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

2. 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.

3. 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

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

5. 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

6. 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.

7. 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.

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

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

10. 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
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.

11. 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.

12. 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.

13. CHARM-Added Trial

14. 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

15. CHARM-Added trial

16. CHARM-Added trial

17. 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 )
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

18. CHARM-Added trial

19. CHARM-Added trial

20. CHARM-Added trial

21. 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…

22. 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.

23. 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

24. 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.

25. VALIANT

26. VALIANT

27. VALIANT

28. 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.

29. 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

30. 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

31. VALIANT

32. VALIANT
Comparing VALIANT

33. 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

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

35. VALIANT
* Means p<0.05

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

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

38. 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 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%)

39. 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

43. 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…

44. ONTARGET

45. 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

46. 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

47. ONTARGET

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

49. ONTARGET
Nosignificant difference in secondary outcomes

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

51. Apply
CHARM-Added trial
VALIANT
ONTARGET
sad

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

53. References
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