Cardiovascular disease (CVD) affects 1 in every 6 Australians and 67% of families. It was responsible for over 600,000 years of healthy Australian lives lost in 2004. Of these years, 81% (490,711) were lost due to premature death (YLL) and 19% lost due to disability (YLD). Despite decreased mortality from acute events (heart attack and stroke), CVD remains the number one cause of death in Australians, with a death every ten minutes.1
It is no surprise that CVD attracts a lot of dollars from the health care budget. Direct costs to the health care system were approximated at $7.6 billion (11% of total health spending) in 2004, a figure expected to rise to $11.5 billion by 2011.1
Thought to hold the key to CVD prevention and treatment is the cardiovascular continuum. Developed in the late 1980s and completed in 1991, the cardiovascular continuum draws a bridge between cardiovascular risk factors and clinical manifestations through an underlying series of pathophysiological events.2
Associate Professor John Beltrame, Consultant Cardiologist at the Queen Elizabeth Hospital, Lyell McEwin Health Service and Senior Lecturer at the University of Adelaide, said that "the cardiovascular continuum represents the spectrum of CV status extending from health to end-stage CV disease. This continuum progressively includes CV risk factors (hypertension, hypercholesterolaemia, diabetes etc), to asymptomatic CV disease (silent atherosclerosis), symptomatic CV disease (angina, intermittent claudication, TIA), CV events (myocardial infarction, stroke, death) and end-stage disease (eg heart failure)."
Central to this model is oxidative stress and subsequent angiotensin II production. Risk factors such as hypertension, diabetes, hyperlipidaemia and smoking all create oxidative stress and consequently endothelial dysfunction. Aside from the deleterious effects such as inflammation and promotion of atherosclerosis, endothelial dysfunction also appears to enhance local tissue angiotensin converting enzyme (ACE), a powerful stimulator of reactive oxidant species. Hence a vicious cycle of increasing endothelial dysfunction, inflammatory changes and tissue damage follow.2
A clearer understanding of the pathophysiological processes involved allows for targeted interventions. By intervening pharmacologically early in the continuum we may be able to interrupt or slow disease progression.2 A/Prof Beltrame said "GPs play a vital role in the management of the CV continuum since early intervention is more likely to have a greater benefit. Hence if the GP can promote good CV health such as quitting smoking, this will have a major impact on subsequent outcomes."
With angiotensin II being a powerful player, therapies targeted at inhibiting the renin angiotensin-aldosterone system (RAAS) are receiving a lot of attention with several large clinical trials. More recently the focus has been on angiotensin receptor antagonists (ARAs) due to their potential for activation of the protective AT2 receptor and to avoid angiotensin II escape.2
The Losartan Intervention For Endpoint reduction in hypertension study (LIFE)3 compared the effects of losartan and atenolol on a combined primary endpoint (cardiovascular morbidity, myocardial infarction and stroke) in patients with hypertension and left ventricular hypertrophy (LVH). Compared to atenolol (Tenormin), losartan (Cozaar) antihypertensive therapy significantly reduced:3
- the combined primary endpoint of cardiovascular death, stroke or MI (-13%), notably a 25% reduction in stroke;
- LVH while having similar effects on blood pressure, suggesting a direct cellular role in RAAS inhibition; and
- the rate of new onset diabetes (-25%).
The Candesartan in Heart failure – Assessment of Reduction in Mortality and morbidity (CHARM) study4 compared candesartan (Atacand) with placebo in three separate subgroups: those with left ventricular ejection fraction (LVEF) <40% not receiving ACE inhibitors; those with LVEF <40% currently receiving ACE inhibitors; and those with LVEF >40%. Compared to controls, candesartan resulted in a significant reduction in hospital admissions for heart failure and also cardiovascular deaths for those with LVEF <40%. While survival was not altered by candesartan in patients with LVEF >40%, reduced hospital admissions for heart failure suggest that some clinical benefits were obtained with candesartan therapy.4
Several studies investigating the role of RAAS blockade post MI have shown mixed results.5,6,7 Both the OPtimal Therapy In Myocardial infarction with the Angiotensin II Antagonist Losartan (OPTIMAAL)5 and the Evaluation of Losartan In The Elderly (ELITE-II)6 trials found that captopril lowered the incidence of all-cause mortality, sudden death and resuscitated arrest compared to losartan. However, some question if the inferior performance of losartan, compared to captopril, was due to the relatively low dose (50mg b.d.) of losartan used.
