistically “significant” minor imbalances in the overall PREDIMED study cohort showed P values close to 0.050 (with the exception of age and body mass index). The actual observed differences varied in direction in groups and were small and clinically meaningless. Adjusted estimates, regardless of the factors that we adjusted for, were essentially unchanged (1). The Figure shows new Kaplan–Meier survival curves with the outcome of diabetes or cardiovascular events (whichever occurred first) and using inverse probability weighting to account for potential confounding due to minor imbalances in baseline factors. When using cardiovascular events or diabetes as outcomes among participants who initially did not have diabetes to account for the possibility of competing risks between cardiovascular disease and diabetes, the age- and sex-adjusted HRs of the Mediterranean diet supplemented with extra-virgin olive oil group and the Mediterranean diet supplemented with nuts group versus the control group were 0.68 (CI, 0.52 to 0.87) and 0.76 (0.59 to 0.98), respectively. The overall higher cardiovascular risk in the control group led to stronger inverse associations. When we also included all-cause death in this composite outcome, the age- and sex-adjusted HRs of the Mediterranean diet supplemented with extra-virgin olive oil group and the Mediterranean diet supplemented with nuts group versus the control group were 0.72 (CI, 0.57 to 0.91) and 0.80 (0.64 to 1.01), respectively. From a practical point of view, the relevant issue for residual confounding is not statistical significance but the magnitude of the absolute between-group differences and their clinical relevance, which translate into changes between crude and adjusted estimates (2). Therefore, substantial residual confounding was not an issue in the PREDIMED study. We have already published (in supplements © 2014 American College of Physicians 157
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930510/ by a University of California San Diego User on 06/07/2017
Letters Figure. Incidence of diabetes or cardiovascular end points. 20
Emilio Ros, MD, PhD Institut d’Investigacions Biome`diques August Pi Sunyer, Hospital Clinic, University of Barcelona Barcelona, Spain
Incidence of Diabetes or
Cardiovascular End Point, %
18
Jordi Salas-Salvado´, MD, PhD Centro de Investigacio´n Biome´dica en Red de Fisiopatologı´a de la Obesidad y Nutricio´n, Instituto de Salud Carlos III Madrid, Spain
16 14 12 10
6
Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-1725.
4
References
2
1. Estruch R, Ros E, Salas-Salvado´ J, Covas MI, Corella D, Aro´s F, et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279-90. [PMID: 23432189] 2. Greenland S, Rothman KJ. Introduction to stratified analysis. In: Rothman KJ, Greenland S, Lash T, eds. Modern Epidemiology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2008:262. 3. Ruiz-Canela M, Estruch R, Corella D, Salas-Salvado´ J, Martı´nez-Gonza´lez MA. Association of Mediterranean diet with peripheral artery disease: the PREDIMED randomized trial. JAMA. 2014;311:415-7. [PMID: 24449321] 4. Andersen PK, Geskus RB, de Witte T, Putter H. Competing risks in epidemiology: possibilities and pitfalls. Int J Epidemiol. 2012;41:861-70. [PMID: 22253319] 5. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496-509.
8
0 0
1
2
3
4
5
Follow-up, y Control MedDiet + nuts MedDiet + EVOO
Kaplan–Meier curves adjusted for potential confounding factors using inverse probability weighting are shown with the outcome of diabetes or cardiovascular primary end points (whichever occurred first). Weights were computed taking into account age, sex, body mass index, waist– height ratio, education level, total energy intake, and baseline adherence to the MedDiet. EVOO ⫽ extra-virgin olive oil; MedDiet ⫽ Mediterranean diet.
