Evidence-Based Medicine ACE-Inhibitor and ARB; combination therapy

Assess 64 year old Hispanic male with history of DMII, HTN, HLD and CAD, presents to nephrology clinic for chronic renal insufficiency follow up. Patient with well controlled diabetes, hyperlipidemia and hypertension. Physical exam is unremarkable, no peripheral neuropathy or documented retinopathy.

Assess Medication regimen Asprin 325mg daily Plavix 75mg daily Lisinopril 40mg daily Lopressor 25mg twice a day Nifedipine ER 30mg daily Lipitor 80mg daily Glipizide 5mg Actos 45mg

Assess Lab GFR Serum creatinine of 2.3mg per deciliter Microalbumin/Creatinine 384

ASK Diabetic nephropathy ACE-Inhibitor and ARB combination Preventing progression Decreasing risk factors for cardiovascular event ACE-Inhibitor and ARB combination Decrease proteinuria Would patient benefit from combination therapy? Decreasing risk for cardiovascular events? CALM, COOPERATE…decreasing progression of renal disease

ASK P- A patient with DMII, CAD and CKD. I- Addition of ARB to ACE-Inhibitor therapy. C- ACE-Inhibitor monotherapy O- decreased incidence of cardiovascular events.

ASK Over the last 16 years effects of ACE-Inhibitors have been extensively documented. Two trials in 2003 compared combination therapy of ACE-Inhibitor and ARB to ACE-Inhibitor monotherapy, in patients with CHF and acute MI. Trial in 2008 compared combination therapy to ACE-Inhibitor monotherapy in patients with vascular disease or high-risk diabetes. Background Wide benefits to patients with cardiovascular disease.

Acquire PubMed EBM review Search: PubMed For: ACEI and ARB combination therapy EBM review ACP Journal Club, Cochrane, Keyword: ACEI and ARB combination therapy

Acquire NMCSD homepage (nmcsdintranet) Reference Material Medline/OVI Library homepage Journals NEJM Lancet Databases PubMed@NMCSD EBM reviews

Appraise Effects of candersartan in patients with chronic heart failure and reduced left ventricular systolic function taking angiotensin converting enzyme inhibitor: the CHARM Added trial. J McMurray, J Ostergren, P Swedberg et al., The Lancet 362 (2003), pp 767-771. Reduction in cardiovascular events in patients with CHF and reduced left-ventricular ejection fraction with the addition of angiotensin II type 1 receptor blocker to angiotensin converting enzyme-inhibitor monotherapy. Start with these two studies and move on to the more substantial journal.

CHARM-Added trial Between March 1999 and November 1999, eligible patients in 618 centers in 26 countries were enrolled. Ages 18 years old or greater left ventricular ejection fraction less then 40% or lower measured within the past 6 months NYHA functional class II-IV Treatment with an ACE-inhibitor at a constant dose of 30 days or longer. Patients were randomly assigned to candesartan or matching placebo group.

CHARM-Added trial Treatment (double-blind) starting dose was 4mg/8mg daily dose was doubled every 2 weeks, as tolerated. Blood pressure, serum creatinine and Potassium. Target dose was 32mg once daily starting from 6 weeks. Follow-up 2, 4, 6 weeks, at 6 months and, thereafter at every 4 months until the end of the trial.

CHARM-Added Trial

CHARM-Added trial 2548 patients enrolled 1276 candesartan group 1272 placebo group Enalapril, lisinopril, captopril and ramipril. Similar dosing in in both groups Beta-blocker 64% candesartan, 68% placebo Spirnolactone 20% candesartan, 25% placebo Patient with similar starting points

CHARM-Added trial

CHARM-Added trial

CHARM-Added trail Results 483 (38%) patients in candesartan and 538 (42%) in the placebo group experienced primary outcome of cardiovascular death or admission to hospital for CHF. Unadjusted hazard ratio 0.85 (95% CI 0.75-0.96) p= 0.011 Covariate adjustment p= 0.010 Candesartan reduced cardiovascular mortality and the risk of admission to hospital for CHF. 302 (24%) CV deaths in candersartan, 347 (27%) in the placebo group. p= 0.029 Covariant adjustment p= 0.021

CHARM-Added trial

CHARM-Added trial

CHARM-Added trial

CHARM-Added Trial Discussion Possible cardiovascular benefit of ACE-Inhibitor and ARB combination therapy. Increase in adverse events Application to our patient after review two more articles…

Appraise Valsartan, Captopril, or Both in Myocardial Infarction Complicated by Heart Failure, Left Ventricular Dysfunction, or Both (VALIANT) M Pfeffer, J Mcmurray, E Velasquez et al., NEJM 2004;350(2): 203 Effects of ARB, ACE-Inhibitor monotherapy and combination therapy in death from any cause, after acute myocardial infarction.

