- Email: [email protected]
The CHARM programme
CORRESPONDENCE
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Doctors in conflict Sir—My delay in responding to your Commentary of Sept 201 results only from my utter speechlessness regarding its content. Your blithe comparison of the lives—and deaths—of David Applebaum and Mahmoud al-Zahar crosses every boundary of good taste. Applebaum was a civilian. He was also a trauma specialist who dedicated his life to saving the lives of countless patients—Palestinian as well as Israeli. al-Zahar was a co-founder of Hamas— an organisation whose primary purpose is the destruction of the state of Israel, and until then, the violent murders of as many Israeli men, women, and children as possible. The fact that he studied surgery in Cairo makes him no less a terrorist—it only emphasises the stark difference between what a doctor should be and what he was. How dare you compare the two! Something very basic has become distorted for such an incomprehensible comparison to be made. The only common denominator between the two men is the fact that both had an MD. This is where any possible comparison ends. Mahmoud al-Zahar chose, of his own volition, a path of terror. Hamas has set as its goal the destruction of the state of Israel and the establishment of a Palestinian state on the entire territory thereof. They, and other Islamic terrorist organisations such as Islamic Jihad and the Al-Aqsa Brigade, are not waging a war of liberation, they are waging a campaign of sheer, unadulterated terror. In pursuit of their bloody objective, they will choose any route, even if it means sacrificing their own youngsters or killing Israeli women and children. Luckily, British residents have not experienced murderers in the form of “shahidim” blowing themselves up in the midst of diners enjoying a peaceful meal in a restaurant or on city buses carrying children. Yes, they have experienced car bombs rigged by the Irish Republican Army (IRA), and I imagine that in those days your view of terrorism was slightly different. The time that has passed is apparently the explanation for the double standard you express. You, as Editor of a respected medical journal, must be exceedingly careful not to put a respectable face on terror and cold blooded murder.
I do not wish to enter here into the question of whether the current policy of killing terrorist leaders and murderers is wise or even retaliatory, in the simplistic way you assert. It is the decision of the Israeli government that no murderer will go free, exactly as British and American forces bravely and correctly sought to root out terrorism in Afghanistan and Iraq. The fact remains that Israel never seeks to kill Palestinian civilians. If we never again have a reason to strike out at terrorism, we would be only too happy. You write in your Commentary that “to somebody living outside the Middle east, the Israeli-Palestinian conflict seems little more than a perpetual cycle of vengeance”. If you truly believe this, we Israelis have obviously not succeeded in relating the severity and seriousness of the situation. We are fighting here for our future, the future of our children, and the future of our national homeland established according to the decision of international bodies and the UN in 1948. Were we simply dealing with a cycle of violence and revenge, the conflict would have ended long ago. I agree with you regarding the potential role of doctors in an attempt to direct the process to more constructive human elements. Unfortunately, repeated attempts, through many channels, both local and international, to engage in dialogue with our Palestinian counterparts and with physicians in other Arab countries such as Egypt and Jordan, have been unsuccessful. Finally, I object strenuously to your implication that I would deviate from “a universally accepted code of medical ethics”. Doctors in Israel practise at the highest level of medical ethics, and no one is suggesting that we ignore or abandon these principles. I only stated that doctors here must grapple with complex ethical issues, as they do on a daily basis; Sami Viskin’s article2 is an excellent testament to this reality. The fact that Hadas Ziv of Physicians for Human Rights-Israel writes that Israeli doctors and the Israel Medical Association (IMA) adopt official government policies on matters of ethical behaviour3 does not make it a fact; nor does Derek Summerfield’s
relentless tirade regarding the IMA and its position on torture.4 The fact is that the IMA has been working for years, behind the scenes and without fuss, to ensure that human and medical rights in the territories are maintained. Just a few weeks ago we initiated the first “refresher” course on ethical matters for medical officers in the Israeli Defense Force and Israeli doctors serving reserve duty in the territories. In a booklet that each doctor receives are examples of ethical dilemmas and optimum solutions, as well as international treaties and declarations to which we are signatories, and to which, with deep conviction, we are dedicated. However, you and your readers must believe that there is no justification for the murder of entire families, such as occurred in Haifa in September, or for the murder of the likes of Applebaum and his young daughter, Nava. No editorial spin can make it otherwise. Yoram Blachar Israel Medical Association, 2 Twin Towers, PO Box 3604, Ramat-Gan 52136, Israel (e-mail: [email protected]) 1
2 3
4
Horton R. Doctors in conflict: understanding Israel’s despair. Lancet 2003; 362: 928–29. Viskin S. Cardiology or politics? Lancet 2003; 362: 82. Ziv H. The role of the Israel and World Medical Associations. Lancet 2003; 362: 1827–28. Summerfield D. Medical ethics, the Israeli Medical Association and the state of the World Medical Association: open letter to the BMA. BMJ 2003; 327: 561.