and technical appendices [1, 3]) many competing risk and multiple imputation analyses to account for potential biases due to dropouts. These ancillary analyses also support our main conclusions. Andersen and associates (4) have dealt in depth with the issue of competing risks. They recommend the use of the Fine and Gray method (5) for competing risk analysis; our results were essentially unchanged when we used this model. Although Andersen and associates acknowledge the potential difficulties in interpretation of this approach, they also state that “both rates and risks for all competing events remain useful and tend to supplement each other when studying models for competing risks” (italics added). In this context, the use of a composite outcome including all competing events (that is, the combination of new-onset diabetes, cardiovascular events, and death) also reinforces our main conclusions. Miguel A. Martı´nez-Gonza´lez, MD, PhD University of Navarra Pamplona, Spain Ramo´n Estruch, MD, PhD Institut d’Investigacions Biome`diques August Pi Sunyer, Hospital Clinic, University of Barcelona Barcelona, Spain Dolores Corella, DPharm, PhD University of Valencia Valencia, Spain
OBSERVATION Rivaroxaban in a Patient With Disseminated Intravascular Coagulation Associated With an Aortic Aneurysm: A Case Report Background: Progressive disseminated intravascular coagulation (DIC) causes bleeding due to consumption coagulopathy and excessive fibrinolytic activation and organ failure due to microcirculatory dysfunction (1). Disseminated intravascular coagulation associated with aortic aneurysms is characterized by marked fibrinolytic activation (2). When severe bleeding develops, DIC has conventionally been treated with a continuous heparin infusion (3), but the restrictions on patients are great and continuous intravenous infusion is problematic for outpatient care. Patient-administered subcutaneous heparin injections with a longer half-life are frequently selected (4), but the treatment burden remains high. Control of DIC with oral anticoagulants might reduce this burden substantially but requires inhibition of activated clotting factors. Warfarin decreases levels of vitamin K– dependent clotting factors without inhibiting activated clotting factors and is therefore ineffective in DIC. New oral anticoagulants that inhibit the activated form of the clotting factors thrombin and factor X are now being used to prevent stroke during atrial fibrillation and to prevent and treat venous thromboembolism. These agents might be effective in DIC. Objective: To report a patient with chronic DIC and an aortic aneurysm treated with rivaroxaban, a new oral anticoagulant with activity against activated factor X. Case Report: A 75-year-old man with an acute aortic dissection and a thoracic aortic aneurysm was treated conservatively. When we examined him 2 years after the event, the thoracic aortic aneurysm
158 15 July 2014 Annals of Internal Medicine Volume 161 • Number 2
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930510/ by a University of California San Diego User on 06/07/2017
www.annals.org
Letters Figure. Changes in coagulation and fibrinolytic markers and
Fibrinogen level Platelet count
−28
−7 0
14
35
56
77
98
5 4 3 2 1 0
FDP/D-Dimer,
−28
−7 0
14
35
56
77
98
60 50 40 30 20 10 0
100 80 60 40 20
PAP level 2-AP level
−28
−7 0
14
35
56
77
98
10 8 6 4 2
Day
To convert fibrinogen values to mol/L, multiply by 0.0294. To convert platelet count values to ⫻ 109/L, multiply by 10. To convert D-dimer values to nmol/L, multiply by 5.476. Reference values for TAT, ⬍4.0 ng/mL. Reference values for ␣2-AP, 70% to 130%. Reference values for PAP, ⬍1.1 g/mL. ␣2-AP ⫽ ␣2-antiplasmin; FDP ⫽ fibrin degradation products; PAP ⫽ plasmin–␣2–antiplasmin complex; TAT ⫽ thrombin– antithrombin complex.
