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» Literature Review »
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| The Medical Treatment of Coronary Artery Disease in Patients with Chronic Kidney Disease |
| Author : Rarsari Soerarso |
| Jumat, 08 Januari 2010 10:53:32 |
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| Dept. Cardiology & Vascular Medicine |
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INTRODUCTION
The prognosis of patients with end-stage kidney disease (ESKD), also called chronic kidney disease (CKD) stage 5, remains poor, with one-year mortality rate of approximately 20 %. The biggest single contributor to this high mortality is cardiovascular disease, which account for over half of all deaths. In a large US community study involving over one million people, an independent, graded relationship was observed between estimated glomerular filtration rate (eGFR) and rates of death, cardiovascular events and hospitalization.1 (fig.1)
PATHOLOGY OF CORONARY ARTERY DISEASE IN CKD
The vascular complications in CKD are attributable to two different but associated mechanism, namely atherosclerosis and arteriosclerosis. Atherosclerosis is an intimal disease that (in the general population) is characterized by fibroatheromatous plaques and occlusive disease. In CKD, there are distinct morphological differences comprising increased plaque calcification and increased intimal and medial thickness. These differences promote chronic myocardial ischaemia and fibrosis, which may explain the high levels of sudden cardiac death and heart failure in CKD compared with lower incidence of acute plaque rupture.1
The other characteristic feature in CKD is thickening and calcification of the medial arterial layer known as arteriosclerosis. Increased collagen content, hyperplasia and hypertrophy of the vascular smooth muscle cells results in wall hypertrophy and stiffening of large conduit arteries. The consequences of these alterations are2 :
• An increased left ventricular afterload with development of left ventricular hypertrophy and increased myocardial oxygen demand
• Altered coronary perfusion and sub-endocardial blood flow distribution.
These changes have been described in patients with mild CKD and ESKD, and undoubtedly contribute to the high incidence heart failure and fibrosis seen in patients with ESKD. This is often termed as “ uraemic cardiomyopathy”. The high prevalence of cardiac damage may explain why hypertension is not associated with an increased mortality in dialysis patients, in contrast with the general population.2-4
MEDICAL TREATMENT
The landmark trials which have firmly established anti-platelet therapy, ACE inhibitor, beta blockers and lipid powering agents as effective treatment, in the general population with atherosclerotic disease, have systematically excluded patients with moderate to severe CKD. These agents are underused compared to the level of prescription in the general population, probably due to the concerns about limited efficacy and toxic effect when renal clearance is reduced. 5
Anti-platelet therapy
Rates of aspirin use are low in patients with CKD. Despite the poor prognosis of CKD patients after myocardial infarction, the rate of aspirin use was only 61% in dialysis patients and 74% in patients with GFR of < 35 ml/min, compared to 89% in patients with normal GFR. In part this may be due to safety concern. Uraemia is associated with prolonged bleeding times and impaired platelet function. Bleeding time is further prolonged by aspirin in CKD. The available information on the efficacy of aspirin in CKD is limited but encouraging. In a study of over 1000 patients with ESKD and 145.000 controls following myocardial infarction, the benefit of aspirin treatment on 30-day mortality was similar to that in patients with normal renal function.6
More powerful anti-platelet therapy with parenteral platelet glycoprotein IIb/IIIa inhibitor (GP IIb/IIIa) is an effective treatment in ACS, but these agents continue to be underused in patients with CKD despite their poor cardiovascular outcomes. Although the risk of major bleeding was doubled in a study by Freeman et al, the use of GP IIb/IIIa still reduced in-hospital mortality following ACS in 310 patients with CKD (eGFR < 60 ml/min). Although bleeding was more common in CKD patients and increased with abciximab, the relative risk of bleeding with abciximab did not differ according to the eGFR, so it is concluded that abciximab is safe for use in patients with CKD of any stage.5-6
Lipid lowering therapy
Inn contrast to the situation in patients with normal renal function, there remains substansial uncertainty regarding the beneficial effects of cholesterol reduction with statin therapy in ESKD patients. Lipid profiles in patients with CKD are atherogenic, with predominance of triglycerides, reduced HDL, elevated oxidized LDL-C and apolipoprotein. Total cholesterol concentration however, tends to be low rather than elevated. The reason why the efficacy of lowering cholesterol may be questioned in patients with CKD include 7 :
• There is no evidence relating cholesterol concentration to cardiovascular risk in CKD
• Although the association between CAD risk and cholesterol concentration is ‘log-linear’ in the general population, the absolute reductions in cholesterol are smaller at lower levels of cholesterol typically found in CKD
• Although statins substansially reduce the risk of deaths from atheromatous coronary artery and cerebrovascular disease in the general population, the absolute risk of atheromatous arterial disease in CKD is not clear.
