Reports
Hypertension Management: Prevention and Treatment of Heart Failure
This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.
PRIORITY PRESS - 31st Annual Congress of the European Society of Cardiology
Barcelona, Spain / August 29-September 2, 2009
Hypertension is a major risk factor for the development of heart failure. Estimates from the Framingham Heart Study indicate that in 40% of men and 60% of women, who develop heart failure, persistent hypertension is the predominating contributory factor. Thus, lowering blood pressure (BP) in patients with hypertension is one of the most important measures for prevention of heart failure and has been shown in extensive randomized, placebo-controlled trials to reduce the incidence by up to half.
Relation Between Hypertension and Heart Failure
There is a paradox between the need to lower BP in patients with hypertension and the poor prognosis associated with hypotension in patients with heart failure mentioned Dr. Marc A. Pfeffer, Harvard Medical School and Brigham and Women’s Hospital, Boston, Massachusetts. Since the late 1960s, physicians have been aware of the importance of identifying people with hypertension and effectively treating them to lower their cardiovascular (CV) risks. A definitive reduction in the incidence of heart failure is one of the many benefits of antihypertensive therapy. Dr. Pfeffer noted that in the most recent, and probably last placebo-controlled trial in hypertension, HYVET (Hypertension in the Very Elderly Trial), antihypertensive treatment reduced the rate of heart failure by 64% in the very elderly (Beckett et al. N Engl J Med 2008; 358:1887-98).However, in patients with impaired cardiac function, he continued, physicians direct therapy to prevent development of hypoperfusing hypotensive conditions. In patients with low ejection fraction (EF <u><</u>0.40) in the CHARM trials, low systolic BP (SBP) or diastolic BP (DBP) was associated with a higher risk of CV death or heart failure hospitalization (Meredith et al. JACC 2008;52:2000-7). However, patients with SBP <u><</u>110 mm Hg received the same therapeutic benefit from candesartan as patients with higher SBP, although they were more likely to discontinue treatment due to renal dysfunction, hypotension or hyperkalemia.
ACCESS: Beyond BP Control
Organ-protective effects beyond BP reduction have been demonstrated with ARBs in numerous outcomes trials and ongoing trials will provide further information about the selective benefits of ARBs, stated Dr. Peter A. Meredith, Department of Medicine and Therapeutics, Glasgow University, UK.
The ACCESS (Acute Candesartan Cilexetil Therapy in Stroke Survivors) trial challenged conventional thinking that treatment in patients with high BP after a stroke should be withheld until the patient has stabilized, usually about seven days, according to Dr. Meredith. In ACCESS, patients were randomized in the first seven days to candesartan or placebo, after which both groups were given active therapy. The study was stopped early after a significant (P<0.05) effect on combined mortality and vascular complications was seen for the ARB vs. placebo (Schrader et al. Stroke 2003; 34:1699-703). This small-scale study generated an interesting hypothesis that is currently being evaluated in the SCAST (Scandinavian Acute Stroke Trial). SCAST has a similar design to ACCESS, with eligible patients presenting with acute stroke within 30 h with SBP <u>></u>140 mm Hg. Patients are randomly assigned to candesartan (dose increasing from 4 to 16 mg daily) or placebo for seven days. The primary outcomes are death or disability and a composite event of “vascular” death, myocardial infarction or stroke during the first six months.
The renal benefits of ARBs were seen in diabetic patients in the IDNT, IRMA II, RENAAL and MARVAL trials. “A very clear overall message from all these studies was that the renoprotective effects associated with an ARB were independent of the BP lowering,” Dr. Meredith noted. This was examined further in the SMART study in which supramaximal doses of candesartan (up to 128 mg/day) were administered in patients with persistent proteinuria. After 30 weeks of treatment, proteinuria was significantly reduced in patients on candesartan 128 mg/day compared with those who had taken 16 mg/day despite no evidence of a differential in BP and no difference in serum creatinine, eGFR, or urinary sodium excretion. (Burgess et al. J Am Soc Nephrol 2009;20: 893-900).