had enlarged and chronic DIC was present. His platelet count was 53 ⫻ 109/L (reference values, 130 to 350 ⫻ 109/L), fibrinogen level was 2.3 mol/L (reference values, 5.4 to 11.2 mol/L), fibrin degradation products level was 48.9 mg/L (reference values, ⬍5.0 mg/ L), and D-dimer level was 97.5 nmol/L (reference values, ⬍5.5 nmol/L). After insertion of a stent 45 days later, DIC was alleviated. His platelet count was 132 ⫻ 109/L 13 days after stent insertion but decreased again to 54 ⫻ 109/L 12 days later. Approximately 1 month later, the patient self-extracted a tooth and gingival bleeding required local therapy. His platelet count remained at approximately 20 ⫻ 109/L over the ensuing 3 months, and purpura became pronounced on his trunk. He was hospitalized, and treatment with oral rivaroxaban, 10 mg/d, was started after we obtained approval from our hospital’s medical ethics committee and informed consent from the patient. His platelet count did not increase, but his fibrinogen level returned to normal and all bleeding symptoms resolved completely (Figure). For 1.5 years, he has received rivaroxaban continuously; had no further bleeding; and had stable markers of DIC, including low platelet counts. Discussion: We are aware of 1 other patient with DIC who received treatment with rivaroxaban, but that patient had a rare
www.annals.org
Tomoe Hayashi, MD, PhD Noriharu Nakagawa, MD Yasuko Kadohira, MD Eriko Morishita, MD, PhD Hidesaku Asakura, MD, PhD Kanazawa University School of Medicine Kanazawa, Japan Disclosures: Authors have disclosed no conflicts of interest. Forms can
Day
g/mL
-AP, %
TAT level FDP level D-Dimer level
PAP,
2
120 100 80 60 40 20 0
TAT, ng/mL
g/mL
Day
10 4/ L
300 250 200 150 100 50
Platelet Count,
Fibrinogen, mg/dL
rivaroxaban administration.
congenital condition in which blood and lymph vessels did not form properly (the Klippel–Trenaunay–Weber syndrome) (5). Our patient had DIC in association with an aortic aneurysm, and his DIC was alleviated with rivaroxaban. Disseminated intravascular coagulation occurs fairly commonly in association with aneurysms, and we believe that potential benefits of new oral anticoagulants, such as rivaroxaban, for these patients should be investigated further.
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0131.
References 1. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999;341:586-92. [PMID: 10451465] 2. Takada A, Takada Y, Mori T, Sakaguchi S. Prevention of severe bleeding by tranexamic acid in a patient with disseminated intravascular coagulation. Thromb Res. 1990;58:101-8. [PMID: 1693450] 3. Jelenska MM, Szmidt J, Bojakowski K, Grzela T, Palester-Chlebowczyk M. Compensated activation of coagulation in patients with abdominal aortic aneurysm: effects of heparin treatment prior to elective surgery. Thromb Haemost. 2004;92:997-1002. [PMID: 15543326] 4. Ontachi Y, Asakura H, Arahata M, Kadohira Y, Maekawa M, Hayashi T, et al. Effect of combined therapy of danaparoid sodium and tranexamic acid on chronic disseminated intravascular coagulation associated with abdominal aortic aneurysm. Circ J. 2005;69:1150-3. [PMID: 16127203] 5. Randrianarisoa E, Kopp HG, Balletshofer BM, Jaschonek K, Kanz L, Haering HU, et al. Management of disseminated intravascular coagulopathy with direct factor Xa inhibitor rivaroxaban in Klippel-Tre´naunay syndrome. Blood Coagul Fibrinolysis. 2013;24:766-70. [PMID: 24030117]
CORRECTION Correction: In the Clinic: Screening for Colorectal Cancer In a recent In the Clinic, a statement in the Patient Information page was incorrect. The sentence on fecal occult blood testing should read as follows: High-sensitivity fecal occult blood test uses one of several chemical reactions to see if stool contains any blood, which can be a sign of polyps or cancer. This has been fixed in the online version.
Reference 1. Weinberg DS, Schoen RD. In the Clinic: screening for colorectal cancer. Ann Intern Med. 2014;160:ITC5-1-16. [PMID: 24798544]
15 July 2014 Annals of Internal Medicine Volume 161 • Number 2 159
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930510/ by a University of California San Diego User on 06/07/2017
Annals of Internal Medicine COMMENTS
AND
RESPONSES
2. Hu FB, Stampfer MJ, Haffner SM, Solomon CG, Willett WC, Manson JE. Elevated risk of cardiovascular disease prior to clinical diagnosis of type 2 diabetes. Diabetes Care. 2002;25:1129-34. [PMID: 12087009] 3. Kopel E, Sidi Y, Kivity S. Mediterranean diet for primary prevention of cardiovas-
Prevention of Diabetes With Mediterranean Diets
cular disease [Letter]. N Engl J Med. 2013;369:672. [PMID: 23944308] 4. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a com-
TO THE EDITOR: We believe that Salas-Salvado´ and colleagues’ sub-
peting risk. J Am Stat Assoc. 1999;94:496-509.
