title: Higher cardiovascular risk and impaired benefit of antihypertensive treatment in hypertensive patients requiring additional drugs on top of randomized therapy:  is adding drugs always beneficial?
abstract: BACKGROUND
  In antihypertensive treatment trials, when randomized therapies do not reach target, additional drugs are administered. However, patients requiring (add-on) or not requiring add-on therapy (no-add-on) may be at different cardiovascular risk and differently susceptible to benefits of antihypertensive treatment.
  
  
  RESULTS
  The Felodipine Event Reduction study included 9711 Chinese hypertensive patients receiving 12.5  mg/day hydrochlorothiazide and randomized to associating either felodipine (5  mg/day) or placebo. Within 6 months, add-on therapy (further diuretic and other drugs) was required by 2185 patients, whereas 7243 did not require it. Despite significant SBP/DBP reductions by add-on therapy, outcome incidence remained much lower in no-add-on than in add-on patients: hazard ratios for various outcomes, after adjusting for baseline variables and blood pressure (BP) at time of add-on decision, were 0.22-0.368 (P always <0.001) and remained substantially unchanged when further adjusted for the small SBP/DBP difference persisting during follow-up treatment (-2.4/-1.1  mmHg in no-add-on). When felodipine was compared to placebo, the benefit of a lower SBP/DBP caused by felodipine was evident in the no-add-on patients (hazard ratio 0.45-0.68, P always <0.001), but it was lost in the add-on group (hazard ratio 0.91-1.17).
  
  
  CONCLUSIONS
  Comparing patients more or less easily responding to antihypertensive treatment may identify patients at high risk of outcomes and less susceptible to benefits of a lower BP. It remains to be more directly investigated to what extent adding drugs to drugs is effective in reducing outcomes of patients in whom simple antihypertensive therapy does not achieve goal BP.
authors.affiliation: Divisions of Hypertension and Biometrics, FuWai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences, Beijing, China.
authors.forename: Yuqing
authors.initials: Y
authors.lastname: Zhang
authors.forename: Xuezhong
authors.initials: X
authors.lastname: Zhang
authors.forename: Lisheng
authors.initials: L
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Wang
authors.forename: Xinran
authors.initials: X
authors.lastname: Tang
authors.forename: Alberto
authors.initials: A
authors.lastname: Zanchetti
mesh_terms: D000368:Aged; D000959:Antihypertensive Agents / Q000008:administration & dosage*; D001794:Blood Pressure / Q000187:drug effects; D002318:Cardiovascular Diseases / Q000453:epidemiology / Q000401:mortality / Q000517:prevention & control; D002681:China / Q000453:epidemiology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D015736:Felodipine / Q000008:administration & dosage; D005260:Female; D006801:Humans; D006852:Hydrochlorothiazide / Q000008:administration & dosage; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D012307:Risk Factors; D016896:Treatment Outcome
chemical_list: D000959:Antihypertensive Agents; D006852:Hydrochlorothiazide; D015736:Felodipine