Statins and ACE Inhibitors: Do They Work in Conditions for Which They Were not Developed?
Statins and ACE Inhibitors: Do They Work in Conditions for Which They Were not Developed?
Abstracts & Commentary
By Jonathan Abrams, MD, Professor of Medicine, Division of Cardiology, University of New Mexico, Albuquerque. Dr. Abrams serves on the speaker's bureau for Merck, Pfizer, and Parke-Davis.
Synopsis: Commonly used drugs in patients with coronary disease or COPD may be beneficial in the absence of specific guideline recommendations at present.
Sources: Klein BE, et al. Statin Use and Incident Nuclear Cataract. JAMA. 2006;295;2752-2758; Mancini GB, et al. Reduction of Morbidity and Mortality by Statins, Angiotensin-Converting Enzyme Inhibitors, and Angiotensin Receptor Blockers in Patients with Chronic Obstructive Pulmonary Disease. J Am Coll Cardiol. 2006;47:2554-2560; Al-Mallah MH, et al. Angiotensin-Converting Enzyme Inhibitors in Coronary Artery Disease and Preserved Left Ventricular Systolic Function: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Am Coll Cardiol. 2006;47:1576-1583; Danchin N, et al. Angiotensin-Converting Enzyme Inhibitors in Patients with Coronary Artery Disease and Absence of Heart Failure or Left Ventricular Systolic Dysfunction: An Overview of Long-Term Randomized Controlled Trials. Arch Intern Med. 2006;166:787-796.
Statins, and drugs interfering with the rennin angiotensin system (ACEI, ARB), have been a remarkable success story. In selected subsets of individuals, these drugs prevent major events and are truly lifesaving. There is emerging evidence that expanded use of statins and ACE inhibitors may represent the therapy of the future.
Statins
Two recent reports are concordant with many others, suggesting patients who take statins may have benefits over and above LDL-cholesterol lowering and the adverse effects of coronary artery disease. A study from the University of Wisconsin Department of Ophthalmology suggests that statin drugs may reduce the risk of age-related cataracts, particularly nuclear cataracts, the most common eye disorder. Klein and colleagues studied a cohort of residents from Wisconsin who were 43-84 years of age and were followed with eye examinations for up to 15 years. All subjects had a baseline eye examination, with study visits at 5-year intervals for as many as 3 follow-up evaluations. This analysis deals with the 3000 individuals examined on the third follow-up as to the presence of any cataract, the type of cataract, and the grading of the cataract. Photographs of the lens were taken, and a scale of cataract severity, based on whether an opacity of the nucleus, was identified; the nuclear had to have a score > 3 on a 5-step severity scale. Cortical and posterior subcapsular cataracts were also assessed. Lipid levels were obtained. The present analysis included subjects who had photographs of both eyes at the third and fourth examination. "Logistic regression was used to examine the incidence of cataract with respect to statin use, adjusting for age, and other confounders."
Of the 2962 individuals participating in the third examination, less than half (1340) were free of any evidence of a cataract. Data collection for the fourth examination used data from 214 persons who were taking a statin at the time of the third examination. Having a cataract of any type other than nuclear was not related to statin use; after age adjustment, the odds ratio for the development of an incident cataract was 0.74 (NS). When cataracts were classified by type (nuclear, cortical, posterior subcapsular), the age adjusted odds ratio was 0.55 (P = 0.006) for nuclear cataracts and 1.28 and 0.82 for the 2 other classifications of cataracts. Individuals developing a nuclear cataract were older, more likely to be female, and had a lower socioeconomic/educational status. Smoking had little effect on the protective aspects of statins. The odds ratio for the 45 individuals who were examined at 3 5-year intervals was 0.29, while the odds ratio for those on statins after 2 visits was 0.61; individuals beginning statins between the third and fourth visit showed no benefit. There was a suggestion that simvastatin was more protective than the other statins, but the numbers are small.
