Letters
Annals of Internal Medicine COMMENT
AND
RESPONSE
Low-Dose Aspirin for Prevention of Morbidity and Mortality From Preeclampsia
Ste´phanie Roberge, MSc Suzanne Demers, MD Emmanuel Bujold, MD, MSc Universite´ Laval Que´bec, Canada Disclosures: Authors have disclosed no conflicts of interest. Forms can
TO THE EDITOR: Henderson and colleagues (1) observed that low-
dose aspirin reduces the risk for preterm birth, preeclampsia, and intrauterine growth restriction. However, we believe that they should have developed some important details before concluding that lowdose aspirin therapy should be started after the first trimester. Although the authors reported that 8 trials initiated low-dose aspirin treatment before 16 weeks of gestation, only 5 of them effectively randomly assigned study participants at a mean (or median) gestational age of less than 16 weeks. For example, CLASP (Collaborative Low-Dose Aspirin Study in Pregnancy) initiated randomization at 12 weeks of gestation, but some women were randomly assigned as late as 32 weeks for a mean gestational age of 19.4 weeks at randomization (2). After stratification of the studies according to mean or median gestational age at initiation of low-dose aspirin therapy, we repeated meta-analyses for the 3 main outcomes using the same data collected by the authors. Five trials recruited 854 women at a mean gestational age of 16 weeks or less, and 8 trials recruited 11 330 women at a mean gestational age of more than 16 weeks. According to gestational age at initiation of low-dose aspirin therapy, the Mantel– Haenszel test indicated significant differences in the relative risk (RR) for intrauterine growth restriction (RR, 0.45 [95% CI, 0.29 to 0.69] vs. 0.94 [CI, 0.80 to 1.12]; P ⫽ 0.002) and preterm birth (RR, 0.33 [CI, 0.17 to 0.66] vs. 0.91 [CI, 0.85 to 0.97]; P ⫽ 0.004), suggesting greater benefits of low-dose aspirin therapy started at 16 weeks or earlier with a similar trend for preeclampsia (RR, 0.56 [CI, 0.37 to 0.85] vs. 0.85 [CI, 0.68 to 1.06]; P ⫽ 0.08). The 4 trials that recruited most of their participants in the first trimester (⬍14 weeks of gestation) showed greater and significant reduction of preeclampsia (RR, 0.50 [CI, 0.31 to 0.79]; P ⬍ 0.001) than studies that recruited women mainly in the second and third trimesters (RR, 0.86 [CI, 0.70 to 1.04]; P not significant). According to these analyses, initiation of low-dose aspirin therapy at a mean gestational age of 16 weeks or less is associated with significant reduction of all 3 outcomes of approximately 50%, whereas low-dose aspirin therapy initiated in the second trimester is not. This finding concurs with those of our earlier meta-analyses that included more trials (3, 4). We agree that a large randomized trial should be done to confirm the benefits of low-dose aspirin therapy started in the first trimester to prevent adverse pregnancy outcomes in high-risk women. On the other hand, the literature shows slight, if any, benefits of low-dose aspirin therapy initiated after 16 weeks of gestation. Therefore, we believe that low-dose aspirin therapy should be started at approximately 12 weeks of gestation in agreement with recommendations from other national societies and should not be delayed until the second trimester in women at high risk for adverse placentamediated outcomes of pregnancy (5).
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0365.
References 1. Henderson JT, Whitlock EP, O’Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;160:695-703. [PMID: 24711050] doi:10.7326/M13-2844 2. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet. 1994;343:619-29. [PMID: 7906809] 3. Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E. Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis. Ultrasound Obstet Gynecol. 2013;41:491-9. [PMID: 23362106] doi:10.1002/uog.12421 4. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010;116:402-14. [PMID: 20664402] doi: 10.1097/AOG.0b013e3181e9322a 5. National Institute for Health and Clinical Excellence. Hypertension in Pregnancy: The Management of Hypertensive Disorders during Pregnancy. Manchester, United Kingdom: National Institute for Health and Clinical Excellence; 2010 [updated 2011]. Accessed at http://guidance.Nice.Org.Uk/cg107 on 16 April 2014.
