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Eur Heart J. 2012

Eur Heart J. 2012. Meta-analysis. Context : The impact of RAAS inhibitors (ACE inhibitors and ARBs) is: Well established for the reduction in cardiovascular morbidity across specific populations (other than in hypertension per se) .

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Eur Heart J. 2012

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  1. Eur Heart J. 2012

  2. Meta-analysis Context : The impact of RAAS inhibitors (ACE inhibitors and ARBs) is: • Well established for the reduction in cardiovascular morbidity across specific populations (other than in hypertension per se). • Not convincingly demonstrated with regard to mortality in hypertensive patients. Primary hypothesis: RAAS inhibitors as a class of drugs will produce: - A significant furthermortality reduction: - In their main indication, hypertension. - In patients representative of those treated in the 21st century. Van Vark LC, Bertrand M, Akkerhuis KM, et al. EurHeart J . 2012 Apr 17. Epub ahead of print. doi:10.1093/eurheartj/ehs075.

  3. Meta-analysis: methodology Inclusion criteria: • Prospective, randomized, controlled morbidity-mortality trials that compared active treatment (ACE inhibitor or ARB) with control, published between Jan 2000 and Mar2011. • Trials including a large majority of hypertensive patients (>66% of studied population, according to the definition used in these trials). • Different hypertensive populations for whom the benefits of RAAS inhibition would be expected to be mainly due to BP reduction. • All-cause mortality:a prespecified end point or reported in the principal study publication. Van Vark LC, Bertrand M, Akkerhuis KM, et al. EurHeart J . 2012 Apr 17. Epub ahead of print. doi:10.1093/eurheartj/ehs075.

  4. Meta-analysis: methodology Exclusion criteria: • Trials in specific populations (heart failure, acute coronary syndrome, stroke, atrial fibrillation, post--cardiac surgery, hemodialysis trials). • Post hoc and subgroup analyses. • Less than 66% of the studied population being hypertensive. • All-cause mortality not reported. • Trials with RAAS inhibitors simultaneously investigated in both arms (ONTARGET, ACCOMPLISH, INVEST, etc). Van Vark LC, Bertrand M, Akkerhuis KM, et al. EurHeart J . 2012 Apr 17. Epub ahead of print. doi:10.1093/eurheartj/ehs075.

  5. Baseline characteristics of study population Amlo=amlodipine, ARB=angiotensin receptor blocker, Diur= diuretic, FU=follow-up, HCTZ=hydrochlorothiazide, Indap=indapamide, IR=incidence rate/1000 patient-years, SBP=systolic blood pressure. Van Vark LC, Bertrand M, Akkerhuis KM, et al. EurHeart J . 2012 Apr 17. Epub ahead of print. doi:10.1093/eurheartj/ehs075.

  6. 20 trials: all-cause mortality reduction Random effects model HR (95% CI) P RENAAL 1.03 (0.83-1.29) IDNT 0.92 (0.69-1.23) LIFE 0.88 (0.77-1.01) ALLHAT 1.03 (0.90-1.15) ANBP-2 0.90 (0.75-1.09) SCOPE 0.96 (0.81-1.14) Pilot HYVET 0.99 (0.62-1.58) JMIC-B 1.32 (0.61-2.86) VALUE 1.04 (0.94-1.14) MOSES 1.07 (0.73-1.57) ASCOT-BPLA 0.89 (0.81-0.99) 0.03 JIKEI HEART 1.09 (0.64-1.85) 0.03 ADVANCE 0.86 (0.75-0.98) HYVET 0.79 (0.65-0.95) 0.02 PRoFESS 1.03 (0.93-1.14) TRANSCEND 1.05 (0.91-1.22) CASE-J 0.85 (0.62-1.16) HIJ-CREATE 1.18 (0.83-1.67) KYOTO HEART 0.76 (0.40-1.30) NAVIGATOR 0.90 (0.77-1.05) 0.032 Overall 0.95 (0.91-1.00) 2.0 0.75 1.33 0.50 1 N=158 998 RAAS inhibitor better Control better P for heterogeneity 0.266; I215% Van Vark LC, Bertrand M, Akkerhuis KM, et al. EurHeart J . 2012 Apr 17. Epub ahead of print. doi:10.1093/eurheartj/ehs075.