The VALsartan In Acute myocardial iNfarcTion (VALIANT)7 followed, which compared valsartan 160 mg, captopril 50 mg three times daily, or in combination. The results showed no significant difference between the ARA and the ACE inhibitor in either overall mortality or the combined endpoint of fatal and nonfatal cardiovascular events. Given the overall mortality in this study was similar to that seen in other placebo-controlled studies of ACE inhibitors, it would be reasonable to conclude that inhibition of the RAAS by ACE inhibitor or ARA is effective at reducing post-MI mortality.
While many physicians agree that ACE inhibitors and ARAs have an important role in the clinical management of cardiovascular disease, in clinical practice many patients are taking doses well below those shown in clinical trials to provide symptomatic and prognostic benefit.8 For heart failure, enalapril has been shown to give greater symptomatic benefit with greater improvements in functional capacity by New York Heart Association with 20mg twice daily compared to 5mg twice daily.8 In a separate study, patients receiving enalapril 15mg twice daily were less likely to deteriorate than those patients receiving 2-5mg twice daily.9 It has also been shown that low dose ACE inhibition is associated with higher rates of death and hospitalisation for any reason and with increased hospitalisations for heart failure.10
A/Prof Beltrame said "clinical trials frequently utilise a target dose and thus the benefits demonstrated by the trial can only be confidently inferred at that dose. This is particularly important in studies where the medication was shown to be of prognostic benefit for CV events. For therapies targeting symptoms (eg angina), dosages should be titrated to alleviate symptoms".
For prevention of progressive disease, optimal treatment is vital. It is essential that patients are receiving the drugs best suited to their condition and at optimal doses. Given that we now know the underlying pathophysiology of CVD is a progressive chain of events, it is also important that we treat these patients earlier rather than later and avoid the vicious cycle of endothelial dysfunction. While health professionals can strive to provide the best medical care, the battle cannot be won by doctors alone. Non-compliance is major hindrance to optimal patient care. Outside of clinical trials, long term compliance in patients with hypertension or dyslipidaemia is frequently unsatisfactory.11 An Australian study showed that of 32,000 patients started on lipid-altering drugs in a single month of 1999, within 6 months 30% had discontinued therapy.12
Simons et al11 analysed claims for antihypertensive drugs from the Medicare Australia Pharmaceutical Benefits Scheme during the period 2004-2006 with a focus on ARA, ACE inhibitor and calcium channel blockers (CCB). While long term persistence was poor for all three classes of drugs, persistence was particularly poor with CCB. Compared to those patients receiving ARA, 57% more patients on CCB discontinued therapy by the end of the study period. ARAs performed slightly better that ACE inhibitors in terms of median persistence time and long term persistence, however, these differences were not deemed significant.11
Within the ARA class, candesartan (Atacand) or telmisartan (Micardis) had the best persistence by a 10-20% margin; in the ACE inhibitor class, perindopril (Coversyl) showed the best persistence compared to other ACE inhibitors by a 25% margin; and of the CCBs, lercanidipine (Zanidip) had the best persistence by at least 25%.11
It is possible that the ARAs may have performed slightly better due to increased tolerability. By acting on the receptor they avoid some of the common side effects of ACE inhibitors associated with reduced bradykinin degradation such as cough and angioedema.11 It was found in the ONTARGET study13 that 80 mg of telmisartan daily, as compared with 10 mg of ramipril daily, resulted in fewer episodes of cough or angioedema, but this benefit was in part offset by increased rates of hypotensive symptoms, but not syncope.13 Hence the effectiveness of medical therapies in the prevention and treatment of cardiovascular disease rests not only with the health professional but also on the response of the patient.
Compliance could further be increased by improved patient education, fewer side effects, simple dosing schedules and combination products.13 A/Prof Beltrame has found patient non-compliance to be major problem, he said "particularly in the treatment of CV risk factors where the condition is asymptomatic (eg hypertension & hypercholesterolaemia)."
New developments to enhance prevention and treatment of CVD are emerging. Carotid intima-media thickness (IMT) has proven to be a noninvasive evaluation of early carotid atherosclerosis. With good correlation between ultrasound measurements and histology, ultrasound has been used in many clinical trials to predict future clinical cardiovascular events. Lorenz et al14 undertook a systematic review and meta-analysis of data to examine the association between IMT and ability to predict future clinical cardiovascular end points. They found carotid IMT to be a strong predictor of future vascular events such that for an absolute carotid IMT difference of 0.1 mm, the future risk of MI increased from 5% to 15%, and the risk of stroke increased from 5% to 18%. Importantly, changes in carotid IMT can be used to assess the effectiveness of therapeutic interventions.14
"There are a number of tests which are associated with increased risk of CV events. The question is whether these tests provide any additional information to the conventional risk factors", said A/Prof Beltrame.