IN RESPONSE: Dr. Roberge and colleagues suggest that alternate analyses of our data reveal important effects of the timing of initiation of low-dose aspirin therapy for preventing preeclampsia, intrauterine growth restriction, and preterm birth. Unfortunately, metaanalyses of the available evidence are not well-suited for identifying such effects. Many of the included studies enrolled women initiating treatment across a range of gestational ages. Of note, the 2 largest included trials cannot be precisely classified, having enrolled participants beginning at 12 to 13 weeks of gestation, with 49% initiating aspirin therapy before 20 weeks of gestation in the MFMU (Maternal-Fetal Medicine Units) trial (1) and 69% doing so at 20 weeks of gestation or earlier in CLASP (2).We did sensitivity analyses using the stratification of studies suggested by Dr. Roberge and colleagues but used metaregression with the Knapp–Hartung modification, a more conservative test that accounts for small samples. Our results were similar for preterm birth and intrauterine growth restriction but did not significantly differ for preeclampsia between early and late initiation. Our review reported evidence of small-study effects for preterm birth and intrauterine growth restriction, possibly because of publication bias. With the categorization recommended by Dr. Roberge and colleagues, only the small studies would be pooled in the group of women who began therapy before 16 weeks of gestation, heightening the risk for drawing conclusions from a biased subset of the evidence. Confounding was evident in metaregression, because the effects of early initiation lost statistical significance when we controlled for sample size and population risk. © 2014 American College of Physicians 613
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Letters Beyond our concerns about small-study effects and confounding, when investigating study-level characteristics to apply to individuals, there is risk of bias due to the ecological fallacy. Withinstudy results that examine individuals are more likely to be valid. Both of the large studies included in our review reported subgroup analyses, finding no differences in effects using the cut point of 20 weeks of gestation. Moreover, an important individual-patient data meta-analysis done by the Perinatal Antiplatelet Review of International Studies (PARIS) Collaboration was able to categorize patients rather than studies and found no evidence of effect differences by timing of aspirin initiation (3). We continue to believe that current evidence does not support claims of differential effects by timing of aspirin initiation. Our review, a previous Cochrane review (4), and individual patient-data meta-analyses suggest that modest benefits may be obtained with initiation of low-dose aspirin therapy even after 20 weeks of gestation (3). Nonetheless, we wholly support recommendations for welldesigned trials to test whether initiation before 16 weeks confers more benefit. Jillian T. Henderson, PhD, MPH Elizabeth O’Connor, PhD Evelyn P. Whitlock, MD, MPH Kaiser Permanente Research Affiliates Evidence-based Practice Center Portland, Oregon Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-2844. References 1. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, et al. Lowdose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 1998;338:701-5. [PMID: 9494145] 2. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet. 1994;343:619-29. [PMID: 7906809] 3. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369:1791-8. [PMID: 17512048] 4. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007:CD004659. [PMID: 17443552]
Case Report: A 78-year-old woman presented in December 2003 with muscle pain in the hips and shoulders and morning stiffness. She had a history of hypercholesterolemia treated with atorvastatin, 10 mg/d, for 9 months and hypertension treated with candesartan, 8 mg/d, and bisoprolol, 2.5 mg/d. Laboratory studies revealed an erythrocyte sedimentation rate (ESR) of 61 mm/h and a platelet count of 487 ⫻ 109 cells/L. The patient was diagnosed with PMR and advised to stop atorvastatin therapy. Her symptoms gradually resolved. Five months after presentation, ESR was normal at 13 mm/h. In February 2006, her low-density lipoprotein cholesterol level was 4.5 mmol/L (174 mg/dL), and therapy with rosuvastatin, 5 mg twice weekly, was resumed. Symptoms of PMR recurred and progressed, and she reported visual disturbances. Temporal arteries were tender on palpation. Hematoxylin– eosin staining of a biopsy specimen of the temporal artery showed panarteritis comprising lymphocytes, neutrophils, eosinophils, and macrophages with giant cells (Figure 1). Intimal thickening with clear luminal narrowing was also noted (Figure 2). An ESR of 95 mm/h and a C-reactive protein level of 2381.0 nmol/L were found on laboratory studies. Giant cell arteritis (GCA) with PMR was diagnosed. Rosuvastatin therapy was discontinued, and the patient was treated with prednisolone, 40 mg/d, the dosage of which was slowly tapered. Her symptoms abated over the next few months, and the ESR and C-reactive protein level decreased to 6 mm/h and less than 95.2 nmol/L, respectively. In June 2008, prednisolone therapy was stopped. A few months later, PMR and GCA relapsed. This time, relapse was not preceded by statin therapy. The patient again received corticosteroids, which resulted in a good response until she died in February 2009. Discussion: The patient’s presentation strongly suggested statininduced PMR and GCA. Both are part of the same disease spectrum and are associated with the HLA-DRB1*04 allele (3), the presence of
Figure 1. Inflammatory cells.
OBSERVATION Giant Cell Arteritis and Polymyalgia Rheumatica After Reexposure to a Statin: A Case Report Background: Statins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are widely used to prevent cardiovascular diseases and are generally regarded as safe. However, adverse reactions, such as myalgia, myositis, rhabdomyolysis, muscle weakness, and cramps with or without elevated serum creatine kinase levels, may occur (1). Furthermore, we have recently described that statins may also be associated with polymyalgia rheumatica (PMR) (2).