group analysis (1), which found that a Mediterranean diet enriched with extra-virgin olive oil reduces risk for diabetes, is methodologically flawed. During the study, more participants were lost to follow-up in the low-fat diet control group (10.5%) than in the Mediterranean diet groups supplemented with olive oil (4.1%) or mixed nuts (6.9%). The authors state that participants in the control group “who withdrew had a worse cardiovascular risk profile at baseline than those who remained in the study.” This fact indicates that the entire control group in the subgroup analysis had a potentially higher cardiovascular risk profile at baseline than the intervention groups. A higher cardiovascular risk profile at baseline in the control group could coexist with a higher likelihood of baseline prediabetes and hyperinsulinemia, particularly in women (2). Although the original trial stratified randomization by sex, the trial and the subgroup analysis evaluated more women in the control group than in the Mediterranean diet groups (3). Therefore, the control group could have a higher risk for incident diabetes during follow-up. Also of note is that meaningful between-group differences at baseline (such as the difference between the sexes) are often associated with differential distribution among groups of other, unmeasured baseline factors that are related to outcomes and therefore may lead to substantial confounding. Although Salas-Salvado´ and colleagues did extensive multivariable adjustment in their analyses, we do not believe that such analyses would resolve substantial “residual” confounding. To sort through some of these issues, we believe that examining whether the subgroup analysis evenly represented the baseline cardiovascular risk (for example, by mean 10-year Framingham cardiovascular risk score) across the 3 comparison groups and by sex is important. We also recommend that the authors perform a competing risk analysis (4) that accounts for competing cardiovascular morbidity outcomes that could occur before the diabetes outcome. We propose that the results of these analyses be presented and discussed and that the simple Kaplan–Meier curves in the article be redrawn to reflect the new analyses (5).
5. Andersen PK, Geskus RB, de Witte T, Putter H. Competing risks in epidemiology:
Eran Kopel, MD, MPH Yechezkel Sidi, MD Shaye Kivity, MD Chaim Sheba Medical Center Tel Hashomer, Israel Disclosures: Authors have disclosed no conflicts of interest. Forms can
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0108.
References 1. Salas-Salvado´ J, Bullo´ M, Estruch R, Ros E, Covas MI, Ibarrola-Jurado N, et al. Prevention of diabetes with Mediterranean diets: a subgroup analysis of a randomized trial. Ann Intern Med. 2014;160:1-10. [PMID: 24573661]
possibilities and pitfalls. Int J Epidemiol. 2012;41:861-70. [PMID: 22253319]
IN RESPONSE: With regard to the potential “imbalances” in the baseline characteristics of participants in the PREDIMED (Prevencio´n con Dieta Mediterra´nea) study and competing risk analyses, sex distribution was the only potentially relevant “imbalance” in our trial. The control group included a slightly higher proportion of women than the Mediterranean diet intervention groups. Female sex was associated with a lower risk for new-onset diabetes (age-adjusted hazard ratio [HR], 0.81 [95% CI, 0.63 to 1.04]) and cardiovascular events (age-adjusted HR, 0.45 [CI, 0.35 to 0.57]) in the overall cohort. It was also associated with a lower risk for cardiovascular disease among participants with diabetes (age-adjusted HR, 0.52 [CI, 0.39 to 0.70]). The estimates for the intervention effect changed minimally after adjusting for sex (0.8% change for the Mediterranean diet supplemented with extra-virgin olive oil group and 2.1% change for the Mediterranean diet supplemented with nuts group). After the potential confounding effect of sex was removed, the apparent protection from the Mediterranean diet