The CHARM programme Sir—The CHARM trial series (Sept 6, p 759)1–4 stands out in its methodological rigour. By contrast, the trials’ presentation inflates the benefit of candesartan treatment in heart failure. The primary outcome overall was allcause death. Overall mortality rate was 23% with candesartan, and 25% with placebo (CHARM-Overall).1 A calculation of more precise percentages from the numbers presented yields 23·3% and 24·9%, respectively. The absolute difference therefore is 1·6% in 7600 patients treated for more than 3 years. Annual mortality rates differ by about
THE LANCET • Vol 362 • November 15, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
1675
CORRESPONDENCE
0·5%. The annual mortality rates given in the Results section1 are 8·1% versus 8·8%—a yearly difference of 0·7%. Accordingly, overall mortality was on the margin of statistical significance. From these absolute risk reduction rates (0·5–0·7% per year), the number needed to treat for 1 year to prevent one death is between 200 and 143. If the cost of candesartan 32 mg is US$2 per day, the yearly cost of treating 143–200 patients is between $104 000 and $146 000. Overall mortality was higher with candesartan in CHARM-Preserved4— ie, 244 versus 237 deaths (not significant). The proportion of patients admitted to hospital at least once, for any reason, did not differ, neither overall nor in any single CHARM trial. Admission rates only differed with respect to number of overall admissions. The important numbers for clinical decision-making are overall mortality and overall morbidity. Emphasis on cardiovascular benefits makes only limited sense when the intervention is also associated with life-threatening complications such as hyperkalaemia, hypotension, shock, and renal failure. Digging into the body of the text of all four articles required about 2 hours’ work. Presentation of overall mortality and overall morbidity clearly, in abstract and tables, would save a substantial amount of time and help readers to make up their own minds.
heart failure. This finding goes against the ideas that arose from the subgroup analysis of the Valsartan Heart Failure that too much Trial2,3—namely, neurohumoral-inhibition could be harmful to patients with heart failure. Since CHARM is a study whose power relies on its large numbers, one cannot but notice that the positive findings could not be extended to the subgroup of patients already on spironolactone (1272 patients). In these patients, the composite endpoint of cardiovascular death and first admission for heart failure was far from significant—a fact that deserved more discussion. Since we do not know the data for the patients on spironolactone, we must assume that, as in the Randomized Aldactone Evaluation Study (RALES),4 they must have been some of the most seriously ill patients enrolled. We tend to forget that spironolactone also acts on the reninangiotensin-aldosterone system (RAAS), and that spironolactone is much more than a diuretic. Candesartan and the other angiotensin II type 1 receptor blockers work close to spironolactone in the RAAS chain (or network, to be more precise). By contrast,  blockers interact with RAAS on the other side of the network, because they are renin inhibitors. The question is: do we need spironolactone and candesartan for patients with NYHA class III/IV heart failure?
