Cardio classics revisited – focus on the role of candesartan

Figures & data

Figure 1 The CV continuum. Copyright © 2004, Elsevier. Adapted with permission from Julius S, Kjeldsen SE, Weber M, et al; VALUE trial group. Outcomes in hypertensive patients at high cardiovascular risk treated with regimens based on valsartan or amlodipine: the VALUE randomised trial. Lancet. 2004;363(9426):2022–2031.

Abbreviations: LVH, left-ventricular hypertrophy; CAD, coronary artery disease; CHF, congestive heart failure; TIA, transient ischemic attack.

Table 1 Summary of ARB efficacy studies

Study name	Date published	Study drug	Control group(s)	Population studied	Primary endpoint	Primary endpoint results	Statistical significance
Trials in broad (at-risk) patient populations
LIFE	2002	Losartan	Atenolol	Hypertension and LVH	CV mortality, MI, or stroke	HR: 0.87	95% CI: 0.77–0.98; P = 0.021
SCOPE	2003	Candesartan	Placebo	Older patients (70–89 yrs) with hypertension	CV death, nonfatal stroke or nonfatal MI	RRR: 10.9%	95% CI: −6.0–25.1; P = 0.19
VALUE	2004	Valsartan	Amlodipine	Hypertension and high cardiac risk	First cardiac event	HR: 1.04	95% CI: 0.94–1.15; P = 0.49
JIKEI HEART	2007	Valsartan	Non-ARB antihypertensive therapy	Hypertension, coronary heart disease, HF, or a combination of these disorders	MI; hospital admissions for stroke, TIA, HF or angina; dissecting aneurysm of the aorta; doubling of serum creatinine; or transition to dialysis	HR: 0.61	95% CI: 0.47–0.79; P = 0.0002
ONTARGET	2008	Telmisartan	Ramipril	Vascular disease or high-risk diabetes without HF	MI, stroke, death from CV causes, or hospitalization for HF	RR: 1.01	95% CI: 0.94–1.09
		Telmisartan + ramipril	Ramipril			RR: 0.99	95% CI: 0.92–1.07
TRANSCEND	2008	Telmisartan	Placebo	CVD or diabetes with end-organ damage who were intolerant of ACE inhibitors and who did not have HF	MI, stroke, death from CV causes, or hospitalization for HF	HR: 0.92	95% CI: 0.81–1.05; P = 0.216
Trials in specific patient populations along the CV continuum
MOSES	2005	Eprosartan	Nitrendipine	High-risk hypertensive patients with a history of a cerebral event	Total mortality and all CV and cerebrovascular events	IDR: 0.79	95% CI: 0.66–0.96; P = 0.014
PRoFESS	2008	Telmisartan	Placebo	Recent history of ischemic stroke	Recurrent stroke	HR: 0.95	95% CI: 0.86–1.04; P = 0.23
OPTIMAAL	2002	Losartan	Captopril	Acute MI and heart failure	All-cause mortality	RR: 1.13	95% CI: 0.99–1.28; P = 0.07
VALIANT	2003	Valsartan	Captopril	Acute MI with HF and/or LV systolic dysfunction	All-cause mortality	HR:1.00	97.5% CI: 0.90–1.11; P = 0.98
		Valsartan + captopril	Captopril			HR: 0.98	97.5% CI: 0.89–1.09; P = 0.73
ELITE II	2000	Losartan	Captopril	HF (NYHA class II–IV) with LVEF ≤ 40%	All-cause mortality	HR 1.13	95.7% CI: 0.95–1.35; P = 0.16
Val-HeFT	2001	Valsartan	Placebo	HF (NYHA class II-IV) with LVEF < 40%	All-cause mortality	RR: 1.02	98% CI: 0.88–1.18; P = 0.80
					Combined mortality and morbidity	RR: 0.87	97.5% CI: 0.77–0.97; P = 0.009
CHARM-Added	2003	Candesartan	Placebo	HF: systolic dysfunction who were receiving ACE inhibitors	CV mortality and HF hospitalization	HR: 0.85	95% CI: 0.75–0.96; P = 0.011
CHARM-Alternative				HF: systolic dysfunction who were intolerant of ACE inhibitors		HR: 0.77	95% CI: 0.67–0.89; P = 0.0004
CHARM-Preserved				HF with preserved LVEF (>40%), with or without background ACE inhibitor use		HR: 0.89	95% CI: 0.77–1.03; P = 0.118
I-PRESERVE	2008	Irbesartan	Placebo	HF and preserved LVEF (≥45%).	Death (any cause) or hospitalization for a CV cause	HR: 0.95	95% CI: 0.86–1.05; P = 0.35