Hematoxylin– eosin stain showing lymphocytes (blue arrow), eosinophils (red arrow), and macrophages and giant cells (black arrow) (original magnification, ⫻100).
614 21 October 2014 Annals of Internal Medicine Volume 161 • Number 8
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Letters which was not determined in this patient. Between 16% and 21% of patients with PMR have GCA (3). Of note, PMR in this patient resolved after statin therapy was discontinued and PMR and GCA recurred after statin therapy (that is, rosuvastatin) was resumed. This sequence of events suggests that statins may trigger PMR and GCA in sensitive patients. However, this patient relapsed later without a preceding statin challenge, showing that the disease process had become independent of the external trigger, which often occurs in drug-induced vasculitis (4). The mechanism of statin-associated PMR and GCA is not clear. Because many patients receiving statins develop myalgia and/or more severe muscle disease (1), mild myopathic damage probably plays a role in statin-associated PMR and GCA. In statin-associated necrotizing myopathy, these drugs have recently been postulated to induce neoantigens as a result of muscle damage, which are subsequently presented to the immune system. A similar mechanism may operate in statin-associated PMR and GCA (2). Indeed, in an animal model we recently showed that statin use leads to dysregulation of immune responses, possibly resulting in autoimmunity (5). In summary, we report the first case to our knowledge of GCA combined with PMR that was probably induced by a statin, rosuvastatin. Of interest, in this patient, previous use of atorvastatin had been followed by a first episode of PMR. We propose that PMR should be suspected when a patient receiving statin therapy presents with myalgia of the hips and shoulders combined with morning stiffness. Hilda J.I. de Jong, MSc Maastricht University Medical Centre Maastricht, the Netherlands Ronald H.B. Meyboom, MD Utrecht Institute for Pharmaceutical Sciences, Utrecht University Utrecht, the Netherlands Markku J. Helle, MD Mikkeli Central Hospital Mikkeli, Finland Olaf H. Klungel, PharmD Utrecht Institute for Pharmaceutical Sciences, Utrecht University Utrecht, the Netherlands Leo Niskanen, MD Pharmacovigilance, Finnish Medicines Agency Fimea Helsinki, Finland Jan Willem Cohen Tervaert, MD Maastricht University Maastricht, the Netherlands Disclaimer: The funding source had no role in the design and conduct
of the study; collection, analysis, or interpretation of the data; or decision to submit the manuscript for publication. Financial Support: The National Institute for Public Health and the
Environment funded this study (project S340040). Dr. Klungel has received funding for pharmacoepidemiologic research from the Dutch private–public Top Institute Pharma (grant T6.101 Mondriaan) and the
Figure 2. Panarteritis.
Hematoxylin– eosin stain showing panarteritis of the temporal artery (original magnification, ⫻200). Innovative Medicines Initiative Joint Undertaking under grant agreement n8 115004, resources of which include financial contribution from the European Union’s Seventh Framework Programme (FP7/20072013) and European Federation of Pharmaceutical Industries and Associations’ in-kind contribution. Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽L14-0027. References 1. Rallidis LS, Fountoulaki K, Anastasiou-Nana M. Managing the underestimated risk of statin-associated myopathy. Int J Cardiol. 2012;159:169-76. [PMID: 21813193] doi:10.1016/j.ijcard.2011.07.048 2. de Jong HJ, Saldi SR, Klungel OH, Vandebriel RJ, Souverein PC, Meyboom RH, et al. Statin-associated polymyalgia rheumatica. An analysis using WHO global individual case safety database: a case/non-case approach. PLoS One. 2012;7:e41289. [PMID: 22844450] doi:10.1371/journal.pone.0041289 3. Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet. 2008;372:234-45. [PMID: 18640460] doi:10.1016/S0140-6736(08)61077-6 4. Slot MC, Links TP, Stegeman CA, Tervaert JW. Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: a long-term followup study. Arthritis Rheum. 2005;53: 108-13. [PMID: 15696557] 5. Vandebriel RJ, De Jong HJ, Gremmer ER, Klungel OH, Tervaert JW, Slob W, et al. Statins accelerate the onset of collagen type II-induced arthritis in mice. Arthritis Res Ther. 2012;14:R90. [PMID: 22537858] doi:10.1186/ar3814
