Pulmonary Embolism in a Patient With ADPKD Treated With Tolvaptan: From the Clinical Experience to the Analysis of the Food and Drug Administration Adverse Event Reporting System Registry

Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary kidney disorder (estimated prevalence of 1 per 1000–1 per 2500 live births)1co-chairs E.A.F. Harris T. Sandford R. members E.A.F. Roundtable participants. European ADPKD forum multidisciplinary position statement on autosomal dominant polycystic kidney disease care: European ADPKD forum and multispecialist roundtable participants.Nephrol Dial Transplant. 2018; 33: 563-573https://doi.org/10.1093/ndt/gfx327Crossref PubMed Scopus (24) Google Scholar characterized by the development and growth of multiple bilateral cysts eventually leading to end-stage renal disease and renal replacement therapy.1co-chairs E.A.F. Harris T. Sandford R. members E.A.F. Roundtable participants. European ADPKD forum multidisciplinary position statement on autosomal dominant polycystic kidney disease care: European ADPKD forum and multispecialist roundtable participants.Nephrol Dial Transplant. 2018; 33: 563-573https://doi.org/10.1093/ndt/gfx327Crossref PubMed Scopus (24) Google Scholar Tolvaptan, a selective vasopressin V2 receptor antagonist, is currently the only pharmacologic agent approved for ADPKD capable of slowing the kidney cyst growth and the progression of kidney disease.2van Gastel M.D.A. Torres V.E. Polycystic kidney disease and the vasopressin pathway.Ann Nutr Metab. 2017; 70: 43-50https://doi.org/10.1159/000463063Crossref PubMed Scopus (25) Google Scholar The resulting aquaretic adverse events (AEs) (polyuria, pollakiuria, and nocturia) may cause dehydration and did not seem to diminish over time,2van Gastel M.D.A. Torres V.E. Polycystic kidney disease and the vasopressin pathway.Ann Nutr Metab. 2017; 70: 43-50https://doi.org/10.1159/000463063Crossref PubMed Scopus (25) Google Scholar thus supporting the need to inform patients for adequate liquid intake and maintaining long-term vigilance. Data on the risk/benefit profile of tolvaptan in ADPKD come mainly from randomized controlled trials and small real-world studies.3Blair H.A. Tolvaptan: a review in autosomal dominant polycystic kidney disease.Drugs. 2019; 79: 303-313https://doi.org/10.1007/s40265-019-1056-1Crossref PubMed Scopus (13) Google Scholar The latest prospective, multinational, open-label safety study enrolling subjects who completed previous trials (median exposure 651 days) confirmed the occurrence of treatment-emergent aquaretic AEs and the importance of tight hepatic monitoring as effective risk minimization strategy.4Torres V.E. Chapman A.B. Devuyst O. et al.Multicenter study of long-term safety of tolvaptan in later-stage autosomal dominant polycystic kidney disease.Clin J Am Soc Nephrol. 2020; 16: 48-58https://doi.org/10.2215/CJN.10250620Crossref PubMed Scopus (11) Google Scholar Therefore, postmarketing studies are needed to evaluate rare and unexpected AEs, which are not fully appreciated in randomized controlled trials.5Raschi E. Gatti M. Gelsomino F. et al.Lessons to be learnt from real-world studies on immune-related adverse events with checkpoint inhibitors: a clinical perspective from pharmacovigilance.Target Oncol. 2020; 15: 449-466https://doi.org/10.1007/s11523-020-00738-6Crossref PubMed Scopus (32) Google Scholar We herein describe the occurrence of acute pulmonary thromboembolism in a patient with risk factors exposed to tolvaptan. To evaluate the possible association between tolvaptan and thromboembolism, we also analyzed the Food and Drug Administration Adverse Event Reporting System. A 44-year-old woman presented to the emergency department with persistent dyspnea and chest pain on July 2020. She referred a past medical history of portal vein and caudal vena cava thrombosis during estrogen-progestogen therapy in 2009, treated with warfarin for 11 months. A heterozygous mutation for factor V Leiden was found. The patient was also affected by ADPKD and started administration of tolvaptan 60 mg/daily in October 2019 (120 mg/daily at hospital admission). On physical examination, tachycardia of 139 beats per minute and increased respiratory rate of 30/min with slight reduction of oxygen saturation level (96%) were observed, without signs of heart failure. Burning pain on lower limbs, without clinical signs of deep vein thrombosis, was referred. Kidney function was stable (creatinine 1.09 mg/dl, estimated glomerular filtration rate 62 ml/min) with signs of fibrinolysis as D-dimer was 2.97 mg/l (normal value <0.55 mg/l). Troponin I was 12.8 ng/l with normal B-type natriuretic peptide (30 pg/ml). In the suspicion of acute pulmonary embolism, a contrast-enhanced computed tomography angiogram was performed and confirmed the presence of bilateral massive pulmonary thromboembolia. Inferior