ACE inhibitor and angiotensin II receptor blockers
There is a large amount of experimental and clinical evidence that pharmacological blockade of the renin-angiotensin system slows progressive renal dysfunction. This effect persists even in severe CKD without an increase in major adverse events, including hyperkalaemia and acute renal failure. The renoprotective effect of both ACE inhibitors and ARBs seems to be due not only to their antihypertensive effect but also to a specific antiproteinuric effect. This is consistent with the view that protein acts as mediators of fibrosis once they have leaked through the glomerular barrier. Given that cardiovascular mortality appears to be directly associated with worsening renal function, it would seem logical that preserving renal functionwith either an ACE inhibitors or ARBs would improved cardiovascular survival of CKD patients as a whole.8
ACE inhibitors decrease cardiovascular mortality in a number of conditions, including hypertensons, type-2 diabates, post MCI, heart failure and in patients with (or at high risk of) CAD. In HOPE study, treatment with ramipril in 980 patients with CKD ( serum creatinie 124-199 umol/l) resulted in a near-equal reduction in cardiovascular events to that observed with renal function. The impact of ACE inhibitor therapy on total mortality, heart failure related hospitalization and cardiovascular mortality was actually greater in patients with CKD than in those without (fig. 3).8,9
ARBs reduce mortality in heart failure and in patients with hypertensive left ventricular hypertrophy. Two studies have examined the effect of ARBs on patients with diabetic nephropathy. Both have secondary composite outcome of cardiovascular mortality and morbidity, and both failed to demonstrate a beneficial effect. To our knowledge, there are no published data on cardiovascular outcomes with ARB treatment in non-diabetic and type-1 diabetic renal disease. RAS blockade with both ACE inhibitors and ARBs has additional renoprotective benefit when compared to monotherapy in non-diabetic renal disease and in incipient diabetic nephropathy, which is independent of blood pressure changes. Current evidence suggests that combination treatment is currently best reserved for patients with significant proteinuria (> 1 g/day) despite optimal blood pressure control on monotherapy with either an ACE inhibitor or ARB. 8
Over recent years, experimental and clinical evidence has been accumulating to suggest that aldosterone may be an important mediator in the progression of renal dysfunction and cardiovascular disease in CKD. Intriguingly, spironolactone appears to lower blood pressure in oligo-anuric haemodialysis patients, suggesting non-renal actions of aldosterone.10
Beta blockers
Beta blocker are used infrequently after ST elevation myocardial infraction (STEMI) in CKD patients. In 1724 patients admitted to a single coronary care unit in the USA, their use was most frequent in patients with GFR > 81,5 ml/min, at 8%, but fell to 52,9% in patients with GFR < 46 ml/min and to 47% in patients on dialysis. Across the range of GFR values, beta blocker and aspirin in combination reduced in-hospital mortality by 78% in patients on dialysis, 64,3% in those with GFR 46-63 ml/min, and 75% in those with GFR 63-81,5 ml/min.11
CONCLUSION
In contrast to the abundance of information from controlled trials on the treatment of coronary artery disease in the general population, there are few high quality trial data on which to base such treatment in patients with CKD.
The limited evidence available would suggest that medical strategies are probably effective in treating coronary artery disease in early stage CKD, but for patients with ESKD, treatment including statins may be ineffective in reducing mortality.
The need for randomized controlled trials is clear. The effectiveness of current secondary preventive drugs used in the general population requires confirmation in patients with CKD. Identification of patients with early stage CKD is crucial, as prevention (rather than treatment0 of both atherosclerosis and arteriosclerosis vascular disease associated with CKD, is likely to be the most successful strategy.
Refferences
1. Edwards N.C , Steeds RP, Ferro CJ , Townend JN . The treatment of coronary artery disease in patients with chronic kidney disease. QJ med 2006;99:723-736
2. London GM, Maechais SJ, Guerin AP. Arterial stiffness and function in end-stage renal disease. Adv Chronic Kidney 2004; 1:202-9
3. Safar ME, London GM, Plante GE. Arterial stiffness and kidney function. Hypertension 2004; 43: 163-8
4. Mattace-Raso FU, van der Cammen TJ, Hufman A, van Popele NM et al. Arterial stiffness and risk of coronary artery disease and stroke; the Rotterdam Study. Cirulatin 2006; 113:657-63
5. Landray MJ, Thambyrajah J, et al. Epidemiological evaluation of known and suspected cardiovascular risk factoring chronic renal disease. Am j kidney Dis 2001;18:537-46
6. Mosenkis A, bern JS et al. use of low molecular weight heparinsand GPIIa/IIIb inhibitor in patients with chronic kidney disease. Semin Dial
7. Shogi T, Nishizawa T, et al. Atherogenic lipoprotein changes in the absence of hyperlipidemia in patients with chronic renal failure treated by hemodialysis. Atherosclerosis 1999;131:229-36
8. Casa JP, Chua w et al. effects of inhibitors of the renin-angiotensin system and other anti-hypertensive drugs on renal outcomes: systematic review and meta-analysis. Lancet 2005; 366:2026-33
9. effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus; resuts of the HOPE study and MICRO-HOPE substudy. Heart outcomes prevention evaluation study investigation. Lancet 1000;355:253-9
10. Ibrahim HN, Bigassi R, et al. Aldosterone in renal disease. Curr opin Nephrol hypertension 2003;12:159-64
11. Mc Cullough PA, Sandberg SR, Borzak S, et al. Benefits of aspirin and beta blocker after myocardial in patients with chronic kidney disease. Am Heart j 2002; 144:226-32
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