CORRECTION Correction: Vitamin D With or Without Calcium Supplementation for Prevention of Cancer and Fractures In a review and meta-analysis on the effects of vitamin D and calcium on fracture (1), there was an error in categorizing 3 studies (2– 4). These studies involved interventions that combined vitamin D with calcium supplementation, but their comparison groups (called a placebo group in 2 papers [2, 3]) received a calcium sup-
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Letters Figure 2. Results of random-effects model meta-analysis of the effects of combined vitamin D and calcium supplementation as compared with placebo on total fracture in randomized, controlled trials. Relative Risk (95% CI)
Study (Reference)
Institutionalized
Events/Total, n/N Control Combined Vitamin D and Calcium Supplementation
Vitamin D, Calcium, History of Fracture Study IU/d Fracture Definition Quality mg/d
Chapuy et al (21)
0.74 (0.56–0.97)
80/1387
110/1403
800
1200
None
Hip
Poor
Chapuy et al (22)
0.62 (0.36–1.07)
27/393
21/190
800
1200
None
Hip
Fair
Subtotal (I2 = 0.0%; P = 0.588)
0.7 1(0.55–0.91)
107/1780
131/1593
Community-dwelling Jackson et al (33)
0.97 (0.92–1.03)
400
1000
Some
Total
Good
Dawson-Hughes et al (23)
0.46 (0.23–0.90)
11/187
26/202
700
500
None
First NV
Fair
Porthouse et al (29)*
1.08 0.61–1.91)
24/607
22/603
800
1000
Some
Total
Fair
Porthouse et al (29)†
0.96 (0.64–1.43)
34/714
69/1391
800
1000
Some
Total
Fair
Salovaara et al (30)
0.84 (0.63–1.13)
78/1586
94/1609
800
1000
Some
Total
Poor
Subtotal (I2 = 29.9%; P = 0.222)
0.92 (0.78–1.07)
2102/18 176 2158/18 106
2249/21 270 2369/21 910
Community-dwelling with a history of fracture Grant et al (25)
1.02 (0.90–1.17)
387/2646
377/2643
800
1000
All
Total
Good
Harwood et al (32)
0.57 (0.15–2.22)
3/39
5/37
800
1000
All
Hip
Poor
Subtotal (I2 = 0.0%; P = 0.399)
1.02 (0.89–1.16)
390/2688
382/2680
Overall (I2 = 39.3%; P = 0.106)
0.91 (0.81–1.01)
0.2
0.5
0.8 1.0 1.2 1.5 2.0 2.5
2746/25 738 2882/26 183
5.0
NS ⫽ not specified; NV ⫽ nonvertebral. * Equally allocated groups. † Unequally allocated groups; 2 women were randomly assigned to the control group for every 1 woman randomly assigned to the treatment group.
plement. Thus, they should not have been combined in the randomeffects model meta-analysis of the effects of combined vitamin D and calcium supplementation as compared with placebo on total fracture, which was presented in Figure 2. These studies have been excluded from an updated meta-analysis, and a new Figure 2 is provided here. The revised analysis included 9 randomized, controlled trials comparing the combination of vitamin D (400 to 1000 IU/d) and calcium (500 to 1200 mg/d) supplementation with placebo in a total of 51 921 persons. The summary point estimates (pooled relative risks) of effect for vitamin D plus calcium and 95% CIs have changed only slightly (from 0.88 [CI, 0.79-0.99] to 0.91 [CI, 0.81-1.01]). However, the overall conclusion remains the same: Combined vitamin D and calcium supplementation can reduce fracture risk; the effect may be smaller in community-dwelling older adults than in institutionalized elderly persons.
References 1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated metaanalysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155:82738. [PMID: 22184690] doi:10.7326/0003-4819-155-12-201112200-00005 2. Flicker L, MacInnis RJ, Stein MS, Scherer SC, Mead KE, Nowson CA, et al. Should older people in residential care receive vitamin D to prevent falls? Results of a randomized trial. J Am Geriatr Soc. 2005;53:1881-8. [PMID: 16274368] 3. Komulainen MH, Kro¨ger H, Tuppurainen MT, Heikkinen AM, Alhava E, Honkanen R, et al. HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial. Maturitas. 1998;31:45-54. [PMID: 10091204] 4. Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res. 2000;15:1113-8. [PMID: 10841179]
616 21 October 2014 Annals of Internal Medicine Volume 161 • Number 8
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Annals of Internal Medicine COMMENT
AND
RESPONSE
Low-Dose Aspirin for Prevention of Morbidity and Mortality From Preeclampsia
Ste´phanie Roberge, MSc Suzanne Demers, MD Emmanuel Bujold, MD, MSc Universite´ Laval Que´bec, Canada Disclosures: Authors have disclosed no conflicts of interest. Forms can