Christoph Pechlaner
*M G Gama, G Rocha
Department of General Internal Medicine, Innsbruck University Hospital, A-6020 Innsbruck, Austria (e-mail: [email protected])
Internal Medicine B, Department of Medicine, Hospital S João 4400 Porto, Portugal (e-mail: [email protected]) 1
1
2
3
4
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362: 759–66. McMurray JJV, Östergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced leftventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003; 362: 767–71. Granger CB, McMurray JJV, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced leftventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003; 362: 772–76. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved leftventricular ejection fraction: the CHARMPreserved Trial. Lancet 2003; 362: 777–81.
Sir—In the study presented by Marc Pfeffer and colleagues,1 the addition of candesartan to the usual care of patients with heart failure resulted in a significant reduction of cardiovascular death and hospital admission because of
1676
2
3
4
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme Lancet 2003; 362: 759–66. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345: 1667–75. Massie BM. Neurohormonal blockade in chronic heart failure: how much is enough? Can there be too much? J Am Coll Cardiol 2002; 39: 79–82. Pitt B, for the RALES investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709–17.
Sir—The results of the CHARM studies1 suggest that angiotensin II type 1 (AT1) blockers share the established cardioprotective effects of ACE inhibitors, and raise the issue of whether AT1 blockers also yield cerebrovascular protection. In SCOPE,2 candesartan compared with placebo plus add-on therapy significantly decreased the stroke risk by 23% with only a 3 mm Hg lower systolic
blood pressure; and in LIFE,3 losartan compared with atenolol reduced the risk of stroke by 25% with only a 1 mm Hg lower systolic blood pressure. By contrast, blood-pressureindependent stroke protection by ACE inhibitors is far from proven. In the EUROPA trial,4 8 mg perindopril failed to reduce stroke risk despite reducing systolic blood pressure by 5 mm Hg. This finding therefore suggests that, independently of blood pressure, AT1 blockers might be better than ACE inhibitors with respect to stroke prevention. These observations are further supported by the AT2-receptormediated brain anti-ischaemic effects seen in rodent models of acute stroke.5 In these models, pre-administration of an AT1 blocker decreases the severity of neurological outcome, whereas this protection is cancelled out by coadministration of either an AT2receptor blocker or an ACE inhibitor. This finding suggests that stroke prevention is linked to activation of unopposed AT2-receptors by AT1blockers which, by contrast with ACE inhibitors, increase angiotensin-II formation by blunting AT1-mediated inhibition of renin secretion. We would therefore be interested to know whether stroke risk has been reduced in CHARM-Alternative compared with the CHARM-Added trial. Indeed in the former trial, only  blockers are co-administered, so that the AT1-blocker-mediated increase in angiotensin II would be inhibited to a lesser extent than in the CHARMAdded trial, in which ACE inhibitors were co-administered in all patients and  blockers in 55% of the patients. Jeanette Mansour, Marcel Peltier, Roxana Oprisiu, Jean Michel Achard, *Albert Fournier *Departments of Nephrology (JM, AF) and Cardiology (MP), CHU-Amiens, 80054 Amiens Cedex 1, France; and Department of Physiology (JMA), CHU-Limoges, Limoges, France (e-mail: [email protected]) 1
2
3
4
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362: 759–66. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003; 21: 875–86. Dahlöf B, Devereux R, Kjeldsen S, 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: 995–1003. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled multicentre trial. Lancet 2003; 362: 782–88.