Dr. Meredith suggested that there are significant pharmacological differences with respect to efficacy and duration of action within the ARB class. He discussed a recently completed meta-analysis of the antihypertensive effects of candesartan and losartan focused on eight direct comparator trials (Meredith et al. J Hum Hypertens 2009; In press). The results revealed a 3.2-mm Hg mean difference in SBP in favour of candesartan across all the trials that was sustained in subanalyses restricted to trials of monotherapy and low-dose or high-dose therapy. A difference in DBP was seen also in its favour. “On a population basis this result is important, because of the continuous relationship between risk and benefit and the level of BP,” Dr. Meredith told delegates.
Optimizing Hypertension Management
Despite the evidence that antihypertensive treatment reduces CV morbidity and mortality as well as CV risk, in daily practice, BP goals are not being reached in most patients, confirmed Prof. Gerd Bönner, MEDIAN Kliniken Bad Krozingen, Germany. Registries and epidemiological analyses indicate that worldwide, only an average of 20 to 25% of patients achieve BP levels <140/90 mm Hg, the goal in uncomplicated hypertension.
ACE inhibitors and ARBs are highly organ-protective and can be prescribed as first-line strategies in all patients, especially those with end-organ damage, Prof. Bönner noted. The optimal combination therapy with a renin-angiotensin system (RAS) blocker is a diuretic such as hydrochlorothiazide (HCTZ) or indapamide as used in the LIFE and HYVET trials, respectively. Prof. Bönner noted that in the CARLOS study, greater BP reduction was achieved with candesartan/HCTZ 16/12.5 mg compared with losartan/HCTZ 50/12 mg at 24 h and at 48 h. Thus the BP-lowering effect of candesartan has a longer duration of effect that would be maintained even after a missed dose.
Prof. Bönner added that he and colleagues have investigated BP lowering with doses of candesartan/HCTZ >16/12.5 mg (Bönner Blood Press 2008;17(suppl 2):22-30). During a run-in period, ARB monotherapy was administered at a dose of 16 mg for two weeks, then at 32 mg for the following six weeks. About one third of patients were well-controlled on monotherapy; the remaining patients were randomized to ARB monotherapy 32 mg, candesartan 32 mg/HCTZ 12.5 mg or candesartan 32 mg/HCTZ 25 mg over eight weeks. During this double-blind treatment phase, BP was reduced by 6.1/5.6 mm Hg in the ARB monotherapy 32 mg group, 13.0/8.8 mm Hg in the candesartan/HCTZ 32/12.5 mg group and 15.5/10.0 mm Hg in the candesartan/HCTZ 32/25 mg group. Rates of BP normalization and responders also increased with dose intensification.
Preventing Heart Failure
Beyond BP control, there are other influential risk factors for heart failure such as left ventricular hypertrophy (LVH), diabetes and atrial fibrillation. Meta-analyses have identified ACE inhibitors and ARBs as the most effective antihypertensive agents in reducing LV mass and preventing new-onset diabetes. In CHARM patients, treatment with the ARB reduced the incidence of atrial fibrillation by 20% compared with placebo (Ducharme et al. Am Heart J 2006;152:86-92).
Dual blockade of the RAS with an ACE inhibitor and an ARB had been proposed as a means of obtaining further BP control as well as incremental nephroprotective and cardioprotective effects. The recent findings of the ONTARGET study, in which this combination in patients with vascular disease or diabetes was associated with more adverse events without an increase in benefit, have led to calls to stop administration of dual RAS blockade in clinical practice. “I believe this is a mistake,” stated Prof. Luis Ruilope, Hospital 12 de Octubre, Madrid, Spain. He noted that in CHARM-Added, adding candesartan up to 32 mg to patients already on an ACE inhibitor produced a 15% relative risk reduction of CV mortality and heart failure hospitalization. “ONTARGET was unrelated to the situation of heart failure,” he said. He noted that BP data from ONTARGET showed that, like CHARM, patients with the lowest SBP had higher CV mortality with active therapy. “Hypotension marks a poor prognosis in this type of patients and tolerability should be monitored when adding medication to further lower blood pressure,” Prof. Ruilope said. “I do not think that dual RAS blockade can be completely discounted, at least in heart failure with systolic dysfunction.”