Abbreviations: ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CI, confidence interval; CV, cardiovascular; HF, heart failure; HR, hazard ratio; IDR, incidence density ratio; LVH, left ventricular hypertropy; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; RR, relative risk; RRR, relative risk reduction; TIA, transient ischemic attack.

Figure 2 Kaplan-Meier curves for the primary composite endpoint in the life study: losartan vs atenolol in patients with hypertension and LVH. Copyright © 2002, Elsevier. Adapted with permission from Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359(9311):995–1003.

Abbreviation: CI, confidence interval.

Figure 3 Kaplan-Meier curves of the cumulative frequency of the combined primary endpoint (cv morbidity and mortality) in the jikei heart study: valsartan vs non-ARB treatment. Copyright © 2007, Elsevier. Adapted with permission from Mochizuki S, Dahlöf B, Shimizu M, et al. Valsartan in a Japanese population with hypertension and other cardiovascular disease (Jikei Heart Study): a randomised, open-label, blinded endpoint morbidity-mortality study. Lancet. 2007;369(9571):1431–1439.

Abbreviations: ARB, angiotensin II receptor blocker; CI, confidence interval,

Figure 4 Kaplan-Meier curves for the primary outcome (death from CV causes, MI, Stroke, or hospitalization for HF) in ONTARGET. Copyright © 2008, Massachusetts Medical Society. Adapted with permission from ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–1559.

Abbreviations: ONTARGET, Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial; CI, confidence interval.

Figure 5 Kaplan-Meier estimates of the rate of death from any cause in the VALIANT Study: valsartan, captopril or their combination in Post-MI patients. Copyright © 2003, Massachusetts Medical Society. Adapted with permission from Pfeffer MA, McMurray JJ, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med. 2003;349(20):1893–1906.

Abbreviations: VALIANT, Valsartan in Acute Myocardial Infarction; CI, confidence interval.

Figure 6 Kaplan-Meier Cumulative Event Curves for the Combined Primary Endpoint (CV Morality + Hospitalization for Heart Failure): Candesartan vs Placebo in ACE-inhibitor-intolerant Patients – CHARM-alternative. Copyright © 2003, Elsevier. Adapted with permission from Granger CB, McMurray JJ, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced left-ventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet. 2003;362(9386):772–776.

Abbreviations: CHARM, Candesartan in Heart failure Assessment of Reduction in Mortality and Morbidity; CHF, congestive heart failure; CI, confidence interval.

Table 2 Ongoing ARB trials with primary CV endpoints across the CV continuum

Study name	ARB	Study population	n (approx.)	Primary endpoint(s)	Novelties
ACTIVE-I^Citation27	Irbesartan	Atrial fibrillation and ≥1 risk factor for stroke	9,000	Composite of CV events (stroke, non-CNS systemic embolism, MI, or vascular death)
CORAL^Citation28	Candesartan	Renal artery stenosis	1,080	Composite CV and renal endpoint: CV or renal death, MI, hospitalization for CHF, stroke, doubling of serum creatinine, and need for renal replacement therapy
KYOTO HEART^Citation29	Valsartan	High-risk hypertension	3,000	Composite of CV/renal events (stroke, TIA, MI, HF, angina, dissecting aortic aneurysm, lower limb arterial obstruction, emergency thrombosis, transition to dialysis or doubling of serum creatinine)
NAGOYA HEART^Citation30	Valsartan	Hypertension with diabetes or impaired glucose tolerance	3,000	Fatal or nonfatal MI, fatal or nonfatal stroke, admission due to CHF, coronary revascularization, sudden cardiac death
NAVIGATOR^Citation31	Valsartan	Impaired fasting glucose	9,518	Progression to diabetes; extended CV composite (CV death, nonfatal MI, nonfatal stroke, hospitalization for HF, revascularization or hospitalization for unstable angina); core CV composite (CV death, nonfatal MI, nonfatal stroke, or hospitalization for HF)
ROADMAP^Citation32	Olmesartan	Type 2 diabetes with normoalbuminuria	4,400	Occurrence of microalbuminuria (CV morbidity and mortality as secondary endpoint)
SCAST^Citation33	Candesartan	Acute stroke	2,500	Death or disability at 6 months; combination of vascular death, myocardial infarction, or stroke during the first 6 months
VALISH^Citation34	Valsartan	Isolated systolic hypertension	3,000	Composite of CV events (sudden death, fatal or nonfatal stroke, fatal or nonfatal MI, death due to HF, other CV death, unplanned hospitalization for CV disease, and renal disorder)
VART^Citation35	Valsartan	Hypertension	797	CV morbidity and mortality