THE LANCET • Vol 362 • November 15, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
COMMENTARY
CORRESPONDENCE e-mail submissions to [email protected]
Doctors in conflict Sir—My delay in responding to your Commentary of Sept 201 results only from my utter speechlessness regarding its content. Your blithe comparison of the lives—and deaths—of David Applebaum and Mahmoud al-Zahar crosses every boundary of good taste. Applebaum was a civilian. He was also a trauma specialist who dedicated his life to saving the lives of countless patients—Palestinian as well as Israeli. al-Zahar was a co-founder of Hamas— an organisation whose primary purpose is the destruction of the state of Israel, and until then, the violent murders of as many Israeli men, women, and children as possible. The fact that he studied surgery in Cairo makes him no less a terrorist—it only emphasises the stark difference between what a doctor should be and what he was. How dare you compare the two! Something very basic has become distorted for such an incomprehensible comparison to be made. The only common denominator between the two men is the fact that both had an MD. This is where any possible comparison ends. Mahmoud al-Zahar chose, of his own volition, a path of terror. Hamas has set as its goal the destruction of the state of Israel and the establishment of a Palestinian state on the entire territory thereof. They, and other Islamic terrorist organisations such as Islamic Jihad and the Al-Aqsa Brigade, are not waging a war of liberation, they are waging a campaign of sheer, unadulterated terror. In pursuit of their bloody objective, they will choose any route, even if it means sacrificing their own youngsters or killing Israeli women and children. Luckily, British residents have not experienced murderers in the form of “shahidim” blowing themselves up in the midst of diners enjoying a peaceful meal in a restaurant or on city buses carrying children. Yes, they have experienced car bombs rigged by the Irish Republican Army (IRA), and I imagine that in those days your view of terrorism was slightly different. The time that has passed is apparently the explanation for the double standard you express. You, as Editor of a respected medical journal, must be exceedingly careful not to put a respectable face on terror and cold blooded murder.
I do not wish to enter here into the question of whether the current policy of killing terrorist leaders and murderers is wise or even retaliatory, in the simplistic way you assert. It is the decision of the Israeli government that no murderer will go free, exactly as British and American forces bravely and correctly sought to root out terrorism in Afghanistan and Iraq. The fact remains that Israel never seeks to kill Palestinian civilians. If we never again have a reason to strike out at terrorism, we would be only too happy. You write in your Commentary that “to somebody living outside the Middle east, the Israeli-Palestinian conflict seems little more than a perpetual cycle of vengeance”. If you truly believe this, we Israelis have obviously not succeeded in relating the severity and seriousness of the situation. We are fighting here for our future, the future of our children, and the future of our national homeland established according to the decision of international bodies and the UN in 1948. Were we simply dealing with a cycle of violence and revenge, the conflict would have ended long ago. I agree with you regarding the potential role of doctors in an attempt to direct the process to more constructive human elements. Unfortunately, repeated attempts, through many channels, both local and international, to engage in dialogue with our Palestinian counterparts and with physicians in other Arab countries such as Egypt and Jordan, have been unsuccessful. Finally, I object strenuously to your implication that I would deviate from “a universally accepted code of medical ethics”. Doctors in Israel practise at the highest level of medical ethics, and no one is suggesting that we ignore or abandon these principles. I only stated that doctors here must grapple with complex ethical issues, as they do on a daily basis; Sami Viskin’s article2 is an excellent testament to this reality. The fact that Hadas Ziv of Physicians for Human Rights-Israel writes that Israeli doctors and the Israel Medical Association (IMA) adopt official government policies on matters of ethical behaviour3 does not make it a fact; nor does Derek Summerfield’s
relentless tirade regarding the IMA and its position on torture.4 The fact is that the IMA has been working for years, behind the scenes and without fuss, to ensure that human and medical rights in the territories are maintained. Just a few weeks ago we initiated the first “refresher” course on ethical matters for medical officers in the Israeli Defense Force and Israeli doctors serving reserve duty in the territories. In a booklet that each doctor receives are examples of ethical dilemmas and optimum solutions, as well as international treaties and declarations to which we are signatories, and to which, with deep conviction, we are dedicated. However, you and your readers must believe that there is no justification for the murder of entire families, such as occurred in Haifa in September, or for the murder of the likes of Applebaum and his young daughter, Nava. No editorial spin can make it otherwise. Yoram Blachar Israel Medical Association, 2 Twin Towers, PO Box 3604, Ramat-Gan 52136, Israel (e-mail: [email protected]) 1
2 3
4
Horton R. Doctors in conflict: understanding Israel’s despair. Lancet 2003; 362: 928–29. Viskin S. Cardiology or politics? Lancet 2003; 362: 82. Ziv H. The role of the Israel and World Medical Associations. Lancet 2003; 362: 1827–28. Summerfield D. Medical ethics, the Israeli Medical Association and the state of the World Medical Association: open letter to the BMA. BMJ 2003; 327: 561.