TO THE EDITOR: Henderson and colleagues (1) observed that low-
dose aspirin reduces the risk for preterm birth, preeclampsia, and intrauterine growth restriction. However, we believe that they should have developed some important details before concluding that lowdose aspirin therapy should be started after the first trimester. Although the authors reported that 8 trials initiated low-dose aspirin treatment before 16 weeks of gestation, only 5 of them effectively randomly assigned study participants at a mean (or median) gestational age of less than 16 weeks. For example, CLASP (Collaborative Low-Dose Aspirin Study in Pregnancy) initiated randomization at 12 weeks of gestation, but some women were randomly assigned as late as 32 weeks for a mean gestational age of 19.4 weeks at randomization (2). After stratification of the studies according to mean or median gestational age at initiation of low-dose aspirin therapy, we repeated meta-analyses for the 3 main outcomes using the same data collected by the authors. Five trials recruited 854 women at a mean gestational age of 16 weeks or less, and 8 trials recruited 11 330 women at a mean gestational age of more than 16 weeks. According to gestational age at initiation of low-dose aspirin therapy, the Mantel– Haenszel test indicated significant differences in the relative risk (RR) for intrauterine growth restriction (RR, 0.45 [95% CI, 0.29 to 0.69] vs. 0.94 [CI, 0.80 to 1.12]; P ⫽ 0.002) and preterm birth (RR, 0.33 [CI, 0.17 to 0.66] vs. 0.91 [CI, 0.85 to 0.97]; P ⫽ 0.004), suggesting greater benefits of low-dose aspirin therapy started at 16 weeks or earlier with a similar trend for preeclampsia (RR, 0.56 [CI, 0.37 to 0.85] vs. 0.85 [CI, 0.68 to 1.06]; P ⫽ 0.08). The 4 trials that recruited most of their participants in the first trimester (⬍14 weeks of gestation) showed greater and significant reduction of preeclampsia (RR, 0.50 [CI, 0.31 to 0.79]; P ⬍ 0.001) than studies that recruited women mainly in the second and third trimesters (RR, 0.86 [CI, 0.70 to 1.04]; P not significant). According to these analyses, initiation of low-dose aspirin therapy at a mean gestational age of 16 weeks or less is associated with significant reduction of all 3 outcomes of approximately 50%, whereas low-dose aspirin therapy initiated in the second trimester is not. This finding concurs with those of our earlier meta-analyses that included more trials (3, 4). We agree that a large randomized trial should be done to confirm the benefits of low-dose aspirin therapy started in the first trimester to prevent adverse pregnancy outcomes in high-risk women. On the other hand, the literature shows slight, if any, benefits of low-dose aspirin therapy initiated after 16 weeks of gestation. Therefore, we believe that low-dose aspirin therapy should be started at approximately 12 weeks of gestation in agreement with recommendations from other national societies and should not be delayed until the second trimester in women at high risk for adverse placentamediated outcomes of pregnancy (5).
be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms .do?msNum⫽L14-0365.
References 1. Henderson JT, Whitlock EP, O’Connor E, Senger CA, Thompson JH, Rowland MG. Low-dose aspirin for prevention of morbidity and mortality from preeclampsia: a systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2014;160:695-703. [PMID: 24711050] doi:10.7326/M13-2844 2. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet. 1994;343:619-29. [PMID: 7906809] 3. Roberge S, Nicolaides KH, Demers S, Villa P, Bujold E. Prevention of perinatal death and adverse perinatal outcome using low-dose aspirin: a meta-analysis. Ultrasound Obstet Gynecol. 2013;41:491-9. [PMID: 23362106] doi:10.1002/uog.12421 4. Bujold E, Roberge S, Lacasse Y, Bureau M, Audibert F, Marcoux S, et al. Prevention of preeclampsia and intrauterine growth restriction with aspirin started in early pregnancy: a meta-analysis. Obstet Gynecol. 2010;116:402-14. [PMID: 20664402] doi: 10.1097/AOG.0b013e3181e9322a 5. National Institute for Health and Clinical Excellence. Hypertension in Pregnancy: The Management of Hypertensive Disorders during Pregnancy. Manchester, United Kingdom: National Institute for Health and Clinical Excellence; 2010 [updated 2011]. Accessed at http://guidance.Nice.Org.Uk/cg107 on 16 April 2014.