Klein et al conclude that there is "…an inverse association between use of statins and incidence of nuclear cataract, but not incidence of cortical or posterior subcapsular cataracts." They speculate that the efficacy of statin use in preventing nuclear cataract is "biologically plausible because oxidative stress and inflammation have been shown to be related to nuclear cataracts, and statins have been reported to counter such effects." Klein et al call for clinical trials to better elucidate their findings. They point out that "potential healthcare implications…between statin use and cataract incidence are great because nuclear cataract is the most common type of age related cataract."
In another report, statins and ACE inhibitors were found to have a positive effect on the prognosis of individuals with chronic obstructive pulmonary disease (COPD). This Canadian study is complex in design. The hypothesis was that "medications currently associated with CV risk reduction might have a substantial effect on the clinical outcome of COPD by "…reducing the CV component of adverse morbidity and mortality." Mancini and colleagues suggest that pleiotropic effects of statins, ACE inhibitors, and angiotensin receptor blockers (ARBs) might further contribute to a beneficial outcome. They employed the large Quebec Linked Database to determine whether there was "evidence suggesting dual cardiopulmonary protection properties." In essence, they employed a retrospective cohort study using nested case-control assessment to determine the association between various CV drug utilization and risk of hospitalization for COPD, myocardial infarction (MI), and death. The COPD patients from Quebec were identified by prescription use of bronchodilator therapies. Two cohorts were examined: one consisting of elderly (> 65) revascularized patients and a second cohort with a lower CV risk profile (also > 65). The latter group had to be free from an MI within 5 years of the study entry. Patients were followed for the occurrence of study end point (see above); careful coding was performed for all hospitalizations due to COPD or acute MI.
The results are positive for the use of statins or angiotensin system blockers. In the high-risk cohort, statins were associated with a substantial risk reduction for hospitalization for COPD (RR 0.72, P = 0.009), as well as the combination of the statin with an ACE inhibitor or an ARB (RR 0.6, P = 0.0012). Steroid use had little clinical impact. Risk ratios for MI were reduced by all 3 drug classes, particularly by the combination of a statin with either an ACE inhibitor or ARB. Indications for death were reduced by ARBs (RR, 0.63; P = 0.001), statins (RR, 0.50, P = < 0.0001), and statins with ACE inhibitors or ARBs (RR, 0.42; P = < 0.0001). The combined end point of death or MI was substantially reduced by all 3 agents, alone or in combination with a risk ratio for statins alone of 0.48, P = < 0.0001. The combination of a statin with an ACE inhibitor or ARB had the greatest association, with risk reduction of 0.39 or 71%, P = 0.0001. The low-risk patients had a similar reduction in risk, except for a lack of benefit in prevention of MI. Of interest, efficacy of ACEI demonstrated a non-statistical reduction of hospitalization in non-steroid users.
Mancini et al conclude, "this observational study suggests that the cardioprotective effects of statins, ACE inhibitors, and ARBs extends to COPD patients…" They acknowledge that the mechanism of risk reduction is unclear, and certainly could in part be due to the co-existence of COPD and CAD, as well as numerous CVD risk factors in such individuals. However, the data suggest that "…of special importance, these agents also seem to affect pulmonary disease itself, as suggested by reduced hospitalizations for COPD." The mechanism suggested is reduction in pulmonary injury by statins and angiotensin II blockers. Mancini et al point to the large cohort in this study, who they believe to be representative of the general population. They admit that "our analyses and conclusions much considered speculative," and may call for randomized clinical trials; acknowledging that the outcomes in the interesting analysis are "best seen as hypothesis generating." They call for randomized clinical trials, in part because the lack of interventions that modify outcomes in COPD. Mancini et al conclude, "These results provide strong impetus for a paradigm shift in the scientific approach to treatment of COPD and that properly controlled clinical trials are warranted to validate these important observations."