The CHARM programme Sir—The CHARM trial series (Sept 6, p 759)1–4 stands out in its methodological rigour. By contrast, the trials’ presentation inflates the benefit of candesartan treatment in heart failure. The primary outcome overall was allcause death. Overall mortality rate was 23% with candesartan, and 25% with placebo (CHARM-Overall).1 A calculation of more precise percentages from the numbers presented yields 23·3% and 24·9%, respectively. The absolute difference therefore is 1·6% in 7600 patients treated for more than 3 years. Annual mortality rates differ by about
THE LANCET • Vol 362 • November 15, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.
1675
CORRESPONDENCE
0·5%. The annual mortality rates given in the Results section1 are 8·1% versus 8·8%—a yearly difference of 0·7%. Accordingly, overall mortality was on the margin of statistical significance. From these absolute risk reduction rates (0·5–0·7% per year), the number needed to treat for 1 year to prevent one death is between 200 and 143. If the cost of candesartan 32 mg is US$2 per day, the yearly cost of treating 143–200 patients is between $104 000 and $146 000. Overall mortality was higher with candesartan in CHARM-Preserved4— ie, 244 versus 237 deaths (not significant). The proportion of patients admitted to hospital at least once, for any reason, did not differ, neither overall nor in any single CHARM trial. Admission rates only differed with respect to number of overall admissions. The important numbers for clinical decision-making are overall mortality and overall morbidity. Emphasis on cardiovascular benefits makes only limited sense when the intervention is also associated with life-threatening complications such as hyperkalaemia, hypotension, shock, and renal failure. Digging into the body of the text of all four articles required about 2 hours’ work. Presentation of overall mortality and overall morbidity clearly, in abstract and tables, would save a substantial amount of time and help readers to make up their own minds.
heart failure. This finding goes against the ideas that arose from the subgroup analysis of the Valsartan Heart Failure that too much Trial2,3—namely, neurohumoral-inhibition could be harmful to patients with heart failure. Since CHARM is a study whose power relies on its large numbers, one cannot but notice that the positive findings could not be extended to the subgroup of patients already on spironolactone (1272 patients). In these patients, the composite endpoint of cardiovascular death and first admission for heart failure was far from significant—a fact that deserved more discussion. Since we do not know the data for the patients on spironolactone, we must assume that, as in the Randomized Aldactone Evaluation Study (RALES),4 they must have been some of the most seriously ill patients enrolled. We tend to forget that spironolactone also acts on the reninangiotensin-aldosterone system (RAAS), and that spironolactone is much more than a diuretic. Candesartan and the other angiotensin II type 1 receptor blockers work close to spironolactone in the RAAS chain (or network, to be more precise). By contrast,  blockers interact with RAAS on the other side of the network, because they are renin inhibitors. The question is: do we need spironolactone and candesartan for patients with NYHA class III/IV heart failure?