vena cava compression by hepatic or right renal cysts was ruled out by computed tomography and magnetic resonance imaging. Results of echocardiography performed revealed mild dilation and hypokinesia of the right ventricle with positive McConnell’s sign (hypokinetic right ventricular free wall with sparing of the apex); the inferior vena cava was completely collapsed. Troponin I was 12.8 ng/l (the 99th percentile upper reference limit was 11.6 ng/l). The patient was deemed at intermediate high-risk pulmonary embolism, so anticoagulation treatment with low-molecular-weight heparin (enoxaparin 8000 U twice daily) was started plus i.v. fluid loading. Her kidney function was stable (creatinine = 0.86 mg/dl), with slightly elevated liver function enzymes (aspartate transaminase = 42 U/l, alanine transaminase = 78 U/l, gamma-glutamyl transferase = 66 U/l). Tolvaptan was discontinued, and enoxaparin was switched to a direct oral anticoagulant, rivaroxaban 20 mg. She was discharged on day 17 with stable medical condition (creatinine = 0.8 mg/dl, aspartate transaminase/alanine transaminase/gamma-glutamyl transferase = 40/82/55 U/l), without resuming tolvaptan. After 3 months of anticoagulation therapy, reduction of the thrombus at the main pulmonary trunk and partial occlusion at the left pulmonary artery with left lung infarct lesions was found; some segmental filling defects were also revealed in the right pulmonary basilar branches. At the cardiologic assessment at 6 months, the patient was still symptomatic and despite echocardiogram results revealed a normal right ventricle size and contractile function with normal pulmonary artery pressure (15 + 5 mm Hg), the complete workup for chronic thromboembolic pulmonary hypertension was completed according with both guidelines of the European Society of Cardiology on acute pulmonary embolism and pulmonary hypertension.6Konstantinides S.V. Meyer G. Becattini C. et al.ESC guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS).Eur Heart J. 2020; 41: 543-603https://doi.org/10.1093/eurheartj/ehz405Crossref PubMed Scopus (967) Google Scholar Finally, chronic thromboembolic disease (persistence of thromboembolic burden but without pulmonary hypertension at rest) was confirmed and the patient received lifelong anticoagulation therapy for 2 previous venous thromboembolism episodes not related to major transient or reversible risk factors. Kidney and liver function enzymes were in normal range (creatinine = 0.93 mg/dl, aspartate transaminase = 15 U/l, alanine transaminase = 23 U/l, gamma-glutamyl transferase = 23 U/l). The Food and Drug Administration Adverse Event Reporting System is a publicly available global spontaneous reporting system collecting real-world data on suspected adverse drug reactions. We retained reports of interest, specifically “embolic and thrombotic events,” up to September 2020, building on previous experience in pharmacovigilance.7Raschi E. Fusaroli M. Ardizzoni A. et al.Thromboembolic events with cyclin-dependent kinase 4/6 inhibitors in the FDA Adverse Event Reporting System.Cancers. 2021; 13: 1758https://doi.org/10.3390/cancers13081758Crossref PubMed Scopus (7) Google Scholar The cases were described in terms of demographic and clinical information, including causality assessment (see Supplementary Methods). Overall, 57 thromboembolic events were found (24 explicitly venous and 21 arterial), involving mostly the lung (in 32% of the cases), periphery (23%), nervous system (21%), and heart (18%), with pulmonary embolism being the most frequently reported AE (13 cases). There were 32 cases (61.5% of the reports specifying sex) that occurred in males, 61.4% were submitted by physicians, and the median age was 51 years. It should be noted that 12 cases concerned people of more than 60 years of age, but this is in line with the lack of age limits for reimbursement in multiple countries (6 of these reports are from Japan and 2 from France).S1 Most of the reports were serious (65%), such as resulting in death (6 cases), life-threating event, disability, hospitalization, requiring intervention, or another serious event. Median latency (i.e., time from the prescription of tolvaptan and the onset of AE), calculated on 19 cases, was approximately 5 months, with 50% of the thromboembolic events occurring between 2 months and 10 months. In 34 cases (59.6%) tolvaptan was discontinued (positive dechallenge result in 17 cases). Cardiovascular drugs, mainly amlodipine, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers, were recorded in 35 cases, and antigout agents were found in 15 cases. Potential risk factors were recorded in 16 cases (28%), mostly sex hormones and diuretics (11% each). In 11 cases (19.3%), antithrombotic therapy was documented (in 3 cases specified as therapy for the thromboembolic event). Most frequently co-reported events