intervention was even stronger. Other statistically “significant” minor imbalances in the overall PREDIMED study cohort showed P values close to 0.050 (with the exception of age and body mass index). The actual observed differences varied in direction in groups and were small and clinically meaningless. Adjusted estimates, regardless of the factors that we adjusted for, were essentially unchanged (1). The Figure shows new Kaplan–Meier survival curves with the outcome of diabetes or cardiovascular events (whichever occurred first) and using inverse probability weighting to account for potential confounding due to minor imbalances in baseline factors. When using cardiovascular events or diabetes as outcomes among participants who initially did not have diabetes to account for the possibility of competing risks between cardiovascular disease and diabetes, the age- and sex-adjusted HRs of the Mediterranean diet supplemented with extra-virgin olive oil group and the Mediterranean diet supplemented with nuts group versus the control group were 0.68 (CI, 0.52 to 0.87) and 0.76 (0.59 to 0.98), respectively. The overall higher cardiovascular risk in the control group led to stronger inverse associations. When we also included all-cause death in this composite outcome, the age- and sex-adjusted HRs of the Mediterranean diet supplemented with extra-virgin olive oil group and the Mediterranean diet supplemented with nuts group versus the control group were 0.72 (CI, 0.57 to 0.91) and 0.80 (0.64 to 1.01), respectively. From a practical point of view, the relevant issue for residual confounding is not statistical significance but the magnitude of the absolute between-group differences and their clinical relevance, which translate into changes between crude and adjusted estimates (2). Therefore, substantial residual confounding was not an issue in the PREDIMED study. We have already published (in supplements © 2014 American College of Physicians 157
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930510/ by a University of California San Diego User on 06/07/2017
Letters Figure. Incidence of diabetes or cardiovascular end points. 20
Emilio Ros, MD, PhD Institut d’Investigacions Biome`diques August Pi Sunyer, Hospital Clinic, University of Barcelona Barcelona, Spain
Incidence of Diabetes or
Cardiovascular End Point, %
18
Jordi Salas-Salvado´, MD, PhD Centro de Investigacio´n Biome´dica en Red de Fisiopatologı´a de la Obesidad y Nutricio´n, Instituto de Salud Carlos III Madrid, Spain
16 14 12 10
6
Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-1725.
4
References
2
1. Estruch R, Ros E, Salas-Salvado´ J, Covas MI, Corella D, Aro´s F, et al; PREDIMED Study Investigators. Primary prevention of cardiovascular disease with a Mediterranean diet. N Engl J Med. 2013;368:1279-90. [PMID: 23432189] 2. Greenland S, Rothman KJ. Introduction to stratified analysis. In: Rothman KJ, Greenland S, Lash T, eds. Modern Epidemiology. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2008:262. 3. Ruiz-Canela M, Estruch R, Corella D, Salas-Salvado´ J, Martı´nez-Gonza´lez MA. Association of Mediterranean diet with peripheral artery disease: the PREDIMED randomized trial. JAMA. 2014;311:415-7. [PMID: 24449321] 4. Andersen PK, Geskus RB, de Witte T, Putter H. Competing risks in epidemiology: possibilities and pitfalls. Int J Epidemiol. 2012;41:861-70. [PMID: 22253319] 5. Fine JP, Gray RJ. A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496-509.
8
0 0
1
2
3
4
5
Follow-up, y Control MedDiet + nuts MedDiet + EVOO
Kaplan–Meier curves adjusted for potential confounding factors using inverse probability weighting are shown with the outcome of diabetes or cardiovascular primary end points (whichever occurred first). Weights were computed taking into account age, sex, body mass index, waist– height ratio, education level, total energy intake, and baseline adherence to the MedDiet. EVOO ⫽ extra-virgin olive oil; MedDiet ⫽ Mediterranean diet.