IN RESPONSE: Dr. Roberge and colleagues suggest that alternate analyses of our data reveal important effects of the timing of initiation of low-dose aspirin therapy for preventing preeclampsia, intrauterine growth restriction, and preterm birth. Unfortunately, metaanalyses of the available evidence are not well-suited for identifying such effects. Many of the included studies enrolled women initiating treatment across a range of gestational ages. Of note, the 2 largest included trials cannot be precisely classified, having enrolled participants beginning at 12 to 13 weeks of gestation, with 49% initiating aspirin therapy before 20 weeks of gestation in the MFMU (Maternal-Fetal Medicine Units) trial (1) and 69% doing so at 20 weeks of gestation or earlier in CLASP (2).We did sensitivity analyses using the stratification of studies suggested by Dr. Roberge and colleagues but used metaregression with the Knapp–Hartung modification, a more conservative test that accounts for small samples. Our results were similar for preterm birth and intrauterine growth restriction but did not significantly differ for preeclampsia between early and late initiation. Our review reported evidence of small-study effects for preterm birth and intrauterine growth restriction, possibly because of publication bias. With the categorization recommended by Dr. Roberge and colleagues, only the small studies would be pooled in the group of women who began therapy before 16 weeks of gestation, heightening the risk for drawing conclusions from a biased subset of the evidence. Confounding was evident in metaregression, because the effects of early initiation lost statistical significance when we controlled for sample size and population risk. © 2014 American College of Physicians 613
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Letters Beyond our concerns about small-study effects and confounding, when investigating study-level characteristics to apply to individuals, there is risk of bias due to the ecological fallacy. Withinstudy results that examine individuals are more likely to be valid. Both of the large studies included in our review reported subgroup analyses, finding no differences in effects using the cut point of 20 weeks of gestation. Moreover, an important individual-patient data meta-analysis done by the Perinatal Antiplatelet Review of International Studies (PARIS) Collaboration was able to categorize patients rather than studies and found no evidence of effect differences by timing of aspirin initiation (3). We continue to believe that current evidence does not support claims of differential effects by timing of aspirin initiation. Our review, a previous Cochrane review (4), and individual patient-data meta-analyses suggest that modest benefits may be obtained with initiation of low-dose aspirin therapy even after 20 weeks of gestation (3). Nonetheless, we wholly support recommendations for welldesigned trials to test whether initiation before 16 weeks confers more benefit. Jillian T. Henderson, PhD, MPH Elizabeth O’Connor, PhD Evelyn P. Whitlock, MD, MPH Kaiser Permanente Research Affiliates Evidence-based Practice Center Portland, Oregon Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽M13-2844. References 1. Caritis S, Sibai B, Hauth J, Lindheimer MD, Klebanoff M, Thom E, et al. Lowdose aspirin to prevent preeclampsia in women at high risk. National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. N Engl J Med. 1998;338:701-5. [PMID: 9494145] 2. CLASP: a randomised trial of low-dose aspirin for the prevention and treatment of pre-eclampsia among 9364 pregnant women. CLASP (Collaborative Low-dose Aspirin Study in Pregnancy) Collaborative Group. Lancet. 1994;343:619-29. [PMID: 7906809] 3. Askie LM, Duley L, Henderson-Smart DJ, Stewart LA; PARIS Collaborative Group. Antiplatelet agents for prevention of pre-eclampsia: a meta-analysis of individual patient data. Lancet. 2007;369:1791-8. [PMID: 17512048] 4. Duley L, Henderson-Smart DJ, Meher S, King JF. Antiplatelet agents for preventing pre-eclampsia and its complications. Cochrane Database Syst Rev. 2007:CD004659. [PMID: 17443552]
Case Report: A 78-year-old woman presented in December 2003 with muscle pain in the hips and shoulders and morning stiffness. She had a history of hypercholesterolemia treated with atorvastatin, 10 mg/d, for 9 months and hypertension treated with candesartan, 8 mg/d, and bisoprolol, 2.5 mg/d. Laboratory studies revealed an erythrocyte sedimentation rate (ESR) of 61 mm/h and a platelet count of 487 ⫻ 109 cells/L. The patient was diagnosed with PMR and advised to stop atorvastatin therapy. Her symptoms gradually resolved. Five months after presentation, ESR was normal at 13 mm/h. In February 2006, her low-density lipoprotein cholesterol level was 4.5 mmol/L (174 mg/dL), and therapy with rosuvastatin, 5 mg twice weekly, was resumed. Symptoms of PMR recurred and progressed, and she reported visual disturbances. Temporal arteries were tender on palpation. Hematoxylin– eosin staining of a biopsy specimen of the temporal artery showed panarteritis comprising lymphocytes, neutrophils, eosinophils, and macrophages with giant cells (Figure 1). Intimal thickening with clear luminal narrowing was also noted (Figure 2). An ESR of 95 mm/h and a C-reactive protein level of 2381.0 nmol/L were found on laboratory studies. Giant cell arteritis (GCA) with PMR was diagnosed. Rosuvastatin therapy was discontinued, and the patient was treated with prednisolone, 40 mg/d, the dosage of which was slowly tapered. Her symptoms abated over the next few months, and the ESR and C-reactive protein level decreased to 6 mm/h and less than 95.2 nmol/L, respectively. In June 2008, prednisolone therapy was stopped. A few months later, PMR and GCA relapsed. This time, relapse was not preceded by statin therapy. The patient again received corticosteroids, which resulted in a good response until she died in February 2009. Discussion: The patient’s presentation strongly suggested statininduced PMR and GCA. Both are part of the same disease spectrum and are associated with the HLA-DRB1*04 allele (3), the presence of
Figure 1. Inflammatory cells.
