Clinical cases Coversyl 10 mg For upgraded benefits in hypertension A
Editorial This brochure, Clinical cases Coversyl 10 mg for upgraded benefits in hypertension, illustrates a variety of hypertensive patients you may encounter and shows how effective Coversyl 10 mg is at reducing blood pressure and cardiovascular complications in these types of patient. Throughout this issue, you will discover why Coversyl up to 10 mg holds a privileged position among antihypertensive drugs, both as a monotherapy and as an alternative to other therapies. This brochure presents reports on 5 patients from real-life clinical practice and explains the most appropriate therapeutic strategies according to evidence-based medicine. We hope you will appreciate this brochure, which will not only provide you valuable scientific information, but also advice and practical guidance for improving the management of hypertension Coversyl 10 mg.
Contents SOMMAIRE 1 A newly diagnosed patient p 2 2 A hypertensive patient p 4 newly diagnosed patient 3 A hypertensive patient p 6 on an ACE inhibitor 4 A hypertensive patient p 8 dyslipidemia dyslipidemia 5 A hypertensive patient p 10 coronary artery disease coronary artery disease Note: This brochure presents results expressed Coversyl arginine (5 or 10 mg/day), which is bioequivalent to Coversyl 4 or 8 mg/day (perindopril tert-butylamine). 1
1. A newly diagnosed hypertensive patient The CONFIDENCE Study: This study is the first demonstration of the antihypertensive benefits of uptitration to perindopril 10 mg/day* in hypertensive patients out CAD. Therefore, uptitration to the full dose of perindopril may be considered as an effective approach for improving the management of hypertensive patients. Tsoukas G et al. Am J Cardiovasc Drugs. 2011; 11 (1): 45-55. Case report Man 53 years old Relatively marked obesity: weight 105 kg, height 185 cm (body mass index 30 kg/m 2 ) Smoker (one cigar every evening) Little physical activity At a recent visit to the doctor for episodes of insomnia, the general practitioner noted a high blood pressure of 160/102 mm Hg. The rest of the examination was normal. A complete examination was ordered because of these BP values, his obesity, and his moderate smoking. The examination was intended to confirm the existence of high blood pressure, determine other risk factors, and assess possible consequences of the high blood pressure, whose precise duration was not known. The examination Laboratory tests Cholesterol was in the normal range, but blood sugar was 1.15 g/l (6.38 mmol/l). Electrocardiogram Sinus rhythm of 66 beats/min PR interval = 0.16 sec QRS axis =+ 70 Normal ventricular repolarization Comments This patient has systolic-diastolic high blood pressure and two risk factors, obesity and moderate smoking. In addition, his blood sugar is considered to be at the limit of normal. Antihypertensive treatment involves proposing a therapeutic class to this patient that offers BPlowering efficacy and protection of target organs. It was recommended that the patient lose weight, take regular physical exercise (1 hour of walking a day), and stop smoking. Quarterly surveillance measurement of blood pressure and a plasma glucose assay was also advised. Therapeutic objective: Choose an appropriate first-line therapy Choose the right dose Control BP SBP <140 mm Hg and DBP < 90 mm Hg Reduce risk of cardiovascular events and mortality Why Coversyl 10 mg? 1. ACE inhibitors: a first-choice option in young hypertensive patients The joint BHS/NICE guidelines for the treatment of hypertension were updated and now recommend that in newly diagnosed patients under 55 years of age, an ACE inhibitor be used as the first-line treatment (Figure 1). 1 NCGC/NICE 2011 hypertension guidelines < 55 yrs 55 yrs or any age if black A* C A* + C A* + C + D Consider 4th-line drug a-blocker further diuretic therapy β-blocker consider seeking specialist advice A = ACE inhibitor or low cost ARB (*consider ARB if ACE inhibitor intolerant) C = calcium channel blocker D = thiazide-like diuretic (e.g. indapamide or chlorthalidone, instead of hydrochlorothiazide) Figure 1. ACE inhibitors are recommended as the first-choice treatment in young hypertensive patients. NCGC/NICE 2011 guidelines in clinical management of primary hypertension in adults (NCGC: National Clinical Guidelines Center, NICE: National Institute for Health and Clinical Excellence). 2 *Results expressed Coversyl arginine 10 mg/day, which is bioequivalent to Coversyl tert-butylamine 8 mg/day used in the CONFIDENCE study.
