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CASE REPORT Table of Contents   
Year : 2007  |  Volume : 10  |  Issue : 1  |  Page : 58-60
Increased prothrombin time and lactic acidosis: Rofecoxib drug interaction with acenocoumarin and metformin

Department of Anaesthesiology and Cardiothoracic and Vascular Surgery, Sanjay Gandhi Postgraduate Institute, India

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How to cite this article:
Tewari P, Nath SS, Mazumdar G. Increased prothrombin time and lactic acidosis: Rofecoxib drug interaction with acenocoumarin and metformin. Ann Card Anaesth 2007;10:58-60

How to cite this URL:
Tewari P, Nath SS, Mazumdar G. Increased prothrombin time and lactic acidosis: Rofecoxib drug interaction with acenocoumarin and metformin. Ann Card Anaesth [serial online] 2007 [cited 2022 Aug 8];10:58-60. Available from:

   Introduction Top

Management of type 2 diabetes mellitus usually involves drugs to control blood glucose levels and it goes along with pharmacotherapy of other pathological disorders. Therefore, drug-to-drug interaction becomes important. We report increased prothrombin time and lactic acidosis setting in the postoperative period in a patient who was type 2 diabetic and had undergone aortic valve replacement under cardiopulmonary bypass.

   Case report Top

A 61-year-old female patient underwent aortic valve replacement for severe aortic stenosis. She was a known case of type 2 diabetes mellitus and her blood glucose level was controlled with diet modifications and metformin 1 gm twice daily for the last one and half years. Other laboratory parameters were within normal limits. Preoperative transthoracic echocardiography (TTE) revealed ejection fraction (EF) 71.46%, fractional shortening (FS) 40.81%, a thick, doming, bicuspid aortic valve with peak and mean gradients of 64 and 40 mm Hg respectively. Aortic valve replacement was performed with a 21-sized St Jude Medical Reagent mechanical valve on cardiopulmonary bypass with cold blood cardioplegic arrest. The aortic cross clamp and cardiopulmonary bypass times were 41 and 61 minutes respectively. Postoperative TTE showed EF 63%, FS 34.69% and normal functioning aortic valve prosthesis with sharp opening and closing angles, good excursion, peak velocity of 1.9 m/sec and peak and mean gradients of 14 and 9 mm Hg respectively. She was discharged from the hospital after 10 days with normal renal functions (Serum creatinine 1.4 mg/dL) and adequate diabetes control (random blood glucose 150 mg/dL). Her medications included ramipril 2.5 mg and metformin 1 gm twice daily, frusemide 5 mg, and acenocoumarin 3 mg once daily to keep effective international normalized ratio (INR) more than 2.5. Oral rofecoxib 50 mg twice daily was prescribed for pain relief for one week and she was advised to come for first follow up after one month.

The patient was readmitted in emergency department after 8 days of discharge with complaints of diminished urine output, severe gingival bleeding, increasing breathlessness, a regular pulse rate of 118 beats/min, arterial pressure 110/44 mm Hg, respiratory rate of 32/min, normal heart sounds and a clear aortic valve closing click. Laboratory investigations revealed blood glucose 120 mg dL, serum lactate 14 meq/L, pH 6.9, arterial carbon dioxide tension, (PaCO 2 ) 18 mm Hg, arterial oxygen tension (PaO 2 ) 186 mm Hg, sodium 130 meq/L, potassium 6.98 meq/L, standard bicarbonate 3.3 meq/L, base deficit -27.9 meq/L, serum creatinine 8.7 mg dL and blood urea 28.3 mg/dL. Her prothrombin time (PT) was 30 with a control of 12 seconds. TTE showed normally functioning aortic prosthesis and ventricular functions. The chest x-ray was within normal limits. She did not have fever or increase in polymorphs on differential leucocyte count, thus ruling out sepsis. A provisional diagnosis of type B lactic acidosis was made and she was transferred to cardiac intensive care unit. Due to deteriorating respiratory status she was electively put on assisted ventilation. The other therapy included dopamine (5 µg/Kg/min), sodium bicarbonate (100 ml intravenous single dose), phytomenadione (5 mg intravenous single dose), and four units of fresh frozen plasma (FFP). Lactate free continuous veno-venous haemofiltration (CVVH) was started to control lactic acidosis.

After 12 hours, the pH was 7.278, standard bicarbonate 9.5 meq/L, base deficit -15.6 meq/L, and anion gap of 26.7 meq/L, and after 24 hours the pH was 7.361, standard bicarbonate 10.2 meq/L, base deficit - 13.5 meq/L, anion gap 26.3 meq/L and serum creatinine level was 2 mg/dL. CVVH was continued for 78 hours. On third day, her creatinine and blood lactate levels further came down to 1.5 mg/dL and 1.2 meq/L respectively and her arterial blood gas examination revealed pH of 7.5, standard bicarbonate 22.7 meq/L and base deficit of 0.1 meq/L. She was extubated and made complete recovery. Her previous records showed that she was on long term therapy with ramipril and metformin but never had renal compromise. She was discharged on oral ramipril, metformin, frusemide and acenocoumarin. The patient was found to be doing well in subsequent follow-ups.