Christoph Pechlaner
*M G Gama, G Rocha
Department of General Internal Medicine, Innsbruck University Hospital, A-6020 Innsbruck, Austria (e-mail: [email protected])
Internal Medicine B, Department of Medicine, Hospital S João 4400 Porto, Portugal (e-mail: [email protected]) 1
1
2
3
4
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362: 759–66. McMurray JJV, Östergren J, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and reduced leftventricular systolic function taking angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet 2003; 362: 767–71. Granger CB, McMurray JJV, Yusuf S, et al. Effects of candesartan in patients with chronic heart failure and reduced leftventricular systolic function intolerant to angiotensin-converting-enzyme inhibitors: the CHARM-Alternative trial. Lancet 2003; 362: 772–76. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart failure and preserved leftventricular ejection fraction: the CHARMPreserved Trial. Lancet 2003; 362: 777–81.
Sir—In the study presented by Marc Pfeffer and colleagues,1 the addition of candesartan to the usual care of patients with heart failure resulted in a significant reduction of cardiovascular death and hospital admission because of
1676
2
3
4
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme Lancet 2003; 362: 759–66. Cohn JN, Tognoni G, for the Valsartan Heart Failure Trial Investigators. A randomized trial of the angiotensinreceptor blocker valsartan in chronic heart failure. N Engl J Med 2001; 345: 1667–75. Massie BM. Neurohormonal blockade in chronic heart failure: how much is enough? Can there be too much? J Am Coll Cardiol 2002; 39: 79–82. Pitt B, for the RALES investigators. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med 1999; 341: 709–17.
Sir—The results of the CHARM studies1 suggest that angiotensin II type 1 (AT1) blockers share the established cardioprotective effects of ACE inhibitors, and raise the issue of whether AT1 blockers also yield cerebrovascular protection. In SCOPE,2 candesartan compared with placebo plus add-on therapy significantly decreased the stroke risk by 23% with only a 3 mm Hg lower systolic
blood pressure; and in LIFE,3 losartan compared with atenolol reduced the risk of stroke by 25% with only a 1 mm Hg lower systolic blood pressure. By contrast, blood-pressureindependent stroke protection by ACE inhibitors is far from proven. In the EUROPA trial,4 8 mg perindopril failed to reduce stroke risk despite reducing systolic blood pressure by 5 mm Hg. This finding therefore suggests that, independently of blood pressure, AT1 blockers might be better than ACE inhibitors with respect to stroke prevention. These observations are further supported by the AT2-receptormediated brain anti-ischaemic effects seen in rodent models of acute stroke.5 In these models, pre-administration of an AT1 blocker decreases the severity of neurological outcome, whereas this protection is cancelled out by coadministration of either an AT2receptor blocker or an ACE inhibitor. This finding suggests that stroke prevention is linked to activation of unopposed AT2-receptors by AT1blockers which, by contrast with ACE inhibitors, increase angiotensin-II formation by blunting AT1-mediated inhibition of renin secretion. We would therefore be interested to know whether stroke risk has been reduced in CHARM-Alternative compared with the CHARM-Added trial. Indeed in the former trial, only  blockers are co-administered, so that the AT1-blocker-mediated increase in angiotensin II would be inhibited to a lesser extent than in the CHARMAdded trial, in which ACE inhibitors were co-administered in all patients and  blockers in 55% of the patients. Jeanette Mansour, Marcel Peltier, Roxana Oprisiu, Jean Michel Achard, *Albert Fournier *Departments of Nephrology (JM, AF) and Cardiology (MP), CHU-Amiens, 80054 Amiens Cedex 1, France; and Department of Physiology (JMA), CHU-Limoges, Limoges, France (e-mail: [email protected]) 1
2
3
4
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: the CHARM-Overall programme. Lancet 2003; 362: 759–66. Lithell H, Hansson L, Skoog I, et al. The Study on Cognition and Prognosis in the Elderly (SCOPE): principal results of a randomized double-blind intervention trial. J Hypertens 2003; 21: 875–86. Dahlöf B, Devereux R, Kjeldsen S, 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: 995–1003. EUROPA Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled multicentre trial. Lancet 2003; 362: 782–88.
THE LANCET • Vol 362 • November 15, 2003 • www.thelancet.com
For personal use. Only reproduce with permission from The Lancet.