2. Objective: full-dose monotherapy 10 mg Recently, a large survey of treated hypertensive patients followed by non-specialist or specialist physicians was carried out in central and eastern European countries. Results of this study, called the Blood Pressure control rate and CardiovAscular Risk profile (BP-CARE) study, provided do not differ from those seen in Western Europe. This study assessed the proportion of risk factors associated hypertension to quantify total CV risk. It shows that in real-life clinical practice, about 70% of hypertensive patients had a very high-risk profile a combination of 1 or more risk factors (Figure 2). 2 Main risk factors % Total cholesterol (>200 mg/dl) 59.3% Visceral obesity (M>102 cm, W>88 cm) 47.2% Age (M>55yrs, W>65yrs) 46.3% Metabolic syndrome 40.4% Low HDL (M<40, W<50 mg/dl) 30.4% 3. Dose-dependent efficacy of Coversyl 10 mg In the CONFIDENCE trial, 4 conducted in 8298 hypertensive patients of whom 56% were newly diagnosed patients, uptitration to Coversyl 10 mg was shown to provide superior blood pressure-lowering efficacy. In this untreated population, Coversyl 5 to 10 mg significantly decreased blood pressure by 21.5/11.5 mm Hg from baseline (P<0.001) (Figure 4). In the overall population, mean blood pressure decreased significantly from baseline by 18.5/9.7 mm Hg over 12 weeks (P<0.001). At the second visit, uptitration to Coversyl 10 mg provided an additional mean 10.1/5.3 mm Hg blood pressure reduction. Therefore, uptitration to Coversyl 10 mg is an effective approach for superior blood pressure-lowering efficacy, especially when concomitant risk factors are present. 0-5 Newly diagnosed patients treated Coversyl (n=4617) Further BP efficacy when Coversyl is uptitrated from 5 mg to 10 mg (n=1943) 0 SOMMAIRE newly diagnosed patient Smoking 15.1% Stroke 11.5% -11* -5-5 Figure 2. Most hypertensive patients have associated risk factors. Blood Pressure control rate and CardiovAscular Risk profile (BP-CARE) study. 2-15 The latest guidelines for the management of arterial hypertension from the ESH/ESC state that in cases of mild BP elevation 1 or 2 risk factors, treatment can start a single drug, initially at low dose, the possibility of uptitrating to the full dose of the same agent (Figure 3). 3 Therefore, using the full dose of Coversyl 10 mg is a reasonable option in this patient hypertension associated risk factors (ob esity, smoking). Mild BP elevation Low/moderate CV risk Conventional BP target Single agent at low dose -20-21 * -25 Further BP decrease (mm Hg) SBP DBP 4. Provide lifesaving benefits In the ASCOT trial, 5 20% of the 19 257 hypertensive patients were newly diagnosed. Amlodipine + Coversyl, in comparison a β-blocker + diuretic, significantly reduced total mortality by 11%, cardiovascular mortality by 24%, fatal and nonfatal stroke by 23%, and new-onset diabetes by 30%. Further BP decrease (mm Hg) SBP DBP Figure 4. Uptitration to Coversyl 10 mg provides further blood pressure-lowering efficacy dyslipidemia coronary artery disease Previous agent at full dose Two- to three-drug combination at full doses Switch to different agent at low dose Full-dose monotherapy If goal BP not achieved If goal BP not achieved Figure 3. Full-dose monotherapy option. Adapted from the 2007 guidelines for the management of arterial hypertension from the ESH/ ESC. 3 What to do for this newly diagnosed patient? Lifestyle modifications: Weight control, physical exercise, stop smoking. Laboratory parameters: Glycemia Clinical management: Introduce Coversyl 5 mg and uptitrate to Coversyl 10 mg after 1 month (for greater arterial protection or if blood pressure target is not achieved). 3
