Statins, Aspirin, Beta Blockers, ACE Inhibitors Prevention

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1 Statins, Aspirin, Beta Blockers, ACE Inhibitors Prevention Dr Selwyn Wong Cardiologist Ascot and Middlemore Hospitals

2 Primary vs Secondary Prevention

3 NZ Primary Care Guidelines - Lipids Lipid levels (TC about 4 8 mmol/l) in people without CVD should be interpreted in the context of their cardiovascular risk. Recommended starting doses for statin treatment: -Known CVD or CVD risk >20%, simvastatin 40 mg -5-year CVD risk 15 20% simvastatin 20 mg and uptitrate If LDL-C targets are not met, options include increasing simvastatin to 80 mg, substituting atorvastatin or combining simvastatin with nicotinic acid or ezetimibe

4 June 8, 2011 Maximum Simvastatin Dose Increased risk of muscle injury cited. The U.S. Food and Drug Administration today is announcing safety label changes for the cholesterollowering medication simvastatin because the highest approved dose--80 milligram (mg)--has been associated with an elevated risk of muscle injury or myopathy, particularly during the first 12 months of use Risk increased in elderly and renal impairment

5 Statin Debate Wall St Journal Jan 2012

6 WSJ Statin Debate; Yes No sense why a medication that slows the progression of hardening of the arteries would be harmful the day or week before a heart attack, but helpful the day or week after a heart attack. Evidence supports the selective use in high risk for heart disease. Similarly, they have been shown to do the same in patients without heart disease, but who are at high risk of developing heart disease Generic statins cost about $50 a year Initiation of medication motivates patients with realisation of how serious their cardiovascular risk actually is. Dr. Blumenthal is a professor of medicine and director of the Johns Hopkins Ciccarone Center for the Prevention of Heart Disease and editor in chief of "Preventive Cardiology A Companion to Braunwald's Heart Disease."

7 WSJ Statin Debate; No Leap of logic: Drs treated millions of healthy people with statins to prevent heart disease. No evidence that taking statins prolongs life. Using the most optimistic projections, for every 100 healthy people who take statins for five years, one or two will avoid a heart attack. One will develop diabetes. WOSCOPs high-risk group of men for whom the benefits of statins were most likely to outweigh the risks;..smokers and obese, and some had heart disease. Those results can't be extrapolated to most Americans taking statins Dr. Redberg is a professor of medicine and director of women's cardiovascular services at the University of California, San Francisco.

8 WSJ Statin Debate; No Fortunately, there is a proven, widely available treatment for people at high risk for heart disease that does prolong survival. This treatment is cheaper and more effective than any statin or other known drug, with virtually no adverse side effects. The treatment, which has been available for decades, involves almost no additional costs to patients, insurance companies or the government. Numerous studies have shown dramatic results in not only lowering cholesterol, but in preventing heart attacks and in prolonging life. This treatment is proper diet and exercise. Statins present a moral hazard, since some people will make less effort to follow a healthy diet and get regular physical activity because they feel falsely reassured by their medications

9 WSJ Statin Debate; Poll

10 FDA Warning 29/2/2012 FDA added new safety warnings to statin drugs noting increased risks of Type 2 diabetes and memory loss Statins may increase users risk of brain-related effects like memory loss and confusion. Statins labels will now also warn patients and doctors that the drugs may cause a small increase in blood sugar levels and Type 2 diabetes. Significant increase in the risk of DM associated with highdose statin therapy. JUPITER - 27% increase in diabetes mellitus PROVE-IT TIMI 22 substudy showed that high-dose atorvastatin can worsen glycemic control.

11 Statin Debate- JAMA April 2012

12 Statin Debate- JAMA April 2012 Should a 55-year-old man who is otherwise well, with systolic blood pressure of 110 mm Hg, total cholesterol of 6.5mmol/L, and no family history of premature CHD be treated with a statin?

13 JAMA Statin Debate - No Meta-analysis of 11 trials including persons with person-years of follow-up in healthy but high-risk men and women showed no reduction in mortality 2011 Cochrane review among persons without documented coronary disease came to similar conclusions. Data from observational studies - much higher rates for statin-associated myopathy and other adverse events in actual use than the 1% to 5% rate reported in clinical trials. Numerous anecdotal reports/small trial have suggested that statin therapy causes cognitive impairment. True extent of cognitive impairment associated with statins remains understudied.

14 JAMA Statin Debate - No The risk of diabetes; JUPITER, which found a 3% risk of developing diabetes in the rosuvastatin group, significantly higher than in the placebo group. Do the potential benefits outweigh the potential risks -Based on all current evidence, a healthy man with elevated cholesterol will not live any longer if he takes statins. -For every 100 patients with elevated cholesterol levels who take statins for 5 years, an MI will be prevented in 1 or 2 patients. -However, 1 or more patients will develop diabetes and 20% or more will experience disabling symptoms, including muscle weakness, fatigue, and memory loss.

