title: Safety of Fixed Dose of Antihypertensive Drug Combinations Compared to (Single Pill) Free-Combinations: A Nested Matched Case-Control Analysis.
abstract: To compare serious adverse events of fixed-dose dual antihypertensive drug combination (FIXED) to component-based free-combination (FREE).A population-based nationwide cohort from the French Health Insurance System included subjects over 50 years with first time claims (new user) in the second half of 2009 for a calcium-channel blocker or a thiazide-like diuretic in combination with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker as FREE or FIXED. We designed a nested matched case-control analysis with 304 cases, hospitalized for hypotension, syncope, or collapse (n = 224), renal failure (n = 19), hyponatremia, hyper- or hypokalemia (n = 61) and 1394 controls matched for gender, age, date of inclusion in the cohort, and administrative county. Subjects with a medical history of cardiovascular disease, chronic renal failure, or cancer were excluded.The mean age ± SD was 73 ± 10 years and 70% were women. Based on the last delivery preceding the index date, 1414 patients (83%) were exposed to FIXED. Homogeneity of FIXED effect compared to FREE across components of the main composite outcome was rejected (P = 0.0099). FIXED formulation significantly increased the odd of the most frequent component (ie, hypotension, syncope, or collapse): OR = 1.88 (95% CI: 1.15-3.05) compared to FREE after adjusting for confounding factors including dose.Serious adverse event occurring in the early phase of treatment deserves attention of physicians because it could alter the benefit/risk ratio of antihypertensive drug combination.
authors.affiliation: From the Pharmacoepidemiology Team (CTAD-PEPI), Rennes, France (EN, AH, EO); Université Européenne de Bretagne, Université Europeenne de Bretagne, Université de Brest, INSERM CIC 1412, IFR 148 et CHU de Brest, France (EN); CHU de Brest, France (AH); Emergency Department (JB), Cardiology Department (FP), and Nephrology Department (CV), Rennes University Hospital, Rennes, France; ESH Hypertension Excellence Centre (FP, CV); INSERM, CESP, UMR-1018, Villejuif, Paris, France (P-YS), and Pharmacovigilance, Pharmacoepidemiology and Drug Information Center, Rennes, France (EO).
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Nowak
authors.forename: André
authors.initials: A
authors.lastname: Happe
authors.forename: Jacques
authors.initials: J
authors.lastname: Bouget
authors.forename: Francois
authors.initials: F
authors.lastname: Paillard
authors.forename: Cécile
authors.initials: C
authors.lastname: Vigneau
authors.forename: Pierre-Yves
authors.initials: PY
authors.lastname: Scarabin
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Oger
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D057911:Angiotensin Receptor Antagonists / Q000627:therapeutic use; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000959:Antihypertensive Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D001794:Blood Pressure; D002121:Calcium Channel Blockers / Q000627:therapeutic use; D016022:Case-Control Studies; D004338:Drug Combinations; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006973:Hypertension / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D049993:Sodium Chloride Symporter Inhibitors / Q000627:therapeutic use
chemical_list: D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D002121:Calcium Channel Blockers; D004338:Drug Combinations; D049993:Sodium Chloride Symporter Inhibitors