VALIANT 14,808 eligible patients were enrolled between December 1998 through June 2001 from 931 centers in 24 countries. Men and Women 18 years of age or older who had acute MI (between 0.5 and 10 days previously) that was complicated by clinical or radiological signs of heart failure Evidence of left ventricular systolic dysfunction (an ejection fraction <0.35 on echocardiogram or contrast angiography and <0.40 radionuclide ventriculography) At randomization SBP >100mm Hg Serum Creatinine of less then 2.5mg per decilitir Contraindication Previous intolerance or contraindication to an ACE-Inhibitor or ARB. Clinically significant valvular disease Disease known to limit life expectancy severely Absence of written informed consent Or both

VALIANT Randomly assigned in a 1:1:1 ratio Valsartan monotherapy, 4909 Valsartan plus captopril, 4885 Captopril monotherapy, 4909 Patient was unaware of regimen, independent drug- distribution group and although data processing and site management and analysis was performed by one identity, only data and safety monitoring board in this identity was aware of treatment-group assignments.

VALIANT

VALIANT

VALIANT

VALIANT Therapy Initial Dose increased in four steps 20mg Valsartan, 20mg Valsartan and 6.25mg of Captopril, or 6.5mg Captopril. Dose increased in four steps goal of 80mg Valsartan, 40mg Valsartan bid and 25mg of Captopril tid, or 25mg of Captopril tid while in the hospital goal 160mg Valsartan, 80mg Valsartan bid, and 50mg Captopril tid, , or 50mg Captopril tid by three month visit. Follow-Up Study visits took place 6 times during the first year and at 4 month intervals thereafter.

VALIANT RESULTS All but 77 (0.5%) patients received study medications. Median duration of follow up 24.7 months 139 (0.9%) patients were lost to follow up or withdrew consent 24/23/30 53/48/38

VALIANT Results Mortality Cardiovascular Morbidity and Mortality Similar in three treatment groups Hazard ratio for death 1.00 (p=0.98) Valsartan vs Captopril and 0.98 (p=0.73) Captopril vs combination. Cardiovascular Morbidity and Mortality Similar in three treatment group

VALIANT

VALIANT Comparing VALIANT

VALIANT Results Noninferiority of Valsartan Tolerability and Safety Mortality Intention-to-treat Pre- protocol population Tolerability and Safety No longer taking medication at one year 15.3% Valsartan, 19.0% combination, 16.8 Captopril Dose at one year At three month goals …analysis

VALIANT Tolerability and Safety (continued) Discontinuation Own decision Adverse events Highest rate occurring in valsarten-and-captopril group …but not statistically significant

VALIANT * Means p<0.05

VALIANT Discussion Improved survival and reduced rates of major nonfatal cardiovascular events No added benefit in combination therapy Combination therapy had increased adverse events.

Appraise Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events The ONTARGET Investigators NEJM 2008; 350 (2):1547-1559 Effects of ARB, ACE-Inhibitors, combination therapy in death from cardiovascular causes, MI, stroke, or hospitalization for heart failure.

ONTARGET 29,019 patients were recruited from 733 centers in 40 countries. Single-Blind run in-period 2.5mg ramipril daily x 3days 40mg telmisartan and 2.5mg ramipril daily x 7 days 5mg ramipril and 40mg telmisartan x 11-18 days 3399 (11.7%) patients were excluded Poor compliance (3.9%) Withdrew from study(2.1%) Symptomatic hypotension(1.7%) Elevated K level (0.8%) Elevated serum creatinine level(0.2%) Other (3.0%) Death(0.1%)

ONTARGET 25,620 patients underwent randomization 8542 patients received 80mg telmisartan daily 8576 patients received 5mg ramipril daily 8502 patients received combination therapy After two weeks dose of ACE-Inhibitor was increased to 10mg daily. Two weeks Dose increased

ONTARGET Follow up 25577 (99.8%) patients were followed until primary event occurred or until the end of the study (median, 56months). At 2 years, 81.7% of Ramipril group was receiving full dose, 75.3% in combination group. At 2 years, 88.6% of Telmisartan group was receiving full dose, 84.3% in combination group. 2029 patients (23.7%) in Ramipril group and 1796 (21.0%) in Telmisartan group discontinued the study drug (combination group, 22.7%) Combination group stopped both drugs…

ONTARGET

ONTARGET Blood pressure Serum Creatinine Potassium Telmisartin and combination group maintained slightly lower blood pressure levels. Serum Creatinine Number of patients with increased levels was similar in three groups. Potassium Similar number of patients with levels more then 5.5 mmmol per liter in monotherapy groups. (283/287) Significantly higher levels in combination group 480 patients p=<0.001

ONTARGET Primary Outcomes 1412 (16.5%) in Ramipril group, 1423 (16.7%) patients in Telmisartan group 1386 (16.3) patients in combination group Telmisartan was noninferior to Ramipril, nor was it superior Upper boundary of CI for RR of primary outcome was lower then predetermined (noninferiority) Lower boundary of CI (not superior) No significant difference in total number of deaths between mono therpay groups. Higher number of deaths in combination group, but not statistically significant. Confidence Interval for the relative risk for of the primary outcome in telmisartan group was compared to 1014/989…1065

ONTARGET

Kaplan-Meier Curves for the Primary Outcome in the Three Study Groups

ONTARGET Nosignificant difference in secondary outcomes

ONTARGET Patients who have vascular disease or high risk diabetes, Telmisartan is equally effective to Ramipril. No additional benefit from combination therapy

Apply CHARM-Added trial VALIANT ONTARGET sad

Conclusion Continue patient on Lisinopril. If patient develops side effects, can use ARB to prevent cardiovascular events.

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