were thirst and pollakiuria (6 cases each). A highly probable/probable causality was found in 51% of the cases and probable in 49% (Table 1).Table 1Individual case assessmentCaseaCountries are coded using their ISO 3166-1 alpha-2 code.Thromboembolic eventCountryaCountries are coded using their ISO 3166-1 alpha-2 code.AgeSexLatency (d)DiscontinuationRisk factorsAntithromboticsAquaretic eventsSeriousnessCausalityVenous thromboembolism1Deep vein thrombosisNL48MYProbable2Pulmonary embolismUS51M54NCitalopramHOPossible3Pulmonary embolism; thrombosisDEFNDesogestrelHOPossible4Deep vein thrombosis; pulmonary embolismUS46M1035Y (D)Acute kidney injuryHOHighly probable5Deep vein thrombosis; pulmonary embolismDE46M468YHOProbable6Deep vein thrombosisGB48FNDesogestrelPossible7Pulmonary embolismFR67M1Y (D)Escitalopram; furosemideASAHOPossible8Pulmonary embolismFR67M69Y (D)HOHighly probable9Deep vein thrombosisUS42MYEnoxaparinProbable10Budd-Chiari syndromeDE51FYSpironolactone; torasemideEnoxaparinHOPossible11Pulmonary embolism; thrombosisCA33FY (D)MedroxyprogesteroneHOPossible12Pulmonary embolismUS51MNPollakiuriaProbable13Pulmonary thrombosisUS58FNHOHighly probable14Pulmonary embolismESMNDEAProbable15Portal vein occlusionUS35MYErythropoietinThirstLTPossible16Portal vein occlusionUS35MNProbableVenous thromboembolism17Pulmonary thrombosisAUFNNocturiaProbable18Pulmonary thrombosisUSMNTestosteroneHOPossible19Pulmonary thrombosisUS77M101NTestosteronePolydipsia, pollakiuria, nocturia, dry mouthDEAPossible20Pulmonary thrombosisAUFNThirst, nocturia, dry mouthProbable21Deep vein thrombosis; pulmonary embolismJP58M144Y (D)Hypernatremia, dehydrationHOHighly probable22Pulmonary embolismJP43MY (D)WarfarinHighly probable23Pulmonary embolismFR40FYProbable24Pulmonary embolismDENProbableArterial thromboembolism1Hepatic artery thrombosisBE45F201YNomegestrolPossible2Retinal artery occlusionJP75MY (D)HOHighly probable3Myocardial infarctionDE51YProbable4Cerebellar infarction; stress cardiomyopathyJP66F271Y (D)HOHighly probable5Myocardial infarctionFR57M184Y (D)HOHighly probable6AmaurosisDEM298Y (D)ASAHOHighly probable7Transient ischemic attackJP62F315Y (D)HOHighly probable8Lacunar infarctionJP57MYFurosemideHypernatremiaHOPossibleArterial thromboembolism9Transient ischemic attackJP50FY (D)Highly probable10Myocardial infarctionIT40MY (D)HOHighly probable11Myocardial infarctionCAWarfarinDEAProbable12Blindness transientCA55F1NHydrochlorothiazidePollakiuria; hypotensionPossible13Acute myocardial infarctionSE44FNHOProbable14Myocardial infarctionUS65M155YProbable15Retinal vein occlusionFR44NProbable16Myocardial infarctionCA49MNWarfarinDEAProbable17Amaurosis fugaxAT61FNHydrochlorothiazideHOPossible18Peripheral artery occlusionAU47MNPollakiuriaProbable19Stress cardiomyopathyIT45FY (D)HOHighly probable20Acute myocardial infarctionKR36MNDEAProbable21Transient ischemic attackUS66MY (D)FluticasoneClopidogrelThirst; hypotension; hypernatremia; dehydration; acute kidney injuryHOPossibleOther nonspecified thromboembolism1Cerebral infarctionJP59MYHypovolemiaHOProbable2Disseminated intravascular coagulationJP51F146YDehydration; acute kidney injuryDEAProbableOther nonspecified thromboembolism3ThrombosisUS40FYEscitalopramApixabanThirst; pollakiuriaHOPossible4Cerebral infarctionJP58FYclopidogrelProbable5Cerebral infarctionJP66MYDSProbable6ThrombosisUS56M1NHOProbable7Cerebral infarctionJP80MHOProbable8ThrombosisCA49M1Polydipsia; nocturiaProbable9ThrombosisUS32MNApixabanHOProbable10Cerebral infarctionJP63MYFurosemideHOPossible11Cerebrovascular accidentTW41F83Y (D)HOHighly probable12Cerebrovascular accidentUS441NProbableASA, acetylsalicylic acid; AT, Austria; AU, Australia; BE, Belgium; CA, Canada; D, dechallenge; DE, Germany; DEA, death; DS, disability; ES, Spain; F, female; FR, France; GB, United Kingdom; HO, hospitalization; ISO, International Organization for Standardization; IT, Italy; JP, Japan; KR, South Korea; LT, life threatening; M, male; N, no; NL, Netherlands; SE, Sweden; TW, Taiwan; US, United States; Y, yes.a Countries are coded using their ISO 3166-1 alpha-2 code. Open table in a new tab ASA, acetylsalicylic acid; AT, Austria; AU, Australia; BE, Belgium; CA, Canada; D, dechallenge; DE, Germany; DEA, death; DS, disability; ES, Spain; F, female; FR, France; GB, United Kingdom; HO, hospitalization; ISO, International Organization for Standardization; IT, Italy; JP, Japan; KR, South Korea; LT, life threatening; M, male; N, no; NL, Netherlands; SE, Sweden; TW, Taiwan; US, United States; Y, yes. After the publication of TEMPO 3:4 trial, tolvaptan was approved worldwide to slow the progression of cyst development and end-stage renal disease of ADPKD in adults. Aquaretic events and liver injury were key treatment-emergent AEs, whereas thromboembolism was not identified as a safety issue.

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