and technical appendices [1, 3]) many competing risk and multiple imputation analyses to account for potential biases due to dropouts. These ancillary analyses also support our main conclusions. Andersen and associates (4) have dealt in depth with the issue of competing risks. They recommend the use of the Fine and Gray method (5) for competing risk analysis; our results were essentially unchanged when we used this model. Although Andersen and associates acknowledge the potential difficulties in interpretation of this approach, they also state that “both rates and risks for all competing events remain useful and tend to supplement each other when studying models for competing risks” (italics added). In this context, the use of a composite outcome including all competing events (that is, the combination of new-onset diabetes, cardiovascular events, and death) also reinforces our main conclusions. Miguel A. Martı´nez-Gonza´lez, MD, PhD University of Navarra Pamplona, Spain Ramo´n Estruch, MD, PhD Institut d’Investigacions Biome`diques August Pi Sunyer, Hospital Clinic, University of Barcelona Barcelona, Spain Dolores Corella, DPharm, PhD University of Valencia Valencia, Spain
OBSERVATION Rivaroxaban in a Patient With Disseminated Intravascular Coagulation Associated With an Aortic Aneurysm: A Case Report Background: Progressive disseminated intravascular coagulation (DIC) causes bleeding due to consumption coagulopathy and excessive fibrinolytic activation and organ failure due to microcirculatory dysfunction (1). Disseminated intravascular coagulation associated with aortic aneurysms is characterized by marked fibrinolytic activation (2). When severe bleeding develops, DIC has conventionally been treated with a continuous heparin infusion (3), but the restrictions on patients are great and continuous intravenous infusion is problematic for outpatient care. Patient-administered subcutaneous heparin injections with a longer half-life are frequently selected (4), but the treatment burden remains high. Control of DIC with oral anticoagulants might reduce this burden substantially but requires inhibition of activated clotting factors. Warfarin decreases levels of vitamin K– dependent clotting factors without inhibiting activated clotting factors and is therefore ineffective in DIC. New oral anticoagulants that inhibit the activated form of the clotting factors thrombin and factor X are now being used to prevent stroke during atrial fibrillation and to prevent and treat venous thromboembolism. These agents might be effective in DIC. Objective: To report a patient with chronic DIC and an aortic aneurysm treated with rivaroxaban, a new oral anticoagulant with activity against activated factor X. Case Report: A 75-year-old man with an acute aortic dissection and a thoracic aortic aneurysm was treated conservatively. When we examined him 2 years after the event, the thoracic aortic aneurysm
158 15 July 2014 Annals of Internal Medicine Volume 161 • Number 2
Downloaded From: http://annals.org/pdfaccess.ashx?url=/data/journals/aim/930510/ by a University of California San Diego User on 06/07/2017
www.annals.org
Letters Figure. Changes in coagulation and fibrinolytic markers and
Fibrinogen level Platelet count
−28
−7 0
14
35
56
77
98
5 4 3 2 1 0
FDP/D-Dimer,
−28
−7 0
14
35
56
77
98
60 50 40 30 20 10 0
100 80 60 40 20
PAP level 2-AP level
−28
−7 0
14
35
56
77
98
10 8 6 4 2
Day
To convert fibrinogen values to mol/L, multiply by 0.0294. To convert platelet count values to ⫻ 109/L, multiply by 10. To convert D-dimer values to nmol/L, multiply by 5.476. Reference values for TAT, ⬍4.0 ng/mL. Reference values for ␣2-AP, 70% to 130%. Reference values for PAP, ⬍1.1 g/mL. ␣2-AP ⫽ ␣2-antiplasmin; FDP ⫽ fibrin degradation products; PAP ⫽ plasmin–␣2–antiplasmin complex; TAT ⫽ thrombin– antithrombin complex.