2. A hypertensive patient Perindopril-based regimens were associated a statistically significant reduction in all-cause mortality (HR, 0.87; 95% CI, 0.81 to 0.94; P<0.0001), whereas the remaining ACE inhibitors were not. No significant reduction in all-cause mortality could be demonstrated ARBs. Meta-analysis on all-cause mortality in hypertension trials: Bertrand ME et al. Eur Heart J. 2011;Vol.32(Abstract Supplement):13. Case report Man 54 years old No particular cardiovascular history, either personal or family Travels a lot in Europe Treated losartan 50 mg/day in the morning for 2 years. He has experienced recent episodes of asthenia, for which he has been seeing a doctor. He has no suggestive symptoms or signs. Blood pressure values 1 month apart revealed high systolic blood pressure diastolic pressure at the upper normal limit (158/85 mm Hg). The rest of the clinical examination was normal. The examination Laboratory tests Total cholesterol: 156 mg/dl (4.02 mmol/l) HDL cholesterol: 37 mg/dl (0.95 mmol/l) LDL cholesterol: 107 mg/dl (2.74 mmol/l) Plasma glucose: 91 mg/dl (5.05 mmol/l) Electrocardiogram Sinus rhythm of 80 beats/min PR interval = 0.14 sec QRS axis = - 10 Normal repolarization Comments This patient continues to have high blood pressure in spite of treatment losartan, which suggests that his medical treatment should be reconsidered and that regular physical exercise and a healthy diet be recommended. Therapeutic objective: Provide further BP-lowering efficacy Control BP SBP <140 mm Hg and DBP <90 mm Hg Ensure 24-hour BP control Provide cardiovascular protection (evidencebased medicine) and lifesaving benefits Why Coversyl 10 mg? 1. Switch to the right dose of Coversyl In patients, it is usual to add a thiazide diuretic and then prescribe a fixeddose ARB/hydrochlorothiazide combination. This is easy to do, but are optimal efficacy and cardiovascular protection actually provided? Recent data showed that the use of a diuretic such as hydrochlorothiazide (HCTZ) could increase the risk of new-onset diabetes 1 or lead to a higher risk of events. 2,3 In this particular clinical case, the renin-angiotensin system has been inhibited by the ARB losartan, but the BP of this patient is not controlled by this agent anymore. One of the options from the latest guidelines for the management of arterial hypertension from the ESH/ESC states that it is reasonable to switch to another agent, at the full monotherapy dose of this agent, if the BP goal is not achieved. 4 Unlike ARBs, by simultaneously inhibiting the interaction of angiotensin II its different receptors (AT1, AT2, AT4) and by increasing levels of circulating bradykinin, Coversyl provides a more complete mode of action to inhibit the renin-angiotensin system. This increased level of circulating bradykinin may explain Coversyl s additional benefits in terms of cardiovascular protection. Therefore, losartan treatment could be switched to Coversyl (up to 10 mg) for further blood pressure-lowering efficacy and proven cardiovascular benefits (the dose of Coversyl should be individualized according to the patient profile and blood pressure response). 2. Further BP-lowering efficacy In the CONFIDENCE trial, hypertensive patients on other ACE inhibitors or sartans were switched to Coversyl, and uptitrated to 10 mg if necessary. 5 In this everyday hypertensive population, Coversyl provided a further 16/8 mm Hg BP decrease in patients after switching from a sartan (Figure 1). Therefore, Coversyl, up to a dose of 10 mg, is an excellent choice for patients on sartans. 4
ARBs 0-5 -15-20 Irbesartan -16-6 Further BP decrease (mm Hg) Switch from Valsartan to COVERSYL -15 SBP Losartan -15 3. Ensure 24-hour BP control BP: blood pressure; SBP: systolic blood pressure; DBP: diastolic blood pressure Compared the main ARBs, Coversyl has a high T:P ratio (Trough to Peak ratio= 75%- 100%), leading to proven 24-h efficacy and BP control (Figure 2). 6-6 Telmisartan -13-6 n 1774 Figure 1. The CONFIDENCE Trial. Coversyl further decreased blood pressure in hypertensive patients on sartans. DBP the risk of stroke and heart failure, they have no significant impact on myocardial infarction and mortality reduction when compared placebo or active treatments. In contrast, a combined analysis of individual data from ADVANCE, EUROPA, and PROGRESS showed that a Coversyl-based regimen significantly and consistently reduced major cardiovascular events, such as mortality, stroke, and also MI (Figure 3). 