I know the trials in heart failure but how do I manage my patient? Should I use statins? Aldo P Maggioni, MD, FESC ANMCO Research Center Firenze, Italy
Disclosures Aldo P Maggioni served as a member of the Steering Committee of GISSI-HF, partially supported by AstraZeneca. Further, he received honoraria for presentations from AstraZeneca
Why to use a statin in patients with HF?
Rationale for using statins in HF All the following mechanisms may target important components of the complex physiopathology of the HF syndrome: LDL reduction is clearly associated with the prevention of coronary disease progression and ischemic events Pleiotropic actions of statins, including anti-inflammatory antihypertrophic antifibrotic and antioxidant effects improvement of endothelial dysfunction inhibition of neurohormonal activation prevention of cardiac arrhythmias
Rate per 100 person-years Statin Use and Outcome in HF: Death and HF Hospitalization Ischemic vs Non-ischemic Etiology Kaiser Permanente 24,598 patients with HF propensity adjusted cohort study 35 30 25 20 15 10 5 Rate of death Rate of hospitalization No statin Statin No statin Statin 35 30 25 20 15 10 5 0 Overall Baseline CHD No baseline CHD 0 Overall Baseline CHD No baseline CHD Go et al JAMA 2006
The evidences: the CORONA and GISSI-HF trials
CORONA: Study Design 371 centres in 21 countries (Europe and S. Africa) - Systolic HF of ischemic etiology - Age 60 years - Ejection fraction 0.40 (NYHA III/IV) or 0.35 (NYHA II) - Receiving optimal HF therapy Rosuvastatin 10 mg n=2514 Placebo n=2497 0 to 4 weeks 1 2 Randomization 2 to 4 weeks Follow-up visits 6weeks 3 monthly Closing date 20 May 2007 Eligibility Optimal HF treatment instituted Placebo run-in Median follow-up 2.7 years Kjekshus J et al, Eur J Heart Fail 2005;7:1059-69. Kjekshus J et al, N Engl J Med 2007;357
LDL cholesterol Mean LDL at Baseline and % Change During Follow-up % change in mean +10 0-10 -20-30 -40-50 Baseline mean values Placebo 3.56 mmol/l (137 mg/dl) Rosuvastatin 3.54 mmol/l (137 mg/dl) Follow-up time 3 months 15 months 1.96 (76) 2.01 (78) Closing visit Mean 36 months 2.02 (78) Net difference -45% -41% -34% p<0.0001 p<0.0001 p<0.0001 n= 2339/2366 n= 1980/2021 n= 1553/1618 Kjekshus J et al. N Engl J Med 2007;357
hscrp Median hscrp at Baseline and % Change During Follow-up median % change +10 0-10 -20-30 -40 Baseline median values Placebo 3.50 mg/l Rosuvastatin 3.50 mg/l Follow-up time 3 months 15 months Closing visit Mean 36 months Net difference -25% -34% -37% p<0.0001 p<0.0001 p<0.0001 n= 2310/2336 n= 1957/1993 n= 1534/1599 Kjekshus J et al. N Engl J Med 2007;357
Primary Endpoint CV Death or Non-fatal MI or Non-fatal Stroke 35 Per cent 30 25 20 Placebo n = 732 (29.3%) Rosuvastatin n = 692 (27.5%) 15 10 5 Hazard ratio = 0.92 95% CI 0.83 to 1.02 p = 0.12 0 0 6 12 18 24 30 36 Months of follow-up No. at risk Placebo 2497 2315 2156 2003 1851 1431 811 Rosuvastatin 2514 2345 2207 2068 1932 1484 855 Kjekshus J et al, N Engl J Med 2007;357
Adverse Events Item Placebo Rosuvastatin n=2497 n=2514 (n) (n) All adverse events 13635 13258 All serious adverse events 5536 5146 ALT > 3 times ULN after random. At least once 24 25 More than once 5 3 Doubling of s/creatinine 1 32 23 Any muscle symptoms 2 207 225 CK > 10 times ULN 3 1 CK > 10 times ULN + muscle symptoms 3 1 0 Rhabdomyolysis 0 0 1 With follow-up value above ULN 2 Active questioning or adverse event 3 Started after initiating physiotherapy Kjekshus J et al, N Engl J Med 2007;357