   Discussion Top

The present patient was not in cardiac failure, but had signs of renal failure, normal blood glucose levels, type B lactic acidosis and coagulopathy. She was receiving angiotensin-converting enzyme (ACE) inhibitor, frusemide, metformin, acenocoumarin and rofecoxib. Metformin, a biguanide is frequently used in patients with type 2 diabetes and can cause type B lactic-acidosis (MALA), which is a rare but serious side effect with an estimated incidence of 0.03/1000 patient years. [1] The risk factors for MALA were age more than 60 years and renal failure. The development of renal insufficiency may have been hastened by concomitant use of rofecoxib.

Rofecoxib, a nonsteroidal anti-inflammatory drug (NSAID), has renal toxicities similar to that of non-selective NSAIDs and produces quantitative changes in urinary prostaglandin excretion, glomerular filtration rate, sodium retention and their consequences. [2] The risk of renal injury was increased due to pre-existing diabetes, cardiac surgery with the use of cardiopulmonary bypass, diuretics, ACE inhibitors and age. [3]

Very high anticoagulation effect with acenocoumarin leading to gingival bleeding in the presence of normal liver functions is difficult to explain. Anticoagulation is not affected in presence of renal failure or due to interaction with either frusemide or ACE inhibitor. There are two reports of increase of dicoumarol anticoagulant effect by tolbutamide and chlorpropamide. [4],[5] Metformin has been shown to decrease the half life of phenprocoumon and increase the requirement of the anticoagulant. [6] Recently, Schier reported warfarin causing haematoma induced obstructive­uropathy which resulted in MALA. [7] Whereas nonselective NSAIDS have been shown to increase the anticoagulation of warfarin, [8] this is not well known with rofecoxib, a COX-2 Inhibitor. Australian adverse drug reactions bulletin [9] has compiled 21 cases of increase in INR with the use of celecoxib (COX-2 inhibitor NSAID) out of 2218 reports of all kinds of suspected drug interactions. Since celecoxib can inhibit CYP2C9 enzyme (cytochrome P450 group) and as this enzyme mainly metabolizes warfarin, some individuals may have higher warfarin levels and increased prothrombin time. Malhi and others 10 have shown that this accounts to CYP2C9 gene polymorphism. Variant genes *2 and *3 show reduced activity of this enzyme and carriers of *3 variant are at risk of bleeding, although this genetic variation seems to be more common in white people. No report of such interaction is present regarding rofecoxib, but same metabolic pathway may cause this kind of interaction. Thus, we believe that the rofecoxib, prescribed to the patient in high dose may have led to renal insufficiency causing MALA. Metformin was prescribed again as rofecoxib was discontinued and also because it is cheap and has good long term usage profile in type 2 diabetes.

In conclusion, management of an elderly patient with diabetes undergoing heart valve replacement under CPB merits very good glucose control during the perioperative period. Twenty four hours after surgery, the patient was treated with ACE inhibitors, diuretics and metformin for 8 days in the ward and was doing alright. However, at discharge, rofecoxib prescribed in high dose seems to be the most probable cause to add to insult resulting in renal insfficiency. This, under the setting of diabetes and metformin therapy caused MALA and also it might have resulted in enhanced anticoagulation.[10]

   References Top

1.Chang CT, Chen YC, Fang JT, Huang CC. Metformin associated lactic acidosis -Case report and literature review. J Nephrology 2002; 15: 398-402.  Back to cited text no. 1    
2.Capone ML, Tacconelli S, Sciulli MG, Patrignani P. Clinical pharmacology of selective COX-2 inhibitors. Int J Immunopathol Pharmacol 2003; 16(2 suppl):49-58.  Back to cited text no. 2    
3.Ahmad SR, Kortepeter C, Brinker A, Chen M, Betz J. Renal failure associated with use of celecoxib and refecoxib. Drug Saf 2002; 25: 537-544.  Back to cited text no. 3    
4.Solomon HM, Schrogie JJ. Effect of phenyramidol and bishydroxycoumarin on the metabolism of tolbutamide in human subjects. Metabolism 1967; 16: 1029-1033.  Back to cited text no. 4  [PUBMED]  [FULLTEXT]
5.Kristensen M, Hansen JM. Accumulation of chlorpropamide caused by diacoumarol. Acta Med Scand 1968; 183: 83-86.  Back to cited text no. 5  [PUBMED]  
6.Ohnhaus EE, Berger W, Duckert F, Oesch F. The influence of dimethyliguanide on phenprocoumon elimination and its mode of action. Klin Wchsch 1983; 61: 851-858.  Back to cited text no. 6    
7.Schier JG, Hoffman RS. Metformin-induced acidosis due to warfarin adverse drug event. Ann Pharmacother 2003; 37: 1145.  Back to cited text no. 7    
8.Wells PS, Holbrook AM, Crowther NR, Hirsh J. Interactions of warfarin with drugs and food. Ann Int Med 1994; 121: 676-683.  Back to cited text no. 8  [PUBMED]  [FULLTEXT]
9.Interaction of celecoxib and warfarin on adverse drug reactions bulletin, February 2001, Vol 20, No.1. Available online at .  Back to cited text no. 9    
10.Malhi H, Atac B, Daly AK, Gupta S. Warfarin and celecoxib interaction in the setting of cytochrome P450 (CYP2C9) polymorphism with bleeding complication. Postgrad Med J 2004; 80: 107-109.  Back to cited text no. 10    

Correspondence Address:
Prabhat Tewari
Consultant Cardiac Anaesthetist, Nottingham City Hospital, Hucknall Road, NG5 1PB, Nottingham, United Kingdom

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0971-9784.37927

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