OBSERVATION Giant Cell Arteritis and Polymyalgia Rheumatica After Reexposure to a Statin: A Case Report Background: Statins, or 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are widely used to prevent cardiovascular diseases and are generally regarded as safe. However, adverse reactions, such as myalgia, myositis, rhabdomyolysis, muscle weakness, and cramps with or without elevated serum creatine kinase levels, may occur (1). Furthermore, we have recently described that statins may also be associated with polymyalgia rheumatica (PMR) (2).
Hematoxylin– eosin stain showing lymphocytes (blue arrow), eosinophils (red arrow), and macrophages and giant cells (black arrow) (original magnification, ⫻100).
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Letters which was not determined in this patient. Between 16% and 21% of patients with PMR have GCA (3). Of note, PMR in this patient resolved after statin therapy was discontinued and PMR and GCA recurred after statin therapy (that is, rosuvastatin) was resumed. This sequence of events suggests that statins may trigger PMR and GCA in sensitive patients. However, this patient relapsed later without a preceding statin challenge, showing that the disease process had become independent of the external trigger, which often occurs in drug-induced vasculitis (4). The mechanism of statin-associated PMR and GCA is not clear. Because many patients receiving statins develop myalgia and/or more severe muscle disease (1), mild myopathic damage probably plays a role in statin-associated PMR and GCA. In statin-associated necrotizing myopathy, these drugs have recently been postulated to induce neoantigens as a result of muscle damage, which are subsequently presented to the immune system. A similar mechanism may operate in statin-associated PMR and GCA (2). Indeed, in an animal model we recently showed that statin use leads to dysregulation of immune responses, possibly resulting in autoimmunity (5). In summary, we report the first case to our knowledge of GCA combined with PMR that was probably induced by a statin, rosuvastatin. Of interest, in this patient, previous use of atorvastatin had been followed by a first episode of PMR. We propose that PMR should be suspected when a patient receiving statin therapy presents with myalgia of the hips and shoulders combined with morning stiffness. Hilda J.I. de Jong, MSc Maastricht University Medical Centre Maastricht, the Netherlands Ronald H.B. Meyboom, MD Utrecht Institute for Pharmaceutical Sciences, Utrecht University Utrecht, the Netherlands Markku J. Helle, MD Mikkeli Central Hospital Mikkeli, Finland Olaf H. Klungel, PharmD Utrecht Institute for Pharmaceutical Sciences, Utrecht University Utrecht, the Netherlands Leo Niskanen, MD Pharmacovigilance, Finnish Medicines Agency Fimea Helsinki, Finland Jan Willem Cohen Tervaert, MD Maastricht University Maastricht, the Netherlands Disclaimer: The funding source had no role in the design and conduct
of the study; collection, analysis, or interpretation of the data; or decision to submit the manuscript for publication. Financial Support: The National Institute for Public Health and the
Environment funded this study (project S340040). Dr. Klungel has received funding for pharmacoepidemiologic research from the Dutch private–public Top Institute Pharma (grant T6.101 Mondriaan) and the
Figure 2. Panarteritis.
Hematoxylin– eosin stain showing panarteritis of the temporal artery (original magnification, ⫻200). Innovative Medicines Initiative Joint Undertaking under grant agreement n8 115004, resources of which include financial contribution from the European Union’s Seventh Framework Programme (FP7/20072013) and European Federation of Pharmaceutical Industries and Associations’ in-kind contribution. Disclosures: Disclosures can be viewed at www.acponline.org/authors /icmje/ConflictOfInterestForms.do?msNum⫽L14-0027. References 1. Rallidis LS, Fountoulaki K, Anastasiou-Nana M. Managing the underestimated risk of statin-associated myopathy. Int J Cardiol. 2012;159:169-76. [PMID: 21813193] doi:10.1016/j.ijcard.2011.07.048 2. de Jong HJ, Saldi SR, Klungel OH, Vandebriel RJ, Souverein PC, Meyboom RH, et al. Statin-associated polymyalgia rheumatica. An analysis using WHO global individual case safety database: a case/non-case approach. PLoS One. 2012;7:e41289. [PMID: 22844450] doi:10.1371/journal.pone.0041289 3. Salvarani C, Cantini F, Hunder GG. Polymyalgia rheumatica and giant-cell arteritis. Lancet. 2008;372:234-45. [PMID: 18640460] doi:10.1016/S0140-6736(08)61077-6 4. Slot MC, Links TP, Stegeman CA, Tervaert JW. Occurrence of antineutrophil cytoplasmic antibodies and associated vasculitis in patients with hyperthyroidism treated with antithyroid drugs: a long-term followup study. Arthritis Rheum. 2005;53: 108-13. [PMID: 15696557] 5. Vandebriel RJ, De Jong HJ, Gremmer ER, Klungel OH, Tervaert JW, Slob W, et al. Statins accelerate the onset of collagen type II-induced arthritis in mice. Arthritis Res Ther. 2012;14:R90. [PMID: 22537858] doi:10.1186/ar3814
