Valsartan in the Treatment of Heart Attack Survivors

Figures & data

Figure 1 Angiotensin II formation and degradation pathways. Updated from Jugdutt BI. 1998. Angiotensin receptor blockers. In: Crawford MH (ed). Cardiology Clinics Annual of Drug Therapy. Philadelphia: WB Saunders Pub, Vol 2, pp 1–17. Copyright © 1998. Reprinted with permission from Elsevier, with data from Ferrario CM, Trask AJ, Jessup JA. 2005. Advances in biochemical and functional roles of angiotensin-converting enzyme 2 and angiotensin-(1-7) in regulation of cardiovascular function. Am J Physiol, 289:H2281-90. Copyright © 2005.

Abbreviations: ACE, angiotensin-converting enzyme; CAGE, chymostatin-sensitive angiotensin II generating enzyme; t-PA, tissue plasminogen activator.

Figure 2 Major cardiovascular effects of angiotensin II. Updated from Jugdutt BI. 1998. Angiotensin receptor blockers. In: Crawford MH (ed). Cardiology Clinics Annual of Drug Therapy. Philadelphia: WB Saunders Pub, Vol 2, pp 1–17. Copyright © 1998. Reprinted with permission from Elsevier.

Abbreviations: AT₁, angiotensin II type 1; AT₂, angiotensin II type 2; B₁, bradykinin 1; B₂, bradykinin 2; NADPH, nicotinamide adenine dinucleotide phosphate, reduced.

Table 1 Major trials of ACE inhibitors in heart failure and myocardial infarction

Year, Trial, Reference	N	Disease	Drug	Outcome
1987 The CONSENSUS Trial Study Group	253	HF	Enalapril	27% ↓ mortality; ↓morbidity
1991 The SOLVD Investigators (symptomatic)	2569	HF	Enalapril	16% ↓ mortality; ↓ morbidity
1992 The SOLVD Investigators (asymptomatic)	4228	HF	Enalapril	8% ↓ mortality (NS); ↓ morbidity
1992 CONSENSUS II, Swedberg et al	6090	MI	Enalapril	No decrease in mortality; hypotension
1992 The SAVE Trial, Pfeffer et al	512	MI	Captopril	19% ↓ mortality; ↓ morbidity
1993 The AIRE Study Investigators	2006	MI	Ramipril	27% ↓ mortality; ↓ morbidity
1994 GISSI-3 Trial (6-week effects)	19 394	MI	Lisinopril	11% ↓ mortality; ↓ morbidity
1995 ISIS-4 Trial	58 050	MI	Captopril	7% ↓ mortality; ↓ morbidity
1995 TRACE Study, Kober et al.	6676	MI	Trandolapril	34.7% ↓ mortality; ↓ morbidity
1995 CCS-1, Lisheng et al	13 634	MI	Captopril	6% ↓ mortality; ↓ morbidity
1995 SMILE, Ambrosioni et al	1556	MI	Zofenopril	29% ↓ mortality; ↓ morbidity
1996 The GISSI-3 Trial (6-month effects)	19 394	MI	Lisinopril	6.2% ↓ (mortality + LV dysfunction) combined
1997 HEART, Pfeffer et al	352	MI	Ramipril	↓ LV remodeling

Abbreviations: ↓, decrease in; ACE, angiotensin-converting enzyme; AIRE, Acute Infarction Ramipril Efficacy; CCS, Chinese Captopril Study; CONSENSUS, Cooperative New Scandinavian Enalapril Survival Study; GISSI, Gruppo Italiano per lo Studio della Sopravivvenza nell' Infarcto Miocardio; HEART, Healing and Early Afterload Reducing Therapy; HF, heart failure; ISIS-3, Fourth International Study of Infarct Survival; LV, left ventricular; MI, myocardial infarction; N, number of patients; NS, non-significant; SAVE, Survival and Ventricular Enlargement Trial; SMILE, Survival of Myocardial Infarction Long Term Evaluation; SOLVD, Studies of Left Ventricular Dysfunction; TRACE, Trandolapril Cardiac Evaluation.

Figure 3 Pathways of ACE-inhibitor and ARB-induced cardiovascular protection. Updated from Jugdutt BI. 1998. Angiotensin receptor blockers. In: Crawford MH (ed). Cardiology Clinics Annual of Drug Therapy. Philadelphia: WB Saunders Pub, Vol 2, pp 1–17. Copyright © 1998. Reprinted with permission from Elsevier.