GISSI Heart Failure Gruppo Italiano per lo Studio della Sopravvivenza nell'infarto Miocardico All treatments of proven efficacy for chronic HF (e.g., ACE-inhibitors, betablockers, diuretics, digitalis, spironolactone) were positively recommended. 6,975 patients 356 centers in Italy HF, receiving optimized therapy n-3 PUFA 1g (3,494) Placebo (3,481) 4,574 Patients 2,401 pts not eligible 1,576 treated with statins 395 contraindications to statins 430 Investigator s decision 3.9 years of follow-up rosuvastatin 10 mg (2,285) Placebo (2,289) 1, 3, 6, 12 months and then every 6 months until the end of the trial 15% RRR of all-cause mortality, from 25% to 21%; power = 90%; 2-sided a=0.045 Primary end points 15% reduction of all-cause mortality (p< 0.045) 20% reduction of all-cause mortality or CV hospitalizations (p<0.01)
LDL cholesterol (mg/dl) (2175 pts) Rosuvastatin Placebo 140 130 120 110 100 90 80 70 60 50 130 122 118 121 89 83 Baseline 1 year 3 years By time F=242.6, p<0.0001 By time and treatment F=390.7, p<0.001 No difference between Baseline Values, p=0.597 10,0% 5,0% 0,0% -5,0% -10,0% -15,0% -20,0% -25,0% Rosuvastatin 7,0% Placebo 1 year 3 years -2,0% -30,0% -27,0% -35,0% -32,0%
Time to all-cause death log-rank test p=0.660 Rosuvastatin: 657/2285 (28.8%) Placebo: 644/2289 (28.1%) adjusted HR (95.5% CI)* 1.00 (0.898 1.122), p value 0.943 unadjusted HR (95.5% CI) 1.03 (0.917 1.145), p value 0.660 Rosuvastatin Placebo Rosuvastati n Placebo *Estimates were calculated using a Cox proportional hazards model, adjusting for: hospitalisation for HF in the previous year, prior pace-maker, gender, diabetes, pathological Q waves, ARBs.
Time to all-cause death or hospitalisation log-rank test p=0.594 Rosuvastatin: 1305/2285 (57.1%) Placebo: 1283/2289 (56.1%) for CV reasons Rosuvastatin Placebo adjusted HR (99% CI)* 1.01 (0.908 1.112), p value 0.903 unadjusted HR (99% CI) 1.02 (0.923 1.130), p value 0.594 Rosuvastati nplacebo *Estimates were calculated using a Cox proportional hazards model, adjusting for: hospitalisation for HF in the previous year, prior pace-maker, gender, diabetes, pathological Q waves, ARBs.
Rosuvastatin: Predefined subgroup 1.08 1,08 analysis Age <70 years (median) Age 70 years (median) LVEF 40% LVEF >40% Ischemic etiology Non-ischemic etiology NYHA II NYHA III-IV Diabetes No diabetes Total cholesterol # 192 mg/dl 0.97 0,97 1,02 1.02 1,05 1.05 1,03 1.03 1,02 1.02 1,00 1.00 1.02 1,02 1,00 1.00 1.02 1,02 1.06 1,06 * The 95%CI was calculated by Cox proportional hazards model. # Median value. Data on total cholesterol were available for 4537 patients. No significant interactions were shown for any subgroup Total cholesterol # >192 mg/dl 1,00 1.00 0,5 0,6 0,7 0,8 0,9 1,0 1,1 1,2 1,3 1,4 1,5
GISSI-HF: Adverse drug reactions Rosuvastatin (n. 2285) Placebo (n. 2289) Patients who permanently discontinued study treatment due to ADR, n (%) Gastrointestinal disorders 34 44 Astenia 1 - Allergic reaction 7 7 Liver dysfunction 26 12 Lipid abnormality - 1 Creatine phosphokinase increase 4 1 Renal dysfunction 6 4 Acute renal failure 2 - Hepatocellular jaundice - 1 Acute dermatitis* 1 - Muscle-related symptoms 23 21 Patients who perrmanently discontinued 104 (4.6) 91 (4.0) 0.36 2 - study treatment due to serious ADR, n (%) Acute renal failure 1 - Acute dermatitis* 1 - ADR=adverse drug reaction * Diagnosed as Stevens Johnson Syndrome by the investigator, not confirmed by an expert adjudicator p
The role of statins after CORONA and GISSI-HF The recommendations for primary and secondary prevention of CV events are not modified by the trials results
The role of statins after CORONA and GISSI-HF The recommendations for primary and secondary prevention of CV events are not modified by the trials results In patients with CHD but without HF/LVD, statins can prevent the occurrence of the first episode of overt HF
The effects of simvastatin on the incidence of HF in patients with CAD J Card Fail 1997; 3:249-54 Simvastatin Placebo 35 30 25 20 15 10 5 0 P<0.001 P<0.015 Total mortality % CHF occurence %