15 Statin Debate- JAMA April 2012

16 JAMA Statin Debate - Yes WOSCOPS (Pravastatin 40 mg) 6595 men TC 7.0 ± 0.6mmol/L 31% reduction in MI and CHD-related death AFCAPS/TexCAPS (Lovastatin 20 to 40 mg) 6605 asymptomatic LDL 5.7±0.5 mmol/l, low HDL 0.9± 0.1mmol/L 37% reduction1st major CE, 40% reduction in MI JUPITER (Rosuvastatin 20 mg) healthy men and women Normal LDL-C < 3.4 mmol/l and elevated hscrp 44% reduction MI, CVA and revascularization 20% reduction total mortality

17 JAMA Statin Debate - Yes Patient in this common clinical scenario would have an intermediate 10-year risk for developing CHD (~10%) Coronary Artery Calcium scan to reclassify intermediate risk patients 50% chance CAC score of 0 - estimated 10-year CHD event rate of less than 2% simple presence of CAC increases that risk nearly 4-fold 13% chance CAC score >100, - estimated 10-year CHD event rate >12%

18 Statins What to do?? Total cholesterol > 8mmol/L - treat Total cholesterol 4-8mmol/L; risk assess NZGG 20% treat, 15% lifestyle/treat, 10% statins or CAC Atorvastatin or Simvastatin?initially low dose Rosuvastatin now a viable option Efficacy of treatment never proven in an individual patient!!

19 Statins and Plaque Rupture

20 Aspirin in Primary Prevention Based on evidence from nine large-scale primary prevention trials of men and women without established cardiovascular disease (CVD), aspirin produces a statistically significant and clinically important reduction in the risk of a first MI. However, aspirin has not been shown to lead to a statistically significant reduction in the rates of stroke or cardiovascular death. The totality of randomized evidence suggests no differences in response to aspirin between men and women

21 Aspirin in Primary Prevention LANCET 2009 Meta analysis 6 trials, 95,000 men and women, aspirin (75-500mg/day) v placebo Serious vascular events %/yr aspirin v 0.57%/yr controls. Driven by 1st non-fatal MI (0.18 versus 0.23%/yr). Aspirin significantly é rate of major GI/extracranial bleeds (0.10 v 0.07%/yr). ê similar for women and men. Archives of IM 2012 Meta analysis 9 trials, n= Mean follow-up of six years, aspirin treatment ê total CVE by 10%, driven primarily by ê nonfatal MI, but there was a 30% é risk of nontrivial bleeding events. The number needed to treat to prevent one cardiovascular event was 120, compared with 73 for causing a nontrivial bleed.

22 Aspirin in Primary Prevention Low-risk patients (10-yr risk <10 %), the absolute benefit on occlusive vascular events may be less than the absolute risk of major bleeding. Moderate risk patients (10-yr risk 10-19%) the randomized data on benefits and risks are sparse, so clinical decision making should be made on an individual basis. In these patients it should also be noted that aggressive risk-preventative strategies (i.e. statins) will reduce both MI and CVA with little hazard. Available data suggest that daily doses of aspirin between 75 and 325 mg are equally safe and effective.

23 Beta-Blockers in Primary Prevention Beta-blockers (BB) have been widely used in HTN and recommended as first-line agents in guidelines. Meta-analyses - uncomplicated HTN v other agents é risk of stroke, especially in elderly No benefit for all-cause mortality, cardiovascular morbidity/mortality. pseudo-antihypertensive efficacy (failure to lower central aortic pressure), lack of effect on regression of target end organ effects like left ventricular hypertrophy and endothelial dysfunction, and adverse effects Risk benefit ratio for BB 1 st line Rx is not acceptable

24 HTN Treatment in Primary Prevention In the absence of a specific indication, there are three main classes of drugs that have been used for initial monotherapy: thiazide diuretics, long-acting calcium channel blockers, and ACE inhibitors or angiotensin II receptor blockers (ARBs). Each of these classes of drugs has been equally effective in monotherapy trials if the attained blood pressure is similar. Beta blockers are NOT commonly used for initial monotherapy in the absence of a specific indication, since they may have an adverse effect on some cardiovascular outcomes, particularly in older patients

25 HTN Target ESH April "We just don't know." London, UK - That was the brave declaration from a number of experts speaking at the European Society of Hypertension (ESH) There is much that remains unknown in the field. Evidence for seemingly straightforward issues, such as what should be the ideal number to lower blood pressure to in different groups of individuals, is lacking In the meantime, guidelines need to offer the best direction they can for those who have the task of treating hypertension, which is increasingly falling upon the shoulders of general practitioners and family doctors

26 NZ Primary Care Guidelines Everyone with a BP 170/100 mm Hg should have drug treatment and specific lifestyle advice BP range 115/70-170/100 mmhg, decisions to treat should be based on the individual s cardiovascular risk Most of the treatment benefit is achieved by reaching the following BP levels: <140/85 mm Hg in people without clinical CVD <130/80 mm Hg in people with diabetes or CVD <130/80 mm Hg in people with CKD and significant albuminuria (urine protein/creatinine >100 mg/mmol)

27 ACEI in Primary Prevention European Heart Journal Advance Access published April 17, 2012 Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin angiotensin aldosterone system inhibitors involving patients RAAS inhibition was associated with a 5% reduction in all-cause mortality (HR: 0.95, 95% CI: , P 1/ ), and a 7% reduction in cardiovascular mortality (HR: 0.93, 95% CI: , P 1/ ). The observed treatment effect resulted entirely from the class of ACE inhibitors, which were associated with a significant 10% reduction in all-cause mortality (HR: 0.90, 95% CI: , P 1/ )

28 ACEI in Primary Prevention ACE inhibitor/arb may be more effective in younger patients Calcium channel blocker may be more effective in elderly and black patients DM with confirmed microalbuminuria should be treated with an ACE inhibitor or angiotensin 2 receptor blocker (ARB) whether or not hypertension is present

29 Statins, Aspirin, Beta Blockers, ACE Inhibitors Statins all high-risk, moderate risk with discussion/ discretion Aspirin risk equivalent of secondary prevention/high-risk with discussion/discretion Beta-blockers not a first-line agent in HTN ACE Inhibitors appropriate as first-line agent