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin II type 1 receptor blocker; cGMP, cyclic guanosine 3′ 5′ monophosphate; EDHF, endotheliumderived hyperpolarizing factor; eNOS, endothelial nitric oxide synthase; NADPH, nicotinamide adenine dinucleotide phosphate, reduced; NO, nitric oxide; PAI-1, plasminogen activator inhibitor-1; PGI₂, prostacyclin; PKC_ɛ, protein kinase C_ɛ; t-PA, tissue plasminogen activator.

Table 2 Major trials of ARBs in heart failure and myocardial infarction

Year, Trial, Reference	N	Disease	ARB	Comparator	Outcome
1997 ELITE, Pitt et al	722	HF	Losartan	captopril	Unexpected 46% ↑ in mortality (2º end-point)
1999 RESOLVD, McKelvie et al	768	HF	Candesartan	enalapril	Early trend in ↑ mortality and HF (2º end-point)
2000 ELITE II, Pitt et al	3152	HF	Losartan	captopril	Not superior
2001 Val-HeFT, Cohn et al	5010	HF	Valsartan	ACE-Is	Not superior; ↓ composite end-point
2002 OPTIMAAL, Dickstein et al	5477	MI	Losartan	captopril	Not superior (non-inferiority criteria not met)
2003b CHARM-Overall, Pfeffer et al	7601	HF	Candesartan	ACE-Is	Improved 1º outcome (mortality and morbidity)
2003 CHARM-Added, McMurray et al	2548	HF	Candesartan	ACE-Is	Improved 1º outcome (clinical, morbidity)
2003 CHARM-Alternative, Granger et al	2028	HF	Candesartan	ACE-Is	Improved 1º outcome (mortality and morbidity)
2003 CHARM-Preserved, Yusuf et al	3023	HF	Candesartan	ACE-Is	Similar 1º outcome (improved 2º outcome)
2003a VALIANT, Pfeffer et al	14 703	MI	Valsartan	captopril	Not superior, non-inferior

Abbreviations: ↑, increase in; ↓, decrease in; ACE, angiotensin-converting enzyme; ACE-Is, ACE inhibitors; ARB, angiotensin II type 1 receptor blocker; CHARM, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; ELITE, Evaluation of Losartan in the Elderly; HF, heart failure; MI, myocardial infarction; N, number of patients; RESOLVD, Randomized Evaluation of Strategies for Left Ventricular Dysfunction; Val-HeFT, Valsartan Heart Failure Trial; VALIANT, Valsartan in Acute Myocardial Infarction; 1º, primary; 2º, secondary.

Figure 4 Chemical structures of valsartan and some other AT₁ receptor blockers.

Abbreviations: AT₁, angiotensin II type 1.

Figure 5 Double jeopardy in MI survivors.

Abbreviations: CAD, coronary artery disease; CV, cardiovascular; CVD, cardiovascular disease; MI, myocardial infarction; PVD, peripheral vascular disease.

Table 3 Cause of heart failure in some trials of ACE inhibitors and ARBs

Year	Trial	Cause of heart failure (history)
1987	CONSENSUS	72%–74% CAD; 47%–48% MI
1991	SOLVD, symptomatic	70%–72% ischemia; 65%–66% MI
1992	SOLVD, asymptomatic	83%–84% ischemia; 79%–81% MI
1997	ELITE	34%–35% ischemia; 25% MI
1999	RALES	55% ischemia
2000	ELITE II	79% ischemia; 58%–59% MI
2001	Val-HeFT	57%–58% CAD
2003	CHARM-Overall	52%–53% MI
2003	CHARM–Added	62%–63% ischemia; 55%–56% MI
2003	CHARM-Alternative	67%–70% ischemia; 61%–62% MI
2003	CHARM-Preserved	56% ischemia; 44%–45% MI

Abbreviations: CAD, coronary artery disease; CHARM, Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity; CONSENSUS, Cooperative New Scandinavian Enalapril Survival Study; ELITE, Evaluation of Losartan in the Elderly; MI, myocardial infarction, RALES, Randomized Aldactone Evaluation Study; SOLVD, Studies of Left Ventricular Dysfunction, Val-HeFT, Valsartan Heart Failure Trial.

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