Hospitalization for HF (n.27,546 patients) Scirica BM J Am Coll Cardiol 2006; 47: 2326-31
The role of statins after CORONA and GISSI-HF The recommendations for primary and secondary prevention of CV events are not modified by the GISSI-HF results In patients with CHD and without HF/LVD, statins can prevent the occurrence of the first episode of overt HF In patients with chronic HF, LDL reduction with statins does not affect patients survival
Which are the guidelines recommendations on statin treatment in patients with HF? ESC guidelines 2008 Class of recommendation IIb, level of evidence B (only CORONA results were available) Rosuvastatin did not reduce the primary endpoint or all-cause death. The hospitalizations for HF were reduced significantly The value of statins in HF patients with nonischemic etiology is not known ACC/AHA update 2010 statins are not mentioned
Clinical implications for my patient: a personal point of view
No prescription of statins to patients with HF of non-ischemic etiology Possible discontinuation of statins in patients with HF without persistent signs/ symptoms of ischemia, also to avoid multiple drug use or to not worsen compliance to other drugs proven to be effective in HF Maintainance of treatment in specific cases if the physician deems it useful, being reassured in doing so by the proven safety of the statins also in HF patients
Another, more prominent opinion. The survival benefit from statin treatment appears to stem primarily from the prevention of progression of CAD In clinical conditions where CAD does not significantly contribute to the cause of death, such as in advanced HF, statins seem to be less likely to improve survival U Laufs, F Custodis and M Böhm Heart. 2008;94:1138 1140
The rate of athero-thrombotic events in chronic HF is low Placebo Rosuva Follow-up CORONA MI % 6.0 5.2 Stroke % 5.4 4.9 GISSI-HF MI % 3.1 2.7 Stroke % 2.9 3.6 2.5 years 3.9 years
But, which is the rate of use of statins in real clinical practice?
ESC-HF Pilot (2009-2010) 3226 out-patients with chronic HF Statin use across European countries Poland Romania Greece Italy Spain Denmark Norway Sweden Austria France Germany Netherlands
IN-HF OnLine Chronic HF: Statin prescriptions (n. 17,450 pts) CORONA GISSI-HF Years
Conclusions Pleiotropic effects of statins do not seem to play a relevant role in HF (anti-inflammatory effects?)
Circulation. 2009;120:2188-2196
P value for interaction= 0.062 hs-crp =>2.0 mg/l hs-crp <2.0 mg/l Circulation. 2009;120:2188-2196
Conclusions Pleiotropic effects of statins do not seem to play a relevant role in HF (anti-inflammatory effects?) The rate of atherothrombotic events is generally so low in chronic HF, that their possible prevention through LDL reduction does not have a relevant impact on patient survival When statins are considered necessary (i.e. recent ischemic event), no evidence of harm has been shown by RCTs
Conclusions Specific RCTs did not show a beneficial effect of statins in patients with HF Up to now, US and European guidelines do not include definite recommendations regarding the use of statins In clinical practice, cardiologists are prescribing statins in about half of the patients with HF (even more frequently than in the past)
GISSI-HF: Trial design 3.9-years median follow-up (6 patients have been lost to follow-up) n. 3494 patients n-3 PUFA 1g daily n. 2285 patients Rosuvastatin 10 mg daily 6975 patients 4574 patients (eligible for rosuvastatin randomization) n. 3481 patients Placebo n. 2289 patients Placebo n. 2401 patients not eligible for rosuvastatin: 1576 treated with statin 395 contraindications to statins 430 Investigator decision
Statin use in patients admitted for Acute HF 2008-2010 2009-2010 1868 pts 1892 pts