ACE Inhibitors
Currently, there is a significant debate about whether angiotensin receptor enzyme inhibitors have a favorable impact on individuals with coronary artery disease who have preserved left ventricular systolic function, no evidence of chronic renal disease, diabetes, or hypertension. The present confusion results from the somewhat surprising results of the PEACE trial, which did not demonstrate benefit from trandolapril in reducing CAD events, compared to placebo. On the other hand, the HOPE and EUROPA trials did show a substantial benefit, although the risks of an event in these 2 studies were higher than in PEACE, particularly in the HOPE trial. Such results have suggested to some that the benefit from ACE inhibitors may not be due to their biologic effect on the angiotensin system, but rather by their modest blood pressure lowering action.
Two recent meta-analyses have been published to help resolve the conundrum of ACE inhibitor efficacy in individuals with preserved cardiac function. Al-Mallah and colleagues examined 6 trials that met inclusion criteria and performed random-effect model meta-analysis quantified by heterogeneity within the population. A total of almost 17,000 patients were randomized to ACE inhibitors, and another 17,000 randomized to placebo. Angiotensin-converting enzyme blocker was associated with a 17% decrease in cardiovascular mortality, P = 0.01; a 16% decrease in non-fatal MI, P = 0.003; and a 13% decrease in all-cause mortality, P = 0.04. Al-Mallah et al calculate that treatment of 100 patients for an average of 4.4 years prevents one death, MI, non-fatal MI, or coronary revascularization. Thus, this analysis suggests that there is a modest, favorable effect of ACE inhibitors on the outcome of patients with CAD and preserved left ventricular systolic function.
In another meta-analysis, Danchin and colleagues performed an extensive literature search of studies using ACEI in subjects with preserved LV function, followed for at least 2 years; CAD was common. Seven trials were identified that met inclusion criteria (5/7 with CAD, 2/7 with vascular disease); all with LVEF > 35. Exclusion of the HOPE, PEACE, or EUROPEA data did not materially alter the results. MI was reduced by 18% (P = < .001). Stroke or TIA was decreased by 23%, P = 0.001. Blood pressure did not seem to influence results.
Commentary
The thrust of these reports, none of which are randomized, prospective, controlled trials, is that commonly used drugs in patients with coronary disease or COPD may be beneficial in the absence of specific guideline recommendations at present. The statin story is easier to deal with because of the well known pleiotropic or non-LDL effects. Statins are HmGCoA reductase agents, blocking the conversion of HmG-CoA to mevalonate. This interaction has a number of potential results. Mevalonate reduction is associated with a decrease in kinase AKT, which results in a decrease in nitric oxide synthase activity. There is also a decrease in the farnesyl-PP and geranylgeranyl-PP pathways. The end result of the inhibition of these various pathways is complex and certainly not fully resolved. However, there clearly may be decreases in oxidative stress, reversal of eNOS down regulation, as well as decreases in endothelin-1 and PA1-1. Clinical studies in a variety of conditions have associated statin utilization with beneficial actions; however, most of these reports are not prospective, randomized data. Thus, cancer, sepsis, heart failure, atrial fibrillation, dementia, and aortic stenosis make up an, as yet, incomplete list of a number of potential associations between statin use and favorable outcome.
The 2 ACEI meta-analyses support the conclusions of the HOPE and EUROPA randomized trials, but do not shed any further light on potential mechanisms of this effect. Also, the meta-analyses do not extend the observations beyond the CAD patient or patients with multiple risk factors for CAD. In conclusion, common CV drugs may turn out to be even more beneficial than realized, due to a variety of cellular action that are not completely understood. The concept that statins and ACEI may have efficacy in non-CAD patients is exciting, but we must be quite cautious, as yet, as the randomized controlled trial data (especially for statins) is rather meager as of today.
Commonly used drugs in patients with coronary disease or COPD may be beneficial in the absence of specific guideline recommendations at present.Subscribe Now for Access
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