Markers of kidney dysfunction are also proving to be non-invasive methods of assessing coronary risk. Until recently the strength of this association has not been clearly defined. Perkovik et al15 performed a systematic review of published cohort studies. In their findings, proteinuria was associated with ~50% increase in coronary risk (risk ration 1.47). Albuminuria showed a dose-response relationship such that microalbuminuria conferred a 50% greater risk of coronary heart disease (risk ratio 1.47) while those with macroalbuminuria had their risk more than doubled (risk ratio 2.14). From these results it would be reasonable to incorporate proteinuria studies into the assessment of an individual’s cardiovascular risk and treatment effectiveness. A/Prof Beltrame said that "assessment of proteinuria is essential in cardiovascular risk assessment because it provides important information in relation to renal damage, which if untreated may eventually result in dialysis."
- Access Economics. The shifting burden of cardiovascular disease in Australia. National Heart Foundation, 2005. Available at: www.heartfoundation.com.au/ media/ nhfa_shifting_burden_cvd_0505.pdf
- Dzau V. The cardiovascular continuum and renin-angiotensin-aldosterone system blockade. Journal of Hypertension, 2005; 23 (suppl 1): S9-S17.
- Dahlof B, Devereux R, Kjeldsen S, Julius S, Beevers G, de Faire U, Fyhrquist F, Ibsen H, Kristiansson K, Lederballe-Pedersen O. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet 2002; 359: 995-1003.
- Pfeffer MA, Swedberg K, Granger CB, Held P, McMurray JJV, Michelson EL, Olofsson B, Ostergren J, Yusuf S. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-overall programme. Lancet 2003; 362: 759-766.
- Dickstein K, Kjekshus J, the OPTIMAAL Steering Committee, for the OPTIMAAL Study Group. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet 2002; 360:752-760.
- Pitt B, Poole-Wilson P, Segal R, Martinez FA, Dickstein K, Camm AJ, Konstam M, Riegger G, Klinger G, Neaton J. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial – the Losartan Heart Failure Survival Study ELITE II. Lancet 2000; 355: 1582-1587.
- Pfeffer MA, McMurray JJ, Velazquez EJ, Rouleau JL, Kober L, Maggioni AP, Soloman SD, Swedberg K, Van de Werf F, White H, Leimberger JD, Henis M, Edwards S, Zelenkofske S, Sellers MA, Califf RM. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003; 349:1893-1906.
- 8. Pacher R, Stanek B, Globits S, Berger R, Hulsmann M, Wutte M, Frey B, Schuller M, Hartter E & E Ogris. Effects of two different enalapril dosages on clinical, haemodynamic and neurohumoral response of patients with severe congestive heart failure. European Heart Journal 1996; 17: 1223-1232.
- Vagelos R, Yee G, Boyle M. Failure of low but not high dose chronic enalapnl therapy to suppress serum angiotensin converting enzyme (ACE) activity in heart failure. Am J Cardiol 1992; 19: 145A.
- Milton P, poole-Wilson PA, Armstrong PW, Cleland JGF, Horowitz JD, Massie BM, Ryden L, Thygesen K, Uretsky BF. Comparative effects of low and high doeses of the angiotensin converting enzyme inhibitor lisinopril on morbidity and mortality in chronic heart failure. Circulation 1999; 100: 2312-2318.
- Simons LA, Ortiz M, Calcino G. Persistence with antihypertensive medication: Australia-wide experience, 2004-2006. MJA 2008; 188: 224-227.
- Simons LA, Simons J, McManus P, Dudley J. Discontinuation rates for use of statins are high [letter]. BMJ 2000; 321: 1084.
- ONTARGET Investigators. Telmisartan, Ramipril, or Both in Patients at High Risk for Vascular Events. NEJM 2008; 358(15): 1547-1559.
- Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: A systematic review and metaanalysis. Circulation 2007; 115: 459-467.
- Perkovic V, Verdon C, Ninomiya T, Barzi F, Cass A, Patel A, Jardine M, Gallagher M, Turnbull F, Chalmers J, Craig J, Huxley R. The relationship between proteinuria and coronary risk: a systematic review and meta-analysis. PLoS Med 5(10): e207. doi:10.1371/journal.pmed.0050207