Abbreviations: ACTIVE-I, atrial fibrillation clopidogrel trial with irbesartan for prevention of vascular events; CORAL, cardiovascular outcomes in renal atherosclerotic lesions; NAGOYA HEART, novel antihypertensive goal of hypertension with diabetes – hypertensive events and ARB treatment; NAVIGATOR, nateglinide and valsartan in impaired glucose tolerance outcomes research; ROADMAP, randomized olmesartan and diabetes microalbuminuria prevention; SCAST, Scandinavian candesartan acute stroke trial; VALISH: valsartan in elderly isolated systolic hypertension; VART, valsartan amlodipine randomized trial; CNS, central nervous system; CV, cardiovascular; MI, myocardial infarction; HF, heart failur; CHF, congestive heart failure; TIA, transient ischemic attack.

Table 3 Functional capacity at the various treatment steps (mean ± SD)

	Pl	Pl + Asp	Can	Can + Asp
Oxygen consumption at peak exercise (ml/min/kg)	15 ± 3.5	14 ± 5.6	17 ± 3.2*	17.1 ± 3.1*
Dead space/Tidal volume ratio	0.21 ± 0.03	0.22 ± 0.06	0.18 ± 0.04*	0.18 ± 0.04*
Exercise tolerance time(s)	514 ± 186	515 ± 132	580 ± 169*	602 ± 26*

Notes:

* Difference from Pl and from Pl+Asp is significant at P < 0.01. Copyright © 2009, John Wiley and Sons. Reproduced with permission from De Rosa ML, Chiariello M. Candesartan improves maximal exercise capacity in hypertensives: results of a randomized placebo-controlled crossover trial. J Clin Hypertens. 2009;11(4):192–200.

Abbreviations: Pl, placebo; Asp, aspirin; Can, candesartan.

Table 4 Maximal exercise blood pressure and heart rate and oxygen reserve and LVM at the various treatment

Steps (mean ±SD)	Pl	Pl + Asp	Can	Can + Asp
Maximal systolic BP (mmHg)	202 ± 4	203 ± 4	192 ± 5*	190 ± 4*
Δ systolic BP	55 ± 4	56 ± 3	58 ± 5	58 ± 4
Maximal diastolic BP (mmHg)	99 ± 5	92 ± 2	85 ± 3*	78 ± 2*
Δ diastolic BP	5 ± 5	5 ± 4	6 ± 3	6 ± 4
Maximal Heart Rate (b/min)	161 ± 4	166 ± 2	170 ± 5*	176 ± 3*
Δ Heart Rate	84 ± 4	84 ± 3	96 ± 4*	98 ± 4*
VO2 rest/mass (ml/kg/min)	4 ± 3	4 ± 2	4 ± 4	4 ± 1
LV mass (g)	170 ± 4	170 ± 8	169 ± 2*	169 ± 3*
Oxygen reserve (ratio)	3.8 ± 0.3	3.5 ± 0.2 4	3 ± 0.4*	4.3 ± 0.1*
Δ effort (Borg scale)	19 ± 0.3	19 ± 0.2	19 ± 0.4	19 ± 0.2

Notes: Δ = change with exercise

* Difference from Pl and from Pl + Asp is significant at P < 0.01. Copyright © 2009, John Wiley and Sons. Reproduced with permission from De Rosa ML, Chiariello M. Candesartan improves maximal exercise capacity in hypertensives: results of a randomized placebo-controlled crossover trial. J Clin Hypertens. 2009;11(4):192–200.⁹⁸

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