had enlarged and chronic DIC was present. His platelet count was 53 ⫻ 109/L (reference values, 130 to 350 ⫻ 109/L), fibrinogen level was 2.3 mol/L (reference values, 5.4 to 11.2 mol/L), fibrin degradation products level was 48.9 mg/L (reference values, ⬍5.0 mg/ L), and D-dimer level was 97.5 nmol/L (reference values, ⬍5.5 nmol/L). After insertion of a stent 45 days later, DIC was alleviated. His platelet count was 132 ⫻ 109/L 13 days after stent insertion but decreased again to 54 ⫻ 109/L 12 days later. Approximately 1 month later, the patient self-extracted a tooth and gingival bleeding required local therapy. His platelet count remained at approximately 20 ⫻ 109/L over the ensuing 3 months, and purpura became pronounced on his trunk. He was hospitalized, and treatment with oral rivaroxaban, 10 mg/d, was started after we obtained approval from our hospital’s medical ethics committee and informed consent from the patient. His platelet count did not increase, but his fibrinogen level returned to normal and all bleeding symptoms resolved completely (Figure). For 1.5 years, he has received rivaroxaban continuously; had no further bleeding; and had stable markers of DIC, including low platelet counts. Discussion: We are aware of 1 other patient with DIC who received treatment with rivaroxaban, but that patient had a rare
www.annals.org
Tomoe Hayashi, MD, PhD Noriharu Nakagawa, MD Yasuko Kadohira, MD Eriko Morishita, MD, PhD Hidesaku Asakura, MD, PhD Kanazawa University School of Medicine Kanazawa, Japan Disclosures: Authors have disclosed no conflicts of interest. Forms can
Day
g/mL
-AP, %
TAT level FDP level D-Dimer level
PAP,
2
120 100 80 60 40 20 0
TAT, ng/mL
g/mL
Day
10 4/ L
300 250 200 150 100 50
Platelet Count,
Fibrinogen, mg/dL
rivaroxaban administration.
congenital condition in which blood and lymph vessels did not form properly (the Klippel–Trenaunay–Weber syndrome) (5). Our patient had DIC in association with an aortic aneurysm, and his DIC was alleviated with rivaroxaban. Disseminated intravascular coagulation occurs fairly commonly in association with aneurysms, and we believe that potential benefits of new oral anticoagulants, such as rivaroxaban, for these patients should be investigated further.
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0131.
References 1. Levi M, Ten Cate H. Disseminated intravascular coagulation. N Engl J Med. 1999;341:586-92. [PMID: 10451465] 2. Takada A, Takada Y, Mori T, Sakaguchi S. Prevention of severe bleeding by tranexamic acid in a patient with disseminated intravascular coagulation. Thromb Res. 1990;58:101-8. [PMID: 1693450] 3. Jelenska MM, Szmidt J, Bojakowski K, Grzela T, Palester-Chlebowczyk M. Compensated activation of coagulation in patients with abdominal aortic aneurysm: effects of heparin treatment prior to elective surgery. Thromb Haemost. 2004;92:997-1002. [PMID: 15543326] 4. Ontachi Y, Asakura H, Arahata M, Kadohira Y, Maekawa M, Hayashi T, et al. Effect of combined therapy of danaparoid sodium and tranexamic acid on chronic disseminated intravascular coagulation associated with abdominal aortic aneurysm. Circ J. 2005;69:1150-3. [PMID: 16127203] 5. Randrianarisoa E, Kopp HG, Balletshofer BM, Jaschonek K, Kanz L, Haering HU, et al. Management of disseminated intravascular coagulopathy with direct factor Xa inhibitor rivaroxaban in Klippel-Tre´naunay syndrome. Blood Coagul Fibrinolysis. 2013;24:766-70. [PMID: 24030117]
CORRECTION Correction: In the Clinic: Screening for Colorectal Cancer In a recent In the Clinic, a statement in the Patient Information page was incorrect. The sentence on fecal occult blood testing should read as follows: High-sensitivity fecal occult blood test uses one of several chemical reactions to see if stool contains any blood, which can be a sign of polyps or cancer. This has been fixed in the online version.
Reference 1. Weinberg DS, Schoen RD. In the Clinic: screening for colorectal cancer. Ann Intern Med. 2014;160:ITC5-1-16. [PMID: 24798544]
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