CORRECTION Correction: Vitamin D With or Without Calcium Supplementation for Prevention of Cancer and Fractures In a review and meta-analysis on the effects of vitamin D and calcium on fracture (1), there was an error in categorizing 3 studies (2– 4). These studies involved interventions that combined vitamin D with calcium supplementation, but their comparison groups (called a placebo group in 2 papers [2, 3]) received a calcium sup-
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Letters Figure 2. Results of random-effects model meta-analysis of the effects of combined vitamin D and calcium supplementation as compared with placebo on total fracture in randomized, controlled trials. Relative Risk (95% CI)
Study (Reference)
Institutionalized
Events/Total, n/N Control Combined Vitamin D and Calcium Supplementation
Vitamin D, Calcium, History of Fracture Study IU/d Fracture Definition Quality mg/d
Chapuy et al (21)
0.74 (0.56–0.97)
80/1387
110/1403
800
1200
None
Hip
Poor
Chapuy et al (22)
0.62 (0.36–1.07)
27/393
21/190
800
1200
None
Hip
Fair
Subtotal (I2 = 0.0%; P = 0.588)
0.7 1(0.55–0.91)
107/1780
131/1593
Community-dwelling Jackson et al (33)
0.97 (0.92–1.03)
400
1000
Some
Total
Good
Dawson-Hughes et al (23)
0.46 (0.23–0.90)
11/187
26/202
700
500
None
First NV
Fair
Porthouse et al (29)*
1.08 0.61–1.91)
24/607
22/603
800
1000
Some
Total
Fair
Porthouse et al (29)†
0.96 (0.64–1.43)
34/714
69/1391
800
1000
Some
Total
Fair
Salovaara et al (30)
0.84 (0.63–1.13)
78/1586
94/1609
800
1000
Some
Total
Poor
Subtotal (I2 = 29.9%; P = 0.222)
0.92 (0.78–1.07)
2102/18 176 2158/18 106
2249/21 270 2369/21 910
Community-dwelling with a history of fracture Grant et al (25)
1.02 (0.90–1.17)
387/2646
377/2643
800
1000
All
Total
Good
Harwood et al (32)
0.57 (0.15–2.22)
3/39
5/37
800
1000
All
Hip
Poor
Subtotal (I2 = 0.0%; P = 0.399)
1.02 (0.89–1.16)
390/2688
382/2680
Overall (I2 = 39.3%; P = 0.106)
0.91 (0.81–1.01)
0.2
0.5
0.8 1.0 1.2 1.5 2.0 2.5
2746/25 738 2882/26 183
5.0
NS ⫽ not specified; NV ⫽ nonvertebral. * Equally allocated groups. † Unequally allocated groups; 2 women were randomly assigned to the control group for every 1 woman randomly assigned to the treatment group.
plement. Thus, they should not have been combined in the randomeffects model meta-analysis of the effects of combined vitamin D and calcium supplementation as compared with placebo on total fracture, which was presented in Figure 2. These studies have been excluded from an updated meta-analysis, and a new Figure 2 is provided here. The revised analysis included 9 randomized, controlled trials comparing the combination of vitamin D (400 to 1000 IU/d) and calcium (500 to 1200 mg/d) supplementation with placebo in a total of 51 921 persons. The summary point estimates (pooled relative risks) of effect for vitamin D plus calcium and 95% CIs have changed only slightly (from 0.88 [CI, 0.79-0.99] to 0.91 [CI, 0.81-1.01]). However, the overall conclusion remains the same: Combined vitamin D and calcium supplementation can reduce fracture risk; the effect may be smaller in community-dwelling older adults than in institutionalized elderly persons.
References 1. Chung M, Lee J, Terasawa T, Lau J, Trikalinos TA. Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated metaanalysis for the U.S. Preventive Services Task Force. Ann Intern Med. 2011;155:82738. [PMID: 22184690] doi:10.7326/0003-4819-155-12-201112200-00005 2. Flicker L, MacInnis RJ, Stein MS, Scherer SC, Mead KE, Nowson CA, et al. Should older people in residential care receive vitamin D to prevent falls? Results of a randomized trial. J Am Geriatr Soc. 2005;53:1881-8. [PMID: 16274368] 3. Komulainen MH, Kro¨ger H, Tuppurainen MT, Heikkinen AM, Alhava E, Honkanen R, et al. HRT and Vit D in prevention of non-vertebral fractures in postmenopausal women; a 5 year randomized trial. Maturitas. 1998;31:45-54. [PMID: 10091204] 4. Pfeifer M, Begerow B, Minne HW, Abrams C, Nachtigall D, Hansen C. Effects of a short-term vitamin D and calcium supplementation on body sway and secondary hyperparathyroidism in elderly women. J Bone Miner Res. 2000;15:1113-8. [PMID: 10841179]
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