9 5. Provide lifesaving benefits A recent meta-analysis evaluated the impact of RAAS inhibitors on further mortality reduction for their main indication, hypertension. 10 This metaanalysis included 165 971 patients treated either ACE inhibitors or ARBs for a mean follow-up of 4.1 years. Nearly all (92%) of the trial participants were hypertensive a mean baseline systolic BP of 153 mm Hg. SOMMAIRE newly diagnosed patient Coversyl 24-h efficacy evaluated by T/P ratio T/P ratio (%) 750% Losartan Irbesartan Valsartan Time (h) 58-78% 50-60% 69-76% Figure 2. Compared the main ARBs, Coversyl has an optimal T:P ratio. 4. Provide cardiovascular protection High-risk period for MI stroke 8 12 16 20 24 4 8 Figure 3. Coversyl-based regimens reduce major cardiovascular events in patients vascular disease. With ARBs, there is conflicting evidence regarding the risk of myocardial infarction (MI), the so-called MI paradox. 7 Following publication of this article, further ARB trials were performed. Professors Messerli & Bangalore conducted a new metaanalysis to evaluate the cardiovascular outcomes, notably MI, associated ARBs. 8 This metaanalysis confirmed that if ARBs significantly reduce Figure 4. Impact of antihypertensive treatments on mortality reduction showing the significant benefit of Coversyl-based regimens. This meta-analysis showed that Coversylbased regimens further decrease mortality by a significant 13% (P<0.001) (Figure 4). In contrast, in this meta-analysis, ARB results showed no significant impact on total mortality. In conclusion, by further decreasing the risk of total mortality compared other agents, Coversyl provides unique lifesaving benefits. What to do for this patient? Clinical management: In this clinical case, although the renin-angiotensin system was already being inhibited by the ARB losartan, the results were inadequate. It was possible to switch from losartan treatment to Coversyl 10 mg once daily for greater BP control (the dose should be individualized according to the patient profile and blood pressure response). Lifestyle modifications: Physical exercise, balanced diet. dyslipidemia coronary artery disease 5
3. A hypertensive patient on an ACE inhibitor The PREFER Study: Perindopril 5 10 mg/day lowers blood pressure and pulse pressure and improves blood pressure control among hypertensive patients who were previously unresponsive to other ACE inhibitor-based regimens. Ionescu DD et al. Clin Drug Investig. 2009; 29 (12): 767-776. Choosing correct dosages to ensure effective and homogeneous 24-hour BP reduction. The Correct Administration of Antihypertensive Drugs. Taddei S et al. Am J Cardiovasc Drugs. 2011; 11 (1): 13-20. Case report Woman 53 years old Still active, but sometimes she experienced considerable fatigue a sensation of tachycardia, but no suspicious chest pain Mild-to-moderate high blood pressure No other coronary risk factors Treated ramipril 10 mg/day No other treatment. Cardiac auscultation revealed a very discreet systolic murmur from a mitral insufficiency diagnosed some time ago. In spite of treatment ramipril, her blood pressure values remained high at 156/88 mm Hg. The examination Electrocardiogram sinus rhythm of 75 beats/min, PR interval = 0.20 sec QRS axis = +25 Normal repolarization Ultrasonography Heart volume: normal a conserved ejection fraction Grade I mitral insufficiency in the left atrium in normal limits. No pulmonary hypertension. This ultrasonography was identical to one conducted 2 years before. Comments The symptomatology of this patient is unrelated to her mitral insufficiency, which does not involve the heart or lungs. Her symptoms might result from increased pressure values that can be managed by changing the angiotensin-converting enzyme inhibitor and possibly adding a calcium channel blocker or a diuretic if possible. Therapeutic objective: Provide further BP-lowering efficacy Control BP SBP <140 mm Hg and DBP <90 mm Hg Ensure 24-hour BP control Provide cardiovascular protection (evidencebased medicine) and lifesaving benefits Why Coversyl 10 mg? 1. Change to another ACE inhibitor In young hypertensive patients under 55 years old, guidelines recommend ACE inhibitors as a first-line option. 