  7. All-cause mortality: effect of ACE inhibitors Random effects model P HR (95% CI) ALLHAT (lisinopril) 1.03 (0.90-1.15) ANBP-2 (enalapril) 0.90 (0.75-1.09) Pilot HYVET (lisinopril) 0.99 (0.62-1.58) JMIC-B (lisinopril, enalapril) 1.32 (0.61-2.86) ASCOT-BPLA (perindopril) 0.03 0.89 (0.81-0.99) ADVANCE (perindopril) 0.03 0.86 (0.75-0.98) HYVET (perindopril) 0.79 (0.65-0.95) 0.02 Overall 0.90 (0.84-0.97) 0.004 N= 76 615 1.33 0.50 0.75 1 2.0 HR (log scale) ACE inhibitor better Control better Van Vark LC, Bertrand M, Akkerhuis KM, et al. EurHeart J . 2012 Apr 17. Epub ahead of print. doi:10.1093/eurheartj/ehs075.

  8. All-cause mortality: effect of ARBs Random effects model P HR (95% CI) RENAAL (losartan) 1.03 (0.83-1.29) IDNT (irbesartan) 0.92 (0.69-1.23) LIFE (losartan) 0.88 (0.77-1.01) SCOPE (candesartan) 0.96 (0.81-1.14) VALUE (valsartan) 1.04 (0.94-1.14) MOSES (eprosartan) 1.07 (0.73-1.57) JIKEI HEART (valsartan) 1.09 (0.64-1.85) PRoFESS (telmisartan) 1.03 (0.93-1.14) TRANSCEND (telmisartan) 1.05 (0.91-1.22) CASE-J (candesartan) 0.85 (0.62-1.16) HIJ-CREATE (candesartan) 1.18 (0.83-1.67) KYOTO HEART (valsartan) 0.76 (0.40-1.30) NAVIGATOR (valsartan) 0.90 (0.77-1.05) Overall 0.99 (0.94-1.04) 0.683 N=82 383 0.50 0.75 1 1.33 2.0 ARB better HR (log scale) Control better Van Vark LC, Bertrand M, Akkerhuis KM, et al. EurHeart J . 2012 Apr 17. Epub ahead of print. doi:10.1093/eurheartj/ehs075.

  9. ACE inhibitors and ARBs have different modes of action “The differences in the modes of action between ACE inhibitors and ARBs, and the small-but-definite BP-independent reduction in CAD mortality with ACE inhibitors, which has not been observed with ARBs or other antihypertensive agents, might contribute to thisfinding.” “Both drugs block angiotensin II, but ACE inhibitors are characterized by a decrease in the degradation of bradykinin leading to a release of nitric oxide and prostaglandins resulting in additional vasodilatation.” Van Vark LC, Bertrand M, Akkerhuis KM, et al. EurHeart J . 2012 Apr 17. Epub ahead of print. doi:10.1093/eurheartj/ehs075.

  10. Conclusions • Among RAAS inhibitors, only ACE inhibitors have demonstrateda significant 10% mortality reduction in hypertensive patients (P=0.004). • No significant reduction in all-cause mortality could be demonstrated with ARBs (HR, 0.99 [0.95-1.04]; P=0.683). • The difference in treatment effect between ACE inhibitors and ARBs was statistically significant (P-value for interaction 0.036). • The largest mortality reductions were observed in ASCOT-BPLA, ADVANCE, and HYVET, which studied the ACE inhibitor perindopril (pooled HR, 0.87 [0.81-0.93]; P<0.001). • Because of the high prevalence of hypertension, the widespread use of ACE inhibitors may result in an important gain in lives saved. Van Vark LC, Bertrand M, Akkerhuis KM, et al. EurHeart J . 2012 Apr 17. Epub ahead of print. doi:10.1093/eurheartj/ehs075.

  11. Clinical implications • “The findings are relevant to clinical practice, as they are based on data from well-designed randomized trials encompassing a broad population of patients with high BP, who were well-treated for concomitant risk factors and who represent usual hypertensive patients seen today.” • “The estimated absolute mortality reduction was 3.8 per 1000 patient-years for the class of ACE inhibitors… Since the prevalence of hypertension in Western populations is high, despite the widespread use of BP-lowering medication, a wider application of ACE inhibitors may have substantial effects on the population level.” • “The observed mortality reduction may be used as an additional argument to stimulate patients to adhere to the prescribed treatment.” Van Vark LC, Bertrand M, Akkerhuis KM, et al. EurHeart J . 2012 Apr 17. Epub ahead of print. doi:10.1093/eurheartj/ehs075.

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