1 This patient is on ramipril, therefore it would be useful to change from this to another ACE inhibitor that simultaneously provides further blood pressurelowering efficacy, 24-h blood pressure control, and cardiovascular protection. Figure 1. The PREFER Trial. Coversyl further decreased blood pressure in hypertensive patients on other ACE inhibitors. In the PREFER study, 2 the antihypertensive efficacy of Coversyl 5 and 10 mg was evaluated in 824 hypertensive patients inadequately controlled on previous treatment ACE inhibitors. They were receiving an ACE inhibitor as monotherapy (21.5%) or in combination (78.5%) β-blockers, diuretics, or CCBs. At 3 months, the switch 6
to Coversyl (up to 10 mg in 57% of patients) provided an additional reduction in blood pressure of -26/-13 mm Hg, whatever the ACE inhibitor initially prescribed at usual dosage (Figure 1). Therefore, the PREFER trial shows that choosing Coversyl, at a dose up to 10 mg, is a valuable option in patients on other ACE inhibitors. 2. Ensure 24-hour BP control and optimal ACE inhibition There is no class effect among ACE inhibitors. They are commonly believed to be similar, as they all belong to the same class of drugs. However, although all ACE inhibitors inhibit the angiotensinconverting enzyme and decrease blood pressure, they also present many pharmacokinetic and pharmacodynamic differences Coversyl has very high and long-lasting tissue ACE affinity, a very high bradykinin/angiotensin ratio, as well as the best 24-hour BP control (Figure 2). 3-7 Tissue ACE affinity 3 (Tissue potency DD50) Bradykinin 4 /angiotensin ratio 24-hour efficacy 5-7 (T/P ratio) Coversyl +++ 1.44 75%0% Quinapril Ramipril + 1.09 45-63% ++ 1.16 50-60% Trandolapril NA 1.08 50-90% Enalapril - 1 55-70% Figure 3. Impact of antihypertensive treatments on mortality reduction showing the significant benefit of Coversyl-based regimens. Although the HOPE study has shown that ramipril significantly reduced the primary end point (MI, stroke, and death from CV causes) in highrisk cardiac patients, the HOPE study was not selected in this meta-analysis as less than 66% of patients were hypertensive (only 47% of the population was hypertensive in the HOPE trial). Overall, this meta-analysis also shows that there is no class effect for ACE inhibitors to further reduce mortality in hypertensive patients. The authors concluded that Coversyl-based regimens further decrease mortality by a significant 13% (P<0.001) (Figure 3). In contrast, in this meta-analysis, results other ACE inhibitors showed no significant impact on total mortality. Therefore, Coversyl provides unique lifesaving benefits by further decreasing the risk of total mortality compared to other ACE inhibitors. SOMMAIRE newly diagnosed patient dyslipidemia Figure 2. Comparison of ACE inhibitor characteristics. In addition, Coversyl has an excellent tolerability profile, a very low rate of cough that is not dose-dependent. 8 A recent meta-analysis involving 200 000 patients from 125 ACE inhibitor trials reported the lowest incidence of cough for Coversyl of the 9 main ACE inhibitors (including ramipril, benazepril, enalapril, etc.) observed. 9 3. Provide lifesaving benefits in hypertension A recent meta-analysis evaluated the impact of RAAS inhibitors on further mortality reduction for their main indication, hypertension. 10 This meta-analysis included 165 971 patients treated either ACE inhibitors or ARBs for a mean follow-up period of 4.1 years. Nearly all (92%) of the trial participants were hypertensive (inclusion criteria: >66% of patients had hypertension), a mean baseline systolic BP of 153 mm Hg. What to do for this patient? Clinical management: In this clinical case, the renin-angiotensin system was already being inhibited by the ACE inhibitor ramipril, at the maximum dose of 10 mg. Therefore, one could switch from ramipril 10 mg directly to Coversyl 10 mg once daily (eventually, if blood pressure control is insufficient, add a calcium channel blocker or a diuretic, such as indapamide SR, according to NICE/BHS recommendations). coronary artery disease 7